Comprehensive Organic Functional Group Transformations II - V 4 (Carbon With Two Heteroatoms, Each Attached by A Single Bond)

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Editors-in-Chief
Professor Alan R. Katritzky, FRS
University of Florida, Gainesville, FL, USA
Professor Richard J. K. Taylor

University of York, York, UK
Editors-in-Chief
Alan Katritzky, educated at Oxford, held faculty positions at
Cambridge and East Anglia before migrating in 1980 to the
University of Florida, where he is Kenan Professor and Director
of the Center for Heterocyclic Compounds. He has trained some
800 graduate students and postdocs, and lectured and consulted
worldwide. He led the team which produced Comprehensive
Heterocyclic Chemistry and its sequel CHECII, has edited Advances
in Heterocyclic Chemistry, Vols. 1 through 86 and conceived the plan
for Comprehensive Organic Functional Group Transformations. He
founded Arkat-USA, a nonprofit organization which publishes
Archive for Organic Chemistry (ARKIVOC) electronic journal
completely free to authors and readers at (www.arkat-usa.org).
Honors include 11 honorary doctorates from eight countries and
membership or foreign membership of the National Academies of
Britain, Catalonia, India, Poland, Russia, and Slovenia.
Richard Taylor is currently Professor of Organic Chemistry at the

University of York, where his research focuses on the development
of novel synthetic methodology and the synthesis of natural
products and related compounds of biological/medicinal interest.
The methodology is concentrated primarily on organometallic,
organosulfur, and oxidation processes, and the targets include
amino acids, carbohydrates, prostaglandins, and polyene and
polyoxygenated natural products, particularly with activity as
antibiotics and anti-cancer agents.
Richard Taylor is a graduate and postgraduate of the University
of Sheffield. After his studies at Sheffield, he carried out postdoctoral
research at Syntex, California (Dr. I. T. Harrison) and University
College London (Professor F. Sondheimer). His first academic
appointment was at the Open University in Milton Keynes. This
post gave Professor Taylor the opportunity to contribute to Open
University textbooks, radio programs and television productions on
various aspects of organic chemistry. Professor Taylor then moved to UEA, Norwich, where he
established his independent research program, before taking up his present position in York in 1993.
Richard Taylor has just finished his term as President of the Organic Division of the Royal Society
of Chemistry and was awarded the 1999 RSC Tilden Lectureship and the 1999 RSC Heterocyclic
Prize. He is currently the UK Regional Editor of the international journal Tetrahedron.
Volume Editors
EDITOR OF VOLUME 1
Janine Cossy did her undergraduate and graduate studies at the

University of Reims. After a postdoctoral stay with Barry Trost, for
two years (1980–1982) at the University of Wisconsin, she returned to
Reims, where she became a Director of Research of the CNRS in
1990. In the same year she moved to Paris to become Professor of
Organic Chemistry at the ESPCI (Ecole Supérieure de Physique et
de Chimie Industrielles de la Ville de Paris). She is interested in
synthetic methodologies (radicals, organometallics, photochemistry,
thermal reactions, ring expansions, enantioselectivity, synthesis of
heterocycles, synthesis of solid support) and in their applications to
the synthesis of natural products and biologically active molecules.
EDITOR OF VOLUME 2
Chris Ramsden was born in Manchester, UK in 1946. He is

a graduate of Sheffield University and received his Ph.D.
(W. D. Ollis) in 1970 and D.Sc. in 1990. After postdoctoral work
at the University of Texas (M. J. S. Dewar)(1971–1973) and
University of East Anglia (A. R. Katritzky)(1973–1976), he worked
in the pharmaceutical industry. He moved to Keele University as
Professor of Organic Chemistry in 1992. His research interests are
heterocycles and three-center bonds and applications of their
chemistry to biological problems.
EDITOR OF VOLUME 3
Keith Jones was born in Manchester. He studied at Cambridge

University for his B.A. in Natural Sciences (1976) and stayed to
carry out research with Professor Sir Alan Battersby obtaining his
Ph.D. in 1979. In 1979, he moved to a lectureship at King’s College
London. In 1984, he caught up with his postdoctoral research by
spending a year working with Professor Gilbert Stork at Columbia
University, New York. After returning to King’s College, he
became a reader in 1995. In 1998, he moved to a chair in organic
and medicinal chemistry at Kingston University. His research
interests cover natural product synthesis, heterocyclic chemistry
and the use of radicals in synthesis. He has been a visiting
professor at Neuchatel and Barcelona Universities as well as the
Australian National University.
EDITOR OF VOLUME 4
Professor Gary Molander was born in Cedar Rapids, Iowa. He

received his B.S. degree at Iowa State University and subsequently
entered the graduate chemistry program at Purdue University in
1975, obtaining his Ph.D. degree in 1979 under the direction of
Professor Herbert C. Brown. He joined Professor Barry Trost’s
group at the University of Wisconsin, Madison 1980 as a
postdoctoral research associate, and in 1981 he accepted an
appointment at the University of Colorado, Boulder, as an
Assistant Professor of chemistry, where he rose through the
academic ranks. In 1999 he joined the faculty at the University of
Pennsylvania, and in 2001 was appointed Allan Day Professor of
Chemistry. Professor Molander’s research interests focus on the
development of new synthetic methods for organic synthesis and
natural product synthesis. A major focus of his research has been
the application of organolanthanide reagents and catalysts to
selective organic synthesis.
EDITOR OF VOLUME 5
Ray Jones started his chemistry career as an undergraduate

and then completing a Ph.D. at Cambridge University under the
supervision of Professor Sir Alan Battersby, in the area of alkaloid
biosynthesis. After a year as an ICI Postdoctoral Fellow in the
laboratories of Professor Albert Eschenmoser at the ETH Zurich,
he was appointed as Lecturer in Organic Chemistry at University
of Nottingham in 1974. He progressed to Senior Lecturer at
Nottingham and then took up the Chair of Organic Chemistry
at the Open University in 1995, before moving to the Chair of
Organic and Biological Chemistry at Loughborough University in
2000.
His research interests span heterocyclic and natural product
chemistry, with over 100 publications. Example topics include
the acyltetramic acids and pyridones, Mammea coumarins, spermine
and spermidine alkaloids, imidazolines as templates for (asymmetric)
synthesis, dipolar cycloadditions, and unusual amino acids and
peptide mimetics.
EDITOR OF VOLUME 6
Eric F. V. Scriven is a native of Wales, UK. After working at

BISRA and ESSO Ltd, he attended the University of Salford and
graduated in 1965. He obtained his M.Sc. from the University of
Guelph, and his Ph.D. from the University of East Anglia (with
Professor A. R. Katritzky) in 1969. After postdoctoral years at the
University of Alabama and University College London, he was
appointed Lecturer in organic chemistry at the University of
Salford. There, his research interests centered on the reactivity of
azides and nitrenes. While at Salford, he spent two semesters on
secondment at the University of Benin in Nigeria. He joined Reilly
Industries Inc. in 1979 and was director of Research from 1991
to 2003. He is currently at the University of Florida. He edited
Azides & Nitrenes (1984), and he and Professor H. Suschitzky were
founding editors of Progress in Heterocyclic Chemistry, which has
been published annually since 1989 by the International Society of
Heterocyclic Chemistry. He also collaborated with Professors
A. R. Katritzky and C. W. Rees as Editors-in-Chief of Comprehensive Heterocyclic Chemistry II
(1997). His current research interests are in novel nitration reactions, ionic liquids, and
applications of polymers in organic synthesis.
Preface
Comprehensive Organic Functional Group Transformations (COFGT 1995) presented the vast
subject of organic synthesis in terms of the introduction and interconversion of functional groups,
according to a rigorous system, designed to cover all known and as yet unknown functional
groups.
Comprehensive Organic Functional Group Transformations II (COFGT-II), designed for specia-
list and nonspecialist chemists, active in academic, industrial, and government laboratories, now
updates the developments of functional group transformations since the publication of the
COFGT 1995. COFGT-II is structured in precisely the same manner as the original COFGT
work, allowing truly comprehensive coverage of all organic functional group transformations.
COFGT-II, in combination with COFGT 1995, provides an essential reference source for the
all-important topic of methodologies for the interconversion of functional groups in organic
compounds, and provides an efficient first point of entry into the key literature and background
material for those planning any research involving the synthesis of new organic compounds. With
the increase in our understanding of the way in which the chemical structure of compounds
determines all physical, chemical, biological, and technological properties, targeted synthesis
becomes ever more important. The making of compounds is germane not only to organic
chemistry but also to future developments in all biological, medical, and materials sciences.
The availability of the work in electronic format through ScienceDirect will greatly enhance its
utility.
The Editors-in-Chief would like to extend their warm thanks to the Volume Editors, the
chapter authors, and the Elsevier staff for operating in such an efficient and professional manner.
A. R. Katritzky
R. J. K. Taylor
Introduction to Volume 4
The original Comprehensive Organic Functional Group Transformations, published in 1995, was a
landmark publication, outlining in detail the most highly effective synthetic routes to virtually all
imaginable organic functional groups. In a discipline over 100 years old and as ‘‘mature’’ as
synthetic organic chemistry, one might have thought that the vast majority of the best synthetic
methods for all of these useful functional groups would have been thoroughly explored. However,
the past ten years have witnessed enormous advances. Thus, the imagination, creativity, and
experimental skills of organic synthesis chemists continue to provide astounding new entries to
these important structures.
These are superbly analyzed and highlighted by a very talented group of authors in Volume 4
of the present edition of Comprehensive Organic Functional Group Transformations. The outline
and overall content of this volume have been retained from the previous, successful work. In this
updated compendium, highly efficient and creative new approaches to carbons with two heteroatoms,
each attached by a single bond, are highlighted. The authors have performed a marvelous job in their
individual contributions. I congratulate them and thank them for their hard work and dedication.
Gary Molander
Philadelphia, USA
July 2004
Explanation of the reference
system
Throughout this work, references are designated by a number-lettering coding of which the first
four numbers denote the year of publication, the next one to three letters denote the journal, and
the final numbers denote the page. This code appears in the text each time a reference is quoted.
This system has been used successfully in previous publications and enables the reader to go
directly to the literature reference cited, without first having to consult the bibliography at the end
of each chapter.
The following additional notes apply:

1. A list of journal codes in alphabetical order, together with the journals to which they refer
is given immediately following these notes. Journal names are abbreviated throughout
using the CASSI ‘‘Chemical Abstracts Service Source Index’’ system.
2. The references cited in each chapter are given at the end of the individual chapters.
3. The list of references is arranged in order of (a) year, (b) journal in alphabetical order
of journal code, (c) part letter or number if relevant, (d) volume number if relevant, and
(e) page number.
4. In the reference list the code is followed by (a) the complete literature citation in the
conventional manner and (b) the number(s) of the page(s) on which the reference appears,
whether in the text or in tables, schemes, etc.
5. For non-twentieth-century references, the year is given in full in the code.
6. For journals which are published in separate parts, the part letter or number is given (when
necessary) in parentheses immediately after the journal code letters.
7. Journal volume numbers are not included in the code numbers unless more than one
volume was published in the year in question, in which case the volume number is included
in parentheses immediately after the journal code letters.
8. Patents are assigned appropriate three-letter codes.
9. Frequently cited books are assigned codes.
10. Less common journals and books are given the code ‘‘MI’’ for miscellaneous with the
whole code for books prefixed by the letter ‘‘B-’’.
11. Where journals have changed names, the same code is used throughout, e.g., CB refers to
both Chem. Ber. and to Ber. Dtsch. Chem. Ges.
JOURNAL ABBREVIATIONS
AAC Antimicrob. Agents Chemother. CLY Chem. Listy
ABC Agric. Biol. Chem. CM Chem. Mater.
AC Appl. Catal. CMC Comp. Med. Chem.
ACA Aldrichim. Acta COC Comp. Org. Chem.
AC(P) Ann. Chim. (Paris) COFGT Comp. Org. Func. Group Transformations
AC(R) Ann. Chim. (Rome) COMCI Comp. Organomet. Chem., 1st edn.
ACH Acta Chim. Acad. Sci. Hung. CONAP Comp. Natural Products Chem.
ACR Acc. Chem. Res. COS Comp. Org. Synth.
ACS Acta Chem. Scand. CP Can. Pat.
ACS(A) Acta Chem. Scand., Ser. A CPB Chem. Pharm. Bull.
ACS(B) Acta Chem. Scand., Ser. B CPH Chem. Phys.
AF Arzneim.-Forsch. CPL Chem. Phys. Lett.
AFC Adv. Fluorine Chem. CR C.R. Hebd. Seances Acad. Sci.
AG Angew. Chem. CR(A) C.R. Hebd. Seances Acad. Sci., Ser. A
AG(E) Angew. Chem., Int. Ed. Engl. CR(B) C.R. Hebd. Seances Acad. Sci., Ser. B
AHC Adv. Heterocycl. Chem. CR(C) C.R. Hebd. Seances Acad. Sci., Ser. C.
AHCS Adv. Heterocycl. Chem. Supplement CRAC Crit. Rev. Anal. Chem.
AI Anal. Instrum. CRV Chem. Rev.
AJC Aust. J. Chem. CS Chem. Scr.
AK Ark. Kemi CSC Cryst. Struct. Commun.
AKZ Arm. Khim. Zh. CSR Chem. Soc. Rev.
AM Adv. Mater. (Weinheim, Ger.) CT Chem. Tech.
AMLS Adv. Mol. Spectrosc. CUOC Curr. Org. Chem.
AMS Adv. Mass Spectrom. CZ Chem.-Ztg.
ANC Anal. Chem. CZP Czech. Pat.
ANL Acad. Naz. Lincei DIS Diss. Abstr.
ANY Ann. N. Y. Acad. Sci. DIS(B) Diss. Abstr. Int. B
AOC Adv. Organomet. Chem. DOK Dokl. Akad. Nauk SSSR
AP Arch. Pharm. (Weinheim, Ger.) DOKC Dokl. Chem. (Engl. Transl.)
APO Adv. Phys. Org. Chem. DP Dyes Pigm.
APOC Appl. Organomet. Chem. E Experientia
APS Adv. Polym. Sci. EC Educ. Chem.
AQ An. Quim. EF Energy Fuels
AR Annu. Rep. Prog. Chem. EGP Ger. (East) Pat.
AR(A) Annu. Rep. Prog. Chem., Sect. A EJI Eur. J. Inorg. Chem.
AR(B) Annu. Rep. Prog. Chem., Sect. B EJM Eur. J. Med. Chem.
ARP Annu. Rev. Phys. Chem. EJO Eur. J. Org. Chem.
ASI Acta Chim. Sin. Engl. Ed. EUP Eur. Pat.
ASIN Acta Chim. Sin. FCF Fortschr. Chem. Forsch.
AX Acta Crystallogr. FCR Fluorine Chem. Rev.
AX(A) Acta Crystallogr., Part A FES Farmaco Ed. Sci.
AX(B) Acta Crystallogr., Part B FOR Fortschr. Chem. Org. Naturst.
B Biochemistry FRP Fr. Pat.
BAP Bull. Acad. Pol. Sci., Ser. Sci. Chim. G Gazz. Chim. Ital.
BAU Bull. Acad. Sci. USSR, Div. Chem. Sci. GAK Gummi Asbest Kunstst.
BBA Biochim. Biophys. Acta GC Green Chem.
BBR Biochem. Biophys. Res. Commun. GEP Ger. Pat.
BCJ Bull. Chem. Soc. Jpn. GSM Gen. Synth. Methods
BEP Belg. Pat. H Heterocycles
BJ Biochem. J. HAC Heteroatom Chem.
BJP Br. J. Pharmacol. HC Chem. Heterocycl. Compd. [Weissberger-Taylor series]
BMC Biorg. Med. Chem. HCA Helv. Chim. Acta
BMCL Biorg. Med. Chem. Lett. HCO Heterocycl. Commun.
BOC Bioorg. Chem. HOU Methoden Org. Chem. (Houben-Weyl)
BP Biochem. Biopharmacol. HP Hydrocarbon Process
BPJ Br. Polym. J. IC Inorg. Chem.
BRP Br. Pat. ICA Inorg. Chim. Acta
BSB Bull. Soc. Chim. Belg. IEC Ind. Eng. Chem. Res.
BSF Bull. Soc. Chim. Fr. IJ Isr. J. Chem.
BSF(2) Bull. Soc. Chim. Fr., Part 2 IJC Indian J. Chem.
BSM Best Synthetic Methods IJC(A) Indian J. Chem., Sect. A
C Chimia IJC(B) Indian J. Chem., Sect. B
CA Chem. Abstr. IJM Int. J. Mass Spectrom. Ion Phys.
CAN Cancer IJQ Int. J. Quantum Chem.
CAR Carbohydr. Res. IJS Int. J. Sulfur Chem.
CAT Chim. Acta Turc. IJS(A) Int. J. Sulfur Chem., Part A
CB Chem. Ber. IJS(B) Int. J. Sulfur Chem., Part B
CBR Chem. Br. IS Inorg. Synth.
CC J. Chem. Soc., Chem. Commun. IZV Izv. Akad. Nauk SSSR, Ser. Khim.
CCA Croat. Chem. Acta JA J. Am. Chem. Soc.
CCC Collect. Czech. Chem. Commun. JAN J. Antibiot.
CCHT Comb. Chem. High T. Scr. JAP Jpn. Pat.
CCR Coord. Chem. Rev. JAP(K) Jpn. Kokai
CE Chem. Express JBC J. Biol. Chem.
CEJ Chem. -Eur. J. JC J. Chromatogr.
CEN Chem. Eng. News JCA J. Catal.
CHE Chem. Heterocycl. Compd. (Engl. Transl.) JCC J. Coord. Chem.
CHECI Comp. Heterocycl. Chem., 1st edn. JCO J. Comb. Chem.
CHECII Comp. Heterocycl. Chem., 2nd edn. JCE J. Chem. Ed.
CHIR Chirality JCED J. Chem. Eng. Data
CI(L) Chem. Ind. (London) JCI J. Chem. Inf. Comput. Sci.
CI(M) Chem. Ind. (Milan) JCP J. Chem. Phys.
CJC Can. J. Chem. JCPB J. Chim. Phys. Physico-Chim. Biol.
CJS Canadian J. Spectrosc. JCR(M) J. Chem. Res. (M)
CL Chem. Lett. JCR(S) J. Chem. Res. (S)
JCS J. Chem. Soc. PB Polym. Bull.
JCS(A) J. Chem. Soc. (A) PC Personal Communication
JCS(B) J. Chem. Soc. (B) PCS Proc. Chem. Soc.
JCS(C) J. Chem. Soc. (C) PH ‘Photochemistry of Heterocyclic Compounds’, O.
JCS(D) J. Chem. Soc., Dalton Trans. Buchardt, Ed.; Wiley, New York, 1976
JCS(F1) J. Chem. Soc., Faraday Trans. 1 PHA Pharmazi
JCS(F2) J. Chem. Soc., Faraday Trans. 2 PHC Prog. Heterocycl. Chem.
JCS(P1) J. Chem. Soc., Perkin Trans. 1 PIA Proc. Indian Acad. Sci.
JCS(P2) J. Chem. Soc., Perkin Trans. 2 PIA(A) Proc. Indian Acad. Sci., Sect. A
JCS(S2) J. Chem. Soc., (Suppl. 2) PJC Pol. J. Chem.
JEC J. Electroanal. Chem. Interfacial Electrochem. PJS Pak. J. Sci. Ind. Res.
JEM J. Energ. Mater. PMH Phys. Methods Heterocycl. Chem.
JES J. Electron Spectrosc. PNA Proc. Natl. Acad. Sci. USA
JFA J. Sci. Food Agri. POL Polyhedron
JFC J. Fluorine Chem. PP Polym. Prepr.
JGU J. Gen. Chem. USSR (Engl. Transl.) PRS Proceed. Roy. Soc.
JHC J. Heterocycl. Chem. PS Phosphorus Sulfur (formerly); Phosphorus Sulfur Silicon
JIC J. Indian Chem. Soc. (currently)
JINC J. Inorg. Nucl. Chem. QR Q. Rev., Chem. Soc.
JLC J. Liq. Chromatogr. QRS Quart. Rep. Sulfur Chem.
JMAC J. Mater. Chem. QSAR Quant. Struct. Act. Relat.
JMAS J. Mater. Sci. RC Rubber Chem. Technol.
JMC J. Med. Chem. RCB Russian Chemical Bull.
JMOC J. Mol. Catal. RCC Rodd’s Chemistry of Carbon Compounds
JMR J. Magn. Reson. RCM Rapid Commun. Mass Spectrom.
JMS J. Mol. Sci. RCP Rec. Chem. Prog.
JNP J. Nat. Prod. RCR Russ. Chem. Rev. (Engl. Transl.)
JOC J. Org. Chem. RHA Rev. Heteroatom. Chem.
JOM J. Organomet. Chem. RJ Rubber J.
JOU J. Org. Chem. USSR (Engl. Transl.) RJGC Russ. J. Gen. Chem. (Engl. Transl.)
JPC J. Phys. Chem. RJOC Russ. J. Org. Chem. (Engl. Transl.)
JPJ J. Pharm. Soc. Jpn. RP Rev. Polarogr.
JPO J. Phys. Org. Chem. RRC Rev. Roum. Chim.
JPP J. Pharm. Pharmacol. RS Ric. Sci.
JPR J. Prakt. Chem. RTC Recl. Trav. Chim. Pays-Bas
JPS J. Pharm. Sci. RZC Rocz. Chem.
JPS(A) J. Polym. Sci., Polym. Chem., Part A S Synthesis
JPU J. Phys. Chem. USSR (Engl. Transl.) SA Spectrochim. Acta
JSC J. Serbochem. Soc. SA(A) Spectrochim. Acta, Part A
JSP J. Mol. Spectrosc. SAP S. Afr. Pat.
JST J. Mol. Struct. SC Synth. Commun.
K Kristallografiya SCI Science
KFZ Khim. Farm. Zh. SH W. L. F. Armarego, ‘Stereochemistry of Heterocyclic
KGS Khim. Geterotsikl. Soedin. Compounds’, Wiley, New York, 1977, parts 1 and 2.
KO Kirk-Othmer Encyc. SL Synlett
KPS Khim. Prir. Soedin. SM Synth. Met.
L Langmuir SR Sulfur Reports
LA Liebigs Ann. Chem. SRC Supplements to Rodd’s Chemistry of Carbon Compounds
LC Liq. Cryst. SRI Synth. React. Inorg. Metal-Org. Chem.
LS Life. Sci. SS Sch. Sci. Rev.
M Monatsh. Chem. SSR Second Supplements to Rodd’s Chemistry of Carbon Com-
MC Mendeleev Communications pounds
MCLC Mol. Cryst. Liq. Cryst. SST Org. Compd. Sulphur, Selenium, Tellurium [R. Soc.
MI Miscellaneous [journal or B-yyyyMI for book] Chem. series]
MIP Miscellaneous Pat. SUL Sulfur Letters
MM Macromolecules SZP Swiss Pat.
MP Mol. Phys. T Tetrahedron
MRC Magn. Reson. Chem. T(S) Tetrahedron, Suppl.
MS Q. N. Porter and J. Baldas, ‘Mass Spectrometry of TA Tetrahedron Asymmetry
Heterocyclic Compounds’, Wiley, New York, 1971 TAL Talanta
N Naturwissenschaften TCA Theor. Chim. Acta
NAT Nature TCC Top. Curr. Chem.
NEP Neth. Pat. TCM Tetrahedron, Comp. Method
NJC Nouv. J. Chim. TFS Trans. Faraday Soc.
NJC New J. Chem. TH Thesis
NKK Nippon Kagaku Kaishi (J. Chem. Soc. Jpn.) TL Tetrahedron Lett.
NKZ Nippon Kagaku Zasshi TS Top. Stereochem.
NMR T. J. Batterham, ‘NMR Spectra of Simple Heterocycles’, UK Usp. Khim.
Wiley, New York, 1973 UKZ Ukr. Khim. Zh. (Russ. Ed.)
NN Nucleosides & Nucleotides UP Unpublished Results
NZJ N. Z. J. Sci. Technol. URP USSR Pat.
OBC Organic and Biomolecular Chemistry USP U.S. Pat.
OCS Organomet. Synth. WOP PCT Int. Appl. WO (World Intellectual Property
OL Org. Lett. Organization Pat. Appl.)
OM Organometallics YGK Yuki Gosei Kagaku Kyokaishi
OMR Org. Magn. Reson. YZ Yakugaku Zasshi
OMS Org. Mass Spectrom. ZAAC Z. Anorg. Allg. Chem.
OPP Org. Prep. Proced. lnt. ZAK Zh. Anal. Khim.
OPRD Org. Process Res. Dev. ZC Z. Chem.
OR Org. React. ZN Z. Naturforsch.
OS Org. Synth. ZN(A) Z. Naturforsch., Teil A
OSC Org. Synth., Coll. Vol. ZN(B) Z. Naturforsch., Teil B
P Phytochemistry ZOB Zh. Obshch. Khim.
PA Polym. Age ZOR Zh. Org. Khim.
PAC Pure Appl. Chem. ZPC Hoppe-Seyler’s Z. Physiol. Chem.
PAS Pol. Acad. Sci. ZPK Zh. Prikl. Khim.
List of Abbreviations
TECHNIQUES/CONDITIONS
18-C-6 18-crown-6
))))) ultrasonic (sonochemistry)
heat, reflux
AAS atomic absorption spectroscopy
AES atomic emission spectroscopy
AFM atomic force microscopy
approx. approximately
aq. aqueous
b.p. boiling point
CD circular dichroism
CIDNP chemically induced dynamic nuclear polarization
CNDO complete neglect of differential overlap
conc. concentrated
CT charge transfer
ee enantiomeric excess
equiv. equivalent(s)
ESR electron spin resonance
EXAFS extended X-ray absorption fine structure
FVP flash vacuum pyrolysis
g gaseous
GC gas chromatography
GLC gas–liquid chromatography
h Planck’s constant
h hour
HOMO highest occupied molecular orbital
HPLC high-performance liquid chromatography
h light (photochemistry)
ICR ion cyclotron resonance
INDO incomplete neglect of differential overlap
IR infrared
l liquid
LCAO linear combination of atomic orbitals
LUMO lowest unoccupied molecular orbital
MCD magnetic circular dichroism
MD molecular dynamics
min minute(s)
MM molecular mechanics
MO molecular orbital
MOCVD metal organic chemical vapor deposition
m.p. melting point
MS mass spectrometry
MW molecular weight
NMR nuclear magnetic resonance
NQR nuclear quadrupole resonance
ORD optical rotatory dispersion
PE photoelectron
ppm parts per million
rt room temperature
s solid
SCF self-consistent field
SET single electron transfer
SN1 first-order nucleophilic substitution
SN2 second-order nucleophilic substitution
SNi internal nucleophilic substitution
STM scanning tunneling microscopy
TLC thin-layer chromatography
UV ultraviolet
vol. volume
wt. weight
REAGENTS, SOLVENTS, ETC.

Ac acetyl CH3CO-
acac acetylacetonato
acam acetamide
AcO acetate
AcOH acetic acid
AIBN 2,20 -azobisisobutyronitrile
Ans ansyl
Ar aryl
ATP adenosine 50 -triphosphate
9-BBN 9-borabicyclo[3.3.1]nonyl
9-BBN-H 9-borabicyclo[3.3.1]nonane
BEHP bis (2-ethylhexyl) phthalate
BHT 2,6-di-t-butyl-4-methylphenol (butyrated hydroxytoluene)
binap 2,20 -bis(diphenylphosphino)-1,10 -binaphthyl
bipy 2,20 -bipyridyl
Bn benzyl C6H5CH2- (NB avoid confusion with Bz)
t-BOC t-butoxycarbonyl
bpy 2,20 -bipyridyl
BSA N,O-bis(trimethylsilyl)acetamide
BSTFA N,O-bis(trimethylsilyl)trifluoroacetamide
Bt benzotriazole
BTAF benzyltrimethylammonium fluoride
Bz benzoyl C6H5CO- (NB avoid confusion with Bn)
Bzac benzoylacetone
CAN ceric ammonium nitrate
Cbz carbobenzoxy
chalcogens oxygen, sulfur, selenium, tellurium
CH2Cl2 dichloromethane
COD 1,5-cyclooctadiene
COT cyclooctatetraene
Cp cyclopentadienyl
Cp* pentamethylcyclopentadienyl
18-crown-6 1,4,7,10,13,16-hexaoxacyclooctadecane
CSA camphorsulfonic acid
CSI chlorosulfonyl isocyanate
CTAB cetyl trimethyl ammonium bromide
DABCO 1,4-diazabicyclo[2.2.2]octane
DBA dibenzylideneacetone
DBN 1,5-diazabicyclo[4.3.0]non-5-ene
DBU 1,5-diazabicyclo[5.4.0]undec-5-ene
DCC dicyclohexylcarbodiimide
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DEAC diethylaluminum chloride
DEAD diethyl azodicarboxylate
DET diethyl tartrate (þ or )
DHP dihydropyran
DIBAL-H diisobutylaluminum hydride
diglyme diethylene glycol dimethyl ether
dimsyl Na sodium methylsulfinylmethide
DIOP 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane
DIPT diisopropyl tartrate (þ or )
DMA dimethylacetamide
DMAC dimethylaluminium chloride
DMAD dimethyl acetylenedicarboxylate
DMAP 4-dimethylaminopyridine
DME dimethoxyethane
DMF dimethylformamide
DMI N,N0 -dimethylimidazolidinone
DMN diaminomaleonitrile
DMSO dimethyl sulfoxide
DMTSF dimethyl(methylthio)sulfonium fluoroborate
DPPB 1,2-bis(diphenylphosphino)butane
DPPE 1,2-bis(diphenylphosphino)ethane
DPPF 1,10 -bis(diphenylphosphino)ferrocene
DPPP 1,2-bis(diphenylphosphino)propane
Eþ electrophile
EADC ethylaluminium dichloride
EDG electron-donating group
EDTA ethylenediaminetetraacetate
EEDQ N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline
Et ethyl
Et2O diethyl ether
EtOH ethanol
EtOAc ethyl acetate
EWG electron-withdrawing group
HMPA hexamethyl phosphoramide
HMPT hexamethylphosphoric triamide
IpcBH2 isopinocampheylborane
Ipc2BH diisopinocampheylborane
KAPA potassium 3-aminopropylamide
K-selectride potassium tri-s-butylborohydride
LAH lithium aluminium hydride
LDA lithium diisopropylamide
LICA lithium isopropyl cyclohexylamide
LITMP lithium tetramethyl piperidide
L-selectride lithium tri-s-butyl borohydride
LTA lead tetraacetate
MAO monoamine oxidase
MCPBA 3-chloroperoxybenzoic acid
MCT mercury cadmium telluride
Me methyl
MEM methoxyethoxymethyl
MEM-Cl methoxyethoxymethyl chloride
MeOH methanol
MMA methyl methacrylate
MMC methylmagnesium carbonate
MOM methoxymethyl
Ms methanesulfonyl (mesylate)
MSA methanesulfonic acid
MsCl methanesulfonyl chloride
MVK methyl vinyl ketone
NBS N-bromosuccinimide
NCS N-chlorosuccinimide
NMO N-methylmorpholine N-oxide
NMP N-methyl-2-pyrrolidone
Nu nucleophile
PPA polyphosphoric acid
PCC pyridinium chlorochromate
PDC pyridinium dichromate
Ph phenyl
phen 1,10-phenanthroline
Phth phthaloyl
PPE polyphosphate ester
PPO 2,5-diphenyloxazole
PPTS pyridinium p-toluenesulfonate
Pr propyl
Pyr pyridine
Red-Al sodium bis(methoxyethoxy)aluminum dihydride
SDS sodium dodecyl sulfate
SEM trimethylsilylethoxymethyl
Sia2BH disiamylborane
SM starting material
TAS tris(diethylamino)sulfonium
TBAF tetra-n-butylammonium fluoride
TBDMS t-butyldimethylsilyl
TBDMS-Cl t-butyldimethylsilyl chloride
TBDPS t-butyldiphenylsilyl
TBHP t-butyl hydroperoxide
TCE 2,2,2-trichloroethanol
TCNE tetracyanoethylene
TEA tetraethylammonium
TES triethylsilyl
Tf triflyl (trifluoromethanesulfonyl)
TFA trifluoroacetyl
TFAA trifluoroacetic anhydride
THF tetrahydrofuran
THP tetrahydropyranyl
TIPBSCl 2,4,6-triisopropylbenzenesulfonyl chloride
TIPSCl triisopropylsilyl chloride
TMEDA tetramethylethylenediamine [1,2-bis(dimethylamino)ethane]
TMS trimethylsilyl
TMSCl trimethylsilyl chloride
TMSCN trimethylsilyl cyanide
Tol tolyl C6H4(CH3)–
TosMIC tosylmethyl isocyanide
TPP meso-tetraphenylporphyrin
Tr trityl (triphenylmethyl)
Tris tris(hydroxymethyl)aminomethane
Ts 4-toluenesulfonyl (tosyl)
TTFA thallium trifluroacetate
TTMSS tris(trimethylsilyl)silane
TTN thallium(III) nitrate
X halogen or leaving group
Volume 4 - Synthesis: Carbon With Two Heteroatoms Each Attached by a Single Bond
Part I: Tetracoordinated Carbon Functions Bearing Two

Heteroatoms, R2CX1X2
4.01 Dihaloalkanes, R1R2C(Hal)2, Pages 1-26, J. L. Méndez-Andino

4.02 Functions Incorporating a Halogen and a Chalcogen,
Pages 27-128, N. W. A. Geraghty
4.03 Functions Incorporating a Halogen and Another
Heteroatom Group Other Than a Chalcogen, Pages 129-191,
L. F. Silva, Jr. and A. M. Aguilar
4.04 Functions Bearing Two Oxygens, R12C(OR2)2, Pages
193-236, J. O. Hoberg and B. L. Stocker
4.05 Functions Incorporating Oxygen and Another
Chalcogen, Pages 237-269, E. P. Cormier and G. A. Molander
4.06 Functions Incorporating Two Chalcogens Other
Than Oxygen, Pages 271-322, V. Reboul, J. -F. Brière and P. Metzner
4.07 Functions Incorporating a Chalcogen and a Group 15
Element, Pages 323-356, K. M. George and G. A. Molander
4.08 Functions Incorporating a Chalcogen and a Silicon,
Germanium, Boron, or Metal, Pages 357-410, N. G. Bhat
4.09 Functions Bearing Two Nitrogens, Pages 411-441, M. Hiersemann
4.10 Functions Incorporating a Nitrogen and Another
Group 15 Element, Pages 443-494, C. S. Kenesky and G. A. Molander
4.11 Functions Incorporating a Nitrogen and a Silicon, Germanium,
Boron, or a Metal, Pages 495-537, C. Chu
4.12 Functions Containing One Phosphorus and Either Another Phosphorus
or As, Sb, Bi, Si, Ge, B, or a Metal, Pages 539-573, R. A. Aitken
4.13 Functions Containing at Least One As, Sb, or Bi with or without
a Metalloid (Si or Ge) or a Metal, Pages 575-593, E. Fouquet and A. Hervé
4.14 Functions Containing at Least One Metalloid (Si, Ge, or B) Together
with Another Metalloid or Metal, Pages 595-625, N. G. Bhat
4.15 Functions Containing Two Atoms of the Same Metallic Element,
Pages 627-671, A. P. Sadimenko
4.16 Functions Containing Two Atoms of Different Metallic Elements,
Pages 673-694, A. P. Sadimenko
Part II: Tricoordinated Carbon Functions Bearing Two
Heteroatoms, R2C=CX1X2
4.17 Functions Incorporating Two Halogens or a Halogen

and a Chalcogen, Pages 695-733, D. J. Jean, Jr. and G. A.
Molander
4.18 Functions Incorporating a Halogen and Another

Group Other Than a Halogen or a Chalcogen, Pages 735-
787, C. V. Stevens and B. Vanderhoydonck
4.19 Functions Bearing Two Chalcogens, Pages 789-833,

D. C. Oniciu
4.20 Functions Containing a Chalcogen and Any Group

Other Than a Halogen or a Chalcogen, Pages 835-876, B.
Bessieres
4.21 Functions Containing at Least One Nitrogen and No

Halogen or Chalcogen, Pages 877-956, G. L. Patrick
4.22 Functions Containing at Least One Phosphorus,

Arsenic, Antimony or Bismuth, and No Halogen,
Chalcogen or Nitrogen, Pages 957-1053, P. Ba czewski, J.
Drabowicz, A. Szadowiak, R. őurawiŴski, P. Kie basiŴski and
M. Miko ajczyk
4.23 Functions Containing at Least One Metalloid (Si, Ge,

or B) and No Halogen, Chalcogen, or Group 15 Element;
Also Functions Containing Two Metals, Pages 1055-1102,
S. J. Collier
4.24 Tri- and Dicoordinated Ions, Radicals, and Carbenes
_ _
Bearing Two Heteroatoms (RX2C+, RX2C·, RX2C , X2C :),
Pages 1103-1125, A. J. Arduengo and D. Ńapu
4.01
Dihaloalkanes, R1R2C(Hal)2
J. L. MÉNDEZ-ANDINO
Procter & Gamble Pharmaceuticals, Mason, OH, USA
4.01.1 GENERAL METHODS 2

4.01.2 DIFLUOROALKANES—R1R2CF2 2
4.01.2.1 Difluoroalkanes from Alkanes 2
4.01.2.2 Difluoroalkanes from Dihaloalkanes 2
4.01.2.3 Difluoroalkanes from Trihaloalkanes 3
4.01.2.4 Difluoroalkanes from Alkenes 4
4.01.2.5 Difluoroalkanes from Alkynes 6
4.01.2.6 Difluoroalkanes from Difluorocarbene 7
4.01.2.7 Difluoroalkanes from Aldehydes and Ketones 8
4.01.2.8 Difluoroalkanes from Imines 9
4.01.2.9 Difluoroalkanes from Dithianes 9
4.01.3 DICHLOROALKANES—R1R2CCl2 9
4.01.3.1 Dichloroalkanes from Alkanes 9
4.01.3.2 Dichloroalkanes from Dihaloalkanes 9
4.01.3.3 Dichloroalkanes from Trihaloalkanes 10
4.01.3.4 Dichloroalkanes from Alkenes 11
4.01.3.5 Dichloroalkanes from Alkynes 12
4.01.3.6 Dichloroalkanes from Dichlorocarbene 12
4.01.3.7 Dichloroalkanes from Aldehydes and Ketones 13
4.01.3.8 Dichloroalkanes from Imines 14
4.01.4 DIBROMOALKANES—R1R2CBr2 14
4.01.4.1 Dibromoalkanes from Alkanes 14
4.01.4.2 Dibromoalkanes from Dihaloalkanes 15
4.01.4.3 Dibromoalkanes from Trihaloalkanes 16
4.01.4.4 Dibromoalkanes from Alkenes 16
4.01.4.5 Dibromoalkanes from Alkynes 17
4.01.4.6 Dibromoalkanes from Dibromocarbene 18
4.01.4.7 Dibromoalkanes from Aldehydes and Ketones 19
4.01.4.8 Dibromoalkanes from Imines 19
4.01.5 DIIODOALKANES—R1R2CI2 20
4.01.5.1 Diiodoalkanes from Alkanes 20
4.01.5.2 Diiodoalkanes from Trihaloalkanes 20
4.01.5.3 Diiodoalkanes from Alkenes 20
4.01.5.4 Diiodoalkanes from Alkynes 21
4.01.6 FLUOROHALOALKANES—R1R2CFHal 21
4.01.6.1 Chlorofluoroalkanes—R1R2CFCl 21
4.01.6.1.1 Chlorofluoroalkanes from alkenes 21
4.01.6.1.2 Fluorochloroalkanes from chlorofluorocarbene 21
4.01.6.1.3 Fluorochloroalkanes from imines 21
4.01.6.2 Bromofluoroalkanes—R1R2CFBr 22
4.01.6.2.1 Bromofluoroalkanes from bromofluorocarbene 22
4.01.6.3 Fluoroiodoalkanes—R1R2CFI 22
4.01.6.3.1 Fluoroiodoalkanes from alkanes 22
4.01.7 CHLOROHALOALKANES—R1R2CClHal 22
4.01.7.1 Chlorobromoalkanes—R1R2CClBr 22
4.01.7.1.1 Chlorobromoalkanes from bromochlorocarbene 22
1
2 Dihaloalkanes, R1R2C(Hal)2
4.01.7.2 Chloroiodoalkanes—R1R2CClI 23
4.01.7.2.1 Chloroiodoalkanes from alkanes 23
4.01.8 BROMOIODOALKANES—R1R2CBrI 23
4.01.8.1 Bromoiodoalkanes from Alkanes 23
4.01.8.2 Bromoiodoalkanes from Dihaloalkanes 23
4.01.1 GENERAL METHODS

The review by Hill (COFGT (1995)) should be consulted for general methods for the preparation
of aliphatic halogenated compounds and for the synthesis of difluoro- and dichloroalkanes from
alkanes.
4.01.2 DIFLUOROALKANES—R1R2CF2
4.01.2.1 Difluoroalkanes from Alkanes

Pentafluoriodide–triethylamine–hydrogen fluoride complex (IF5–NEt3–3HF) is a novel fluorina-
tion reagent <2001CL222>. IF5–NEt3–3HF is a stable, nonhazardous, and inexpensive reagent
that allows selective fluorination of alkanes to produce gem-difluoro compounds under mild
conditions. Reported results indicate that the reagent is very effective for the difluorination of
thioether substrates (see Chapter 6.02). Difluorination products are obtained in poor-to-moderate
yield when fluorinating a variety of alkanes (Equations (1) and (2)).
IF5 /Et3N–3HF, CH2Cl2, 4 h, rt F

OH O ð1Þ
50% F
O O O O
IF5/Et 3N–3HF, hexane, 24 h, reflux
O O ð2Þ
25%
F F F
4.01.2.2 Difluoroalkanes from Dihaloalkanes

The substitution of gem-dihalides by fluoride is still mostly accomplished by employing potas-
sium, mercury, and antimony fluoride salts. Antimony(V) halides and chromium(III) oxide have
been used to catalyze challenging and unpredictable HF-fluorinations of highly halogenated
hydrocarbons <1996JFC(76)49>. 4-Chloro-1,1,1,3,3-pentafluorobutane is the main product of
the antimony(V) fluoride-promoted fluorination reaction of 4-fluoro-1,1,1,3,3-pentachlorobutane
(Equation (3)). Interestingly, during this halogen-exchange process, all chlorines are replaced by
fluorine and vice versa. These halogen-exchange reactions have proved to be very difficult to
accomplish whenever adjacent carbons are halogenated. These challenging transformations have
been effected by employing a chromium(III) oxide-catalyst in the vapor phase (Equation (4)).
Porous calcium fluoride (PCF) is a novel material that has found application as a solid-phase
fluorinating material (Equation (5)) and as a support for catalysts in hydrogenation reactions.
PCF is prepared by treating commercial soda lime with anhydrous hydrogen fluoride
<2002JFC(116)65>.
Cl Cl SbF5, HF, 145 °C, 10 h F F

Cl Cl F F
Cl ð3Þ
F
Cl 32% F
Dihaloalkanes, R1R2C(Hal)2 3
F Cr2O3, HF, 350 °C, 8–10 h F

F F
Cl ð4Þ
F F
Cl 23% F
Cl F
Cl Porous-CaF2, 100 °C, 1 h F

O O ð5Þ
Cl 66% F
Geminal difluorocyclopropanes having an electron-withdrawing group are accessible by treat-

ment of the corresponding dichlorocyclopropanes with tetra-n-butylammonium fluoride (TBAF)
under mild conditions (Equations (6) and (7)) <1996TL4085>. This synthetic pathway seems
more efficient than the sluggish reaction between an electron-deficient alkene and the weakly
electrophile difluorocarbene, whose generation is troublesome. Bromide–fluoride exchange is
expected to be an easier reaction compared to the chloride–fluoride exchange. This could be
noticed in the halogen-exchange reaction of gem-dibromides with silver tetrafluoroborate
(AgBF4) under mild conditions <2001TL3555>. This convenient synthetic protocol has been
employed in the synthesis of fluorinated [2,2]-paracyclophanes (Equation (8)).
O O
TBAF, DMF, 0 °C, 4 h
PriO PriO ð6Þ
Cl F
Cl 47% F
O O
TBAF, DMF, 0 °C, 4 h
PriO PriO ð7Þ
Cl F
47% F
Cl
Br AgBF4, CH2Cl2, 20 h F
Br F ð8Þ
Br F
50%
Br F
4.01.2.3 Difluoroalkanes from Trihaloalkanes

Monosaccharides containing the difluoromethyl functionality have been prepared by reduction of
the bromodifluoromethyl group with tri-n-butyltin hydride (Equation (9)) <1998EJO919>.
Under similar reaction conditions, ,-difluoro--lactones have been synthesized from bromo-
difluoromethyl substrates via an intramolecular radical cyclization <1999JOC252>. This intra-
molecular radical cyclization proved to be highly diastereoselective and suitable for the production
of optically active ,-difluoro--lactones with the proper choice of appropriate substrates
(Equations (10) and (11)). The bromodifluoromethyl group can also be reduced electrochemically
using tetrakis(dimethylamino)ethylene (TDAE) as reductant (Equation (12)) <2001JFC(109)39>.
In addition, the generated difluoromethyl heterocyclic anion can be trapped with aromatic
and heterocyclic aldehydes and ketones to produce the corresponding ,-difluoro--hetero-
arylated alcohols in moderate yields (Equation (13)).
AcO AcO
O
OMe Bu3SnH, AIBN, PhMe, 60–80 °C O
OMe
OAc OAc ð9Þ
AcO 81% AcO
CF2Br CHF2
F
F
Bu3SnH, AIBN, C6H6, 80 °C
CF2Br O
O ð10Þ
O O 74%
92/8 trans/cis
F
Bu3SnH, AIBN, C6H6, 80 °C F
CF2Br
OTMS
>70% O ð11Þ
O OTMS
98% ee
N TDAE, DMF, –20 °C to rt, 1.5 h N

CF2Br CHF2 ð12Þ
O 89% O
O O
PhCHO, TDAE, DMF OH
N
CF2Cl –20 °C to rt, 1.5 h N
ð13Þ
N N F Ph
F
57%
-Bromo-,-difluoroallyl derivatives undergo nucleophilic substitution reactions in the pre-

sence of palladium catalysts to afford 1,3-disubstituted 3,3-difluoroalkenes (Equation (14))
<2000CFB885>. Also in the presence of palladium catalysts, iodofluoromethyl alkyl ketones
react with alkenes to give the corresponding ,-difluoro--iodoketone in moderate-to-good
yields (Equation (15)) <1995JOC5570>. Activation of the bromodifluoromethyl group by indium
metal has found application in the synthesis of homopropargylic gem-difluoroalcohols in aqueous
media (Equation (16)) <2000JOC6547>.
Me PhSnBu3, Pd(OAc)2 Me
EtO2C PPh3, THF, 50 °C EtO2C
F F ð14Þ
EtO2C EtO2C
F 73% F
Br Ph
O C4H9-n O
Pd(PPh3)4, rt, 0.5 h
I + C4H9-n ð15Þ
n-C4H9 n-C4H9
F H 62% F FH I
F
F F OH
O In(0), H2O–THF, 3 h, rt
TIPS + TIPS Ph ð16Þ
Br H Ph 72%
F F
The fluoride ion-promoted alkylation of 2,2-difluoro-2-trimethylsilylacetates with a variety

of electrophiles such as aldehydes, ketones, imines, acyl halides, and alkyl halides produces
gem-difluoroacetates in good yields (Table 1) <1999JOC6717>. The reaction between this Refor-
matsky-type reagent and an ,-unsaturated aldehyde selectively produces the corresponding 1,2-
adducts. This -alkylation process is efficient when allyl and benzyl halides are employed, but has
not led to satisfactory results with other alkyl halides.
4.01.2.4 Difluoroalkanes from Alkenes

Alkenes and fluoroalkenes commonly serve as precursors to gem-difluoro compounds. Difluoro-
methyl groups can be generated from a vic-fluorination reaction involving fluoroalkenes and
xenon difluoride (XeF2) in the presence of silicon tetrafluoride (SiF4) <1999EJO3151>. The
products are obtained in high yield, and common side reactions, such as rearrangements and
polymerization, are not observed (Equations (17) and (18)). 1-Fluoro-1-alken-3-ols react with
diethylaminosulfur trifluoride (DAST) in an SN20 process to afford the corresponding 1,1-difluoro-
methyl-3-alkene products with high stereoselectivity (Equation (19)) <1995TL4223>. Difluoro-
methyl-substituted alcohols or amides can be prepared by treating alkenyl trifluoroborates with
2 equiv. of SelectfluorTM, a commercially available electrophilic fluorinating agent <1997SL606>.
This practical method led to alcohol derivatives in aqueous media, while producing amides in
nitrile solvents (Equations (20) and (21)).
Table 1 Reaction of n-hexyl 2-trimethylsilyl-2,2-difluoroacetate with various electrophiles

O O
Electrophile
TMS E
OC6H13–n OC6H13–n
TBAF or KF-CuI
F F F F
Entry Substrate Method Product Yield (%)

OH O
1 PhCHO A Ph OC6H13-n 82
F F
OH O
O
2 A Ph OC6H13-n 76
Ph H
F F
O OH O
3 B OC6H13-n 92
F F
PhHN O
NPh
4 B Ph OC6H13-n 83
Ph H
F F
O O
O
5 B Ph OC6H13-n 60
Ph Cl
F F
O O
O
6 A O OC6H13-n 45
O Cl
F F
Cl O
7 B OC6H13-n 85
F F
Reproduced by permission of American Chemical Society from J. Org. Chem., 1999, 64 (18), 6720; # American Chemical Society (<1999JOC6717>).
Method A: TBAF. Method B: KF-Cul.
XeF2, SiF4, rt F
F ð17Þ
93% F F
F XeF2, SiF4, rt F
F 3C ð18Þ
F F 94% F
OH DAST, CH2Cl2, –70 °C, 0.5 h F
n-C6H11 F n-C6H11 F ð19Þ

50–80%
>95/5 (E )/(Z )
+
H N Cl OH
+
BF3K N 2BF4–, water, rt F ð20Þ
Ph F Ph
H 69% F
+ O
H N Cl
+
BF3K N 2BF4– , acetonitrile, rt HN
ð21Þ
Ph F
F
H 82% Ph
F
Difluoroenol derivatives are suitable materials for the synthesis of a range of difluoromethyl
ketone derivatives <2001OL2859>. Some difluoroenols are readily available and have been
employed in a variety of synthetic sequences in which the latent difluoroketone is released in
the final step under mild conditions (Equation (22)). Similarly, a difluorinated version of
Danishefsky’s diene undergoes hetero-Diels–Alder reactions with aldehydes and imines to pro-
duce gem-difluorinated six-membered heterocycles (Equations (23) and (24)) <2001OL3103>.
Difluoroenamines, which are easily prepared from trifluoromethylimines, are also precursors to
difluoromethyl-containing compounds <2002TL2069>. For example, trifluoromethylimines react
with dimethylsulfonium methylide to yield difluoromethylaziridines in excellent yields (Equation (25)).
Bu3Sn S
OMEM O S
i. 5% PdCl2(PPh3)2, DMF, 85 °C ð22Þ
F OTf F
ii. Me3SiCl, MeOH
F F
58% over two steps
O
OTMS i. PhCHO, ZnBr2 , CH2Cl2
F
F ii. TFA/CCl4 ð23Þ
OBu-n F
F 64% O Ph
Bn
N O
OTMS F
F Me H, ZnI2, CH3CN F ð24Þ
OBu-n
53% N Me
F
Bn
Cl
TMS Me3S(O)I, NaH, DMSO, rt N Cl
N F ð25Þ
F 92% Ph
Ph F
F
4.01.2.5 Difluoroalkanes from Alkynes

The addition of HF across an alkyne represents a general method for the preparation of difluoro-
alkanes (COFGT (1995)). Mild and selective reagents are desirable for the introduction of fluorine
into functionalized molecules. 6HF–NEt3 complex has proven to be a very mild reagent for
hydrofluorination reactions <1996SL529>. Treatment of ethynylbenzene with 6HF–NEt3 complex
promotes difluorination at the internal alkynyl carbon producing (1,1-difluoroethyl)benzene in
excellent yield (Equation (26)). Complementarily, treatment of ethynylbenzene with SelectfluorTM
promotes difluorination at the terminal alkynyl carbon to produce ,-difluoroketones in good
yields (Equations (27) and (28)) <1995JOC259>. AccufluorTM is a commercially available fluor-
inating agent that under similar conditions promotes the difluorination of alkynes and phenols to
produce ,-difluoroketones in good-to-excellent yields (Equation (29)) <1996SL693>.
6HF–Et 3N, 40 h F F
H ð26Þ
97%
N Cl
N 2BF4–
F O
SelectfluorTM, CH3CN, H2O, 80 °C
ð27Þ
F
H Ph
58% F
N Cl
N 2BF4– O
F , CH3CN, H2O, 80 °C Me ð28Þ
Me Ph
78% F F
OH
N
N 2BF4–
F O ð29Þ
AccufluorTM, CH3CN, H2O, 80 °C
But
Ph
72%
F F
4.01.2.6 Difluoroalkanes from Difluorocarbene

Practical methods for difluorocarbene generation are limited, and this process continues to
challenge the organic chemist. The generation and reactivity of difluorocarbene has been exten-
sively reviewed in the past (COFGT (1995) and references within). Trimethylsilylfluorosulfonyl-
difluoroacetate (TFDA) has been identified as a convenient source of difluorocarbene at
moderate temperatures Scheme 1 <2000OL563>.
FSO2CF2CO2TMS + F– FSO2CF3COO– + TMSF

(TFDA)
FSO2CF3COO– CF2: + SO2 + CO2 + F–
Scheme 1
Difluorocarbene formation is catalyzed by fluoride under nitrogen atmosphere. This method

allows the addition of difluorocarbene to alkenes as well as electron-deficient alkenes (Equations
(30) and (31)), which has not been efficiently achieved by previous methods. Due to the mild
reaction conditions, TFDA has effectively been applied to the preparation of highly reactive
cyclopropenes (Equation (32)) <2002JOC9421>.
O TFDA, 0.01 equiv. NaF, 105 °C, 2 h F

F O
ð30Þ
O Ph 89% O Ph
F
O TFDA, 0.01 equiv. NaF, 105 °C, 2 h F
O ð31Þ
O 73%
O
TFDA, NaF, diglyme, 120 °C, 1 h Ph I

I ð32Þ
82%
F F
An alternative difluorocarbene source is 10,10-difluorobicyclo[4.3.1]deca-1,3,5-triene, which has

been prepared from indane in four synthetic steps and in 55% overall yield <2003JFC(119)75>.
This triene differs from other difluorocarbene precursors because it is an effective photochemical
source of difluorocarbene (Equation (33)).
hν (>280 nm), 55 h, triglyme F F

+ CF2 ð33Þ
77%
4.01.2.7 Difluoroalkanes from Aldehydes and Ketones

The conversion of carbonyl groups to gem-difluoro compounds is an important transformation
that continues to find applications in organic synthesis. Many methods and reagents to achieve
this functional group transformation have been reviewed in the literature. Hill (COFGT (1995))
should be consulted for general methods and procedures for the conversion of carbonyls to gem-
difluoroalkanes.
DAST continues to find applications for the generation of the difluoromethyl functionality
<1995TL2389, 2000JFC(102)317>. DAST reacts under mild conditions that are tolerated by
many functional groups, including carboxylic acid derivatives (Equations (34)–(36)). In addition,
DAST is easy to handle and practical for most laboratory procedures. However, utilization of
DAST in large-scale industrial settings is limited by its thermal instability.
H H
O F Me O
DAST, CH2Cl2
O ð34Þ
F
O O O O
58–63%
F3C CF3 F3C CF3
CH2CO2CH3 CH2CO2CH3
Tos N DAST, 90 °C Tos N
CH2CH2CO2CH3 CH2CH2CO2CH3 ð35Þ
87% F
O
H F H
Ph O Ph O
DAST, 90 °C
O F F
N N ð36Þ
81%
CCl3 CCl3
Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-FluorTM) is an alternative reagent having

greater thermal stability and good performance in fluorination reactions of carbonyl compounds
at lower temperatures <1999CC215, 1999JOC7048, 2001OL2713>. Similar to DAST, Deoxo-
FluorTM reacts with alcohols but does not react with carboxylic acid derivatives. In contrast,
Deoxo-FluorTM reacts with carboxylic acids to produce acid fluorides in good yields (Equations
(37)–(41)). In addition, Deoxo-FluorTM has found significant application in the preparation of gem-
difluoro compounds from thiocarbonyl derivatives (see Chapter 6.02) <2000JOC4830>.
O (CH3OCH2CH2)2NSF3 (Deoxo-Fluor) F F
cat. HF, CH2Cl2, 16 h, rt ð37Þ
H H
95%
O (CH3OCH2CH2)2NSF3 (Deoxo-Fluor) F F
cat. HF, CH2Cl2, 16 h, rt
H H
ð38Þ
H 94% H
O F F
O Deoxo-Fluor, 0.2 equiv. HF, CH2Cl2, 16 h, rt F F

ð39Þ
PhO PhO
98%
F
O Deoxo-Fluor, 0.2 equiv. HF, CH2Cl2, 16 h, rt
F ð40Þ
85%
O F F
Deoxo-Fluor, 0.2 equiv. HF, CH2Cl2, 16 h, rt
O O ð41Þ
Ph Ph
81%
O O
4.01.2.8 Difluoroalkanes from Imines

The treatment of aziridines with hydrogen fluoridepyridine complex continues to be a common
method for the preparation of gem-difluoroalkanes with adjacent amino groups (COFGT (1995),
<1995JFC(73)165>). Pentafluoroiodidetriethylaminehydrogen fluoride complex (IF5NEt33HF)
reacts with hydrazones to yield the corresponding gem-difluoro compound in modest-to-good yields
(Equations (42)) <2001CL222>.
Ph IF5/Et 3N–3HF, EtOAc, 1 h, rt Ph

F
N ð42Þ
Ph NH2 70% Ph F
4.01.2.9 Difluoroalkanes from Dithianes

1,1-Difluoromethyl alkanes can be prepared from the corresponding 2-alkyl-1,3-dithiane by
treatment with bromine trifluoride as a fluorinating agent <2003OL769>. Moderate yields of
the desired products are obtained under mild conditions (Equations (43)–(45)). The main limita-
tion of this methodology is that the use of bromine trifluoride in the presence of unsaturated
systems can lead to undesired products resulting from electrophilic bromination reactions.
BrF3, CFCl3, 0 °C, 1–2 min F F

S S ð43Þ
n-C10H21 H n-C10H21 H
75%
S
( )8
S BrF3, CFCl3, 0 °C, 1–2 min F F
( )8 ð44Þ
S S 70% F F
S BrF3, CFCl3, 0 °C, 1–2 min

F ð45Þ
S 65%
F
4.01.3 DICHLOROALKANES—R1R2CCl2
4.01.3.1 Dichloroalkanes from Alkanes

The review by Hill (COFGT (1995)) should be consulted for the preparation of aliphatic gem-
dichloro compounds and the synthesis of dichloroalkanes from alkanes.
4.01.3.2 Dichloroalkanes from Dihaloalkanes

,-Dichloroalcohols are prepared simply by the addition of lithium (t-butyldimethylsilyl)di-
chloromethane to carbonyl compounds <1999JOM(572)31>. In addition, these types of gem-
dichloro compounds are obtained from the protonation of acyllithium reagents generated
in situ from alkyllithiums and carbon monoxide in the presence of dichloromethane
(Equations (46)–(49)).
O THF, –78 °C TBDMSO

Cl Cl then MeI, HMPA
+ H ð46Þ
Ph
TBDMS Li
71% Cl Cl
Cl THF, ether, pentane OH

–110 °C, 1 h Cl
Li + CO + ð47Þ
H Cl
H 81–84% Cl

–110 °C, 1 h
Li + CO + Ph ð48Þ
H Cl
Ph 89–97% Cl Cl

–110 °C, 1 h Cl
+ CO + ð49Þ
Li H Cl
H 40% Cl
4.01.3.3 Dichloroalkanes from Trihaloalkanes

The reduction of the trichloromethyl group to dichloromethane has widely been reported in the
literature (Hill, COFGT (1995)). This transformation usually involves the use of tin or iron salts,
as well as zinc or copper metals. In some cases, standard catalytic hydrogenolysis conditions are
suitable to achieve the reduction (Equation (50)) <2000TL9357>. Alternatively, electrochemical
methods can be effectively employed for the production of gem-dichloro compounds from the
corresponding trichloromethane-containing substrate (Equation (51)) <2001T4925>.
O O
Cl H2, Pd/C, EtOAc–MeOH Cl
HN NH
Cl ð50Þ
Cl 90% Cl
O O
1.10 V vs. SCE O OH

O OH
LiClO4, AcOH, CH3CN
Cl Cl ð51Þ
N N
H Cl H
Cl 70% Cl
Cl Cl
Highly functionalized gem-dichloro - and -lactams are prepared from trichloromethane

substrates via a radical cyclization reaction. These reactions are mediated by multidentate
amine-derived copper(I) complexes, and the generated dichloro radical reacts with alkene and
alkyne functionalities (Equations (52) and (53)) <2001TL1999, 2001TL2901>. The regiochemical
outcome of the reactions can be controlled by changes in multidentate amine–metal complex.
CuCl, bipyridine Cl
Cl3C CH3CN, heat Cl
Cl
ð52Þ
O N 85–86% N
Bn O
Bn
N
N Cl
Cl3C H3C Cl
CuCl, CH2Cl2, 24 h, rt ð53Þ
O N 75% O
N
Ts
Ts
In addition, gem-dichloro - and -lactams can be prepared via a similar nickel-catalyzed

radical cyclization (Equations (54) and (55)) <1998T1029, 2001JOM(624)316>. Pentachloro-
acetone undergoes [4+3]-cycloadditions to furans to produce a variety of 2,2,3,3-tetrachloro-8-
oxabicyclo[3.2.1]oct-6-en-3-ones in moderate-to-good yields (Equation (56)) <1999JOC3398>.
Cl Ni(0), AcOH, (PhSe)2 Cl O

Cl Cl
O 2-propanol, reflux
Cl N
PhSe ð54Þ
N 77%
Cl Cl
Ph Cl Cl Ni(0), AcOH Cl O
S
2-propanol, reflux
N O N ð55Þ
65% Bn
Bn
O O
O Cl Cl
Cl Cl CF3CH2ONa/CF3OH Cl Cl
+ ð56Þ
Cl O
Cl Cl 81%
4.01.3.4 Dichloroalkanes from Alkenes

The reaction of ,-unsaturated aromatic carboxylic acids with 2 equiv. of N-chlorosuccinimide
(NCS) affords the corresponding ,-dichloromethylbenzyl alcohols <2000T1369>. This
Hunsdiecker-type halodecarboxylation reaction is catalyzed by tetrabutylammonium trifluoroacetate
(TBATFA) under mild aqueous conditions (Equation (57)). This practical method is suitable for
the preparation of ,-dibromo- and ,-iodomethylbenzyl alcohols when the corresponding
N-halosuccinimide is employed (see Sections 4.01.3.4 and 4.01.5.3). Interestingly, the corre-
sponding (E)-haloalkenes are obtained under anhydrous conditions.
O NCS, cat. TBATFA HO H

CH3CN–H2O, rt Cl
OH ð57Þ
73% Cl
O O
The dichloromethylation of diarylethenes with dichloromethane by benzophenone photo-

sensitization in the presence of t-butylamine affords the corresponding alkylation products in
moderate yields (Equation (58)). A dichloromethyne radical (CHCl2) is believed to be the
reactive species in this photo-induced alkylation reaction <1996JOC6438>. The cycloaddition
reactions of halo-substituted vinyl sulfoxides provide access to some specific gem-dichloro
compounds. The Diels–Alder reaction of (2,2-dichloro-1-fluoro-ethenesulfinyl)benzene with
cyclopentadiene and 1,3-diphenylisobenzofuran under conventional heating as well as under
microwave irradiation produce the corresponding cycloadducts in good yield (Equations (59)
and (60)) <2000T3539>.
Ph hν, Ph2CO, ButNH2

Ph Cl
+ CH2Cl2 ð58Þ
Ph 62% Ph Cl
O Microwave, 7 min
S F or toluene, reflux, 10 h F SOPh
Ph + Cl + Cl
70–75% ð59Þ
SOPh F
Cl Cl
Cl Cl
1/5 endo/exo
O Ph Microwave, 7 min O
or toluene, reflux, 24 h F
S F
Ph + O Cl ð60Þ
80–90%
Cl Cl SOPh
Ph Cl
1/1 endo/exo
4.01.3.5 Dichloroalkanes from Alkynes

Terminal alkynes continue to be important substrates for the preparation of dichloromethyl
ketones. Terminal alkynes submitted to electrochemical oxidation conditions in a divided cell
and in the presence of lithium chloride resulted in the exclusive formation of the corresponding
1,1-dichloro-2,2-methoxy compound in good yields (Equations (61) and (62)) <2000SL89>.
–2e, NaI, MeOH, divided cell Cl

H Ph ð61Þ
Cl
74%
MeO OMe
–2e, NaI, MeOH, divided cell Cl

n-C6H13 H n-C6H13 ð62Þ
Cl
60%
MeO OMe
The same alkyne chloromethoxylation reaction can be easily achieved by employing iodoso-
benzene dichloride in methanol (Equation (63)) <2002ZOR(E)902>. The corresponding dichloro-
methyl ketones are obtained after hydrolysis of the ketal product.
PhICl2, MeOH Cl
H Ph ð63Þ
Cl
65%
MeO OMe
4.01.3.6 Dichloroalkanes from Dichlorocarbene

Dichlorocarbene can be generated by several methods under a variety of reaction conditions.
Phase-transfer conditions are the most widely used to generate dichlorocarbene as one of many
synthetic protocols leading to novel organic molecules. The most common phase-transfer condi-
tions for the preparation of dichlorocarbene still involves chloroform, aqueous sodium or potas-
sium hydroxide, and a phase-transfer reagent such as benzyltriethylammonium chloride (TEBA),
which continues to be a widely used reagent for this purpose. These methods have found
application in the synthesis of highly functionalized gem-dichlorocyclopropanes. For example,
vinylic selenides are reacted with dichlorocarbene to produce the corresponding 2,2-dichloro-
1-selenopropanes with retention of configuration in good yields (Equation (64)) <1998SC1667>.
Bun Cl Cl
SeCH3 CHCl3, NaOH, BnEt3N+Cl–
Bun SeCH3 ð64Þ
H Cl 76% H Cl
A new phase-transfer reagent, 2-benzylidine-N,N,N,N0,N0,N0 -hexaethylpropane-1,2-diammonium

dibromide (Diquat), has been reported to be ideal for the generation of dichlorocarbene and its
subsequent reactions <1999SC4101, 2001AC(206)19>. The use of Diquat in selective dichlorocy-
clopropanation reactions comes along with advantages such as faster reaction times, lower base
concentrations, and higher yields than standard TEBA reaction conditions (Equations (65)–(67)).
Cl
Diquat (Dq-Br) = Ph–CH=C[CH 2NEt+3 Br –]2 Cl
CHCl3, NaOH, 45 °C, 0.5 h ð65Þ
98%
Diquat (Dq-Br)
CHCl3, NaOH, 45 °C, 0.5 h
ð66Þ
Quant. Cl
Cl
O Diquat (Dq-Br) Cl
O Cl
CHCl3, NaOH, 45 °C, 0.5 h
O ð67Þ
O
84%
Cetyltrimethylammonium chloride (CTAC) is a phase-transfer reagent that has found applica-

tion in stereospecific CH insertion reactions of dichlorocarbene. The synthesis of optically
active ,-dichloromethylated tertiary alcohols has been accomplished by generating dichloro-
carbene from a chloroform–sodium hydroxideCTAC phase-transfer system <2000CL1180,
2003CL4>. The CH insertion reaction of dichlorocarbene and protected chiral secondary
alcohols is stereospecific and proceeds with retention of configuration (Equations (68)–(71)).
CHCl3, NaOH, n-C16H33N(CH3)+3 Cl–
OH OH
80 °C, 18 h
H CHCl2
ð68Þ
H3C
C6H13-n H3C C H -n
6 13
39%
CHCl3, NaOH, n-C16H33N(CH3)+3 Cl–

OTMS 80 °C, 18 h OTMS
ð69Þ
H CHCl2
H3C H3C
Ph 60% Ph
O CHCl3, NaOH, n-C16H33N(CH3)+3 Cl–

O O
Ph 80 °C, 12 h O ð70Þ
H Ph
CHCl2
86%
OTBDMS +
CHCl3, NaOH, n-C16H33N(CH3)3 Cl–
OTBDMS
H 80 °C, 12 h
H3C
Ph CHCl2 ð71Þ
H3C
Ph
87%
4.01.3.7 Dichloroalkanes from Aldehydes and Ketones

The conversion of aldehydes and ketones to dichloroalkanes by phosphorus pentachloride is still a
widely used synthetic protocol. Similar reagents such as PCl3, SOCl2, and SO2Cl2 are also employed
for the same purpose. Most of these reagents are toxic and/or moisture sensitive. New general
methods involving more stable reagents and mild reaction conditions are still not available.
Benzyl dichlorides can be prepared by reaction of the aryl aldehyde with a Vilsmeier-type
reagent formed in situ by reduction of carbon tetrachloride <1999SC4015>. The reduction is
promoted by a combination of copper(0) and nickel(0) in DMF solvent at 60 C. The protocol
works efficiently in 100 mmol scale, and the desired dichloro compound is obtained in good-to-
excellent yields (Equations (72) and (73)). The limitations of this protocol are that it is exclusive to
benzaldehydes and that it uses excess amounts of Cu(0)/Ni(0). Another dichlorination protocol
limited to benzaldehydes involves the use of boron trichloride in hexanes under reflux conditions
<2000TL579>. This method is notable because the desired dichlorination products are obtained
in excellent yields (Equations (74) and (75)).
O Cl
CCl4, Cu(0), Ni(0), DMF, 5 h
H Cl
ð72Þ
78%
Br Br
O Cl
CCl4, Cu(0), Ni(0), DMF, 5 h
H Cl
ð73Þ
H 90% Cl
O Cl
O Cl
BCl3, hexane, reflux, 2 h
H Cl
ð74Þ
99%
Br Br
O Cl
H BCl3, hexane, reflux, 4 h

Cl
ð75Þ
H 98% Cl
O Cl
4.01.3.8 Dichloroalkanes from Imines

Aliphatic gem-dichloride compounds can be produced from a copper(II) chloride-promoted
oxidation of hydrazones <1997T557>. The hydrazones are easily prepared from the corresponding
aldehyde or ketone with hydrazine hydrate in the presence of 4 Å molecular sieves.
Treatment of hydrazones with copper(II) chloride–lithium t-butoxide in THF produces gem-
dichlorides in moderate yields (Equations (76) and (77)). A variation of this method simply
consists of using copper(II) chloride–triethylamine in methanol (Equations (78) and (79)). This
procedure proved to be practical and more efficient than the copper(II) chloride–lithium
t-butoxide oxidative system. Analogously, the use of copper(II) bromide leads to gem-dibromo
compounds (see Section 4.01.4.8).
NH2 CuCl2, LiOBut, THF, 1 h, rt Cl Cl
N
ð76Þ
Ph H Ph H
55%
NH2 CuCl2, LiOBut, THF, 2 h, rt

N Cl Cl
ð77Þ
Ph CH3 Ph CH3
75%
NH2 CuCl2, NEt3, MeOH, 0 °C, 1 h

N Cl Cl
ð78Þ
Ph H 67% Ph H
NH2 CuCl2, NEt3, MeOH, 0 °C, 1 h Cl

N ð79Þ
Cl
56%
4.01.4 DIBROMOALKANES—R1R2CBr2
4.01.4.1 Dibromoalkanes from Alkanes

The review by Hill (COFGT (1995)) should be consulted for the preparation of aliphatic gem-
dibromo compounds and the synthesis of dichloroalkanes from alkanes.
Tolylamines undergo electrophilic aromatic substitution when treated with electrophilic
halogenating reagents. Methods for direct benzylic halogenation of tolylamines are unknown.
Nevertheless, benzylic gem-dibrominations have been achieved by preparing the succinimide derivative
of the corresponding tolylamine followed by treatment with molecular bromine <2002S221>.
The synthetic sequence produces the desired gem-dibromo compound in excellent yield
(Equation (80)). In addition, simple changes to the reaction conditions lead to benzylic mono-
bromination product exclusively.
O O
Br2 (2.5 equiv.), CCl4, reflux, 8 h
N N ð80Þ
CH3 94–96% CHBr2
O O
Complex mixtures of mono-, di-, and tribrominated products are not uncommon when preparing
,-dibromoketones from the corresponding alkyl ketone. The selective synthesis of ,-dibromo-
methyl aryl ketones is possible by employing dioxane dibromide and silica gel under microwave
irradiation and solvent-free conditions (Equation (81)) <2003TL439>. Exclusive monobromination
can be obtained by limiting the amount of dioxane dibromide and reducing the irradiation time.
This method is not suitable for the preparation of ,-dibromomethyl alkyl ketones.
O O
Dioxane dibromide
Br
SiO2, microwave, 8 min ð81Þ
Cl Br
90% Cl
,-Dibromomethyl-o-hydroxyacetophenone can be obtained from 4-hydroxycoumarin deriva-

tives in a vanadium pentoxide-promoted bromination reaction (Equation (82)) <2000OL247>.
Dibromomethyl ketones have efficiently been prepared from 2-ethyl-2-acetyl-1,3-dithiane-1-oxide
by deprotonation followed by the addition of N-bromosuccinimide (NBS) <1995T1285>. The
reaction leads exclusively to the dibromination product, and good yields are obtained separately
for both anti and syn isomers (Equation (83)).
O O OH
Bu4NBr, H2O2, V2O5, CH3CN–H2O
O ð82Þ
55%
OH Br Br
–
–O O
O LHMDS, THF, –78 °C; then NBS O
Et + Et
+S S Br ð83Þ
75%
S S Br
4.01.4.2 Dibromoalkanes from Dihaloalkanes

Reactions of dibromomethyllithium with carbonyl compounds and carboxylic acid derivatives are
still widely used transformations for the preparation of gem-dibromo compounds (Hill COFGT
(1995)). These methods have found applications in natural product synthesis. For example, the
total syntheses of (+)-13-carbaartemisinin and (–)-cylindrocyclophane A both employ a dibromo-
methyllithium reaction to generate an ,-dibromoalcohol and ,-dibromoketone, respectively
<1996JMC1885, 2001JACS5925>. All of these methods are suitable for most laboratory
preparations, but the required low temperatures (100 C to 78 C) for the generation of
dibromomethyllithium could represent a challenge for some industrial settings.
Reaction of dibromomethyllithium with cyclic sulfates produces 1,1-dibromo-3-hydroxy-
alkanes. The cyclic sulfates are easily prepared from 1,2-diols, and the alkylation reactions
proceed in good yields (Equations (84) and (85)) <1996S259>. In addition, the method applies to
cyclic sulfamates to produce the corresponding 1,1-dibromo-3-aminoalkanes (Equation (86)). Another
synthetic strategy into 1,1-dibromo-3-hydroxyalkanes involves the reaction of t-butyldimethyl-
silyldibromomethyllithium with oxiranes followed by 1,4-rearrangement of the silyl group
<1996T503>. This silyl group migration from carbon to oxygen produces a carbon-centered
lithium anion that can further react with electrophiles such as alkyl halides or simple aldehydes
(Equations (87) and (88)).
O SO2 Et2O–THF, –100 °C, 4 h; OH Br

Li then H2SO4/H2O
+ O ð84Þ
Br Br Br
88–95%
O SO2 Et2O–THF, –100 °C, 4 h; OH Br

Li O then H2SO4/H2O
+ Br ð85Þ
Br Br O O O O
68%
Bn Et2O–THF, –100 °C, 4 h; Bn

Li N SO2 then H2SO4/H2O
NH Br
+ O ð86Þ
Br Br Br
62%
THF, –78 °C; then H3O+ TBDMSO Br

Br Br O
+ ð87Þ
TBDMS Li Br
83%
THF, –78 °C;

Br Br O then MeI, HMPA TBDMSO Br Br
+ ð88Þ
TBDMS Li
60%
4.01.4.3 Dibromoalkanes from Trihaloalkanes

2,2-Dibromo-3-hydroxy-alkyl acid esters can be prepared via Cr(II)-mediated alkylation of alde-
hydes with tribromoacetates. These Reformatsky-type synthetic intermediates can be prepared in
good yields under relatively mild conditions using either stoichiometric or catalytic amounts
of chromium(II) salts (Equation (89)) <2003JACS3218>. The catalytic system requires the use
of manganese(0) and TMSCl. These synthetic intermediates can be further reacted to produce
(Z)--bromoacrylates in excellent yields.
Br Br PhCHO, CrCl2, THF, 0 °C, 12 h OH O

O ð89Þ
Br Ph O
65%
O Br Br
gem-Dibromo--lactams can be prepared from tribromomethane substrates via a radical

cyclization reaction. These reactions are mediated by manganese decacarbonyl under irradiation
conditions, and the generated dibromo radical reacts with an alkene to produce the corresponding
gem-dibromo--lactam (Equation (90)). The product is obtained in good yields and the by-
products are easily removed by a simple DBU work-up <2000JSC(P1)1187>.
Br
Br Br Br Br
Mn2(CO)10, TEMPO, hν, CH2Cl2 O N
O N 72% O ð90Þ
N
PMB
PMB
TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical
PMB = p-methoxybenzyl
4.01.4.4 Dibromoalkanes from Alkenes

Addition of hydrogen bromide or bromine to bromoalkenes is still the most common method to
produce gem-dibromo compounds. Valuable examples of these methods have been presented by
Hill (COFGT (1995)).
Dibromodiazaoxindoles can be prepared from pyrimidines by treatment with pyridinium

tribromide in t-butanol (Equation (91)) <2001TL999>. Radical allylic bromination of 1,1-
dibromo-2-methylpropene with NBS produces exclusively 3,3-dibromo-2-(bromomethyl)-1,1-
dichloroprop-1-ene (Equation (92)) <2000S139>. It is interesting that treatment with an excess
of brominating reagent did not produce the expected bis(gem-dibromo) compound.
Br
N Pyridinium tribromide, t-BuOH, rt Br
N ð91Þ
N O
Cl N 98% N
H Cl N
H
NBS (3.2 equiv.), (BzO)2 (0.15 equiv.) Cl Cl

Cl Cl CCl4, reflux, 10 h
Br Br ð92Þ
90%
Br
The reaction of ,-unsaturated aromatic carboxylic acids with 2 equiv. of NBS affords the
corresponding ,-dibromomethylbenzyl alcohols <2000T1396>. This Hunsdiecker-type halo-
decarboxylation reaction is catalyzed by TBATFA under mild aqueous conditions (Equations
(93) and (94)). This practical method is suitable for the preparation of ,-difluoro- and
,-iodomethylbenzyl alcohols when the corresponding N-halosuccinimide is employed
(see Sections 4.01.2.4 and 4.01.5.3). Interestingly, the corresponding (E )-haloalkenes are
obtained under anhydrous conditions.
O NBS, cat. TBATFA HO H
CH3CN–H2O, rt Br
OH ð93Þ
80% Br
O O
O NBS, cat. TBATFA HO H

CH3CN–H2O, rt CH3
OH ð94Þ
90% Br Br
O O
4.01.4.5 Dibromoalkanes from Alkynes

Enantiomerically enriched ,-dibromo--butanolides can be prepared from an electron-rich
alkyne and the corresponding terminal epoxides. The Lewis acid-catalyzed reaction between an
enantiomerically enriched terminal epoxide and 1-morpholino-2-trimethylsilyl acetylene produces
a cyclic ketene aminal <2002JACS2456>. Sequential treatment with NBS leads to the efficient
synthesis of the corresponding enantiopure ,-dibromo--butanolides in excellent yields
(Equation (95)). The titanium tetrabromide-promoted reaction between electron-deficient alkynes
and aryl aldehydes leads to the corresponding ,-dibromo compounds in moderate yields
(Equations (96) and (97)) <2002T9063>.
O
BF3–OEt2, CH2Cl2, 0 °C O
O
N Ph then NBS
+ O Br ð95Þ
>99% ee 96% Ph Br
TMS
>99% ee
O Br
O TiBr4, ClCH2CH2Cl Br
H 70 °C, 14 h
O
+ CO2CH3 ð96Þ
56%
H
O2N O2N
2.5/1 (E )/(Z )
O Br
H Br
CN TiBr4, ClCH2CH2Cl
+ 70 °C, 48 h
CN
ð97Þ
H 42%
O2N O2N
5/1 (E )/(Z )
The regioselective methoxybromination of alkynes can be accomplished by employing tetrabutyl-

ammonium tribromide, which is a stable, nontoxic, and nonhygroscopic solid <1997SC2865>. This
method allows easy preparation of the corresponding gem-dibromo compounds under mild reaction
conditions in moderate-to-good yields (Equations (98) and (99)).
Bu3nN+ Br3–
MeOH, rt, 8 h Br
ð98Þ
H Br
76% MeO OMe
Bu3n N+ Br3– , MeOH

Br Br
ultrasound, 4 h ð99Þ
MeO2C CO2Me MeO2C
CO2Me
62% MeO OMe
4.01.4.6 Dibromoalkanes from Dibromocarbene

Bromoform is still the main source of dibromocarbene. Carbene generation and reactions can
occur under anhydrous or phase-transfer conditions (COFGT (1995), <1997TL3395>). Strong
bases such as potassium t-butoxide or potassium carbonate promote these reactions under
anhydrous conditions. The most common phase-transfer conditions for the preparation of dibro-
mocarbene use bromoform, aqueous sodium or potassium hydroxide, and a phase-transfer
reagent such as TEBA (Equations (100) and (101)). These methods continue to find application
in the synthesis of novel gem-dibromo compounds (Equation (102)) <2002JOC7303>.
CHBr3, 50% NaOHaq
Et3BnNCl, 0 °C Me3Si
Me3Si ð100Þ
Br
85% Br
CHBr3, t-BuOK, pentane, 0 °C Me3Si

Me3Si
Br ð101Þ
83% Br
(EtO)2P O
Br
O CHBr3, K2CO3, 18-crown-6 O Br O
toluene, reflux (EtO)2P P(OEt)2 ð102Þ
O
83%
O O
(EtO)2P O
It is possible to generate dibromocarbene from ethyl tribromoacetate via a bromophilic attack

of the carboethoxydibromomethyl anion to diethyl dibromomalonate (Mebane and co-workers
<1999TL1459>). For example, 7,7-dibromo-bicyclo[4.1.0]heptane is the main product in the
reaction of dibromalonate and sodium methoxide in cyclohexene (Equation (103)).
Br Br NaOMe, cyclohexene, 0 °C
Br ð103Þ
EtO2C CO2Et 60% Br
4.01.4.7 Dibromoalkanes from Aldehydes and Ketones

The conversion of aldehydes and ketones to dibromoalkanes by phosphorus pentabromide is still
a widely used synthetic protocol. Similar reagents such as PBr3 and PCl3Br2 are also employed for
the same purpose (Equation (104)) <2002JOC5369>. Most of these reagents are toxic and/or
moisture sensitive. A variation to these protocols involves the use of triphenyl phosphitebromine
reagent (Equation (105)) <2002CEJ4506>.
CHO PCl3, Br2, CH2Cl2, 0 °C CHBr2

ð104Þ
76%
CHO CHBr2
Br Br
P(OPh)3–Br2, CH2Cl2, 0 °C, 0.5 h
ð105Þ
65%
O Br
H Br
Benzyl dibromides can be prepared by reaction of the aryl aldehyde with a Vilsmeier-type reagent
formed in situ by reduction of carbon tetrachloride (Equation (106)). The reduction is promoted by
a combination of copper(0) and nickel(0) in DMF solvent at 60 C. The limitations of this protocol
are that it is exclusive to benzaldehydes and that it uses excess amounts of Cu(0)/Ni(0).
O Br
CBr4, Cu(0), Ni(0), DMF, 5 h
H Br ð106Þ
51%
Cl Cl
4.01.4.8 Dibromoalkanes from Imines

Aliphatic gem-dibromide compounds can be produced from a copper(II) bromide-promoted
oxidation of hydrazones <1997T557>. The hydrazones are easily prepared from the correspond-
ing aldehyde or ketone with hydrazine hydrate in the presence of 4 Å molecular sieves.
Treatment of hydrazones with copper(II) bromide–lithium t-butoxide in THF produces gem-
dibromides in moderate yields (Equations (107) and (108)). A variation of this method simply
consists of using copper(II) bromide–triethylamine in methanol (Equations (109) and (110)). This
procedure proved to be practical and more efficient than the copper(II) bromidelithium
t-butoxide oxidative system. Analogously, the use of copper(II) chloride leads to gem-dichloro
compounds (see Section 4.01.3.8).
NH2 CuBr2, LiOBut, THF, 1 h, rt Br Br

N
ð107Þ
Ph H 70% Ph H
NH2 CuBr2, LiOBut, THF, 2 h, rt Br Br

N
ð108Þ
Ph CH3 82% Ph CH3
NH2 CuBr2, NEt3, MeOH, 0 °C, 1 h Br Br

N
ð109Þ
Ph H 73% Ph H
NH2 CuBr2, NEt3, MeOH, 0 °C, 1 h

Br
N ð110Þ
Br
64%
4.01.5 DIIODOALKANES—R1R2CI2
Methods for the preparation and isolation of gem-diiodo compounds are limited mostly due to
the relative instability of the gem-diiodo functional group compared to the other gem-dihalo
species. Hill (COFGT (1995)) should be consulted for common methods for the preparation of
gem-diiodo compounds.
4.01.5.1 Diiodoalkanes from Alkanes

Chiral 1,1-diiodo compounds can be prepared from 2-deoxy-2-iodo-sugars via an alkoxy radical
fragmentation reaction. This reaction is promoted by (diacetoxyiodo)benzene and iodine under
irradiation with two 80 W tungsten filament lamps <2001AG(E)2326>.
The corresponding gem-diiodo compounds are produced in high yields under mild conditions
that are compatible with most common protecting groups. This method allows the preparation of
1-iodo-1-halo compounds from the corresponding 2-deoxy-2-halo-sugar (Equation (111)).
AcO O OH (Diacetoxyiodo)benzene, I2 OAc I

CH2Cl2, irradiation, reflux
AcO I ð111Þ
AcO I
92% OAc OAc
OAc
4.01.5.2 Diiodoalkanes from Trihaloalkanes

Diiodomethylation of carbonyl compounds provides an entry into ,-diiodoalkanols. This
transformation can be easily carried out by using diiodomethylsamarium (Equations (112) and
(113)), which is prepared in situ from iodoform and samarium diiodide <1998TL1409>.
O OH
SmI2, 0 °C
+ CHI3 I ð112Þ
H
61%
I
OH
SmI2, 0 °C
O + CHI3
I
ð113Þ
49%
I
4.01.5.3 Diiodoalkanes from Alkenes

The reaction of ,-unsaturated aromatic carboxylic acids with 2 equiv. of N-iodosuccinimide (NIS)
affords the corresponding ,-diiodomethylbenzyl alcohols <2000T1396>. This Hunsdiecker-type
halodecarboxylation reaction is catalyzed by TBATFA under mild aqueous conditions (Equation
(114)). This practical method is suitable for the preparation of ,-difluoro- and ,-chloromethyl-
benzyl alcohols when the corresponding N-halosuccinimide is employed (see Sections 4.01.2.4 and
4.01.3.4). Interestingly, the corresponding (E)-haloalkenes are obtained under anhydrous conditions.
Simple 1,1,2-triiodo compounds can be prepared by treatment of the corresponding vinylstannane
with iodine in carbon tetrachloride (Equation (115)) <2001JACS1768>.
O HO H
NIS, cat. TBATFA, I
OH CH3CN–H2O, rt ð114Þ
I
O 60% O
I
I2, CCl4, rt
Bu3Sn ð115Þ
I
78%
I
4.01.5.4 Diiodoalkanes from Alkynes

As is well documented in the literature, 2 equiv. of hydrogen iodide adds to terminal alkynes to
produce diiodoalkanes (see Hill (COFGT 1995)). In this case, diiodination occurs at the internal
alkynyl carbon (Equation (116)). In order to achieve diiodination at the terminal alkynyl carbon,
Marek and co-workers have developed a practical method for the synthesis of 1,1-diiodoalkanes
from the corresponding alkynes <1999CC2207>.
HI I I
H3C H ð116Þ
Treatment of the alkynes with diisobutylaluminum hydride leads to corresponding

1,1-bis(diisobutylalumino)alkanes, which upon reaction with iodine produces the desired gem-
diiodo compounds in good yields (Equations (117) and (118)).
HAlCl2, toluene, 90 °C; then I2 I
n-C6H13 H n-C6H13 ð117Þ
81% I
HAlCl2, toluene, 90 °C; then I2 I

Ph H Ph ð118Þ
50% I
4.01.6 FLUOROHALOALKANES—R1R2CFHal
4.01.6.1 Chlorofluoroalkanes—R1R2CFCl
4.01.6.1.1 Chlorofluoroalkanes from alkenes

The reaction of 5-fluorouracil with NCS produces highly functionalized 5-chloro-5-fluoro-5,6-
dihydrouracils in high yields <1998JCS(P1)3145>. When the reaction is carried out in methanol,
5-chloro-5-fluoro-6-methoxy-5,6-dihydrouracil is obtained as a single stereoisomer (Equation (119)).
O O
NCS, MeOH, 50 °C F
F
HN HN Cl ð119Þ
91% H
O N O N
H H O
4.01.6.1.2 Fluorochloroalkanes from chlorofluorocarbene

Chlorofluorocarbene has been generated from trichlorofluoromethane by reduction with low-
valent titanium (Ti[0]) <2001JOC1216>. Addition of chlorofluorcarbene to alkenes yields the
corresponding chlorofluoromethyl compound (Equation (120)).
Cl CFCl3, TiCl4, LiAlH4, Cl F
THF, 0 °C F Cl Cl
Cl
95% +
ð120Þ
Isomer ratio 1:1
4.01.6.1.3 Fluorochloroalkanes from imines

Oximes have been transformed into chlorofluoromethyl groups by treatment with chlorine in
hydrogen fluoride as a medium. Complex mixtures of gem-dihalo compounds are usually
obtained from these reactions, but their solvent-dependent product distribution can be controlled
to produce the desired product (Equation (121)) <1995JFC(70)207>.
Cl2, HF, EtOH, –10 °C Cl

N ð121Þ
OH 59% F
4.01.6.2 Bromofluoroalkanes—R1R2CFBr
4.01.6.2.1 Bromofluoroalkanes from bromofluorocarbene

Bromofluorocarbene has been generated from tribromofluoromethane by reduction with low-
valent titanium (Ti[0]) <2001JOC1216>. Addition of bromofluorocarbene to alkenes yields the
corresponding bromofluoromethyl compound (Equation (122)).
Cl CFBr3, TiCl4, LiAlH4, Br F

THF, 0 °C
ð122Þ
33% Cl
4.01.6.3 Fluoroiodoalkanes—R1R2CFI
4.01.6.3.1 Fluoroiodoalkanes from alkanes

Chiral 1-fluoro-1-iodo compounds can be prepared from 2-deoxy-2-fluoro-sugars via an
alkoxy radical fragmentation reaction. This reaction is promoted by (diacetoxyiodo)benzene
and iodine under irradiation with two 80 W tungsten filament lamps (Equation (123))
<2001AG(E)2326>.
AcO O OH (Diacetoxyiodo)benzene, I2, OAc I

AcO F AcO F ð123Þ
96% OAc OAc
OAc
1:1 dr
4.01.7 CHLOROHALOALKANES—R1R2CClHal
4.01.7.1 Chlorobromoalkanes—R1R2CClBr
4.01.7.1.1 Chlorobromoalkanes from bromochlorocarbene

Bromochlorocarbene has been generated from dibromochloromethane by deprotonation with
potassium t-butoxide in anhydrous solvent <2001JOC1216>. Addition of bromochlorocarbene
to alkenes yields the corresponding bromochloromethyl compound (Equation (124)).
Cl Br Cl
CHClBr2, KOBut, Cl Cl Br Cl
pentane, 0 °C +
ð124Þ
60%
Isomer ratio 1:1

4.01.7.2 Chloroiodoalkanes—R1R2CClI
4.01.7.2.1 Chloroiodoalkanes from alkanes

Chiral 1-chloro-1-iodo compounds can be prepared from 2-deoxy-2-chloro-sugars via an alkoxy
radical fragmentation reaction (Equation (125)). This reaction is promoted by (diacetoxyiodo)ben-
zene and iodine under irradiation with two 80 W tungsten filament lamps <2001AG(E)2326>.
AcO Cl AcO Cl ð125Þ
95% OAc OAc
OAc
1:1 dr
4.01.8 BROMOIODOALKANES—R1R2CBrI
4.01.8.1 Bromoiodoalkanes from Alkanes

Chiral 1-bromo-1-iodo compounds can be prepared from 2-deoxy-2-bromo-sugars via an alkoxy
radical fragmentation reaction (Equation (126)). This reaction is promoted by (diacetoxyiodo)ben-
zene and iodine under irradiation with two 80 W tungsten filament lamps <2001AG(E)2326>.
AcO Br AcO Br ð126Þ
OAc 99% OAc OAc
1:1 dr
4.01.8.2 Bromoiodoalkanes from Dihaloalkanes

Iodobromocyclopropanes have been stereoselectively synthesized in good yields by trapping a
magnesium carbenoid prepared from ethyl 2,2-dihalo-1-methyl-cyclopropanecarboxylate
(Equations (127) and (128)) <2002AG(E)351>.
Me Br PriMgBr, THF, –50 °C Me Br

then I2 ð127Þ
EtO Br EtO I
O 85% O
PriMgBr, THF, –50 °C

Me I Me I
then (BrCl2C)2
ð128Þ
EtO I EtO Br
O 80%
O
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Biographical sketch
José Méndez-Andino was born in Fajardo, Puerto Rico. He obtained a

B.S. in industrial chemistry from University of Puerto Rico-Humacao in
1995 and his Ph.D. in synthetic organic chemistry from The Ohio State
University in 2000 under the supervision of Professor Leo A. Paquette.
After working in the laboratory of Professor Gary A. Molander at
University of Pennsylvania, he joined Procter & Gamble Pharmaceuti-
cals in 2002. His scientific interests include green chemistry, organo-
metallic reagents, natural product synthesis, and medicinal chemistry.
# 2005, Elsevier Ltd. All Rights Reserved Comprehensive Organic Functional Group Transformations 2
No part of this publication may be reproduced, stored in any retrieval system ISBN (set): 0-08-044256-0
or transmitted in any form or by any means electronic, electrostatic, magnetic
tape, mechanical, photocopying, recording or otherwise, without permission Volume 4, (ISBN 0-08-044255-2); pp 1–26
in writing from the publishers
4.02
Functions Incorporating a Halogen
and a Chalcogen
N. W. A. GERAGHTY
National University of Ireland, Galway, Republic of Ireland
4.02.1 HALOGEN AND OXYGEN DERIVATIVES—R12CHal(OR2) 27

4.02.1.1 -Haloalcohols (Geminal Halohydrins)—R2CHal(OH) 27
4.02.1.2 -Haloethers—R12CHal(OR2) 30
4.02.1.2.1 -Fluoroethers—R12CF(OR2) 30
4.02.1.2.2 -Chloroethers—R12CCl(OR2) 47
4.02.1.2.3 -Bromoethers—R12CBr(OR2) 56
4.02.1.2.4 -Iodoethers—R12CI(OR2) 62
4.02.1.3 Other Derivatives of -Halo Alcohols—R12CHal(OR2) and R12CHal(OX) 63
4.02.1.3.1 -Haloalkyl esters—R12CHal(OCOR2) 63
4.02.1.3.2 -Haloalkyl haloformates—R12CHalOCOHal and carbonate derivatives—
R12CHalOCOOR2, etc. 68
4.02.2 HALOGEN AND SULFUR DERIVATIVES—R12CHal(SR2), etc. 70
4.02.2.1 Dicoordinate -Halosulfur Derivatives—R12CHal(SR2) 70
4.02.2.1.1 -Halosulfides—R12CF(SR2) 70
4.02.2.1.2 Other dicoordinate -halosulfur derivatives—R2CHal(SX), etc. 85
4.02.2.2 Tricoordinate -Halosulfur Derivatives—R12CHalS(O)R2, etc. 89
4.02.2.2.1 -Halosulfoxides—R12CHalS(O)R2 89
4.02.2.2.2 Other tricoordinate -halosulfur derivatives—R12CHalS(O)X 98
4.02.2.3 Tetracoordinate -Halosulfur Derivatives—R12CHalS(O)2R2, etc. 99
4.02.2.3.1 -Halosulfones—R12CHalS(O)2R2 99
4.02.2.3.2 Other tetracoordinate -halosulfur derivatives—R12CHalS(O)2R2 111
4.02.3 HALOGEN AND SELENIUM OR TELLURIUM DERIVATIVES—R2CHal(SeR0 ),
R12CHal(TeR2), etc. 114
4.02.3.1 -Haloselenium Derivatives—R12CHal(SeR2), etc. 114
4.02.3.1.1 Dicoordinate -haloselenium derivatives—R12CHal(SeR2) 114
4.02.3.1.2 Tri- and tetracoordinate -haloselenium derivatives—R12CHalSe(O)R2,
R12CHalSe(O)2R2, etc. 117
4.02.3.2 -Halotellurium Derivatives—R2CHal(TeR0 ), etc. 117
4.02.3.2.1 Dicoordinate -halotellurium derivatives—R12CHal(TeR2), etc. 117
4.02.3.2.2 Tri- and tetracoordinate -halotellurium derivatives—R12CHalTe(O)R2,
R12CHalTe(O)2R2, etc. 118
4.02.1 HALOGEN AND OXYGEN DERIVATIVES—R12CHal(OR2)
4.02.1.1 a-Haloalcohols (Geminal Halohydrins)—R2CHal(OH)

The chemistry of this functional group is dominated by the fact that it is inherently unstable
relative to the corresponding ketone and hydrogen halide, and so claims in respect of the
synthesis of molecules containing it should be viewed with scepticism unless supported by
27
28 Functions Incorporating a Halogen and a Chalcogen
appropriate spectroscopic evidence. Much of the work relating to the preparation of simple
-haloalcohols has been carried out in the gas phase. Under these conditions it is claimed that
the reaction of hydrogen fluoride with formaldehyde in the presence of formic acid produces
fluoromethanol <1998MI2146>, and that the near UV laser photolysis of a mixture of dichloro-
methane, methane, and oxygen at 298 C results in the formation of a range of products
including chloromethanol <1996JPC14372>. This -chloroalcohol has also been prepared by
the UV irradiation of gaseous mixtures of methanol, chlorine, and nitrogen at room tempera-
ture, and in this case it has been characterized using IR spectroscopy and the kinetics of its
decay to HCl and formaldehyde have been studied <1999MI776>. A number of more highly
halogenated -haloalcohols have also been prepared. The photocatalytic oxidation of trichloro-
ethene on the surface of BaY zeolite coated optical fibres using visible light gives a range of
products which includes 1,2,2-trichloroethanol <2000JA404>. The -haloalcohol was found to
be ‘‘unstable on storage.’’ The use of high-energy electrons to produce radicals has found
application in the gas phase synthesis of some -haloalcohols (Scheme 1). Thus irradiation of
a gaseous mixture of 2-chloro-1,1,1-trifluoroethane, Cl2, and O2 produces a peroxyl radical
which in turn forms a product mixture containing 1-chloro-2,2,2-trifluoroethanol
<1995JPC13437> (Scheme 1, X = Cl). In the same way irradiation of a mixture of 1,1,1,2-
tetrafluoroethane, oxygen, and sulfur hexafluoride gives 1,2,2,2-tetrafluoroethanol
<1997MI673> (Scheme 1, X = F).
High-energy
electrons X X X
F3CCH2X F3 C F3 C + F3 C
X = Cl, O2, Cl2 O O O OH
X = F, O2, SF6
Scheme 1
The synthesis of a number of more highly functionalized -haloalcohols has been reported.
The ultrasonically mediated oxidation of vinyl bromide with potassium permanganate was
found to give an 88% yield of 1-bromoethane-1,2-diol in 15 min, but spectroscopic data for
the product were not provided <1998TL7463>. In a similar fashion the oxidation of the vinyl
bromide component of 5-bromouracil with aqueous diperiodoargentate(III) leads to the for-
mation of a geminal bromohydrin <1998IJC(A)1106> (Equation (1)). The synthesis of the
highly fluorinated compound 1 has been claimed but again no physical data (other than
boiling point), and in this case no experimental details either, were given <2001MI897>. It
has been suggested <1961JA4670> that perfluorination and ring strain can contribute to make
-haloalcohols more stable relative to the corresponding ketone and hydrogen halide. An
-carbonyl group may also play a stabilizing role, as cyclic 2-chloro-2-hydroxy-1,3-diketones
are among the best characterized representatives <1981CB1951> of this particular functional
group. One or more of these structural features are present in many of the more satisfactorily
characterized -haloalcohols which have been synthesized recently. For example, the addition
of a halogen to the metastable fluorinated enol 2, which can be prepared from readily
available methyl 3,3,3-trifluoropyruvate, gives a mixture of the -haloalcohol 3 and the
trihalopyruvate 4 (Scheme 2) <1996JOC7521>. In this case complete conversion of 3 to 4
requires distillation where the halogen used is Cl2 or ICl, and treatment with quinoline where
Br2 is involved. The NMR data provided for the product mixture unambiguously confirm the
formation of the -haloalcohol in this case. The addition of bromine to the stable perfluori-
nated enol 5 leads to the formation of the -bromo alcohol 6 (Equation (2)) <1996JOC5109>.
Although it could not be isolated, reverting to the enol and bromine, 19F-NMR data provide
convincing evidence for its formation. The silver tetrafluoroborate promoted solvolysis of the
bromofluoromethyl ketone 7, giving the geminal fluorohydrin 8 which is unstable in even
dilute base, is a key step in the synthesis of the anthracycline antibiotic 14-fluorodoxorubicin
(Equation (3)) <2002TL2867>.
Functions Incorporating a Halogen and a Chalcogen 29
O O
Br
Br
HN aq. [Ag(IO4)2]+ HN OH ð1Þ
O N O N OH
H H
F
F3 C OH
O
F
1
Distillation, X = Y = Cl; X = I, Y = Cl
quinoline, X = Y = Br
F CO2Me XY, CH2Cl2 XF2C CO2Me XF2C CO2Me
+
F OH –60 °C Y OH O
2
3 4
4 steps 3/4: X = Y = Cl, 1:3 X = Cl, 83%

X = Y = Br, 2:3 X = Br, 80%
F3 C CO2Me
X = I, Y = Cl, 1:3 X = I, 67%
O
Scheme 2
OH
Br OH
F F F
F Br2
F F Br ð2Þ
0 °C, MeCN
F F F F
F F F F
5 6
O OH O F O
O OH F
Br OH
AgBF4, DMSO
OH OH
95% ð3Þ
O O OH OH O O OH OH
Me Me
7 8
Two groups have reported that the ring opening of epoxides can lead to the formation of
-haloalcohols. Thus the BF3-mediated ring opening of the chloroepoxide 9 leads to the formation
of the anthracyclinone 10 in which perhaps significantly the -haloalcohol again has an adjacent
fluorine atom (Equation (4)) <1996G771>. However, although it has been claimed that ring
opening of the epoxide 11 in a similar fashion gives a mixture of the - and -haloalcohols 12 and
13, the 1H-NMR data provided are not consistent with the structure of the former (Equation (5))
<1998JA12849>.
O OH O OH
Cl Cl
BF3.Et2O
OH
O
no solvent
F ð4Þ
15 min
O OH O OH
10
9
CN
N+ Cl– Cl
H Cl
Ph Ph Ph
OH + ð5Þ
O
ZnCl2, Cp2TiCl2, THF
11 OH
12
13
4.02.1.2 a-Haloethers—R12CHal(OR2)
As would be expected on the basis of their reactivity, many -haloethers (geminal halohydrin
ethers) possess limited thermal stability and are susceptible to hydrolysis. A number of low
molecular weight -haloethers are lachrymatory and linked to the fact that they are strong
alkylating agents, concerns have been expressed about the carcinogenic character of others
<1969MI481>.
4.02.1.2.1 a-Fluoroethers—R12CF(OR2)
There has been an extremely high level of activity over the last few years in areas relating to the
synthesis of -fluoroethers. This activity is due in the first instance to the importance of H or OH
replacement by F as a strategy for the enhancement of biological activity. It is also due to the fact
that perfluorinated ethers are materials of considerable industrial importance, finding use, for
example, as lubricants, inert fluids, and in the biomedical area <B-1994MI463>, and that
partially fluorinated ethers have been considered as CFC replacements <1996CT44>. As a result
of these interests, a very large amount of work relating to the synthesis of fluoroethers, using a
wide range of techniques, has been carried out. A relatively large number of the compounds
prepared contain the -fluoroether functional group.
Although electrochemical fluorination in anhydrous hydrogen fluoride (see below) and
reaction with higher transition metal fluorides such as CoF3 (Equation (6))
<1996JFC(80)86> are the principal methods used in industry for the production of perfluoro
organic compounds, interest in the use of elemental fluorine as a reagent for this purpose has
increased in recent years (Table 1). The safety problems associated with the use of fluorine
however, which include the extremely exothermic nature of its reaction with CH bonds,
present problems in relation to scale up. The use of microreactors for elemental fluorine
(Table 1, entry 1) has been described and this may encourage further developments in the
area. Liquid phase reactions (Table 1, entries 2 and 3) and the use of UV light to promote
fluorination (Table 1, entries 4 and 5) have also been reported. The first synthesis of a
perfluorinated carbohydrate has been carried out using the so-called LaMar direct fluorination
procedure (Table 1, entry 6). This method was also used to prepare a range of perfluoro crown
ethers including the 24-crown-8 14, which was obtained as a mixture of stereoisomers
(Equation (7)) <1994JA5172>.
OCH3 OCF3
F3 C F2/CoF3 F3 C F
CF2CF3 CF2CF3
ð6Þ
F
CF3 130–300 °C
CF3
Table 1 Direct fluorination route to -fluoroethers
Entry Reactant Product Conditions Yield (%) References
1 F3CHFCF2C O CF2CFHCF3 F3CF2CF2C O CF2CF2CF3 F2/N2 91 <1999CC883>
(i) rt; (ii) 280 C
F F
F F F F
2 OCH3 OCF3 F2 93 <1999JFC(94)157>

F3C F3C F 30 to 80 C
CF2CF3 CF2CF3 14 h
F
CF3 CF3
3 F3C CF2CF2CF3 F3C CF2CF2CF3 20% F2/N2 78 <2001JFC(112)109>

F2ClCCCl2F
F F F FF F F
20–40 C
O O O O O O 0.2 MPa
O O
F3C
CF3
4 F F F F 20% F2/N2 73 <2000JFC(101)97>

CF3 F3C CF3 h
F 120 h
O F O FFF
F F F F CF3 FF F
F3C O CF3 F3C O CF3

F F
F F F F F F F F
Table 1 (continued)
Entry Reactant Product Conditions Yield (%) References
5 F F F2, h 29 <1995JFC(75)197>
F F F F F
F F CFC solvent
F F F 40 to 28 C
O O
F
12 h
F F F F F
F F F F
Cl F Cl
6 H F F F2/N2 20 <1999JOC8127>
O F NaF
O H
O F 15 days
O
O
O 90 to 40 C
O F3C
H H O O
F3 C CF3
F F O
CF3
F F F F F
F
FF F
F
O O O
F FF O FF
NaF/F2 FF
O F O
O –80 to 25 °C O
F F F
F F
F F F
O 8 days O ð7Þ
O F O
3hh% F
FF F F
O O F O O F
F F
F
F
F F F F
F F
14
Electrochemical fluorination is an attractive alternative to the use of elemental fluorine for the
replacement of hydrogen in molecules which are sufficiently polar to be soluble in anhydrous hydrogen
fluoride. The method does not involve the production of fluorine, the organic solute being fluorinated at
the anode, and it has been used to prepare primary, secondary, and tertiary -fluoroethers. The crown
ether 15 reacts under these conditions to give bis--fluoromethyl ether 16 (Equation (8)) <2000T8877>
and the benzooxazinone 17 undergoes fluorination in the 2-position (Equation (9)) <2001SL1644>.
The electrochemical fluorination of a number of esters carrying morpholine substituents leads to the
formation of mixtures of products, which include a number of -fluoroethers <1998JFC(87)193,
2001JFC(111)115>. Thus, methyl cis-dimethylmorpholinopropionate gives a product mixture which
contains the -fluoroethers 18 and 19 (Equation (10)), and methyl cis-dimethylmorpholinoacetate, in
addition to the corresponding acid fluoride (47%) and N-perfluoroalkyl deivative (2%), gives a small
amount of the oxazepan 20. The electrochemical fluorination of a number of biologically interesting
flavones (Scheme 3) resulted in the formation of significant amounts of -fluoroether 21, together with
traces of a second, 22, which was unstable under the reaction conditions <1999JOC3346>.
Et3N.5HF
O O
MeCN, 20 °C
F O O O F
O O electrolysis O O ð8Þ
O 90%
15 16
Et4NF.4HF
O O F
DME, 20 °C
ð9Þ
N O electrolysis N O
51%
17
F3 C F3 C F F3 C F
F F
Electrolysis F F
O N CH2CH2CO2Me O N CF2CF2CF + O N CF2CF3
anhy. HF F F ð10Þ
O
F3 C F3 C F F F3 C F F
18, 29% 19, 21%
F F F
F3 C F
F O N R
F F
F F
20
Et3N.3HF
O O O O
F H
R R F R R
Electrolysis F F
+ +
Et3N.3HF F F
O Ph O Ph O O
Ph Ph
21 22
Et3N.3HF
Electrolysis
R=H 58% 19% 0%

R = Me 20% 2% Trace
R = Cl 62% 24% 0%
Scheme 3
A number of substitution reactions have been used to assemble the -fluoroether functional
group. Thus, perfluoroisopropoxide displaces chloride and triflate anions (Equation (11)) to give
the ethers 23 <1995JOC3423> and 24 <1995JFC(73)17>, respectively. The nucleophilic displace-
ment of fluorine from CF2 groups by ethoxide <1994JFC(66)39, 1998JFC(91)221>, t-butoxide
<1996JOC5109>, and malonate anions (Equation (12)) <1998JFC(88)169> has also been used
synthetically.
F7C3 Cl O F
F3CO2S
F
n-F7C3 O CF3 F F3 C CF3 F F F F3 C O F
F F ð11Þ
M+ = Cs+, diglyme –
O M+ = K+, diglyme CF3 F F F
F CF3 +
100 °C , 18 h M rt, 1 h
23, 58% 24, 88%
CF3 O F3 C F O
EtO OEt F CF2CF3 F3 C F3 C
NaH OEt OEt
+ + ð12Þ
O O Et2O
F3 C CF3 F3 C O OEt F3 C O OEt
F
66% 33%
A wide variety of addition reactions have been used to produce -fluoroethers of equally diverse
structural types. The fluoroalkenes which are often involved are strongly electron deficient and so the
nucleophilic addition of XH bonds (X = N, O, S) occurs readily. Although the uncatalyzed addition
of methanol to such alkenes has been reported (Equation (13)) <2000JFC(104)239>, these reactions
usually involve the prior generation of the appropriate anion. In this way the phenoxide anion derived
from 25 (Equation (14)) affords the -fluoroether 26 <2000JFC(105)129>. The regiochemistry of the
addition to trifluorovinyl ethers is controlled not only by the inductive effect of the fluorine sub-
stituents but also by the stabilization of the intermediate carbanion by negative hyperconjugation
<B-1995MI729>. The perfluoroalkyl vinyl ether 27 is easily synthesized <2000JFC(106)13> and is
also commercially available, and so has been used as a model compound in a number of studies of this
type of addition reaction (Table 2). Primary and secondary amines react directly with 27, forming
imines, amine adducts, or the corresponding amides according to the reaction conditions or separa-
tion technique employed (Table 2, entry 1). In one case the use of a polyfunctional amine, diethano-
lamine, results in the formation of the novel cyclized product 28 (Equation (15)) <2000JFC(106)13>.
Alcohols, phenols, and thiols must first be converted to their anions (Table 2, entries 2–7) and
although a range of solvents can be employed for the addition reaction, alternatively the use of
THF or dioxane is reported to lead to the formation of -substituted tetrahydrofurans (THFs) and
dioxanes <1999MI125>.
F3 C CF3 MeOH F3 C CF3 F3 C CF3

F H +
F CF3 6 h, 20 °C MeO CF3 MeO CF3 ð13Þ
50% 50%
OH
MeO2C CO2Me
F F F F F MeO2C CO2Me
25 F F F F F
F O Li
+ ð14Þ
O SO3– O O –
F3 C F F F + i. ButLi, DMF, 40 °C O SO3
F Li
ii. DMF, 3 days, 20 °C F F F3 C F F F
90% 26
CF3
F OCF2CFOCF2CF2CF3
F F
27
Table 2 Nucleophilic addition reactions of 27

Entry Product Conditions Yield (%) References

1 O CHFORf i. Piperidine, THF, 0–20 C 63 <1999ZPK1345>
C ii. H2O
N
2 MeOCF2CHFORf MeONa, 20 C 54 <2000JFC(106)13>

Me(CH2)15OH, BunLi,
3 Me(CH2)15OCF2CHFORf 41 <2002JFC(117)149>
THF/hexane, 5 days, 20 C
4 N(CH2CH2OCF2CHFORf)3 N(CH2CH2OH)3, KOH, DMSO 80 <2000JFC(106)13>
5 OCH2CH2OCF2CHFORf OCH2CH2OH
F F F F
67 <2000JFC(106)13>
F F F F
F F , KOH, DMSO
6 OCF2CHFOR f OH
61 <2002JFC(117)149>
, BunLi, THF/hexane,
5 days, 20 °C
7 SCF2CHFORf i. PhSH, BunLi, THF/hexane, 55 <2002JFC(117)149>

10 min, 70 C
ii. THF, 122 h, 75 to 20 C
a
Rf = F3CCF2CF2OCF(CF3)CF2.
CF3
NEt3, DMF O OCF2CFOCF2CF2CF3
27 + HN(CH2CH2OH)2 O
100 °C, 4 h ð15Þ
N F
87%
28
-Substituted THFs, which again are -fluoroethers, can also be formed by the highly regio-
selective addition of radicals generated photochemically or using dibenzoyl peroxide from THFs
and dioxolanes (Scheme 4) <1996JFC(80)125, 1999JFC(94)141>. Hydrolysis of the initially
formed dioxolanes gives the corresponding diols (Scheme 4). -Fluoroethers have also been
produced by the photochemical addition of methanol, and primary and secondary alcohols to
perfluorovinyl ethers (Equation (16)) <1996JFC(80)135>.
HO F
O OC3F7
F F
HO OC3F7
81% O O
(56:44 mixture i. , hν, 2 h F F
O F OC3F7 86%
of diastereomers)
hν, 8 h F F ii. HCl, MeOH, H2O +
+ 3 h, heating
HO
OC3F7
OC3F7 HO
O
F F
F F F
F
~5% ~5%
Scheme 4
F OC3F7 hν, 1 h OC3F7 OC3F7

HO + HO
F F EtOH F F F
ð16Þ
F F
F
71% 5%
The stability of polyfluorinated ethers in the presence of Lewis acids is critically dependent on
their structure. Perfluorinated ethers are stable up to quite high temperatures whereas partially
fluorinated ethers react at room temperature, sometimes undergoing a cleavage-based decom-
position reaction. Ethers of the type Rf CH2OCF2Rf are more stable and in the presence of SbF5
participate in an addition reaction with tetrafluoroethene or 1,2-difluoro-1,2-dichloroethene
resulting in the replacement of one of the fluorine atoms on the -carbon and the generation of
-fluoroethers (Scheme 5) <2001JFC(112)117>.
F F
SbF6 CF2CF3
25 °C, 12 h
F F
F3CCH2OCF2X F3CCH2O=CFX F3CCH2OCFX
SbF5
X = CF2H 76% X = CFHOC3H7 22%

X = CFHCF3 58% X = CFHCl 62%
Scheme 5
A number of -fluoroether-forming reactions which involve the addition of radicals to alkenes

have been reported. Photochemically generated radicals are involved in the cyclization of the
!-bromo vinyl ethers 29 <1994JA4521> and 30 <1996JOC4824>, which give the cyclic -fluoro-
ethers 31 and 32, respectively (Equation (17)). In both cases a significant amount of reduction also
occurs, the cyclization/reduction ratio being, for example, 1:2.71 in the case of 30. The reaction of
29 was remarkable in that no five-membered ring product was obtained, a result which is in
contrast to those reported previously <1971JCS(C)3959>. The homolytic cleavage of the OF
bond in hypofluorites has also been used as a source of radicals. Thus, trifluoromethyl-
hypofluorite reacts with the perfluoroalkene 33 to give a mixture of regioisomers which includes
the -fluoroether 34 (Equation (18)) <1995TL3543>. The reaction of the peroxy hypofluorite 35 with
perfluorobutadiene gives the -fluoroether 36, the result of a regiospecific 1,2-addition, together
with a mixture of 1,4-addition products (Equation (19)) <1995JFC(74)83>. The bis-hypofluorite
37 behaves in an analogous fashion reacting with fluoroalkenes to give dioxolanes which contain
the -fluoroether functional group (Scheme 6) <1995JFC(71)111>.
Br F n = 1, Et3SiH F
F F F H
F n = 2, Bu3GeH F F
F CF2 F
O n CF2 n + F CF2 n
hν HF2C O O ð17Þ
F conversion F
29, n = 1 29, 90% 31, n = 1
30, n = 2 30, 98% 32, n = 2
F F OCF3 F F
F3 C CF3 F3COF
F3 C CF3 F3 C CF3
F + F CO
–196 to 20 °C, 20 h 3 ð18Þ
CF3 F F CF3 F F CF3 F F
45 °C, 8 h
33 34 2.3:1
F3C O O
O F
F F F
F F F
F F3 C O O F F3 C O O F
35 O O ð19Þ
F +
F F F CF3 F F F F F CF3
F F –196 °C to rt
36
F F F3C F F3C F
F F
F F O O
O O F CF(CF 3)2 F CF3
F CF(CF3)2 F F
O O
–60 °C, hν 24 h
F F F3 C CF3
F3 C CF3 43% –196 to 25 °C
37 46/54 cis/trans
28%
F F 24 h
–196 to 25 °C
F CF3 95%
F F
O O
F F
F CF3
Scheme 6
Two cycloaddition reactions have been reported which allow structurally complex -fluoro-
ethers to be prepared. The major product of the reaction of diphenyl ketene with the diene 38
is the [2+2]-adduct 39, with only small amounts of the -fluoroether containing
[4+2]-product 40 being formed (Scheme 7). However, prolonged heating of 39 in hexane
containing dimethyl acetylenedicarboxylate (DMAD) results in its essentially quantitative
conversion to 40 <1996JCS(P1)1157>. The fact that irradiation of the diazirine 41 (Scheme
8) generates fluoro(trifluoroethoxy)carbene has considerably greater synthetic potential in
terms of a general route for the preparation of -fluoro--cyclopropyl ethers. The carbene is
nucleophilic in character and although it does not react with acrylonitrile, it does add to the
more electrophilic -chloroacrylonitrile to give a 2:1 mixture of diastereomeric cyclopropanes
<1993TL7549>.
Ph Ph
F Ph F
C O
O Ph O O
+
O Hexane O O
heating Ph F
38 20 h Ph O
77% 14%
O
39 40
DMAD, hexane
heating, 2 days
97%
Scheme 7
CN
Cl
F3 C F3 C F3 C CN
O N hν O Cl O
N
F 18%
F F
41
Scheme 8
Fluorocarbon epoxides are important intermediates in the preparation of fluorinated com-

pounds for the pharmaceutical and agrichemical industries, with hexafluoropropylene oxide
(HFPO) being by far the most widely used. The addition of acyl fluorides to this compound or
its oligomerization, both promoted by fluoride ion, have been a rich source of -fluoroethers
(Table 3). In addition to the usual sources of fluoride, the ammoniumperfluorocyclobutane
ylide 42 (Table 3) has also been used for this purpose to good effect <1996T9755>. The key
step in these reactions is regiospecific attack by the nucleophile at the more sterically hindered
ring carbon of HFPO, a process which is controlled by the electron withdrawing effect of the
CF3 group. A similar regiospecificity is observed in the reaction of methanol with HFPO
<2002JFC(115)67> and with 43 (Scheme 9), and in the reaction of the alkoxide derived from
the alcohol 44 with HFPO (Scheme 10) <1997JOC7844>, all of which give -fluoroethers.
The formation of the minor product 45 (Scheme 10) is probably the result of an initial ring-
opening due to regiospecific attack of fluoride in the standard way, followed by reaction of the
acyl fluoride thus formed with the alkoxide. On heating to temperatures close to 200 C,
HFPO exhibits another useful property in that it fragments producing difluorocarbene. This
behavior has been exploited in the formation of the -fluoroether 46 (Equation (20))
<1995JA5397>.
Table 3 -Fluoroethers from hexafluoropropylene oxide

Entry Co-reactant Product Conditions References
1 O O F CF3 KF, diglyme <1999JFC(94)65>
(CF2)4 F O
F F O (CF2)5
O F
2 O O F3 C F F F O KF, tetraglyme, <1995JFC(75)163>

F O 0 C, 16 h
O F
F F
O F F F CF3
3 O F F F CF3 O CsF, tetraglyme <2002JFC(114)51>

F CF3
F3C O
O F
F F
F F F F F CF3
4 O F F O
F CF3 F F
O
F 3C F F F
F F <1996T9755>
F F F CF3 F + F
NEt3
, MeCN, 2 h
42
5 O O O F F O CsF, diglyme <1998ZOR1786>

(CF2)2 O
F OMe MeO F
F F F F F CF3
6 O F F O KF, MeCN <1995MI151>

ClF2CCF2 O
F ClF2C F
F F F CF3
7 O KF, diglyme, <1995ZOR1145>

F F F CF3
30 h, 43 C
F O F
F11 O
F11
F F F CF3 O
O O MeOH, heating O
MeOH, rt, 6 h F CXF2
CClF2 CF3
MeO X = Cl X=F MeO
F OMe F F F OMe
40% 73%
X = F, HFPO
X = Cl, 43
Scheme 9
O O
F O CF3 O
NaH, DME, 3 h ROH CF3
CF3 + CF3
RO RO
ROH F
F F F F RO F
F OR
45, 13% 78%
ROH = O OH
O
44
Scheme 10
F O CXF2
F F F CF3 F
F F F CF3 F
F F MeO2C O
MeO2C O O F
O F 190 °C ð20Þ
F F F F F F
F F F F F 83% F
46
The regioselective and stereoselective introduction of a fluorine atom into a molecule

continues to present a formidable synthetic challenge. A range of reagents have been devel-
oped for this purpose and of these diethylaminosulfur trifluoride (DAST) continues to be the
most widely used for primary, secondary, and tertiary -fluoroethers. Its recent use has been
reviewed <2002S2561>. The selective introduction of fluorine is of particular importance in
synthetic carbohydrate chemistry where glycosyl fluorides are important synthetic intermedi-
ates (Table 4). In this context using DAST generally involves the direct replacement of an
anomeric OH group with a fluorine atom, a process that can occur with either inversion or
retention (Table 4, entry 1) of configuration, and results in the formation of what is an
-fluoroether. In some cases a competing elimination reaction can be involved (Table 4, entry 3).
The behavior of 2-uloses is different in that reaction with DAST gives rise to difluoro
derivatives. In many cases gem-difluoro compounds are obtained, but in others fluorination is
accompanied by a 1,2-transposition leading to the formation of 1,2-difluoro compounds which
also contain the -fluoroether group (Table 4, entry 4). Ring contraction, again resulting in the
formation of an -fluoroether, can also occur (Table 4, entry 6). The conversion of a glycosyl
chloride to the corresponding fluoride, with inversion of configuration, has been achieved using
a combination of DAST and AgOTf <1996CL337, 1996MI857>.
DAST has also been used with noncarbohydrate systems with, for example, the epoxy alcohol
47 undergoing exclusive CC bond cleavage to give an -fluorovinyl ether (Equation (21))
<2001JFC(107)271>. This reaction was subsequently developed in the context of cyclic epoxy
alcohols so that it now constitutes a reasonably general method for the synthesis of cyclic
-fluoroethers although they are generally formed together with an -fluoro epoxide (Equation
(22)) <2002OL451>. The outcome of the reaction is sensitive to the relative stereochemistry of
the alcohol and the epoxide, and to the nature of the alcohol with the hydroxy cyclododecene
oxide 48 giving selectively an -fluorovinyl ether 49 (Equation (23)). DAST has also been used
in a Pummerer-type process to produce primary -fluoroethers (Equation (24)) <1999ACS41>.
Deoxo-Fluor ([bis(2-methoxyethyl)amino]sulfur trifluoride) is similar to DAST in that it is a
source of nucleophilic fluorine, however it does have a somewhat different reactivity profile. It
has been used to convert the bisindandione hydrate 50 into the cyclic polyfluoroether 51
(Equation (25)) <2002JOC1918>. Hypervalent iodoarene difluorides are yet another source of
nucleophilic fluorine and once again they have been used in the preparation of glycosyl fluorides
<1996T149>.
Table 4 Preparation of -fluoroethers by the selective fluorination of carbohydrates using DAST
Entry Product Reactant Conditions Yield (%) References
1 OBn OBn THF, 45 min, 88 <1995T5657>
20 C
BnO BnO
O O OMOM
OMOM
BnO BnO
F OH
OBn OBn
BnO
BnO
BnO
BnO O
O CH2Cl2, 2 h, 75 ()
2 <1998BCJ2893>
BnO OH 60 to 0 C 25 ()
BnO F
OBn
OBn
BnO BnO
BnO
BnO BnO CH2Cl2, 4A
BnO
3 H H H H molecular sieves, 88 mixture <2001AG(E)1475>
O H H
O O O 30 min, 78 to 25 C
O
CO2Bn CO2Bn
O
F O CO2Bn OH
3:1
Table 4 (continued)
O
O O
O
4 F F C6H6, 24 h, rt 78 mixture <1994T9125>
O Bn
F OBn F OBn
Ph O
Ph O
O
O O
O
O 53 ()
5 O O OH CH2Cl2, 30 min <1995CAR(269)227>
O F 47 ()
N3
N3 O
O
O
O
OMe
6 F CH2Cl2, 8 h, 20 C 72 <2001T6733>
F O
OMe
O F
DAST, CH2Cl2
H19C9 rt, 10 min
H19C9 O
ð21Þ
OH 76%
47
O O
DAST, pentane O
HO F + F
rt, 15 min ð22Þ
total yield: 58% 2/1 syn/anti
63:37
F
O
HO
O
DAST, pentane
rt, 15 min
ð23Þ
total yield: 86%
48 49
DAST, CH2Cl2
S OPh 36 h, rt F OPh ð24Þ
O 75%
O HO OH (MeOCH2CH2)2NSF3 O
O
OH (Deoxo-Fluor) F F
CH2Cl2, 4 h, 20 °C
HO ð25Þ
HO OH O 65% O
F F
50 51
HF, most frequently used in pyridine solution, has also been extensively used for the selective
introduction of fluorine into complex polyfunctional molecules through the replacement of an
hydroxy group, an example being the formation of a glycosyl fluoride from peracetylated sialic
acid 52 (Equation (26)) <2000JOC6145>. In keeping with the general pattern for these reactions
this conversion proceeds with retention of configuration. In an analogous manner, HF/NEt3 has
been used in the replacement of a mesityl group (Equation (27)) <1994MI1225> whereas the
reaction of the primary alcohol 53 in anhydrous HF results in rearrangement and the formation
of the -fluoroethers 54 and 55 (Equation (28)) <1995TA307>. An alternative method of using
HF–pyridine to introduce a fluorine atom into a carbohydrate molecule involves epoxide fluor-
idolysis (Equation (29)) <2002JA10036>. In the noncarbohydrate area, the electrochemical
fluorination of cyclic ethers has been developed as a general method of producing cyclic
-fluoroethers (Equation (30)) <2002TL1503>. The electrolysis takes place in the absence of
solvent, using 5HFEt3NF as the supporting electrolyte, and the product is isolated by simple
distillation from the electrolysis solution.
OAc OAc
AcO H AcO H
AcO H HF–Pyr AcO H
H H ð26Þ
AcO O 4 h, 0 to 20 °C AcO O
NHAc NHAc
HO 70% from F
sialic acid
OAc OAc
52
O OMs O X
Et3N, HX
CF3 CF3
ð27Þ
O O X = F, 4 h, 80 °C O O
X = Cl, 3 h, 120 °C
OH
F F
O O anhy. HF O
O O
10 min, –5 °C O
O + ð28Þ
O O O HO O
H H H
O O HO
53 54, 20% 55, 18%
O F
HF–Pyr, CH2Cl2 HOCH2
O O
0.5 h ð29Þ
AcO OC 8H17 AcO OC 8H17 + 10%
C-5 epimer
AcO NHAc AcO NHAc
X X Isolated yields
( )n HF.5Et3N ( )n X = CH2, n = 0, 56% ð30Þ
Electrolysis X = O, n = 1, 59%
O O F X = O, n = 0, 20%
The most frequently used source of electrophilic fluorine is N-fluorobenzenesulfonimide,

((PhSO2)2NF) and this has been used with a range of bases to produce -fluoroethers through the
selective introduction of fluorine into molecules containing an acidic hydrogen. It has been used
together with sodium bis(trimethylsilyl)amide <1996JMC1021> or sodium hexamethyldisilazane
<1998BMCL3275> to fluorinate the malonate derivatives 56 (Equation (31)), the products being
used in the synthesis of fluorinated heterocyclic systems and phosphate mimics. A combination of this
fluorinating agent, LDA and ButLi, has been employed to fluorinate the trianion of the thymine
derivative 57 (Equation (32)) <2001JOC2624>. An alteration in the reaction conditions allows the
-fluoro-30 -sulfonate to be obtained as a single product in 48% yield. The reagent has also found
application in the carbohydrate area, producing the -fluoroether 58 from a protected diulose
(Equation (33)) <1998JOC8475>. An alternative source of electrophilic fluorine is Selectfluor
(1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)), which has, for
example, been used to fluorinate 2-alkoxymalonates, forming -fluoroethers (Equation (34))
<1999TA1223>. Interestingly, dimethyl 2-fluoro-2-methoxymalonate has also been prepared by
direct fluorination using NaH/F2 at 15 C (51%) <1996JFC(78)165>. More impressively Select-
fluor, together with a chiral base, has been used in an asymmetric fluorination of the benzofuran 59
(Equation (35)) <2001JA7001>. Although not commonly used, an XeF2 promoted fluorodecarbox-
ylation of a chiral substrate giving an optically inactive -fluoroether 60 (Equation (36)) has been
reported <1993JOC705>. The stereochemical outcome of the reaction has been used to argue for the
involvement of radicals in the reaction. XeF2 has also been used to convert hemithioacetals to
primary -fluoroethers <1996ACS850>. BrF3, described as ‘‘under-utilized,’’ has been used to
convert 2-(2-cyanoethyl)-cyclohexanone to the oxadecaline 61 (Equation (37)) <2001JFC(111)161>.
The reaction is made possible by the presence of both the ketone and nitrile groups in the starting
material, as neither cyclohexanone or 2-(cyanoethyl)cyclohexane reacts with BrF3.
i. THF, –78 °C
But (TMS)2NNa (X = Br)
O X But O X
NaHMDS (X = H)
But But ð31Þ
O ii. THF, –78 °C O
(PhSO2)2NF F
O O
56
H H
O N O i. LDA, THF, –78 °C O N O
ii. ButLi, THF, –78 °C
O N MeO2C O N
MeO2C
iii. –78 °C, THF, H
F 21% O N O
(PhSO2)2NF + ð32Þ
HO HO
MeO2C O N
57
F
19%
PhSO3
H O O i. LDA, THF/HMPA, –78 °C H O O

O ii. (PhSO2)2NF O
O O ð33Þ
O H 45% O F
O O
58
OMe NaH, THF, Selectfluor F OMe

RO OR 20 min, rt RO OR
72% ð34Þ
O O O O
R = Me, 86%
R = Et, 72%
Selectfluor,
O dihydroquinidine acetate, O F
CO2Et 3A molecular sieves,
CH2Cl2/MeCN, –80 °C, 5 h CO2Et ð35Þ
O 92% O
59 80% ee
F3 C OMe XeF2, CDCl3, 4 h F3 C OMe

ð36Þ
Ph CO2Me 95% Ph F
60
BrF3, 0 °C, 15 min F

O F
CCl3F
CN F
70% ð37Þ
O H
61
The replacement of a bromine atom with a fluorine atom forms part of a selective fluorination
method in synthetic carbohydrate chemistry which involves a preliminary photochemical bromina-
tion, a process which is often highly regio- and stereoselective. Replacement of the bromine involves
either AgF (Equation (38)) <2002JA10036, 1998T13267>, in which case the reaction generally
proceeds with inversion and can sometimes involve competitive elimination of HBr <1998T13267>,
or AgBF4 which results in retention (Equation (39)) <2000CAR(329)539, 1996JA241>. The
replacement of a bromine atom with a fluorine atom is also possible using CF3ZnBr <1997S159>.
AcO AcO F
Br
O O
AgF, MeCN
AcO OAc 39 h, rt AcO OAc
O O ð38Þ
AcO 56% AcO
O O
AcO AcO
Br AgBF4, toluene F
4A molecular sieves O
O
40 min AcO F ð39Þ
AcO F
11%
AcO OAc AcO OAc
In addition to the these reasonably general methods of preparing -fluoroethers, a number

have been synthesized by methods which only apply to a particular compound. Thus the
perfluorinated bisepoxide 62 undergoes an unusual rearrangement to give the 1,4-dioxine 63
(Equation (40)) <1995CC629, 1995JFC(72)231>, the product containing an -fluoroether group-
ing. The reaction of N-fluoropyridinium triflate with a base in acetone, proceeding via a carbene
intermediate, gives a mixture of products which includes the -fluoroether 64 (Equation (41))
<1996JFC(77)161>. The cyclohexa-2,5-dienone 65 is formed by the oxidation of 4-fluorophenol
with phenyliodonium acetate (Equation (42)) <1997T4387> and a further unstable cyclohexa-2,4-
dienone 67, which could only be characterized spectroscopically by the reaction of methoxide with
66 (Equation (43)) <2002EJO614>. Finally, it has been reported that a fluorofullerene with the
formula C60F18O, formed by the reaction of [60]-fullerene with K2PtF6, probably contains an
-fluoroether subunit 68 <2000JCS(P1)2212>.
F F3 C 200 °C CF3
O F3 C O
F 24 h F
F3 C
O 96% F ð40Þ
CF3 CF3 F3 C O
CF3
62 63
+ + +
+N O N O
Et3N, rt, 5 min N O N F N
F ð41Þ
SO2CF3
F3CSO3–
F
64
OH O
PhI(OAc)2, MeOH,
rt, 5 min
ð42Þ
X = F, Br
X X OCH3
65
F OMe
NaOMe, DMSO F
18 h
ð43Þ
66 67
O
F F
68
4.02.1.2.2 a-Chloroethers—R12CCl(OR2)
The traditional methods of preparing -chloroethers include the direct -chlorination of ethers,
the reaction of acetals with acetyl chloride, and the chloroalkylation of ketones and aldehydes.
There are only two recent examples of the preparation of -chloroethers by the direct
-chlorination of ethers. These are the low temperature chlorination of chloromethyl ethyl ether
to give chloromethyl 1-chloroethyl ether <1996TL9241>, and the chlorination of 69 (Equation
(44)) <1994JFC(68)287> which actually involves the formal addition of chlorine to the aromatic
double bond. The chloroalkylation of formaldehyde (Equation (45)) <1998JOC3694,
2002TL6317> and other aldehydes <1995AP531> continues to be used for the preparation of
primary and secondary -chloroethers, respectively. The reaction of hemiacetals with thionyl
chloride, essentially one half of the chloroalkylation procedure, has been successfully used for
the preparation of tertiary -chloroethers in molecules containing a wide variety of other func-
tional groups (Table 5). The outcome of this reaction can depend on the precise manner in which
it is carried out. Thus in the synthesis of the -chloroether 70a (Table 5, entry 1) if thionyl
chloride and pyridine are added together to the corresponding alcohol, a mixture of 70a and an
alkene is obtained. If, however, the thionyl chloride is added first on its own, followed by
pyridine, no elimination occurs. Unlike most -chloroethers, the -chlorinated lactyl esters 71
obtained from ethyl trifluoropyruvate (Table 5, entry 4) were found to be quite stable to
hydrolysis because of the strongly electron-withdrawing trifluoromethyl group and could be easily
purified by aqueous work up followed by distillation. Secondary allylic alcohols also gave
hemiacetals with ethyl trifluoropyruvate but on treatment with thionyl chloride these gave a
mixture of hydrated ethyl trifluoropyruvate and allylic chlorides.
F F
Cl Cl
F O F O
Cl2, hν Cl
Cl ð44Þ
F O F O Cl
Cl
F F
69
H2C O
OH O Cl
HCl, CHCl3 ð45Þ
Cl Cl Cl Cl
0 °C, 65%
The addition of Cl2, or the regioselective Markovnikov addition of HCl, to enol ethers has
been found to be a convenient way of preparing -chloroethers (Table 6). N-Chlorosuccini-
mide (NCS) in the presence of acetic acid has also been used to chlorinate an enol ether, the
reaction giving a mixture of all the possible stereoisomeric products (Equation (46))
<1996MI701>. Although the nature of the chlorinating agent is not clear, a radical mechan-
ism has been suggested for the reaction in dichloromethane between the electron deficient
olefin 72 and MCPBA which results in its chlorination (Scheme 11) <1998TL6453>. If the
reaction is carried out in the presence of a radical scavenger and methanol, then an
-chloromethyl ester is obtained <1998TL4659, 2002CAR(337)2077>. The mechanism suggested
for this process <1998TL4659> involves the initial slow epoxidation of the electron-deficient
olefin, with the hydroquinone protecting the peracid from decomposition (Scheme 11).
Subsequent rearrangement of the dichloroepoxide gives an acid chloride, which reacts with
methanol to give the methyl ester. The chlorination of compounds related to 72 has also been
carried out in the standard way using Cl2 (Table 6, entry 6). The regiochemistry of the addition
of benzenesulfenyl chlorides to carbohydrate enol ethers is also such as to produce -chloro-
ethers <1995JOC3378>. The reaction can be highly stereoselective as is the case for the addition
of 2,4-dimethylphenylsulfenyl chloride to the sialyl glycal 73 (Equation (47)), which gives only
4% of the minor trans-isomer <1996JA8187>. The reaction with benzenesulfenyl chloride is less
stereoselective and it was found that the anomeric ratio of the products is a function of the
solvent used <1996CAR(284)207>.
Table 5 Preparation of -chloroethers by reaction of hemiacetals with thionyl chloride

H H
O O
O O
O O
H H i. SOX2, 30 C X = Cl, 74
1 H O H O <2002OL757>
ii. Pyr X = Br, 86
F3C X F3C OH
70a, X = Cl; 70b, X = Br
X CO2Et X CO2Et
X=S
SOCl2
CF3 CF3 <1998H2253>
2 O O Pyr/C6H6
Cl OH X=O
20 C
<2000JHC1003>
X = S, O X = S, O
O O
O O
O O SOCl2, Pyr
3 O O O O 75 <1994T9343>
2 h, 0 C
H H
Cl HO
O O
O O
O O
RO F3C i. ROH, C6H6
OEt OEt
ii. SOCl2 <1995JOC6289,
4 F3C Cl O 65–80
Pyr/C6H6 1995CC1969>
R = Me, allyl, alkynyl, benzyl R = Me, allyl, alkynyl, benzyl 30 min, 0 C
71
Table 6 Preparation of -chloroethers by the addition of Cl2 or HCl to enol ethers
Cl
Cl O Cl O
P P HCl gas, CH2Cl2
1 <1996ZOR1657>
40 C, 35 min
Cl Cl
OAc OAc
OAc OAc
HCl gas, MeCN, 4A
AcO AcO molecular sieves,
2 H O H O 85 <1995CAR(267)239>
Cl LiCl 6 days, rt,
AcHN AcHN CO2Me 20 C
CO2Me
N3 N3
Cl O R1
O R1
O
O S
S
Cl HN
3 HN Cl2, THF/CH2Cl2, rt <1999H(50)713>
R2
R2
R1 = Me; R2 = 4-Me, 2,4,6-Me, 2-OMe,
R1 = Me; R2 = 4-Me, 2,4,6-Me, 2-OMe,
4-OMe, 4-Cl, 2-NO2
4-OMe, 4-Cl, 2-NO2
R1 = Ph; R2 = H
R1 = Ph; R2 = H
Table 6 (continued)
Cl O
O
MeO CX3
MeO CX3 Cl2, CCl4, 0 C 90 <2001S431>
Cl
4 X = F, Cl
X = F, Cl
O O
Cl
5 Cl Cl2, CCl4, 1 h, 60 C <2000IZV2109>
O CF3 O CF3
O O A: Cl2, CH2Cl2,
Cl 5 min, rt
CCl3 A: 88
6 O O B: Et4N+Cl 3, <1998TL6453>
O O B: 77
Cl Cl CH2Cl2,0 C,
H H H H 15 min
O O O O
OAc OAc
AcO AcO
H O NCS, AcOH H O CO2Me
AcO CO2Me ð46Þ
AcO
120 °C Cl
AcO H
AcO Cl
OAc MCPBA
OAc MCPBA
Cl Cl CH2Cl2/MeOH OAc
O O O Cl
CH2Cl2 hydroquinone O
CCl3 rt, 16 h Cl
rt, 3 h Cl
H H H H
H H
O O 49% O O 53%
O O
72
OAc OAc
Cl O Cl O
O O
OMe MeOH Cl
H H H H
O O O O
Scheme 11
AcO AcO
OAc OAc
AcO SCl AcO
H O H O Cl
CH2Cl2, 0 °C AcHN
AcHN CO2Me ð47Þ
CO2Me
85%
AcO AcO
73
Addition reactions involving chloroalkenes have also been used to assemble -chloroethers. The
Michael-type addition of alcohols to -chloroenones <2000JFC(102)147> and the addition of
chloro(alkoxy)carbenes to -chloroacrylonitrile (Scheme 12) <1995TL3083, 1995JFC(73)101> are
both reactions of this type, as is the intramolecular addition of an alcohol to a chloroalkene which
has been used as the key ring-closing step in the synthesis of a cyclic -chloroether (Equation (48))
<1995ZOR58>. The mechanism for the novel cyclization of the pyrrole derivative 74, which occurs
in the presence of a large excess of NCS and gives 75 and the -chloroether 76, is not understood
(Equation (49)) <1996JOC9289>. A number of -chloroethers have also been produced via
cycloaddition reactions. These include the photochemical oxa-Diels–Alder reaction between the
carbonyl group of quinone and the chlorodiene 77a <1994JA5108> (Scheme 13). The diene 77a
also undergoes a thermal reaction with diphenyl ketene to give the -chloroether 78a, a [4+2]-
adduct, as the minor product; the major product, a [2+2]-adduct can however be thermally
converted to 78a (Scheme 13) <1995JCS(P1)1499>. The chlorofuran 79 undergoes a microwave-
assisted indium triflate catalyzed intramolecular Diels–Alder reaction to give another -chloroether
80 (Equation (50)) <2000TL8639>. Addition reactions involving epoxides have also been used to
construct -chloroethers. The EtAlCl2 induced ring-opening of the epoxide 81 at 78 C produces
the -chloroether 82 as a single diastereomer (Equation (51)) <1995JOC5029>. The reaction is not as
stereoselective at higher temperatures, giving a 1:1 mixture of diastereomers at 0 C. Its outcome also
depends on the nature of the Lewis acid and epoxide used. The epoxide 83, for example, in the
presence of EtAlCl2 gives a mixture of -chloroether and tetraol at 78 C (Equation (52)), whereas
with TiCl4 at 0 C the tetraol is the only product formed.
hν, pentane
1 R2 rt to 25 °C, 6–24 h R1O CN
R O N
+
Cl N CN Cl R2
~25%
R1 = Me, F3CCH2; R2 = Cl
R1 = F3C(CF2)6CH2; R2 = H
Scheme 12
O
H2SO4, HgSO4
X OH
70 to 75 °C
ð48Þ
X = Cl, 61% O
X = Br, 66% X
X = Cl, Br
O
O Cl O
Excess NCS, EtOH H
CHCl3, rt, 18 h N
HN Cl + O
S N ð49Þ
S S
Cl Cl OEt
Ph
74 Trace
45%
75 76
X
H
O
Ph H
C O O
O Ph
H Ph H
Cl O X H THF, reflux
O O 77a: hexane Ph
H O DMAD
H O reflux, 72 h X = Cl, 65%
O hν, C6H6, 11 h + X = Cl, 48 h
H X = Br, 44% 85%
16% 77b: THF
O X X = Br, 24 h
H reflux, 48 h H 11%
O
77a, X = Cl; 77b, X = Br O
O
Ph O
Ph H
H X = Cl, 15%
X = Br, 10%
78a, X = Cl; 78b, X = Br
Scheme 13
Br NTol
In(OTf)3, 8 min
NHTol O +
microwaves NTol
Cl O Cl O ð50Þ
Cl 10%
79 80%
80
EtAlCl2
CH2Cl2, hexane OH
EtO O
1 h, –78 °C F3 C ð51Þ
F3 C 78% Cl
OEt
81
82
EtAlCl2 OH
EtO O CH2Cl2, hexane F3C
1 h, –78 °C +
Cl
HO ð52Þ
F3 C OEt
EtO CF3
83
34% 28%
A wide range of substitution reactions involving chloride, oxygen, and carbon nucleophiles have
been used to prepare -chloroethers. The importance of glycosyl chlorides, formally -chloroethers, in
synthetic carbohydrate chemistry means that a lot of the work in this area relates to their synthesis. The
use of traditional reagents such as AcCl/HCl <1995MI227, 1995CPB1844, 1995OPP637, 1997T11109,
1999CAR(317)198, 2001BMCL141, 2002JOC7565, 2002S1959>, or AcCl on its own
<1994JMC3419, 1997MI139, 1997SL650, 2000CAR(323)1, 2000EJO2643, 2001JCS(P1)1098,
2001AG(E)366, 2001MI227, 2002OL3067, 2002SL1487>, to replace an acetate group on the anomeric
carbon with chlorine continues to be the most widely used method of carrying out this functional group
transformation. The conversion of the acetate 84 (Equation (53)) <2002CAR(337)755> and the
alcohol 85 (Equation (54)) <2000OL3361> to their corresponding chlorides are representative exam-
ples of this type of reaction. HCl <1998ACS141> and TiCl4 <1994TL3179>, both in dichloro-
methane, are other reagents that have been used for this purpose. Glycosyl chlorides have also been
prepared by procedures that involve the nucleophilic displacement of leaving groups other than acetate.
Thus the reaction of the bromogalactose derivative 86 with LiCl in DMSO gives a mixture of anomers
from which each can be isolated by fractional crystallization after different reaction times (Equation
(55)) <1996T9121>. ICl has been used to prepare the glycosyl chloride 87 presumably through chloride
ion displacement of a sulfenyl iodide from the thioglycoside (Equation (56)) <1997TL8233>. A radical-
based replacement of bromine in the bromoglucosyl chloride 88 with an allyl group gives a high yield of
the glycosyl chloride 89 as a single diastereomer (Equation (57)) <1997TL8185, 2001EJO2939>. The
corresponding D-galacto and D-manno derivatives gave yields of 51% and 34%, respectively.
AcO AcO
OAc OAc
AcO H AcO H
AcCl, HCl (gas)
O OAc O Cl
2 days, rt ð53Þ
AcHN AcHN
CO2Bn 90% CO2Bn
AcO AcO
84
OH OAc
HO AcO
AcCl, AcOH
O +
CO2– NH4 O CO2H
rt, 15 h
HO AcO ð54Þ
OH 95% Cl
HO AcO
85
AcO AcO AcO

O CN LiCl, DMSO O Cl O CN
AcO rt AcO + AcO
Br CN Cl ð55Þ
AcO OAc AcO OAc AcO OAc
86 44% (18 h) 49% (7 days)
AcO AcO
OAc OAc
ICl, CH2Cl2
AcO AcO
10 min, 0 °C
O CO2Me O Cl
AcHN AcHN ð56Þ
SMe CO2Me
AcO AcO
1/5 α/β
87
AcO Sn(n-Bu)3 AcO

O Cl AIBN, C6H6, hν O
AcO 50 min, 30 °C AcO
Cl
ð57Þ
Br
AcO OAc 86% AcO OAc
88 89
Substitution reactions have also been used in the synthesis of noncarbohydrate -chloro-
ethers with, for example, the ZnCl2 reaction of AcCl with acetals being widely used to convert
cyclic and acyclic 1,3-dialkoxymethanes to primary -chloroethers (Equation (58))
<1995JOC2532> and 2-alkyl-1,3-dialkoxymethanes to the corresponding secondary com-
pounds (Equation (59)) <1998BCJ915>. AcCl has also been used in the conversion of the
acetal 90 to a relatively unstable -chloroether, which was dehydrohalogenated directly
(Scheme 14) <1994TL7785>. The displacement of mesylate by chloride ion, for example,
has been used in the preparation of a chlorotetrahydroflurodioxole (Equation (27))
<1994MI1225> and it has been reported that treating the acetal 91 with PCl5 produces the
-chloroether 92 (Equation (60)) <2000CEJ684>. The reaction between the lithium enolate of
ethyl dichloroacetate and the acylcyclohexenone derivatives 93 has been used in a synthesis of
highly functionalized furans (Scheme 15) <1997SL1259>. A key element in the synthesis is the
fact that in general the -chloroethers 94 undergo spontaneous dehydrohalogenation. The
-chloroethers 94a and 94b are quite stable however and treatment with DBU is required to
complete the synthesis. The stability of these -chloroethers was attributed to ‘‘a conformation
effect due to the alkyl group on the ring.’’ The issue is, however, complicated by the fact that
the -keto ester 95 gives an -chloroether 96 (Equation (61)) which is also stable, whereas the
1,3-diketones corresponding to 95 gave a furan directly, with no -chloroether being isolated.
Nucleophilic displacement of chloride from a dichloromethane by methoxide has been used in
the preparation of the -chloroether 97 (Scheme 16) <1995JOC5931>. Although the product
is obtained in very low yield and as an inseparable mixture with 98, it has been used to
prepare an extensive range of bicyclo[2.2.1]heptane adducts 99 in 15–55% yields through
Diels–Alder reactions with monosubstituted alkenes (Scheme 16), 1,4-naphthaquinone, diethyl
acetylenedicarboxylate, 4-phenyl-[1,2,4]triazole-3,5-dione, N-phenylmaleimide, and 1,3-dioxol-2-
one. Each of the adducts contains the -chloroether group and the cycloaddition is completely
face selective.
O AcCl, ZnCl2 O O ð58Þ

Et2O, 1 h, rt
O O Cl
O O AcCl, SOCl2
O Cl
2 h, 60 °C ð59Þ
Ph 63% Ph
MeO AcCl Cl Et3N

O O O
CHCl3, 20 h ButOH, CH2Cl2
90
Scheme 14
O Cl
PCl5, 20 °C
O O ð60Þ
O O
91 92
O R3 O R3
LiCCl2CO2Et
O THF, –78 °C OLi
Cl
R1 R1
CO2Et
R2 R2 Cl
93
O R3 O R3
–HCl
O O
R1
R1
CO2Et CO2Et
R2 R2 Cl
94
a: R1 = R3 = H; R2 = Me
b: R1 = Pri; R2 = R3 = H
Scheme 15
O O
LiCCl2CO2Et EtO2C Ph
EtO THF, –78 °C Cl ð61Þ
O CO2Et
Ph
95 96
Cl Cl Cl OMe Cl Cl
MeOH, KOH
Cl Cl Cl Cl Cl Cl
THF, 3 h, rt
+
1.5:1, 6%
Cl Cl Cl Cl MeO Cl
97 98
Reflux,
R
CH2Cl2, C6H6,
20 h–10 days
or toluene
MeO Cl
Cl
Cl R = naphthyl, phenyl, m-nitrophenyl,
p -bromophenyl, ethoxy
Cl
R Cl
99
Scheme 16
4.02.1.2.3 a-Bromoethers—R12CBr(OR2)
-Bromoethers are less stable and thus more reactive than the corresponding chloro com-
pounds. In synthetic terms the main difference between -bromo- and -chloro ethers is the
much greater involvement of radical reactions in the synthesis of the former due to the facility
with which bromine atoms can be produced. However, many standard reactions can be applied
successfully to both classes of compound. Thus, for example, the addition of bromine to vinyl
ethers has been used to prepare a wide range of -bromoethers (Table 7). These reactions
generally proceed in high yield although the stability of the products appears to vary greatly.
The dibromo adduct 100 (Table 7, entry 1) was reported to be too sensitive for long-term
storage and the dibromocyclobutane 101 (Table 7, entry 2) underwent hydrolysis on chromato-
graphy to give the ring opened product 102. However, it is reported that the bromoether 103
(Table 7, entry 3) and related compounds prepared by the same method, are particularly stable
and indeed are formed with high diastereoselectivity (90:10). Bromination of dienes can result in
the formation of 1,4-adducts (Table 7, entry 4) and in polyfunctional molecules there is the
possibility of intercepting an intermediate bromonium ion (Table 7, entry 7). The attempted
bromination of the cyclophane 104 results, remarkably, in the formation of a product to which
the structure 105, containing an -bromoether, has been tentatively assigned (Equation (62))
<2000JOC5360>. Pyridinium tribromide, a commercially available reagent which is useful for
small scale brominations, has been used to brominate the 2-styryl-4-chroman-4-one 106, resulting
in the formation of a mixture which contains the -bromoether 107 (Equation (63))
<1999H(51)481>.
MeO2C CO2Me
Br CO2Me
H
102
Table 7 Preparation of -bromoethers by the addition of Br2 to enol ethers

O
O
OMe
OMe Br2, CH2Cl2 99% <2000SL1419>
1 Br Br
100
MeO2C
MeO2C
Br Br Br2, CH2Cl2, rt,
2 >35% <1997JCS(P1)2155>
MeO2C OMe 15 min
MeO2C OMe
101
CF3
Ph OEt CF3
Br2, CH2Cl2,
3 Br Ph 92 <1998S288>
12 h, rt
Br OEt
103
MeO OMe MeO OMe

Br MeOH,
4 96% <1997TL4811>
MeO Br2, Et2O
O CN O CN
CF2Cl F3C O CF2Cl

F 3C O
5 Br Br2, h 53 <1994IZV174>
O CF2Br O
F F
O
Br O NaBr,
6 CH2Cl2, H2O 84 <2001H825>
electrolysis
Br
Br Br
Br
7 Br2 <2000TL6709>
O
OH
Br
Br Br
Br2, dioxane Br
0 °C Br Br
ð62Þ
20% O
(CH2)6
O
104 105
Br
O C6H4-p-OMe PyrH+, Br3– O C6H4-p-OMe
AcOH, 20 °C
O O
106 32%
Br ð63Þ
Br
O C6H4-p-OMe O C6H4-p-OMe
+ +
Br
Br Br
O O
10% 22%
107
2-Bromofurans have three of the four components of -bromoethers already in place and CC
bond formation at the 2-position completes the assembly of this functional group. This has been
achieved through cycloaddition reactions with dimethyl maleate, DMAD (Scheme 17),
<1996JCS(P1)2699> and hexafluoro-2-butyne (Equation (64)) <1996JCS(P1)1095>. In the
same way addition reactions which create a CO bond at the 1-position of bromoalkenes also
produce -bromoethers. The bromodiene 77b undergoes an oxa-Diels–Alder reaction with the
carbonyl group of diphenyl ketene to give the -bromoether 78b (Scheme 13)
<1996JCS(P1)1157>, and as was the case for the chloro analog, the major product in the reaction
can be converted thermally to this compound <1995JCS(P1)1499>. The intramolecular insertion
of an alcohol into a bromoalkene has also been reported (Equation (48)) <1995ZOR58>.
Br Br
MeO2C CO2Me CO2Me
O O
MeO2C CO2Me CO2Me
CO2Me
Br
17%
DMAD CO2Me 4%
O
+ S O +
4-methoxyphenol O 4-methoxyphenol
Br C6H6, 4.5 h, 120 °C C6H6, 22 h, 120 °C Br
CO2Me CO2Me
O O
CO2Me CO2Me
58%
48%
Scheme 17
O
THF, 24 h
140 °C CF3
F3 C CF3 + ð64Þ
Br
O
11% Br CF3
In terms of substitution reactions, the most widely used reagent for the introduction of bromine is
N-bromosuccinimide (NBS). It has been used to prepare all classes of -bromoethers. The
reactions are generally radical in character and are promoted by the use of peroxides, AIBN, or
irradiation, NBS thus effectively providing a source of bromine atoms. In synthetic carbohydrate
chemistry, NBS has been used to produce -bromoethers through the introduction of Br at
anomeric and nonanomeric carbons. The relative merits of various radical-mediated brominations
in synthetic carbohydrate chemistry, including the use of NBS, have been reviewed <2002TL8849>.
The standard procedure for the bromination of anomeric carbons involves the use of benzoyl
peroxide as an initiator <1995MI1307, 1995MI1295, 1995TL2149, 1999SL1151, 2001OL2415>.
This approach has been used for both pyranoses <2002TL8849> (Equation (65)) and furanoses
<1996TA383> (Equation (66)) and usually proceeds with retention of configuration. There is one
instance of a furanose being brominated photochemically at the anomeric position <1996SC75>.
The captodative effect has been adduced to account for the regioselectivity of these brominations
<1996TA157>. Selective bromination at C-5 in pyranosides is also possible using NBS and again
produces an -bromoether (Equation (67)) <2000CAR(329)539>. In this case photochemical
promotion of the reaction is usually involved <1996JA241, 2001CJC510, 2002JA9756,
2002JOC4505> although benzoyl peroxide has occasionally been used <2002TL8849>. The regio-
selectivity of this radical bromination has been attributed to the well-established preference of such
reactions to occur at tertiary carbons <2000CAR(329)539> and to the captodative effect
<1995JOC1880>. Although primary and secondary amides are not compatible with photochemical
bromination using NBS, the use of phthaloyl protecting groups has proved successful
<2002JA10036>. Bromination at C-5 generally proceeds with retention of configuration.
AcO NBS, (BzO)2 AcO N

O N CCl4, 40 min O S ð65Þ
AcO reflux AcO
S 67% Br
AcO OAc AcO OAc
O O O O
NBS, (BzO)2
H CCl4 H ð66Þ
Br
OH OH
MeO2C O MeO2C O
AcO NBS, hν AcO Br

O CCl4, 9 h O
AcO F reflux AcO F ð67Þ
52%
AcO OAc AcO OAc
NBS has also been been used widely to generate -bromoethers in noncarbohydrate systems.
This includes the bromination of 1,4-dioxines using AIBN <2002T1533> or benzoyl peroxide
(Equation (68)) <1996AJC533> as initiator, as well as that of the functionally related 4-oxodiox-
olanes (Equation (69)) <2001HCA3766, 1995JOC1880>. NBS reactions can involve the formation
of HBr and in the case of 5-cyclodecyn-1-one 108 this leads to the formation of intermediate 109,
bromination of which gives the -bromoether 110a (Scheme 18) <1995JOC2714>. In keeping with
the proposed involvement of 109, reaction of 108 with a 13C label in the 5-position leads to the
formation of 110b. NBS has also been used to create an -bromoether at the 6-position of a
penicillin derivative through the displacement of a diazo group (Equation (70)). The reaction is
carried out in methanol and leads to the formation of 111a (64%) <1995T10723>. An occasionally
used alternative to NBS, N-bromoacetamide is less selective in this case leading to the formation of
mixture of 111a (10%) and a dibromo derivative 111b (15%). It has been reported however that
N-bromoacetamide gives 111c selectively, although in modest yield (37%) <1994JHC909>. Forma-
tion of the -bromoether 112 from the corresponding diazo compound using NBS is equally
chemoselective although the stereochemistry of the bromine atom is reversed <1998SL322>.
NBS, (BzO)2 CO2Et

O CO2Et O
CaCO3, 18 h
reflux
Br ð68Þ
O 99% O Br
Ph O Ph Br O
NBS, hν
AIBN, CCl4
O O reflux, 10 min O O ð69Þ
CO2Bn 52% CO2Bn
O Br Br
NBS, Et2O Br
Br2 X
2 h, hν
O
(HBr) 69%
OH
108 110a, X = C12
109
110b, X = C13
Scheme 18
NBS or BrNHAc
N2 H R2 H
S CH2Cl2/MeOH S
Br
1h N
N
O O ð70Þ
CO2R CO2R1
111a, R1 = Bn, R2 = OMe

111b, R1 = Bn, R2 = Br
111c, R1 = CH2OCO2But, R2 = OMe
O
Br H O
MeO S
N
O
O But
75%
112
Pyranose brominations, again resulting in the formation of -bromoethers, have also been carried
out using a variety of other reagents. A particularly useful assessment of various methods for radical
bromination has been carried out in an attempt to identify a suitable replacement for methods that
involve the use of the undesirable carbon tetrachloride <2002TL8849>. This concluded that a
biphasic system based on KBrO3–Na2S2O4 had considerable potential in this regard for both anome-
ric and nonanomeric centers <2002TL8849> (Equation (71)). Other methods for anomeric bromina-
tion include Br2/CHCl3 <2000TA405, 2000TA1719, 2002TL8849>, and Br2/BaCO3/CCl4
<2000TA1719>, both of which involve irradiation, (TMS)2NLi/CBr4 <1995TL2145> and HBr/
AcOH <1999TL57>. Br2/CCl4, again under irradiation, has also been used to brominate C-5 in a
pyranoside <2002TL8849>. The introduction of bromine at the anomeric carbon through acid-
assisted nucleophilic displacement of OH and OAc is also a standard approach for the synthesis of
glycosyl bromides. Thus HBr and HBr/AcOH have been used to convert hemiacetals to the corre-
sponding bromide <1995LA2081>; AcOH can co-crystallize with the product given by the latter, a
problem that is avoided by using HBr. The substitution of OAc has been achieved using HBr/
Ac2O/AcOH <1995LA2081, 2002JOC7407>, HBr/AcOH <1999CAR(316)85>, and PBr3
<1999CAR(316)85>. The displacement of p-nitrobenzoate <2000CAR(329)549> and chloroace-
tate <1997JCS(P1)1973> using TiBr4, and the direct one-pot conversion of isopropylidene acetals
113 to glycosyl bromides 114 (Equation (72)) <1995LA2081>, have also been reported.
KBrO4, Na2S2O4
AcO AcO
CH2Cl2–H2O
O O
rt, 64 h CONH2
AcO CONH2 ð71Þ
AcO
68% Br
AcO OAc AcO OAc
33% HBr
O O O Br
AcOH, rt
RO RO
O 113a, 5 h OAc
113b, 20 h
ð72Þ
RO OMs RO OMs
113a, R = OAc 114a, R = OAc

113b, R = OBn 114b, R = OBn
A number of nonstandard approaches have been used to produce -bromoethers. A completely

different approach to anomeric bromination involves chloroperoxidase catalyzed bromohydration
of the vinyl ether 115 in the presence of KBr and H2O2 (Equation (73)) <1995JCS(P1)967>. In
the same way, the bromination of the epoxide 116 is an unusual method of introducing a bromine
atom at C-5 (Equation (74)) <1999JOC144>. The low yield of isolated product in this case is due
in large measure to the decomposition of the -bromoether 117 during chromatography on SiO2.
Although the use of acetyl chloride is a standard synthetic carbohydrate chemistry method of
replacing acetate with chloride, and in so doing creating an -chloroether, acetyl bromide is in
general much less widely used. The only recent example of the corresponding use of acetyl
bromide involves the displacement of methoxide from the acetal 118 (Equation (75))
<2000JOC3085>. In the same way thionyl bromide is rarely used to prepare -bromoethers
despite the fact that the reaction of thionyl chloride with acetals is a standard method of
producing -chloro ethers. The only example of the use of thionyl bromide in this respect is the
stereoselective preparation of the halogenoartemisin derivative 70b from the corresponding hemi-
acetal (Table 5, entry 1) <2002OL757>.
AcO
O OAc
AcO
HO Br
i. Chloroperoxidase HO
O KBr, H2O2, rt, 3 h O AcO OAc
OH
HO HO 57%
ii. Ac2O, DMAP, Pyr Br + ð73Þ
HO OH HO OH AcO
O OAc
115
AcO
OAc
AcO OAc
14%
MeO2C MeO2C
O O TiBr4, CH2Cl2 Br O
OBn 30 min, –78 °C HO OBn
ð74Þ
26%
BzO OBz BzO OBz
116 117
MeO OMe AcBr, CH2Cl2 MeO Br

20 °C, 4 h
ð75Þ
Br Br 75% Br Br
118
4.02.1.2.4 a-Iodoethers—R12CI(OR2)
Although -iodoethers are relatively unstable, they are increasingly finding application as inter-
mediates in synthetic carbohydrate chemistry where a variety of nucleophilic substitutions have
been used to prepare glycosyl iodides. Acetate displacement has been achieved using a variety of
reagents including HI/AcOH (Equation (76)) <1997TL5921>, I2/thioacetic acid <2000OL369>,
I2/Et3SiH <2002SL269>, TMSI <1999CAR(316)47, 2002OL2039>, NaI/TMSCl/molecular
sieves <1995H(41)937>, and BiI3/TMSCl <1997CAR(297)175>. The displacement of hydroxyl
from the anomeric center has been carried out using a polymer-bound triarylphosphane–iodine
complex and imidazole <1999EJO3147>. TMSI has been used to introduce iodine in place of an
OTMS group <1998MI1181, 2001OL2081> and I2/HMDS to displace a pivalate group
<2003CC1266>. Nucleophilic attack by iodide is again effectively involved in the formation of
the cyclic -iodoether 119 through 1,4-addition of TMSI followed by hydrolysis (Scheme 19)
<1994T8237>. The potential of a 2-iodofuran as an -iodoether precursor has been exploited in
the intramolecular Diels–Alder reaction of 120 (Equation (77)) <1997JHC1315>. The strained
nature of the propellane 121 is responsible for its ring-opening reactions with I2, which gives the
diiodo compound 122 through addition to the bicyclobutane bridge bond, and the -iodoether
123 through the rearrangement of an intermediate formed during the addition process (Equation
(78)) <2000T1115>. Finally, the remote oxidation of the angular methyl group in the eudesma-
nolide 124 results in the formation of a range of products including the -iodoether 125 (Equation
(79)) <1994JOC6395>.
AcO AcO
OAc OAc
AcO AcO
HI, AcOH
H O CO2Bn H O CO2Bn ð76Þ
3 h, 0 °C
AcN AcN
H OAc 100% H I
AcO AcO
I I
TMSCl, NaI O
O aq. NH4Cl O
MeCN, 30 min TMSO
O O
96% O O
O
H H
119
Scheme 19
Tol N O
Tol N O I C6H6, reflux
I
H
120a, 48 h, 95% 1
R R2
120b, 240 h, 90% ð77Þ
R2
R1
120a, R1 = Me, R2 = H
120b, R1 = R2 = Me
O OH H
n I2, Et2O Bun I Bun
Bu
–90 to 20 °C
+ O
ð78Þ
I I
121
22% 61%
122 123
I
C6H5I(OAc)2 O
HO cyclohexane
H 10.5 h, 40 °C H Other
+
AcO hν AcO products ð79Þ
H H
O 5% I O
O O
124 125
4.02.1.3 Other Derivatives of a-Halo Alcohols—R12CHal(OR2) and R12CHal(OX)
4.02.1.3.1 a-Haloalkyl esters—R12CHal(OCOR2)
(i) -Fluoroalkyl esters—R12CF(OCOR2)

The reaction of acyl fluorides with formaldehyde gives fluoromethylcarboxylates <1995T5807>.
The -fluoroalkyl ester functional group can also be constructed by the addition of fluorine or
fluorine-containing reagents to enol esters. Thus, the anodic fluorination of the camphanyl enol
ester 126 results in a mixture of diastereomeric -fluoroalkyl esters 127 (Equation (80))
<1994TA1909>. Similarly the reaction of t-butyl hypofluorite, a source of electrophilic t-butox-
ylium ion (ButO+), with indenyl acetate results in the the formation of a product mixture from
which the unstable -fluoroalkyl ester 128 was isolated in low yield (Equation (81))
<1998JOC4632>. The perfluorination of the secondary alkyl esters 129 (Equation (82))
<1998JA7117> and 130 (Equation (83)) <1994JOC5883>, and the selective introduction of
fluorine at the secondary -carbon of -valerolactone (Equation (84)) <2002TL1503> are the
only recent examples of an obvious route to -fluoroalkyl esters. The substitution reaction of
BzCl with perfluoroisopropoxide, generated by the reaction of hexafluoroacetone with fluoride
anion, gives the -fluoroalkyl ester 131 (Equation (85)) <1994JFC(69)103>.
OCOR HF, Et3N OCOR

MeCN F
electrolysis
F ð80Þ
R = camphanyl
126 127
F OAc O
OAc OBut + OBut

ButOF, CHCl3
0 °C 6% 45%
128
ð81Þ
O O
Cl
+ + F
Cl
15% 13%
F2, He
O F2ClCCCl2F O CF3
25 °C ð82Þ
n-H11C5 O C9H19 n-F11C5 O C9F19
F
>70%
129
O F2 O
O O
ClCH2CHClCH2Cl
5.5 h ð83Þ
31%
F14
130
Et3NF.5HF
20 °C
O
O
O
O ð84Þ
electrolysis
F
25%
BzCl F
F3 C CF3 1,8-Bis(dimethylamino)naphthalene F3 C CF3
hydrofluoride, MeCN, 10 h BzF + ð85Þ
O O
Bz
131
(ii) -Chloroalkyl esters, R12CCl(OCOR2)

The thionyl chloride-mediated halolactonization of -keto carboxylic acids allows cyclic -chloro-
alkyl esters to be prepared in high yield. The standard reagent used for this transformation is
SOCl2 (Table 8, entries 1–3 and 6–7), although (COCl)2 (Table 8, entry 4), PCl3 (Table 8, entry 5),
and PCl5 (Table 8, entry 8) have also been successfully used. Another route to -chloroalkyl
Table 8 Preparation of -chloroalkyl esters from -keto carboxylic acids

Cl CO2H
R
O O
O R
1 R = Ph SOCl2, DMF, 17 h, rt 100 <1999SL997>

2 R = 2,5-Me2C6H3 SOCl2, DMF, 20 h, rt 87 <1993HCA1821>
3 2-Quinolinyl SOCl2, rt, 0.5 h, reflux <1995KGS938>
O
CO2H
O O
X
X
R Cl R
4 R = Me, X = OMe (COCl)2, C6H6, 20 min, 70 C <1995JCR(M)526>

5 R = Ph, X = NO2 PCl3, 48 h, rt 91 <1998ZPK2029>
O O
O Cl
HO2C
R
R X X n
n
6 R = H, n = 2, X = CH2 SOCl2, 2 h, 0 C 100 <1995LA797>

7 R = Me, n = 1, X = CO SOCl2, 15 min, reflux 85 <1998SC3041>
8 R = Me, n = 2, X = CH2 PCl5, 30 min, 60 C 56 <1995LA797>
esters, which could be generally useful, involves the Baeyer–Villiger oxidation of the -chloro-
cyclobutanone 132 (Scheme 20) <2002JOC3651>. However, as is often the case, the regiochemistry
of this Baeyer–Villiger reaction is crucially dependent on the stereochemistry of the reactant. The
Baeyer–Villiger product 133 was converted to another -chloroalkyl ester via hydrogenolyis of the
CN bond. The photochemical reaction of chloranil and norbornene gives a complex -chloroalkyl
ester 134 (Equation (86)), which is the end result of a series of rearrangements that occurs following
an initial [4+2]-cycloaddition <1999JCS(P1)2813>. The addition of HCl to the ketene 135 results
in the formation of the -chloroalkyl ester 136 (Equation (87)) <1995JPR659>, presumably the
result of intramolecular trapping of the intermediate carbocation.
H
O
O
Cl(CH2)3 N
H
Cl CO2Bn
48%
O H MCPBA, NaHCO3 H
O MCPBA, NaHCO3
+
CH2Cl2, rt, 30 min CH2Cl2, rt, 30 min
O R1 O H
Cl N R1 = Cl N R1 = (CH2)3Cl
H R2 = (CH2)3Cl R2 H
Cl(CH2)3 CO2Bn CO2Bn R2 = Cl O
67% 132 Cl(CH2)3 N
H
Cl CO2Bn
42%
H2
133
Pd(OH)2/C
MeOH, 6 h
O
O
Cl H H
85%
N
Scheme 20
Cl
Cl H O
O Cl H
hν, C6H6 Cl
Cl Cl Cl
4 h, 10 °C
+ O + ð86Þ
H Cl
Cl Cl Cl H
Cl O
O O
67% Trace
134
Ph Ph
H
CH2Cl2, HCl O
C
O 3 min, 0 °C
O O ð87Þ
82%
H
C6H4-p-NO2 Cl C6H4-p-NO2
135 136
(iii) -Bromoalkyl esters—R12CBr(OCOR2)

The ionic addition of bromine to enol esters has also been used extensively to produce
-bromoalkyl esters (Equation (88)) <1995T3979>. In one case hydroquinone has been used to
ensure that radical allylic bromination does not compete (Equation (89)) <1995JOC1814>. The
trans-stereochemistry of the -bromoalkyl benzoate 137 (Equation (90)) has been attributed to
steric control by the C-4 substituent and charge stabilization in the intermediate bromonium ion
due to the benzoyloxy substituent <1995CAR(269)99>. Interestingly, the same product is
obtained when the reaction is irradiated and, as is the case with furanose 138 (Equation (91)),
allylic bromination does not appear to be a problem. The possibility of intramolecular intercep-
tion of intermediate bromonium ions is demonstrated by the formation of the dibromolactone 139
(Equation (92)) <1998JOC6000, 1998JCS(P1)2031>. The enol ester to -bromoalkyl ester trans-
formation is also involved in the formation of the dibromotetradecamycin 140 <1995JAN1330>.
O2N O2N
O Br2, CH2Cl2 O
O rt O ð88Þ
92% O Br Br
O
Br2, CH2Cl2
AcO AcO
hydroquinone
Br Br Pr n
Pr n i. –4 °C, 15 min ð89Þ
ii. rt, 24 h
Br
O O O O
Br
BzO Br2, CH2Cl2 BzO

O 24 h, rt O
BzO O BzO O
87% ð90Þ
Br
OBz Br OBz
137
OBz OBz
BzO BzO
H Br2, CH2Cl2 H
O O
O hν, 7 h, –15 °C O
BzO BzO
ð91Þ
87% Br OBz
OBz H Br
138
Ph Br Ph
Br2, rt H
CCl4 or CH2Cl2 O
C
O
O O ð92Þ
H
CO2Me Br CO2Me
139
O
O
O Br
H
O Br
OH
OH
140
The allylic bromination of furanones has been used in the preparation of -bromoalkyl esters, which
are useful in the synthesis of metabolites of marine algae and sponges (Table 9, entries 1–3), with use
being made of all the standard initiators: AIBN, (BzO)2, and light. The formation of the dibromoad-
ducts 141 (Table 9, entry 2) and 142 (Table 9, entry 4) results from initial allylic bromination, followed
by dehydrobromination and bromination of the alkene thus formed. Brominated furanones containing
the -bromoalkyl ester group have also been prepared from -keto carboxylic acids by -bromination
of the ketone followed by acid promoted cyclization (Equation (93)) <1997T15813>. -Bromoalkyl
esters have also been produced by bromination of a pagodane bis-lactone <1997LA2069> and through
the rearrangement of 3,3-dibromocamphor (Equation (94)) <1998AJC97>
Table 9 Preparation of -bromoalkyl esters by allylic bromination

Br
Br
NBS, CCl4 55,
1 Pr i
60 C, 88 <1995JOC1814>
O O
Br Pri O O 2.5 h, h
Br
Br
Br
NBS, AIBN,
2 O O CCl4, 72 h, 63 <1994T12457>
Br O O
reflux
141
Cl Cl
Cl OMe OMe
Cl NBS, AIBN,
3 CCl4, 15 min >46 <1995JCS(P1)1483>
O
reflux
Br O O O
Br
Br
O O
NBS, (BzO)2,
4 N N CHCl3, 3 h, <2002CPB1479>
O SO2Ph O reflux
SO2Ph
142
i. Br2, HBr
n-H25C12 Br n-H25C12 Br
n-H25C12 AcOH, CH2Cl2
Br +
HO2C O ii. H2SO4, 20 min O O
O O
110 to 120 °C Br Br
ð93Þ
n-H25C12
+
O Br
O
Br
i. AgNO3, AcOH
O reflux O
ii. H2SO4 ð94Þ
Br O
Br
Br
(iv) -Iodoalkyl esters—R12CI(OCOR2)

The Finkelstein reaction continues to be the most important method of preparing -iodoalkyl
esters <1999BMCL1921, 1995TL655>. The tandem oxidative cleavage–iodination of the hemi-
acetal 143 (Equation (95)) also results in the formation of an -iodoalkyl ester <1998JOC8092,
1998JOC2099>. Only one tertiary -iodoalkyl ester has been reported since 1995: the remote
oxidation of the angular methyl group in the eudesmanolide 124 with iodobenzene diacetate
results in the formation of a range of products including the -iodoalkyl ester 125 (Equation (79))
<1994JOC6395>.
AcO H C6H5IOAc2 AcO

O CH2Cl2, I2 O
CHO
O OH 1.5 h, rt O
O OAc ð95Þ
O
67%
OAc
I
143
4.02.1.3.2 a-Haloalkyl haloformates—R12CHalOCOHal and carbonate derivatives—

R12CHalOCOOR2, etc.
(i) -Haloalkyl haloformates—R12CHal(OCOHal)

The preparation of fluoromethyl fluoroformate by the reaction of the commercially available
chloromethyl chloroformate with KF in the presence of a crown ether has been reported
<1995T5807>. The reaction of aldehydes with trichloromethyl carbonate, from which phosgene
is formed in situ, continues to be used to prepare -chloroalkyl chloroformates (Equation (96))
<2001TL7751, 2002S365>.
O O Pyr, THF O Cl O
H –65 to 60 °C
ð96Þ
OBn + Cl3CO OCCl3 Cl O OBn
90%
O O
(ii) -Haloalkyl alkyl and aryl carbonate derivatives—R12CHalOCOOR2, etc.

The reaction of alcohols and phenols with chloromethyl chloroformate is a convenient way to
prepare -chloroalkyl carbonates <1995JMC3983>. The photosensitized cycloaddition reaction
of dichlorovinylene carbonate 144 with naphthalene (Scheme 21) <1996LA303> produces a fused
bis(-chloroalkyl) carbonate 145 which is quite stable and can be purified by sublimation.
Dichlorovinylene carbonate also undergoes a Diels–Alder reaction with cyclopentadiene to give
another bis(-chloroalkyl) carbonate (Scheme 21) <2000MI1062>. The same functional group is
again created when phosgene reacts with butane-2,3-dione in the presence of pyridinium hydro-
chloride (Equation (97)) <1993SC847>.
PhC(O)Me H
O Cl
Cl hexane, 50 h
hν O
O O O
naphthalene O
O
O
O Cl
40–50% Cl Cl 39%
Cl H
144 145
Scheme 21
O
N+
O O O Cl– O O ð97Þ
H
+
Cl Cl Pyr, 16 h, 4 °C Cl
82% Cl
The reaction of fluoromethyl fluoroformate with amines has been used to prepare O-fluoro-
methyl carbamates <1995T5807>. -Chloroalkyl carbamates are available through the reaction
of amines with chloromethyl chloroformate <1997JA7230, 1995JOC4549, 2003BMCL65>. The
addition reaction of imidazoles and thiazoles with silyl enol ethers in the presence of chloro-
methyl chloroformate also results in the formation of carbamates via an unstable N-acylated
quaternary azole salt (Equation (98)) <2000T4383>. Six-membered cyclic -chloroalkyl carba-
mates 146 have been prepared in high yield by the reaction between phosgene and a range of
substituted 2-aminotrifluroacetophenones (Equation (99)) <2001BMCL1177>. Chlorination of
oxazol-2-ones 147 gives a mixture of two five-membered cyclic -chloroalkyl carbamates, the
composition of the product mixture depending on the nature of the N-aryl group (Equation (100))
<1998MI5305>.
O
COCl O
S
S OTMS Cl
+ MeCN, Et3N ð98Þ
N Cl
N
30 min, 0 °C
99% O O
O
F3 C Cl
COCl2, toluene
CF3 reflux O
X X
ð99Þ
NH2 N O
X = 6-Cl, 6-F, 5,6-diF H
146
But Cl Cl OH
Cl
Cl2, CCl4 But But
N Ar rt
O N Ar + N Ar
O O ð100Þ
O
O O
147 0–62% 0–99%
The reaction of the -chloroalkyl chloroformate 148 with sodium ethanethiolate gives the
-chloroalkyl thiocarbonate 149 which can be converted to the corresponding iodo compound
using a Finkelstein reaction (Scheme 22) <2002S365>. Chloromethyl chloroformate undergoes a
similar reaction with ethanethiolate <1999ACS594>.
CO2Bun
NaSEt, Et2O O CO2Bun NaI, acetone O CO2Bun
O
16 h, 20 °C 4 h, rt
EtS O Cl EtS O I
Cl O Cl 94% 96%
149
148
Scheme 22
4.02.2 HALOGEN AND SULFUR DERIVATIVES—R12CHal(SR2), etc.
4.02.2.1 Dicoordinate a-Halosulfur Derivatives—R12CHal(SR2)
4.02.2.1.1 a-Halosulfides—R12CF(SR2)
(i) -Fluorosulfides—R12CF(SR2)
-Fluorosulfides are important intermediates in the preparation of fluorine containing -lactams,
amino acids, and other substances of importance in human and veterinary medicine. Many,
however, are not stable to standard purification and full characterization must take place at the
level of the sulfoxide or sulfone. The selective introduction of a fluorine atom into a molecule can
be achieved electrochemically or using one of a range of reagents of which the best known is
DAST. In its original form electrochemical fluorination suffered from a lack of selectivity and
from the fact that fluoride ions are poor nucleophiles. Recent developments have led to significant
improvements and the method now provides an alternative to the use of DAST and other
chemical fluorinating agents (Table 10) <1998JFC(87)215>. The use of additives has occasionally
proved beneficial in providing a clean reaction (Table 10, entry 5) and the formation of dimers
and desulfurized products has been observed (Equation (101)) <1999JFC(99)189>. The fluorina-
tion reaction involves initial oxidation of the S atom at the anode giving a radical cation (Scheme
23). The subsequent loss of an -proton and of another electron gives an -carbocation which
reacts with fluoride ion.
Et4NF.3HF
N SPh DME, 20 °C, rt N SPh N F
F +
S CN S CN S CN
53% 5% ð101Þ
NC N
N
+ S
S CN
H H F
–e– –H+ + F–
S S –e– S S
+
Scheme 23
A very extensive range of chemical reagents is also available for the preparation of mono-
-fluorosulfides, most of which are commercially available (Table 11). In addition to DAST
<1995TL5007, 1996TL8759> and DAST/NBS <1994TL85>, they include HF/pyridine/NBS or
NIS (Table 11, entry 1) <1994TL85>, Bun4NH2F3/1,3-dibromodimethyl-5,5-hydantoin (Table 11,
entry 2), MeDAST (Table 11, entry 3) <1995TL5007>, F2IC6H4Me (Table 11, entry 4)
<2001TL8523, 2002JCS(P1)2816>, and IF5/Et3N/HF (Table 11, entry 5). The recent use of
DAST for the fluorination of sulfides has been reviewed <2002S2561>. These reagents have
somewhat different selectivity/reactivity profiles but all are considered to proceed via a fluoro-
Pummerer-type mechanism. Reagents such as DAST, which are based on the N-SF3 group, have
limited thermal stability and this restricts the usefulness of these reagents if the reaction requires
forcing conditions. The use of N-fluoropyridinium triflates (Table 11, entry 6), and Selectfluor
(Table 11, entry 7b), sources of electrophilic fluorine, for the fluorination of sulfides has been
reviewed <1996CR1737>. Selectfluor is usually employed to -fluorinate a sulfide attached to an
active methylene group <1995TL5007>, but it has also been used to fluorinate an unactivated
sulfide in the presence of Et3N (Table 11, entry 7a). There has been only one recent example of
the generation of -fluorosulfides through the deoxyfluorination of a sulfoxide, a previously
Table 10 Electrochemical preparation of -fluorosulfides

CO2Et CO2Et
Ph Ph 0.37 M Et3N3HF,
1 S CO2Et S CO2Et 77 <1995JOC3459>
F MeCN, rt
Ph Ph
S S
F
O O Et4NF3HF, rt,
2 71 <1997JOC8773>
MeCN
N N
Ph Ph
Ph Ph
S S
F
O O Me4NF4HF, rt,
3 64 <1997SL655>
N
MeCN
N
Ph Ph
O O
F
S S
4 Ph N Ph N Et3N3HF, rt, MeCN 69 <1999ACS887>
N N 0.33 M Et4NF3HF,
5 55 <1998JFC(87)203>
F
S
DME, Ph2S
S
Ph Ph
S Ph S Ph
F Cl
Cl
6 O Et4NF4HF, DME, rt 42 <1999JFC(99)189>
O
O O
Ph
S Ph
F S
F Et3N3HF, MeCN,
7 75 <1995T2605>
CO2Me Ph 13 C
CO2Me
Ph
Table 11 Preparation of -fluorosulfides by selective monofluorination
SMe
F SMe
SMe
SMe n-C11H23 HF–pyridine, NIS,
1 n-C11H23 55 <1995TL8243>
F F CH2Cl2, 0 C
F F
F SMe SMe Bun4NH2F3,

Ph Ph 1,3-dibromo-
SMe SMe
2 5,5-dimethyl 58 <1998BCJ2687>
F F F F hydantoin, CH2Cl2,
20 min, rt
F F O
MeO2C MeO2C
OPh MeDAST, CH2Cl2,
3 F 75 <1996TL4941>
S S rt, 48 h
Ph Ph PhO
O O Ph O O Ph
F Difluoroiodotoluene,
4 62 <2002JCS(P1)2809>
CH2Cl2, 0 C, 7 h
PhS PhS
IF5-Et3N-3HF,
5 82 <2002BCJ1597>
S CO2Me S CO2Me hexane, 36 h, 40 C
F
F 1-Fluoropyridinium
Ph S Ph S
Ph Ph triflate,
6 77 <1999S676>
CN CN ClCH2CH2Cl,
3.5 h, reflux
H H
O N O O N O a: i. Selectfluor,
OAc OAc MeCN, rt,
O N O N 15 min 80 <1999JOC7048>
F ii. Et3N, MeCN,
7 10 min
AcO X AcO X b: (2-methoxy-ethyl)-
p-MeOC6H4 p-MeOC6H4 aminosulfur tri- <1995SC725>
fluoride, SbCl3,
a, X = S a, X = S
b, X = SO b, X = SO
CH2Cl2, 16 h, rt
commonly used synthetic method. This involved the use of bis(2-methoxyethyl)aminosulfur tri-
fluoride (Table 11, entry 7b), which is reported to have enhanced reactivity and thermal stability
relative to DAST. Its use has been reviewed <2002S2561>.
An extensive range of tertiary -fluorosulfides has been prepared through the addition of
-fluoro--thioester enolate ions to aldehydes and ketones (Scheme 24) <1996TL8759,
1998T10801, 2002T4759>. ,-Unsaturated aldehydes are reported to undergo exclusive
1,2-addition <1998T10801>. An intramolecular variation of this reaction involves the addition
of anions from -fluoro--thionitriles and esters to a cyano group (Equation (102))
<1995JOC7654, 1998BCJ2387>, the product 150 being obtained as a single diastereomer whose
stereochemistry was not determined. The addition of sulfur nucleophiles to fluorinated epoxides
also leads to the formation of compounds with an -fluorosulfide functional group. Thus, the
addition of thiosemicarbazones (Equation (103)) <2003JFC(120)41> and thiosemicarbazides
<2000JFC(104)155> to a range of fluorinated epoxides gives 4-hydoxy-5-fluoro-1,3-thiazolinyl
derivatives. In a similar fashion thiourea affords a 5-fluorothiazol-4-one (Equation (104))
<2001JFC(108)1>. Ring opening of hexafluoropropylene oxide with phenyl sulfide anion also
gives on -fluorosulfide (Equation (105)) <1999JCS(P1)569>.
EtO NH
CN K2CO3, 1 h 2
F rt, EtOH F
ð102Þ
N S CN CN
60% N S
150
O LDA, THF OLi i. PhCHO O HO H O H OH

SEt –78 °C SEt –78 °C
MeO MeO MeO Ph + MeO Ph
ii. NH4Cl
F F F SEt F SEt
0 °C anti
syn
52% 14/86 syn/anti
Scheme 24
F5 C 2
S F
F Dioxane
O S OH
F5 C 2 N reflux
N NH2 C2F5
C 2 F5 + N N ð103Þ
H 53% N
F
H
90/10 (E )/(Z )
90/10 (E )/(Z )
F NaHCO3, MeOH O
O H2N N
F2ClC 15–30 °C ClF2 ð104Þ
F S
+
H2N 32% H2N S F
F
F i. KOH, MeOH O
O 24 h
F3 C + PhSH F3 C
F ii. THF, rt SPh ð105Þ
F PhS F
15 h
74%
A number of substitution reactions have also been used to prepare -fluorosulfides. Thus the
nucleophilic displacement of iodide from a fluoroiodomethylene by thiolate has been reported
(Equation (106)) <2001CC2428>. The -fluorosulfenyl chloride 151 undergoes an extensive
range of substitution reactions, generating -fluorosulfides with substrates which include ketones,
1,3-diketones, pyrrole, and DMAP (Scheme 25); it also generates -fluorosulfides through addi-
tion to alkenes (Scheme 25) <1996IZV1745>.
F F PhSNa, DMF F F
I SPh
CF3 20 °C CF3 ð106Þ
F 70% F
NMe2
Cl
F CF3 MeO2C S MeO2C S
Cl
S CO2Me F3 C F F3 C F
8 h, 20 °C CHCl3, 24 h NMe2
151
81% 20 °C
69%
Scheme 25
(ii) -Chlorosulfides, R12CCl(SR2)

-Chlorosulfides are important synthetic intermediates as they are easily prepared in high yield by
chlorination of the readily available sulfides, and as the presence of a good leaving group on the
-carbon facilitates reaction at this center particularly in terms of CC bond formation. They
have limited thermal stability and can decompose on chromatography, and so if required for
synthetic purposes they are generally used immediately without purification. The standard
method for preparing -chlorosulfides continues to be the direct chlorination of the appropriate
sulfide using NCS or sulfuryl chloride (SO2Cl2). The former has the advantage that it is a solid,
easily handled, reagent that is compatible with a wider range of functional groups as it is does not
produce HCl when it reacts with the sulfide. However SO2Cl2 is more reactive and should be
considered if NCS does not produce satisfactory results.
In the preparation of -chlorosulfides, NCS is almost always used in CCl4 as the reaction
by-product, succinimide, is insoluble in this solvent and can thus be removed after the reaction
by simple filtration. NCS has been used for chlorinating secondary and tertiary alkyl sulfides
containing a very wide range of functional groups (Table 12); there are relatively few examples
of its use with primary sulfides <2001T5369, 1996IJC(B)1331>. The reaction is usually carried
out at 0–20 C but occasionally refluxing is required (Table 12, entry 1). In general the reaction
results in clean monochlorination but there are examples where a mixture is obtained as a result
of the product reacting further with the reagent (Equation (107)) <1995TL467>. The reaction
of NCS with unsymmetrical sulfides is regiospecific with the product being that which results
from reaction at the center having the more acidic hydrogen (Table 12, entries 2–6).
Cl
Cl H
H NCS H Ph H
Ph N Ph N N Ph ð107Þ
CCl4 S Tol N
S Tol S Tol S Tol
+ +
O O O
O
Table 12 Preparation of -chlorosulfides by chlorination using NCS

O O
PhS
PhS
Cl NMe NMe CCl4, 48 h,
1 93 <1995T12797>
reflux
O O
SPh
SPh
C6H4-o-Br
C6H4-o-Br
N
2 N CCl4, rt <1997H37>
SMe
O SMe
O
Cl
MeO2C SMe
MeO2C SMe
3 CCl4, 2 h, rt >78 <1997JCS(P1)835>
Cl
Cl MeS Ph
MeS Ph
CCl4, 1.5 h,
4 O O >77 <1999TL451>
O O 25 C
O
O
OAc
5 OAc CCl4, 1 h, 0 C 100 <1996S1131>
SEt
Cl SEt
PhS PhS
Cl MeS
MeS SPh SPh
6 CCl4, 15 h, rt >59 <1995T2929>
N N
C6H4-p-OMe O C6H4-p -OMe
O
S Cl S
7 N O N O CH2Cl2, 5 h, rt >82 <1997JCS(P1)309>

Me Me
Cl SPh
Ph Ph
8 Ph CCl4, 20 h, rt >90 <2001T5369>
The main alternative to NCS in terms of chlorinating sulfides is SO2Cl2. Although a much
wider range of solvents has been used with this reagent, including benzene, CCl4, hexane,
pyridine, and CHCl3, the usual reaction conditions involve CH2Cl2 at 0–25 C. The general
features of the reactions (Table 13) involving this reagent are similar to those involving NCS
with the reagent being used with secondary and tertiary alkyl sulfides containing a wide range of
functional groups. Chlorination of the furanone 152 (Table 13, entry 1) occurs readily with
SO2Cl2 but has been reported to be problematic with NCS. The reactions are again regiospecific
with chlorination occurring on the -carbon carrying the most acidic hydrogen (Table 13, entry 2).
Many of the reactions of this type do not involve stereogenic centers, and even where there is
the possibility of diastereomers being produced, the stereochemistry of the products may not have
been determined as both isomers are subsequently converted to a common product. However, the
results for a number of reactions show that chlorination can be highly stereoselective (Table 13,
entries 1, 3, and 4), the process resulting in an inversion at the -carbon. These reactions again
involve a Pummerer-type mechanism and the migration of Cl+ from the sulfur is generally to the
less hindered side. Chlorination of the dithiolodithiine 153 (Table 13, entry 5) is reported to be
stereospecific, the migration of Cl+ following chlorination of the second sulfur again occurring to
the less hindered side.
A range of varied addition reactions has been employed in preparing -chlorosulfides. This
includes the addition of Cl2 to amido-5,6-dihydrooxathiines giving -chlorosulfides which can in
turn be cyclized using base to give bicyclic azetidinones containing the same functional group
(Scheme 26) <1999H(50)713>. A similar transformation has been achieved using PCl5 (Equation
(108)) <1999KGS836>. The addition reactions of chloro- and sulfanylalkenes can also produce
-chlorosulfides. The addition of dichlorocarbene to a 1-chlorovinyl thioether (Equation (109))
<1998SC1667>, the regioselective addition of an alkyl/thio radical pair to 2-chloroacrylonitrile
(Equation (110)) <1995T1867>, and the addition of benzenesulfenyl chloride to the vinyl sulfide
154 (Equation (111)) <2002EJO4024> are examples of such reactions. The classical addition of a
thiol to an aldehyde in the presence of HCl has been used to prepare a secondary -chlorosulfide
(Equation (112)) <1998JOC3706>. In this case it was found that SOCl2 was required to drive the
equilibrium involving the initially formed hemithioacetal to completion. A modified version of
this reaction involving TMSCl instead of HCl has also been used to prepare primary -chloro-
sulfides <1996BMCL2053, 1998ZOR1305>.
Cl O
S
O O N
Cl2, CH2Cl2 Cl O C6H4-p-OMe
S C6H4-p-OMe S C6H4-p-OMe NaH, THF
N THF, rt N rt 31%
H H
+
O O
Cl S Cl
Scheme 26
O Ph O Ph
PCl5, CHCl3 Cl
10 h, 20 °C ð108Þ
Cl
S Ph 80%
S
Ph
PTC, NaOH Cl
SPh Cl
CHCl3, rt
SPh
ð109Þ
X X = Cl, 98%
X = I, 68% X
Table 13 Preparation of -chlorosulfides by chlorination using sulfuryl chloride (SO2Cl2)

O C6H4-p-OMe
O C6H4-p-OMe
Cl CH2Cl2, 3 h,
1 82 <1999JCS(P1)3667>
O SPh 20 C
O SPh
152
HO HO
S S
Cl H H
2 NPh NPh C6H6, 2 h, rt, 94 <1995H(41)921>
O O O O
Ph SPh Ph SPh
Cl
3 CH2Cl2, 0 C <2000TL5577>
BnN O BnN O
H H
Cl SPh SPh
4 MeO2C N O
CCl4, 30 min, rt 97 <1998JCS(P1)3689>
MeO2C N O
Cl S S S
S
O O
5 S
CCl4, 24 h, reflux 60 <2000CC1117>
Cl S S S
153
Cl SPh SPh
6 CCl4, 2 h, 0 C 97 <2000T389>
O O O O
OMe OMe
CO2Me CO2Me
CH2Cl2, 20 min,
7 S 48 <1997T5195>
S 0 C
Cl
AcO AcO
OH NBn OH NBn
H H
Cl
8 Ph CH2Cl2, 0 C 100 <2000TA2267>
Ph S CO2-(–)-menthyl
S CO2-(–)-menthyl
Cl
N S CN
Cl CN ð110Þ
O
CH2Cl2, 0 to 5 °C S N
hν
O
56%
PhSCl, CH2Cl2 Cl
SPh SPh
5 min
ð111Þ
>71%
SPh
154
Cl SPh
CHO
i. PhSH, HCl
Et2O, 12 h ð112Þ
ii. SOCl2
Substitution reactions involving bromochloromethane have been widely used to alkylate thiols
producing chloromethyl sulfides (Equation (113)) <1996IJC(B)1331, 1995CC307,
1996JCS(P1)359, 1999SC1003>. This reagent has also been employed in constructing an alkynyl
chloromethyl sulfide using S8 as the source of sulfur (Equation (114)) <2000JA7012>. Pummerer
rearrangements are an important way of transforming -halosulfoxides into -halosulfides
<1995T6819> and the use of SOCl2 to convert the sulfoxide 155 to the chloromethyl sulfide
156 (Equation (115)) <2001JCR(S)110> is typical of the standard approach adopted. An alter-
native approach involves treating an arylmethyl sulfoxide with a trialkylsilyl halide and a base to
give a mixture of an -siloxy and an -chlorosulfide (Scheme 27) <1995TL2299, 1995T6819>.
The reaction gives only the -chlorosulfide if an o-hydroxymethyl group is present. The use of
SOCl2 to convert an -hydroxy sulfide to an -chlorosulfide has also been reported
<1995JMC4393> and N-acylation with (chloromethylsulfanyl)acetyl chloride is a versatile
method of introducing an -chlorosulfide group (Equation (116)) <2000CPB399>.
i. NaH, THF
SH rt, 1 h S Cl
ii. BrClCH2 ð113Þ
MeO 50% MeO
i. BunLi, S8
TMS H TMS SCH2Cl ð114Þ
ii. BrClCH2
60%
N O N
SOCl2, CH2Cl2
S S Cl
24 h, 20 °C Cl S
S ð115Þ
O N 83% N
155 156
Ph Ph TBDMSCl Ph TBDMSCl Ph
DBU, CH2Cl2 DBU, CH2Cl2
rt, 1 h R rt, 1 h OH
+
R=H R = OH
S Cl S OTBDMS S S Cl
94%
O
45% 25%
Scheme 27
Cl
Cl O
O O O
H MeS Cl S
O N
O
ð116Þ
CH2Cl2, Et3N O N
O
O Br 20 min, 0 °C O Br
Carbohydrate chemistry also provides a number of examples of substitution reactions being

used to construct -chlorosulfides. Thus, treating the dithioacetal 157 with AcCl gives the
-chlorosulfide 158 as a 1:1 mixture of diastereomers (Equation (117)) <1997JOC1234>. Other
examples include the displacement of acetate from the thiopyranose 159 using chloride (Equation
(118)) <1998T4521> and the use of dichloromethyl methyl ether to convert a thiopyranoside to
the corresponding thioglycosyl chloride (Equation (119)) <2001TL1197>. Finally in what is a
reversal of the commonly used sulfide to sulfone oxidation, catalytic hydrogenation of the sulfone
160a gives the corresponding -chlorosulfide (Equation (120)) <1998JOC9490>.
EtS SEt EtS Cl
H OAc H OAc
AcCl, BF3.Et2O
AcO H 4 h, reflux AcO H
AcO H AcO H ð117Þ
H OAc H OAc
CH2OAc CH2OAc
157 158
AcO AcO
OAc OAc
AcO HCl, AcOH AcO
H S Ac2O, 24 h, 0 °C H S Cl
OAc ð118Þ
AcHN AcHN
CO2Me CO2Me
AcO AcO
159
BnO BnO
Cl2CHOMe,
S S
ZnCl2, 50 °C
BnO OMe BnO Cl ð119Þ
>40%
BnO OBn BnO OBn
O O H2,10% Pd/C
S S
X CH2Cl2 X
ð120Þ
X = Cl, 60%
160a, X = Cl X = Br, 25%
160b, X = Br
(iii) -Bromosulfides—R12CBr(SR2)
The greater reactivity and hence lower stability of -bromosulfides makes them less attractive
than the chloro analogs as synthetic intermediates and in almost all cases necessitates their
immediate use following preparation. Most of the approaches used in the synthesis of -chloro
sulfides have found application in preparing the bromo compounds as well, the main difference
being the involvement of radicals in the majority of the reactions used. Thus, the bromination of
sulfides (Table 14) is one of the most widely used methods of preparing secondary and tertiary
-bromosulfides, with NBS and Br2 being the most commonly used reagents for the purpose.
Table 14 Preparation of -bromosulfides by bromination of sulfides
O
O
S
1 OMe S NBS, pentane, 0 C 70 <1998T10801>
OMe
Br
S NBS, CCl4, 0.5 h,

2 <1995JCS(P1)2845>
S reflux
Br
AcO Br AcO
S Br S
AcO AcO Br NBS, CCl4, 36 h,
3 30 <1996CAR(282)237>
Br reflux, h
AcO OAc AcO OAc
O C6H4-p -Cl O C6H4-p -Cl

N N N N
4 Br Br2, AcOH, h 70 <1995IJC(B)54>
PhS PhS
N S Ph N S Ph
HNPh HNPh
Table 14 (continued)
Ph Ph
N N N N N N
Br
5 O O Br2, AcOH, h 72 <1999IJC(B)218>
Ph N S Ph N S
NPh O NPh O
H H
H O
O N
H
N Br R
N S CO2Et
6 R Br2, AcOH, h 90 <1996IJC(B)373>
N S CO2Et HNPh
HNPh R = H, Ph, Tol
R = H, Ph, Tol
O Br O
Br2, CH2Cl2, 4 h,
7 100 <1996S198>
S Br S reflux
O O
Br2, Et2O, 2 h,
8 91 <1999H(50)259>
10 C to rt
Br
S S
As with NCS, the reactions of NBS are generally regiospecific, giving rise to bromination at the
carbon carrying the more acidic hydrogen or at that carbon which can give the more stable
radical (Table 14, entries 1 and 2). Dehydrohalogenation occurs more readily for -bromo than
for -chlorosulfides and this can result in the formation of product mixtures (Equation (121))
<1995H2701>. The conversion of a thiophene ring to a 2,3-dibromo-2,3-dihydrothiophene using
NBS has also been reported <1997TL6501>. Bromination using Br2 usually involves irradiation,
the reaction being subject to the same considerations as that involving NBS. Thus the regiochem-
istry is determined by the stability of possible intermediate radicals (Table 14, entry 4) and the
final product can be formed by bromination of a sulfide, dehydrobromination and the addition of
Br2 to the vinyl sulfide thus formed (Table 14, entry 7).
EtO2C CO2Et EtO2C CO2Et E t O2C CO2Et E t O2C CO2Et

N NBS, CCl4 N N N
2 h, 25 °C + +
ð121Þ
S O Br S O S O Br S O
hν
35% 38% 8%
The direct addition of Br2 to vinyl sulfides (Equation (122)) <1998JOC3952, 1998ZOR1792,
1995PS(104)5> has also been used to prepare -bromosulfides. The conversion of the unsaturated
sulfoxide 161 to the brominated product 162 using TMSBr is also believed to involve Br2,
(Equation (123)) <2002T10145> which is produced in situ as the sulfur function is reduced.
Examples of the other types of addition reaction by which -bromosulfides could possibly be
constructed, the addition of a sulfide to a vinyl bromide (Equation (124)) <2000T10159> and of
an electrophilic carbon to a 1-bromovinyl thioether (Scheme 28) <1995JOC8283>, have also been
reported. Recent preparations of primary -bromosulfides have been based exclusively on the
addition of a thiol to formaldehyde in the presence of a brominating agent (Equation (125))
<1998JOC7348> (Equation (126)) <1996JFC(79)27>.
Br2, Et2O
S S Br
–78 °C ð122Þ
S 78% S Br
TMSBr, CHCl3 Br
O
4 h, 20 °C
S S
Ph 95% Ph ð123Þ
Br
161 162
SPh BF3.2AcOH SPh

( )n CH2Cl2 ( )n
N
Br ð124Þ
Br N
n = 1, >64%
O n = 1, 2 n = 2, >58% O
O
Br Br Br Br O
N NMe H
N N
NaI
S acetone S O S NMe
N N N
Br Br C6H6, 24 h H
Br O
Br
33% 2/1 exo/endo
Scheme 28
SH (HCHO)n , 49% HBr, SCH2Br

toluene, 40 °C ð125Þ
Cl Cl
i. (HCHO)n, NEt3
F13C6 3 days, rt
F13C6 ð126Þ
SH SCH2Br
ii. PBr3, 40 °C
4h
The displacement of acetate using HBr/AcOH is the standard method of producing thioglyco-
syl bromides. These unstable -bromosulfides are important synthetic intermediates and are
generally used immediately after preparation without purification. The reaction has been used
for both thiopyranoses (Equation (127)) <1997CAR(304)271, 1998HCA2043> and thiofuranoses
(Equation (128)) <1999TL1937, 1999JOC7912>. The displacement of hydroxide from the anome-
ric carbon by bromide has also been reported <1998CAR(308)297>. Finally the reduction of the
sulfone 160b gives the corresponding -bromosulfide (Equation (120)) <1998JOC9490>. This
involved a hydrogen pressure of 30 bar, in contrast to the chlorosulfone which was reduced at
atmospheric pressure.
S 30% HBr, AcOH S

AcO OAc CHCl3, 1 h, 0 °C AcO Br
ð127Þ
61%
AcO OAc AcO OAc
OAc 30% HBr, AcOH Br

S CH2Cl2, 20 min, rt S
F ð128Þ
BzO BzO F
OBz OBz
(iv) -Iodosulfides—R12CI(SR2)
The standard method of preparing primary -iodosulfides involves the displacement of chloride
by iodide in acetone (Equation (129)) <1995T10593>. The reaction has been used to prepare
simple <1998CEJ1480, 2000JOC3460>, steroidal <1997MI567>, and heterocyclic -iodosulfides
<2000BMC2317> in high yield. The reaction of F3CSCu with CH2I2 (Equation (130))
<1996JFC(76)7>, and the CsOH promoted cleavage of the -thioester 163 followed by alkylation
with CH2ClI (Equation (131)) <2001AG(E)1122>, also afford -iodosulfides. The preparation
using NIS of a secondary -iodosulfide 164, formally an -iodoalkyl thioester, has been reported
(Equation (132)) <2000JA7825> and the addition of dichlorocarbene to a 1-iodovinyl thioether
produces a tertiary analog (Equation (109)) <1998SC1667>.
S Cl NaI, acetone S I
30 min, reflux ð129Þ
Cl 96% Cl
CH2I2, 8 h
F3CSCu F3 C F3 C CF3
S I + S S ð130Þ
85–90 °C
45% 44%
SMe i. CsOH.H2O, DMF

Se SMe
Se ii. CH2Cl2 Se Se
CO2Me ð131Þ
Se Se S 62% Se Se S I
163
O O
O I O
H
S NIS, CH2Cl2 H
S
20 °C
TBDMSO EtS O ð132Þ
(CH2)5 EtS (CH2)5
MeO2C
MeO2C
CO2Me CO2Me
164
4.02.2.1.2 Other dicoordinate a-halosulfur derivatives—R2CHal(SX), etc.
(i) -Chloroalkanesulfenyl chlorides—R2CCl(SCl)

The reaction of active methylene compounds with SOCl2 continues to be the standard method of
preparing -chloroalkanesulfenyl chlorides (Equation (133)) <1996BSF903, 1998JOC9840,
1999ACS133, 2002ZN(B)922>. The reaction is believed to involve an intermediate sulfinyl chloride
and can be highly diastereoselective <1999ACS284>, although it may not be possible to separate
the diastereomers. Sulfur dichloride has been used in place of SOCl2 in these reactions
<2002EJO2039>. -Chloroalkanesulfenyl chlorides have also been prepared by the reaction of
Cl2 with thioxocyclobutanes <1999EJO83> and 1,3-diketone disulfides <1996MI895> (Scheme 29).
PCl5 reacts with thioxocyclobutanes in a similar fashion <2002JOC5690>. The reaction of SO2Cl2
with dipropyl disulfide produces an -chloroalkanesulfenyl chloride <1997MI4414>, as does its
reaction with 1,3-dicarbonyl compound derived disulfides and trithiolanes, a 2,2-dichloro- or a
2,2-di(chlorothio)-1,3-dicarbonyl compound being formed as a by-product in some cases
<2002EJO2039> (Scheme 30).
O O
SOCl2, 35 °C Cl
3h SCl ð133Þ
Me Me
60%
Et Et
Cl2, CCl4 Cl
S
10 min, rt SCl
97%
O O
O O
p-MeOC6H4O C6H4-p-OMe
S Cl2, CCl4 Cl SCl
rt p-MeOC6H4O C6H4-p-OMe
S
p-MeOC6H4O C6H4-p-OMe O O
O O
Scheme 29
MeO2C CO2Me
SO2Cl2, CCl4
Cl Cl SCl
S 3 h, rt
S
Cl 93% MeO2C CO2Me
MeO2C CO2Me
SOCl2, CCl4
R S R Cl Cl
3 h, 20 °C ClS Cl ClS SCl
+ +
R S S R R R
R R R R
R = CONHBut, CO2Me
R = CONHBut, 26%, 0%, 57%
R = CO2Me, 47%, 49%, 0%
Scheme 30
(ii) Miscellaneous dicoordinate -halosulfur derivatives—R2CHal(SX)

-Chloroalkanesulfenyl chlorides can be used to construct a range of other dicoordinate -halo
sulfur derivatives. They would be expected to undergo easy substitution with nucleophilic reagents
and thus they react, for example, with thiocarboxylic acids to give acetyl -chloroalkyl disulfides
(Scheme 31) <1996MI895, 1998JOC9840, 1999EJO83, 1999ACS133, 2002EJO2039,
2002JOC5690>. In the same way reaction with thiophenols gives aryl -chloroalkyl disulfides
<2002EJO2039> and with morpholine gives an -chloroalkyl sulfenamide <1996MI895>
(Scheme 32). Although the reaction of the -chloroalkanesulfenyl chloride 165 with sulfinate
anion affords an -chloroalkylsulfanylsulfonyl derivative 166, the result of a simple substitution,
two reduction products, a trithiolane 167 and an -chloroalkyl disulfide 168 are also obtained
O O S
SCl MeC(O)SH S
Cl CCl4, 3 h Cl O
50–60 °C
91%
Cl MeC(O)SH Cl
SCl CCl4, 3 min S S
50–60 °C S S O
ClS
Cl 57% O Cl
Scheme 31
Ph
S
ClS Cl PhSH, CCl4 S Cl
R R 3 h, 50–60 °C R R
O O 75% O O
R = OMe; R = OEt
O
O
ClS Cl
N N
p-XC6H4 C6H4-p-X H S Cl
CCl4, rt p-XC6H4 C6H4-p-X
O O
X = OMe, Br, Cl, F, Me O O
Scheme 32
<2002EJO2039> (Equation (134)), the latter probably arising via a thione intermediate. In
contrast to the behavior of 165, the corresponding N,N0 -di-t-butylmalonamide 169 gives a
trithiolane 171 and an -chloroalkyl disulfide 172, but none of the sulfanylsulfonyl 170 (Equation
(134)). The -chloroalkyl disulfide 168 has also been obtained by the electrochemical reduction of
the -chloroalkanesulfenyl chloride 165, in which case it is formed as the sole product in high
yield (88%) and can be isolated in an analytically pure form without chromatography
<2002EJO2039>.
O O
RC CR
O O
TolSO2Na SO2Tol Cl S
RC CR
ClS Cl Bun4NHSO4 S Cl S
+ + S Cl ð134Þ
H2O, benzene
RC CR RC CR RC S S CR RC CR
O O 5 h, 20 °C O O O O O O
165, R = MeO 166, R = MeO, 40% 167, R = MeO, 17% 168, R = MeO, 28%
169, R = ButNH 170, R = ButNH, 0% 171, R = ButNH, 23% 172, R = ButNH, 65%
Heating 169 at 190 C in the presence of S gives the -chloroalkyl disulfide 172 (39%), together
with 171 (27%) and N,N0 -di-t-butyl-2,2-dichloromalonamide (25%) <2002EJO2039>. -Chloro-
alkyl disulfides have also been prepared by the addition of -chloroalkanesulfenyl chlorides to
thiones <2002JOC5690>, the reaction of N,N0 -di-t-butylmalonamide and bis(2,2,2-trichloroethyl)
malonate with thionyl chloride, and the reaction of a benzoyl -chloroalkyl disulfide with
morpholine <2002EJO2039> (Scheme 33). Although when the -chloroalkanesulfenyl chloride
165 is heated at high temperature with S, it gives, like 169, an -chloroalkyl disulfide, the major
product is -chloroalkyl trisulfide 173, another dicoordinate -halosulfur derivative (Equation
(135)). It is not clear how 173 is formed in this case but it was also obtained in low yield (10%),
together with 165 (58%) and 168 (25%), from the reaction of dimethyl malonate with SOCl2
<2002EJO2039>.
Cl
SCl CH2Cl2, 20 °C O
O + S O S S
Cl O
Cl
O O
RC CR
SOCl2, Pyr Cl S
R R
10 h, 20 °C S Cl
O O RC CR
R = OCH2CCl3, ButNH O O
R = OCH2CCl3, 71%
172, 69%
Bz
S
S Cl Morpholine
MeO2C S S CO2Me
MeOC COMe Et2O
167 + 168 +
O O MeO2C S S CO2Me
28% 33% 26%
Scheme 33
S,190 °C MeO2C S S CO2Me

6h S Cl
165 167 + 168 + Cl
CO2Me CO2Me ð135Þ
20% 15%
173
52%
An -chloroalkyl thiosulfenyl chloride 174 is obtained when the -chloroalkyl trisulfide 173 is
treated with sulfuryl chloride <2000EJO2583> (Equation (136)). The -chloroalkylthiosulfenyl
chloride 175, together with an -chloroalkyl disulfide, is formed in the reaction of thiones with
sulfur dichloride, SCl2 (Equation (137)) <2002JOC5690>. The reaction of these -chloroalkyl
thiosulfenyl chlorides with nucleophiles facilitates the preparation of a further dicoordinate
-halosulfur derivative, an acetyl -chloroalkyl trisulfide 176, and their addition to thiones provides
another route to -chloroalkyl trisulfides <2002JOC5690> (Scheme 34). -Chloroalkyl tetrasul-
fides have also been prepared by the reaction of a 2,2-di(chlorothio) malonate with p-toluenesulfi-
nate anion <2000EJO2583> and the reaction of thiones with disulfur dichloride (S2Cl2)
<2002JOC5690> (Scheme 35).
Cl
S
SO2Cl2
173 165 + S Cl
ð136Þ
RC CR
O O
174
SCl2, 10 min
S S S S
S O CCl4/CH2Cl2 Cl O + O O
Cl Cl Cl ð137Þ
30%
30%
175
S O MeC(O)SH
S S CCl4, 30 min
S S
O S O CH2Cl2, 20 °C 50 °C S O
Cl Cl 175
48% O Cl
81%
176
Scheme 34
There has been little work in this area that involves the other halogens. The reaction of distilled
SCl2 with hexafluoropropene gives an -fluoroalkylsulfenyl chloride in an isolated yield of 65%,
together with smaller amounts of an -fluoroalkylthiosulfenyl chloride, and -fluoroalkyl tri-
and tetrasulfides (Equation (138)) <2001JFC(112)325>. An -bromoalkyl disulfide, which even
at 20 C was only stable for 3–4 days, was obtained by brominating the 1,2-dithiin 177
(Equation (139)) <1996T12677>.
TolSO2Na
Bu4nNHSO4 CO2Me TolO2S SO2Tol
ClS SCl S S
H2O, benzene MeO2C S S Cl
MeOC COMe S S CO2Me + MeOC COMe
Cl
O O 12 h, 20 °C CO2Me O O
31% 40%
MeO2C S S CO2Me
+
MeO2C S S CO2Me
13%
S2Cl2, CH2Cl2 Cl
20 min S S O
S O O S S
55% Cl
Scheme 35
Cl
F SCl2, HF/BF3 S
ClS F S F CF3 CF3
F 12 h, 100 °C
+ + S
F3 C F3 C CF3 F3 C CF3 F3 C S S CF3
F Cl
F
72% 6% 6% ð138Þ
CF3 CF3
+ S S
F3 C S S CF3
F F
Trace
Ph Br Ph
Br2, CCl4
Br
S –5 °C S
S 65% S ð139Þ
Br
Ph Ph Br
177
4.02.2.2 Tricoordinate a-Halosulfur Derivatives—R12CHalS(O)R2, etc.
4.02.2.2.1 a-Halosulfoxides—R12CHalS(O)R2
This functional group is generally assembled from the appropriate sulfide through halogenation
followed by oxidation, or the reverse. A key issue in relation to the oxidation step is preventing
sulfone formation as a result of over-oxidation.
(i) -Fluorosulfoxides—R12CFS(O)R2
The preparation of -fluorosulfoxides has been reviewed <1996CR1641>. The availability of
-fluorosulfides through the chemical or electrochemical fluorination of sulfides and the ease with
which they can be oxidized to the corresponding sulfoxides explains why sulfide oxidation is
currently the standard route to secondary and tertiary -fluorosulfoxides. MCPBA is an almost
universal choice as oxidizing agent and it can be used at temperatures as low as 78 C (Scheme
36) <1995JFC(71)9, 1998JOC1205, 2000BCJ1633, 2001OL593>. There has been one report of the
use of NBS for the oxidation of a primary -fluorosulfide <1999JOC7048>. The oxidation of a
sulfide creates a new chiral center and although the diastereoselectivity of this process for
appropriately substituted secondary and tertiary -fluorosulfides is generally low, it can vary
dramatically depending on the structure of the substrate. Thus oxidation of the syn-isomer 178
(Scheme 37) affords a single sulfoxide, a selectivity that has been attributed to the directing effect
of the hydroxyl group, whereas the anti-isomer 179 gives a 1:1 mixture of diastereomeric
sulfoxides <2002T4759>. The MCPBA oxidation of 180 is also reported to be diastereospecific
<2001JOC7020>.
F MCPBA, CH2Cl2 F
NC Ph 5 min, –20 °C NC Ph
S S
O
p-MeOC6H4 N NH2 p-MeOC6H4 O N NH2

S S
MCPBA, CH2Cl2
O N O N
F N –20 to –10 °C, 3 h F N
N N
85%
OAc OAc
H F MCPBA, CH2Cl2 H F
n-C5H11 –30 °C, 3 h n-C5H11
H SPh H SPh
F F O
Scheme 36
ButS F But( O)S F

MCPBA, CH2Cl2
Ph OMe Ph OMe
–78 °C, 2 h
OH O 90% OH O
178
ButS F MCPBA, CH2Cl2 But( O)S F

Ph OMe –78 °C, 2 h Ph OMe
OH O 98%
OH O
179
F CO2Me F CO2Me
MCPBA, CH2Cl2
S N Ph 20 °C, 15 h N
O S Ph
37%
O O
180
Scheme 37
The selective -fluorination of sulfoxides is also a practical route to this particular functional
group. The electrophilic fluorinating agent, [(1-chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]-
octane bis(tetrafluoroborate)](Selectfluor), is a particularly attractive reagent in this regard
as the required -sulfinyl anion can be readily generated. The regioselective fluorination of
chiral -keto sulfoxides has been reported (Equation (140)) <1997JFC(84)79>, an important
feature of the process being the fact that the sulfinyl stereogenic center is unaffected. The
reaction results in thermodynamic mixtures of diastereomeric -monofluorinated -keto sulfox-
ides. Significant amounts of ,-difluorinated products can be formed with -unsubstituted
-keto sulfoxides (Equation (141)). Treating the -phenylsulfanyl lactone 181 with 2 equiv. of
difluoroiodotoluene results in the fluorooxidation of the sulfide (Equation (142)). The stereochemistry
of the product is the result of diastereospecific fluorination followed by a diastereoselective oxidation
which gives a 5:2 mixture of sulfoxides <2002JCS(P1)2809>. A broadly similar transformation has
been reported for -thioacids, which undergo an electrochemical fluorooxidative decarboxylation
<1998JFC(87)215>. Elemental fluorine has also been used to fluorinate sulfoxides. The reaction of
the cyclopropyl sulfoxide 182 with fluorine, which is believed to occur via a sulfurane derivative, is
slightly stereoselective with the fluorine being introduced preferentially from the side of the phenyl
sulfinyl group, resulting in inversion of configuration (Equation (143)) <1996TL8507>. The use of
fluorine can result in the formation of a sulfone by-product <1996CPB703> and, with a methyl
sulfoxide, in the formation of both mono- and difluorinated products <1995CL581>.
i. NaH, THF
O O 0 °C, 30 min O O
Ph S rt, 1 h Ph S
Tol Tol ð140Þ
ii. Selectfluor
O O F
rt, 0.5 h
67%
i. NaH, THF
O O O O O O
0 °C, 30 min
F S rt, 1 h F S F S ð141Þ
Tol Tol + Tol
ii. Selectfluor, DMF F F F F F
F
rt, 0.5 h
O 2 equiv. difluoroiodotoluene O O Ph
O Ph
rt, 10 h, CH2Cl2
F ð142Þ
41% PhS
PhS
181 O
CO2But CO2But CO2But

5% F2/N2
MeCN, –20 °C O
O + ð143Þ
S F S
Ph S F
Ph O Ph
182 35% 14%
-Fluorosulfoxides have been prepared recently by a small number of other methods (Scheme
38). Thus, the standard thermal- or microwave-assisted Diels–Alder reactions of 1-fluoro-1-
sulfinylalkenes result in the formation of -fluorosulfoxides <2000T3539>. Standard thioenolate
chemistry has been used to elaborate primary and secondary -fluorosulfoxides <1996CR1641,
1998T5557, 2002T4759> and the first enantioselective synthesis of (S)-1-(fluoromethyl)sulfinyl-4-
methylbenzene 183 has also been reported <2001EJO911>.
(ii) -Chlorosulfoxides—R12CClS(O)R2
In general, as with their fluoro analogs, the preparation of most -chlorosulfoxides begins with
the appropriate sulfide and uses a chlorination–oxidation or oxidation–chlorination sequence to
generate the required functional group. The recent literature in this area is dominated by the use
of MCPBA, NCS, and the application of thioenolate chemistry to convert relatively simple
-chlorosulfoxides to more structurally complex derivatives containing the same functional group.
The only reagent now being used for the oxidation of secondary and tertiary -chlorosulfides is
MCPBA, with reactions generally being carried out in CH2Cl2 at low temperature (Scheme 39)
<1996T2349, 1997T7805, 2001T493, 2001T5369, 2002T4217>. The diastereoselectivity of
-chlorosulfide oxidation is generally low, and if chromatography is to be used to obtain a pure
diastereomer, the stability of the -chlorosulfoxides on silica must be considered. A range of
oxidizing agents have been used for primary -chlorosulfoxides, largely because chloromethyl-
phenylsulfide has been used as a convenient and readily available standard for assessing the
performance of new oxidizing agents. This includes two hypervalent iodine systems, periodic acid/
FeCl3 <2002S2484> and the (t-butylperoxy)iodane 184 <1997JOC4253>. Calcium hypochlorite
(Ca(OCl)2) on moist alumina <1997S1161> is reported to be superior in terms of yield and/or
reaction time to reagents used previously for the oxidation of chloromethyl phenyl sulfide and
because its use avoids the SO and CS cleavage, and dichlorination, that can occur with some
oxidants. The Mn(acac)3 catalyzed oxidation of chloromethyl phenyl sulfide using sodium chlorite
(NaClO2) <1996JCS(P1)2693>, and its oxidation with H2O2 in the presence of methyltrioxo-
rhenium <1996BCJ2955> have also been reported.
F Toluene, reflux S(O)Ph F

Ph Cl 10 h, 70% F S(O)Ph
S +
+ Cl Cl
O Cl Microwaves
7 min, 75% Cl Cl
5:1
F i. LDA, THF/hexane
30 min, –78 °C HO
But
S CO2Me F CO2Me
ii. But
O S CO2Me
MeO2C CHO O
THF, hexane
2 h, –78 °C
i. LDA, THF O O NaOMe

O O O
–75 °C MeOH
F Ph S P + F S
Ph Ph OH
Ph ii. O Ph Tol Ph Tol
F
S Omenthyl 183
Tol 98% ee
Scheme 38
O
Ph S Cl Ph S
MCPBA, CH2Cl2 Cl
Ph Ph –50 to –30 °C
Ph Ph
1:1
O
Ph S MCPBA, CH2Cl2 Ph S
Ph 1 h, –50 °C Ph
Cl Cl
91%
Scheme 39
ButOO
I O
184
NCS is the reagent of choice for the -chlorination of all classes of sulfoxide (Scheme 40)
<1995JCS(P1)1397, 1997T7805, 1998JOC4954>. The reaction occurs in high yield at room tem-
perature with CH2Cl2 being the usual solvent. The chlorination of secondary sulfoxides results in
the creation of a second chiral center, and although the diastereoselectivity is generally not high, the
individual diastereomers can be separated, for example, by crystallization <1999AG(E)338>

(Equation (144)). Chlorination with SO2Cl2 has been used occasionally to produce -chlorosulf-
oxides, an example being the chlorination of a silylated 6-hydroxysulfoxide (Equation (145))
<1997TL4407>. SO2Cl2 has been used to convert the ,-unsaturated sulfoxide 185 to an ,-
dichlorosulfoxide (Equation (146)) <2001EJO1643>, and to convert the macrocyclic ,-acetylenic
sulfide 186 to an -chlorosulfoxide in a one-pot reaction (Equation (147)) <1996JOC9385>.
NCS, CH2Cl2
Ph Ph
S rt, 10 h S Cl
O 93% O
Ph O Ph O
S NCS, CCl4 S
rt, 17 h
Cl
ButO 2C CO2But 90% ButO 2C CO2But
3:1
Scheme 40
O O O
NCS, K2CO3
rt Tol Ph + Tol Ph
Tol Ph ð144Þ
Cl Cl
97% ee 97% ee 6.4:1
O i. SO2Cl2, –78 °C O
S OTES S OH ð145Þ
Ph ii. MeOH, HCl Ph
45% Cl
O SO2Cl2, CH2Cl2 O
–78 °C, 10 min S
S TMS
TMS –78 °C to rt, 60 min Cl ð146Þ
79% Cl
185
1.7:1
O
S
S Cl
SO2Cl2, Pyr
CH2Cl2, 20 min
ð147Þ
–78 °C
O O
O O 96%
O O
O O O
O
2:1
186
Oxidative cycloadditions of 2-chloro- and 2,5-dichlorothiophene are also a source of -chlorosulf-

oxides. The BF3-promoted Diels–Alder reaction of thiophene S-monoxide, formed from the latter in
situ by MCPBA oxidation, with the electron-poor dienophile N-phenylmaleimide results in the
selective formation of the endo-adduct 187a (Equation (148)) with the sulfinyl lone pair directed
toward the newly formed alkene bond <1997JOC7926>. It is suggested that the Lewis acid complexes
with the monoxide, making it less nucleophilic and thus less susceptible to oxidation to the sulfone.
However, the same reaction in the absence of BF3 gives a higher yield of adduct, albeit in a longer
reaction time, and no sulfone is formed <1998JCR(S)346>. The biological oxidative dimerization of
2-chlorothiophene, which gives an -chlorosulfoxide (Equation (149)), also involves an S-monoxide
produced in this case by the dioxygenase catalyzed sulfoxidation of the thiophene <2003OBC984>.
BF3.Et2O X O
Ph
MCPBA, CH2Cl2 Y
X S X O N O 2 h, –20 °C S O NPh
+
X = Cl, Y = H Y ð148Þ
Y Y O
18% X
187a, X = Cl, Y = H
187b, X = Br, Y = H
187c, X = Y = Br
X
Pseudomonas putida H
X S UV4 mutant strain
18 h X O S
S ð149Þ
H
O
X = Cl, 18%
X = Br, 15%
X = I, 12%
The addition and substitution reactions of thioenolates generated in the usual way from primary
and secondary -chlorosulfoxides have been used extensively in the last few years to produce
further secondary and tertiary -chlorosulfoxides, respectively (Table 15). Thus the substitution
of -chlorosulfoxides with iodomethane, primary and secondary alkyl halides, and benzyl halides
have all been reported (Table 15, entries 1 and 2), the product being obtained as a mixture of
diastereomers in all cases. ,!-Bis--chlorosulfinyl compounds have been alkylated in the same
way, although a poor yield is obtained for those with a short connecting methylene chain (Table 15,
entries 3 and 4). The addition of -chlorosulfinyl carbanions to carbonyl compounds in general
has been the subject of considerable interest <1995JCS(P1)1397, 1998JOC6200>. The reaction of
the anions from diastereomeric mixtures of 1-chloroalkyl phenyl sulfoxides with symmetrical
carbonyl compounds such as acetone, below 40 C, takes place with complete chiral induction
from the sulfur chiral center and so the reaction of the bis--chlorosulfinyl compound 188 gives
only two diastereomers (Table 15, entry 5). The reaction of the imine 189 with -chlorosulfoxide
190 gives a single diastereomer <2001T3891>, 1,2 and 1,3 chiral induction taking place simulta-
neously. The reaction of chloromethyl phenyl sulfoxide with lactones (Table 15, entry 8) and
esters has also been reported <1997T7843> and again affords a range of more complex
-chlorosulfoxides as diastereomeric mixtures (Table 15, entries 8). (R)-Chloromethyl p-tolylsulf-
oxide has been used as a starting material for these addition and substitution reactions, thus
producing the respective products in chiral form (Equation (150)) <2001T3891>.
O LDA O LDA
NHPh
n-C10H21I PhCH=NPh n-C10H21 Ph
S Cl S Cl
Tol Tol TolS(O) H ð150Þ
99% 93% Cl
n-C10H21
Two diastereomers Single enantiomer
(iii) -Bromosulfoxides—R12CBrS(O)R2
Although there is currently little synthetic interest in -bromosulfoxides, a small number have been
prepared by a variety of diverse methods. The addition of Br2 to a range of vinyl sulfoxides, for
example, gives -bromosulfoxides, in some cases accompanied by a variety of by-products
(Equation (151)) <1999ZOR1785>. Surprisingly, the AgNO3-assisted bromination of the sulfoxide
191 (Equation (152)) is the only example of a sulfoxide to -bromosulfoxide transformation
reported recently <2000CEJ3359>. In keeping with the behavior of the corresponding chloro
compounds, the oxidative addition of 2,5-di- and 2,3,4,5-tetrabromothiophenes to N-phenylmalei-
mide gives the polycyclic -bromosulfoxides 187b (42%) and 187c (45%) (Equation (148)), respect-
ively, no BF3 being used in these cases <1998JCR(S)346>. The biological oxidative dimerization of
1-bromothiophene (Equation (149)) <2003OBC984> also parallels that of the analogous chloro
compound. -Sulfinyl carbanions feature in a number of reactions that have been used to produce
-bromosulfoxides. Thus the -sulfinyl carbanion derived from bromomethyl phenyl sulfoxide has
Table 15 Preparation of primary and secondary -chlorosulfoxides using thioenolate chemistry
O O
S S LDA, HMPA/THF,
Tol Tol
1 Cl n-C10H21 n-C10H21I 95 <2001T493>
Cl 2 h, 60 to 25 C
O O
Ph S Ph S i. LDA, THF, 65 C,
Tol Tol 10 min
2 Bn Cl 100 <1996T2349>
Cl ii. BnBr, THF,
65 to 35 C, 2 h
O O Cl
Cl Pri
S Ph S Ph LDA, HMPA/THF,
3 Ph S Ph S PriI 71 <2001T493>
Cl Pri Cl O 4.7 h, 50 C
O
O O O O LDA, HMPA/THF,
4 S S S S MeI 13 <2001T493>
Ph Ph Ph Ph 3 h, 78 to 50 C
Cl Cl Cl Cl
OH
O Cl
S Tol
Tol S
Cl O
OH
a Cl O
Tol S LDA, THF, acetone,
S Tol a: 49
5 10 min, <2002T4217>
HO b: 29
O
O Cl 60 C
Cl 188
S
Tol S Tol
Cl O
OH
O
S Et
Tol OH
Cl
H Bun
O
a S Et
Tol LDA, THF, pentanal,
a: 38
6 10 min <1998JOC4954>
Cl b: 45
O 78 C
S Et
Tol OH
Cl
n
Bu H
b
Cl
PhCH=NC6H4-p-OMe
Tol
n-C10H21 NHC6H4-p -OMe S n-C10H21 189
LDA, THF, 30 min,
7 TolS(O) Ph O 78 <2000T4415>
–78 °C
Cl H
190
OH O
8 Ph O O 94 <1998TL9215>
Ph O S Cl
S(O)Ph Ph LDA, THF,
Cl –78 °C
been added to the carbonyl group in cyclopentadecanone to give a secondary -bromosulfoxide

(Equation (153)) <1998T5557>. The -sulfinyl carbanion from sulfoxide 192 reacts in an unusual
way with 193 as the formation of the -bromosulfoxide 194 is competitive with the conjugate
addition that initiates the formation of the chrysanthemate precursor 195 (Equation (154))
<1999JCS(P1)3403>. The selective 1,4-addition of allylmalonate anion to -bromovinyl phenyl
sulfoxide also produces a secondary -bromosulfoxide (70%) <1997T7805>.
Br
Et Cl Br2, CCl4
Et Cl
S 50 °C S Et S O
Br + S Et + BrHC CCl2 + ð151Þ
O Cl O Cl
4% BrCl2C H
5%
36% 25%
Br2, AgNO3
O Pyr, MeCN O
S 60 min, –40 °C S ð152Þ
p-ClC6H4 Ph p-ClC6H4 Ph
191 44% Br
i. LDA, THF
O –78 °C, 10 min OH
O + O ð153Þ
S Br
Ph ii. THF, –78 °C
S
10 min
Br Ph
i. LDA, THF O O
O
–78 °C, 5 min S S
S Tol TMS Tol
Tol TMS +
ii. CO2Et Br CO2Et ð154Þ
192 Br TMS
24% 64%
193 194 195
THF, –105 °C
(iv) -Iodosulfoxides—R12CIS(O)R2
Only three new -iodosulfoxides have been reported in the last 9 years. They were formed by the
reaction of vinyl p-tolyl sulfoxide with NIS in aqueous DMSO giving 2-iodo-2-(toluene-
4-sulfinyl)ethanol in 96% yield as a 6:1 mixture of diastereomers which were inseparable by
chromatography <1997JOC6326>, the iodination of an -sulfinyl carbanion giving an unstable
-iodosulfoxide (Equation (155)) <1998HCA1048>, and the biological oxidative dimerization of
2-iodothiophene (Equation (149)) <2003OBC984>.
i. LiHMDS, THF/hexane
O O
–78 °C, 30 min
S CO2Et ii. I2, –78 °C, 30 min S CO2Et ð155Þ
Tol Tol
52% I
6:4
4.02.2.2.2 Other tricoordinate a-halosulfur derivatives—R12CHalS(O)X

The oxidative fragmentation of a -silyl sulfoxide produces an unstable sulfinyl chloride 196
whose formation can be confirmed spectroscopically and which can be converted to the sulfinate
197 by reaction with 3-phenylpropanol (Equation (156)) <2001EJO1643>. The formation of an
N-thiazolyl sulfinamide by the addition of chloroacetate to an N-sulphinylamine (Equation (157))
<1995JIC525> has also been reported. Surprisingly, it has been found that the reaction of certain
very hindered alcohols with methanesulfonyl chloride (Equation (158)) <2000SL1354> gives not
only the expected mesylate but also a chloromethanesulfinate, the latter on occasions actually
being the major product. The addition of benzyltriethylammonium chloride improves the yield of
the sulfinate further. The reaction is believed to involve a sulfene intermediate formed by the
elimination of HCl from methanesulfonyl chloride under the basic conditions. A similar result has
been reported for chloromethanesulfonyl chloride <1998T21>.
SO2Cl2, CH2Cl2 PhCH2CH2CH2OH
O i. –78 °C, 10 min K2CO3, 3 h Cl O
Cl O
S ii. –78 °C to rt, 1 h –78 to 20 °C
S S
TMS Cl O Ph
27%
Cl Cl
196 197
ð156Þ
ClCH2CO2Et
Et3N, C6H6 N O
N
O 3 h, reflux ð157Þ
S S CO2Et
S N S N
74% H
Cl
H H H
OH OSO2Me OS(O)CH2Cl
+ ð158Þ
MeSO2Cl, Pyr, DMAP: 1:1, 78%

MeSO2Cl, Pyr, DMAP, 1 equiv., BnEt3N+Cl–: 1:9, 72%
4.02.2.3 Tetracoordinate a-Halosulfur Derivatives—R12CHalS(O)2R2, etc.
4.02.2.3.1 a-Halosulfones—R12CHalS(O)2R2
(i) -Fluorosulfones—R12CFS(O)2R2
The preparation of -fluorosulfones has been reviewed <1996CR1641>. Selective mono--fluor-
ination (Table 16) is currently the most widely used method of producing -fluorosulfones, and
given the acidity of a sulfones’s hydrogens it is not surprising that this is usually accomplished
using electrophilic fluorinating agents such as Selectfluor <1996JA2519>, N-fluorobenzenesulfoni-
mide <2000CPB1484> or N-fluoro-o-benzenesulfonimide <1995JOC4730>. The yields obtained
are generally good (Table 16, entries 1–4). The regiochemistry of the process is determined at the
deprotonation step with bases such as NaHMDS delivering the kinetically controlled product
(Table 16, entry 2). The stereochemistry of the process, in the few reported examples where it is
relevant, is dependent on the structure of the substrate (Table 16, entries 2 and 3). Elemental
fluorine has been used to convert both sulfoxides and sulfones to -fluorosulfones (Table 16, entries
5 and 6). The fluorination of -sulfonyl esters is catalyzed by metal salts (Table 16, entry 6), an effect
that has been attributed to the ability of the cation to accelerate enolate formation <1998JF(92)45>.
The yields obtained are modest with ,-difluorinated sulfones, and in the case of sulfoxides some
unfluorinated sulfones being obtained in varying amounts as by-products. The product distribution
obtained on fluorooxidation of the sulfoxide 198 indicates that fluorination occurs preferentially with
inversion of configuration (Equation (159)) <1998TL4687>. The oxidation of -fluorosulfides
<2001JOC7030, 2001TL4861> and sulfoxides <2002JCS(P1)2816> with MCPBA, and of -fluoro-
sulfides with CrO3 <2001CC2428>, have also been used to prepare -fluorosulfones (Scheme 41).
The yields with simple substrates are generally good but the use of CrO3 would clearly not be
compatible with many functional groups. Treating the -fluoro--hydroxy sulfoxide 199 with
SO2Cl2 resulted in the oxidation of the sulfoxide as well as the chlorination of the alcohol (Equation
(160)) <2002T4759>.
Table 16 Preparation of -fluorosulfones by selective fluorination
i. NaHMDS, THF
O O 10 min, 78 C;
S CO2Me O O 30 min, 78 to 0 C
1 Ph S CO2Me 88 <1995JOC4730>
Ph ii. N-fluoro-o-
F benzenesulfonimide
0 C, 2 h
H
H
TBDMSO i. NaHMDS, THF,

TBDMSO
2 H
H
HMPA, 78 C 51 <1996TL6753>
ii. (PhSO2)2NF
S O
S O
1/3 cis/trans
O
F O
Pr n Pr n i. BunLi, THF
PhSO2 PhSO2 ii. N-fluoro-
3 F N C6H4-p -F 70 <2000BMCL1443>
N C6H4-p -F benzenesulfonimide,
78 to 20 C
N CO2Et
N F CO2Et
SO2
SO2 KH, Selectfluor,
N
4 N THF 88 <2000JOC4169>
0–20 C
F
Ph CO2Et
S
O O
a Ph CO2Et
S
a: 50
5 O F2, MeCN, 20 C <1995CL581>
b: 19
F F
Ph CO2Et
S
O O
S COMe
O O i. NaH, MeCN, 1 h,
S COMe a: 45
5 C,
a O O b: 5
6 ii. F2, 4 h, 5 C <1998JFC(92)45>
Cu(NO3)22.5H2O,
4 h, 5 C
F F
S COMe
O O
b
F2, MeCN Cl O Cl O
Cl O
–20 °C +
F F
NAc NAc NAc
PhS(O) PhS(O)2 PhS(O)2
2:1 36% 22%
198 ð159Þ
Cl O Cl O
+ F +
NAc NAc
PhS(O)2 PhS(O)2
10% 10%
Ph F MCPBA, CH2Cl2 O F
S 1 h, 0 °C Ph S
O N O N
O Bun O Bun
O O
2.4 equiv. MCPBA
O O CH2Cl2, 20 °C O O O
Ph
SPh 79% S
O
F F
F F F F O
Ph
CrO3, AcOH S
SPh 3 h, reflux
O
F3 C F F3 C F
74%
Scheme 41
Ph Ph
SO2Cl2, CH2Cl2 O
F S O F S
Ph 2 h, 20 °C Ph O
CO2Me ð160Þ
CO2Me
OH 59% Cl
1:1
199
Fluorovinyl sulfones can be transformed into cyclic -fluorosulfones through thermal-

<1996TL8237, 1997T17127> and microwave-assisted <1998TL6529> Diels–Alder reactions,
although the vinyl sulfone 200 gives an -fluoro sulfone with Danishefsky’s diene 201 which is
the result of conjugate addition rather than [4+2]-cycloaddition (Scheme 42). The 1,3-dipolar
cycloaddition of fluorovinyl sulfones with N-oxides <1997BSB677> also generates cyclic
-fluorosulfones, and although the reaction of N-oxide 202 with fluorovinyl sulfone 203 is
regiospecific, a mixture of regioisomers is generally obtained (Equation (161)). Fluoromethyl
phenyl sulfone, an important reagent for the introduction of a fluoromethyl group, has been
prepared by the Darzens condensation of benzaldehyde with 204a under PTC conditions and
by reduction of 204b with Zn (Scheme 43) <2001JOC643>. The chemistry of the anions
derived from -fluorosulfones has been reviewed <1996CR1641>. More complicated -fluoro-
sulfones have been built up by adding the fluoromethyl sulfinyl carbanion derived from
fluoromethyl phenyl sulfone to ketones <2001CPB312>. The radical dephosphonylation of
the -(phenylsulfonyl)phosphonate 205 gives -fluorobenzyl phenyl sulfone (Equation (162))
<2002JOC3065>.
O O F F F
S +
Ph
MeCN, 3 days S(O)2Ph F
F rt F Ph(O)2S
1.4:1
Ph
O Ph
O O F Cl
S Ph F
Ph Cl O
Microwaves, 4 min F
F
92% S(O)2Ph
Ph
Two isomers
OMe
CONEt2 F
CONEt2
O TMSO OMe O O O
201 S(O)2Ph
S
F Ph 72 h, 150 °C
O toluene, 8 h O
F 66%
S(O)2Ph 100 °C, 57% CONEt2
200
Scheme 42
Ph +
N Ph
Ph
O O O
S – N Ph
Ph F 202 O ð161Þ
F Toluene, reflux F
27 h, 51% F S(O)2Ph
203
Ph +
N Ph
Ph
O O O
S – N Ph
Ph F 202 O
F Toluene, reflux F
27 h, 51% F S(O)2Ph
203
PhCHO
Zn, MeOH 50% NaOH
O O O O O O BnEt3N+F– O O O O
reflux, 16 h S +
S + S S S Ph
Ph CClFH Ph CH2F Ph CClFX Ph CH2F Ph
4 h, 20 °C
204a, X = H 15% 15%
76%
16% 204b, X = Cl
Scheme 43
Bu3nSnCl, AIBN
F Ph polymethylhydrosiloxane F
Ph i KF, toluene, H2O, reflux
S P(O)(OPr ) 2 Ph ð162Þ
S Ph
O O 60% O O
205
(ii) -Chlorosulfones—R12CClS(O)2R2
The preparation of -chlorosulfones from the appropriate sulfide using NCS followed by
MCPBA remains the most widely used method of preparing this functional group. The oxidation
step simply involves stirring the -chlorosulfide with 2–3 equiv. of MCPBA in CH2Cl2 at room
temperature (Table 17, entries 1–4). In many cases this sulfide to -chlorosulfone transformation
is carried out as an effective one-pot procedure with no attempt being made to characterize the
intermediate -chlorosulfide (Equation (163)) <2000JOC8367, 2002OL3047>. It has been
reported that 10/11-membered ring sulfides give low yields with by-products that are possibly
unsaturated sulfones being formed <2000JOC8367>. -Chlorosulfones have also been prepared
from -chlorosulfoxides using MCPBA (Table 17, entry 5 and 6) and an extensive range of other
oxidants which includes KHSO5 <1997T7805>, KMnO4 <1997T7805>, peracetic acid
Table 17 Preparation of -chlorosulfones by oxidation of -chlorosulfides and -chlorosulfoxides

using MCPBA
O
S N CO2 But S N CO2 But MCPBA,
1 O CH2Cl2, 58 <2000CJC1060>
Cl
18 h, 20 C
Cl
O O
S Cl S Cl
BnO BnO
2 BnO OBn MCPBA <2001TL1197>

BnO OBn
OBn OBn
Cl Cl
H H
X O X
S S
Y O Y MCPBA, 64
3 H H <1998TL5459>
CH2Cl2 84
X = Y = Cl
X = Y = Br
X = Br, Y = Cl
Cl Cl
SO2Ph SPh 2.2 equiv.
MCPBA,
4 EtO2C N O EtO2C N O 85 <1998JCS(P1)3689>
CH2Cl2,
18 h, rt
Cl Cl
Ph Ph 1 equiv.
5 S S MCPBA, 85 <1997T7805>
CO2Et O O CO2Et O CH2Cl2, rt
Cl Cl
Si O Si
S O
MCPBA,
S
6 O
CH2Cl2, >90 <1998S665>
Si Si 0 C, 10 h
<1996JOC9385>, H2O2/Ac2O <1996ZOR1709>, CrO3 <1997AJC683>, F2 <1996CPB703>,

H2O2/MeReO3 <1996BCJ2955>, and H5IO6/[Mn(IV)-Mn(IV)(-O)3(1,4,7-trimethyl-1,4,7-triaza-
cyclononane)2](PF6)2 <1998TL7055> which is claimed to give selective oxidation in the presence
of other easily oxidizable groups.
ButO 2C ButO 2C
N i. NCS, CCl4 N
3 h, reflux
ð163Þ
ii. 2.6 equiv. MCPBA
S CH2Cl2, 18 h, reflux S
O O Cl
The various combinations by which -chlorosulfones can be produced from sulfides by the
alternative oxidation–chlorination sequence are less convenient than the NCS/MCPBA
approach and so this route is less frequently used. The -chlorination of sulfones involves the
initial generation of an -sulfonyl anion which then interacts with the chlorinating agent. NCS/
NaHCO3 is one of the most frequently used combinations for achieving this transformation
(Equation (164)) <2000JOC7203>. The stereochemistry of the reaction of 206 is subject to
steric control, with chlorination occurring preferentially from the less hindered side of the
azetidinone ring, trans to the Ph group. Radical chlorination of sulfones using NCS/AIBN is
also possible <1996T6903>. The use of ButOCl with the sulfone 207 results in the formation of
a dichlorosulfone as the major product (Equation (165)) <1998JOC2086>. Carbon tetrachlo-
ride and other perchlorinated hydrocarbons have also been used as chlorinating agents under
basic conditions. The reaction involves a single electron transfer (SET) from the -sulfonyl
carbanion to the chloroalkane giving a radical anion/radical pair, with transfer of a chlorine
atom completing the formation of the -chlorosulfone (Scheme 44) <1995PJC1422,
1996TL7457, 2003JOC500>.
NCS, NaHCO3
O Bz MeCN, H2O O Bz O Bz
N N Ph
3 h, 40 °C O S N
Cl +
ð164Þ
Ph S Ph 69% Ph S O
Ph Ph
O O Cl
O O
67:33
206
TMS i. BunLi, THF/hexane TMS TMS

–78 °C to rt
O O ii. ButOCl, –78 °C to rt O O
+ O O ð165Þ
S S
Tol S
Tol Tol
207 Cl Cl Cl
21% 41%
Carbanions from aryl -chloroalkyl and any other sulfones that cannot undergo the
Ramberg–Backlund reaction react with the usual range of electrophilic partners. Thus the
carbanion from chloromethyl phenyl sulfone reacts with alkyl halides <2002CPB463>,
ketones <2002TL2285> (Scheme 45), and iminium salts <2001IZV2136>, and that from
chloromethyl styryl sulfone with acrylonitrile and benzaldehyde <1997LA2337> (Scheme 46).
Interestingly, it has now been reported that chloromethyl methyl sulfone can be efficiently
(98%) added to benzaldehyde at 78 C, the addition occurring faster than the Ramberg–
Backlund reaction <2003TL1473>. The reaction of dichloromethyl phenyl sulfone with
ketones under SET conditions also gives a secondary -chloroalkyl sulfone (Equation (166))
<2001SC47>.
Cl3CCCl3, TBABr
O O 50% NaOH, O O
S 1.5 h, CH2Cl2 S
Ph Ph
77% Cl
CCl4, KOH O O
O O
S ButOH, 30 min S
Ph reflux Ph Cl
100%
CO2But CO2But
NH LDA, Cl3CCCl3 Cl NH
O S THF, –78 °C O S
OH OH
O 71% O
67:33
Scheme 44
i. NaH, DMF O
O O 15 min, 0 °C O O O O OH
S Cl S Cl S
Ph Ph LDA, THF Ph
ii. I
–78 °C Cl
DMF, 2 h, 0 °C
30%
Scheme 45
CN
O O PhCHO, ButOK
BnEt3N+Cl–, 50% NaOH
S Cl THF, 15 min O O O O
Ph MeCN, 1 h, 0 °C
–70 °C S Cl S Cl
Ph Ph
Ph OH 68% 38%
NC CN
Scheme 46
O O O Sm, SmI2, CrCl3

O O
S Cl THF, 2.5 h, 20 to 40 °C
Ph S ð166Þ
+ Ph
Cl 62% OH
Cl
Chloromethyl phenyl and related sulfones undergo vicarious nucleophilic substitution with
aromatic systems containing an electron withdrawing group, the process resulting in the loss of
the -Cl. However, if the aromatic system contains an alternative leaving group (Scheme 47)
<1995T7277, 1995T8339, 1996JHC1567, 2002EJO1412>, or if a dichloromethyl aryl sulfone is
used (Equation (167)) <1995PJC918, 2001PJC1465>, the product of the reaction is a secondary
-chloroalkyl sulfone. Chloromethyl tolyl sulfone reacts with pyridazinium methylides to give
mixtures of secondary -chloroalkyl sulfones and the products of vicarious nucleophilic substitu-
tion as a result of its disproportionation to dichloromethyl tolyl sulfone and methyl tolyl sulfone
under the reaction conditions <1998JCS(P1)1637>. The formation of the -chloroalkyl sulfone
208 involves the initial addition of an -chlorosulfonyl carbanion to the carbonyl group of
1-methoxyanthraquinone to give an oxirane, rearrangement of which to an anthracenyl ketone
followed by displacement of phenylsulfonyl anion by another -chlorosulfonyl carbanion gives
the observed product (Equation (168)) <1998T6147>.
O O Cl
Br S Cl SO2Ph
Ph
tOK
Bu
S NO2 S NO2
62%
O O
S Cl
N Ph N
N KOH, DMSO/Et2O N
1 h, rt PhO2S
NC N Ph N Ph
68%
Cl
Scheme 47
O O Cl SO2Tol
S Cl
Tol
O2N N O2N N
Cl
N N ð167Þ
N ButOK, DMF N
12 min, –30 °C
39%
O O
2 equiv. S Cl
O OMe Ph O OMe
ButOK, DMSO
1 h, 20 °C
61% ð168Þ
O PhO2S
O
Cl
208
-Chloroalkyl sulfones have also been produced by a variety of cycloaddition reactions. These
include the addition of SO2 to a 1-chlorodiene in a sealed tube (Equation (169)) <1998JOC9490>, the
Diels–Alder reactions of sulfenes derived from -chloroalkylsulfonyl chlorides (Equation (170))
<1995LA2151> and those of tetrachlorothiophene dioxide <2000EJO743> for which monoclonal
antibody catalysis has been reported <2002CJC657>. Other processes used to prepare -chloroalkyl
sulfones include the fluoride-induced dechlorotrimethylsilylation of 209 via an o-quinodimethane
intermediate (Equation (171)) <1998JOC2086>, the preparation of chloromethyl phenyl sulfone by
the diphenyl selenide catalyzed reduction of chlorobromomethyl phenyl sulfone using NaBH4
<1997TL5651>, and the addition of chloromethanesulfonyl halides to strained -bonds in bicy-
clo[4.1.0.02,7]heptanes <1996ZOR1701, 1999ZOR1189> (Scheme 48).
X SO2, 12 h X
50 °C O
S ð169Þ
O
X = Cl, 13%
X = Br, 11%
O O
S Cl
Cl O
NEt3, MeCN S ð170Þ
O
–40 °C, 48% Cl
TMS TBAF, MeCN

0 °C, 45 min
O O rt, 15 min
S Tol ð171Þ
Tol 51% S
Cl O O
Cl Cl
209
O O O O SO2CH2Cl
SO2CH2X H
S X S Cl
Br Cl
H H H H H H
CaCO3, CH2Cl2 hν, CH2Cl2
R Br R R Cl
14 h, 0 °C 9 h, 20 °C
R = Ph, X = Cl, 69% R=H
R = Ph, X = Br, 30%
Scheme 48
(iii) -Bromosulfones—R12CBrS(O)2R2
Although the methods used to prepare -bromosulfones closely parallel those used to prepare
-chlorosulfones, there are differences in the approach adopted. Thus the halogenation/MCPBA
combination which is the method of choice of preparing -chlorosulfones has not been used at all
since 1995 for constructing -bromosulfones. Instead, the standard method for the bromo
compounds is the reverse oxidation/bromination procedure. However, as for -chlorosulfones,
the approach employed for brominating sulfones generally involves the use of base and a source
of electrophilic bromine: NBS/Et3N <2000BMCL847> (Equation (172)), NBS/NaHCO3 (Scheme
49) <2000JOC7203, 2002MI1015>, Br2/BunLi <1998JOC2086, 2003JOC500>, and Br2/LDA
(Equation (173)) <1996TL7457>. The bromination of aryl isopropyl sulfones in the presence of
O2 is complicated by the fact that oxidative cleavage of the sulfonyl carbanion competes with
bromination, leading to the formation of arenesulfonyl alcohols, bromoarenes, and arenesulfonyl
bromides, the composition of the product mixture depending on when the Br2 is introduced, the
amount used and when the final work-up is carried out <2003JOC500>. Although in general
these methods give mixtures of diastereomers (Equation (173)), the use of NBS/Et3N results in the
stereospecific bromination of the cephalosporin 210 (Equation (172)), and the stereochemical
outcome for the azetidinone 211 (Scheme 39) is dependent on the nature of the N-substituent. A
,-unsaturated sulfone has been brominated using Br2 alone <2000PS(167)133>, an example of
radical allylic bromination. The use of CBr4 (Equation (174)) <1997TL5651>, CBr2F2
<2001CC81, 2002EJO1305>, and CBrCl3 <2003JOC500> as brominating agents under basic
conditions has also been reported. Although the use of any of these reagents with dialkyl sulfones
can occasionally result in isolable -bromosulfones (Equation (175)) <1998TL8179>, the princi-
pal product is usually that resulting from a subsequent Ramberg–Backlund reaction <2001CC81,
2002EJO1305>. Cyanogen bromide is a little used alternative to NBS but it has been employed
for the regio- and stereoselective bromination of the cephalosporin 212 (Equation (176))
<1997SC3395, 1998T6565>.
O O O O
N H N H
S S Br
NBS, NEt3 ð172Þ
N N
O O
CO2CHPh2 CO2CHPh2
210
NBS or NIS, NaHCO3

O t-BOC NBS or NIS, NaHCO3 O R O Bz
Ph MeCN, H2O N
O S N MeCN, H2O N
X
3 h, 40 °C 40 °C
O Ph S Ph S Ph
X Ph Ph
R = t-BOC O R = Bz O
O O
X = Br, 81% 211 X = Br, (trans ): 50%; (cis ): 14%
X = I, 84% X = I, (trans ): 71%; (cis ): 0%
Scheme 49
H H
LDA, Br2 Br Nt-BOC
Nt-BOC
THF, –78 °C
O O ð173Þ
S S
OH 63% OH
O O
67:33
SO2Ph CBr4, BunLi SO2Ph

–78 °C Br
ð174Þ
36% Br
SO2Ph SO2Ph
42:58
Bn CBr2CF2, KOH/Al2O3 Bn Br
Ph CH2Cl2, ButOH Ph
Bn SO2 5 °C Bn SO2
ð175Þ
52%
Bn Bn Bn Bn
1:1
O O
O O CNBr, NEt3
PhO H PhO O O
N S CH2Cl2 N H
S Br
1 h, rt
N
ð176Þ
N
O O
CO2Me CO2Me
212
The behavior of -bromosulfonyl carbanions is entirely consistent with that of their chloro
analogs. Thus primary and secondary -bromosulfones which cannot participate in the Ramberg–
Backlund reaction have been converted to anions that undergo 1,2-addition to ketones
<2002TL2285>, aldehydes <2002TL2285> and iminium salts <2001IZV2136>, and Michael
addition to ,-unsaturated aldehydes <2002TL2285>, giving mixtures of diastereomeric pro-
ducts with unsymmetrical substrates. 1,2-Addition products have also been obtained under
radical conditions using the SmI2 promoted reaction of p-tolyl dibromomethyl sulfone with
cyclopentanone (Equation (177)) <2001SC47>. These -bromosulfonyl carbanions have also
been alkylated using alkyl halides <1997TL5651>. A particularly convenient one-pot alkylation
bromination protocol has been developed for the synthesis of tertiary -bromosulfones such as
213 (Equation (178)) <1998JOC2086>. Although standard vicarious nucleophilic substitution
with -bromomethyl aryl sulfones involves the loss of Br, the presence of an alternative leaving
group in the electrophilic partner allows the Br to be retained and results in the formation of
secondary -bromosulfones <2002EJO1412>.
O O O SmI2, THF O O
S Br 2.5 h, 20 to 45 °C S
Tol + Tol ð177Þ
OH
Br 50% Br
TMS i. BunLi, BunBr TMS

ii. BunLi, 2 equiv. Br2
O O O O
S 72% S ð178Þ
Tol Tol
Bun Br
213
-Bromovinyl sulfones are efficient Michael acceptors and the addition of C- (Scheme 50)
<1997T7805>, N- (Equation (179)) <1995TL7767, 1997SL1043>, O- (Scheme 50)
<1997TL1995>, and S-nucleophiles (Equation (180)) <1997SL1043> results in the formation
of a diverse range of -bromosulfones. A mixture of products may be obtained if the initially
formed -bromosulfone can undergo the Ramberg–Backlund reaction <1997SL1043>. Interest-
ingly, this approach has not been used to prepare -chlorosulfones in the period covered by this
review. A number of stereogenic reactions of this type are diastereospecific (Equation (179))
<1995TL7767> including the stereospecific syn addition of hydroxylamines to 214, a result that
is consistent with a concerted mechanism (Equation (181)) <2001TL8251>. A very modest de
value is obtained in the reaction of (S)-1-phenylethylamine with benzyl -bromovinyl sulfone
<1997SL1043>. The Michael-type addition of oxyradicals to the -bromovinyl sulfone 215 also
gives an -bromosulfone, the addition being stereospecific with respect to the -substituent
(Equation (182)) <1999JFC(99)73>.
MeO2 C CO2Me PhCH2OH

i. NaH, THF O O 6 M NaOH
O O
S Bu4nNBr, C6H6 O O O Ph
S CO2Me 0 °C, 30 min S
Ph Ph
Ph
Br CO2Me ii. THF, 0 °C Br 80%
Br
83%
Scheme 50
Conc. aq. NH3 NH2

AcO AcO
dioxane, 3 h, rt ð179Þ
S Br S Br
O O 87% O O
PriSH, ButOK
O O O O
ButOH
Ph S Ph S Ph SPri ð180Þ
SPri +
Br Br 65%, 72/28 (E )/(Z )
24%
Br BnNHOH.HCl H OH
Br
Ph Et3N, EtOH, 12 h, rt Ph NBn
S S ð181Þ
O O Ph 83% O O H Ph
214
F F F
PriOH, (BzO)2 OH OH
1 h, 110 °C ð182Þ
Br +
S S Br S Br
O O O O O O
215 60% 10%
The addition of Br2 to ,-unsaturated sulfones has also been a source of -bromosulfones.
The reaction can be carried out thermally (Equation (183)) <1995JPR363, 1995TL7767,
1998ZOR1792, 2001KGS840> or photochemically (Equation (184)) <1999JFC(99)73>. In
many cases the stereochemistry of the product has not been determined as it is used immediately
in processes which involve the loss of any stereochemical elements. Secondary dehydrobromina-
tion products may be formed <1995JPR363>. The addition of bromomethanesulfonyl bromide
to strained -bonds in bicyclo[4.1.0.02,7]heptanes (Scheme 48) <1999ZOR1189> and related
reactions <1996ZOR1709, 1998ZOR1190> also produce -bromosulfones, as does the addition
of SO2 to 1-bromo-1,4-butadiene (Equation (169)) <1998JOC9490>. The reductive monodebro-
mination of ,-dibromosulfones using NaOH/CHCl3 <2003JOC500> and NaBH4/(PhSe)2
<1997TL5651> has also been reported.
C6H4-p-NO2 C6H4-p-NO2
Br2, CH2Cl2
Br
2 h, rt Ph ð183Þ
Ph
S Br S
O O O O
F F Br
Br2, CCl4
12 h, hν ð184Þ
S Br
S
O O 72% O O
(iv) -Iodosulfones—R12CIS(O)2R2
The methods described previously for -chloro- and -bromosulfones can, in general, be used in
the preparation of -iodosulfones. Thus NIS/NaHCO3 has been used in the kinetically controlled,
highly stereoselective, iodination of the azetidinone 211 (Scheme 49) <2000JOC7203> and the
-iodosulfonyl carbanion derived from phenyl iodomethyl sulfone has been alkylated with alkyl
halides <1997TL879> and added to ketones <2002TL2285>. I2/BunLi can also be used to
introduce iodine, with the sulfone 216 undergoing iodination via an alanate to give predominantly
the iodoethyl product (Equation (185)) <1997JCS(P1)323>. Alkyl mercuric halides add to vinyl
sulfones to give an -mercuric halide from which the mercury can be displaced using I2 (Scheme
51) <1995JA3952>. The addition of NaI is reported to result in the faster initiation of the
reaction.
i. BunLi, 0 °C
O O 30 min, THF/hexane O O O O
S S S ð185Þ
ii. Et3Al, I2, +
216 30 min, 41% I I
Major product
C6H6/DMSO
HgCl I
Ph 40 to 45 °C, hν I2
S R Ph R Ph
S S
O O RHgCl, 24 h O O O O
R = Pri, 46%
R = cyclohexyl, 37%
Scheme 51
4.02.2.3.2 Other tetracoordinate a-halosulfur derivatives—R12CHalS(O)2R2

A very wide variety of -halomethanesulfonamides and methanesulfonates have been prepared
using chloromethanesulfonyl chloride, whose preparation from 1,3,5-trithiane using KOCl in
aqueous HCl has been reported <1997AJC1027>, and bromomethanesulfonyl bromide. Primary
and secondary -halomethanesulfonamides have been prepared from the corresponding amines
using DMAP in the presence of Pri2EtN (Equation (186)) <1999JOC9225, 2000JOC7119>.

Preventing bis-sulfonylation can be a problem with some primary amines and it is reported that
bis-sulfonylation followed by monodesulfonylation is a convenient method of obtaining the
monosulfonylated product in such cases <2001T5009> (Scheme 52). Monosulfonylated amines
have been converted to the bis-product using DMAP/Pri2EtN <2001JOC3564>. These -halo-
methanesulfonamides can be N-alkylated under solid–liquid PTC <2001T5009> or Mitsunobu
conditions (Equation (187)) <1999JOC9225, 2001JOC3564>, and protection and deprotection
based on the t-BOC group occurs in high yield <2001JOC3564>. More structurally complex
-halomethanesulfonamides are available through ring-closing metathesis reactions of bis-N-alke-
nylated sulfonamides (Equation (188)) <2001JOC3564> and the intramolecular cyclization of
-sulfonyl radicals, generated in the standard way using AIBN/TMS3SiH (Equation (189))
<2001JOC3564>.
BrCH2SO2Br
Br
DMAP, Pr2i NEt
NH O O S N O ð186Þ
CH2Cl2, 18 h O
0–20 °C, 50%
ClCH2SO2Cl, Et3N NaOH, H2O

N N N
CH2Cl2, 5–20 °C, 2 h 30 min, 20 °C
SO2CH2Cl SO2CH2Cl
NH2 N 64% overall N
SO2CH2Cl H
Scheme 52
O O PPh3, DEAD O O
Br S toluene, THF Br S
N
+ HO N ð187Þ
H 30 min, 99%
O O
Grubb’s cat.
Br S O O
N CH2Cl2, 40–50 °C ð188Þ
Br S N
98%
O O
Cl S O Cl
O S O
C6H6, AIBN O N O N
Cl S O
TMS3SiH S S
N O + O ð189Þ
Br S
O O 3 h, reflux
Ph
59% 14%
The N-sulfonylisothiourea 217 <1997AJC1027>, the isothiazole 218 <1996JFC(79)71>, and

the thiazetidine 219 <2000JA3375>, which has been alkylated under standard conditions, are
further examples of tetracoordinate -halosulfur derivatives that are structurally related to
sulfonamides (Scheme 53). The electrochemical fluorination of the sulfonamide 220 gives a
mixture containing the -fluorosulfonyl fluoride 221 <1996JFC(79)71> (Equation (190)).
ClCH2SO2Cl H2N S Ph
H2N S Ph Na2CO3, EtOAc
N
NH HCl 2 days, rt ClCH2SO2
69%
217
O Br O
O Br2, 2 h O
S S
CCl4, CH2Cl2 Br
p-MeOC6H4 N N
p-MeOC6H4
NEt2 NEt2
218
i. LDA, 5 min
BnNH2 Br O THF/hexane Me O
Br Br
EtOH, 24 h, 20 °C S –78 °C
O S
N O
SO2F ii. MeI, THF/hexane N
11% Bn –78 to 20 °C Bn
219 60%
Scheme 53
O F F
F3 C SO2F F3 C SO2F F3 C
i HF SO2F
Pr S NH2 F3CSO2F +
+ +
O F F F F F F F3 C F ð190Þ
electrochemical
30% 2% 1% 22%
220
221
A very large number of -chloromethanesulfonates have been prepared using chloromethane-

sulfonyl chloride. Chloromethanesulfonate is an extremely efficient leaving group that has been
found to be superior to methanesulfonate in terms of reactivity and to trifluoromethanesulfonate
in terms of stability <1999S1373>. Chloromethanesulfonates are generally prepared by stirring
an alcohol at 0 C in CH2Cl2 containing a base such as pyridine <2000T7123>, lutidine
<2003CEJ389>, or DMAP/pyridine (Equation (191)) <2000JA10482>. Pyridine has also been
used as the solvent for these reactions (Equation (192)) <1999JOC5280, 2003BMCL937>.
-Fluoromethanesulfonates have been prepared by the reaction of the silver salts of fluorometha-
nesulfonic acid with alkyl iodides (Equation (193)) <1998ACS42>, the parent acid being pre-
pared by heating fluoromethanesulfonyl chloride in refluxing methanol. The electrophilic
fluorinating agent N-fluorobenzenesulfonimide has been successfully used to monofluorinate the
neopentyl sulfonate 222 (Equation (194)) <1998JOC8052>, but the corresponding methyl, ethyl,
and isopropyl esters afforded only decomposition products. The cycloaddition of SO3 to trifluoro-
ethene gives the cyclic -fluoromethanesulfonate 223 (Equation 195) <2000JFC(105)137>. The
-chloromethanesulfonate 224 has been obtained by the stereoselective halogenation of an
-sulfonyl carbanion using hexachloroethane (Equation (196)) <1995TL711>.
O ClCH2SO2Cl O
I I
Pyr, DMAP ð191Þ
HO CH2Cl2, 3 h O
–78 to 20 °C SO2CH2Cl
OBn ClCH2SO2Cl OBn

Pyr, rt, 30 min
BnO OTBDMS BnO OTBDMS ð192Þ
98% O OBn
OH OBn
ClCH2O2S
FCH2SO3–Ag+
O O
I MeCN, 7 h, rt ð193Þ
I O S F
F S O
23% O O
i. ButLi, THF F
t
Bu O –78 °C, 30 min But O
S Ph S Ph
O O O O
ð194Þ
ii. (PhSO2)2NF
222 –78 °C, 1 h
89%
F F
F F SO3, rt
F
F 61% O S O ð195Þ
O
223
i. BunLi, THF/hexane
O –78 °C O
S S ð196Þ
H O ii. Cl3CCCl3, –78 °C Cl O
O O
79% 224
4.02.3 HALOGEN AND SELENIUM OR TELLURIUM DERIVATIVES—R2CHal(SeR0 ),

R12CHal(TeR2), etc.
4.02.3.1 a-Haloselenium Derivatives—R12CHal(SeR2), etc.
4.02.3.1.1 Dicoordinate a-haloselenium derivatives—R12CHal(SeR2)

In keeping with the behavior of the lighter chalcogens, the electrophilic fluorinating agent
(PhSO2)2NF has been used to monofluorinate the -selenolactone 225 stereoselectively (Equation
(197)) <1998BMCL1589>. The alternative approach of adding benzeneselenenyl bromide to the
silyl enol ether derived from the -fluoroketone 226 has been used to prepare, again stereoselec-
tively, the related -selenothiolactone 227 (Scheme 54) with the opposite stereochemistry
<2002OL305, 2002JMC4888, 2003JMC389>. The -fluoroselenide 227 is stable to the diisobutyl-
aluminum hydride (DIBAL-H) reduction, acetylation and reaction with the lithium amides
obtained from purine and pyrimidine derivatives which precede the oxidative elimination that
completes the synthesis of a synthetic nucleoside. The reaction of benzeneselenenyl fluoride with
2-diazo-3-phenylpropionate to give the corresponding 2-fluoro-2-phenylselenenyl compound
<2000JOM(611)158> is a recent extension of an established method of preparing -chloro- and
-bromo--benzeneselenenyl ketones. NCS <2000T7495> and NBS <2001H465> continue to be
used to produce -haloselenides, although the formation of by-products as a result of the
elimination of benzeneselenol has been reported <2000T7495> (Scheme 55).
i. LiHMDS, THF
OTBDPS –78 °C OTBDPS
O O
O ii. (PhSO2)2NF, THF O
ð197Þ
PhSe 87% PhSe F

225
OTBDMS OTBDMS
OTBDPS i. LiHMDS, THF PhSeBr
S S
O
S –78 °C TMSO THF, –78 °C O
F
ii. TMSCl, THF
F F SePh
–78 to 20 °C
226 227
Scheme 54
NCS, CCl4 Cl
SePh
Cl 2 h, reflux SePh
Cl
CO2Et
78% CO2Et
40:60
NBS, CH2Cl2
30 min, 0 °C Br
NC Se CN 91% NC Se CN
NCS, CH2Cl2 Cl
SePh SePh
2 h, reflux Cl
+
CO2Et 22% CO2Et
CO2Et
77:23
Scheme 55
The NCS/NBS reactions involve a Pummerer-type process as does the rearrangement of

selenium(IV) dichlorides which, in the case of 228 (Equation (198)), has been carried out in
Ac2O <1995ZOR1548> although it is generally effected thermally or in the presence of pyridine.
Rearrangement of the alkenylselenium(IV) dichloride 229 (Equation (199)) leads to the formation
of a dichloro adduct (2000T7495) in high yield. The conversion of the bis-selenoacetals 230 to
-haloselenides using NBS and SOCl2 (Scheme 56) <1995SC117> is yet another example of how
Pummerer-type processes play an important role in functional group transformations involving
chalcogen ethers. Surprisingly, tris-(phenylseleno)-methane under these conditions is reported to
give chloromethyl phenyl selenide in good yield (67%) <1995SC117>. The mixed acetals 231
<1995SC117> and 232 <1995JOC6141> (Scheme 57) demonstrate an interesting chemospecifi-
city in that in each case it is the lower chalcogen which acts as the leaving group. The -bromo-
selenide 233 is described as being very labile.
Ac2O, 10 min
O Cl Cl O O O
90–100 °C
Se Se ð198Þ
Ph Ph Ph Ph
23%
228 Cl
Cl Cl
Se CHCl3, 3 h, rt Se
Ph Ph Cl
94% Cl ð199Þ
CO2Et CO2Et
229 46:54
SOCl2, CH2Cl2 NBS, CCl4

PhSe 1.5 h, reflux PhSe 1 h, reflux PhSe
R R R
Cl 78% PhSe 70% Br
R = Me, 78% 230 R = CO2Et, 70%
Scheme 56
NBS, CCl4
Ph Ph 2 h, rt Ph
S Se Br Se
70%
231
BCl3, 15 min BBr3, CH2Cl2

Cl OMe Br
CH2Cl2, hexane 3 h, –78 °C
n-C6H13 SeMe –78 °C n-C6H13 SeMe n-C6H13 SeMe
84%
232 233
Scheme 57
-Haloselenides have also been prepared by a variety of substitution reactions, a typical

example being the selenenylation of the anion derived from the -chloro ester 234 (Equation
(200)) <1999TL4969>. The reaction of the lactone 235 with a large excess (10 equiv.) of PhSeCl
and in the presence of an ion-exchange resin gives an -chloro--seleno derivative (Equation
(201)) <2002T61>, the production of which involves the reaction of the initially formed selenyl
derivative with a second molecule of PhSeCl in which the chlorine acts as an electrophile. The
reaction of aryl diselenides with Zn and CH2ClI <2001TL4597>, or KBH4 and CH2Cl2
<1998SL1191>, gives aryl selenomethyl chlorides. It has been suggested that these reactions
involve an initial SET to the halide to give a radical anion that either attacks the diselenide
directly, or is converted to a radical which could also interact with the diselenide producing the
arylselenomethyl chloride. The standard NaI in acetone procedure has been used to convert
phenylselenomethyl chloride to the iodide <2001JOC1966>, and the selenomethyl chloride
grouping is sufficiently stable to permit the acid catalyzed addition of water to the ethynyl
bond in 236 (Equation (202)) <2001T3297>. At high temperature and in the presence of a
mixture of Se and Cu, perfluoroalkyl iodides undergo a substitution process resulting in the
formation of -fluoro selenides (Equation (203)) <2000JFC(102)301>. The Cu acts as a catalyst
and as an iodine scavenger. Finally the addition, under PTC conditions, of dibromo- and
dichlorocarbene to -halovinyl selenides 237 gives -halocyclopropyl selenides (Scheme 58)
<1998SC1667>.
PhSeBr
Cl LDA, THF Cl SePh
(–)-menthyl-O –78 °C (–)-menthyl-O
ð200Þ
O 66% O
234
MeO MeO O
O 10 equiv. PhSeCl
Amberlite IR120
O O
EtOAc, rt, 3 days O ð201Þ
O O N O
N
37%
p-MeOC6H4 p-MeOC6H4 PhSe Cl
235
SiO2, TFA
CH2Cl2 O
72 h, 40 °C ð202Þ
Ph SeCH2Cl Ph
Se Cl
82%
236
I F Se/Cu CF3 CF3

15 h, 220–230 °C F F ð203Þ
F3 C CF3 F3C Se CF3
PTC, NaOH Cl
SPh Cl
CHY3, rt
SPh
X
X
237
X = Y = Br, 16%
X = Br, Y = Cl, 79%
X = I, Y = Cl, 67%
E-237, X = I, 71
Scheme 58
4.02.3.1.2 Tri- and tetracoordinate a-haloselenium derivatives—R12CHalSe(O)R2,

R12CHalSe(O)2R2, etc.
Selenones and selenoxides are thermally unstable and readily undergo elimination reactions. No
further advances have occurred in this area in terms of the synthesis and characterization of these
materials since the publication of chapter 4.02.3.1.2 in <1995COFGT(4)41>.
4.02.3.2 a-Halotellurium Derivatives—R2CHal(TeR0 ), etc.
4.02.3.2.1 Dicoordinate a-halotellurium derivatives—R12CHal(TeR2), etc.

The commercial availability of perfluoroalkyl iodides has facilitated the synthesis and characterization
of a number of new compounds in this area. Thus the thermal reaction of heptafluoro-2-iodo-
propane in the presence of a mixture of Se and Cu produces a mixture of the -fluorotelluride 238
and ditelluride 239 (Scheme 59) <1996JCS(D)4463>. As in the corresponding selenium reaction
AgCN, 81%
–196 to 22 °C CF3
F CN
F3 C Te
241
Te/Cu CF3 CF3 CF3

I F
15 h, 150 °C F F F
+ Te CF3 I2, CHCl3
F3 C CF3 F3 C Te CF3 F3 C Te F
–196 to 20 °C
CF3
238 30% 239 10% 100%
CF3 SnMe3H, Et2O CF3

–196 to – 40 °C hν, furan, 16 h F
F SnMe3 I
F3 C Te rt F3 C Te
64%
242 240
Scheme 59
(Equation (203)), the Cu acts as an iodine scavenger and a catalyst. The telluride 238 can be
converted photochemically to the ditelluride 239, reaction of which with I2 gives the -fluoro-
tellurenyl iodide 240 that is only stable in solution (Scheme 48) (2000JCS(D)11). The ditelluride
239 has also been converted to the air-stable perfluorocyanotellurium compound 241 (Scheme 59)
<2000JCS(D)11>. The reaction of 238 with SnMe3H gives a light-sensitive perfluoroalkyl tri-
methylstannyl telluride 242. The pyrolysis of the corresponding perfluoroethyl compound 243
results in the formation of a perfluoroalkyltellurocarbonyl fluoride 244 that can be trapped by a
diene to give a volatile -fluoro dihydrotelluropyran 245 that is extremely air-sensitive and
decomposes at room temperature with separation of tellurium (Scheme 60)
<1996JCS(D)4463>. Perfluoro-n-propyltrimethylstannyl fluoride gives the same reaction
<2000JCS(D)11>.
Sealed tube Te
Te CHCl3, 150 °C, 4 h Te
F3CF2C SnMe3 F
F CF2CF3
243 244 CF2CF3
245
86%
Scheme 60
4.02.3.2.2 Tri- and tetracoordinate a-halotellurium derivatives—R12CHalTe(O)R2,

R12CHalTe(O)2R2, etc.
The reaction of the telluride 246 with XeF2 and Cl2 gives the tetracoordinated -fluorodihalo-
tellurium(IV) compounds 247 and 248, respectively (Scheme 61) <2000JFC(102)301>. Attempts
to make the corresponding dibromotellurium compound failed.
CF3 CF3 XeF2, CH2Cl2 Cl2, CH2Cl2

CF3 CF3 CF3 CF3
F F 3 h, –78 to 0 °C 70 min, –30 to 22 °C F F
F F
F3 C Te CF3 F3 C Te CF3
84% F3 C Te CF3 79%
F F Cl Cl
248 246
247
Scheme 61
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Biographical sketch
Niall Geraghty grew up in Bray, just south of Dublin, and studied as an

undergraduate and postgraduate in Trinity College, Dublin. He
obtained his B.A. (Mod) in 1975 and his Ph.D. in 1978 for work carried
out under the direction of Professor Wesley Cocker. After a postdoc-
toral period working with the CNRS in Paris (Thiais) in the research
groups of Dr. Zoltan Welvart and Dr. George Bram, he took up a
lecturing position in the then University College Galway, now the
National University of Ireland, Galway, in the West of Ireland where
he is now a Senior Lecturer. His research interests include carbon–
carbon bond formation in unactivated systems using photochemically
generated radicals, and the metal-catalyzed reactions of diazo com-
pounds with strained small ring systems.
4.03
and Another Heteroatom Group
Other Than a Chalcogen
L. F. SILVA Jr. and A. M. AGUILAR
Universidade de São Paulo, São Paulo, Brazil
4.03.1 HALOGEN AND NITROGEN DERIVATIVES—R12CHal(NR22), R12CHal(NR2X),

R2CHal(NX2), R2CHal(NY) 130
4.03.1.1 -Halo Amines—R12CHalNR22 and [R12CHalNR23]+X (Where R1, R2 = H, Alkyl or Aryl) 130
4.03.1.1.1 N-Haloalkyl amines—R12CHalNR22 (where R1, R2 = H, alkyl, or aryl) 130
4.03.1.1.2 N-Haloalkyl ammonium salts—[R12CHalNR23]+X (where R1, R2 = H,
alkyl, or aryl) 131
4.03.1.2 N-Substituted -Halo Amines—R12CHal(NR2X), R2CHal(NX2), R2CHal(NY) 132
4.03.1.2.1 -Halo amine derivatives—R12CHal(NR2X), R2CHal(NX2) (singly bonded nitrogen) 132
4.03.1.2.2 Other -halo amines—R2CHal(NY) (doubly bonded nitrogen) 138
4.03.2 HALOGEN AND PHOSPHORUS DERIVATIVES—R12CHalPR2,
R12CHalPR22, R12CHalPO(OR2)2, etc. 145
4.03.2.1 Dicoordinate Phosphorus Derivatives—R12CHalPR2 145
4.03.2.2 Tricoordinate Phosphorus Derivatives—R12CHalPR22, etc. 146
4.03.2.2.1 Primary and secondary -halophosphines—R2CHalPH2, R12CHalPH(R2) 146
4.03.2.2.2 Tertiary -halophosphines—R22CHalPR12 146
4.03.2.3 Tetracoordinate Phosphorus Derivatives—[R12CHalPR23]+X , R12CHalP(O)R22,
R12CHalPO(OH)R2, R12CHalPO(Hal)R2, R2CHalPO(OH), etc. 149
4.03.2.3.1 -Halophosphonium salt—[R12CHalPR23]+X 149
4.03.2.3.2 -Halophosphine oxides and sulfides—R12CHalP(Y)R22 150
4.03.2.3.3 -Halo oxo acids of phosphorus 151
4.03.2.3.4 Miscellaneous 160
4.03.2.4 Penta- and Hexacoordinate Phosphorus Derivatives—R12CHalPR24, [A]+[R2CHalPX5], etc. 160
4.03.3 -HALO ARSENIC, ANTIMONY, AND BISMUTH DERIVATIVES 161
4.03.4 -HALO ALKYLMETALLOIDS—R2CHalMETALLOID 161
4.03.4.1 -Halo Silicon Derivatives—R12CHalSiR23 161
4.03.4.1.1 Alkyl- and aryl(-haloalkylsilanes) 161
4.03.4.1.2 Halo (-haloalkyl)silanes 163
4.03.4.1.3 (-Haloalkyl)oxysilanes 164
4.03.4.1.4 Miscellaneous -halo silicon derivatives 165
4.03.4.2 -Halo Germanium Derivatives—R12CHalGeR23, etc. 165
4.03.4.2.1 Alkyl- and aryl(-haloalkyl)germanes 165
4.03.4.2.2 Halo (-haloalkyl)germanes 166
4.03.4.2.3 Miscellaneous (-haloalkyl)germanes 166
4.03.4.3 -Halo Boron Derivatives—R12CHalBR22, etc. 166
4.03.4.3.1 (-Haloalkyl)boron hydrides 166
4.03.4.3.2 Alkyl- and aryl(-haloalkyl)boranes 167
4.03.4.3.3 Halo (-haloalkyl)boranes 167
4.03.4.3.4 (-Haloalkyl)oxyboranes 167
129
130 Functions Incorporating a Halogen and Another Heteroatom Group
4.03.5 -HALO METAL DERIVATIVES 169

4.03.5.1 Group 1 and Group 2 Derivatives—R2CHalLi, etc. 169
4.03.5.1.1 -Haloalkyllithium derivatives 169
4.03.5.1.2 -Haloalkylmagnesium derivatives 170
4.03.5.2 Transition Metal Derivatives—R2CHalFeXn, etc. 172
4.03.5.2.1 Derivatives of chromium, molybdenum, and tungsten 172
4.03.5.2.2 Derivatives of manganese, iron, and cobalt 173
4.03.5.2.3 Derivatives of ruthenium, rhodium, and palladium 174
4.03.5.2.4 Derivatives of rhenium, osmium, iridium, and platinum 177
4.03.5.2.5 Derivatives of copper, silver, and gold 178
4.03.5.2.6 Derivatives of zinc, cadmium, and mercury 179
4.03.5.3 Group 3 and Group 4 Derivatives—R2CHalSnX3, etc. 180
4.03.5.3.1 Derivatives of aluminum, gallium, indium, and thallium 180
4.03.5.3.2 Derivatives of tin 180
4.03.5.3.3 Derivatives of lead 181
This chapter aims to present the synthesis of molecules incorporating a halogen and another
group other than a chalcogen (N, P, As, Sb, Bi, Si, Ge, B, Li, Mg, Cr, Mo, W, Mn, Fe, Co, Ru,
Rh, Pd, Re, Os, Ir, Pt, Cu, Ag, Au, Zn, Cd, Hg, Al, Ga, In, Th, Sn, and Pb) bonded to the same
carbon atom. This implies that nearly half of the stable elements of the periodic table are involved
in the reactions that are described in this chapter.
4.03.1 HALOGEN AND NITROGEN DERIVATIVES—R12CHal(NR22), R12CHal(NR2X),

R2CHal(NX2), R2CHal(NY)
This section covers the synthesis of compounds bearing the N-(-haloalkyl) unit, which is present in a
wide range of compounds. The most important structural motifs included in this broad definition are,
in the order of appearance in the section, N-haloalkyl amines, N-haloalkyl ammonium salts, -halo
amides, -halo carbamates, N-thio -halo amides, -halo nitroso derivatives, -halo nitro compounds,
-halo azo alkanes, -halo heteroarylium salts, -halo isocyanates, and 2-halo azirines (Figure 1).
R R O R R O
R R R R
X N R X N OR
X NR2 X NR3 R R
+
N-Haloalkyl amines N-Haloalkyl ammonium salts α -Halo amides α -Halo carbamates
R R O
R R R R R R
X N R
SO2 X NO X NO2 X N N R
N-Thio α -halo amides α -Halo nitroso derivatives α -Halo nitro derivatives α -Halo azo alkanes
R N
N R R X R=H, alkyl or aryl
R
R X = F, Cl, Br or I
X X N C O R
α -Halo heteroarylium salts α -Halo isocyanates α -Halo azirines
Figure 1 Examples of -halo nitrogen derivatives.
4.03.1.1 a-Halo Amines—R12CHalNR22 and [R12CHalNR23]+X (Where R1, R2 = H, Alkyl or Aryl)

This section describes the synthesis of N-haloalkyl amine derivatives and of N-haloalkyl ammo-
nium derivatives.
4.03.1.1.1 N-Haloalkyl amines—R12CHalNR22 (where R1, R2 = H, alkyl, or aryl)

The preparation of N-haloalkyl amines has been described in several articles. In the following
paragraphs, several examples of the synthesis of N-haloalkylamines are discussed.
Functions Incorporating a Halogen and Another Heteroatom Group 131
The electrochemical fluorination of trialkylamines affords compounds such as 1

<1997JFC143>, although in low yields. The N-fluoromethylamine 2 has also been prepared
<1988JA1964>. The cleavage of aminals led to haloalkylamines <1957CB2003, 1960CB1305,
1996JA3720>, as exemplified for the preparation of N-fluoromethylmorpholine utilizing oxalyl
fluoride (Equation (1)) <1970CB104>.
C2F5 CH3
F 3C N N
C2F5 Bn
F F
1 2
O
F
F
O ð1Þ
N N Ether, –20 °C N F
O O 79% O
Treatment of an N,N-di(methoxymethyl)amine or an N-methoxymethylamine with trichloro-

methylsilane led to the corresponding chloride derivative (Equation (2)) <1990SL617,
1995T10737>. Tris(chloromethyl)amine has been obtained by treatment of hexamethylenetetr-
amine with phosphorus pentachloride <1971AG(E)653, 1973CB69>. The reaction of secondary
amines with CH2ClBr <1983JFC371> gave the corresponding chloromethylamines 3, 4, and 5,
albeit the ionic form—an iminium chloride—may contribute significantly in compounds with this
structure <1987JOC1857, 1990JOC2254>.
MeO MeSiCl3, Et2O
MeO
0 °C, 15 min
N OMe N Cl
ð2Þ
MeO 100% MeO
OMe
N N N
Cl Cl Cl
3 4 5
4.03.1.1.2 N-Haloalkyl ammonium salts—[R12CHalNR23]+X (where R1, R2 = H,

alkyl, or aryl)
The general method for preparing halomethylammonium salts is the treatment of a trialkylamine
with a dihalomethane, which is a particular case of the Menschutkin reaction. A detailed study of
the quaternization reaction of tertiary amines has been performed by Isaacs and co-workers
<1986T601>. The reaction of dichloromethane with brucine <1998MI573, 1999MI778>, with
zacopride 1 <1994BMCL945>, with DABCO <1973IC102>, with galanthamine
<1994HCA1611>, and with ferrocenylmethyldimethylamine <1998JOM(570)201> gave the cor-
responding N-chloromethylammonium salts. Similarly, treatment of trimethylamine with CH2Br2
yielded the bromo derivative 6 <1971JCS(C)3471>, which can be transformed into the corre-
sponding tetrafluoroborate salt by an anion exchange reaction (Scheme 1) <1999JCS(P2)1187>.
This anion exchange reaction can be similarly performed using the iodides <1996JA11313,
1999JCS(P2)1187> or chlorides <1999JCS(P2)1187>, as starting material. The Menschutkin
reaction has also been utilized for the synthesis of a variety of iodomethyl compounds, from
diiodomethane <1971AG(E)330, 1996CC1637, 1996JA11313, 1997TL7041, 1999JCS(P2)1187,
1999JOC1798>. Alkyliodine(III) dichlorides can be prepared by oxidation of iodomethyl ammo-

nium salts with chlorine (Equation (3)) <1999TL1839>. Reaction of trialkylamines with mixed
dihalomethanes generated a number of different halides <2000MI55>, such as 7
<1991JMC2031> and 8 <2002MI347>. An ammonium salt bearing an N-fluoromethyl group
has been obtained from the corresponding amine <1986ZAAC(537)63>.
CH2Br2 AgBF4
CH3CN + CH3CN +
Me3N Me3N Br Me3N Br
93% Br
– 90% BF4–
6
Scheme 1
Cl2
+ CH2Cl2 +
Et3N I Et3N ICl2 ð3Þ
– 84% BF4
–
BF4
X OH
OR2
N+
Y– +
R1 Br– N 18F
7 8
X = Cl, Br or I; Y = Br or I
R1 = H or Me; R2 = H or COMe
SelectfluorTM 9, whose chemistry has been reviewed <1998JFC1, 1999JFC157>, is a powerful

electrophilic fluorination agent that is produced on a large scale. This useful compound for the
pharmaceutical companies can be prepared by the sequence of steps shown in Scheme 2
<1992CC595, 1996JCS(P1)2069, 1996JFC43>.
Cl Cl Cl
– –
N Cl NaBF4
–
N
CH2Cl2 N BF4 N BF4
+ CH3CN + BF3·Et2O +
80% 85% 92%
N N N +N
–
BF4
F
9
Scheme 2
4.03.1.2 N-Substituted a-Halo Amines—R12CHal(NR2X), R2CHal(NX2), R2CHal(NY)

N-Substituted haloamines can be classified into two different groups. The first are those having a
nitrogen singly bonded, which include compounds such as -halo amides, -halo carbamates and
N-thio -halo amides. The second group contains molecules such as -halo nitroso derivatives,
-halo nitro derivatives, -halo nitro compounds, -halo azo alkanes, -halo heteroarylium salts,
-halo isocyanates, and 2-halo azirines, which have a doubly bonded nitrogen. In the following
paragraphs, the synthesis of these compounds is presented according to this classification.
4.03.1.2.1 a-Halo amine derivatives—R12CHal(NR2X), R2CHal(NX2) (singly bonded nitrogen)
(i) -Halo amides and imides
(a) By replacement of an -hydroxy group. The most widely used method for the synthesis of
N-chloroalkyl amides is the replacement of a hydroxyl group by a halogen. This protocol is useful
to obtain either -chloroamides or -chlorolactams. The most commonly used reagent to promote
such a functional group transformation is thionyl chloride, which has been used in the synthesis
of a wide range of chloro amides <1980JOC1577, 1981TL2689, 1987JHC1381, 1991ZOB2679,
1994ZOB1048, 1995SL97>. Another reagent employed is oxalyl chloride (Equation (4))
<2002OL387, 2003JOC5819>. For the preparation of N-bromomethylamides from the correspond-
ing hydroxy derivative, HBr <1971JOC1379> and PBr3 <1972BCJ2531> have been used.
H COPh Oxalyl chloride H COPh

N CH2Cl2, rt, 12 h N ð4Þ
EtO2C OH Quantitative EtO2C Cl
The transformation of an amide into the corresponding N-halomethyl amide can also be
performed by a two-step procedure called halomethylation, through an N-hydroxyalkyl inter-
mediate. This hydroxy derivative is obtained by reaction of an amide with paraformaldehyde. For
the second step, thionyl chloride (Scheme 3) <1995T9551, 1994JOC1719, 1995JCS(P1)1317> or
trimethylsilyl chloride (Equation (5)) <1994JOC1719, 1984ZOB2645, 1991ZOB2024,
1992SC2381, 1995TL2483> can be utilized. The halomethylation process can be directed toward
the synthesis of -bromo amides using HBr (Equation (6)) <2001T7675, 1994SL933>.
O (CH2O)n, K2CO3 (cat.) O O

SOCl2
Ph H2O , 70 °C, 1 h CCl4
HN N HO N N Ph Cl N N Ph
67% 70%
O O O O O O
Scheme 3
(HCHO)n
TMSCl
N O O ð5Þ
82% N
H
Cl
O (HCHO)n, HBr O Br
NH AcOH, 80 °C, 4.5 h N ð6Þ
N O N O
88%
A variation of the halomethylation process has been used by Ciufolini and co-workers, for
the introduction of an -chloroacetate moiety, in their studies toward the total synthesis of
()-muscoride A (Scheme 4) <2003AG(E)1411>.
O CHOCO2Et, THF O
n-C6H13 reflux, 12 h n-C6H13
Ph Ph
NH2 N CO2Et
N N
H
O O OH
SOCl2, rt O n-C6H13
Ph
90% N CO2Et
N
(2 steps) H
O Cl
Scheme 4
(b) By direct halogenation. There are examples in the literature describing the preparation of
haloalkyl amides by direct halogenation using chlorine (Equation (7)) <1979LA1447>. Bromo-
methylamides are intermediates in the succinimidation of N,N-dimethylamides by NBS
<1984JCS(P1)281>.
O O
Cl2, hν
Me
Cl3C N 63% Cl3C N Cl ð7Þ
Me
Cl
(c) By cleavage of gem-diheteroatomic compounds. The cleavage of the triazine 10 promoted by

3-butenoyl chloride gave the chiral nonracemic amide 11 (Equation (8)) <1992H349>. The
reaction of triazines with oxalyl chloride gives imidazolidinediones, through an N-chloromethyl
amide intermediate <1993T10609>. Halomethyl amides are also intermediates in the reaction of
tris(trimethylsilylmethyl)hexahydro-1,3,5-triazine with acyl chlorides <1985CPB4596>.
Ph Ph
CH2Cl2 Ph O
O 0 °C, 20 min
N N
+ N
Cl ð8Þ
N
Cl
Ph 11
10
(d) By addition of electrophiles to imines and enamines. The addition of acyl chlorides to imines
is an efficient method for the preparation of N-chloroalkyl amides (Equation (9)) <1968JA2875,
1963CB600, 1963JOC2592, 1974JOC3745, 1975CB2917>. The reaction also occurs with acyl
bromides instead of chlorides <1969JOC1192>.
Ph O Ph O
PhCOCl, benzene
N reflux, 48 h Ph N N ð9Þ
Me Me Cl Me
+
Ph 100%
H Cl H Ph H
The addition of chlorine to enamines is also an effective approach for the synthesis of chloro
amides (Equation (10)) <1973JOC126, 1991ZOB1910>. An analogous reaction can also be
performed using bromine, as well as hydrogen chloride <1973JOC126>.
F3CCO2H Cl
NHAc Cl2, CCl4 NHAc
Cl ð10Þ
CO2H Yield not
CO2H
reported
(e) By miscellaneous methods. The cleavage of a protected N-hydroxymethyl group followed by

halogenation is an efficient method to prepare -halo amides. This approach can be an alternative to
the traditional halogenation of a hydroxy derivative. Thus, a two-step protocol, in which a pivalate
ester is the intermediate, has been developed for the N-bromomethylation of amides (Scheme 5)
<1995SL423>. The action of HCl, HBr, or SOCl2 on alkoxymethyl compounds led to the corre-
sponding halides <1982JOC3169>. Similarly, treatment of N-[(trimethylsiloxy)methyl]amines with
TMSCl, TMSBr, or TMSI gave the corresponding N-halomethylamides <1984ZOB1437>.
But O Cl
O O O
CH3CN, NEt(Pr)2 HBr
reflux, 16 h O AcOH Br
NH N O N
90%
80%
O O O
Scheme 5
Reaction of 6-phthalimidopenicillanate with chlorine or with sulfuryl chloride afforded chloro-

alkyl amides by opening of the thiazolidine ring <1971JA6267>. Similarly, N-(chloro-
methyl)phthalimides have been obtained in good yield from thiophthalimides, utilizing sulfuryl
chloride <1979JOC1178>.
The reaction of a chloro isocyanate with a phosphorane led to a phosphorus amide, in good
yield (Equation (11)) <1997ZOB391>.
CN
NCCH=PPh3 H
Cl N C O CH3CN, 2 h, rt Cl N ð11Þ
PPh3
CCl3 68% CCl3 O
(ii) -Halo carbamoyl derivatives

The strategies used so far for the synthesis of -halo carbamoyl derivatives are quite similar to
those mentioned for -halo amides, whose section may be consulted for additional insights
concerning the synthesis of the halo carbamoyl derivatives. For this reason, this section is
organized in a similar manner as the previous one.
(a) By replacement of an -hydroxy group. Thionyl chloride can efficiently promote the
transformation of the hydroxy group of an -hydroxy carbamoyl derivative into the correspond-
ing chloride (Equation (12)) <1968JOC2887, 1998TL8845, 1985JHC1479, 1986LA1133,
1993PS(85)183>. This type of functional group transformation can also be performed using
phosphorus pentachloride <1991TL3123, 1992JCS(P2)857>.
H SOCl2, CH2Cl2 H
Cl3C N Pyr, reflux, 60 min Cl3C N
CO2Me CO2Me
ð12Þ
99%
OH Cl
Treatment of a carbamate with paraformaldehyde led to an N-hydroxymethyl intermediate,

which reacted in situ with trimethylsilyl chloride, giving the desired chloromethyl carbamate
(Equation (13)) <1996TL5597, 1999T4831>.
(HCHO)n, TMSCl,
O O
Benzene, MgSO4, 3 h, rt
H ð13Þ
O N Quantitative O N Cl
Me Me
(b) By direct halogenation. The reaction of an alkyl amide with chlorine can afford the
corresponding chloroalkyl carbamoyl compound, in good yield (Equation (14))
<1974JOC2897>. The utilization of sulfuryl chloride has also been reported for the chlorination
of N-methylformanilide, leading to N-chloromethyl-N-phenylcarbamoyl chloride, in 64% yield
<2000JFC111>. There are several reports describing the preparation of -bromo carbamates by
bromination using either bromine <1982AG(E)203, 1983LA599, 1985T1693> or NBS
<1983LA599, 1984JCS(P1)281, 1985T1693>.
O Cl2
O
hν, CCl4
Ph Ph ð14Þ
N Cl N Cl
80%
Me
Cl
(c) By cleavage of gem-diheteroatomic compounds. Bis(trichloromethyl)carbonate can mediate

the cleavage of the triazines leading to a chloromethyl carbamoyl chloride (Equation (15))
<2000JFC111>. This kind of transformation is also promoted by phosgene <1974JOC2897>,
as well as acyl halides <1962BEP621378, 1981CPB1747, 2000M953>. The preparation of com-
pounds such as N-chloromethyl-N-methylformamide by the cleavage of gem-diamines has been
reported <1981CB3421, 1986BSF449>.
O
Cl3C CCl3 O
O O
N N CHCl3, 0 °C to reflux ð15Þ
N Cl
N 65%
Cl
(d) By addition of electrophiles to imines and enamines. The addition of phosgene to an imine
led to a halo carbamoyl chloride (Equation (16)) <1987JHC945, 1974JOC3745>.
Et COCl2, benzene Et
25–30 °C, 2 days Cl
N CH2 N ð16Þ
78% COCl
Et Et
(iii) N,N-Difluoro -halo amines

No further advances have occurred in this area since the publication of chapter 4.03 in
<1995COFGT(4)95>.
(iv) N-Oxy -halo amines

In studies toward the synthesis of polyfluorinated oxaziridines <1996CRV1809>, the reaction of
the imine 12 with chlorine has been carried out, leading to the desired heterocyclic compound
(Equation (17)) <1981USP4287128>.
Cl2 F O
F
K2CO3
N C(CF3)2 F3C N C(CF3)2
F3C ð17Þ
CF3 CF3
12
(v) N-Thio -halo amines

The approaches utilized for the synthesis of N-thio-N-halomethyl amides are similar to that used in
the preparation of N-halomethyl amides and carbamates, which are described above. Thus, reaction
of N-thio-N-hydroxymethyl amide with PBr3 gave the desired bromide, in excellent yield (Equation
(18)) <1994JMC2623>. Similarly, chloromethyl derivatives were synthesized from the corresponding
alcohol, after treatment with thionyl chloride <1992PS(70)99, 1996JHC615>. Treatment of a thio-
amide with chloromethyl phenyl sulfide, followed by reaction with sulfuryl chloride led to chloro
N-thioamides in good overall yield (Equation (19)) <1995JMC739, 1995JMC4687, 1998BMC661>.
O O
PBr3, ether ð18Þ
N N
S OH 92% S Br
O O O O
+ –
i. PhSCH2Cl, n-Bu4N Br
O O
toluene, reflux, 48 h
ii. SO2Cl2, CH2Cl2, rt, 16 h ð19Þ
NH N
MeO S 77% MeO S Cl
O O O O
The bromomethylation procedures mentioned earlier (see Equation (6) and Scheme 5) were also
suitable for the synthesis of N-thioamides in an efficient manner <1994SL933, 1995JMC4687,
1995SL423>. Groutas and co-workers reported the chloromethylation reaction of N-thioamides
using formaldehyde sodium bisulfite adduct, instead of paraformaldehyde (Equation (20))
<1999JA8128, 2001SC3055>. N-Thio-N-iodomethyl amides have been obtained by reaction of
the corresponding chlorides with NaI in anhydrous acetone <1998BMCL539, 1999BMCL2199>.
OH
O O
Cl
SO3Na , SOCl2, reflux
NH N
N S 91% N S ð20Þ
O O
O O
Treatment of the imine 13 with alkylsulfonyl fluorides and caesium fluoride led to the sulfo-
namide 15, after quenching the caesium salt intermediate 14 with sulfuric acid (Scheme 6)
<1994JFC277>.
F3CSO2F, CsF H
Cs
F3C MeCN, 80 °C, 16–24 h F H2SO4 F
NH F3C N F 3C N
SO2CF3 SO2CF3
F3C 87%
CF3 CF3
13
14 15
Scheme 6
(vi) N-Amino -halo amines

The addition of bromine into the enamine derivative 16 led to the N-bromoalkyl compound 17 in
excellent yield (Equation (21)) <1999JOC346>. N-Amino -halo amines have also been obtained
from the reaction of bis-trialkylhydrazinomethane with trichloroacetyl fluoride <1970CB3930>.
Br2, CCl4
N N
rt, 45 min Br
N N ð21Þ
N 93% N Br
16 17
Reaction of the N-hydroxymethyl group of a triazole with thionyl chloride gives the corre-
sponding chloride in 90% yield (Equation (22)) <1952JA3868, 1987JCS(P1)781>. Reaction of
this chloride with sodium bromide (or iodide) yielded the corresponding 1-bromo- (or 1-iodo)-
methylbenzotriazole <1993ACS167>.
OH Cl
N SOCl2 N ð22Þ
N N
N 90% N
(vii) N-Nitro -halo amines

The seminal work concerning the synthesis of N-nitro-N-haloalkyl amines has been performed by
Majer and Denkstein <1966CCC2547>. Treatment of N,N-bis(acetoxymethyl)-N-nitroamine
with HCl led to the corresponding chloride in good yield (Equation (23)). A similar procedure
was used in the preparation of N-(chloromethyl)-N-nitro-methylamine. The latter compound was
also obtained from the cleavage of N-(piperidinomethyl)methylnitroamine promoted by acetyl
chloride. The above-mentioned approaches were used in the synthesis of other N-nitro haloamines
<2002WOP60881>.
HCl, dioxane NO2
NO2
0 °C, 48 h ð23Þ
AcO N OAc Cl N Cl
90%
(viii) N-Phosphoryl -halo amines

The chloro derivative 18 has been synthesized from the corresponding alcohol, utilizing thionyl
chloride in benzene <2002ZOB1802>.
OCl
H
P(OEt)2
MeO2C N
CF3
18
(ix) Miscellaneous -halo amides

The chloroboration of the diazadiene 19 with boron trichloride afforded the unusual and crystal-
line diazaborolidine 20 (Equation (24)) <2001CC1136>.
Pri Pri Pri

N BCl3 Cl
Hexane N Pri
B Cl
ð24Þ
Cl N
N Pri
Pri Pri Pri
19 20
4.03.1.2.2 Other a-halo amines—R2CHal(NY) (doubly bonded nitrogen)

In this section, synthetic methods developed toward the synthesis of -halo amines with a
nitrogen doubly bonded will be described. In this class of compounds are included -halo nitroso
derivatives, -halo nitro derivatives, -halo azo alkanes, -halo heteroarylium salts, -halo
isocyanates and 2-halo azirines.
(i) -Halo nitroso derivatives

The preparation of -halo nitroso compounds has been restricted to gem-chloronitroso com-
pounds, which are formed when chlorine gas is passed through a solution of an oxime in
anhydrous diethyl ether. Such a reaction, known for several decades <1953JCS3483,
1954CB1449, 1954JCS4215>, constitutes the most used method for the preparation of this class
of compounds <1971RTC(90)866, 1995JCS(P2)1381, 1995JFC207>. In the presence of either
Lewis or Bronsted acids, oximes are transformed into the corresponding gem-dichloro compounds
through a chloro nitroso intermediate (Scheme 7) <1993JOC1939>.
NOH Cl2, ether NO Cl

BF3·Et2O, 8 h Cl
Cl
82%
Scheme 7
Other reagents, namely t-BuCOCl <1992JA5900> and nitrosyl chloride (Equation (25))
<1958JOC1517, 1982MM894>, are also effective to transform an oxime moiety into the
gem-chloro nitroso functionality.
NH NOCl, CH2Cl2
ON Cl
0 °C, 45 h ð25Þ
CO2Et CO2Et
89%
The oxidation of oximes to chloro nitro compounds occurs through chloro nitroso intermedi-
ates. Thus, the following section might be consulted for insights concerning the synthesis of
-halo nitroso derivatives.
(ii) -Halo nitro derivatives

Based on the starting material, the approaches to the synthesis of gem-halo nitro compounds can
be classified into three different categories. The first constitutes the halogenation of nitro
compounds, whereas the second is the halogenation/oxidation of oximes. Finally, in the third a
molecule that already bears the gem-halo nitro moiety is transformed into a relatively more
complex halo nitro derivative.
(a) Halogenation of nitro compounds. The typical protocol for the synthesis of halo nitro
compounds is the treatment of a nitro derivative with a source of halogen under basic conditions
<1940JOC100, 1960JCS2976, 1977JOC3764>. Using this standard protocol all halogens have
been introduced into a number of nitro compounds utilizing several slightly different variations of
the general procedure (Table 1).
In addition to the above-mentioned protocols, the preparation of a gem-halo nitro compound
has also been achieved by trapping with bromine a nitro enolate, obtained from a conjugate
addition (Equation (26)) <1969JOC2049>.
i. NaOH
O2N Br NO2
NO2 ii. Br2
+ ð26Þ
O2N 68% NO2 NO2
(b) Halogenation–oxidation of oximes. The oxidation of oximes into gem-halo nitro com-
pounds can be performed under a variety of conditions, although only the preparation of
bromides and chlorides has been reported. This transformation occurs in two steps, through a
halo nitroso intermediate, which is oxidized in situ. The -chloro nitro derivatives are usually
obtained by treating the oxime with Cl2, followed by oxidation with NaClO (Equation (27))
<1980TL1117, 1989JOC2869> or ozone <1976JOC733, 1985JOC2498>. The gem-bromonitro
derivatives are obtained in an analogous fashion using bromine <1953JA4044, 1984JOC2041,
1984JOC4078, 1988JOC443, 1988JOC4969> or NBS (Equation (28)) <1953JA4047,
1988JOC443, 1988JOC4645>.
i. Aq. hypochlorous acid
benzene, 27 °C, 25 min
ii. n-Bu4N+HSO–4, NaClO ð27Þ
27 °C, 55 min Cl
NOH
98% NO2
i. NBS, NaHCO3
ii. HNO3 Br ð28Þ
NOH
72% NO2
A few alternatives to the standard protocol have also been reported. Some new halogenating
agents, namely 21, 22, 23, and 24, have been developed to convert an oxime into the
corresponding halo nitro compound <1991JOC316>. A biocatalytic version of this functional
group transformation has been reported for the synthesis of either chlorides or bromides
(Equation (29)) <1996JOC8692>. Oxone in the presence of sodium chloride or potassium
bromide is effective to obtain nitro compounds, in good yield (Equation (30)) <1998TL4385,
1999T6211>.
O O O
Br
Br Br Cl Cl Cl Cl
N N N N N N N
O
O N O O N O N O O N O
H Br Na Cl
21 22 23 24
Chloroperoxidase C. fumago
KCl (or KBr), H2O2, pH 5.0, 5 h X
NOH ð29Þ
NO2
X = Cl, 54%
X = Br, 58%
Table 1 Reagents and conditions for the conversion of nitro compounds into gem-halo nitro compounds
Entry Reagents and conditions Product (yield, %) References
1 (i) NaH, THF, rt, 2 h; O <1992JOC2196>
(ii) FClO3, 0 C, 2 h F
CO2Et
NO2
(100)
2 (i) NaH, THF; F <1969JOC4176>

(ii) FClO3, 0 C EtO2C CO2Et
NO2
(76)
3 (i) NaOH, H2O, 50 C; NO2 <1969JOC2049>

(ii) I2, KI, rt, 10 min
I
(64)
4 (i) t-BuOK, t-BuOH, 30 min; <1978T3129>

(ii) Br2, H2O
Br
NO2
(66)
5 (i) t-BuONa, t-BuOH; NO2 NO2 <1987JA5452>

(ii) Br2, CH2Cl2, 0 C, 5 min
Br Br
(79)
6 (i) NaOH, H2O; NO2 <1970JOC846>

(ii) F2, 0–5 C
CO2Et
F
(85)
7 (i) NaOH, H2O; 1-Chloro-1-nitropropane (95) <1962JOC2930>

(ii) Cl2
8 (i) NaOH, H2O; 1-Bromo-1-nitroethane (69) <1986JCS(P1)1171>

(ii) Br2, 0 C, 30 min
9 F 2-Fluoro-2-nitropropane (83) <1984JA452>

SO2N
But, n-Bu4NOH,
Toluene, –20 °C
10 (i) KOH, CH3OH; 2-Chloro-2-nitropropane (95); <1986S828>

(ii) NCS (or NBS), rt, 2-Bromo-2-nitropropane (90)
45 min (or 30 min).
11 h, TiO2, AgF 2-Fluoro-2-nitropropane (47) <1990JA2016>
12 (i) MeONa, MeOH, 65 C, 10 min; F <1994JOC6800>

(ii) AcOF, 0 C, <1 min. NO2
(90)
Oxone®, NaCl (or KBr)

Al2O3, CHCl3 X
NOH ð30Þ
X = Cl, 79% NO2
X = Br, 81%
(c) From -halo nitro derivatives. A useful strategy for the synthesis of gem-halo nitro com-
pounds is the manipulation of a molecule that already bears this moiety to a new one, which is
usually relatively more complex. In this context, several transformations (reduction, decarboxyla-
tion followed by alkylation, etc.) of halo nitro substrates have been investigated, allowing the
synthesis of different substituted gem-halo nitro molecules (Equation (31)) <1990JOC3562,
1987JOC5061, 1989JOC5453, 1993JOC3483>. When 5-chloro-5-nitrobarbituric acid 25 is added
to morpholine, the formation of the morpholine salt 26 was observed (Equation (32))
<2002JOC7833>.
F F O
HO OH + F Collidine, 24 h O O ð31Þ
NO2 F O NO2
85% O F F F F
O2N Cl Morpholine O2N Cl

O O 15 min, reflux O – O
O +
H2N
HN NH 57% HN N ð32Þ
O O O
25 26
Bromonitro compounds can be transformed into the corresponding chloro derivatives, through
a nitronate intermediate (Equation (33)) <1986S826>. A gem-bromonitro derivative is the inter-
mediate in the alkylation of an enamine with bromonitromethane <1999JOC9653>.
i. EtSH, MeONa, MeOH

NO2 ii. NCS NO2
ð33Þ
Br 100% Cl
(iii) -Halo azo alkanes and -halo azides

The synthesis of halo azo alkanes, which are the starting materials for a wide range of useful
molecules, has often been reported in the literature. These studies are divided into three different
groups in this section. As the chemistry of 3-halodiazirines has received great attention in the last
decade, the synthesis of these compounds is discussed separately from that of the other halo azo
derivatives. Then, the halogenation of hydrazones and the cycloaddition of halo alkenes to diazo
alkanes are described.
(a) Preparation of 3-halodiazirines. In 1965, Graham <1965JA4396, 1981JOC5048> reported
that 3-halodiazirines can be obtained by oxidative cyclization of amidines promoted by
sodium hypochlorite (or hypobromite) (Equation (34) <2003JOC4819>). As halodiazirines
are useful compounds for the generation of carbenes, the research concerning Graham’s
reaction has been intense in the 1990s <1992ACR31, 2002JMC1879>, providing straightfor-
ward access to a wide range of substituted halodiazirines <1980CB2040, 1983JA6513,
1989AG(E)225, 1990JOC2005, 1991CB1207, 1993HCA197>, such as 27 <1993JA7584>, 28
<1989JCR(S)374>, and 29 <1993JA7584>. This method can also be used in the preparation
of either 3-alkyl- or 3-aryl 3-fluorodiazirines (Scheme 8, <1985JA2743> and Scheme 9,
<1987TL5801>). The use of a phase-transfer catalyst led to higher yields of diazirines as
compared to the traditional Graham conditions (Scheme 10) <2003MI3287>. The preparation
of labeled <1990JA368, 1999TL29> and of hindered <1995TL8761> diazirines has also been
reported.
NaOCl, NaCl
NH DMSO, LiCl Ph
N ð34Þ
Ph NH2 N
69% Cl
Cl Cl Cl
N N N
N N N
F
N
O2N F
27 28 29
NaOBr TBAF
NH DMSO, LiBr Ph 25 °C, 4 h Ph
N N
Ph NH2 38% N N
Br 65% F
Scheme 8
NaOCl, NaBr
NH F3C
DMSO, LiBr N TBAF, CH3CN F3C N
F3C NH2 N N
30% Br 60% F
Scheme 9
ButOCl, CH2Cl2
–
n-Bu4N+HSO4 NaOH,
NH.HCl Ar
NaCl N
Ar NH2 N
Cl
N N
N N
Cl Cl
Cl
N N
60% 25% 40%
Scheme 10
(b) Halogenation of hydrazones. The halogenation of hydrazones has been mainly applied to
the synthesis of the chloro azo molecules, although there are reports concerning the corresponding
bromo <1989CJC1125> and fluoro derivatives <1991JOC4695>. The chlorination of hydrazones
is a general method to obtain a broad range of gem chloro azo compounds in good-to-excellent
yields (Equation (35)) <1993T9973, 1995M431, 1996S274, 1998JCS(P1)947, 1998M1293,
1998S721, 1999S1313, 2003S1231>. The reagent of choice for this efficient transformation is
t-butyl hypochlorite in CH2Cl2 or in CHCl3 <1972JOC386, 1992S710>, although chlorine has
also been used <1972JOC383>. The chlorination of 2,3-diazabuta-1,3-dienes (or ketazines), which
is best performed utilizing chlorine as an oxidant <1970JA4586, 1970JA4593>, has been intensively
used for the preparation of dichloro azo compounds (Equation (36)) <1975JOC3529, 1999CAR67,
1999T751, 2001MI372>. Treatment of hydrazones with IF led to difluorides, through a fluoro azo
intermediate <1991JOC4695>.
H
N
N R1 ButOCl, CH2Cl2 Cl N N R1
–30 to –10 °C, 1 h
ð35Þ
S R1 = 2,4,6-Cl3C6H2: 90% S
R1 = CO2Et: 92%
Cl2
Ar Cl Cl
N Me –60 °C, 30 min ð36Þ
Me N Ar N N Ar
Quantitative
Ar Me Me
(c) Cycloaddition of halo alkenes to diazo alkanes. Another approach for the synthesis of halo
azo compounds is the [2+3]-cycloaddition of halo alkenes to diazo alkanes. Thus, reaction of
6-chloro-2,3,4,5,6-pentafluorocyclohexa-2,4-dienone with diazomethane gave the corresponding
halo azo derivative, as a mixture of diastereomers (Equation (37)) <2000JCS(P1)1929>.
O O
Cl CH2N2 F Cl
F N
F Et2O, 0 °C, 2 h F ð37Þ
N
F F 52% F
F
F F
(iv) -Halo heteroarylium salts

N-(1-Haloalkyl)heteroarylium salts react with a broad range of nucleophiles giving rise to several
interesting molecules, including a number of structurally diverse heterocyclic derivatives. Based
on a three-component reaction, a general approach for the synthesis of these compounds was
developed by Anders and co-workers. Prior to these studies, only a few papers reported the
preparation of halo heteroarylium salts. The syntheses and applications of N-(1-haloalkyl)hetero-
arylium salts have been reviewed <2000AHC183>. In the following paragraphs an overview of
their synthesis is presented.
(a) Three-component synthesis. The three-component reaction utilizing equimolar amounts of
pyridine, an aliphatic or an aromatic aldehyde, and thionyl chloride (or bromide) led to pyridi-
nium salts, in good-to-excellent yield (Equation (38)) <1987BSB719, 1989JOC4808>. The reac-
tion tolerates substituted pyridines as well as other N-heterocycles such as isoquinoline and
imidazole <1987BSB719, 1989JOC4808>. Formaldehyde can also be used as starting material
under slightly different experimental conditions (Equation (39)) <1999JOC3113>. Because the
pyridinium halides formed in this three-component reaction are useful starting materials, a
number of new N-(1-haloalkyl)heteroarylium salts have been synthesized since the 1990s
<1991CB2013, 1992BSB233, 1992BSB509, 1992SC3291, 1992T1263, 1993S867, 1994H815,
1997LA745, 1998JST55, 2001JOC720, 2001S1327>.
SOCl2 R Yield (%)

R H CH Cl , –50 °C
+ 2 2 R
H N
+
4-MeC6H4 83 ð38Þ
N O (C6H5)CH 82
Cl Cl – Ethyl 89
R2 R1 R2 X Yield (%)
R1
SOX2, 0 °C R1
R2 H H Cl 90
H H CH3CN (or CH2Cl2)
+ H N H H Br 73
H + ð39Þ
N O NMe2 H Cl 78
– CN H Cl 30
X X
H CN Cl 77
H CO2Me Cl 86
(b) Miscellaneous methods. The N-halomethyl pyridinium moiety is formed by treating pyridyl
platinum complexes with CH2Cl2 (Equation (40)) <1989JOM(361)255, 1992JCR(S)296,
1992JOM(425)155>. Reaction of trichloromethylarenes with pyridine led to pyridinium halides
<1995KGS1375, 1995TL5075>.
PMe2Ph PMe2Ph
CH2Cl2, NaClO4
Pt Cl Pt Cl
N Yield not ð40Þ
PMe2Ph reported
N PMe2Ph
+
ClO4–
Cl
(v) -Halo isocyanates

There are several methods for the synthesis of -haloalkyl isocyanates which are covered in a
review article <1980S85>. The most common method used for the preparation of these com-
pounds is the treatment of imino derivatives with phosgene (Equation (41)) <1969CB2972,
1994LA1069>. However, alternative procedures have been developed to perform such an addi-
tion reaction under phosgene-free conditions (Equation (42)) <1977ZOR271, 1996ZOR1432,
1998ZOR310>.
COCl2, toluene
But 0–130 °C But
NH
ð41Þ
Ph N C O
Ph 85% Cl
CCl3NCO, toluene
F3C reflux, 4 h F3C
NH
ð42Þ
Ph N C O
Ph 70% Cl
(vi) 2-Halo-2H-azirines
2H-Azirines have a number of applications, and are the smallest unsaturated heterocyclic com-
pounds bearing nitrogen. An efficient two-step protocol for the synthesis of 2-halo-2H-azirines
has been developed. This method is based on the reaction of oxophosphonium ylides with NCS or
NBS, which, after elimination of triphenylphosphine oxide, gives haloazidoalkenes. Subsequently,
these compounds are transformed into the desired halo-azirines by heating (Scheme 11)
<1999TL789>. Using such a strategy, several 2-halo-2H-azirines have been obtained
<2000TL7217, 2001T6203, 2002JOC66, 2003T2345, 2003TL6313>. This two-step approach
appears to be a good alternative to the known methods for the synthesis of halo-azirines, namely,
the thermal or the photochemical decomposition of vinyl azides <1966JCS(C)2304,
1970JCS(C)2172, 1971JA1482, 1979CC419, 1979JOC3281, 1981TL2905, 1996JOC4351>.
O NCS or NBS
MeO2C X
CO2Me TMSN3, CH2Cl2, 5 min
MeO2C
X = Cl: 75%
PPh3 N3 CO2Me
X = Br: 89%
Heptane
Reflux, 3 h N
X
X = Cl: 99% MeO2C CO2Me
X = Br: 98%
Scheme 11
(vii) Miscellaneous -halo amines

The complex pentacarbonyl(fluoromethyl isocyano)chromium has been prepared from pentacar-
bonyl(dichlorofluoromethyl isocyanide)chromium by reduction utilizing tributyltin hydride
<1992JOM(436)185>. Other compounds with similar structure were also obtained
<1993AG(E)1456, 1999JOM(592)41>.
Treatment of the imine of hexafluoroacetone with carbon tetrachloride, in the presence of

catalytic amounts of aluminum chloride, resulted in the formation of an imidoyl chloride
(Equation (43)) <2001JFC123>. The analogous compounds 30 and 31 were obtained from reaction
of a dihalide with Ph2C¼NSiMe3 <1987T2945> or with Ph2C¼NLi <1969JCS(A)1742>, respec-
tively. The preparation of pyrazolium salts, such as 32, has been described <2000JCS(P1)4356>.
Synthetic methods to obtain 1-chloroalkylcarbodiimides <1997ZOR108> and 2,4-dichloroimida-
zoles <1988ZOR986> are also available.
AlCl3 (cat.)
F3C NH 65–100 °C Cl
+ CCl4 F3C N CCl2 ð43Þ
CF3 82% CF3
Ph
N
Ph Ph Ph N
Br N Ph SbCl–6
N+
Ph Cl Bu t
Cl
30 31 32
4.03.2 HALOGEN AND PHOSPHORUS DERIVATIVES—R12CHalPR2,

R12CHalPR22, R12CHalPO(OR2)2, etc.
The chemistry of molecules bearing a carbon bonded to both halogen and phosphorus is involved
in several important applications. Thus, the syntheses of these compounds have been intensively
investigated and will be described in the following sections. This section is organized according to
the coordination number of the phosphorus, ranging from di- to hexacoordinate. However, the effort
has been concentrated toward the synthesis of tri- and tetracoordinate phosphorus compounds, which
have as the most important members, in order of presentation, the dialkyl (-haloalkyl)phosphines,
the halo (-haloalkyl)phosphines, the -halophosphonium salts, the -halophosphinic acid esters,
and the -halophosphonic acid esters (Figure 2).
Tricoordinate:
R X
R R
R P R P
R X
X X
Dialkyl Halo
(α -haloalkyl)phosphines (α -haloalkyl)phosphines
Tetracoordinate:
R O O
R R R R
R P R P OR R P OR
+ R R OR
X X X
α -Halophosphonium α -Halophosphinic α -Halophosphonic
salts acid esters acid esters
Figure 2 Examples of -halo phosphorus derivatives.
4.03.2.1 Dicoordinate Phosphorus Derivatives—R12CHalPR2

The formation of stable dicoordinate phosphorus compounds bearing a haloalkyl moiety has not
been reported. However, 2H-phosphirenes, such as 33, are intermediates in the formation of the
1H-phosphirenes 34 from phosphalkynes and tetrachlorocyclopropene (Scheme 12)
<1991SL433>. Other similar examples were also reported, as previously reviewed
<1995COFGT(4)95>. A review concerning three-membered carbo-phosphorus heterocycles,
including 1H- and 2H-phosphirenes, has been published <1990CRV997>.
Cl
Cl P C But P
Et2O, 25 °C But P
But
Cl
26–65% Cl
Cl Cl
33 34
Scheme 12
4.03.2.2 Tricoordinate Phosphorus Derivatives—R12CHalPR22, etc.

The tricoordinate phosphorus derivatives bearing a haloalkyl moiety can be divided into two different
groups. The first contains primary and secondary -halophosphines, whereas the second group includes
tertiary -halophosphines. This classification will be utilized in the presentation of the syntheses of these
compounds in the following paragraphs. The free phosphines, whose syntheses are also described in this
section, share a common feature: they are very sensitive to oxidative conditions.
4.03.2.2.1 Primary and secondary a-halophosphines—R2CHalPH2, R12CHalPH(R2)

The synthesis of primary and secondary -halophosphines has been restricted to the fluoro and
chloro derivatives. Since the publication of COFGT (1995), <1995COFGT(4)95>, there have been
no advances in the synthesis of fluorophosphines. However, some improvements in the known
approaches for the synthesis of -chlorophosphines have been achieved, and this is discussed below.
The most general method for the synthesis of chloroalkylphosphines is the reduction of a chloro-
alkylphosphonate, for which several conditions have been utilized. Based on the reported results, the
most efficient reducing reagent for this transformation is dichloroalane (Equation (44)) <1993IC5021,
1995JST135, 1996IC6667>. As phosphines are readily oxidized, whenever an aqueous work-up is
necessary, it has to be performed utilizing only deoxygenated water (Equation (45)) <1998CC457>.
Another reducing agent able to promote this reaction is aluminum hydride <1989PS(44)27>. Lithium
aluminum hydride has also been used <1987TL5811>. However, in this case reduction of the CCl
bond also occurred, leading to methylphosphine derivatives together with the desired product
<1989PS(44)27>. A boron-catalyzed reduction of phosphonates has also been developed. In such a
protocol the substrate is mixed with a mixture of anhydrous tris(pentafluorophenyl)borane and a
silane, leading to the phosphine in excellent yield (Equation (46)) <2002TL5569>. Another approach
to the synthesis of chlorophosphines is heating of the chloromethylphosphinic acid, to give chlor-
omethylphosphine, although in low yield <1966JOC2424>.
AlHCl2
O H
tetraglyme
Cl P Cl P ð44Þ
82%
OEt
i. AlHCl2, THF, –80 to 20 °C

O ii. Deoxygenated H2O, –10 °C H
P iii. MgSO4 P ð45Þ
OEt H
70%
Cl OEt Cl
H3SiPh (or H2SiPh2)

3–5 mol.% B(C6H5)3
O H
toluene, 20 °C ð46Þ
Cl P Cl P
OEt H
OEt 95%
4.03.2.2.2 Tertiary a-halophosphines—R22CHalPR12

There are several methods for the synthesis of tertiary -halophosphines, which are divided in this
section according to the substitution pattern on the phosphorus. Thus, in the following sections will
be discussed the synthesis of, in order of presentation, dialkyl (or aryl) (-haloalkyl)phosphines,
halo (-haloalkyl)phosphines, amino (-haloalkyl)phosphines, alkoxy (-haloalkyl)phosphines,

and phosphoryl (-haloalkyl)phosphines. In addition to these, a number of other approaches
have also been reported, as previously reviewed <1995COFGT(4)95>.
(i) Dialkyl (or aryl) (-haloalkyl)phosphines

Diphenyl(chloromethyl)phosphine is the starting material of choice in several studies. Thus, its
preparation has been carefully investigated. The reaction of diphenylphosphine and dichloromethane
under basic conditions, developed by Stelzer <1990CB995>, has been utilized by several groups
<1996OM3360, 2000MI94>. This procedure was recently optimized, leading to diphenyl(chloro-
methyl)phosphine in 95% yield (Equation (47)) <2001S626>. The phosphorus of a hetetocyclic
compound can displace a chlorine in dichloromethane, leading to the introduction of the chloro-
methyl unit (Equation (48)) <1985CC1010>.
CH2Cl2, KOH, Bu4NCl

Ph H2O, toluene, rt, 14 h Ph
ð47Þ
P P Cl
Ph H Ph
95%
CH2Cl2
0 °C, 30 min
Yield not ð48Þ
P P
reported
Li
Cl
Several studies toward the synthesis of phosphacycles have been performed. The synthesis of the
diphosphabutadiene 37 has been achieved by dimerization of the carbenoid 36, formed by treating
the dichloromethylene compound 35 with butyllithium (Scheme 13) <1995AG(E)555>. The
preparation of an analogous compound was also reported <1998JOM(553)135>. The heterocycle
37 can be transformed into the bicyclic compound 38 after heating, through a carbene intermediate
<1995AG(E)555>. Alternatively, under acidic conditions the compound 37 led to a -elimination
product 39 <1996PS(109-110)613> (Scheme 14).
n-BuLi, THF Ar Cl
Ar Cl –100 °C to rt Ar Cl P
P P
Cl 63% Li P
35 36 Cl Ar
Ar = 2,4,6-t-Bu3C6H2 37
Scheme 13
Ar
P Cl
But
100 °C Cl P
toluene, 45 min
37
quantitative But
38
Cl
AlCl3 Ar P P
37 But
Yield not
reported Cl
Ar = 2,4,6-t-Bu3C6H2 But
39
Scheme 14
Another strategy for the synthesis of heterocyclic compounds bearing a (haloalkyl)phosphine

moiety is the well-known [4+2]-cycloaddition. Thus, treatment of the unsaturated ,-dichloro-
phosphine 40 with base led to the phosphalkene 41, which gave the bicyclic compound 42,
after an intramolecular Diels–Alder reaction (Scheme 15) <1998CC457>. An intermolecular
version of this reaction was also reported in the synthesis of the -fluorophosphine 43 from
Me2N-P¼C(F)CF3 and cyclopentadiene <1992ZN(B)321>.
H i. Et3N, –30 °C Ph H
P ii. –30 to 20 °C P
Ph Cl
Cl Cl 70% Cl P
Ph
40 41 42
Scheme 15
NMe2
P
Me
F
43
(ii) Halo (-haloalkyl)phosphines

An efficient method to obtain monochloro(chloroalkyl)phosphines is by reacting the correspond-
ing dichloride with a Grignard reagent or with an organolithium compound. Thus, the chloro
phosphines R(Cl)PCH2Cl (R = cyclohexyl, CHMeEt, 2,4,6-t-Bu3C6H2 or 2,4,6-i-Pr3C6H2) were
prepared from Cl2PCH2Cl <1997ZN(B)883>.
Chloromethylphosphines were also prepared in a two-step procedure from chloromethylphos-
phine oxide, which is transformed into the corresponding thio derivative by P4S10. Then, in the
second step a sulfur exchange reaction with tributylphosphine gives dichloro(chloromethyl)-
phosphine (Scheme 16) <1986PS(28)289, 1961JA2299>. The halogen exchange reaction mediated
by magnesium bromide allowed the conversion of R(Cl)PCH2Cl (R = cyclohexyl) to R(Br)PCH2Cl
<1997ZN(B)883>.
O S
P4S10 n-Bu3P
Cl PCl2 Cl PCl2 Cl PCl2
68%
(2 steps)
Scheme 16
(iii) Amino (-haloalkyl)phosphines

Reaction of secondary amines with dichloro(chloromethyl)phosphine gave the corresponding chloro
amino phosphine in good yield (Equation (49)) <1993JOM(462)111>. An analogous reaction also
occurred using R2NSiMe3 (R = Et or i-Pr) <1997ZN(B)883>. Under basic conditions, a nitrogen
of the phosphorus amide 44 can promote an intramolecular displacement of the chloride, leading to
the heterocyclic compound 45, in good yield (Equation (50)) <2002ZOB1157>.
NHR2
Cl pyridine NR2
Cl P Cl P ð49Þ
Cl R = Et: 88% Cl
R-Pri: 80%
O Et3N H
Cl P CH3CN N O
NHCONH2 Cl P
86% ð50Þ
Cl NH
44 45
The unusual heterocyclic compound 46, which bears an amino (-haloalkyl)phosphine moiety,
was isolated from the base-catalyzed reaction of ClCH2PCl2 with 2-aminopyridine
<1986PS(28)289>. Amino (bromoalkyl)phosphines were prepared from R(Cl)PCH2Cl
(R = Ph2N, Et2N, and i-Pr2N) by a halogen exchange reaction promoted by magnesium bromide
<1997ZN(B)883>.
N Cl
N P
P N
Cl N
46
(iv) Alkoxy (-haloalkyl)phosphines

Reaction of a phenol with dichloro(chloromethyl)phosphine gave the chloro phenoxy (chloro-
methyl)phosphine, in good yield (Equation (51)) <1993JOM(462)111>.
ArOH
Cl OAr
pyridine
Cl P Cl P ð51Þ
Cl 70% Cl
Ar = 2,6-Pr2i C6H3
(v) Phosphoryl (-haloalkyl)phosphines

The amino phosphine 47, which possesses a PP bond, was isolated from the base-catalyzed
reaction of ClCH2PCl2 with thiobenzamide <1986PS(28)289>.
Ph
N S
Cl P
P Cl
Cl Cl
47
4.03.2.3 Tetracoordinate Phosphorus Derivatives—[R12CHalPR23]+X , R12CHalP(O)R22,

R12CHalPO(OH)R2, R12CHalPO(Hal)R2, R2CHalPO(OH), etc.
4.03.2.3.1 a-Halophosphonium salt—[R12CHalPR23]+X

(Haloalkyl)phosphonium salts are useful reagents in organic synthesis, whose main application is
in the introduction of an unsaturated CC moiety. Thus, several methods have been developed
for their synthesis. An excellent review covering the preparation and application of these
compounds, as well as other phosphorus derivatives, has been published <2000S182>. Some
-halophosphonium salts, such as (chloromethyl)triphenylphosphonium chloride, are commer-
cially available.
A straightforward approach to the synthesis of (halomethyl)trialkylphosphonium salts is the
reaction of triphenylphosphine with an electrophile such as dihalomethane. Thus, when diethyl-
phosphine was treated with carbon tetrachloride, chloro(chloromethyl)diethylphosphonium chlo-
ride was formed <1993PS(85)41>. Reaction of chloroiodomethane with triphenylphosphine gave
(chloromethyl)triphenylphosphonium iodide in 70% yield <1979BCJ1197>. The preparation of
(bromomethyl)triphenylphosphonium bromide has been performed in an analogous manner
<1965JOC2208, 2002JCS(P1)2260>.
The halomethylation protocol described for the synthesis of N-halomethyl derivatives (see
Scheme 3 and Equations (5) and (6)) can also be used with phosphorus compounds. Thus,
reaction of triphenylphosphine with paraformaldehyde led to the hydroxymethyltriphenylphos-
phonium chloride, which gave (chloromethyl)triphenylphosphonium chloride when treated with
thionyl chloride (Scheme 17) <2002JCS(P1)2260>.
(CH2O)n, HCl
Ph SOCl2, CH2Cl2 Ph
Ether, 2 h Ph P+ Reflux, 1 h Ph P+
Ph3P OH Cl
Ph 52% Ph
–
Cl (2 steps) Cl–
Scheme 17
Reaction of triphenylphosphine with chlorocarbene, generated from dichloromethane and

butyllithium, gave chloromethyltriphenylphosphonium chloride <1960JA1510, 1961JA1613,
1961JA1617>. Similarly, treatment of triphenylphosphine with tetrachloromethane in the pres-
ence of water gave the same product <1977S699>.
The direct halogenation of alkylphosphonium salts to afford (haloalkyl)phosphonium salts in
good yields can be used for the preparation of iodoalkyl derivatives (Equation (52)) <1987S498,
1990S631>.
i. I2, K2CO3, NaOH
O 0–5 °C, 2 h O
+
+ ii. rt, 4 h Ph3P ð52Þ
Ph3P Ph
Ph Br–
Br– 84% I
Other approaches for the synthesis of (haloalkyl)phosphonium salts have been described for all
halogens in COFGT (1995) <1995COFGT(4)95>.
4.03.2.3.2 a-Halophosphine oxides and sulfides—R12CHalP(Y)R22

The synthesis of -halophosphine oxides and sulfides has been the subject of several reports.
These studies allowed the preparation of halo derivatives of all halogens with a variety of
substitution patterns. A detailed description of these methods was previously reviewed
<1995COFGT(4)95>. In the following paragraphs, some new and additional aspects are
discussed.
Aiming toward the synthesis of terminal monofluoro olefins, (fluoromethyl)diphenylphosphine
oxide 49 has been prepared from the corresponding tosylate 48, after treatment with anhydrous
potassium fluoride. The phosphane oxide 49 can be elaborated into more complex halo deriva-
tives by an aldol-type reaction with aldehydes, leading to compounds such as 50, as a mixture of
diastereomers (Scheme 18) <2001EJO897>. In somewhat analogous fashion, the (-chloro-
benzyl)diphenylphosphine oxide can be prepared from benzaldehyde and chlorodiphenylphos-
phine (Equation (53)) <2002JCS(P1)2260>.
i. LDA, THF, –70 °C

O KF, TEG O ii. C6H5CHO
160 °C, 15 min –70 °C, 15 min
Ph P OTs
Ph P F
Ph 80% Ph 73%
48 49
O OH O OH
TEG: triethylene glycol
Ph P C6H5 + Ph P
Ph C6H5
F Ph
F
50a 50b
Scheme 18
Cl
O Ph2PCl, 150 °C Ph
Ph P Ph ð53Þ
H Ph 68%
O
Treatment of tris(hydroxymethyl)phosphine oxide 51 with PCl5 led to the corresponding

chloride 52. Other phosphines were also obtained with this reagent <1990ZOB808>. The chloride
52 can be transformed into the bis(benzyloxy)derivative 53, although a significant amount of
the tris(benzyloxy) compound 54 is also formed in the reaction (Scheme 19) <2001T9149>.
Alkylphenyl(chloromethyl)phosphine oxides can be submitted to traditional nitration conditions,
affording alkyl(chloromethyl)(m-nitrophenyl)phosphine oxides <1990ZOB1511>.
O PCl5 O NaH, BnOH O

HO CHCl3, 60 °C Cl
P OH P Cl toluene, reflux, 3 h X P OBn
82%
OH Cl OBn
51 52 53 X = Cl: 60%
54 X = OBn: 37%
Scheme 19
4.03.2.3.3 a-Halo oxo acids of phosphorus
(i) -Halophosphinic acids and derivatives
(a) -Halophosphinic acids. The alkylation (followed by hydrolysis) of dihalo(alkyl)phosphines

with carbonyl compounds, the homologation of halo(alkyl)phosphines promoted by diazo-
methane, and the hydrolysis of halo(alkyl)phosphines appear to be the most useful methods to
obtain -halophosphinic acids. These reactions, as well as others, were previously discussed
<1995COFGT(4)95>.
(b) -Halophosphinic halides. When a (chloromethyl)phosphinate is mixed with phosphorus
oxychloride, the (chloromethyl)phosphinic chloride is formed. This reaction tolerates the presence of
several P-alkyl groups (Equation (54)) <1995JCS(P1)2045>. As phosphinates are readily available,
this reaction constitutes a general approach to the synthesis of (chloroalkyl)phosphonic chlorides.
Other useful methods for the synthesis of some chlorides, as well as other halogenides, are the
halomethylation of dihalophosphines and the reaction of aldehydes with dihalophosphines
<1995COFGT(4)95>.
R Yield (%)
O O
Cl P POCl3, 0 °C Cl P
Me 71
R R Et 50 ð54Þ
D D
D OEt D Cl
Pr 57
CH=CH 2 61
Ph 61
(c) -Halophosphinic acid esters. Reaction of -chlorophosphonochloridate with both satu-

rated and unsaturated aliphatic Grignard reagents gave the corresponding phosphinates in good
yields (Equation (55)) <1995JCS(P1)2045, 1993IC5021, 1996IC6667, 1996JCS(P1)2179>. Alter-
natively, the analogous phosphinate 57 bearing a phenyl group has been obtained from
phenyl(trichloromethyl)phosphinate 56, which was prepared by a Michaelis–Arbuzov reaction
from 55 and tetrachloromethane. Subsequently, the two chlorines of the compound 56 were
replaced by a deuterium (Scheme 20) <1995JCS(P1)2045, 1996JCS(P1)2179>. Thus, by selecting
the reaction conditions it is possible to substitute a PCl bond by a PR bond, where R may be
alkyl, alkenyl, or aryl.
R Yield (%)
O RMgCl
O
Cl P THF, ether Me 82
Cl Cl P ð55Þ
R Et 60
D D
D OEt D OEt Pr 54
CH=CH2 76
O i. n-BuLi, TMSCl, THF, –80 °C O

OEt CCl4, 80 °C ii. D2O, THF, –80 °C Cl P
Ph P P Ph
Cl3C Ph D
OEt 85% OEt 95% D OEt
55 56 57
Scheme 20
Phosphinic esters are also obtained from the corresponding chloride by an ethanolysis reaction
(Equation (56)) <1995JCS(P1)2045, 1996JCS(P1)2179>. The preparation of trimethylsilyl
bis(chloromethyl)phosphinate 58 was achieved from chloro bis(chloromethyl)phosphine oxide
using a variety of different silylating reagents <1999ZOB1788, 2001ZOB354, 2003ZOB159>.
Analogous phosphinates have also been obtained utilizing a similar approach <1999ZOB1788>.
O CF3CH2OH O
Cl P Et3N, THF, 20 °C
Cl
Cl P ð56Þ
O CF3
D
D Me 75% D
D
Me
O
Cl P
OSiMe3
Cl
58
Phosphonates are also suitable starting materials for the synthesis of chloroalkylphosphinates,
using a route that features two alkylation reactions utilizing organometallic reagents, as well as
the selective replacement mediated by POCl3 of the POR bond by a PCl bond (Scheme 21)
<1996JCS(P1)2179>.
O n-BuLi, MeI O POCl3

Cl Cl
LiCl, THF, –80 °C
(EtO)2P (EtO)2P Me 70 °C, 3 h
81% 73%
Me Me
O Cl MeMgCl, Et2O O Cl
THF, –70 °C to rt
Cl P Me Me P Me
74%
OEt Me OEt Me
Scheme 21
The halogenation of esters constitutes another possible route to synthesize halophosphinic

esters. This approach allowed preparation of the bromide and the chloride derivatives in reason-
able yields. However, the fluoride counterpart was obtained together with the corresponding
difluoride (Scheme 22) <1992JMC4885>.
One of the most commonly used reagents for transforming a hydroxy group into the corresponding
chloride, namely, a mixture of thionyl chloride and pyridine, has been explored for the preparation
of chloro phosphinate derivatives, although the yields were only moderate (Scheme 23)
<1996JCS(P1)2179>.
KOBut, FClO3 O O O O
F
toluene P P P P
EtO OEt + EtO OEt
Ph OEt Ph OEt
F F
50% 30%
O O i. NaOH, Br2, H2O, –5 °C O O
P P ii. SnCl2, acetone, H2O, rt
OEt P P
EtO EtO OEt
Ph OEt Ph OEt
51% Br
i. NaOCl, pH 7.3, 0 °C O O
ii. Na2SO3, H2O, acetone, 0 °C
P P
EtO OEt
52% Ph OEt
Cl
Scheme 22
i. EtOH
ii. MeCHO O OH SOCl2 O Cl
Alumina-KF Pyr, toluene
Ph PCl2 Ph P Ph P
38%
OEt Me (3 steps) OEt Me
Scheme 23
(d) -Halophosphinic amides and carbamoyl derivatives. The most common method for the
synthesis of (haloalkyl)phosphinic amides is the reaction of a primary or secondary amine with a
halo (haloalkyl)phosphine oxide <1995COFGT(4)95, 1998ZOB23>. In the past few years, efforts
have been directed mainly toward the synthesis of heterocyclic compounds bearing an exocyclic
P-chloromethyl unit.
The amide 60 has been prepared by the reaction of the chloride 59 with a carbamate. The amide
thus obtained was transformed into the heterocycle 61 under basic conditions <2002ZOB1157>.
Similarly, the chloride 59 gave 62 (Scheme 24) <2001ZOB354>. An annulation strategy has been
utilized for the preparation of heterophosphacyclanes such as 65 (Equation (57)) <1999ZOB865>.
Addition of ammonia to bis(chloromethyl)phosphinic isocyanate led to the amide 66
<2002ZOB1145>, which affords the heterocyclic compound 67 by a cyclization reaction mediated
by triethylamine <2000ZOB247, 2002ZOB1157>. The analogous two-step procedure, utilizing
diethylamine instead of ammonia, resulted in the isolation of a different heterocyclic compound
69, because in the latter case only the oxygen can act as an effective nucleophile (Scheme 25)
<2002ZOB1145>. The N,N-diethyl (-chlorobenzyl)phosphinic amide has been obtained by the
reaction of benzyl chloride with t-butyl tetraethylphosphorodiamidite <2002ZOB2061>.
H2NCO2Et O O Et3N O
CH2Cl2, K2CO3 benzene N OEt
Cl P P
O N OEt
81% H 77% O
Cl P Cl Cl
Cl 60 61
Cl O O
59 Et2NCOSiMe3 Cl P
NEt2
67%
Cl
62
Scheme 24
Me
O O Benzene O
Me 20 °C, 12 h N O
Cl P Cl P EtO P
N SiMe3 + NCO
57% N Cl ð57Þ
OEt Cl P
63 64 O
Cl
65
O H
NH3, ether O N
Cl P Et3N, CH3CN O
NHCONH2 Cl P
O 70% 86%
Cl NH
Cl P 66
NCO 67
Cl O
64 O
Et2NH, ether Cl P Et3N, ether N
Cl P NEt2
NHCONEt2
69% 52%
Cl O
68 69
Scheme 25
(e) -Halothio- and -haloselenophosphinic acid derivatives. Sulfur can act as an oxidant,
allowing the introduction of the P¼S bond, in reasonable yield (Equation (58))
<1995PS(102)133>. The formation of halothiophosphinic acid derivatives can be performed
from isothiocyanates (Scheme 26) <2002ZOB1145>. The preparation of the phosphinothiolate
derivative 70 from the corresponding PCl derivative has been reported utilizing three different
procedures <2001ZOB354>. The synthesis of other -halothio- and -haloselenophosphinic acid
derivatives has also been reported <1995COFGT(4)95>.
S
Cl PNEt2 S8, rt, 2 h Cl PNEt2 ð58Þ
Pri 58% Pri
Morpholine
Et3N, benzene S N O
Cl P N
S
98%
Cl P S
NCS ButNH2
Cl Benzene S N
Cl P NHBut
38%
S
Scheme 26
S
Cl P
OSiMe3
Cl
70
(f) -Halophosphinic anhydrides. Several routes were developed to obtain -halophosphinic

anhydrides <1995COFGT(4)95>, as exemplified in the synthesis of the anhydride 71, which has
been performed by several different protocols (Scheme 27) <1999ZOB1788, 2001ZOB354,
2002ZOB1157>.
(g) Miscellaneous -halophosphinic acid derivatives. Treatment of bis(dichloromethyl)phosphi-
nic acid with sodium <2001MI501>, with silver <2001MI501>, with lithium <2001MI1096>,
with lanthanum <2001MI396>, or with copper salts <2001MI838> led to the formation of the
corresponding crystalline complexes.
(ii) -Halophosphonic acids and derivatives
(a) -Halophosphonic acids. Several methods are known for the synthesis of -halophosphonic
acids <1995COFGT(4)95>. However, in the last few years, the most commonly used method
was hydrolysis of the corresponding ester, which can be prepared by several methods. The
reagent of choice to mediate such a transformation is bromotrimethylsilane (TMSBr), utilizing
59 59
EtO2P(O)H 65% 27% 58

Et3N, PhH
O H2NCONH2 O O K2CO3 O
Cl P Benzene, K2CO3 Cl P P Cl Benzene Cl P
Cl O NHCONH2
28% 36%
Cl Cl Cl Cl 66
59 71
O
MeCONH2
46% 30% Me C NHSiMe3
K2CO3, CH2Cl2
59 59
Scheme 27
dichloromethane as solvent. Several examples of this reaction have been reported, which refer
mainly to ethyl -fluorophosphonate derivatives, although isopropyl esters have also been hydro-
lyzed (Equation (59)) <1981JOC4573, 1998BMCL345, 1998CC1087, 1999JCS(P1)1051,
2000JCS(P1)1271, 2002JOC3065, 2003JOC5320>. The classical conditions for the hydrolysis of
an ester, namely, an aqueous solution of sodium hydroxide, led to the partial hydrolysis of an
ethyl -fluorophosphonate ester <1999JCS(P1)1051>. In the case of a t-butyl phosphonate, the
hydrolysis can be performed under acidic conditions utilizing an aqueous solution of acetic acid
(Equation (60)) <2003JMC3680>.
O TMSBr, CH2Cl2 O
i
Ph P OPr rt, 3 days Ph P OH ð59Þ
OPr i OH
75%
F F
O HO
F AcOH:H2O (4:1) F
OBut OH
O 75 °C, 15 h HO ð60Þ
P OBut P OH
O 50% O
N N
(b) -Halophosphonic dihalides. An efficient reagent to transform readily available phosphonic

acid esters into alkylphosphonyl dichlorides is a mixture of phosphorus oxychloride and phos-
phorus pentachloride (Equation (61)) <1993BSF485>. This transformation was performed with
dimethyl (bromomethyl)phosphonate using exclusively PCl5 <1998JCS(P1)211>. Bromomethyl-
phosphonic dibromide can be prepared from CH2Br2 and PBr3/AlBr3 <1997JCS(P1)527,
1998JCS(P1)211>. Other methods for the preparation of -halophosphonic dihalides have been
described, as previously reviewed <1995COFGT(4)95>.
O P(O)Cl3, PCl5 O
Cl P 110 °C, 4 h
OEt Cl P ð61Þ
Cl
OEt 88% Cl
Me Me
(c) -Halophosphonochloridates. Chloromethylphosphonates, which are readily available, can

be selectively chlorinated utilizing POCl3, leading to -halophosphonochloridates, in an efficient
manner (Equation (62)) <1995JCS(P1)2045, 1991SC793, 1993IC5021, 1996IC6667, 1999ZOB339>.
Another method to prepare phosphonochloridates is the monoesterification of a phosphorus
dihalide, utilizing several different sources of an alkoxy group such as alcohol and silyl ethers
(Equation (63)) <1997JCS(P1)527, 1998JCS(P1)211, 1999ZOB1788>.
O POCl3 O
Cl P 80 °C, 4 h
OEt
Cl P ð62Þ
Cl
D D
D OEt 70% D OEt
O TMSOR O
20 °C, 2 h
Cl P Cl P ð63Þ
Cl OR
Cl R = Me: 60% Cl
R = Et: 45%
(d) -Halophosphonamidic halides. The formation of -halophosphonamidic halides can be

efficiently achieved by a selective substitution reaction of a phosphonic dichloride and an amine.
Thus, the chloromethyl phosphorus derivative 73 has been prepared in 87% yield from the
dichloride 72 and trimethyl(N,N-diethylamino)silane (Equation (64)) <1999ZOB1788>.
Et2NSiMe3
O O
20 °C, 2 h
Cl P Cl P
Cl NEt2 ð64Þ
Cl 87% Cl
72 73
(e) -Halophosphonic acid esters. During the last few years, a tremendous effort has been
made toward the synthesis of -halophosphonic esters, especially for the -fluoro derivatives.
Some review articles related to this subject have been published <1997CRV3401, 1997S727,
2001JFC13, 2002YGK740>.
Phosphate ester derivatives have an important role in living organisms. However, it is readily
cleaved under physiological conditions by phosphatase enzymes, making impractical the proposi-
tion of new drugs with such a moiety. The replacement of the POC bonds by the PCHFC
unit is an alternative to increase stability without losing high affinity for the enzymatic site,
because the CHF moiety can mimic the bridging oxygen of the phosphate ester sterically and
electronically <1984JCS(P1)1119>. Thus, synthetic approaches to obtain fluoro phosphonates
that mimic the phosphate moiety have been thoroughly investigated <2001JFC13>.
The synthesis of -fluorophosphonates can be efficiently performed utilizing fluorinating
reagents. One such reagent is N-fluorodibenzenesulfonimide (NFBS) <1991SL395>. This reac-
tion is usually performed by treating an anion of the phosphonate with NFBS (Equation (65))
<1996TL8089, 1998CC1087, 2000JOC227>, although variations of this protocol to increase both
yield and selectivity have been reported (Scheme 28) <1998TL3693, 2000S576>. An analogous
fluorinating reagent, the N-fluorobenzenedisulfonimide (NFOBS), has also been developed. The
use of perchloryl fluoride for the fluorination of methanediphosphonate esters has been reported
<1981JOC4573>. Selectfluor1 (F-TEDA-BF4, Scheme 2) has been used to prepare -fluoro-
phosphonate (Equation (66)) <1999JCS(P1)1051, 2002EJO2640>. A three-step procedure –
sulfonylation, fluorination, and desulfonylation – is an alternative protocol to introduce the
fluorine atom into a phosphonate ester utilizing Selectfluor1 <1996JA2519, 2002JOC3065>.
O i. NaHMDS, THF, –78 °C O
ii. NFBS, THF, –78 °C
EtO P Ph EtO P Ph ð65Þ
EtO EtO
69% F
i. 2 equiv. LDA, THF

O –78 °C, 10 min O
TMS
(EtO)2P ii. TMSCl, THF, 0 °C (EtO)2P
Li
NFBS, THF O EtOLi, EtOH O
–78 to 0 °C, 15 min TMS 0 °C, 30 min
(EtO)2P (EtO)2P
89%
F (3 steps, one-pot) F
Scheme 28
O i. NaH, THF, 0 °C to rt, 90 min O

ii. Selectfluor, THF, DMF, rt
EtO P CO2H
EtO P CO2H ð66Þ
EtO EtO
17% F
The fluorination of -hydroxy phosphonates has been studied utilizing different reagents. One
of the most commonly used is (diethylamino)sulfur trifluoride (DAST), which gives a good yield
of the desired fluorinated molecule <1993JOC1336, 1993JOC5598, 1996JOC5159, 2000JOC4498,
2003JMC3680, 2003JOC5320>. However, racemization has been observed when an enantiomeri-
cally enriched substrate was used. A similar result was obtained utilizing 1,1,2,3,3,3-hexafluoro-
propyldiethylamine (PPDA) (Equation (67)) <1996T11725>.
OH F
DAST (or PPDA), CH2Cl2
P(OEt)2 –78 °C (0 °C), 1.5 h (or 12 h)
P(OEt)2 ð67Þ
O O
81%
88% ee (or 49%)
8% (or 5%) ee
The TBAF-mediated nucleophilic displacement of a triflate has been applied to the synthesis of
a fluorophosphonate (Equation (68)) <1999JCS(P1)1051>. Fluorophosphonates have been
accessed by a hydrolytic kinetic resolution of the racemic fluoro epoxide 74, utilizing a cobalt
salen complex (Equation (69)) <2003JOC5320>. A Diels–Alder reaction has been used to obtain
the fluoro-phosphonate 76 <2000CC395>. The hydrogenation of (-fluoropropargyl) phospho-
nates allowed the synthesis of unsaturated fluoro derivatives, such as 77 <1998T15541>. Magne-
sium chloride in the presence of triethylamine can promote the acylation reaction of
fluorophosphonates, leading to compounds such as 78, although in low yield <1999T12983>.
O O
TBAF, THF, rt, 1 h
EtO P OTf EtO P F ð68Þ
EtO 67% EtO
(R,R )-75
F H2O, THF F OH F
O OEt O OEt OEt
+ HO
P OEt P OEt P OEt
O 48% O 36% O
74 90% ee
H H ð69Þ
N N
M M = Co(OAc)
But O O But
But But
(R,R )-75
O
P(OEt)2 F
O O O
F
P(OEt)2 (EtO)2P
Ph
F CO2Et
Ph
76 77 78
A general approach to the synthesis of functionalized -fluorophosphonates is the displace-

ment of a leaving group from a gem-heteroatom-fluoro substrate to form a new CC bond. The
palladium-catalyzed addition of the gem-iodo-fluoride 79 to allyl alcohol giving 80 is an
example of such a transformation (Equation (70)) <2003JOC5320, 1998JFC39>. It is also
possible to use the Michaelis–Arbuzov reaction between the triethyl phosphite and the bromide
81 to obtain 82 (Equation (71)) <1991JOC273, 1994JOC7085>. Reaction of (EtO)2P(O)CFHBr
with zinc in THF led to the organometallic species (EtO)2P(O)CFHZnBr, which can be treated
with electrophiles, such as allyl halides and diethylchlorophosphate <1999TL2681>, to provide
functionalized fluorophosphonates <1999TL2681>. A two-step approach was investigated by
Berkowitz utilizing the reaction of the potassium salt of diethyl (-fluoro--phenylsulfonyl-
methyl)phosphonate with triflates or iodides. The -fluoro sulfonylphosphonate, thus obtained,
is desulfonated with Na(Hg) (Scheme 29) <2001OL2009>. In a similar fashion, the lithium
derivative of the diethyl(dibromofluoromethyl) phosphonate 83 is alkylated to give the silylated
fluoro intermediate 84, which afforded the desired compound 86, after hydrolysis (Scheme 30)
<1995CC719, 1996T165>. Several functionalized -fluorophosphonates have been synthesized
using an analogous approach <1993CC1711, 1997JCS(P1)1135, 1997JOC7260, 1997T6391,
1998MI49, 1998TL4477, 2003TL3987>. This procedure has also been used for the synthesis
of -chlorophosphonates <1998CC457>. The chemistry of silylphosphonates, as well as several
other aspects, has been reviewed <2001SL447>.
OH
F I F
OEt Pd(PPh3)4 OEt
I P OEt HO ð70Þ
79% P OEt
O O
79 80
F (EtO)3P F
140–150 °C EtO
Br CO2Et ð71Þ
71% EtO P CO2Et
O
81 82
KHMDS
O O O THF, HMPA
I + EtO P S –78 °C to rt
EtO 71%
F
O O O Na(Hg)
MeOH, THF O
EtO P S
NaH2PO4, rt EtO P
EtO F EtO
79%
F
Scheme 29
O
n-BuLi, TMSCl O OTf
O O
THF, –78 °C, 10 min –78 °C, 40 min
Br P OEt TMS P OEt
Br OEt Li OEt
F F
83 84
O F i. LiOH, EtOH, 0 °C O F
O O ii. NH 4Cl, ether O
O
P(OEt)2 83% P(OEt)2
TMS
86
85
Scheme 30
Chlorophosphonates can also be prepared by a variety of different methods. The preparation of

chlorophosphonates has been performed from the corresponding hydroxy compound utilizing
SOCl2 in triethylamine <1989PS(44)27, 1997S207>. This functional group transformation can
also be performed using a mixture of PPh3 and CCl4 <1990S717> or P(O)Cl3 <1965JA2777,
1992JOC1622>. The chlorinating agent hexachloroethane mediates the transformation of alkylpho-
sphonates into the corresponding -chloro phosphorus compounds <1998TL3693, 1999T2671,
2000JCS(P1)3311, 2001JOM(624)203> in a protocol similar to that described for the fluorination
with NFBS (see Equation (65)). When chlorine was bubbled through a solution of the phosphonate
87 in benzene, the corresponding -chloro phosphonate 88 was obtained in good yield (Equation
(72)) <1993ZOB93>. The ester ClCH2P(O)(OPh)2 was obtained by treatment of chloromethylpho-
sphonic dichloride with phenol in the presence of triethylamine <1995JST135>. Bis(trimethylsilyl)
(chloromethyl)phosphonate has been prepared from a phosphorus dihalide derivative (Equation
(73)). Mixed esters of -chloro (Equation (74)) <2003ZOB159, 2000ZOB699> and of -fluoropho-
sphonate <1985JCS(P1)233> can also be prepared.
O O Cl2, rt O O
P Benzene P
H OMe H OMe ð72Þ
OMe 82%
Cl OMe
87 88
O (Me3SiO)3P or O
Cl P (EtO)2POTMS ð73Þ
Cl P
Cl OTMS
Cl 53–57% OTMS
O O
(EtO)2PN(SiMe3)2
Cl P Cl P ð74Þ
Cl OTMS
OPh 81% OPh
An asymmetric approach to the synthesis of -aminophosphonates has been developed through

an -chlorophosphonate intermediate, formed by a Darzens-type reaction of a chiral, non-
racemic sulfinimine and diethyl 1-chloroethylphosphonate (Equation (75)) <1999OL1053,
1999TL249, 2003JOC2410>. Optically active 1-chloro-2-hydroxypropanephosphonates were
obtained by resolution mediated by Candida antartica lipase B (CALB) <2003OBC3564>. The
corresponding bromide was obtained by a dynamic kinetic resolution <1995JA2931>.
ClCH(Me)P(O)(OEt)2 O O
O LiHMDS, THF, S S
–78 °C, 20 min Ar NH O Ar NH O
S +
Ar N Ph P(OEt)2 P(OEt)2
Ph Ph ð75Þ
Ar = p -Tolyl Cl Cl
56% 23%
(Ss, 1R, 2R ) (Ss, 1S, 2R or S)
The preparation of a variety of -bromo- and -iodophosphonates has been described by a

halogenation reaction. Such a transformation has been performed from -hydroxyphosphonates
utilizing thionyl bromide <1997S207>, a mixture of N,N0 -carbonyldiimidazole (CDI) and allyl
bromide (or methyl iodide) <1996T10215>, PI3 <1997S207>, or NaI <1997T7291>. The direct
transformation of a methylene phosphorus derivative into the corresponding -bromo or
-iodophosphonate has been described using bromine <1961JOC1733>, dibromotetrachloro-
ethene, or iodine <1999T2671, 2000JCS(P1)3311, 2001JOM(624)203>.
(f) -Halophosphonic diamides. Aiming toward the synthesis of optically active -fluoro-
alkylphosphonic acids, the electrophilic fluorination of a chiral phosphonamide using N-fluoro-
benzenesulfonimide (NFSI) was investigated, allowing the synthesis of the desired molecule in
70% de by careful adjustment of the effects of both base and counter-ion in the course of the
reaction (Equation (76)) <2000JCS(P1)1271>. In addition, a straightforward approach to obtain
-halophosphonic diamides is reaction of an -halophosphonic dihalide with an amine
<1995COFGT(4)95, 1997JCS(P1)527>.
Me Me Base Yield (%) (de)

N i. Base, THF, –78 °C, 2 h N
O O n-BuLi 68 (68%)
ii. NFSI, 2 h ð76Þ
P P LiHMDS 81 (70%)
Ar Ar
N * N NaHMDS 69 (18%)
Me F Me KHMDS 71 (37%)
(g) -Halophosphonamidates. Starting from an -halophosphonic dihalide, it is possible to

form selectively the required PO and PN bonds. Depending on the structure of the dihalide,
the order in which these bonds are formed might be crucial for the success of the route. Thus,
when bromomethylphosphonic dibromide 89 is treated successively with an alcohol and an amine,
the phosphonamidates are obtained (Equation (77)) <1997JCS(P1)527>. However, adding the
amine first led to the formation of the corresponding phosphonic diamide <1997JCS(P1)527>.
Furthermore, using bromomethylphosphonic dichloride as substrate it is possible to
introduce first the amine group and, then the alcohol <1998JCS(P1)211>. This different
behavior is explained by the fact that the bromide is a better leaving group than the
chloride <1998JCS(P1)211>. The preparation of phosphonamidates has also been performed
by electrophilic fluorination using a protocol analogous to that described for the phosphonic
diamides (see Equation (76)) <2000JCS(P1)1271>.
i. (–)-Menthol
Et3N, CH2Cl2
O O
ii. Bu tNH2 Br P OR* ð77Þ
Br P Br
Br 27% NHBut
89 90
The phosphonamidate 91 can be obtained in 24% yield by treating the corresponding isocya-
nate with diethyl hydrogen phosphate <2000ZOB337>. A higher yield (74%) was obtained
utilizing gaseous ammonia in ether instead of the phosphate <2000ZOB247, 2002ZOB1145>.
O
Cl P
NHCONH2
OPh
91
4.03.2.3.4 Miscellaneous
The chloromethylphosphole 93, prepared from 92, can participate in cycloaddition reactions,
leading to bicyclic P-chloromethyl derivatives <1985CC1010>. The synthesis of tungsten-phos-
phorus complexes bearing a haloalkyl moiety, such as 94 <1995SL353>, 95. <1988JOM(354)83>,
and 96 <2000JOC652> has also been reported.
Cl
Br Ph Ph Ph
P P P P H
P Cl
Cl (OC)5W (CO)5W
W(CO)5 W(CO)5
Cl
92 93 94 95 96
4.03.2.4 Penta- and Hexacoordinate Phosphorus Derivatives—R12CHalPR24,

[A]+[R2CHalPX5], etc.
The synthesis of the pentacoordinate phosphorus derivative 98 bearing an unusual four-
membered 1,3,2,4-diazadiphosphetidine ring was reported (Equation (78)) <1993MI285>.
Another heterocyclic compound bearing a pentacoordinate phosphorus was prepared from
o-aminophenol and chloromethylphosphonic dichloride (Equation (79)) <2001ZOB363>.
Additional examples of penta- and hexacoordinate phosphorus derivatives have also been
reported, as previously reviewed <1995COFGT(4)95>.
O o-H2NC6H4OH O
Cl Cs2CO3, dioxane O
P N Cl H2N P N Cl
Cl 24% Cl NH2
N P Cl N P O ð78Þ
O O
97 98
Cl
NH2 Et3N
O O O
Benzene ð79Þ
+ ClCH2P P
OH Cl 24% N N
Cl H H
4.03.3 a-HALO ARSENIC, ANTIMONY, AND BISMUTH DERIVATIVES

Treatment of arsenic(III) oxide with dichloroacetic acid in the presence of sodium hydroxide gave
arsonochloroacetic acid (HO2CCHCl-AsO3H2), in 25% yield. Decarboxylation of this acid gave
chloromethylarsonic acid, in 84% yield <1995MI726>. The synthesis of other -halo arsenic
compounds has also been reported, as previously reviewed <1995COFGT(4)95>.
4.03.4 a-HALO ALKYLMETALLOIDS—R2CHalMETALLOID
4.03.4.1 a-Halo Silicon Derivatives—R12CHalSiR23

This section outlines the syntheses of compounds bearing a carbon bonded to both silicon and
halogen. The reactions were divided according to the substitution pattern on the silicon, which
led to the following groups: alkyl and aryl(-haloalkyl)silanes, halo (-haloalkyl)silanes,
(-haloalkyl)oxysilanes, and miscellaneous -halo silicon derivatives.
There are several silanes bearing a halomethyl unit that are commercially available, which
might be used as a building block in the synthesis of relatively more complex silanes. Examples
are (chloromethyl)trimethylsilane, (chloromethyl)triethoxysilane, (chloromethyl)dimethylisopro-
poxysilane, (chloromethyl)dimethylphenylsilane, (chloromethyl)trichlorosilane, (bromomethyl)-
chlorodimethylsilane, etc.
In addition to the methods described here, others also have been reported, as previously
reviewed <1995COFGT(4)95>.
4.03.4.1.1 Alkyl- and aryl(a-haloalkylsilanes)
(i) Compounds with SiH bonds

Several (fluoromethyl)silicon derivatives have been prepared by reduction of the SiCl and CBr
bonds of (fluorodibromomethyl)dichlorosilanes with excess of tributyltin hydride (Equation (80))
<1993OM4930>. Starting with a substrate such as (chloromethyl)methyldichlorosilane, it is possi-
ble to run the reaction with a Grignard reagent that replaces only one of the SiH bonds by a
SiR bond, thus leading to a relatively more complex silane (Equation (81)) <1989OM2031>.
Br
Br n-Bu3SnH, rt H
Cl F Si
F Si R = H: 98% H ð80Þ
Cl R
R R = Me: 95%
R = Et: 82%
ArBr, Mg
H Et2O, 24 h H
Cl Si Cl Si
H Ar ð81Þ
Me 32–42% Me
Ar = Ph, p-Me, p-F, m-CF3
(ii) Compounds with Sialkyl and Siaryl bonds
(a) -Fluorosilanes. An efficient method to obtain -fluorosilanes is the C-silylation of fluoro-

acetates utilizing LDA and trimethylsilyl chloride (Equation (82)) <1996T291>. An analogous
result has been obtained when triisopropylsilyl triflate was used instead of TMSCl <1998TL9613>.
i. LDA, TMSCl, THF, pentane O
O ii. Tartaric acid, H2O
F ð82Þ
F O
O
71% SiMe3
(b) -Chlorosilanes. The most commonly used method to synthesize -chlorosilanes is the
coupling of a (chloroalkyl)chlorosilane with an organometallic species. The reaction is usually
performed utilizing a Grignard reagent, tolerating the use of both aliphatic and aromatic halides
<1985OM1779, 1989OM2031, 1992JOC6552, 1994HAC265, 1995JOC8403, 2002JOC3561>.
Chlorosilanes are the typical substrates, albeit the use of a methoxysilane has also been reported
(Equation (83)) <1995OM251, 2003OM4343>. A copper-catalyzed Grignard coupling can
provide an alternative to the traditional conditions (Scheme 31) <2003T2451>. Although
Grignard reagents are most often used, organolithium compounds have been employed in several
applications in the synthesis of -chlorosilanes <1984OM1051, 1990OM2201, 1992JOC6552,
1994OM332, 2002JOC3561>, as exemplified in the studies of Tacke and Handmann toward the
synthesis of silicon-containing -amino acids (Equation (84)) <2002OM2619>.
CH2=CHMgBr
Ph THF, 20 h Ph ð83Þ
Si Cl Si Cl
C6H11 OMe C6H11 CH=CH2
91%
i. CH2=CHCHCH2MgCl
c -C6H11MgBr Cl CuCN, THF, rt
Cl R
Si Cl CuCN, Et2O, reflux Si Cl ii. I2, reflux, PhH Si Cl
Me Cl Me c -C6H11 Me c -C6H11
41% 38%
R=
Scheme 31
N OEt i. n-BuLi
ii. Me2Si(CH2Cl)2 N OEt N OEt
+
EtO N ð84Þ
EtO N EtO N
Me2Si Cl Me2Si Cl
85:15
The coupling of a chlorosilane with an alkynyllithium followed by a selective reduction

provides a useful strategy for the synthesis of chlorosilane bearing a vinyl group (Scheme 32)
<1992JOC6552>. A somewhat analogous approach is the hydrosilylation of alkynes with
HSiMe2(CH2Cl) (Equation (85)) <1984OM1655>. The introduction of an SiC bond into a
molecule to obtain a chlorosilane can also be performed using diazomethane <1994MI241>.
n-BuLi Me i. DIBAL-H Me
Me Si Cl + Si Cl
Si Cl 1-Octyne Me
ii. H3O
Me
Cl Me
C6H11 C6H11
Scheme 32
H2PtCl6, THF Cl
Cl
Pr iOH, 6 h ð85Þ
+ SiMe2
SiMe2
H 73%
Classical methods to transform a hydroxy compound into a chloride can also be used for the
preparation of (1-chloroalkyl)silanes <1992JOC386>. As the required (1-hydroxyalkyl)silane deriva-
tives are readily available from the reaction of silyl anions and aldehydes, this approach can be used to
obtain a broad spectrum of chloroalkylsilanes efficiently. The chlorination of chloro(methyl)silanes can
afford chloro(chloromethyl)silanes <1994MI241>. A method for the gas-phase chlorination of tetra-
methylsilane to prepare (chloromethyl)trimethylsilane has been developed <2001MIP1283625-A>.
(c) -Bromosilanes. Bromosilanes can be prepared by several different methods. A classic
reaction is the direct bromination of an alkylsilyl compound promoted by NBS, which usually
occurs in excellent yield (Equation (86)) <1991JOC3908>.
Me3Si Me3Si Br
NBS
CO2Me CCl4, hν CO2Me ð86Þ
95%
Another approach is the reduction of a silane, which has been performed under two different
conditions. Treatment of the dibromide 99 with butyllithium gave the monobromo derivative 100,
after quenching with an acid (Equation (87)) <2002JOC3561>. When Ph2MeSiCHBr2 was reacted
with lithium tributylmagnesate (n-Bu3MgLi), a bromine–magnesium exchange reaction took place,
leading to Ph2MeSiCH2Br in 89% yield after quenching with methanol <2001AG(E)2085>.
i. n-BuLi, Et2O, –78 °C, 10 min Z Yield (%)

Br
ii. HBr, –78 °C, 10 s
p-Z Ph p -Z Ph CF3 56
Br iii. H2O, rt Br
Si Si Cl 67 ð87Þ
Ph Ph
Ph Ph H 44
Me 45
99 100 OMe 39
The coupling of a lithiated phenyl sulfone with (bromomethyl)chlorodimethylsilane occurs

exclusively at the more reactive site—the SiCl bond—leading to a bromosilane, in good yield
(Equation (88)) <1997JOC7142>.
BrCH2SiMe2Cl
SO2But n-BuLi, THF SO2But
ð88Þ
87%
Si Br
Me Me
Aiming toward the synthesis of silylaziridines, the electrophilic addition of bromoazides,

prepared prior to use, to vinyl silanes was performed, giving the desired product in good yield
and selectivity (Equation (89)) <2000JCS(P1)1173>.
i. Br2, NaN3, CH2Cl2
HCl, 45 min
SiMe3 N3 Br ð89Þ
ii. 45 min, 0 °C H
H
Ph 84% Ph SiMe3
(d) -Iodosilanes. Iodoalkyl silanes are usually prepared by a halogen–iodide exchange reaction
from the corresponding bromides or chlorides <1947JA1976>. The typical protocol involves refluxing
the substrate with potassium iodide in anhydrous acetonitrile <1984OM1051>, although sodium
iodide can also be used <1994TL2047>. Several (iodomethyl)diphenylsilanes have been prepared by
this method from (chloromethyl)diphenylsilanes (Equation (90)) <2002JOC3561>. In addition, (iodo-
methyl)diphenyl(p-trifluoromethylphenyl)silane was prepared from the corresponding chloride in 65%
yield after the reaction with NaI in acetonitrile. Treating (p-dimethylaminophenyl)(bromomethyl)-
diphenylsilane with KI/CH3CN led to (p-dimethylaminophenyl)(iodomethyl)diphenylsilane in 55%
yield <2002JOC3561>. The exchange reaction of silanes ClCH2SiMe2(CH2)2R mediated by NaI where
R can be Et2MeSi, Et3Si, Ph3Si, or Et3Ge, gave the corresponding iodides in good yield <2001MI85>.
Z Yield (%)
KI, CH3CN
Ph 82 °C, 48 h Ph Cl 29
Ph Ph ð90Þ
Si Cl Si I H 60
Me 49
Ph-Z-p Ph-Z-p OMe 39
4.03.4.1.2 Halo (a-haloalkyl)silanes

There are two approaches to the synthesis of halo (-haloalkyl)silanes based on a halogenation
reaction. In the first, the hydrogen to be substituted is bonded to a silicon, whereas in the second
it is bonded to a carbon. The former case has been performed with chlorides or bromides in
several (fluoromethyl)silanes. For the synthesis of chlorides, the halogenation can be performed
utilizing SnCl4 <1993OM4930>, leading to (fluoromethyl)chlorosilanes. In the reaction with
bromine, substitution of all hydrogens occurs, furnishing (fluoromethyl)tribromosilanes
<1993OM4930, 1996JOM(511)293> (Scheme 33). Chlorination of dichlorodimethylsilane in
tetrachloromethane gave a mixture of dichloro(dichloromethyl)methylsilane and dichloro(chloro-
methyl)methylsilane, which can be separated by distillation <2001JST137>. New processes for
the production of (chloromethyl) chlorosilanes by a chlorination reaction have been developed for
compounds such as (ClCH2)CH3SiCl2, (ClCH2)(CH3)2SiCl, (ClCH2)SiCl3, (ClCH2)2CH3SiCl, and
(ClCH2)CH3SiCl2 <2001MIP1317488-A, 2002GEP10154943>.
SnCl4, 5 h Cl
F Si
H 98% H
F Si H
H
H
Br2, 2 days Br
F Si
75% Br
Br
Scheme 33
The reduction of a carbonhalogen bond can lead to halo (-haloalkyl)silanes. The previously
mentioned reduction of fluorodibromomethyl chlorosilanes promoted by n-Bu3SnH (see Equation
(80)) can take place exclusively at the dibromomethyl moiety by controlling the reaction time.
Thus, in such a case the isolated product is a fluoromethyl chlorosilane (Equation (91))
<1993OM4930>. A transition metal-catalyzed dechlorination of (polychloromethyl)silanes with
trichlorosilane, giving (chloromethyl)silanes, has been investigated. The transition metal com-
pounds tested were, in decreasing order of reactivity, Pd(OAc)2, PdCl2, Pt-C, H2PtCl6, Ni(OAc)2,
NiCl2, Pd(PPh3)2Cl2, and K2PtCl4 <1998OM570>.
n-Bu3SnH
Br
Br 25 °C, 24 h Cl
Cl F Si ð91Þ
F Si 81% Me
Me Me
Me
The coupling of chlorosilanes with organomagnesium and organolithium compounds discussed

above is also useful for preparing highly branched chlorosilanes (Scheme 31) <2002JOC3561>.
This strategy, for instance, has been used for the coupling of the organolithium
(2,4-LiBrC6H4)2NMe with the chloro silane Cl3SiCHClCH3, giving the tricyclic silicon hetero-
cycle 101 <1984OM1051>.
Me
N
Br Si Br
Cl
Cl
101
4.03.4.1.3 (a-Haloalkyl)oxysilanes
Hydrolysis of the bromosilane 102 led to the disiloxane 103 (Equation (92)), whereas the
cyclotetrasiloxane (CH2FMeSiO)4 has been obtained from the dibromosilane CH2FMeSiBr2,
under similar reaction conditions <1996JOM(511)293>.
Br Et2O, H2O Me Me
F Si O
Me F Si Si F
Me 64% ð92Þ
Me Me
102 103
In their studies toward the synthesis of compounds bearing cyclopentyl units by radical
cyclizations, Malacria and co-workers prepared a series of (bromomethyl)dimethylsilyl ethers
<1998JOC6764>. The approach to obtain these compounds consisted of the reaction of an unsa-
turated alcohol with (bromomethyl)dimethylsilyl chloride under basic conditions (Equation (93))
<1999JOC4920>.
Y Yield (%) (Condition)
(CH2)3CH(OCH2)2 73 (a)
OH Br Si CH2OCPh3 83 (a)
O SiMe3 89 (a)
Pri + Br SiMe2Cl a, b, or c
Pri Pri H 81 (a)
Y a: Et3N, DMAP, CH2Cl2 Pri t-Bu 92 (a)
b: Imidazole, DMF Y Ph 83 (b)
c: n-BuLi, THF (S)-SO-p-Tol 95 (b)
SO2-p-Tol 50 (c)
P(O)MePh 57 (c)
ð93Þ
4.03.4.1.4 Miscellaneous a-halo silicon derivatives

The (fluoromethyl)bromosilane 104 can be elaborated into the trisilylamine 106 in a two-step
sequence. In the first reaction, two nucleophilic attacks on the nitrogen toward two different
SiBr bonds occurred, leading to 105. In the second, the formation of the third NSi bond took
place through a lithiated intermediate (Scheme 34) <1996JOM(511)293>.
F
Me Me
H F SiMe2Br Si
Br Et2O, NH3 Me Me
N n-BuLi, hexane Me Me
F Si F Si Si F N
Me 70% 51% F Si Si F
Me Me Me
Me Me
104 105 106
Scheme 34
4.03.4.2 a-Halo Germanium Derivatives—R12CHalGeR23, etc.

Investigations of the bioisosterism of carbon and germanium compounds have led to a contin-
uous advance in the chemistry of germanium compounds, including the synthesis of the halo
germanium derivatives described in this section <1999PS(151)69>. As the carbonhalogen bond
is less reactive than the germaniumhalogen bond toward carbon nucleophiles, the general
approach to obtain such compounds is by reacting a halo(halomethyl)germanium derivative
with an organometallic species. Other methods have also been reported, as previously reviewed
<1995COFGT(4)95>.
4.03.4.2.1 Alkyl- and aryl(a-haloalkyl)germanes

The reaction of a chlorogermane derivative with an organometallic species has been utilized for
the synthesis of several (chloroalkyl)germanes. The introduction of an alkyl (or alkenyl or aryl)
group into a trichlorogermane using Grignard reagents can be performed with excellent control,
allowing the efficient synthesis of substituted (chloroalkyl)germanes, such as 107, which is an
alkyl alkenyl aryl germane (Scheme 35) <1996JOM(521)305, 2001JOM(640)140>. When the
target germane compound bears two identical substituents, its preparation is straightforward
from Grignard reagents. Thus, the dimethyl(chloromethyl)germane compound 109 has been
obtained from 108, in 90% yield (Equation (94)) <2002OM113>.
c -C5H9MgCl PhMgCl, THF

Cl Cl Et2O, rt to reflux, 20 h Cl
Ge Cl rt to reflux, 3 days
Ge
Cl Cl 56% Cl 87%
CH2=CHMgCl
Ph Ph
Cl THF, reflux, 1 h Cl
Ge Ge
Cl 81% CH=CH2
107
Scheme 35
Cl MeLi, Et2O Me
Cl Cl
Ge Ge ð94Þ
Cl 90% Me
108 109
4.03.4.2.2 Halo (a-haloalkyl)germanes

The reaction of tri- or dichloro (-chloromethyl)germane compounds with Grignard reagents can
also be used to obtain the corresponding monoaryl (or alkyl) derivatives, in an efficient manner
(Scheme 35) <1996JOM(521)305, 1998OM1687, 2001JOM(640)140, 2002OM113>. Another
approach is the copper-catalyzed homologation of chlorogermanes using diazomethane.
By treating germanium tetrachloride with diazomethane, it was possible to obtain either
trichloro(chloromethyl)germane <1955JA907, 1996JOM(510)157> or dichlorobis(chloromethyl)-
germane <1994CB639>.
4.03.4.2.3 Miscellaneous (a-haloalkyl)germanes

The chemistry of (-haloalkyl)germane derivatives bearing a GeGe or GeSi bond was also
investigated. Treating the chloro(chloromethyl)germane derivative 110 with Me2PhGeLi led to a
mixture of the compounds 111 and 112, which bear a GeGe bond (Equation (95))
<1989OM1237>. Alkyllithium reagents also react with halogermanes, as demonstrated by react-
ing ClGeMe2SiMe3 with ClCH2Li, which lead to ClCH2GeMe2SiMe3 <1993OM3979>.
i. Me2PhGeLi, THF
Hexane, –95 °C
Me ii. H2O Me Me
Me Ge Cl Me Ge Cl + Me Ge GeMe2Ph ð95Þ
Cl GePhMe2 GePhMe2
110 111 (57%) 112 (19%)
4.03.4.3 a-Halo Boron Derivatives—R12CHalBR22, etc.

This section aims to summarize the synthetic methods for the synthesis, in order of presentation, of
(-haloalkyl)boron hydrides, of alkyl- and aryl(-haloalkyl)boranes, of halo (-haloalkyl)boranes,
and of (-haloalkyl)oxyboranes. In the latter group are included -haloboronic esters, which are
useful compounds in asymmetric synthesis and have experienced significant progress recently.
4.03.4.3.1 (a-Haloalkyl)boron hydrides

The reaction of vinyl halides with boron hydrides occurs with formation of (-haloalkyl)boron
hydride, as previously reviewed <1995COFGT(4)95>.
4.03.4.3.2 Alkyl- and aryl(a-haloalkyl)boranes

The synthesis of isolable alkyl (-haloalkyl)boranes has been described in a few papers which
were previously discussed <1995COFGT(4)95>. An additional example of the formation of a
(-haloalkyl)borane and its use in situ has been reported. Treatment of dicyclohexylborane with
propargyl bromide led to the -bromoallylborane 113, which was trapped with aldehydes
<2000JOC8767>.
Br
113
4.03.4.3.3 Halo (a-haloalkyl)boranes

A few examples of the synthesis of halo (-haloalkyl)boranes have been reported in the literature,
as previously reviewed <1995COFGT(4)95>.
4.03.4.3.4 (a-Haloalkyl)oxyboranes
Since the pioneering work of D. S. Matteson, halo boronic esters are well-established reagents for
asymmetric synthesis. Studies toward their preparation have been investigated by several
researchers, and are summarized here. Several review articles are available for additional exam-
ples and further information <1986S973, 1988ACR294, 1989CRV1535, 1998T10555,
1999JOM(581)51>.
The most widely used method for the synthesis of -haloalkyl boronic esters is the homologa-
tion reaction of boronic esters promoted by halomethyllithium <1983OM1529>. This reaction
occurs in a highly stereoselective manner and with excellent yield, constituting an efficient method
for the synthesis of -chloro (Equation (96)) <1986JOC3150, 1995OM2855, 1998SL253> and
-bromo (Equation (97)) <1995OM2855, 1998SL253, 2000JOC6650> boronic esters.
i. CH2Cl2, n-BuLi
THF, –100 °C, 10 min Cl
ii. ZnCl2, rt, 18 h Ph3CO O
O B ð96Þ
Ph3CO B O 81% O
i. LDA, CH2Br2
THF, –78 °C TBSO N3
N3 O ii. ZnCl2, 25 °C O
B ð97Þ
95% B
TBSO O O
Br
A similar homologation reaction also occurs with borates, instead of boronic esters, as substrates.
Thus, treatment of the borate 114 with iodomethyllithium afforded the corresponding boronate
115, in good yield (Equation (98)) <1985OM1687, 1996JOC100>. Alternatively, the -halo
boronate obtained by this method might be hydrolyzed in situ, leading to the corresponding
boronic acid (Equation (99)) <1997BSF583>. The reaction of boronic acids with chiral diols can
lead to optically active boronates <1997BSF583>. An example of the use of the two latter reactions
in the synthesis of an enantiomerically pure boronic ester is the efficient preparation of the iodide
118 (Scheme 36) <2000JCS(P1)3250>.
n-BuLi, CH2I2
THF, hexane, –78 °C
B(OPri)3 I B(OPri)2 ð98Þ
70%
114 115
i. ClCH2Br, n-BuLi, THF

–78 °C, rt, overnight
ii. Aq. 1 M HCl OH ð99Þ
B(OMe)3 Cl B
60% OH
i. ClCH 2Br, n-BuLi, THF

MeO MeO
–78 °C, O O
Cl B I B
ii. TMSCl, –78 °C to rt NaI
iii. 116, Et2O O Acetone O
B(OMe)3
95% MeO 96% MeO
HO OH
117 118
MeO OMe
116
Scheme 36
Reaction of (R),(R)-2,3-butanediol dichloromethylboronate with t-butylmagnesium chloride in

the presence of anhydrous zinc chloride led to the corresponding chiral, nonracemic boronate
ester <1991JOC3286>. Some cyclic boronates, 119, 120, and 121, have been obtained by trans-
esterification of diisopropyl iodomethylboronate with the corresponding diols <1997TL765>.
Diisopropyl (-iodopentyl)boronate has been synthesized from the corresponding chloride by a
halogen exchange reaction <1999TL9183>. A large-scale route for the iodo boronate 122 has
been developed (Scheme 37) <1986JOC1610>.
O O O
B I B I B I
O O O
119 120 121
i. n-BuLi, TMEDA, –78 °C

ii. B(OMe)3, THF, –78 °C CH3I, NaI
O O
iii. AcOH, pinacol, THF CH3CN
S S B I B
41% O 90% O
122
Scheme 37
The bromination of the cyclic anhydride of isopropylboronic acid occurs smoothly using
bromine giving, after reaction with ethylene glycol, a boronic ester in good overall yield
(Scheme 38) <2003JOM(680)100>.
Br Br
O O O
B B Br2, light B B HOCH2CH2OH Br B
O O O O O
B B 80%
(2 steps)
Br
Scheme 38
4.03.5 a-HALO METAL DERIVATIVES

This section outlines the synthesis of molecules bearing a halogen and a metal bonded to the same
carbon and are called carbenoids. This name was first used by Closs and co-workers in the 1960s in
their studies concerning -haloalkyllithium compounds <1964JA4042>, referring now to molecules
bearing a metal and leaving group in the same carbon. The common name for this organometallic
species is the ‘‘Köbrich reagent,’’ named after the pioneering researcher <1963ZN(B)1125>.
With the evolution of laboratory techniques, occurring mostly due to evolution of the laboratory
techniques, carbenoids have become important synthetic intermediates. The generation of a carbene
is probably the most important application, because this highly reactive intermediate plays
an important role in new methods for the formation of CC bonds. Some review articles
covering several aspects of the chemistry of carbenoids have been published <1998AG(E)430,
2001CRV697>.
In this section, molecules bearing an -halo metal unit that were not isolated are also included.
4.03.5.1 Group 1 and Group 2 Derivatives—R2CHalLi, etc.

This section will describe the synthesis of lithium and magnesium carbenoids. The preparation of
useful -halomethyllithium compounds is discussed separately from the other -haloalkyl-
lithiums. Subsequently, the formation of -halomagnesium derivatives is discussed. A review
concerning some aspects of these compounds has already been published <2003CSR225>.
4.03.5.1.1 a-Haloalkyllithium derivatives
(i) -Halomethyllithium compounds

The preparation of -halomethyllithium compounds through a lithium–halogen exchange reac-
tion is performed by reacting a dihalomethane with an organolithium. Low temperature, usually
78 C, is crucial, because these intermediates are unstable <1995COFGT(4)95>. Thus, some
recent studies have been performed mainly to increase the stability of this organometallic reagent.
Concellón and co-workers reported the preparation of epoxides from aldehydes and ketones
using ICH2Li, describing for the first time that -halomethyllithium could be formed and handled
at 0 C. The protocol consisted of treating CH2I2 with MeLi in THF <2001T8983>. A study
concerning the preparation of dihalolithium compounds was reported, showing an aspect that
might be useful in future studies toward the corresponding halolithium derivatives. The stability
of Hal2CHLi, which usually decomposes at 65 C for the chloride and at 100 C for the
bromide and iodide, was increased significantly by complexation with transition metals, such as
Ti(O-i-Pr)4 <1988AG(E)943>.
(ii) Other -haloalkyllithium compounds

There are two general approaches to prepare lithium carbenoids. The first is the reaction of an
organolithium reagent (or lithium metal) and a gem-dihalo derivative, leading to a lithium–
halogen exchange as discussed above for -halomethyllithium compounds. In this method the
reactions are carried out at low temperatures, in which the carbenoids are stable. The second
approach is the -metallation of an organic halide, promoting a lithium–hydrogen exchange. This
reaction can be applied only for alkyl fluorides or chlorides, because for these halogens the
lithium–halogen exchange does not occur at a competitive rate. An advantage of this method is
that halides are usually more available than the corresponding gem-dihalo derivative. Examples of
both approaches are described in the following paragraphs.
The preparation of (3-pyridinylchloromethyl)lithium was performed utilizing lithium diisopro-
pylamine at low temperature (Equation (100)). In the presence of the ketones, this carbenoid
furnished epoxides, whereas aziridines were obtained from Schiff ’s bases <1996JOC4148>.
Similarly, treatment of allyl chloride with LDA led to the formation of -chloroallyllithium,
which is a versatile reagent for alkylation reactions <1981JOC1506, 1992OM1948,
1996JOC7513>.
Cl Cl
LDA
H THF, –78 °C Li ð100Þ
N N
Treatment of the dibromocyclopropane 123 with MeLi gave the halolithium 124, which
provided a cyclic ether by an intramolecular nucleophilic attack of the carbenoid moiety on the
ester group (Equation (101)) <1998TL9081, 2000T4799>. A similar process has also been
reported utilizing amides instead of esters <2001T1593>. A similar gem-bromolithium cyclo-
propane derivative was formed from the corresponding dibromide, using n-butyllithium
<1993JOC2958>. Under similar conditions, a fluoro carbenoid was formed from 1-fluoro-
1-iodo-2,2-diphenylcyclopropane <1993JOC546>.
MeLi
Br R1 Et2O, –90 °C Br R1
O Ph O Ph ð101Þ
Br Li
123 O 124 O
Hoffmann and co-workers investigated the stereoselectivity of the halogen–lithium exchange

reactions of gem-dibromides and of gem-diiodides. The reaction of the gem-dibromo compound
125 with n-butyllithium, for example, led to the carbenoids 126 and 127, in 3:1 ratio (Equation
(102)) <1995TL4595, 1996T7421>.
n-BuLi, –110 °C OR Br OR Br
OR Br Trapp–solvent mixture
+ ð102Þ
Br Li Li
125 R = TBDMS 126 3:1 127
An important aspect of -iodolithium compounds was also investigated, i.e., studying the
formation of 133 and 134 from the reaction of the diiodide 129 with n-butyllithium. In this
system, the iodine ate-complexes 129 and 130 are formed irreversibly and transformed into the
corresponding organolithium compounds 131 and 132, leading to the iodides 133 and 134 in the
same ratio under different quenching conditions (Scheme 39). Therefore, the stereoselectivity of
the formation of the ate complexes 129 and 130 defines the ratio in which the isomeric carbenoids
are generated <1998EJO1851, 1999JCS(P2)731>.
OR I n-BuLi RO I Li RO I Li
–110 °C – +
I I I
Bu Bu
128 129 130
R = TBDMS
RO I RO I RO I RO I
+ MeOD
Li Li D + D
131 132 133 134
Yield (%) Ratio
In situ 80 68:32
1 min 77 70:30
5 min 80 72:28
30 min 78 70:30
Scheme 39
4.03.5.1.2 a-Haloalkylmagnesium derivatives

The most commonly used method for the formation of -haloalkylmagnesium derivatives is
the reaction of a gem-dihalo compound with magnesium or with an organomagnesium
reagent. The crucial step in this general procedure is the halide–magnesium exchange reaction,
which was first reported by Villiéras, who demonstrated that the reactive magnesium carbe-
noids HCBr2MgCl can be prepared from HCBr3 using i-PrMgCl in THF at 78 C
<1967BSF1520>. Some advances in the preparation of -haloalkylmagnesium derivatives
have been reported recently.
The formation of some -chlorobenzylmagnesium chlorides from the reaction of ,-dichloro-
arylmethanes with magnesium has been reported in studies toward the synthesis of alkylarylcar-
binols (Equation (103)). Lithium can also be used to promote this reaction, through a lithium
carbenoid, although lower yields were observed <1997JOM(531)101>. Another protocol for the
preparation of -halobenzyl carbenoids is the treatment of a gem-dihalide with magnesium under
ultrasonic irradiation (Equation (104)). These organomagnesium compounds were reacted with
imines leading to aziridines <2001TL2759>.
Mg
Ar Cl Ar Cl
THF, rt ð103Þ
Cl MgCl
X X
Mg, Et2O
Br ))) MgBr ð104Þ
X = Cl or Br
The bromine–magnesium exchange reaction of ,-dibromo oxime ethers was used to prepare
pyrimidines through the organomagnesium intermediate 136, which was generated from the
reaction of a Grignard reagent with 135 (Equation (105)) <2002JA9032>.
OMe OMe
N n-BuMgBr N
–98 °C Br
Br Ph ð105Þ
Ph
Br MgBr
135 136
The stereoselective preparation of functionalized cyclopropylmagnesium carbenoids from a

dihalocyclopropanecarboxylate has been utilized for the synthesis of cyclopropyl derivatives.
The diastereoselectivity of the reaction depends on the solvent used. Thus, a stereoselective
Br–Mg exchange was observed by performing the reaction in diethyl ether (dr>99:1), whereas
the use of THF resulted in a lower diastereoselectivity (dr>65:35) (Equation (106))
<2002AG(E)351>. The formation of cyclopropanes was also achieved from a carbenoid
prepared by treatment of dichlorodiphenylmethane with magnesium in DMF (Equation (107)).
The formation of the dimerization product Ph2C¼CPh2 albeit in small amount indicated that
the reaction might also occur by a carbene intermediate <2003SL485>. The cyclopropanation
reaction promoted by carbenes, formed from magnesium carbenoids, was used in the
reactions with allylic alcohols, furnishing cyclopropyl alcohols in modest yields <1997TL7349>.
PriMgCl, Et2O
Me X –50 °C, 10 min Me X
ð106Þ
EtO2C X EtO MgCl
X = Br or I O
Mg, DMF
Ph Cl –5 °C Ph Cl ð107Þ
Ph Cl Ph MgCl
The formation of the carbenoid 138 from the reaction of a trialkylmagnesate with the gem-
dibromocyclopropane 137 was reported. The addition of eletrophiles to 138 gave double-alkylated
cyclopropane derivatives as a diastereomeric mixture (Equation (108)) <2002CEJ1730>.
n-Bu3MgLi, THF
n-C6H13 –78 to –30 °C n-C6H13
Br Br
ð108Þ
Br Mg(n-Bu)2
137 138
To obtain a better understanding of the reactions of Grignard reagents with electrophiles, several
studies have been performed to elucidate the mechanism of the halogen–magnesium exchange
<2003CSR225>. This addition is usually considered as a polar addition process, but there is evidence
that free radicals may also be involved. An approach to decide between these two alternatives involves
the use of a chiral nonracemic secondary Grignard reagent, since the loss of optical activity or the
formation of rearrangement products would indicate the presence of radicals formed by a single
electron transfer (SET) process. The preparation of chiral nonracemic secondary Grignard reagents is
very difficult to achieve by standard protocols because an achiral radical intermediate is involved.
Hoffmann and co-workers used the magnesium carbenoid chemistry to access such compounds
<2000AG(E)3072, 2000CEJ3359>. Thus, the enantiomerically pure -chloroalkyl sulfoxide 139
was treated with EtMgCl, furnishing the carbenoid 140. Subsequently, reaction of 140 with a second
molecule of EtMgCl, followed by quenching with phenyl isothiocyanate, gave 141 as a single
enantiomer (Scheme 40) <2000AG(E)1642>. Other contributions to elucidate the mechanism of
the halogen–magnesium exchange reaction were the experiments performed to identify the intermedi-
ate in the formation of the colorless 144. Supported by experiments such as, isotope effect, NMR
spectroscopy, and kinetic studies, the deep-yellow -ate complex 143 was proposed as the intermediate
(Scheme 41) <1998AG(E)824, 1999CEJ337, 2003OM2925>.
O EtMgCl, THF S
i. EtMgCl
S –78 to –30 °C ClMg ii. PhNCS Ph
Ar Ph Ph N Ph
Cl Cl H
139 140 141
Scheme 40
PriMgBr, THF I + MgBr I

I –78 °C, 2 min
Ph – 2h Ph
Ph I MgBr
I
142 143 144
Scheme 41
4.03.5.2 Transition Metal Derivatives—R2CHalFeXn, etc.

The preparation of complexes bearing an -haloalkyl unit can be performed by several methods,
the most used are: (i) the reaction of a metal complex bearing a halo-metal bound with a
diazo compound, usually diazomethane. This leads to an (-haloalkyl)metal derivative by an
insertion-type reaction, where the halogen of the product is that of the starting material. Copper
is frequently used as a catalyst in such a reaction; (ii) the oxidative addition of a transition metal
to a gem-dihalo-alkane which gives a halo (-haloalkyl)metal complex where both halogens, as
well as the alkyl chain, come from the dihalo derivative used as reagent.
Studies concerning -halometal derivatives have been reviewed <1991AOC235>.
4.03.5.2.1 Derivatives of chromium, molybdenum, and tungsten

The synthesis of the chloromethyl complex trans-[CrCH2Cl(acac)2L], where L is H2O, CH3OH, or
pyridine, using CrCl36H2O as starting material, was described. The protocol consisted of the treat-
ment of this chromium salt with amalgamated zinc, CHCl3, and HCl, giving a solution of the complex
[Cr(CHCl2)(H2O)5]2+. This complex was resubmitted to the treatment with CrCl36H2O, amalga-
mated zinc and HCl, affording the complex [Cr(CH2Cl)(H2O)5]2+. Addition of acetylacetone to a
buffered solution of the latter complex gave trans-[CrCH2Cl(acac)2(H2O)], in 15% yield, which was
treated with pyridine, furnishing trans-[CrCH2Cl(acac)2(py)], in 73% yield <1987IC2542>.
A general approach for the introduction of the halomethyl unit is the copper-catalyzed
homologation using diazomethane, used in the preparation of the following molybdenum
complexes. Thus, the preparation of (-C5H5)Mo(NO)2(CH2X) complexes 146–148 has been achieved
by the dropwise addition of CH2N2 to a slurry of Cu and the coresponding (-C5H5)Mo(NO)2X
complex 145. The same procedure was used to prepare (-C5Me5)Mo(NO)2(CH2Cl). The direct
formation of the iodomethyl derivatives by treatment of the (-C5H5)Mo(NO)2I with CH2N2/Cu is

especially sluggish. However, 148 and (-C5Me5)Mo(NO)2(CH2I) were obtained in good yield from
the corresponding chlorides under classic conditions for chloride–iodide exchange using NaI
<1996OM2534>. Such a reaction was also used in the preparation of the (iodomethyl)tungsten
complex 156 from the bromide derivative 155, in 87% yield <1993JOM(453)85>.
Mo NO OC Mo X OC W X
ON
X OC CO OC CO
145 X = Cl or Br 149 X = CH2OMe 153 X = CH2OMe

146 X = CH2Cl 150 X = CH2Cl 154 X = CH2Cl
147 X = CH2Br 151 X = CH2Br 155 X = CH2Br
148 X = CH2I 152 X = CH 2I 156 X = CH2I
The chlorine and bromine derivatives (150 and 151) were prepared in 80% and 40% yield,
respectively, by treating the (methoxymethyl)molybdenum complex 149 with the appropriate
hydrogen halide. The same procedure was utilized to obtain the (halomethyl)tungsten complexes
154 and 155, in 90% and 40% yield, respectively <1967JCS(A)1508>.
A straightforward method to obtain halomethyl complexes is the generation of an anion of
the complexes followed by treatment with a dihalomethane. The (chloromethyl)molybdenum
complex 150 could be prepared in 70% yield by the reaction between the sodium anion
Na[(-C5H5)Mo(CO)3] and the dihalide ClCH2I. However, an analogous reaction with CH2I2
furnished the complex 152, in low yield (17%), whereas treatment with CH2Br2 did not give the
corresponding bromethyl derivatives 151 <1973JOM(54)9>. The reaction between the tungsten
sodium anion Na[(-C5H5)W(CO)3] and ClCH2I furnished a mixture of the derivatives 154 and
156, in 60% and 12% yield, respectively <1973JOM(54)9>.
4.03.5.2.2 Derivatives of manganese, iron, and cobalt

The preparation of the chloromethyl and (bromomethyl)manganese complexes by an electrophilic
halogen exchange between boron trihalides and (fluoromethyl)manganese complex occurred in
good yield (Equation (109)) <1984OM305>. The iodomethyl complex fac-Mn(CO)3(dppp)CH2I was
prepared from the corresponding methoxy ether fac-Mn(CO)3(dppp)CH2OCH3 by reaction with
trimethylsilyl iodide <1999JOM(592)61>. The (chloromethyl)manganese complex Mn(CO)5CH2Cl
was prepared from the reaction between the metal anion of Na[Mn(CO)5] and ClCH2I, giving
Mn(CO)5CH2Cl, in 45% yield. The same procedure was utilized to prepare the complex cis-
[Mn(CO)4(PPh3)CH2Cl] from Na[Mn(CO)4(PPh3)] and ClCH2I, in 60% yield <1982JOM(236)221>.
CH2F CH2X
OC CO BX3, CH2Cl2 OC CO
Mn Mn ð109Þ
OC CO OC CO
CO X = Cl: 77% CO
X = Br: 79%
The reaction of a trialkylmanganate with the dibromocyclopropane 157 led to the -bromo-
manganate 158, formed by a bromine–manganese exchange (Equation (110)). Subsequently, the
intermediate 158 was transformed into a poly-alkylated cyclopropane derivative by a double
alkylation process <2000T2131, 2001T10063>.
C6H13 C6H13
Br n-Bu3MnMgBr Br
Br Mn n-Bu ð110Þ
n-Bu
157 158
The synthesis of (halomethyl)iron complexes has been performed using a similar procedure to that
employed to prepare the molybdenum and tungsten complexes 150 and 151 and 154 and 155,
respectively. Thus, treatment of (methoxymethyl)iron complex 159 with the corresponding hydrogen
halide furnished the complex 160 and 161, in 90% and 75% yield, respectively <1967JCS(A)1508>.
The preparation of the chloromethyl complex 160 using the metal anion of Na[(-C5H5)Fe(CO)2] and
ClCH2I furnished the desired product in low yield (13%) <1973JOM(54)9>.
OC Fe X
CO
159 X = CH2OMe
160 X = CH2Cl
161 X = CH2Br
Several cobalt(III) complexes have been prepared in studies toward the synthesis of models of
vitamin B12 and its derivatives. The perchlorate salt of (bromomethyl)cobalt complex 163 was
prepared in 76% yield by treating 162 with N-methylimidazole, followed by addition of CH2Br2
and NaBH4 <1985IC3908>. The same procedure was employed to prepare 167 from 166,
although in low yield (20%) <1997IC3854>. Treatment of 163 with a cation-exchange resin,
led to 164 in 77% yield. Reaction of 164 with pyridine furnished 165 in 31% yield. Other analogs
of 164 were also prepared <1997IC3854>.
N N
N
Co
N N
O N N
H O Co
L N
O N
162 R = L = Br H O
163 [R = CH2Br; L = N-methylimidazole]ClO4 R
164 [R = CH2Br; L = H2O]ClO4 166 [R = Br]ClO4
165 [R = CH2Br; L = pyridine]ClO4 167 [R = CH2Br]ClO4
The synthesis of another class of perchlorate salts of (halomethyl)cobalt complexes has been
described, where a reduction of cobalt(III) to cobalt(I) is involved. Thus, the complex 168 was
reacted with NaBH4 in the presence of a catalytic amount of palladium chloride, giving a Co(I)
species which displaced the iodide of ICH2Cl, leading to the complex 169 in 45% yield (Equation
(111)) <2001EJI267>. The preparation of the corresponding bromomethyl and (iodomethyl)-
cobalt derivatives was also reported <2001IC5541>.
2+ 1+
N N
Me OH O Me OH O
Me NaBH4, PdCl2 N Me
N N
N ICH2Cl H Co N
H Co Me H Me
N N
ð111Þ
H 45% H
N N
Me Me
N CH2Cl
168 169
4.03.5.2.3 Derivatives of ruthenium, rhodium, and palladium

The preparation of the (chloromethyl)ruthenium complexes 171 and 172 has been performed using
conditions similar to those described for the preparation of the corresponding molybdenum complexes.
Thus, the addition of ethereal diazomethane to a solution of the complex 170 in the presence of Cu
powder furnished the complex 171 in good yield, together with a minor amount of the complex 172.
Similarly, the complex 172 was prepared in 95% yield by two consecutive additions of CH2N2, both
using fresh Cu powder <1991JA9180>. The same procedure was employed in the preparation of the
allyl(chloromethyl) complex 173 from (-C5Me5)Ru(-C3H5)Cl2 <1995JOM(487)65>, in 52% yield.
In this case no trace of (-C5Me5)Ru(-C3H5)(CH2Cl)2 was detectable in contrast to the synthesis of
171. The (chloromethyl)ruthenium complex (-C5H5)Ru(CO)2(CH2Cl) could be prepared in 15% yield
from the corresponding (methoxymethyl)ruthenium complex (-C5H5)Ru(CO)2(CH2OMe) by treat-
ment with hydrogen chloride <1982JOM(236)221>.
Ru Ru
ON R2 Cl
R1 CH2Cl
170 R1 = R2 = Cl 173
171 R1 = Cl; R2 = CH2Cl
172 R1 = R2 = CH2Cl
The most common method used for the formation of a CRh -bond is by the oxidative
addition of gem-dihalogenoalkanes to a rhodium complex, giving the corresponding (halo-
methyl)rhodium complex. Depending on both substrate and reaction conditions, this reaction
can occur by three different mechanisms: an oxidative insertion, a nucleophilic SN2 substitution
<2001IC560>, or a radical pathway. The reaction of (-C5H5)Rh(C2H4)PMe3 and a dihalogeno-
alkane (ClCH2I, CH2Br2, CH2I2) gave the corresponding (halomethyl)rhodium complexes 174–
176 in 51%, 23%, and 78% yield, respectively <1985CB261>. Similarly, the complexes 177 and
178 were obtained in 43% and 65% yield, respectively, from (-C5Me5)Rh(CO)2 <1985CB3032>.
Other (halomethyl)rhodium complexes containing phosphine ligands, such as 179, were similarly
prepared <1985CB3032, 1985JOM(281)317, 1998EJI1605>.
Me3P Rh CH X Rh CH X Rh CH X
2 OC 2 (MeO)3P 2
X2 I I
174 X = Cl, X2 = I 177 X = Cl 179 X=Cl
175 X = X2 = Br 178 X = I
176 X = X2 = I
The oxidative addition of CH2Cl2 to the rhodium(I) complex [Rh2(C8H14)4(-Cl)2], in the

presence of a monodentate nitrogen ligand furnished a (chloromethyl)rhodium(III) complex in
77% yield, whose geometry is probably as shown in 180. Reaction of trans-[RhCl(CO)(PEt3)2]
with CH2I2 furnished the complex 181 in 67% yield. The reaction of the same starting material
with ClCH2I furnished [RhCl(I)(CH2Cl)(CO)(PEt3)2] in 20% yield as a mixture of isomers
<1994JCS(D)1963>. The rhodium compounds 182 and 183 were obtained in analogous fashion.
L CH2X
Cl CH2Cl RP CO
Rh Rh
L Cl Cl PR
L X
180 L = 4-t-Bu-py, X = Cl 181 R = Et3, X = I

182 R = Me3, X = I
183 R = Et2Ph, X = I
Vrieze and co-workers reported an extensive study concerning the preparation of (chloro-
methyl)rhodium(III) complexes containing trinitrogen ligands. Such a class of ligand can stabilize
the rhodium complex by donation of electrons, facilitating reactions where nucleophilic properties
are important. Thus, the rhodium(I) complexes participate in oxidative addition with alkyl
chlorides furnishing (chloroalkyl)rhodium(III) complexes such as 184 and 185 in 94% and 79%
yield, respectively (Equation (112)) <1997OM887>. The preparation of other (halomethyl)rho-
dium complexes bearing tridentate ligands has also been reported. Other interesting kinds of
tridentate ligands are the hybrid ligands which contain both P and N donor atoms
<1991OM2706, 1997JCS(D)1075, 1997JCS(D)3777>.
R1 R2 R1 R2
N R3–Cl N
–96 °C to rt Cl
N Rh Cl N Rh Cl
R3 ð112Þ
N N
R1 R2 R1 R2
184 R1 = H, R2 = i-Pr, R3 = CH2Cl

185 R1 = H, R2 = i-Pr, R3 = CHClPh
The synthesis of the (halomethyl)rhodoximes [RhX(dmgH)2(PPh3)] 187–189, was achieved in

37%, 74%, and 14% yield, respectively, by reduction of the rhodoxime 186 with NaBH4 in
methanolic KOH, followed by reaction of the generated rhodium anion with ClCH2F, CH2Cl2, or
CH2Br2 <1993JOM(463)65, 2001JOM(622)172>.
X
H
O O
N
N
Rh
N
O N
H O
PPh3
186 X = Cl
187 X = CH2F
188 X = CH2Cl
189 X = CH2Br
The preparation of the (chloromethyl)palladium complex trans-[PdCl(CH2Cl)(Pt-t-Bu2H)2] was

performed in 70% yield by the oxidative addition reaction of CH2Cl2 with the complex
Pd(PBut2H)3 <1993OM2432>. Several (chloromethyl)palladium complexes were prepared by a
ligand exchange reaction, utilizing as substrate a complex that already bears the halomethyl
moiety. Thus, the introduction of ligands such as sulfides, amines, and phosphines has been
performed in quantitative yield from the chloromethyl complex [Pd(CH2Cl)Cl(COD)]. Examples
of complexes obtained by such a strategy are 190–193 <1995OM2741>.
L Cl
L CH2Cl N CH2Cl CH2Cl
Pd Pd Pd Pd
Cl L N Cl Cl Cl L
190 L = pyridine N N = 2,2'-bipyridine L = SMe2

191 L = PPh3 192 193
The treatment of L2Pd(Me)Cl with [Li(Et2O)2.4][B(C6F5)4], CO, and vinyl chloride furnished the
(chloroalkyl)palladium complexes 194–197 in good yield (83–96%). Utilizing NMR techniques, the
formation of such complexes was proposed based on the formation of a cationic palladium acyl
complex L2Pd{(C¼O)Me}+, which would react with vinyl chloride by 2,1 insertion yielding the
palladium complexes 194, 195, 196, and 197 (Scheme 42) <2003OM1878>.
[Li(Et2O)2.4] Cl
Cl
[B(C6F5)4]
Me Me Cl
CO + + +
L2Pd L2Pd L2Pd L2Pd Me
O
Cl CO Me
O B(C6F5)4
B(C6F5)4
B(C6F5)4 194 L = 4,4'-M e2bipy
195 L = 4,4'-t -Bu2bipy
dmpe = 1,2-bis(dimethylphosphinoethane) 196 L = dppp
197 L = dmpe
Scheme 42
The presence of the palladium carbenoid 198 was proposed in the mechanism of Pd(0)-
catalyzed cross-coupling of functionalized arylmagnesium compounds with chloro- or bromo-
pyridines to prepare polyfunctional pyridines in good yields (Equation (113)) <2001TL5717>.
CO2Et – + CO2Et
ArPdLn Mg–X
Cl
Cl N LnPd N ð113Þ
Ar MgX
198
4.03.5.2.4 Derivatives of rhenium, osmium, iridium, and platinum

The cleavage of complexes bearing a methoxymethyl ether moiety is a general approach to obtain
rhenium complexes in good yield. Thus, cis-[Re(CO)4(PPh3)CH2I] was prepared from the reaction
of cis-[Re(CO)4(PPh3)CH2OCH3] and TMSI <1999JOM(592)61>. Similarly, Re(CO)5CH2OCH3
furnished Re(CO)5CH2Cl, Re(CO)5CH2Br, or Re(CO)5CH2I when treated with HCl, TMSBr, or
TMSI, respectively. However, an analogous approach failed for the preparation of the fluoro
counterpart Re(CO)5CH2F, for which the reaction of Na[Re(CO)5] with ICH2F has been utilized
<1993OM1073>. Two different strategies have been developed to access tetracoordinate rhenium
complexes bearing a halomethyl unit. The first was the treatment of a methyl hydride complex
with dichloromethane (Equation (114)), whereas the second was the halogen addition to a ReC
double bond (Equation (115)) <1998OM51>. On heating, the tetracoordinate rhenium complex
[(-C5Me5)Re(NO)(PPh3)(ClCH2Cl)]+ gave the oxidative addition product [(-C5Me5)-
Re(NO)(PPh3)(Cl)CH2Cl)]+ in 70% yield <1988JOM(354)C33>.
+ +
H CH2Cl2 Cl
Re
ð114Þ
Re
94% CH2Cl
CH3
+ +
H X2, CH2Cl2 X
Re Re ð115Þ
H 81–86% CH2Cl
X = Cl, Br or I
Compounds of iridium bearing an -chloromethyl unit have been prepared by standard

procedures, as previously described <1995COFGT(4)95>.
The method of choice for the synthesis of iridium complexes bearing an -halomethyl unit
is the treatment of an iridium complex with a dihalomethane compound. Using this approach,
chloro, bromo, and iodo derivatives have been obtained. The complex [-C5Me5IrCl(CH2Cl)PMe3]
was prepared from the reaction of [-C5Me5Ir(Ox)PMe3] (where Ox = oxalate) with CH2Cl2,
under photochemical conditions <1991IC836>. Treatment of [Ir(CO)2(-pz)]2 (where pzH =
pyrazole) with CH2I2 gave [Ir2(CO)4(-pz)2I(CH2I)], as the main product <1986CC285>.
The conversion of trans-[IrCl(CO)(PMe3)2] into trans-[IrCl2(CH2Cl)(CO)(PMe3)2] and the
conversion of trans-[IrClBr(CH2Br)(CO)(PMe3)2], or trans-[IrClI(CH2I)(CO)(PMe3)2] was per-

formed using CH2X2, where X = Cl, Br, or I <1980IC3236>. A binuclear (iodomethyl)iridium(II)
complex could be prepared using a similar approach (Equation (116)) <1987AG(E)444>.
The complex [Ir2(-aza)2(CH2I)(I)(CO)4], (where aza = 7-azaindolate) was similarly
prepared <1993JOM(445)273>. The insertion of a methylene into the chloroiridium complex
[IrCl(CO)(PPh3)2] was performed using diazomethane, yielding [Ir(CH2Cl)(CO)(PPh3)2]
<1966JA1654>.
S N S N
N
CH2I2 ð116Þ
N
S S
Ir Ir I Ir Ir CH2I
OC OC OC OC
CO CO CO CO
In contrast to other transition metals, there is a great diversity of methods available for the
synthesis of -haloplatinum derivatives. In analogy with iridium and rhenium, treatment of a
platinum complex with a dihalomethane compound affords the corresponding halomethyl deri-
vative. Thus, for example, a mixture of cis- and trans-[PtBrMe2(CH2Br)(1,10-phenanthroline)]
was obtained from [PtMe2(1,10-phenanthroline)] and CH2Br2 <1985OM1406>. The chloride–
iodide exchange reaction using NaI in acetone has been used to obtain a bis(iodomethyl)platinum
derivative (Equation (117)) <1988OM2082>. Another approach for the synthesis of molecules
bearing an -haloplatinum moiety is the transformation of a starting material that already bears
such a unit to the desired compound by exchanging one of the ligands <1991JCS(D)949,
1999OM2428>. In this fashion, [Pt(CH2Cl)(dppm)(PPh3)] (where dppm = Ph2PCH2PPh2) was
prepared in 56% yield from [Pt(dppm)(CH2Cl)2] and triphenylphosphine <1996JOM(517)227>.
NaI, rt
Ph3P CH2Cl acetone Ph3P CH2I
Pt Pt ð117Þ
Ph3P CH2Cl 85% Ph3P CH2I
The preparation of -haloalkylplatinum derivatives can be efficiently achieved by the insertion

reaction of a diazo compound into a halo-platinum bond <1986OM1171>. When diazomethane
is used, the insertion of a methylene unit occurs, leading to the corresponding (halomethyl)-
platinum derivative in good yield (Equation (118)) <1998JOM(554)105, 2001JOM(617-618)671>.
In the case of platinum complexes, the insertion reaction has also been performed utilizing diazo
compounds other than diazomethane, allowing the synthesis of -haloalkylplatinum compounds
<1987OM28, 1993OM2445>. Using this approach, Pt(dppe)Cl2 was reacted with ethyl diazo
acetate, giving a platinum(II) chloro ester in 80% yield (Equation (119)) <1991OM2989,
1997OM3083>.
Ph2 Ph2
CH2N2, rt
Ph P Cl Ph P CH2Cl
CH2Cl2, 12 h
H N Pt H N Pt ð118Þ
Me P Cl 80% Me P CH2Cl
Ph2 Ph2
Ph2 N2CHCO2Et Ph2 Cl

P Cl CH2Cl2, 20 °C P
Pt Pt CO2Et ð119Þ
P Cl 80% P Cl
Ph2 Ph2
4.03.5.2.5 Derivatives of copper, silver, and gold

The reaction of chloro complex [AuCl(PPh3)] with Mg(CH2Cl)Cl led to the corresponding
(chloromethyl)gold complex [Au(CH2Cl)(PPh3)], which furnished [Au(CH2I)(PPh3)] by chloride–
iodide exchange promoted by LiI in the presence of NaOMe and triphenylphosphine
<1998ZAAC(624)1303>. The preparation of other -halo metal derivatives bearing copper, silver,
or gold has been previously reviewed <1995COFGT(4)95>.
4.03.5.2.6 Derivatives of zinc, cadmium, and mercury

The chemistry concerning the synthesis of -halozinc derivatives has experienced a great advance in
the 1990s. The main reason for this was their use in asymmetric cyclopropanation reactions, motivat-
ing the search for new halomethylzinc compounds that could improve the efficiency of the reaction.
Some review articles cover several aspects of organozinc compounds, including examples of
-halozinc derivatives <1993JOC588, 1995SL1197, 2002T9463>. The iodomethyl zinc Zn(CH2I)2ZnI2
is the classic Simmons–Smith reagent. Later, Zn(CH2I)2 was used by Denmark and co-workers in their
studies toward diastereoselective cyclopropanation reactions <1992JA2592>. To expand the scope and
efficiency of this transformation, Charette and his group investigated the chemistry of several new
iodomethyl reagents, including a detailed study of their structure.
Treating diethylzinc with diiodomethane in dichloromethane led to EtZnCH2I <1995JOC2966,
1996JA4539>. Similarly, the chloromethylzinc carbenoid ZnCH2Cl was also prepared
<2001JA12168>. When EtZnCH2I was prepared in the presence of an ether such as 18-crown-6,
crystals of IZnCH2I18-crown-6 could be grown, which allowed its solid-state structure to be solved
by X-ray analysis <1996JA6792>. The preparation of stable iodomethylzinc reagents, such as 199,
was achieved in good yield by treatment of bis(iodomethyl)zinc in dichloromethane with 1,10 -bipyr-
idine <2000JA4508>. Moreover, the cyclopropanation reagent 200 was prepared from the corre-
sponding gem-diiodide 1-triisopropylsilyloxy-3,3-diiodopropane and Et2Zn <1997AG(E)1090>.
Other reagents utilized in cyclopropanation reactions are iodomethyl zinc alkoxides, which can be
prepared from an alcohol and Zn(CH2I)2 (Equation (120)) <1995JA11367>. The preparation and
solid-state structure of several halomethylzinc alkoxides have also been investigated <2001JA12160,
2002CC466>. Similar reagents are obtained from the treatment of diethylzinc, diiodomethane, and a
phenol, leading to phenoxide zinc carbenoids such as 201 <2000AG(E)4539>.
OZnCH2I
N N I I
Zn TIPSO OTIPS
IH2C CH2I Zn
199 200 201
Zn(CH2I)2
– 40 °C, CD2Cl2
ð120Þ
Ph OH Ph OZnCH2I
Quantitative
The reaction of a lithium enolate with bis(iodomethyl)zinc led to the formation of a carbon-
bound zincate, bearing the iodomethyl unit (Equation (121)) <1996JA11970>. In an analogous
manner, several zincate carbenoids, such as 202, were obtained from the reaction of the corre-
sponding organolithium with a dialkylzinc <1993JOC2958>. Alternatively, a zincate such as 203
may be generated from gem-dihalo compounds and dialkylzinc derivatives in the presence of
lithium bromide <2000OL2849, 2001SL818>. Furthermore, the carbenoid 204 was formed in a
stereoselective manner from 1,1-dibromo-2-phenylcyclopropane and dilithium tetramethylzincate
in THF at room temperature <2001JOC300>. The chloride 205 originated from the correspond-
ing gem-bis-zinc derivative after reaction with PhSO2Cl <1993SL665>.
Li+ O
OLi (ICH2)2Zn –
(IH2C)2Zn ð121Þ
Bn R
R
Ph ZnEt2Li ZnBu Ph ZnMe3Li2 Cl ZnOSOPh

Ph
Br I Br Hept
202 203 204 205
No further advances have occurred in the synthesis of cadmium and mercury derivatives since
the publication of chapter 4.03 in <1995COFGT(4)95>.
4.03.5.3 Group 3 and Group 4 Derivatives—R2CHalSnX3, etc.
4.03.5.3.1 Derivatives of aluminum, gallium, indium, and thallium

Treatment of a solution of tri(isobutylaluminum) in dichloromethane at 40 C with diiodo-
methane in the presence of a catalytic amount of oxygen gave i-Bu2AlCH2I, which was directly
used in the cyclopropanation of allylic alcohols <2001JOM(617–618)702>. Transmetallation of
an -halolithium derivative to the corresponding dimethylaluminum derivative has been per-
formed using dimethylaluminum chloride (Equation (122)) <1999CEJ337>. The formation of
other -haloaluminums, as well as -halothalliums and -halogalliums, have been reported, as
previously reviewed <1995COFGT(4)95>.
Me2AlCl, THF
I –105 °C, 15 min I
ð122Þ
Ph Ph
Li AlMe2
The preparation of Br2InCH2Br has been described by treating indium(I) bromide with an excess
of dibromomethane in acetonitrile. Similarly, Br2In(dioxane)2CH2Br and Br2In(THF)2CH2Br were
also obtained <1999OM99>. Reaction of Br2InCH2Br with Et4NBr gave [(Et4N)][Br3InCH2Br], in
95% yield <1999OM99>. The preparation of Br2In[OPPh3]2CH2Br from Br2In(dioxane)2CH2Br
and triphenylphosphine oxide was also described <2001JOM(626)68>. The reaction of a gem-
dichloride with indium powder led to the formation of -haloindium, which was reacted in situ with
carbonyl compounds (Equation (123)) <1996T2803>.
In, LiI, )))
Cl DMF, 3 h, rt In
ð123Þ
Cl Cl
4.03.5.3.2 Derivatives of tin

Several approaches can be utilized for the synthesis of -halo tin derivatives, as previously
reviewed <1995COFGT(4)95>. In the 1990s, only a few new methods and/or examples have
been reported. Bis(chloromethyl)dibutyltin can be prepared by metallation, followed by addition
of electrophile (Equation (124)) <1994OM24>. The introduction of the bis(chloromethyl) unit
has also been achieved treating tin tetrachloride with diazomethane in toluene, leading to
Cl2Sn(CH2Cl)2 in 85% yield. When the latter compound was submitted to the same conditions,
Sn(CH2Cl)4 was obtained in 40% yield. Hydrolysis of the stannane Cl2Sn(CH2Cl)2 in benzene
gave [Cl(CH2Cl)2SnOSn(CH2Cl)2Cl]2, in good yield <2002JOM(646)138>. The geminal dizinc
derivative CH2(ZnI)2 promoted the methylenation of Me3SnCl in THF, giving Me3SnCH2I in
26% yield <1994JOC2668>. The synthesis of some (1-bromoalkyl)tributyltin derivatives has been
described by transformation of an -hydroxy tin intermediate into the corresponding bromide by
reaction with CBr4/PPh3 (Equation (125)) <1995CC981, 1999OL945, 2001JOC8983>. Treatment
of tributyltin hydride with LDA and paraformaldehyde gave (hydroxymethyl)tributyltin, which
was transformed into the bromo and iodo derivatives using CBr4/Ph3P and NIS/Ph3P, respec-
tively <1994SC1117>.
i. i-Pr2NLi
ii. (CH2O)n
iii. MesCl ð124Þ
Bu2SnH2 Bu2Sn Cl
43% Cl
i. Bu3SnH, LDA, THF, –78 °C

S S ii. CBr4, PPh3, CH2Cl2 S S
H SnBu3 ð125Þ
R 67% R
O Br
R = SiPh2Me
4.03.5.3.3 Derivatives of lead

No further advances have occurred in this area since the publication of chapter 4.03 in
<1995COFGT(4)95>.
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Biographical sketch
Luiz F. Silva, Jr. was born in São Paulo, Andrea Maria Aguilar was born in São Paulo,
Brazil, in 1971. He studied chemistry at the Brazil, in 1973. She received her B.Sc. in
University of São Paulo, where he received his chemistry in 1995 at University of São Paulo
B.Sc. in 1993. In 1994, he joined the group of at Ribeirão Preto, where she also obtained her
Professor Helena M. C. Ferraz, at the Uni- M.Sc. in 1998, under the supervision of Pro-
versity of São Paulo, receving his Ph.D. in fessor G. V. J. da Silva. In 1999, she joined
1999. He then worked one year as a FAPESP the group of Professor H. M. C. Ferraz at
postdoctoral research associate with Professor University of São Paulo at São Paulo, where
Gary A. Molander, at the University of Penn- she received her Ph.D. in 2003, working on
sylvania. He returned to Brazil and worked the total synthesis of the sesquiterpene muti-
two years as a FAPESP postdoctoral research sianthol, employing a thallium(III)-mediated
associate in the group of Professor Ferraz. In ring contraction in the key step. She is cur-
April of 2002, he accepted an appointment at rently working as postdoctoral research
the University of São Paulo, as Assistant Pro- associate in the group of Professor L. F. Silva, Jr.
fessor of Chemistry. His current research
interests focus mainly on the total synthesis
of bioactive compounds (natural or synthetic)
and the study of ring contraction reactions.
Further information concerning current
research projects can be obtained at his web-
site at http://www.iq.usp.br/wwwdocentes/
luizfsjr/index.htm. Besides chemistry, he also
enjoys sport and high mountain climbing.
4.04
Functions Bearing Two Oxygens,
R12C(OR2)2
J. O. HOBERG
University of Wyoming, Laramie, WY, USA
and
B. L. STOCKER
Victoria University of Wellington, Wellington, New Zealand
4.04.1 -DIOLS—R2C(OH)2 194

4.04.1.1 -Diols by Hydration of Carbonyl Compounds Bearing Electron-withdrawing Groups 194
4.04.1.2 -Diols by Oxidation of Active Methyl or Methylene Groups 196
4.04.1.3 -Diols from Strained Cyclic Ketones 197
4.04.2 HEMIACETALS—R12C(OH)OR2 198
4.04.2.1 Hemiacetals from Aldehydes and Ketones by Addition of Alcohols 198
4.04.2.1.1 Acyclic hemiacetals 198
4.04.2.1.2 Cyclic hemiacetals from hydroxy carbonyl derivatives 199
4.04.2.2 Hemiacetals from Esters 205
4.04.2.2.1 By reduction 205
4.04.2.2.2 By addition of carbanions 206
4.04.2.3 Hemiacetals from Enol Ethers 210
4.04.2.4 Hemiacetals from Acetals by Deprotection 211
4.04.2.4.1 From noncarbohydrate substances 211
4.04.2.4.2 From carbohydrate substances 211
4.04.3 ACETALS—R12C(OR2)2 212
4.04.3.1 General Methods 213
4.04.3.1.1 From aldehydes and ketones 213
4.04.3.1.2 From acetals 217
4.04.3.1.3 From enol ethers and alcohols 217
4.04.3.1.4 From silyl enol ethers and enol acetates 220
4.04.3.1.5 From gem-dihalides by alkylation 220
4.04.3.2 Symmetrical Acetals 221
4.04.3.2.2 From orthoesters and nucleophiles 221
4.04.3.2.3 From alkenes and alkynes 222
4.04.3.2.4 From dithioacetals and O,S-acetals 222
4.04.3.2.5 Electrochemical methods 223
4.04.3.2.6 Miscellaneous methods 223
4.04.3.3 Unsymmetrical Acetals 224
4.04.3.3.1 From -substituted ethers and alcohols 224
4.04.3.3.2 From ethers 224
4.04.3.3.3 From cyclic hemiacetals 224
4.04.3.3.4 By hetero-Diels–Alder reactions 224
4.04.3.3.5 Mixed alkyl silyl acetals 224
4.04.4 OTHER DIOXYGEN DERIVATIVES 225
4.04.4.1 Synthesis of R12C(OCOR2)2 225
193
194 Functions Bearing Two Oxygens, R12C(OR2)2

4.04.4.1.2 From carboxylic acids 226
4.04.4.1.3 By oxidation of aromatic methyl and methylene groups 226
4.04.4.1.4 By oxidation of furan derivatives 226
4.04.4.2 Synthesis of R12C(OCOR2)OR3 227
4.04.4.2.1 From ethers 227
4.04.4.2.2 From enol ethers and enol esters 228
4.04.4.2.3 From carboxylic acids and carboxylic derivatives 228
4.04.4.2.4 From alcohols and carboxylate derivatives 229
4.04.4.2.5 From hemiacetals 229
4.04.4.2.6 From acetals 229
4.04.4.2.7 From aldehydes and ketones by oxidation 229
4.04.4.3 Other Derivatives 230
4.04.4.3.1 1,2,4-Trioxalanes (ozonides) 230
4.04.4.3.2 1,2,4-Trioxane 230
4.04.4.3.3 R12C(OR2)O2R3 231
4.04.4.3.4 R12C(OR2)OX and R2C(OX)2 (X = heteroatom) 231
4.04.1 a-DIOLS—R2C(OH)2
The addition of water or an alcohol to a ketone, giving, respectively, a hydrate or hemiacetal, is
an equilibrium that generally favors the starting materials. The unstable tetrahedral adducts,
however, can often be isolated or spectroscopically detected when one of the following criteria is
met: the addition of water or alcohol relieves strain, a strong electron-withdrawing substituent,
such as a polyhalogenated derivative, stabilizes the hydrate or hemiketal, or a carbonyl function is
adjacent to the position to be attacked. For example, upon storage, sterically unencumbered
nosylates (Ns = p-nitrobenzenesulfonate) are readily hydrated (Equation (1)) <1997JOC2458>,
and when t-butyl trifluoroacetoacetate 1 was left without protection from atmospheric moisture,
solid hydrate 2 was formed (Equation (2)) <1997CC359>.
NsO O Storage NsO HO OH

R1 R1
R2 OEt R2 OEt
O Toluene, reflux O ð1Þ
R1 = H, Me
R2 = H, Me Bui, Pri, C5H11, Ph, Bn, COOEt
O O OH O HO OH O
F3C OBut F3C OBut F3C OBut ð2Þ
1 2
4.04.1.1 a-Diols by Hydration of Carbonyl Compounds Bearing Electron-withdrawing Groups

Numerous studies have been conducted to determine the equilibrium constants and rates of
hydration for carbonyl compounds bearing electron-withdrawing substituents. The hydration
constant, Kh, of 3-(phenylacetamido)pyruvic acid 3 in organic solvents has been reported as
8.5 103 M1 (Equation (3)) <1997JOC4479>. Although modest, this value is larger than that
of pyruvate (1.3 103 M1), which is reasonable in view of the electron-withdrawing amido
substituent present in the amido acid. The greater electron-withdrawing ability of the trifluor-
omethyl functionality, however, results in a hydration constant for trifluororacetoacetic acid of
2.90 103 M1 <1999JA8345>. Remarkably, dissolving the (bis)arene ruthenium complex 4 in
wet solvents also led to its clean conversion into the new hydrated (bis)areneruthenium complex 5,
as evidenced by the absence of an aldehyde resonance and the presence of a new proton nuclear
magnetic resonance (NMR) at 6.16 ppm (Equation (4)) <2003JA1188>. This provides the first
example of the highly electronegative character of the aromatic rings in the dicationic bis(arene)-
ruthenium complexes extending to substituents attached to the arene rings. The astonishing
equilibrium constant for the hydration of 4, where R = H, was reported to be approximately
1.1 104 M.
Functions Bearing Two Oxygens, R12C(OR2)2 195
O H2O HO OH
PhCH2COHN PhCH2COHN –
(Kh = 8.5 × 10–3) ð3Þ
CO2– CO2
– H2O
3
O HO
OH
H2O
R R
Ru2+ Ru2+ ð4Þ
4 R = H, Me 5
Polyfluorinated carbonyl compounds, such as 6–9, add water readily to form hydrates.
Such hydration has been found to be considerably more favorable in cyclic rather than
acyclic systems with quantum mechanical calculations indicating that this difference can be
attributed to the steric hindrance in the acyclic adducts <1996TL9165>. An alternative
approach for the synthesis of the hydrate of ketone 8 involves bromination of an enol
followed by hydrolysis <1996JOC5109>, while hydrated 6 may be synthesized by hydrolysis
of the corresponding oxime <1996JA2556>. Following loss of hydrogen fluoride in the
presence of H2O, perhalogenated bicyclic compounds, such as 10, are readily hydrated
(Equation (5)) <1996JA9454>.
O O
O O
H Br
F5 F7 F7
F7
H H
6 7 8 9
X
I OH HO OH
F F H F F
H2O F F
F F –HF F F
F F F ð5Þ
F F F
F F F F
F F + H2O F
X = I, Br H
10
Trifluoroacetyl enone 11 also readily adds H2O, or MeOH, to afford hydrate 12 or the
hemiacetal, respectively (Equation (6)) <2001HCA3818>. The quantitative formation of these
C¼O addition products becomes evident from the NMR spectrum with the signal of the C-atom
adjacent to the CF3 group shifting from 185 ppm (C¼O) to values of around 95 ppm. Diketone
derivative 13, formed by the hydrolysis of the corresponding imine, exists primarily in its hydrated
form (Equation (7)) <1995JA10203>.
O O O OH
H2O CF3
CF3 OH
– H2O ð6Þ
11 12
R R H
H
N N NH2 H 2O N N NH2
H2N H2N
HO ð7Þ
O HO
O O
13
Acyclic hydrated ketones bearing perhalo groups are abundant. For example, after treatment
with hydrochloric acid in water, the HCl salts of N-protected amino trifluoromethyl ketones are
easily isolated <2000JOC3241>. -Halo pyruvamides are similarly hydrated by heating in H2O at
60 C for 1 h <1997T13739>, while liquid -cyanovinyl trifluoromethyl ketone 14 is readily
hydrated in the presence of water to give 15 (Equation (8)) <2002S71>.
NC CF3 H2O, Et2O NC CF3

O 30 min, rt, 97% HO OH ð8Þ
14 15
Indeed, the ease of hydrolysis of many polyhalogenated ketone derivatives is best reflected by
their preferential isolation after other organic transformations. For example, the Claisen con-
densation of phenylpropionitriles with ethyl trifluoroacetate using lithium diisopropylamide
(LDA) afforded -ketonitriles in their more stable hydrated form <2002TL9233>, while treat-
ment of N-methanesulfonylpiperidine with butyllithium in tetrahydrofuran (THF) at 78 C to
30 C, followed by addition of ethyl trifluoroacetate, yielded trifluoroacetylated methanesulfo-
namide in its hydrated form <1997S866>. Similarly, 4-hydroxy-1,1,1,3,3-pentafluoro-2-hexanone
hydrate may be synthesized by the aldol-type reaction between lithium pentafluoropropen-2-olate
and propionaldehyde <1999OS151>. Oxidation of tetrahydrofuran derivative 16 with KMnO4
also gave the hydrated ketone 17 in good yield (Equation (9)) <1995TL6091>. Ring opening of
epoxide 18 with diphenylphosphoric acid in a refluxing solution of hexafluoropropan-2-ol,
similarly resulted in the isolation of hydrated ketone adducts 19 in yields of 53–74% (Equation
(10)). Ring opening of the epoxide with other nucleophiles, however, gave only ketone derivatives
<2002EJO3402>.
HO
KMnO4 (2 equiv.) HO OH
CF3
O CF3 ð9Þ
F F Aq. NaOH, 20 °C O
F
F
81%
16 17
O
Ph P OH
O Ph HO OH
F3C H R
F3C ð10Þ
EtO R HFIP, reflux, 6 h H OP(O)Ph2
53–74%
18 19
R = Ph, C6H13, CH2CH2Ph
4.04.1.2 a-Diols by Oxidation of Active Methyl or Methylene Groups

In the late 1990s and early 2000s, dimethyldioxirane (DMDO) has become an increasingly
versatile oxidizing reagent. A highly efficient nickel(II)-catalyzed oxidation of 2-alkylated
1,3-dicarbonyl substances to the corresponding hydroxy derivatives by DMDO has been
described <1996T5799>. This procedure may be adapted to the synthesis of gem-diols such
as 20 (Equation (11)). Alternatively, DMDO has been used in the synthesis of thianinhydrin
21, either by oxidation of diazodione 22 or enamine 23 (Equation (12)) <1997T4239>. Sodium
periodate has also been used to oxidize enamines flanked by two carbonyl derivatives
<1996JOC1872>.
O O
O O DMDO, Ni(OAc)2
Me OEt ð11Þ
Me OEt HO OH
Acetone/ H2O, 20 °C
95%
20
O O O
OH NMe2
DMDO DMDO
N2
S
OH
S ð12Þ
S Acetone, 85% Acetone, 86%
O O O
22 21 23
A noteworthy, but somewhat more substrate specific reaction, is the autooxidation of enol 24 to diol
25 (Equation (13)) <1998T14053>. Examples of autooxidation of simple enols have been documented
in the literature, and the intermediacy of four-membered cyclic peroxy hemiacetals in the cleavage step
has also been noted. Acetal 24 was itself synthesized via an intramolecular spiroacetalization, followed
by intramolecular conjugate addition. The unprecedented photooxidation of cyclic allenes gives rise to
cyclic 1,2,3-trione hydrates (Equation (14)) <2000OL1383>. The formation of these compounds
points to a novel photooxidation mechanism involving both singlet and triplet oxygen.
OH O
OH O
CHO OH
Ce(NH4)2(NO3)6
H Air HO
72% O O ð13Þ
O O H O O H
O O
24 H 25 H
H
OH O
HO
O2, TPP, hν, CCl 4 O
ð14Þ
n = 3, 7 (73, 68%)
n n
4.04.1.3 a-Diols from Strained Cyclic Ketones

Highly strained, cyclic ketone derivatives are particularly susceptible to nucleophilic attack, as
illustrated by the ozonolysis of 26 leading to the preferential isolation of hydrated adduct 27
(Equation (15)) <1999TL447>. During the synthesis of the two lactones from levoglucosenone,
oxidation of the hydroxyl group of 28 under Swern conditions also gave 3,4-dianhydro--D-lyxo-
hexopyranos-2-ulose 29 as the hydrated adduct (Equation (16)) <1995BCJ670>.
HO OH
H H
N N i. O3, MeOH, –78 °C N N
O O O O
N N ii. DMS N N ð15Þ
H H
HO OH
26 27
O O
O O
(COCl)2, DMSO, CH2Cl2
OH ð16Þ
OH Et3N, 88%
O O OH
28 29
The combination of adjacent diketone moieties in cyclic ring systems further favors the formation
of gem-diols. Oxidation of 30 with bromine afforded the hydrated ketone in good yield (Equation
(17)) <2000JA7811>, while oxidation of 31, using Des-Martin periodinane, gave ketone hydrate as
the major product 32 (Equation (18)) <1998JCS(P1)3141>. Minor amounts of a regioisomer that is
presumed to be derived from silyl group migration was also observed in this reaction.
H OH H OH
H O H O
N N
Ph Br2, CH2Cl2 Ph
O O
ð17Þ
TMSO 84% O
OH
OTMS HO
30
H
O OH OH
O OH
O Des-Martin periodinane (1.1 equiv.)
O
Ph ð18Þ
O CH2Cl2, 18 °C, 1.5 h Ph
TBDMSO H O
TBDMSO H
31 32
Although the hydrogenolytic removal of the o-oxalyl protecting group in substrates analogous
to 33 has been previously discussed, liberation of the free cyclopropane 34 may also be achieved
with Pd/C (Equation (19)) <2001TL3183>. It is anticipated that cyclopropanes such as 34 will act
as transition state analog inhibitors of hydrolytic enzymes.
NHCO2Me HO OH
O H2, Pd/C
R2
O R1 NHCO2Me ð19Þ
R2 EtOAc (100%) R1
33 R1 = H, Me 34
R2 = Me, Et
4.04.2 HEMIACETALS—R12C(OH)OR2
4.04.2.1 Hemiacetals from Aldehydes and Ketones by Addition of Alcohols
4.04.2.1.1 Acyclic hemiacetals

Electron-withdrawing groups adjacent to a ketone are frequently used to stabilize acyclic hemi-
acetals. For example, -cyanovinyl trifluoromethyl ketone readily adds MeOH to give the
corresponding hemiacetal in 30 min <2002S71>, while refluxing racemic pyruvamide 35 in the
appropriate solvent yields stable hemiketal 36 exclusively as one diastereomer after selective
crystallization (Equation (20)) <1997T13739>.
O R1 R2 O R 1 R2
ROH, reflux X = Cl or Br
H2N X H2N X R = Me or Et
ð20Þ
O 48–74% RO OH R1 = aromatic
35 R2 = H, –(CH2)4–
36
In a manner analogous to that previously discussed for the synthesis of -diols, acyclic
hemiacetals may be synthesized by the addition of methanol to dicationic bis(arene) ruthenium
complexes. To assess the stereoselectivity of the carbonyl addition reaction, the o-anisaldehyde
complex 37 was reacted with CD3OD at 30 C, which gave within 10 min, two diastereomeric
hemiacetal complexes, 38a and 38b, with a de of 94% (Equation (21)) <2003JA1188>.
O H O O
OCD3 OCD3
CD3OD
O H OD
OD H
Ru2+ Ru2+ +
30 °C Ru2+
ð21Þ
37 38a 38b
97:3 (10 min)
47:53 (10 days)
4.04.2.1.2 Cyclic hemiacetals from hydroxy carbonyl derivatives
(i) By oxidation of diols

Manganese dioxide is a mild and selective oxidizing reagent for the oxidation of one hydroxy
group in the presence of another. This is illustrated in the synthesis of the C33C38 fragments of
Amphotericin B and Nystatin, whereby the benzylic hydroxyl was selectively oxidized (Equation
(22)). Through the intermediacy of ketone 39, hemiacetal 40 was derived in 83% yield
<1998SL201>.
OH R OH O R OH
MnO2 (15 equiv.) O
Ph Ph Ph R
ð22Þ
CH2Cl2, 0 °C to rt, 2 h
t OH
R = SiBu Ph2 83%
39 40
(ii) By reduction of dicarbonyl derivatives

Although NaBH4 is frequently used for the reduction of symmetrical dicarbonyl compounds, it
may also be used for the selective reduction of one carbonyl derivative in the presence of an
other, as illustrated by the well-reported reduction of the 16-ketone of the cholestan-16,22-dione.
Such intramolecular hemiacetal formation has been applied in the synthesis of furostan 41
(Equation (23)) <2001TL77>.
O
OH
OR
O OR O
NaBH4, PriOH ð23Þ
RO 64% RO
R = Bz-protected glucose 41
(iii) By addition of carbanions to dicarbonyl derivatives

The selective alkylation of an aldehyde in the presence of a ketone provides a convenient means to
synthesize hemiacetal derivatives (Equation (24)). Here the aldehyde is methylated, using an
excess of Me2Ti(Oi-Pr)2, giving rise to four cyclic hemiacetals. The major isomer (2R*, 4aR*,
8aS*) was, however, easily separated by flash chromatography <1995HCA663>.
O CHO O
HO
i ð24Þ
Me2Ti(OPr )2, THF
CO2Et CO2Et
80%
O O O O
(iv) Miscellaneous methods for the generation of hydroxy carbonyl derivatives

Numerous natural product syntheses involve the formation of hemiacetals via the cyclization of
an unmasked hydroxy or phenoxy group in the presence of a carbonyl functionality. The
deprotection of silyl ethers using tetrabutylammonium fluoride or hydrogen fluoride, followed
by intramolecular hemiacetal formation, is particularly common in the synthesis of many natural
products such as apoptolidin <2000OL1439>, the callipeltoside A aglycons <2002AG(E)841>,
the acyl side chain segment of polyoxypeptin A <2002TL9391>, and the C(19)–C(27) fragment of
rifamycin S <2001OL481>. Deprotection of an acetate group using a solution of sodium
methoxide in methanol was a key step during studies toward the synthesis of brevetoxin/cigua-
toxin <2002T1921>, while debenzylation, followed by hemiacetal cyclization, was the final step in
the synthesis of isofebrifugine <2001OL477> and the B-ring system of Taxol <1995CL181>.
Surprisingly, during studies into the synthesis of the AB subsection of the taxanes, the treatment
of benzylative derivative 42 with trifluoroacetyl (TFA) or with Zn(OTf)2 gave, via a reversible
1,5-hydride migration, hemiacetal 43 in 40–45% yield, Scheme 1 <1995TL1015>.
H H
H H
BnO
H H H
TFA
H OH H
O
H H
O
42
43
HO O HO
H H H
O OH O
Scheme 1
Alternative examples include the debenzylation of fluoro-pyruvamide 44 with titanium tetra-

chloride to form the new morpholine derivative 45 as a single diastereomer (Equation (25))
<1998T3799>. Upon hydrogenation with Pd/C, the highly strained tricyclo[3.2.1.0]octane 46
underwent concurrent debenzylation and ring expansion to form hemiacetal 47 (Equation (26))
<2001T997>. Similarly, the collective acid hydrolysis of both an imine-protected carbonyl and a
silyl-protected hydroxyl moiety lead to the formation 2,2-dichloro-5-hydroxypentan-2-one in a
14:86 equilibrium mixture with its cyclic form <1996S1131>.
H HO OH H
N TiCl4, CH2Cl2 N O
CF3
OH ð25Þ
O 76% O
Ph O CF3
44 45
HO
BnO
H CO2Et O
Pd/C, EtOAc CO2Et O CO2Et
BnO HO ð26Þ
84% 1:1
O O
47
46 O
Numerous oxidative strategies have been adapted for the synthesis of hemiacetals. Ozonolysis
can be used to generate a ketone moiety to participate in intramolecular cyclization with a
neighboring hydroxyl group (Equation (27)) <1999JA7540>. Similar methods have been applied
to the synthesis of sialic acid derivatives <2000OL2003, 2000SL865>. Interesting variations on
this method include the ozonolysis of dihydrofurans 48 (Equation (28)) <2001OL861>, while
ozonolysis of sultone 49, followed by eliminative work-up, delivered the expected hemiacetal 50 as
a single stereoisomer in excellent yield (Equation (29)) <2000TL7629, 1998EJO2073>.
O OTBDMS O OTBDMS
PhHN PhHN
OH i. O3, 10:1 CH2Cl2/MeOH, –78 °C ð27Þ
O
p-MeOBn CPh2 ii. Me2S, 72% p-MeOBn OH
Me Me Me Me
i. O2/O3, CH2Cl2, –78 °C OH

CO2Pr i O
CO2Pri ð28Þ
O ii. DMS
R HO O R
R = Me, 64%
48 R = Bui, 58%
Et H H H H H
O O i. O3, NaHCO3, CH2Cl2 Et O OH
SO2 MeOH, –78 °C O H
TBDMSO TBDMSO O ð29Þ
ii. Ac2O, Pyr, CH2Cl2 S OMe
49 O O O
OH 25 °C to reflux, 87%
50
The epoxidation of an olefin followed by the intramolecular attack of a hydroxy nucleophile is

another versatile method for the synthesis of hemiacetals. Epoxidation of homoallylic alcohol 51
with dimethydioxirane afforded tetrahydrofuran derivative 52 as a mixture of diastereomers
(Equation (30)) <1995TL6475>. Similarly, the stereoselective epoxidation of cyclooctene 53
with 3-chloroperoxybenzoic acid (MCPBA), followed by acid-catalyzed intramolecular ring-
closure, led to the isolation of L-idose analog 54 (Equation (31)) <2001TL1769>.
O O O OBn
OH DMDO, acetone/CH2Cl2
OBn 100% O ð30Þ
O OH
51 52
HO O
BnO
MCPBA BnO OH
BnO OMe BnO ð31Þ
CH2Cl2, 20 °C OH
BnO OBn
51% H
53 54
The regioselective epoxidation of furan derivatives such as 55, followed by bond reorganization
leading to pyranose derivatives of the type 56 (Scheme 2), has become a popular means by which
to synthesize the core structures of many natural products <1998AG(E)185, 1999T3553,
2002EJO3974>. The free hydroxyl group accelerates oxidation of the proximal furan and yields
for these reactions are typically good (76–93%). Similar oxidative ring expansions may be
conducted using Achmatowicz conditions (N-bromosuccinimide (NBS)/THF/H2O)
<2000OL863>. Another interesting adaptation of epoxides in the synthesis of hemiacetals
OH O
H HO OH
H O H O H
O DMDO
O O
H OH
H H O H
OPiv PivO PivO
55
56
Scheme 2
involves the base induced rearrangement of cis,cis-1,5-cyclooctadiene dioxide (Equation (32))

<1997T1855>. Using a mixed lithium diethylamine/t-butoxide system, this method was success-
fully applied in the synthesis of functionalized bicyclo[3.3.0]octanes <2001OL441>.
OH
LDEA/LiOBut (3 equiv.) O ð32Þ
O O
–20 °C, 4 h, 80% HO 70:30 O
The versatility of alkenes as precursors in the synthesis of hemiacetals is further exemplified by

the regioselective Wacker oxidation of cycloheptene 57 to yield hemiacetal 58 in 70% yield
(Equation (33)) <2003JOC2115>. The potassium permanganate oxidation of 1,5,9-trienes, com-
mencing with a kinetically controlled attack of the C¼C bond of the ,-unsaturated ester 59,
provides lactol 60 as a 6:1 mixture of epimers (Equation (34)) <2000CC1735>. Additionally,
osmium tetroxide has been used to dihydroxylate olefins, which in the presence of a carbonyl
group cyclize to form hemiacetals, as illustrated during the syntheis of laurencial (Equation (35))
<1998T1395> or the C-ring of Taxol <1995JOC7849>. Oxidation of bicyclic derivatives 61 with
catalytic RuCl3 and NaIO4 yields -keto hemiacetal 62 in good-to-high yields (Equation (36))
<2002JOC3783>. It has also been illustrated that Hyperforin, which contains a 1,3-diketone
functionality and exists as a mixture of interconverting tautomers, is extremely easy to oxidize by
MCPBA at the enolate double bond. The newly formed hydroxyl subsequently attacks a neigh-
boring ketone to give a hemiacetal in 100% yield <2002MI433>.
HO 10% PdCl2, CuCl HO O
HO OH
HO N CBz O2, H2O, DMF, 50 °C, 70% Bn N ð33Þ
HO Bn CBz
57 58
CO2Me KMnO , AcOH, acetone

4 HO OH
O HO ð34Þ
Acetate buffer (pH 6.5), 52% CO2Me
OH
59 60
O
OH
OsO4, Pyr
O ð35Þ
83%
OH
MeO OMe MeO OMe

X1 X2 R Cat. RuCl3·3H2O
O X2 R
NaIO4, 0 °C
HO
X1 X2 X2 ð36Þ
Me MeCN:H2O (6:1) O Me
HO Me 74–89%
Me
X1 = Cl, Br; X2 = Cl, Br, H 62
61
R = H, Me
Although less prevalent, there are nevertheless numerous oxidative strategies for the synthesis
of hemiacetals from nonalkene precursors. For example, the (EtO)3Si substituent in 63 was
oxidatively removed to afford hemiacetal 64 in 43% yield (Equation (37)) <1997TL5737>,
while the periodate cleavage of a 1,2-diol, followed by intramolecular nucleophilic attack on the
newly formed carbonyl by a hydroxy substituent, was the final synthetic step in the synthesis of
roflamycoin <1997JA2058>. Dimethyldioxirane has also been successively used to oxidize the
benzyl ether carbon of flavinoids. This method is of interest as it shows opposite selectivity to that
of other reagents that reportedly perform the oxyfunctionalization on the C-4 benzylic carbon
<1997TL4651>. The oxidative cyclization of iodo ketones may also yield hemiacetals, as illu-
strated in the synthesis 6-oxa-5-pregnane (Equation (38)) <1996JOC6673>. Oxidation of the
iodide to the highly labile iodoso intermediate, followed by displacement by the neighboring
ketone to form an oxocarbenium ion and subsequent nucleophilic attack by H2O from the axial
side, gives intermediate 5-hydroxy-6-oxasteroid in 67% yield.
(EtO)3Si O H2O2, NaHCO3 O
THF, MeOH OH ð37Þ

N 43% N
63 64
OAc OAc
HO2C HO2C
MCPBA, CH 2Cl2/H2O ð38Þ
0 °C, 7 h, 67%
AcO O I AcO O
OH
The stereoselective oxidation of unactivated CH bonds represents a unique method for
synthesizing hemiacetals. With oxone as an oxidizing agent, regioselective oxidation at a site
to that of a keto group affords a mixture of trans-hemiacetal and cis-hemiacetal (Equation (39))
<2003JA158, 2000JOC4179>. Alternatively, Cr[IV] can effect certain CH oxidations, as
illustrated by the unprecedented chemoselective oxidation of ether 65 (Equation (40))
<2002JA13978>. One other example has been reported, an unsaturated derivative, which
provides the analogous epoxy hemiacetal in 66% yield <2002JA13978>.
O Oxone/NaHCO3
CO2Me OH + OH ð39Þ
MeCN/H2O, rt, 62% O CO2Me O CO2Me
10:1
OBz
OBz
O
O CrO2(OAc)2 (0.05 equiv.) OH ð40Þ
Ac2O (3 equiv.), H5IO6 (3 equiv.) AcO

AcO 65 –40 °C, 20 min, 69%
Reductive strategies may also be used for the synthesis of hemiacetals. Palladium on carbon
catalyzes the reduction of azabicyclic peroxides under a hydrogen atmosphere to give the
corresponding 7-aza-2-oxabicyclo[3.3.0]octan-8-ones in almost quantitative yields (Equation
(41)) <1999TL3765>. 1,6-Dioxadecalins may be synthesized by the desulfonylation of phenyl-
sulfonyl[4,5] spiroketals. This process involves Na(Hg) desulfonylation, cleavage of the axial
C5O1 bonds to form diastereoselective enones, further in situ reduction of the conjugated
double bond, and cyclization to the most stable cis- or trans-fused hemiacetal (Equation (42))
<1996TL3179>.
R2 R3 R3
R1 H2, Pd/C R2
N R4 N R4
O R1 O
O CH2Cl2, 40 °C OH O
OH O ð41Þ
77–100%
R1, R2 = aryl, alkyl
R3 = H, CO2Et, CN, CO2Me, CO2Bu
R4 = Me, Et, Bui, Bn
O R1
SO2Ph O OH
R2 O Na(Hg), Na2HPO4 O R1
2 O
O MeOH, rt, 60–98% R2 O OH + R ð42Þ
H
R1
R1 = H, Me, Ph
R2 = H, Me
Cyclopropanes such as 66 may undergo acid-catalyzed ring expansion to afford eight-

membered hemiketals 67 in good yield (Equation (43)) <2002JA9056>. The cyclopropane is
synthesized in four steps from an alkenyl Fischer carbene with high enantioselectivity. Treatment
of dioxane 68 with a base, such as 1,4-diazabicyclo[2.2.2]octane (DABCO), led to the rapid
formation of ketone 69 that exists in equilibrium with hemiacetal 70 (Equation (44))
<1999T14739>. Alternatively, the mild decomposition of various -diazo carbonyl compounds
in the presence of clay or zeolite catalysts yields 3-furanones in good yields <2002SL407,
2001TL5113>. More specifically, cyclopropane hemiacetals may be synthesized by using the
Ti(II)-mediated coupling of monosubstituted olefins with carbonate derivatives (Equation (45))
<1996JOC4878>. While reaction yields are modest, a broad range of functional groups can be
conveniently introduced and the specific example shown is produced as a single diastereomer.
O
HCl, acetone, rt HO
O
H 72–90%
R1 H ð43Þ
R R R1
66 67
R1 = Me, Et
R2 = Ph, 2-furyl, 2-thienyl, 4-MeOC6H4
O
H CH3 HO
Me
O Me
DABCO (20 mol.%)
O OH O
ð44Þ
H 76%
68 69 70
OH
O
C5H9MgCl O
O O H ð45Þ
OTIPS + OTIPS
ClTi(OPri)3, THF
0 °C, 53% HO
Hemiacetals may also arise as a consequence of aldol-type reactions. Tetrahydropyran-2,4-diols can be

synthesized stereoselectively by a Ti(Oi-Pr)2Cl2- <1999EJO2007> or ZnBr2 <2001SL1992>-mediated
domino aldol reaction (Equation (46)). A large number of aldehydes have been studied and reported.
5-Deoxy ketose derivatives may also be synthesized in modest yields from a one-pot 2-deoxyribose-
5-phosphate aldolase and fructose-1,6-diphosphate aldolase catalyzed reactions <1995JA2947>. Alter-
native aldol-type reactions include the formation of dioxane derivative 71 in 57% yield after reaction of
an -bromoketone with 3,4-dihydroxybenzaldehyde (Equation (47)) <1996TL7955>.
i. LDA, THF, –40 °C, 1 h OH

O OH
ii. Ti(Oi Pr)2Cl2, –40 °C, 30 min Ph O R1 ð46Þ
Ph
iii. R1CHO, 10–50% Ph
OTHP OTHP
H3C HO CHO K2CO3, acetone H3C OH
+ O CHO
H3C Br reflux, 57% H3C ð47Þ
O HO
O
71
Other condensation-type reactions include the synthesis of oxazapines, such as 72, synthesized
via the condensation of 1,1,1-trifluoro-3-(isobutoxymethylene)-2-propanones with aromatic
o-hydroxylamines under microwave irradiation conditions <1997T5847>. 2-Hydroxymorpholines
73 may be prepared through a three-component, one-pot, Petasis reaction involving the
coupling of a 1,2-amino alcohol, a boronic acid, and a glyoxal derivative <2001TL3591>,
while 5-alkyl(aryl)-5-hydroxy-3,4-diarylfuranones 74 are synthesized in good yields via a tandem
esterification and oxidative cyclization process <2002TL8715, 2002SL947>.
H
OH R
R N R1 O Ar1 OH
R5
O
O CF3 R2 N R4
Ar2
OH R3 O
72 73 74
R = H, Me R1 = H, Me; R2 = H, Ph R = Et, Ph
R3 = Bn, Me; R4 = aryl
There are numerous other methods for the formation of hemiacetals, although many of these
are substrate specific. Examples include the first synthesis of cis,cis,cis,trans-[5.5.5.5]-fenestranes
using a novel lead tetraacetate mediated ring expansion of a bicyclo[3.3.0]octane subunit
<1996TL7687>, studies toward the synthesis of the reduced furanochroman subunit involving
cleavage of a silyl ether with concomitant retro-aldol reaction and epoxide ring opening to
provide, upon cyclization, the desired hemiacetal <2000OL2507>; the preparation of trifluoro-
methyl lactol derivatives via base-induced cyclobutanol ring opening <1996SL57>, and the highly
diastereoselective cycloisomerization of acyclic trienones, based upon the Nazarov reaction
(Equation (48)) <1998JOC2430>. Finally, a nickel-catalyzed carbonylation of -keto alkynes
under phase-transfer conditions affords unsaturated hydroxy lactones in the absence of sterically
demanding groups on the keto function <1995OM5438>.
Me
O Me
O
R3 R2 HO R2 H
Me BF3. OEt2, CH2Cl2
–78 °C–rt, H2O R3
R4 R1 Me ð48Þ
n
42–89%
R 4 R1
R1, R2 = H, Me
n = 1, 2
R3 = Me, Et, But, –(CH2)4–
4 = H,
R –(CH2)4–
4.04.2.2 Hemiacetals from Esters
4.04.2.2.1 By reduction
Ddiisobutylaluminum hydride (DIBAL-H) remains a popular reagent for the reduction of
lactones. Reduction of lactone 75 in methylene chloride at 78 C, followed by acidic work-
up, afforded a mixture of lactol epimers 76 in 89% yield (Equation (49)) <1997TL3339>.
Similarly, DIBAL-H reduction of lactone 77 yielded lactol 78 in 77% yield (Equation (50))
<1997TL3817>.
SMDBTO SMDBTO
O DIBAL-H, CH2Cl2 O
O
ð49Þ
89% OH
SMDBTO SMDBTO
75 76
O O DIBAL-H, CH2Cl2 O O
O OH
O –78 °C, 77% O ð50Þ
OH OH
77 78
Enantiomerically pure cyclopropane hemiacetals may be obtained by the lipase-catalyzed

kinetic resolution of their acylated congeners, followed by a reduction of the ester using lithium
aluminum hydride (LAH). Lipases from Candida antarctica and Pseudomonas cepia are both
suitable for this purpose, showing enantiodivergent behavior towards the acyl derivatives and
leading to products with high yields and high enantiomeric excess (Equation (51))
<2001OL189>.
OAc i. Lipase OH
R R
OEt OEt
ii. LAH ð51Þ
34–98% y
R = Bu, Ph C5H11, C6H13
95–99% ee
4.04.2.2.2 By addition of carbanions

The intermolecular addition of carbanions to lactones remains an extremely versatile method by
which to synthesize a variety of hemiacetals (Table 1). Because of the high reactivity of the
reagents required to generate R3CMgX or R3CLi, the intramolecular version of the addition of
Grignard and alkyllithium reagents to ketones has always proven to be problematic. However,
developments involving the synthesis of organomercurials and their subsequent reaction with
Me3CuLi2 have led to the development of a novel and mild way for the intramolecular addition of
organometallics across a carbonyl group (Equation (52)) <1995JOC1482>. Additionally, the
reaction of methyllithium with dibromocyclopropanes 79 results in a lithium–bromide exchange
and cyclization of the derived lithiocyclopropane to form hemiacetals 80 stereoselectively
(Equation (53)) <2000T4799>.
O
HO
O R R
Me3CuLi2 O
HgMe ð52Þ
23–65%
OMe R = Me, Ph, But OMe
n
n
Br R
MeLi, Et2O, –90 °C Br R
Br
O 60–82% R1
R1
HO O ð53Þ
O
79 R = H, Me 80
R1 = Me, Pr, CF3, Ph, vinyl, Pri, Bui
Samarium diiodide has become an increasingly versatile reagent in organic synthesis. For
example, reduction of chloro lactones with SmI2, in the presence of a catalytic amount on NiI2
and visible light, leads to nucleophilic acyl substitution, and provides a viable method by which to
synthesize various hemiacetals (Equation (54)) <2000JOC8333, 2002JOC3861>. This method has
been successfully applied toward the synthesis of natural products such as variecolin
<2001OL2257> and the phorbol esters <2000OL2873>. Hemiacetals may also be synthesized
from acyclic diiodoesters via an SmI2-promoted Reformatsky-type reaction followed by a nucleo-
philic acyl substitution (Equation (55)) <2002JOC3459>.
O
O xs SmI2, NiI2, hν
O ð54Þ
THF, 91% OH
Cl
O HO
I xs SmI2, NiI2, hν
O O n
HO O ð55Þ
I THF, 58–90%
R n R
R = aryl, alkyl; n = 1, 2
Table 1 Hemiacetal formation by the addition of carbanions to lactones
Substrate Nucleophile Product Yield (%) References
O NMe RMgBr r O NMe

R = alkyl, aryl R 74–97 <1996BCJ2079>
O O 0 C OH O
H
BnO
O O H Li
O
H O 90 <1996JOC3003>
OBn O OH
H OTBS
H
OTBS
H
Cl
BnO Cl N Cl
O O N
BnO N 77 <1996TL5325>
N O
OBn OBn
LDA, –78 °C OH Cl
OBn OBn
MgBr 80
OH <1996SL625>
O ds = 7:3
rt, 24 h
O HCF2PO(OEt)2 HO CF2PO(OEt)2
76 <1997T10623>
LDA, 78 C
O O
Table 1 (continued)
Substrate Nucleophile Product Yield (%) References
O OMe Cl
O MgBr
MeO N
88
O CH2Bn O <1998OPRD186>
Cl 82% de
OMe
MeO N
OH
O CH2Bn
H H OH
O O O CH2PO(OMe)2
H H MePO(OMe)2 H H
93 <2000JOC8490>
BuLi, 78 C
H H
Tol
(R)-methyl tolyl S 90 (n = 1)
n O n O <2000T7927>
O sulfoxide OH O 84 (n = 2)
MeO MeO OH
O O O
CH2I2 CH2I 58 <2000SL1691>
O O O O
O TMS
O HO
O H TMS 67 <2001T2345>
O
O O
O
OBn OBn
BnO O RLi BnO O
BnO R = CH2CO2Et R = CH2PO(OMe)2R = CH2SO2Oet BnO R
81–95 <2001TL6907>
O R = Bn, allyl BnO
OBn OH
OBn OBn
BnO O O
O BnO
BnO OH 70 <2002TL7101>
I P(OEt)2 BnO
O
OBn BnO
CH2PO(OEt)2
OBn OBn
89
BnO O BnO O
R = Me
BnO AlR3 BnO <2002TL7101>
R 69
O BnO
OBn OH R = Et
OBn OBn
BnO O Benzothiazole O S
BnO 78 <2003TL13>
BnO BuLi BnO N
O BnO
OBn OH
4.04.2.3 Hemiacetals from Enol Ethers

Enol ethers are particularly facile to hydrolysis. Upon silica gel chromatography, enol ether 81
was hydrolyzed to give the more thermodynamically stable trans-hemiacetal 82 (Equation (56))
<1995JOC2668>. Such ease of hydrolysis upon silica gel chromatography was exploited in the
synthesis of the taxoid C-ring system <2000EJC4029>. Under slightly more forcing conditions,
enol ethers may be hydrolyzed with H2SO4/H2O <2000EJO2145> or with p-toluenesulfonic acid
in THF/H2O <2000JA10482>. Treatment of enol ether 83 with pyridinium hydrogen fluoride in
dichloromethane led to hemiacetal 84 as a single isomer (Equation (57)) <2002SL817>. The exact
mechanism of this reaction is not known; however, it is well known that the HFPyr cleaves silyl
ethers as well as the dioxolane group, and it has thus been proposed that the reaction proceeds
through an intermediate acetal. Halogens may also be added across the double bond of an enol
ether during the synthesis of hemiacetals <2002AJC327, 2000JOC4679>.
O H2O O
HO
silica gel ð56Þ
R R
38–99%
81 R = alkyl, aryl 82
TMS
O
HF.Pyr (70:30) HO
O O OH
O CH2Cl2, rt, 12 h H ð57Þ
N
61% O Bn
N
O Bn
83 84
A novel method of synthesizing an enol ether, which undergoes subsequent hydrolysis upon
work-up, involves the electrophilic-mediated cyclization of alkenyl-substituted -keto esters.
Iodine, phenylselenium bromide, or phenyltellurium trichloride have been used as electrophiles
with yields in the range 38–65% (Scheme 3) <2002JOC4122>.
O O
O O OH
OEt I2, NaHCO3 I OEt I OEt H2O O
I OEt
CH2Cl2, rt
6 h, 55%
Scheme 3
Hemiacetals may be synthesized via the epoxidation, and subsequent ring opening, of enol
ethers. Epoxidation of exo-glycal 85 with DMDO followed by nucleophilic ring opening of
epoxide 86 yields a variety hemiacetals 87 in good-to-moderate yield (Scheme 4) <1995SL167>.
However, when the exo-glycal was epoxidized with MCPBA, the intermediate epoxide reacted
with the formed MCPBA directly to give the ring-opened product. Additionally, epoxidation and
subsequent hydrolysis of pyranoside 88 produced hemiacetal 89 in 71% yield (Equation (58))
<2001OL3353>.
BnO BnO
BnO
O DMDO Nu– O
BnO O BnO
BnO BnO X
BnO BnO
BnO 33–89% BnO
BnO O OH
85 X = SPh, N3, CN
86 87
Scheme 4
HO OTMS
OTMS
O 1,1,1-trifluoroacetone, oxone O
SMTO SMTO
SMTO SMTO ð58Þ
NaHCO3, Na2EDTA, CH3CN, H2O OH
OMe OMe
1 h, 71% 89
88
4.04.2.4 Hemiacetals from Acetals by Deprotection
4.04.2.4.1 From noncarbohydrate substances

The formation of hemiacetals via the deprotection of their corresponding acetals is frequently
applied in the synthesis of many natural products. In particular, hemiacetals are often derived
from their methoxy acetal counterparts, as is the case for the synthesis of allocaythin B3
(Equation (59)) <2000OL2125>. Synthesis of the nonisomerized hemiacetal was achieved using
a solution of p-toluenesulfinic acid in acetone/H2O. Very mild hydrolysis conditions were also
required for the synthesis of variecolin, whereby deprotection of a methoxy acetal was achieved
using catalytic amounts of PdCl2(MeCN)2 in CH3CN/H2O <2001OL2257>. The final sequence
in the synthesis of (+)-phorboxazole A required the deprotection of a methoxy acetal, using 6%
HCl in THF <2001JA4834>.
OMe OMe
O OBz O OBz ð59Þ

10% HCl, THF
MeO H HO H
85%
O O
The final synthetic sequence in the formation of the C(1)–C(8) segment of (+)-aucutiphycin
required hydrolysis of bicyclic ketal 90 to give target hemiketal 91 (Equation (60)). Under the
hydrolysis conditions, the C(1)–C(3) side chain equilibrated to the equatorial position
<2002TL1147>. Similarly, the final sequence in the synthesis of ()-syringolide involved deprotecting
a hemiacetal using a large excess of p-toluenesulfonic acid in acetone/water <2000CJC275>. During
the asymmetric synthesis of N-acetylneuraminic acid, a triacetonide was consecutively deprotected
and cyclized using methanolic HCl <2000CC227>.
O HO OH
TsOH, H2O, THF OH
EtO2C O ð60Þ
O OH 81%
90 91 CO2Et
Hemiacetal 93 is formed from acetal 92 via a slightly more elaborate procedure involving
neighboring group participation and weak alkaline hydrolysis (Equation (61)) <2001TL5989>.
The mechanism suggested for this process consists of a departure of bromide, followed by
addition of water to the transient carbocation.
O
HO
O
Br NH3, H2O, n-BuOH O

O ð61Þ
7 days, 97% H H
H H
HO
HO H
H 92 93
4.04.2.4.2 From carbohydrate substances

Protection and deprotection of the anomeric hydroxy group is an essential feature of oligosac-
charide synthesis. Many glycosyl donors, however, have a transient lifetime and are used directly
for glycosidation reactions. For a general review on carbohydrate chemistry, see
<2001AG(E)1576>. One of the more robust protecting groups for the anomeric hydroxyl is the
benzyl acetal, which may be cleaved under a variety of conditions including standard hydrogena-
tion <2002JA5380> or with FeCl3 in CH2Cl2 <2002TL8879>. Several benzyl derivatives have
been developed to allow for deprotection under a variety of conditions. Examples of such
derivatives include the p-methoxybenzyl ether, oxidatively cleaved using cerium ammonium
nitrate <2001JOC4233>; the o-nitrobenzyl ether, cleaved under photochemical conditions
<2000JOC8011>; or the slightly more elaborate bicyclic derivative 94, cleaved under acidic
conditions with p-toluenesulfonic acid (Equation (62)) <2000SL1241>.
BnO OAc
BnO O OAc
OH BnO
BnO TsOH O
N O BnO ð62Þ
O BnO
MeOH
OH
O
94
Methoxy acetals may be cleaved under acidic conditions similar to those previously discussed,
while silyl ethers can be cleaved using a fluoride source such as tetra-n-butylammonium fluoride
(TBAF), HF or Olah’s reagent <2000EJO3541, 2000OL3043, 2002JA10036>. The allyl group is
frequently used to protect the anomeric position with transition metal catalysts commonly used
for the cleavage of this moiety <2003CEJ307, 2000S2263>. Alternatively, allenyl ethers may be
cleaved under relatively mild conditions using catalytic OsO4 and N-methyl morpholine N-oxide
<1999T11331>. The n-pentenyl glycoside protecting group remains, in the early 2000s, a popular
choice for protection of the anomeric position <2001JOC8165>.
A variety of methods exist for the selective deprotection of an anomeric acetate in the
presence of other acetate moieties. These include the use of t-butylamine <2002JCS(P1)242>,
hydrazine acetate <2001TL1007>, and ammonia <2001MI165>. Acetals are hydrolyzed under
acidic conditions, including the use of trifluoroacetic acid <2000MI549> or aqueous acetic
acid <2000JA619>. Under the latter conditions, the furan derivative 95 equilibrated to the
pyranose form (Equation (63)).
HO O O Me 50% aq. HOAc HO O

BnO OH ð63Þ
O Me 100 °C
BnO OH
95
4.04.3 ACETALS—R12C(OR2)2
Reviews of the preparation and use of acetals as protecting groups <B-1999MI002,
1991COS(6)631> and chiral reagents <1999PAC1511> have appeared. The synthesis of certain
specific types of acetals will not be covered here unless methods have more general applicability.
The reader should therefore consult reviews for more details on the preparation of spiroacetals
<1999JHC1373, 1999T7661, 1998CUOC395, 2001CUOC233> and glycoside coupling methods
<B-2000MI003, B-1997MI001, 2000CRV4423>.
This section is divided into three parts: general methods (suitable for symmetrical and unsym-
metrical acetals), methods for symmetrical acetals 96 (R1 = R2), and those for unsymmetrical
acetals 96 (R1 6¼ R2). The methods described in the general section (Section 4.04.3.1) can be
applied to the preparation of symmetrical acetals; however, some of these methods are restricted
to the preparation of cyclic unsymmetrical acetals from an unsymmetrical diol, and do not allow
the use of two different monohydric alcohols. Such restrictions will be obvious or will be indicated
at appropriate points in the discussion. Methods covered in the sections on symmetrical
(Section 4.04.3.2) and unsymmetrical acetals (Section 4.04.3.3) represent the general situation
found in the literature, but an appropriate choice of reaction components may result in the
crossing of boundaries between sections. The reader should therefore consult all sections to
avoid overlooking a potentially useful method. Intramolecular variants of many of the methods
are also feasible.
R3O OR4
R1 R2
96
4.04.3.1 General Methods
4.04.3.1.1 From aldehydes and ketones
(i) With alcohols and protic or Lewis acid catalysts

The formation of acetals via the reaction of alcohols with aldehydes and ketones under acidic
conditions is an equilibrium process that proceeds via the common, intermediate oxonium ion 97
(Scheme 5) <1981S501>. In general, it is necessary to shift the equilibrium in favor of the
product by removing the water by-product, either by physical or chemical methods. The most
commonly used method for the removal of water involves heating the carbonyl with an alcohol or
diol in an inert solvent such as benzene, toluene, or xylene, which under continuous azeotropic
distillation with a Dean–Stark or similar water separatory head <1938CB1803> results in
removal of water. Examples are shown in Table 2 using monohydric alcohols and 1,2- or
1,3-diols. In general, cyclic acetals are usually formed more easily than acyclic acetals and
functionalized alcohols may also be used.
O R3O OH OR3 R3O OR3

R3OH H+ R3OH
R1 R2 R1 R2 R1 R2 R1 R2
H+ –H2O
97
Scheme 5
Table 2 Acetals prepared by azeotropic removal of water

Entry Substrate Conditons Acetal Yield (%) References
1 O
HO
OH O O
PPTS, benzene
19 h
CH(CO2Me)2 89 <1997CEJ441>
CH(CO2Me)2
2 CHO
R HO O
OH
R = squalene TsOH, 4 h, benzene R O 86 <2002JCS(P1)1477>
derivatives
3 O
R2 R3 R 3
R2
HO OH
R1 R3 R3 O O
R1 = H, CH3 or But 60–82 <1997T6215>
2 1
R = H or CH3 R
R3 = H, CH3 or CO2Et
TsOH, benzene
a
PPTS = pyridinium p-toluenesulfonate.
The order of carbonyl reactivity is generally: aliphatic aldehydes > aromatic aldehydes > acyclic
ketones and cyclohexanones > cyclopentanones > ,-unsaturated ketones, and ,-disubstituted
ketones > aromatic ketones. This variation of reactivity thus makes chemoselectivity in polycarbo-
nyl systems feasible. Steric hindrance in the alcohol slows down the rate of acetal formation. In some
cases, particularly for saturated aliphatic aldehydes and primary alcohols, the equilibrium conver-
sion to the acetal may be quite high.
In situations of an unfavorable equilibrium for acetal formation, the water can be completely
removed by reaction with a suitable reagent. Orthoesters, the most widely used reagents for this
purpose due to the mild conditions, react with the water to form an ester and an alcohol as shown
in the general reaction in Equation (64). This is a general procedure that is particularly suitable for
the preparation of ketone acetals and examples are illustrated in Table 3. The mechanism of this
reaction is well established <1955JOC1695, 1969CC1175>. The orthoformate is usually chosen to
match the alcohol, but with higher-boiling alcohols trimethyl or triethyl orthoformate can be used,
and the ethanol or methanol and alkyl formate distilled out of the reaction mixture to displace the
equilibrium. This may not be necessary for cyclic acetals if an excess of diol is used.
O R1OH, H+ R1O OR1

+ R1OH + R1OCOR2 ð64Þ
R R (R2O)3CR2 R R
An alternative to the above removal of water are dehydrating reagents (the well-established
references are supplied for convenience) such as molecular sieves <1971RTC1141, 1972S419,
1977RTC44>, calcium sulfate <1974JOC2815>, copper sulfate <1978JOC438> and alumina
<1979CB3603>. Although this approach often allows acetalization to be carried out at room
temperature (rt) or below, it appears to give high yields with only more reactive aldehydes or ketones.
In addition to the numerous examples of protic acids, Lewis acids and heterogeneous catalysts
listed in chapter 4.04, COFGT (1995) <1995COFGT(4)159>; further catalysts have been
reported in Table 4. The choice of catalyst is governed by the reactivity of the carbonyl group,
the substrate chemical and thermal stability, and of course, the reaction conditions. The use of
weaker acids, such as ammonium chloride, calcium chloride, alumina, or lanthanide halides can
be used for the acetalization of aldehydes, but often acids such as TsOH are used for convenience.
Ketones generally require stronger acids such as HCl, H2SO4, or TsOH. Protection under
microwave irradiation in solvent-free conditions has also been reported <1997TL7867>. Acetal
formation from ketones with electron-withdrawing groups, such as fluoro substituents, has been
accomplished <1996TL8663>, and in addition the use of bis(fluoroalkoxy)triphenylphosphoranes
leads to fluorinated acetals (Equation (65)) <1995JOC5696>.
O RFH2CO OCH2RF
+ Ph3P(OCH2RF)2
CF3 CF3 F3C CF3 ð65Þ
RF = CF3 (60%), CF2CF3 (73%), (CF2)2H (56%), (CF2)4H (46%)
(ii) With silyl ethers

The reaction of silyl ethers with carbonyl compounds, as in Equation (66), is well established and
variations of trimethylsilyl triflate (TMSOTf) catalyzed reactions were reviewed in chapter 4.04,
COGFT (1995) <1995COFGT(4)159>. Subsequent work has revealed that acid-sensitive groups
such as tetrahydropyranyl (THP)-ethers are deprotected at temperatures higher than 78 C using
this protocol. Therefore, an alternative is the use of iodine, which gives excellent yields (with some
shown) and is highly chemoselective. Complete selectivity for aldehydes was observed in the
presence of ketones when using only 2 equiv. of the 1,3-bis(trimethylsiloxy)propane <2002S784>.
Yield
R1 R 2 (%)
O TMSO OTMS O O + TMSOTMS Ph H 95 ð66Þ
R1 R2 I2 (3–7 mol.%), CH2Cl2, rt R1 R2 Bu H 91
85–97% Ph Me 94
BnCH2 Me 80
Table 3 Acetal formation using orthoesters as dehydrating agents
Entry Substrate Conditions Acetal Yield (%) References
1 O EtOH, (EtO)3CH OEt R = H, 89 <2000EJO3825>
Br pTsOH, 12 h, rt Br OEt R = Me, 72
R R
2 O EtOH, (EtO)3CH EtO OEt 79 <2000T6299>

HCl, 3 days, rt

HCl, 3 days, rt

HCl, 3 days, rt
5 MeOH, (MeO)3CH OMe 82 <1999EJO2143>

CHO LaCl3, 0.5 h, rt
2
2
OMe
6 CHO MeOH, (MeO)3CH CH(OMe)2 84 <1999JA866>

LaCl3, 0.5 h, rt
RN RN
O O
O NBOC O NBOC
Table 4 Catalysts for the acetalization of aldehydes and ketones

Alcohol or orthoformate Catalyst Yield (%) References
HOCH2CH2OH CsOH, CsF 49 <1997T16597>
HOCH2CH2OH, MeOH ZnCl2 >95 <2001EJO399>
MeOH, EtOH, (RO)3CH Bu4NBr3 89–96 <2002JOC5842>
MeOH, EtOH, (RO)3CH Bi(OTf)3 68–98 <2002JOC5202>
MeOH, (MeO)3CH MCM-41a 18–93 <1998TL9457>
HOCH2CH2OH, ROH CdI2, microwave 80–92 <1999CL1283>
EtOH, (EtO)3CH DDQ 79–98 <1999CL1199>
EtOH, (EtO)3CH NBS 85–98 <1999SL1456>
HOCH2CH2OH, (EtO)3CH ZrCl4 80–98 <1999SL321>
MeOH Ce3+-montmorillonite 18–95 <1995JOC4039>
MeOH, (MeO)3CH B10H14 85–93 <2002TL2699>
MeOH, (MeO)3CH RhCl2CF3triphos 80 <2001HCA898>
a
MCM-41 siliceous mesoporous material.
(iii) Condensation of 1,2-diketones with 1,2-diols

Preparation of diacetals from 1,2-diketones and 1,2-diols was introduced by Ley as a method for
the protection of trans-1,2-diols in carbohydrates (Equation (67)) <1997JCS(P1)2023>. This
method is adaptable to commercially available phenanthrene-9,10-quinone and cyclohexane- or
cycloheptane-1,2-diones. The method also includes the use of 2,2,3,3-tetramethoxybutane rather
than butanedione <1996JOC3897>.
OH OH
O OH OMe OH
O (MeO)3CH, CSA O ð67Þ
+ HO
HO
O
O
MeOH, 95%
O OMe OMe OMe
(iv) Condensation of o-hydroxybenzaldehydes with dimethoxypropane

The formation of benzopyrans 96 (Scheme 6) is accomplished in high yields by iodine-catalyzed
condensation of o-hydroxybenzaldehydes with dimethoxypropane <2000JCS(P1)3082>. Yields
for this reaction ranged from 75% to 90% for the 13 substrates reported and include R = H
(90%), 6-OMe (86%), 4-Me (88%), and 4-Br (84%). Mechanistically this was considered to occur
via formation of 97, which underwent nucleophilic attack by 2-methoxypropene and subsequently
led to the products. This method has been extended to scandium triflate-catalyzed reactions
<2000TL7943> and to the formation of 4-amino benzopyrans by using o-hydroxybenzaldimines
<2001TL4405>.
MeO OMe
OH O OMe
CHO I2
R R
OMe
96
H
OH O
OMe OMe
OMe OMe
97
Scheme 6
A similar reaction involves a catalytic ene-like reaction of aldehydes with vinyl ethers. For
example, 2-methoxy propene gives 98 in high yields (Equation (68)) <1997T16299>. This meth-
odology has been used in the synthesis of several natural products such as chlorovulone(II) and
phyllanthocin.
OMe
0.5 mol.% of
OMe
1:1 Yb(fod)3:AcOH O OMe
RCHO +
SiO2
ð68Þ
R
R = H (100%), C3H7 (81%), 2-I-C6H4 (99%) 98
4.04.3.1.2 From acetals
(i) With alcohols

Acetals formed from low boiling alcohols such as methanol or ethanol can be exchanged with higher
boiling alcohols under acidic conditions. A method that is often used is the treatment of 1,2-diols with
2,2-dimethoxypropane and an acid catalyst such as pyridinium p-toluenesulfonic acid (PPTS)
<2001EJO1865>. Yields are generally very high (>90%) with these reactions. The method is also
very useful for the preparation of chiral, optically active acetals when reaction with the corresponding
ketone is low yielding. As depicted in Table 5, several chiral acetals have been prepared. Spiro acetals
are also conveniently formed using acetal exchange (Equation (69)) <1995JA3653>.
O
O
ð69Þ
PPTS O
HO CH2Cl2
95% O
OH
(ii) By acetal interchange

No examples of this transformation have been reported in the period 1993–2003.
4.04.3.1.3 From enol ethers and alcohols
(i) By acid catalysis

Addition of alcohols to enol ethers via the acid-catalyzed formation of oxonium ion 99 is a
standard method for the protection of alcohols. As shown in Scheme 7, excellent yields are
obtained and these types of reactions often provide products of exceptional purity, thus bypassing
the need for purification <2001JA9033, 1999JOC5301, 1995TL1653>. Typically, catalysts such as
PPTS are used at 0 C or room temperature.
(ii) With electrophiles

Alcohols can also add to enol ethers with the aid of electrophiles. Past variations of this type of
addition include the use of NBS (Equation (70)), in which reports have focused on tin-based
radical chemistry of the subsequently formed acetal <1997T10479, 1998JOC1668> or elimination
of HBr <2000JA12169>. This addition has also been extended to dienes of type 100 to provide
1,4-addition in modest yields (Equation (71)) <1999SL1841>. An additional variation on a past
theme is asymmetric methoxyselenenylation of alkyl vinyl ethers <2001TL1559>, which allows
for deselenenylation to give chiral acetals (Scheme 8). Diastereomeric ratios of the addition
products 101 range from 1:1 to 9:1, and one example of a deselenenylation to provide a chiral
acetal was performed. This gave 102 in 90% yield and 74% ee.
Table 5 Acetal formation from chiral alcohols
Entry Substrate Chiral alcohol Acetal Yield (%) References
1 MeO OMe OH CO2Me
CO2Me O
OH 70 <1997TA1039>
O
2 MeO OMe HO HO
Ura Ura
Ar Ar O O
Ar = p-C6H4OMe
HO OH O O 95 <2001TL1789>
Ar Ar
3 MeO OMe
HO OH MeO
O
MeO OMe HO2C CO2H O CO2Me
72 <1999TL1583>
MeO CO2Me
4 MeO OMe
TIPSO TIPSO
71 <2001EJO1865>
OH OH O O
MeO
TMS OH TMS O
OCOBut OCOBut
+OMe 97%
OMe
H+ OH
CO2Me
99 C11H23 MeO
O
98% CO2Me
C11H23
Scheme 7
Br
Me(MeO)C CH2
ð70Þ
OH NBS O
OMe
R R OMe
NBS Br
OEt OEt ð71Þ
MeOH
100 R = alkyl, 47–50%
Ar*Se
Ar*SeX OR2 Bu3SnH
OR2 OEt
R1 MeOH R1 AIBN Ph
53–92% OMe OMe
R1 = H, Ph, alkyl 101 102
R2 = Et, Bun, But, Bui, C5H11
Scheme 8
(iii) Miscellaneous enol ethers

Two addition areas, involving anodic oxidation and radical coupling, have been reported.
Azidomethoxylation of enol ethers by anodic oxidation gives regioselective addition in yields
of 52–82% (Equation (72)) <1995TL7483>. Enol ethers used were R1, R2 as cyclic systems
from 5- to 12-membered rings or H and Me groups, with R3 generally a Me or But group. A
1:1 ratio of diastereomers was obtained in the single example of diastereoselective reaction.
Additionally, the synthesis of -dialkoxy carboxylic acid derivatives has been achieved via a
radical coupling with catalytic nickel and borohydride exchange resin (BER) (Equation (73))
<1996SL1224>.
N3
NaN3, MeOH
OR3 OR3
R1 R1 ð72Þ
Et4NOTS OMe
R2 R2
2e–
O
O R
R Ni(OAc)2, BER X
X + O
NaI, MeOH O ð73Þ
Br 10 equiv.
65–95% OMe
X = OEt or NEt2
4.04.3.1.4 From silyl enol ethers and enol acetates

As reported in chapter 4.04 of <1995COFGT(4)159>, silyl enol ethers react with alcohols in a
similar manner as the enol ethers described above, but no new notable variations have been
reported in this area up to 2003. However, two reactions of silyl ketene acetals have been reported
that are of significant interest. Reaction of 103 with alkynes such as dimethyl acetylenedicarbox-
ylate under solvent-free conditions gives the [2+2]-cycloaddition products 104 at room tempera-
ture (Equation (74)) <2000EJOC3381>. Ethyl propynoate and ethynyl methyl ketone were also
used providing comparable yields. Acetals of type 105 were also obtained by Mukaiyama aldol
reactions with lactone carbonyls (Equation (75)) <2001TL4437>. Aldol reaction and migration
of the silyl group gave the acetal as a single diastereomer.
CO2Et O OTMS
O OTMS CO2Et
+
( )n ( )n ð74Þ
n = 1, 98%
CO2Et H CO Et
n = 2, 92% 2
103 n = 3, 93% 104
TBSO
Ph O O OTBS Ph O
TiCl4 CO2Et
+ OEt CH2Cl2 ð75Þ
Ph N Ph N
Cbz 85%
Cbz
105
4.04.3.1.5 From gem-dihalides by alkylation

Displacement of both halides from geminal dihalides with alkoxides is an additional method
for the formation of acetals (see <1995COFGT(4)159> for an extended coverage) and is
facilitated by a neighboring aromatic group. New work in this area has involved displacement
with concurrent rearrangement upon treatment with alkoxides. For example, treatment of the
dichloroazetidines with NaOMe gives high yields of the aziridines 106 (Scheme 9)
<2002JOC2075>. The azetidines are synthesized in four convenient steps from benzaldehyde
derivatives comprising electron donating and withdrawing groups in high yields.
MeO OMe
R
NaOMe
Cl
Cl MeOH N
83–94% Pri R
NPri
106
Cl Ar OMe MeO Cl– +OMe

Cl
Ar Ar
Ar
NPri NPri NPri N
Cl– Pri
Scheme 9
Treatment of pyrrolines 107 with NaOMe gave pyrroles in good yields (Scheme 10)
<1999T4133>. Mechanistically, the conversion was reported as initial aromatization of the
pyrroline 107, followed by a consecutive loss of HCl and attack of methoxide to produce the
pyrrole after a sequential process. A final report involves the opening of trihalocyclopropanes
(Equation (76)) in the presence of triethylbenzylammonium chloride (TEBA), which give good
yields of acetylenic acetals <1998ACS1029>. Isopropanol has also been used in place of ethanol
with comparable yields. The starting cyclopropanes are easily prepared via dihalocarbene addition
to halogenated olefins <1996ACS446>.
Cl Cl HMeO OMe
N N
R NaOMe R R = Me, 80%
Cl R = Pr, 83%
Cl Cl
107
H Cl Cl Cl HMeO Cl
N N N
–OMe
R R R
–HCl
Cl Cl Cl
Scheme 10
R NaOH EtO
TEBA OEt
Br H
EtOH R ð76Þ
Br Br
CH2Cl2
R = Me, 79%
R = H, 81%
4.04.3.2 Symmetrical Acetals

Formation of symmetrical acetals using orthoformates or acetal exchange is covered in
Sections 4.04.3.1.1 and 4.04.3.1.2
4.04.3.2.2 From orthoesters and nucleophiles
(i) With organometallic reagents

The displacement of an alkoxy group from an orthoester with a carbon nucleophile, specifically
Grignard reagents, was covered in COGFT (1995) <1995COFGT(4)159>. Subsequent develop-
ments in this area involve the use of allyl silanes such as 108 as the nucleophile (Equation (77)),
<1996HCA346>.
TMSO TMSO MeO OMe

SiMe3 (MeO)3CCO2Me
SnCl4 CO2Me ð77Þ
65%
108
In a reversal of polarity, nucleophiles are generated from orthoesters by treatment with

‘‘Cp2Zr.’’ The dialkoxyallylic zirconium species 109 is prepared from triethylorthoacrylate,
which is then reacted with aldehydes as shown in Scheme 11 <1997TL5829>. In all cases, an
sp2-R group was used such as Ph (91%), furan (90%), or methylvinyl (58%). This reaction has
also been applied to the reaction of chiral aldehydes giving diastereoselectivities in 8:1 to 12:1
ratios <2000JOC918>.
OH
OEt “Cp2Zr” EtOCp2Zr OEt i. RCHO
R
OEt OEt ii. NH 4Cl
OEt EtO OEt
58–96%
109
Scheme 11
(ii) With enolate derivatives

An example of the formation of a symmetrical diethyl acetal via a Neber rearrangement of a tosyl
oxime has been reported (Equation (78)) <1999TL6739>.
OTS
N EtO OEt
NH2
i. KOEt, EtOH ð78Þ
N ii. HCl, Bu tOMe N 2HCl
82%
4.04.3.2.3 From alkenes and alkynes
(i) From alkenes and alcohols with electrophilic metal derivatives

No examples of this transformation have been reported in the decade 1993–2003.
(ii) From alkynes and alcohols with electrophilic metal derivatives

The mercury-catalyzed addition of alcohols to alkynes has been known since the 1930s. An
alternative to the use of toxic mercury has been reported involving a cationic gold(I) complex.
The catalyst, prepared from methyl(triphenylphosphine)gold, catalyzes a range of alkynes as
shown in Equation (79) <1998AG(E)1415>. The majority of reactions were performed with
R1 = Me (with either methanol, ethanol, or isopropanol); thus, no yields are reported and only
gas chromatography turnover numbers are given. The turnover numbers are up to 105.
RO OR
ROH ð79Þ
R1 H R1 Me
Au(1)
(iii) From electron-deficient alkynes and alkenes by conjugate addition of alcohols

Conjugate addition of methanol to a range of conjugated alkynes with both NBS and
N-iodosuccinimide (NIS) has been reported (Equation (80)) <1998JOC4433>. A mechanism
is postulated for the dihalo acetal formation, which could then be reduced with tributyltin
hydride.
O MeO OMeO R X = Br X=I

MeOH
H H R Me 75% 95%
R
NBS or Ph 90% 40% ð80Þ
NIS X X
Pr 90% 70%
40–95% OMe 95%
4.04.3.2.4 From dithioacetals and O,S-acetals

The alcoholysis of dithioacetals with PhI(OCOCF3)2 is one of the standard methods for the
formation of acetals from dithioacetals and the use of this in a complex natural product synthesis
has been reported <1999AG(E)1669>. Another method is the use of NBS, which gives excellent
yields of acetals from both O,S- and dithioacetals (Scheme 12) <2002T4513>. With
O,S-acetals, both methanol and ethanol were used and an extensive range of substrates ranging
from aliphatic to substituted aromatic derivatives were tested.
R1OH 85–97%
S O
NBS (1 equiv.) 5 min
R R
HO OH 30–95%
S S O O
NBS
R R R R
Scheme 12
4.04.3.2.5 Electrochemical methods

Several methods for acetal formation have been developed, although these are substrate specific.
Electrolysis of alkylidenemalonates in methanol or ethanol in the presence of sodium or potas-
sium halides gives modest-to-good yields of acetals 110 (Equation (81)) <1998T14529>. Simi-
larly, electrolysis of aryl alkyl ketones in the presence of an NaI–NaOH system produces the
hydroxy acetals 111 (Equation (82)) <2000T9999>. The majority of studies were performed with
a phenyl aromatic moiety and several representative R groups are shown. The electrochemical
cleavage of double bonds conjugated to aromatic groups has also been reported to give
dimethoxy acetals; however, mixtures of products in modest yields are obtained
<1996JOC3256>.
R2 R2
R1 CO2Me –e R1 CO2Me
mX, MeOH
CO2Me MeO OMe CO2Me ð81Þ
56–78%
110
R1, R2 = H, Me, or Et
X = I or Br
O
–e MeO OMe
Ar CH2R NaI NaOH Ar CHR
ð82Þ
MeOH OH
111
R = Me (75%), Pr (77%), Pr i (70%)
4.04.3.2.6 Miscellaneous methods

Several reports on the conversion of -chloro--(alkylthio)carbonyls to acetals have appeared
(Equation (83)) <2000T6541>, including its use in natural product synthesis <2000T6541>.
R groups used were combinations of Me, Et, or Ph. Variations on this include the use of
carboxylic acids <1998T4889> and the use of -chloro--phenylselanyl esters <2000T7495>.
O O
Hg(OAc)2
R1 R1 ð83Þ
R2 MeOH, rt R2
Cl SEt 79–94% MeO OMe
Fischer-type carbene complexes have also been converted to acetals by reaction with alkynyl-
lithiums followed by treatment with iodine then methanol (Equation (84)) <1997OM5137>.
OMe i. Li R MeO OMe

(CO)5W Ph
Ph ii. I2, MeOH ð84Þ
R
R = n-C5H11 (95%), Ph (85%), CH2CH2OTBS (90%)
4.04.3.3 Unsymmetrical Acetals
4.04.3.3.1 From a-substituted ethers and alcohols

The vast majority of glycoside-coupling methods involve the substitution of a leaving group from
the anomeric carbon of a carbohydrate. Numerous methods and leaving groups have been
developed for this process and the topic has been extensively reviewed <B-2000MI003,
B-1997MI001, 2000CRV4423> and thus will not be covered here.
4.04.3.3.2 From ethers

Two examples for the formation of acetals from ethers have been reported and these are both
substrate specific. First, hypervalent iodine oxidation of allyl phenol 112 afforded quinone
monoketal 113 in 70% yield as part of a two-step process (Equation (85)) <2000JA10484>.
Second, the photolysis of diazoanthrone 114 gave acetal 115 as a mixture of product and starting
material (Equation (86)) <1998TL6675>.
OMe MeO OMe
TBDPSO MeOH TBDPSO

PhI(OAc)2 ð85Þ
Br Br
OH O
112 113
Et
N2 OPr MeO O
MeOH
ð86Þ
hν
70%
O O
114 115
4.04.3.3.3 From cyclic hemiacetals

Protection of cyclic hemiacetals as the acetal during a complex synthesis is usually accomplished
with acidic conditions and an alcoholic solvent. Methanol is generally used as the solvent, as in
the following <1999OL957, 1995T9393, 1999T4315>. These reactions are usually high yielding,
80–95%, and employ acid catalysts such as HCl or CSA.
4.04.3.3.4 By hetero-Diels–Alder reactions

Two modes of reaction are possible in the hetero-Diels–Alder reaction as shown in Scheme 13.
Promotion of type 1 via Eu(fod)3 and SnCl4 <2002EJOC514>, high pressure <2002EJOC3126>,
and high-temperature <1997S628> have all been reported. Yields for the Eu(fod)3 catalyst were
in the range 60–98% and SnCl4 in 10–99%, and in both cases complex mixtures of diastereomers
were obtained. Alternatively, high-temperature reactions gave yields of 66–71%, while
high-pressure reactions gave a modest 35–45%. Reports on type 2 were briefly discussed in
<1995COFGT(4)159>. There have not been any new reports in the period up to 2003.
4.04.3.3.5 Mixed alkyl silyl acetals

Several methods for the preparation of mixed alkyl silyl acetals such as 116 have appeared
(Equation (87)). A general method involves treatment of the in situ formed hemiacetal
with silyltriflates in the presence of a base. Examples of t-butyldimethylsilyl <1997TL6577>,
triethylsilyl <2000AG(E)2533>, and triisopropylsilyl <1998T3495> have all appeared. Similarly,

intramolecular nucleophilic attack at esters and trapping of the resulting acetal oxide with
silyltriflates has been reported (Equation (88)) <1996T9035>. Methyl, ethyl, and butyl esters
were used in both lactam and lactone systems, with the R1 group primarily methyl.
O OR O OR
+ Type 1
R1 R1
OR1
O R O OR1
R Type 2
Scheme 13
O
OBn OBn
TBDMSOTf
TBDMSO ð87Þ
Et3N, CH2Cl2
O HO 93% O
116
OTBDMS
S CO2R S OR
TBDMSOTf ð88Þ
R1 O Et3N R 1 O
X X
19–83%
Formation of oxasilacyclopentane acetals, such as 117, has been an active area of interest in the
period 1993–2003. These are conveniently formed via diastereoselective conjugate addition of the
hydrosilyl anion [Mes2SiHLi(THF)2] to an ,-unsaturated ester followed by intramolecular hydro-
silylation using catalytic n-Bu4NF (Scheme 14) <2002JA12648>. Diastereoselectivity in the example
shown was 98:2, with several other examples reported in which the lowest ds was 93:7 in 63% yield.
Mes
Mes
Si O
CO2Et i, ii
O O OEt
O 75% O
117
i. Mes2SiHLi (THF)2, Me2CuLi LiCN (5 mol.%), Me2Zn

ii. Bu4NF 10 mol.%, 0 °C
Mes = mesityl
Scheme 14
4.04.4 OTHER DIOXYGEN DERIVATIVES
4.04.4.1 Synthesis of R12C(OCOR2)2
(i) From aldehydes

The reaction of aldehydes with acetic anhydride and a catalyst is the most common procedure for
the preparation of 1,1-diacetoxy alkanes (Equation (89)). In addition to the protic and Lewis
acids reported in COGFT (1995) <1995COFGT(4)159>, more recent catalysts include NBS
<2000SL623>, bismuth triflate <2001TL8133>, and lithium tetrafluoroborate <2001SL1921>. Het-

erogeneous catalysts include zeolites <1995TL601, 1995S1077>, sulfated zirconia <2002TL2709>,
and expansive graphite <1997SC3379>. Yields for most of these catalysts were modest to good and
differences in yields between aliphatic and aromatic are observed. Additional anhydrides can be used in
this reaction. For example, the reaction of pent-4-enoic anhydride with benzaldehyde and sulfuric acid
catalyst gave the corresponding acylal in 96% yield <1995JOC772>.
OAc
Ac2O ð89Þ
R O catalyst R OAc
(ii) From ketones

The reaction of anhydrides with ketones and an acid catalyst is usually not as general as with
aldehydes. However, some catalysts have been developed for this. Solid sulfated zirconia has been
reported to give high yields of the diacetate <1996JCR(S)68>, while Sc(OTf)3 has been used for
the preparation of mixed derivatives <2000TL2389>.
Keto diacids such as 118 (Equation (90)) can also be dehydrated to produce spirolactones
<2001OL3619>. Aromatic groups used were phenyl, 4-alkyl, 4-methoxy, and 2- or 3-chlorophenyl
substituted, all in excellent yields.
HO2C O
O O
Ar O O O O
TFAA Ar
Ar O + ð90Þ
CH2Cl2, rt
84–92%
HO2C O Ar Ar Ar
118
4.04.4.1.2 From carboxylic acids

4.04.4.1.3 By oxidation of aromatic methyl and methylene groups

Oxidation of aromatic appendages is a standard method and several examples are given in
<1995COFGT(4)159>. An example, shown in Equation (91) involves oxidation of bicyclic 119
using lead(IV) acetate in refluxing chloroform <1999TL6117>.
Pb(OAc)4
CO2Me CO2Me ð91Þ
N 95% N
AcO
H OAc H
119
4.04.4.1.4 By oxidation of furan derivatives

No examples of this transformation were reported within the decade 1993–2003.

In a new variation of an old reaction, alkynes yield furanones when treated with acetic acid in the
presence of manganese triacetate (Equation (92)) <2000T9339>. Substrates involved in the study
were R = Ph with R1 as H, Me, propyl, Ph, and SiMe3; R = SiMe3, R1 = butyl, R = octyl, R1 = H,
and R, R1 = propyl.
R O
AcOH, Ac2O R1 ð92Þ
1 O
R R
4 equiv. Mn(OAc)3
40–86% O
As expected, the Baeyer–Villiger oxidation of spirocyclic 1,3-ketones and lactones led to

spirocyclic bis-lactones with good regioselectivity and yields of 38–90% <1998TL4459>. Also
reported was the reaction of hydroxy cyclobutenones 120 with PhI(OAc)2, which give rise to
5-acetoxy-2(5H)-furanones (Equation (93)) <1999JOC8995>. An additional report on the for-
mation of acetoxy furanones was the rearrangement of 121 with either acetic or propanoic acid.
However, only modest yields were obtained (Equation (94)) <1997T1843>.
O
EtO O EtO
PhI(OAc)2
O
30–84% ð93Þ
EtO EtO
R OH R OAc
120
R = Me, Bu, Ph, 2-furyl or CH=CH2
O O R2COO O
R R2CO2H O
O R
Heat
R1 N R1 NHCOPh
Ph ð94Þ
121
R, R1, R2 = Me (64%); R = Et, R1, R2 = Me (49%);

R, R1 = Me, R2 = Et (19%)
4.04.4.2 Synthesis of R12C(OCOR2)OR3

Numerous spiroacetals contain this functional group and reviews on their formation have appeared
<1999JHC1373, 1999T7661, 1998CUOC395, 2001CUOC233>. However, a few are mentioned below.
4.04.4.2.1 From ethers

Oxidation of aliphatic ethers is a commonly used procedure as discussed in <1995COFGT(4)159>,
and a variation of this is the oxidation of methoxyphenols. Treatment of the methyl ethers 122
with PhI(OAc)2 in dichloromethane led to the formation of 123 in 93–99% yields (Equation (95)).
In all cases, the R substitutent was an alkyl group that was terminated by a silyl-protected alcohol.
The advantages of using PhI(OAc)2 instead of typical lead oxidants such as Pb(OAc)4 are
the absence of toxic lead salts and the removal of PhI and residual AcOH by-products by drying
under vacuum <1998JOC9597>. PhI(OAc)2 was also used in the formation of benzopyranone 124,
which was obtained in 97% yield from 125 <2002JOC9475>.
OMe MeO OAc
OH O
PhI(OAc)2
ð95Þ
30 min R
R
122 123
O O OMe
O O
OH
O
125 124
4.04.4.2.2 From enol ethers and enol esters

Dispiroketals are conveniently prepared by the reaction of glycolic acid with bi(dihydropyran)
and catalytic Ph3PHBr (Equation (96)) <1999JCS(P1)1647>. Glycolate 126 is obtained as a
single racemic diastereoisomer, and this strategy has also been adapted to the synthesis of 127 and
128 <2001SL1793>.
O O
O OH PH3P HBr
+
O
O
CH2Cl2 OO
ð96Þ
OH 67% O
126
O OR
OO
OR
127, R = allyl, 82%
128, R = Bn, 95%
Carbonylation of an enol triflate followed by tandem silyloxy-Cope rearrangement gives

exclusively 129 in 46% yield (Equation (97)) <1999JA890>. Variations and mechanistic discus-
sions of this procedure have also been presented <2000OL2905>. In brief, a mechanism involving
isomerization of a -allyl palladium species generated through an allenic intermediate is proposed.
TESO
TESO O O
O CO, PhCN
Me Me
Pd(PPh3)4 ð97Þ
O
OTf
HO
129
A final, less complex, transformation involves irradiation of pyranones bearing pendant

alcohols (Equation (98)). These undergo intramolecular 1,6-addition to furnish the spirolactones
130 in yields of 65% for n = 1 and 75% for n = 2 <1995TL8531>.
O O
O (CH2)nOH hν O
ð98Þ
CHCl3
65–75% O
n
130
4.04.4.2.3 From carboxylic acids and carboxylic derivatives

Several methods for the formation of spirolactones from acids have appeared. Treatment of 131
with p-toluenesulfonic acid gave 132, albeit in low yields (Equation (99)) <2000AJC845>. Alter-
natively, a similar spirolactone has been prepared by a palladium-induced cyclization of hydro-
xyalkynoic acid 133 (Equation (100)) <1995JCS(P1)1309>. This is reported as an unstable
molecule and no yield is given. A more general method involves cyclization of the keto alcohols
as shown in Equation (101) <1996T9553>. Yields are generally very good (62–95%) and the keto
alcohols are prepared in one step by reaction of the ortho-lithiated diethylbenzamides with
lactones. A similar general method involves oxidative cyclization using iodobenzene diacetate
and iodine under photolytic conditions (Equation (102)) <2000TL3955>. In all cases with the
latter example, the aromatic ring contains one or two methoxy groups, and when n = 1 good
yields are obtained (72–82%) while with n = 2 a 44% yield results. Various substituents on the
pendent alkyl chain are used as well.
OH O
TsOH O
TBDPSO OH TBDPSO O
10% O ð99Þ
O
131 132
OH Pd(PhCN)2Cl2 O O
HO
THF O ð100Þ
O
133
O O
R NEt2 R
TsOH
O
OH 62–95% ð101Þ
()
n O
O
()
R = H, 4- or 6-MeO n
n = 1 or 2
O O
R R
O PhI(OAc)2, I2 O
hν ð102Þ
R O R
44–78%
()
n
HO ( )n
4.04.4.2.4 From alcohols and carboxylate derivatives

4.04.4.2.5 From hemiacetals

Acylation of hemiacetals is a general method and an example is shown in Equation (103). The
cyclopropane hemiacetals were readily prepared via cyclopropanation of the silylketene acetals
followed by methanolysis. Acetylation with acetic anhydride gave the acyl alkyl acetals in high
yield <2001OL189>.
i. Et2Zn, CH2I2
TMSO ii. MeOH AcO
iii. Ac2O, Pyr EtO
R ð103Þ
EtO R
R = Bu, Ph, C5H11, C6H13
4.04.4.2.6 From acetals

4.04.4.2.7 From aldehydes and ketones by oxidation

Baeyer–Villiger oxidation of -alkoxy ketones to acyl alkyl acetals is a high-yielding method
(Equation (104)). Application to lactones has been developed extensively. For example, 135 can
be routinely prepared from the corresponding cyclobutanones 134 in high yields
<2002JOC7649>, where R is a chiral oxazolidinone. An alternative ring expansion involves the
reaction of hydroxycyclobutenones with PhI(OAc)2 in methanol (Equation (105)). This gave the
furanones in yields of 52–88%, in which an acyl cation is proposed as the key intermediate
<1999JOC8995>. The synthesis of diacetal compounds 136 via dimethyldioxirane-induced

sequential cyclization of bicyclic olefins has also been reported (Equation (106)). Yields of
86–90% were obtained <2000T341>.
BnO O BnO
O O
EtO MCPBA
EtO ð104Þ
55–80%
R
R
134 135
O
EtO O EtO
PhI(OAc)2 O
MeOH EtO
ð105Þ
EtO OMe
R OH R
R = Me (79%), Bu (78%), Ph (88%), CH2COPh (79%), CCPh (52%)
O O
i. (3 equiv.) HO
CHO O
ii. HCl ð106Þ
O R O O
R
R = Me, Bu, C8H17 136
A final ring expansion, only involving pendant carbonyls and treatment with base, involves the
rearrangement of azetidinones 137 (Equation (107)). Good yields of the enaminones 139 were
obtained, in which a tandem E1cB-elimination–rearrangement followed by ring opening to give
intermediate 138 was postulated <2000JOC3453>. A limiting factor appears to be the required
use of the p-methoxyphenyl (PMP) protecting group.
O
R1 R1 NHPMP R1 NHPMP
X R2 Na2CO3 R2
N O OMe
MeOH R2 O O OMe
O PMP MeO OH
137 138 139
Yield ð107Þ
X R1 R 2 (%)
Br Et H 85
Cl Me H 76
Cl Cl H 80
PhO H Me 80
PhO H Ph 70
4.04.4.3 Other Derivatives
4.04.4.3.1 1,2,4-Trioxalanes (ozonides)

No discussion is offered here and the reader is referred to <1995COFGT(4)159> for references to
reviews on the subject.
4.04.4.3.2 1,2,4-Trioxane
No discussion is offered here as these have been reviewed elsewhere <2002PHC317>.
4.04.4.3.3 R12C(OR2)O2R3
No discussion is offered here, however, a review on the chemistry of artemisinin and other
C(OR)O2R antimalarials has been published <1999H1681>.
4.04.4.3.4 R12C(OR2)OX and R2C(OX)2 (X = heteroatom)

No discussion is offered here, however, a review on general methods for the preparation of
-hydroxy hydroperoxides and their application in oxidations has been published <1996S179>.
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Biographical sketch
John Hoberg was born in the United States in Bridget Stocker was born in Wellington, New
1962. He received his B.A. in chemistry from Zealand, and received her B.C.A. and B.Sc.
Jamestown College and his Ph.D. from Mon- degrees at Victoria University of Wellington
tana State University with Professor P. W. in 2000. Continuing on at Victoria University,
Jennings in 1990. After two years of postdoc- she obtained both a B.Sc.(hons) degree in
toral work with G. Molander at the Univer- chemistry (2001) and, as a top achiever doc-
sity of Colorado, he joined the National toral scholar, a Ph.D. (2004) under the super-
Renewable Energy Laboratory in Golden, vision of Professor J. Hoberg. Her doctoral
CO. In 1998 he moved to Victoria University research involved studies towards the synth-
of Wellington, New Zealand and in 2004 esis of the marine natural product, Peloruside
joined the chemistry department at the Uni- A, with emphasis on the control of 1,5-anti-
versity of Wyoming, USA. His research inter- induction in boron-mediated aldols, and the
ests lie in the area of carbohydrate and synthesis of novel platinum anticancer pro-
organometallic chemistry, asymmetric and drugs. She is currently at ETH, Zurich as a
natural product synthesis. postdoctoral fellow with Professor P. Seeber-
ger working towards the synthesis of biologi-
cally important complex oligosaccharides.
4.05
Functions Incorporating Oxygen and
Another Chalcogen
E. P. CORMIER and G. A. MOLANDER
University of Pennsylvania, Philadelphia, PA, USA
4.05.1 FUNCTIONS CONTAINING OXYGEN AND SULFUR 237

4.05.1.1 Monothioacetals and Other Derivatives with Dicoordinate Sulfur 237
4.05.1.1.1 Acyclic compounds 237
4.05.1.1.2 Compounds with oxygen in a ring 241
4.05.1.1.3 Compounds with sulfur in a ring 246
4.05.1.1.4 Cyclic monothioacetals 248
4.05.1.2 Derivatives with Tricoordinate Sulfur 252
4.05.1.2.1 -Alkoxy sulfoxides 252
4.05.1.2.2 ,-Epoxy sulfides 252
4.05.1.3 Derivatives with Tetracoordinate Sulfur 253
4.05.1.3.1 -Alkoxy sulfones and related compounds 253
4.05.1.3.2 ,-Epoxy sulfones 256
4.05.2 FUNCTIONS CONTAINING OXYGEN AND EITHER SELENIUM OR TELLURIUM 257
4.05.2.1 Dicoordinate Selenium and Tellurium Derivatives 257
4.05.2.1.1 From enol ethers, ethers, lactones, other acetals, and other compounds 257
4.05.2.1.2 From ring-opening reactions and -halo ethers 262
4.05.2.1.3 Rearrangements and multicomponent reactions 264
4.05.2.2 Tricoordinate Selenium Derivatives 265
4.05.1 FUNCTIONS CONTAINING OXYGEN AND SULFUR

This section contains methods for the synthesis of compounds containing a substituted carbon
connecting oxygen to sulfur. Monothioacetals are reviewed first, which are not only useful
carbonyl protecting groups, but also useful intermediates in organic synthesis. This is followed
by a description of the corresponding molecules with tri- and tetracoordinated sulfur.
4.05.1.1 Monothioacetals and Other Derivatives with Dicoordinate Sulfur
4.05.1.1.1 Acyclic compounds
(i) From carbonyl compounds, enols, and other acetals

Generally, monothioacetals have been synthesized by Lewis acid mediated transacetalization of acetals
such as RSH/BF3Et2O, RSH/MgBr2, Me2BBr/RSH/PriNEt2, Bu4nSn(SPh2)n/BF3Et2O, and PhSH/
Et3Al. As an alternative, two milder catalytic approaches have been developed as shown in Table 1.
237
238 Functions Incorporating Oxygen and Another Chalcogen
Catalytic lithium bromide reacts chemoselectively with acetals to produce the corresponding mono-
thioacetals efficiently <2001SL1581>. Competitive monothioacetalizations demonstrate preferential
reaction with benzylic acetals over tertiary carbon centered O,O-acetals which are more reactive than
quaternary carbon centered O,O-acetals. Additionally, tetrahydropyranyl (THP) and methoxymethyl
(MOM) ethers are less reactive than benzylic and trisubstituted acetals. In this chapter, no comparison
is made between ethers and quaternary acetals. Dicyanoketene ethylene acetal (DCKA) is also used to
catalyze the monothioacetalization of acetals <1995T10477>. This catalyst is an alternative to Lewis
acids and is efficient particularly for the conversion of ,-unsaturated acetals to monothioacetals.
DCKA catalysis has been further developed as a polymer support that is recyclable <1998TL5799>.
Table 1 Monothioacetalization of acetals

a
Acetal Conditions Nucleophile R Yield (%) References
A PhSH Me 99 <2001SL1581>
A PhSH Pri 93 <2001SL1581>
PHCH(OR)2 A EtSH Me 68 <2001SL1581>
C PhSH Me 83 <1998TL5799>
OR B PhSH CH3 77 <1995T10477>

B TMS-SPh CH3 90 <1995T10477>
OR
A PhSH Bu 82 <2001SL1581>
O OR B PhSH n-C5H11 93 <1995T10477>
C PhSH n-C5H11 86 <1998TL5799>
OR B TMS-SPh Me 87 <1995T10477>
C TMS-SPh Me 80 <1998TL5799>
OR
OR
OR B TMS-SPh CH3 74 <1995T10477>
OR
B TMS-SPh CH3 91 <1995T10477>
OR
a
Conditions A: LiBr (20%), toluene, 25 h, B: Dicyanoketene dimethyl acetal (0.2 equiv.), DMF, C: DCKA polymer, CH3CN.
O,S-Acetals can be formed selectively from enol ethers in one step with thiophenol or etha-
nethiol <1995SC3155>. Acyclic enol ethers do not require an acid catalyst while the cyclic enol
ethers require Lewis acids such as BF3OMe2.
-Selenopropynal diethyl acetals provide stabilized cations that can react with mild nucleophiles
to afford monothio- and monoselenoacetals <1995CC149>. Monothioacetal 1 is synthesized from
the diethyl acetal upon treatment with Bui2AlSPh in 72% yield. Opening tartrate acetals is another
route to form thioacetals <2003JA428>. The addition of bromodimethyl borane to acetals followed
by thiophenol produces hemithioacetal 2 in 68% yield with 6:1 diastereoselectivity.
MeO2C CO2Me
OEt
PhSe O OH
SPh
Cy SPh
1 2
Enantioselective acetylation of hemiacetals is achieved by a dynamic kinetic resolution

<1995TL8493>. A thiol and aldehyde condense to form a racemic hemithioacetal in which one
enantiomer is acylated by ‘‘pseudomonas fluorescens’’ lipase as shown in Table 2. This method
has been applied to the enantioselective enzymatic synthesis of lamivudine, an antiviral agent
<1995TL6961>.
Functions Incorporating Oxygen and Another Chalcogen 239
Table 2 Enantioselective acetylation of hemithioacetals

O OAc R1 SR2
+ R2SH
R1 H Lipase, ButOMe OAc
Entry R1 R2 Time (days) Yield (%) ee %, Configuration

n
1 MeO(CO) Bu 9 63 >95, (S)
2 MeO(CO) EtSiO(CH2)2 9 87 90, (S)
3 BnOCH2 Bun 5 79 62, (R)
4 AcOCH2 EtSiO(CH2)2 6 73 >90, (S)
5 AcOCH2 (MeO)2CH(CH2)2 4 78 55, (S)
Source: <1995TL8493>.
(ii) From sulfoxides

A novel deoxygenation of sulfoxides to the corresponding sulfides can be achieved using a titanocene
methylidene complex 3 generated from the Tebbe or Petasis reagents <2000AG(E)2529>. In contrast
to previous methods with harsh reagents and long reaction times, this reaction method is complete
within 3 h, proceeds at low temperatures (40 to 0 C), and tolerates various functional groups as
shown in Table 3. Kobayashi and co-workers have reduced sulfoxides with an equimolar amount of
ferrocene and trifluoroacetic anhydride (TFAA) to give a mixture of sulfides and -trifluoroacetoxy-
methyl sulfides <2000CL400>. The latter product is a result of a Pummerer rearrangement, typical
for sulfides containing an -methyl group.
Me
Cp2Ti
Me
Table 3 Reduction of sulfoxides

O 3
S THF, – 40 °C to 0 °C S
R R R R
Starting Material Product Time (h) Yield (%)
Ph
O O S Ph
O O S
O
2 50
O
O S O S
Ph Ph
TsO TBDMS TsO TBDMS
OPMBa
1 76
OPMB
O
O S O S
O Ph O Ph
Ph O O Ph O O
0.5 84
O O
Source: <2000AG(E)2529>.
a
PMB = para-methoxy benzyl.
Pummerer-type reactions provide various -substituted sulfides from the corresponding sulf-
oxides. The reaction of sulfinyl diacetic acid amide ester with t-butyldimethylsilyl triflate
(TBDMSOTf) affords the corresponding amide -acetoxy sulfide 4 or the ester -acetoxy sulfide
5 by a chemoselective Pummerer reaction <2002TL1519>. Chemoselectivity can be tuned by the
use of different solvents: more polar aprotic solvents favor 5 and less polar protic solvent favors 4.
OAc
S
S
AcO CO2Me 2-Pyr S-Tolp
CO2Me
NH
NH TBDMSO R
O Ph
O Ph
Ph
Ph R = H, Me, Et
4 5 6
Asymmetric Pummerer-type reactions have been reported in which the deprotonation of the
sulfoxides is the enantio-determining step. For example, ethoxy vinyl esters react with chiral sulfoxides
as shown in Scheme 1 <1997TA303>. A highly stereoselective Pummerer reaction was achieved by
reacting chiral -substituted sulfoxides with O-silylated ketene acetals in the presence of catalytic ZnI2
in tetrahydrofuran (THF) <1997JCS(P1)1763>. The -siloxy sulfides 6 were obtained in good yields
(49–75%) and excellent enantioselectivity (>99%).
OAc
O EtO2C S
Tolp
EtO2C S OEt
Tolp OAc
77% 58% ee
R
O
O O
S CO2Et
S CO2Et OEt
O R
R = Aryl, Me, CH2Cl2
O
19–63% 53–81% ee
Scheme 1
An aromatic Pummerer-type reaction affords quinone O,S-acetals as shown in Equation (1)

<2001JOC2434>. These quinone thioacetals aromatize when reacted with nucleophiles to afford
sulfenylation products.
OH O
2
cat. TsOH
OCOR toluene
+ ð1Þ
OEt 70–90%
S+ R1S OCOR2
R1 O–
(iii) From vinyl sulfides, ,-unsaturated nitriles, and other reactions

Monothioacetals are also produced from -halo sulfides, -halo ethers and thiols, as reported
in COFGT (1995) <1995COFGT(4)215>. An application of -ether sulfides is the synthesis of
-thionucleosides <2003JMC389>. An iodo ester is treated with potassium thioacetate in
dimethylformamide (DMF) to afford the corresponding thioacetate 7.
O
SR N
OTBDPS = Cby
MeO2C F CbyO OCby
SAc
NBn2
R = Me or Ph
7 8
A regio- and stereoselective lithiation with s-butyllithium is achieved by deprotonation of a

dicarbamate via a bis-chelate complex to afford a stereohomogeneous and regioisomerically pure
product 8 <1998S1274>. This method is also used to form the seleno product (see Section
4.05.2.1.1, Equation (31)).
Vinyl sulfides react with sodium trifluoromethanesulfonate (CF3SO2Na) and t-butyl hydrogen
peroxide by a single electron transfer producing a stabilized cation <1999PS(153)323>. This cation
is then trapped by a nucleophile such as methanol to afford -trifluoromethylthioacetal 9.
Fuchigami and co-workers have reported an electrosynthesis of 3,3,3-trifluoropropyl phenyl
sulfide <1998JFC209>. Platinum electrodes are used to carry out this anodic oxidation in
methanol containing Et3N3HF to afford -trifluoromethylated O,S-acetal 10.
SPh F3C OMe
F3C OMe EtO2C SPh
9 10
Mixed thioacetals can also be formed from reactions of magnesium carbenoids as shown in
Equation (2) <1999SL1820>. The magnesium carbenoid containing an ester reacts with various
electrophiles such as diphenyl disulfide.
O O O
PriMgCl (PhS)2
R O I R O MgCl R O SPh ð2Þ
t
R = Bu 81%
R = Cy 88%
Monothioacetals 11 are also prepared from Michael addition of benzenethiolate to substituted

acrylonitriles <1995JOC4299>. This method provides -phenylsulfenyl nitriles without competi-
tive addition to the nitrile. Oxetanes 12 are synthesized from the Paternò–Büchi photocycloaddi-
tion of aromatic aldehydes with silyl O,S-ketene acetals <2000JA4005>. Similar reactions are
conducted with the corresponding O,Se-acetals (vide infra).
PhS CN O
Ar OSiR3
MeO H
H SR1
11 12
4.05.1.1.2 Compounds with oxygen in a ring
(i) From ethers, enols, aldehydes, and other acetals

Hex-1-ene-3-ulose reacts with various sulfur nucleophiles in a Michael-type addition to afford
-deoxy-thioulosides <1996TL3453>. ZnI2 or KCN/18-crown-6 is used to catalyze the reaction
shown in Table 4.
Radical additions to alkenes are promoted by hypervalent iodine as shown in Equation (3)
<1996TL1889>. Iodobenzene diacetate (IBDA) oxidizes a thiocyanate anion to a radical that can
subsequently add to alkenes to provide dithiocyanate derivatives. In addition, dialkyl ethers react
with IBDA, sodium azide, and diphenyl sulfide to afford mixed O,S-acetals in good yields
<1995SL1129>. This method can also be applied to O,Se-acetals (see Table 13).
Table 4 Michael-type addition to hex-1-ene-3-ulose

OAc
H OAc
O
O
H AcO
AcO O SR
O
Nucleophile Catalyst Yield (%)

n
Bu STMS KCN/18-crown-6 46
allylSH ZnI2 22
Z-Cys-O-allyl ZnI2 41
Source: <1996TL3453>.
O KSCN (2 equiv.) O SCN

( ) ( )
n
n IBDA (2 equiv.) SCN ð3Þ
n=1 60% (1:1 cis:trans)
n=2 60% (1:1 cis:trans)
A three-component reaction process is described with dihydropyran, oxo-acetic acid ethyl ester,
and sulfur nucleophile as shown in Equation (4) <1999TL4751>. The reaction is promoted by
TiCl4 and affords functionalized tetrahydropyrans. Additionally, thiols readily add to dihydro-
pyran in the presence of vanadyl(IV) acetate <2001JMOC(A)169>. This method is a mild,
heterogeneous reaction that provides the corresponding THP thioacetals in good yield as depicted
in Equation (5). This is the first reported transition metal-catalyzed tetrahydropyranylation with
thiols.
O O O SR
RSH, TiCl4
H CO2Et CO2Et ð4Þ
R = Et 35%
R = Ph 46%
O RSH, VO(OAc)2 O SR
n
R = Bu 96%
R = Cy 95% ð5Þ
R = p-Cl-C6H5 48%
R = p-MeO-C6H5 54%
A regioselective opening of a substituted furanose with organostannanes provides the corre-

sponding thioacetal as shown in Equation (6) <1995TL5469>. Trimethylsilyl triflate mediates the
S-glycosidation in which the -anomer is formed preferentially.
BnO O O BnO O SPh

O i. Bu3SnSPh OH
ð6Þ
O ii. MeOH, ∆ O
O O
84%
Oxiranes are produced by the reaction of sulfonium ylides with aldehydes <1995T10593>. This
chapter includes ylides that contain thioalkyl substituents, which are unexpectedly stable as shown
in Equation (7).
O + 50% NaOH, DMF O

+ S ð7Þ
Ar H S 90% Ar S(CH2)3SCH3
(ii) By cycloadditions, photochemistry, and Pummerer-type reactions

This section does not include hetero Diels–Alder reactions, although a number of papers have
been published in the period 1995–2003.
Oxidative cycloadditions of 1,3-dicarbonyls with vinyl phenyl sulfides have been reported
<1997TL2095, 1997TL5671>. These radical reactions can be mediated by metal salts of
Mn(III), Ce(IV), Co(II), and Ag(I). Dicarbonyls react with various alkenes in acetonitrile
with Ag2CO3 and celite to form 3-acyl-furans and -dihydrofurans in good yields as shown in
Table 5.
Table 5 Oxidative radical cycloaddition of 1,3-dicarbonyls

to form dihydrofurans
O
R3
O O SPh R2 R3
R1 R2 Ag2CO3 /Celite
R1 O SPh
Dicarbonyl R3 Product Yield (%)

O
O O
Me 83
O SPh
O
O O EtO
Me 63
OEt
O SPh
O O
H SPh 77
O O
O O
Me SPh 86
O O
O O
H SPh 77
O O
Source: <1997TL5671>.
1,3-Dipolar cycloadditions provide access to five-membered heterocycles. Isoxazoles are

obtained by heating nitrolic acids, forming nitriles that subsequently undergo cyclizations in the
presence of alkenes (Equation (8)) <2000TL1191>.
O–
NO2 N+ SPh N O
Bn OH
Bn ð8Þ
N 95% SPh
Bn
Solid-state photochemistry of aroylbenzothioates affords asymmetric phthalide formation

<1998JA12770>. Scheme 2 depicts a novel absolute asymmetric reaction involving an intra-
molecular cyclization and phenyl migration.
STolo STolo Ph
Phenyl STolo
hν/Pyrex migration
O *O
O
O 65%
O– O
Ph Ph
30% ee
Scheme 2
A two-component [3,3]-sigmatropic rearrangement provides dihydrobenzofurans as shown in

Equation (9) <2000OL2729>. This reaction proceeds via reduction of the sulfoxide and oxidation
of the carbons involved. Elimination of thiophenol leads to substituted benzofurans.
X
OH (CF3CO)2O SPh
Ph R1
+ O
X S ð9Þ
R2 19–55%
R1 O
X = O or H, H R2 = H, CH3, Br
R1 = CH3, H
Sulfoxide-directed lactonization affords a stereoselective synthesis of enantiomerically pure

-butyrolactones by a Pummerer-type reaction followed by a [3,3]-sigmatropic rearrangement
as shown in Scheme 3 <1999EJO111>. Trichloroacetyl chloride with zinc dust and copper(II)
chloride generate dichloroketene which reacts with vinyl sulfide derivatives to afford lactones.
Tolp R H H Cl
S+ R Cl R
+
O– [3,3] Tolp – Cl
TolP Cl S+ O
Cl S O
O O– O
Cl
O
Cl
O
Cl
R = CF3 51% H R
R = CF2CH2 53% TolpS H
R = CClF2 60%
Scheme 3
Treatment of N-acylamino-2-thiophenol with N-chlorosuccinimide (NCS) followed by addi-

tion of SnCl4 affords the corresponding monothioacetal in good yield as shown in Equation (10)
<2002TL7393>. An asymmetric Pummerer-type reaction provides a stereoselective synthesis
of -hydroxy--sulfenyl--butyrolactone as shown in Equation (11) <2000TL4189>. This is
the first highly diastereoselective (>98% de) formation of the lactone under the Pummerer
conditions.
i. NCS (1.0 equiv.), PhCl

HN N
Ph SPh ii. SnCl 4 (0.1 equiv.), 0 °C ð10Þ
O Ph SPh
O
73%
O
OTBMS
O O i. TFAA, CF3CO2Na
S O ð11Þ
OBut ii. NaHCO3
Tolp
95% TolpS OTBMS
Padwa and co-workers have explored a Pummerer cyclization–deprotonation–cycloaddition

sequence to access naturally occurring alkaloids <2000JOC2368>. -Acyl sulfoxides generate
thionium ions that are good electrophiles to react with various nucleophiles as shown in Scheme 4.
O
O O O O
S Ac2O S+ SEt Base
N Et N Et N
O O+ H
O O SEt
O
Methyl acrylate BF3·OEt 2
N SEt N CO2Me
O+
O
SEt
N N
H
CO2Me OH
(±)-Lupinine
Scheme 4
(iii) By phase transfer catalyst

Phase transfer catalysis (PTC) is a convenient and useful method for carbohydrate synthesis
because mild conditions can be used and reactions can be performed on large scale. Anomeric
nucleophilic substitutions have been reported using mild PTC conditions for stereospecific entry
to 1-thio--D-mannosides and 1-thio--L-rhamnosides <1996MI27>. Glycosyl bromides and
chlorides are treated with thiophenol as the nucleophile and tetrabutylammonium hydrogen
sulfate (TBAHS) as the phase transfer reagent to afford the corresponding phenyl thioglycosides.
Ethyl acetate is shown to be a superior solvent in comparison to dichloromethane because the
thiols can react with the latter to form bis(4-nitrophenylthio)methane. Allyl mercaptan can also
serve as a nucleophile <2000JMOC(A)9>.
Tetrabutylammonium thiocyanate and tetrabutylphosphonium bromide are also used in PTC

for the synthesis of alkyl and aryl thioglycosides <1999JMOC(A)65>. The phosphonium salt is
more effective than the ammonium salt.
4.05.1.1.3 Compounds with sulfur in a ring

Starting material 13 is obtained in four steps from L-arabinose for the synthesis of pentofuranose
derivatives 14 as shown in Scheme 5 <1996JCS(P1)1665>. This mild method allows incor-
poration of sensitive functional groups as well as stereocontrol of the substituent at C-3.
BnS SBn BnS SBn

4 steps
L-Arabinose
HO R1
R = Ac
O R1 = N3 R2O
O R3 = Bz R3O
13
Bu4NI S Hg(OAc)2 S
BaCO3, DMF R3O SBn AcOH R3O OAc
R1 R1
14
17% for 10 steps
Scheme 5
Synthesis of a five-membered thiophene in a thienoquinolone system is accomplished via a

sulfoxide rearrangement <1998T11603>. Sulfoxide 15 undergoes a [2,3]-sigmatropic rearrange-
ment to give an intermediate allene. The allene subsequently undergoes a [3,3]-sigmatropic
rearrangement followed by aromatization and formation of the monothio hemiacetal as shown
in Scheme 6.
Ar
O
O
S CCl4, reflux S
O N 92–96% O N
Me Ar Me
15
Ar Ar Ar
OH
O O
H S
S SH
O N O N O N
Me Me Me
Scheme 6
Shimizu and co-workers have reported the [4+ + 2]-type polar cycloadditions of 2-benzothiopyry-
lium salt with alkenes and dienes as shown in Scheme 7 <1996CC2185, 2000TL2161>. For the dienes,
a [2+ + 4]-type reaction competes with the desired reaction to afford another cycloadduct.
Me R
R
MeOH
H
R = Me 36%
R=H 46% OMe
S
S+
BF4– R R H
H
MeOH
R = Ph 49% S OMe
R = OMe 45%
R = 4-MeO-C6H4 46%
Scheme 7
Thietanes 16 are derived from the 2 + 2 reaction of ammonium hydrosulfide with

3-adamantylidene-1,1,1-trifluoropropane-2-one <1996JOC1986>. This 2-thietanol is stabilized
by the trifluoromethyl and geminal fragments as well as the adamantane structure.
CF3
S
OH
16
Reaction of thiazoliums and benzothiazolium N-phenylacylides with electron-deficient acety-

lenes and dimethyl acetylenedicarboxylate (DMAD) in wet DMF affords the corresponding
hemiacetals as shown in Scheme 8 <1996JCS(P1)629>. The proposed mechanism begins with
the reaction with DMAD followed by interaction of the carbonyl and sulfur in a [1,5]-sigmatropic
rearrangement. Thiazoles are also prepared from a ring–ring interconversion as shown in
Scheme 9 <2000SC875>.
R2
S
R2 R2 CO2Me
S S R1 N
R1 + X R1 X DMAD
Br – N N+ O CO2Me
HC–
O O
X
X
X = H, Br, NO2 HO S
MeO2C
R1, R2 = Me, H, Ph R2
N
68–85% MeO2C R1
Scheme 8
R NO R O
R Cl
N 3 M HCl
R Cl N
S N S N
O HO
R
R R
S OH O
HS
R N
N O
N 25–65% O N Cl
O O Cl
R = Me, H, –C4H4–
Scheme 9
4.05.1.1.4 Cyclic monothioacetals

Thioacetals are commonly used protecting groups for aldehydes and ketones in multistep synth-
eses. They also serve as acyl carbanion equivalents.
(i) From carbonyl compounds, O,O-acetals, and xanthates

Monothioacetals are commonly prepared from 2-mercaptoethanol using strongly acidic condi-
tions. Various catalysts are reported that avoid these harsh conditions. These catalysts are used
with 2-mercaptoethanol or propanol and are highly selective for aldehydes over ketones.
Bismuth trichloride is used as a catalyst for the protection of carbonyls as 1,3-oxathiolanes
<1995SL984>. The bismuth salt is nontoxic, inexpensive, and easy to handle. Khan and
co-workers report perchloric acid as well as organic tetra-n-butylammonium tribromide as cat-
alysts to form monothioacetals <2002SL463, 2002TL2843>. Chlorinated silica gel is used in a
ratio of 500 mg per mmol acylal <2001PS(176)165>. One report covers the use of bromine,
N-bromosuccinimide (NBS) and 2,4,4,6-tetrabromo-2,5-cyclohexadienone <2002PS(177)1047>.
NBS is further investigated for oxathioacetalization, thioacetalization, and transthioace-
talization <2002TL6947>. Zirconium tetrachloride, lithium tetrafluoroborate, and indium tri-
fluoromethanesulfonate are also efficient and chemoselective catalysts. <2000SL805, 2001SL238,
2002SL1535>.
For the synthesis of ,-unsaturated oxathiones, thiols can add 1,2 or 1,4 to ,-unsaturated
carbonyls. Various Brønsted and Lewis acids were screened and the heterogeneous catalyst
aminopropyl silica gel hydrochloride (APSGHCl) as a supported catalyst proved to be superior
<2002T10455>. This catalyst is simply removed by filtration.
The reduction of cyclic xanthates 1,3-oxathiolane-2-thiones to 1,3-oxathiolanes has been
reported using 2,20 -azobisisobutyronitrile (AIBN) and tributyltin hydride <1995HAC325>. A
competing reaction forms the corresponding alkene stereoselectively. Using higher concentrations
of tributyltin hydride diminishes the formation of alkene.
(ii) By intramolecular alkylation

The synthesis of a 1,6-epithio bridge sugar is achieved from the corresponding bromo tosylate as
shown in Equation (12) <1996AJC343>. This method is also applied to seleno sugars (vide infra).
Thiabicycle 17 is synthesized from the addition of mercaptoacetates to dihydropyrones as shown
in Equation (13) <1998MC198>. Acetoamide pyranose 18 is converted to the thioamide by
treatment of Lawesson’s reagent as shown in Equation (14) <1996JA6804>.
OTs S
H2S, Et3N OAc
AcO O O ð12Þ
AcO
AcO 60% R OAc
Br
OR1
O
R O H
HSCH2COR1 S
R
Piperidine R CF3 ð13Þ
O CF3 O
R = Me, –(CH2)5– R OAc
17
R1 = Me, Et, (CH2)5
64–78%
OAc OAc
O AcO O
AcO OAc Lawesson’s reagent
AcO AcO ð14Þ
HN O N S
>68%
18
Thia-cage compounds 19 are synthesized from the tetraoxa-cage compounds when exposed to
Lawesson’s reagent as shown in Scheme 10 <2001JOC4610>. Novel camphor thioacetal 20 is
synthesized from the reduced exo product of camphor-10-sulfonyl chloride as shown in Equation
(15) <2001JCR(S)405>.
O
i. O3, –78 °C
O O
ii. Lawesson’s reagent
O O
O 94%
S
Lawesson’s reagent
O
89% O O
19
Scheme 10
i. LAH S
ii. p-Toluenesulfonic acid, O ð15Þ

O camphorquinone O
SO2Cl
20
Benzoxathiinones are synthesized by a highly regio- and stereoselective method as shown in

Equation (16) <2001JCS(P1)1649, 2001SL415>. Copper(I) iodide is used to achieve cyclization
and affords 21 in 25–70% yield.
i. ArI, (PPh3)2PdCl2 (3.5 mol.%), O

O
CuI (6 mol.%)
OMe ii. 5 M methanolic HCl O
iii. HCl S ð16Þ
S
iv. CuI (20 mol.%), Et3N Ar
Ar = Ph, 4-Me-C6H4, 4-MeO-C6H4, 21
1-naphthyl, 2-naphthyl, 3-Cl-C6H4
(iii) By cycloaddition reactions

Thiocarbonyls react with oxiranes as shown in Scheme 11 <1999HCA2316>. Pathway A is
believed to proceed via a 1,3-dipolar cycloaddition of an intermediate carbonyl ylide. Pathway
B occurs with cleavage of the carbon–oxygen bond and results in opening of the oxirane when
activated by an electrophile. A silica gel mediated reaction of thiocarbonyls with oxiranes affords
1,3-oxathiolanes as shown in Equation (17) <2002H333>. 1,3-Dipolar additions are also reported
for adamantane-2-thiones with benzonitrile oxides to provide oxathiazoles as shown in Equation (18)
<1997JOC4672>.
Pathway A
O
O S
+
S
Pathway B
O
Scheme 11
O O
CH2Cl2, N2
S + ð17Þ
BF3·Et2O or SiO2 S
Ph Ph
S N N
Ph Et3N S O S O
+ N OH ð18Þ
Cl X = F, Cl, Br
X
75–82% X X
o-Thioquinones undergo a hetero-Diels–Alder reaction with 2-methylfuran as shown in Equa-

tion (19) <2000SL61>. In an attempt to reduce –chloro sulfenyl chlorides, the thiocarbonyl
compound is formed and undergoes a dimerization via a [4 + 2]-cycloaddition as shown in
Equation (20) <1998SUL19>.
Me Me
OH O Pyr O
+ ð19Þ
70 °C
SNPhth S O
92%
O O Me O
Cl
PPh3 or I– S
Et O
SCl O S ð20Þ
Me Me 46%
O O S
Et Et
Me
O
Et
A tandem reaction mediated by benzyltriethylammonium tetrathiomolybdate results in the

formation of monothioacetals as shown in Equation (21) <2000AG(E)4316>. The first step
involves a sulfur transfer reaction mediated by the molybdenum to afford a ketosulfide followed
by reduction and subsequent Michael addition.
O O
(BnNEt3)2MoS4
ð21Þ
S
Cl 80%
O O
Oxathioles are produced from a rhodium(II) catalyzed cycloaddition as shown in Equation (22)
<2002TL5997>. Methyl acetoacetate affords carbomethoxy iodonium ylides that cyclize when
treated with diaryl thiones and rhodium acetate. Macrocyclization via photolysis of methylthio-
methyl (MTM) ester has been reported and is shown in Equation (23) <2000JOC9028>.
MeO2C
MeO2C MeO2C
PhI(OAc)2 +IPh Ar2C=S S
– Ar
MeOC KOH, MeOH MeOC Rh2(OAc)4 Me ð22Þ
O Ar
120–125 °C
58% 65%
S
O O S O
hν HO
O
ð23Þ
N ( )n n = 2, 3 N ( )n O
O O
1,3-Oxathianes are also synthesized via intramolecular Pummerer reactions. ,-Unsaturated

sulfinyl compounds are treated with p-toluenesulfonic acid (p-TSA) to afford the oxathianes 22 as
shown in Equation (24) <1995CC1197>. -Hydroxy sulfoxides also undergo this rearrangement
as shown in Equation (25) <1999H291>. Furthermore, iodooxathianes are synthesized from the
,-unsaturated sulfinyl compound via an iodonium-promoted intramolecular Pummerer reaction
depicted in Equation (26) <2000H465>.
R4
R4 p-TSA R3
R3
R2
R2 50–80% O S
– S+ R1 ð24Þ
O 1
R = Me, Et, Ph R1
R2 = H, NO2 22
R3 = R4 = H, –(CH2)3–
O– Ph
p-TSA,
Ph S+ OH S O
3 Å mol-sieves ð25Þ
R R
R R = Me 91%
R
R = H 49%
I
N-iodosuccinimide
ð26Þ
–O S+ Ph 23% (36:1) O S
Ph
A sila-Pummerer rearrangement of cyclic sulfoxides leads to a 1,3-oxathioacetal as shown in

Equation (27) <1999TL185>. This thermal conversion is the first example of a sila-Pummerer
rearrangement leading to a ring expansion.
O O
Si S ∆ Si ð27Þ
S
97% (crude)
4.05.1.2 Derivatives with Tricoordinate Sulfur
4.05.1.2.1 a-Alkoxy sulfoxides

Oxidation of sulfides to sulfoxides is commonly achieved by 3-chloroperoxybenzoic acid
(MCPBA) or hydrogen peroxide. On large-scale operations of glycosyl sulfides, however, this
method is problematic because low temperatures are required to prevent sulfone formation and
completion of the reaction is not realized at low temperatures. In addition, the by-product
m-chlorobenzoic acid is formed and is difficult to remove. To circumvent these drawbacks, Karkala
and co-workers screened conditions to find a simple, inexpensive approach for the preparation of
glycosyl and noncarbohydrate sulfides <1996JOC8347>. The oxidation method they support is a
combination of hydrogen peroxide (1.2 equiv.), and acetic anhydride (1.1 equiv.) in dichloro-
methane. Reaction times can be reduced by using aprotic perfluorinated solvent mixtures without
overoxidation to the sulfones <2001TA2389>.
Asymmetric oxidation of racemic 2-substituted-1,3-oxathianes was achieved using a catalytic
di--oxo Ti(salen) and urea hydrogen peroxide system <2003CHIR24>. Kinetic resolution led to
the corresponding sulfones with high enantiomeric excess. Ketosulfoxides were unexpectedly
produced from 5,6-dihydro-1,4-oxathiins when exposed to singlet oxygen <2000OL1205>. The
proposed rearrangement shown in Scheme 12 details the formation of the ketosulfoxides in
preference to the dicarbonyl.
O
1 O S
O S O2 S R2
R1 O
R1 R2 R1 R2
O O O
23
O S+ O– O S+ O– O S+ O–
1
R1 R2 R R2
R 1 O R2 O O
24 25
Yield (%)
R1 R2 23 24 25 References
Ph Me 90 <2000OL1205>
Me CO2Me 47 23 <2000OL1205>
Ph CO2Et 16 30 <2000OL1205>
Me COMe 64 21 <2000OL1205>
Scheme 12
4.05.1.2.2 a,b-Epoxy sulfides

A general approach to sulfinyloxiranes involves deprotonation of an -halo sulfoxide, then
addition of a ketone or aldehyde, followed by cyclization of the resulting halohydrin. Satoh has
reviewed oxiranyl anions that included sulfinyloxiranes <1996CRV3303>. Hydroxy chloro sulf-
oxides are treated with potassium t-butoxide to afford sulfinyloxiranes.
Asymmetric epoxidation of electron-deficient alkenes is achieved by nucleophilic epoxidation of
vinyl sulfoxides <1998JOC4954>. The epoxidation of both vinyl and dienyl sulfoxides was
studied, as shown in Table 6. Alkene geometry is preserved in the resulting oxiranes with good
yield and facial selectivity. Sodium proved to be the superior counterion compared to lithium and
potassium by providing shorter reaction times and decreased amounts of overoxidized
by-products. Increased substitution on the alkene leads to reduced or no reactivity. Cyclic
substrates were also examined (Entries 9–11). Cyclohexenyl sulfoxides afford mixtures of products
when treated under oxidative conditions while the activated keto sulfoxides afford the ,-epoxy
sulfides smoothly. When epoxidizing (E)-2-sulfinyl dienes, the metal cation influences facial
selectivity (Entries 12–15). This sulfur-directed synthetic strategy is displayed in the formal
syntheses of ()-trans-Kumausyne and (+)-Kumausallene <1998JOC9612>.
Table 6 Epoxidation of vinyl sulfoxides
MOO-But
Alkenyl sulfoxide α, β-Epoxy sulfoxides
THF, 0 °C
Entry Producta R1 R2 M Time Yield (%)b

1 O Bun Tolp Na 90 min 75 (13:83:4)
2 S 2 Bun Tolp K 9 min 65 (94:6)
3 R (CH2)2Ph Tolp Na 220 min 67 (2:97:1)
O
4 Bun But K 75 h 65 (8:82)
R1
5 O Me Tolp Li 150 min 63 (6:92:2)

6 S 2 Me Tolp Na 100 min 80 (98:2)
7 O
R Pri Tolp Na 2 days 90 (13:85:2)
8 Pri But K 1 days 87 (3:73:1)
R1
O O
9c n=1 Na 17 min 44 (36:5)
10c S Li 10 min 48 (9:91)
Ph n=1
11 O n=0 Na 160 min 60 (3:92:5)
( )n
12 R1 H Li 120 min 75 (20:80)

Bun
13 H Na 90 min 61 (8:84:8)
14d Ph Li 2 h 74 (2:12:86)
15 O CH2OH Na 120 min 80 (3:97)
S
Tolp O
16 R1 H H Na 25 min 81 (95:5)
R2
17 H H Na 90 min 94 (2:98)
18 Bun H Me Na 160 min 60 (3:92:5)
O
S
Tolp O
Source: <1998JOC4954>.
a b
-Epoxy sulfoxide shown; Combined yield of pure products followed by ratio of sulfone:-epoxide:
c
-epoxide; Reaction carried out at 78 C; d Reaction carried out at 20 C.
The above method is further developed using 0 -hydroxy sulfoxides and sulfones (vide infra)
<2002JOC8166>. For (E)-0 -hydroxyalkyl vinyl sulfoxides, as the size of the substituent at the
allylic position increases, so does stereoselectivity to afford the antiepoxides. Substitution at the
-carbon has a greater effect upon selectivity. Finally, changes in the metal cation can also enhance
the reaction selectivity. Cyclic 0 -hydroxyalkyl sulfoxides were also investigated resulting in sulfone
formation. The (Z)-0 -hydroxyalkyl vinyl sulfoxides are more reactive than the (E)-isomers.
4.05.1.3 Derivatives with Tetracoordinate Sulfur
4.05.1.3.1 a-Alkoxy sulfones and related compounds

Common oxidants used to oxidize sulfides to sulfones are MCPBA, hydrogen peroxide, and
KMnO4 <2003TA79>. Conversion of monocyclic O,O-acetals to the corresponding 1,3-
oxathiane dioxides can be achieved in one step using phenylsulfinic acid and CaCl2 as shown in
Scheme 13 <1996JOC7860>. This method was applied in the enantioselective total synthesis of
(+)-amphidinolide T1 <2003JA2374>.
PhSO2H, CaCl2
O O >53% O SO2Ph
PhSO2H, CaCl2
TMS
O O 95% O SO2Ph
Scheme 13
1,3-Dipolar cycloadditions provide entry to five-membered heterocycles. Aryl sulfonylethenes

undergo 1,3-dipolar cycloadditions in the presence of chloramine-T to afford bifunctional bispyr-
azoline and bisisoxazolines as shown in Equation (28) <2003PS(178)171>. Nitrones can also add
to unsaturated methylsulfones via a 1,3-dipolar cycloaddition <1999JCR(S)566>. This reaction
provides trisubstituted isoxazolidines 26 as a mixture of regioisomers. Isoxazolidines 27 are also
prepared from araldoximes in the presence of chloramine-T <1999JCR(S)610>.
O O ArCHNOH, N O
S Chloramine-T Ar ð28Þ
Ar
23–78% S
Ar Ar Ar O2
MeO2S H
H R N O
Ar
O Ph
N SO2Ar
ArCO
Me
26 27
A rhodium catalyzed CH insertion of phenyl sulfones leads to cyclization as shown in

Scheme 14 <2000TL4773>. Rh2(OAc)4 forms the carbenoid from the diazo compound to provide
access to furan derivatives.
O
R1
SO2Ph cat. Rh(OAc)4 O
R2
R1 N2 O
R2 OH SO2Ph
R1 R2 Yield (%)
H CH3 60
H C3H7 56
H C6H5 70
CH3 CH3 75
Scheme 14
Sulfur dioxide reacts without any additives to electron-rich dienes, such as 1-methoxy-1,3-
butadine, below 60 C to provide sulfolene 28 as shown in Scheme 15 <2000CEJ1858>.
Reactions also proceed at 110 C in the presence of Lewis acids. The corresponding sultine is
not detected and 28 is used in situ to form sulfur heterocycles.
Sodium aryloxymethanesulfonates can be synthesized using microwave irradiation to promote
the condensation of aryl alcohols with sodium chloromethanesulfonate <1999JCR(S)720>. A
typical reaction is shown in Equation (29). The phenol can be derived from cresol, naphthol,
allylphenol, etc. This method is superior to the Barber method, which generally uses temperatures
up to 220 C for 4 h.
OMe O
O3, SO2
O S OEt
SO2 O
SO2 EtOH MeO OEt
28
65%
OMe
X OMe
O
S
O
Scheme 15
OH OCH2SO3Na
ClCH2SO3Na
NaOH
ð29Þ
40 s, 100 W
95%
Trost and co-workers have demonstrated the use of sulfinates as nucleophiles in asymmetric
allylic alkylation reactions. They are used in catalytic asymmetric synthesis of -acetoxysulfones
as desymmetrizing reagents of allylic gem diesters as shown in Table 7 <2000JA6120>.
Trisubstituted alkenes react slower than disubstituted alkenes, and electron-withdrawing groups
do not affect the reaction. The chirality of the product can be inverted by changing the chirality
on the ligand. The acetoxysulfones serve as aldehyde equivalents that allow for differentiation of
the enantiotopic faces of ,-unsaturated aldehydes.
Table 7 Asymmetric allylic alkylation of allylic gem diesters
OAc OAc
Conditions H
R1 OAc R1 SO2Ph
R2 R2
R1 R2 Time (h) Yield (%) ee (%)

C6H5 CH3 24 85 95
o-NO2-C6H4 H 2 93 85
n-C3H7 H 4 94 98
n-C6H13 H 6 73 95
EtO2C CH3 12 85 98
Source: <2000JA6120>.
Conditions: 6 mol.% 29, 2 mol.% -allylpalladium chloride dimer, sodium
benzenesulfinate.
O O
NH HN
PPh2 Ph2P
29
4.05.1.3.2 a,b-Epoxy sulfones

Stereoselective formation of ,-epoxy sulfones has been reported, using metal alkyl peroxides as
well as metal-catalyzed reactions. Stereocontrolled nucleophilic epoxidations of 0 -hydroxyalkyl
vinyl sulfones have been studied by Jackson and co-workers <1995JCS(P1)141>. Epoxidation of
-unsubstituted-0 -hydroxyalkyl sulfones yields syn epoxides in high diastereoselectivity using
lithium t-butyl peroxide. In contrast, triisopropylsilyl ethers lead to the antiepoxide. Epoxidation
of (E)-0 -hydroxyalkyl--phenyl vinyl sulfones provides antiepoxides and their corresponding
triisopropylsilyl ethers afford syn epoxides. These initial findings have been expanded by de la
Pradilla and co-workers in the epoxidation of both vinyl sulfoxides and sulfones and are shown in
Table 8 <2002JOC8166>.
Table 8 Epoxidation of 0 -hydroxy vinyl sulfoxides
MOO-But
alkenyl sulfoxide α, β-epoxy sulfones
Entry Producta R1 R2 Conditions Yield (%)b

1 Et Li, THF 75 (50:50)
2 OH Pri Li, THF 63 (68:32)
3 SO2Tolp But Li, THF 81 (75:25)
4 R1 Et Li, Et2O 75 (5:95)
O
5 Pri Li, Et2O 60 (15:85)
Bun
6 But Li, Et2O 88 (24:76)
OH
7 Et Li, THF 70 (28:72)
8 SO2Tolp Et Li, Et2O 73 (2:98)
R1
O
Bun
9 OH Et Bun Li, THF 76 (97:3)

10 SO2Tolp Ph Bun Li, THF 86 (93:7)
11 R1 Ph Bun Li, Et2O 68 (94:6)
O
12 Et Ph Li, THF 67 (100)
R2
Source: <2002JOC8166>.
a
Syn sulfone shown where the stereochemistry is defined for the hydroxyl and epoxide functionalities, relative to the
extended conformation of the longest carbon chain. b Combined yield of pure products followed by ratio of anti:syn sulfone.
A mild oxidation of cephalosporins is accomplished using dimethyldioxirane. Dimethyldioxir-

ane can be used under neutral conditions as a solution in acetone. The oxidant is examined for
cephem sulfones and their derivatives as shown in Equation (30) <1995TL7111>.
O O
R1 R1 O
S S
O R2 O R2
COOR3 ð30Þ
COOR3
Yield (%)
R1 = C6H5OCH2CONH, R2 = Cl, R3 = CHPh2 95
R1 = C6H5CH2CONH, R2 = CH3, R3 = CH2OAc 85
Epoxidation of vinyl sulfones and N-(p-tolylsulfonyl)vinylsulfoximines proceeds with varying

selectivity based on metal cation and substitution <1998JCS(P1)4097>. Substrate 30 gave the
best yield and selectivity when treated with lithium t-butyl peroxide in THF.
R
O
O
O Ph Ph O
S S
30 R = PhO2S, TolO2SN , TolO2SN
Another method reports catalytic oxidation of sulfur followed by epoxidation of acyclic

0 -hydroxyl vinyl sulfones to afford the corresponding epoxy sulfones as shown in Table 9
<1999JCS(P1)1247>. These reactions are highly stereo- and regioselective for electron-deficient
alkenes and can be expanded to carbohydrate fragments.
Table 9 Metal-catalyzed expoxidation of hydroxy vinyl sulfones
OH O OH OH
ButOOH
S SO2R3 SO2R3
R1 R3 VO(acac)2 R1 R1
O + O
C6H6, rt
R2 R2 R2
31 32
R1 R2 R3 31 32 References
p
Et Bu Tol 76 <1999JCS(Pl)1247>
(CH2)2Ph Bu But 54 <1999JCS(Pl)1247>
Et Ph Tolp 60 <1999JCS(Pl)1247>
Ph vinyl Tolp 67 <1999JCS(Pl)1247>
The Darzens reaction is also used to synthesize ,-epoxysulfones. An asymmetric Darzens’ reaction
using chloromethyl phenyl sulfone with aromatic and aliphatic aldehydes is accomplished using phase-
transfer catalyzed conditions to afford ,-epoxysulfones <2002T1407>. Chiral quaternary ammo-
nium salts from cinchona alkaloids act as the catalyst to produce enantioselectivities up to 83%.
4.05.2 FUNCTIONS CONTAINING OXYGEN AND EITHER SELENIUM OR

TELLURIUM
4.05.2.1 Dicoordinate Selenium and Tellurium Derivatives

This section contains methods for compounds containing oxygen with selenium or tellurium.
Novel examples are described that parallel and expand the chemistry generally associated with
sulfur compounds.
4.05.2.1.1 From enol ethers, ethers, lactones, other acetals, and other compounds
(i) From enol ethers and ,-unsaturated nitriles

Monoselenoacetals are produced from enol ethers under mild conditions upon treatment with
benzeneselenol as shown in Table 10 <1996JCR(S)206>. Furthermore, Michael addition of
benzeneselenide anions to activated alkenes has been reported and was expanded to ,-unsatu-
rated nitriles to provide functionalized selenides <1995JOC4299>. The addition is chemoselec-
tive; no addition to the nitrile moiety is observed, thus providing only -phenylsulfenyl nitriles.
Azido-benzeneselenylation is achieved using sodium azide, IBDA, and diphenyl diselenide
(Table 11) <1995CJC343>. The azido radical is generated in situ and adds to alkenes. The
resulting radical is trapped by the selenium reagent to afford vicinal phenylseleno azides. This
method has been applied to various glycols, but there are limitations. For the perbenzylated
glycols, reaction conditions were modified to prevent oxidative cleavage of the benzyl group.
Table 10 Monoselenoacetals prepared from enol ethers
R1 R1 SePh
R4 R4
R3 R3
R2 R2
R1 R2 R3 R4 Time (h) Yield (%) References

a
OEt H H H 2 80 <1996JCR(S)206>
OMe H Me H 3 85a <1996JCR(S)206>
OMe [CH2 ]3 H 5 85a <1996JCR(S)206>
OMe [CH2 ]4 H 4 80a <1996JCR(S)206>
O [CH2 ]3 H H 10 90a <1996JCR(S)206>
O [CH2 ]4 H H 10 90a <1996JCR(S)206>
H H OMe CN 23 74b <1995JOC4299>

a b
Conditions: PhSeH; KH, HMPA, PhSeH.
Table 11 Selenoglycosides via azidoselenation
R1 R3 R
1
R3
O R2 O
R2 1 R1
R N3
SePh
R1 R2 R3 Procedurea Yield (%) References

b
OAc OAc H A 91 <1995CJC343>
OAc H OAc A 92c <1995CJC343>
OBn OBn H B 82b <1995CJC343>
OBn H OBn B 75c <1995CJC343>
a
Procedure A: (PhSe)2, NaN3, PhI(OAc)2, B: N-phenylselenophthalimide, (CH3)3SiN3, (Bun)4NF. b
Inseparable
mixture of equatorial (gluco) and axial (manno) isomers. c Only the equatorial isomer is formed.
It is noted that this addition works well for D-galactal. However, D-glucal leads to a mixture of
gluco and manno products. In addition, disaccharide-based glycols are low yielding because of
their low reactivity. Novel one- and two-pot selenoglycosylations overcome these setbacks as
shown in Table 12 <2002OL4623>.
(ii) From ethers

Similar to the reactions of enol ethers, dialkyl ethers react with iodobenzene diacetate, sodium
azide, and diphenyl diselenide to afford the monoselenoacetals in good yields (Table 13)
<1995SL1129>. The azido radical reacts with the ethers generating an -oxyradical, which is
trapped by the selenium reagent.
Table 12 One- and two-pot selenoglycoside formation
R2 OAc R2 OAc
O 1 O
R1 R
AcO AcO SePh
AcHN OAc AcHN
R1 R2 Procedurea Yield (%) References

b
OAc H A 82 <2002OL4623>
OAc H B 92b <2002OL4623>
H OAc A 46b <2002OL4623>
H OAc B 80b <2002OL4623>
OAc H A 44c <2002OL4623>
OAc H B 72c <2002OL4623>
a b
A: i, TMSOTf, ii, PhSeH, CSA, B: PhSeTMS, TMSOTf. Both substituents
equatorial. c Both substituents axial.
Table 13 Monoselenoacetals prepared from ethers

Ether Time (h) Producta Yield (%) References
5 71 <1995SL1129>
SePh
O O
5 55 <1995SL1129>
O O SePh
O
3 O 86 <1995SL1129>
O
O SePh
But-OCH3 6 But-OCH2SePh 90 <1995SL1129>

a
Conditions: PhI(OAc)2, NaN3, and (PhSe)2 at rt.
(iii) From lactones

Phenylselanyltetrahydrofurans are prepared via a one-pot procedure from -lactones as shown in
Table 14 <2001S867>. This reaction proceeds via nucleophilic attack of the selenophenol to the
cyclic oxonium ion. This method cannot be extended to -lactols because they react via -hydroxy
aldehydes, rather than a cyclic oxocarbenium ion, to afford acyclic diselenide products.
Table 14 One-pot procedure from lactones
O SePh
O R3 i–iii
O R3
R1 R2 R1 R2
i. HAI(Bui)2; ii. PhSeH, BF3·OEt2; iii. H2O
R1 R2 R3 Yield (%) trans:cis References

H H Me 91 85:15 <2001S867>
H Me H 83 54:46 <2001S867>
Me H H 84 26:74 <2001S867>
-Lactones open to acyclic acids when treated with sodium phenylselenide. Analogously,
dioxolanone rings open with the selenium anion in THF-hexamethylphosphoramide (HMPA) at
reflux to produce selenide acid 33 <2001JOC1966>.
CO2H OEt
PhSe
O SePh SePh
33 34
(iv) From acetals

The reaction of O,O-acetals with benzeneselenol is reported using tris(phenylseleno)borane,
diisobutylaluminum bezeneselonate, and various Lewis acids <1995COFGT(4)215>. Further-
more, a regioselective cleavage can be accomplished by modification of solvent systems
<2002JOC3301>. The synthesis of -selenium-substituted propynal monoselenoacetals can
provide propargyl cations stabilized by the chalcogen atom. Nucleophilic addition of the
Bui2AlSePh to -selenopropynal diethylacetal affords the monoselenoacetal 34 in 41% yield
<1995CC149>.
(v) From other
(a) From carbamates. A regio- and stereoselective lithiation can be achieved by deprotonation
of dicarbamate 35 via a bis-chelate complex to afford a stereohomogeneous and regioisomerically
pure seleno product 36 (Equation (31)) <1998S1274>.
i. BusLi SePh
CbyO OCby ii. PhSeCl
NBn2
CbyO OCby ð31Þ
61%
NBn2
35 36
(b) Ring-forming reactions. Oxetanes can be synthesized from the Paternò–Büchi reaction, a
[2+2]-photocycloaddition of excited carbonyl compounds with alkenes <2001S1243>. There is
high regioselectivity as shown in Table 15. These compounds are useful as synthetic intermediates
for functionalized oxetanes.
Table 15 Synthesis of 3-selanyl-3-siloxyoxetanes via photocyclizations
Ar OTBDMS
O Me OTBDMS
hν > 320 nm SeR
+
Ar H O Me
Me SeR
Me
Ar R Yield (%) trans:cis References

p-CNC6H4 Ph 94 68:32 <2001S1243>
p-CNC6H4 Me 70 86:14 <2001S1243>
Ph Ph 84 68:32 <2001S1243>
2-Naph Ph 0 <2001S1243>
Oxaselenazines 37 can be prepared from the corresponding selenoamide <2001BCJ511>. As

shown in Equation (32), the amide can react with 2,4,6-trimethyl-1,3,5-trioxane as well as
pivaldehyde to afford the all-cis oxaselenazine products. However, treatment with benzaldehyde
only afforded recovery of the starting material.
Ar Se R
Se El, BF3.OEt 2
N O
Ar NH2
Me ð32Þ
37
El = 2,4,6-trimethyl-1,3,5-trioxane Ar = C6H5 R = Me 56%
El = pivaldehyde Ar = p-ClC6H4 R = But 44%
Gallagher and co-workers have extended an azomethine ylide strategy from -lactam-based
oxazolidinone to selenoketones <2000T5579>. Compound 38 reacts as a 1,3-dipolarophile to
afford selenapenam 39 with total regiocontrol (Equation (33)).
H H
O Se Se OMe
O + 80 °C
N N Ph
O Ph OMe
40% O ð33Þ
CO2PNB CO2PNB
38 39
PNB = CH 2C6H4-4-NO2
In an attempt to prepare acetylenic selenolates, Petrov and co-workers have treated selenodia-
zole with a weak base to afford 2-benzylselenobenzofuran as shown in Equation (34)
<2000RJOC605>. The mechanism proceeds by formation of a phenolate followed by intramo-
lecular proton transfer to the heterocycle. This heterocyclic anion extrudes nitrogen to form an
alkyneselenolate followed by intramolecular cyclization generating a selenium anion. This anion is
trapped in situ by benzyl chloride.
i. K2CO3, Me2CO
ii. BnCl
Se– SeBn
65% O O ð34Þ
HO N
N
Se
A novel samarium(II) iodide mediated cyclization provides 5-selenopentopyranose carbohy-

drates as shown in Equation (35) <2000T3995>. The ketyl radical adds to the selenium atom,
which is followed by loss of the benzyl group.
OBn OBn Se OH
BnSe SmI2, HMPA
CHO ð35Þ
50% BnO OBn
OBn OBn
Oxaselenolanone 40 is prepared from hydrolysis of the -ester selenium dimer. The dimer is
reduced and then condensed with an aldehyde to afford the desired lactone as shown in Equation
(36) <1997JMC2991>.
O
i. aq. AcOH
O ð36Þ
(SeCH2COOEt)2 ii. H3PO2, BzOCH2CHO
Se
33% BzO
40
Dihydroselenophenes 41 are synthesized from 1,2,3-selenadiazoles via thermal

<2000JOM(611)488> or radical <2002JOC1520> reactions (see Table 16). The vinyl radical is
generated by extrusion of nitrogen, which then adds to alkenes. The resulting alkyl radical
subsequently cyclizes. A competing reaction is dimerization of the selenadiazole to produce the
1,4-selenide 42.
Table 16 Reactions of 1,2,3-selenadiazole with olefins

N Se
N + R R+
Se Se Se
41 42
Yield (%)
R Conditions 41 42 References
OBu 130 C 12 74 <2000JOM(611)488>
OBu cat. Bu3SnH/AIBN, 80 C 11 56 <2002JOC1520>
OCOCH3 cat. Bu3SnH/AIBN, 80 C 7 67 <2002JOC1520>
4.05.2.1.2 From ring-opening reactions and a-halo ethers
(i) From ring-opening reactions
(a) From orthoesters. There are many examples of ring opening of sugar orthoesters using
benzeneselenol. Examples include reactions in the presence of catalytic amounts of HgBr2 to
afford the selenoglycosides 43 <2000CEJ1416> and 44 <2002CEJ2608>. In addition, orthoesters
of D-arabinose that are treated with SnCl4 undergo an acid-catalyzed ring opening to yield
-glycoside 45 <2000TL7447>. Another method avoids the use of mercury and tin and intro-
duces the selenium at the -position (Scheme 16) <2000TL2391, 2000JOC4315>.
OBn OBn HO
OAc OBz
O O O
BnO BnO
BnO BnO SePh
SePh
SePh OAc OBn
43 44 45
OR PhSeH, 3 Å molecular OR
O sieves, MeNO2, reflux O
RO RO
RO RO SePh
OO Yield >59 – 65% OAc
MeO R = Bn, PMB

PMB = p -methoxybenzyl
Scheme 16
(b) From epoxides. Selenoglycosides can also be accessed from the corresponding epoxides
(Table 17) <2000JOC5547>. Under basic conditions, this reaction is stereospecific.
Table 17 Synthesis of selenoglycosides

OR RO
OTBS SePh
O
TBSO
TBSO
OTBSOH
i. dimethyldioxirane; ii. PhSeH, conditions

Conditions R Yield (%) References
(CF3CO2)O TBS 53 , 28 <2000JOC5547>
Et3N Tr >56 only <2000JOC5547>
(ii) -Halo ethers

The displacement of a halide or acetate by benzeneselenol and potassium selenobenzoate under
basic or acidic conditions has been reported to prepare selenoglycosides. Additionally, treatment
of various halo glycosides with sodium borohydride and either diselenides or diaryltellurides
affords the corresponding chalcogen glycoside (Table 18) <1996SL929, 1997AJC233>. This is
an efficient one-pot synthesis that is mild and proceeds with inversion of stereochemistry.
Table 18 Synthesis of chalcogenoglycosides
R4 OR2 R4 OR2
5
(R X)2, NaBH4 O
R12 O R12
R O XR5
R O
R3 R3
Br
R1 R2 R3 R4 R5 X Yield (%) References

OBz Bz OBz H Ph Te 80 <1996SL929>
OBz Bz OBz H p-MeC6H4 Te 89 <1996SL929>
OBz Bz OBz H p-MeOC6H4 Te 88 <1996SL929>
OBz Bz OBz H p-Me2NC6H4 Te 68 <1996SL929>
OAc Ac OAc H p-MeOC6H4 Te 75 <1996SL929>
H Bz OBz OBz p-MeC6H4 Te 60 <1996SL929>
OAc Ac OAc H p-MeC6H4 Te 54 <1996SL929>
OAc Ac OAc H Ph Se 94 <1997AJC233>
OAc Ac OAc H Me Se 87 <1997AJC233>
OBn Bz OBz H Ph Se 88 <1997AJC233>
OAc Ac OAc H Ph Te 93 <1997AJC233>
Ikeda and co-workers have reported a novel procedure for the synthesis of phenylselenogly-
coside 46 that avoids elimination side products. Using N,N-di-isopropylethylamine, 46 is
synthesized in excellent yield through SN2 displacement of the corresponding chloro glycosides
(Equation (37)) <2002BMCL2309>. This can be expanded to seleno phosphonates as shown
in Equation (38). Condensation of bromo sugar 47 and seleno acid salt 48 yields phosphoroate
49 <2000HAC292>.
OAc OAc OAc OAc

Cl PhSeH, Pr2i NEt CO2R
AcO AcO
AcHN O CO2R AcHN O SePh ð37Þ
AcO R = Me, 97% AcO
R = Bn, 92%
46
AcO Br AcO Br
O O OCH2(CH3)3 AcO O
AcO + – P
AcO AcO O ð38Þ
95% OCH2(CH3)3
Se OCH2(CH3)3 Se P
Br
OCH2(CH3)3
47 48 49
PTC is another method for the synthesis of selenoglycosides. Carrière and co-workers use
TBAHS under mildly basic conditions in ethyl acetate to synthesize the glycosides as shown in
Equations (39) and (40) <2000JMOC(A)9>.
OAc PhSeH, TBAHS, OAc

AcO Cl 1.5 M Na2CO3 AcO Cl
OAc OAc ð39Þ
AcHN O CO2Me 70% AcHN O SePh
AcO AcO
OAc PhSeH, TBAHS, OAc

O 1.5 M Na2CO3 O ð40Þ
AcO AcO SePh
AcO 95% AcO
AcHN AcHN
Cl
The synthesis of 1,6-episeleno bridged sugar 50 is accomplished from bromo tosylate 51

(Equation (41)) <1996AJC343, 1999AJC885>. Attempts to prepare the 1,6-epitelluro sugar
analogs with sodium hydrogen telluride were unsuccessful.
OTs Se
OAc
R O NaBH4, Se O
AcO ð41Þ
AcO R OAc
Br R = OAc, 56%
51 R = OMs, 76% 50
4.05.2.1.3 Rearrangements and multicomponent reactions

Homolytic cleavage of diphenyl diselenide can be accomplished using irradiation with visible
light. A highly selective three-component reaction is achieved starting from diphenyldiselenide
using a tungsten lamp. The resulting benzeneseleno radical adds selectively to alkynes to afford
the -phenylselenovinyl radical, which subsequently adds to alkenes as shown in Table 19
<1999AG(E)2027>.
Table 19 Three-component coupling using ethyl propiolatea

Alkene Product Yield (%) References
C4H9O
C4H9O SePh
PhSe CO2Et 89 <1999AG(E)2027>
MeO MeO
SePh
78 <1999AG(E)2027>
PhSe CO2Et
TMSO TMSO
SePh
71 <1999AG(E)2027>
PhSe CO2Et
O O 70 <1999AG(E)2027>
SePh
SePh CO2Et
a
Conditions: Ethyl propiolate, alkene, (PhSe)2, 15 C, h > 300 nm.
The examples of seleno-Pummerer reactions are not as prevalent as their sulfur counterparts
because of the facile elimination of the selenoxides. In these reactions, most substrates lack -hydro-
gens to the selenoxide. When selenoxide 52 is heated at reflux in a mixture of acid and carbon
tetrachloride, the Pummerer-type reaction is obtained with no elimination side products (Scheme
17). The excess acid protonates 52, thereby hindering the syn elimination <1995AJC445>.
While developing methods for -functionalization of arylseleninylacetates, Shimada and co-
workers observed some novel transformations when selenides were treated under acidic conditions
as shown in Table 20 <2000TL4637>.
A domino Michael-seleno Pummerer-type reaction occurs with 1,3-dicarbonyl compounds and
vinyl phenyl selenoxide in the presence of hexamethyldisilane and various chlorosilanes to yield
compounds 53–56 <2000JCS(P1)2577>. (This method also provides a means to add the formyl-
methyl unit to carbonyl compounds.) In addition, it can be extended to p-chlorophenyl vinyl
selenoxides 57 and 58. Because of the lack of -hydrogens, selenurane 59 and selenium salt 60
undergo a 1,2-rearrangement to provide 61 upon treatment with triethylamine <2001HAC317>.
O
H2O2 i or ii
SePh SePh SePh
N 100% N N
85%
EtO2C EtO2C 52 EtO2C OAc
i. AcOH, 35%; ii. acetic anhydride
Scheme 17
Table 20 Synthesis of -acetoxyselenides
On
O O
Conditions
SePh SePh
O O
OR1
n R1 Conditions Comments
1 CH3CO (CH3CO)2O, allyltrimethylsilane 62% yield
1 CF3CO TFAA, CDCl3 decomposition upon purification
0 H MCPBA stable compound, no yield reported
SePh SePh O
O O
OTMS SePh
OTBDPS
CO2Me O OTMS
CO2Me
O
53 54 55
O Se-p-Cl-Ph O Se-p-Cl-Ph
SePh O
OTMS
OTMS
Ph OTES
CO2Et CO2Me
O
56 57 58
O O
O
Se Se+
BF4– Se
Cl
59 60 61
4.05.2.2 Tricoordinate Selenium Derivatives

Phenyl selenides can be treated with MCPBA or ozone to provide selenoxides that are susceptible
to elimination due to the -oxygen. No further advances on the information in chapter 4.05,
COFGT (1995) <1995COFGT(4)215> have occurred in this area, in the period 1993–2003.
ACKNOWLEDGMENTS
The authors wish to thank J. W. Cormier and J. A. C. Romero for their support in the
preparation of this chapter.
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Biographical sketch
Elizabeth Pollina Cormier was born in Professor Gary Molander was born in Cedar
Vineland, NJ, USA. Her research experiences Rapids, IA, USA. He received his B.S. degree
began at the State University of New York at at Iowa State University, IA in 1975 working
Stony Brook under Professor I. Ojima, where with Professor R. C. Larock. He entered the
she conducted structure activity relationships graduate chemistry program at Purdue Uni-
of peptide mimetics and synthetic studies of versity in 1975, obtaining his Ph.D. degree in
taxanes. She attended Dartmouth College 1979 under the direction of Professor H. C.
where she received her B.Sc. in 2000. There Brown at West Lafayette, Indiana. He joined
she was the recipient of a Howard Hughes Professor B. Trost’s group at the University of
Medical Institute Undergraduate Fellowship Wisconsin, Madison as a National Institutes
for her work with Professor P. A. Jacobi on of Health postdoctoral fellow in 1980, and in
the synthesis of biologically active tetrapyr- 1981 he accepted an appointment at the Uni-
roles. She joined the Department of Chemis- versity of Colorado, Boulder, as an assistant
try at the University of Pennsylvania in 2000 professor of chemistry. He was promoted to
where she is currently pursuing her Ph.D. with Associate Professor in 1988 and Professor of
Professor G. A. Molander. Her research Chemistry in 1990. In 1999 he joined the
focuses on novel synthetic methods using faculty at the University of Pennsylvania,
samarium(II) iodide. and in 2001 was appointed Allan Day
Professor of Chemistry. His research interests
focus on the development of new synthetic
methods for organic synthesis and natural
product synthesis. A major area of research has
also been the application of organolanthanide
reagents and catalysts to selective organic
synthesis.
4.06
Functions Incorporating Two
Chalcogens Other Than Oxygen
V. REBOUL, J.-F. BRIÈRE, and P. METZNER
Université de Caen, Caen, France
4.06.1 FUNCTIONS CONTAINING TWO SULFURS—R12C(SR2)SO2R3, etc. 271

4.06.1.1 Introduction 271
4.06.1.2 Two Dicoordinated Sulfurs—R12C(SR2)2 272
4.06.1.2.1 gem-Dithiols 272
4.06.1.2.2 Hemidithioacetals 272
4.06.1.2.3 Dithioacetals 272
4.06.1.3 One Dicoordinated Sulfur and One Higher Coordinated Sulfur—R21C(SR2)SO2R3, etc. 287
4.06.1.3.1 -Thiosulfoxides 287
4.06.1.3.2 -Thio sulfones 295
4.06.1.3.3 Other derivatives 297
4.06.1.4 Bis(sulfoxides) 298
4.06.1.4.1 Oxidation 298
4.06.1.4.2 From methylene bis(sulfoxides) 299
4.06.1.4.3 From various precursors 299
4.06.1.5 One Tricoordinated and One Higher Coordinated Sulfur—R12CS(O)R2S(O)2R3 300
4.06.1.6 Two Tetracoordinated Sulfurs—R12C[S(O)2R2]2 301
4.06.1.6.1 Bis(sulfones) 301
4.06.1.6.2 Bis(sulfonic) acids and their derivatives 305
4.06.1.6.3 Other compounds 305
4.06.2 FUNCTIONS CONTAINING ONE SULFUR AND ONE SELENIUM
OR TELLURIUM—R12CSR2SeR3, etc. 305
4.06.2.1 Dicoordinated Sulfur Derivatives 305
4.06.2.2 Tricoordinated Sulfur Derivatives 307
4.06.2.3 Tetracoordinated Sulfur Derivatives 308
4.06.3 FUNCTIONS CONTAINING SELENIUM AND/OR TELLURIUM—R12C(SeR2)2,
R12C(SeR2)TeR3, etc. 310
4.06.3.1 Diselenium Derivatives 310
4.06.3.2 Ditellurium Derivatives 313
4.06.1 FUNCTIONS CONTAINING TWO SULFURS—R12C(SR2)SO2R3, etc.
4.06.1.1 Introduction
Dithioacetals and their various oxides are versatile tools in organic synthesis. The former have
been routinely used for the protection of the carbonyl group.
The impetus given by the Umpolung strategy continues to be largely exploited. These acyl
anion equivalents were used in a sequence of deprotonation and treatment with a variety of
electrophiles. A review <2003T6147> has highlighted the applications of 1,3-dithianes in the field
271
272 Functions Incorporating Two Chalcogens Other Than Oxygen
of total synthesis of natural products from 1990 to 2000. Chemoselective oxidation reactions have
been achieved to allow access to the various oxides of dithioacetals. The late 1990s and early
2000s have seen the achievement of efficient enantioselective syntheses of dithioacetal oxides,
mostly using the Andersen reaction or asymmetric oxidation. Addition to the double bond of
ketene dithioacetal oxides has also been proved to be useful.
4.06.1.2 Two Dicoordinated Sulfurs—R12C(SR2)2

There are three types of compounds that contain two dicoordinated sulfur atoms: gem-dithiols,
hemidithioacetals, and dithioacetals. The first two have received little attention since 1995 but
dithioacetal functions have been much studied.
4.06.1.2.1 gem-Dithiols
No further advances have occurred in this area since the publication of chapter 4.06.1.2 in
COFGT (1995) <1995COFGT(4)243>.
4.06.1.2.2 Hemidithioacetals
No further advances have occurred in this area since the publication of chapter 4.06 in COFGT
(1995) <1995COFGT(4)243>.
4.06.1.2.3 Dithioacetals
(i) From aldehydes, ketones, and related compounds

For the preparation of dithioacetals, two general reactions have been described: ‘‘dithioacetaliza-
tion’’ from aldehydes or ketones and ‘‘transthioacetalization’’ from acetals or acylals (gem-
diacetates) (Scheme 1). Few examples have been reported from carbonyl derivatives such as
enol ethers or hydrazones. These transformations involved thiols or dithiols in the presence of
Brønsted or Lewis acids as catalysts.
O
Dithioacetalization aldehyde or
R1 R2 ketone
R3S SR3
R1 R2
or ( )n
Cat., 2 R3SH or
HS SH
( )n
S S ( )n
R4O OR4 O O acetal or
R1 R2 or acylal
R1 R2 R1 R2
Transthioacetalization
Scheme 1
Among all the catalysts, boron trifluoride etherate (BF3Et2O) remained the most favored one.
However, this reagent was not always efficient and it was necessary to find useful alternatives. For
example, reaction of the sensitive hydroxy aldehyde 1 and propane-1,3-dithiol, in the presence of boron
trifluoride etherate, led only to decomposition of 1 (Equation (1)). Using lithium perchlorate in anhydrous
diethyl ether, the corresponding dithiane was obtained in a remarkable 90% yield <2000S69>.
Functions Incorporating Two Chalcogens Other Than Oxygen 273
O S
H S H Cat. Solvent Temp. (°C) Yield (%)
Me SH SH Me
BF3·Et2O CH2Cl2 0 0 ð1Þ
OH Cat.
OH LiClO4 Et2O rt 90
TIPSO 1 TIPSO
Thus, since 1995, many new methodologies have been developed and it is frequently not easy to
perceive the improvements. Indeed, the yields were often excellent (>90%) and it is possible
to discriminate the types of the carbonyl functions. The usual order of reactivity observed
is: aliphatic aldehyde > aliphatic ketone > ,-unsaturated aldehyde or aromatic aldehyde >
,-unsaturated ketone or aromatic ketone. These methods have been partially surveyed in two
reviews in 1995 and 2000 <B-1995MI133, 2000RCR947>. The new catalysts for the
dithioacetalization reaction of aldehydes and ketones are listed in Table 1.
Table 1 Catalysts for dithioacetalization reaction of aldehydes and ketones

Amount Solvent
Catalysts (mol.%) (mol l1) Temp. Time References
BiX3 or
Bi2(SO4)3 0.04–10 CH3CN (1.25) rt 2–10 h <1995SL984>
X = Cl, Br, I
CAN 10 CHCl3 (0.20) rt 16 h <1995T7823>
LiBr 25–40 Neat 75–80 C 15–180 min <1999S58>
HCl (anhyd.)a 5 MeOH (0.28) rt 5–30 min <1999SC697>
InBr3 10 CH2Cl2 or H2O (0.40) rt 15–120 min <2000TL9695>
LiBF4 10 CH3CN (1.00) rt 30–210 min <2001SL238>
CdI2 50 Neat MWd 75 s <2001JCR(S)313>
InCl3 30 CH2Cl2 (n.d) rt 10 min–28 h <2001TL359>
InCl3 10 CH2Cl2 (0.33) rt 2–7 h <2002SC715>
I2 10 THF (0.50) rt 0.5–7 h <2001TL4425>
NBS 15 CH2Cl2 (0.10) rt 30–180 min <2002SL474>
NBS 30 CH2Cl2 (0.10) rt 20–25 min <2002TL6947>
Sc(OTf)3 4 CH2Cl2 (0.08) rt 20–360 min <2002TL1347>
TBABb 30 Neat 110–115 C 40–120 min <2002JCS(P1)1520>
DBSAc 1–10 H2O (1.00) 40 C 4h <2002JA11971>
CH2Cl2MeOH: 5–1
NiCl2 10 rt 8 min–18 h <2003TL919>
(0.33)
a b c d
From acetyl chloride and MeOH. TBAB ‘‘tetrabutylammonium bromide’’. DBSA ‘‘dodecylbenzensulfonic acid’’. MW
‘‘microwave irradiation’’.
Transthioacetalization has been used as an alternative method for the preparation of dithio-
acetals (Table 2).
Table 2 Catalysts for transthioacetalization of acetals

Amount Solvent
Catalysts (mol.%) (mol l1) Temp. Time References
ZrCl4 3–5 CH2Cl2 (0.2) rt 2 min–24 h <1999SL319>
InCl3 5 ClCH2CH2Cl (0.5) 81–85 C 7–20 min <2002SL727>
Frequently, the same catalyst can be employed for both dithioacetalization and transthio-
acetalization reactions (Table 3).
Table 3 Catalysts for both dithioacetalization and transthioacetalization reactions from aldehydes, ketones,
and acetals
Catalysts Amount (mol.%) Solvent (mol l1) Temp. Time References

WCl6 4–10 CH2Cl2 (0.2) 0–5 C 2–60 min <1998SL739>
LiOTf 5 Neat 90–110 C 5–180 min <1999TL4055,
2001BCJ2401>
MoCl5 1–10 CH2Cl2 (0.2) rt 2–180 min <2001PS207>
Trichloro- 10 CHCl3 (0.2) rt 0.75–2 h <2001SL1641>
isocyanuric acid
I2 10 CHCl3 (0.2) rt 5–420 min <2001JOC7527>
H3PW12O40 0.1–2 Neat rt 1 min–24 h <2002S59>
NBS 10–40 CHCl3 (0.2) rt 5–170 min <2002PS1047>
NBS 30 CH2Cl2 (0.1) rt 20–25 min <2002TL6947>
TABCOa 20–50 CHCl3 (0.2) rt 3–240 min <2002PS1047>
Br2 10–40 CHCl3 (0.2) rt 4–160 min
In(OTf)3 8–10 CH2Cl2 (0.2) rt 6 min–4 h <2002T7897>
Sc(OTf)3 2 [bmim]+[PF6] (1.0)b rt 8–15 min <2003TL3337>
a b
TABCO ‘‘2,4,4,6-tetrabromo-2,5-cyclohexadienone’’. [bmim]+ ‘‘1-butyl-3-methylimidazolium cation’’.
Heterogeneous catalysts have also been developed in view of their usually easier work-up
(Table 4).
Table 4 Heterogeneous catalysts for the preparation of dithioacetals from carbonyl compounds, from
acetals, or from acylals
Solvent
Catalysts Amount (mol l1) Temp. Time References
Dowex-50W-X8 0.01 g/mmol Neat rt 35–200 min <1995JCR(S)108>
ZrCl4SiO2 10–60 mol.% CH2Cl2 (0.20) rt 1 min–3 h <1996TL4621>
TaCl5SiO2 10 mol.% CH2Cl2 (0.50) rt 2–10 min <1997T14997>
Cu(OTf)2SiO2 20 mol.% Neat 75–80 C 30 min–5 h <1999SL415>
‘‘Silica chloride’’ a,b 0.2–0.3 g/mmol CH2Cl2 (0.20) rt 10–240 min <2000SL263>
‘‘Silica chloride’’ a,c 0.5 g/mmol CH2Cl2 (0.08) rt 0.5–4.25 h <2001PS165>
I2Al2O3 10 mol.% Neat rt 9–40 min <2001CL794>
H-Rho zeolite 0.5 equiv.d Hexane (0.50) 70 C 1–6 h <1996JCR(S)494>
Envirocat EPZG 0.01 g/mmol C6H6 (0.67) 80 C 30–140 min <1996SC1579>
Fe3+-Montmorillonite 0.033 g/mmol CH2Cl2 (n.d.) rt 4h <1996SC2993>
Envirocat EPZ10 0.02 g/mmol CH2Cl2 (0.33) 40 C 4h <1998JCR(S)452>
Koalinitic clay 0.01 g/mmol C6H6 Reflux 4h <1998JCS(P1)965e,
or CCl4 (0.40) 1998JOC1058>
Zeolite HY, CaY or 1 equiv.d Hexane (ND) 70 C 1h <1999GC173>
MgY
Bentonitic clay 0.109 g/mmol Toluene (0.12) 105 C under 3h <2001SC1587>
(TAFF) 585 mmHg
POCl3Montmorill- 0.10 g/mmol CH2Cl2 (0.60) rt 2 min–3 h <2001SC1669>
onite clay
a
Prepared by refluxing silica gel with SOCl2 for 48 h. b Only for transthioacetalization of acetals. c Only for transthioacetalization of
acylals. d By weight with respect to carbonyl compound. e Preparation of dithioacetals also from oximes, enamines, and
tosylhydrazones.
In the case of acetal 2 (Scheme 2), the catalyst was used not only for the transdithioacetalization
reaction but also to facilitate the deprotection of the paramethoxybenzyl (PMB) group <2001OL177>.
Acetals can also be synthesized from enol ether derivatives. Thus, the reaction of methyl
propenyl ether with ethanethiol can be conducted without solvent, or in the presence of BF3Et2O
(82% yield) or HCl gas (53% yield) <1995SC3155>. Ethyl-3,3,3-trifluoropropenyl ether can be
also transformed to the corresponding dithioacetal in 91% yield by reaction with 1,3-propane-
dithiol <1998JCS(P1)279>. With endocyclic enol ethers, the reaction generally requires a stronger
Lewis acid such as TiCl4 (Equation (2)).
OMe
OPMB
O SH SH
BF3
MeO O OMe BF3·Et2O S O OH O
MeCN, 0 °C
2
S OMe
OH 6-endo-tet
S S OH OH O
O O S S OMe
80%
Scheme 2
O PhSH, TiCl4 PhS SPh

n = 1: 80% ð2Þ
OH
( )n ( )n n = 2: 85%
12–24 h
However, in the case of acid-sensitive substrates like enol ether 3 (presence of the O,O-ketal and
the t-butoxy group), this titanium Lewis acid led only to degradation products. This problem was
solved using a slight excess of trimethylsilyltrifluoromethanesulfonate (TMSOTf) at 78 C
(Equation (3)) <2003TL1491>. This unusual thioacetalization procedure has also been employed
with success for aldehydes or ketones as starting material (80–93% yield).
SH
ButO HS Bu tO
H H
TMSOTf (1.25 equiv.)
MeO MeO S ð3Þ
OMe –78 °C, 4 h
OMe 80% OMe S
O O
3
In connection with the synthesis of biotin, Lewis acids were also used for the intramolecular
cyclization of silyl enol ether 4 (Scheme 3). Depending on the conditions, the thioacetal 6 and/or
the bicyclic compound 7 were formed. The reaction proceeded via the generation of an immonium
ion 5 and liberation of thiophenol. When t-butyldimethylsilyl phenyl sulfide (PhSTBS) was added,
followed by a catalytic amount of TBSOTf, thioacetal 6 was the exclusive product obtained in
70% yield <2001JOC6197>.
O
Bn N N Bn
O O H H
SPh
Bn N N Bn Bn N N Bn S
Lewis SPh
H 6
SPh acid and/or
S S
OTBS OTBS O
4 5 Bn N N Bn
Conditions % of 6 % of 7
SPh
AlCl3, –78 °C to rt 0 55
S
BF3.OEt2, 0 °C to rt 0 43
7
TBSOTf, 0 °C to rt 20 30
PhSTBS, TBSOTf, 0 °C to rt 70 0
Scheme 3
The direct dithioacetalization of N,N-dialkylhydrazones by 1,2-ethanedithiol could be pro-

moted with BF3Et2O or p-TsOH (Equation (4)) to afford the corresponding dithiolanes in nearly
quantitative yields <1998TL7955>. This transformation should find further applications, in
particular when the (S)- and (R)-1-amino-2-(methoxymethyl) pyrrolidine auxiliaries are used
(SAMP/RAMP methodology). Dithioacetalizations of other tosylhydrazones, oximes, and enamines
have also been examined <1998JCS(P1)965>.
O Ph OMe O Ph
N HS SH
S
N
CH2Cl2
0 °C to rt S
ð4Þ
Conditions Yield (%) ee (%)
BF3·OEt2 (2 equiv.), 16 h 90 ≥98

p -TsOH (1.1 equiv.), 3 d 97 ≥95
Only one example dealing with unsymmetrical dithioacetals synthesis from aldehydes has been
described (Equation (5)). An electron-deficient thiol (e.g., 4-mercaptopyridine) and an electron-
rich thiol (e.g., benzyl mercaptan), in the presence of BF3Et2O, must be used for this purpose
<1998SL289>. Mechanistic considerations have been discussed <2002SL984>.
N HS S
CHO +
HS S
ð5Þ
MeO BF3·Et2O
MeO
90%
The synthesis of a polymeric reagent containing an odorless propane-1,3-dithiol function has

been reported (Scheme 4). It was applied to the solid-phase synthesis of ketones <1998TL9263,
2000JOC4839, 2002EJO1546> and subsequent reduction to alkanes <2003SL1201>.
PhCHO Ketones
i–vi
S Alkanes
SH BF3·Et2O
S Ph
Cl SH
H
i. H2C(CO2Et)2, K2CO3, Cs2CO3; ii. LAH; iii. PhSO2Cl;
iv. Styrene, AIBN; v. CH3COSK; vi. LAH
Scheme 4
Instead of thiols or dithiols, various compounds were used as alternative sources of the sulfur
moiety: Bui2AlSPh for the transformation of -phenylselenopropynal diethyl acetal <1995CC149>;
mercapto-thioacetic acid in the presence of an aldehyde to give the 1,3-dithiolane-4-one, a precursor of
1,3-dithiolane nucleosides <1999CC1245>; thioacetate derivatives (Equation (6)) under acidic con-
ditions (HCl), for the synthesis of photolabile molecular systems as dithiane-spiro-crown ethers
<2001S1133, 2001OL2633>; or in the presence of a polystyrene supported sulfonic acid (10 mol.%
in water) <2003OL101>.
CH2O, HCl,
AcS SAc reflux, 16 h S S
ð6Þ
AcS SAc 76% S S
-Amino acids were transformed into dithiazines (Equation (7)) via the reaction with sodium
hydrosulfide in aqueous formaldehyde <2002OL4129>.
R R Yield (%)
R NaHS H 61
S N CO2H ð7Þ
H2N CO2H PhCH2 71
Formalin
0 °C S Pri 67
Bui 74
Finally, an electrochemical reduction of diaryl or dialkyl disulfide compounds in the presence

of a ketone or an aldehyde and trimethylchlorosilane afforded dithioacetals in moderate yield
(55–80%) <1996MI272>.
(ii) From other dithioacetals and related compounds

The preparation of dithioacetals from other dithioacetals is, of course, the archetypal synthetic
reaction of the dithioacetals. Although in the strictest sense of the term such reactions are not
really functional group transformations, they permit the conversion of a dithioacetal derived from
an aldehyde to the dithioacetal of a ketone. These compounds have found particularly wide use
for the Umpolung reactions of the carbonyl moiety, since the anions generated from dithioacetals
are strongly stabilized by sulfur atoms and are equivalent to acyl anions. Surprisingly, no review
on this area has been published since the publication of chapter 4.06 in COFGT (1995)
<1995COFGT(4)243>. Thus, the report in 1989 by Page et al. is strongly recommended for a
more thorough account of the possibilities of such reactions <1989T7643>. It is not intended to
cover this area again, and this subsection will only be devoted to the chemistry that has received
much attention since 1995. The addition of lithiated dithianes to epoxides and aziridines has been
described. The reaction of lithiated dithianes with enantiopure N-sulfonylated aziridines leads, via
regiospecific nucleophilic ring opening, to enantiopure N-tosyl 2-(20 -dithianyl) secondary amines
in good yields <1995JCS(P1)2439>. Both the conversion of vicinal diols into epoxides and
nucleophilic epoxide opening with 2-lithio-1,3-dithiane can be performed in an efficient one-pot
operation <1995JOC8122>. The synthesis of enantiomerically pure 1,2-epimino-3,4-epoxybutane
has been described. This 1,4-bis electrophile offers a new route to targets with a 1,2-aminohy-
droxyl functionality, as in the cyclopentane synthesis depicted in Scheme 5 <2001S577>. This
silicon-mediated domino approach was also used for the synthesis of pyrrolidine <2000SL92>
and highly functionalized carbocycles <1999TL2921>.
MeS SMe
O O SMe
Ts Li TMS
N Ts N SMe
THF, –80 °C TMS
DMPU
MeS SMe
BF3·Et2O OTMS
Ts N SMe
42% SMe
TsHN OH
Scheme 5
High chemoselectivity was achieved for the addition of lithium dithiane anions to vinyl
epoxides by making use of the steric nature of the dithiane substituent. Thus, addition of
unencumbered lithiated dithianes 8a to vinyl epoxides 9 gave SN2 adducts 10, whereas sterically
hindered anions derived from 8b led primarily to SN20 adducts 11 (Scheme 6). Furthermore, the
SN2 addition to cis vinyl epoxides provided exclusively anti-adducts, while trans epoxides gave the
corresponding syn-adducts <2002JA14516>.
i. ButLi, THF, HMPA

OH
–78 to –25 °C, 1 h S S OH
S S or S S
ii. R2 R1 R2
R1 H R1 R2
9
O
8a (R1 = H, Ph, Me3Si) 10 (SN2 anti ) 11 (SN2')
–78 to 25 °C, 3 h
8b (R1 = Et, Pri, SiPr 3i )
R2 = cyclohexyl, octyl, CH2OTBDPS, CH2CH2OBn
Scheme 6
1,3-Dithiane can also be efficiently deprotonated by sodium 2-(2-ethoxyethoxy)ethoxide/

sodium amide complex base <1996T15147>. The effect of hexamethylphosphoramide (HMPA)
on the reactivity of epoxides, aziridines, and alkyl halides with bis-thio substituted organolithium
reagents has been examined. This cosolvent displayed either rate accelerating or rate retarding
effects on the SN2 reactivity <2002JA13386>. The role of HMPA in controlling the ratio of 1,2-
to 1,4-addition to cyclohexenones and hexenal by sulfur-substituted organolithium reagents has
also been studied (Equation (8)) <1999JOC14, 2001JA6527>. The complexation effect of HMPA
to lithium causes ion pair separation and lowers the Lewis acidity of the lithium cation which
enhances 1,4-addition. The use of quinuclidine N-oxide has also been proposed as another
alternative to the carcinogenic HMPA <1999CC59>.
O
Me Li O S
–78 °C HO S
S S + Me +
S
Me S
ð8Þ
Solvent 1,2-Addition (%) 1,4-Addition (%)
THF >99 0
THF/HMPA <5 >95
(2 equiv.)
2-Trimethylsilyl-1,3-dithiolane was described as a masked dithiolane anion <2001TL4557>.

Under fluoride-ion catalysis, this compound reacted with different aldehydes, ketones, and allyl
bromide. A representative example is given in Equation (9).
O S TBAF (1 equiv.) Ph S
+ TMS ð9Þ
Ph H S DMF, rt HO S
79%
2-Lithio-2-(trimethylsilyl)-1,3-dithiane reacted with tosyl azide to give transient 2-diazo-1,3-
dithiane, which decomposed to give the corresponding carbene (Scheme 7), whose -reactivity
toward various alkenes and alkynes has been examined <1995CC1999, 1997T9269>.
S SiMe3
S TMS ButLi, TsN3 S S
S N NTs N2
S H –70 °C N S S
R
R
R = CO2Me: 35% S
R
R = SO2Ph: 38%
S
R
Scheme 7
A carbene can also be generated from dithiooxadiazoline by heating. This species undergoes
cycloaddition reactions with isocyanates (generated in situ from acyl azides) to produce pyrro-
lones and indolones (Scheme 8) <1999JOC1766>. This methodology was applied to the synthesis
of isatin derivatives <1999TL6891, 2000T10101>.
PrS SPr
PrS
SPr PrS
∆ NCO
N O
O N
N PrS PhH, reflux
86% SPr
PrS
Scheme 8
Nonconventionally fused bicyclic -lactams have been synthesized in two steps

<1998JOC8898>: [2+2]-cycloaddition of bis(ethylthio)acetyl chloride with propargyl imines
and the subsequent iodination reaction (Scheme 9).
EtS SEt SEt

O SEt
SEt O
NEt3 I2 S
O Cl N SiEt3
+ Bn N
CH2Cl2 92% Bn
94% H I
Bn N SiEt3 SiEt3
Scheme 9
A reaction involving rearrangement of an aromatic ring fused cyclic dithiane alcohol by

N-chlorosuccinimide has been developed (Equation (10)) <1999JOC6380>. The corresponding one-
carbon ring expanded 1,2-diketones was thus obtained. Photolysis of 2-phenylseleno-1,3-dithiane
in the presence of electron-deficient alkenes, gave the addition products (Equation (11)). These
reactions illustrate a radical atom transfer process arising from a heteroatom-stabilized radical
<1996TL2743>. A catalytic amount of Ni(0) allowed the conversion of an acyl chloride into
2-acyldithianes, not directly obtainable by other methodologies (Equation (12)) <1995TL9185>.
Aldehydes and ketones were protected as thioacetals (Equation (13)) by an exchange reaction
with 2,2-dimethyl-1,3-dithiolane, catalyzed by an acidic solid catalyst without solvent under
microwave irradiation <2000GC252>.
S NCS
OS
HO S Dry CH2Cl2
S
ð10Þ
75%
S SePh
S OBun hν, benzene
+ OBun ð11Þ
S
S SePh O 75%
O
O Ni(dppe)Cl2 (cat.)
S S R = H: 20%
+ S S R = Me: 72%
ð12Þ
O
Ph Cl THF, 0 °C R
R Li
Ph
O
MWI
Ph H (15 min, 90 °C) O
+ S S + ð13Þ
Amberlyst®15 (10%) Ph H H3C CH3
S S
95%
H3C CH3
(iii) From ketene dithioacetals

The transformation of a ketene dithioacetal to a saturated dithioacetal can be achieved either with
a CH bond formation or with the creation of a CC bond at the carbon.
(a) With CH Bond Formation. Two general methods have been developed allowing the
reduction of ketene dithioacetals to substituted dithianes: zinc in acetic acid and magnesium in
methanol <1997T17151>. Ketene dithioacetals have been used as glycosyl donors for the synth-
esis of O-glycosides <1999PJC973> and disaccharides (Equation (14)) <2000TA3737>.
BnO
BnO TMSOTf BnO
BnO CH2Cl2 BnO
BnO S + R OH O S
O
OBn –78 to –30 °C BnO ð14Þ
S 76% S
HO OR
O
R OH = BnO
BnO
BnO OMe
Various radical reactions with ketene dithioacetals have been investigated. The trifluoromethy-
lation of ketene dithioacetals derived of mannose was carried out in the presence of trifluoro-
methyl bromide, sulfur dioxide, and sodium formate (Equation (15)) <1997JOC9107>.
MeS SMe MeS SMe
CF3Br CF3
O HCO2Na /SO2 O
O O ð15Þ
OH NaHCO3 /pyridine OH
DMF, 6 h
O 60% O
O O
The intramolecular radical cyclization of a brominated ketene dithioacetals was used for the
synthesis of spiroundecane compounds (Equation (16)) <1995TL1365> and for the asymmetric
synthesis of the lactam ring of carbapenem antibiotics (Equation (17)) <1996T489>.
Br Bu3SnCl (0.1 equiv.)

NaCNBH3 (2 equiv.) S
S
S ð16Þ
AIBN, ButOH, reflux
S
49%
PhS PhS
Et PhS SPh Bu3SnH
Et SPh Et SPh
Br AIBN
O N +
N N ð17Þ
Toluene, reflux O Me O Me
Ph Me
H 70% Ph H Ph H
77:23
Base-induced cyclization of ureas or thioureas (Equation (18)) led to the formation of hydan-
toin derivatives in excellent yields <1995TL6257>.
X O K2CO3 (2 equiv.) O R1 X Yield (%)

EtOH R1 Me O 97
R1 HN
BnHN N SMe Me S >99 ð18Þ
H Reflux, 30 min X N Et O 95
MeS SMe Bn SMe Et S >99
(b) With CC bond formation. Ketene dithioacetals can be used as starting materials for
cycloaddition. The dithioallene, obtained in quantitative yield by treatment of the alcohol 12 with
ButOK, treated with an excess of diphenyl ketene (generated in situ), led to [2 + 2]-cycloadducts
(Scheme 10) in moderate yield <1996JOC8132>.
Ph Cl
O But
EtS P(OEt)2 ButOK EtS But EtS
Ph O EtS
EtS OH EtS NEt3
98% Benzene, rt Ph
But Ph O
66%
12
Scheme 10
Additions of methylene dithiolane to unsaturated chiral lactams, mediated by dimethyl alumi-

num chloride, gave very high endo-selectivity of the cyclobutane [2 + 2]-adducts (Equation (19))
<1995JOC4359>. Under the same conditions, ethylene dithiomethyl ketal did not afford the
cyclobutane adduct.
S R R Yield (%)
R Ph H
Ph O Me
O H 92
S N
N Ph 89 ð19Þ
Me2AlCl S Bun
O 88
O Toluene S
0–20 °C Heptn 86
Both the [4+3]- and [6+3]-cycloadditions (Equation (20)) were observed when fulvene ketene
dithioacetal reacted with 2-oxyallyl cation (generated in situ) <1997JOC7717>.
S S
S S Me S
S Me
+ Fe2(CO)9
+ Me
O Me ð20Þ
Me Me O
Me Me Me Me O
Me Me
Br Br 1:2.2
[6 + 3] [4 + 3]
Ketene dithiolane can also be used as a dienophile in the aza-Diels–Alder reaction with
N-arylimines (Equation (21)). Among the dienophiles tested, 1,4-benzodithiafulvenes were the
most effective in the construction of the tetrahydroquinoline core <2002OL4411>.
Ph
N Sc(OTf)3
S Ph CH3CN S S
+ Ph
ð21Þ
S 3h
81% N
CO2Me H
CO2Me
23/1 anti/syn
The reaction of dialkylated vinyl ketene dithioacetal with in situ generated 2-methoxycarbonyl-
p-quinone furnished the Diels–Alder adduct in 55% yield (Equation (22)) <1995TL4625>.
Me O O Me
H
Me Me
55%
+ E = CO2Me ð22Þ
MeS
E
E
SMe O O MeS SMe
The rearrangement of cyclopropyl ketone 13 catalyzed by SnCl4 afforded two types of products
with regard to the nature of the substituents of the aryl ring (Scheme 11). With a phenyl group,
only the carboxythioate was obtained. However, with the p-methoxy group, the bicyclo[3.3.0]oct-
enone was isolated as a single product <1998T531>.
O SMe
Me SMe
72%
O SMe Ar = 4-MeOC6H4
Ar
SMe SnCl4 H
Me O
MeNO2 O Me
rt SMe
56% Ar = C6H5
Ar 13
Ar
Scheme 11
A triple Umpolung sequence has been described for the preparation of substituted indanes
<1996T14951>, in which a ketenedithioacetal was generated in situ (Scheme 12).
O OH
OLi
O H O
BuLi O
O Br O
O S
+ 84% Li S Bu
S S S
S Li Single diastereoisomer
Scheme 12
2-Phenylthio-1,3-dithiane underwent vicarious nucleophilic substitution with various nitro-

arenes <2000TL5111> to provide p-dithianyl nitroarenes regiospecifically in one step in good
yields (Scheme 13).
O
NO2 N O
NO2
ButOK AcOH
Cl Cl
+ S
Cl
S DMSO, rt 90%
S S
PhS
S
S
Scheme 13
An asymmetric synthesis of dithiolane aldols was achieved (Equation (23)) by using silyl ketene
acetals and a chiral oxazaborolidinone <1996TA2181>.
O
RCHO N B OH O R Yield (%) ee (%) ð23Þ
+ Ts H
S OTMS R OEt CH3 73 83
CH2Cl2, –78 °C S S
3h Heptn 80 98
S OEt
(iv) From thiocarbonyl compounds

The only cycloaddition reactions that have been investigated involve dithioesters, thioketones, or
trithiocarbonates. Mloston et al. have developed an easy access to thiocarbonyl ylides (Scheme 14),
generated from the cycloadduct of a thiocarbonyl compound and diazomethane <1999T11475>.
This 1,3-dipole reacts in situ with thiocarbonyl compounds (thione or dithioester) to afford the
corresponding 1,3-dithiolanes. Two cycloadducts can thus be obtained depending on the ‘‘thiophilic’’
or ‘‘carbophilic’’ attack of the 1,3-dipole. This regioselectivity was controlled by steric or electronic
effects <2000EJO1685, 2000EJO1695>. The dipole can also react with thiols to lead to dithioacetals
via thionium ions <1999PJC635, 2001T145>.
N2
R S CH2N2 N N R S R S
R CH2 CH2
R S R + R
R
R'
R'SH
S
R'
R S +
CH3 R'S–
R Thiophilic Carbophilic
attack attack
R S S
SMe R
R
SR' R S R R'
S
R R'
R' R'
Scheme 14
The sulfur ylide 16, generated by a 1,3-dipolar cycloaddition of a benzyne derivative (formed by
thermolysis of 2-carboxybenzenediazonium chloride 14) to the ethylene trithiocarbonate 15, can
be trapped by hydrogen chloride (generated from 14) to give a sulfonium chloride 17 (Scheme 15).
Reduction of this sulfonium salt with NaBH4 afforded the dithiacetal 18 in excellent yield, while
treatment with KOH led to the sulfoxide 19 <1996BCJ2349, 1998BCJ1187>.
S
N2+Cl– S S S
∆ S 15
S
CO2H
16
14 (2 equiv.) N2, CO2, HCl
HCl 62%
S S H
S S
i or ii
S S Cl
(O)n
18 (n = 0) 17
19 (n = 1)
i. NaBH4, EtOH, 95%; ii. KOH, EtOH, H2O, 95%
Scheme 15
An azomethine ylide and a dithioester as dipolarophile have been used for the synthesis of
bicyclic -lactams (Scheme 16) <1997JOC3438>. A similar reactivity was reported with phtha-
lazinium-2-methanide and cyanodithioformate <1998JCS(P1)869>.
Portella and co-workers have described the [4 + 2]-cycloaddition between 2,3-dimethyl-
1,3-butadiene and fluorinated thiocarbonyl compounds as dienophiles (Scheme 17)
<2001TL2133, 2002TL5809>.
H S H
O MeCN S SMe
O N Ph SMe
N O 71% N Ph
O 80 °C CO2PNB O
CO2PNB CO2PNB
Azomethine ylide 4:1
Scheme 16
S EtS
F SEt MgX2 F3C SEt F3C
F3C CF2 SEt 240 °C S
X F X F
S8, 210 °C X = Br; 80%
99% X = Cl; 89%
F F
F3C F3C S
S Crude >90% S S
S S
Unstable
Scheme 17
(v) From various precursors

Compounds bearing an acidic methylene group may be disulfenylated by the action of a base
followed by a reaction with a sulfenylating reagent. Only a few examples of sulfenylation have
been described, and two of them are depicted in Scheme 18. One employs a thiosulfonate
<1999S258, 2001JOC2828> and the second uses a disulfide <1997TA2433, 2000JOC7990> as
the sulfenylating agent.
H
H OTBS
OTBS LiHMDS
O SPh
O O
O PhSSO2Ph
75% SPh
MeO O OMe
MeO O OMe
i, ii O ( )5 OMe
O ( )5 OMe
96% SPh
MeO
MeO Me
SPh
i. LDA (3 equiv.), THF, –78 °C, 10 min
ii. PhSSPh (2 equiv.), –78 °C –> rt, 5 h
Scheme 18
A new and efficient sulfenylation agent has been developed by Tanaka and co-workers:
3-phenylsulfenyl-2-(N-cyanoimino)thiazolidine (Equation (24)) <2000SL33>.
NEt3 (2.4 equiv.) O

O N S
+ PhS CO2Et
CO2Et Me ð24Þ
Me
NCN 0 °C, 4 h PhS SPh
98%
(2.0 equiv.)
1,2-Dithiolane is a convenient precursor for dithioacetals by reaction with sulfonium ylides

(Equation (25)) <1995PS(106)227> or sulfoxonium ylides <1996PS(116)253>. Instead of
ylides, pyridylmethyllithium can also be used for the synthesis of 2-pyridyl-1,3-dithianes
<1996PS(112)101>.
Me Me S S ButOK, rt, 12 h S
S Et
+ Ph
Et ð25Þ
Ph I– Et Et ButOH / THF (2 /1)
S
91%
Other functional groups can be transformed into dithioacetals, e.g., sulfoxides (Scheme 19).
Indeed, Kobayashi et al. have revealed that the reaction of sulfoxides bearing an acidic proton
with magnesium amides (generated in situ) afforded the corresponding symmetrical dithioacetals
via a Pummerer-type carbonium ion <1995BCJ1401>. This reaction was used to approach
akuammiline alkaloids <1996JOC1239> and for the racemic synthesis of ethoxycarbonyl-
methyl-2-hydroxy-cyclohexanones <1998TA3445>. In the presence of thiols, unsymmetrical
dithioacetals can be synthesized using the same strategy <1996BCJ2645, 2002BCJ1367>. This
reaction has also been extended to vinyl sulfoxides <1997JOC8015>.
EtMgBr (4 equiv.)
O Tetramethyl-
S piperidine (8 equiv.) Ph S 86% S S
Me CH2 Ph Ph
Et2O, 0 °C to rt
overnight
O SH EtMgBr (6 equiv.)
Et2NH (12 equiv.) S S
S +
Et2O, 0 °C to rt Et
N
overnight
Et
(3 equiv.) 67%
Scheme 19
The reaction of tris(methylthio)methyllithium with aromatic, heteroaromatic, and aliphatic

esters afforded, in excellent yields, the dimethyl -keto dithioacetals (Scheme 20)
<1995JOC6017>. This reaction was then applied to acyl chlorides, anhydrides, thiol esters, and
N,N-dimethylamides <1996JOC9572>. Depending on the reagent ratios and the reaction condi-
tions, the trimethyl -keto trithioorthoesters can also be selectively obtained. By rearrangement in
the presence of catalytic amounts of trityl perchlorate or methanesulfonic acid, these compounds
led to ,-bis(methylthio)thiolcarboxylates in very good yield <1997JOC7228>.
(MeS)3CLi O
(2.2 equiv.) SMe
i. (100%) Ph
O SMe
Ph OMe (MeS)3CLi O
O iii
(1.25 equiv.) Ph
ii. (97%) Ph C(SMe)3 SMe
92% MeS SMe
i. BuLi (2.4 equiv.), THF, –78 °C;
ii. BuLi (1.1 equiv.), THF, –95 °C then
N-(methylthio)phthalimide (0.18 equiv.), –95 °C to rt, 1 h;
iii. Ph3C+ClO4– (0.15 equiv.) or MeSO3H (0.5 equiv.), CH2Cl2, rt
Scheme 20
Reaction of allyl silanes with tris(phenylthio)methane in the presence of ZnBr2 furnished the
corresponding homoallylthioacetals in moderate yields <1996TL6085>. Regioselective oxidation
of the p-alkylthiomethylphenols to the monosubstituted p-quinone methides with K3[Fe(CN)6]
followed by the addition of thiols provided the corresponding dithioacetals in excellent yields
(Scheme 21) <1995PS(107)119>.
OH
OH O
But But
But But But But
i ii
100% 100%
MeO C8H17
C8H17 C8H17 S S
S S
O
i. K3[Fe(CN)6], KOH, rt;
ii. MeO2C–CH2–SH, NEt3 (10 mol.%) or NaOH (250 mol.%), hexane
Scheme 21
Preparation of dithioacetals can be achieved by the double conjugate addition of a thiol

derivative to acetylenes bearing electron-withdrawing groups (esters or ketone). Thus, by reaction
with benzyl thiol in the presence of Bun3P as catalyst, the ethynyl phenyl ketone was transformed
to the corresponding dithioacetal in almost quantitative yield (Equation (26)) <1996SC1539>.
Dithioacetalization of aldehydes can also be performed from sulfonyl chlorides <1999TL3179>.
For this purpose, the corresponding thiols were generated in situ by reduction with the combined
use of zinc metal and dichloromethylsilane in dimethylforamide (Equation (27)). This reaction is
promoted by zinc chloride, formed during the reduction process, acting as a Lewis acid.
Ph BnSH (2 equiv.) BnS Ph
O SBn O ð26Þ
Bun3 P (10 mol.%), THF
99%
Zn (3.5 equiv.)
Me2SiCl2 (3 equiv.) SPh
PhCHO + PhSO2Cl Ph
ð27Þ
DMF, Cl(CH2)2Cl SPh
75 °C, 1 h
88%
Preparation of an enantiopure hemicyclic dithioacetal from L-valine (Scheme 22) and 2-chloro-
thiolane has been described <1996T12745>.
5 steps
CO2H i. BuLi N
N
ii. S
NH2 SH Cl
L-valine S S
82% 1:1
Scheme 22
Using the same strategy, unsymmetrical dithioacetals (hemithioacetals) were synthesized by a

one-pot reaction of thioacetic acid esters and -chlorosulfides (Scheme 23) <2002PS(177)709>.
Dihalides can also be used for the direct formation of dithianes and dithiepines via a one-pot
reaction with carbon disulfide and sodium borohydride (Scheme 24) <2000OL1133>.
Finally, the dithioacetal function was obtained accidentally as a by-product or with a poor yield. Two
interesting examples are depicted in Scheme 25: the conversion of trichloromethyl compounds
<1999S225> and the transformation of 1,2-diol to the corresponding dithioacetals <1998TL6027>.
KOH Ph
O Cl S
79% Ph
O S CH3 DMSO, H2O O S O S S
Scheme 23
i S
Br Br
83% S
i S
Br
Br 79% S
i. CS2 (1.5 equiv.), NaBH4 (3 equiv.), THF, reflux overnight
Scheme 24
N PhSH/PhSNa (1/1) N SPh

CCl3 (3 equiv.)
N N SPh
THF, rt
H H
40%
OH SPh PhS SPh
OH (PhS)2 (3 equiv.)
n
Bu3 P (3 equiv.)
+
THF, rt
O O O O O O
34% 34%
Scheme 25
4.06.1.3 One Dicoordinated Sulfur and One Higher Coordinated Sulfur—R21C(SR2)SO2R3, etc.
4.06.1.3.1 a-Thiosulfoxides
(i) Oxidation of dithioacetals

Following the trend of chapter 4.06 in COFGT (1995) <1995COFGT(4)243>, the mono-oxida-
tion of dithioacetals remains a widely used transformation toward -thio sulfoxide derivatives.
The efficiency of this approach has to be considered in terms of selectivity: (i) the regioselectivity
of unsymmmetrical dithioacetals; (ii) the chemoselectivity, in order to prevent overoxidation
reactions leading to bis-sulfoxides or sulfones formation; (iii) the diastereoselectivity, usually
associated with the facial discrimination of cyclic 2-substituted 1,3-dithioacetals; and, eventually,
(iv) the enantioselectivity, allowing the differentiation of the enantio- or diastereotopic sufur atom
lone pairs. As far as the asymmetric synthesis of sulfoxides is concerned, the reader is advised to
have a look at Chapter 2.03.2, which provides a more general discussion.
The selective oxidation of thioglycosides of type 20 (Equation (28)) has been investigated in
order to gain insight into the structure–activity relationship of these potential antithrombotic
drugs <2002TA3423>. With magnesium monoperoxyphthalate (MMPP) as oxidant, an almost
equal amount of endo 21 and exo 22 sulfoxides was obtained. By using 1 equiv. of NaIO4,
however, the exo-(R)-sulfoxide 22 was formed as the main product. During the course of the
reaction, minor analogs such as bis-sulfoxides and sulfones were also characterized. Similarly, the
oxidation of a related compound, namely the 4-cyanophenyl 1,5-dithio--D-xylopyranoside deri-
vative, proceeded with 3-chloroperoxybenzoic acid (MCPBA), but a single endo-sulfoxide was
isolated <1997CAR53>.
HO
OH O
HO S
OH O 21
S S
O Oxidation + CN
S HO ð28Þ
OH
CN
S
20 O 22
Oxidant 21 (%) 22 (%) S
O CN
MMPP 44 38
NaIO4 3 51
The conversion of 2,4,6-trithiaheptane to the corresponding unsymmetrical sulfoxide is a

relevant example of a regioselective and chemoselective reaction (Equation (29)). For this specific
case, it has been shown that potassium chromate in hot acetic acid was more selective than
hydrogen peroxide or barium ferrate <1999SUL141>, in spite of the harsh reaction conditions.
O
S S S S
Oxidation
+ +
S S S S S S S OS
Me Me Me O Me Me Me Me Me ð29Þ
O
H2O2, 1,4-dioxane, reflux 51% 7%
BaFeO4, AcOH, reflux 22% 2% 1%
K2CrO4, AcOH, reflux 50% 2%
With unfunctionalized 1,3-dithiane as a model substrate, different approaches have been

employed displaying no overoxidation reactions (Scheme 26). Carnell et al. have described the
synthesis of a stable perhydrate derived from -bromocyclohexanone and 30% H2O2
<2000T6571>. This oxidant yielded the corresponding -thio sulfoxide chemoselectively in
dichloromethane as solvent albeit no reaction was observed in tetrahydrofuran (THF). This
perhydrate is considered to be a useful selective oxidant in synthesis because of its poor reactivity
toward alkenes or ketones. Another approach (Scheme 26) consisted of treating a dialkyl sulfide
precursor with triflic anhydride to give a dialkyl(trifluoromethanesulfonyl)sulfonium salt inter-
mediate <1997JOC2483>. Subsequent treatment with water provided the corresponding sulfoxide
without sulfone formation.
O OH
OH
Br
CH2Cl2, rt
80% O
S S S S
R O
S S CF3 ii. H2O, AcONa
R O
i. Tf2O, –30 °C OTf 51%
Scheme 26
One important trend since 1995 in the field of the oxidation reaction has been the elaboration
of organocatalysis processes, which has been reviewed <2001CRV3499>. Organic substances able
to mediate selective catalytic oxidation of dithioacetals, in the presence of a co-oxidant, have been
successfully described. For instance, Page et al. showed that simple oxime derivatives promoted
the mono-oxidation of 2-phenyl-1,3-dithiane with hydrogen peroxide as co-oxidant
<1997SL1355>. Efficient biomimetic processes, by analogy with microsomal flavin adenine
dinucleotide containing monooxygenase (FADMO), have been established (Scheme 27).
A detailed examination of the substitution pattern of various flavin derivatives showed the
effectiveness of structure 23 to promote the oxidation of 1,3-dithiane <2001CEJ297>. Even
with 2 equiv. of H2O2 after a 1h reaction, the formation of overoxidized products was not
detectable. Further development of this process toward an aerobic catalyzed oxidation reaction
has also been successfully demonstrated with lumiflavin 24 in the presence of hydrazine mono-
hydrate <2003JA2868>. The use of trifluoroethanol as solvent, given its high solubility of
molecular oxygen, turned out to be essential to allow a smooth and selective mono-oxidation.
Due to the low loading of these kinds of catalysts and the reaction conditions, these oxidative
approaches can be considered to be economical and environmentally friendly systems.
23 (1.7%)
30% H2O2, MeOH, 20 min, 25 °C
99% O
S S S S
24 (1%)
NH2NH2·H2O (1 equiv.), O2
TFE, 35 °C, 2 h
97%
Me H Me
N N O N N O
, ClO4
N N
N Me N Me
Et O Et O
24 23
Scheme 27
Given the wide application of 1,3-dithiane-1-oxides in chemistry affording the diastereoselective

preparation of various organic compounds, their syntheses from the oxidation of the correspond-
ing 1,3-dithioacetals have been realized with a variety of reagents. Readers should check chapter
4.06 of COFGT (1995) <1995COFGT(4)243>, as well as subsequent papers of the Page group
<1997T1061, 1998T14581>, which provide an overview of the various classical oxidative condi-
tions being employed. Indeed, most of the work has been achieved with 2-substituted 1,3-
dithianes or 1,3-dithiolanes, and the chemo- as well as the stereoselectivity of the oxidation
seems to be substrate and reaction-condition dependent. In the case of seven-membered rings,
high diastereoselectivity has been reported for the resulting trans-sulfoxides <2001RJGC960>.
Organometallic catalysis remains an active field of chemistry in the early 2000s, displaying great
improvement toward the smooth and selective oxidative reaction of sulfur atoms. With only 1%
of the air stable methyltrioxorhenium 25 (Scheme 28), the mono-oxidation reaction of an acyclic
dithioacetal proceeded selectively at low conversion <1996BCJ2955>. Nonetheless, the stoichio-
metry of the reagents has to be controlled in order to prevent overoxidation processes. Further-
more, using ethanol as the solvent seems to be crucial for the success of the reaction. A striking
Me
Re 25 O O O
S S O O S S S S
O
Ph Ph Ph Ph + Ph Ph
H2O2, EtOH
MTO (%) H2O2 Time (min) Sulfoxide (%) Disulfoxide (%)

1 1.1 180 60 0
1.5 1.2 90 85 14
O
S 2–3% ReOCl3(PPh3)2 26 S
Ph Ph
S UHP, MeCN S
85%
Scheme 28
solvent effect has also been observed with rhenium complex 26 as a homogeneous catalytic
activator of urea-hydrogen peroxide (UHP) <1998TL5655>. Although the oxidative transforma-
tion afforded the corresponding sulfoxide with trans selectivity in acetonitrile, a slow reaction rate
was measured in CH2Cl2 or CHCl3. The tolerance of other oxidant sensitive functional groups
such as alkenes is another point of interest of rhenium catalysis.
An important systematic examination of the titanium-catalyzed oxidation of various 2-substituted
1,3-dithianes and 1,3-dithiolanes (Table 5) has been published by Della Sala et al. <2002S505>. They
demonstrated that Cp2TiCl2 gave comparable selectivities to that of the classical Ti(PriO)4 but improved
yields considering the chemoselectivity. This cyclopentadienyl Ti(IV) complex turned out to be less
moisture sensitive and could be used with as little as 1% loading in the presence of 4 Å activated
molecular sieves and t-butyl hydroperoxide (TBHP) as a co-oxidant. The diastereoselectivity of the
reaction is generally excellent, affording trans derivatives, except for 2-carbonyl dithianes, which are
known to be problematic substrates due to epimerization at the -position of the carbonyl function.
Table 5 Representative examples of titanium catalyzed oxidation of cyclic

dithioacetals to monosulfoxidesa
Substrate Catalyst (%) Time (h) Yield (%) Trans:cis
S S 5 5 86 98:2
Ph H
S S 5b 3 72 98:2
Ph H
S S 5 5 91 96:4
Me H
S S
1 16 85 98:2
Ph H
S S
5 25 63 80:20
O H
S S 1 30 69 72:28
Ph Me
S S 1 22 69c 93:7
HO H
a b
CH2Cl2, molecular sieves 4 Å, TBHP, 0 C. Ti(PriO)4 was used. c
4% of bis-sulfoxide
was obtained.
As has already been discussed in COFGT (1995) <1995COFGT(4)243>, singlet oxygen can
oxidize dithioacetals, and insights into the mechanism of this reaction have been provided
<1999JOC5620, 2001JA4966>. Advances in the chemistry of dithiiranes, a unique three-
membered ring dithioacetal, have been reviewed and the synthesis of dithiane-1-oxide derivatives
has been described <1996MI869, 1999RHA1>.
The elaboration of enantiomerically enriched 1,3-dithioacetal 1-oxide is an important field of
research, taking into account the richness of such derivatives as chiral nonracemic auxiliaries.
Within chapter 4.06 of COFGT (1995) <1995COFGT(4)243>, the relevance of the modified
Sharpless reagent for the asymmetric synthesis of cyclic 2-substituted 1,3-dithioacetals has been
pointed out. The reaction is usually performed by either the Kagan-modified procedure (dithio-
acetal: TBHP:titanium tetraisopropoxide:diethyl tartrate (+ or ) (DET):water in a ratio of
1:1.1:1:2:1 or the Modena-modified procedure (1:0.5:0.25:1:0)). As a rule of thumb, a coordinated
group at the 2-position, for instance encountered within cyclic 2-acyl-1,3-dithioacetals, is required
for a highly enantioselective process, and the formation of the anti diastereoisomer is usually
predominant. In the case of acyl dithiolanes, Maycock and co-workers have reported an improved
diastereoselectivity by using anhydrous modified Sharpless conditions <1995TL6537>. Although
a three-step sequence is required (enol ether formation–oxidation–ketone regeneration), they
showed subsequently (Equation (30)) that a better stereoselectivity was obtained when the oxida-
tion step was realized with enol silyl ethers <1997TL5047>. Up to 19% enantioselectivity
improvement was measured in the dithiolane series, in comparison with the direct oxidation of
the corresponding ketone. This technique was, however, not general to six-membered ring
dithiane compounds.
i. (+)-DET, TBHP,
S S Ti(PriO)4 (2:1.5:1), –20 °C S S O
R1 R2 ii. TBAF, H2O R1 R2 ð30Þ

TBDMSO 53–80% O
R1, R2 = H, Me, Et, Pr 85–98% ee
1:0 to 20:1 dr
Since the publication of COFGT (1995) <1995COFGT(4)243>, several examples of asym-

metric synthesis of 1,3-dithiane 1-oxides (DiTOX) have been described with closely related
Sharpless modified protocols <1995JCS(P1)2673, 2000T9683>. A subsequent paper by Page
and co-workers giving a compilation of various results with those substrates <1996T2125>
should be consulted. The preparation of simple chiral building blocks lacking a coordinating
group, such as the 1,3-dithiane 1-oxide, occurred with low selectivity with the previously
mentioned method. Alternatively, the diastereoselective oxidation reaction of 1,3-dithianes
bearing a removable chiral auxiliairy at the 2-position, such as diacetone-D-glucose (DAG),
has been successfully reported <1996JCS(P1)1879>.
In 1995, Bolm and Bienewald established an efficient catalytic asymmetric sulfoxidation (Scheme
29). This reaction is promoted by vanadium complexes and successfully applied on dithioacetals
with nonchelating groups. This process is easily performed in an open reaction vessel with the cheap
H2O2 as the oxidizing agent <1995AG(E)2640>. The best results were obtained with N-salicyli-
dene-amino alcohol ligand 27 in the 2-aryl-1,3-dithiane series <1998SL1327> and a catalyst loading
of 0.1% was still successful. An erosion of the enantioselectivity was, however, measured with
1% VO(acac)2
( )n ( )n n Yield (%) ee (%)
1.5% ligand 27
S S O S S
1 81 33
30% H2O2 (1.1 equiv.)
Ph 2 84 85
Ph rt, CH2Cl2
( )n ( )n n Yield (%) ee (%)

2% complex 28
S S S S O 1 83 92
MeOH, 0 °C
2 91 99
Ph UHP (1 equiv.) Ph
But
N Cl N
Ti
O Cl O
But
PhPh
OH N But
27 OH
28
Scheme 29
2-alkyl-dithiane derivatives. Sharzewski and co-workers further extended this approach with salen
ligand analogs synthesized from D- or L-valinol, both enantiomers of which are readily available
<1999TA3457>. Katsuki et al. have published an impressive enantioselective mono-oxidation with
Ti(salen) complex 28 <2002TL3259>. Up to 99% enantiomeric excess (ee) was obtained and the
reaction does not require a halocarbon solvent. These two methods proved to be very chemo- and
diastereoselective for a large range of cyclic dithioacetals.
Page et al. have continued to improve the efficiency of novel camphorsulfonyl oxaziridine
oxidants and have reported a reliable synthesis (1(S))-()-1,3-dithiane 1-oxide <1999OS37> in
large quantities. These nonmetal catalysis methods have been recently reviewed <2001CRV3499>
and generally provide an environmentally preferable approach to that of transition metal cata-
lyzed methods. It has also been shown that the oxidation reaction could take place with H2O2 as
the terminal oxidant (Equation (31)) in the presence of enantiomerically pure sulfonylimines
<1995SL773>. The reverse selectivity obtained compared to their oxaziridine analogs suggested
the formation of an -hydroperoxyamine intermediate <1995TA2911, 1999PS(153/4)247>. The
same method has been applied to acyclic 1,3-dithioacetals <2001IJC(B)1132>.
OMe
(1 equiv.)
OMe
R Yield (%) ee (%)
ð31Þ
O2S N
S S S S Ph 100 98
DBU (4 equiv.), H2O2/H2O O
COBut 46 78
R CH2Cl2, 20 °C R
Biocatalysis constitutes an important alternative to chemical oxidative processes and provides

an ecologically tolerant approach. Progress in the field of dithioacetals has allowed broadening of
the scope of biosulfoxidation reactions with regard to both their usual substrate dependence and
scale-up performances. Colonna et al. <1995CC1123, 2002HAC467> have reported a high-
yielding mono-oxidation of unsubstituted 1,3-dithiane, 1,3-dithiolane, and bis(methylthio)-
methane with a cyclohexanone monooxygenase (CMO) from Acinetobacter calcoaceticus
NCIMB 9871. More than 98% ee values were measured in favor of the (R)-monosulfoxides,
and with the formation of sulfone derivatives a kinetic resolution has been assumed in some cases.
This method was extended to 2-substituted analogs but an erosion of the enantioselectivity was
observed for the major trans-products <1996TA565>. Unfortunately, these enzymes are depen-
dant upon an expensive cofactor, namely nicotinamide adenine dinucleotide phosphate
(NADPH). Alternatively, Furstoss and co-workers have developed a whole-cell approach using,
for instance, a culture of Acinetobacter calcoaceticus NCIMB 9871 <1996TL6117, 1997T9695>
on a preparative scale that turned out to be as efficient as the pure CMO. A recombinant strain of
Baker’s yeast expressing cyclohexanone mono-oxygenase, and designed to perform oxidation
reactions, has shown promising results with 2-substituted 1,3-dithiane or 1,3-dithiolane
<1999JHC1533>. Almost complete enantioselectivities were obtained with cyclic dithioacetals
bearing an ether or ester functionality at the C-2 position in order to improve their water
solubility. A readily available chloroperoxidase from the marine fungus Caldariomyces fumago
as noncofactor dependent enzyme revealed oxidative properties toward benzo[1,3]dithiole, but
low yield and selectivity were obtained <1998CHIR246>. Cultures of a mutant strain (UV4) of
Pseudomonas putida containing dioxygenase enzymes afforded a selective mono-oxidation of
(methylthio)methyl phenyl sulfide <1995CC119> giving 97% ee but with a moderate yield.
Contrary to the chemical oxidation, this system favored the reaction of the alkylaryl over the
dialkyl sulfur atom <2001JCS(P1)3288>.
(ii) From -thio sulfoxide carbanions

Alkylation of -thio sulfoxide carbanion derivatives <1995COFGT(4)243> has continued to attract
some interest in the late 1990s and early 2000s as an acyl anion equivalent leading to ketone or ester
functions. The deprotonation of the dithioacetal 1-oxide precursor usually occurred with strong bases
such as BunLi, lithium diisopropylamide (LDA) or NaH, and these Umpolung reagents have been
exemplified in total synthesis of naturally occurring Ciguatoxin <2002S1835> and new -lactam
drugs <2001BMCL137>. Intramolecular reactions allowing the synthesis of cyclic ketones have been
also described toward the elaboration of cyclopropanated sugars <1996ZN(B)1517>. Similarly,
Fleming et al. have developed a straightforward synthesis of the indolizidine and quinolizidine cores
(Scheme 30) by an intramolecular conjugate addition of a thio sulfoxide anion to an ,-unsaturated
nitrile <1997JOC1305>. The high diastereoselectivity obtained is noteworthy in this series.
CN
O CN CN
S i. BunLi N O2 N
S S S
N ii. NH4Cl S 79% S
O O
O
Scheme 30
The diastereoselective course of the intermolecular process is another point of interest. In this
regard, Voss and co-workers <1997T2459> have studied the alkylation of the supposed config-
urationally stable 2-(methylthio)thiolane 1-oxide -carbanion (Equation (32)) generated by means
of various sodium and lithium bases. Up to 98% of diastereoisomeric excess was obtained with
LDA and an aromatic aldehyde. Complete selectivities were even obtained with aliphatic aldehydes,
which are considered to be more difficult electrophiles than their aromatic homologs, in correlation
to their steric hindrance. By using methyl iodide as the electrophile, the alkylated product was
formed with an 80% de, but the more bulky 2-(tert-butylthio)thiolane 1-oxide has to be used.
A related study was subsequently realized with epoxides as the electrophile <1999EJO1481>.
Base RCHO de (%) Yield (%)
i. Base, –30 °C SMe BunLi/ TMEDA PhCHO 40 76

S SMe ii. RCHO, S OH LDA PhCHO 98 76 ð32Þ
–78 °C to rt LDA ButCHO 98 33
O O R
LDA CyCHO 98 59
LDA MeCHO 43 64
During a study aiming at the formation of polyhydroxylated structures <1999TA973>, the

selective addition of the lithium salt of the commercially available ethyl ethylthiomethyl sulfoxide
(EETMS) to a chiral aldehyde led to the major anti diol with an 88:12 ratio after LiAlH4 sulfinyl
group reduction (Scheme 31). The synthesis of the other polyhydroxylated isomers was also
examined.
S(O)Et
O O OH
O CHO SEt O S(O)Et
TBDMSO BunLi TBDMSO SEt
LiAlH4 THF, 45 °C
O OH O OH
O SEt + O SEt
TBDMSO SEt TBDMSO SEt

88:12
Scheme 31
Metzner and co-workers have developed an alternative procedure <1996TL4507> to prepare

dithioacetal oxides starting from aliphatic sulfine derivatives, easily obtained by oxidation of the
corresponding dithioesters (Scheme 32). These sulfines underwent a rapid thiophilic addition of
alkyllithium nucleophiles at low temperature affording the thioacetal compounds after protona-
tion. The alkylation reaction of the -thio sulfoxide anion intermediates by MeI was also
achieved. However, the obtained products spontaneously formed the corresponding ketones. It
was also shown that the stereochemistry could be reversed by converting the lithiated anion
intermediate to an aluminum ate complex <1999EJO2859>. This methodology was applied to the
elaboration of 2-cyclopenten-1-ones derivatives through a domino process <1999TL2319>. Simi-
larly, the thiophilic attack of allyl silanes onto sulfines derived from aromatic and aliphatic
dithioester via fluoride ion activation has been reported <1996JOC7174>.
O O
S MCPBA S i. R2Li, –78 °C, THF R2 S H
R1 SMe 0 °C, CH 2Cl2 R1 SMe ii. H2O R1 SMe
R1 R2 Yield (%) de
Pri Me 58 87:13
n-C8H17 Me 42 61:39
Cy Me 63 83:17
Cy Bun 80 70:30
Scheme 32
(iii) By various methods

In comparison with the previous approaches, other methods have been used sparingly in the
literature for the elaboration of -thio sulfoxide moieties. As already disclosed in chapter 4.06 of
COFGT (1995) <1995COFGT(4)243>, this building block has been envisaged via three different
routes (Scheme 33). The first consisted of the reaction between a thiolate nucleophile and a
chloromethyl sulfoxide <1997JCR(S)90>. The second route was applied according to the
Andersen reaction via the addition of an -phenylthio methyllithium to menthyl p-chlorobenzene
sulfinate <1999NJC973>. Then, the corresponding thio sulfoxide was obtained in enantiopure
form after recrystallization.
R1(O)S + R2S 1 2
R1S(O) + SR2
R1(O)S SR2
R1(O)S + R2S 3
Scheme 33
In the period 1998–2003, improved procedures were described for the third pathway (Scheme
33). Wladislaw et al. have reported the sulfenylation reaction of -keto sulfoxides (Equation (33))
in a two-phase solid–liquid system, by means of a phase-transfer catalyst, e.g., benzyltriethyl-
ammonium chloride (TEBA) <2000PS(157)139>. The best result was obtained with a bulky t-butyl
group (R = But). In the case of the phenylsulfinyl group (R = Ph), an improved diastereoselec-
tivity was achieved (4:1) with N-benzylquininium chloride as chiral phase-transfer catalyst but no
enantioselective process took place <1999T12023>.
O O O O R Yield (%) de
K2CO3, TEBA
S S Me 57 1:1 ð33Þ
Ph R MeSO2SMe Ph R
But 73 1:0
CH2Cl2, benzene SMe
Ph 28 2:1
Enantio-enriched -keto sulfoxides (Scheme 34) have been successfully used to carry out a
diastereoselective sulfenylation reaction affording the acetal products that proved to be unstable
<1998TA3445>. However, the subsequent in situ aldol reaction revealed a 1,2-asymmetric
induction of the thioacetal S-oxide moiety. Interestingly, with respect to the sulfenyl group, the
opposite induction was observed during the addition of the enolate. It is believed that the
configuration of the -thio sulfoxide depends upon the thiosulfonate (R = Tol or Pri) used as
the electrophile for the first step of this sequence. After deprotection, these structures led to
nonracemic -hydro keto derivatives.
O O EtO2C CO2Et
S LiCH2CO2Et OH O HO O
Tol S S
SR –78 °C Tol Tol
SR + SR
i. LHMDS, THF, HMPA

R Yield (%) de
ii. RSO2SR
Tol 78 18:82
O O
S Pri 72 89:11
Tol
75:25 diastereoisomeric
mixture at C-2
Scheme 34
A completely different approach, based on 1,3-dipolar cycloaddition (Scheme 35), has been
validated by Mloston and Heimgartner <1995PJC1649>. Even though this method was applied
to a specific substrate, it has been shown that the in situ generated thiocarbonyl-S-ylide could
react with a sulfine as dipolarophile to give an -thio sulfoxide compound.
O
O O
Me Me Me Me S
THF, 50 °C O
Me Me Me Me O
–N2 75% O S
S N
S Me
N S
CH2 Me Me
O Me
Scheme 35
4.06.1.3.2 a-Thio sulfones

-Thio sulfone derivatives are also a classical equivalent of the ketone functionality involved in
various synthetic transformations, though less studied than their -thio sulfoxide counterparts.
Most of the preparative methods based on CS bond formation or alkylation of the thioacetal
S,S-dioxide anion were already described in chapter 4.03 of COFGT (1995)
<1995COFGT(4)243>. Therefore, we will first focus on improved procedures and then describe
the subsequently developed methods.
The synthesis of optically active 2-acyl-2-alkyl-1,3-dithiolane-1,1-dioxides <2002HCA4079>
(see also <1995COFGT(4)243>) has been achieved by the oxidation of their sulfoxide precursors.
The best conditions made use of OsO4 and N-methylmorpholine N-oxide (NMO) in acetone. The
sulfanylation reaction of an -sulfonyl carbanion, resulting from the deprotonation with a strong
base such as BunLi, is, however, a more widely used pathway to -thio sulfone derivatives
<1995TL7531>. An alternative approach has been described (Equation (34)) via a decarboxyl-
ative sulfanylation sequence <2000PS(161)1>. A mechanistic examination revealed that the
decarboxylation reaction took place either before the CS bond formation with R = Ph or
subsequently with an alkyl group (e.g., R = Me). By analogy with the synthesis of -thio
sulfoxide synthesis, the sulfanylation process of -sulfonyl substituted esters and thioesters, i.e.,
bearing an electron withdrawing group, can be smoothly effected in a two-phase solid–liquid
system, by means of a phase transfer catalyst, e.g., TEBA <1997PS(123)197>.
PhO2S CO2H NaH (2 equiv.), DMSO PhO2S SMe R Yield (%)

Me 56 ð34Þ
R MeSSMe, rt R
Ph 70
Alternatively, the construction of -thio sulfones via, on the one hand, the addition of a thiolate
derivative to an aryl or an alkylsulfonylhalogenomethane has been achieved <2000BMCL847,
1995H2263>. On the other hand, an ((arylsulfonyl)methyl)iodonium salt (Equation (35)) can be

used as an efficient electrophilic reagent with thiophenolate anion <1997JA4775>.
CH2Cl2, rt
ArSO2CH2IPh OTf + PhSLi ArSO2CH2SPh ð35Þ
90%
The alkylation of the methylene carbon of the anion of -thio sulfone building blocks is usually
performed after deprotonation with BunLi and reaction with good electrophiles such as aziridines,
aldehydes, methyl iodide, etc. <1998TL147, 2001JHC579, 1995COFGT(4)243>. Moreover, the
difluorination reaction at the -position of these acetals has been achieved with IF5–Et3N–3HF as
a reagent <2002BCJ1597>. Furthermore, the development of cyanomethylenetributylphosphane, as
a new Mitsunobu like reagent (Equation (36)), allowed a straightforward reaction of (methylsulfenyl)
(4-tolylsulfonyl)methane with alcohols <1995TL2531>. This process has to be carried out at high
temperature and a double alkylation reaction with benzyl alcohol as electrophile could be observed.
R Yield (%)
Bu3P=CHCN
TolO2S SMe + ROH TolO2S SMe Bu n
94 ð36Þ
Benzene, 120 °C Bn 41
R
2-octyl 72
As described in (1995) <1995COFGT(4)243>, phenyl vinyl sulfone derivatives can act as an

efficient radical trap at the -position of alkyl radicals generated from the so-called Barton ester.
-Pyridylthio sulfone compounds are then formed by recombination of the in situ formed
pyridylthio group and the -radical of the sulfonyl moiety. This methodology has been exempli-
fied by Barton’s group to effect the one-carbon homologation of carboxylic acids
<1995AJC407>. Taking advantage of this process, Gester and Renaud have investigated the
stereochemical outcome of 1,3-dioxolan-4-yl and oxiranyl cyclic radicals in order to gain insight
into the 1,2-asymmetric induction <1997S1261>. It has been shown that boronate ester inter-
mediates (Scheme 36), generated in situ by hydroboration of the corresponding alkenes, are
efficient radical precursors in this reaction upon irradiation <2000AG(E)925, 2000CC1017>.
The success of this one-pot method is based on the Barton carbonate pyridine-2-thione-N-
oxycarbonyl (PTOC-OMe) as a chain transfer reagent as depicted in Scheme 36.
O
HB
O SO2Ph
(2 equiv.) PTOC-OMe SPy
O
B Cy
10% Me2NCOMe 150 W lamp SO2Ph
O
CH2Cl2 10 °C
75%
O
R + R SPy +
N S MeO O
OCOOMe
PTOC-OMe
Scheme 36
The intramolecular cyclization of an iminyl radical onto an olefinic moiety (Equation (37)) has
been examined by Gagosz and Zard <1999SL1978>. The new carbon-centered radical formed
upon irradiation of the corresponding ketoxime xanthate was trapped by an external phenyl vinyl
sulfone to give a functionalized -thio sulfone product. This xanthate chemistry was also applied to
the trifluoromethylation reaction of vinyl sulfone, but poor yields were obtained <2001OL1069>.
MeS S
CH2Cl2, rt
O Visible light SO2Ph
ð37Þ
N + SO2Ph N SCOSMe
250 W lamp
58%
Ketene dithioacetal S,S-dioxides proved to be efficient radical acceptors due to the captodative effect
of both sulfur groups, allowing thereby a thioacetal S,S-dioxide synthesis via alkylation reactions.
Ogura and co-workers have established (Scheme 37) that the photochemical addition of 1-hydro-
xyalkyl radical, generated by hydrogen abstraction from the corresponding alcohol with excited triplet
benzophenone, occurred with high yield on the allylic alcohol double bond <1997T12101>, as
depicted in Scheme 37. After removal of the thiomethyl ether function, it turned out that the addition
proceeded with high diastereoselectivity due to an efficient 1,2-asymmetric induction. This group also
applied this methodology to acyl radical addition <1999TL2537>. It has also been demonstrated that
even hydrocarbons possessing no activated CH bond such cyclohexane could react with ketene
dithioacetal S,S-dioxides under the same conditions <2000JOC297>. In the same paper, an alternative
source of radical precursors was successfully based on the CSn bond activation of tetraalkylstan-
nanes via photoinduced electron transfer (PET) oxidation.
OH SMe hν, Ph2CO OH SMe Raney Ni OH
Me SO2Tol PriOH Me SO2Tol EtOH, rt Me SO2Tol

97% 84%
Me OH Me OH
Me Me
95:5
Scheme 37
Finally, as will be shown with ketene thioselenoacetal S,S-dioxides in Section 4.06.2.3, ketene
dithioacetal S,S-dioxides can undergo a cyclopropanation reaction <1997JCS(P1)3035>.
4.06.1.3.3 Other derivatives

Despite the widespread chemistry of -thio sulfoxides (Section 4.06.1.3.1), -thio sulfilimines,
their nitrogen analogs, have been far less studied <1996JCS(P1)313>. The sulfimidation reaction
of dithioacetal precursors has been described by means of chloramine-T with moderate yields
<1998HAC29>. Interestingly, the asymmetric synthesis of various cyclic dithioacetals (Equation
(38)) has been examined with N-(p-tolylsulfonyl)imino(phenyl)iodinane as the sulfimidating
reagent <1998JCS(P1)2373>. The copper catalyzed sulfimidation of the simplest 1,3-dithiane
(R = H) showed poor enantioselectivity with a chiral bis-oxazoline as the best ligand. The
asymmetric induction was slightly improved with 2-functionalized dithianes together with a
high diastereoselectivity in favour of the trans-isomers.
5% CuOTf −
TsN = IPh (1 equiv.) + NTs
S R S R + S R
S Toluene, –20 °C S NTs S
+ −
ð38Þ
O O R Yield (%) de ee (%)
6%
N N H 79 20
Ph Ph Me 72 96:4 40
The formation of an -thio sulfilimide derivative with a cyclization approach onto a sulfonium
intermediate is described in Scheme 38 <1995HAC167>. Moreover, the subsequent potassium
permanganate oxidation took place regioselectively to the sufilimine moiety.
S SMe i. NCS S i. NaH (69%) S

+ O
ii. AgClO4 S ii. KMnO4 (33%) S
NH2 N Me N
–
+ Me
69% H ClO4–
Scheme 38
During the study of the reactivity of 1-benzylsulfonyl-1,1-dihydropolyfluoroketone precursor

29, various types of -thio sulfones 30 were synthesized as shown in Equation (39)
<2002JFC175>.
SNPhth
H(F2C)3 PhthNSCl H(F2C)3
SO2CH2Ph SO2CH2Ph ð39Þ
20 °C
O O
29 30
4.06.1.4 Bis(sulfoxides)
4.06.1.4.1 Oxidation
The standard oxidation of dithioacetals and -sulfanyl sulfoxides has been efficiently used either
for producing new synthetic intermediates or in the context of biologically active molecules.
The most common reagents are 3-chloroperoxybenzoic acid (MCPBA) <1998JOC3481,
1998JOC7306, 1998BMCL731> and NaIO4 <2002TA3423, 1998BMCL3331>, but UHP cata-
lyzed by rhenium(V) oxides <1998TL5655> or MMPP <2002TA3423> have also been used for a
generally selective oxidation (Equation (40)). However, oxone <1995TL833> was not selective.
Ph UHP Ph
Re(V)OCl3(PPh3)2 (0.02 equiv.) O O
S S S S ð40Þ
MeCN, rt, 18 h
85%
In connection with the interest of C2 symmetric, enantioenriched bis(sulfoxides), the groups of

Aggarwal <1998JOC3481, 1998JOC7306, 1998JCS(P1)2771> and Maycock <1995TL6537> have
further investigated the enantio- and diastereoselective oxidation of a number of dithianes and
dithiolanes. Optimum conditions for ethyl 1,3-dithiane-2-carboxylate involved <1998JOC7306>
the Modena version of the Sharpless-type oxidation, leading to the trans-bis(sulfoxide) with high
enantioselectivity and in good yield (Scheme 39). Hydrolysis and decarboxylation furnished the
unsubstituted ((R),(R))-trans-1,3-dithiane-1,3-dioxide.
CO2Et CO2Et NaOH

i O O H2O O O
S S S S S S
60% 83%
>97% ee >99% ee
+8% Monoxide
+19% Trioxide
i. PhCMe2OOH (2 equiv.), Ti(OPri)4 (0.5 equiv.), (+)-DET (2 equiv.)
H2O (1 equiv.), CH2Cl2, –40 °C, 2 days
Scheme 39
In search of a practical synthesis of (1(R),3(R))-2-methylene-1,3-dithiolane-1,3-dioxide, Aggarwal

et al. investigated the enantioselective oxidation of 1,3-dithiolanes bearing a methylene with an
eliminatable group linked to carbon 2 <1998JCS(P1)2771>. They found again that, for these
substrates, the Modena oxidizing system is more reactive than the Kagan reagent and that the
enantioselectivity is largely dependent upon the substrate. The benzyl ether was found to give the
optimum yield and enantio- and diastereoselectivity (Scheme 40).
The synthesis of an acyclic derivative has also been investigated using a Bolm-type oxidizing
agent: hydrogen peroxide with vanadium catalysis, in the presence of a Schiff base in a catalytic
amount (Equation (41)). Imines prepared from a variety of salicylaldehydes and enantiopure 1,2-
amino alcohols have been screened, leading to some success with a leucinol derivative
<2001JCR(S)263>.
O O
S OBn i S OBn ii, iii S
S 68% 77%
S S
>98% ee
O O
i. PhCMe2OOH (2 equiv.), Ti(OPr i)4

(0.5 equiv.),
(+)-DET (2 equiv.), H2O (1 equiv.), CH 2Cl2, –30 °C, 40 h
ii. NHMe2, MeCN; iii. EtN(Pri)2, MeI, MeCN
Scheme 40
NO2
N * Pri
Ph
OH O O ð41Þ
OH O
(0.03 equiv.) + S S
S S S S
Ph Ph H2O2 (2.3 equiv.) Ph * Ph Ph * * Ph
VO(acac)2 (0.02 equiv.) 32% 20%
CH2Cl2/H2O, 0 °C 72% ee 50% de
84% ee
4.06.1.4.2 From methylene bis(sulfoxides)

As trans-1,3-dithiane-1,3-dioxide is available (Scheme 39) with both relative and absolute stereo-
control, it has been used as a chiral acyl anion equivalent, and full papers have appeared on this.
Deprotonation with sodium hexamethyldisilylazide (NaHMDS) and reaction with aromatic alde-
hydes provided <1995JOC2174, 1997T16213> alcohols with excellent stereocontrol of the new
stereogenic center. It has been explained by an equilibration of the diastereomeric sodium alcohol-
ates. It was elegantly applied <2002JOC8618> to the synthesis of (R)-salbutamol (Equation (42)).
O OH O
i. NaHMDS S
S Py/ THF, 0 °C, 30 min
S
S O O ð42Þ
O ii.
O CHO
O
O Single diastereomer
0 °C, 2 h
89%
Analogous condensation reactions with aldehydes have been performed <1997JOC1139> with five-
membered analogs, with good stereoselectivity under kinetically controlled conditions. In the acyclic
series, ((S ),(S ))-bis-p-tolylsulfinylmethane has been used in the synthesis of ketenedithioacetal dioxides
<2002JOM130>. The latter have been used as chiral electron poor alkenes for cycloaddition with
dienophiles <1997TA409>.
4.06.1.4.3 From various precursors

Though it requires a stoichiometric amount of a chiral source, the Andersen reaction of a carbanionic
species with a stereodefined sulfinate is an attractive entry to enantiopure sulfoxides. In the main,
two cheap sources, menthol and DAG, have been used for the easy preparation of diastereomerically
pure sulfinate esters and their subsequent reaction <1997TA3647, 2000T3749, 2000TA2991,
2000TA1183> with sulfoxide carbanions (Equation (43)). Detailed procedures have been reported
for the synthesis of the C2 symmetrical (S,S)-bis-p-tolylsulfinyl)methane from both menthyl
<1997TA3647> and DAG <2000TA2991> p-toluenesulfinates in, respectively, 80 and 82% yields.
O i. LDA (1.25 equiv.) O O

S THF, –40 °C, 0 °C, –78 °C S S
p-Tol p -Tol p -Tol
O
(R ) ii. (1 equiv.) ((S),(S) ) ð43Þ
S
p-Tol OMenthyl (R )
–78 °C, 1 h
80%
[4+2]-Cycloaddition of dienes to ketenedithioacetal dioxides provided spiro-bicyclic bis(sulf-

oxides), as shown by Aggarwal and co-workers <1995JOC4962, 1998JCS(P1)2771>. It took
advantage of the C2 symmetry of (1(R),3(R))-2-methylene-1,3-dithiolane-1,3-dioxide in reaction
with cyclopentadiene and electron-rich acyclic dienes. Under Lewis acid catalysis the reaction was
very rapid. The adducts were obtained as single diastereoisomers (Equation (44)) <1995JOC4962,
1998JCS(P1)2771>. Other dienes were examined: e.g., furan and dihydropyridines.
O
BF3·OEt2
S EtCN, –78 °C, 20 min O
+ S >97:3 dr ð44Þ
S 74%
S
O O
For the reaction of acyclic compounds bearing electron-withdrawing groups with cyclopenta-
diene and acyclic dienes, it was necessary to use 13 kbar of pressure and a Lewis acid catalyst
(Equation (45)) <1997TA409>, but a good-to-high stereoselectivity was attained.
O O 13 kbar, CH2Cl2
SOTol
S S rt, 24 h
Tol + CO2Et
Tol ð45Þ
76% SOTol
EtO2C CO2Et CO2Et
87:13 dr
1,3-Dipolar cycloaddition was investigated with nitrones. It is regioselective in favor of

isoxazolidines, and a single diastereomer was obtained <1998JOC3481> (Equation (46)).
The ketenedithioacetal is a chiral ketene equivalent, as was demonstrated in the construction of
the tropane skeleton with oxidopyridinium betaines as the dipole <2003OBC1884>.
O
O Ph
S Me O CH2Cl2, 13 h, rt Me
+ N S N ð46Þ
S 86% S O
Ph
O O
(5 equiv.)
Dimerization of transient unsaturated sulfines afforded unsaturated dithiane dioxides <2002TL499>.
4.06.1.5 One Tricoordinated and One Higher Coordinated Sulfur—R12CS(O)R2S(O)2R3

Few literature reports have appeared on this type of compounds. Oxidation of -sulfanyl sulfones
by MCPBA provided -sulfinyl sulfones in good yields in the acyclic <1998JOC2993> (Scheme
41) or cyclic series <1999BMC837>.
i O O ii O O O
PhSO2Me S S S S
70% p-Tol p -Tol 99% p-Tol p -Tol
BunLi,
i. THF, –78 °C, 1 h; ii. (p -TolS)2, THF, –78 °C, 1 h
ii. MCPBA, CH2Cl2, –78 °C, 15 min
Scheme 41
4.06.1.6 Two Tetracoordinated Sulfurs—R12C[S(O)2R2]2
4.06.1.6.1 Bis(sulfones)
(i) From dithioacetals and their derivatives

The direct introduction of two oxygen atoms per sulfur atom was achieved for 1,3,5-trithiane
using a combination of inexpensive UHP and trifluoroacetic anhydride in acetonitrile
<1999SC2235>.
(ii) From methylene and alkylidene disulfones

As these compounds exhibit a high acidity of the CH adjacent to both sulfonyl groups, a great
deal of synthetic work has involved their carbanions and subsequent treatment with electrophiles.
It is a popular synthon for step-to-step construction of functionalized molecules.
Standard conditions have been used throughout the period 1995–2002: phase-transfer catalysis
was efficient <2001EJO2659, 2000JOC2528> and strong bases, such as NaH, were also employed
<1999CEJ187, 1998S1052, 1997HCA623, 1997HCA2047>, efficiently providing the alkylated
products. In place of an alkyl halide, an alcohol was used <2002TL3939> through a Mitsunobu-
type reaction (Equation (47)), again in connection with the significant acidity of the CH2 of
diphenylsulfonylmethane, which is necessary for this process.
(PhSO2)CH2
PPh3, DEAD O
O O
O C6H6, 23 °C, 3 h ð47Þ
OSiButPh2 OSiButPh2
OH PhO2S SO2Ph
An intramolecular Mitsunobu reaction version has led to bicyclic fused carbocycles

<1995TL8577>. Three-membered ring electrophiles were utilized in conjunction with carbanions
of bis(sulfones). An oxirane was used <1998AG(E)633>. Reissig and co-workers have extensively
studied the ring opening of activated vinylcyclopropanes by soft nucleophiles, such as the anions
of bis(sulfones) <1995SL1223, 1998S1052, 1999CEJ187>. They have developed an elegant
method for the formation of medium to large carbocycles (Equation (48)).
SO2Ph CsF, BnEt3N+Cl– MeO C
2
Me2ButSiO DMF, 90 °C
SO2Ph SO2Ph ð48Þ
CO2Me 42% SO2Ph
O
N-Alkylamides have been obtained by the reaction of a sodium (bis)sulfone carbanion with
oxazolinium salts <1996JOC10>.
Treatment of a lithiated (bis)sulfone with cyclohexadienyl tricarbonyl iron salts furnished
tricarbonyl iron complexes of dienes <1997TL505>.
The soft nature of bis(sulfone) carbanions makes them prone to perform a conjugate addition
with acceptors. As an application, Padwa et al. have used ‘‘multisulfone’’ reagents for a new
synthesis of fused cyclopentenes (Equation (49)) <1996JOC3829, 1995JA7071>.
SO2Ph
SO2Ph
i. KH, THF, rt, 45 min
MeO2C SO2Ph
SO2Ph
ii.
PhO2S MeO2C SO2Ph ð49Þ
SO2Ph 27%
0 °C, 1 h +31% of benzenesulfinate
elimination product
Other Michael acceptors have included a pyrrolidinyl enone <1999SL1307> and conjugated
hydrazones <1998T7581>.
The scope of the Michael addition has been extended by the use of a ruthenium catalyst,
[RuH2(PPh3)4], leading to a practical reaction of bis(sulfones) with an unsaturated aldehyde and a
ketone <1996JA8553>.
When it is desired to alkylate a (bis)sulfone not classically on the carbon adjacent to both
sulfonyl groups, but rather on the terminal methyl group, a possible route is to use a dianion. For
that example, a methylsulfanyl group was added on the central position. The dianion of [methyl-
sulfanyl] [bis(methylsulfonyl]methane was prepared, alkylated on the more reactive terminal anion
site, and subsequently desulfanylated <2002TL1377>. The monoalkylation is, however, not fully
selective (Scheme 42). Geranyl and farnesyl derivatives have also been prepared by alkylation of
the trianion <1996BOC242>.
O O O O O O O O
i, ii iii O O O O
S S S S (CH2)4Me
S S (CH2)4Me
76% 100%
SEt SEt
+17% Dialkylated product
i. BunLi (1.67 equiv.); ii. I(CH2)4Me; iii. NaSEt, EtSH, EtOH
Scheme 42
(iii) From ketene dithioacetal tetraoxides

The activated double bond of such compounds is susceptible to undergoing a variety of cyclo-
addition reactions.
The formation of a cyclopropane ring has been achieved by the addition of trimethylsulfoxo-
nium ylide in moderate yields <1997JCS(P1)3035>. The dipolar cycloaddition reaction of
diazomethane has been effected regioselectively to produce 5,5-bis(sulfonyl)-4,5-dihydro-3H-pyr-
azoles, which could be cleaved photochemically (simply with room light) to afford the previous
cyclopropanes <1997JCS(P1)695>.
Construction of functionalized tetrahydrofuran rings was achieved by Yamamoto and co-workers
using palladium-catalyzed [3 + 2]-cycloaddition reactions to unsaturated alkenes and a variety of
sources of -allyl complexes: allyl carbonates <2001JOC7142>, vinyl oxiranes (Equation (50))
<1998JOC3067>, and allenes <1999JOC694>.
Pd(PPh3)4 (0.5 equiv.) SO2Ph
O SO2Ph THF, 40 °C, 1 h
+ SO2Ph ð50Þ
47% O
SO2Ph
Bis(cyclopentadienyl)zirconocene underwent conjugate addition to unsaturated bis(sulfones)

<2002JOC7019>.
(iv) Palladium(0) catalysis

Tremendous developments have appeared on this topic in the period 1995–2002, as bis(sulfones)
usually accompany malonates as a source of nucleophiles for the model investigations and
applications of the palladium catalyzed allylation reactions. Bis(sulfones) feature CH acidity,
easy construction of various starting materials, and versatile transformations.
The quest for a reaction achieved under neutral conditions has been successful due to Poli and
co-workers <1998JOC9608> using a standard -allyl intermediate (Equation (51)).
Pd2(dba)3 (0.05 equiv.)
SO2Ph PPh3 (0.5 equiv.)
+ SO2Ph
Ph OAc Ph ð51Þ
SO2Ph
THF, reflux, 12 h SO2Ph
73%
Titanated nucleophiles have been shown to perform an efficient heterobimetallic-catalyzed allyl-

ation <1999JOC2962>. Diethylzinc has been used as a base for an asymmetric process catalyzed by
an (R)-binap palladium complex, with 92% ee, but with very moderate yield <1999CC1895>.
Most developments have dealt with applications to the construction of complex structures,
natural products, and bioactive molecules. As a typical example (Equation (52)), a bis(sulfone)
has been prepared in the field of prostacyclins by reaction of an allyl carbonate and a palladium
catalyst in the presence of a phosphine <1999CC307>. Subsequent bis(desulfonyation) provided
the corresponding alkene.
CO2Me CO2Me
Pd2(dba)3, DPPE (1:2 ratio)
m-TolCH(SO2Ph)2
THF, 50 °C ð52Þ
PhO2S SO2Ph
O OMe 97%
The efficiency of this process has been exploited <2000T8263> for the rapid synthesis of a
11
C-labeled tracer for radio imaging of receptors in a living human brain (using the position emission
tomography technique).
Cyclohexenyl carbonates <1999T3467> and esters <1997T3957>, derived from sugars, have
been used as a source of -allyl palladium complexes. Fürstner et al. have used functionalized
vinyl oxiranes in the palladium catalyzed reaction with bis(phenylsulfonyl)methane as a key step
for the total synthesis of cristatic acid (Equation (53)) <2000OL2467> and furanoterpene ircinin-4
<1999SL29>.
CH2(SO2Ph)2
O Pd(PPh3)4 cat., DPPE cat. ButMe2SiO OPMB
t
Bu Me2SiO OPMB PhO2S OH ð53Þ
THF, rt
98% SO2Ph
An intramolecular version was shown to be efficient for the macrocyclization of the aglycon
part of fluviricin B1 <1997AG(E)1486>.
Other three-membered rings were successful for similar allylation reactions: vinyl aziridines
bearing an N-phosphinyl group <1996SL847> with opening of the ring, and cyclopropenyl
methyl carbonates with attack on the external terminus of the attractive 1,2-methano--allyl-
palladium intermediate (Equation (54)) <2000SL1467>.
Pd(PPh3)4, BSA
O OMe SO2Ph THF, rt, 1 h ð54Þ
+ SO2Ph
O SO2Ph 45% SO2Ph
A great deal of variation has been reported for the source of the allylating agent: simple alkynes
are efficient <1998JA10262>. Allenes have been largely employed, either in an intermolecular
version or for the synthesis of a variety of rings by an intramolecular process <1995JA5156>.
Yamamoto and co-workers have developed a smooth formation of five- or six- membered carbo-
cycles <1996TL7453>, and six- to eight-membered cyclic ethers <1999TL1747>. Trost et al.
explored the synthesis of larger rings and obtained a remarkably good yield of a 17-membered
ring product (Equation (55)) <1997AG(E)1750>. The efficiency of this process is largely dependent
upon the substrates and ring size formation.
[Pd(All)Cl]2 (0.5 equiv.)

SO2Ph DPP (0.125 equiv.) SO2Ph
SO2Ph
MeONa (0.1 equiv.) SO2Ph
ð55Þ
0.01 M, batch THF, 100 °C
60–68%
DPP = 1,3-bis(diphenylphosphino)propane
Abundant results from Hoffmann and co-workers have dealt with the cyclization of allyl
acetates as a key step for the synthesis of natural products incorporating medium-sized ring
ethers. Access to an eight-membered ring was optimized for the synthesis of enantiopure
()-trans-lanthisan <1995T155>. The best result was obtained with an allyl chloride. Conditions
for the formation of (Z) or strained (E)-configured nine-membered rings were investigated
<1998AG(E)633, 1995T145>. Preparation of 10-membered ring ethers (Equation (56)) was
effected in 80–81% yield <1998TL7085>.
PhO2S OTMS
MeO2CO OTMS Pd2(dba)3
DPPE PhO2S
O SO2Ph ð56Þ
THF, 66 °C O
Et SO2Ph
80%
Et
Further developments have appeared on the enantioselective allylation of nucleophiles using

a chiral C2 symmetric palladium ligand, ((R),(R))-1,2-di(20 -diphenylphosphinobenzamido-
cyclohexane). Trost and co-workers have studied allyl bis(esters), in which two CO bonds
are enantiotopic (Equation (57)). The reaction with bis(sulfones), as pro-nucleophiles, led to
moderate-to-good enantioselectivities <1995JA7247, 2001JA3687>. Derivatives of tartaric acid
(TADDOL) have been tested with almost no enantioselectivity <1995HCA1636>.
O O
Me NH HN
PhO2S SO2Ph OAc ð57Þ
PPh2 Ph2P
+ TBDPSO Me
OAc NaH, [Pd(C3H5)Cl]2, THF, 0 °C
PhO2S SO2Ph
TBDPSO 58%
OAc
92% ee
Reactions other than allylation have involved sulfones as CH acids. An efficient arylation of
bis(sulfones) has been disclosed <2002TL2539>, using aryl bromides and iodides in the presence
of 2 mol.% of Pd2(dba)3CHCl3, PPh3, and NaH as a base in dioxane at 70 C (Equation (58)). As
expected, aryl chlorides are less reactive.
H2C(SO2Ph)2
SO2Ph
NaH (1.5 equiv.)
Br Pd2(dba)3.CHCl3 (0.02 equiv.) SO2Ph
ð58Þ
N PPh3 (0.12 equiv.) N
Dioxane, 70 °C
90%
An elegant asymmetric Heck reaction <1996JA7108>, with attack of the intermediate -allyl
palladium complex by a sodium (bis)sulfone afforded a bicyclic skeleton (Equation (59)) that
could be further elaborated into a sesquiterpene, ()-capnellene.
NaCH(SO2Ph)2 (2 equiv.) PhO2S

SO2Ph
OTf Pd(OAc)2.CHCl3 (0.063 equiv.) H
(S)-BINAP (0.12 equiv.)
ð59Þ
DMSO, rt
Me Me
75%
66% ee
(v) Various precursors

Double oxidation of sulfanyl sulfones by hydrogen peroxide gave a bis(sulfone) <2001EJO2659>.
In search of a Brønsted acid with high catalytic activity, Yamamoto and co-workers
<2001AG(E)4077> and also Barrett <1999JOC2910, 2002SL1299, 2002T3835> have synthesized
a variety of bis(triflyl)methanes. Reaction of a pentafluorobenzyltriflone with t-butyllithium and
subsequent treatment with triflic anhydride led to pentafluorophenyl[bis(triflyl)methane] in excel-
lent yield <2001AG(E)4077>. This was extended to a practical synthesis of a polystyrene-bound
reagent, which was used for various acid catalyzed reactions with high turnover number and
frequency (Equation (60)) <2001AG(E)4077, 2002SL1299>.
i. ButLi (1 equiv.)
F F ii. Tf2O (0.5 equiv.) F F
–78 °C, rt, 1 h SO2CF3 ð60Þ
F F
SO2CF3 iii. HCl 4 M SO2CF3
F F F F
95%
Bis(triflyl)methanes have been produced by reaction of trimethylsilylmethyllithium with triflic

anhydride <1999JOC2910, 2002T3835>. They were used for conversion into tris(triflyl)methanes
and subsequently to their ytterbium(III) and scandium(III) anions, for new applications to acid
catalysis. This was extended to a fluorous biphasic system <2000SL847> in order to recycle and
reuse the catalyst. Carbene generation by photochemical irradiation of bis(sulfonyl)diazomethane,
followed by CH insertion with cyclohexane, or addition to cyclohexene afforded bis(sulfone)
derivatives <2001EJO3771>.
Sulfonyl sulfenes may be generated <1995LA2137, 1995LA2151> by basic reaction of sulfonyl
chlorides (elimination and addition of two molecules), and subsequent [4 + 2]-cycloaddition to
cyclopentadiene, in modest yields versus the addition of the parent sulfene. A bis(sulfonyl)cyclo-
propane was produced <2002JOC922> by an iodocarbocyclization reaction involving iodine and
an unsaturated bis(sulfone) (Equation (61)). Homolysis of the carbon–iodine bond produced the
corresponding radical, which was reacted with electron-rich alkenes to cyclize with subsequent
trapping of the resulting radical.
SO2Ph I2, TiCl4, Et3N
CH2Cl2, rt, 30 min SO2Ph
I ð61Þ
SO2Ph
54% SO2Ph
4.06.1.6.2 Bis(sulfonic) acids and their derivatives

No significant further advances have occurred in this area since the publication of chapter 4.06 in
COFGT (1995) <1995COFGT(4)243>.
4.06.1.6.3 Other compounds

Sulfonylation of sulfoximines was achieved with trifluoromethanesulfonyl fluoride in the presence
of NaF or CsF (Equation (62)) <1998RJOC1117>.
CF3SO2F
O NH NaF O NH O O
S S S ð62Þ
Ph Me MeCN Ph CF3
35%
4.06.2 FUNCTIONS CONTAINING ONE SULFUR AND ONE SELENIUM

OR TELLURIUM—R12CSR2SeR3, etc.
4.06.2.1 Dicoordinated Sulfur Derivatives

The preparation of thioselenoacetal functions could be realized via the four ionic pathways shown
in Scheme 43. The classical methods following these routes, already covered in chapter 4.06
of COFGT (1995) <1995COFGT(4)243>, are still in use in the early 2000s, with the standard
conditions.
R1Se + R2S 1 2 R2Se + SR1
R1S SeR2
R 1Se + R2S R2Se + SR1
3 4
Scheme 43
Since then, according to the first route (Scheme 43), it has been shown (Equation (63)) that the
thiolate intermediate could be generated in situ from the corresponding thioacetate <2002OL4065>.
i. NaOMe, MeOH
S S SePh ð63Þ
ii. BrCH2SePh
O 74%
During the synthesis of heteroanalogs of sugars, the thioacetal moiety turned out to be a convenient
formal precursor of an alkylthiocarbocation (Scheme 43, route 2). For instance, a selenium-containing
glycosyl donor (Equation (64)) was used for further elaboration of an oligosaccharide fragment
containing 4-thio-Galf <2000TA207>. This 4-thio-D-selenogalactofuranoside was prepared by the
reaction of its acetylated precursor with phenylselenol and BF3Et2O as Lewis acid. A second
approach (Equation (65)) <1995JA9783> made use of the reactivity of the trichloroacetimidate
function at the anomeric position of the glycosyl donor. It was shown that the coupling reaction
took place with triethylsilyl triflate when the temperature was allowed to rise to room temperature.
S S
OAc OAc OAc SePh
PhSeH, BF3⋅Et2O
α:β = 1:3 ð64Þ
OAc 94% OAc
OAc OAc
OAc OAc
OBz
HSe S
OAc
BzO OBz
BzO S
OMe AcO
TESOTf S
OAc + AcO Se
ð65Þ
–78 °C to rt AcO BzO
AcO S BzO
57% OMe
AcO
AcO
O CCl3 α:β = 4.5:1
NH
Selenothioic acid S-esters of type 31 (Scheme 44) proved to be an interesting precursor of

thioselenoacetal derivatives <1996CC1461>. On the one hand, upon reduction of compound 31
with sodium borohydride, the obtained intermediate could be trapped by an electrophile such as
iodoethane to give the acetal 32. On the other hand, an acidic aqueous work-up, subsequent to
the reduction step, led selectively to a 5-exo-trig cyclization allowing the synthesis of compounds
34 in moderate yield. Whatever the substrate, the formation of the diselenide 33 was also
observed. This method was extended to -di or -trisubstituted precursors of type 35, providing
a straightforward approach to polyfunctionalized tetrahydroselenophenes 36. For those more
substituted substrates, the reduction step has to be performed with LiAlH4 instead of NaBH4.
The anti-selectivity with respect to both methyl and sulfanyl groups is worth noting.
ii. EtI SeEt Se

)2
Se i. NaBH4, MeOH 48% SBu R SBu
32 33
SBu 50 °C
31 ii. 10% HCl
Se SBu + Se SBu
30%
34a 76:24 34b
Se
LiAlH4, Et2O, 20 °C
SBu +
65% Se SBu Se SBu
35 36a 91:9 36b
Scheme 44
The selenothioic acid S-ester function may also be considered as a dipolarophile. After the
generation of the azomethine ylide intermediate (Scheme 45), the assembly of a variety of novel
bicyclic -lactam skeletons, incorporating heteroatoms, was realized <2000T5586>.
Se H
H
O CO2H Se SBu
Me SBu N
O O N Me
N MeCN, 80 °C 45%
O OPNB O
CO2p-NO2Bn O OPNB
O
(1:1)
Scheme 45
Another type of related 1,3-dipolar cycloaddition has been described between 1,3-benzo-
dithiole-2-selone 37 and a benzyne intermediate (Scheme 46), generated from diazo precursor
38 <1996BCJ2349>. Basic treatment of the obtained sulfonium 39 led to the eight-membered ring
selenoacetal 40.
S
Se H H
S i. (ClCH2)2, reflux H
–N2, CO2, HCl S Se S Se
37 KOH
+
ClN2 ii. HCl S Et2O, H2O
82% S
Cl 73%
O
HO2C
38 39 40
Scheme 46
Thioselenoacetal functions could be found within heterocycles (Equation (66)) such as 1,3-
thiaselenolo[5,4-c]quinoline <1996PJC54>. Their syntheses consisted of an aromatic nucleophilic
substitution performed on structure 41 with selenourea, followed by the formation of the acetal 42
in good yields after hydrolysis. Maslankiewicz and co-workers <1996PJC54> pointed out that
these 1,3-selenido-sulfides appeared less stable than the corresponding 1,3-dithiole analogs. The
alkylation of an -thio carbanion with sulfur electrophiles (Scheme 43, route 4) is also an
important pathway toward thioselenoacetal formation <2000JA11340>.
R2
Se
Cl Se
SR1 i. H2N NH2 , EtOH, reflux S
ð66Þ
ii. Hydrolysis
N N
41a: R1 = CH2Cl 83–86% 42a: R2 = H
41b: R1 = CHCH2 42b: R2 = Me
The preparation of thiotelluroacetals (Equation (67)), hardly described in the literature, could
be realized by treating S(CH2Br)2 with BuTeLi <1996AG(E)528>.
BunTeLi
Br S Br BunTe S TeBun ð67Þ
83%
4.06.2.2 Tricoordinated Sulfur Derivatives

-Seleno sulfoxides have gained some interest since 1995, especially for the preparation of vinyl
sulfoxides, after an oxidative elimination reaction, and also as (arylsulfinyl)methyl radical precursors.
However, their syntheses still take advantage of the classical methods, i.e., reactions between an
electrophilic selenol derivatives (R1Se+) and an -sulfoxide carbanion generated with a base, as fully
exemplified in the previous COFGT (1995) (chapter 4.06.2.1). Two examples are shown in Scheme 47.
The deprotonation of an enantioenriched sulfoxide with LDA (Scheme 47) led to the corresponding
-silylseleno derivatives by reaction with PhSeBr at low temperature <2002JOC640>.
O O O
S LDA, PhSeBr S SePh MCPBA S
R1 R1 R1
–78 °C 0 °C
SiMe3 60–69% SiMe3 94–97% SiMe3
R = Tol: 82:18
R = But: 85:15
Scheme 47
Renaud et al. (Scheme 48) have made use of the base lithium bis(trimethylsilyl)amide (LHMDS)
and PhSeCl as electrophile to form the -seleno sulfoxide. They subsequently performed a radical
addition reaction with homolytic cleavage of the carbon–selenium bond <1998HCA1048>. Follow-
ing this approach, other reagents could be employed such as LDA/(PhSe)2 <1997TL233> or MeLi/
(PhSe)2 <2000JOC7083>.
O O SiMe3 O
S CN S CN SnBu3 S CN
LHMDS
Me PhSeCl Me SePh AIBN, CH2Cl2 Me
–78 °C to rt 95% Me3Si
61% 93:7
88:12
(after recrystallization)
Scheme 48
Weiss et al. have introduced a novel type of 1,1-biselectrophile 43 (Equation (68))

<1998ZN(B)916>. It reacts easily with a selenourea to give the -seleno sulfonium compound
44, a tricoordinated sulfur derivative other than sulfoxide. Using the same approach, -thio
sulfonium salts have also been synthesized (Chapter 4.06.1.3.3).
Me
Me Me Me
N 2TfO
S OTf + Se MeCN S Se
Me Me N ð68Þ
OTf N 79%
N
43 Me 44 Me
4.06.2.3 Tetracoordinated Sulfur Derivatives

As was already fully exemplified in the previous chapter 4.06.2.3 of COFGT (1995), the most
common approach to the synthesis of -seleno sulfones remains the selenenylation (RSe+) of an
-sulfone carbanion (RSO2C). Although usually generated by means of a base <1999JOC9521,
1999JCS(P1)71>, the carbanion at the -position of the sulfonyl group could also be prepared via
a tin–lithium exchange as described in Equation (69), yielding the selenylated product in moderate
yield <2002OL4065>.
O O O O
i. BunLi, THF, –78 °C
S SnBu3 S SePh
ii. (PhSe)2
ð69Þ
35%
It has been shown that ketene thioselenoacetal S,S-dioxides, functionalized with an alkyne
moiety (Equation (70)), could undergo a cyclopropanation reaction by means of a sulfoxonium
ylide reagent <1997JCS(P1)3035>. The cyclopropane structure with an -seleno sulfone function
is thereby obtained in good yield. In the same manner, the analogous -thio sulfones could also
be formed from the corresponding ketene derivatives (Chapter 4.06.1.3.2).
H
But Me3SO+I– But
SO2Ph SO2Ph
ð70Þ
NaH, DMF
PhSe PhSe
79%
An ester substituted O,Se-acetal (Equation (71)) proved to be an efficient radical precursor

upon irradiation <1996S253>, allowing addition to electron poor alkenes, such as vinyl sulfones,
together with phenylselenyl group transfer. The overall radical process gives a functionalized
-seleno sulfone even in the absence of radical initiators such as 20 2-azobisisobutyronitrile (AIBN).
OMe OMe SePh

Sun lamp (300 W)
MeOOC SePh + SO2Ph MeO2C SO2Ph ð71Þ
87%
1:1 (diastereoisomers)
Koizumi and co-workers have developed a synthesis of diastereoenriched -seleno sulfones 47

(Scheme 49) from chiral nonracemic hypervalent selenium compounds 45 <1997JOC4562>. The
selenonium ylide intermediate 46, generated in situ, gave rise to a highly selective asymmetric [2,3]-
sigmatropic rearrangement. The stereochemical outcome of this process was explained by assum-
ing a more stable endo transition state 48. Steric interactions between R and PhSO2 would
therefore favor the transition structure 48b and lead to homoallylic selenides 47.
PhSO2CH2CN [2,3]
O OH OH
Se Et3N, CH2Cl2, –20 °C Se Se
Cl PhO2S
NC
R CN PhO2S
R H
45 46 R 47
R Time (h) dr Yield (%)
Bn 0.5 92:5:2:1 78
Me 1 100:0 87
Prn 1 100:0 83
Hexn 1 100:0 85
Mechanism: Ph 0.5 100:0 30
PhO2 S Bor NC Bor

R Se R Se
Bor = OH
H CN H SO2Ph
endo-TS 48a endo -TS 48b
Scheme 49
During the investigation of the competition between the hetero Diels–Alder reaction and the
cheletropic addition of sulfur dioxide (Equation (72)), the formation of 2-seleno-2,5-dihydrothio-
phene-1,1-dioxide was proven <2002HCA733>. However, these compounds are described as
unstable at room temperature, which has to be taken into account for preparative purposes.
SePh SePh
ð72Þ
+ SO2 SO2
4.06.3 FUNCTIONS CONTAINING SELENIUM AND/OR TELLURIUM—R12C(SeR2)2,

R12C(SeR2)TeR3, etc.
4.06.3.1 Diselenium Derivatives

The literature covered a huge amount of work done toward the formation and the chemistry of
diselenoacetals. An examination of chapter 4.06 in COFGT (1995) <1995COFGT(4)243> as well as,
in some instances, Comprehensive Heterocyclic Chemistry II <1996CHECII679> is recommended.
These reviews provide an overview of the experimental conditions and chemistry that has been done
within that field, especially the important contributions of Krief and co-workers. It could therefore be
pointed out that the main approach toward diselenoacetals, i.e., the reaction of a carbonyl group with
selenol derivatives, is still usually achieved with the originally described procedures through Brønsted or
Lewis catalyst such as the routinely used ZnCl2 <2000JCS(P1)2211, 2002MI481>.
The aforementioned approach has been extended to the synthesis of 1,3-benzodiselenolane
derivatives (Scheme 50) <1999TL6571>. In dichloromethane as solvent, the reaction worked
properly with different kinds of aldehydes and reasonably hindered ketones such as t-butyl methyl
ketone. In terms of reactivity, the selenoacetalization with 1,3-benzodiselenolanes are indeed
closely related to methylselenol but are more efficient than phenylselenol. For more difficult
cases with highly shielded ketones (R1 = Pri, But; R2 = Pri, Et; etc.), zinc chloride in nitromethane
turned out to be more efficient than dichloromethane, affording selenoacetal products in moderate-
to-good yield. As a general trend, some difficulties could be met for selenoacetalization of
aromatic and very hindered ketones. A closely related approach has been also applied to cyclic
aliphatic diselenols <1996TL2667>. Furthermore, the selenoacetalization reaction of enol ether
derivatives in place of ketones has been carried out in the presence of BF3Et2O as Lewis acid
<1996JCR(S)206>.
R1 R 2 CH2Cl2 (%) MeNO2 (%)

SeH
H H 74
SeH ZnCl2 (1 equiv.) Se R1 But H 74
+ Ph H 74
CH2Cl2 Se R
2
R1 or Ph Me 66
MeNO2
O But Me 76
R2 Pri Pri 0 70
But Et 0 8
Scheme 50
Like the selenoboranes and selenosilanes, already described in COFGT (1995)

<1995COFGT(4)243>, the aluminum analogs (Equation (73)) <1995CC149> could be employed
instead of selenol derivatives in order to perform a transacetalization reaction. An electrochemical
synthesis of thioacetals, from the corresponding ketones or aldehydes, was achieved
<1996MI272> in the presence of diaryl or dialkyl selenides and trimethylchlorosilane.
OEt Bu 2i AlSPh (4 equiv.) SePh

PhSe PhSe
BF3·OEt2, rt ð73Þ
OEt SePh
46%
-Hydroxydiselenoacetal compounds could be obtained from the corresponding -lactols

(Equation (74)) <2001S867>. It is assumed that this process involves the opened lactol form,
i.e., the -hydroxy aldehyde, which undergoes a Lewis acid catalyzed selenoacetalization.
O PhSeH, BF3·OEt2 OH SePh

OH
SePh
ð74Þ
59%
Me Me
The addition of selenide salts to gem-dihalides provided another general approach toward diseleno-
acetal derivatives. For instance, Bhasin and Singh have reported (Scheme 51) a convenient method for the
elaboration of 2-pyridylselenomethanes via the in situ formation of the corresponding 2-pyridylselenolate
<2002JOM71>. This intermediate is quantitatively obtained from the reduction of 2,20 -dipyridyl dis-
elenide using hydrazine hydrate in the presence of NaOH in aprotic solvents. The introduction of
polyethylene glycol-400 as the phase transfer catalyst is believed to facilitate the substitution reaction
with halo methanes. A closely related method has been also described via the reduction of diselenide
derivatives with sodium or potassium borohydride <2001JCS(P1)1140, 2001HAC358>.
NaOH, N2H4·H2O CH2I2

N Se PEG-400, C6H6, rt N SeNa 70% N Se Se N
2
Scheme 51
A similar approach, but with the in situ formation of the 2-picolyl selenolate anion from
elemental selenium and the lithiated 2-picoline, has also been reported (Scheme 52)
<2002PS(177)597>. This intermediate reacts with iodomethane to afford the diselenoacetal in a
good yield.
i. LDA
THF
–78 °C CH2I2 Se Se
N N
N Me ii. Se N CH2Se 82%
Scheme 52
Diselenide derivatives (RSe)2 are known as precursors of diselenoacetals by reacting with

diazomethane <1996JCS(D)2719>. In this context, the reaction between diazocompounds 49
(Scheme 53) and divalent selenium species such as phenylselenyl triflate has been studied
<2000SL1813>. As long as mono-substituted diazoprecursors of type 49 are employed, the acetal
products 50 are selectively formed in moderate yield. Nevertheless, with more substituted diazo
precursors 51, different mixtures of mono- and di-selenylated products 52 are obtained with
respect to the temperature at which the reaction has been performed. The diselenoacetals 52a
were eventually obtained, as the sole product, when the reaction was carried out at 78 C.
R
PhSeOTf
RCHN2 PhSe SePh
49 CH2Cl2, 0 °C or 25 °C 50
R = H, CO2Et
37–49%
EtO2C CO2Et PhSeOTf EtO2C CO2Et EtO2C CO2Et

+
CH2Cl2 PhSe SePh
N2 SePh
51 52a 52b
Temp. (°C) Yield (%) 52a:52b
25 72 1:5
0 86 1:2
–78 45 100:0
Scheme 53
The straightforward reaction of allyl silanes with tris(phenylseleno)methane, an easily prepared

reactant, furnished the corresponding homoallyldiselenoacetals via a carbon–carbon bond forma-
tion (Equation (75)) <1996TL6085>. It has been shown that SnCl4 was the most effective catalyst
and few side products such as allylmonoselenides have been detected. These compounds are
interesting precursors of seleno-1,4-butadienes or ,-unsaturated aldehydes. The same approach
could be used for the synthesis of homoallyldithioacetal (Chapter 4.06.1.2.3) with ZnBr2 as the
Lewis acid.
R2
R1 R2 Yield (%)
R1 SiMe3 SnCl4 R2 SePh
H H 72 ð75Þ
+ SePh
CH2Cl2 n-C5H11 H 65
HC(SePh)3 –78 °C R1
H n-C5H11 58
,-Bis(phenylselanyl)carbonyl compounds are encountered in the literature as, for example,

precursors to ,-unsaturated carbonyl derivatives as outlined in Scheme 54. In that field, Paulmier
and co-workers described the selenenylation <2000T7483> of -selenyl ester 53 with LDA as a base.
Compounds 54 were obtained in good yields except for phenyl derivatives (R = Ph). The direct
introduction of the diphenylselenium moiety, providing product 55, was also demonstrated in the
lactone series <1996JCS(P1)1913>. This approach was also used with ketones <1997T6365>,
lactams <1998T6369>, and 2-methyloxazolines <1997TA2433>. For base sensitive structures
N-phenylselanyl morpholine could be employed directly in some cases <1997T16767>.
O O R Yield (%)
R i. LDA, THF, –78 °C R H 57
OEt OEt
ii. PhSeCl Et 96
SePh PhSe SePh
Pri 68
53 54
Ph 40
SePh SePh
SePh
i. LDA, THF, –78 °C OXONE ®
O O ii. PhSeCl O O Al2O3-H2O O O
54% 55 44%
Scheme 54
A systematic investigation of the reactivity of the stable ketene 56 (Scheme 55) was undertaken
by Haas and Radau <1998JFC9>. They disclosed the elaboration of a variety of novel perfluoro-
diselenoacetals via addition reactions or [2+2]-cycloaddition reactions.
F3CSe O
HOMe
F3CSe OMe
F3CSe HSCF3 F3CSe O

C O
F3CSe F3CSe SCF3
56 O
F3CSe
Ph
F3CSe
Ph
Scheme 55
During the study of 1,3-diselenanes of type 57 (Equation (76)), Krief and Defrère
<1996TL8015> demonstrated the ability to perform an addition reaction to acrylonitrile upon
irradiation.
H H SePh
CN (excess)
Me Se SePh Me Se CN ð76Þ
Me
Se hν , hanovia 450 W Me
Se
57 33%
In the same way as for dithioacetals, diselenoacetals can be alkylated with various electrophiles
after deprotonation <1996TL8015, 2000AG(E)414, 1996TL8011>, as already described in
COFGT (1995) <1995COFGT(4)243>. A general review on selenium-stabilized carbanions has
appeared <2000TCC113>. Finally, the synthesis of arylselenoacetals has been carried out on
neutral alumina from -chloro-(phenylselena)alkanes <1995SC117>.
4.06.3.2 Ditellurium Derivatives

Since COFGT (1995) <1995COFGT(4)243>, the ditelluroacetal function could be found within
several structures, especially for their properties as soft donor ligands with metals. A general
discussion on their characteristics and synthesis has been given in the papers of Singh and
Khandelwal and co-workers <1996JOM65, 2002PIA357>. Obviously, the most general method
for the synthesis of ditelluroacetal derivatives consists of the reaction between tellurolate anions
(RTe) and dihalogenomethane compounds. The success of those processes seems to depend
upon the methods used for the preparation of tellurolate (RTe) precursors. During their
investigations toward the synthesis of benzo-1,3-ditelluroles (Scheme 56) <2000MI1127>,
Gadzhieva and Sadekov first tried to generate the sodium salt intermediate with sodium
borohydride (method A) but low yields were obtained for the alkylated products. It was assumed
that poorly reactive trialkylborate complexes with tellurolate anions were formed. Hence, they
performed the same reaction by means of hydrazine in basic media as reductant (method B) and
slightly improved the yield.
Te TeNa Te
i. Method A or B ii. Cl2CHPh
Ph
Te TeNa Te
n
Method A: NaBH4, EtOH 12–15%
Method B: N2H4·H2O, NaOH, DMF 32%
Scheme 56
A multidentate tellurium ligand (Scheme 57), designed for complexation of chromium metals
<1995OM4755>, was prepared from the corresponding anion 58 obtained by insertion of tell-
urium metal in the CLi bond of the corresponding ortho-metallated precursor. The alkylation
reaction of dichloromethane afforded the target ligand 59 as an impure product. Its synthesis was
eventually achieved through a classical two-step synthesis via the dimer 60 which gave a smooth
transformation with diazomethane.
NMe2 NMe2
NMe2 i. BunLi NMe2 CH2Cl2 Te Te
ii. Te TeLi 52%
58 59
Oxidation 50%
NMe2
CH2N2
Te
Te 100%
60 NMe2
Scheme 57
Selvakumar et al. have developed a convenient route to bis(alkyltelluro)methane ligands 62

shown in Scheme 58 <2001PS(171)501>. They carried out the reduction of precursors 61 by
means of sodium borohydride in the presence of chloroform to yield ligands 62. In order to
explain this process (Scheme 54), the formation of carbene species 63–65 generated from chloro-
form under the basic conditions was proposed, followed by hydride reduction and solvent
protonation.
i. NaBH4, H2O NaBH4 CHCl3

Te R2Te2 2RTeNa Te Te
R R
ii. RBr 61 NaOH, H2O 62
R = Et, Pri, Bun, Hexyln
Yield = 58–81%
OH– RTe– RTe– H– (borohydride)

CHCl3 CCl2 RTeCCl (RTe)2C (RTe)2CH2
–Cl– –Cl– –Cl
– H+ (solvent)
63 64 65
Scheme 58
The dimerization of tellurocarbonyl compound <1995JOC4657, 1997TL2501>, usually con-

sidered a transient species, to the thermodynamically more stable 1,3-ditelluretane, can be
formally considered as an access to the ditelluroacetal moiety. An example is given in Equation
(77) in the perfluoroalkyl series <2001PS(171)113>.
Te F Te F
ð77Þ
F F F Te F
The alkylation of ditelluroacetals after deprotonation with lithium amides bases <2000MI1127,
1995CBR861>, is still used, in the early 2000s, for the synthesis of new ditelluroacetals.
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Press, London, 1995, pp. 133–224.
Biographical sketch
Vincent Reboul was born in France in 1968. Jean-François Brière was born in France in
He studied at Orsay University, where he 1971. He joined the group of Professor
obtained a B.Sc. in biochemistry in 1991 and G. Quéguiner at the University of Rouen,
his Ph.D. in 1996 under the direction of France in 1994, working on new heterocycle
Dr. C. Thal at ICSN, Gif-sur-Yvette, France, derivatives as supramolecular enzyme-like cat-
working on organo-iron complexes. He spent alysts. He received his Ph.D. in 1998 and
a year and a half in a postdoctoral position in spent a year and a half in the laboratory of
the laboratory of Professor R. Holton, at Professor H. Hiemstra in Amsterdam, The
Florida State University (Tallahassee), being Netherlands, being involved in the total synth-
involved in the total synthesis of taxol. In esis of the solanoeclepin A, a newly isolated
1998, he obtained his present position as naturally occurring product. Then, he moved
‘‘Maı̂tre de conférences’’ in organic chemistry, to the group of Professor I. E. Markó in 2001
at the University of Caen, in the laboratory of at the Université Catholique de Louvain-la-
P. Metzner. His scientific interests include all Neuve, Belgium, for the development of pla-
aspects of asymmetric synthesis with organo- tinum-N-heterocyclic carbene complexes as
sulfur chemistry. catalysts for hydrosilylation reactions in
order to form silicon oils. He returned to
France in 2002 as a Research Scientist in the
Research Centre of Rhodia Company at Lyon
and was subsequently appointed by the CNRS
as ‘‘Chargé de Recherches’’ in the laboratory
of Dr. P. Metzner at Caen. His research inter-
ests concern the developments of sulfur-based
catalysts for asymmetric synthesis.
Patrick Metzner was born in 1946. He studied at the University of Caen

(France), where he obtained his Ph.D. in 1973 under the direction
of Prof. J. Vialle. He joined the group of Prof. B. M. Trost at the University
of Madison-Wisconsin in 1978–1979. He returned to Caen with a CNRS
position. He was promoted ‘‘Directeur de Recherche’’ in 1990, within the
ENSI Caen and the University, and now heads the CNRS Unit #6507 there.
His research topics focus on sulfur chemistry and asymmetric synthesis.
They involve thiocarbonyl compounds, enethiolates, sulfines, sulfides, and
sulfoxides, sulfur ylides, formation of CC bonds with full stereocontrol
and reactions such as the Claisen rearrangement, epoxidation mediated
by sulfur ylides, chemoselective oxidation of low coordinence sulfur
compounds, and metal catalyzed couplings.
4.07
Functions Incorporating a
Chalcogen and a Group 15 Element
K. M. GEORGE and G. A. MOLANDER
4.07.1 FUNCTIONS CONTAINING A CHALCOGEN AND A NITROGEN FUNCTION 323

4.07.1.1 Functions Bearing Oxygen and Nitrogen 323
4.07.1.1.1 Hemiaminals with tricoordinate nitrogen bearing alkyl, aryl, or acyl substituents 323
4.07.1.1.2 Functions with tricoordinate nitrogen-bearing heteroatom substituents 328
4.07.1.1.3 Functions with dicoordinate nitrogen 329
4.07.1.2 Functions Bearing Sulfur and Nitrogen 331
4.07.1.2.1 Dicoordinate sulfur derivatives 331
4.07.1.2.2 Tricoordinate sulfur derivatives 335
4.07.1.2.3 Tetra- and higher-coordinate sulfur derivatives 337
4.07.1.3 Functions Bearing Selenium or Tellurium, Together with Nitrogen 339
4.07.1.3.1 From compounds containing a multiply bonded functional group 339
4.07.1.3.2 From compounds containing singly bonded functional groups 340
4.07.2 FUNCTIONS CONTAINING A CHALCOGEN AND PHOSPHORUS, ARSENIC,
ANTIMONY, OR BISMUTH 343
4.07.2.1 Functions Bearing Oxygen 343
4.07.2.1.1 Oxygen and phosphorus 343
4.07.2.1.2 Oxygen and arsenic, antimony, or bismuth 348
4.07.2.2 Functions Bearing Sulfur 348
4.07.2.2.1 Sulfur and phosphorus 348
4.07.2.2.2 Sulfur with arsenic, antimony, or bismuth 350
4.07.2.3 Functions Bearing Selenium or Tellurium 350
4.07.2.3.1 Selenium or tellurium with phosphorus 350
4.07.2.3.2 Selenium or tellurium with arsenic, antimony, or bismuth 351
4.07.1 FUNCTIONS CONTAINING A CHALCOGEN AND A NITROGEN FUNCTION
4.07.1.1 Functions Bearing Oxygen and Nitrogen
4.07.1.1.1 Hemiaminals with tricoordinate nitrogen bearing alkyl, aryl, or acyl substituents
(i) From compounds containing multiply bonded functional groups
(a) From aldehydes and ketones. As highlighted in COFGT (1995), the most general method to
generate the OCN synthon is by the condensation of an amine with either an aldehyde or a
ketone. There are, however, many factors inherent in the substrate and reaction conditions that
323
324 Functions Incorporating a Chalcogen and a Group 15 Element
influence the outcome of the reaction. For more detailed background of the behavior of various
ketones and aldehydes with amines, see chapter 4.07.1.1.1 of <1995COFGT(4)293>.
Recently, several groups have contributed research concerning the mechanistic nature of
these reactions <2000JCS(P2)941, 2001JOC7596> along with kinetic and equilibrium data
<1997JCS(P2)909>.
The reaction of phosphoroyldichloroacetaldehyde with ethyleneimine was shown to furnish the
crystalline hemiaminal (hydroxyaziridine) 1, which is known to be stable at room temperature for
long periods of time <1999T8423>.
Hemiaminals 2 derived from trifluoroacetaldehyde act as trifluoromethylating agents,
although there is a need for improvement in terms of the yield and reaction efficiency
<2000TL6411>.
In a final example, a variety of t-butylperoxamines were synthesized via the addition of
secondary amines with formaldehyde and t-butyl hydroperoxide (70% aq.) in MeOH. The pro-
ducts were tested as anti-malarial agents, in which compound 3 showed the highest potency
<2001BMCL2269>.
O Cl H HO HO OH
H N
(EtO)2P C N
F3C NR2
Cl OH
O
1 R = Me, Et, Bun O
2
(b) From amides/imides. The condensation reaction of imides with aldehydes has been widely
used recently, particularly toward the synthesis of ampicillin and thalidomide prodrugs
<1997BMCL3107, 2001BMC1279>.
Acyl carbamates can be selectively reduced with diisobutylaluminum hydride (DIBAL-H)
to provide N-acyl hemiaminals in high yields (Equation (1)). The stable intermediates
undergo intra- and intermolecular addition reactions with the aid of a Lewis acid
<1997TL6545, 2001JOC6988>. Alternatively, the reduced hemiaminal is trapped to afford
the N,O-acetal TMS ether in excellent yield as a stable precursor for the N-acyliminium ion
<2002CC1064>.
O O DIBAL-H OH O
R1 N OR2 R1 N OR2 ð1Þ

H R1 = Alkyl H
R2 = Me, Bn
The cathodic reaction of phthalimide anion in methanol afforded a novel product, N-hydroxy-
methyl-3-hydroxyphthalimidine 4 <1998T7517>.
Recently, it was shown that the condensation of phosphochlorals with benzamide resulted in
the formation of stable phosphorylated hemiamidals, 5 <1999T8423>.
The reaction of N-Cbz-L-phenylalanal and acrylamide under standard Baylis–Hillman reaction
conditions furnished an unexpected non-Baylis–Hillman adduct, which was later identified as the
N-acyl hemiaminal. The scope of this reaction was further explored by using several enantiopure
and racemic aldehydes to provide the corresponding products in moderate-to-very good yields
(Table 1) <1998CL787>.
The -hydroxy allyl ester 6, derived from the condensation reaction of BOC-leucine amide with
allyl glyoxalate hydrate, was homologated further to arrive at a desired synthon to be incorpo-
rated into a variety of modified peptides that represent a novel class of HIV replication inhibitors
<1996BMCL609>.
Functions Incorporating a Chalcogen and a Group 15 Element 325
Table 1 Reactions of aminoaldehydes with acrylamide in the

presence of DABCO
O Acrylamide OH O
R PGHN
H DABCO, CH2Cl2 N
H
NHPG R
Aldehyde Time (h) Yield (%)

N-BOC-L-Valinal 13 73
N-BOC-L-Phenylalanal 18 63
N-BOC-L-Tryptophanal 15 40
N-BOC-L-Prolinal 15 70
N-BOC-L-Serinal(OBn) 15 29
N-BOC-Glycinal 18 82
N-BOC-L-Lysinal 18 48
N-Cbz-L-Valinal 15 78
N-Cbz-Glycinal 14 85
N-BOC-L-Leucinal 13 80
OH O OH O O
(RO)2P H
OH N
N Ph BOCLeu O
N
Cl Cl H
OH
O R = Et, Pri
6
4 5
The total synthesis of ()-mesembrine utilizes an intramolecular nucleophilic attack of an allyl

anion onto an imide intermediate to furnish the desired NCO moiety en route to the natural
product <1997TL1893>.
Recent syntheses of 15-desoxyspergualin have demonstrated the reaction of key amide inter-
mediates with suitable electrophiles to furnish the central -hydroxyglycine unit of the natural
product <1998JOC9723, 2000TA3665, 2001T2757>.
(c) From imines/iminium salts. In a report by Danion and co-workers, it was demonstrated
that the addition of water or acetic acid to iminoesters 7 furnishes the corresponding hemiaminals
and ,-diacetoxy amino esters 8 (Equation (2)) <1996JCS(P1)1833>. In the last few years no
further pertinent examples have been reported, therefore see chapter 4.071.1.1.i.c of
<1995COFGT(4)293> for other reactions under this subheading.
R1 CO2R3 R1 CO2R3
H3O+ or HOAc
R2 R2 NHCO2Me
X NCO2Me X YO
X = Br or OAc
R1 = H, Ph, Me ð2Þ
7 8
R2 = H, Me
R3 = Me, Et
Y = H, Ac
(d) Alkenes. The oxidation of N-methylpyrrole 9, via photooxygenation reaction conditions

with Rose Bengal as a photosensitizer, afforded hydroxy pyrrolidinone 10 (Equation (3)). This
intermediate underwent a key spiro-rearrangement reaction to furnish the desired spirosuccini-
mide product <2000TL4519>.
Me HO Me
N O2, hν, H2O N
O
Rose Bengal ð3Þ
60%
9 10
The bromohydroxylation or alkoxylation of enamide moieties is often used to achieve the

NCO synthon. This transformation has been demonstrated recently in two approaches toward
the synthesis of Thaxtomins A and B, where the resulting bromine functionality is removed along
with protecting groups by catalytic hydrogenation with H2/Pd on charcoal in both the reports
<1996T8525, 1993JOC3473>. In another example, 3-ylidenepyrazine-2,5-diones (or 3-ylidene-
2,5-diketopiperazines) were selectively epoxidized and bromoalkylated to furnish the NCO
synthon in high yields (Scheme 1) <2003S67>.
O O Dimethyldioxirane O
H H H
R2 R3OH, NBS R2 acetone R2
N N N
HO
R1 N Dioxane, 0–20 °C R1 N CH2Cl2, MgSO4 R1 N
O 86–99% 59–95%
Br 3 O O OH O
R R2 = PhCO, MeCO if R2 = H, Me
R1 = Me, Ph, Pri
R3 = H, Me, Et, Pri
Scheme 1
(ii) From compounds containing two singly bonded functional groups
(a) From XCN functions (X = hal, OR, SR, SO2R, NR2). When N-chloromethylphthal-
imide is reacted with organomagnesium reagents, the substrate underwent consecutive chloride
substitution and mono-carbonyl addition to afford substrates 11 and 12 (Scheme 2). When 11 is
treated with a mild acid, the corresponding dehydrated product 13 is obtained. 12 was often
found to react further via intermolecular coupling with the starting material to provide the
addition by-product 14 <2000CJC1285>. A variety (15a–h) of other phthalimide derivatives were
synthesized by the condensation of N-chlorophthalimide with commercially available substituted
phenols with base in DMF or DMSO at room temperature. These compounds were then reacted
in various ways to afford the cyclized or eliminated products <1998JHC1477>. Interestingly, a
series of readily hydrolyzable basic and dibasic esters of ampicillin were produced by alkylation of
the carboxylate function of ampicillin to obtain various prodrugs. Many of the prodrugs possess
the substituted NCO functional group <2001BMC493>.
O
Cl
N
MeMgCl PhMgCl
O O O
Ph
N N
OMgCl OMgCl
Ph
11 12
O
O Ph
O
N O N
N
Ph
13 O
14
Scheme 2
O Substrate X
O p a H
N
o X m b o-Br
c p-Br
O
d o-Cl
15
e m-Cl
f o-F
g o-Br, p-Cl
h m, m-OMe
(b) From OCX functions (X = hal or OR). Acyclic nucleoside analogs 16 and 17 were
prepared from MEM-Cl and silylated pyrimidines. NaI was used to facilitate nucleophilic dis-
placement <2001T7369>. Danikiewicz and Szmigielski provide an efficient, two-step synthesis of
N-alkoxymethyl derivatives of acetanilide, formanilide, and benzanilide by phase-transfer cataly-
sis (PTC) conditions with MOM-Cl. Upon heating the resultant anilides with an excess of
aliphatic alcohols and a catalytic quantity of p-TsOH, a variety of N-alkoxylmethyl derivatives
were obtained as shown in Table 2 <2001SC3047>.
CF3
R
N
F3C OHO
HN Ph O N
MeO
O N O
MeO
O R = COPh, CH2Ph, Et, Pri
16 17
Table 2 Preparation of N-alkoxymethylanilides from the appropriate N-methoxymethylanilides

O O
CH3 R2OH R2
N R1 p-TsOH N R1
O O
R1 R2 T ( C) Time (h) Yield (%)

Me Et 78 1.5 92
Me Prn 60 1 90
Me Pri 82 1.5 83
Me Bun 75 3 70
Me Bui 80 4 74
Me Bus 85 3 90
Me But 60 2 60
Me CH2CH¼CH2 rt 24 81
H Et 78 3 67
Ph Et 78 2.5 93
N-Alkylated fluorouracil and fluorodeoxyuridine derivatives have been prepared in attempts to

improve the biological activity against certain types of cancer <1996CPB1196, 2002HAC211>.
(c) By functionalization of a preformed O,N-acetal. Kawai and co-workers reported a method for
the preparation of CbzGly(OR)OR derivatives using CbzGly(OH)OH and ROH that has
been shown to be applicable to many primary and secondary alkoxyglycine substrates
<1996SC1545>. In an unexpected result, when R = But or Ph, upon reaction with NaCNBH3/HCl
in MeOH, 18 underwent dehydration thereby forming a resonance-stabilized acyliminium ion, and
was subsequently attacked by solvent (MeOH) to afford 19. In contrast, when the reaction was carried
out in aprotic solvents such as THF and TFA, the acyliminium ion was reduced by NaCNBH3 to
furnish the desired compound 20 (Scheme 3) <2002TL9163>.
R HO R MeO R
NaCNBH3 /HCl NaCNBH3 /HCl
NH NH NH
THF MeOH
O O O
20 18 19
R = But, Ph
Scheme 3
4.07.1.1.2 Functions with tricoordinate nitrogen-bearing heteroatom substituents
(i) From compounds containing a multiply bonded functional group
(a) From aldehydes and ketones. Several novel 5-hydroxy-1H-pyrazolines were synthesized by
reacting a series of trichlorobutenones with semicarbazide hydrochloride or thiosemicarbazide, 21
<1999T345>. Reduction of a nitro diester function with Pd/C and ammonium formate in
methanol provided 22 in 89% yield, and this was converted directly to the nitrone due to its
instability <1997JOC2314>. The cyclic pyrazoline-5-ol 23 was prepared by the reaction of
4-nitrophenylhydrazine with 1-(4-methylphenyl)-4,4,4-trifluorobutane-1,3-dione and transformed
to the pyrazole after loss of water with HOAc under refluxing conditions <2001JMC3039>.
OMe F3C
R1 R2 CO2Me OH
Cl3C X = S, O CO2M3 N NO2

N N
HO N R1 = H, Me N OH
X NH2 R2 = Me, Et OH 23
Me
21 22
(b) From imines/nitrones. Schiff bases react readily with oxygen and nitrogen nucleophiles,
yielding products as shown in Equation (4) <1999ZOR1361, 2001ZOR1635>.
O CCl3 O CCl3
ROH
F3C S N CH F3C S N ð4Þ
H
O R = H, Me, 4-C6H4NO2 O OR
(c) From alkenes. No further advances have occurred in this area since the publication of
chapter 4.07.1.1.2.i.c in <1995COFGT(4)293>.
(a) From XCN functions (X = hal). Various novel insecticides and environmentally safe
halofenozide-N-(acyloxy)alkyl derivatives 24 were prepared by reacting the corresponding
chloroalkyl derivatives with suitable carboxylic acids and diisopropylethylamine (DIEA) in
THF <2002S53>. Similarly, substitution of N-chloromethylsulfonamide intermediates with the

sodium salt of various carboxylic acids afforded the corresponding benzylpenicillin ester deri-
vatives 25, albeit in low yields <2000BMC1629>. In a different substitution protocol, several
phenyl esters were lithiated (BunLi) and subsequently trapped with suitable electrophiles
to provide various benzotriazole derivatives en route to polysubstituted thiophenes
<1998JCS(P1)1059>.
PhCH2CONH
S
O O N
N
N O
O O
O
Cl O R1 S N
2
O R
O R
R1 = 4-MeC6H4, 4-NO2C6H4, 4-Hal-C6H4
R = H, Me, Ph, But R2 = Me, Ph, Prn, 4-MeC6H4
24 25
(b) From OCX functions (X = hal). Interestingly, treatment of chloromethyl methyl ether
with 26 and N,N-diisopropylamine afforded the N-alkylated product without formation of the
ether substrate <1999JHC65>. In a different example, thiocarbonate 27 was synthesized from
the reaction of the potassium salt of halofenozide with the appropriate thiocarbonic acid
<2002S53>. Finally, even with an allyl silane side-chain present, methoxymethyl derivative 28
was generated from the reaction of the amide precursor with NaH and MOMCl
<2000TL395>.
OH H TMS
O
MeO H O N N N OMe
N N
S O CO2Me
S Cl O O
O
O SEt
26 27 28
4.07.1.1.3 Functions with dicoordinate nitrogen
(i) From compounds containing a multiply bonded functional group
(a) From aldehydes and ketones. The NCO bond formation of the hydroxythiazolinyl-
thiazole ring system was achieved by the reaction of a thioamide with a thiazole in the presence
of molecular sieves <2001OL2811>. Oxathiazines and oxaselenazines bearing a variety of sub-
stituents were prepared by treating a solution of arenecarbochalcogenoamides with a trioxane
or pivaldehyde and BF3OEt2 as shown in Table 3 <2001BCJ511>.
As a new method to access the isocyanomethyl moiety, a carbonyl precursor underwent
dehydration with phosphorus oxychloride and triethylamine to afford the 1-(isocyanomethyloxy)
benzotriazole in 65% yield (Equation (5)) <1997CPB1369>.
Table 3 Preparation of 6H-1,3,5-oxathiazines and 6H-1,3,5-oxaselenazines
2,4,6-Trimethyl-1,3,5-trioxane (A) R1 X R2
X
or pivaldehyde (B)
N O
R1 NH2
BF3.OEt2, CH2Cl2, rt, 1–3 h
R2
R1 X Reagent R2 Yield (%)

C6H5 S A CH3 95
C6H5 S B C4Ht9 43
p-ClC6H4 S A CH3 38
p-ClC6H4 S B C4Ht9 32
C6H5 Se A CH3 56
C6H5 Se B C4Ht9 32
p-ClC6H4 Se A CH3 53
p-ClC6H4 Se B C4Ht9 44
N POCl3, Et3N N
N N
N 65% N
O O ð5Þ
NH NC
OHC
(b) From hydrazones and oximes. No further advances have occurred in this area since the
publication of chapter 4.07.1.1.3.i.b in <1995COFGT(4)293>.
(c) From alkenes. Azido-substituted diazoketoesters were reacted with Rh2(OAc)4 to give rise
to unexpected 3(2H)-furanones, such as 29, in excellent yields via a [3,3]-sigmatropic shift of the
enol form of the initial furanone <1997TL5087>.
O
N3
O CO2Et
Ph
29
(a) From XCN functions (X = hal). Under ultrasonic conditions, 2H-azirines undergo
halide displacement to give rise to 3-hydroxy-2H-azirines (Equation (6)) <2000TL7217,
2002JOC66>. The reaction of isocyanates with 3-alkoxyphenols in toluene and triethylamine
affords phenylurethane intermediates that cyclize in an intramolecular fashion to generate ben-
zoazineones in moderate yields <2002JFC(116)97>.
N H2O N
CO2Et CO2Et ð6Þ
Ph Br Ultrasound Ph OH
(b) From OCX functions (X = hal, OR). The reaction of haloethers with sodium azide in
solvents such as DMF, acetonitrile, or DMSO provide azidoalkyl alkyl ethers in reliable yields
and is most often used in nucleoside and carbohydrate chemistry <1997MI1115, 1996JMC949,
1999SL1151, 2000MI1977, 2002JCS(P1)1982>. Trimethylsilyl azide and a catalytic amount of
TMSOTf are used often to accomplish the aforementioned transformation <1996T9057,
2002JA3263>.
Notably, the reaction of polyfluoro-epoxy alkanes with either camphor-thiosemicarbazone or
thiourea and thiosemicarbazide yield thiazolinylhydrazones and polyfluoroalkylated 1,3-thiazo-
lines, respectively (Scheme 4) <2000JFC(104)155, 2003JFC(120)41>.
R1 OH Nu R1 F
F CF3 R1 F HO CF3
Path a Path b
S N N S
F O CF3
NHR2 NHR2
Nu = S
R2HN NH2
R1 = CF3, C3F7, H(CF2)3

R2 = H, NH2
Scheme 4
4.07.1.2 Functions Bearing Sulfur and Nitrogen
4.07.1.2.1 Dicoordinate sulfur derivatives
(i) Functions with tetra- and tricoordinate nitrogen bearing alkyl or aryl substituents
(a) From compounds containing multiply bonded functional groups. From aldehydes and
ketones. No further advances have occurred in this area since the publication of chapter
4.07.1.2.1.i.a.1 in <1995COFGT(4)293>.
From thiocarbonyl compounds. No further advances have occurred in this area since the
publication of chapter 4.07.1.2.1.i.a.1 in <1995COFGT(4)293>.
From imines and iminium salts. Dithioethers, such as N,N-dimethyl-bis(methylthio)-orthotri-
fluoroacetamide, formed by the nucleophilic reaction of sodium methyl sulfide with the trifluoro-
thioamidium salt were found to rearrange on treatment with acid to the bis-hemiaminal moiety
(Scheme 5) <1996TL5515>.
SMe SMe H SMe

MeSNa (1.2 equiv.) MeS H+ (5–10 mol.%) MeS
F3C N F3C N F3C N
+ CH2Cl2, rt, 24 h Toluene, reflux
66% 94%
CF3SO–3
Scheme 5
(b) From compounds containing two singly bonded functional groups. From XCN functions
(X = Hal, CN, OR, NR2, or a metal). The photoinduced reaction of ammonium salt 30 provides
equal amounts of the anticipated SRN1 product 31 and hydrogen transfer reduction product 32
(Equation (7)) <2000JOC3460>.
+ hν + +
–
(CH3)3NCH2I + PhS (CH3)3NCH2SPh (CH3)4N
BF4– CH3OD BF4– BF4– ð7Þ
39% 39%
30 31 32
From SCX functions (X = Cl, Br, SR). Treatment of a variety of anilines first with
bromothiazolidinediones in the presence of triethylamine and second with trifluororacetic acid
produced the corresponding thiazolidinediones (Equation (8)) <2000MI164>.
O
i. Br
N R2
OH CO2CMe3 S OH CO2CMe3 O
2
N O R = H, CH3 Y
N
S
Y N R2
NHR1 ii. CF3CO2H N
X X O
R1
X = C, N
Y = bond, -OCH2-
R1 = H, CH3, 4-Br benzyl
ð8Þ
(c) By functionalization of a preformed S,N-acetal. Anilino thioethers 33 undergo concerted

bimolecular nucleophilic substitution with sulfur nucleophiles in aqueous solutions at room
temperature. The mechanism is supported by the lack of an iminium ion intermediate
<1995JA9415>.
X CH3
N
S
–
COO
X = 3-NO2, 4-NO2
33
(ii) Functions with tricoordinate nitrogen bearing acyl or heteroatom substituents
ketones. Addition of thiophenol to a solution of bis(trimethylsilyl)-formamide (BSF)-aldehyde
adducts 34 and a catalytic amount of TMS–OTf provided compounds 35 <1996JCS(P1)895>.
O OTMS O SPh
H N Y H N Y
X X
34 35
X = H; Y = Ph
X = H; Y = Pri
X = OH; Y = Ph
From imines. No further advances have occurred in this area since the publication of chapter
4.07.1.2.1.ii.a.2 in <1995COFGT(4)293>.
From compounds possessing an S = N unit. No further advances have occurred in this area
since the publication of chapter 4.07.1.2.1.ii.a.3 in <1995COFGT(4)293>.
From alkenes. No further advances have occurred in this area since the publication of chapter
4.07.1.2.1.ii.a.4 in <1995COFGT(4)293>.
(X = Hal, OR, NR2, or a metal). Thiol displacement of N-halomethylphthalimides was the most
prevalent reaction found in recent literature examples <2000JMC1620, 2001EJO1831>.
For example, treatment of N-bromomethylphthalimide with thioacetic acid in the presence of
triethylamine followed by deacetylation (conc. HCl) affords the thiol in good yields (Scheme 6).
The resulting thiol was then reacted with a suitable alkyl halide to form a more complex thioether
<1999H1789>. The reaction of chloromethylphthalimide with either 2- or 3-mercaptothiophene
yields the corresponding thienylthiomethylphthalimides 36 in moderate yields <1996JHC321>.
!-Benzyl-!-carbinol lactams 37 were prepared by, first, S-alkylation of N-chloromethylphthalimide
followed by subsequent Grignard carbophilic addition <2000OL1201>.
NH2
O O
Br i. MeC(=O)SH, Et 3N SH CHCOOMe
+ NH2CHCOOMe (CH2)2
N N
ii. HCl, MeOH CH2CH2Br S
O O
K2CO3, MeOH N
O O
Scheme 6
Ar =
O S O
S S Ar
N N
O HO
36 Br
37
The -fluorophthalimide (Scheme 7) was reacted to afford either thioether substitution at the
-fluoro position or a reduction and subsequent cyclization product <1998TL7755>.
H O O Ph O O Ph
S i. LiBH4, THF
NH NH
N –15 °C, 59% N EtSNa, DMF N
O F SEt
S ii. (HSCH 2)2, BF3–OEt2 51%
NH O O
O Ph CHCl3, 0 °C, 56%
Scheme 7
From SCX functions (X = Hal). Reaction of -chlorothioethers with potassium phthalimide

provides the corresponding substituted products 38 <1998JOC3706>. N-Allyloxycarbonylpenta-
fluoroaniline was converted into the N-methylthiomethyl derivative 39 after conversion to its
sodium salt and subsequent alkylation with chloromethyl methyl sulfide in high yield
<1999T6945>. In a different manner, compound 40 was alkylated to give the desired NCS
bond followed by N-5 alkylation (Equation (9)) <1998BMC661>.
S N
O
O Me
S N O
F F
R
F F
R = H, CH3 F
38 39
O O
R1 i. ArSCH2Cl, Et3N R1
NH N SAr
HN S ii. NaH, R2X, THF N S ð9Þ
O R2 O
O O
R1 = Bui, Bn
40 R2 = Bun, Me, Bn, H
(c) By functionalization of a preformed S,N-acetal. The trimethylsilyl trifluoromethanesulfo-

nate (TMS–OTf) promoted -lactam fragmentation of 4-alkylthioazetidin-2-ones demonstrates a
novel method to access N,S-acetals in moderate-to-excellent yields <1996JCS(P1)2321>. The
reaction occurs by a nucleophilic attack of a nitrile group on the generated cation intermediate.
Examples of the scope of this method are provided in Table 4.
Table 4 -Lactam fragmentation of 4-alkylthioazetidin-2-ones
R SR1 R2CN SR1 SR1

0 °C, 5 min–2 h R + R
NHCOR2 NHCOR2
NH
O cat. TMSOTf CN CN
b-Lactam R1 R2 Yield (%) Diastereomeric ratio

Bn Me 50 2.8:1
ButMe2SiO SR1 p-MeOBn Me 47 2.9:1
Allyl Me 45 2:1
NH Pri Me 64 2:1
O
Cyclohexyl Me 84 1.8:1
But Me 89 1:1
But Pr 63 1.1:1
But Ph 46 1.3:1
SR1
NH But Me 91 1.2:1
O
But Pr 77 1.4:1
But Ph 53 1:1
SR1
NH But Me 65 NA
O
PhS SR1
But Me 54 1:1
NH
O
(d) Miscellaneous reactions. Irradiation of the Barton ester using a 300 W sun lamp provides
pyridylthio derivatives as a 3.7/1 syn/anti mixture of isomers in an overall yield of 65% (Equation
(10)) <1996TL2569>.
O O
AIBN
OTIPS OTIPS
N hν N
X SPy ð10Þ
65%
O O
X = COOC5H4NS 3.7/1 syn /anti
Py = 2-pyridyl
(iii) Functions with dicoordinate nitrogen
ketones. No further advances have occurred in this area since the publication of chapter
4.07.1.2.1.iii.a.1 in <1995COFGT(4)293>.
From acid chlorides. No further advances have occurred in this area since the publication of
chapter 4.07.1.2.1.iii.a.2 in <1995COFGT(4)293>.
From thiocarbonyl compounds. No further advances have occurred in this area since the
publication of chapter 4.07.1.2.1.iii.a.3 in <1995COFGT(4)293>.
From imines. No further advances have occurred in this area since the publication of chapter
4.07.1.2.1.iii.a.4 in <1995COFGT(4)293>.
From a preformed S,N-acetal. Reaction of 41 with POCl3 provides the tolyl sulfide isocyanide
42 in moderate yields (Equation (11)) <1996JMC3929>.
STol STol
NHCHO POCl3 NC
ð11Þ
41 42
(X = Hal, OR, NR2). The reaction of diimines 43 with thiophenol in refluxing dioxane affords
imines 44 in good yields (Equation (12)) <1997TL4281, 1998T4375>.
R R H
PhSH, dioxane
N Reflux, 10 h
R N R
N R = Ph, p -anisyl ð12Þ
SPh
R
43 44
From SCX functions (X = Hal or SR). No further advances have occurred in this area
since the publication of chapter 4.07.1.2.1.iii.b.2 in <1995COFGT(4)293>.
4.07.1.2.2 Tricoordinate sulfur derivatives

Recently, the first example of a sulfonium salt S,N-acetal has been described in the literature.
Reaction of the triethyloxonium tetrafluoroborate in dichloromethane with the corresponding
N-methyl thiomethyl parent compound provided the crystalline sulfonium tetrafluoroborate salt
45 in 76% yield <1999T6945>.
Et Me
+ S O
–BF
4 N O
F F
F F
F
45

The 1,3-dipolar cycloaddition of 46 with diazomethane generates 47 as the sole adduct in very
good yield with complete regio- and stereoselectivity (Equation (13)) <1996TA1943>. Similarly,
pyrazoline 48 was synthesized by the cycloaddition of diazomethane with the appropriate tri-
fluoropropene; however, this product readily eliminated PhSOH on thermolysis at 80 C to afford
the pyrazole <1996T4383>.
Tol
Tol O O S O
S CH2N2 N
O
O N O
ð13Þ
Me Me H OEt
H OEt
46 47
N
N
SOPh
F3C
48
(ii) By functionalization of a preformed S,N-acetal

This area mainly comprises different methods to oxidize a variety of sulfides to the corre-
sponding sulfoxides. Ozonolysis is one way to achieve such an oxidation <2001SL712>.
Another method utilizes dimethyldioxirane (DMDO) to oxidize the formamide to the sulfoxide
49 in a 58:19 diastereomeric mixture <1996BCJ1763>. The use of an interesting oxaziridine
reagent often provides controlled oxidation of a thioether to the corresponding sulfoxide.
Specifically, the reaction of 50 with 2-(phenylsulfonyl)-3-phenyloxaziridine gave 51 as a
mixture of four diastereomers (Equation (14)) <1999T13301>. Sulfoxides 52 and 53 were
obtained by the oxidation of the sulfide precursors with NaIO4 <2000T7273>. In the case of
MCPBA, short reaction times are often necessary to avoid over-oxidation to the sulfones. In
this manner, sulfoxides 54 were obtained after reacting with MCPBA for 1–3 min at 0 C
<2000OL1201>.
H H
t -BOCHN O t -BOCHN
N Ph
N CO2R PhO2S N CO2R
O H O +
S S ð14Þ
Ph 82% O Ph
–
R = H, p -nitrobenzyl (PNB), p -methoxybenzyl (PMB)
50 51
Ar =
–
O O
O N Me S Ar
+
S NHCHO Me N
Ph N N N N
CF3 HO
PhOS PhOS
Br
49 52 53 54
4.07.1.2.3 Tetra- and higher-coordinate sulfur derivatives
(a) From aldehydes and ketones. Kinoshita and Nagano recently reported that the reaction of
t-butyl or benzyl carbamate, with ethyl glyoxylate, and sodium p-toluenesulfinate tetrahydrate
produces ethyl N-BOC and N-Cbz--tosylglycinates (Equation (15)) <2000BCJ1605>.
OHCCO2Et
TsNa.4H2O
RNH2 RNHCHCO2Et ð15Þ
HCO2H Ts
R = t-BOC, Cbz
The Ugi reaction is often employed to afford tosylated products. In one case, a variety of
aldehydes or ketones were coupled with L-homoserine along with substituted isocyanides to afford
N-carbamoyl methyl--aminobutyrolactones in good-to-excellent yields (Table 5)
<1998TL7109>. The Ugi reaction may also be applied to the solid-phase synthesis of substrates
<1997T6573>. A variety of -amidoalkyl-p-tolyl sulfones were synthesized by reacting suitable
aldehydes with crude t-butyl carbamate, anhydrous sodium p-toluenesulfinate, water, methanol,
and formic acid and stirring for 15 min <2001TL5093, 2002TL1079>. Carbamate 55 was synthe-
sized using similar reaction conditions, yet required longer times for the completion of the
reaction <2000TL5489>. Sisko and co-workers reported an efficient method for the synthesis
of substituted tosylmethyl isocyanide (TosMIC) precursors. By heating an aldehyde, formamide,
TMSCl, and p-toluenesulfinic acid in a 1:1 solution of toluene:acetonitrile, a wide array of
substituted tosylmethyl formamides were generated. Dehydration of the subsequent products
with POCl3 and triethylamine provided TosMIC derivatives cleanly, even on a 13 kg scale
<1996TL8113>.
Table 5 Synthesis of N-carbamoylmethyl--aminobutyrolactones via the Ugi reaction
CO2H O + _ CF3CH2OH O R2 R1 NHCH2Tos

+ + TosCH N C
2 O
HO NH3 R1 R2 30–40 °C NH O
R1 R2 Time (h) Yield (%) Diastereomeric ratio

CH3(CH2)2- H 60 73 3:1
(CH3)2CH- H 94 97 7:1
(CH3)3C- H 94 92 3:1
H 47 71 8:1
–(CH2)5– 70 72 NA
H O O
N S
EtO2C
55
(b) From sulfonic acid derivatives. Hwu and co-workers have demonstrated that the treatment
of -lactams with MeSO2Cl and Et3N in CH2Cl2 provides the corresponding sulfone derivatives
in excellent yields (Equation (16)) <1999CEJ2705, 1998JMC4681>.
H H
O N R O N R
MeSO2Cl, Et3N
N CO2CH2Ph N CO2CH2Ph ð16Þ
Ph O CH2Cl2, 0 °C Ph O
SO2Me
PhCH2CO2 R = SCOMe, 98% PhCH2CO2
R = N3, 85%
(c) From sulfones. The sulfone carbanion derived from PhSO2CH3 was aminated by
N-carboxamido oxaziridine to provide a novel and direct route to the corresponding -amino
compound 56 <2000TL2247>.
H
PhO2S N NEt2
56
(a) From XCN functions (X = Hal, OR, NR2, or a metal). No further advances have
occurred in this area since the publication of chapter 4.07.1.2.3.ii.a in <1995COFGT(4)293>.
(b) From SCX functions (X = Metal). No further advances have occurred in this area
since the publication of chapter 4.07.1.2.3.ii.b in <1995COFGT(4)293>.
(iii) By functionalization of a preformed S,N-acetal

Sulfones 57 were synthesized by oxidation with potassium permanganate in aqueous acetic acid in
good yields (Equation (17)) <1999T13301>. -Substituted S,N-acetals were obtained by lithiation
and subsequent trapping by electrophiles or deuterium <1997T4835>.
H H
t -BOCHN t -BOCHN
KMnO4 (2 equiv.), HOAc, H2O (4:1)
N CO2R1 N CO2R1
O –10 °C, 3 h O
S O2S ð17Þ
R2 78–87% R2
R1 = H, p -methoxybenzyl 57
(PMB), p -nitrobenzyl (PNB)
R2 = Me, Ph
4.07.1.3 Functions Bearing Selenium or Tellurium, Together with Nitrogen

In recent years, more applications of organoselenium compounds have been presented in the
literature, specifically transformations stemming from selenocarbonyl compounds. Conversely,
the progress of organotellurium chemistry is slow in comparison, thus providing an opportunity
for future growth in this area. For previous reviews of both organoselenium—and tellurium see
chapter 4.07.1.3 in <1995COFGT(4)293>.
4.07.1.3.1 From compounds containing a multiply bonded functional group
(i) From carbonyl compounds

Reaction of an isobutyraldehyde-derived imine with ClCO2Et followed by PhSeH/Et3N provides the
expected Se,N-acetal 58 <1996TL9199>. Selenocysteine can react with acetaldehyde to afford the cyclic
Se,N-acetal 59 <2001BMCL2911>. A new and easily accessible class of chiral selenides 60 containing
oxazolidine was prepared from the reaction of amino alcohols with paraformaldehyde and selenol
<2002S2338>. Treatment of an aqueous or ethanolic solution of primary arylamines with formalin and
NaTeH at rt provided 2H,6H-tetrahydro-1,3,5,7-ditelluradiazocines 61 as solids <2000CL870>.
Irradiation of Barton ester 62 using a 300 W sun lamp provides the corresponding N,Se-acetal
as a 2.3/1 syn/anti mixture of isomers in an overall yield of 63% <1996TL2569>. In a similar
manner, Barton ester 63 was transformed into the N,Se-acetal, 64, by sun lamp irradiation in the
presence of diphenyl diselenide in 63% yield (Equation (18)) <1998HCA268>.
Bn CO2Me
N Se R O
H 3C COOH N
SePh N
H
58 59 Y
n
Te NR TIPSO O
RN Te N
O
60
NPht S
61 R = PhCH2, (CH3)2CH
62
Y = Se, n = 0, 1
(PhSe)2
O O
AIBN
OTIPS OTIPS
N hν N
X 63% SePh ð18Þ
O O
X = COOC5H4NS 2.3/1 syn /anti
63 64
(ii) From seleno- or tellurocarbonyl compounds

It is somewhat challenging to synthesize selenocarbonyl compounds from aldehydes and ketones
because of their instability and preference for oxidation and oligomerization. Despite this, there
are a variety of options to access stabilized substrates. Reaction of a telluroketone–tungsten
complex with a diazo compound affords telluradiazoline 65 in 76% yield <1996CC123>. This
process is much superior to traditional methods to arrive at the telluradiazoline by the reaction of
ketone hydrazones with TeCl2 (via the in situ formation of a telluroketone and diazo compound)
in 26% yield <1997T8137>. Similarly, selenadiazoline 66 was obtained by reacting dihydrazone
with Se2Cl2 in the presence of Bu3N in an intramolecular fashion <2000JOC1799>. Thermolysis
of oxazolidinone 67 with a variety of selenoketones provides racemic selenapenams 68a–e in
moderate yields (25–37%) <2000T5579>.
N N N N H
O
Te Se O
N
O
CO2PNB
65 66 67
p -Nitrobenzyl (PNB)
H H H H H
Se Se Se Se Se C6H4OMe
N N N N N C6H4OMe
O O O O O
CO2PNB PNBO2C PNBO2C PNBO2C PNBO2C
68a 68b 68c 68d 68e
(iii) From iminium salts

No further advances have occurred in this area since the publication of chapter 4.07.1.3.1.iii in
<1995COFGT(4)293>.
(iv) From diazoalkanes

No further advances have occurred in this area since the publication of chapter 4.07.1.3.1.iv in
<1995COFGT(4)293>.
(v) From alkenes

Selenide 69 was formed as a minor product via the capture of the Ni/AcOH promoted radical
with diphenyl diselenide after an initial 5-endo-dig cyclization (Scheme 8) <1996T1397,
1998T1029>.
4.07.1.3.2 From compounds containing singly bonded functional groups
(i) From compounds containing two singly bonded XCN groups (X = Li, Na)
Azabicyclo[2.2.2]octan-3-one is easily lithiated by LDA, and addition of phenylselenyl chloride
provides the 2-substituted product 70 in good yield <2000T1139>. Similarly, -selenation of the
ester moiety of a prolinate proceeded in good yields to afford 71 with the use of LiHMDS as
the base and PhSeCl as the electrophile. The N-BOC deprotection protocol (TFA/CH2Cl2/rt) gave
Cl
Cl3C Cl Me Me
Cl Me Cl Me
O Ni /AcOH O Cl Se2Ph2 Cl SePh
N N
Me CH2Ph 2-Propanol Me CH2Ph N N
Me Me O CH2Ph O CH2Ph
69
Scheme 8
the 1-pyrroline by -elimination of the selenide <1995TL6149, 1996TA2613>. A variety of

other novel compounds, shown in Table 6, were synthesized in a similar manner via lithiation and
subsequent trapping with a suitable selenium electrophile <2000AG(E)2175, 2000AG(E)694,
2000JCS(P1)2415, 2000JOC3716, 2002OL3329, 1996JOC7147, 1996H577>.
Table 6 N,Se-acetal formation via lithiation and selenium trapping

Reaction conditions Product References
H O
N
SePh
CO2CH3 <2000AG(E)2175, 2000AG(E)694>
PhSeH, TsOH, CH2Cl2 N
O
BOCN
O
O
N N O
PhSeH, TsOH <2000JCS(P1)2415>
N
CO2CH3
PhSe
TBSO
H H
(PhCH2Se)2, NaBH4 N <2000JOC3716>

O
PhSe CO2Bu t
PhSe
OTBS
N
NaBH4, HSePh, BF3-OEt2 CO2CH3 <2002OL3329>
N SePh
(PhSe)2 <1996JOC7147>
N
But
SePh
TBDMSO H
N
PhSeCl, AcOH NO2 <1996H577>
N
CO2But
O
PhSeNa was used to open a type of -lactone ring to provide the corresponding Se,N-acetal, 72
<2001JOC1966>.
C6H5
CO2H
O SeC6H5
N N SePh
N CO2C2H5
SePh t -BOC
t -BOC
70 71 72
(ii) From silyl tellurides and magnesium arylselenolate- or tellunolate bromides

Silyl tellurides have been shown to display a unique reactivity toward a variety of electrophilic
substrates, particularly in polar solvents <2000AG(E)3669, 2000OL3671>. Recently, trimethyl-
silyl phenyl telluride [Me3SiTePh] was reacted with 1-chloromethylbenzotriazole 73 to give the
corresponding TeCN acetal products <2001TL5061>. A second new use for selenium and
tellurium arises from the formation of magnesium arylselenolate and aryltellunolate bromides
(Grignard reagents) from arylmagnesium bromide and the elemental Se and Te precursors.
Reaction of the corresponding Grignard reagents with 73 provided the aryl products in good
yields (Scheme 9) <2001MI477>.
N
N
N
Cl
73
N
X = Se, Te 73 N
ArMgBr ArXMgBr N
THF 60–80%
ArX
Scheme 9
(iii) From a preformed N,O-acetal

The following N,Se-acetals were synthesized from the N,O-acetal precursor under a variety of
conditions as shown in Table 7 <1996JA2825, 1998HCA353, 2001TL4737, 2001TL9225>.
(iv) Miscellaneous reactions

Lu and Zhang reported that unsymmetrical -(2-arylcarbonyl-1-phenylhydrazino) diorganyl sele-
nides (and sulfides) were synthesized through a nucleophilic displacement of benzotriazole by
selenolates (or thiolates) promoted by SmI2 as shown in Scheme 10 <1998SC4501>.
Table 7 Preparation of N,Se-acetals from N,O-acetals

Reaction conditions Product References
O N
SePh
PhSeH, TsOH, CH2Cl2 <1996JA2825>

N N
H
Ts
N
PhSeH, TsOH Me <1998HCA353>
SePh
SeCH2Ph
(PhCH2Se)2, NaBH4 NH <2001TL4737>

O
NaBH4, HSePh, BF3-OEt2 N CH2Ph <2001TL9225>
SePh
O O CH2Bt
BtCH2OH + NHPh N
Ph N Ph N Ph
H H
SmI2
RZZR “RZSmI2”
THF/HMPA
O CH2Bt O CH2ZR
“RZSmI2”
N N
Ph N Ph Ph N Ph
H H
Bt = benzotriazolyl; Z = Se, S
R = C6H5, C6H5CH2, p -CH3C6H5, p -ClC6H5, n-C4H9
Scheme 10
4.07.2 FUNCTIONS CONTAINING A CHALCOGEN AND PHOSPHORUS, ARSENIC,

ANTIMONY, OR BISMUTH
4.07.2.1 Functions Bearing Oxygen
4.07.2.1.1 Oxygen and phosphorus
(a) From carbonyl compounds. -Heterophosphonates can be obtained by the addition of

the corresponding phosphite precursor ((RO)2PX) with an aldehyde (ArCHO) via a modified
Arbramov reaction <2001TL3219>. A ‘‘green chemistry’’ application of a modified Arbramov

reaction was recently demonstrated by the successful formation of -hydroxyphosphonates under
microwave irradiation and solvent-free conditions <2002SL2633>.
Reaction of an L-quebrachitol-derived aldehyde with lithium dibenzyl phosphite afforded two
phosphonate intermediates 74 en route to the formation of phosphatidylinositol ether lipid analogs.
Interestingly, the resulting analogs were shown to inhibit human colon and breast cancer cell growth
in biological activity studies <2002TL2835>. The first synthetic example of H-phosphonylphos-
phonate 75 as well as a thorough study of its reactivity with a variety of aldehydes were reported
(Table 8). The resulting hydroxyphosphinyl phosphonate products are particularly desirable sub-
strates due to their significance in biological and medicinal chemistry <2001TL8451>. Both syn- and
anti--amino--hydroxy-H-phosphinates were prepared via an A1Libis(binaphthoxide) (ALB)-
catalyzed hydrophosphinylation of N,N-dibenzyl--aminoaldehydes in a diastereoselective manner
<2001TL5033>. In recent years, there have also been several examples of solid-phase syntheses of a
variety of OCP substrates, including -hydroxy phosphonates 76 as well as unsymmetrical
phosphinic acids 77 (see Tables 9 and 10 <1996TL6073, 2001TL1855, 2001TL125>).
O X
Y
(BnO)2P OBn
BnO
BnO OPMB
BnO
X = H, Y = OH, 48%
X = OH, Y = H, 42%
PMB = p -methoxybenzyl
74
Table 8 Reaction of 75 with various aldehydes

O O
H OEt
P P
EtO OEt
75
Substrate Conditions Products Yield (%)

O OH
OEt
H
P
Et3N, CH2Cl2, 40 C, 5 h O P OEt 60
O OEt
H OH
OEt
O P
Et3N, CH2Cl2, 40 C, 5 h O P OEt 47
O OEt
H OH
OEt
O P
Et3N, CH2Cl2, 40 C, 1.5 h O P OEt 73
O 2N O2N O OEt
H OH
OEt
O K2CO3, CH2Cl2–DMF P
P OEt 45
(9:1) 40 C, 2 h O
MeO MeO O OEt
O H O OH
OEt
O Et3N, CH2Cl2, 40 C, 3 h P 50
O P OEt
O OEt
Table 9 -Hydroxy phosphonates 76 synthesized on solid support

O
R2 P OH1
OR
OH
76
R1 R2 Yield (%)
H p-F-Ph 86
CH3CH2 p-F-Ph 90
PhCH2 Prn 87
PhCH2 Ph 92
PhCH2 p-MeO-Ph 77
PhCH2 p-F-Ph 88
PhCH2 2-Naphthyl 72
PhCH2 3-Thienyl 72
2-CF3-PhCH(CH3) Ph 79
Table 10 Phosphinic acid products from solid-phase synthesis

O
R1 O
R2
P
OH
OH
77
R1 R2 Yield (%)
OH H 70
OH 95
OH
OH O
95
O
H 95
N
H
Me
N
H
95
Me
N O
H 95
(b) From other multiply bonded functional groups. (E)- and (Z)-phosphonic esters react
with dioxirane in a two-phase system to provide the corresponding trans and cis isomers of
diethyl 1,2-epoxyethyl phosphonate 78 <1998JOM(571)189, 2000TL9781, 2002PS(177)1153>. In
a different epoxidation example, the first asymmetric epoxidation catalyzed by cyclohexanone

monooxygenase (CHMO) was recently reported to provide ee values 98% for dimethyl and
diethyl vinylphosphonates <2002TL1797>.
O
R1 P OEt
R2 OEt
O H
R 1 = H, Prn
R2 = Ph, hexyl, anisyl, tolyl, naphthyl
78
(a) From XCP functions (X = hal). The reaction of bis(chloromethyl) phosphinate 79 with
tributyl phosphite in a 1:2 molar ratio yielded pentabutyl ester 80, a standard Arbuzov product.
Interestingly, in an equimolar ratio of the starting compounds, cyclic diphospholane 81 was obtained
instead of the anticipated butyl(chloromethyl)(dibutoxyphophorylmethyl) phosphinate 82 as shown
in Scheme 11. The authors suggest that the high temperature and removal of butyl chloride from the
reaction favors this cyclization <2002ZOB521>. Trisubstituted phosphine oxide 83 was obtained by
the phase-transfer catalyzed Williamson reaction of tris-(chloromethyl)phosphine oxide with a slight
excess of 2-benzyloxyethanol <1999HAC307>. Phosphine oxides are unique in their ability to
complex hard cations, like actinides, and have the potential use to recover actinides from nuclear
waste. Alkoxide displacement of -haloalkyl phosphorus compounds can provide a variety of
phosphine oxides via inter- and intramolecular reactions. In the case of intermolecular reactions,
tertiary phosphine oxides containing pyridine rings were obtained by the nucleophilic substitution of
chloride by the sodium salts of hydroxypyridines and 8-hydroxyquinolines <1996PS(108)189>.
Epoxide 84 was obtained via intramolecular nucleophilic displacement of an -bromide intermediate
<1995JA2931>. Interestingly, formation of epoxide 84 completed the concise total synthesis of the
natural product fosfomycin, which has been used clinically as an antibiotic.
P(OBu)3 OBu
ClCH2P(O)CH2Cl (BuO)2P(O)CH2P(O)CH2Cl O
P O
OBu OBu BuO P
O
79 82
81
(BuO)2P(O)CH2P(O)CH2P(O)(OBu)2
OBu
80
Scheme 11
O OH
H 3C P OH
Ph O O
O P H
3 H
O
83 84
(b) From OCX functions (X = hal). The Arbuzov reaction remains a common approach for
the formation of PC bonds. For example, the reaction of compound 85 with chloromethyl ether
86 provided the OCP bond of 87, albeit in only 29% yield (Equation (19)) <2001BMCL1451>.
Reaction of triphenylphosphine with compound 88 provided the Wittig reagent precursor 89

<2001BMCL33>. Similarly, treatment of 2-chloro-2-ethoxyacetate with triethyl phosphite (at 150 C)
afforded triethyl 2-ethoxyphosphonoacetate 90 in 99% yield, and this was subsequently reacted
with a suitable aldehyde in a Horner–Wadsworth–Emmons fashion. Notably, this sequence was
successfully scaled up for use in a pilot plant <2003OPRD82>.
OBn
O Base O
+ BnO O Cl O
P H P
O 90 °C, 1 h O ð19Þ
O O O O
29%
86
85 87
O O
O O
O O
O O
O O P
O O
Br PPh3
+
88 89 90
–
Br
(iii) By functionalization of a preformed O,P-acetal
(a) Functionalization on oxygen. Coupling of geranyl bromide and a phosphinyl alcohol

provided phosphinoyl ether 91, which was utilized toward the synthesis of ()-(15(E)) and
(15(Z))-16-oxa-2,3-oxidosqualenes <1995TL5719>. Several phosphine oxide diacetates 92
were synthesized and subsequently reacted with a variety of enzymes in order to achieve an
enzymatic resolution <2002PS(177)1557>. Optically active 1-hydroxymethylalkylphenylpho-
sphine oxides 93 were prepared by lipase-catalyzed optical resolution in moderate-to-good
yields <2001TL6569>. In an extension of this result, it was later discovered that the
enzymatic resolutions were up to six times more enantioselective in the ionic liquid 1-butyl-
3-methylimidazolium hexafluorophosphate (BMIM-PF6) than in most common organic
solvents <2002TA735>. Calix[4]arenes bearing four diphenylphosphinylmethoxymethyl
groups have been synthesized by the halogen displacement of chloromethylcalix[4]arene by
diphenylmethylolphosphine oxide. These calix[4]arenes have the potential to act as binders for
metal cations <2002PS(177)1537>.
O
Ph P
Ph
O O R O
P Ph
P OH
R
OAc OAc
R = CH3, C6H5, C6H11 R = Bun, C6H11, But
92 93
91
(b) Functionalization on carbon. No further examples have occurred in this area since the
publication of chapter 4.07.2.1.1.i.d.2 in <1995COFGT(4)293>.
(c) Functionalization on phosphorus. In a standard example of phosphorus homologation,

diphenylphosphine oxide was added to acetaldehyde in the presence of catalytic triethylamine
to afford diphenylphosphinoyl-1-ethanol in 96% yield <1995TL5719>. In a similar transfor-
mation, novel tertiary phosphine oxides such as 94 were synthesized to construct modified
DNA analogs, which were then tested via hybridization to complementary RNA and DNA
<1998SL283>. Treatment of phosphaadamantyl ligands, 95 with a slight excess of Me3SiN3
effected oxidation to the corresponding (trimethylsilyl)phosphinimines, 96, in high yields. The
products were then treated with CpTiCl3 to afford the corresponding titanium complexes that
were shown to effect only minimal catalytic activity in ethylene polymerization
<2000OM3791>. In another effort to prepare ligands for catalysis, the Staudinger reaction
was employed in the resolution of C2-symmetric diphosphines (BINAPFu) with an enantiopure
azide to yield a 1:1 mixture of diastereomeric phosphimines <2001JOC7478>.
O T
PGO R
O PR N SiMe
O P 3
HO
P Me O O O O
O
O
T R = Ph, Cy R = Ph, Cy
BzO 95 96
94
T = thymin–1–yl
4.07.2.1.2 Oxygen and arsenic, antimony, or bismuth

No further examples have been reported in this area since the publication of chapter 4.07.2.1.2 in
<1995COFGT(4)293>.
4.07.2.2 Functions Bearing Sulfur

This section outlines the chemistry of compounds containing sulfur and a group 15 element.
Notably, the past decade has provided novel examples involving As, Sb, and Bi.
4.07.2.2.1 Sulfur and phosphorus
(a) From carbonyl compounds. For standard examples utilizing aldehydes and ketones, see
chapter 4.07.2.2.1.i.a in <1995COFGT(4)293>.
(b) From thiocarbonyl compounds. The reaction of a trialkylphosphine (PR3) and carbon
disulfide (CS2) affords a 1,3-dipolar moiety, which reacts further with either a phosphonylalkyne
or phosphonylalkene to generate a reactive ylide species. This resulting ylide provides 1,3-dithio-
lanes after treatment with an aldehyde via a Wittig reaction <2002HAC633>.
(c) From diazoalkanes. There have been many examples of carbene insertion of diazoalkanes into
either a CS or SS bond. Both copper(II) and rhodium catalysts were tested in the [2,3]-sigmatropic
Wittig rearrangement of an intermediate sulfonium ylide to provide phosphonates 97 <1998S1635>. A
similar example utilizing this carbene method afforded 98 as a ring-closing metathesis (RCM) precursor
that was used to generate a cyclic -thiophosphonate <2001SL605, 2002JOC8123>.
O
O
R2 P(OR1)2
(R2O) 2P S
R1 SR3
97 98
R1 = Me, Ph R1 = Me
R2 = Pri, allyl R2 = H, CO2Me, CO2But
R3 = allyl, CH2CO2Me
(d) From phosphorus ylides. The reaction of polycyclic phosphaalkene with sulfur affords
thiaphosphirane compounds with high selectivity (Scheme 12) <2000T6259>. Upon treatment
with a second equivalent of sulfur, selective formation of thioxothiaphosphirane occurs.
Ph Ph Ph S
P 1/8 S8 or 1/x Sex P X 1/8 S8, toluene P S
O But O But O But
Toluene 25 °C, NEt3
Ph 25 °C, NEt3 Ph 69% Ph
O O O
57–59% when X = S
X = Se, S
Scheme 12
(e) From S-containing heterocycles. Macrocyclic structures, potentially useful in molecular

recognition studies, can be obtained in one step by the reaction of lithiated thiophene with the bis-
electrophile, PhPCl2 <1995JOC7406>. Triethyl phosphite (TEP) can be reacted with a substituted
isothiazole to afford the desired product via a nucleophilic addition at the most electrophilic
center (Equation (20)) <2000T5455>. Addition of triflic acid to a trithio heterocycle produces an
unstable 1,3-dithiolium cation salt which was immediately reacted with triethyl phosphite to yield
a Horner–Wadsworth–Emmons reagent <2001EJO933>.
O O P(OEt)3 O O
S H S
X N 100 °C N
(EtO)2OP ð20Þ
50%
4-MeOC6H4 NEt2 X=H 4-MeOC6H4 H NEt2
(a) From XCP functions (X = Hal, OTs, Li). Lithiation of a di-phosphonic diamide
followed by sulfuration with dithiuram [(CH3)2NCS2]2 provided the SCP bond of 99 in very
good yields and moderate selectivity <1996JA11668>. Displacement of a halide by a nucleophilic
sulfur species is a standard method to obtain a variety of thioesters 100a,b <2001TL5137,
2001OL9>. In the example of a tosylate displacement, the desired -thiophosphine oxides 100c
were synthesized under milder and more versatile conditions than by utilizing the corresponding
Arbuzov reaction of (O-ethyl) diphenylphosphinite with an appropriate (chloromethyl) thioether
<1997T10527>. In general, (chloromethyl) thioethers (RSCX) are limited in availability,
thereby further highlighting this strategy.
O
H3C
R2P SAc
O N
S P
S 100
N
H3C N R CH
3 a R = O-Pri
CH3
b R = Ph
99
c R = Tolp, Bun, or But
(b) From SCX functions (X = Hal, Li). The Arbuzov reaction of R2P(OR) and a desired
SCX (X = Hal) component leads to -thio-phosphonates readily, yet application of this reac-
tion is limited to the relatively few -halothioesters available commercially. Not surprisingly, there
are more examples of lithiated CS species used in recent examples. The formation of diethyl
fluoro(phenylsulfonyl)methylphosphonate begins with the addition of LiHMDS to a solution of
fluoromethyl phenyl sulfone 101 and diethyl chlorophosphate in THF at 70 C <1995SC3583>.
In the deprotonation of (S)-2,2-(N,N-dimethylamino)phenyl methyl sulfoxide 102, LDA was used
to generate an anion that was subsequently reacted with diethyl chlorophosphate <2000OL1451>.
Both sulfinylmethyl phosphonates were then reacted with a variety of aldehydes in Horner–
Emmons reactions.
O
O O S
S F Me
Me2N
101 102
(iii) By functionalization of a preformed S,P-acetal

No further advances have occurred in this area since the publication of chapter 4.07.2.2.1.iii in
<1995COFGT(4)293>.
4.07.2.2.2 Sulfur with arsenic, antimony, or bismuth
(i) Arsenic compounds

Treatment of Ph+
3 AsCH3OTf with (Me2N)2CS provided the first SCAs bond 103 reported to
date <1998MI599>.
+ F3CSO3
–
NMe2
+
Me2N S AsPh3
103
4.07.2.3 Functions Bearing Selenium or Tellurium
4.07.2.3.1 Selenium or tellurium with phosphorus

In recent years, more examples of Se,P-acetals have surfaced. The known compounds still appear
to be restricted to those containing phosphorus(IV) or phosphorus(V) functions. Te,P-acetals are
much less explored, therefore offering considerable promise for future research.
(i) From phosphines

Phosphaalkynes and elemental selenium (or tellurium) react to give the corresponding 1,2,4-
selenadiphospholes <1999S1642>. In a similar synthetic pathway, phospha-tetracycles of sele-
nium compounds were formed <2000CC1745, 2001HAC406>. These tetracyclic cage compounds
have been shown to complex with tungsten and iron carbonyl fragments and have potential
application in transition metal chemistry.
(ii) From phosphorus ylides

The stabilized ylide in Scheme 12 (Section 4.07.2.2.1.i.d) reacts with gray selenium at room
temperature to provide a polycyclic compound with high selectivity <2000T6259>. Similarly,
treatment of a phosphorus ylide and elemental selenium in THF at room temperature successfully
provided selenaphosphirane 104 in excellent yield. The molecular structure was established by
X-ray crystallographic analysis, thus providing a great deal of information concerning these novel
structures <2002JA9706>.
F3C
CF3
O Me
P
Me
Ph Se
104
(iii) From phosphonates and phosphine oxides
(a) With selenium nucleophiles. There are no recent examples using Se compounds as nucleo-
philes. See chapter 4.07.2.3.1.iii.a in <1995COFGT(4)293> for prior examples.
(b) With selenium electrophiles. This is the most commonly used method for compounds
containing a phosphorus(V) functional group. Phosphonates bearing either a -carbonyl group or
an -sulfoxide are easily deprotonated (BunLi, THF, 78 C) and subsequently selenenylated with
PhSeX (X = Br, Cl). Compound 105 <2001TL619> was obtained by this procedure. This com-
pound is most often used to obtain vinyl phosphonates via selenoxide elimination.
O O
P(OEt)2
EtO
SePh
105
Lithiation of difluoromethylphosphonates followed by quenching with PhSeCl or PhSeSePh yields

the corresponding selenyldifluorophosphonate, a good source of phosphonodifluoromethyl radicals
<2001OL185>. Phosphorylated allenes can be deprotonated using LDA in THF and trapped with
PhSeCl to provide phenylseleno-substituted phosphorylated allenes <2000PS(166)265>.
4.07.2.3.2 Selenium or tellurium with arsenic, antimony, or bismuth

There is only one example of a function with SeCAs units possessing an sp3 hybridized
carbon. Similar examples incorporating SeCSb or SeCBi remain unknown and
unexplored.
(i) From a selenediamide

Treatment of a selenide with triphenylarsenic triflate affords the triphenylselenylarsenic salt 106 in
95% yield <1998MI599>.
Me F3CSO–3
Me N
Se +
N AsPh3
Me
Me
106
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Biographical sketch
Kelly M. George was born and brought up in Professor Gary Molander was born in Cedar
Pittsburgh, Pennsylvania. She graduated with a Rapids, Iowa. He received his B.S. degree at
B.A. degree in Chemistry and English from Iowa State University in 1975 working with
Washington and Jefferson College in Washing- Professor Richard C. Larock. He entered the
ton, PA, in 2000. During her time there, she graduate chemistry program at Purdue Uni-
worked under the direction of Professor Mark versity in 1975, obtaining his Ph.D. degree in
Harris on her honors project in chemistry focus- 1979 under the direction of Professor Herbert
ing on synthesis of oligonucleotide analogs C. Brown. He joined Professor Barry Trost’s
derived from 30 -azido-30 -deoxythymidine group at the University of Wisconsin, Madi-
(AZT). During the summer of 1998 and 1999, son as a National Institutes of Health post-
she participated in NSF-sponsored REU pro- doctoral fellow in 1980, and in 1981 he
grams at the University of Virginia and North accepted an appointment at the University of
Carolina State University, where she worked for Colorado, Boulder, as an assistant professor
Professors Glenn J. McGarvey and Russell J. of chemistry. He was promoted to Associate
Linderman, respectively. She is currently a grad- Professor in 1988 and Professor of Chemistry
uate student in the laboratory of Professor Gary in 1990. In 1999 he joined the faculty at the
A. Molander at the University of Pennsylvania. University of Pennsylvania, and in 2001 was
Her research focuses on the synthesis of natural appointed Allan Day Professor of Chemistry.
products utilizing samarium(II) iodide reactions Professor Molander’s research interests focus
as key steps. She recently completed the total on the development of new synthetic methods
synthesis of (+)-isoschizandrin and is currently for organic synthesis and natural product
working on the total synthesis of variecolin. synthesis.
4.08
Functions Incorporating
a Chalcogen and a Silicon,
Germanium, Boron, or Metal
N. G. BHAT
The University of Texas-Pan American, Edinburg, TX , USA
4.08.1 FUNCTIONS CONTAINING A CHALCOGEN AND A METALLOID 358

4.08.1.1.1 Oxygen and silicon—R12C(OR2)SiR33, etc. 358
4.08.1.1.2 Oxygen and germanium—R12C(OR2)GeR13, etc. 370
4.08.1.1.3 Oxygen and boron—R12C(OR2)BR32, etc. 372
4.08.1.2.1 Sulfur and silicon—R12C(SR2)SiR33, etc. 375
4.08.1.2.2 Sulfur and germanium—R12C(SR2)GeR33, etc. 381
4.08.1.2.3 Sulfur and boron—R12C(SR2)BR32, etc. 381
4.08.1.3 Functions Bearing Selenium or Tellurium 383
4.08.1.3.1 Selenium or tellurium and silicon—R12C(SeR2)SiR33, etc. 383
4.08.1.3.2 Selenium or tellurium and germanium—R12C(SeR2)GeR33, etc. 384
4.08.1.3.3 Selenium or tellurium and boron—R12C(SeR2)BR32, etc. 384
4.08.2 FUNCTIONS CONTAINING A CHALCOGEN AND A METAL 384
4.08.2.1 Functions Bearing Oxygen—R12C(OR2)M, etc. 384
4.08.2.1.1 Lithium, sodium, or potassium 384
4.08.2.1.2 Magnesium 390
4.08.2.1.3 Titanium or aluminum 390
4.08.2.1.4 Copper or zinc 390
4.08.2.1.5 Mercury 391
4.08.2.1.6 Tin 391
4.08.2.1.7 Samarium 398
4.08.2.1.8 Zirconium 399
4.08.2.2 Functions Bearing Sulfur—R12C(SR2)M, etc. 400
4.08.2.2.1 Lithium 400
4.08.2.2.2 Beryllium or magnesium 403
4.08.2.2.3 Aluminum, indium, or gallium 403
4.08.2.2.4 Tin 404
4.08.2.2.5 Iron 404
4.08.2.3 Functions Bearing Selenium or Tellurium—R12C(SeR2)M, etc. 405
4.08.2.3.1 Lithium 405
4.08.2.3.2 -Telluro lithium species 406
357
358 Functions Incorporating a Chalcogen and a Silicon, Germanium, Boron, or Metal
4.08.1 FUNCTIONS CONTAINING A CHALCOGEN AND A METALLOID
4.08.1.1.1 Oxygen and silicon—R12C(OR2)SiR33, etc.

The major synthetic pathways leading to systems containing an oxygen with an silicon have been
reviewed in COFGT (1995). The various routes included are those from halomethyl silanes, which
involve displacement of the halide from a halomethylsilane with an oxygen nucleophile, from the
reduction of acyl silanes with LAH, NaBH4, and borane–methyl sulfide complex, from aldehydes
and ketones, which involves nucleophilic addition with silyl anions, from the hydroboration of vinyl
silanes, from epoxidation of vinyl silanes, from alkoxysilanes which involves the rearrangement of
alkoxysilanes to -hydroxysilyl anions under conditions of strong base—the mechanism of which
appears more closely related to the Brook rearrangement. The trapping of metallated ethers, nitriles,
esters, and amides with trialkylchlorosilanes yields the corresponding -silyl compounds.
Moser has recently published a review on silicon compounds <2001T2065>. The major
synthetic pathways to generate systems containing oxygen with an silicon are reviewed below.
(i) From silenes

2-Methylpropionaldehyde reacted with tetramesityldisilene 1 to give the corresponding cycloaddi-
tion product 2 in 74.5% yield (Equation (1)) <1996JOM363>.
O
R
H
Mes Mes Mes2Si O
R
Si Si Mes2Si
THF, hexane
Mes Mes rt, 1 min R ð1Þ
1
R
R = Me, 74.5%
The siloxysilene 3 derived from thermolysis of benzoylpolysilane underwent a facile in situ

cycloaddition with a range of dienes to produce the corresponding cycloadducts 4 with modest-to-
good diastereoselectivity (Scheme 1) <1996TL2491>.
O O Me3Si SiMe3
(Me3Si)3SiLi ∆ or hν Si Si(SiMe3)2
R Cl R Si(SiMe3)3 OSiMe3
R OSiMe3
R
3 4
Scheme 1
(ii) By nucleophilic addition

The allylation of acyl silanes 5 with tetraallyltin in the presence of catalytic amounts of Sc(OTf)3 proceeded
smoothly to afford the silylated homoallylic alcohols 6 in good yields (Equation (2)) <1998TL6737>.
O OH
) Sn
4
R SiMe3 Sc(OTf)3 R ð2Þ
5 CH2Cl2 SiMe3
–20 °C, rt 6
70–75%
Functions Incorporating a Chalcogen and a Silicon, Germanium, Boron, or Metal 359
The diastereoselective addition of dimethylphenylsilyllithium to the trans-2-phenylthiocyclobu-

tyl ketones 7 provided cyclobutanemethanol derivatives 8. The Lewis acid-promoted stereospecific
ring-opening reactions of the resulting cyclobutanemethanol derivatives has been studied. Similar
diastereoselective addition of triethylgermyllithium to trans-2-phenylthiocyclobutyl ketones has
also been reported (Equation (3)) <1997T8349>.
O X OH
X
R3MLi
R1 R2 R1 R2
–78 °C MR3
THF ð3Þ
7 8
X = SPh, MR3 = SiMe2Ph
X = CH2SiMe3, MR3 = SiMe2Ph
X = CH2SiMe3, MR3 = GeEt3
Reactions of the (E)- and (Z)-isomers of (-(trimethylsilyl)acryloyl)(t-butyl)dimethylsilanes 9

with lithium enolate 10 of ,-unsaturated methyl ketones at 80 to 30 C afforded the
corresponding silylated alcohols 11 (Scheme 2) <1998JA4947>.
O Me
OLi Me
Si O
Me OH
Si But –80 °C But
+
Me 30 min
Me3Si (CH2)4CH3 CH3COOH
9 43% Me3Si (CH2)4CH3
10
11
Scheme 2
The acyl silanes 12 reacted with lithium enolate 13 derived from the t-butylacetate to provide
the corresponding silylated alcohols 14 (Equation (4)) <1998TL5243>.
O HO SiMe2But
OLi
THF
SiMe2But +
OBut –85 °C
30 min ð4Þ
X X O OBut
12 13 14
X = Ph, 56%
X = SnBu3, 50%
X = Br, 52%
The amine-stabilized trimethylsilylmagnesium halides reacted with cyclopropyl phenyl ketone

to provide the corresponding silylated alcohols 15 (Equation (5)) <1995AG(E)1030>.
OH
Toluene
C + Me3SiMgBr.Me2N–CH2CH2–NMe2 C SiMe3
–70 °C
O 57% ð5Þ
15
The reaction of acyl silane-enolates 16 with benzaldehyde gave rise to -benzoyloxy--hydro-

xysilanes 17 in a reaction cascade involving aldol addition, hemiacetal formation, stereospecific
intramolecular Cannizarro-type disproportionation, and transesterification. This reaction path-
way was supported by the separate transformation of the proposed intermediates to the final
products (Equation (6)) <1995T3749>.
O
OLi OH O
Ph O OH
R PhCHO
THF R
Si CH2 Si Ph + R
–78 °C to 23 °C Si Ph ð6Þ
But Me But Me
But Me
16
17
R = BnOCH2
R = Me R = BnOCH2, 35% R = BnOCH2, 16%
R = Me, 10% R = Me, 20%
The reaction of bis(acyl silanes) with trifluoromethyltrimethylsilane (TFMTMS) resulted in a

new family of 2,2-difluoro-3-trialkylsilyl ketols. These compounds were submitted to a facile and
effective defluorosilylation. The overall process constituted a new synthesis of cyclic six- and
seven-membered 2-fluoro-1,3-diketones with regiospecific introduction of fluorine. The keto–enol
equilibrium of cyclic 1,3-diketones and the mechanism of the defluorosilylation reaction were also
studied <2001JOC4543>.
Organomanganese halides and organomanganates prepared by transmetallation of organo-
lithium and Grignard reagents added smoothly to the carbonyl group of acyl silanes and of the
substituted aldehydes bearing a chiral center at the -position affording the desired alcohols 18
in good-to-excellent yields and with essentially no undesired products from enolization. Com-
parison of the stereochemical outcome with that observed for other organometallic species
outlined the capability of organomanganese reagents to induce uniformly good diastereoselec-
tivities in a number of cases significantly higher than reported previously for these reactions.
The key role displayed by the trimethylsilyl group in promoting high 1,2-asymmetric induction
clearly emerged in the comparison of acyl silane with the corresponding aldehyde. The sense of
the Cram/anti-Cram selectivity depended upon the nature of the carbonyl reagents engaged in
these reactions (Equation (7)) <2001JOM223>.
O OH
RMn
THF, –60 °C, 30 min
R' SiMe3 R' R ð7Þ
SiMe3
18
Chiral silicon groups, attached as protective groups in proximity to a prostereogenic function-

ality by means of an ether linkage, can act as efficient stereochemical directors, at least in specific
cases. The addition of Grignard reagent 19 to - and -silyloxy carbonyl compounds such as 20
(silyloxy is the stereogenic (Me3C)(BnOCH2)MeSiO-group) afforded the respective product 21
with stereofacial selectivity of up to 85%. The source of the selectivity was discussed along with
its dependence upon structural parameters (Equation (8)) <2002T5885>.
BnO O BnO
CH2Cl2, –78 °C Me OH O O
O MgBr2 O
Si Me 85% Si Me
Me Me ð8Þ
Me O O Me
BrMg
Me Me Me Me Me
20 21
19
Enantiopure (S)--(trimethylsilyl)benzyl alcohol (98% ee) was prepared by Noyori’s transfer

hydrogenation of benzoyltrimethylsilane. The corresponding trimethylsilyl ether was subjected to
Marko’s silyl-modified Sakurai conditions with a variety of aldehydes to afford homoallylic ethers
in high diastereoselectivity. The practicality of the -trimethylsilylbenzyl group as an oxocarbe-
nium ion auxiliary was further demonstrated by its efficient deprotection or conversion to a
benzyl protecting group (Scheme 3) <2002OL147>.
TMS
OTMS
CHO TMS OBn
O Ph TBAF
+ Ph TMS
cat. TMSOTf 97%
C6H11
87% C6H11
98% ee
97:3
Scheme 3
Tris(trimethylsilyl)silyllithium reacted with dibenzosuberenone 22 in ether to give, after carbo-

nyl addition of the lithium silanide and lithium trimethylsilanolate elimination according to a
modified Peterson mechanism, the transient silene 23 which was trapped by addition of the excess
tris(trimethylsilyl)lithium to the siliconcarbon double bond to afford the corresponding silane
24 (Scheme 4) <1996JOM185>.
Me3Si LiO Me3Si

–78 °C –Me3SiOLi
Me3Si Si Li + O Si
ether
Me3Si (Me3Si)3Si Me3Si
22 23
SiMe3
H2O
–LiOH 19% Me3Si Si Li
H2O SiMe3
HO
Me3Si SiMe3
Me3Si Si Si CH
(Me3Si)3Si
Me3Si SiMe3
24
Scheme 4
Lewis acid-catalyzed reaction of allyl- and benzyltrichloroacetimidates with -silyl alcohols

was found to be a general method for the synthesis of -alkoxysilanes. Upon exposure to CsF, these
-alkoxysilanes could be made to undergo a [2,3]-Wittig rearrangement with an efficiency similar to
that realized by the analogous but inherently more toxic -alkoxystannanes <1999OL1111>.
A carbenoid reagent was generated by treatment of dibromofluoromethyl(t-butyl)dimethyl-
silane with n-butyllithium in THF at 78 C and was allowed to react with aldehydes and ketones
to give 1-fluoro-1-silyloxiranes 25 in good yields. Alkylation of the silyl-substituted carbenoid was
also achieved efficiently in good yields (Scheme 5) <1997TL4591>.
Addition of benzaldehyde to an ethereal solution of t-butyldimethylsilyldibromomethyllithium,
derived from t-butyldimethylsilyldibromomethane and lithium diisopropylamide, provided
-bromo--silyl ketone. The use of ketone instead of aldehyde afforded -bromoacyl silane via the
bromosilyl epoxide intermediate. Further treatment of the -bromo--silyl ketone with n-butyl-
lithium afforded lithium enolate, which provided -hydroxy--silyl ketone upon treatment with
aldehyde in ether. The enolate gave the ,-unsaturated ketone or the monosilyl ether of 2-acyl-1,3-
diol in tetrahydrofuran instead of the ether. The use of isopropylmagnesium bromide in place of
n-butyllithium also resulted in a formation of the corresponding magnesium enolate <1996T14533>.
R
Br Br O O
ButMe2Si R
BunLi Z C Li
R'
Z C Br
F R'
F F
Z = Br 25
Z = Si(But)Me2
Scheme 5
A series of acyl silanes including aliphatic-, aromatic-, and bis-acyl silanes, as well as the acyl
silanes bearing other substituents such as a bromine atom and alkenyl, succinimide, and carbonyl
groups, were prepared, and their reactions with samarium diiodide or tributylstannane were
studied. The acyl silanes underwent transformations such as reductions, reductive alkylations,
intramolecular radical cyclizations, pinacol couplings, aldol reactions, and Tishchenko reactions,
depending on the nature of the substrates and reaction conditions. Acylsilanes were generally
reduced to give the corresponding -silylalcohols without transfer of silyl groups. Intramolecular
radical cyclizations of 5-hexenoylsilanes and 1-silyl-1,5-pentanedione were realized to give -
silylcyclopentanols and 1,2-cyclopentanediol derivatives, respectively. On treatment with samar-
ium diiodide in tetrahydrofuran, 1-(trimethylsilyl)-1,6-hexanedione underwent a pinacol coupling
reaction in the presence of ButOH, whereas it underwent a Tishchenko reaction in the presence of
MeOH. The Tishchenko reaction of 1-silyl-1,5-pentanedione gave an -silyllactone. On reaction
with samarium diiodide, 1-(trimethylsilyl)-1,5-hexanedione and 1,5-bis(trimethylsilyl)-1,6-hexane-
dione, underwent, respectively, intramolecular aldol reactions <1996JOC1794>.
Silylated vinyloxiranes substituted on the double bond have been synthesized and reacted under
very mild conditions in the presence of a catalytic amount of palladium(0). They rearranged into
-silylated-,-unsaturated aldehydes not only with complete chirality transfer but also with total
retention of the double bond stereochemistry <1997TL5493>.
Optically active 2-alkylcyclopropanecarboxylic acids were efficiently synthesized from the chiral
-hydroxytrimethyl silanes via a diastereoselective cyclopropanation as the key step <1998TL4311>.
The reaction of adamantoyltris(trimethylsilyl)silane 26 with t-butyldimethylsilylacetylene at
120 C proceeded to give 2-adamantyl-3-t-butyldimethylsilyl-2-trimethylsiloxy-1,1-bis(trimethylsi-
lyl)-1-silacyclobut-3-ene 27 in 63% isolated yield (Equation (9)) <2000JOM248>.
O OSiMe3
(Me3Si)2 Si C R
120 °C, 12 h
(Me3Si)3Si C R + ButMe2SiC CH ð9Þ
63%
R = Ad H SiButMe2
26 27
Reaction of -substituted acryloylsilanes 28 with lithium amides afforded -silylallylic alcohols
29 in high enantiomeric excess (>99%) via the formal hydride transfer from the chiral lithium
amide (Equation (10)) <1999OL237>.
O
HO H
Ph H
SiMe2Bu t
SiMe2But
+ N But THF
R NR2 Li –80 °C ð10Þ
R
28 29
>99% ee
R = Me, 31%
The reaction of lead tetraacetate with the ,-disubstituted -silyl alcohol, readily available via
the nucleophilic addition of dimethylphenylsilyllithium with an ester, proceeded to give the
-silyloxy dimethylphenylsilyl compound 30. This material upon reaction with silica provided
acylsilane 31 in 72% yield (Scheme 6) <2000JOC2292>.
OH
PhMe2SiLi Bn
Ph(CH2)2COOEt SiMe2Ph
THF, –78 °C
90% SiMe2Ph
OSiMe2Ph O
Pb(OAc)4 Bn Bn
OAc SiO 2
94% SiMe2Ph 72% SiMe2Ph
30 31
Scheme 6
The reactions of acyl silanes 32 with KCN under liquid–liquid phase-transfer catalytic condi-
tions proceeded smoothly via the Brook rearrangement to produce O-silylated cyanohydrin
derivatives 33 in excellent yields (Scheme 7) <2000TL4169>.
O KCN – OSiMe2But
–O
Bun4PBr SiMe2But O SiMe2Bu t
(20 mol.%)
SiMe2But
CH2Cl2–H2O CN CN CN
R (1:1)
R R R
32
33
R = Me, 82%, Pri, 93%, But, 95%
Scheme 7
Cyclization of 1,5-bis(acyl silanes) 34 with potassium cyanide gave new silylated cyclo-
pentanones 35 and 36 via a multistep sequence combining nucleophilic addition, two silyl migra-
tions, and -elimination. The nature of the products was very dependent on the competition
between [1,2] carbon-to-oxygen and [1,4] oxygen-to-oxygen silyl migration (Equation (11))
<2001TL6535>.
O OSiMe3
O O OSiMe3
KCN
+ OSiMe3
SiMe3 DMSO SiMe3 ð11Þ
Me3Si 15 min
34 35 36
46% 13%
The reaction of an acyl silane 37 under catalysis by trimethylsilyl trifluoromethanesulfonate in

dichloromethane provided the corresponding trimethylsilyl ether of methyl(trifluoromethyl)-
trimethylsilyl carbinol 38 (Equation (12)) <2001JOC4348>.
CF3SiMe3
O Bu4N+Ph3Sn–F2 (cat.) OSiMe3
CH2Cl2, –85 °C
F3 C SiMe3 ð12Þ
H3C SiMe3 87%
37 CH3
38
A practical synthesis of trifluoroacetyltrimethyl silane 40 was achieved via its ethyltrimethyl-

silylketal 39. It involved electrochemical reduction of the ethyltrifluoroacetate to the corresponding
ketal, which upon treatment with sulfuric acid provided acyl silane in 86% yield (Scheme 8)
<2003TL3741>.
O O
Me3SiO OEt H2SO4 (95%)
2e–, excess TMSCl
rt, 3 h
CF3 OEt 30–56% CF3 SiMe3 86% CF3 SiMe3
39 40
Scheme 8
The 4,6-dideoxyfuranoses have been synthesized by starting from the readily available (E)-5-
dimethylphenylsilyl-2-hexene-4-ol and employing successively three versatile oxyfunctionalization
methods, namely photooxygenation, metal-catalyzed epoxidation, and oxidative desilylation
<2001JOC7365>.
The generation and reactions of oxiranyl anions stabilized by a trifluoromethyl group are
described. Treatment of (S)-2,3-epoxy-1,1,1-trifluoropropane (75% ee) with BunLi followed by
electrophiles gave the corresponding 2-alkylated epoxide with retention of stereochemistry in
moderate-to-good yields. The reaction was applicable to a general synthesis of optically active
trifluoromethylated tertiary alcohols <2002OL173>.
The terminal alkyne was deprotonated with n-butyllithium followed by silylation t-butyldi-
methylsilyl chloride. Hydroboration followed by oxidation provided the corresponding acyl silane
41, which was reduced to silyl alcohol by sodium borohydride (Scheme 9) <1999SL705>.
H TBS O OH
n BH3. SMe2
Bu Li NaBH4
t SiMe2But
THF THF ( ) n – 3 SiMe2Bu EtOH ( ) n–3
( )n–3 TBSCl ( )n – 3 Me3N O 5% HCl
–50 °C reflux OTBS OH
OTBS OTBS
41
n = 5, 75% n = 5, 51% n = 5, 95%
n = 4, 87% n = 4, 49% n = 4, 98%
Scheme 9
Tris(trimethylsilyl)silylmagnesium bromide underwent nucleophilic addition to 2,4,6-triisopropyl-

benzaldehyde followed by hydrolysis to provide the corresponding silyl alcohol 42 (Scheme 10)
<1997JOM185>.
Me3Si O Me3Si OMgBr Me3Si OH

H2O
Me3Si Si MgBr + Me3Si Si CH Me3Si CH
70% Si
Me3Si H
Me3Si Me3Si
42
Scheme 10
(iii) By Wittig rearrangement

A Wittig–Still-type [2,3]-sigmatropic rearrangement of (trimethylsilyl)methyl allyl ethers via silicon–
lithium exchange to provide the silylated alcohols 43 has been developed (Equation (13))
<1996TL2403>.
BunLi
–20 °C to + 20 °C R3Si
O SiR3 2.5 h ð13Þ
R = Me 88%
OH
43
Wittig rearrangements of -alkoxysilanes, promoted by the action of methyllithium, were

studied. Depending on both the substrate and reaction conditions employed, [2,3]-, [1,2]-, or
[1,4]-Wittig rearrangements can be realized. These rearrangements were shown to be initiated
by either Si/Li exchange or deprotonating to the silane. Furthermore, the sigmatropic shifts
can often be followed by other synthetically useful in situ chemical events (Scheme 11)
<1999OL1115>.
Et O
Me3Si OLi Silyl shift Me3Si
MeLi Et
O Et
H3O+
[2,3]-Wittig
92%
SiMe3
Scheme 11
(iv) From deprotonation

Methyl (2-trimethylsilyl)tetrahydrofuran-3-carboxylates were deprotonated with LDA to form the
enolates, which underwent Michael reaction with methylcinnamate. It was believed that the
silicon moiety in such substrates controlled the sense of asymmetric induction observed in
Michael reactions of the derived enolates with methylcinnamate. The LAH reduction of the
conjugate addition product gave the corresponding alcohol 44 (Scheme 12) <1996TL9119>.
Ph
Ph MeO2C
CO2Me MeO2C
LDA CO2Me
DIBAL-H OH
THF
THF
O SiMe3 –78 °C –78 °C O SiMe3
30 min O SiMe3
77% 44
Ph CO2Me
–78 °C
NH4Cl, 40%
Scheme 12
[Methoxy(trimethylsilyl)methyl]arenes were readily prepared by reactions of chlorotrimethyl

silane with (-methoxy)arenylmethyllithium reagents as obtained from (methoxymethyl)arenes
and tert-butyllithium (Equation (14)) <1999JOC4247>.
CH2–OCH3 (CH3)3Si-CH-OCH3
ButLi ð14Þ
(CH3)3SiCl
100%
It has been reported that the propargylic ether was deprotonated with lithium diisopropylamide
followed by silylation to provide the corresponding silylated alkyne. Further treatment with
lithium diisopropylamide followed by reaction with t-butyldimethylchlorosilane and deprotection
of ethoxyethyl group with p-toluenesulfonic acid provided the corresponding -hydroxysilanes 45
(Equation (15)) <2002JOC1786>.
EEO HO SiMe2But
i. LDA
ii. Me2RSiCl
iii. LDA
iv. ButMe2SiCl
ð15Þ
v. p -TsOH
SiMe2R
EE = 1-ethoxyethylacetone, H2O
45
R = Me, 68%
R = Ph, 75%
(v) From silylated alkenes

The preparation of 2-halo-2-trimethylsilyloxirane 46 was achieved by the hydroalumination of an
alkynylsilane with diisobutylaluminum hydride followed by halogenation with either halogens or
NCS and further epoxidation with MCPBA. Treatment of 2-halo-2-trimethylsilyloxirane with
metal salts such as ZnCl2, ZnBr2, NaI, and AgBF4 gave the corresponding -haloacylsilanes in
good yields (Scheme 13) <1995TL5353>.
Bui2AlH, ether n-C6H13 SiMe3 n-C6H13

MCPBA SiMe3
n- C6H13C CSiMe3 C C C C
NCS or Br2 H X X = Cl, 78% H O X
Br, 51%
46
Scheme 13
3-(Trimethylsilyl)allyl alcohol was epoxidized followed by phase-transfer benzylation to yield

an epoxide, which was reacted with n-butyllithium to give, after aqueous work-up, a vinyl silane
47 (Scheme 14) <1996TA763>.
Me3SiCH2Sph
L-(+)DIPT O BunLi Me3Si OBn
Me3Si OH Me3Si OBn
Ti(O-Pri)4 –40 °C to 0 °C
TBHP 65% OH
BnBr 47
Bu4NBr, NaOH
Scheme 14
Catalytic epoxidation of the allylic alcohols using D-()-diisopropyltartrate (DIPT) or

L-(+)-DIPT afforded the corresponding epoxides 48 (Equation (16)) <1995TA577>.
L-(+)-DIPT
or
D-(–)-DIPT O
R1R22Si OH R1R22Si OH
Ti(O-Pri)4 ð16Þ
TBHP 48
R1 = R2 = Me, 84%
R1 = Ph, R2 = Me, 87%
Cyclopropanation of the title compounds was possible under certain conditions (CH2I2/Sm
(Hg)) in special cases, but epoxidation of these alkenes is apparently a general reaction, which
occurred readily in a stereospecific manner with m-chloroperbenzoic acid <1995JOM239>.
The Z vinyl chloride 49 was prepared in a simple way from vinyl silane by oxidation with
m-chloroperbenzoic acid, followed by treatment with hydrochloric acid in 59% overall yield
(Scheme 15) <2000EJO3581>.
Me3Si MCPBA Me3Si O HCl

Et Et
CH2Cl2 Et
Overall
OMOM 0 °C to rt, 1 h Cl OH
OMOM 59%
49
Scheme 15
The one-pot epoxidation of the cyclohexenone derivative 50 with MCPBA provided the
corresponding -silylated epoxide 51 (Equation (17)) <2001TL9123>.
O O
MCPBA O
SiMe2Ph SiMe2Ph
CH2Cl2 ð17Þ
OTHP 0 °C, 1 h
OTHP
50 51
A new chemoselective approach to the synthesis of an epoxide containing an -trimethylsilyl

group and the trimethylsilyl-substituted ethynyl group 52 has been developed based on (3E)-1,4-
bis(trimethylsilyl)-3-buten-1-yne (Equation (18)) <2001T549>. A simple epoxidation reaction,
followed by regioselective -opening of the epoxide ring by metal halides afforded the corre-
sponding halohydrins with a high degree of stereoselectivity. A subsequent -elimination reaction
from these compounds leads to (Z),(E)-dienylhalides and to (Z)-enyne halides <2001T549>.
Me3Si
Me3Si
MCPBA
CH2Cl2, rt ð18Þ
SiMe3 SiMe3
60% O
52
The epoxidation of 2,2-disubstituted vinyl silanes using a fructose-derived chiral ketone as

catalyst and oxone as oxidant provided 2,2-disubstituted ,-epoxysilanes with high enantioselec-
tivity (Scheme 16) <1999JOC7675>.
O O
O
O
O R1 R1
R1 O
SiMe3
SiMe3 TBAF
R2
R2 Oxone R2
O THF O
rt, 2h
CH3CN-dimethoxymethane (DMM)
Scheme 16
(vi) From epoxides

(+)-Cerulenin, a potent fungal inactivator of fatty acid synthases, has been prepared in optically
pure form by a sequence involving reaction of a chiral oxiranyllithium with (4E),(7E)-nonadienal.
The synthesis of the former took advantage of a particularly favorable Sharpless epoxidation and
metalation to a configurationally stable organolithium, while the latter was available in quantity
by a direct and improved route (Scheme 17) <1997JOC636>.
The presence of a suitable diamine ligand is the key to achieving ring lithiation–substitution of
epoxides without the need for activating substituents on the epoxide and constituted a new
synthetic entry to trans-,-epoxysilanes 53 (Equation (19)) <2001OL461>.
O
Me3Si H
O O
Me3Si O Me3Si i. BusLi/–116 °C
PPTS ii. (4E,7E )-nonadienal
OH OEE 77% OEE
OH
EE = ethoxy ethyl
Scheme 17
H
N Me
R1 O BusLi/ N R1 O SiMe ð19Þ
+ Me3SiCl 3
R2 Hexane R2
53
Table 1 Direct synthesis of ,-epoxy silanes from epoxides

Epoxide Product Yield (%)
O
O SiMe3 73
C10H21
C10H21
O
O SiMe3
(CH2)6 71
(CH2)6
O
O
Ph SiMe3 61
Ph
O
O
ButMe2SiO(CH2)3 SiMe3 74
ButMe2SiO(CH2)3
O
O SiMe3 65
ClCH2(CH2)3
ClCH2(CH2)3
O
O
SiMe3
67
Et O
Et O
Ph SiMe3 71
Ph
Copper(I) sulfide mediated the cross-coupling in tetrahydrofuran of -stannylepoxide 54 with

an electrophile such as trimethylsilyl chloride and afforded -trimethylsilyl epoxide 55 in moder-
ate yield (Equation (20)) <1997SL481>.
O O
Me3SiCl
THF
Ph Ph ð20Þ
Cu2S SiMe3
SnBu3
22 h, 70 °C
63% 55
54
Treatment of (S)-2,3-epoxy-1,1,1-trifluoropropane with n-butyllithium followed by electrophiles

such as triphenylsilyl chloride and triphenyltin chloride provided the corresponding 2-silyl and
2-stannylsubstituted epoxides 56 (Scheme 18) <2002OL173>.
O O O
Li E
BunLi/ THF E+
CF3 –102 °C CF3 CF3
30 min 56
+
E = Ph3SiCl, 70%
= Ph3SnCl, 87%
Scheme 18
(vii) From the reduction of carbonyl compounds

The acyl silane 57 was reduced with LAH to give 1,3-dihydroxypropylsilane derivative 58 which was
treated with acetone dimethylacetal affording the 2-silyl-1,3-dioxane derivative 59 (Scheme 19)
<2002T6815>.
OH O OH OH O O
LAH
THF (CH3)2C(OMe)2
Ph SiMe3 Phi SiMe3 Ph SiMe3
–78 °C CH3COCH3 i
Pr i 71% Pr i p -Toluenesulfonic acid (PTSA) Pr
23 °C, 2 h
59
57 58 64%
Scheme 19
Rhodium-catalyzed oxygen transfer was used to generate benzyl 2-silyl-2-oxoacetates in

good yields. The hydrogenation of these compounds led to chiral -silyl-substituted -hydro-
xyacetic acids 60 (Equation (21)) <2002OL2265>. Resolution by means of HPLC using a
chiral stationary phase afforded an enantiomerically pure representative of this class of
compounds, which was successfully applied as a chiral ligand in an asymmetric aldol-type
reaction <2002OL2265>.
R1 R1
R2 R2
H2, Pd/C
Si CO2Bn Si CO2H
R3 EtOAc, rt R3
O OH
ð21Þ
60
R1 = R2 = R3 = Me, 78%
R1 = R2 = R3 = Et, 85%
R1 = R2 = Me, R3 = But, 89%
(viii) Miscellaneous methods

The -(trimethylsilyl)allenyl ketones were prepared in a one-pot operation from propargylic
chlorides and acetyltrimethylsilane. The reaction proceeded through an intermediate containing
an sp3 carbon attached to an oxygen and trimethylsilyl group <1996SC803>.
The bridgehead allyl silane cycloadduct 61 was chlorinated with iodobenzene dichloride to give
the polyhalogenated cyclohexane 62 (Equation (22)) <1997JOC8962>.
H3C H3C
H3C Si O O H3C Si O
Iodobenzene
H2C CH3 dichloride O
ð22Þ
61% CH3
Cl
Br Cl Br
61 62
Methanolysis of the silylated alcohol 63 induced by sub-stoichiometric amounts of methoxide
ion gave the corresponding (2R,3R)-3-trimethylsilyl-2,3-dihydroxy methyl esters 64 in good yields
(Equation (23)) <2002TA1825>.
SiMe3
HO
HO
O R MeONa/MeOH Me3Si
O 0 °C to 25 °C
O 6–12 h CO2Me ð23Þ
HO R
R1 64
R = Me, 91%
R = Et, 85%
63 R = C9H9, 65%
Heating a benzene solution of 1,2-diadamantoyltetrakis(trimethylsilyl)disilane at 120 C gave

an isomerization product, 3,4-diadamantyl-2,2-bis(trimethylsiloxy)-1,1-bis(trimethylsilyl)-1,2-disi-
lacyclobutene in 24% yield. A mechanistic interpretation including a 2,3-disiladiene intermediate
was described. Similar treatment of 1,2-diadamantoyltetrakis(trimethylsilyl)disilane 65 in the
presence of an excess of methanol at 120 C afforded a methanol adduct 66 in 39% yield
(Equation (24)) <2003JOM72>.
O Me3Si SiMe3 O Me3Si Ad SiMe3 OSiMe3
MeOH
C Si Si C Me3Si Si C O Si CH
120 °C, 12 h ð24Þ
Ad Me Si SiMe3 Ad 39% OMe H OMe Ad
3
65 Ad = adamantyl group 66
A new method for the synthesis of optically active -hydroxyalkynylsilanes was described. The
key step of the conversion was the use of the reverse Brook rearrangement of the 2-alkynylsilyl ether
<2000TL6589>.
Treatment of -silylated allylic alcohols with epoxidizing reagents afforded -silylated aldols in
a highly stereocontrolled fashion. The transformation is proposed to proceed either by a reaction
cascade involving stereospecific epoxidation of the allylic alcohol moiety followed by an acid-
supported pinacol-type rearrangement, or by a sequence consisting of a -face-selective electro-
philic attack at the allylic silane moiety with hyperconjugative stabilization of the evolving
carbocation, followed by rearrangement of the thus obtained pentacoordinated silanium ion.
Depending on the reaction conditions, the -face selectivity of the oxidation step is controlled
by the stereogenic C-atom or the more remote Si-center of chirality <1999HCA561>.
The reaction of mixed acetal 67 with trimethylsilyl triflate at 78 C resulted in the somewhat
hydrolytically unstable allyl transfer product in good yield. The trimethylsilyl ether derivative 68
with excess methyllithium provided the trimethylsilyl-substituted derivative 69 as a 34:1 diaster-
eomeric mixture (Scheme 20 and Table 2) <1996JOC2441>. The substituted allyl silanes were
prepared by displacement of methoxy group on silicon (prepared by ozonolysis of 67 in the
presence of methanol) by allyllithio reagents which were in turn generated by transmetallation of
the corresponding allylstannanes. The results are summarized in Table 2 <1996JOC2441>.
4.08.1.1.2 Oxygen and germanium—R12C(OR2)GeR13, etc.

In COFGT (1995), the preparation of -alkoxygermane systems has been described from halo-
methyl ethers, aldehydes, ketones, and nucleophilic substitution of halogermanes.
Me3SiOTf O CH3Li O
O O
CH2Cl2 THF
C5H11 Si OSiMe3 0 °C Si OH
C5H11 Si –78 °C C5H11
70% 91%
68
67 69
Scheme 20
Table 2 Synthesis of substituted allyl silanes

Allylstannane Allylsilane Yield (%)
O O
SnBu3 65
Si
C5H11
O O
SnBu3
Si 71
C5H11
O O
SnBu3
Si 75
C5H11
O O
Ph SnBu3
Si 75
C5H11 Ph
O O
SnBu3 64
Si
Pri
Nucleophilic addition of tri-2-furylgermane 70 to various aldehydes and ,-unsaturated

carbonyl compounds in the presence of a catalytic amount of base such as ButOK and Cs2CO3
afforded -hydroxy germanes and -germyl carbonyl compounds, respectively, in good-to-excel-
lent yields. The reaction of aldehydes proceeded with high chemoselectivity under mild conditions
to produce -hydroxy germanes 71 bearing various functional groups effectively (Equation (25))
<2001T9827>. -Hydroxy germanes could be converted into acylgermanes by Swern oxidation
<2001T9827>.
O OH
Cat. Cs2CO3
)3 GeH + ð25Þ
O DMI, rt R Ge (
R H 3
73–99% O
70 71
In an in-depth study, the capability of acylgermanes to function as acceptors in radical

cyclization was reported <1997JA4797>. The addition of radicals to acylgermanes followed by
rapid fragmentation of the resulting -germylalkoxy radicals provided ketones and germyl free
radicals <1997JA4797>.
4.08.1.1.3 Oxygen and boron—R12C(OR2)BR32, etc.

The different synthetic pathways leading to -alkoxyborane systems have been outlined in
COFGT (1995) from -haloboranes, -haloboronates, carbonylation of organoboranes, and
homologation of dioxaborinanes.
The following synthetic routes represent methods to generate systems containing oxygen to
boron.
(i) From -haloboronates and alkylboronates

Sodium trityloxide with 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane efficiently
yielded 4,4,5,5-tetramethyl-2-[(triphenylmethoxy)methyl]-1,3,2-dioxaborolane 72 (Scheme 21)
<1995OM2855> which can be transesterified with chiral diols to form other [(triphenylmethoxy)-
methyl]-1,3,2-dioxaborolanes <1995OM2855>. These can undergo chain extension with (dichlor-
omethyl)lithium in the normal manner and are potentially useful synthetic intermediates
<1995OM2855>.
Br O
ONa O O
C DMSO 85% B
+ BrCH B
2 C B– C O
0 °C to rt, 18 h O
O OO
72
Scheme 21
Matteson and co-workers have developed a new homologation reaction <2000JOC5403> of

boronic esters with (dialkoxymethyl)lithium reagents. This new process provided a convenient
one-step synthesis of -alkoxy boronic esters 73. When the reaction was catalyzed by zinc
chloride, high diastereoselection was achieved from aryl and sec-alkylboronates (Scheme 22)
<2000JOC5403>.
–
O O
LiCH(OR')2 R
R B
–100 °C B Li+
O THF CH O
R'O
15–20 min
OR'
–
OR'
O
Migration O
R B + NH4Cl R B
–100 °C to –60 °C Li
R'O O 25 °C O
OR'
73
R = –Ph, 65%
Scheme 22
(Trityloxy)methylboronate 74 reacted with (dichloromethyl)lithium to provide chloro boro-

nic ester 75. Subsequent substitution with sodium p-methoxybenzyl oxide efficiently yielded
(R)-[1-(p-methoxybenzyloxy)-2-(trityloxy)ethylboronate] 76 (Scheme 23) <1997TA3855>.
The -bromo boronate ester 77 was also reacted with lithium benzyloxide (easily prepared from
benzylalcohol and n-butyllithium) to produce the corresponding -benzyloxy boronate ester 78
(Scheme 24) <1996OM152>.
OLi Ar CH2
O Cl MeO O
Ph3CO B LiCHCl2
Cy Ph3CO O Ph3CO O
O ZnCl2 B Cy DMSO / THF B Cy
THF, –100 °C to rt, 18 h O rt, overnight
Cy O
95% 85%
74 Cy = cylcohexyl Cy Cy
75 76
Scheme 23
i. CH2Br2
ii. LDA
MgCl O
O O –78 °C O B
B +
CH3O B iii. LDA B O
O THF O O
0 °C to iv. ZnCl2 Br
rt, 1 h rt, overnight 77
98%
LiOBn, 0 °C BnO O
DMSO B
rt, overnight O
43%
78
Scheme 24
-Chloro boronate ester 79 was reacted with sodium benzyloxide to give -benzyloxy boronate
esters 80 (Scheme 25) <1996JA4560>. The stereoselective boronic ester has been used to install all
three chiral centers in a convergent synthesis of highly pure stegobinone, the epimerically labile
pheromone of the drugstore beetle, Stegobium paniceum, and the furniture beetle, Anobium
punctatum. The asymmetric centers were installed via the reaction of (dichloromethyl)lithium
with 1,2-cyclohexylethane-1,2-diol boronic esters <1996JA4560>.
BnO
Cl
LiCHCl2 O
O BnONa B
O ZnCl2 B Cy
Cy DMSO / THF
THF O
B –40 °C to rt, 2 h
O 0 °C to rt, 48 h
O Cy
Cy
80
79
Cy = cyclohexyl
Scheme 25
The reaction of -chloro boronic ester 81 with lithium p-methoxybenzyloxide generated the
corresponding -alkoxy boronate ester 82 (Scheme 26) <1996JOC3106> in 76% yield.
O LiOCH2 OMe O
B B
O DMSO/ THF O
Cl –78 °C to rt, 2 h O
76%
81 OMe
82
Scheme 26
(ii) From -alkoxystannanes

Various -alkoxy boronic esters have been synthesized by borylation of -alkoxyorganolithium
reagents generated via tin/lithium exchange. The results are summarized in Table 3
<1998TL555>. This reaction occurred with retention of configuration and gave access to
-alkoxy boronic esters 83 (Scheme 27) <1998TL555>.
Table 3 Synthesis of alpha-alkoxyboronic esters

-Alkoxystannane Product Yield (%)
OMOM
OMOM O
B
SnBun3 75
O
OMOM
OMOM O
B
70
SnBu3n O
OMOM
OMOM O
B
SnBun3 58
O
OMOM
OMOM O
B
SnBu3n 73
O
O
SnBu3n B
O 30
OMOM
OMOM
OMOM
OMOM O
B
45
SnBun3
O
OMOM
OMOM O
B
SnBun3 55
O
BunLi
OMOM THF, –78 °C OMOM
Bu3SnLi borylating agent
RCHO
CH3OCH2Cl HCl O
R SnBu3 (+)-Pinanediol R B
O
Borylating agents: B(OiPr)3 75%
B(OMe)3 60%
ClB(NiPr)2 5%
83
Scheme 27
(iii) From -alkoxyboronates

The catalytic hydrogenolysis of 2-(benzyloxymethyl)-1,3,2-dioxaborolane to the hydroxymethyl
derivative was immediately followed by silylation with t-butyldimethylsilyl chloride to form the
2-(trialkylsilyloxymethyl)-1,3,2-dioxaborolane 84 or with t-butyldiphenylsilyl chloride to form the
analogous derivative (Scheme 28) <2000JOC6650>.
Cy H2 ButR2SiCl Cy
O O Cy O
5% Pd/C CH3COOEt
B B B
CH3COOEt 0 °C
PhCH2O O Cy 20–25 °C HO O Cy rt, 24 h ButR2SiO O
Cy
24 h 82%
Cy = cyclohexyl 96% 84
R = Me, Ph
Scheme 28

The importance of acyl silanes and functionalization of sulfur-containing compounds is reflected
in two useful reviews <1998JOM181, 2000EJO2171>.
4.08.1.2.1 Sulfur and silicon—R12C(SR2)SiR33, etc.

The major synthetic routes to generate -silylated derivatives from sulfur-stabilized carbanions,
halomethyl silanes, from silylthioethers, reverse Brook rearrangement, from vinyl silanes, from
-arylthiovinyl silanes, from rearrangements of ylides prepared from -thiosilanes, from -silylor-
ganomagnesium compounds, from -silylated O,S-acetals, and from trimethylsilylthiones have
been described in COFGT (1995). Listed below are the major synthetic routes to prepare
compounds containing sulfur to silicon.
(i) From sulfur-stabilized carbanions

Zinc sulfolenylates 85 have been generated by metal exchange processes from lithium sulfoenylate.
These organozinc compounds show very interesting regioselectivity in the reactions with
electrophiles (Scheme 29) <1995TL7105>.
ZnX E
i. BunLi, –105 °C E+
ii. ZnX2, –78 °C –78 °C

SO2 SO2
SO2 THF X = Cl, E+ = D2O, 99%
85 X = Bn, E+ = Me3SiCl, 73%
Scheme 29
The double alkylation of bis[2-(2-lithio-1,3-dithian)-yl]diorganosilane with bis(bromomethyl)dior-

ganosilanes proceeded smoothly in good yields in a mixture of THF-hexamethylphosphoric triamide
(HMPA) or THF-1,1,3,3-tetramethylurea (TMU) to give 1,4-disilacyclohexanes whose conformation
was shown to be a twist-boat on the basis of X-ray analysis (Scheme 33) <1998TL3197>.
The multicomponent linchpin couplings of silyldithianes via solvent-controlled Brook rearran-
gement has been studied <1997JA6925>.
Treatment of trimethylsilylethanes bearing -phenyl groups and -phenylthio, phenylsulfonyl,
or cyano groups with LDA caused elimination–rearrangement mediated by the -carbanionic
species. Mechanistic conclusions were based on the isotopic labeling experiments, the effects of
substituents, and approximate kinetics. These suggested that trimethylsilyl is the migrating group,
that cleavage of the bond to the leaving group was little advanced in the transition structure and
that placing of a substituent to encourage silicon–carbon bond cleavage was mandatory
(Scheme 30) <1996JCS(P1)1511>.
Ph Ph
Li
LDA, THF Me3Si 25 °C, 65% Ph + PhCH2SO2–
Me3Si
Me3Si 20%
SO2 SO2 80%
Ph Ph
Scheme 30
The -dimethyl(1-phenylthio)cyclopropylsilyl group was used as a new masked hydroxyl

group. The phenylcyclopropyl thioether was deprotonated with n-butyllithium in the presence
of potassium-t-butoxide followed by silylation with chlorotrialkylsilanes to provide the -thiosi-
lanes 86 (Scheme 31) <2000T2025>.
Me Me
SPh
BunLi, ButOK PhS Si R
Bu nLi, THF THF, –80 °C
PhS SPh
rt, 2 h RCH2SiMe2Cl
94%
86
R = Ph, 76%
R = vinyl, 86%
Scheme 31
Trimethylsilyldiazomethane was compared with ethyldiazoacetate for the rhodium, copper, and
cobalt catalyzed formation and [2,3] rearrangement of allylsulfonium ylides. At room temperature,
the reaction could be carried out using the allyl sulfide as the limiting reagent by slow addition of
3 equiv. of the diazo compound. Slightly better yields were obtained with trimethylsilyldiazomethane
than with ethyldiazoacetate to generate the -trimethylsilyl thioethers <1999TL1617>.
The reaction of mono- or bissilylated thioanisole derivatives with 3,4-epoxybutyltosylate)
afforded the cyclopentanols. Migratory aptitudes of two different silyl groups in the Brook
1,4-rearrangement was examined giving the order SiMe2Ph > SiMe3 > SiMePh2 <1998T11481>.
Successive treatment of the (Z)--trimethylsilyl allylic alcohols with copper(I) t-butoxide
and allylic halides followed by the tetrabutylammonium fluoride-assisted hydrolysis produced
the allylation products, 2,5-alkadien-1-ols, with complete retention of configuration. Similar
treatment of the organometallic intermediates with aryl and vinylic halides in the presence of
palladium(0) catalyst gave the corresponding cross-coupling products in good yields. The
stereoselective preparation of the starting materials was also described <2002JOC8450>.
A cumene solution of -stannylbenzylphenyl sulfide was treated with BunLi and bis(oxazoline)-
Pri at 78 C and subsequently with benzophenone to give the product with 99% ee. It was
confirmed that the reaction of -lithio benzylphenyl sulfide proceeds through a dynamic kinetic
resolution pathway. The enantioselective reactions of -lithio benzyl 2-pyridyl sulfide gave the
products with stereochemistry reverse to that obtained in the reaction of benzylphenyl sulfide. It
was established that this reaction proceeded through a dynamic thermodynamic resolution
pathway in which the reaction with an electrophile proceeded faster than interconversion between
the diastereomeric complexes <2000JA11340>.
(ii) From thioethers, ethers, and silylated acetals and thioacetals

The tin(IV) chloride promoted reaction of -trimethylsilylthioacetals 87 with trimethylsilyl enol
ethers gave -phenylthio ketones 88 (Equation (26)) <2002JOC8450>.
SiMe3 Me3Si O
OSiMe3
SnCl4/CH2Cl2
SPh + R 3 R1
R3
R1 –78 °C
SPh PhS
R2 12 h R2
87 ð26Þ
88
R1 = Ph(CH2)2 R2 = R3 = –(CH2)4–, 91%
1 = Pri
R R2 = H, R3 = Ph, 75%
R1 = Ph(CH2)2 R2 = H, R3 = Et, 90%
Iron salts efficiently catalyzed the Doyle–Kirmse reaction of allyl sulfides with (trimethylsilyl)-
diazomethane and ethyldiazoacetate in dichloroethane at 83 C to provide the -thiosilyl com-
pound 89. Competitive dimerization was less of a problem with (trimethylsilyl)diazomethane than
with ethyldiazoacetate. Good results were obtained using only 1.5 equiv. of (trimethylsilyl)-
diazomethane, even without slow addition. Phosphine ligands affect the kinetics, but not the
diastereoselectivity. DPPE and BINAP led to higher yields than DPPP, but no enantioselection
was detected with R-(+)-BINAP (Equation (27)) <2000OL1303>.
H SiMe3
RS R1 5% RS SiMe3
+ Fe cat.
R2 ClCH2CH2Cl
N2 84 °C ð27Þ
R1
R2
89
R = Ph, R1 = R2 = Me, 88%
The -thiosilyl compound 90 was deprotonated with BunLi/ButOK followed by alkylation with
alkyl halides to afford the corresponding alkylated products 91 (Equation (28)) <1995TL3861>.
The dimethyl(1-phenylthio)cyclopropylsilyl group has been used as a masked hydroxyl group
<1995TL3861>.
R R2 R
PhS SiMe2 PhS SiMe2

BunLi, ButOK
THF, –80 °C
ð28Þ
R1X
90 91
R = Ph R = Ph; R1 = Me, 87%
R = HC CH2 R = Ph; R1 = allyl, 90%
R = HC CH2 ; R1 = Ph , 90%
Organolithium reagents stabilized by halogeno, thio, silyl, vinyl, and/or phenyl substituent(s) could
cleave THF effectively under the influence of boron trifluoride etherate at lower temperatures. The
softness of these carbanionic reagents seemed to be important for successful reaction <1995CL355>.
The iron-catalyzed Kirmse reaction was used to generate -silyl thioethers 92 via the reaction
of allylthio ether with (trimethylsilyl)diazomethane (Equation (29)) <2002JOC6711>.
Me SR
Me
SR
N2 5 mol.%
DPPEFeCl2
+ SiMe3
ClCH2CH2Cl ð29Þ
Me2Si
80 °C
R = Et, 89%
R = Ph, 91%
Me Me
Me Me
92
Propargyl sulfides were shown to be efficient partners for the iron-catalyzed addition/rearran-
gement reaction with trimethylsilyldiazomethane (Equation (30)) <2001JOC5256>.
5 mol.% DPPEFeCl2 RS SiMe3
SR Me3SiCHN2
ð30Þ
ClCH2CH2Cl
83 °C R'
R'
A general method for the synthesis of -silylated thio cyclic compounds 93 has been described
that employed a Diels–Alder cycloaddition reaction (Scheme 32) <2000JOC9206>.
BuLi Bt O (Me3Si)2S H
Bt O S
Ph Me3SiCl Ph
HCl, MeOH
SiMe3 Me3Si Me3Si S
H
93
Scheme 32
Acyl silanes with terminal -stannyl bromide or xanthate functionalities have been prepared.
-Stannyl radicals generated from these acyl silanes undergo intramolecular cyclizations to give
cyclic silyl enol ethers regiospecifically. The radical processes involve radical cyclization, Brook
rearrangement, and -fragmentation in sequence. A tributylstannyl group serves as the radical
leaving group. The newly formed -bond and -bond are located between the same two carbon
atoms. This approach is limited to the formation of five-membered rings. In another route,
!-bromo--phenylsulfonylacyl silanes are synthesized. The radical cyclizations of these -sulfo-
nylacyl silanes also give cyclic silyl enol ethers. The phenylsulfonyl moiety is the radical leaving
group in this system. Furthermore, the newly formed -bond and -bond are located at adjacent
positions sharing a single carbon atom. The latter approach is effective for both five- and six-
membered ring formation <2001JOC8983>.
Thioacyl silanes containing the ferrocene moiety, easily prepared from the corresponding acyl
silanes with Lawesson’s reagent at room temperature, could be transformed into vinyl silanes,
sulfur heterocycles, and sulfines <1999TL6473>.
A number of 1,4- and 1,5-acylsilane dicarbonyl compounds were synthesized using Corey–
Brook dithiane methods. These dicarbonyl substrates were annulated with the bis(trimethylsilyl)
enol ether of methylacetoacetate in the presence of TMSOTf, affording bicyclic ethers bearing
silicon substituted at the bridgehead position. The annulation reactions proceeded with excellent
regiochemical and good-to-excellent stereochemical control via a neighboring group participation
mechanism <1995JOC130>.
(iii) From dienes and allenes

Reaction of several silylated acetals with hexamethyldisilathiane (HMDST) in the presence of
cobalt(II) chloride hexahydrate afforded a simple, novel, and general entry to thioformylsilanes,
directly trapped in situ as their Diels–Alder cycloadducts 94 (Scheme 33) <1997SL361>. The
results are summarized in Table 4 <1997SL361>.
S
HgO/HgCl2 R'O OR' HMDST
S S R'OH CoCl2.6H2O
H SiR3 H SiR3
S
H SiR3 R3Si
94
Scheme 33
Table 4 Synthesis of thioformylsilanes

Acetal Diene Product Yield (%)
O O
Me3Si S 41
Me3Si H
H
O O
Me3Si S 37
Me3Si H
H
S
O O H 64
Me3Si H SiMe3
O O
Et3Si S 51
Et3Si H
H
MeO OMe
H ButMe2Si S 41
ButMe2Si
H
MeO OMe
S 56
PhMe2Si H PhMe2Si
H
MeO OMe S
H
H
58
PhMe2Si SiMe2Ph
MeO OMe
Ph2MeSi S
H 62
Ph2MeSi H
MeO OMe S
H
H 54
Ph2MeSi SiMePh2
Treatment of different silylated allenes 95 with hexamethyldisilathiane (HMDST) in the pre-

sence of cobalt(II) chloride hexahydrate afforded an easy and high yielding access to
,-unsaturated thioacyl silanes 96, which undergo a self-dimerization reaction to afford poly-
functionalized 1,2-dithiodienes as the major products (Scheme 34) <2003TL2831>. The repre-
sentative examples thioacyl silanes are outlined in Table 5 <2003TL2831>.
SiMe3 SiMe3
Me3Si HMDST
O O SiMe3
CoCl2.6H2O
S + S +
CH3CN S S S
rt, overnight S SiMe3
SiMe3 SiMe3
95 96
65% 16% 25%
Scheme 34
Table 5 Thionation of silylated allenes

Allene Product Yield (%)
SiMe3
Me3Si O O
S
. S 65
SiMe3
SiMe2 Ph
PhMe2Si O O
S
. S 59
SiMe2Ph
SiMePh2
Ph2MeSi O O
S
. S 36
SiMePh2
SiMe2c-C6H11
c-C6H11Me2Si O O
S
• S 42
SiMe2c-C6H11
SiMe3
Me3Si O O
S
. S 57
SiMe3
SiMe2But
ButMe2Si O O
S
· S
29
SiMe2But
(iv) Other routes

A cumene solution of -stannylbenzylphenyl sulfide 97 was treated with BunLi and bis(oxazo-
line)-Pri and subsequently with benzophenone to give the corresponding chiral -thiosilane 98
(Equation (31)) <2000JA11340>.
BunLi
O O
N N S E
Pri Ph *
Ph
S SnBu3 Pri ð31Þ
E+ Ph
Ph Cumene, –78 °C 98
97
+
E = Me3SiCl 57%, 77% ee
= Me3SiOTf 76%, 77%
It has been demonstrated that the reaction of 2-silanaphthalene 99 with excess sulfur afforded a
cyclic trisulfide 100 (Equation (32)) <1999JA11336>.
SiMe3 SiMe3 SiMe3

Me3Si SiMe3
SiMe3 SiMe3
S S SiMe3
Si S8 excess S
Si ð32Þ
benzene
SiMe3 SiMe3 20%
SiMe3 SiMe3
99 100
4.08.1.2.2 Sulfur and germanium—R12C(SR2)GeR33, etc.

Different methods have been reviewed in COFGT (1995) to generate -germylsulfur systems from
-germylorganomagnesium compounds or from germylthioethers: reverse Brook rearrangement,
from halomethylgermanes, and from vinylgermanes. No further advances have occurred in this
area since the publication of chapter 4.08.1.2.2 in <1995COFGT(4)351>.
4.08.1.2.3 Sulfur and boron—R12C(SR2)BR32, etc.

The examples of systems containing an -thioalkylboron unit have been described in COFGT (1995)
from methylphenylthio ethers, diphenyldithioacetals, -haloboronates, alkylation of -phenyl-
thioboronates, and other miscellaneous methods. The following synthetic routes describe the
preparation of systems containing sulfur to boron.
(i) From -thioboronates

Specifically, BrCH2CHF2, BrCH2COOBut, and CH2¼CHCOOMe were allowed to react
with the stabilized anion of (phenylthio)methane boronate, PhSCH2BO2C6H12 derived from
deprotonation of the corresponding (phenylthio)methane boronate 101 to give the substituted
boronate 102. The substituted (phenylthio)methane boronate was converted to the corresponding
sulfonium ion by treatment with methyl iodide and subsequently displaced with iodide. The
-iodo derivative was converted to the amine by conventional methods (Scheme 35)
<2001JOC6375>.
The -thioboronate ester was generated from the 2-bromomethyl-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane. The boronate ester was reacted with lithio(hexamethyl)disilazane followed
by (dichloromethyl)lithium to provide the corresponding -chloro boronate ester 103 which
reacted further with sodiomethanethiol to produce the -thioboronate ester 104 (Scheme 36)
<1997HAC487>. It should be noted that -chloro boronate ester failed to react with lithium
benzyloxide.
LDA
O O
THF, 0 °C
S B S B
CH2 O OBut CH O
Br
O
0 °C to rt, 16 h, 35% OBut
O
101 102
Me O O
Mel
S+ B
O I B
CH3CN CH CH O
NaI 49%
reflux, 5 h OBut OBut
O O
Scheme 35
i. MeOH O
O O ii. CH3CN O
Me3Si B NaSMe rt, 15 min R
Me3Si B B
N O O N N O
rt, N iii. Me3SiNCO
Me3Si Cl THF, or PhCH2NCO H H SMe
3d Me3Si SMe
56.2% R=H 24%
104 R = PhCH2 quantitative
103
Scheme 36
(ii) From sulfones and vinyl sulfides

The reaction of sulfone anions 105 with trialkylboranes followed by thermal isomerization of the
obtained boron compounds in the presence of excess borane–methyl sulfide complex and by
alkaline hydroperoxide oxidation gave primary alcohols (Scheme 37) <2003TL4451>.
R BR32 R
BunLi R OH
SO2Ph rt, 15 h
toluene
SO2Ph H2O2
–78 °C to rt
R1 53–82% R1 R2
R1 Li
NaOH
105
R = –CH2Ph
R1 = H, Me, Et, –CH2Ph
R2 = Et, Bu, and hex.
Scheme 37
-Thioboronate esters 106 are obtained directly in high yield and selectively from metal-
catalyzed additions of BX bonds (X = H, B) to thiocarbonyl compounds and vinyl sulfides
(Equation (33)) <2001OM2130>.
S O
S O O B
Pt(DBA)2
+ B B B O
C6D6 O O
O O
rt, 2 days ð33Þ
93%
106
(iii) From vinylboronates

The vinylboronic esters when reacted with the O-acyl derivative of N-hydroxypyridine-2-thione
underwent the abstraction of thiopyridyl fragment that opened an interesting route to -thio
boronic esters (Equation (34)) <1995T6999>.
O
BL2 BL2
N hν, CH2Cl2
+ R O R ð34Þ
S2-Pyr
S
L = alkoxy ligand
4.08.1.3 Functions Bearing Selenium or Tellurium
4.08.1.3.1 Selenium or tellurium and silicon—R12C(SeR2)SiR33, etc.

The different routes to selenium systems containing an -silicon functionality have been
described in COFGT (1995) by direct deprotonation of selenium compounds, from selenoacetals
and selenoketals, from vinyl selenides, from aldehydes and thioaldehydes, from vinyl silanes,
and from (halomethyl)trimethyl silanes. The preparation of dialkyl tellurides has been achieved
by alkylation of sodium tellurides with alkyl chlorides. Described below are synthetic routes
based on 1-seleno-2-silylethenes leading to systems containing selenium to silicon.
The reaction of (E)-1-(phenylseleno)-2-(trimethylsilyl)ethene 107 and vinylketones in the
presence of a chiral Lewis acid prepared from TiCl4, Ti(OiPr)4, (R)- or (S)-1,10 -binaphthol
(BINOL), and 4 Å molecular sieves (MS4 Å) gave enantiomerically enriched cis cyclopropane
products 108. The enantiomeric excess and chemical yield varied depending on the ratio of TiCl4
and Ti(OiPr)4 to (E)-1-(phenylseleno)-2-(trimethylsilyl)ethene. Reproducible results (43–47%
ee/33–41% yields) for cis-1-acetyl-2-[(phenylseleno)(trimethylsilyl)methyl]cyclopropane) were
obtained using 1.1 equiv. of TiCl4, 0.54–0.65 equiv. of Ti(OiPr)4 and 1.65 equiv. of BINOL. The
observed enantioselectivity was explained by consideration of the structure of the postulated
intermediates, alkoxy titanium–carbonyl complexes, via ab initio MO calculations (Equation
(35)) <1996JOC4046>.
SePh O
TiCl4-Ti(O-Pri)4
+ (R )- or (S )-BINOL
R
Me3Si MS4Å R SiMe3
107
O SePh ð35Þ
108
R = Me
R = Et
R = n-pentyl
R = –But
The reactions of 1-seleno-2-silylethenes with highly electrophilic tricarbonyl-substituted olefins in

the presence of Lewis acids have been investigated. The reaction of 1-(phenylseleno)-2-(trimethylsilyl)
ethane with tris(alkoxycarbonyl) olefins or 1,1-bis(alkoxycarbonyl)-2-acyl olefins in the presence of
ZnBr2 at 30 C gave cis-substituted cyclopropanes exclusively. The origin of the cis stereochemistry
was ascribed to the synclinical addition path of the ZnBr2-coordinated electrophilic olefin. Applica-
tion of the highly functionalized selenium- and silicon-substituted cyclopropane products to the
preparation of a useful synthetic intermediate for the pyrethroid class of insecticides was also
demonstrated <1997JOC2968>.
The reaction of 1-seleno-2-silylethene and methylenemalonate ester in the presence of Lewis acid
(zinc bromide) provided highly functionalized cyclopropanes <1995JOC6546> which were utilized
for further functional group transformations <1999JOC282>. The [2+1]-cycloaddition reactions
of a 1-seleno-2-silylethene 109 to 2-sulfonylacrylates 110 were also studied (Equation (36))
<1999JOC9521>.
SePh
O O H SO2Ar
O SnCl4 EtO2C
+ C S PhSe CO2R + SePh
Ar –78 °C H PhO2S
RO CH2Cl2 Me 3Si 14% ð36Þ
Me3Si
R = Me, Ar = p-Tol, 56%
R = Et, Ar = p-Tol, 34%
109 110
R = Et, Ar = Ph, 26%
The stereoselective [2+1]-cycloaddition reactions of 1-seleno-2-silylethenes with di()-menthyl-

ethane-1,1-dicarboxylates has also been explored <1999JOC2367>.
4.08.1.3.2 Selenium or tellurium and germanium—R12C(SeR2)GeR33, etc.

According to COFGT (1995), few examples of compounds containing a germyl group to a
selenium or tellurium are known. One important method to generate -selenogermane has been
through iodide displacement from (iodomethyl)trimethylgermane using lithium phenylselenide.
No further advances have occurred in this area since the publication of COFGT (1995) (chapter
4.08.1.3.2).
4.08.1.3.3 Selenium or tellurium and boron—R12C(SeR2)BR32, etc.

As indicated in COFGT (1995), there are no reports of significant routes to systems containing a
boron function to a selenium or tellurium.
The selenoalkenyldicyclohexylboranes, readily prepared by the hydroboration of internal
alkylselenoacetylenes with dicyclohexylborane followed by iodination under basic conditions,
produced cis/trans 1,2-disubstituted alkenyl selenides. The mechanism of the reaction probably
would involve a system containing a boron function to a selenium <1996JOM139>.
4.08.2 FUNCTIONS CONTAINING A CHALCOGEN AND A METAL
4.08.2.1 Functions Bearing Oxygen—R12C(OR2)M, etc.

The formation of carbanions adjacent to an oxygen function has been reviewed in COFGT (1995).
A recent review describes the asymmetric [2,3]-Wittig rearrangement as a general tool for the
asymmetric synthesis <1997PAC595>. Another review on the functions bearing oxygen has
appeared in the literature <1997AG(E)2282>.
4.08.2.1.1 Lithium, sodium, or potassium

The synthetic routes leading to an sp3 carbon attached to oxygen and lithium, sodium, or
potassium have been outlined in COFGT (1995), and include direct deprotonation of a saturated
carbon adjacent to oxygen, tin–lithium exchange, reductive lithiation of -phenylthioethers,
halogen–lithium exchange, lithiation of allylic and benzylic ethers, lithiation of -cyano ethers,
and lithiation of O-alkylcarbonates and O-alkylcarbamates. Listed below are routes leading to an
sp3 hybridized carbon attached to oxygen and lithium, sodium, or potassium.
(i) By direct deprotonation

Oxiranyllithium compounds 111 generated from epoxy sulfones by deprotonation with n-butyl-
lithium in THF at 100 C react with alkylhalides to give new substituted epoxides 112 in high
yields (Scheme 38) <1996TL2605>.
Treatment of benzyl ethers of primary alcohols 113 with n-butyllithium afforded terminal
alkenes in good yield (Scheme 39) <1996CL1039>.
O SO2Tol BunLi O O
SO2Tol RX SO2Tol
THF–DMPU
–100 °C Li 41–97% R
111 112
Scheme 38
BunLi THPO(CH2)10OCHPh –78 to 0 °C

THPO(CH2)10 OCH2Ph RCH CH2 + PhCH2OH
–78 °C 79%
THF Li
113
Scheme 39
The stereospecific -lithiation of optically active styrene oxides and the trapping reaction of the
corresponding highly reactive intermediates with electrophiles to produce optically active styrene
oxide derivatives 114 have been described. This method has been applied to the synthesis of an
optically active oral antifungal agent of industrial interest (Scheme 40) <2002OL2445>.
O Bus Li Li E+ E
O O
Ph TMEDA Ph 40–95% Ph
THF
–98 °C 114
10 min
Scheme 40
Enantioselective -deprotonation–rearrangement of a chiral-substituted cyclooctene oxides

using organolithiums in the presence of ()-sparteine or ()--isosparteine gave the functiona-
lized bicyclo[3.3.0]octan-2-ols in 56–72% yields and 83–89% ees <2001OL441>.
Treatment of chiral -benzyloxy-oxycarboxamide 115 with ButLi gave -hydroxycarboxamides
116 in high optical purity through the formation of -lithiated ethers and subsequent 1,2-Wittig
rearrangement (Scheme 41) <2001TL4865>.
O – Li + OH O
Ph
NHPh ButLi O
Ph Li 69%
THF, –78 °C NPh
Ph Ph NHPh
Ph
O Ph
O
116 (94% ee)
115
Scheme 41
The cyclization induced by tin–lithium transmetallation of the enantio-defined stannanes was

shown to proceed with complete retention of configuration at the Li-bearing sp3-carbon to afford
the enantio-enriched ,-disubstituted tetrahydrofurans <1997TL8939>.
The phenylsulfonyl group promotes the dearomatizing cyclization of tethered organolithiums onto
aromatic rings. With an ether tether, the cyclizations create a new tetrahydrofuran ring, and both
cyclization and subsequent electrophilic quenches proceed with high levels of diastereoselectivity.
The sulfonyl group can be removed from the cyclized products oxidatively or reductively. The
dearomatizing cyclization of a naphthylsulfone was used in the synthesis of a close structural analog
of podophyllotoxin (Scheme 42) <2003OL831>.
SO2Ph SO2Ph SO2Ph E

Li PhO2 S H
SnBu3 Li
MeLi E+
O O
O TMEDA O
THF
–78 °C H E+ = NH4Cl, 69%
OMe OMe OMe O
= MeI, 67%
= Br, 71%
= BnBr, 71%
Scheme 42
MOM-protected -hydroxytrimethylstannanes do not undergo tin–lithium exchange cleanly as

their tributyl-counterparts do. Other protecting groups (e.g., N,N-diethylcarbamate) allow for
clean transmetallation to occur presumably due to the formation of a more stable -alkoxyorga-
nolithium species <1998TL9617>.
Aryl methyl alkyl ethers were metallated with BunLi or BusLi in THF at different temperatures,
affording -alkoxy-substituted aryl methyllithium derivatives. At low temperatures, the organo-
metallics derived from methyl and isopropyl ethers are sufficiently stable to react with added
electrophiles affording the expected products. On the contrary, under similar conditions, lithium
derivatives of primary alkyl benzyl ethers rapidly decay to benzyl alcohol (Scheme 43)
<1998T12389>.
Li SiMe3
CH2OCH3 CHOCH3 CHOCH3
BusLi Me3SiCl
THF H2O
–80 °C
68%
F F F
Scheme 43
Stable -methoxy aryl methyl carbanions can be generated by metallation of aryl methyl
methyl ethers with BunLi in THF at 40 C, avoiding Wittig rearrangement to the corresponding
alkoxides. Reaction of these carbanions with various electrophiles afforded the expected products
in satisfactory yields. Connection between the metallation procedure and the reductive electro-
philic substitution of aryl methyl methyl ethers allowed the transformation of compounds into
2-arylpropanoic acids (Scheme 44) <1995TL5641>.
Li CH3
CH2OCH3 CHOCH3 CHOCH3

BunLi CH3I
Hexane / THF –40 °C
–40 °C 1h
1h 86%
Scheme 44
Several substituted five- and six-membered cyclic ,-unsaturated ketones were readily available
by treatment of the corresponding -hydroxy epoxides with an organolithium reagent. The reaction
involves a new carbenoid 1,2-alkyl rearrangement. Evidence for the carbenoid intermediate
has been obtained by intramolecular trapping of the highly reactive species (Scheme 45)
<1995JA12700>.
O O
HO n-C5H11 LiO n-C5H11 LiO n-C5H11 n-C5H11
2BunLi Li –78 °C to rt
1h +
O –78 °C O OLi
THF 70% n-C5H11
18 min 50% 50%
Scheme 45
The enantioselective lithiation and substitution of (E)-cinnamyl N,N-diisopropylcarbamate

through the use of ()-sparteine complexes reactions lead to diastereomeric lithium carbanion
pairs that are configurationally unstable and equilibrate even at temperatures below 50 C.
The initially formed epimer (1S)-epi- is rapidly converted to the thermodynamically more stable
(1R)- (in toluene solution). Carboxylation, acylation with acid chlorides, stannylation, and silyla-
tion take place at the -position with stereoinversion (79%–86% ee) (Scheme 46)
<1998EJO2397>.
HRHS H
Li Li
H
BunLi
OCb Slow
Chiral ligand S OCb R OCb
i
Cb = CON- Pr2
Ph Ph Ph
Me3SiCl Me3SiCl
Chiral ligand = 88% 29%
N N SiMe3 SiMe3
Li
R OCb S OCb
58% ee
Ph Ph
Scheme 46
The metallated epoxides have been used as sources of carbenoids, and the solvent effects on
competing intramolecular carbon–hydrogen and intermolecular carbon–lithium insertions in -
alkoxy epoxide systems have been studied. The slow addition of the organolithium reagent to a
dilute solution of the epoxide favored an intramolecular CH insertion over an intramolecular
CLi insertion into the epoxide-derived carbenoids. Solvation of the carbenoid lithium atoms
was decisive as regards the stereoselectivity of the process <1999JOC9279>.
Treatment of benzyl ethers of primary alcohols with n-butyllithium (BunLi) afforded terminal
olefins in good yield <1996CL1039>.
(ii) By tin–lithium exchange

The [2,3]-Wittig rearrangement of (E)-crotyl propargylic ethers, when induced with a ButLi/chiral
bis(oxazoline) complex, was shown to provide high enantioselectivity (up to 89% ee) along with
high diastereoselectivity <1998TL5513>.
The (E)/(Z)-selectivities in the [2,3]-Wittig rearrangements of secondary -(methyl or silyl)-
allylic ethers were shown to depend critically on the nature of groups on the carbanion terminus,
thereby permitting elucidation of the structural requirements for attaining high (Z)-selectivity
(Scheme 47) <1999TL6257>.
Me Me Me Me
R R R
BunLi
O SnBu3 THF +
O Li R
HO Et HO Et
Et –78 °C
Et 76%
R = n-Bu
R Me Me Me
R 24% 76% R
BunLi
O SnBu3
THF O Li 16% HO Et
Et –78 °C
Et
R = n-Bu
Scheme 47
A chiral derivative of tributylstannylmethanol 117, readily prepared from L-valine, underwent

Sn–Li exchange to provide an -alkoxyorganolithium that added to aldehydes to provide pro-
ducts 118 with up to 91:9 dr. The diastereoselectivity depended on the solvent and alkyllithium
used for transmetallation. Treatment of adducts with acid allowed recovery of the chiral auxiliary
and diol with complete stereochemical integrity (Equation (37)) <2001OL2903>.
BunLi Ph
O Ph O
THF Ph
O SnBu3 PhCHO O ð37Þ
80% OH
117 118
The [2,3]-Wittig rearrangement of an enantiomerically defined -propargyloxy stannane with
butyllithium was shown to proceed with complete inversion of configuration at the Li-bearing
terminus. The periselectivity ([2,3]- versus [1,2]-) of the rearrangement depended upon the nature
of substituents on the group (Scheme 48) <1997SL1045>.
. R .
2,3 R
Wittig +
HO n-C8H17 n-C8H17
R HO
(Retention) (Inversion)
R
SnBu3 BunLi R = H, 56%
O Li R = SiMe3, 67%
THF O
n - C8H17 –78 °C n-C8H17 R = Me, 79%
R
1,2
Wittig
HO n-C8H17
Scheme 48
The Still–Wittig rearrangement gave opposite selectivities for (Z):(E)-alkenes in THF(3:1)

versus toluene (1:3) in the synthesis of serine–proline dipeptide amide isoesters (Scheme 49)
<2001OL1789>.
OH
BnO BnO
BnO BnO
BunLi
+
Bn2N Bn2N
Bn2N –78 °C Bn2N OH
O Li
O SnBu3
THF 3:1
Toluene 1:3
Scheme 49
Treatment of benzyl -(trimethylsilyl)propargyl ether with n-butyllithium was shown to afford

the ortho-[2,3]-Wittig product in remarkable preference to the [1,2]-Wittig product. The factors
governing the periselectivity in this type of carbanion rearrangement were discussed
<2000CL1394>.
The carbamate-protected -alkoxyorganolithium 119 derived from the stannane could be
trapped with benzaldehyde to provide the corresponding secondary alcohol 120 (Scheme 50)
<1998TL9617>.
OCON(Pri)2 OCON(Pri)2
OCON(Pri)2
BusLi PhCHO
n -C5H11 SnMe3 –95 °C 80% n -C5H11 CHOHPh
n- C5H11 Li
119 120
Scheme 50
(iii) By reductive lithiation of thioethers and sulfoxides

Configurationally defined -alkoxylithium reagents were prepared by reductive lithiation of
4-(phenylthio)-1,3-dioxanes. A new and more general synthesis of 4-(phenylthio)-1,3-dioxanes
has been developed on the basis of the reduction and in situ acetylation of 1,3-dioxan-4-ones.
For each of the substitution patterns examined reductive lithiation gave the axial alkyllithium
with 99:1 stereoselectivity. Equilibrations of these alkyllithium reagents were possible with
unhindered substrates to give the equatorial alkyllithiums with excellent stereoselectivities. The
more hindered axial alkyllithium reagents did not equilibrate efficiently. The equilibrium between
alkyllithium reagents strongly favored the equatorial isomer. The inefficient equilibration with
this hindered substrate was attributed to a slow rate of equilibration rather than insufficient
driving force. These alkyllithium reagents could be coupled with a variety of electrophiles with
retention of configuration by direct addition, copper-mediated coupling, or transmetallation to
the corresponding alkylzinc reagents followed by copper-mediated coupling (Scheme 51)
<1999JOC6849>.
SPh
LiDBB Li Li
–20 °C
O O THF, –78 °C
O O 30 min O O
LiDBB = lithium di-t-butylbiphenylide

78% 52%
Acetone
–78 °C Acetone –78 °C
OH OH
O O O O
Scheme 51
The first generation of destabilized oxiranyllithium and oxiranyl Grignard reagent from
sulfinyloxiranes with ButLi or EtMgCl was described. Treatment of -methyl ,-epoxy sulfoxide
(sulfinyloxirane) 121 with ButLi in THF at 100 C gave oxiranyllithium 122 having a carbanion
destabilizing group. The oxiranyllithium reacted with trimethylsilyl chloride to give a new epoxide
123 in good yield. Oxiranyl Grignard reagent could be generated by the reaction of the sulfinyl-
oxirane having at least one aromatic group on its -position with EtMgCl (Scheme 52)
<1995TL8235>.
O O
Ph ButLi Me3SiCl O
H3C Ph Ph
H3C H 3C
Ph THF, –100 °C Li Ph –100 °C
TolS(O) 30 s Ph
10–30 min SiMe3
82%
121 122 123
Scheme 52
(iv) By halogen–lithium exchange

The reaction of equimolecular amounts of chloromethyl ethyl ether and dimethylphenylsilyl
chloride with excess lithium powder (1:7 molar ratio) and a catalytic amount of 4,40 -di-t-butylbi-
phenyl (DTBB) (5 mol.%) in THF at 0 C provided the corresponding ethyl (dimethylphenyl)-
methyl silyl ether 124 (Scheme 53) <1996T1643>.
Li PhMe2SiCl
EtO Cl EtO Li EtO SiMe2Ph
DTBB 86%
THF, 0 °C 124
Scheme 53
4.08.2.1.2 Magnesium
The systems containing magnesium - to an oxygen have been described in COFGT (1995). The
most notable example was the preparation of a Grignard reagent through chloromethyl methyl
ether in diethyl ether as a solvent. No further advances have occurred in this area since the
publication of COFGT (1995) (chapter 4.08.2.1.2).
4.08.2.1.3 Titanium or aluminum

As outlined in COFGT (1995), lithiated carbamates have been metal-exchanged with
tris(dimethylamino)titanium chloride or diisobutylaluminum methanesulfonate resulting in
titanium and aluminum intermediates, which were used in stereoselective aldol reactions with
aldehydes and ketones.
A metallocycle containing -alkoxy titanium species has been shown to be an intermediate in the
reductive cyclization of enones to cyclopentanols catalyzed by bis(trimethylphosphine)titanocene
<1996JA3182>. Lewis acid-assisted cleavage of an orthoformate could give rise to -alkoxy
organozinc carbenoids in the synthesis of alkoxycyclopropanation reaction <1998CC2191>.
(E)-But-2-enyl N,N-diisopropylcarbamate after deprotonation to its lithium/()-sparteine
complex gave with trialkyltin chlorides mixtures of the 3-oxy- and 1-oxy-substituted, enantio-
merically enriched allylstannanes in high regioselectivity and in enantiomeric purity (95% ee)
via a delithiotitanation (inversion) and detitanostannylation (anti-SE0 ) sequence. The titanium
tetrachloride mediated condensation of (S)- and (R)-allylstannanes with aldehydes or ketones
proceeded via titanodestannylation to yield (Z)-anti-homoaldol products with complete chirality
transfer <1996S141>.
4.08.2.1.4 Copper or zinc

In COFGT (1995), several methods were described to generate -alkoxycuprates and -alkoxy-
zinc compounds. The major method to prepare -alkoxycuprates included a route from -
alkoxystannanes by transmetallation with n-butyllithium, followed by the addition of copper(I)
cyanide. The -alkoxyzincates have been prepared from iodomethyl esters with activated zinc in
tetrahydrofuran.
The conjugate addition of -alkoxystannanes 125 via in situ transmetallation using catalytic
copper(I) cyanide proceeded through -alkoxy copper species (Scheme 54) <1996TL3811>.
O
O
S
N R
C
O N CuCN
C
THF O S 30–86% O N
23–50 °C C
R SnBu3 2–8 h
R Cu(CN) S
125
Scheme 54
4.08.2.1.5 Mercury
The -alkoxyorganomercury compounds have been prepared by the photochemistry of -diazo-
mercurials and the reaction of mercuric oxide/mercuric acetate with dialkyl-aralkylhydrazones.
No further advances have occurred in this area since the publication of COFGT (1995)
(chapter 4.08.2.1.5).
4.08.2.1.6 Tin
The -alkoxystannanes were prepared from acylstannanes, from aldehydes and ketones, from
tributylstannylmethyl iodide, from tributyltin chloride, and from tributylstannylacetals as described
in COFGT (1995).
The following section outlines the generation of systems containing oxygen to tin.
(i) From hydrostannation

Hydrostannation of chromium alkynylcarbene complexes 126 with tributyltin hydride provided a
facile, sterically controlled synthesis of alkoxy-substituted propargylstannanes 127. The synthetic
scope and mechanistic implications were reported (Equation (38)) <1995TL1011>.
Cr(CO)5 Bu3SnH
pyridine SnBu3
OMe hexanes, 0 °C Me3Si ð38Þ
Me3Si 61% OMe
126 127
Hydrostannation of readily available chromium and tungsten vinylcarbene complexes 128

with tributyltin hydride provided a facile synthesis of alkoxy-substituted allylstannanes 129.
The results are summarized in Table 6 <1995TL1007>. The preparation of acetal, keto,
methoxy, and silyl-substituted stannane reagents was demonstrated (Equation (39))
<1995TL1007>.
W(CO)5 SnBu3
Bu3SnH
pyridine ð39Þ
Me OMe hexanes, rt Me OMe
128 129
Table 6 Hydrostannation reactions of carbene complexes

Carbene Conditions Product Yield (%)
W(CO)5 SnBu3
Bu3SnH, 3.0 equiv.
Pyridine, 6.0 equiv. 73
Me OMe Hexanes, rt Me OMe
W(CO)5 SnBu3
Bu3SnH, 1.4 equiv.
Ph OMe Hexanes, 0 C Ph OMe
Me W(CO)5 Me SnBu3
Bu3SnH, 3.0 equiv.
Me OMe Hexanes, rt Me OMe
Me Cr(CO)5 Me SnBu3
Me Bu3SnH, 1.4 equiv. Me

Me O DMAP, 3.0 equiv. Me O 42
Hexanes, THF, 0 C
O O
Ph Cr(CO)5 Ph SnBu3
Bu3SnH, 1.5 equiv.
DMAP, 3.0 equiv. 69
MeO OMe Hexanes, THF, 0 C MeO OMe
Cr(CO)5 SnBu3
Bu3SnH, 1.1 equiv.

OMe DMAP, 3.0 equiv. OMe 55
Hexanes, THF, 0 C
Ph Ph
(ii) From carbonyl compounds

The aldehydes were treated with metallated acetylide to give propargyl alcohol. After reduction of
alkynes with LAH to obtain (E) alkenes, the allylic hydroxy group was deprotonated with KH or
KHMDS and alkylated with iodomethyltributyltin to afford the desired stannylated methylallylic
ether derivatives 130 (Scheme 55) <1996TL389>.
O M R2 OH OH
R1 THF or Et2O LiAlH4 ICH2SnBu3 Bu3Sn O
R1 R1
H M = MgBr or CeCl2 52–97% R2 KH or KHMDS R1
24–64% R2 THF, 73–95% R2
130
Scheme 55
A method has been reported for the synthesis of chiral cyclopentanes using tin–lithium
exchange and cycloalkylation reactions. The sec-butyllithium/()-sparteine-mediated deprotona-
tion of an alkylcarbamate and subsequent substitution furnished a highly enantioenriched
stannane as a stable carbanion equivalent. It was transformed into suitable cyclization precursors,
which underwent tin–lithium exchange and stereoselective cycloalkylation when reacted with
n-butyllithium, giving highly enantioenriched cyclopentanes in very good yields. A kinetic
resolution was observed with a higher substituted stannane <2002OL2189>.
The nucleophilic addition of trialkyltinlithium with 1-hexanal resulted in the formation of

-hydroxystannane 131, which was acetylated to give acetylated stannane 132 in 95% yield. The
corresponding MOM derivative 133 was also prepared in 65% yield. The Lewis acid-catalyzed
reduction of the MOM ether with triethylsilane then provided the simple methyl ether derivative 134
(Scheme 56) <1996JOC6492>.
OH OAc
THF AcCl
R3SnLi + C5H11CHO
–78 °C SnR3 Pr2i NEt
C5H11 C5H11 SnR3
131 132
R = Bu R = Bu
R = cyclohexyl R = cyclohexyl, 95%
MOMCl
Pr2i NEt, CH2Cl2
OMOM OMe
TiCl4
Et3 SiH
C5H11 SnR3 C5H11 SnR3
CH2Cl2, –78 °C
133 134
R = Bu R = Bu
R = cyclohexyl, 65% R = cyclohexyl
Scheme 56
The synthesis of -(alkoxyalkyl)stannane-substituted dienes and their conversion into eight-

membered cyclic ethers via ring-closing metathesis was reported. The condensation of lithiotri-
butylstannane 4-pentenal provided the hydroxystannane which was immediately converted to the
mesylate in 62% overall yield. The displacement of the mesylate with allyl alcohol or 3-butenol
provided dienes 135 followed by ring-closing metathesis with ruthenium 136 (Scheme 57)
<1997JA6919>. The results are summarized in Table 7 <1997JA6919>.
Bu3SnLi R R R
O OMs
THF O
O m
Ru m
H n –78 °C Bu3Sn n
HO ( )m
n = 1, 2 MsCl, Et3N KH Bu3Sn n Bu3Sn n

–40 °C Et2O
62% m = 0,1
135 136
R = H, CH3
Scheme 57
The allylsilane-tethered -stannyl ether 137 was prepared by the nucleophilic addition of the
aldehyde with lithiotributylstannane followed by treatment with mesyl chloride, potassium
hydride, and benzyl alcohol in 72% yield (Equation (40)) <2000JOC3252>.
LiSnBu3
TMS MsCl TMS
BnOH, KH SnBu3 ð40Þ
O 72% BnO
137
The intramolecular trans-cyclocarbolithiation of the -lithiated 4-substituted 5-hexynylcarba-

mate (1S,4RS)- employing lithiodestannylation was presented. The cis-/trans-5-exo-dig cyclization
products were formed exclusively. The highly enantioenriched organotin precursor was
synthesized via an asymmetric deprotonation of the corresponding alkylcarbamate by the chiral
complex sec-butyllithium/()-sparteine and subsequent substitution with tributyltin chloride
(Scheme 58) <2002OL2193>.
Table 7 Ring-closing metathesis of acyclic tributylstannyl substituted dienes

Diene Product Yields (%)
O SnBu3
92
Bu3Sn O
O SnBu3
74
Bu3Sn O
SnBu3
O O
38
Bu3Sn
SnBu3
O
O 84
Bu3Sn
SnBu3
O
O 96
Bu3Sn
O SnBu3
96
Bu3Sn O
BusLi O
OCb (–)-Sparteine OCb TBAF, Et2O
TBDMSO TBDMSO OCb
–78 °C, Et2O (COCl)2, DMSO H
Cb = CON-i-Pr2 Bu3SnCl, 88% Et3N, CH2Cl2
SnBu3 SnBu3
–78 °C, 95%
OH
H OCb OTBS
OCb OTBS
LDA TBSOTf
OCb OCb
LiCl 2,6-Lutidine
–78 to –20 °C CbO SnBu3 +
CH2Cl2
92% CbO SnBu3
0 °C CbO SnBu3
86%
Scheme 58
(iii) From acylstannanes

The acylstannane 138 was reduced with (R)-2,20 -dihydroxy-1,10 -binaphthyl-modified lithium alu-
minum hydride (R)-BINAL-H or (S)-BINAL-H followed by the protection of the hydroxyl group
as the (benzyloxy)methyl ether. The reaction provided the nonracemic (-alkoxyalkyl)stannanes
(Scheme 59) <1995JA10889>.
OCH2CH3 O OCH2OBn OCH2OBn

ButLi; Bu3nSnCl i. BINAL-H
or
ii. PhCH2OCH2Cl
H H3O+ Me SnBu3 iii. (Pri)2NEt Me Li Me Li
138 iv. BunLi
Scheme 59
(iv) From alkenylstannanes

Primary ozonides derived from alkenylstannanes displayed an unusual stability and can be
transformed into 1,2-diols by treatment with dimethyl sulfide and borane–methyl sulfide complex.
The observation has been incorporated into the development of a novel one-pot strategy for the
conversion of alkynes into 1,2-diols (Scheme 60) <2002OL383>.
R H O
O3 O O BH3.SMe2 HO OH
C C 58–69% R C H
MeOH R H C
–78 °C C C
H SnR3 H H
SnBu3
H
Scheme 60
The cis-1,2-bis(trimethylstannyl) ethene 139 underwent smooth epoxidation with MCPBA to

provide the corresponding cis-1,2-bis(trimethylstannyl)-substituted epoxides 140 (Equation (41))
<1995JOM239>.
H R O
CHCl3 H R
C C + MCPBA
–20 °C
SnMe3 SnMe3 Me3Sn ð41Þ
SnMe3
139 140
R = CH2OH, –CHMeOH, CMe2OH, –H, Ph
(v) From tri-n-butylstannyllithium

A convenient, general, and efficient one-pot synthesis of primary -alkoxy organostannanes 141
useful as hydroxymethyl anion equivalents was reported (Equation (42)) <1997SL1377>.
THF
–78 °C
Bu3SnLi + MeOCH2Cl Bu3SnCH2OMe ð42Þ
10 min
99% 141
(vi) From tri-n-butylstannyl acetals

-Tributylstannylacetals 142 derived from chiral C2 symmetrical diols were reacted with miscella-
neous organometallic reagents to give chiral -oxygenated organotins 143 and 144 in high yields.
The Lewis acid-promoted ring opening of the these chiral -tributylstannylacetals by organocopper
reagents, allyltins, or silylenol ethers has been considered to occur mainly according to an anti
process (dr = 70/30 to 93/7), the absolute configuration of the newly created center is S when the
reaction was performed with Me2CuLi/BF3 on the -stannylacetal derived from (2S,4S)-
2,4-pentanediol. Of interest was the reverse stereochemical trend obtained using organo-aluminum
reagents (dr = 30/70 to 15/85) since it becomes possible to reach selectively the new chiral center
with a preferential (R)- or (S)-configuration from the same precursor. The obtained -alkoxyalk-
ylstannanes can be transmetallated with n-butyllithium (THF, 78 C) to give configurationally
stable -alkoxyalkyllithiums. Furthermore, if desired, the enantioenriched -alkoxyalkylstannanes
derived from 2,4-pentanediol can be converted into enantioenriched -hydroxyalkylstannanes
(subsequently protected as MOM derivatives) with retention of configuration at the asymmetric
carbon using an appropriate oxidation--elimination sequence (Equation (43)) <1997T7615>.
R
O R1 R R R1 R R
R1M
Bu3Sn n +
Lewis ð43Þ
O acid Bu3Sn O n
OH Bu3Sn O n
OH
R
142 143 144
Reactions of a tin-substituted acetal with alkenols in the presence of an acid resulted in a facile
transacetalization followed by intramolecular cyclopropanation to give the cyclized products 145
in high yields and stereoselectivity (Scheme 61) <1999TL1717>.
OEt C10H21 TMSOTf

+ or C10H21
Bu3Sn OEt OH BF3.OEt2
O OEt
CH2Cl2 SnBu3
C10H21
Acid + Cyclopropanation C10H21
O 95% O
SnBu3 145
Scheme 61
(vii) Kinetic resolution of -hydroxystannanes

Norephedrine carbamate derivatives of -hydroxystannanes 146 and 147 could be readily pre-
pared and the resulting diastereomers were separable by column chromatography. Removal of the
carbamate moiety by reduction provided enantiomerically enriched -hydroxystannanes
(Scheme 62) <2002T10287>.
OH O Ph O Ph
4-O2NC6H4OC(O)Cl
Pri SnBu3 O N Me O N Me
Me +
H H
Pri SnBu3 Pri SnBu3
Ph NH2
146 147
AlH3 AlH3
MOMCl MOMCl
OMOM OMOM
Pr i SnBu3 Pri SnBu3
Scheme 62
(viii) From nucleophilic displacement

Tri-n-butyl[2-(trimethylsilyl)-ethoxymethoxymethyl]stannane 148 was used as a protected precur-
sor for a hydroxymethyl anion which was added to various carbonyl and carboxyl electrophiles
(Scheme 63) <2000SL455>.
LDA TMSCH2CH2OCH2Cl
OH
THF (SEMCl) BunLi
Bu3SnH
0 °C Bu3Sn OH Bu3Sn OSEM RCH OSEM
Pr2i EtN RCHO
15 min 25–99%
CH2Cl2, rt
HCHO 148
rt, 3 h 14 h
70%
Scheme 63
(ix) From nucleophilic addition

The reaction of a stannyl-substituted mixed acetal 149 with organocopper reagent was performed
in the presence of a Lewis acid. The stannyl-substituted ether 150 was obtained in good yield
using boron trifluoride as the Lewis acid (Equation (44)) <1995TL7799>.
O O RCu O R
BF3.Et2O ð44Þ
Et2O, –78 °C
C5H11 SnBu3 C5H11 SnBu3
149 150
The regio- and stereoselective addition of alkynylstannanes to the stannyl-substituted mixed acetals
resulted in propargylic ether derivatives 151 in excellent yields (Equation (45)) <1996TL3819>.
R R
O O O
Me3SiOTf
+ R1 SnBu3
CH2Cl2 R1
C5H11 SnBu3 –78 °C SnBu3 ð45Þ
2h C5H11
R = CH3, H 151
R = CH3, R1 = SiMe3, 87%

R = CH3, R1 = Ph, 98%
R = H, R1 = Ph, 5%
(x) From deprotonation of ethers

The reactivity of the propargyl and allenyllithium intermediates was examined when submitted to
transmetallation and subsequent tri-n-butyltin chloride quench. The metallation was conducted
with t-butyllithium. After transmetallation of propargyllithium and allenyllithium with titanium
tetraisopropoxide, tri-n-butyltin chloride addition to the mixture gave propargylstannane in 89%
yield. When the transmetallation was carried out with diethylaluminum chloride, quenching with
tri-n-butyltin chloride resulted in the formation of the allenylstannane in 83% yield (Scheme 64)
<1996TL5519>.
Bu3Sn
SiMe3
Ti(O-Pri)4
–78 °C MeO
SiMe3 Bu3SnCl
ButLi
–78 °C
Et2AlCl
OMe
–78 °C H SiMe3
Bu3SnCl
MeO SnBu3
Scheme 64
The reaction of (tetrahydrofuran-2-yl)tri-n-butylstannane 152 with LDA followed by treatment

with cyclohexane carbaldehyde afforded the alcohol 153 which upon reduction with DIBAL-H and
sodium borohydride gave the corresponding stannane diol 154 (Scheme 65) <1996TL9115>.
OH
MeO2C OH
OH
CO2Me i. LDA
THF DIBAL-H
–78 °C THF
CHO 0 °C
SnBu3 ii. O SnBu3 citric acid O Bu Sn
O 3
152 0 °C
60% 153 NaBH4, MeOH 154
0 °C
55%
Scheme 65
(xi) Miscellaneous methods

The synthesis of substituted lactones has been carried out by the reaction of -(benzyloxy)crotyl-
stannane with aldehydes in the liquid phase and on a solid support <2001JOC7195>. The reaction of
-stannylmethyllithium with carbon monoxide generated the acyllithium, which underwent anionic
1,2-stannyl rearrangement to give the enolate derivative of an acyltin. The acyltin underwent reaction
with aldehydes to provide the corresponding -alkoxystannyl compounds <1999JOM171>.
The acid-promoted cyclopropanation reactions of -((alkoxycarbonyl)oxy)stannanes 155 with
alkenes were studied (Equation (46)) <1997JA11986>.
OCO2Me R R
BF3.OEt2
+ Ar
Toluene ð46Þ
Ar SnBu3 –23 °C/0.5–1 h R'
R' 45–94%
155
4.08.2.1.7 Samarium
The samarium-promoted reaction of cyclohexanone with mannosyl pyridylsulfones has been
shown to proceed with -alkoxy samarium species <1997TL1767>. The samarium diiodide
promoted radical cyclization leading to the synthesis of 1,2-cis-C-glycoside has been shown to
proceed through -alkoxy samarium species 156 (Scheme 66) <1997CEJ1342>.
OAc
BnO OAc
BnO
BnO O 2SmI2 BnO
BnO O
BnO BnO
BnO O
BnO
X SmI2X
SmI2
(X = SO2Ar, SAr)
156
Scheme 66
The samarium iodide promoted [2,3]-Wittig rearrangement of O,S-acetals yielding homoallyl alco-
hols 157 has been shown to occur through -alkoxy samarium species (Scheme 67) <2001TL415>.
Sml2
SPh OH
Sml2
R1 R2 2,3 -Rearrangement
O R2
R1 HMPA 6–80% R1
rt O
R2
157
Scheme 67
4.08.2.1.8 Zirconium
Tris(pentafluorophenyl)borane, a strong Lewis acid, reacted with the (2-acetaldehyde)zircono-
cene dimer by hydride transfer from the methyl group of an acetaldehyde ligand to boron. One of
the metallaoxirane moieties of the dizirconium complex was then opened to give a salt that was
isolated with an 80% yield (Scheme 68) <1996JOM263>.
H CH3 H CH3 +
H CH3
C C C
Cp2Zr O B(C6F5)3 Cp2Zr O 80% Cp2Zr O

toluene
O ZrCp2 rt O ZrCp2 O ZrCp2
– –
C HB(C6F5)3
C H HB(C6F5)3
H CH3 +
H H H
H H
Scheme 68
Lithiated epoxynitriles inserted efficiently into alkenylzirconocene chlorides via a 1,2-metalate

rearrangement to form intermediates containing an sp3 carbon attached to oxygen and zirconium,
which resulted in substituted 2-cyano-1,3-dienes <2000TL6201>. The addition of (E)-methoxy
enol ether to the zirconocene complex provided a vinylzirconium derivative, which was hydro-
lyzed to the corresponding alkene and underwent reaction with MeOD to provide deuterium
substituted (E)-alkene (Scheme 69) <2000JOC7218>.
Et
Cp
Zr C9H19
C9H19 Cp
THF Zr OMe
OMe 3h
rt Cp Cp
Quantitative
C9H19 H3O+ C9H19

C9H19 MeOD
90% 70%
D
ZrCp2OMe
Scheme 69
It has been demonstrated that the reaction of chromium carbene complexes 158 with sulfur
ylides 159 represented a new stereoselective entry to 2-acylvinylethers 160 (Scheme 70)
<1996OM4612, 1996OM2764>.
O
OR' H3C O
– C R
(Co)5Cr + hν R'O R R2
C + S CHCOR2 + MeCN
(CO)5Cr S R2 60–90%
R H3C CH3 H OR'
158 159 CH3
160
Scheme 70
4.08.2.2 Functions Bearing Sulfur—R12C(SR2)M, etc.
4.08.2.2.1 Lithium
(i) By direct deprotonation
(a) From sulfides. The intramolecular carbolithiation of vinyl sulfides at 105 C in THF had
been found to be stereospecific regarding the formation of the new carbon–carbon bond and
nonstereospecific regarding the formation of the new carbon–lithium bond. The resulting
-durylthioalkyllithium compounds were configurationally stable at 105 C and epimerized at
90 C <1999JCS(P2)183>.
Tris(methylthio)methane was deprotonated with n-butyllithium to give tris(phenylthio)methyl-
lithium, which reacted with 2-exomethylene cyclopentanone to provide the corresponding con-
jugated product bearing a phenylthio group after hydrolysis. Better yields were realized in the
presence of trimethylsilyl chloride (Scheme 71) <1995TL8925>.
O
–78 °C
(PhS)3CH + BunLi LiC(SPh)3
H3O+ C(SPh)3
24%
Scheme 71
The reaction of phenylcyclopropyl thioether with n-butyllithium in the presence of TMEDA

and an electrophile such as an aldehyde or a ketone provided the corresponding addition product.
The addition product was treated with an excess of lithium powder and a catalytic amount of
4,40 -di-t-butylbiphenyl (DTBB), and finally reaction with a second carbonyl compound, either an
aldehyde or a ketone gave, after hydrolysis, the expected cyclopropane 1,3-diols derivatives
<2001T4411>.
1,3-Functionalized cyclopentanes, cylcohexanes, and cycloheptanes were obtained by addition
of lithiated silyldithioacetals to epoxyhomoallyltosylates. The reaction involved a cascade of
epoxide ring opening, Brook 1,4-rearrangement, and tosylate substitution. The method was
particularly suitable for the preparation of cyclopentanes, whereas cyclohexanes and cyclohep-
tanes were formed in yields less than 49%. Use of enantiomerically pure epoxides provided
optically active cyclopentanes as well as oxetanes (Scheme 72) <1996LA1811>.
R4 OLi OSiR22R3
OSiR22R
O
R1S SiR 22R3 OTs
–SiR22R3
SR1 OTs Li OTs

R1S Li R1S R4 R1S R4
SiR22R3 1 R1S
R S
SR1 R4
Scheme 72
(b) From sulfoxides. A stereoselective conjugate addition of the -carbanion derived from
p-tolyl-2-(trimethylsilyl)ethylsulfoxide have been studied. Reaction of p-tolyl -lithio--(trimethyl-
silyl)ethylsulfoxide 161 with ,-unsaturated esters gave the conjugate addition products 162 as a
single diastereomer (Scheme 73) <1997SL449, 2000JOC1758>.
.. ..
O O CO2Me ..
O
S LDA R R
S Li S CO2 Me
THF, –78 °C
p-Tol p -Tol p -Tol
SiMe3 SiMe3 SiMe3
161 162
R = H, 64%
R = Me, 95%
R = Et, 97%
R = Ph, 96%
Scheme 73
Reactions of -sulfinylcarbanions, derived from p-tolylsulfoxides bearing various alkyl groups,

with a variety of electrophiles were examined. The reaction of -sulfinylcarbanions, derived from
the -silylethylsulfoxides, with ketones or trimethyl phosphates gave the syn products with high
stereoselectivity. Interaction between the silicon in the trialkylsilyl group and the carbonyl oxygen in
nucleophiles was postulated to stabilize the transition state, leading preferably to the syn diaster-
eoisomers. This novel silicon–oxygen interaction was supported by an MO calculation study using
the MOPAC 93/PM3 and the Gaussian 94 Beche3LYP/3-21+G* methods <2000JOC469>.
Reaction of thiomethylphosphonates with aryl (or butyl) tellurenyl halides and aldehydes under
basic conditions provides moderate-to-good yields of ketone thio (telluro) acetals, with vinylic
sulfides being by-products of this transformation. Tellurium–lithium exchange by reaction with
BunLi yielded vinylorganolithium species, which were captured with several electrophiles. In the
case of DMF, Z--phenylthio-,-unsaturated aldehydes were obtained <1999T7421>.
The reaction of lithiated (R)-2-(trimethylsilyl)ethyl p-tolylsulfoxide with ,-unsaturated esters
gave 1,4-conjugate addition products as single stereoisomers, whereas the reaction of (R)-2-(trimethyl-
silyl)ethyl p-tolylsulfoxide with 4-,6-, or 7-haloalkenoates afforded cyclopropane-, cyclopentane-, or
cyclohexanecarboxylates, respectively, with high stereoselectivity (Scheme 74) <1997SL449>.
R
O
LDA S 2 3 CO2Me
CO2Me p -Tol 1
R
O SiMe3
S
p -Tol
SiMe3
O
LDA n
S 2 3 CO2Et
Br CO2Et
n p -Tol 1
SiMe3
Scheme 74
The lithiation of 1,1-dimethoxy-3-tosylpropane 163 followed by reaction with acylchlorides

afforded the corresponding keto-ether 164 (Scheme 75) <1995T2763>.
R1 R2COCl Ts R1
BunLi Ts OMe or PhNCO
Ts R1
–78 °C H2O OMe
OMe
MeO OMe R2 O
Li OMe
163 164
Scheme 75
With the -carbonyl functionality properly protected, -hydroxy--dioxolane sulfoxides 165

could be regioselectively alkylated by treatment with methyllithium in THF and quenching the
resulting dianion with a variety of simple alkyl halides to yield sulfoxides 166 in good yields
(Equation (47)) <1995TL4559>.
MeLi/ THF HO
O O O
O HO
O O 0 °C p -Tol S
RX
p -Tol S
–78 to 0 °C
ð47Þ
R
165
166
A new pathway of remote asymmetric induction in Michael reactions involving allylic

-phenylsulfonylcarbanions in chiral donors has been disclosed. The transmission of asymmetry
was found to depend on the presence of an aromatic nucleus bound to the chiral center <1999JOC8>.
(E)- and (Z)-1-(Phenylsulfonyl)-4-(trimethylsilyl)-2-butenes were converted by BunLi to
(E)- and (Z)-1-lithio-1-(phenylsulfonyl)-4-(trimethylsilyl)-2-butenes with retention of the initial
stereochemistry. Reactions with electrophiles (protio and deuterio acids, primary, secondary,
and benzyl halides, chloroformates, chlorothioformates, acid chlorides, epoxides, trialkylsilyl
chlorides, and triethylgermanylchloride) in THF or THF/HMPA gave the corresponding
(E)- and (Z)-1-(phenylsulfonyl)-1-substituted-4-(trimethylsilyl)-2-butenes with stereochemical
retention <1998JOC4181, 1998JOC4193>.
The reactions of -arylsulfonylcarbanions generated from 3-hydroxy- and 3-alkoxy-1-(arylsul-
fonyl)cyclohexane with some electrophiles were suggested to proceed with inversion of configura-
tion at the carbanionic centers <1998JCS(P1)3519>.
Trimethylsilyldithiane was metallated with t-butyllithium in HMPA followed by treatment with
epoxide to afford the corresponding product <1997JA6925>. Similarly, the deprotonated dithiane
was reacted with an aldehyde to provide the corresponding secondary alcohol <1997TL8667>. The
dithiane was metallated with t-butyllithium in HMPA/THF followed by alkylation with an epoxide
and silylation to afford the corresponding product <1997TL8671>.
The thia-Sommelet rearrangement of sulfonium salts with lithium diisopropylamide at low
temperature leading to the formation of hexatrienes containing quaternary stereogenic centers
was reported <1998JA841>.
(c) From sulfones. The sulfone 167 depicted was deprotonated with lithium diisopropylamide
and treated with a Michael acceptor to provide the corresponding conjugate addition product 168
(Equation (48)) <1996TA2423>.
O SO2Ph
O
CO2Me, LDA H
CH2SO2Ph
–78 °C, 30 min CO2Me ð48Þ
O
167 quantitative
O
168
Using 1,2-dimethoxyethane as solvent in the addition of metallated sulfones to aldehydes can

increase yields in the first step of the Julia–Lythgoe olefin synthesis. The addition of metallated
sulfones to ketones was also discussed (Equation (49)) <1996TL5283>.
PhO2S R1
n-C7H15 BunLi, hexane, –78 °C
SO2Ph OH ð49Þ
R1RC=O
NH4Cl·H2O n-C7H15 R
Modification of the Julia–Lythgoe olefination reaction between ketones and primary sulfones
leads to trisubstituted alkenes in good overall yields. Samarium diiodide was shown to play a
crucial role in the reductive elimination step (Scheme 76) <1996TL2089>.
R SmI2
R2 R2 OR3 R R2
BunLi THF
THF RCOR1 HMPA
SO2Ph SO2Ph R2
1 Me3SiCl
–78 to 20 °C R
Li or R1
PhCOCl
SO2Ph 64–73%
Scheme 76
Tetrahydrofuran solutions of acetals 169 reacted with a stoichiometric amount of potassium

t-butoxide, and the resulting carbanion was quenched with methyl iodide to provide the corre-
sponding methylated products 170 and 171 (Scheme 77) <2001T4461>.
O EWG i. ButOK, THF O EWG O EWG

–78 °C, 1 h
+ Me
ii. MeI (1 equiv.)
O O Me O Me
169 170 171
EWG = –CO2Me 46%

EWG = –SO2Ph 80%
EWG = –SO2Ph-p-NO2 11%
Scheme 77
4.08.2.2.2 Beryllium or magnesium

Diorganomagnesium and Grignard reagents were found to react with sulfur-stabilized methyltin
compounds in a 1:1 molar ratio yielding sulfur-functionalized methylmagnesium compounds
(Scheme 78) <2002JOM111>.
Bun3SnCH2S(O)i R + R1MgX Mg CH2S(O)i R X + Bu3nSnR1

(i = 0, 1, 2; R = Me, Ph; R1 = Me, Bun, Ph; X = Cl, Br, I)
,
n
Bun3SnCH2S(O)i R + MgR1R2 Mg CH2S(O)i R R2 + Bu3SnR1
(i = 0, 1, 2; R = Me, Ph; R1/R2 = Me/Me, Bun/Bus)
Scheme 78
4.08.2.2.3 Aluminum, indium, or gallium

The dimethyl(methylthiomethyl)metal compounds 172 (Me2MCH2SMe)2 (M = Al, Ga, In) have
been prepared from LiCH2SMe and the respective dimethylmetal chlorides. Unlike the corre-
sponding lithium compounds, the thiomethyl compounds with AlMe2 and GaMe2 groups are
sublimable and soluble in nonpolar solvents. The compounds (Me2MCH2SMe)2 have been
characterized by elemental analyses, multinuclear NMR spectroscopy, and, in the cases M=Al
and Ga, by single-crystal X-ray crystallography. The Al and Ga compounds are dimeric in the
solid and in nondonor solvents, but are cleaved by stronger donors such as ethers and amines
(Equation (50)) <2002OM3471>.
n-Hexane
2MeSCH2LI + 2Me2MCl (Me2MCH2SMe)2
–78 °C to rt
M = Al, Ga, In 172 ð50Þ
M = Al, 70%
M = Ga, 62%
M = In, 58%
4.08.2.2.4 Tin
As outlined in COFGT (1995), the reaction between alkyl- and arylthiomethyllithiums prepared
from the corresponding sulfides and BunLi/TMEDA, and trialkyltin chlorides was reported to
give -stannyl thioethers.
Unsubstituted and or C-substituted epoxystannanes 173 reacted with lithium phenyl
sulfide to give regio- and stereodefined -phenylthio--hydroxystannanes 174 resulting from
the -opening with inversion of configuration. Alternatively, - or -trans-silylepoxystannanes
afforded stereospecific - or -silylated vinyl sulfides formed by nucleophilic attack at the
carbon which bore the tin group and subsequent syn-elimination of HOSnBu3 (Equation (51))
<2001TL8993>.
R2 R1 R3
PhS– Li+, THF SPh
R2
NH4Cl (aq.)
R1
R3 O –78 to 0 °C or rt HO
SnBu3 SnBu3
174 ð51Þ
173
R1 = R2 = R3 = H, 90%
R1 = R2 = R3 = Me, 85%
R1 = R3 = H, R2 = Ph, 83%
R1 = Me, R2 = R3 = H, 86%
It was reported that various chelated organo-gem-bismetallics could react with two different
electrophiles leading to a new asymmetric stereogenic center with good diastereoselectivity
(Scheme 79) <1995SL723>.
OBut OBut
SnBu3 SnBu3
PhSK But But
I H
O O
H SPh n
Bu Li Li SnMe3
Me3SnCl
SPh SPh
OBut
OBut H H
SnBu3
SnBu3 PhSK
SPh
H
H
I
Scheme 79
Intramolecular carbolithiation of vinyl sulfides to generate configurationally stable -dur-

ylthioalkyllithium compounds at 105 C in THF showed carbolithiation to be nonstereospecific
regarding the newly formed lithium bearing stereocenter. -Durylthioalkyllithium could undergo
reaction with trimethyltin chloride to provide -thio tin compounds 175 and 176 (Scheme 80)
<1997CC2189, 1999JCS(P2)183>.
Ring opening of the cyclopropylallyllithium compound 177 to give the -duryl thio-substituted
alkyllithium compound proceeded in a stereochemically defined manner at the lithium-bearing
stereocenter (Scheme 81) <1999CC33>.
4.08.2.2.5 Iron
Silyl enol ethers 178 were prepared by copper-promoted conjugate addition of Grignard reagents
to cyclopentenone in the presence of trimethylsilyl chloride. The silyl derivative reacted with
methyllithium to generate enolates. Addition to the thiocarbene complex produced the substrates
as mixtures of diastereomers with respect to the iron-bearing carbon atom (Scheme 82)
<2001JOC3449>.
Li
Ph Ph Ph H SDur Ph H SDur
SeMe SDur ButLi Li SDur +
EX
E E
Ph H SDur Ph H SDur
Dur = +
E=D
E = Me
175 E = SnMe3 176
Scheme 80
SeMe Li –107 °C, 30 min

ButLi
DurS H + DurS
DurS DurS H
THF, –107 °C Li
Li
177 SnBr
DurS H + H
DurS
Sn Sn
Scheme 81
O H Fe(CO)2Cp
O BrMgCH2CH2R OTMS CH3Li, Et2O, THF
CuBr2.S(CH3)2(cat.) 0–25 °C SPh
(CH2)n (H2C)n (H2C)n
(CH3)3SiCl, HMPA Cp(CO)2Fe+=CHSPhPF6–
R R
THF, –78 °C 178 THF, –78 to –30 °C
H
Scheme 82
4.08.2.3 Functions Bearing Selenium or Tellurium—R12C(SeR2)M, etc.
4.08.2.3.1 Lithium
The synthesis and reactivity of 1,3-benzodiselenolanes toward lithium diisopropylamide and
butyllithiums were described as well as the original syntheses of aromatic compounds bearing
selenium atoms (Scheme 83) <1999TL6571>.
(Phenylselenenyl) acetonitrile was treated with lithium 2,2,6,6-tetramethylpiperidide (LTMP) to
give -seleno carbanion, which was reacted with ethyltrifluoroacetate to provide the correspond-
ing enol ether 179 (Scheme 84) <2002JOC5678>.
After a detailed study of the hydrozirconation of the acetylenic selenides, it was established that
the initial hydrozirconated product would involve an intermediate containing -seleno zirconium
intermediate <1998T2371>.
Se Ph
Se Ph Se Ph
MeI, THF
–78 °C, 1 h
Se H
Se Li 85% Se Me
Scheme 83
H PhSe
LTMP CF3CO2Et CF3
PhSeCH2CN NC C Li
MsCl NC OEt
PhSe
179
Scheme 84
4.08.2.3.2 a-Telluro lithium species

As indicated in COFGT (1995), selenium–lithium exchange with an alkyllithium has been success-
fully used to generate -telluro lithium species.
The semistabilized telluronium ylides generated in situ from the corresponding telluronium salts
reacted with ,-unsaturated ketones to afford cis-2-vinyl-trans-3-substituted cyclopropyl ketones
with high stereoselectivity and in high-to-excellent yields. Conversely, these enones gave trans-2-vinyl-
trans-3-substituted cyclopropyl ketones, when the corresponding arsonium ylides were employed.
Other factors such as solvent and amount of base also influenced the stereochemistry of this reaction.
A mechanistic rationale was discussed briefly (Scheme 85) <1999T7421, 1997JOC954>.
i. LDA, –78 °C
(EtO)2P(O) R2 SR R2
SR ii. R1TeBr
+
iii. R2CHO SR
R = C6H5
TeR1
R = CH3
LDA, THF R2CHO

–78 °C
(EtO)2P(O)
(EtO)2P(O) R1TeBr SR (EtO)2P(O) SR
SR LDA TeR1
THF
–78 °C THF, –78 °C
TeR1 Li
Li
R = C6H5 R = C6H5 R = C6H5
R = CH3 R = CH3 R = CH3
Scheme 85
ACKNOWLEDGMENTS
I am highly grateful for the financial support provided by the Robert A. Welch Foundation of
Texas (grant no. BG-1387) and the NIH-MBRS funding (grant no. NIH NIGMS 2S06GM08038-32),
while preparing this book chapter.
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Biographical sketch
Narayan G. Bhat was born in Navilgon, India. He studied at Karnatak

University, India, where he obtained a B.Sc. in 1976 and an M.Sc. in 1978.
He obtained his Ph.D. in 1982 from Pune University, India (for the work
carried out at the National Chemical Laboratory, Pune, India) under the
direction of Dr. G. H. Kulkarni. After spending 8 years (1982–1990) as a
Postdoctoral Research Associate in the laboratory of Professor Herbert
C. Brown, 1979 Nobel laureate in chemistry, at Purdue University, West
Lafayette, Indiana, USA, he joined Ethyl Corporation, Baton Rouge, LA.
After working at the Indian Institute of Science as an Assistant Professor of
Chemistry and as an instructor of organic chemistry at the University of
Nebraska, Lincoln, he joined the University of Texas-Pan American, Edin-
burg, Texas in 1996 as an Assistant Professor of chemistry. Currently, he is
an Associate Professor of chemistry and his scientific interests include all
aspects of organic chemistry, in particular organoborane chemistry, selec-
tive organometallic syntheses, and bioorganometallic chemistry. Currently,
his research activities at the University of Texas-Pan American are sup-
ported by the Robert A. Welch Foundation of Texas and the National
Institute of Health.
4.09
Functions Bearing Two Nitrogens
M. HIERSEMANN
Technische Universität Dresden, Dresden, Germany
4.09.1 INTRODUCTION 412

4.09.2 GEMINAL DIAMINO ALKANES–AMINALS 412
4.09.2.1 Condensation of Aldehydes and Ketones with Amines 412
4.09.2.1.1 Acyclic aminals 412
4.09.2.1.2 Cyclic aminals 413
4.09.2.2 Reaction of Amines with Geminal Dihalo Compounds 414
4.09.2.3 Amine Addition to Imines and Iminium Salts 414
4.09.2.3.1 To imines 414
4.09.2.3.2 To iminium salts or enamines 415
4.09.2.4 Reductive Processes 415
4.09.2.5 Reduction of Ureas 416
4.09.2.6 Benzotriazole Derivatives 416
4.09.2.7 Miscellaneous Procedures 417
4.09.3 GEMINALLY SUBSTITUTED ALKANES BEARING ONE AMINO
AND ONE ACYLATED OR SULFONATED AMINO GROUP 418
4.09.3.1 Acylated Derivatives 418
4.09.3.1.1 Acylation of aminals 418
4.09.3.1.2 Condensation of amines and amides with carbonyl compounds 419
4.09.3.1.3 Nucleophilic displacement reactions 420
4.09.3.1.4 Addition of amines and amides to CN multiple bonds 420
4.09.3.1.5 Reductive methods 421
4.09.3.1.6 Cycloaddition procedures 421
4.09.3.1.7 Metal-catalyzed procedures 421
4.09.3.1.8 Benzotriazole derivatives 422
4.09.3.2 Sulfonated Derivatives 423
4.09.4 GEMINALLY SUBSTITUTED ALKANES BEARING TWO ACYLATED
OR SULFONATED AMINO GROUPS 423
4.09.4.1 Acylated Derivatives 423
4.09.4.1.1 Acylation of monoacylated aminals 423
4.09.4.1.2 Condensation of amides with carbonyl compounds 423
4.09.4.1.3 Reductive methods 424
4.09.4.1.4 Nucleophilic addition to imines and enamines 424
4.09.4.1.5 Miscellaneous procedures 425
4.09.4.2 Sulfonated Derivatives 425
4.09.5 GEMINALLY SUBSTITUTED ALKANES BEARING TWO SIMILAR DICOORDINATE
OR HETEROSUBSTITUTED NITROGENS 426
4.09.5.1 gem-Dinitro Alkanes 426
4.09.5.2 gem-Diazidoalkanes 427
4.09.5.3 gem-Diisocyanates and gem-Diisothiocyanates 427
4.09.5.4 gem-Dinitrosamines and gem-Dinitramines 427
4.09.5.5 gem-Dihydroxylaminoalkanes 428
4.09.5.6 gem-Dicarbodiimides 428
4.09.5.7 gem-Diazo Alkanes 428
4.09.5.8 gem-Dihydrazino Alkanes 428
4.09.5.9 gem-Diiminoalkanes and gem-Diisocyanides 429
4.09.5.10 gem-Difluoroaminoalkanes 429
4.09.5.11 gem-Benzotriazol-1-yl Alkanes 430
411
412 Functions Bearing Two Nitrogens
4.09.6 GEMINALLY SUBSTITUTED ALKANES BEARING TWO DIFFERENT

DICOORDINATE OR HETEROSUBSTITUTED NITROGENS 430
4.09.6.1 Nitroalkane Derivatives 430
4.09.6.2 Nitraminoalkane Derivatives 430
4.09.6.3 Azoalkanes and Hydrazino Alkane Derivatives 431
4.09.6.4 Isocyanato Alkane Derivatives 431
4.09.6.5 Benzotriazole Derivatives 431
4.09.6.6 Miscellaneous Derivatives 431
4.09.7 GEMINALLY SUBSTITUTED ALKANES BEARING ONE AMINO GROUP
AND ONE DICOORDINATE OR HETEROSUBSTITUTED NITROGEN 432
4.09.7.1 Aminomethylhydroxylamines 432
4.09.7.2 Aminomethyl Nitramines and Nitrosamines 432
4.09.7.3 Aminomethyl Azides and Triazines 432
4.09.7.4 Aminomethylazo and -hydrazino Compounds 432
4.09.7.5 Aminomethylimines 433
4.09.8 GEMINALLY SUBSTITUTED ALKANES BEARING ONE ACYLATED
OR SULFONATED AMINO GROUP AND ONE DICOORDINATE OR
HETEROSUBSTITUTED NITROGEN 433
4.09.8.1 Acylaminomethylisocyanates and -isothiocyanates 433
4.09.8.2 Acylaminomethylazides 433
4.09.8.3 Acylaminomethyl Nitramines 433
4.09.8.4 Acylaminomethylhydroxylamines and -hydrazines 433
4.09.8.5 Acylaminomethyl Azoalkanes and Iminoalkanes 435
4.09.8.6 Miscellaneous Compounds 436
4.09.1 INTRODUCTION
Although the title of this series implies absolute comprehensiveness, the ubiquity of the functions
bearing two nitrogen atoms connected to an sp3-carbon atom certainly prevents complete cover-
age of the topic. Nevertheless, an attempt has been made to be as comprehensive as possible,
and the author apologizes to colleagues whose published work was not considered during the
preparation of this chapter. The number of general reaction schemes is limited in favor of detailed
explicit examples. Less important work (from the standpoint of the author) was summarized
within the text by using systematic names of compounds that will allow the specialist to identify
any work of interest. Few speculative statements have been made concerning the potential
generality of the summarized procedures. The interested reader should consult the original
literature to draw conclusions about whether or not a certain method may be of value for his/
her intention. The most significant progress has been made in the chemistry of benzotriazole
derivatives, which would certainly justify its own review. The same may be true for bis-imidazolium
compounds, but they are not included in this chapter.
4.09.2 GEMINAL DIAMINO ALKANES–AMINALS
4.09.2.1 Condensation of Aldehydes and Ketones with Amines
4.09.2.1.1 Acyclic aminals

C2-Symmetric chiral methylene aminals have been prepared using a standard procedure (amine +
formaldehyde + acid) summarized in COFGT (1995) (Equation (1)) <2001SC1697, 2002T4439>.
This procedure may be of general interest for the synthesis of chiral ligands provided the aminals
are sufficiently stable.
CO2Bn
+
NH (CH2O)n, H N N
S S ð1Þ
75% S
CO2Bn CO2Bn
Functions Bearing Two Nitrogens 413
1,3,6,8-Tetraazatricyclo[4.4.1.13,8]-dodecane (TATD) has been used as a methylene source for

the synthesis of aminals based on substituted anilines (Equation (2)) <2002SC1407>. This
procedure is of limited generality since it is restricted to acceptor-substituted anilines.
R
NH2
HN N
N N H+ H
+ ð2Þ
N N
R
R = C(=O)CH3:96%
R = NO2:90% R
4.09.2.1.2 Cyclic aminals

Simple achiral imidazolidines and hexahydropyrimidines have been synthesized by condensing
aromatic and aliphatic aldehydes (including aqueous formaldehyde) with 1,2- or 1,3-diamines
<1996JOC3646, 1997HCA966, 2000BMC2113, 2000JOC1200, 2000SC3369, 2002JHC655,
2002ICA75>. Alcohols, toluene, ether, and CH2Cl2 have been used as solvents. The reaction
temperature depends on the substrate structures, and molecular sieves or acid catalysts are
utilized occasionally. Selected examples are depicted in Scheme 1.
N N N N
N N N N Aryl N N Me, Aryl
Ar Aryl, Alkyl
Alkyl, Ph H, Aryl N H, Aryl
<1997HCA966> <2002JHC655> <2002ICA75> <2000SC3369>
Scheme 1
2,3-Dichloro-5,6-dicyano-1,4-benzoquninone (DDQ) has been used as a catalyst for imidazoli-

dine formation from aliphatic and aromatic aldehydes <1995T5813>. Increased reaction times
and inferior yields were reported for the uncatalyzed reaction. The condensation reaction of
aromatic aldehydes and N,N0 -disubstituted ethylenediamines to imidazolidines in a water suspen-
sion medium has been developed <2000GC272>. Diazabicycloalkanes containing medium and
large rings have been synthesized from N-alkenylpropane-1,3-diamines by a sequence consisting
of rhodium-catalyzed double bond hydroformylation and subsequent aminal formation
<1999CC1279, 1999AJC1131>.
Chiral 1,3-diamines are frequently employed as covalently bonded chiral auxiliaries <1995SL255,
1995S1038, 1995JA10767, 1999CC2061, 1999AG(E)2556, 1999TL6241, 2002SL423> or as syn-
thetic intermediates for the synthesis of organocatalysts <2002OL3611> and chiral metal ligands
<2002JOC8191, 1997TA2607, 2000AG(E)4093, 2002TL8059, 2002TA1379>. Representative
examples are depicted in Scheme 2. A three-component reaction to tricyclic aminals from
Br Br
N N Ph
N N N N
Br
N N
CO2CH3
<02JOC8191> <02THL8059> <95SL255> <02OL3611>
Scheme 2
acyclic starting materials has been developed <2001OL2145>. The ring-chain tautomerism of
2-aryl-substituted cis- and trans-configured decahydroquinazolines has been studied by NMR
spectroscopy <2002JOC4734>.
Polycyclic bis(aminals) are accessible by the condensation reaction between -dicarbonyl
compounds and a linear tetraamine (Equation (3)). The stereochemical course of this condensa-
tion as well as the complexation properties of the polycyclic bis(aminals) have been studied
<1998TL6861, 1999JOM259>. Polycyclic bis(aminals) are also useful synthetic intermediates in the
synthesis of cyclen (1,4,7,10-tetraazacyclododecane) and cyclam (1,4,8,11-tetraazacyclotetradecane)
<1999TL2517, 2002CC312, 2003T4573>.
100 mol.% H3C(=O)CHO

CH3CN, H2O, 4 °C, 4 h
then add
NH2 NH2 N N
100 mol.% BrCH2CH2Br ð3Þ
K2CO3, reflux, 48 h
NH HN N N
69% H
An intramolecular aminal formation was the final step in the total synthesis of the alkaloid
tetraponerine <2000JA9584>. After the removal of the nitrogen protective groups, an acetal
served as carbonyl precursor in the presence of dilute aqueous HCl (Equation (4)).
i. H2, Pd/C
H EtOH, 8 h H
ii. 5% HCl, H2O
H
N N N N ð4Þ
R 86%
R
CH(OEt)2
R = BnOC(=O)–
An alternative approach utilized the intermolecular condensation between a cyclic and an

acyclic aminoacetal in the presence of potassium cyanide for the synthesis of another member
of this class of alkaloids (Equation (5)) <1996JOC4949>.
OMe
10% HCl H
NH OMe H2O, KCN CN
+ H ð5Þ
N N
OEt 57%
EtO NH2
4.09.2.2 Reaction of Amines with Geminal Dihalo Compounds

As summarized in COFGT (1995), amines and geminal dihalo compounds form aminals
following an SN2-type process. A recent report describes the copper(0)-mediated conversion of
1,1,1-trifluoro-2,2-dichloroethane and dialkylamines into 1,1-bis(dialkylamino)-2,2,2-trifluoroethanes
<1997JOC1576>. This transformation is limited to dimethylamine and cyclic secondary amines. The
chemistry of 1,1-bis(dialkylamino)-2,2,2-trifluoroethanes has also been the subject of a detailed study
<1997JOC6503>.
4.09.2.3 Amine Addition to Imines and Iminium Salts
4.09.2.3.1 To imines
As was summarized in COFGT (1995), the nucleophilic addition of an amine to an imine has
found only limited application in the literature. This situation has not changed since 1995 and the
interested reader is referred to chapter 4.09.2.3.1 of <1995COFGT(4)403>.
4.09.2.3.2 To iminium salts or enamines

Enamines react with amines inter- or intramolecularly in the presence of an electrophile to
afford an aminal <1998T14845, 1998CC2715, 1999JOC7381, 1999OL1315, 2001CEJ41>. Various
electrophiles can be used to activate the enamine moiety as an intermediate iminium ion for
nucleophilic attack by the amine (Equations (6)–(8)) <2000OL675, 2000CEJ1763, 2001TL4915>.
200 mol.% NCS

240 mol.% Me2S S
R2 R2
240 mol.% Pri2EtN
1
R1 CH2Cl2, –78 °C R
HN N
CO2Et CO2Et ð6Þ
N NCS = N-chloro succinimide N H
H H
R1 = H, OMe
86–99%, de depending on R1,2
R2 = H, CO2Me
R1 I2, HNR3R4 R1
N Na2CO3, THF N NR3R4
ð7Þ
R2 R2 NR3R4
2 1 3,4
R = CN, CO2Me; R = Me, Bn; R = cyclic secondary amines: 79–94%
i. H2, Raney-Ni
CO2Me MeOH, 50 psi, 50 °C
CO2Me ii. AcOH, MeOH, 65 °C
N N ð8Þ
91% CO2Me
NO2 N
H CO2Me
4.09.2.4 Reductive Processes

Indole alkaloids featuring the general framework depicted in Equation (9) have been synthesized by
the reduction of the corresponding amid <1999JOC1086, 2001JOC1186>. Further examples prove
the general utility of this transformation for the synthesis of cyclic aminals <1999JOC8594>.
R2 O R2
N N
N LiAlH4 N ð9Þ
R1 R1
or
EtMe2N·AlH3
The reduction of amidines, amidinium ions, and cyanamides has been covered in chapter 4.09.2.4
of <1995COFGT(4)403>. Recent applications of the reduction of amidinium ions by complex
metal hydrides have been reported <1998TA2245, 2002SC1457>. An application in natural pro-
duct synthesis is outlined in Equation (10) <2002OL4697>. Examples have been reported in which
the amidinium ion is generated and reduced in situ <1996CPB715, 1998JA6500, 2001H1029>. The
stereoelectronic control of the addition of various nucleophiles to the 1,3-dimethyl-5-phenyl-1,4,5,6-
tetrahydropyrimidinium ion has been investigated <2001JA4451>. An example of the dissolving
metal reduction of amidines has been reported <1997T5359>.
LiAlH4, THF
H mol. sieves H
C5H11 C5H11
0 °C to rt ð10Þ
+ H
N N N N
Br–
4.09.2.5 Reduction of Ureas

The reduction of five- and six-membered ureas has been summarized in chapter 4.09.2.5 of
<1995COFGT(4)403>. Recent publications report the utilization of complex metal hydrides for
this transformation <2001EJOC1625, 2002EJOC301>.
4.09.2.6 Benzotriazole Derivatives

Aminomethylbenzotriazoles are usually generated by the condensation of an amine with
an aldehyde (ketone <1995H131>) and 1H-benzotriazole. They can be converted under appro-
priate reaction conditions to synthons that represent nitrogen-stabilized cations <1995H345,
1998S1421, 1999S1027, 2001JOC2865, 2002S199, 2003JOC9088>, anions <1995H131>, or radi-
cals <2000JCS(P2)1375> (Scheme 3). These synthons can be used for a plethora of useful C/C- or
C/heteroatom-bond forming reactions. This chapter will be limited to a short summary on the
synthesis of the readily available aminomethylbenzotriazoles.
O –H2O
NH HN N Bt N
N N
N Bt
Scheme 3
Scheme 4 depicts the general formulas for acyclic aminomethylbenzotriazoles that can be
prepared by stirring of the appropriate aldehyde and amine with 1H-benzotriazole at room or
elevated temperature.
H R1 = alkyl
N Bt R3
R2 = aryl
N R1
N Bt R1–R2 = cycloalkyl
O R2 R3 = H, alkyl, aryl
<1995H345> <1995H131, 1998S1421, 2000JCS(P2)1375,
2002S199, 2001JOC2865>
CO2Et CO2Et R
R X
N Bt N Bt N Bt
X R O H
X = OMe, NH aryl
X = O, CH2 R = allyl, benzyl R = alkyl, aryl
<1999S1027> <1999S1027> <2003JOC9088>
Scheme 4
The synthesis and reactivity of 2-benzotriazolylaziridines and 2H-azirines have been investi-
gated <1999JOC346, 2003JOC9105>.
N,N-Bis(benzotriazolylmethyl)alkanamines can be prepared from primary amines and a two-
fold excess of 1H-benzotriazole and formaldehyde. N,N-Bis[(benzotriazol-1-methyl)alkanamines
have been utilized for the synthesis of various heterocycles <2002JCS(P1)592, 2002S601,
2002JOC8220, 2002JOC8237>. Two examples are depicted in Scheme 5 and Equation (11)
<1999JCS(P1)179, 2002JOC8234>.
MeO
NH2
MeO MeO
EtOH, reflux
+
76% N Bt
N MeO
N Bt
N
400 mol.% AlCl3
OH
CHCl3, 4 h, rt
via: 96%
MeO MeO
+
N Bt N Bt
MeO MeO
–
(Bt)AlCl3
Scheme 5
200 mol.% BunLi, 200 mol.% TMEDA

cyclohexane, rt, 24 h; then add Bu
120 mol.% ZnBr2, THF, 0 °C, 30 min N
SH S
then add 100 mol.%
ð11Þ
Bun
N
Bt
Bt
45%
Several benzotriazolyl- or benzotriazolylmethyl-substituted heterocycles have been prepared

using the well-established condensation chemistry <1998TL1697, 1998JOC6699, 1999T3489,
2000JOC3683, 2002JOC3109, 2002JOC3115, 2002JOC4951, 2002JOC8224, 2002S1646>. Some
representative examples are depicted in Scheme 6.
CO2Et
Ph
NH Bt N N Ph
N O N
Bt
Bt
<1998T1697> <1999T3489> <2002JOC3683>
R O
R
Bt N N
Bt N N p-NO2-Ph
p-Tol Bt N N Bt
<2002JOC3109> <2002JOC3115> <2002JOC4951>
Scheme 6
4.09.2.7 Miscellaneous Procedures

The synthesis of aminals from carbonyl compounds and N,N-dialkyl-1,2-diamines is restricted to
aldehydes whereas ketones often fail to afford the desired aminal. An alternative access to chiral
2,2-dialkyl-substituted imidazolidines utilized the nucleophilic addition of an acetylide anion to an
imidazolinium ion (Equation (12)) <2000OL2659>.
i. CH3I, THF Ph Ph
Ph Ph
ii. LiCCSiMe3
THF, –78 °C N N
N N
then add ð12Þ
100 mol.% TBAF
85%
OTBDMS OTBDMS
Chiral 4,5-dihydroimidazolium ylides, generated in situ from chiral dihydroimidazoles and

an alkylating agent in the presence of a base, undergo an inter- or intramolecular 1,3-dipolar
cycloaddition with suitable dipolarophiles to provide bicyclic and tricyclic aminals <1997TL1647,
2001TL3951>. A representative example is depicted in Equation (13) <1996TL1707>.
BrCH2CO2But
Bn H2C=C(CH3)CO2Me Bn
N N H
DBU, THF, reflux ð13Þ
Ph N 61% Ph N CO2Me
CO2But
The low-valent titanium-mediated reductive cyclization of acyclic imines in tetrahydrofuran

(THF) to imidazolines has been described <1996TL4767>. The reaction of [60]fullerene with
diethyl diazidomalonate afforded an aminal-functionalized fulleroid <1995CC1725>. The [4+1]-
cycloaddition between vinylketenes and a nucleophilic N-heterocyclic carbene that was generated
thermally from 2-trichlormethyl-1,3-imidazoline afforded spirocyclic aminals <2003OL263>.
4.09.3 GEMINALLY SUBSTITUTED ALKANES BEARING ONE AMINO

AND ONE ACYLATED OR SULFONATED AMINO GROUP
4.09.3.1 Acylated Derivatives
4.09.3.1.1 Acylation of aminals

Condensation of a tricyclic bis-aminal with diethyl oxalate afforded a tetracyclic bis-acylated
bis-aminal (Equation (14)) <2000EJOC33>.
H H
N NH EtO O N N O
EtOH, rt, 15 h ð14Þ
+
N NH EtO O 60% N N O
H H
A two-component multistep reaction between 1-pyrroline and 4-aminobutanal diethylacetal

culminated in the intramolecular acylation of an aminal to afford an advanced intermediate for
the total synthesis of tetraponerine alkaloids (Scheme 7) <2000CJC1030>.
10% HCl, H2O, 0 °C, 10 min

then add 1 M KOH (pH 12)
CO2Et
then add (EtO2C)2CH2 H
0 °C to rt, 14 h O
H
NH2 46% N N
EtO OEt
CO2Et CO2Et CO2Et

H H
CO2Et N
CO2Et CO2Et
H
N NH N NH
Scheme 7
4.09.3.1.2 Condensation of amines and amides with carbonyl compounds

The condensation of 2-aminoamides with aldehydes or ketones leads to the formation of imidazolidin-
3-ones (Equation (15)). The reaction mixture is usually heated in methanol dimethylformamide (DMF)
or toluene, and the use of a catalytic amount of acid has been reported.
O R5 O R5
O
∆
ð15Þ
R3 N N R 1 + R2 R2' –H2O R3 N N R1
H H R2 R2'
Chiral imidazolidin-3-ones and pyrrolo[1,2-c]imidazolones have been prepared and utilized as

(immobilized) organocatalysts <2000JA4243, 2000JA9874, 2001TL407, 2001TL411, 2002ASC941>,
(immobilized) transition metal ligands <2001JA2919, 2002TA1769>, covalently bonded chiral aux-
iliaries <1995T3423, 1998CJC234, 2001OL425>, or as synthetic intermediates <1996TA2233,
2000OL2781, 2001TA101>. Representative examples are depicted in Scheme 8.
O Bn O Bn O H
OH
N NH N NH Ph N N
= Silica gel
Ph
<2000JA4243> <2002ASC941> <2001TL407>
O H
n
O N N
= Polystyrene
O
HN Ph
O <2001JA2919>
Scheme 8
6,7-Dimethoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline-1-acetamides have been condensed with

formaldehyde or benzaldehyde to provide pyrimido[6,1-a]isoquinolin-2-ones <1997LA1165>.
2-Formyl- or 2-acetylbenzoic acid was condensed with chiral 1,2-diamines to afford the
corresponding polycyclic monoacylated aminals (Equation (16)) <2002TA933>.
MeO O OMe O
MeO 10 mol.% p -TsOH MeO
OH
H 2N benzene, reflux, 12 h N ð16Þ
O
+
HN 86% H N
Bn Bn
Enantiomerically enriched cyanohydrins have been hydrogenated to oxo carbonic acids and
condensed with chiral diamines in a one-pot procedure to afford the corresponding bicyclic,
monoacylated aminals (Equation (16)) <2003ASC483>. When comparing Equations (16) and
(17), it is instructive to notice the different regioselectivity of the aminal formation.
H
MOMO Pd/C, H2 MOMO N
CN H2N CH3OH, rt
OMe + N ð17Þ
H2N 86%
O O
64/36 S/R
The condensation of O-methyl lactimes with ethyl-6,7-dimethoxy--[1-(1,2,3,4-tetrahydro-

isoquinolyl)]acetate afforded mixtures of tetracyclic, monoacylated aminals (8,13-diazasteroids)
and the corresponding medium-sized tricyclic diamides <1998MI375>. Treatment of 2,3-
diaminonaphthalene with 4-isothiocyanato-4-methyl-2-pentanone led to the formation of a tetra-
cyclic, thioacylated aminal <2000M501>. A tricyclic aminal has been prepared in which one
nitrogen is part of a pyrrole <2000TL4295>.
4.09.3.1.3 Nucleophilic displacement reactions

The nucleophilic displacement of a leaving group from an sp3-hybrized, N-acyl-substituted carbon
atom may proceed via an SN2- or SN1-type (iminium ion intermediate) process. The correspond-
ing transformations are summarized in this chapter regardless of their actual mechanism. Devel-
opments and applications in this area during the 1990s are apparently very limited. The interested
reader is referred to chapter 4.09.3.1.2 of <1995COFGT(4)403> for a more sound summary.
Treatment of -isopropylthioglycines with a variety of different amines in the presence of
N-bromo succinimide (NBS) afforded the corresponding aminals with chemical yields that are
not always useful, depending on the nature of the amine. The best example is depicted in
Equation (18) <2002JOC5408>.
50 mol.% NBS
O S 200 mol.% Et2NH O NEt2
OBn THF, 12 h OBn ð18Þ
N N
H 89% H
O O
5-Alkylaminopyrrolones have been synthesized by the reaction between 5-chloro-1,5-dihydro-

2H-pyrrol-2-ones and primary aromatic, aliphatic as well as alkoxyamines in reasonable yields
<2001S89>. Methyl-N-benzoyl-2-bromoglycinate was trimerized by treatment with NH3. The
corresponding trimethyl-2,20 ,20 -nitrilotris[2-(benzoylamino)acetate] was used for the synthesis of
C3-symmetric peptide derivatives <1995TL857>.
4.09.3.1.4 Addition of amines and amides to CN multiple bonds

Two examples of the nucleophilic addition of amines to the N-acylenamine moiety of a -(4-tolue-
nesulfinyl)-substituted dehydroamino acid have been reported (Equation (19)) <2002TL4495>.
RNH2
O O
CH3OH
Ts'O OMe Ts'O OMe ð19Þ
NHt–BOC RNH NHt-BOC
R = Bn, 92%
Ts' = 4–CH3–C6H4–S(=O)–
R = HCCCH2, 87%
The nucleophilic addition of a phthalimide ion to a di(ethoxycarbonyl)-substituted imine has

been reported <2000TL9713>.
Several examples for the addition of an N-nucleophile to an iminium ion have been reported
<1995JA5604, 1996T13111, 1999S1022, 2002TL3347>. For instance, three-acceptor-substituted
N-methyl-1,4-dihydropyridines add halosuccinimides to afford the corresponding aminals
(Equation (20)) <1998JOC2728>.
O
NXS (X = Cl, Br, I)
N N N ð20Þ
THF, 0 °C, 1 h
70–77% O
NC, MeO2C NC, MeO2C Cl, Br, I
Acid-catalyzed cyclization of a benzyloxycarbonyl-protected tryptophan afforded a tricyclic

aminal (Equation (21)) <2001JMC2276>.
O O
O H
O
F3CCO2H
NHZ NZ ð21Þ
N 52% N H
H H
Z = CO2Bn
A Fischer indole synthesis of N0,N0 -diphenylcyclopentyl-N-trifluoroacetyl-enehydrazines that

proceeds under particularly mild conditions (due to the presence of the N-trifluoroacetyl moiety)
has been reported <1999TL3601>.
4.09.3.1.5 Reductive methods

The reduction of imines and iminium ions has been summarized in chapter 4.09.3.1.2 of
<1995COFGT(4)403>. A recently reported example for the reduction of a bicyclic amidine to
a bicyclic aminal is depicted in Equation (22) <2002T7177>.
O NaBH4 O
N MeOH N
ð22Þ
N 43% N
H
4.09.3.1.6 Cycloaddition procedures

The thermal 1,3-dipolar cycloaddition between in situ generated -lactam-based azomethine ylides and
2H azirines-afforded tricyclic aminals <2002JCS(P1)2014>. The generality of this procedure is ham-
pered by low-to-moderate yields and diastereoselectivities. The best example is depicted in Equation (23).
N
H MeCN, 80 °C H
O + N
sealed tube, 18 h
O ð23Þ
N NO2 66% N
O O
O O NO2
4-NO2Bn 4-NO2Bn
4.09.3.1.7 Metal-catalyzed procedures

The palladium-catalyzed intramolecular cyclization of an aryl iodide onto a 1,2-dienamide
afforded a -allylpalladium complex that was intercepted by a secondary amine to provide the
corresponding aminal (Equation (24)) <1995CC1903>. The regioselectivity of the intermolecular
attack of the amine onto the -allylpalladium complex was determined by the nature of the
inorganic base. Related examples for the intramolecular attack of the -allylpalladium complex
by an amine have also been reported <2001CC964>.
10 mol.% Pd(OAc)2
20 mol.% PPh3
100 mol.% Ag2CO3
MeCN, 80 °C, 6 h ð24Þ
I HN N
77% N
N
O O
Quinazolinones have formed by the copper-catalyzed cyclization of N-alkynyl-substituted

2-aminobenzamide (Equation (25)) <2001TL2883>.
20 mol.% CuI
250 mol.% K2CO3
O 100 mol.% Bu4NBr O
MeCN, 80 °C, 24 h Ar ð25Þ
NHAr N
61–69%
N N Ar'
Me, Bn Ar' Me, Bn
4.09.3.1.8 Benzotriazole derivatives

The preparation of acyclic N-(1-benzotriazol-1-yl-alkyl)amides by the condensation of primary or
secondary amides and aliphatic or aromatic aldehydes with 1H-benzotriazole is well established
<1995SC1197, 1995JCS(P1)1, 1999JOC7622, 2000TL9691, 2000JOC8066, 2002JOC4957>. An
instructive example is depicted in Equation (26) <1998TL3819>. Alternative procedures using
2,2-dichloroacetamides or enamides as the acylamino source have been reported <2002JOC8239,
1997JOC700>. N-(1-Benzotriazol-1-yl-alkyl)amides may be used according to the reactivity
pattern outlined in Scheme 3.
100 mol.% PhCH2CONH2
O 100 mol.% benzotriazole Ph O
20 mol.% p -TsOH O
N toluene, reflux, 16 h N ð26Þ
O H H
HN
N3 67% N3
Bt
The synthesis of N-(benzotriazolylmethyl)thioamides using the condensation chemistry outlined

above has been reported <1995T8703, 1995T13271, 2000JOC8819>. Several benzotriazolyl- or
benzotriazolylmethyl-substituted heterocycles have been prepared using the reliable condensation
strategy <1999TA255, 2001JOC5590, 2001JOC2862, 2002EJOC3133>. Some representative
examples are depicted in Scheme 9.
R O ArS N
O
Bt N O Bt N O Bt N
Bn
<1999TA255> <2001JOC5590> <2001JOC2862>
O
O S
= Polystyrene O
N R
O
<2002EJOC3133> Bt
Scheme 9
The preparation of benzotriazolylimidazolidinone derivatives represents a noteworthy excep-

tion of the general condensation strategy (Equation (27)) <2001JOC2858>.
100 mol.% BusLi

THF, –78 °C, 30 min
Bt then add 100 mol.% Bt Ph
ð27Þ
PhCH=N(p -MeOPh)
Bn N OBut Bn N N
82% p-MeO-Ph
O O
4.09.3.2 Sulfonated Derivatives

A limited number of examples for the synthesis of this specific functionality have been reported
since the publication of COFGT (1995). A tricyclic aminal was regioselectively monosulfonated
to the corresponding sulfonamide by treatment with TsCl <2000H483>. The reduction of a
pyrrolo-benzothiadiazine with various chiral and achiral complex hydrides has been investi-
gated <1996BMC3003>. The highest enantioselectivity was observed using the combination
of lithium aluminum hydride (LAH) and (+)-(2(S),3(R))-4-dimethylamino-3-methyl-1,2-diphe-
nyl-2-butanol (Chirald1) (Equation (28)).
100 mol.% LAH

230 mol.% Ph OH
O O Ph O O
(H3C)2N
S S
N NH ð28Þ
Et2O, 0 °C
N N
98%
76% ee
The oxidation of substituted indoles with N-sulfonyloxaziridines afforded an unusual

1,3-oxazolidinoindole ring system containing an N-monosulfonated aminal <1997JA1159>.
3,5-Dimethyl-N-p-tolylsulfonyl-2,6-dichloro-1,4-benzoquinone imine containing a highly
electrophilic N-tosylimine was treated with aromatic amines to afford the corresponding acyclic
monosulfonated aminal <2000JOU245>.
4.09.4 GEMINALLY SUBSTITUTED ALKANES BEARING TWO ACYLATED

OR SULFONATED AMINO GROUPS
4.09.4.1 Acylated Derivatives
4.09.4.1.1 Acylation of monoacylated aminals

Cyclic monoacylated aminals, either isolated or generated in situ, are frequently acylated using the
corresponding acid chlorides <1995HCA1185, 1996TA1567, 1996SL1109, 1996TA2233,
1998S1463, 2000OL2781, 2001TA101, 2001JMC2276>. Some representative diacylated aminals
prepared by this strategy are depicted in Scheme 10.
Ph, Et, ButO ButO ButO

O O OMe O O
H
N N N NH
Et, Ph But But
N O N N N
H O O O HO2C O
OMe
Ph, Et, ButO BnO ButO Ph
<1996SL1109> <1995HCA1185> <1998SL11463> <1996TA2233>
Scheme 10
4.09.4.1.2 Condensation of amides with carbonyl compounds

Acyclic N,N-alkylidene-bis-amides can be synthesized by the acid-catalyzed condensation of
amides with aldehydes. An application in the context of natural product synthesis is depicted in
Equation (29) <2001TL2645, 2002AG(E)3701>. A more general study on this topic is also
available <1996S1299>.
NH2
i. 50 mol.%
O H H
TMSOTf N N
O
+ ClCH2CH2Cl
rt, 12 h O O
ii. TBAF
ð29Þ
OH O 75% OH O
O O
O O
OTBS OH
The N-BOC-N0 -Fmoc-protected imidazolidine-2-carboxylic acid was prepared by the condensation

between N-BOC-N0 -Fmoc-protected ethylenediamine and glyoxylic acid <1998TL2569>.
-BOC-amino-Fmoc-glycine was synthesized from 9-fluorenylmethylcarbamate, glyoxylic acid, and
t-butyl carbamate by a two-step condensation sequence <1996SC3237>. The sequential intermolecu-
lar condensation and intramolecular acylation between 2-formylbenzoic acid and -aminoamides
afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones (Equation (30)) <2001JCS(P1)1767>.
O
CO2H 10 mol.% p-TsOH
alk toluene, reflux, 12 h alk
+ H2N N
CHO 67–95% ð30Þ
HN O H N O
aryl, alkyl aryl, alkyl
58–99% de
A similar intramolecular strategy was used to synthesize tricyclic N,N0 -diacylaminal from a
cyclic dicyanoketone (Equation (31)) <2000JOC3255, 2002JA13686>.
N
N Conc. H2SO4 O H NH
C O O N
C EtOH, rt ð31Þ
CO2Et CO2Et
43%
EtO2C EtO2C
An example has been reported for a one-pot Rh-catalyzed double bond hydroformylation,
succeeded by an intramolecular condensation of the resulting aldehyde with two acylated amino
groups to afford a diazabicyclo[4.4.0]decane <2002OL4575>.
4.09.4.1.3 Reductive methods

The few reductive methods for the synthesis of N,N0 -diacylated aminals have been summarized in
chapter 4.09.4.1.2 of <1995COFGT(4)403>. No significant progress has been reported since the 1990s.
4.09.4.1.4 Nucleophilic addition to imines and enamines

Addition of electrophiles (H+, PhSe+, I+, Br+) to N-acylenamines has been used to generate
N-acyliminium ions in situ, which react with N-acylnitrogen nucleophiles to afford the corre-
sponding N,N0 -diacylated aminals <1995TL7705, 1999JOC7218, 1999JA11953, 2000OL4205>.
An example is depicted in Equation (32) <2001TL1599>.
PhSe
OTMS OTr i. PhSeBr, MeCN, –23 °C O
+
N ii. ZnBr2, CH3OH, CH2Cl2 OH
N NH HN N N
ð32Þ
t-BOC
85%
TMSO O t-BOC
The generation of a cyclic N-acyliminium ion from a cyclic N-acyl-N,O-acetal followed by the
in situ reaction with a heterocyclic nitrogen nucleophile afforded a related nucleoside analog
(Equation (33)) <1999CL687>.
AcO
AcO
TMSO TiCl4, MeCN O
AcO O
N –10 °C, 3 h ð33Þ
N N HN N O
OAc N
70%
TMSO O OAc
1-Benzoyl-2-t-butyl- and 1-benzoyl-2-isopropyl-3-(10 (S)-methylbenzyl)imidazolidin-4-ones were

prepared by the treatment of the corresponding imino amide with benzoic anhydride at elevated
temperature (Equation (34)) <1995JOC6408>.
Ph Ph
HN O N O
(PhCO)2O, ∆ ð34Þ
R R
N R = But:85% N
R = Pri:65% Bz
The alkylation of imidazoles in the 2-position was achieved with in situ generated allylic
stannanes in the presence of chloroformates to afford the cyclic bis-acylated aminals
<1995SL1117>. It is reasonable to assume that the reaction proceeds via the intermediate
formation of an N-(alkoxycarbonyl)imidazolium ion.
Little work has been published about the addition of nucleophiles to unactivated imines. It
was shown that the succinimide anion adds to an in situ generated di(ethoxycarbonyl)-substituted
N-acylimine <1995SC2723>.
4.09.4.1.5 Miscellaneous procedures

4-Acylamino and 4-sulphonamido -lactams have been prepared by the [2+2]-cycloaddition
between acyclic trisubstituted amidines and the ketene generated in situ from 2-aryloxy or
2-arylamino-substituted acetic acid chlorides <2000T7811>. A representative example is depicted
in Equation (35).
Bz Bz
Et3N, CH2Cl2 PhO N Ph
PhO N 0 °C to rt
Ph ð35Þ
+
N 72% N
O Cl Ph O Ph
A Curtius rearrangement of N-benzyloxycarbonyl- or N-t-butyloxycarbonyl-substituted

(S)-serine has been exploited to synthesize the corresponding protected 4-amino-2-oxazolidinone
(Equation (36)) <2000JOC6595>. A related intermolecular Curtius rearrangement has been
reported <1999JOC8537>.
O
O CO2H (PhO)2P(=O)N3 O HN
OH Et3N, ButOH, reflux O ð36Þ
RO N RO N
H R = But:84%, R = Bn:61% H
The direct bis-amidation of ethyl acetate using ethyl-N-[(4-nitrobenzenesulphonyl)oxy]carbamate

(NsONHCO2Et) was observed. However, the reaction conditions were optimized to support the
formation of the monoamidated product <2001TL1171>.
4.09.4.2 Sulfonated Derivatives

2-Substituted N,N-disulfonated imidazoles have been prepared by the reaction of sulfonic acid
chlorides with imines generated from N-sulfonated ethylenediamines and aldehydes (Equation (37))
<2000MI894>.
O O
p-Tol S O R1SO2Cl p-Tol S O
HN Et3N, MeCN N
R2 R2 ð37Þ
N 10–69% N
R1 S
R2 = Pri, Ar; R1 = CH3, Ph, p -Tol O
O
Treatment of CH2I2 with an aromatic sulfonamide afforded an acyclic bis-sulfonated aminal

in moderate yield (Equation (38)) <1995JCS(P1)83>. In a related alkylation reaction, N,N-
bis(chloromethyl)amides served as the methylene donors for the formation of cyclic N,N0 -disulfo-
nated aminals <1998MI2201>.
(CH2)2CO2Me (CH2)2CO2Me
CH2I2, K2CO3
MeCN
48% Ts ð38Þ
NH N N
Ts Ts
(CH2)2CO2Me
The investigation of the chemical properties of N-(2,2,2-trichloroethylidene)trifluoromethane-

sulfonamide revealed, not unexpectedly, the high electrophilicity of the imine carbon atom.
The reaction of that imine with benzenesulfonamide led to the formation of N-(2,2,2-trichloro-
1-phenylsulfonylaminoethyl)-trifluoromethanesulfonamide <2001JOU1559>.
A limited number of geminally substituted alkanes bearing one acylated and one sulfonated
amino group have been reported <1998MI2201, 2000TL5479, 2002JCS(P1)1105>.
4.09.5 GEMINALLY SUBSTITUTED ALKANES BEARING TWO SIMILAR

DICOORDINATE OR HETEROSUBSTITUTED NITROGENS
4.09.5.1 gem-Dinitro Alkanes

Limited work concerning gem-dinitro alkanes has apparently been published since 1995.
A comprehensive summary of the synthesis of gem-dinitro alkanes can be found in chapter
4.09.5.1 of <1995COFGT(4)403>.
A common strategy toward gem-dinitro alkanes utilizes the direct bis-nitration of a methylene
group with acidic protons. Some examples of this strategy have been published recently. The
synthesis of 3,3,5,7-tetranitrooxindole by the treatment of oxindole with a mixture of sulfuric and
nitric acid has been described <1996TL9263>. Ring-opening reactions of 3,3,5,7-tetranitrooxin-
dole and its transformations into indoles, indazoles, and benzoxazinones have been investigated
<1999T10447>. Bis-nitration of pyrimidin-4,6-diones with nitric acid in concentrated sulfuric
acid afforded 5,5-gem-dinitropyrimidin-4,6-diones in high yields. One of three examples is
depicted in Equation (39) <2000TL2011, 2001TL1793, 2002JOC7833>. The 5,5-gem-dinitropyr-
imidin-4, 6-diones were thermally stable up to 150 C, but hydrolyzed vigorously with water.
O2N NO2
O O 240 mol.% HNO3 O O
H2SO4, 45 °C, 4 h
ð39Þ
HN NH HN NH
94%
O O
The oxidative nitration of oximes of spiro[2.n]alkan-4-ones and bicyclo[n.1.0]alkan-2-ones with

nitrogen pentoxide afforded the corresponding gem-dinitro bicycles <1999JOU839>. The highest
yielding example is depicted in Equation (40). Trinitroazetidine has been prepared by the
treatment of N-p-tosyl-3-azetidinone oxime with nitric acid, urea, and ammonium nitrate
<1995JOC1959>.
NOH 400 mol.% N2O5 O2N NO2

CHCl3, 50 °C, 15 min ð40Þ
56%
Cyclopent-1-encarboxaldehyde was converted in low yield to 2,2-dinitrocyclopentanone

oxime using a mixture of ceric ammonium nitrate (CAN) and NaNO2 <1998TL6617>. 1-Trimethyl-
silylcyclooctene yielded 2,2-dinitrocyclooctylnitrate when treated with acetylnitrate <1999CC1079>.
4.09.5.2 gem-Diazidoalkanes
Treatment of peracetylated 1-bromo--D-glycopyranosyl chlorides with sodium azide under
phase-transfer conditions afforded the corresponding glycopyranosylidene 1,1-diazides
<1996S577>. One of three examples is depicted in Equation (41).
1000 mol.% NaN3

OAc OAc
100 mol.% Bu4NHSO4
AcO O NaHCO3, H2O, CH2Cl2, rt AcO O ð41Þ
AcO Cl AcO N3
AcO 82% AcO
Br N3
Benzylidene diacetate was converted into diazidophenylmethane (decomposes violently

when exposed to elevated temperature) when refluxed with sodium azide in benzene
<1998TL6361>.
4.09.5.3 gem-Diisocyanates and gem-Diisothiocyanates

No further advances have occurred in this area since the publication of chapter 4.09.5.3
<1995COFGT(4)403>.
4.09.5.4 gem-Dinitrosamines and gem-Dinitramines

Silylamines can be converted into nitrosamines by treatment with dinitrogen pentoxide in
CH2Cl2. The application of this method afforded 1,3-(dinitroso)hexahydropyrimidine from
1,3-bis(trimethylsilyl)hexahydropyrimidine (Equation (42)) <1997T4371>.
N2O5, CH2Cl2
–5 to 5 °C, 1 h ð42Þ
N N N N
(H3C)3Si Si(CH3)3 69% ON NO
The nitration of cyclic 1,3-disulfonates afforded a mixture of cyclic gem-dinitro compounds and
acyclic linear polynitramines in low-to-moderate yield. The product distribution depended on
the reaction conditions for the nitration and for the formation of the cyclic 1,3-disulfonates
from formaldehyde, primary amines, and potassium sulfamate (Equation (43)) <2000MI1079,
2000MI1082>.
N N
MeNH2 i. H O, pH 6.5 O2N NO2
2
+ ii. HNO3, Ac2O ð43Þ
CH2O +
+ AcO N
NO2
H2NSO3Na
N N
O2N NO2
4.09.5.5 gem-Dihydroxylaminoalkanes
4,4,5,5-Tetramethyl-4,5-dihydro-1H-imidazolyl-1-oxyl-3-oxides (cyclic nitronylnitroxides) are
being intensively studied for their properties as organic ferromagnets. They can be synthesized
by the oxidation of 4,4,5,5-tetramethyl-imidazolidine-1,3-diols, which in turn are most frequently
synthesized by the condensation of 2,3-bis(hydroxyamino)-2,3-dimethylbutane with aldehydes
<1996MI919, 1997MI275, 1997T16911, 1997S1049, 2000S2137, 2000IC6091, 2001POL1151,
2001CEJ2007, 2001POL1647, 2002ZNB677, 2003JA1607, 2003EJOC167>. Some representative
examples are depicted in Scheme 11.
RCHO R oxidation R
+ – +
H H HO N N OH O N N O
HO N N OH
R, yield for condensation =

O
PPh2 N
Br
HN
N N
61% 25% 62% 55%

<1996MI919> <1997MI275> <1997S1049> <2000S2137>
N N3 OMe
N But OMe
HN N
2 P(=O)Ph
27% 38% 77% 60%

<2001POL1151> <2001POL1647> <2003Ja1607> <2003EJOC167>
Scheme 11
4.09.5.6 gem-Dicarbodiimides
<1995COFGT(4)403>.
4.09.5.7 gem-Diazo Alkanes

Treatment of benzyl cyanide with nitric oxide (NO) in the presence of sodium methoxide afforded
a bis-diazeniumdiolated imidate, PhC[(OMe)¼NH][N(O)¼N(ONa)]2 in low yield
<2000TL8421>. No further advances have occurred in this area since the publication of chapter
4.09.5.7 <1995COFGT(4)403>.
4.09.5.8 gem-Dihydrazino Alkanes

1,2,4,5-Tetrazines were formed unintentionally during the attempted Pictet–Spengler cyclization
of the corresponding hydrazines. The chemoselectivity of this reaction is highly dependent on the
nature of the substituents (Equation (44)) <2000SL137>.
R1 R1
MOMCl, AcOH
rt to 50 °C
R2 HN R2 N
N H NH
N N
+
N ð44Þ
R1 R2
N N
N N
R2 R1
N
R1 = OMe, R2 = H: 95% + 0%
R1 = OMe, R2 = OTBDMS: 60% + 0%
R1 = H, R2 = H: 0% + 33%
R1 = H, R2 = OMe: 0% + 12%
The synthesis of bis(7-azaindol-1-yl)methane and two structural isomers by the reaction

between CH2Br2 and 7-azaindol under phase-transfer conditions has been reported
<2002OL4049>. The preparation and determination of physical properties of silver(I) complexes
of bis(1,2,4-triazol-1-yl)methane have been achieved <2003IC112>. N,N-bis(pyrazol-1-yl-methyl)-
alkylamines have been synthesized by the condensation of 3,5-disubstituted 1-(hydroxymethyl)-
pyrazoles with primary aliphatic amines <2001SC1315>.
4.09.5.9 gem-Diiminoalkanes and gem-Diisocyanides

Treatment of benzaldehyde with ammonia under pressure (7 atm) afforded the corres-
ponding gem-diimino alkane, 1,3,5-triphenyl-2,4-diazapenta-1,4-diene, in quantitative yield
<2002MI2308>. Alternatively, benzaldehyde can be treated with hexamethyldisilazane
and LiBr in THF at elevated temperatures to afford the identical gem-diimino alkane in 94%
yield <2001MI29>.
Diisocyanomethane synthesized from bis(formylamido)methane by treatment with POCl3 and
Et3N H2C(NC)2 decomposes violently at temperatures above 10 C. Highly diluted solutions
of diisocyanomethane are reasonably stable at room temperature (<2002ZAAC863>).
4.09.5.10 gem-Difluoroaminoalkanes
2-[2,2-Bis(difluoroamino)propyl]-5-nitrotetrazole was prepared from the corresponding ketone by
treatment with difluoroamine, which was in turn generated from triphenyl(difluoroamino)-
methane (Equation (45)) <2000MI949>.
HNF2, H2SO2
N N O N N F2N NF2
CH2Cl2, 0 °C ð45Þ
O2N N O2N N
N 92% N
A more general study investigated the scope of the bis(difluoroamination) of ketones with
difluoroamine, which was generated in situ from triphenyl(difluoroamino)methane
<2002CC1712>. gem-Bis(difluoroamino)-substituted heterocyclic nitramines have been synthe-
sized from the corresponding diketones using difluoroamine that was generated from
N,N-difluorourea (Equation (46)) <1998JOC1566, 1999JOC960>.
O F 2N
HNF2, CFCl3 NF2
Ns N fuming H2SO4 Ns N
ð46Þ
N Ns N Ns
60%
F2N
O NF2
4.09.5.11 gem-Benzotriazol-1-yl Alkanes

Reaction of tris(benzotriazol-1-yl)methane with nitroarenes under basic reaction conditions
afforded p-bis(benzotriazol-1-yl)methyl-substituted nitroarenes (Equation (47)) <1996TL347>.
NO2 N 625 mol.% KOH NO2
N N )3CH DMSO, rt, 12 h
Ph Ph
+
68% ð47Þ
Bt Bt
Bis(benzotriazol-1-yl)methane can be prepared from phenyldichloromethane and 1H-benzotria-

zole in the presence of p-toluenesulfonic acid in toluene at reflux <1997TL903>.
4.09.6 GEMINALLY SUBSTITUTED ALKANES BEARING TWO DIFFERENT

DICOORDINATE OR HETEROSUBSTITUTED NITROGENS
4.09.6.1 Nitroalkane Derivatives

2-Nitro-2-nitroso-butyric and propionic acid ethyl ester have been prepared in low yield (20%
and 15%, respectively) by treatment of [1-(ethoxycarbonyl)ethylidene]triphenylphosphorane with
dinitrotetroxide <1996LA845>.
Nitroethane and 1-nitrobutane were converted into the corresponding 1-azido-1-nitroalkanes
(80% and 83% yield, respectively) by treatment with sodium azide and ammonium peroxodisul-
fate (NH4)2S2O8 <2002MI1466>. An alternative procedure utilized potassium ferricyanide
K3Fe(CN)6 as the oxidant. A representative example is depicted in Equation (48)
<1997JOC1872>.
2000 mol.% NaN3
1000 mol.% K3Fe(CN)6
NO2 N3 NO2
200 mol.% NaOH
CH2Cl2, H2O, rt, 12 h
ð48Þ
85%
NO2 N3 NO2
3/2 trans/cis
4.09.6.2 Nitraminoalkane Derivatives

3-Methyl-1-(2-nitrazapropyl)diaziridine was prepared by the alkylation of 3-methyldiaziridine
with the corresponding alkyl bromide (Equation (49)) <1999MI112>.
120 mol.% NaH

THF, rt, 6 h
then add 120 mol.%
N ð49Þ
NO2
HN HN
NH Br N N
NO2
43%
4.09.6.3 Azoalkanes and Hydrazino Alkane Derivatives

Treatment of N3-benzyluracil with N-hydroxylmethylphthalimide in the presence of N,N,N0 ,N0 -
tetramethylazodicarboxamide (TMAD) and PPh3 afforded, under optimized conditions, the
corresponding 1-hydrazylmethyl compound (Equation (50)) <2002TL2633>.
O O
Bn 200 mol.% TMAD Bn
N N
200 mol.% PPh3, DMF
O N O N H ð50Þ
69%
N
OH N CONMe2
CONMe2
(chapter 4.09.6.3 of <1995COFGT(4)403>).
4.09.6.4 Isocyanato Alkane Derivatives

(chapter 4.09.6.4 of <1995COFGT(4)403>).
4.09.6.5 Benzotriazole Derivatives

A number of 1H-benzotriazol-1-yl-substituted alkanes bearing dicoordinated or heterosubstituted
nitrogens are known <2000JHC167, 2000T8025, 2000JOC8077, 2001T2581, 2002TL8055,
2002JOC8230>. These benzotriazole derivatives are usually prepared by the inter- or intramole-
cular condensation of an appropriate amine and an aldehyde with 1H-benzotriazole. Some
representative examples are depicted in Scheme 12.
O O OBn aryl
Bt N
NAr Ph Bt N aryl
Bt N
<2000JHC167> <2000T8025> <2000JOC8077>
Bt
N
N Bt N
<2001T2581, <2002JOC8230>
2002TL8055>
Scheme 12
4.09.6.6 Miscellaneous Derivatives

The direct azidation of enolates of benzodiazepines with 2,4,6-triisopropylbenzenesulfonyl azide
(trisyl azide) afforded the corresponding 3-azidobenzodiazepines <1996TL6685>. A representa-
tive example is depicted in Equation (51).
105 mol.% KHMDS
THF, toluene, –78 °C, 5 min
O O
N then add N
250 mol.% trisyl azide ð51Þ
N3
N 89% N
Ph Ph
4.09.7 GEMINALLY SUBSTITUTED ALKANES BEARING ONE AMINO GROUP

AND ONE DICOORDINATE OR HETEROSUBSTITUTED NITROGEN
4.09.7.1 Aminomethylhydroxylamines
The thermal 1,3-dipolar cycloaddition between imidazolin-3-oxides and dimethyl acetylenedicar-
boxylate afforded the corresponding 3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles with a remark-
able yield (Equation (52)) <2000TL5407, 2001T3413>. (1(S))-(–)--pinene has been employed as
a dipolarophile for the analogous transformation <2001TA1463>.
400 mol.% CO2Me

Ph Ph
MeO2CCO2Me CO2Me
+
– Benzene, 80 °C, 1 h ð52Þ
N N O N N O
aryl 95–98% aryl
H, Ph H, Ph
A structurally modified imidazolin-3-oxide underwent the 1,3-dipolar cycloaddition with a

variety of different alkenes in low-to-moderate yield. The highest yielding example is depicted
in Equation (53) <2000SL967>.
Ph
Ph Toluene, Et3N
+ 20 °C, 24 h N N
– + O Bn
N N O 72% H ð53Þ
Bn O N
O N O
4.09.7.2 Aminomethyl Nitramines and Nitrosamines

(chapter 4.09.7.2 of <1995COFGT(4)403>).
4.09.7.3 Aminomethyl Azides and Triazines

Azide has been incorporated into N,N-dimethylarylamines to afford the corresponding N-azido-
N-methylanilines <1997JA7408>. A representative example is depicted in Equation (54)
<1996JA5192>.
O CH2Cl2
Br Br
reflux, 30 min
+ O ð54Þ
I 91% N N3
N
N3
N-Azido-N-methylanilines have also been prepared in moderate yield by treatment of either

N-(methoxymethyl)anilines or 1,3,5-triarylhexahydro-1,3,5-triazines with TiCl4 and trimethylsilyl-
azide <1995SC969>. A related investigation employed the combination of iodosylbenzene and
trimethylsilylazide as reagent for the azidation of N,N-dimethylarylamines <1998S547>.
4.09.7.4 Aminomethylazo and -hydrazino Compounds

No further advances have occurred in this area since the publication of COFGT (1995) (chapter
4.09.7.4 of <1995COFGT(4)403>).
4.09.7.5 Aminomethylimines
3-Amino-1,4-benzodiazepines have been prepared by the reduction of the corresponding azides
(Equation (47)) with triphenylphosphine <1996TL6685>.
4.09.8 GEMINALLY SUBSTITUTED ALKANES BEARING ONE ACYLATED

OR SULFONATED AMINO GROUP AND ONE DICOORDINATE OR
HETEROSUBSTITUTED NITROGEN
As was concluded in chapter 4.09.8 of <1995COFGT(4)403>, work on compounds that bear one
dicoordinate nitrogen substituent and a sulfonated amino substituent on the same carbon are very
rare. An example can be found in <2000JOU816>.
4.09.8.1 Acylaminomethylisocyanates and -isothiocyanates

<1995COFGT(4)403>.
4.09.8.2 Acylaminomethylazides
Treatment of a highly functionalized, cyclic N-acyl-N,O-acetal with trimethylsilyl azide afforded
the corresponding substituted 6-azido-N-(t-butoxycarbonyl)piperidine in high yield (Equation
(55)) <2000OL4037>.
590 mol.% TMSN3
O O
CO2Bn 190 mol.% BF3·OEt2 CO2Bn
O O
CH2Cl2, – 40 °C, 3 h ð55Þ
CH2Ph CH2Ph
86%
MeO N N3 N
t-BOC t-BOC
Tricyclic diketopiperazin-2,5-diones have been deprotonated and treated with different electro-
philes. Equation (56) depicts an azidation with 2,4,6-triisopropylbenzenesulfonyl azide (trisyl
azide) as the electrophile <2002OL2645>.
100 mol.% KHMDS
O toluene, THF, 78 °C, 3 h; O
MeO2C 120 mol.% trisyl azide MeO2C
N –78 °C, 2.5 h N ð56Þ
N 79% N
H N3
O O
3-Azidomethyl-2-oxazolidinone was prepared by condensation from 2-oxazolidinone, parafor-

maldehyde, and HN3 <2000OL3777>.
4.09.8.3 Acylaminomethyl Nitramines

<1995COFGT(4)403>.
4.09.8.4 Acylaminomethylhydroxylamines and -hydrazines

This chapter verifies that a large number of reactions have been described that provide diverse
compounds containing the acylaminomethylhydroxylamine- and hydrazine-structural element.
The 1,3-dipolar cycloaddition between substituted 3-imidazoline-3-oxides and arylisocyanates
afforded substituted imidazoloxadiazol-2-ones in high yields (Equation (57)) <1997TL2299,

1997T13873, 1999SC3889>. A related 1,3-dipolar cycloaddition of N-oxides derived from poly-
hydroxylated piperidines has been described <1996T4467>.
3
R3NCO Ph R
Ph N
MeCN, reflux
R1 N + R1 N O
N O
–
N O ð57Þ
2
R R2
R1 = Ar; R2 = H, Ar; R3 = Ar: 90–100%
The 1,3-dipolar cycloaddition between a spirocyclic chiral nitrone and different allylglycosides
afforded the expected tricyclic isoxazolidines in good yield and auxiliary-induced diastereoselec-
tivity <2001OL1375>. A representative example is depicted in Equation (58).
OBn OBn
BnO O BnO O
BnO BnO
BnO Toluene BnO
– reflux O ð58Þ
+ + H
O
Pri N
92% Pri N O
O
N N
Treatment of N-chloromethyl-N-benzyloxyacetamide with potassium phthalimide afforded the

N-(phthalimidomethyl)-N-benzyloxyacetamide (Equation (59)) <1995SL97>.
O Cl O O O
K DMF, rt, 4 h
N + N N N ð59Þ
OBn 86% OBn
O O
The mechanism of the formation of a spirocyclic tetrazole by treatment of the corresponding

pyrrolidinone with cerium(IV) ammonium nitrate has been investigated Equation (60)
<1996T10169>.
N N
N 357 mol.% (NH4)2Ce(NO3)6 N
N HN N H2O, MeCN, –5 °C, 45 min N N N
O O ð60Þ
60%
OMe O
The synthesis of a 1,4,5,6-tetrahydropyridazine derivative by an intermolecular hetero-

Diels–Alder reaction has been reported (Equation (61)) <1999BMCL1751>.
N CO2Et
O N
H Na2CO3, MeCN ð61Þ
N CO2Et
Br rt to 50 °C, 16 h O N
+
NHt-BOC 87% AcHN
AcHN
NHt-BOC
A microwave-promoted addition of the N-phenylhydrazone of 1-phenylpyrazol-4-carbaldehyde

onto the imine function of N-trichloroethylidenecarbamate afforded the corresponding addition
product <1999T9623>.
The Diels–Alder cycloaddition between 5-vinyl-2,3-dihydro-1H-pyridin-4-one and diethylazo-
dicarboxylate afforded the corresponding cycloadduct in good yield (Equation (62))
<2003OL321>.
O O
EtO2CN=NCO2Et
toluene, reflux ð62Þ
N
Ph N 93% Ph N N CO2Me
H
PhO2C PhO2C CO2Me
The condensation of 2,2,2-trichloroethylcarbazate with a dihydropyrrole -ketoester was fol-

lowed by an intramolecular azomethine imine 1,3-dipolar cycloaddition to afford a tricyclic
cycloadduct (Equation (63)) <2002JOC7880>.
CbzN Xylenes H
reflux, 30 h
O CO2Me CbzN H
EtO2C 86%
+ EtO2C CO2Me
N NH ð63Þ
H O
N NH2
O O
O CCl3
CCl3 Cbz = BnOC(=O)–
A proposed sequence consisting of an intra- and an intermolecular 1,3-dipolar cycloaddition

was employed to synthesize a triazatricylic compound (Equation (64)) <2002TL6431>.
OCH3 OCH3
Xylene
O O
reflux, 2 h ð64Þ
C N N
+ 64% Ph N
Ph N N N
H
4.09.8.5 Acylaminomethyl Azoalkanes and Iminoalkanes

1
-Pyrazolines have been prepared by the 1,3-dipolar cycloaddition of dehydroamino acid and
diazomethane (Equation (65)) <1996TA537, 1997T3777, 2000TA4903>.
O
H2CN2 MeO2C
O HN R O H
ether, rt, 4 h N R
O O ð65Þ
CO2Me 100% N O
N
R = OBn, OBut, Me
An aza-Wittig reaction that utilized a polymer-supported phosphine (polystyrene-based)

afforded the 3-[(benzylidene-amino)-methyl]-oxazolidin-2-one from 3-azidomethyl-2-oxazolidinone
and benzaldehyde (Equation (66)) <2000OL3777>.
120 mol.%
O
O PPh2
O N N3 ð66Þ
O
THF, rt, 24 h
97% O N N Ph
+ PhCHO
4.09.8.6 Miscellaneous Compounds

The intermolecular Diels–Alder reaction of 6-azido-6-demethoxythebaine and 4-phenyl-4H-1,2,4-
triazoline-3,5-dione (PTAD) afforded the corresponding polycyclic cycloadduct (Equation (67)
<1997M1267>).
Ph O
N3 N
O N N3
120 mol.% PTAD N
Ph N
O Acetone, rt, 20 min N ð67Þ
71% O
OMe
OMe
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Biographical sketch
Martin Hiersemann was born in 1966 in Berlin (Germany). He studied

chemistry at the Freie Universität Berlin. He received his Ph.D. in 1995
under the guidance of Johann Mulzer. As a postdoctoral fellow, he
joined the group of Gary A. Molander for 18 months and worked on
the total synthesis of Cephalotaxine. In October 1997, he returned to
Germany and started an independent research program at the Technical
University Dresden. After finishing his habilitation in May 2002, he was
a Foreign Research Fellow at the University of Tsukuba in the group of
Akira Hosomi and a visiting scientist at Harvard University with David
A. Evans. He was awarded a research grant from the Dr. Otto Röhm
memorial foundation (2001) and the Heisenberg fellowship from the
DFG (2002). He is a recipient of the 2003 Synthesis/Synlett journal
award. The research endeavors of his group are currently directed
toward the development of chiral catalysts for sigmatropic rearrange-
ments and, particularly, natural product synthesis.
4.10
Functions Incorporating a Nitrogen
and Another Group 15 Element
C. S. KENESKY and G. A. MOLANDER
4.10.1 FUNCTIONS CONTAINING ONE NITROGEN AND ONE PHOSPHORUS:

R12C(NR22)PR32, etc. 443
4.10.1.1 Amino Functions: R12C(NR22)PO, R12C(NR22)PR32, R12C(NR22)P(O)R32, etc. 444
4.10.1.1.1 Dicoordinate phosphorus functions: R12C(NR22)PO, etc. 444
4.10.1.1.2 Tricoordinate phosphorus functions: R12C(NR22)PR32, etc. 444
4.10.1.1.3 Tetracoordinate phosphorus functions: R12C(NR22)P(O)R32,
R12C(NR22)P(O)(OR3)2, etc. 447
4.10.1.1.4 Higher-coordinate phosphorus functions 478
4.10.1.2 Other Nitrogen Functions: R12C(NY)PR22, R12C(NHX)PR22, etc. 479
4.10.1.2.1 Dicoordinate phosphorus functions 479
4.10.1.2.2 Tricoordinate phosphorus functions 480
4.10.1.2.3 Tetracoordinate phosphorus functions 480
4.10.2 FUNCTIONS CONTAINING ONE NITROGEN AND ONE ARSENIC,
ANTIMONY, OR BISMUTH 491
4.10.1 FUNCTIONS CONTAINING ONE NITROGEN AND ONE PHOSPHORUS:

R12C(NR22)PR32, etc.
It can be said that the chemistry of organophosphorus compounds stands among the most prolific
and utile domains of organic chemistry today. As there exist a number of categories of organo-
phosphorus functionalities, this chapter will focus on the chemistry of the NCP array, which
appears extensively in the literature. This array of atoms has proven itself to be an attractive
substructure to chemists, as it has been employed as a building block in natural product synthesis,
as ligand architecture in organometallic catalysis, and as the basis of novel biologically active
species in hapten and peptidomimetic synthesis. Although these topics are meritorious and
demonstrate the utility of the NCP array, this work will focus not on the applications of
these substructures, but on the preparations thereof.
Over the period of 1995–2003, a number of publications (ca. 2,500) have appeared that invoke
the preparation and use of organophosphorus compounds of this description. Although most
preparations fall under a narrow number of methods, the scope of these methods has shown itself
to be broad and tolerant of various other functional groups. New methods have also come about,
most notably, methods that effect the highly efficient installation of a stereocenter at the central
carbon. These methods will be offered special attention, as they are both novel and presumably of
great interest to the synthetic chemist.
443
444 Functions Incorporating a Nitrogen and Another Group 15 Element
4.10.1.1 Amino Functions: R12C(NR22)PO, R12C(NR22)PR32, R12C(NR22)P(O)R32, etc.
4.10.1.1.1 Dicoordinate phosphorus functions: R12C(NR22)PO, etc.

During the period 1995–2003, there were no published reports detailing the preparation of the
N–C–P array in which phosphorus had a coordination number of 2.
4.10.1.1.2 Tricoordinate phosphorus functions: R12C(NR22)PR32, etc.
(i) Tricoordinate phosphorus functions by condensation of amines with

-hydroxymethylphosphorus compounds
Condensation of amines with phosphorus bearing hydroxymethyl groups has become a versatile
and convenient method for the preparation of relevant tricoordinate phosphorus compounds. In
general, a phosphine reacts with an excess of formaldehyde to generate a reactive species.
Elimination of the hydroxyl group followed by attack with an amine generates the desired
product with loss of water. An example of this reaction as employed by Karasik and co-workers
<2001POL3321> is shown in Scheme 1. The hydroxymethylphosphine is prepared and
observed spectroscopically prior to the introduction of amine. The authors also report that
although heating does accelerate the condensation of formaldehyde and phosphine, it can lead
to unwanted polymerization by-products.
OR1 OR1
2 equiv. CH2O
R2 PH2 EtOH, 14 h, rt R2 P(CH2OH)2
OR1
OR1 NH2 NH COOH
+ P
R2 P(CH2OH)2 COOH NH COOH
R2
MeOH, overnight, rt
1 2
R = H, R = H, 66%
R1 = H, R2 = Me, 71%
R1 = H, R2 = OMe, 66%
1 2
R = CH2OMe, R = Me, 76%
Scheme 1
Smith and co-workers <2000JCS(D)2771> have reported similar results leading to the synth-
esis of novel pyridylphosphine ligands as shown in Scheme 2. The second step of the scheme
demonstrates a means of oxidizing the tricoordinate phosphorus function 1 to a tetracoordinate
motif to be discussed in Section 4.10.1.1.3.(i).
OH 34 h, H2O2
OH 24 h, PhMe OH OH
H H
P reflux Water
NH2 + N N
N 87% N PPh2 48% N P(O)Ph2
Scheme 2
Functions Incorporating a Nitrogen and Another Group 15 Element 445
Condensations of this sort have also found use in the elaboration of aminobenzoic acids. Smith
and co-workers have produced examples, shown in Table 1, in which diphenylphosphinomethanol
reacts with a series of substrates in suitable yields with small aromatic groups <2002TL1299>.
Table 1 Condensation of aminobenzoic acids with diphenylphosphinomethanola,b

Aminobenzoic acid R1 R2 Yield (%) Product
CO2H H H 88 CO2H
F H 55 H
NH2 N PPh2
Cl H 76
H Cl 90
R1 Br H 77
R2 I H 66 R2
OH H 80
COOH H 94
OMe OMe 63
CO2H CO2H
R1 R1
H H 63
H OMe 96
R2 R2
NH2 HN
PPh2
CO2H CO2H
93
NH2 N PPh2
OMe OMe H
a b
2002TL1299. Conditions: 2 equiv. Ph2PCH2OH, MeOH, rt.
Reactions of this sort also appear applicable to phosphorus bearing three hydroxymethyl
groups. In the following example published by Katti and co-workers, compound 2 accepts
3 equiv. of glycine (Equation (1)) <1999JA1658>.
H
N COOH
CH2OH 3 h, water, rt P ð1Þ
HOCH2 P + 3H2NCH2COOH
CH2OH 82%
NH HN
2
COOH COOH
In systems bearing two proximal phosphorus atoms, it is possible to achieve either

multiple additions such as those described above by employing secondary amines, or cyclization
by using primary amines, which can attack once at each hydroxymethylated phosphorus.
Examples of both processes involving tetrahydroxymethyldiphosphines appear in Table 2
<1999JA1658>.
Through the condensation of a primary phosphine, 2 equiv. of a primary amine, and excess
formaldehyde, it is possible to achieve cyclization via a different pathway. The nitrogen of both
amines attacks the activated phosphorus species, and a third equivalent of formaldehyde effects
Table 2 Condensation of amines with tetrahydroxymethyldiphosphinesa,b

Tetrahydroxymethyldiphosphine Amine Product Yield (%)
HOCH2 P P CH2OH PhNHMe PhMeNCH2 P P CH2NMePh 90

HOCH2 CH2OH PhMeNCH2 CH2NMePh
HOCH2 P P CH2OH NHEt2 Et2NCH2 P P CH2NEt2 62

HOCH2 CH2OH Et2NCH2 CH2NEt2
CH2COOH
N
P
NH2CH2COOH 85
HOCH2 P P CH2OH P
N
HOCH2 CH2OH CH2COOH
CHMeCOOH
N
P
HOCH2 P P CH2OH NH2CHMeCOOH P 78
N
HOCH2 CH2OH CHMeCOOH
CH2COOH
N
NH2CH2COOH P 78
HOCH2 P P CH2OH P
N
HOCH2 CH2OH CH2COOH
a b
<1999JA1658>. Conditions: water, rt, 1–3 h.
cyclization between the newly formed secondary amines. Examples are illustrated in Equation (2)
from work published by Karasik and co-workers <2000POL1455>.
R MOH, MeOH R COOM

12 h, rt N
R PH2 + CH2O + MOOCCH2NH2 R P
N
R R COOM
R = H, M = Na, 84% ð2Þ

R = H, M = K, 62%
R = Me, M = Na, 72%
R = Me, M = K, 63%
R = Pri, M = Na, 46%
R = Pri, M = K, 54%
(ii) Tricoordinate phosphorus functions by condensation of dialkylphosphines with imines

Although this method has been applied more liberally to the synthesis of phosphorus compounds
of higher coordination number, four notable examples avail themselves here.
In the conversion of 3 to a mixture of 4 and 5, Andrieu and co-workers <2001XXX1015>
exploited the inherent stereochemistry of 3 to achieve preferential formation of the anti product
after 12 h of equilibration, though with modest selectivity (Equation (3)).
Ph Ph Ph Ph Ph
+ 12 h, CDCl3 +
PH N Me Ph2P N Me Ph2P N Me ð3Þ
CHPh H H
3 syn-4 anti-5
Conversion = 10% Conversion = 45%
Reports have surfaced demonstrating the preparation of bis(diphenylphosphinomethyl) amino

compounds on solid phase. Arya and co-workers have shown that the condensation of amines on
solid support with formaldehyde and diphenylphosphine leads to dendrimers (Equation (4)),
which the authors have applied to heterogeneous catalysis <2000JOC1881>.
Ph2P
Ph2P
H2N MeOH, reflux 2 h, N
HN HN
then rt, 24 h
Ph2PH + CH2O + ð4Þ
O yield not reported O
H2N N
Ph2P
Ph2P
Typically, the imines employed in the reactions of this class are generated from an aldehyde and
an amine, either in situ or in a separate pot. There are, however, other ways to generate imine
equivalents for use in the condensation. One such method is the use of a triazine as the electro-
phile. Couture and co-workers offer two examples of such a transformation. In the synthesis of
lennoxamine, Couture and co-workers <2000T1491> utilize this approach to generate an early
intermediate, as shown in Scheme 3.
OMe
(CH2O)n MeO Ph2P(O)H OMe

OMe HN
CH2Cl2 N PhMe, reflux
H2N OMe O OMe
OMe 95% 84% P
N N
OMe Ph2
MeO OMe
Scheme 3
Couture and co-workers <1998JCS(P1)1403> use a similar transformation to generate a

derivative of pyrrole (Equation (5)).
Ph2P(O)H
N N PhMe, reflux O
N P ð5Þ
N 94% H Ph2
4.10.1.1.3 Tetracoordinate phosphorus functions: R12C(NR22)P(O)R32,

R12C(NR22)P(O)(OR3)2, etc.
(i) Tetracoordinate phosphorus functions (phosphine oxides, R12C(NR22)P(O)R32) by addition

of dialkylphosphine oxides to imines
A reaction similar to that discussed above generates the phosphine oxide directly, without the
need for subsequent oxidation. Shibasaki and co-workers have shown that the addition of
diphenylphosphine oxide to various imines in the presence of (R)-PrPB, Pr(binaphthylOH)
(binaphthylOK)2, generates the desired products in good yields and selectivities as shown in Table
3. Shibasaki and co-workers <1999TL2565> also detail the use of trialkylphosphine oxide 6 in
asymmetric reduction of a carbonyl.
Table 3 Asymmetric addition of diphenylphosphine oxide to iminesa,b

Imine Product Yield (%) ee (%)
H
N N POPh2
Me Me 72 82c
S S
Me Me
POPh2
Me N Me HN 98 91c
Me S Me S
POPh2
N Me HN Me 98 93c
S Me S Me
POPh2
Me N Me HN 95 92c
Me S Me S
POPh2
N HN
Et Et 98 81c
S Et Et
S
POPh2
Me N Et Me HN Et 76 82c
Me S Et Me Et
S
POPh2
Me N Me Me HN Me 50 92c
Me S Me Me Me
S
POPh2
Me N Me HN 63 75d
Me Me
6
a b c d
<1999TL2565>. Conditions: (R)-PrPB (3,3), Ph2P(O)H, PhMe/THF 7:1. 50 C, 50 h. rt, 96 h.
Couture and co-workers <2001EJO2559> have exploited a similar reaction to generate sub-
stituted aryl derivatives (Table 4). The aldehyde condenses with the primary amine in situ,
followed by the addition of diphenylphosphine oxide with azeotropic removal of water.
Table 4 Reactions of aldehydes with amines and diphenylphosphine oxidea,b
R1
R 1 R2
R2 NMeR
R3
R3 CHO Amines P(O)Ph2 Yield (%)
1 1
R =H NHMe(p-methoxybenzyl) R =H 75
R2 = H R2 = H
R3 = H R3 = H
R1 = H NHMe(p-methoxybenzyl) R1 = H 77
R2 = OMe R2 = OMe
R3 = H R3 = H
R1 = OMe NHMe(p-methoxybenzyl) R1 = OMe 85
R2 = OMe R2 = OMe
R3 = OMe R3 = OMe
78
R1 = O NHMe(p-methoxybenzyl) R1 = O
2 CH2 2 CH2
R =O R =O
R3 = OMe R3 = OMe
R1 = H NH2Me R1 = H 94
R2 = OMe R2 = OMe
R3 = OMe R3 = OMe
a b
<2001EJO2559>. Conditions: 0 C, PhMe, 1 h, then add Ph2P(O)H, reflux for 1 h with Dean-Stark trap.
Couture and co-workers <2000BMC2113> also published access to the desired atomic array
using imines generated in situ by the thermal decomposition of triazines. After isolation of
-aminotrialkylphosphine oxide 7, the amine is coupled to an acid to generate a -amidotrialkyl-
phosphine oxide (Scheme 4).
Ph2(O)P
X
Ph2P(O)H DCC, DMAP, NEt3 X
N Ph2(O)P CH2Cl2 N
PhMe, reflux
X X MeO
N N HN O
MeO COOH RO
X 7
OMe
RO
OMe
X = CH2, 94% X = CH2, R = Bn, 84%
X = (CH2)2, 97% X = CH2, R = Me, 78%
X = (CH2)2, N/A
Scheme 4
(ii) Direct synthesis of tetracoordinate phosphorus functions in which phosphorus bears

a hydroxyl group via addition of phosphorus to imines
Although there do exist a number of references that document the generation of the above-
mentioned functionality, most such sources arrive at the desired compound via generation of the
phosphonate ester or analogous species and subsequent hydrolysis to acquire the POH array.
Examples of such endeavors will appear later in Section 4.10.1.1.3.(iii), which details the genera-
tion of -aminophosphonate esters. This section focuses on the direct generation of the targets
without the intermediacy of a phosphonate ester or analogous compound.
In the search for novel ligand architecture, Giovenzana and co-workers have prepared an eight-
membered bidentate ring through the condensation of glycine and formaldehyde in the presence
of hypophosphorous acid (Equation (6)). In addition to its synthesis, the authors describe its
coordination properties <2002TL8387>.
HO O
HCl, H2O P
HOOC
rt, 3 days
NH2CH2COOH + CH2O + H3PO2 N N ð6Þ
yield not reported COOH
P
O OH
In course of the synthesis of phosphinyl peptidomimetics, Ebetino and co-workers have

exploited a similar transformation to generate compound 8. The amine and aldehyde are effi-
ciently condensed in the presence of hypophosphorus acid to yield 8, which in turn undergoes
further transformations as shown in Scheme 5 <2002JOM212>. Although amides similar to
-amidophosphonate 9 can be realized through acylation, as shown here, the direct synthesis of
such compounds is discussed in Section 4.10.1.2.3.
PO2H2 48% HBr, reflux

CHO H2O, reflux
+ Ph2CHNH2HCl + H3PO2
86% NHCHPh2 94%
Ac2O, Et3N TMSCHN2

PO2H2 PO2H2 MeOH, C6H6 PH(O)OMe
MeOH
NH2 100% NHAc 100% NHAc
Scheme 5
While studying nitric oxide synthase, Massa and co-workers utilized this approach to generate
racemates of potential inhibitors. Condensation of an aldehyde, 10, with one of the two sources of
nitrogen produces the transitory imine, which is trapped by a phosphorus nucleophile, as depicted
in Scheme 6 <2000HAC505>. The products were further elaborated to the final targets.
PH(O)(OH)
O CHO Ph2CHNH3+ H3PO–2 O
EtOH, reflux NHCHPh2
N
N
yield not reported
O
O
10
i. AcCl, NH2COOBn P(O)Me(OH)

O CHO MePCl2 O
ii. H2O NHCOOBn
N
98% N
O
O
10
Scheme 6
Haemers and co-workers have utilized an alternative approach, in which a triazine serves as an
imine surrogate, in the preparation of proline analogs. Reaction of the triazine with bis(trimethyl-
silyl) phosphonite renders an intermediate, which is further silylated with BSA, alkylated, and
finally hydrolyzed to the phosphinic acid as shown in Scheme 7 <1995S1074>.
HP(OTMS)2 BSA
N N CHCl3, 16 h, rt O 15 min OTMS
N P H N P
N TMS OTMS TMS OTMS
R R
Overnight, rt R MeOH, H2O
N P
(OTMS) 5 h, rt N P OH
TMS 2
TMS O
R = CO2Me, 74%
R = CN, 80%
Scheme 7
(iii) Preparation of compounds bearing phosphonate esters and closely derived functionalities
via addition of phosphorus to imines
Among all classes of molecules bearing the NCP array of interest, undoubtedly the most widely
prepared and studied group is that which includes phosphonate esters. These compounds appear
prolifically in the literature, and offer the greatest number of examples of the condensation reactions
typical to the synthesis of the functionality discussed in this chapter. The first method of interest,
condensation of nucleophilic phosphorus with imines, resembles reactions described previously.
The first example of reactions of this class comes from Massa and co-workers. Oxidation
of alcohol 11 to the aldehyde, followed by condensation with benzylamine, addition of
LiP(O)(OEt)2, and deprotection, renders diamine 12 in 10% yield with only one purification
over four steps as shown in Scheme 8 <2000HAC505>.
(COCl)2, DMSO Benzylamine, MgSO4

Et3N, CHCl2, –78 °C CH2Cl2, rt
t-BOCHN OH t-BOCHN
CHO
11
LiP(O)(OEt)2, THF O
t-BOCHN 0 °C to rt t-BOCHN P 1 N HCl
(OEt)2
10%
N HN over 4 steps
Ph Ph
O
H2N P
(OEt)2
HN
Ph
12
Scheme 8
Condensations of a similar nature have also rendered unique furyl-substituted aminophospho-

nates. Lewkowski and co-workers have produced a series of compounds with various alkyl
substituents in their search for novel plant protection agents (Table 5) <2000OPP453>.
Table 5 Generation of furan-substituted amino phosphonatesa

Substrate Reagent Conditions Yield (%) Product
NH2 Neat, rt, 5 h 74

CHO O
O O N
HP(O)(OR)2 1 equiv. Phosphite, O

R = Et toluene, 40 C, NA P
O R = PhCH2 7 h, rt, 12 h 54 (OR)2
N O
R = Ph 69 HN
O
O
ButNH2 Neat, rt, 5 h 78

O CHO O
N But

R = Et toluene, 40 C, 52 P
O R = PhCH2 7 h, rt, 12 h 73 (OR)2
N But O
R = Ph 57 HN But
PhCH(Me)NH2 Neat, rt, 5 h 64

O CHO O
N CH(Me)Ph

O R = PhCH2 7 h, rt, 12 h 69 (OR)2
O
N R = Ph 53 HN CH(Me)Ph
CH(Me)Ph
O CHO Neat, rt, 5 h 88 O

N CH -1-naphthyl
2
CH2NH2

O R = PhCH2 7 h, rt, 12 h 53 (OR)2
N CH -1-naphthyl O
R = Ph 53 HN CH -1-naphthyl
2
2
a
<2000OPP453>.
In course of the development of a Cox-2 inhibitor, a Merck team prepared an aminopho-

sphonate for use as a nucleophile in a Horner–Wadsworth–Emmons (HWE) coupling. 6-Methyl-
nicotinate was condensed with aniline and diphenylphosphate to render aminophosphonate 13
(Equation (7)), which was coupled with another aldehyde <2000JOC8415>.
1.2 equiv. Aniline

1.7 equiv. Diphenyl phosphite NHPh
CHO
Isopropyl acetate, 60 °C (OPh)2
P ð7Þ
87%
Me N O
Me N
13
Couture and co-workers expounded further on the competence of such compounds for use
in HWE reactions. The group prepared a series of aminophosphonates via condensation
(Table 6) and demonstrated their efficacy in olefination reactions. Couture and co-workers
<2001S1462> also demonstrate the applicability of these reactions to diphenylphosphine
oxides (see Section 4.10.1.1.3.(i)).
Table 6 Formation of aminophosphonate HWE substratesa,b

OMe
R1 OMe R1
2 2
R R
+ + P(O)H(R6)2
NR5
R3 CHO R3
R4 NHR5
R4 P(O)(R6)2
R1 R2 R3 R4 R5 R6 Yield (%)
H OMe OMe Br Me Ph 70
H H H H Me Ph 75
H OMe H H Me Ph 77
OMe OMe H H Me Ph 78
OCH2O H H Me Ph 78
OMe OMe OMe H Me Ph 85
H OMe H H Et Ph 82
H OMe H H Bu Ph 75
OMe OMe H H Me OEt 66
OCH2O H H Me OEt 62
H OMe H H Et OMe 71
H OMe H H Bu OMe 65
a
<2001S1462>. b Conditions: 1 equiv. aldehyde, 1 equiv. amine, toluene 0 C to reflux for 1 h, added 1 equiv. P source, reflux for 1 h
with Dean-Stark trap.
Del Pozo and co-workers have applied aminophosphonates to their search for potent HIV
inhibitors. In the generation of a series of peptide mimics, the condensation of imines with
phosphates gives rise to the target molecules. Del Pozo and co-workers <2000SL698> have
also synthesized trialkylphosphines via the same protocol and note that they spontaneously
oxidize to the trialkylphosphine oxide on work-up (Table 7).
Table 7 Synthesis of peptide mimicsa
R2
O O H O
N P N
O Ph (R3)2 O Ph
R1 R2 R1
R1 R2 R3 Conditionsb Yield (%)

(CH3)2CHCH2 Ph CH3CH2O A 78
(CH3)2CHCH2 Ph CH3O A 73
(CH3)2CHCH2 2-Furyl CH3O A 74
PhCH2 Ph Ph B 58
Me Ph Ph B 45
PhCH2 3-Pyridyl Ph B 42
(CH3)2CHCH2 Ph Ph B 64
H Ph Ph B 45
(CH3)2CHCH2 2-Furyl Ph B 31
a b
<2000SL698>. A: (R3)2P(O)H, neat, 100 C, 3 h; B: (R3)2PH, BunLi, THF, 78 C to rt, then [O].
Interesting aminophosphonates can be prepared from N,O-acetals. The result is a heterocycle

bearing a pendant phosphonate ester. Martens and co-workers <1996SC3685> have exploited
this protocol as shown in Table 8.
Table 8 Preparation of phosphonates with

N,O-heterocyclesa,b
N,O-Acetal Product
H
(EtO)2(O)P N
N
Me O
Me O Me
Me
H
N (EtO)2(O)P N
But But
O H H
Me Me O
Me Me
(EtO)2(O)P
Me N Me Me NH Me
Me O Me Me O Me
(EtO)2(O)P
Me N Me NH
Me O Me O
(EtO)2(O)P
Me N Me NH
Me O Me O
(EtO)2(O)P
Me N Me Me NH Me
Me O H Me O H
(EtO)2(O)P
Me N Pri Me NH Pri
Me O H Me O H
(EtO)2(O)P
Me N But NH But
Me
Me O H Me H
O
a b
<1996SC3685>. Yields = 35–75%.
An intriguing use of heterocycle-pendant phosphonates appears in the work of Liu and

co-workers. The authors achieve convenient assembly of compound 14, which is oxidized to
dihydro-2H-pyrrole-N-oxide 15 as described in Scheme 9. This compound finds use as a spin
trap in ESR experiments <2002JOC7624>.
In addition to serving as appendages to heterocycles and medium-sized rings, phosphonates can
also be prepared as pendants to cyclopropyl groups. Fadel has published a useful synthesis of
1-aminocyclopropane phosphonates from cyclopropanone mixed acetals. Ethyl-3-chloropropionate
is sonochemically converted directly into mixed ketal 16 (Equation (8)), which undergoes in situ
hydrolysis to the hemiketal and participates in the three-component condensation as portrayed in
Table 9 <1999JOC4953>.
P(O)(OEt)2
BunLi, PhCH2Br HP(O)(OEt)2 MCPBA
Me N N
N 68% 90% 35%
H
Ph Ph
14
P(O)(OEt)2
+
N
–
O Ph
15
Scheme 9
Na, TMSCl
O ether, ))))), 3 h OTMS
Cl OEt 85% OEt ð8Þ
16
Table 9 Synthesis of 1-aminocyclopropane phosphonates from 16a

Phosphorus
Amine source Conditionsb Time (days) Solvent Product Yield (%)
O
P (OEt)2
PhCH2NH2 P(OEt)3 A 3 EtOH 68
NHCH2Ph
O
P (OEt)2
PhCH(Me)NH2 P(OEt)3 A 3 EtOH 68
NHCH(Me)Ph
O
P (OEt)2
PhCH(Me)NH2 P(OEt)3 A 4 EtOH/THF 87
(1:1) NHCH(Me)Ph
O
P (OMe)2
PhCH(Me)NH2 P(OMe)3 A 3 MeOH 71
NHCH(Me)Ph
O
P (OEt)2
PhCH(Me)NH2 P(OEt)3 B 1 EtOH 95
NHCH(Me)Ph
a b
<1999JOC4953>. 1 equiv. 16, 1.5 equiv. phosphorus source, 55 C; A: 1.5 equiv. amine HCl; B: 1.5 equiv. free amine and 4 equiv. HOAc.
It is also possible to generate -amino--cyclopropyl phosphonates, the study of which has

offered insights into the reactivity of -chloroimines. Tordo and co-workers have found that while
such imines tend to cyclize to five-membered heterocycles, they exist in equilibrium with enamines
that give rise to cyclopropyl derivatives. Tordo and co-workers <1999S2036> have explored the
mechanism by preparing both products directly and comparing the results to those obtained from
the aforementioned equilibrium (Scheme 10).
1 equiv. HP(O)(OEt)2
NH3, 60 °C, 2.5 h
O NH NH2
Cl Cl Cl
85% 15%
1 equiv. HP(O)(OEt)2
1.1 equiv. HP(O)(OEt)2
P(O)(OEt)2 P(O)(OEt)2 NH , 60 °C, 2.5 h O
rt, 7 days 3
Me Me
N Me
N H NH2
98% 50%
Scheme 10
Hägele and co-workers have applied the addition of diethyl phosphite to imines in fluorinated
systems. The reaction proceeds in decent yield (Equation (9)) <1996JFC75>.
F HP(O)(OEt)2 F F H
F
N N
R Ph 60 °C, 8 h R Ph
P(O)(OEt)2 ð9Þ
R = F, 65%
R = Me, 64%
Another unique reaction appears in the work of Dimukhametov and co-workers, wherein the
authors employ phosphorus compounds both as electrophiles and nucleophiles. An imine-bearing
phenol attacks phosphorus, and phosphorus subsequently attacks the imine intramolecularly. The
yields are good and represent mixtures of diastereomers (Equation (10)) <2001MC196>.
P(Cl)(OR)2 OP(OR)2
CHCl3, rt O O
OH P
N CHPh OR
H N Ph ð10Þ
N CHPh –
H
Cl
R = CH 2CH2Cl, 73%
R = Et, 79%
Honek and co-workers <1999OL1395> have demonstrated the stepwise condensation by

isolating the intermediate hemiaminal in good yield and adding nucleophiles in a subsequent
step (Scheme 11).
Formalin, PhH
reflux, 16 h O
Ph Dean-Stark Ph OH Ph P OEt
NH2 NH NH R
Ph 85% Ph Ph
Conditions: R = OEt: diethyl phosphite, 5 h, 100 °C, 96%

R = CH(OEt)2: ethyl diethoxymethylphosphonate, 48 h, 50 °C
48%
Scheme 11
Although the conventional method for the condensation of imines with sources of phosphorus
is a stalwart procedure that continues to find widespread use, as with all methods it lends itself to
novel improvements. Certainly the alluring utility of these compounds has enticed groups to
discover more expedient routes to the products and reagents to enhance efficiency.
Yadav and co-workers have formulated a highly attractive method for the preparation of these
compounds. The montmorillonite, KSF-catalyzed condensation of diethyl phosphite with imines
generated in situ proves itself to be quite effective in toluene at reflux, yet far more so under
microwave irradiation at room temperature. Several examples of this truly remarkable rate and
yield enhancement appear in Table 10 <2001S1131>.
Table 10 Preparations of aminophosphonates under heating vs. microwave irradiationa

Heatingb: time, Microwavec: time,
Carbonyl Amine yield (%) yield (%)
CHO Me
6 h, 70 3 min, 85
H2N
Ph
CHO Ph 8 h, 75 3 min, 82
H2N
Cl Ph
CHO
H2NPh 10 h, 72 5 min, 90
CHO Ph
8 h, 70 6 min, 81
H2N
Ph
CHO 5 h, 74 4 min 89
H2N
CHO
H2NPh 7 h, 80 5 min, 83
Cl
CHO
H 2N 5 h, 72 3 min, 90
Me
CHO H 2N Cl 7 h, 70 5 min, 85
O 10 h, 65 6 min, 80
H2N
MeO CHO
H2N
8 h, 75 5 min, 91
MeO
CHO
H2NPh 6 h, 77 4 min, 88
Me
Heatingb: time, Microwavec: time,
Carbonyl Amine yield (%) yield (%)
O CHO
H2N 5 h, 80 3 min, 92
O
Cl CHO
H2NPh 6 h, 73 5 min, 87
Cl
O
12 h, 68 8 min, 78
H2N
O
10 h, 70 7 min, 75
H2N
Cl
CHO
H2N 6 h, 75 5 min, 90
CHO
H2NPh 6 h, 78 4 min, 85
H2N 7 h, 80 3 min, 87
CHO
a
<2001S1131>. b 5 mmol amine, 5 mmol aldehyde, 5 mmol diethyl phosphite, 1.5 g montmorillonite clay, toluene, reflux. c
5 mmol
amine, 5 mmol aldehyde, 5 mmol diethyl phosphite, 1.5 g montmorillonite clay, toluene, irradiation.
Other catalysts, particularly Lewis acids, have found applications to the synthesis of amino
phosphonates. Chandrasekhar and co-workers <2001TL5561> have demonstrated the utility of
TaCl5SiO2 as a catalyst for the condensation. Mixtures of equimolar portions of an aniline, an
aldehyde, and a diethylphosphate in the presence of 10 mol.% TaCl5SiO2 lead to the efficient
construction of a number of targets as displayed in Table 11.
Qian and co-workers have screened a number of metal complexes, mostly triflates, in search of
an effective catalyst for the three-component condensation. Upon testing a series of Lewis acids
on a system of benzaldehyde, benzylamine, and diethyl phosphite (Table 12), Qian and Huang
<1998JOC4125> found Yb(OTf)3 to be a promising candidate.
After further studies, Qian demonstrated Yb(OTf)3 to be highly effective in the reaction of
amines and diethyl phosphite with several aldehydes as depicted in Table 13 <1998JOC4125>.
Qian has also applied these conditions to chiral amines in an effort to achieve stereoinduction
from the intrinsic chirality of the system (Table 14). The yields are excellent, and the selectivities
observed suggest that the method holds potential <1998JOC4125>.
Other Lewis acids and conditions have also proven themselves effective in promotion of
the three-component reaction. Ranu and co-workers have published a thorough examination
of the use of InCl3 as a catalyst, both with and without sonication, in the condensation of
both aldehydes and ketones with amines and diethyl phosphite. Although aldehydes react
swiftly at room temperature and ketones perform well in THF at reflux, sonication greatly
enhances reaction rate, in some cases reducing reaction time by more than half (Table 15)
<1999OL1141>.
Table 11 Preparations of aminophosphonates catalyzed by TaCl5SiO2a,b

Carbonyl Amine Time (h) Yield (%)
CHO
22 92
Me H2N
CHO
19 88
MeO H2N
CHO OMe
18 94
MeO H2N
OMe
CHO 18 93
H2N
CHO
20 90
H2N
CHO
24 84
OH H2N
CHO OH
O 24 81
O H2N
CHO OMe
18 93
Me H2N
CHO F
18 94
Me H2N
OMe
O CHO 20 92
H2N
CHO
H2NPh 77 88
Me
H2N
S CHO 20 93
F
Carbonyl Amine Time (h) Yield (%)
CHO H2N
24 87
NO2 HO
Cl
CHO H2N 18 88
Cl OMe
Me
H2N 20 92
CHO
H2N
22 85
CHO
F
H2N
CHO 24 82
O2N
O H2N
22 81
O
H2N 24 87
F
a b
<2001TL5561>. 1 mmol amine, 1 mmol aldehyde, 1 mmol diethyl phosphite, 10 mol.%
TaCl5SiO2, CH2Cl2, rt.
Table 12 Evaluation of a series of metal complexesa

Additive, rt P(O)(OEt)2
CHO cat.
H2N
+ + HOP(OEt)2 N
H
Catalyst Solvent Additive Yield (%)

None CH2Cl2 MgSO4 Trace
La(OTf)3 (10 mol.%) CH2Cl2 MgSO4 34
Sm(OTf)3 (10 mol.%) CH2Cl2 MgSO4 56
Yb(OTf)3 (10 mol.%) CH2Cl2 MgSO4 89
Yb(OTf)3 (10 mol.%) CH2Cl2 4 Å mol. sieves 87
Yb(OTf)3 (10 mol.%) THF MgSO4 67
Yb(OTf)3 (10 mol.%) CH3CN MgSO4 71
Yb(OTf)3 (10 mol.%) PhMe MgSO4 30
SnCl4 (100 mol.%) CH2Cl2 MgSO4 21
SnCl4 (120 mol.%) CH2Cl2 MgSO4 68
a
<1998JOC4125>.
Table 13 Evaluation of 10 mol.% Yb(OTf)3 as a catalysta,b

Aldehyde Amine Product Yield (%)
P(O)(OEt)2
CHO 89
H2N N
H
P(O)(OEt)2
CHO H2N N 92
H
MeO MeO
P(O)(OEt)2
CHO H2N 88
N
H
Me Me
P(O)(OEt)2
CHO 93
H2N N
H
O2N O2N
P(O)(OEt)2
H2N
O CHO
O N 85
H
P(O)(OEt)2
CHO H2N 71
N
H
P(O)(OEt)2
CHO 65
N
H
H2N
P(O)(OEt)2
CHO H2N 89
N
H
P(O)(OEt)2
CHO H2N 79
N
H
a b
<1998JOC4125>. Conditions: 1.1 equiv. amine, 1.2 equiv. diethyl phosphite, 125 mg MgSO4, CH2Cl2, rt.
Table 14 Use of 10 mol.% Yb(OTf)3 in condensations generating stereochemistrya,b

Aldehyde Amine Product (major isomer) Yield (%) Selectivity
Ph
CHO
95 78:22
(EtO)2 OMe
OMe P N
H2N O H
Ph
CHO
92 57:43
(EtO)2
P N Me
H2N Me O H
Ph
CHO 82 74:26
(EtO)2
H2N P N
OMe O H OMe
p-MeOC6H4
CHO 91 78:22
(EtO)2 OMe
P N
OMe H
MeO H2N O
p-MeOC6H4 88 57:43
CHO
(EtO)2
P N Me
MeO H2N Me O H
CHO p-MeOC6H4
81 74:26
(EtO)2
H2N P N
MeO OMe O H OMe
a b
<1998JOC4125>. Conditions: 1.1 equiv. amine, 1.2 equiv. diethyl phosphite, 125 mg MgSO4 CH2Cl2, rt.
Table 15 Condensations catalyzed by InCl3 both with and without sonicationa,b
O InCl3, THF R1
+ R3NH 2 + HOP(OEt)2 R 2 C NHR3
R1 R2 P(O)(OEt)2
Time with/without Yield with/without

R1 R2 R3 sonication (h) sonication (%)
H Ph Ph 5 11 93 92
H Ph PhCH2 5 12 95 93
H Ph PhCH(Me) 6 12 90 90
H Ph Prn 5 12 90 89
H Ph Cyclohexyl 7 15 90 88
H p-MeOPh Ph 6 10 92 92
Time with/without Yield with/without
R1 R2 R3 sonication (h) sonication (%)
H p-MeOPh Me2CH 7 12 90 88
H p-O2NPh Ph 7 12 82 80
H (E)-PhCH¼CH Ph 6 10 85 85
H m-HOPh Ph 6 10 93 91
H 2-Pyridyl Ph 7 11 92 92
H 2-Pyridyl PhCH(Me) 7 14 90 90
H (E)-PrnCH¼C(Et) PhCH2 7 14 89 88
H Me2CH PhCH2 6 13 88 86
H Prn Me2CH 6 14 87 85
H (E)-Me2C¼CH(CH2)2 PhCH2 6 13 89 87
C(Me)¼CH
Et Et PhCH2 9 11 82 80
Me Ph PhCH2 9 12 85 81
CH(Me)CH(OH)Ph PhCH(OH)CH(Me) PhCH2 9 14 90 89
Cyclohexanone PhCH2 6 9 87 85
4-But cyclohexanone PhCH2 7 10 80 80
Indanone PhCH2 6 9 80 79
Me (E)-PhCH¼CH PhCH2 7 12 76 75
CH2COOEt Me PhCH2 7 10 85 82
a b
<1999OL1141>. Conditions: 1 mmol aldehyde, 1 mmol amine, 1 mmol diethyl phosphite, 10 mol.% InCl3, ketones at reflux,
aldehydes at rt.
Kobayashi and co-workers have not only applied new Lewis acids to the reaction, but have
done so in a way that results in a more environmentally compatible protocol. They have found
that the employment of a Lewis acid surfactant, scandium(III) trisdodecyl sulfate, enables the
condensation to progress effectively in aqueous media as opposed to the more typical organic
solvents. Table 16 illustrates Kobayashi’s search for effective conditions, and Table 17 offers a
number of examples of this quick and reliable condensation <2000CC669>.
Table 16 Inspection of surfactant catalystsa,b

10 mol.% cat. Ph
Ph H2O, 30 °C, 30 min
Phosphorus Ph NH
PhCHO + NH2 +
source (OEt)2
Ph Ph P
O
Catalyst Phosphorus source Yield (%)

Sc(OSO3(CH2)11CH3)3 P(OEt)3 71
NaOSO3(CH2)11CH3 P(OEt)3 8
Sc(OTf)3 P(OEt)3 6
p-HOSO3C6H4(CH2)11CH3 P(OEt)3 18
Sc(OSO3(CH2)11CH3)3 P(OEt)3 31c
Sc(OSO3(CH2)11CH3)3 HOP(OEt)2 Trace
a b
<2000CC669>. Conditions: 1 equiv. aldehyde, 1 equiv. amine, 2.5 equiv. phosphorus
source. c Neat.
Lee and co-workers have also made progress in both finding an effective Lewis acid catalyst
and formulating an environmentally sound protocol. This group has screened lanthanide triflates
for use in the three-component condensation exploiting an ionic liquid solvent. Use of [bmim][X]
(Figure 1) as a reaction medium allows recovery and recyclability of solvent and appears to
promote the reaction as effectively as the traditional solvents. The authors examined several
combinations of catalyst and solvent in the condensation of benzaldehyde, aniline, and diethyl
phosphonate and found many systems effective (Table 18) <2001CC1698>.
Table 17 Catalytic activity of Sc(OSO3(CH2)11CH3)3 in watera,b

10 mol.% cat.
R2
H2O, 30 °C, 30 min NH
R1CHO + R2NH2 + P(OEt)3
R1 P(O)(OEt)2
R1CHO R2NH2 Time (min) Yield (%)
Ph
60 83
PhCHO Ph NH2
PhCHO PhNH2 20 88
OMe
20 86
PhCHO
NH2
Ph NH2 60 84
PhCHO
Ph NH2
60 78
PhCHO
NH2 60 80
PhCHO
Cl CHO PhNH2 30 85
Cl CHO
PhNH2 20 80
O Ph
CHO 120 78
Ph NH2
Ph
CHO
60 83
Ph NH2
Ph
CHO
60 95
Ph Ph NH2
OMe
20 53
CHO
Ph NH2
a b
<2000CC669>. Conditions: 1 equiv. aldehyde, 1 equiv. amine, 4 equiv. triethyl phosphite.
Lee and co-workers <2001CC1698> went on to demonstrate the utility of recycled catalysts,
showing that reactivity is retained after use especially with Sc(OTf)3, which shows efficacy in five
iterations (Table 19).
N – – – –
N X = PF6 , SbF6, BF4, OTf
bmim
Figure 1 [bmim] [X] as reaction medium.
Table 18 Screening of lanthanide triflates in ionic liquidsa,b

10 mol.% cat.
[bmim][X], 20 °C NHPh
PhCHO + H2NPh + HP(O)(OEt)2
Ph P(O)(OEt)2
Solvent Catalyst Yield (%)

[bmim][PF6] Yb(OTf)3 95
[bmim][PF6] Sc(OTf)3 80
[bmim][PF6] Dy(OTf)3 94
[bmim][PF6] Sm(OTf)3 99
[bmim][PF6] Yb(OTf)3H2O 63
[bmim][PF6] La(OTf)3H2O 39
[bmim][PF6] Sm(OTf)3c 95
[bmim][PF6] Sm(OTf)3d 74
[bmim][SbF6] Sm(OTf)3 71
[bmim][BF4] Sm(OTf)3 18
[bmim][OTf] Sm(OTf)3 89
[bmim][PF6] In(OTf)3 90
a b
<2001CC1698>. Conditions: 0.25 mmol benzaldehyde, 0.25 mmol aniline, 1 mmol diethyl phosphonate.
c d
1 mol.% catalyst. The catalyst used was that recovered from the previous entry.
Table 19 Efficacy of catalysts on successive usea
Yield of iterative use (%)

Catalyst 1st 2nd 3rd 4th 5th
Sc(OTf)3 97 94 97 93 99
Yb(OTf)3 57 54 NA NA NA
Sm(OTf)3 87 87 NA NA NA
Gd(OTf)3 84 77 NA NA NA
InCl3 86 50 NA NA NA
a
<2001CC1698>.
The authors document the condensation of a number of aldehydes with aniline and triethyl
phosphite in [bmim][PF6] with catalytic Sc(OTf)3 (Table 20). In addition to being high yielding,
the procedure is claimed to be more environmental friendly than the previous protocols
<2001CC1698>.
Though the use of metals as catalysts for these reactions is quite common, the incorporation of
aminophosphonates into stable metal complexes appears scant in the literature. A particularly
notable example of such a complex is found in the synthesis of a series of ferrocenylaminopho-
sphonic esters by Lewkowski and co-workers. Even in the presence of the pendant ferrocenyl
moiety, the reactions proceed in useful yields (Table 21) <2001JOM105>.
As seen in previous examples, it is possible to utilize a triazine as a masked imine. Stevens and
co-workers <1998SL180> provide an example of the use of tri-(N)-allyltriazine as a component
of the condensation, though the yields are low (Scheme 12).
Another interesting route that avoids the direct use of the imine is the amino hydroxylation
protocol developed by Doye and co-workers. Amino hydroxylation, both intermolecular (Table
22) and intramolecular (Table 23) followed by attack with a phosphorus source, perfects an
efficient one-pot procedure for generation of the targets <2002EJO457>.
Table 20 Use of Sc(OTf)3 in [bmim][PF6]a,b

1 mol.% Sc(OTf)3
[bmim][PF6], 20 °C NHPh
RCHO + H2NPh + P(OEt)3
R P(O)(OEt)2
Aldehyde Yield (%)
CHO
97
MeO CHO >99
CHO
90
Me
>99
Me CHO
Me CHO >99
F CHO
93
F3C CHO
97
CHO >99
CHO
S 93
CHO
90
O
a b
<2001CC1698>. Conditions: 0.25 mmol aldehyde, 0.25 mmol aniline, 1 mmol triethyl
phosphite.
The literature offers a small number of examples of the generation of stereochemistry in the
condensation of amines with aldehydes and phosphates. A notable example is found in the work
of Houghten and co-workers, who in the course of devising phosphono peptides condense the
components in solid phase and set a stereocenter between nitrogen and phosphorus by exploiting
an existing stereocenter. The true product of the condensation is the resin-bound dimethyl
phosphonate, though the reported yields are for the phosphonic acid recovered after liberation
from the resin with concomitant hydrolysis (Table 24) <2002TL4103>.
Royer and co-workers have devised a moderately selective method of adding phosphates to
imines bearing chiral auxiliaries to generate substituted piperidines. The product of the condensa-
tion can be elaborated into a series of related compounds (Scheme 13). The authors also
demonstrate the use of an -cyanoamine in a similar system (Scheme 14) <1997T3627>.
Table 21 Synthesis of ferrocenyl aminophosphonatesa,b
NR1 NR1
HP(O)(OR2)2
Fe Fe P(O)(OR2)2
R1 R2 Yield (%)
CH2Ph Et 75
CH2Ph CH2Ph 62
CH2(2-Fur) Et 51
CH2(2-Fur) CH2Ph 88
C(CH3)3 Et 59c
C(CH3)3 CH2Ph 70
CHPh2 Et 75
CHPh2 CH2Ph 72
(R)-CH(CH3)Ph Et 62
(R)-CH(CH3)Ph CH2Ph 65
CHPh2 Ph 72
a
<2001JOM105>. b Conditions: 5 mmol imine, 5 mmol dialkyl phosphite, toluene, reflux,
7 h, then rt 12 h. c Reaction run in acetonitrile.
HP(O)(OR)2
30 min, rt 15 h, 100 °C H O
NH2 N
+ CH2O N P
98% (OR)2
N N
R = Et, 37%
R = Pri, 44%
R = Bun, 32%
Scheme 12
Table 22 Intermolecular amino hydroxylation routea,b

Alkyne Amine Product Yield (%)
Ph Ph MeO NH2 MeO NH 68

P(O)(OEt)2
Ph
Ph
Et Et MeO NH2 MeO NH 76

P(O)(OEt)2
Et
Et
Ph Ph c
Ph Me NH2 NH 97
Ph Ph Me P(O)(OMe)2
Ph
Ph Ph
c
Ph Et NH2 NH 88
Ph Ph Et P(O)(OMe)2
Ph
a
<2002EJO457>. b Conditions: i. 1.4 mmol alkyne, 1.4 mmol amine, 3 mol.% Cp2TiMe2, toluene, 110 C, 72 h;
ii. 1.4 mmol diethyl phosphite, 5 mol.% Me2AlCl, 25 C, 2 h. c Neat, dimethyl phosphite was used.
Table 23 Intramolecular amino hydroxylation routea,b

Aminoalkyne Product Yield (%)
Bn
Ph NH2
(EtO)2(O)P N 78
H
Ph NH2 Bn
N 86
(EtO)2(O)P H
H NH2 Me
N 85
(EtO)2(O)P H
NH2
NH
52
Ph Bn P(O)(OEt)2
MeO
MeO NH2
66
(EtO)2(O)P N
H
CF3
CF3
58
NH2
(EtO)2(O)P N
H
a
<2002EJO457>. b Conditions: i. 1 mmol aminoalkyne, 5 mol.% Cp2TiMe2, toluene, 110 C, 9 h;
ii. 1 mmol diethyl phosphite, 5 mol.% Me2AlCl, 25 C, 2 h.
Table 24 Solid-phase synthesis of phosphono peptidesa,b

i. Aldehyde, BF3·OEt2
O R1 O H O R1
dimethyl phosphite
H2N NH2 P N NH2
N ii. HF (HO)2 N
R2 H O R3 R2 H O
R1 R2 R3CHO Yield (%) dr

PhCH2 PhCH2 Ph 85 4:1
PhCH2 HOOCCH2 Ph 79 2:3
PhCH2 Me Ph 83 1:2
PhCH2 Me Pr 88 1:4
PhCH2 HOOCCH2 Pr 86 NA
PhCH2 PhCH2 Pr 92 NA
PhCH2 (CH3)2CH2 Bu 80 2:3
Me PhCH2 Bu 71 NA
Me PhCH2 Ph 53 NA
Me PhCH2 Pr 65 NA
H PhCH2 Bu 88 5:3
PhCH2 Me 4-PriC6H4 70 4:5
a b
<2002TL4103>. Conditions: i. 10 equiv. aldehyde, 10 equiv. dimethyl phosphite, 3 equiv. BF3OEt2, rt,
16 h; ii. HF, 0 C, 7 h.
Ph NaBH3CN
P(OEt)3, MeOH Ph EtOH–HOAc Ph
H2N OH reflux, 2 h rt, 30 min OH
+ (EtO)2(O)P N O (EtO)2(O)P N
58% 63%
CHO CHO
79:21 dr
H2, Pd(OH)2/C
EtOH, rt, 24 h
76%
i. 6 N HCl, reflux, 5 h
H ii. Propylene oxide H
(EtO)2(O)P N EtOH, reflux (HO)2(O)P N
96%
Scheme 13
CN Ph
N
O
P(OEt)3, ZnBr2 P(OMe)3, ZnBr2

CH2Cl2, rt, 50 h CH2Cl2, rt, 50 h
66% 62%
33:67 dr 33:67 dr
(EtO)2(O)P Ph (MeO)2(O)P Ph
N N
O O
NaBH3CN, H2 (1 atm)
EtOH–HOAc (2:1) 10% Pd/C
rt, 30 min EtOH, rt, 24 h
63% 68%
(EtO)2(O)P Ph (EtO)2(O)P
OH
N NH
Scheme 14
Two novel chiral auxiliaries appear in a paper by Smith and co-workers that allow stereo-
selective addition of lithium diethyl phosphite to an imine via the chelation-controlled transition
state 17 (Figure 2). Although the results acquired for the use of t-butyl ester auxiliary seen in
ButO O
O Li P(OEt)2
H N
Ph C6H11
H
17
Figure 2 Chelation-controlled transition state 17.

Equation (11) appears inconsistent, the methyl ether-derived auxiliary found in Table 25 furnishes
highly reliable selectivities. Both auxiliaries are liberated by hydrogenolysis <1995JA10879>.
HP(O)(OEt)2, ButOLi
CH2Cl2, –70 to 25 °C
38%, 94% de H
ButO2C N C6H11 ButO2C N P(O)(OEt)2
ð11Þ
Ph Ph C6H11
HP(O)(OEt)2, BunLi
THF, –78 to 25 °C
75–80%, 94–96% de
Table 25 Stereoselective addition of LiP(O)(OEt)2 to iminesa
OMe RCHO, PhH OMe HP(O)(OEt)2 OMe O H2, 1 atm O

H
NH2 Na2SO4 BunLi, THF N P(OEt)2 Pd(OH)2 H2N P(OEt)2
N R
0 to 25 oC 25 °C, 18 h EtOH, 25 oC
Ph 1h Ph Ph R 22–24 h R
Addition Free amine Free amine

RCHO Imine yield (%) product yield (%) yield (%) ee (%)b
CHO 90 68 94 96
CHO
89 70 87 99
CHO 82 82 86 97
CHO 84 81 89 99
MeCHO 90 77 99 99
CHO 95 78 98 98
CHO
MeS 84 69 89c 75
BnO CHO 92 38 100 98
CHO
ButO2C 95 37 83 96
CHO
82 90 88 71
a b c
<1995JA10879>. as per Mosher amide. 5 equiv. Pd black, H2, AcOH, 25 C, 48 h.
One can also fathom a system in which the phosphorus moiety bears the chiral auxiliary.
Kolodiazhnyi and co-workers have described the use of two auxiliaries in good yield with variable
selectivity. Bornyl and menthyl groups pendant to the phosphonate induce asymmetry at the
neighboring carbon as seen in Table 26 <1998TA1645>.
Table 26 Synthesis of amino phosphonates with chiral

auxiliaries on phosphorusa
PhCHO, PhCHR2NH2 O Ph
(R1O)2P(O)H P
(R1O)2 NHCHR2Ph
R1 R2 Yield (%) de (%)

()-Bornyl H 90 50
()-Menthyl H 94 50
()-Menthyl Me 85 84
a
<1998TA1645>.
Martens and co-workers have developed a highly efficient protocol for the addition of
binaphthylphosphorus esters to certain imines. The results of the addition, catalyzed by
BF3OEt2, are shown in Table 27 <2000TL7285>.
Table 27 Asymmetric hydrophosphorylation of imines with binaphthylphosphorus estersa
BF3.OEt2, CH2Cl2,
R 1 N R3 0–21 °C, 5 d
+ O
R4 O H
R2 S O P
O O N R3
P
O H R1 R4
S
R2
R1/R2 R3/R4 Yield (%) drb

Me/Me Me/Me 47 83:17
Me/Me –(CH2)5– 47 >95:5
–(CH2)5– Me/Me 37 80:20
–(CH2)5– –(CH2)5– 68 >95:5
H/H –(CH2)5– 30 >95:5
a b
<2000TL7285>. Determined by NMR.
Similar imines find use in the highly effective protocol developed by Martens and co-workers.
Various binaphthol–lanthanide metal complexes catalyze the hydrophosphonylation with
dimethyl phosphite, in some cases in both high yield and selectivity (Table 28) <1998JA3089>.
Table 28 Hydrophosphonylation catalyzed by lanthanide–binaphthol complexesa,b

O
(MeO)2 P
N HP(O)(OMe)
NH
Me Me Me Me
Me S Me Me S Me
Catalystc
(20 mol.%) Solvent Temp. ( C) Time (h) Yield (%) eed (%)
(R)-LPB THF/PhMe 1:7 rt 144 53 61
(R)-LPB THF/PhMe 1:7 50 50 55 64
(R)-PrPB THF/PhMe 1:7 50 50 51 84
(R)-SmPB THF/PhMe 1:7 50 40 97 93
(R)-GdPB THF/PhMe 1:7 50 50 77 95
(R)-DyPB THF/PhMe 1:7 50 50 76 97
(R)-YbPB THF/PhMe 1:7 rt 20 42 97
(R)-YbPB THF/PhMe 1:7 rt 50 86 98
c
Catalyst
(20 mol.%) Solvent Temp. ( C) Time (h) Yield (%) eed (%)
(R)-YbPB THF/PhMe 1:7 50 20 89 94
(R)-YbPB THF/PhMe 1:7 50 50 90 96
(R)-YbPB THF 50 50 52 95
(R)-YbPB PhMe 50 50 79 85
(R)-YbPB THF/PhMe 1:7 50 60 56 94
(R)-YbPB THF/PhMe 1:7 50 60 39 94
a
<1998JA3089>. b 0.3 mmol imine, 1.5 mmol HP(O)(OMe)2. c
P = potassium, S = sodium, L = lithium, B = (R)-(+)-binaphthol.
d
ee determined by chiral stationary phase HPLC.
The inherent chirality of the imine can play an important role in directing the stereochemical
outcome of the reaction. Heydari and co-workers present an example of the application of lithium
perchlorate/diethyl ether (LPDE) in the condensation of imines with dimethyl phosphite. After
demonstrating the utility of the protocol in achiral systems (Table 29), the authors apply the
reaction to chiral imines to achieve reasonable selectivities (Table 30) <1998TL6729>.
Table 29 Use of LPDE as a catalyst in condensationa

5 M LPDE
rt, 10 min (R2)2N P(O)(OMe)2
R1CHO + HN(R2)2 + HP(O)(OMe)2
R1
R1 R2 Yield (%)
i
Pr Et 97
Prn Et 95
Bn Et 99
Ph Et 90
4-MeOPh Et 87
Pri Bn 93
Prn Bn 97
Bn Bn 95
Ph Bn 95
4-MeOPh Bn 90
a
<1998TL6729>.
Table 30 Use of LPDE as a catalyst in condensation using chiral iminesa

2 M LPDE
–15 °C, 30 min
RCHO + Amine + HP(O)(OMe)2 Product
Amine R Product Yield (%) dr

i
Me Pr H 95 79:21
But Ph N P(O)(OMe)2 96 82:18
Ph NH2 C6H11 92 80:20
Bn Me R 90 83:17
NH2 Pri H 90 88:12

OH
But Ph N P(O)(OMe)2 95 91:9
Ph C6H11 94 90:10
R
HO
a
<1998TL6729>.
Fadel and co-workers have furnished examples of the preparation of aminocyclopropane

phosphonate esters by exploiting the substitution pattern on the cyclopropyl group. A series of
hemiaminals is heated in a phosphate solvent to effect solvolysis with moderate facial selectivity
directed by a pendant methyl group (Table 31) <2000EJO2153>.
Table 31 Generation of aminocyclopropane phosphonatesa

TMSCl
OTMS EtOH OH R1NH2 OH P(OR2)3 P(O)(R2)2
Me Me Me Me
OMe OMe NHR1 NHR1
R1 P(O)(OR2)2 Time (h) Yield (%) dr

b
CH2Ph P(OEt)3 140 62 88:12
(S)-CH(Me)Ph P(OMe)3 65 48b,d 73:27
(S)-CH(Me)Ph P(OEt)3 68 80b 87:13
CH2Ph P(OEt)3 22 69c 86:14
(S)-CH(Me)Ph P(OMe)3 21 67c,d 80:20
(S)-CH(Me)Ph P(OEt)3 22 82c 87:13
(R)-CH(Me)Ph P(OEt)3 22 82c 87:13
a
<2000EJO2153>. b cat. TMSI, 3 mmol acetal, 4.5 mmol amineHCl, 3.6 mmol P(OR2)3, 55 C. c
As per previous referenceb with
free amine and 4 equiv. AcOH. d In MeOH.
(iv) Preparation of compounds bearing phosphonate esters and closely derived functionalities
via nucleophilic substitution
While not so common as the attack of phosphorus on an imine, the nucleophilic addition of
phosphorus sources to amines with neighboring leaving groups is a motif that appears quite
attractive as a means of generating the systems in question. The lone pair on nitrogen enhances
the efficacy of halogens and other leaving groups, thus availing an effective method.
Burger and co-workers provide an example of the utility of both bromomethyl- and chloro-
methylamines in the synthesis of aminophosphonates and aminophosphine oxides. An amine
reacts with p-formaldehyde in the presence of a halogen source to render the halomethylamine
(Scheme 15), which is then treated with one of the several nucleophiles to furnish the product in
very good yields (Table 32) <1998JCS(P1)2091>.
R1 O
R2
HN O
F3C CF3
(CH2O)n (CH2O)n
PBr3 SOCl2
R1 O R1 O
R2 R2
Br N O Cl N O
F3C CF3 F3C CF3
R1 = R2 = H, 41% R1 = R2 = Me, 98%

R1 = Pri, R2 = H, 55%
R1 = Bui, R2 = H, 80%
R1 = H, R2 = Ph, 88%
Scheme 15
A similar approach manifests itself in the work of Katritzky and co-workers, who have
demonstrated the utility of the benzotriazolyl moiety as an effective leaving group for use
with phosphorus nucleophiles, among many others. Katritzky offers examples of the zinc
Table 32 Reaction of halomethylamines with phosphorus nucleophilesa
R1 O R1 O
5 mmol Halomethylamine R2
R2 OMe 6 mmol Nucleophile
N O + P 4 R3 N O
X
R3 R
R4 P F C CF3
F3C CF3 O 3
R1 R2 R3 R4 Time Yield (%)
R1 O H H OMe OMe 30 min 66

R2 Pri H OMe OMe 30 min 95
Bui H OMe OMe 30 min 83
Br N O
Bui H OMe Ph 30 min 94
F 3C CF3 H Ph OMe OMe 30 min 90
H Ph Ph Ph 30 min 95
R1 O
R2
Cl N O Me Me OMe OMe 3h 83
Me Me Ph Ph 5 days 62
F3C CF3
a
<1998JCS(P1)2091>.
bromide-catalyzed addition of triethyl phosphite to a spectrum of nitrogen compounds including

cyclic amines, anilines, diamines, N,O-acetals, and other heterocycles. The couplings tend to be
high yielding and efficient (Table 33) <2002JOC3115, 2002JOC3109, 1999JOC1979, 2002S601,
2002JCS(P1)592>.
Table 33 Addition of P(OEt)3 to benzotriazolylmethylamines catalyzed by ZnBr2

Amine Product Yield (%) References
75 <2002JOC3115>
Bt N N Bt (EtO)2(O)P N N P(O)(OEt)2
Bt P(O)(OEt)2
Ph N N Ph N N 70 <2002JOC3109>
Ph Ph
Bt N O N O 77 <1999JOC1979>
(EtO)2(O)P
N N 87 <2002S601>
Bt P(O)(OEt)2
S S
79 <2002JCS(P1)592>
N N
Bt P(O)(OEt)2
Amine Product Yield (%) References
Me Me
S S
76 <2002JCS(P1)592>
N N
Bt P(O)(OEt)2
O O
N N 70 <2002JCS(P1)592>
Bt P(O)(OEt)2
Me Me
N N
73 <2002JCS(P1)592>
N N
Bt P(O)(OEt)2
Lavilla and co-workers provide an example of the use of a transient electrophile generated
in situ from a parent dihydropyridine. Compound 18 is treated with bromine, and the dibromide
is immediately introduced to triethyl phosphite to render the aminophosphonate ester as shown
in Equation (12) <2000XXX1763>.
Me Br2, –78 °C Me 2.5 equiv. P(OEt)3 Me

N THF N Br –78 °C N P(O)(OEt)2
65% ð12Þ
NC NC Br NC Br
18
An interesting variant on the substitution motif appears in the work of Liu and co-workers.
Electrophiles are prepared via the Vilsmeier reaction and 2 equiv. of diethyl phosphite is added.
The first equivalent displaces chloride, and the second adds to the resultant iminium ion
(Scheme 16). Liu generates a series of -amino-gem-bisdiethyl phosphonates through this
protocol (Table 34). Compounds derived from formamides undergo HWE couplings with
aldehydes to render -diethyl phosphonoenamines (Table 35) <1999HAC271>.
R1 O POCl3 R1 OP(O)Cl2 R1 Cl
Cl–
N N N
R2 R3 R2 R3 R2 R3
–
OPOCl2
(EtO)2P(O)H R1 P(O)(OEt)2 (EtO)2P(O)H R1 (P(O)(OEt)2)2
N N
R2 R3 R2 R3
HCl –
OPOCl2 HOPOCl2
Scheme 16
Table 34 Generation of -amino-gem-bisdiethyl phosphonatesa

i. 1 equiv. POCl3
R1 O R1 (P(O)(OEt)2)2
ii. 2 equiv. HP(O)(OEt)2
N CH2Cl2, 0–30 °C, 10 h N 3
R2 R3 R2 R
R1 R2 R3 Yield (%)
H Me Me 66.1
H Et Et 63.2
H H Me 50.2
H Pri Pri 58.5
H Me Ph 80.7
H (CH2)5 75.3
H (CH2)2O(CH2)2 77.9
Me Me Me 51.3
Me Et Et 46.2
Me Pri Pri 57.2
Me Me Ph 38.6
Me (CH2)5 50.4
Me (CH2)2O(CH2)2 55.3
Ph Me Me 30.2
PhCH2 Me Me 36.8
a
<1999HAC271>.
Table 35 HWE couplings involving amino-gem-bisdiethylphosphonatesa
1 equiv. NaH, 1 equiv. R3CHO

(EtO)2(O)P P(O)(OEt)2 R3
THF, 15 to 30 °C, 1 h (EtO)2(O)P
(Z)
R1 N R2 R1R2N
R1 R2 R3 Yield (%) (Z)/(E)

(CH2)5 Et 34 92/8
(CH2)5 Ph 40 67/33
(CH2)2O(CH2)2 Ph 34 45/55
Me Me Ph 40 10/90
Me Me Et 29 20/80
Me Me 4-NO2Ph 46 32/68
a
<1999HAC271>.
In one final example, the roles of nucleophile and electrophile are reversed. In the synthesis of a
series of transcarbamoylase inhibitors, Hilvert and co-workers added amines and sodium azide to
compound 19 with displacement of pentafluorophenyl sulfonate to generate the phosphonyl
phosphinates found in Scheme 17 <1999JMC2633>.
(v) Preparation of -aminophosphonates via metal carbene insertions

Recent advances in transition metal chemistry have popularized the use of -azido esters in
synthesis on account of their ability to form reactive metal–carbene complexes with certain transi-
tion metals. This utility has translated into the use of -azidocarbethoxymethyldiethyl phosphonates
O O
P P OSO2C6F5
(EtO)2
OEt
19
NHCO2But H2N NHCO2But 5 equiv. NaN3

H2N ethanol, rt
CO2But CO2 But 24 h
98%
2.5 equiv. Amine, CH2Cl2 2.5 equiv. Amine, CH2Cl2

0 °C then 40 °C, 3 h 0 °C then 40 °C, 3 h
72% yield not reported
NHCO2But RHN NHCO2But O O

RHN P P N3
CO2But CO2But (EtO)2
OEt
O O
R= P P
(EtO)2
OEt
Scheme 17
for the preparation of -aminocarbethoxymethyldiethyl phosphonates by treatment with a metal

complex in the presence of an amine. Although only one example appears here, others involving the
generation of amido- and carbamatophosphonates are available in Section 4.10.1.2.4.
Kondo and co-workers demonstrated the efficacy of this reaction with 2-iodoaniline. Heating
in toluene with the azide and Rh2(OAc)4 as a catalyst furnished the product in 78% yield as
shown in Equation (13) <2002CC210>.
1 mol.% Rh2(OAc)4 I
N2 I
toluene, 80 °C, 6 h
+ HN ð13Þ
(EtO)2(O)P CO2Et H2N 78%
(EtO)2(O)P CO2Et
(vi) Preparation of -aminophosphonates via generation and reduction of -iminophosphonates

Reduction of imines neighboring phosphonates provides a useful entry into the desired system,
though the reaction is not highly exploited in the literature. The three references that follow
demonstrate the versatility of this method.
Ryglowski and Kafarski published the reductive amination of acylphosphonates. Addition of
trimethyl phosphite to a series of acid chlorides provides the acylphosphonates, which are reduc-
tively aminated and hydrolyzed to the corresponding acids as shown in Table 36 <1996T10685>.
Yuan and co-workers offer an alternative approach. Phosphites add into imidoyl chlorides, and
the resultant imines are reduced. Thus, Yuan and co-workers <1998HAC139> produce a series
of -trifluoromethyl--aminophosphonates in high yields (Table 37).
A similar procedure proves itself applicable to the reduction of oximes. Demir and co-workers
show that the treatment of an -oximinophosphonate with sodium borohydride in the presence of
either MoO3 or NiCl2 effects reduction to the amine. Yields vary, and in some cases are quite
good (Table 38) <1996TL407>.
Table 36 Reductive amination of acylphosphonatesa,b

i. Ph2CHNH2
O P(OMe)3 O ii. NaBH(OAc)3
R Cl R P(O)(OMe)2
Ph i. HCl, H2O Ph
ii. Propylene oxide
N Ph HN Ph
R P(O)(OMe)2 R P(O)(OH)2
R Yield c (%)
Me 60
Et 60
Bui 55
PhCH2CH2 35
2-FC6H4 30
a
<1996T10685>. b Specific conditions not provided. c
Yields from
acylphosphonates to phosphonic acids.
Table 37 Use of imidoyl chloridesa
R1 1 equiv. P(OR2)3 R1 R1
N N NaBH3CN NH
heat
F3C Cl F3C P(O)(OR2)2 F 3C P(O)(OR2)2
Step one
R 1
R 2
Temp. ( C) Time (h) Yield (%) Step two Yield b (%)
Ph Et 80 6 94 60c
4-MeOC4H5 Et 80 10 95 99
PhCHMe Et 100 40 80 99
PhCHMe Me 100 40 82 99
PH2CH Et 100 40 67 99
a b c
<1998HAC139>. NaBH3CN, glacial AcOH, rt, 10 h. NaBH3CN, EtOH, rt, 20 h.
4.10.1.1.4 Higher-coordinate phosphorus functions

Although pentacoordinate phosphorus rarely appears in the manifestation of the PCN array
and is an uncommon substructure in synthesis, one unique example presented here depicts the
generation of such compounds. Etemad-Moghadam and co-workers publish the coupling of
spirophosphoranes to a number of long-chain imines on route to novel phosphorus acid
amphiphiles. The products of the couplings (-aminoalkyl)spirophosphoranes prove unstable
to purification, so yields are not reported, and the stereochemical outcomes of the couplings
are not clearly defined. Nonetheless, the chemistry found in Equation (14) is noteworthy
<2000EJO281>.
Table 38 Reduction of oximinophosphonates to aminophosphonatesa
HO 5 equiv. NaBH4
N NH2
MeOH, rt, 6 h
cat. R P(O)(OEt)2
R P(O)(OEt)2
Yield (%)
R 1.5 equiv. MoO3 2 equiv. NiCl2

Me 59 51
Et 64 61
Pri 68 67
PhCH2 71 73
69 52
O
67 61
S
71 66
Ph 92 79
Cl 77 76
Cl
91 83
Me Me
a
<1996TL407>.
O O
Me Me
Me Me
O N(CH2)n Me rt, CH2Cl2 O NH(CH2)n Me
O O
O P H +
CHR O P
O O R
Me Me
Me Me
O n = 9, R = Ph O
n = 11, R = Ph
ð14Þ
n = 13, R = Ph
n = 15, R = Ph
n = 17, R = Ph
n = 17, R = Me
n = 17, R = (CH2)10Me
n = Me(CH2)7CH=CH(CH2)8, R = Ph
4.10.1.2 Other Nitrogen Functions: R12C(NY)PR22, R12C(NHX)PR22, etc.
4.10.1.2.1 Dicoordinate phosphorus functions

During the period 1995–2003, there were no published reports detailing the preparation of the
NCP array in which phosphorus had a coordination number of 2.
4.10.1.2.2 Tricoordinate phosphorus functions

Although compounds of this class do appear in the literature, the reports tend largely toward the
coupling of a compound such as those found in Section 4.10.1.1.2 to an electrophile so as to
generate an amido or a carbamato tricoordinate phosphorus function by methods beyond the
scope of this chapter.
4.10.1.2.3 Tetracoordinate phosphorus functions

Compounds of this category appear prolifically in the literature and take the form of various
nitrogen functions: amides, carbamates, ureas, hydrazines, imines, etc. The chemistry employed to
generate such compounds is quite similar to the methods discussed in Section 4.10.1; so many
such reactions are revisited herein.
(i) Preparation of tetracoordinate phosphorus compounds via addition of phosphorus

to CN double bonds
Reactions found here closely resemble those described previously in Section 4.10.1.1.3.(iii), and
constitute the most widely executed protocol toward the tetracoordinate phosphorus products.
The generic mechanism involves the attack of the appropriate phosphorus nucleophile on a CN
double bond either pre-existing or generated in situ. Several examples follow.
In their efforts toward the synthesis of phycocyanobilin, Kinoshita and co-workers prepared a
series of lactams bearing exocyclic diethyl phosphonates. The authors explain that the parent
lactams, upon treatment with BF3OEt2, eliminate acetate to generate an electrophilic site for
the attack by triethyl phosphite. Note that complete conversion to the products also involves loss
of the t-butyl group followed by decarboxylation (Equation (15)) <2000BCJ497>.
O 3 equiv. P(OEt)3 O
R1 3 equiv. BF3 .OEt

2
R1 NH
NH
OAc rt, 2 days
R2 R2 P (OEt)2
CO2But
O
ð15Þ
R1 = Me, R2 = Et, 67%
R1 = Et, R2 = Me, 76%
R1 = Me, R2 = 4-MeC6H4, 68%
R1 = Me, R2 = 4-MeOC6H4, 61%
Cristau and co-workers provide an example for the generation of -amidophosphonates by the
attack of sodium diethyl phosphite on a series of acylimines. The authors also apply this protocol
to the synthesis of a sulfonamide (Table 39) <1998S1167>.
N-Benzyloxycarbonyl--aminoalkylphosphinic acids succumb to synthesis via the three-
component condensation as shown by Coward and co-workers. The condensation of an alkyl-
phosphonous acid, or its adamantylammonium salt, with benzyl carbamate and an aldehyde
renders the products in useful yields through a convenient protocol (Table 40) <1996TL4335>.
Chloro phosphites have proven themselves competent partners in similar condensations. Xu and
co-workers have published the condensation of benzyl carbamate and various aldehydes with
both chloro phosphites and chlorodithioalkyl phosphites as shown in Table 41. The authors
propose that water liberated during imine formation hydrolyzes the chloro phosphates and chloro-
dithioalkyl phosphates to dialkyl phosphates and dithioalkyl phosphates, respectively, which subse-
quently serve as nucleophiles <2000HAC417>.
Similar chemistry is possible with alkoxydichlorophosphine and dichlorophenylphosphine. Dai
and co-workers demonstrate the efficiency of both with benzyl carbamate and aromatic alde-
hydes, as shown in Table 42. The authors suggest that the tetracoordinate phosphorus product
results from hydrolysis of PCl bonds <1997SC3341, 1997S415>.
Table 39 Addition of NaP(O)(OR3)2 to acyl iminesa,b
i. NaP(O)(OR3)2
NR1 THF, 12 h, 20 °C R1HN P(O)(OR3)2
Ph R2 ii. 1 N HCl, 0 °C Ph R2
R1 R2 R3 Yield (%)
PhC(O) Ph Et 85
PhC(O) 2-MeC6H4 Et 75
PhC(O) 1-Naphthyl Et 90
2-MeC6H4C(O) Ph Et 60
MeC(O) Ph Et 35
PhCH2OC(O) Ph Et 52
PhC(O) Ph CH2Ph 85
Ts Ph Et 96
a b
<1998S1167>. 6.37 mmol NaP(O)(OR3)2, 7 mmol acylimine, 78 C to 20 C.
Table 40 Three-component condensation rendering alkylphosphinic acidsa,b
O O O R3
AcCl, 0 °C O
R1H2C P H + R3CHO +
PhCH2O NH2 to rt, 6 h PhCH2O N P R1
OR2 H OH
R1 R2 R3 Yield (%)
H Adamantyl-NH3+ H 67
H Adamantyl-NH3+ But 69
H Adamantyl-NH3+ Ph 61
H Adamantyl-NH3+ 4-MeOC6H4 72
Prn H H 50
O
N
H Ph 73
O
EtO CH2 H Me 75
EtO CH2 H Et 48
O
H 4-MeOC6H4 71
EtO CH2
a
<1996TL4335>. b Conditions: 1 equiv. alkylphosphonous acid, 1 equiv. aldehyde, 1 equiv. carbamate, 0 C for
30 min, then rt for 6 h.
A unique approach to the preparation of N-Cbz--phosphono acids appears in the work of

Toone and co-workers. Treatment of a protected -hydroxy- or -methoxy amino acid with PCl3
and P(OMe)3 results in the elimination of the oxygenic substituent followed by the addition of
trimethyl phosphite as depicted in Equation (16) <1999JOC9153>.
Table 41 Three-component condensation with chloro phosphites and chlorodithioalkyl

phosphitesa,b
O O R1
C6H6, rt, (R2)2
+ R1CHO + P(R2)2Cl PhCH2O N P
PhCH2O NH2 6 h to overnight
H O
R1 R2 Yield (%)
Ph OEt 87
2-MeOC6H4 OEt 71
4-ClC6H4 OEt 69
4-BrC6H4 OEt 74
PhCH2 OEt 67
Bui OEt 69
Pri OEt 67
Me OEt 56
Ph OMe 78
2-MeOC6H4 OMe 64
4-ClC6H4 OMe 66
4-BrC6H4 OMe 64
PhCH2 OMe 50
Bui OMe 57
Pri OMe 58
Me OMe 55
Ph SPri 43
2-MeOC6H4 SPri 38
4-ClC6H4 SPri 40
a b
<2000HAC417>. 3 mmol benzyl carbamate, 3.1 mmol aldehyde, 3.3 mmol phosphorus compound.
Table 42 Three-component condensation with dichlorophosphorus compounds
O O PhR1
R2
+ R1 CHO + PCl2R2
PhCH2O NH2 PhCH2O N P
H O OH
R1 R2 Yield (%) References

H Ph 85 <1997S415>a
4-Me Ph 76 <1997S415>a
3-Cl Ph 72 <1997S415>a
4-Cl Ph 68 <1997S415>a
2,4-Cl Ph 80 <1997S415>a
2-MeO Ph 66 <1997S415>a
4-MeO Ph 83 <1997S415>a
3-NO2 Ph 77 <1997S415>a
4-NO2 Ph 79 <1997S415>a
H OMe 80 <1997SC3341>b
4-Cl OMe 67 <1997SC3341>b
H OEt 87 <1997SC3341>b
4-Me OEt 72 <1997SC3341>b
2-MeO OEt 69 <1997SC3341>b
4-MeO OEt 66 <1997SC3341>b
4-Cl OEt 72 <1997SC3341>b
3-NO2 OEt 74 <1997SC3341>b
4-NO2 OEt 83 <1997SC3341>b
H Prn 79 <1997SC3341>b
4-Cl Prn 67 <1997SC3341>b
H Bun 72 <1997SC3341>b
4-Cl Bun 68 <1997SC3341>b
a
Conditions: 5 mmol benzyl carbamate, 5 mmol aldehyde, 5 mmol dichlorophenylphosphine, AcCl, 0 C
for 0.5 h then rt for 1 h, concentrated then stirred in 10:1 C6H6/H2O at rt for 2 h. b Conditions: 5 mmol
benzyl carbamate, 5 mmol aldehyde, 5 mmol alkoxydichlorophosphine, AcCl, rt for 6 h then 40 C for 4 h,
concentrated then stirred in 10:1 C6H6/H2O at rt for 2 h.
O O
PCl3, then P(OMe)3 CbzHN
CbzHN
OR1 OR1
OR 2 P(O)(OMe)2 ð16Þ
R1 = TCE, R2 = Me, 71%
R1 = CH2CH2TMS, R2 = H, 88%
Three-component condensations have proven themselves amenable to enhancements involving

chiral auxiliaries. Both Chung and co-workers and Roos and co-workers demonstrate the applic-
ability of several auxiliaries to condensations involving diethyl phosphite, which in some cases
offer dr values greater than 100:1. Results appear in Table 43 <1996TA21, 1998SC3877>.
Table 43 Three-component condensations involving diethyl phosphite aided by chiral auxiliaries

Chiral material Aldehyde Yield (%) de (%) or dr References
O CHO
NH2 71 14.4 <1996TA21>a
O O
CHO
O N NH2 84 34.1 <1996TA21>a
Ph Me
O CHO
O NH2 75 >99 <1996TA21>a
SO2N(C6H11)2
O CHO
O NH2 73 96.4 <1996TA21>a
SO2N(Pri)2
O CHO
O NH2 77 96.7 <1996TA21>a
SO2N(2,4,6-(Me)3C6H2)2
O MeO CHO
O NH2 76 >99 <1996TA21>a
SO2N(C6H11)2
O
CHO
O NH2 79 >99 <1996TA21>a
SO2N(C6H11)2
Chiral material Aldehyde Yield (%) de (%) or dr References
O Me CHO
O NH2 75 >99 <1996TA21>a
SO2N(C6H11)2
O CHO
O NH2 76 >99 <1996TA21>a
SO2N(C6H11)2
O O
CHO
MeN N NH2
70 >100:1 <1998SC3877>b
Me Ph
O O
CHO
MeN N NH2
52 >100:1 <1998SC3877>b
Me Ph
O O
MeN N NH2
MeCHO 42 66:34 <1998SC3877>b
Me Ph
O O
O2N CHO
MeN N NH2 68 >100:1 <1998SC3877>b
Me Ph
a b
Conditions: 3 mmol chiral material, 4 mmol diethyl phosphite, 5 mmol aldehyde, AcCl, 0 C for 30 min, rt for 1 h. Conditions:
1 mmol chiral material, 1.5 mmol diethyl phosphite, 1.5 mmol aldehyde, AcCl, 0 C for 30 min, rt for 1 h.
The addition of phosphorus nucleophiles to CN double bonds also proves to be a useful route
to -ketosulfiniminophosphonates. Davis and co-workers have been successful in the asymmetric
addition of lithium diethyl phosphite to enantiopure keto sulfinimines in both high yields and
selectivities as shown in Table 44 <2001OL1757>.
Evans and co-workers <1997JOC7532> have executed similar experiments also in good yield
and selectivity, as shown in Table 45.
Hou and co-workers have demonstrated similar asymmetric additions in the presence of a
nearby chiral azirine, which also has the potential to influence the stereochemical outcome of the
reaction. Despite the second source of chirality, good selectivites seem attainable with either
epimeric azirine (Table 46) <2002JOC2902>.
The examples discussed thus far have explored the generation of systems in which nitrogen
bears a common electron-withdrawing group, amides, carbamates, etc. Although of less routine
interest to the chemist than the compounds discussed previously, the three-component condensa-
tion has also found applications to systems bearing N-heteroatom bonds. Heydari and co-workers
have demonstrated the efficacy of condensations involving dimethylhydrazine and N-hydroxy-
aniline. Acidic catalysts aid the reaction, which tends to be high yielding and fast. In reactions
Table 44 Asymmetric addition of lithium diethyl phosphite to enantiopure

keto sulfiniminesa
O
O R1 S
LiP(O)(OEt)2 4-MePh NH
S
4-MePh N R2 –78 °C, THF R2
P(O)(OEt)2
R1
R1 R2 Yield (%) de (%)

Me 4-MeOPh 73 >95
Me 4-MePh 91 >95
Me Ph 92 >95
Et Ph 93 >95
Me 4-NO2Ph 93 >95
Me But 97 >95
a
<2001OL1757>.
Table 45 Asymmetric addition of metallated phosphites to keto sulfiniminesa
O H O R1
MP(O)(OR2)2
S S
4-MePh N R1 –78 °C, THF 4-MePh N P(O)(OR2)2
H
R1 R2 M Yield (%) de (%)

Ph Et Li 85 84
Ph Et Na 80 93
4-MeOPh Et Li 50 84
4-MeOPh Et Na 50 90
Ph Pri Li 82 97
a
<1997JOC7532>.
Table 46 Asymmetric additions to a pair of epimersa

R M Yield (%) syn:anti
O O
S S
N Ph-4-Me HN Ph-4-Me
MP(O)(OR)2
H –78 °C, THF P(O)(OR)2
N N
Bn Bn
NEt2 Li 96 84:16
NEt2 Na 92 62:38
OMe Li 95 85:15
O O
S S
N Ph-4-Me HN Ph-4-Me
MP(O)(OR)2
H –78 °C, THF P(O)(OR)2
N N
Bn Bn
NEt2 Li 94 <1:99
NEt2 Na 93 22:78
OMe Li 94 <1:99
a
<2002JOC2902>.
involving P(OMe)2(OTMS), note the transfer of TMS from the phosphite to the hydroxylamine
(Table 47) <2002CL1146, 2001TL3629>.
Table 47 Three-component condensations in the presence of NN and NO bonds
R3 O
Cat., rt
R1CHO + P(OMe)2(OR2) + R3 NHR4 N P
LiClO4.OEt2 R5 (OMe)2
R1
R1 R2 R3 R4 R5 Catalyst Yield (%) References

Pri Me NMe2 H H TMSCl 94 <2002CL1146>a
Prn Me NMe2 H H TMSCl 90 <2002CL1146>a
But Me NMe2 H H TMSCl 94 <2002CL1146>a
Hexyl Me NMe2 H H TMSCl 95 <2002CL1146>a
2-furyl Me NMe2 H H TMSCl 76 <2002CL1146>a
4-NO2Ph Me NMe2 H H TMSCl 86 <2002CL1146>a
4-BrPh Me NMe2 H H TMSCl 89 <2002CL1146>a
Pri Me Ph OH OH AcOH 89 <2002CL1146>a
Prn Me Ph OH OH AcOH 96 <2002CL1146>a
But Me Ph OH OH AcOH 90 <2002CL1146>a
C6H11 Me Ph OH OH AcOH 87 <2002CL1146>a
3-Pyridyl Me Ph OH OH AcOH 87 <2002CL1146>a
4-NO2Ph Me Ph OH OH AcOH 85 <2002CL1146>a
Pri TMS Ph OH OTMS 97 <2001TL3629>b
Prn TMS Ph OH OTMS 95 <2001TL3629>b
Bun TMS Ph OH OTMS 99 <2001TL3629>b
Hexyl TMS Ph OH OTMS 90 <2001TL3629>b
C6H11 TMS Ph OH OTMS 87 <2001TL3629>b
Ph TMS Ph OH OTMS 90 <2001TL3629>b
4-MeOPh TMS Ph OH OTMS 85 <2001TL3629>b
2-Furyl TMS Ph OH OTMS 90 <2001TL3629>b
3-Pyridyl TMS Ph OH OTMS 95 <2001TL3629>b
(E)-PhCH¼CH TMS Ph OH OTMS 95 <2001TL3629>b
a
Conditions: 0.8 mmol LiClO4OEt2, 2.2 mmol nitrogen source, 2 mmol aldehyde, 2.2 mmol phosphite, 2.2 mmol catalyst, 1 h.
b
Conditions: 0.8 mmol LiClO4OEt2, 2.2 mmol nitrogen source, 2 mmol aldehyde, 2.2 mmol phosphite, 15 min.
(ii) Preparation of tetracoordinate phosphorus compounds via nucleophilic displacement

of leaving groups
The displacement of leaving groups as a means of coupling to the products discussed here is just
as common and useful as it is in the synthesis of amino compounds and proceeds via the same
mechanisms as reactions discussed in Section 4.10.1.1.3.(iv). Typically, the phosphorus source acts
as the nucleophile, though there do exist a few examples of reactions in which the nitrogen source
serves such a role.
Couture and co-workers have developed a method for the synthesis of tetracoordinate phos-
phorus compounds bearing formamides and N-BOC-amines. The reaction involves the condensa-
tion of the nitrogen source with p-formaldehyde and TMSCl to generate an -chloroamide or
carbamate, which reacts with a phosphorus nucleophile to render the products in good yield
(Table 48) <1995TL2483>.
Plénat and co-workers have exploited the displacement of halogens in their synthesis of 2,4,5-
imidazolidinetriones. Displacement of chloride from N-chloromethyl-2,4,5-imidazolidinetrione by
either triphenylphosphine (Equation (17)) or O,O-diethyl dithiophosphate (Equation (18)) affords
the desired products in suitable yields. Better yields are realized when other nucleophiles attack
N-bromomethylphthalimide. Those products are then converted to the desired products through a
three-step protocol (Scheme 18) <1995T9551>.
Table 48 Attack of phosphorus nucleophiles on chloromethylamides and carbamatesa
O O 3 O
(CH2O)n P(OEt)(R )2, 1 h
(R3)2
R1 NH R1 N Cl R1 N P
TMSCl Toluene, reflux
R2 R2 R2 O
R1 R2 R3 Yield (%)
H Me OMe 71
H CH2Ph OMe 70
H Me OEt 72
H CH2Ph OEt 75
H Ph OEt 70
H Me Ph 82
H CH2Ph Ph 80
H Ph Ph 75
OBut CH2Ph OEt 65
OBut CH2Ph Ph 68
a
<1995TL2483>.
O PPh3, acetonitrile O
reflux, 120 h
Cl
N NPh – ClPh +P N NPh ð17Þ
3
67%
O O O O
O P(S)(OEt)2SH O
Na2CO3, acetone
Cl
N NPh
(EtO)2P(S)S
N NPh ð18Þ
reflux, 4 h
O O 66% O O
O O
Br P(OEt)3 or R NH2NH2, H2O R
N N
P(OEt)Ph2 NH2
O O
R = P(O)(OEt)2, 100% R = P(O)(OEt)2,100%
R = P(O)Ph2, 90% R = P(O)Ph2, 99%
PhNCO (COCl)2 O
O
CH2Cl2 Et2O, 3 h
N NPh
R N NHPh reflux R
reflux, 1 h
H
O O
R = P(O)(OEt)2, 88% R = P(O)(OEt)2, 83%
R = P(O)Ph2, 99% R = P(O)Ph2, 95%
Scheme 18
Katritzky and co-workers have applied the benzotriazole (Bt) group to this reaction. A mixture
of triethyl phosphite and -Bt-lactam reacts in the presence of a zinc bromide catalyst to render
products in good yield as shown in Table 49 <2000JOC4364>.
Table 49 Use of benzotriazole as a leaving groupa,b
O O
ZnBr, P(OEt)3
NR NR
0 °C, 10 h, CH2Cl2
Bt P(O)(OEt)2
R Yield (%)
CH2CH2OH 49
4-MeOPhCH2 79
3,4-MeOPhCH2 78
4-MeOPhCH2CH2 76
Ph
HO
CH2 85
Ph
MeO 67
CH2
O
a
<2000JOC4364>. b Conditions: 1.3 mmol lactam, 1.3 mmol
ZnBr2, 2.1 mmol P(OEt)3.
An example of a cyclic phosphite acting as the nucleophile appears in the work of Leusen and
co-workers. Two similar cyclic phosphites react with cationic formamides to displace trimethyl-
amine as found in Equation (19) <1998EJO1511>.
O
–
Me3N+ N H I
OR H
O NCHO
P MeNO2, reflux, 2 h P
O O O O
ð19Þ
Ph Ph
NMe3, RI
R = Me, 63%
R = Et, 77%
Cases in which nitrogen acts as a nucleophile displacing a leaving group from the phosphorus
compound are less prominent in the literature, though equally useful as the methods seen thus far. In
the synthesis of a series of nucleobase compounds, Dahl and co-workers <2000JCS(P1)2015> utilize this
reaction to displace 4-nitrobenzene sulfonates from phosphines and phosphonates (Equations (20)–(22)).
NH2 N=CHNBu2
NH2
N N N N
N 4-NO2PhSO3CH2P(O)R2 Bu2NCH(OMe)2
N ð20Þ
NaH, DMF, rt N N N N
N N R = Ph, 56%
H R = OEt, 55%
P(O)R2 P(O)R2
O
O
4-NO2PhSO3CH2P(O)R2 BzN
BzN
ð21Þ
K2CO3, DMF O N
O N
H R = Ph, 44% P(O)R2
R = OEt, 66%
OTMS O
N 4-NO2PhSO3CH2P(O)Ph2
HN
acetonitrile ð22Þ
TMSO N O N
P(O)Ph2
Yuanand and co-workers have demonstrated the synthesis of 1-hydrazinoalkylphosphonic

acids via displacement of -mesylates from phosphonates with hydrazine. The reactions proceed
in moderate yields, as shown in Table 50, and the products were subsequently converted to their
oxalate salts <1996S507>.
Table 50 Displacement of mesylates with hydrazinea

OMs NH2NH2.H2O, NHNH2
R P(O)(OEt)2 EtOH, 50 °C, 15 h R P(O)(OEt)2
R Yield (%)
H 50
Me 53
Et 56
PhCH2 61
Ph 55
4-MePh 60
4-MeOPh 52
4-FPh 54
4-ClPh 53
a
<1996S507>.
While involved in hapten synthesis, Gouverneur and co-workers have used the combination of
DEAD and triphenylphosphine to couple N-(phenoxycarbonyl)-O-t-BOC hydroxylamine to
-hydroxy phosphonates. The yields vary widely, yet the reactions are still clean (Table 51).
Removal of the t-BOC group completes the synthesis <1996TL6331>.
Table 51 Displacements assisted by DEAD/PPh3a
O 2 equiv. DEAD/ 2 equiv. PPh3, PhOCO O

1.5 equiv. PhOCONHO-t-BOC,
HO P N P
(OBn)2 t-BOCO (OBn)2
THF, rt, 1–2 h
R R
R Yield (%)
Me 53
Et 50
Pri 29
Bui 64
CH2CH2Ph 96
a
<1996TL6331>.
Sharpless and co-workers offer examples of an intramolecular displacement that affords

N-substituted azirines in high yield (Equation (23)) <1999JOC8379>.
R
NHR O
K2CO3, DMF N
P
(OEt)2 (OEt)2
P
OMs ð23Þ
MeO O
MeO
R = Ts: 25 °C, 2 h, 95%
R = CO 2Et: 80 °C, 3 h, 93%
(iii) Preparation of tetracoordinate phosphorus compounds via metal carbenoid insertions

As the reactions of diazo compounds with transition metals become increasingly popular in
synthesis, this method becomes useful in the synthesis of compounds of interest here. Moody
and co-workers <2001TA1657> have demonstrated the reactions of diazophosphonic acid deri-
vatives with a variety of nucleophiles including a carbamate as shown in Equation (24). Moody
has published a similar reaction by using -diazo--phosphonate esters in the synthesis of
phosphonoglycine derivatives and in peptide synthesis (Table 52) <1995SL921, 1997CC2391>.
2 equiv. CbzNH2, toluene

Ph O Ph
O O O
P cat. Rh2(OAc)4, 5 h, 80 °C
Ph P ð24Þ
N Ph
Me Me N
Me N2 56% Me NHCbz
Table 52 Carbenoid insertions

1
Substrate R R2 R3 Yield (%) References
t
O OBu H 75 <1995SL921>a
OCH2Ph H 73 <1995SL921>a
R1 NHR2 Me H 79 <1995SL921>a
Et H 66 <1995SL921>a
OBut Pr 46 <1995SL921>a
NHMe H 40 <1995SL921>a
R1 H H Cbz 81 <1997CC2391>b
Me H t-BOC 88 <1997CC2391>b
R2 NH2
P Me H Cbz 80 <1997CC2391>b
R3 O Pri H t-BOC 80 <1997CC2391>b
Bui H t-BOC 82 <1997CC2391>b
(CH2)2 Cbz 80 <1997CC2391>b
a
Conditions: 1 mmol triethyldiazophosphono acetate, 5 mmol NH compound, toluene, 2 mol.% Rh2(OAc)4, reflux overnight.
b
Conditions: triethyldiazophosphono acetate, toluene, Rh2(OAc)4.
(iv) Preparation of tetracoordinate phosphorus compounds via miscellaneous methods

In addition to the more widely employed methods, the literature offers a small number of
interesting and unique entries into the desired system. Kondo and co-workers have developed a
means of generating -carbamato--phosphono esters. The reaction stands distinct from others
seen thus far in which it involves the direct attack of triethylphosphine on a carbonyl. The yields
are high, as shown in Scheme 19 and Equation (25), and the conditions seem suitable for the
functionalization of -lactams <1996JCS(P1)3>.
Me Me i. Me3SiBr, 10 °C, 5 min

P(OEt)3, toluene
Ph N O Ph N P(OEt)3
reflux, 7 h
O CO2Et O CO2Et ii. H2O 100%
Me O
Ph N P
(OEt)2
O CO2Et
Scheme 19
TBSO Me TBSO Me
H H H H
i. P(OEt)3, toluene, reflux, 7 h
COSEt ii. Me3SiBr, toluene, 10 °C, 2 h COSEt
ð25Þ
N O N P(O)(OEt)2
O 87% O
CO2Et CO2Et
Armstrong and co-workers have demonstrated the amination of phosphonate ester enolates by
N-carboxamido oxaziridines. Attack by the enolate on the N-carboxamido oxaziridine results in
formation of the desired compound with loss of 2-cyanobenzaldehyde, as shown in Equation (26)
<2000TL2247>.
O
O i. 1.06 equiv. LDA, –78 °C, 1 h
(EtO)2
P ii. 1 equiv. P N NEt2
(EtO)2 O
O H
N NEt2
O
ð26Þ
CN
–78 °C, 3 h, warm to rt over 90 min
51%
4.10.2 FUNCTIONS CONTAINING ONE NITROGEN AND ONE ARSENIC,

Compounds of this description are seldom the target of synthesis and the literature offers only
one example from the years surveyed. Weber and co-workers have studied the reaction of arsa
alkenes with fumarodinitrile (Equation (27)). The organometallic species adds to the electron
deficient olefin effecting cyclization to a 2:1 mixture of diastereomers <2002OM1998>.
CN
2 Cp(CO)2Fe As
Ph
Me2N CN
Cp(CO)2Fe Ph H CN 24 h, rt
As + +
ether ð27Þ
NMe2 NC H
50%
CN
1 Cp(CO)2Fe As
Ph
Me2N CN
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Biographical sketch
Craig S. Kenesky is currently a graduate stu- Professor Gary Molander was born in Cedar
dent at the University of Pennsylvania work- Rapids, Iowa. He received his B.S. degree at
ing in the laboratories of Professor Amos Iowa State University in 1975 working with
B. Smith, III. He received his B.A. in chemistry Professor Richard C. Larock. He entered the
from The Johns Hopkins University in 1999, graduate chemistry program at Purdue Uni-
whereupon he began his graduate studies. His versity in 1975, obtaining his Ph.D. degree in
research interests include the synthesis of 1979 under the direction of Professor Herbert
architecturally complex natural products of C. Brown. He joined Professor Barry Trost’s
biological significance, and the design, synth- group at the University of Wisconsin, Madi-
esis, and evaluation of novel nonpeptidal pep- son as a National Institutes of Health post-
tidomimetics, carbohydrate-derived scaffolds, doctoral fellow in 1980, and in 1981 he
and drugs targeting HIV and cancer. accepted an appointment at the University of
Colorado, Boulder, as an assistant professor
of chemistry. He was promoted to Associate
Professor in 1988 and Professor of Chemistry
in 1990. In 1999 he joined the faculty at the
University of Pennsylvania, and in 2001 was
appointed Allan Day Professor of Chemistry.
Professor Molander’s research interests focus
on the development of new synthetic methods
for organic synthesis and natural product
synthesis. A major area of research has also
been the application of organolanthanide
reagents and catalysts to selective organic
synthesis.
4.11
Functions Incorporating a Nitrogen
and a Silicon, Germanium, Boron,
or a Metal
C. CHU
AstraZeneca R&D Charnwood, Loughborough, UK
4.11.1 FUNCTIONS CONTAINING A NITROGEN AND A METALLOID:

R12C(NR22)MR3n (M = Si, Ge, B), etc. 496
4.11.1.1 Nitrogen and Silicon Functions 496
4.11.1.1.1 -Aminosilanes 496
4.11.1.1.2 N-Acyl--aminosilanes 500
4.11.1.1.3 C-Silylaziridines 502
4.11.1.1.4 Trimethylsilylmethyl azide and -silyl azides 504
4.11.1.1.5 Trimethylsilylmethylisocyanide, -isocyanate, and -isothiocyanate 505
4.11.1.1.6 -Iminosilanes and related compounds 506
4.11.1.1.7 -Diazosilanes 508
4.11.1.1.8 N-(Silylmethyl) heterocycles 510
4.11.1.2 Nitrogen and Germanium Functions 510
4.11.1.3 Nitrogen and Boron Functions 513
4.11.1.3.1 -Aminoboranes and borohydrides 513
4.11.1.3.2 -Aminoboronic acids 517
4.11.2 FUNCTIONS CONTAINING A NITROGEN AND A METAL: R12C(NR22)MLn
(M = Li, K, Mg, Sn, Zn), etc. 519
4.11.2.1 -Metallated Amine Functions 519
4.11.2.1.1 Lithium, potassium, and magnesium 520
4.11.2.1.2 Tin and zinc 524
4.11.2.2 -Metallated Imine Functions 527
4.11.2.2.1 Lithium 527
4.11.2.2.2 Tin 528
4.11.2.3 -Metallated Aziridines 529
4.11.2.4 -Metallated Isocyanides and Isothiocyanates 530
4.11.2.4.1 Isocyanides 530
4.11.2.4.2 Isothiocyanates 531
4.11.2.5 Metallation of N-Methyl Heterocycles 532
4.11.2.6 -Metallated Nitroalkanes 533
495
496 Functions Incorporating a Nitrogen and a Silicon, Germanium, Boron, or a Metal
4.11.1 FUNCTIONS CONTAINING A NITROGEN AND A METALLOID:

R12C(NR22)MR3n (M = Si, Ge, B), etc.
4.11.1.1 Nitrogen and Silicon Functions
4.11.1.1.1 a-Aminosilanes
The chemistry of -aminosilanes has been a growing area of interest because -aminosilanes have
been shown to be useful intermediates in synthesis, most notably as ylide precursors. A recent
review by Aizpurua and Palomo <2002MI411-01> has covered the main synthetic routes to
-aminosilanes and in this section some of these methodologies will be discussed.
(i) Reaction of an amine with a halomethyl silane and its further functionalization
The alkylation of ammonia or an amine by halomethyl silanes in an inert solvent is the most
straightforward method used to prepare -aminosilanes 1 (Equation (1)), but its development is
restricted by the limited availability of functionalized halomethyl silanes and the complication of
overalkylation. Only chloromethyl- and iodomethyltrimethylsilane are widely used to prepare
trimethylsilylmethylamines. In order to overcome the problem of overalkylation, either a large
excess of amines was needed or a two-step procedure using a masked amino group (such as an
azido or phthalimide group) was employed (see Sections 4.11.1.1.4 and 4.11.1.1.2). Despite these
issues, a number of publications on this reaction have been listed in chapter 4.11 of COFGT
(1995) and will not be repeated here.
H R2 R2
1
R 3Si X N R13Si N
R3 R3 ð1Þ
X = Cl, I 1
A typical example of -aminosilane synthesis from an amine and its subsequent use as an ylide
presursor was published by Mariano and co-workers <1996TL571> in their studies of the
stereochemical features of oxidative Mannich cyclizations. They prepared -aminosilane 2 in
moderate yield from the alkylation of an amino alcohol 3 with chloromethyltrimethylsilane.
The resulting -aminosilane 2 was further functionalized by N-benzylation. After the introduction
of the vinyl trimethylsilyl group, the intermediate 4 was treated with TCN, which underwent
single electron transfer (SET) and transformed the -silylamine into an amine radical cation. This
was followed by rapid desilyation to generate the iminium ion 5, which is the substrate for
Mannich cyclization (Scheme 1). The results of the oxidative Mannich cyclization of related
-aminosilanes were informative regarding the stereochemical selectivity of this reaction.
Me TMSCH2Cl Me BnBr, K2CO3 Me

HO HO HO
NH2 K2CO3, MeCN NH MeCN, 77% N
Bn
67%
TMS TMS
3 2
i. Swern Oxidation, 99%
ii. (E)-TMSCH = CHSnBu3,
BunLi, THF, 80%
iii. Ac2O, DMAP, Pyr,
CHCl3, 80%
OAc OAc OAc

Me Me TCN Me
TMS TMS
+
N N MeCN N
Bn Bn Bn
TMS
5 4
TCN = Ce(n-Bu4N)2(NO3)6
Scheme 1
Functions Incorporating a Nitrogen and a Silicon, Germanium, Boron, or a Metal 497
Coelho and Blanco <2001SL1455> in their study of the selectivity of intramolecular reactions
of chiral silicon compounds also made use of a similar alkylation reaction. They synthesized the
chiral -aminosilane 6 in moderate yield by direct alkylation of benzylamine with chloromethyl-
silane 7 at 100 C (Scheme 2). This intermediate 6 was then acylated to give silatriene 8, which
was shown to undergo intramolecular Diels–Alder reaction to give product 9 as a mixture of
diastereomers with a moderate de of 58%.
H
Cl N Ph
Et3N, 100 °C
Ph NH2 Me Si Me Si
Cy 85% Cy
7 6
O
O O Et3N, CH2Cl2
Cl 0 °C, 73%
Ph Ph
N O N O
Me Si Toluene
Me Si O
Cy reflux, 76% Cy
58% de
O
9 8
Scheme 2
(ii) Hydrosilylation of enamines

An alternative direct synthesis of -aminosilanes is the hydrosilylation of enamines, but it has not
been widely studied. Pioneering efforts by Skoda-Földes and co-workers <1991JOM(408)297> have
demonstrated a rhodium-induced hydrosilylation of enamides with trialkylsilanes (Equation (2)). Murai
and co-workers <1998OM926> have widened the scope of this reaction to allow other N-substitutions
including those on N-alkenylureas and identified rhodium acetate as the preferred catalyst.
Et3Si
Et3SiH
O N O N ð2Þ
(Ph3P)3RhCl
92%
Sieburth and co-workers in their study of peptidomimetics developed a practical synthesis

of BOC-protected -aminosilanes by hydrosilylation. The N-BOC enamine 10 (prepared using
Overman’s Curtius rearrangement protocol) was reacted with slight excess of silanes in the
presence of 5% rhodium acetate in refluxing toluene to provide moderate-to-good yields of the
hydrosilylation products 11 (Scheme 3) <2000TL10175>. The difference in product yields was
consistent with a combination of steric and electronic effects for this transformation. Deprotec-
tion of product 11 using TFA proceeded smoothly and the -silylamine products 12 were
characterized as their hydrochloride salts.
H H
N HSiR3 N SiR3 i. CF3CO2H H3N+ SiR3
t-BOC t-BOC
Rh2(OAc)4 ii. HCl Cl–
toluene, reflux
10 46–86% 11 12
SiR3 = Si(OEt)3, Si(CH3)2Ph, SiCH3Ph2
Scheme 3
(iii) Reaction of halomethylamines and methyleneiminium salts with metallosilanes

Halomethylamines and methyleneiminium salts are considered synthetically equivalent entities,
but the availability of -chloroalkylamines and related compounds is poor in comparison. An
example of metallosilane displacement of halomethylamine was shown in Equation (3) where
tris(chloromethyl)amine 13 is exhaustively silylated to give the amine 14 in 74% yield
<1973HCA1117>. A related example of the use of metallosilane to prepare -aminosilanes was
reported by Sun and Moeller where the phenyl sulfonyl proline derivative 15 was silylated using a
cuprate reagent to give the N-Cbz protected silylated proline derivative 16 (Equation (4))
<2002OL1547>.
Ph2MeSiLi
N Cl N SiMePh2
3 THF, 20 °C 3 ð3Þ
13 74% 14
Cbz i. PhSO2Na, TFA Cbz

CO2Me CO2Me
N MgSO4, CH2Cl2, 85% N
MeO PhMe2Si ð4Þ
ii. PhMe2SiLi, CuCN
15 THF, 66% 16
Maimi-Jamal and co-workers <1999JCS(P1)3709> reported a one-pot three-component synth-

esis of a variety of -silylated N,N-dialkylamines 17 by the addition of a metallosilane (e.g.,
phenyldimethylsilyllithium) to iminium intermediates 18 generated in situ from aryl aldehydes and
(trimethylsilyl)dialkylamines in a 5 M ethereal LiClO4 solution (Scheme 4). This methodology is
general for most aryl aldehydes to give the corresponding -aminosilane in good-to-excellent
yields. In the case of enolizable aldehydes such as isobutyraldehyde, the yield of the reaction was
lowered by the formation of enamine as side product in the iminium ion formation step.
1 1 1
Me3SiNR2 H +R R23 SiLi NR2
Ar CHO N 2
LiClO4, Et2O Ar R1 50–95% Ar SiR3
18 17
R1 = H, Me, (CH2)4
SiR32 = SiMe 2Ph, SiMePh2, SiPh3
Scheme 4
(iv) Silylation of aminomethyllithium reagents

In general, this approach to the synthesis of -aminosilanes is only applicable to alkyl species with
an ‘‘activated’’ -nitrogen atom or that with additional anionic stabilization. This is due to the
fact that carbanionic centers are not noticeably stablized by an -amino functionality; hence, the
deprotonation of methylamines even with strong bases is normally unsuccessful. The ‘‘activated’’
-nitrogen atom could be part of an N-nitrosoamine or amidine group that facilitates lithiation,
and a few examples of these reactions could be found in chapter 4.11 of COFGT (1995).
The use of directed metallation groups also facilitates the preparation of silanes via amino-
methyllithium intermediates. t-BOC-piperidine is readily metallated by s-BuLi/TMEDA to afford,
after quenching with TMSCl, the 2-silylpiperidine 19 (Equation (5)) <1989TL1197>. In an
extension of this methodology, Barberis and Voyer published the first example of an enantio-
selective [1,2] silicon rearrangement to afford an N-t-BOC -aminosilane 20. When N-silyl-
protected N-t-BOC-benzylamine 21 was subjected to enantioselective deprotonation using the
chiral complex s-BuLi/(–)-sparteine, the chiral benzyllithium intermediates underwent a [1,2]
silicon shift to give good yields of product 20 with ee up to 72% (Scheme 5) <1998TL6807>.
i. BusLi, TMEDA
N N TMS
ii. TMSCl, 94% ð5Þ
ButO O ButO O
19
O N SiR3 O
BusLi
N OBut N Li O N OBut
(–)-Sparteine H
SiR3
N OBut
21 SiR3 20
SiR3 = SiMe3, Si(i-Pr)3
Scheme 5
A more direct route to a lithiated methylamine has been investigated by Karsch and co-workers
<1997CB1777>. They have successfully dilithiated a series of N,N0 -dimethyl–methylenediamine
derivatives 22 with t-BuLi and reacted the doubly lithiated species 23 with a range of halosilanes
to give the corresponding silylated products such as 24 and 25 (Scheme 6). It is interesting to note
that the deprotonation takes place exclusively at the methyl groups rather than the methylene
carbon atom. Furthermore, the monolithiated species was not detected spectroscopically, and in
subsequent reactions no monosubstitution product was found. This can be explained by a
kinetically favored second metallaton step due to complexation of the lithium ion.
R R
N N
Me3SiCl
CH2 CH2
R R TMS TMS
R
N N
R 2 × ButLi N N
CH2 CH2 24
Me Me Me2SiCl2
Li Li R R
N N
22 23
R = Me, Cy, Pr i Si
Me Me
25
Scheme 6
(v) Reduction of silylmethyl azides

Many methods are known for azide reduction and they may be applied to silylmethyl azides.
Chapter 4.11 of COFGT (1995) has reported two publications that made use of the Staudinger
reaction to reduce silylmethyl azides 26 to the respective amine 27 via the iminophosphorane
intermediate 28 (Scheme 7) <1986BCJ2537, 1988SC1975>. Other groups have shown that
LiAlH4 is also an effective reducing agent for conversion of silylmethyl azides into the desired
-aminosilanes <1996TL555, 2001OL3955>. For example, Chakraborty and Laxman
<2002TL2645> prepared the -trimethylsilylamine intermediate 29 from trimethylsilylmethyla-
zide derivative 30 using LiAlH4 reduction in their total synthesis of (+)-crocacin D (Equation (6)).
Ph3P H2O
PPh3
TMS N3 TMS N TMS NH2
80–90%
26 28 27
Scheme 7
OH OH
LiAlH4, Et2O
TMS TMS
0 °C to rt ð6Þ
N3 NH2
OH OH
30 29
4.11.1.1.2 N-Acyl-a-aminosilanes
Acylation of aminosilanes is the most straightforward and common method to access the title
compounds. A cross section of examples covering a broad range of circumstances has been
discussed in chapter 4.11 of COFGT (1995). A typical example is demonstrated by the following
acylation reaction. N-Methyl trimethylsilylmethylamine 31 was acylated with 2-furylformyl chloride
32 to afford the -amidosilane 33 in excellent yield (Equation (7)) <1992JOC5419>.
O O
10% aq. NaOH O
O
TMS NHMe Cl TMS N
92% ð7Þ
Me
31 32 33
Primary and secondary amides are readily alkylated by silylmethyl halides. Mariano and
co-workers have utilized this procedure to prepare some intermediates for oxidative Pictet–
Spengler cyclizations. For example, 2-arylethyl--silylamide 34 was synthesized by alkylation of
2-arylethylamide 35 with TMSCH2I. The -silylamide 34 readily underwent CAN oxidation to
afford the corresponding tetrahydroisoquinoline 36 (Scheme 8) <1998JOC860>. They have
demonstrated an alternative Pictet–Spengler cyclization reaction that is mild and is applicable
to systems that possess particularly acid-sensitive functionalities.
MeO TMSCH2I MeO CAN MeO
NHCOPh 67% NCOPh 60% NCOPh

MeO MeO MeO
35 34 TMS 36
Scheme 8
Sommer and Rockett <1951JA5130> first prepared N-silylmethylphthalimides from phthalimide

37 (Equation (8)). A more recent example was reported by Tacke and Handmann <2002OM2619>
in pursuit of the synthesis of silicon-containing -amino acids. Using 3,6-diethoxy-2,5-dihydropyr-
azine 38 as a masked amino acid, they first prepared the chloromethylsilane derivative 39
and reacted that with potassium phthalimide to afford 40. The amino acid and -aminosilane
functionalities were unmasked by acid hydrolysis to give target compound 41 (Scheme 9). This
chemistry was also applied asymmetrically based on Schöllkopf’s methodology <1983T2085>.
O O
TMS Cl TMS
NH N
K2CO3, DMF ð8Þ
O 120 °C, 89% O
37
N-Silylmethylphthalimides (and N-silylmethylimides) 42 themselves are substrates for photo-

chemical reaction, and this has been the subject of investigation by Mariano and co-workers. In
three publications, they described the synthesis of a wide range of unusual polycyclic compounds
starting from N-silylmethylimide or N-silylmethylphthalimide derivatives <1995JOC2353,
1995JA2698, 1996JOC3304>. In all cases the silyl analogs 42 were irradiated, and they underwent
a process involving the excited state C to O migration of a TMS group to generate azomethine
N OEt i. n-BuLi N OEt
ii. Me2Si(CH2Cl)2
EtO N EtO N
Me2Si Cl
38 39
KPhth
[Aliquat-336]
75%
O
H2N N OEt
OH
HCl/H2O O
SiMe2 EtO N
85%
NH2 Me2Si N
O
41 40
Scheme 9
ylide species 43. This high-energy intermediate then reacted in a number of different ways to
provide a range of N-heterocycles such as 44 and 45. A selection of them is shown in Scheme 10.
A related reaction using -silylcarbamates as starting material was reported by Meggers and
co-workers (Equation (9)) <1995AG(E)2137>.
Me
TMSO O
Me
O N
O OTMS O
TMS hν + – 84% 44
N N CH2
R1
O O
TMSO R2
42 43
R1 R2
N
62–93%
R1 = CO2Me, CN O
2 = H, 45
R Me, CO 2Me
Scheme 10
O
ACD (5–20 mol.%),
O Cy
BP (30 mol.%) N OMe
Cy E
N OMe + MeCN/MeOH
TMS hν (λ > 345 nm)
25–67% E
ACD = 9,10-anthracenedicarbonitrile ð9Þ
BP = biphenyl
O
E CO2Me Ph
= N Me
Me CO2Me
CO2Me CHO
O
A novel method to generate N-acyl--aminosilane has been published by Szymoniak and

co-workers. They used a zirconocene catalyst similar to that used by Honda and Mori (in their
research into aza-Brook rearrangement of -silylallylamine) <1996JOC1196> to mediate an unusual
retro-Brook rearrangement of 2-aza-1,3-dienes 46 to produce -silylated amides after hydrolysis
<2000TL3053>. The azadiene 46 was treated with the Negishi zirconium reagent which, after
base hydrolysis, gave -silylamide 47 in 60% yield (Scheme 11). They theorized that the driving force
of the retro-Brook rearrangements was the strongly oxophilic character of zirconium, and
they proposed the mechanism shown in Scheme 11. It is interesting to find that no trace of the
silylation at C-4 was detected, possibly because of the steric bulk of the C-5 phenyl group.
i. Cp2ZrCl2, 2x n-BuLi
OSiMe3 THF, –78 °C to rt Me3Si O
Ph Ph
Ph N ii. NaHCO3 aq. Ph N
60% H
46 47
“Cp2Zr” H2O
Ph Ph
[1,4] shift Me3Si

N ZrCp2
N ZrCp2
O
O SiMe3
Ph Ph
Scheme 11
4.11.1.1.3 C-Silylaziridines
There exist a number of synthetic routes to silylaziridines, but it is most common to assemble the
silylaziridines by the reaction of suitable silylalkenes with either nitrenes or azide. Direct intra-
molecular nucleophilic displacement of halides can also lead to the preparation of silylaziridines,
but they are not as well investigated. A number of examples have been described in chapter 4.11
of COFGT (1995): therefore, this section will be focusing on some new syntheses of silylaziridines
and their application as versatile synthetic intermediates.
Since 1999 a few reports have been published highlighting the preparation of silylaziridines
from N-sulfonylaldimines using trimethylsilyldiazomethane (TMSD). Both Jørgensen and
co-workers <1999JCS(P1)2293>, and independently, Shioiri and co-workers <2000TL9455>,
have demonstrated that TMSD is a versatile reagent for the aziridination of -imino esters and
aryl-N-sulfonylaldimines (Equation (10)). Good yields of silylaziridines with high cis selectivity
were afforded. Jørgensen and co-workers also carried out the reaction asymmetrically using a
chiral Lewis acid complex and moderate enantioselectivity was obtained (Equation (11)). In
2002, Aggarwal and co-workers <2002JOC2335> expanded this methodology to a range of
N-sulfonylimines derived from aromatic, heteroaromatic, aliphatic, and unsaturated aldehydes.
In most cases average-to-good yields of products were obtained and high diastereoselectivity
for cis product was also observed. In contrast, they found that an -imino -ester gave predomi-
nantly the trans product in high yield and they proposed an alternative mechanism involving
intermediate 48, which was broken down to the desired silylaziridine 49 upon treatment with silica
gel (Scheme 12).
ArSO2
ArSO2 H Me3SiCHN2
N
N
Toluene, reflux
R2 Me3Si R2 ð10Þ
60–88%
Ar = 2,4,6-Me3C6H2
R2 = aryl
ArSO2 L=
ArSO2 H Me3SiCHN2
N PTol2
N ð11Þ
L-CuClO4 (10 mol.%) Me3Si CO2Et PTol2
CO2Et
–78 °C, 55%,
72% ee
19/1 cis/trans
SiMe3 ArSO2
Ts SiMe3 Ts
N THF dry SiO2
+ N N
N
EtO2C H N2 –78 to 0 °C N
PhH, rt, 91%
EtO2C EtO2C SiMe3
H
48 49
89/11 trans/cis
Scheme 12
Taylor and co-workers also reported a related reaction, but instead of TMSD, they used the
carbanion 50 derived from chloromethyltrimethylsilane and s-BuLi to carry out a Darzens-like
reaction to afford the silylaziridine 51 (Scheme 13) <2000JCS(P1)1173>. In the same paper they
explored other preparations of silylaziridines from vinyl silanes. They found that the addition of
bromoazide to vinyl silanes followed by the reduction of the azide with a reducing agent (such as
LiAlH4 or PPh3) gave average-to-good yields of silylaziridines 52 via intermediate 53 (Scheme 14).
This could also be achieved by using an organoazide reagent instead of bromoazide. Atkinson
and co-workers have also investigated the use of vinyl silanes as precursors to silylaziridines. They
devised a diastereoselective aziridination reaction using enantiopure 3-acetoxyaminoquinazoli-
none derivative 54 to obtain an 11:1 ratio of diastereoisomers of aziridines 55 (Scheme 15)
<1996TL5179>.
–
Ph NPh Ph
N N
+ Me3Si Cl Cl
Pri
Pri H Pri SiMe3
SiMe3
50 51
Scheme 13
R1 Br
LiAlH4
BrN3 or PPh3
N3 SiMe3
R2
R1
N
SiMe3 R1 SiMe3
N R2
R2N3 N N –N
2
52a R2 = H, Ph
52b R2 = CH2SiMe3
R1 SiMe3
53a R2 = H, Ph
53b R2 = CH2SiMe3
Scheme 14
Q* H
N Ph (Me3Si)2NH CsF, KCN
+ N N
Me Ph H Ph H
O N SiMe3 dr 11/1 DMF, 76%
H SiMe3 H CN
NH OSiMe2But
AcO
54 ( = Q*NHOAc) 55
Scheme 15
Silylaziridines can undergo a variety of reactions and it is beyond the scope of this review to go
into details. For example, they readily ring open when treated with nucleophiles under strongly
acid conditions (Equation (12)) <2000JCS(P1)439>. The same publication also showed that
silylaziridines are good intermediates for the synthesis of other aziridine derivatives. Silylaziridines
undergo desilylation when treated with fluoride ion and the aziridine anion 56 can be trapped
with electrophiles such as aldehydes (Scheme 16) <2000JCS(P1)439>. Alternatively if the nitro-
gen atom of the silylaziridine bears a potential leaving group 55, elimination of the silyl group to
give the azirine intermediate followed by the addition of the cyanide ion is observed in the
presence of CsF and KCN (Scheme 15) <1997JCS(P1)897>.
Pr n Pr n
N HX H2N SiMe3
H H H X–
Ph SiMe3 H ð12Þ
Ph X
X = Cl, Br, I, CF3CO2
Ph Ph Ph
F– RCHO
N N N
CO2Me CO2Me CO2Me
SiMe3 –
OH
R
56 R = n-Bu, Ph
Scheme 16
4.11.1.1.4 Trimethylsilylmethyl azide and a-silyl azides

Trimethylsilylmethyl azide (TMS-MA, b.p. 58–61 C/80 mmHg) is a relatively stable alternative
synthon for reactions, which formally require the shock-sensitive methyl azide. TMS-MA is
reportedly stable in refluxing toluene and is stable at refrigerator temperatures for at least six
months. Both Tsuge and co-workers <1983CL1131> and Nishiyama and Tanaka
<1983CC1322> independently reported its synthesis (Equation (13)). Other applications of
TMS-MA include its use in the preparation of trimethylsilylmethylisocyanate and isothiocyanate
(see Sections 4.11.1.1.5) and as a 1,3-dipolarophile to generate triazolines 52b, which readily give
silylaziridines 53b (Scheme 14) <1984H1955>.
NaN3, DMF
Me3Si Cl Me3Si N3 ð13Þ
80 °C, 97%
The most common synthesis of -silyl azides is by nucleophilic addition to silyloxiranes to

afford -hydroxy--silyl azides <1986CL1193>. The silyl group exerts a powerful directing effect
such that the nucleophilic attack occurs exclusively at the carbon bearing the silicon, resulting
in regioselective ring opening of the silyloxiranes. Chakraborty and Reddy <1990TL1335,
1991TL679> demonstrated that the normal preference for C-3 ring opening of 2,3-epoxy alcohols
by nucleophiles is reversed when a silyl group is attached to C-2. Bassindale and co-workers made
use of this chemistry to prepare a selection of alkyl -hydroxy--silyl azides 57 with good-
to-excellent yields (Scheme 17) <1996TL(37)555>. They were then reduced to the corresponding
silylamino alcohols with no loss of ee compared to that of the initial -silyloxiranes 59. In their
related study of the regioselective ring opening of ,-epoxy-,-vinyl silanes, Malacria and
co-workers <2002SL553> also found azide ion attack solely on the carbon bearing silicon giving
a single regioisomer and diastereomer 61 (Equation (14)).
O NaN3 HO SiMe3 LiAlH4 HO SiMe3

SiMe3
R NH4Cl R N3 Et2O R NH2
MeOH/H2O 20% NaOH aq.
59 Reflux 57 85–90% 58
Scheme 17
O NaN3 HO SiMe3
SiMe3
R NH4Cl N3 ð14Þ
MeOH/H2O R
60 Reflux 61
Furstner and co-workers reported a useful synthesis of enamides from vinyl silanes via the
corresponding -silyl azides <2001OL3955>. The conversion of (E)-alkenylsilanes 62 into
(E)-enamides 63 is outlined in Scheme 18. The regio- and stereospecific epoxysilane ring opening
with azide ion was followed by reduction and Peterson elimination. All products were obtained as
a single diastereomer, and the configuration of the starting material was transferred to the final
product with high integrity. This sequence of reactions to afford enamide from vinyl silane has
also been reported by Chakraborty and Laxman <2002TL2645> in their total synthesis of
(+)-crocacin D.
O O
OH
O NaN3, NH4Cl
SiMe3 SiMe3 N3
Ph Ph Ph
Acetone/CH 2Cl2 MeOH/H2O
89% SiMe3
68%
62
LiAlH4, Et2O
93%
OH
H i. RCOCl, THF, NEt3
N R2 NH2
Ph Ph
ii. KOBut, –35 °C to rt
O SiMe3
56–79%
63
Scheme 18
4.11.1.1.5 Trimethylsilylmethylisocyanide, -isocyanate, and -isothiocyanate

The title compounds have received considerable attention as small molecule synthons for a range
of imine derivatives and heterocycles. Numerous syntheses of trimethylsilylmethylisocyanide 64
have been reported. Smith and Livinghouse published a practical account of its synthesis by
lithiation of methylisocyanide followed by silylation with TMSCl (Equation (15)) <1984SC639>.
An alternative preparation involved the silylmethylation of formamide via its sodium salt and
gave the formamido silane 65, which was dehydrated under Ugi conditions to liberate trimethyl-
silylmethylisocyanide 64 (Scheme 19) <1986SC865>. The advantage of the latter method is that it
avoids the use of the toxic, volatile, and odorous MeNC.
i. BuLi, CH2(OMe)2, –95 °C

ii. TMSCl (2 equiv.)
Me NC
ð15Þ
TMS NC
85%
64
TMSCH2Cl POCl3, Pr2i NH

H2NCHO TMS NHCHO TMS NC
NaH, DMF, 120 °C 75%
73% 65 64
Scheme 19
If trimethylsilylmethylisocyanide 64 is heated with elemental sulfur in an inert solvent, the

trimethylsilylmethylisothiocyanate 66 is produced (Equation (16)) <1982BCJ1163>. A more
accessible route to the isothiocyanate 66 involves direct lithiation of methylisothiocyanate and
trapping of the anion with TMSCl (Equation (17)) <1997S423>. This method could be applied to
the synthesis of bis- and tris(trimethylsilyl)methylisothiocyanates by increasing the equivalents of
LDA and TMSCl used. An improved synthesis of isothiocyanate 66, which uses CS2 as the sulfur
source is reported to give reproducibly better yields and is readily adapted to afford trimethyl-
silylmethylisocyanate 67 by using CO2 (Scheme 20) <1984JOC2688, 1985H2489>.
S, PhH, reflux S
C
TMS NC TMS N ð16Þ
76%
64 66
S
S LDA, TMSCl C
Me C TMS N ð17Þ
N THF, Et2O, hexane, –95 °C
50% 66
S CS2, Ph3P CO2, Ph3P O

C C
TMS N TMS NC TMS N
THF, 94% THF, 68%
66 64 67
Scheme 20
Trimethylsilylmethylisothiocyanates are versatile intermediates for building small heterocycles.

Nishiyama and co-workers <1997H1405, 1997H1913> published a three-step synthesis of oxazo-
lines 68a–68c starting from silylisothiocyanate 66. The silylisothiocyanate 66 serves as a precursor
for the generation of an aminonitrile ylide functional group equivalents (such as isothioureas 69a,
dithiocarbonates 69b, or iminothiocarbonates 69c). They are prepared by the addition of amines,
thiols, or alcohols, respectively, to a silylisothiocyanate. All the above aminonitrile ylide equiva-
lents readily undergo 1,3-dipolar cycloadditions with aldehydes to give the corresponding oxazo-
lines 68 (Scheme 21) <1997H1405, 1997H1913>. A similar reaction was reported by Tsuge and
co-workers <2001H249> where the same aminonitrile ylide equivalents were treated with alkenes
as the 1,3-dipolarophiles to give pyrrolines.
O
i. R1R2NH, R3SH, R6
SMe
S R5 R6 R5 O
C or R4OH C
TMS N TMS N X
ii. MeI, reflux F–, 60 °C N X
66 69a X = R1R2N 68a X = R1R2N
69b X = R3S 68b X = R3S
69c X = R4O 68c X = R4O
Scheme 21
The synthesis and reactivity of other N-silylmethylheterocumulenes were published by Seconi and
co-workers <1995JOC6032>. They prepared the intermediate 70 from bis(trimethylsilyl)methyl azide
71 and Ph3P. This intermediate was transformed into isocyanate 72a, isothiocyanate 72b, carbodi-
imides 72c, or ketene imines 72d by the addition of a range of reagents (Scheme 22). The reactivity of
these N-silylmethylheterocumulenes and their use in synthesis were also investigated in the paper.
CO2 (for 72a)

Ph3P BSM CS2 (for 72b) BSM
BSM N3
N PPh3 N C X
PhNCO (for 72c)
PhCH=C=O (for 72d) 72a X = O (81%)
71 70
72b X = S (83%)
BSM = bis(trimethylsilyl)methyl 72c X = NPh (82%)
72d X = CHPh (71%)
Scheme 22
4.11.1.1.6 a-Iminosilanes and related compounds

Silylmethylimines are readily prepared from -aminosilanes and carbonyl compounds, particu-
larly trimethylsilylmethylamine. Bonini and co-workers <1997SL1321> investigated the regio-
selective addition of organocuprates to 1-aza-1,3-dienes 73, which were synthesized by the
condensation of ,-unsaturated aldehyde 74 with trimethylsilylmethylamine or bis(trimethyl-

silyl)methylamine. The treatment of the 1-aza-1,3-dienes 73 with a range of organocuprates gave
satisfactory-to-good yields of highly selective 1,4-addition products (75a–75c) apart from one
exception. It was surprising to find that heteroaromatic ligands gave predominantly 1,2-products
76 over 1,4-addition products (Scheme 23).
O + H2N SiMe3 4 Å mol. sieves N SiMe3

H PhH, rt H
74 73
i. RM*BF3, –78 °C to rt
ii. NaOH 1 M
H
N SiMe3 + N SiMe3
R R H
76 RM = (Thienyl)2Cu(CN)Li (40%) 75a RM = Bu2Cu(CN)Li (85%)
75b RM = Ph2CuLi (60%)
75c RM = (PhMe2Si)2CuLi (45%)
Scheme 23
Vedejs and Martinez first disclosed the potential of N-(trimethylsilylmethyl)iminium salts such
as 77 for the generation of azomethine ylides and subsequently a range of nitrogen heterocycles
(Scheme 24) <1979JA6452, 1980JA7993>. Since then, the desilylation of -iminosilanes has
become the most frequently used means of producing azomethine ylides, prompting considerable
interest in efficient routes to the iminosilane precursors. The communication from Fishwick and
Foster clearly demonstrated this methodology as a mean to synthesize a number of spiro-fused
pyrrolidines <1996TL5163>. The -silyliminium salts 79 are prepared by standard synthetic
methods, and the introduction of fluoride ions leads to the generation of 1,3 dipole intermediate
80. In the presence of alkenes, alkynes, or other dipolarophiles, dipoles 80 undergo highly
regioselective cycloaddition to afford novel spirocycles 81 in good-to-excellent yields (Scheme
25). A similar method has been used by Pearson and Mi <1997TL5441> to synthesize a collection
of indolizidines and pyrrolizidines.
+ MeO2C CO2Me
TMSOTf Ph N TMS DMAD, CsF
Ph NMe Me
Diglyme – Diglyme Ph N
TfO
Me
77 78
Scheme 24
Me
Me Me
TfO– CsF, MeCN 1,3-Dipolarophile N
N+ N+
– R2
X SiMe3 X X
R1
79 80 81
X = O, S, CH2
CO2Me O O
N
1,3-dipolarophile =
Me
MeO2C CO2Me
Scheme 25
Recently, Komatsu and co-workers <2003T197> applied this reaction to solid-phase synthesis
of pyrrolidines and pyrroles. Polymer-supported azomethine ylides were generated from
the corresponding -silylimines 82 either by treatment with a trifluorosilane, or by thermal
1,2-silatropy (Scheme 26). The resulting azomethine ylides were then reacted with dipolarophiles
and good yields of cyclization products 83 were afforded after cleavage from the resin. The
stereoselectivity of the reaction was dependent on the method used to generate the azomethine
ylide and substrate dependent, but when the corresponding reaction was carried out in solution
phase, higher selectivity was observed.
O H2N SiMe3 L
+
O R N SiMe3
R = H, Ph, p-F-C6H4, p-MeOC6H4 82 R
N-phenylmaleimide
F3SiPh, toluene
L
HO H H
N R N R
TFA, CH2Cl2
(61–81% overall)
O O O O
N N
Ph Ph
83
Scheme 26
Other related compounds such as -silylmethylamidines and thioimidates have been discussed
in detail in COFGT (1995) and will not be repeated here.
4.11.1.1.7 a-Diazosilanes
Silyl-substituted diazoalkanes and diazocarbonyl compounds 84 are important precursors for
silylcarbenes or -carbenoids. The most widely used application of these compounds is their ability
to undergo photochemical Wolff rearrangement to give the corresponding silylketenes 85
(Scheme 27). Silylketenes are stable to typical [2+2]-cycloaddition reactions and readily isolable
compounds unlike their nonsilylated counterparts, which makes them versatile synthetic
intermediates.
O O O
hν 1 R 13Si C
R31Si R3Si
R2 R2
R2
N2
84 85
Scheme 27
In 1985, Maas and Brückmann <1985JOC2801> reported the first synthesis of -silyldi-
azocarbonyl compounds from diazocarbonyl- and trialkylsilyl triflate in the presence of Hünig’s
base. This method is applicable to a range of diazocarbonyl derivatives <1999CC1199>, and it
not only tolerates alkyl or aryl groups on the silicon, but even a chloride. Maas and Bender
prepared -(chlorosilyl) diazoacetates 86 and showed that they can be converted into azidosilyl-
87a, isocyanatosilyl- 87b, or isothiocyanatosilyl- 87c substituted diazoacetates (Scheme 28)
<1999S1175>.
Other silyldiazocarbonyl derivatives have been prepared to give silylketenes with unique
properties. A number of silyl vinylketenes had been synthesized from 0 -silyl-0 -diazo-,-
unsaturated ketones 88 by Danheiser and co-workers <1998JOC8380>. They found that the
silyl vinylketenes 89 behave as the diene components in Diels–Alder reactions with electron-
deficient alkenes and alkynes rather than undergo [2+2]-cycloaddition reactions like other
vinylketenes (Scheme 29). In a separate paper, Danheiser and co-workers <2002OL2465>
Hünig’s base
R O Et2O, 0 °C R O
+ H Si
tBu Si
tBu
OTf OMe 76–90% OMe
Cl Cl
N2 N2
86
NaN3, KOCN,
or KSCN
MeCN, rt
R O
tBu Si
OMe
X
N2
87a X = N3 (64–95%)
87b X = NCO (58–91%)
87c X = NCS (43–72%)
Scheme 28
O Pr3i SiOTf, Hünig’s base, O

R1 N2 Et2O, hexane R1 N2
0 °C to rt Si(Pri)3
R2 75 – 89% R2
88
hν (300 nm)
PhH
OH
DMAD O
(Pri)3Si CO2Me (Pri)3Si C
Toluene, 150 °C
73–95% R1
R1 CO2Me
R 2 R2
89
Scheme 29
reported a [4+1]-annulation process between silyl arylketenes and TMSD to afford 2-indanone
derivatives 90 (Scheme 30). The silyl arylketenes 91 were synthesized using the same methodol-
ogy developed by Maas and Brückmann.
O
O hν (300 nm) TMSCHN2 Si(Pri)3
C
N2 PhH CH2Cl2–hexane
52–89% Si(Pri)3 then SiO2 O
Si(Pri)3
R 36–91% R
R
91 90
R = H, 2-Cl, 4-Br, 3-Me, 3-Pr i, 4-CO2Me
Scheme 30
In 1999, Arrowood and Kass <1999T6739> published a different synthetic use for silyldiazo-
carbonyl derivatives . They treated ethyl trimethylsilyldiazoacetate 92 with trimethylsilylacetylene
either under irradition or in the presence of rhodium(II) octanoate dimer catalyst to give
cyclopropane 93. This was followed by selective desilylation of the vinylsilyl group to afford the
target 3-carbomethoxy-3-(trimethylsilyl)cyclopropane 94 in an overall yield of 48% (Scheme 31).
Cyclopropane 94 was shown to be a stable and interesting compound that could be subjected to a
range of further functional group interconversions to afford other cyclopropane derivatives.
Me3Si CO2Et Me3Si CO2Et

Me3Si CO2Et Rh2(O2CC7H15)4 K2CO3
+ SiMe3
N2 65% SiMe3 EtOH, reflux
80%
92 93 94
Scheme 31
4.11.1.1.8 N-(Silylmethyl) heterocycles

Vedejs’ methodology for the generation of azomethine ylides from aminosilanes is readily
extended to allow access to ylides formed from -silyl heterocycles (Section 4.11.1.1.6). Alterna-
tively, silylmethylation of a wide range of heterocycles under basic conditions is an efficient and
popular process. The five-membered azoles and related heterocycles are readily alkylated with
trimethylsilylmethyl chloride under a variety of conditions (Equation (18)) and the details can be
found in chapter 4.11 of COFGT (1995).
NMe2 NMe2
BuLi, HMPA
Me3Si Cl ð18Þ
N 76% N
H SiMe3
Although N-alkylation is usually dominant, varying amounts of C-alkylation can also be

observed depending on the substrates and reaction conditions. Katritzky and co-workers have
been investigating the use of benzotriazole (Bt) as a synthetic auxiliary, and they found that it
could be applied to a novel synthesis of highly branched and sterically hindered N-silylalkylated
carbazoles and indoles <1995OM734>. The N-(benzotriazole-1-ylmethyl)carbazole 95a and -indole
95b derivatives are readily synthesized from alkylation of carbazole or indole with BtCH2Cl.
Deprotonation of 95 followed by silylation with a selection of alkyl- and/or arylsilyl chlorides
afforded the corresponding intermediates 96. When they were treated with an excess of Grignard
reagents in toluene under reflux good-to-excellent yields of desired N-silylmethylcarbazole and
indole derivatives 97 were achieved (Scheme 32).
n-BuLi, THF
–78 °C then SiR1R2R3 R4MgBr SiR1R2R3
Ar Bt
R1R2R3SiCl Ar Bt Toluene Ar R4
75–94%
96 97
95a Ar = indol-1-yl
1,
95b Ar = carbazol-9-yl R R2, R3 = Me, iPr, iBu, tBu, Ph
Scheme 32
The silylmethylation of pyridine and substituted pyridines is also possible by alkylation with
TMSCH2OTf, affording the pyridinium salts 98 (Scheme 33). The triflate salts can be desily-
lated with fluoride ions generating an azomethine ylide species which in turn can be intercepted by
DMAD and other dipolarophiles <1984CL279, 1984H701>.
R CO2Me
R
Me3SiOTf DMAD, CsF
+ R CO2Me
CH2Cl2 N 36–82% N
N TfO–
83–99%
SiMe3
98
Scheme 33
4.11.1.2 Nitrogen and Germanium Functions

Synthetic routes to -aminogermanes closely parallel those already described for the correspond-
ing silanes. This parallel stretches across almost all of the established synthetic organogermanium
chemistry and is discussed in depth in a useful review of that subject <1982COMC-I(2)365>.
Alkylation of amines by germylmethyl halides is by far the most frequently encountered

preparative route. An early example is the synthesis of the germylmethylamine 99 (Scheme 34).
Interestingly, the chlorogermane 99, which cannot be obtained by reaction with a single equiva-
lent of lithium amide, is accessible by the treatment of 100 with TMSCl <1977JOM(132)77>.
Terunuma and co-workers have prepared a series of germylmethylamines (Scheme 35) and
demonstrated their base-catalyzed fragmentation to trialkylgermanes. This is contrary to the
reactivity pattern of silylmethylamines, which undergo a Brook rearrangement under the same
conditions <1991CL97>. The reaction of germylmethyl halides with potassium cyanate and
ammonia affords -germylureas 101, which have been used to prepare germyldiazomethanes
102 (Scheme 36). The transiently produced isocyanates are not isolated <1985TL5547,
1986CPB3273>.
Cl LiNMe2 NMe2 TMSCl Cl

Cl Ge Me2N Ge Me2N Ge
Hexane, 60 °C 94%
82% 100 99
Scheme 34
i. BuLi
BnNH2 ii. H2O
R3Ge Cl R3Ge NHBn Bu NHBn + R3GeH
~80% 63–91%
Scheme 35
i. NaNO2, H2SO4
KOCN, NH3 ii. KOH
RMe2Ge Cl RMe2Ge NHCONH2 RMe2Ge N2
DMF 20–30% overall
R = Me, Ph 101 102
Scheme 36
Silylated amides 103 will also react readily with chloromethylgermanes, typically under neutral
conditions, in a nonpolar solvent (Scheme 37). This chemistry and a subsequent radical-
mediated, intramolecular hydrogermylation have been used to prepare the azagermine 104
<1988JOM(346)1>. A benzo-fused version of 104 is accessible by similar chemistry
<1988JOM(339)259>. Other germanium-containing heterocycles such as 105 and 106 have also
been synthesized by cycloaddition reactions <1995ZN(B)289, 1997CC1553>.
Cl Cl
TMS Cl Ge i. LAH, Et2O
Ge ii. AIBN
MeCON Ge
MeCON
PhH, reflux PhH, reflux EtN
57% 50%
103 104
Ph
N R1
F3C R1 = mesityl
N CMe R2 R2 = 2,4,6-tris[bis(trimethylsilyl)methyl]phenyl
Ge 3 Ge N
F3C R3 R3 = 2,4,6-triisopropylphenyl
Cl Cl O
105 106
Scheme 37
Germanium hydrides will add to aldimines in a nonregioselective manner to generate a mixture

of germylmethylamines 107 and aminogermanes 108 (Equation (19)). The selectivity is reagent
and substrate sensitive. The authors ascribe the product distribution to the operation of two
competing (radical and ionic) mechanisms although the ionic mechanism, favoring formation of a
CGe bond, generally predominates <1979JOM(168)43>. A similar addition to nitrones and
related compounds has also been demonstrated <1972JOM(34)C18>. Germanium hydrides will
also undergo hydrogermylation with 2- and 2,3-substituted 1-vinylpyrroles 109 including 1-vinyl-
4,5,6,7-tetrahydro-indole in the presence of H2PtCl6 to give a mixture of - 110 and/or - 111
germano substituted adducts (Equation (20)) <1996ZOB(66)86>.
GeClPh2 H
Ph2ClGeH
Ph NR Ph NHR Ph NR
80 °C ð19Þ
GeClPh2
107 (25%) 108 (21%)
Et3GeH,
H2PtCl4
R1 N R1 N R1 N
GeEt3
40–80% R2 ð20Þ
R2 GeEt3 R2
109 110 111
R1 = H, Me2CH, R2 = Ph; R1R2 = (CH2)4
Acylgermane hydrazones and oxime ethers undergo radical cyclizations to give good yields of
cyclic hydrazones and oximes <1998JOC4711>. The acylgermane derivatives 112 are accessible
via a copper-mediated coupling of acid chlorides and LiGePh3 followed by condensation with
N,N-dimethylhydrazine or o-benzylhydroxylamine (Scheme 38). Thus, under photolysis, !-halo-,
phenylseleno-, and vinylacylgermane hydrazones and oxime ethers cyclize to their respective cyclic
adducts 113.
O i. LiGePh3 OBn OBn

N N
ii. H2NOBn Photolysis
Cl GePh3
PhH, 95%
Br Br
112 113
Scheme 38
Lastly, and perhaps the most usefully, Sato and co-workers have established a flexible lithia-
tion-germylation reaction of aminoacetonitriles which uses readily available reagents to prepare a
host of -aminogermanes 114 (Scheme 39). The intermediate germylnitriles 115 can be isolated
and purified. Both alkyl and aryl substituents are tolerated although the yields of the Grignard
addition vary dramatically with substitution. The Grignard reaction also generates variable
amounts of the by-products 116 and 117 <1991S169>. Analogous chemistry is reported in the
preparation of an organogermylbis(pyrazol-1-yl)methane ligand 118 from bis(pyrazol-1-yl)-
methyllithium 119 with Ph3GeBr (Scheme 40). Treatment of this ligand 118 with W(CO)5(THF)
in refluxing THF results in the heterobimetallic complex Ph3GeCHPz2W(CO)4 120 as the major
product <2002JOM(658)198>.
R1 R1
R1 LDA, Me3GeCl R3MgX, Et2O
N CN N R3
N CN R2 R2
R2 THF, –78 °C 19–82%
55–77% GeMe3 GeMe3
115 114
R1 R1 O
N GeMe3 N
R2 R2 R3
116 117
Scheme 39
Me Me Me Me Me Me
N N Ph3GeBr N N W(CO)5(THF) N N
Li Ph3Ge Ph3Ge W(CO)4
N N N N THF, reflux N N
Me Me Me Me Me Me
119 118 120
Scheme 40
4.11.1.3 Nitrogen and Boron Functions

The research into the chemistry of aminomethylboron compounds has traditionally been limited,
primarily due to the reactivity of -aminoboranes, which are frequently air or moisture sensitive and
readily undergo -transfer rearrangements. However, a growing awareness of the value in medicinal
chemistry of -aminoboronic acids as serine protease inhibitors has prompted a steadily increasing
output of synthetic work in this area since the first disclosure of significant biological relevance in 1977.
4.11.1.3.1 a-Aminoboranes and borohydrides

-Aminoboranes have generally been synthesized by reactions between a nitrogen ylide and a trialkyl- or
triarylborane. Muster and Stevens <1967TL995> first described the reaction of an unstabilized N-ylide
with boranes (Scheme 41). The presumed initial zwitterionic borohydride intermediate 121 rapidly
underwent -transfer reactions to a new borane 122 with loss of the amine substituent. The overall
process amounted to methylene insertion by the ylide. Bickelhaupt and Barnick <1968RTC188>
subsequently isolated the relatively stable adduct 123 (Scheme 42) and demonstrated its conversion
into the boronic acid 124 as part of a chemical proof of the structure of intermediate 123.
+ – BR23 + – 2 –R13N – 2
R 13N CH2 R13N BR3 R22 BR2
121 122
Scheme 41
+ – BPh3 + – 2 AcOH, HCl +

R13N CH2 R13N BR 3 R13N B(OH)2 Cl–
THF 96%
78% 123 124
Scheme 42
Stable imidazol-2-ylidene carbenes are related to nitrogen ylides and they too react with a
trialkyl- or triarylborane to give a zwitterionic adduct. Seibert and co-workers <1998EJI843,
1999EJI789> have reported the synthesis and rearrangement of 125 when treated with n-BuLi to
give the lithium salt 126 (Scheme 43). Vagedes and co-workers reported an alternative synthesis to
the related arylborane derivatives 127 (Scheme 44) since they demonstrated that when the
arylborane derivative 128 was deprotonated with MeLi, instead of rearrangement as reported
by Seibert, aryl substitution took place to give 129 <2002EJI2015>. Both compounds 127 and
129 were characterized by X-ray crystallography. This methodology has been used to prepare a
new class of bisimidazole–borate ligands 130 <2000JCS(D)1255>.
–
BEt3 BEt3 Li+
N N N –
H Li+ BEt3
N N N
125 126
Scheme 43
N n-BuLi N BAr3 N –
H – Li+ BAr3
N N (Ar = Ph, C6F5) N N
Li+
N
127 Me –
B M
B(C6F5)3 X
N
F5C6 C6F5
F N
B(C6F5)3 + B
N MeLi N – 130
F
H
N X = OPr i, Cl, Pz, Ph
N
F F
128 129
Scheme 44
Trialkylboranes will also react with isocyanides to generate dipolar adducts which are prone to thermal
dimerization processes. Phenylisocyanide and tributylborane react together to generate a zwitterion 131,
which quickly dimerizes to the isolated diboradihydropyrazine 132 (Scheme 45) <1965LA(687)1,
1972LA(755)67>. Thermolysis of the pyrazine 132 prompts a second BC migration, giving the
diborapiperazine 133. Tamm and co-workers isolated the thermally unstable monomeric iminoborane
adduct 134 at low temperature (20 C). It is converted into the ylidene 135 when treated with a catalytic
amount of KF in methanol (Scheme 46). The X-ray structure of 134 and 135 was reported. Dimerization
of 134 was also observed upon heating <1996OM1251>. The benzoxazol-2-ylidene 135 was also
synthesized via a different route by Lambert and co-workers <1996OM452> in the same year.
Bu2 Bu
Bu
Bu3B + – Ph B Bu 200 °C Ph B
N N Bu
Ph NC Ph N C BBu3 Bu
N+ 90% N
Bu B Ph B Ph
131 Bu
Bu2 Bu
132 133
Scheme 45
OTMS OTMS O
BPh3 MeOH –
+ BPh3
+
NC T < –20 °C N KF N
C – H
BPh3
134 135
Scheme 46
Despite the handling difficulties experienced with many borane derivatives, the ease with which
alkyl migration from boron to an adjacent carbon can occur has led to some useful synthetic
methodology. Pelter and co-workers have extensively characterized the utility of cyanoborate salts
as precursors for -migration chemistry. The salts 136 are readily prepared from trialkylboranes and
KCN in organic solvents and react with any of a range of acylating agents (usually AcCl, PhCOCl, or
trifluoroacetic anhydride (TFAA)) to generate the oxazaborolines 137 in which two alkyl groups have
transferred from boron to carbon (Scheme 47). Oxidative cleavage of the heterocycles 137 completes
an overall synthesis of symmetrical ketones in excellent yield <1975JCS(P1)129>. A feature of the
alkyl migration is the general insensitivity to steric congestion in the transition state, such that
secondary alkyl groups also migrate readily. Use of TFAA as the acylating reagent in diglyme can
induce the third and final B-alkyl substituent to migrate, giving the presumed intermediate boronate
derivative 138 (Scheme 48). Oxidative cleavage liberates tertiary carbinols, again in good yield, usually
associated with small amounts of ketone <1975JCS(P1)138>.
The chemistry of oxazaboroline such as 139 has also been investigated by Denniel and co-workers
<1995TL6875>. They reported the synthesis of oxazaborolines 139 and 140 by hydroboration of
acetamidoacrylate, deprotonation and N-acylation or N-alkylation of the resulting complex (Scheme
49). These boron complexes could in turn be converted to N- or C-substituted alaninate derivatives. When
140 was treated with a strong acid at room temperature, methylalaninate 141 was afforded in almost
R1 R1
R13B
(65–100% overall) O
KCN H2O2
Et2O NaOH
R1 R1 R1
– R2COX – + O R1
R13B CN R1
R13B C N B N B N
R2 R1 O
K+
X– O R2 R2
136 137
Scheme 47
R R R R
R TFAA R H2O2 R
B N TFA O B NCOCF3 R OH
O Diglyme O NaOH R
CF3 CF3 80–90%
138
Scheme 48
quantitative yields, while refluxing in toluene with one molar equivalent of pyridine, the betaine 140
rearranges and 142 was generated after hydrolysis (Scheme 49). It is interesting to find that, unlike most
oxydialkylorganoborates, no BO migration of the cyclohexyl group was observed <1975JCS(P1)129>.
MeO2C MeO2C Me MeO2C Me Me E

i. R2BH – E+ – + i. TFA
NH R2B N K+ R2B N E N
ii. ButOK O rt ii. H2O MeO2C Me
O
O Me Me O
Me
139 140 141
R = cyclohexyl i. 110 °C
E = H, Me, COMe, COPh ii. H2O
E Me
NH
MeO2C Me
O
142
Scheme 49
The chemistry of low-molecular weight -aminoboranes is made more challenging by their

extreme volatility. Nevertheless, some synthetic details are available. Chloromethyldimethylbor-
ane undergoes straightforward SN2 displacement with nucleophlies including lithium azide, which
generates the gaseous azidomethyl species (Scheme 50). Hydrogenation of the azide over platinum
gave aminomethyldimethylborane 143, which is essentially monomeric <1965JA488>. Miller and
co-workers <1983OM1529> have synthesized the isomeric -aminoborane 144 as its trimethyla-
mine complex by the reaction of the cationic borane 145 with t-butyllithium (Equation (21)). It is
characterized as a nonvolatile liquid that behaves as a nucleophile and strong base <1964IC1196,
1969IC275>. Related chemistry has been extensively surveyed by Miller and co-workers, which
has been covered in chapter 4.11 of COFGT (1995).
LiN3 H2, Pt
Cl BMe2 N3 BMe2 H2N BMe2
–196 to 0 °C 50%
80% 143
Scheme 50
+ – ButLi – +
(Me3N)2BH2 Cl– Me2N BH2NMe3 ð21Þ
Hexane
145 50% 144
This methodology has recently been extended to the preparation of an N-chelated rhodium(I)
(dialkylamino)borate complex 146 <2002IC6541>. The ligand 147 was synthesized according to
Scheme 51, and interestingly it was found that clean deprotection of 148 only took place in the
presence of a large excess of DABCO. The lithium salt 147 underwent facile transmetallation with
{(NBD)RhCl2} to afford the rhodium complex 146 as a yellow crystal. The reactivity of the
[Ph2B(CH2NMe2)2]Rh(I) fragment has been explored by exchanging the NBD ligand for other
ligands such as CO, PR3, and CH3CN.
Me2
N
BunLi BH3 i. 1/2 Ph2BCl BH3
H3B NMe3 Me2N Ph2B
CH2Li (THF) ii. TMEDA BH3
THF N
Me2
Li+(TMEDA)2
148
xs DABCO
Toluene
100 °C, 10 h
Me2
N 1/2 {(NBD)RhCl}2 – NMe2
Ph2B Rh Ph2B Li+
N NMe2
Me2
146 147
(NBD = norbornadiene)
Scheme 51
The hydroboration of unsubstituted enamines generally gives -boron addition but Singaram
and co-workers have demonstrated that ,-disubstituted enamines can give good yields of
-boron addition products 149 (Scheme 52) <1991JOC5691>. In the absence of an oxidative
work-up, the aminoborane intermediate 149 reacts further with borane to give decomposition
products containing BN bonds (150a and 150b). Wipke and co-workers have used organic
reaction prediction software (IGOR2) to compare computational and experimental observations
of the outcome of enamine hydroboration and have achieved a good agreement <1993JA440>.
Boronates can also be obtained by this methodology, using an aqueous work-up protocol.
O H BH2
O BH3*SMe2 BH3*SMe2
N B N
Pr N +
N Pr
Pr O
BH2 O
149 150a 150b
Scheme 52
(Dimethylamino)bis(trifluoromethyl)borane 151 possesses unique properties in aminoborane

chemistry, and it provides a synthetic route to some novel -boroamino compounds. Brauer
and co-workers <1996JOM(524)225> reported the formation of zwitterion 152 by treating
borane 151 with aryl Grignard reagents. They hypothesize the rearrangement mechanism as
shown in Scheme 53. In a separate publication, they found a simple entry to the azonia-
boratacyclopropane 153 from borane 151 and diazomethane derivatives. The three-membered
heterocycle intermediate 153 undergoes hydrolysis to form 154, while nitriles and carbonyl
compounds insert into the BN bond to give five-membered heterocycles 155 and 156, respec-
tively (Scheme 54) <1999EJI255>. Investigation of the influence of the diazomethane substituents
on reactivity and stability of the intermediate 153 was described.
MgBr
F
+ – –
– B N
F3C B N
MgBr+ F3C B N
F 3C F3C F
F3C
– B N+ F F
F 3C 152
151
Scheme 53
R
OH
Me2N B 154
H2O F3C CF3
R R
F3C RCHN2 CF3
MeCN
– B N+ CF3 N B CF 155
N B 3
F3C –N2 N
CF3 O
151 153 R
CF3
N B CF 156
3
O
Scheme 54
4.11.1.3.2 a-Aminoboronic acids

Although several examples of aminomethylboronate syntheses were described up to 1977, the
appearance of a landmark publication in that year documenting a boronate amino acid isostere as
a useful inhibitor of the serine protease chymotrypsin <1977JA6435> triggered a surge in
synthetic and medicinal interest which is ongoing. Aspects of aminomethylboronic acid chemistry
including methods for their synthesis have appeared as subsections in three general reviews of
boronic acids and boronates by Matteson <1989CRV1535, 1989T1859, 1991PAC339>.
Matteson and Cheng <1966JOM(6)100> reported the first general synthetic method (Scheme 55)
relying on the generation of an -iodoboronate 157 and subsequent displacement by a secondary
amine. This preparative method failed when ammonia or primary amines were used <1978JA1325,
1979JOM(170)259>, but it can be overcome in the case of primary aromatic amines by using N-
silyl-N-lithioamines (Scheme 56). Metallation and silylation of hindered arylamines such as 158
followed by remetallation gives a nucleophilic species that reacts cleanly with pinacol iodometha-
neboronate to give a stable aminomethyl derivative 159 that can readily be distilled and directly
acylated without the need to desilylate <1986JOC1610>.
i. I HgI, HN
NaI
BBr3 (BuO)2B I (HO)2B N
ii. BuOH
157
Scheme 55
Much of the research in this area is concentrated on the synthesis of novel -aminoboronic
acids as amino acid isosteres. These -aminoboronic acids can be incorporated into peptides to
give possible serine protease inhibition properties. Almost all of these exploitations of amino-
methylboronates have relied upon essentially the same strategy for assembly of the NCB
functionality, specifically, the homologation, amination sequence pioneered by Matteson and
co-workers.
NH2
i. BunLi, TMSCl O RCOCl O
Et Et
B B O
ii. BunLi, O N TMS O N
Ar Ar R
O
158 159
B R = CH2Cl, 64%; CH2Br, 66%;
O I CHCl2, 83%
Scheme 56
This methodology was demonstrated by Mantri and co-workers <1996JOC5690> in their

synthesis of -aminoboronic acids. They treated dichloromethylboronates 160 with Grignard
reagents to give an intermediate ate complex that efficiently rearranges to the -chloroboronate
161 (Scheme 57). Substitution reactions of -chloroboronates 162 with primary amines have been
shown to be sluggish by early research; therefore, lithium hexamethyldisilazide (LHMDS) is used to
introduce the amino function after acidic work-up to give the desired -aminoboronic ester 163
<1981JA5241, 1984OM614>. Direct acylation of the HMDS intermediate is also possible.
O MgBr
Cl O Cy O Cl O Cy (+)-Pinanediol Cl O
B B B
Cl O ZnCl2, THF O 64% (2 steps) O
Cy –78 °C, Cy
O O
160 O 161 O 162
>99% de i. LiN(SiMe3)2
ii. HCl (3 equiv.)
100%
Ac-(D)-Phe-Pro NH O Ac-(D)-Phe-Pro-OH Cl– H3N O

B B
O NMM, i-BuOCOCl, Et3N O
O 80% O
O O
163
(NMM = N-methylmorpholine)
Scheme 57
The above approach is widely used in the preparation of -aminoboronic acids, but it depends
greatly on the availability of the side chain as Grignard or organolithium reagents. A modified
approach was reported by Kettner and co-workers where the -side chain substituent is derived
from the reaction of an electrophile with the stabilized PhSCH2BO2–pinacol methide anion to
give 164 and the amino group is installed afterwards using the typical route <2001JOC6375>.
The overall synthesis is shown in Scheme 58 and three different side chains have been prepared
using this methodology.
Cl O PhSH PhS O i. LDA PhS O

B B F B
O Hünig’s base O ii. BrCH2CHF2 O
56% F
164
MeI, NaI
49%
+
Cl– H3N O i. LiN(SiMe3)2 I O
F B F B
O ii. HCl O
F 52% F
Scheme 58
The choice of boronate ester is diverse, both achiral, cyclic boronates derived from ethylene glycol or
pinacol have been used as well as the esters of (+)- or ()-pinanediol, which give up to 99% ee in the
equivalent diastereoselective chloroboronate synthesis <1983OM1536, 1984OM1284>. More recently,
Wilson and co-workers reported a solid supported synthesis of peptide boronic acids, which made use
of a pinacol-like diol linker to resin <2000BMCL1577>. The diol 165 was synthesized by a three-step
sequence, and it was treated with boronate ester 166 to give -chloroboronate 167. Using the
methodology described previously, -aminoboronic ester 168 was generated (Scheme 59). It was
then attached to resin followed by conventional high throughput peptide synthesis to give novel
-aminoboronic acid incorporated peptides after acidic cleavage from the polymer support.
Cl OPri HO i. THF, 100% Et O

B B
OPri HO ii. EtMgBr, THF O
Cl CO2But Cl CO2But
166 165 167
i. LiN(SiMe3)2,
–78 °C to rt
ii. CF3CO2H, Et2O
i. Fmoc-Leu-OH, NMM
i-BuOCOCl, CH2Cl2
Et O 36% over 4 steps Et O
B H B
O N ii. CF3CO2H, CH2Cl2 O
HN H2N CO2But
Fmoc-Leu iii. MBHA resin, HBTU CF3CO2H
O Hünig’s base, DMF
168
(NMM = N-methyl morpholine
MBHA = 4-methylbenzhydrylamine)
Scheme 59
Since the initial disclosure of aminomethylboronates as chymotrypsin inhibitors, many disclo-

sures of increasingly more complex structures designed to inhibit key serine proteases (including
elastase, thrombin and cathepsin G) have appeared. An overview of these inhibitors has been
covered in book by Powers <B-1986MI411-01> and a brief summary of them can be found in
chapter 4.11 of COFGT (1995).
4.11.2 FUNCTIONS CONTAINING A NITROGEN AND A METAL: R12C(NR22)MLn

(M = Li, K, Mg, Sn, Zn), etc.
This section reviews the synthesis of -metallated nitrogen compounds, focusing on those in
which the nitrogen atom is a component of an amine, imine, or equivalent species. The synthesis
of metallated nitroalkanes (nitronates) is beyond the scope of this article to review in depth, but
general methods are briefly surveyed, with emphasis on other comprehensive reviews.
4.11.2.1 a-Metallated Amine Functions

A thorough and well-organized review of nitrogen-stabilized carbanions by Gawley and Rein
appeared in 1991 which underscores the need for additional carbanion-stabilizing groups to
ensure the stability and utility of many -lithiated amines, exemplifying this with amidines in
particular <1991COS(3)65>. This review will aim to give an update on currently available
methods for synthesis of unstabilized -amino anions and their masked, stabilized equivalents.
Some further specific examples and discussions on the nature of the CM bond will be found in
two general reviews of carbanion chemistry <1980T2531, 1987MI411-01>.
The literature contains a vast array of -metallated amines in which the metal is either tin or,
particularly, lithium. Potassium, magnesium, and zinc have all found occasional utility. The
remaining metals that occur with regularity in most aspects of organic chemistry are very poorly
represented in this area, despite the apparently obvious potential for transmetallation from
accessible organolithium species.
4.11.2.1.1 Lithium, potassium, and magnesium

A comprehensive review on lithiation adjacent to a nitrogen can be found in Clayden’s book on
organolithium compounds <B-2002MI411-01>. He concentrates mainly on the chemistry of
‘‘dipole stabilized’’ -lithiation and their use in synthesis. This section will cover a broader
range of the preparation of -lithiated amine functional groups.
(i) Unstabilized carbanion equivalents

Alkali metallation of unstabilized tertiary amines has been achieved using strong bases and
generally proceeds in a nonspecific manner, producing the most thermodynamically stable anion.
One of the most efficient examples, by Ahlbrecht, is the metallation of N-methylpiperidine by the
Lochmann–Schlosser base (s-BuLi/t-BuOK) as shown in Scheme 60 <1984TL1353>. The reaction
is successful for most N-methyl tertiary amines. The lithium analogs are known, but direct
deprotonation often required an extra amino group in the molecule. The -lithio amines such as
169 <1987CB2081>, 170 <1990RTC305>, and 23 <1997CB1777> are formed by treating the
respective amine with BuLi. This is presumably due to intramolecular chelation of the metal.
BusLi, ButOK PhCHO, –78 °C
N 0 °C N 73% N
Me OH
K
Ph
Li R R
N N
Me2N N Me2N N NMe
Me Me Li Li Li
169 170 23
Scheme 60
In the case of amines without extra coordinating groups present, the lithiated species can be
prepared by transmetallation. Peterson established one of the earliest site-specific protocols
(Scheme 61), which relies on prior synthesis of the -aminostannane and transmetallation by
BuLi <1971JA4027>. Tsunoda and co-workers described an alternative methodology which
requires a thioaminal precursor <1991TL1975>. In 2000, Gawley and co-workers reported an
investigation on the stereoselectivity of SE2 reactions of unstablilized -aminoorganolithiums
<2000JA3344>. 2-Lithiopyrrolidines and -piperidines 171 generated from transmetallation of
the respective aminostannane derivatives were quenched with a selection of electrophiles, and
they found there is evidence for both polar and SET mechanisms depending on the nature of the
electrophile. The results are summarized in Scheme 62.
BusLi Ph Ph Ph
R2N SnBu3 R2N Li R2N
0 °C
Scheme 61
(ii) Dipole-stabilized carbanion equivalents

A very wide range of carbanion-stabilizing groups has been appended to the amino group itself to
stabilize the metallation process. These groups include amides, carbamates, formamidines, nitro-
samines, dithiocarbamates, thioamides, and allyl groups, which are readily removed after metalla-
tion. The typical sequence of reactions is shown in Scheme 63, where MG denotes a metallation
directing group. A review by Beak and co-workers comprehensively surveys essentially all of the
known examples of -metalloamine synthetic equivalents to that date <1984CRV471>. They are
Retention: Inversion:
(CH2)n (CH2)n
NR1 NR1
ClCO2Me, or
CO2Me R3X R3
(MeO)2CO
75–85% 75–80% Racemization:
(CH2)n (CH2)n (CH2)n
NR1 ArCHO Ph2CO NR1
NR1
~75% ~70%
HO Ar Li Ph OH
Ph
R22CO 171 BnBr or
BrCH2CO2t-Bu
(CH2)n ~80–86% (CH2)n
60–90%
NR1 NR1
R1 = Me, allyl
R2 OH n = 1, 2 R4
R2
Scheme 62
also covered in detail in Clayden’s book on organolithium compounds <B-2002MI411-01>.

Other groups such as carbonyl or cyano can also be present to the amino group to stabilize
the carbanion by delocalizing electron density into enolate equivalents, but they are not easily
removed to reveal the amino function and are not discussed in detail here.
Add directing E Remove directing E

R1 group (MG) R1 i. Metallate R1 group (MG) R1
NH N MG N MG NH
R2 R2 ii. E+ R2 R2
Scheme 63
The metallation of amides and carbamates by directed deprotonation is the most widely applied
method to generate -litho amines. These intermediates have been shown by Dieter and co-workers to be
versatile reagents for palladium-catalyzed coupling with aryl iodides in the presence of CuCN (Scheme
64) <1995TL3613>. They have also reported the preparation of -aminoalkylcuprates from the
corresponding -lithiocarbamates 172 and their subsequent addition reactions to alkynyl species
(Scheme 65) <2000OL2283, 2001OL3855>. Adducts from the addition reactions are good pre-
cursors for pyrrole synthesis.
(CH2)n (CH2)n (CH2)n

BusLi ArI, CuCN
N N Li N Ar
TMEDA Pd cat.
ButO O ButO O 54–71% ButO O
Ar = Ph, p-MeOC6H4, p-MeC6h4, o-MeC6H4

n = 1, 2
Scheme 64
Transmetallation from lithium to magnesium has infrequently been used to generate -amino
Grignard reagents in situations where the change of metal enhances yield or selectivity. For
example, Strekowski and co-workers have investigated the conjugate addition of -metalloamine
173 with nitroalkenes <1995TL225>. They found that the -lithioamino adduct only gave good
yield of addition product at 100 C and the yield decreased at higher temperature. By contrast,
the Grignard reagent 173a generated from transmetallation of -lithioamine 174 gave good yields
at 78 C and the range of substrates can be extended if the corresponding organocuprate reagent
173b is formed (Scheme 66).
R3
R1 R2 PhOH
Me3SiCl
R3 COR4 O R2 R4
N CH2Cl2 N
i. s-BuLi, THF
t-BOC R3 R 4
–78 °C, TMEDA 41–79%
R1
R1 R2 R1 R2
or (–)-sparteine
N ii. CuCN.2LiCl N Li R3 Ar
Pd(PPh3)4
t-BOC –55 °C t-BOC R1 R 2
K2CO3, ArI
172 OMs C R4 R2 R4
N DMF, 80 °C N
R3 57–71%
R4 t-BOC R3 R1
Scheme 65
Me BunLi Me
N SnBu3 N Li
t-BOC THF t-BOC
–78 °C
174
MgBr2 or
NO2 ZnCl2, CuCN.2LiCl
NO2
Me R1 R2 Me
N R2 N M
62–86%
t-BOC R1 t-BOC
R1 = 1-naphthyl, Ph; R2 = H 173a M = MgBr

R1, R2 = (CH2)4 173b M = Cu(CN)ZnCl
Scheme 66
The -metallated amino compounds have received little attention from structural chemists in
the past. In 1999, Weston and Ahlbrecht reported the first structural investigation of 1-dimethyl-
aminoallylalkali compounds. They synthesized the simple -lithioamine 175 through a Sn–Li
exchange reaction (Scheme 67) and its potassium analog 176 by direct deprotonation with the
Lochmann–Schlosser base (t-BuLi/t-BuOK) (Scheme 67). Their research has concluded that both
lithium and potassium derivatives exist exclusively in the endo conformation in THF as demon-
strated by NMR studies. Ab initio calculations also reveal that the endo-structure is thermody-
namically more stable than the exo conformation <1999T2289>.
ClSnMe3 SnMe3
t-BuLi, t-BuOK MeLi
N pentane, 0 °C N K+ THF, –78 °C N THF, –78 °C N Li+
176 175
Scheme 67
(iii) Chiral, nonracemic -aminolithium reagents

A number of -lithiated amine equivalents have been established in which the stabilizing group is
chiral resulting in a configurationally stable carbanion, retaining its formal sp3-hybridization.
High ee values are readily achieved in cyclic systems, although when low ee values are obtained,
they are probably the result of poor selectivity in removal of one diastereotopic proton from a
pair. Consequently, methods which rely on transmetallation to lithium from more stable organo-
metallics (usually stannanes) can achieve excellent selectivity, especially at low temperature
<1991JA8546, 1992JOC2220>.
The use of organolithium and chiral diamine complexes for asymmetric deprotonation of BOC-
protected amines has also been published. Beak and co-workers reported that i-PrLi/()-sparteine
complexes 177 carry out the asymmetric lithiation of BOC-pyrrolidine and the resulting
configurationally stable lithiated species 178 can be trapped with electrophiles to give 2-substi-
tuted BOC-pyrrolidines 179 with high ee (Scheme 68) <1994JA3231>. They have also studied the
mechanism and kinetics of the deprotonation reaction. Their results show that there is evidence
for a prelithiation complex of pyrrolidine and chiral lithium base 177, and that the deprotonation
reaction is the rate determining step <1995JOC7092>.
ButO O N N ButO O ButO O

E+
+
N Li N Li N E
Pri iPr
Li
(Et2O)n 178 179
177
Scheme 68
Gawley and co-workers have made an elegant comparison of the effectiveness of chiral
auxiliaries oxazoline 180 and oxazolidinone 181 in lithiation and methylation reactions. They
demonstrated that 181 gave almost complete diastereocontrol, while 180 proceeded with poor
selectivity (Equation (22)) <1989JOC3002>. They further studied the difference in selectivity
observed in the reaction of -metallated pivalamides and oxazolines 182–185 with carbonyls.
They found that when -lithiotetrahydroisoquinoline 182 or 183 was treated with benzophenone,
a deep blue solution was produced, indicative of the presence of a ketyl radical, and that
transmetallation to 184 or 185 with MgBr2OEt2 prior to the addition of benzophenone showed
no indication of ketyl formation <1991TL1941>. The results are summarized in Table 1. They
explained their findings by the competing SET and polar mechanisms. Thus, in some instances,
the polar process is slower for the lithiated species, and SET followed by radical coupling
produces racemic addition products nonselectively.
Me
BuLi, THF O
Aux Aux 180 Aux =
Ph N Ph N
Me –78 °C, then MeI Me 4:1 ratio N Pri
O ð22Þ
181 Aux = N O
50:1 ratio
Pri
Table 1 Addition of -metallated tetrahydroisoquinoline to benzophenone
Ph2CO
N N
Z Z
M
Ph OH
Ph
Z M ESR Selectivity
182 Pivalamide Li + NA
183 Oxazoline Li + 1:1
184 Pivalamide Mg NA
185 Oxazoline Mg 10:1
The seminal work of Meyers and co-workers in developing chiral formamidines as dipolar,
carbanion-stabilizing groups represents perhaps the most effective means of generating nonrace-
mic -aminolithium reagents <1984T1361>. Many representative examples are included in the
aforementioned review by Gawley with a fuller discussion than is possible here. High induction is
best achieved when the metallated amine forms part of a five-, six-, or seven-membered ring, and
benzo-fused systems such as tetrahydroisoquinolines give near perfect diastereoselection. For
example, metallation of octalin 186 followed by benzylation and removal of the formamidine
chiral auxiliary gives a key intermediate 187 in the synthesis of dextrophan (Equation (23))
<1986JOC872>.
i. BuLi, THF, –78 °C

N NH
ii. p-MeOC6H4CH2Cl
N –100 °C ð23Þ
iii. H2NNH2, H+
OBut OMe
186 187
4.11.2.1.2 Tin and zinc

The synthesis of -aminostannanes parallels to some extent the methods available for preparation
of the analogous silanes (Section 4.11.1.1). Thus, Abel and co-workers <1975JOM(97)159> have
described a complementary synthetic approach to the foregoing methods using R3SnCH2I (cf.
TMSCH2I) as the tin source. Secondary amines gave a good yield of the -aminostannane
products 188, but reaction with primary amines often result in a mixture of mono- and dialky-
lated products (see also reference <1976JOM(113)C13>). This method is particularly well suited
to the synthesis of -stannylmethylaziridines, -piperidines, and some heteroaromatic systems (see
Equation (24)). Coldham and co-workers also reported a similar reaction where an acyclic
secondary amine 189 was treated with Bu3SnCH2OMs to afford the corresponding -aminostan-
nane 190, which was a key intermediate for their investigation into the synthesis of pyrrolidines by
anionic cyclization (Equation (25)) <1997TL7621>.
SnMe3
Me3SnCH2I
H
N Base N
R1 R2 R1 R2
65–82% 188
ð24Þ
H H
H H N N
N = N
R 1 R2
i. PhCH2NH2 R
R DMF, heat
N
OMs ii. MsOCH2SnBu3 SnBu3 ð25Þ
MeCN, K2CO3 Ph
189 190
R = H, Me
Besides alkylation of amines, alkylation of amide and carbamate NH functions have shown to
be an alternative method to synthesize -aminostannanes. Chong and co-workers published a
simple preparation of -aminostannanes by alkylation of amides to first give -amidostannane
intermediate 191. After reduction with alane (LiAlH4 gave competing destannylation), the desired
-aminostannanes 192 were produced in good-to-excellent yields (Scheme 69) <1996JOC7627>.
Alkylation of carbamates has also been reported by Jeanjean and co-workers <2000EJO1297>.
The oxazolidinone chiral auxiliary 193 was alkylated with -bromo-organostannane 194 to give a
good yield of -stannylcarbamate 195. The stannane 195 was then treated with n-BuLi and CO2
to provide the protected amino acid derivative 196 in 78–85% yields (Scheme 70).
A different approach was carried out by Quintard and co-workers, who used readily available
aminals such as 197 that react with Bu3SnMgCl (prepared in situ from Bu3SnH and PriMgCl) to
give excellent yields of the stannanes 198 (Scheme 71). Yields for the two-step process were in the
range 45–90% overall <1984S495>. Coldham and co-workers have also shown that iminium ions
O O
Bu3SnCH2I LiAlH4, H2SO4 R2
R2 R2 R1 N
R 1 N R1 N
BunLi, THF THF, 0 °C to rt SnBu3
H 0 °C to rt SnBu3 83–97%
51–92% 191 192
Scheme 69
SnBu3
O Br SMe O SnBu3 O CO2H
194 BunLi, CO2
O NH O N SMe O N SMe
NaH, DMF THF, –78 °C
R Ph 87–90% 78–85%
R Ph R Ph
193 195 196
R = H, Ph
Scheme 70
also react with Bu3SnLi to give stannanes as shown in Scheme 72. The iminium ion was prepared
by the condensation of pyrrolidines 199 with formaldehyde in the presence of benzotriazole
catalyst, prior to reaction with Bu3SnLi <1997JCS(P1)1481>. The stannane intermediate 200
provided access to the corresponding -amino-organolithium by Li–Sn exchange, which under-
goes addition to aldehydes to give -amino alcohols in good yields and modest diastereo-
selectivities. Yields were generally comparable to the aminal process, although the versatility is
undoubtedly greater.
PhCHO, BuOH Bu3SnMgCl

N K2CO3 N Et2O, 81% N
H 84%
Ph OBu Ph SnBu3
197 198
Scheme 71
i. CH2O PhCHO, BuLi

benzotriazole THF, –78 °C
N ii. Bu3SnLi N 88% N
H OMe OMe OMe
Ph
Bu3Sn
199 200 OH
20% de
Scheme 72
Stannylcarbinols 201, prepared by the addition of Bu3SnLi to aldehydes, can be converted into
phthalimidomethylstannanes 202 under Mitsunobu conditions as shown in Scheme 73. Hydrazi-
nolysis and BOC protection gives an acylaminostannane 203, which can be further alkylated at
nitrogen under standard conditions <1992JOC2220, 2002JOC3625>. Enantiomerically enriched
aminomethyltin species are accessible in a similar manner; enantioselective reduction of acylstan-
nane 204 with (S)-BINAL-H gives a carbinol, which is readily converted into imide 205 with
inversion of the carbinol stereochemistry (Equation (26)). The overall enantioselectivity of the
process is dependent on the reduction step <1992JOC2220>.
O
O Bu3SnLi Bu3Sn OH Phthalimide R1
N
R1 H R1 H Ph3P, DEAD SnBu3
62–76% O
201 202
i. H2NNH2
ii. (t-BOC)2O
75–85%
t-BOC R1 NaH, R2X t-BOC R1

N HN
R2 SnBu3 DMF SnBu3
85–100%
203
Scheme 73
O i. (S)-BINAL-H NH(Cbz)2
Et SnBu3 ii. (Cbz)2NH Et SnBu3 ð26Þ

Ph3P, DEAD
204 ~90% ee
205
The interchangeability of Sn and Li by transmetallation in either direction is a straightforward

process and several -aminostannanes have been prepared from lithium derivatives discussed in
the previous section. For example, the BOC-protected benzylamine derivative was asymmetrically
deprotonated by n-BuLi/()-sparteine and the anion was quenched with Me3SnCl to give stan-
nane 206 as an intermediate for the synthesis of novel amino acids 207 (Scheme 74)
<1997JOC1574>. A related reaction, which utilizes the 1,1-addition of stannanes to Fischer
carbene complexes to generate chiral organostannane derivative 208 was published by Wulff
and co-workers. The imidazolidinone carbene complex 209 was treated with Bu3SnH in refluxing
hexane, and high stereoselectivity of the product 208 can be achieved in the synthesis of the
product depending on the side chain (Equation (27)) <1998OM3696>.
i. BunLi, SnMe3 i. BunLi, CO2H

Ar (–)-sparteine Ar (–)-sparteine Ar
N Ph N Ph N Ph
BOC ii. Me3SnCl t-BOC ii. CO2 t-BOC
95% 81%
206 207
92% ee 90% ee
Scheme 74
(CO)4Cr O Bu3Sn O
Me Bu3SnH (1.5 equiv.) Me
N N N N
Pyridine (3 equiv.)
Hexane, reflux ð27Þ
Ph Me Ph Me
52%,
209 208
98/21 (S)/1(R)
Few reports give details of -aminozinc derivatives despite evidence in those papers that such
species are relatively stable and can in some cases be isolated. Wittig and Schwarzenbach
<1961LA(650)1> were the first to prepare bis(trimethylaminomethyl)zinc chloride 210 by the
reaction of ZnCl2, diazomethane, and Me3N (Equation (28)). Recently, Zhu and co-workers have
reported the use of the -zinc-substituted methylphthalimide in their synthesis of a modified
uridine derivative. They required the iodide fragment 211 to couple to a ribose derivative in which
the two phthalimide groups were introduced by using the organozinc derivative 212 in the
presence of CuI in good yield (Scheme 75) <2002MI(21)723>.
CH2N2, ZnCl2 2+
Me3N Me3N Zn NMe3 2Cl– ð28Þ
210
Nphth Nphth
Cl i. NaI, acetone, i. BH3, H2O2
85% OH–, 57%
ii. Nphth ZnCuI ii. Ph3P, I2 I
Cl Imidazole, 98%
71%
212 Nphth Nphth
211
O
Nphth = N
Scheme 75
4.11.2.2 a-Metallated Imine Functions
4.11.2.2.1 Lithium
This section addresses lithiation by deprotonation; lithiation by metal exchange with organo-
stannanes was briefly discussed in Section 4.11.2.1.2.
The lithiation of unactivated amines can be achieved by first generating an aldimine or
ketimine, which is able to delocalize the new carbanion as the aza-allyl anion 213. The process
is most successful with N-methylbenzophenone imine 214, which offers increased anion stability
and complete regiocontrol of the alkylation site <1977CB2659>. Hydrolysis then releases the
newly substituted amine 215 as shown in generic form in Scheme 76. Examples of -lithiated
imines are tabulated in Beak’s 1984 review <1984CRV471>.
BuLi or Li+
Ph2CO Ph Ph i. E+
LDA
RNH2 N H2N E
N
Ph R Ph – ii. HCl (aq.)
214 (R = Me) 213 215
Scheme 76
Additional stabilization of the incipient aza-allyl carbanion increases the lifetime of the
metallated intermediate. Lithiated imines of glycine 216 have been used as glycine carbanion
synthons, especially in the synthesis of unnatural -amino acids. In a recent example de
Meijere and co-workers have reported the preparation of deuterated amino acid 217 contain-
ing a cyclopropyl group as part of the total synthesis of the novel antibiotic belactosin A.
They utilized the lithiated aminoacetate derivative 216 to add the amino acid function to the
iodide 218 in good yield (Scheme 77) <2000SL1741>. Other glycine synthons have been
published such as Schöllkopf’s elegant bis-lactim ether. This can be deprotonated asymmetrically
to -lithio carbanion 219, which can be quenched with a variety of electrophiles to yield 220
selectively (Scheme 78) <1983T2085>. The details of this methodology are covered in chapter 4.11
of COFGT (1995).
The related diaza-allyl anion 221 can be generated by metallation of the azo compound
222. Baldwin and co-workers have extensively investigated the lithiation of t-butylhydrazone 222 and
its subsequent reaction with an aldehyde or ketone. The initial azo intermediate 223 was easily
isomerized back to a hydrazone 224 on exposure to BuLi. Final hydrolysis of the hydrazone 224
completes a useful and general synthesis of -hydroxyketones 225 (Scheme 79) <1983CC1040,
1986T4223>.
N CPh2
Li
N(t-BOC)2 CO2But N(t-BOC)2 NH2.HCl
216 HCl (aq.)
N CPh2 NH2.HCl
I THF, –78 °C to rt 93%
DD 82% DD CO2But D CO2H
218 217
Scheme 77
MeO MeO MeO

N BuLi N E+ N
N N N
OMe OMe OMe
Li E
219 220
Scheme 78
O
BuLi, THF But N R1
0 °C But R1 R
2 R3 N
But N R1 N
N N
H LiO R2
R3
222 221
223
BuLi
then H2O
(CO2H)2
O R1 H2O But N R1
N
H
HO R2 (43–95% HO R2
R3 overall) R3
225 224
Scheme 79
4.11.2.2.2 Tin
Pearson and co-workers have published a number of creative syntheses using -stannylimine
derivatives 226 as precursors to lithio imines, which undergo [4s + 2s]-cycloadditions to
anionophilic alkenes, generating pyrrolidines and related compounds. They have reported a
variety of synthetic routes to -stannylimine derivatives 226, such as the Staudinger reaction
of azidomethylstannane 227 with Ph3P in the presence of an aldehyde, and the more conventional
condensation of aldehydes or ketones with -aminostannanes 228 (Scheme 80) <1992JOC6354>.
This chemistry has been applied successfully to the synthesis of complex polycyclic pyrrolidines
containing natural products <1995JA12336, 1997TL3369>.
RCHO RCHO
Bu3Sn N3 Bu3Sn N R Bu3Sn NH2
Ph3P
227 226 228
Scheme 80
Recently, Pearson and Aponick have extended the use of -stannylimines to prepare tetra-
hydroazepines via ring-closing metathesis. They found that treatment of (2-azaallyl)stannanes 229
with 2 equiv. of allyl Grignard reagent afforded good yields of dienes 230, which were subjected
to ring-closing metathesis to give 2,3,6,7-tetrahydroazepines 231 in 75–98% yields (Scheme 81)
<2001OL1327>.
i. MgBr
R2 SnBu3 RCM
R2 R2
R3 N R1 ii. R 4COX N R1 R3 N R1
R3
COR4
COR4
229 230 231
Scheme 81
4.11.2.3 a-Metallated Aziridines

The chemistry of aziridinyl anions was not widely known and studied until Satoh published a
review on this subject in 1996 <1996CRV3303>. -Metallated aziridines can serve as key
intermediates for the synthesis of more complex aziridines and amines bearing a chiral qua-
ternary center. Florio and co-workers have reported a convenient route to oxazolinylaziridines
based on the deprotonation and alkylation of simpler oxazolinylaziridines. Treatment of oxazo-
line 232 with LDA then Schiff base 233 afforded aziridine 234. Lithiation of aziridine 234 with
n-BuLi at 78 C resulted in the formation of aziridinyllithium 235, which could be trapped
with a number of electrophiles to give functionalized aziridines 236a–236b (Scheme 82)
<1999TL6101>. If the electrophile is an arylaldehyde, the reaction takes place with complete
anti-diastereoselectivity to give 236b. (Acetaldehyde was shown to be much less anti-diastereo-
selective (anti/syn ratio = 2/1).) It is noteworthy that deprotonation–alkylation reactions of
oxazolinyloxiranes are nonstereoselective.
Ph Ph
N Cl i. LDA, –78 °C N BunLi N
N N
O O THF O
ii. PhN H –78 °C Li
232
234 235
233
E+ or
RCHO
Ph Ph
N N
E = D, Me, SiMe3, allyl, CMe2OH N or N
O
(70–98%) O
R = Me, Ph, m-Cl-C6H4, p -MeO-C6H4, R E
m-MeO-C6H4 (55–90%) OH
236b 236a
Scheme 82
The generation of aziridinylmagnesium is possible as Satoh and co-workers have demonstrated.

They prepared the aziridinylmagnesium species 237 by the sulfoxide-metal exchange of sulfinyla-
ziridines 238, and in the presence of catalytic amounts of CuI good-to-excellent yields of alkyla-
tion products were afforded with a variety of electrophiles <2000TL6495>. The alkylated
aziridines 239 were converted regioselectively to the corresponding amines 240 by hydrogenation
with Pd(OH)2 in quantitative yield. If the sulfoxide starting material is optically pure, this
methodology leads to the asymmetric synthesis of amines bearing a quaternary chiral center
with little to no loss of chirality (Scheme 83).
Finally, it is also possible to prepare -stannylaziridines 241 as shown by Vedejs and
Kendall <1997JA6941>. The -lithioaziridines 243 generated from lithiation of the aziridines
242 were treated with Bu3SnCl to give the desired -stannylaziridines 241 (Scheme 84). The
borane acts as an activator for substituted aziridine synthesis and it is easily cleaved in
refluxing ethanol.
O Ph Ph
i. PhCH=NPh N EtMgBr N
S R R Ph R Ph
Tol ii. ButOK
Cl TolS*(O) H BrMg H
238 >98% ee 237
Br
MeO
10% CuI
98%
Ph
H2, Pd(OH)2 N
R NHPh R Ph
CH2Ph 100%
H
MeO 240 MeO 239

97% ee 98% ee
Scheme 83
Li SnBu3
i. BH3/ THF
82% H Bu3SnCl H
N +N – +N –
ii. BusLi BH3 82% BH3
TBSO TBSO TBSO
242 243 (major) 241
Scheme 84
4.11.2.4 a-Metallated Isocyanides and Isothiocyanates
4.11.2.4.1 Isocyanides
Lithiated isocyanides are readily generated by alkyllithiums and are unusual stabilized carbanions
in that the terminal isocyanide carbon is an electrophilic center; the immediate products of
alkylation 244 often react further, typically by a cyclization to generate five-membered hetero-
cycles 245. The synthesis and chemistry of -lithiated isocyanides are the subject of two compre-
hensive reviews <1977AG(E)339, 1984CRV471> and well-described preparative details are
available for the generation and silylation of LiCH2NC <1984SC639>. The potential of these
reagents for the synthesis of oxazolines, thiazolines, imidazolines, pyrrole derivatives, and related
compounds are summarized in Scheme 85.
–
X X X
Li
+ +
R N – R N – R N
C X = O, N, S, C C
244 245
Scheme 85
For example, cyclization of lithiated isocyanides with carbonyl equivalents generates a new
heterocyclic carbanion, which is generally protonated on work-up. This reaction is applied in an
elegant synthesis of the cyclopenta[c]pyridine ring system in natural products ()-plectordorine
and (+)-oxerine (Scheme 86) <2000TL10251>. The anionic intermediate can undergo further
tandem reactions to give disubstituted heterocycles <1980JOC2548>.
Me Me Me
OTBDMS LiCH2NC OTBDMS H+ OTBDMS
O
O THF, –78 °C –O +
then AcOH O N OH O N
–
66% C
Steps
Me
Me
OTBDMS O
Steps OTBDMS
HO
N O N
R R
(–)-plectrodorine, R = CO2Me
(+)-oxerine, R = H
Scheme 86
Tosylmethylisocyanide (TosMIC, 246) is a versatile isonitrile that has been utilized in the
synthesis of substituted -hydroxyaldehydes, nitriles, pyrroles, imidazoles, and thiazoles. Van
Leusen and co-workers have described the synthesis of TosMIC by the lithiation of MeNC followed
by reaction with TsF (Equation (29)) <1972TL2367>. Details of the chemistry of TosMIC can be
found in several useful leading references and overviews <1977TL2949, 1979CPB2857, 1980S325>.
i. BuLi
Me NC
ii. TsF, 87% S NC ð29Þ
O2
246
4.11.2.4.2 Isothiocyanates
Lithiated isothiocyanates without additional carbanion-stabilizing groups are only rarely invoked
as intermediates in the literature. Metallation of MeNCS is reported to give the thiazolinethione
247 (Scheme 87) <1981AG(E)126>. A much more practical method for the generation of an
equivalent carbanion has been achieved by desilylation of TMSCH2NCS using tetraalkyl-
ammonium fluorides <1981AG(E)126, 1982BCJ1163> (see also Section 4.11.1.1.5). The resultant
salt 248 has been intercepted with a range of electrophiles, including carbonyl compounds which
afford oxazolinethiones 249 (Scheme 88). Stabilized lithiated isothiocyanate have been used in the
preparation of functionalized thiazolidines. The lithium salt of isothiocyanate (and isocyanate) 250
was reacted with cyclic imine 251 to give a bicyclic product 252 in 75% yield as a pair of diastereomers
<1983TL4503> (Equation (30)).
S S
S RLi S
Me C C MeN N NHMe
N Li N
S
247
Scheme 87
R
R
S R4NF – S R2CO
C H2C C O
R4N+
TMS N N
S N
248 H
249
Scheme 88
CO2Et
R
BF3.OEt2 H R
EtO2C HN
Li + N S
XCN –78 °C N S ð30Þ
X
Me Me 50–75%
Me Me
250 251
252
X = S, O
4.11.2.5 Metallation of N-Methyl Heterocycles

Nitrogen heterocycles, especially -excessive heteroaromatic systems bearing an N-methyl
substituent, can frequently be lithiated on that sp3-carbon, either by deprotonation or trans-
metallation from Si and Sn species, to give a dipole-stabilized carbanion. An important
consideration and a major restriction is that the reaction is only practical if competing -
metallation of the aromatic ring is suppressed or impossible. This aspect is discussed in more
detail in Gschwend and Rodriguez’ monumental review of heteroatom-facilitated lithiations
<1979OR(26)1>. This could be demonstrated by the -lithiation of N-alkyl group in pyrazoles
published by Katritzky and co-workers <1983T2023>. The 1,3,5-trimethylpyrazole 253 was
deprotonated exclusively at the N-methyl group and the lithio-derivative 254 was successfully
trapped with a range of electrophiles (Scheme 89). A list of other examples can be found in
chapter 4.11 of COFGT (1995).
Me Me Me
BunLi, –78 °C E+
N N N
Me N Me N 80–99% Me N
Me Li E
253 243
E = D, Et, COPh, C(OH)Ph2, etc.
Scheme 89
Among the variety of -metallated N-methyl heterocycles reported, the benzotriazole

derivatives have found the most use in synthesis. As described in Section 4.11.1.1.8, benzo-
triazole 95 was -lithiated and subsequently quenched with electrophile TMSCl to give 96.
Application of a similar chemistry was again published by Katritzky and co-workers where
they found that some -benzotriazole ethers 255 can be used as masked acyl anion equiva-
lents and can be used to prepare alkyl, aryl, alkenyl, and alkynyl ketones. For example, the
1,6-diketone 256 was synthesized in good yields following the protocol in Scheme 90
<1999JOC2124>.
BunLi, THF BunLi (2 equiv.) OPh

OPh OPh
–78 °C then THF Bt
R R
Bt RBr Bt R Br(CH2)4Br Bt
255 81–92% OPh
R = alkyl, Ph, Bn, vinyl, phenylacetynyl 1 N HCl, MeOH

81–83%
O
R
R
O
256
Scheme 90
4.11.2.6 a-Metallated Nitroalkanes

The synthesis and chemistry of -anions derived from nitroalkanes is a vast, mature area which
cannot be accommodated in this review. A comprehensive coverage of the topic can be found in
Ono’s book on the chemistry of nitro group <B-2001MI411-01>. Two named reactions embrace
the majority of nitroalkane chemistry and both require -nitro anions as intermediates. These are
the Henry reaction and the Nef reaction. The Henry reaction covers the condensation of
aldehydes and ketones (and usually Michael acceptors) with nitroalkanes and has been reviewed
<1959OR(10)179, 1970MI411-01, B-2001MI411-01>. The Nef reaction covers all hydrolyses of
nitronates to carbonyl compounds. A review in 1990 comprehensively surveyed the known
examples of, and conditions for, the Nef reaction <1990OR655>. There has been no significant
breakthrough in this area even though much research has been devoted to the new developments
and application of these reactions in modern organic synthesis.
ACKNOWLEDGEMENTS
The author is grateful to John Steele (AstraZeneca R&D Charnwood) who wrote the original
edition of this resourceful chapter and gave the author the opportunity to update it, Suzanne
Pears (Information Science, Library & Archives, AstraZeneca R&D Charnwood) for her helpful
discussion in the fine art of SciFinder1 data mining, and Gareth Pritchard (Department of
Chemistry, Loughborough University) for proofreading this chapter.
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Biographical sketch
Chester Chu was born in Hong Kong. He received his B.A. in chemistry
in 1996 and his D. Phil. in synthetic organic chemistry in 1999 from
Oxford University, where he worked with Professor Sir Jack E. Baldwin
on the biomimetic synthesis of penicillin. Since 2000, he has pursued
postdoctoral work with Professor Marc A. Tius in the Chemistry
Department of University of Hawaii, followed by a second postdoctoral
work with Dr. Gareth J. Pritchard in 2001 in the Chemistry Department
of Loughborough University back in the UK. He has been working at
Astrazeneca R&D Charnwood as senior research chemist in the med-
icinal chemistry department since 2002.
4.12
Functions Containing One
Phosphorus and Either Another
Phosphorus or As, Sb, Bi, Si, Ge, B,
or a Metal
R. A. AITKEN
University of St. Andrews, St. Andrews, UK
4.12.1 FUNCTIONS CONTAINING TWO PHOSPHORUS ATOMS 540

4.12.1.1 Symmetrical Dicoordinate Phosphorus Functions 540
4.12.1.2 Asymmetrical Systems Containing One Dicoordinate Phosphorus 540
4.12.1.3 Symmetrical Tricoordinate Phosphorus Functions 541
4.12.1.3.1 From 1,1-dihalo alkanes 541
4.12.1.3.2 By nucleophilic substitution on 1-haloalkylphosphines 541
4.12.1.3.3 From 1,1-dimetallo alkanes 542
4.12.1.3.4 By electrophilic substitution on 1-metalloalkylphosphines 542
4.12.1.3.5 From diphosphenes 542
4.12.1.3.6 From 1,3-diphosphaalkenes 542
4.12.1.3.7 From carbonyl compounds 543
4.12.1.3.8 From 1,1-diphosphino alkenes 543
4.12.1.3.9 From phosphaalkenes 543
4.12.1.3.10 From phosphaalkynes 544
4.12.1.3.12 By reduction of tetracoordinate systems 546
4.12.1.3.13 Interconversions 546
4.12.1.4 Asymmetrical Systems Containing at Least One Tricoordinate Phosphorus 546
4.12.1.4.1 From 1-haloalkylphosphines 546
4.12.1.4.2 From 1-metalloalkylphosphorus compounds 546
4.12.1.4.3 By electrophilic attack on phosphorus ylides 547
4.12.1.4.4 From vinylphosphorus compounds 547
4.12.1.4.6 By oxidation of symmetrical tricoordinate systems 548
4.12.1.5 Symmetrical Tetracoordinate Systems 548
4.12.1.5.1 From reactions of 1,1-dihalo alkanes with phosphorus nucleophiles 549
4.12.1.5.2 From reactions of 1-haloalkylphosphorus compounds with phosphorus anions 549
4.12.1.5.3 From reactions of 1-haloalkylphosphorus compounds with phosphines 549
4.12.1.5.4 From Arbuzov reactions of 1-haloalkylphosphorus compounds 549
4.12.1.5.5 From 1,1-dimetallo alkanes 550
4.12.1.5.6 From electrophilic substitution on 1-metalloalkylphosphorus compounds 550
4.12.1.5.7 From diphosphorus-substituted carbenes 551
4.12.1.5.8 By electrophilic attack on phosphorus ylides and from 1,3-diphosphaalkenes generated
in other ways 551
4.12.1.5.9 From 1,1-diphosphorus-substituted alkenes 552
4.12.1.5.10 From vinylphosphorus compounds 553
4.12.1.5.11 From alkynes 553
539
540 Phosphorus and Either Another Phosphorus or As, Sb, Bi, Si, Ge, B, or a Metal

4.12.1.5.13 By oxidation of tricoordinate species 554
4.12.1.5.14 Interconversions 555
4.12.1.6 Penta- and Hexacoordinate Systems 556
4.12.2 FUNCTIONS CONTAINING ONE PHOSPHORUS AND ONE ARSENIC, ANTIMONY, OR
BISMUTH 557
4.12.2.1 Phosphorus and Arsenic Functions 557
4.12.2.2 Phosphorus and Antimony Functions 557
4.12.2.3 Phosphorus and Bismuth Functions 557
4.12.3 FUNCTIONS CONTAINING PHOSPHORUS AND A METALLOID 557
4.12.3.1 Dicoordinate Phosphorus Derivatives 557
4.12.3.2 Tricoordinate Phosphorus Derivatives 557
4.12.3.2.1 Tricoordinate phosphorus and silicon functions 557
4.12.3.2.2 Tricoordinate phosphorus and germanium or boron functions 559
4.12.3.3 Tetracoordinate Phosphorus Derivatives 559
4.12.3.3.1 Tetracoordinate phosphorus and silicon functions 559
4.12.3.3.2 Tetracoordinate phosphorus and germanium or boron functions 561
4.12.3.4 Higher-coordinate Phosphorus Derivatives 561
4.12.3.4.1 Higher-coordinate phosphorus and silicon functions 561
4.12.3.4.2 Higher-coordinate phosphorus and germanium or boron functions 562
4.12.4 FUNCTIONS CONTAINING PHOSPHORUS AND A METAL 562
4.12.4.1 Group 1 and 2 Derivatives 562
4.12.4.1.1 Compounds containing phosphorus and lithium 562
4.12.4.1.2 Compounds containing phosphorus and sodium 562
4.12.4.1.3 Compounds containing phosphorus and potassium 562
4.12.4.1.4 Compounds containing phosphorus and beryllium 563
4.12.4.1.5 Compounds containing phosphorus and magnesium 563
4.12.4.1.6 Compounds containing phosphorus and heavier group 1 and 2 metals 563
4.12.4.2 Compounds Containing Phosphorus and a Lanthanide 563
4.12.4.3 Transition Metal Derivatives 563
4.12.4.3.1 Compounds containing phosphorus and scandium or yttrium 563
4.12.4.3.2 Compounds containing phosphorus and titanium, zirconium, or hafnium 563
4.12.4.3.3 Compounds containing phosphorus and vanadium, niobium, or tantalum 564
4.12.4.3.4 Compounds containing phosphorus and chromium, molybdenum, or tungsten 564
4.12.4.3.5 Compounds containing phosphorus and manganese or rhenium 564
4.12.4.3.6 Compounds containing phosphorus and iron, ruthenium, or osmium 564
4.12.4.3.7 Compounds containing phosphorus and cobalt, rhodium, or iridium 565
4.12.4.3.8 Compounds containing phosphorus and nickel, palladium, or platinum 565
4.12.4.3.9 Compounds containing phosphorus and copper, silver, or gold 566
4.12.4.3.10 Compounds containing phosphorus and zinc, cadmium, or mercury 566
4.12.4.4 Group 13 and 14 Derivatives 567
4.12.4.4.1 Compounds containing phosphorus and aluminum 567
4.12.4.4.2 Compounds containing phosphorus and gallium, indium, or thallium 567
4.12.4.4.3 Compounds containing phosphorus and tin or lead 567
4.12.4.5 Actinide Derivatives 567
4.12.1 FUNCTIONS CONTAINING TWO PHOSPHORUS ATOMS
4.12.1.1 Symmetrical Dicoordinate Phosphorus Functions

New examples of this rare functional group are the products 2 obtained by treating the
triphosphabenzene 1, a cyclic trimer of ButCP, with MeMgBr or PhMgBr followed by hydrolysis
(Scheme 1) <2003AG(E)1863>. As will be described in Section 4.12.1.3.10, the use of PriMgCl
in this reaction gives a different product. Compound 1 also undergoes a Diels–Alder reaction with a
wide variety of alkenes to give products 3 <2001EJO3425>.
4.12.1.2 Asymmetrical Systems Containing One Dicoordinate Phosphorus

Further examples of this rare functional group are the four compounds 4 that result from treating
the phosphaalkyne ArCP (Ar = 2,4,6-tri-t-butylphenyl) with 0.5 equiv. of an alkyllithium,
RLi, followed by quenching with methanol <2002CC1744>. Rather unexpectedly, an attempt to
alkylate rather than protonate the presumed intermediate from ButLi, by adding MeI, gave the
stable diradical 5 <2003AG(E)3802>.
Phosphorus and Either Another Phosphorus or As, Sb, Bi, Si, Ge, B, or a Metal 541
R
But P But i. RMgBr But P But
ii. H2O
P P P P
Bu t But H
1 R3 R1
2
R4 R2
R2 R1
R3 R4
Bu t P But
P P
But
3
Scheme 1
Me
Ar P P
Ar Ar • • Ar
H P P
R But
4 R = Me, Bu, Bus, But 5
4.12.1.3 Symmetrical Tricoordinate Phosphorus Functions

There have been a large number of developments in the synthesis of compounds of this type since
the publication of chapter 4.12.1.3 in <1995COFGT(4)543> and these are categorized according
to the starting materials used.
4.12.1.3.1 From 1,1-dihalo alkanes

Sequential treatment of tri-p-tolylphosphine with lithium, ButCl, and CH2Cl2 gives the bis(phosphine)
Tol2PCH2PTol2 in 37% yield <1997JPC(A)4666>. Reaction of the aminophosphine
PhPH(CH2)3NH2 with sodium in liquid ammonia followed by CH2Cl2 affords the product 6 of
interest as a polydentate ligand <1996BCJ1947>.
H2N P P NH2
Ph Ph
6
4.12.1.3.2 By nucleophilic substitution on 1-haloalkylphosphines

A further example of this rather uncommon approach is provided by the reaction of
chloromethylphosphine-containing ylide 7 with Ph2P–TMS to give first 8 and then 9 (Equation (1))
<2000ZN(B)519>.
Ph Ph Ph
Ph2P–TMS Ph2P–TMS
Ph3P P Cl Ph3P P PPh2 Ph3P P PPh2
ð1Þ
Cl –TMSCl Cl –TMSCl PPh2
7 8 9
4.12.1.3.3 From 1,1-dimetallo alkanes

Further examples of this approach have appeared including the treatment of 2-picoline twice
with BuLi followed by Pri2PCl to give 10 in 40% overall yield <1999M783> and formation of 11
by treating the trimethyloxazoline with 2 equiv. of LDA followed by 2 equiv. of Ph2PCl
<2000JCS(D)1067>.
Ph2P N
PPr2i
N
Ph2P O
PPr2i
10 11
4.12.1.3.4 By electrophilic substitution on 1-metalloalkylphosphines

Reaction of Me2PCH2Li with dichlorophosphines, RPCl2, gives Me2PCH2P(R)CH2PMe2
while with PCl3 the tetrakis(phosphine) (Me2PCH2)3P is formed <1997JOM(529)151>. A range of
unsymmetrical bis(phosphines), R12PCH2PR22 can be prepared by the treatment of
R12PCH2SnPh3 or R12PCH2SnMe3 either with an alkyllithium followed by R22PCl or with
R22PCl alone at 240 C <1999JCS(D)1867>. Reaction of the zirconacycle 12 with Et2PCl or
Ph2PCl gives phosphinophospholanes 13 <1997CC1239> while treatment of 12 with ArN¼PCl
(Ar = 2,4,6-tri-t-butylphenyl) followed by water gives the aminophosphine product 14
<2003AG(E)2176>. Reaction of the terpyridyl-containing phosphine 15 with LDA followed by
Ph2PCl gives the diphosphine 16 in 97% yield (Equation (2)) <2000CC1125>.
Ph
Zr P R2P P P P
Cp2 Ph Ph Ph
ArNH
12 13 14
Ph2P Ph2P PPh2

i. LDA
ii. Ph2PCl
N N N N ð2Þ
N 97% N
15 16
4.12.1.3.5 From diphosphenes

The diphosphene ArP¼PAr (Ar = 2,4,6-tri-t-butylphenyl) reacts with MeOTf by P-methylation
and treatment of the resulting salt with diethylamine leads to cyclization to the diphosphirane 17
<1999AG(E)3329>. The reaction of Pri2NCP with diazo compounds, R1R2C¼N2, takes a
complex course but the last stage is addition to the diphosphene function in 18 to give the final
products 19 <1996CB1271>.
R1
R1 P R1 R2
P
P P
ArP PAr R2 R2
N N
17 NPr2i NPr2i
18 19
4.12.1.3.6 From 1,3-diphosphaalkenes

The triphosphabenzene 1, a cyclic trimer of ButCP, reacts with NaOMe or NaOEt to give the
product 20 that exists, as determined by X-ray diffraction, with two alkoxy groups equatorial and
one axial (Equation (3)) <2000CC2015>. The polycyclic compound 21, formed from tropone and
ButCP, undergoes Diels–Alder reaction with 2,3-dimethylbutadiene followed by a rearrange-
ment to afford product 22 (Equation (4)) <1996PS(109)425>.
But P But 3ROLi RO

ROH But
P OR But
P P P P
But ð3Þ
R = Me, Et
But RO
1 20
O O
P P
P P
ð4Þ
But But
But But
21 22
4.12.1.3.7 From carbonyl compounds

Acid-catalyzed reaction of benzene-1,2-diphosphine with 1,3-pentanedione gives the remarkable
polycyclic product 23 (Equation (5)) <1999CC901>.
PH2 O O cat. H+ O
O
+ P
P ð5Þ
PH2
23
4.12.1.3.8 From 1,1-diphosphino alkenes

The tetraphosphinobutadiene 24 and the butatriene 25 both undergo cyclopropanation upon
treatment with Me2S¼CH2 (Scheme 2) <1995CB365>.
Ph2P Ph2P
Me2S=CH2
PPh2 PPh2
Ph2P Ph2P
PPh2 PPh2
24
Ph2P PPh2 Me2S=CH2 Ph2P

• • •
Ph2P PPh2 Ph2P PPh2
Ph2P
25
Scheme 2
4.12.1.3.9 From phosphaalkenes

Treatment of the phosphaalkenyl Grignard reagent 26 with PbCl2 gives the diphosphabicyclo
[1.1.0]butane derivative 27 <2001CC663>, while with Me2SnCl2 the bicyclo[2.1.0] system 28 is
formed <2000JCS(D)3233> (Scheme 3).
But
t t
Bu Bu
Me2SnCl2 P PbCl2 P P
MgCl
P
Me2Sn
P But
26
But
28 27
Scheme 3
4.12.1.3.10 From phosphaalkynes

There has been a great deal of progress in this area largely due to the work of Regitz since the publication
of chapter 4.12.1.3.15 in <1995COFGT(4)543>. A short review has been published <1997CB823>.
New products containing one or more PCP functions derived from ButCP include 29 obtained in
95% yield by the reaction with selenium <1999S1642> and 30 obtained in 5% yield from the same
reaction <2000CC1745>. Remarkably, treatment of 29 with bromine gives 31 <1999S1642>.
Tetracyclic products 32 and/or 33 analogous to 29 can also be formed by the reaction of ButCP with
3,5-disubstituted 1,2,4-oxadiphospholes <1999EJO587>, 1,2,4-thiadiphospholes <2002JOM(655)7>,
or 1,2,4-selenadiphospholes <2001HAC406> giving products with Y = O, S, and Se, respectively. While
reaction with tungsten pentacarbonyl-complexed aminophosphinidenes gives products analogous to 32
[Y = ArNHP!W(CO)5], benzylphosphinidene, PhCH2P:, first rearranges to PhCH¼PH which
gives 34 <1995CB991>. Reaction of ButCP with 4,6-di-t-butyl-1,3,2-diazophosphinine gives com-
pound 35 in 70% yield <1998EJO2039>. Reaction of cycloheptatrienone (tropone) with ButCP and
similar phosphaalkynes takes a remarkable course to give the pentacyclic 2:1 adducts 36
<1995JOC5884>. When butadienylcyclo-octatetraenylhafnium is treated with ButCP and the result-
ing adduct hydrolyzed, the products include 37 and 38 <1999EJI763>. Reduction of ButCP with
sodium amalgam gives a mixture of diphospholide and triphospholide salts and when these are treated
with acid or PdCl2(COD), the Diels–Alder dimers 39 and 40 are formed <1997JOM(536)273>.
The reaction of ButCP and other phosphaalkynes with 1,3-dienes, R1CH¼C(R2)C(R3)¼
CHR4, to give products of structure 41 or 42, has been further examined <1995BSF652>, and
adducts of this type have been obtained from ButCP and 1-trimethylsilylbutadiene
<1999EJO1041> as well as from 2,4,6-Me3C6H2CP and butadiene <1998S1305>. Treatment
of such adducts with Br2 or ICl leads to cleavage to give 43 <1998S427>.
Se Br
But P
But P But P But
P Se But Se
But Se
P P P P P But
But
But P
Se Br
But 30 But
29 31
Y But But N
Y
R But R
P But P But But P But
R P
R P But
P P P P
P P P P
But
But But Ph But
32 33 35
34
O
But P But But But But
PO P But P
P P P
O P t But
P H Bu P P P P
R But
37 38 But But
R 39
36 But But
But P P
P But
P
Bu t But
40
R2
R2 R3
R1 R3
R1 R4 R2 R4
R3 R1 But
R4 But
But
P P
P P P X2
P
X1 But
But But
42 43
41
In addition to methods starting from monomeric phosphaalkynes, there have been several
new reactions reported, which begin from readily accessible cyclic dimers or trimers, and these
are also considered here. The diphosphacyclobutadiene 44 undergoes cyclo-addition with
N-methylmaleimide and electron-rich alkynes to give adducts 45 but with electron-poor alkynes
to give the isomeric products 46 (Scheme 4) <2002JOM(643)409>. As already mentioned, the
triphosphabenzene 1 undergoes Diels–Alder cyclo-addition with a wide variety of alkenes to give
bicyclic products 3 but with cyclopropene there is a further homo-Diels–Alder reaction to give 47
<2001EJO3425>. With terminal alkynes RCCH this also occurs to give products 48
<2000S529>. Treatment of 1 with PriMgCl followed by hydrolysis takes a different course
than for MeMgBr and PhMgBr and gives the product 49 <2003AG(E)1863>. Homo-Diels–
Alder reaction between the Dewar isomer of 1, compound 50, and alkynes gives tetracyclic
products 51 (Equation (6)) <1997JOM(529)215, 1999S1363>.
But
But R1
But But
P
P
P P P
P
But R2
But
R1 R2
44 45
46
Scheme 4
R
P But But
But P But But But But P
P P P P P H
P
But But Pri
R
49
47 48
But But
But P
But But
But P
P P
+ R1 R2 ð6Þ
P P
R1 R2
50
51

Upon prolonged heating the 1,3-diphosphabenzene 52 undergoes cyclization to give products
including 53 <2001S463>. The tricyclic zirconium compound 54 reacts with diethyl oxomalonate
to give 55 and with tetracyanoethylene to give 56 both in low yield <1999S639>. Prolonged
storage of compound 57, prepared by a complex sequence of reactions, resulted in partial
hydrolysis of the silyl enol ether to give 58 <1999EJO2633>.
But P But But But

But But EtO2C
TMS P
P P EtO2C P
But Cp2Zr P P
t P O
TMS Bu
But But
52 53
54 55
But
NC
NC P N N N N
P
NC N P P N N P P N
NC Ac Ac Ac Ac
But But
TBDMSO But O
56 58
57
4.12.1.3.12 By reduction of tetracoordinate systems

A new method for deprotection of chiral bis(phosphine–borane adducts) such as 59 involves
treatment with TfOH followed by KOH (Equation (7)) <2000TL6461>.
i. TfOH
BH3 BH3 ii. KOH
But P P
But P P ð7Þ
But But
59
4.12.1.3.13 Interconversions
Conversion of Cl2PCH2PCl2 into Ar2PCH2PAr2 may be achieved by reaction with ArLi
<1994T4303, 2001CC699>, while treatment with Me3SnF gives F2PCH2PF2 in 63% yield
<1995ZN(B)1583>. Niobium-catalyzed hydrogenation of Ph2PCH2PPh2 to give
(C6H11)2PCH2P(C6H11)2 has been reported <1995CC849>, and lithiation of Ph2PCH2PPh2
followed by iodine oxidation gives the tetrakis(phosphine) 60 in 15% yield <1995BSF691>.
The ferrocene derivatives 61 have been prepared by reacting dilithiated ferrocene with
(R2N)ClPCH2P(NR2)Cl <2003EJI1169>.
NR2
Ph2P PPh2 P
Fe
Ph2P PPh2 P
60 NR2
61 R = Me, Et
4.12.1.4 Asymmetrical Systems Containing at Least One Tricoordinate Phosphorus

There have been relatively a few developments in the synthesis of compounds of this type since
the publication of chapter 4.12.1.4 in <1995COFGT(4)543>. These are categorized according to
the starting materials used.
4.12.1.4.1 From 1-haloalkylphosphines

Interaction of the NPPh2 and CH2Cl functions present in 62 occurs spontaneously at room
temperature resulting in the formation of the salt 63 (Equation (8)) <2000ZN(B)519>.
Ph Ph
rt –
Ph3P P + Cl
Ph3P P Cl
PPh2 ð8Þ
Ph2P PPh2 Ph2P N
N
62 63
4.12.1.4.2 From 1-metalloalkylphosphorus compounds

Problems in the synthesis of (PriO)2P(O)CH2PPh2 from (PriO)2P(O)CH2Li and Ph2PCl can be
overcome by using Ph2PBr, which gives the product in 72% yield <1995PS(102)91>. Treatment
of functions such as RCH2P(O)(OEt)2 with BusLi followed by (EtO)2PCl initially gives 64 but on
addition of water this is hydrolyzed to 65 <1995JMC2596>. Asymmetric synthesis of compounds
66 has been achieved by the reaction of RPMe2BH3 with BusLi in the presence of sparteine,
followed by RPCl2 and finally MeMgCl <2001MI118>. Treatment of the selenophosphonate 67
with BuLi followed by Me2NPCl2 gives the product 68 <2002JOC146>.
O O O
BH3
(EtO)2P P(OEt)2 EtO P P(OEt)2
R P P
H R
R R
66
64 65
Se
MeO Se NMe2Se
P BnO
BnO P P P OMe
MeO OBn
67 68
4.12.1.4.3 By electrophilic attack on phosphorus ylides

The phosphine-substituted ylide, Ph3P¼C(Ph)PHPh, reacts with HBF4 to give 69, with MeI to
give 70, and with CS2 to give 71 <1998EJI381>. The compound 72, obtained from Ph3P¼CHPh
and PCl3, undergoes twofold addition of HCl to give first 73 then 74 (Scheme 5)
<1997JOM(529)87>. Prior treatment with LiAlH4, MeLi, or PhLi gives compounds 75 which
are similarly converted into 76 and 77 <1996ZN(B)267>. Both the sulfur and selenium
compounds 78 react with ylides such as 79 to give products 80 (Equation (9)) <1995CB1015>.
Ph Ph Ph S
+ + +
Ph3P PHPh Ph3P PMePh Ph3P P S–
BF4– I– Ph
69 70 71
Ph Ph Cl– Ph Ph Cl– Cl– Ph Ph Cl–

HCl HCl
+ + + +
Ph3P P PPh3 Ph3P P PPh3 Ph3P P PPh3
Cl Cl
72
73 74
Ph Ph Ph Ph BF4– –
BF4 Ph Ph BF4–
HBF4 HBF4
+ + +
Ph3P P PPh3 Ph3P P PPh3 Ph3P P PPh3
R R R
75 R = H, Me, Ph 76 77
Scheme 5
Et Et Et Et
Y + Ph3P CHEt
Ph3P P Ph3P P P PPh3 ð9Þ
Y Y
79
78 Y = S, Se
80
4.12.1.4.4 From vinylphosphorus compounds

Treatment of the vinylphosphine oxide Ph2P(O)CH¼CH2 with Cp2Zr followed by PhPCl2 gives
the phosphirane 81 <1998CC1177>.
O Ph
P
Ph2P
81

The lithiation of Ph2PCH2PPh2 followed by iodine oxidation, which was already mentioned to give
60 as a minor product, gives 82 as the main product <1995CC37, 1995BSF691>. Reaction
of ButCP with LiCH(TMS)2 takes a complex course to afford the remarkable product 83 in
64% yield <2002JOM(645)256>. The compound 84 (Ar = 2,4,6-tri-t-butylphenyl) reacts in a 2:1
ratio with azides, RN3, to give the spirodiphosphetanes 85 as minor products <1994TL1527>.
Treatment of the ruthenium(II) complex 86 with AgClO4 or AgBF4 gives the dicationic
diphosphinocarbene complex 87, which reacts with water to afford 88 in 70% yield (Scheme 6)
<2003AG(E)4767>.
Me2
Ph2P TMS Si But RN Ar But
But
But P
Ph2P P PPh2 P P TMS PAr
Ph2
P
TMS But But Ar But
82 But
84
83 85
+ 2+
Ph2 Ph2
P Ag+ P
(ButNC) 4Ru I (ButNC) 4Ru :
P P
–AgI Ph2
Ph2
86 87
H2O
2+
Ph2
P
(ButNC)4Ru
PPh2
O
88
Scheme 6
4.12.1.4.6 By oxidation of symmetrical tricoordinate systems

A convenient new method for oxidation of Ph2PCH2PPh2 to Ph2P(O)CH2PPh2 involves
Pd-catalyzed reaction with 1,2-dibromoethane and NaOH in a two-phase system
<1999JA5831>, while conversion of the same bis(phosphine) into Ph2P(¼NAr)CH2PPh2
using a variety of fluorinated aryl azides has been examined <1998JA11364>. Competition
between the phosphine and phosphinite functions is observed upon reaction of the pentacyclic
compound 36 with electrophiles: alkyl halides lead to quaternization of the phosphine center
while oxidation, treatment with sulfur or selenium, and reaction with azides all lead to oxidation
at the phosphinite center <1996S87>.
4.12.1.5 Symmetrical Tetracoordinate Systems

the publication of chapter 4.12.1.5 in <1995COFGT(4)543>. These are categorized according to
the starting materials used.
4.12.1.5.1 From reactions of 1,1-dihalo alkanes with phosphorus nucleophiles

Reaction of PhCH2CH2P(OTMS)2 with CH2Br2 followed by hydrolysis gives the bis(phosphinic
acid) 89 in 47% yield <1997JGU1857>, while the tris(phosphine oxide) 90 may be formed by the
reaction of either 1,1,2-trichloroethane, 1,1-dichloroethene, or (E)-1,2-dichloroethene with
Ph2P(O)H and a base under phase-transfer catalysis conditions <1994JGU1134>. The conversion
of the 1,1-ditosylate 91 into the tris(phosphonate) 92 in 71% yield using (EtO)2P(O)H/NaH
(Equation (10)) may also be considered in this category <1997PS(129)13>.
O O
O O
P P Ph2P PPh2
Ph Ph
HO HO Ph2P
89 O
90
O (EtO)2P(O)H O
(EtO)2P CO2Et NaH (EtO)2P CO2Et
TsO OTs 71% ð10Þ

(EtO)2P P(OEt)2
O O
91 92
4.12.1.5.2 From reactions of 1-haloalkylphosphorus compounds with phosphorus anions

A new example of this type is the reaction of 93 with the anion derived from 94 to give 95 in 60%
yield (Equation (11)) <1995MI129>.
O O O
O NaH P P CH(OEt)
P OTs P CH(OEt) (EtO)2CH 2
(EtO)2CH + H 2 OEt ð11Þ
EtO OEt EtO
60%
94 95
93
4.12.1.5.3 From reactions of 1-haloalkylphosphorus compounds with phosphines

Reaction of (R1O)2P(O)CH2OTf with R23P may be used to obtain the following phosphonate/
phosphonium salts: (MeO)2P(O)CH2P+Ph3 OTf (83%), (EtO)2P(O)CH2P+Ph3 OTf (82%),
(BnO)2P(O)CH2P+Ph3 OTf (84%), and (EtO)2P(O)CH2P+Bu3 OTf (72%) <1996JOC7697>.
4.12.1.5.4 From Arbuzov reactions of 1-haloalkylphosphorus compounds

Significant new developments in this area include the use of microwave irradiation to promote the
reaction of (EtO)2P(O)CH2I with (EtO)3P giving a 91% yield of (EtO)2P(O)CH2P(O)(OEt)2 in
3 min <2000PS(160)195>, and use of the silyloxyphosphine Bu2POTMS to convert
R2P(O)CH2Cl into R2P(O)CH2P(O)Bu2 for R = Ph (63%) and Bu (80%) <1999JGU1047>. By
working at high temperature under vacuum to ensure the removal of the otherwise troublesome
benzyl chloride, the Arbuzov reaction can now be achieved with tribenzyl phosphite and this has
allowed, for example, the conversion of (BnO)2P(O)CH2Cl into (BnO)2P(O)CH2P(O)(OBn)2 in
92% yield and BnOP(O)(CH2Cl)2 into compound 96 in 71% yield <1995TL5183,
1995HCA670>. This has been applied also in the synthesis of compounds such as 97
<2001T9149> and of (BnO)2P(O)CH2P(O)(OBn)2 from (BnO)2P(O)CH2Br in 37% yield
<1999BMCL3069>. Reaction of BuOP(O)(CH2Cl)2 with 2 equiv. of (BuO)3P gives the product
98 as expected but, if only 1 equiv. of (BuO)3P is used, the intermediate undergoes an intramo-
lecular Arbuzov reaction to give the cyclic product 99 in 83% yield <2002JGU486>.
O O O O O
RO OR OBn O
P P P BnO P P BuO OBu
RO OR OBn P P
OR
OBn O O
96 R = Bn
98 R = Bu 97 99
4.12.1.5.5 From 1,1-dimetallo alkanes

Further examples of the twofold lithiation of a CH2 group and reaction with (EtO)2P(O)Cl
include reaction of a series of N-farnesyllactams to give products 100 <2002JOC5709>, and
treatment of MeCN with 3 equiv. of LDA and 2 equiv. of (EtO)2P(O)Cl to afford 101 in 93%
yield <2000JCS(P1)3311>. In the last reaction the use of 2 equiv. of LDA gives only the
monophosphonate.
O O O
PO(OEt)2 EtO
N P P OEt
PO(OEt)2 EtO OEt
(CH2)n CN
100
101
4.12.1.5.6 From electrophilic substitution on 1-metalloalkylphosphorus compounds

In chapter 4.12.1.5.7 of <1995COFGT(4)543> it was mentioned that lithiated phosphonates
such as (MeO)2P(O)CH2Li undergo self-condensation at normal temperatures, but this may
be avoided by working at low temperature. This has allowed their use in synthesis of a
variety of enzyme inhibitors containing the function (MeO)2P(O)CH2P(O)(OEt)R by reac-
tion with appropriate phosphonochloridates, RP(O)(OEt)Cl <1995MI737, 1995RTC332,
1995JMC1005>. Reaction of (EtO)2P(O)CH2Li with BnOCH2P(OEt)(O)Cl has been used
to obtain BnOCH2P(OEt)(O)CH2P(O)(OEt)2 in 73% yield <1999JMC2633>. Reaction of
(EtO)2P(O)CH2Li with racemic phosphinoylchlorides, PhP(R)(O)Cl, followed by hydrolysis
and resolution using quinine or quinidine gives the chiral phosphine oxide/phosphonic acids
102 <2001JMAC1106>. The first methylenephosphonate/hydrogenphosphinate 103 has been
obtained by treating (EtO)2P(O)CH2Li with the borane adduct of (EtO)2PCl, removal of the
borane protection to give (EtO)2PCH2P(O)(OEt)2, and partial hydrolysis using acetic acid
<2001TL8451>. A convenient one-pot procedure for synthesis of compounds 104 involves
treatment of (EtO)2P(O)CH2R with BuLi followed by EtOP(O)Cl2 and finally a nucleophile
NuH such as an alcohol, phenol, thiol, or amine <1996S731>. A range of the previously
unknown mono-, di-, and triamide esters of methylenediphosphonic acid (X1X2P(O)CH2P(O)X3X4),
where between one and three X groups are NEt2, NBu2, N(octyl)2 and the remainder are OMe,
OEt, or OPri, have been prepared by reaction of X1X2P(O)Me with LDA followed by X3X4P(O)Cl
<1997ACS932>. Treatment of (PriO)2P(O)SPh with MeLi or BuLi results mainly in simple
displacement of the SPh group by Me or Bu, but a significant side reaction involves further
deprotonation of this product and reaction with the starting material to give products 105 in yields
of 26% (R = H) and 16% (R = Pr) <1996BSF951>. While (BnO)2P(O)CH2Li is found not to
react with electrophiles such as BnOPCl2 and (Me2N)2PCl, this can be overcome by moving to the
selenium analog (BnO)2P(Se)CH2Li, which reacts to give products 106 and 107, respectively
<2001TL5439>. Kinetic resolution is observed when 2 equiv. of the racemic compound 108 are
treated with the chiral chlorophosphine borane adduct 109 to give the product 110 with high
selectivity (Equation (12)) <2001C694>.
O O O O O O O O
Ph OH H OEt EtO Nu PriO OPri
P P P P P P P P
R OH EtO OEt EtO OEt PriO OPri
102 R = Me, Et 103 R R
104 105 R = H, Pr
Se Se Se
BnO OBn BnO NMe2
P P P P P
BnO OBn BnO NMe2
BnO
107
106
– –
BH3 BH3 –
BH3 BH3
–
P+ Li +
2 P+ P+ P+ ð12Þ
Cl Ph
Ph
108 110
109
4.12.1.5.7 From diphosphorus-substituted carbenes

Electrolysis of (EtO)2P(O)CCl2P(O)(OEt)2 in the presence of activated alkenes such as methyl
acrylate and acrylonitrile gives the cyclopropanediphosphonates 111 in 40–75% yield
<1999S1903>. Treatment of C60 with (MeO)2P(O)CH(Br)P(O)(OMe)2 and DBU gives 112 in
41% yield and subsequent reaction with TMSI gives the corresponding diphosphonic acid
<2000SL1816>.
O O
(MeO)2P P(OMe)2
O O
(EtO)2P P(OEt)2
R1
R2
111
R1 = H, Me
R2 = CO2Me, CN 112
4.12.1.5.8 By electrophilic attack on phosphorus ylides and from 1,3-diphosphaalkenes generated

in other ways
A range of cationic phosphonolipids 113, of interest for gene transfection, have been prepared in
60–80% yield by the reaction of long-chain dialkoxyphosphoryl chlorides with simple nonstabi-
lized ylides (Equation (13)) <2000JMC4617>. The unusual cyclic triylide 114 reacts with HBF4 in
Et2O to give the salt 115 <1997AG(E)2349> and with aqueous HCl to give the triphosphinic acid
116 <1999AG(E)829>. Treatment of compound 117 with BuLi followed by Me3P results in
carbenoid formation, interaction with Me3P to give an ylide, and a series of proton transfers to
produce 118 (Equation (14)) <1994AG(E)982>.
O +
(R1O)2P(O)Cl + R22R3P CH2 R1O P PR22R3
1
R O
Cl–
113 ð13Þ
1=C
R 14H29, C18H35
R2, 3
R = Me, Et, Pri
+ +
(Me2N)2P P(NMe2)2 HO O
(Me2N)2P P(NMe2)2
+ O P P OH
P 3BF4–
P
(NMe2)2 (NMe2)2 P
114 HO O
115 116
i. BuLi
CCl2 ii. Me3P Ar
Ar P P PMe2
NAr ArN ð14Þ
117 118
Ar = 2,4,6-Bu3t C6H2
4.12.1.5.9 From 1,1-diphosphorus-substituted alkenes

The addition of nucleophiles to diphosphonates 119 to give products 120 (Equation (15)),
described in chapter 4.12.1.5.14 of <1995COFGT(4)543>, has been used widely and the range
of nucleophiles used has been extended considerably. Examples include addition of the anion of
Meldrum’s acid <2001JOC3704>, a carbohydrate-derived amide in the synthesis of sialidase
inhibitors <1998HCA1896>, PH phosphoranes <1995PS(103)125>, the anions of aryl and
heteroaryl methyl ketones in the synthesis of antiinflammatory and antiarthritic compounds
<1998BMCL1093>, sulfur-containing aryllithium and aryl Grignard reagents
<1999PS(144)325>, 3-pyridyllithium <2003S1971>, substituted imidazoles <1998CPB1703>,
and a variety of enolate anions <1994JMC4449>. Addition of the anion of nitromethane to
the tetraethyl ester has been re-examined and found to give either the previously reported
monoadduct or the double addition product 121 depending on the conditions
<1996PS(112)137>. Treatment of the tetraethyl ester with sodium phthalimide results in double
Michael addition followed by a Wadsworth–Emmons reaction to afford 122 <2000PS(156)107>.
Pyridine and a range of other nitrogen heterocycles add to vinylidenediphosphonic acid to give
zwitterionic products such as 123 <1995BAU1528>. The diphosphonate 124 reacts with NaCN
to give product 125 in 70% yield (Equation (16)) <1994PS(86)13>.
O O O O
Nu–
(RO)2P P(OR)2 (RO)2P P(OR)2
ð15Þ
Nu
119 120
O O O
(EtO)2P P(OEt)2 O–
O N O OH
P(OEt)2 PO(OEt)2 P
PO(OEt)2 N+
O2N P(OEt)2 PO(OH)2
O (EtO)2OP
123
121 122
But But
PO(OEt)2 NaCN PO(OEt)2
O HO CN ð16Þ
PO(OEt)2 PO(OEt)2
t
But Bu
124 125
A number of methods involving the formation of cyclopropanediphosphonates have been

reported. Treatment of tetraethyl vinylidenediphosphonate with ethyl bromoacetate and LDA
results in cyclopropanation to give 126 in 72% yield <1999SC4251>, and use of substituted
-bromo esters similarly gives 127 <2002SC1543>. Addition of tribromomethyllithium followed
by base treatment gives 128 <2003S1971>, and the aziridines 129 resulting from reaction with
sulfonamides and iodosobenzene undergo transfer hydrogenation with ammonium formate to
afford 130 <2003S1971>. Cyclopropanation of the double bond in 131 with Me2S¼CH2 gives 132
(Equation (17)) <1995CB365>.
O O O O O O
(EtO)2OP PO(OEt)2 (EtO)2OP PO(OEt)2 (EtO)2OP PO(OEt)2
CO2Et Br
CO2Et R Br
126 127 128
O O O O
(EtO)2OP PO(OEt)2 (EtO)2OP PO(OEt)2
NSO2R
NHSO2R
129 130
Ph2(S)P
Ph2(S)P
Me2S CH2 P(S)Ph2
P(S)Ph2
Ph2(S)P ð17Þ
Ph2(S)P
P(S)Ph2
P(S)Ph2
132
131
4.12.1.5.10 From vinylphosphorus compounds

Addition of phosphite anions to a variety of fluorine-containing vinylphosphonates has been
examined. Thus, sodium diethylphosphite adds to compounds 133 with loss of F to give 134
<1995PS(104)197, 1996PS(111)62>, and the fluoroaryl compounds 135 similarly give 136
<1996JFC(77)71>. Removal of the ethyl ester group in compounds 135 generally results in
a change in the site of addition to give 1,2-diphosphonates, but for ArF = C6F5 only the original
regioselectivity is preserved with additional ring substitution to afford 137 <1996JFC(77)71>.
Ar Ar PO(OEt)2
CHPO(OEt)2 (EtO)2OP F
F3C F 2C PO(OEt)2
133 134 F F
PO(OEt)2
ArF ArF PO(OEt)2 F
CHPO(OEt)2 PO(OEt)2
EtO2C EtO2C PO(OEt)2
137
135 136
4.12.1.5.11 From alkynes

A detailed mechanistic study on the twofold addition of compounds such as (EtO)2P(O)H and
Ph2P(O)H to alkynes, RCCH, in the presence of KOH to give products 138 and 139 has
appeared. A variety of conditions including thermal, photochemical, ultrasound, and radical were
examined <1997JOC2414>. An improved method involving the treatment of HCCCO2Et
with (EtO)2P(O)H, KOH and alumina gives 140 in 95% yield <1999TL2311>.
O O O O O O
(EtO)2P P(OEt)2 Ph2P PPh2 (EtO)2P P(OEt)2
R R CO2Et
138 139 140

Treatment of compound 141 with an excess of diethyl phosphite gives 142 in 81% yield (Equation
(18)) <1994PS(86)13>. Heating the benzoylphosphonate 143 with trimethyl phosphite gives 144
for R = But, while for R = H the cyclic product 145 is obtained (Scheme 7) <1997JCS(P1)2545>.
But But
OMe (EtO)2P(O)H PO(OEt)2
O HO
ð18Þ
PO(OEt)2
t
But Bu
141 142
PO(OMe)2
PO(OMe)2
NMeBut
R = But
O 144
Heat
PO(OMe)2 (MeO)3P
NRMe PO(OMe)2
143 R=H O
P
N OMe
Me
145
Scheme 7
4.12.1.5.13 By oxidation of tricoordinate species

New oxidative transformations of Ph2PCH2PPh2 include its conversion, by oxidation and
reaction with ArN3, into the previously unknown oxide/imines Ph2P(O)CH2P(¼NAr)Ph2
<2000S2085>, reaction with 2,3-diazido-1,4-naphthoquinone to give 146 in 51% yield
<1997JOC4082>, and with di(2-azidobenzyl)amine to give a 97% yield of 147
<1997JOM(529)121>. Treatment with iodine gives the expected bis(iodophosphonium salt) in
solution but in the solid state this exists as the molecular complex 148 <1998JCS(D)2379>.
Electrochemical oxidation of tetraphenylporphine in the presence of Ph2PCH2PPh2 leads to
dimeric structures linked by Ph2P+CH2P+Ph2 <2001EJI659>. Reaction of compound 68
with benzyl alcohol followed by MCPBA gives 149 <2002JOC146>. More radical oxidation
processes are observed with cyclopolyphosphines. When compound 150 is treated with sulfur and
DBU the dithiadiphospholane 151 is produced in 40% yield, while the treatment with selenium
gives 152 in 94% yield. The dimethyl analog 153 reacts with selenium to give a 68% yield of the
selenadiphosphetane product 154 <2001CC2288>.
O O
N N
N H
N N
N N
N N N N
Ph2P PPh2
O Ph2P PPh2 O
147
146
I2 I2 O O O
MeO P P P OMe
Ph2P PPh2 BnO BnO OBn
148 149
S S Se Se
PhP PPh S Ph Se Se
P P P P
PhP PPh Ph
Ph S Ph
151 152
150
PhP PPh Se Se Se
PhP PPh P P
Ph Ph
153 154
4.12.1.5.14 Interconversions
New interconversions based on Cl2P(O)CH2P(O)Cl2 include its reaction with CF3CH2OH
and Et3N to give (CF3CH2O)2P(O)CH2P(O)(OCH2CF3)2 in 90% yield <1998TL6263,
1999PS(144)681>, an improved preparation of (BnO)2P(O)CH2P(O)(OBn)2 <2002SC211>, and
formation of symmetrical diphosphonic acid diesters (RO)(HO)P(O)CH2P(O)(OH)(OR) and tetra-
esters (RO)(MeO)P(O)CH2P(O)(OMe)(OR) and (RO)2P(O)CH2P(O)(OR)2 using tetrazole as a
catalyst <2001T8637, 2002SC2683>. The PH of hydrogen phosphinates such as
(EtO)2P(O)CH2P(O)H(OEt) reacts with aldehydes to give 155 <2001TL8451> and may be replaced
by an aryl group in a palladium-catalyzed process <2002SC2951> or by Me using NaN(TMS)2 and
MeI <1995JMC2596>. Selective mono-deprotection of (BnO)2P(O)CH2P(O)(OBn)2 can be achieved
with DABCO or quinuclidine <1995JOC2946> and the resulting POH converted into PCl
using oxalyl chloride <1995TL4785>. The new compounds (HO)PhP(O)CH2P(O)Ph(OH) and
(HO)MeP(O)CH2P(O)Me(OH) have been prepared by HCl hydrolysis of the corresponding diethyl
esters <2000BAU1045>. Transesterification of (MeO)2P(O)CH2P(O)(OMe)2 occurs on treatment
with chloromethyl pivalate and NaI to give the tetrakis(pivaloyloxymethyl) ester <1999TL8491>.
Amino acid-functionalized phosphonates 156 have been prepared from in situ generated
(EtO)2P(O)CH2P(O)Cl(OEt) and amino acid esters <1994TL5425>. Reaction of compound 152
with TMSCN removes one selenium atom to give 157, while with Bu3P a more profound change
results to give 158 and with potassium reductive cleavage affords 159 <2003EJI1461>.
R1
O O OH O O
Se Se Se
(EtO)2P P (EtO)2P P N CO2R2 P P
R
OEt EtO H Ph Ph
155 156 157
PhP Se Se Se –
Se Ph Ph P Se
P P P 2K+
Ph Se –Se Ph
158 159
The range of interconversions involving functionalization of the central carbon of

(EtO)2P(O)CH2P(O)(OEt)2 and related compounds has been extended considerably. Preparation
of (EtO)2P(O)CD2P(O)(OEt)2 with 93% D has been reported <1994JCS(P1)821>, and new compounds
(EtO)2P(O)CH(R)P(O)(OEt)2 have been prepared with R = CH2TMS <2001T4423>, CH2CO2Me
<1999S1056>, CO2Bn <1997CC87>, CH2CH(OBn)CH2NEt2, and CH2CH(OH)CH2N(Bn)2
<2001JCS(P1)1086>. Alkylation using farnesyl bromide <1997BMCL2435> and bromoalkyl-
phosphonates <2002PS(177)231> has also been reported. Radical addition by either selenide-
<1995TL6403> or xanthate-functionalized <2003SL387> bis(phosphonates) to alkenes has also been
used to access 2-alkylated products. Conjugate addition of the anion of (EtO)2P(O)CH2P(O)(OEt)2
may be carried out using phase-transfer catalysis conditions <1998JOU52> and a range of hetero-
cyclic Michael acceptors have also been used <2003SL785>. If iodine is added, ring closure to
cyclopropane diphosphonates occurs and this provides an alternative approach to compounds such
as 126 <1994SC1425>. Functionalization of C60 with methylenediphosphonate groups has been
achieved using (EtO)2P(O)CH2P(O)(OEt)2, I2, and a large excess of NaH to give both mono-
<2000TL3947> and difunctionalized <2001T7331> products, while the latter may also be obtained
as a mixture of isomers by the treatment with (EtO)2P(O)CHBrP(O)(OEt)2 and NaH
<2002JCS(P2)1173>. A detailed study of the C-2 alkylation of (BnO)2P(O)CH2P(O)(OBn)2 has
also been reported <1999BMC901>.
4.12.1.6 Penta- and Hexacoordinate Systems

There have been relatively few developments in this area since the publication of chapter 4.12.1.6 in
<1995COFGT(4)543>. Reaction of (Et2N)2PCH2P(NEt2)2 with either hexafluoroacetone followed
by HF <1999EJI1665> or hexafluorothioacetone dimer followed by warming to room temperature
<2001EJI2377> gives (Et2N)2F2PCH2PF2(NEt2)2. The bicyclic compound 160 reacts with hexa-
fluoroacetone to give the remarkable structure 161 <2001EJI195>. Treatment of the heterocycle
162 with tetrachloro-o-benzoquinone affords compound 163, which reacts with diethylamine to give
164. This interacts both with aryl azides <1996PS(109)493> and simple isocyanates
<1995TL2021> in a most unusual way to give products 165 and a mixture of 166 and 167,
respectively.
O O O
NMe CH(CF )
3 2
MeN NMe O O
MeN P O MeN
NMe
P P CF3
P MeN NMe
MeN NMe Cl2P P O
MeN CF3 ClP PCl Cl
NMe O
O O 162 Cl
160 161
Cl
O Cl
O 163
MeN MeN
NMe NMe
+ –
(Et2N)2P P O (Et2N)2P P O
Cl NO Cl
O Ar
Cl Cl
Cl Cl
Cl Cl
164 165
O O
MeN MeN
NMe NMe
+ –
+ –
(Et2N)2P P O (Et2N)2P P O
Cl Cl
O O O
N RN
O R
Cl Cl
Cl Cl
Cl Cl
166 167
4.12.2 FUNCTIONS CONTAINING ONE PHOSPHORUS AND ONE ARSENIC,

4.12.2.1 Phosphorus and Arsenic Functions

There have been very few developments in this area since the publication of chapter 4.12.2.1 in
<1995COFGT(4)543>. Treatment of Me2PCH2Li with AsCl3 gives (Me2PCH2)3As
<1997JOM(529)151> and five compounds of the type R12PCH2AsR22 have been
prepared from R12PCH2SnPh3, PhLi, and R22AsCl <1999JCS(D)1867>. Two compounds
Me3As+CH2P(O)(OR)2 I (R = C14H29, C18H35), of interest as lipids for DNA transfection,
have been obtained by the reaction of Me3As¼CH(TMS) with (RO)2P(O)Cl followed by acid
hydrolysis <2000AG(E)629>.
4.12.2.2 Phosphorus and Antimony Functions

There have been very few developments in this area since the publication of chapter 4.12.2.2 in
<1995COFGT(4)543>. Treatment of Me2PCH2Li with SbCl3 gives (Me2PCH2)3Sb
<1997JOM(529)151>, and reaction of the zirconacycle 12 with PhSbCl2 results in transmetalla-
tion to give 168 <1997CC1239>.
Sb P
Ph Ph
168
4.12.2.3 Phosphorus and Bismuth Functions

The first compound containing this function has now been described. Treatment of Me2PCH2Li
with BiCl3 gives (Me2PCH2)3Bi <1997JOM(529)151>.
4.12.3 FUNCTIONS CONTAINING PHOSPHORUS AND A METALLOID
4.12.3.1 Dicoordinate Phosphorus Derivatives

There have been no significant developments in this area since the publication of chapter 4.12.3.1
in <1995COFGT(4)543>.
4.12.3.2 Tricoordinate Phosphorus Derivatives
4.12.3.2.1 Tricoordinate phosphorus and silicon functions

the publication of chapter 4.12.3.2.1 in <1995COFGT(4)543>. These are categorized according
(i) From 1-metalloalkylsilanes

Several routes from TMSCH2MgCl to products of the type TMSCH2PR1R2 have been
described including transmetallation with CdCl2 followed by reaction with ArPCl2 to give
TMSCH2P(Cl)Ar in 53% yield (Ar = 2,4,6-(CF3)3C6H2) <1994JOM(469)125>, reaction
with Bn*PBr2 followed by MeMgCl to afford TMSCH2P(Me)Bn* (Bn* = 2-bromobenzyl)

<1994ZN(B)1606>, and reaction with PhP(Cl)N(Me)Ph followed by MeLi to give
TMSCH2P(Me)Ph in 85% yield <1998CC149>. Grignard reagents with other groups on
silicon have also been used and PhMe2SiCH2MgCl reacts with Ph2PCl to give PhMe2-
SiCH2PPh2 <2001JOM(629)7>, while (PriO)3SiCH2MgCl and PCl3 give [(PriO)3SiCH2]3P
which is reduced by LiAlH4 to afford (H3SiCH2)3P <1998JMAC1749>.
(ii) From 1-haloalkylsilanes

Treatment of MeSi(CH2Cl)3 with Ph2PLi gives MeSi(CH2PPh2)3 <1995ICA(235)215>. In the
course of studies on P/N macrocycles, ClCH2SiMe2NHSiMe2CH2Cl has been reacted with
PhPHLi to give PhPHCH2SiMe2NHSiMe2CH2PHPh <1996CC2783>, while treatment of
PhNHSiMe2CH2Cl with BuLi and PhPH2 gives PhN(Li)SiMe2CH2P(Ph)CH2SiMe2N(Li)Ph
<2001JA3960>.
(iii) From 1-metalloalkylphosphines

An improved procedure for the reaction of Me2PCH2Li with MeSiCl3 gives MeSi(CH2PMe2)3
in 52% yield <1997JA11244>. Treatment of HC(SiMe2Br)3 with Ph2PCH2Li gives
HC(SiMe2CH2PPh2)3 in 69% yield <2000JCS(D)2183> and the same reagent has been used to
convert terminal –SiMe2Cl functions in dendrimers into –SiMe2CH2PPh2 <1999CC1623,
2002EJO1085>. Dendrimers with terminal –SiCl3 groups are similarly converted into the analogs
with –Si(CH2PMe2)3 using Me2PCH2Li <2002JCS(D)1997>. Treatment of the fluorenylphos-
phine 169 with BuLi followed by TMSCl gives a 67% yield of 170 <2002EJI678>, while
reaction of (Me2P)2C(TMS)Li with PhSiCl3 leads via a series of rearrangements to the unexpected
product 171 <1995JOM(501)167>.
(iv) From 2-silylphosphaalkenes and -phosphaalkynes

An ene reaction between (TMS)2NP¼CH(TMS) and PhP¼C(Me)NMe2 gives the product 172
<1997JOC7605>, while TMSCP reacts with butadiene and 2,3-dimethylbutadiene to give
products 173 <1999EJO363>.
But TMS
But P But Ph PMe2
P But N TMS
N TMS Si PMe
H TMS P
Me2P Me2
169 170 171
R
NMe2
R
PhP TMS
P
(TMS)2N P P
TMS TMS
172 173
R = H, Me
(v) From phosphino(silyl)carbenes

Full details of the addition of (Pri2N)2P(TMS)C: to alkenes to give 1-phosphino-1-silylcyclo-
propanes have appeared <2000JA4464>, and by using acrylates and acrylamides with a chiral
auxiliary group this addition has been achieved asymmetrically <2001JOC8240>.
(vi) Miscellaneous methods

Heating compound 174 with diphenylacetylene leads to the loss of Ph2MeSiF and rearrangement
to afford 175 in 78% yield <2001JA9210>, while compound 176 rearranges by a 1,3-silyl shift on
boiling in toluene to give 177 (Ar = 2,4,6-But3C6H2, 85%) <1997CC293>.
Me F Ph Me
ArN ArN
Ph2MeSi Si PEt2 Si PEt P P TMS
Ph TMS TMS TMS
TMS
TMS
176 177
174
175
(vii) Interconversions
Treatment of TMSCH(Ph)PCl2 with HSiCl3 and Et3N gives TMSCH(Ph)P(SiCl3)2
<1996JOM(521)417>.
(viii) By reduction of tetracoordinate phosphorus functions

Deprotection of the bis(borane) adduct of compounds such as Ph2PCH2SiMe2CH2PPh2 may be
achieved using HBF4Me2O <1995T7655>.
4.12.3.2.2 Tricoordinate phosphorus and germanium or boron functions

There have been no significant developments in this area since the publication of chapters
4.12.3.2.2 and 4.12.3.2.3 in <1995COFGT(4)543>.
4.12.3.3 Tetracoordinate Phosphorus Derivatives
4.12.3.3.1 Tetracoordinate phosphorus and silicon functions

the publication of chapter 4.12.3.3.1 in <1995COFGT(4)543>. These are categorized according
(i) From 1-metalloalkylsilanes

The Grignard reagent TMSCH2MgCl reacts with (EtO)2CHP(O)H(OEt) to give
(EtO)2CHP(O)(H)CH2TMS in 72% yield <1999SL1633>, while the organocerium reagent
TMSCH2CeCl2 reacts with Ph2P(O)Cl to give TMSCH2P(O)Ph2 in 54% yield
<1999EJO2299>. The compound 83 mentioned earlier in Section 4.12.1.4.5 also contains a
function of this type.
(ii) From reactions of 1-haloalkylsilanes with phosphorus nucleophiles

Treatment of enantiomerically pure Ph(But)P(O)H with LDA followed by ClCH2SiMe2CH2Cl
gives the chiral product 178 with no racemization <2000EJO3205>. Reaction of the phosphirene
179 with TMSCH2OTf gives the salt 180 <1998S175>.
Ph Ph
O Me2 O +
But P Si P Ph P Me P TMS
Ph But Me
But Bu t TfO–
178 179 180
(iii) From 1-metalloalkylphosphorus compounds

The reaction of (MeO)2P(O)CH2Li with R3SiCl, R2SiCl2, and RSiCl3 to give
R3SiCH2P(O)(OMe)2, R2Si[CH2P(O)(OMe)2]2, and RSi[CH2P(O)(OMe)2]3, respectively, has been
carried out for R = C12H25 and C18H37 <1999JOM(575)126>. Treatment of Ph2P(¼NTMS)Me
with BuLi followed by Et2NSiMe2Cl gives Ph2P(¼NTMS)CH2SiMe2NEt2 in 72% yield
<1999JCS(D)3413>.
Various attempts to control the relative and absolute stereochemistry of silylation adjacent to
phosphorus have been described. A -stereocenter directs -silylation to give predominantly the
anti product such as in 181 <1996TL7461, 1998JCS(P1)3405>, while more remote auxiliary
groups have been examined in lithiation and silylation to obtain products such as 182
<2001JOC5566> and 183 <2001EJO3031>. Control of the stereochemistry of conjugate addition
of organometallics to vinylphosphine oxides followed by trapping with TMSCl has also been
achieved using both chiral organometallics to give products such as 184 <1998TL1637> and a
chiral phosphorus compound to give products such as 185 <2000SL1771>. Further examples of
the reaction of lithiated chiral phosphine–borane adducts with both Me2SiCl2 and Ph2SiCl2 to
give products such as 186 have been described. The lithium compounds may be obtained either
from an enantiomerically pure phosphine–borane adduct <1998OM668, 2001JOM(624)333> or,
for R = Me, by enantioselective deprotonation of ArP(BH3)Me2 in the presence of sparteine
<1995JA9075, 2001S2341>. Silylation of phosphetane oxides and sulfides bearing a P-menthyl
group to give products such as 187 <1996JOM(522)223> and 188 <1997T4363> has also been
examined.
Me O BH3 O
H
H (EtO)2P N Ph
PPh2 Ph2P N
Ph OBn
TMS TMS O
TMS O Et
181 183
182
Ph
O BnN Ph O O R BH3 Me BH3
2
Ph2P P R P Si P Ar
R N Ar R
TMS Tr TMS
186
184 185
TMS
TMS S
O
Men P
Men P
Bn
187 188
The regioselectivity of lithiation and silylation of ,- and ,-unsaturated phosphonates

has been further examined and, although -silylation usually predominates, there are cases
where -silylation occurs <1996JCS(P1)931, 2000JOC4175>. The P-methyl groups of cyclophos-
phazenes may be converted into CH2Si(OMe)3 by the treatment with BuLi followed by
(MeO)3SiCl <1999M89>. Reaction of (RO)2P(O)CCl3 with 2 equiv. of BuLi and TMSCl
initially gives the carbenoid (RO)2P(O)C(Cl)(Li)TMS and when this reacts with ,!-dihalides
the cyclic products 189 result <1995S239>. In an unusual process, reaction of 190 with an excess
of MeLi gives both the cyclic product 191 (42%) and the acyclic product 192 (26%)
<1998JOC2338>.
O
TMS Me2
(RO)2P TMS Si
PO(OEt)2 P P TMS
(CH2)n OEt
Ph Ph O Ph O OEt
189 190 191 192
n = 3–5
(iv) From reactions of phosphorus ylides with silyl halides and from 2-silyl phosphaalkenes
generated in other ways
Reaction of (Me2N)3P¼CH2 with TMSOTf and (MeO)3SiOTf gives the expected phosphonium
triflates, while with Pri2PCl2 only one chlorine is displaced to give (Me2N)3P+CH2PPri2(Cl) Cl
<1997ZN(B)669>. The cyclic oligomers of R1R2Si¼S react with a wide range of simple ylides to
give zwitterionic products such as 193 and 194 <2000BAU920> and these may undergo further
transformations as illustrated by reaction of 193 with EtBr to give 195 and of 194 with AcCl to
give 196 <2000BAU933>. The phosphonium salt But2P+¼CHTMS AlCl4 undergoes Diels–
Alder cycloaddition with dimethylfulvene to give 197 and 198 and with anthracene to give 199
<1997JOM(535)91>.
+ S– + S– + SEt + Cl
Ph3P Si Et3P Si Ph3P Si Et3P Si
Me2 Me2 Me2 Br– Me2Cl–
193 194 195 196
+
– TMS PBu2t
AlCl4 –
– AlCl4
+ AlCl4
PBu2t +
PBu2t
TMS TMS
199
197 198
(v) From 1-silyl-1-phosphorus-substituted alkenes

Catalytic hydrogenation of 200 gives 201 in 99% yield <1998JOC6239>. Conjugate addition of
alkyllithiums to -silylallenylphosphonates 202 gives products 203 <1994RTC547>. Stereoselec-
tive addition of a chiral heterocyclic anion to (EtO)2P(O)C(¼CH2)TMS to give 204 has been
examined <2002TA233>.
4.12.3.3.2 Tetracoordinate phosphorus and germanium or boron functions

There has only been one significant development in the synthesis of compounds of this type since
the publication of chapters 4.12.3.3.2 and 4.12.3.3.3 in <1995COFGT(4)543>. The cyclic trimer
of Me2Ge¼S reacts with Et3P¼CHMe to give the zwitterionic product 205 in 84% yield
<2001BAU1679>.
4.12.3.4 Higher-coordinate Phosphorus Derivatives
4.12.3.4.1 Higher-coordinate phosphorus and silicon functions

There has only been one significant development in the synthesis of compounds of this type since
the publication of chapter 4.12.3.4.1 in <1995COFGT(4)543>. The compound F4PCH2TMS
(whose preparation remains unpublished) reacts with Me2P(O)CH2N(Me)TMS with loss of

TMSF to afford 206 in 90% yield <1995ZN(B)1818>.
O O O O
(EtO)2P TMS (EtO)2P TMS (EtO)2P TMS (EtO)2P TMS
•
OEt OEt R
200 201
202 203
EtO O
H
P(OEt)2
N O Me
+ S–
i N TMS Et3P Ge Me2P N
Pr Me2 P TMS
F3
OEt
205 206
204
4.12.3.4.2 Higher-coordinate phosphorus and germanium or boron functions

As stated in chapters 4.12.3.4.2 and 4.12.3.4.3 of <1995COFGT(4)543> compounds of this type
remain unknown.
4.12.4 FUNCTIONS CONTAINING PHOSPHORUS AND A METAL
4.12.4.1 Group 1 and 2 Derivatives
4.12.4.1.1 Compounds containing phosphorus and lithium

A detailed study of the configurational stability of -lithiated phosphine oxides
R12P(O)CH(Li)R2 has concluded that they are not configurationally stable even at 78 C on a
short timescale <1995TL8473, 1996JCS(P1)2567>. The X-ray structure of (Ph2P(O)CH2Li)2
(TMEDA)2 has been reported <1999CC1401> and X-ray structures of Me2P(¼NTMS)CH2Li,
which exists as a cyclic tetramer, and Pri2P(¼NTMS)CMe2Li, which exists as a dimer,
show considerable ‘‘aza-enolate’’ character in each case with the lithium located closer to N
than to C <1996CB253>. Treatment of nitriles RCH2CN with (EtO)2P(O)Cl and 2 equiv.
of LDA gives the -lithiated phosphonates 207 <2000JCS(P1)3311, 1994RTC45>. Reaction of
(2-methoxybenzyl)di-p-tolylphosphine with BuLi in diethyl ether gives a lithiated derivative,
which exists in the solid state as the dimeric structure 208 <2001AG(E)183>.
4.12.4.1.2 Compounds containing phosphorus and sodium

Reaction of compound 208 with NaOBut results in transmetallation to give the sodium derivative
209 <2001AG(E)183>.
4.12.4.1.3 Compounds containing phosphorus and potassium

The ease of conversion of R1R2P(O)CH2CN into the potassium derivatives R1R2P(O)CH(K)CN
has been determined for a range of phosphonates, phosphinates, and phosphine oxides
by the measurement of their pKa values in DMSO using MeS(O)CH2 K+ as a base
<1994JGU1735>.
4.12.4.1.4 Compounds containing phosphorus and beryllium

There have been no significant developments in this area since the publication of chapter
4.12.4.1.4 in <1995COFGT(4)543>.
4.12.4.1.5 Compounds containing phosphorus and magnesium

4.12.4.1.5 in <1995COFGT(4)543>.
4.12.4.1.6 Compounds containing phosphorus and heavier group 1 and 2 metals

The first compounds containing a PCCa function have been prepared by the treatment of 208
and 209 with CaI2. In the first case the reaction proceeds with loss of Me to give 210, which exists
in the solid state as a cubane tetramer, while in the second case the methoxy groups are retained
to give the sodium calcate structure 211 <2001AG(E)183>.
O OEt2
Tol2 OEt Tol2
R P(OEt)2 P
2
P OEt2
Li OMe Na OMe
Li CN MeO Li MeO Na
P P
207 Et2O Tol2 Et2O Tol2
Et2O
R = H, alkyl, (CH2)4CN
208
209
Et2O
PTol2
Na+ PTol2
Ca(THF) Tol2P
PTol2
O
Ca– OMe
210
O MeO
Me
211
4.12.4.2 Compounds Containing Phosphorus and a Lanthanide

in <1995COFGT(4)543>.
4.12.4.3 Transition Metal Derivatives
4.12.4.3.1 Compounds containing phosphorus and scandium or yttrium

4.12.4.3.1 in <1995COFGT(4)543>.
4.12.4.3.2 Compounds containing phosphorus and titanium, zirconium, or hafnium

The zirconacycles 212 and 12 react with diazo compounds to give the zwitterionic adducts 213
and 214, respectively (Scheme 8) <2003NJC675>.
RCH=N2 +
PPh2 – PPh2
Zr Zr
Cp2 Cp2 N
N CHR
212 213
RCH=N2
– +
Zr P Cp2Zr PPh
Cp2 Ph
N
12 N CHR
214
Scheme 8
4.12.4.3.3 Compounds containing phosphorus and vanadium, niobium, or tantalum

4.12.4.3.3 in <1995COFGT(4)543>.
4.12.4.3.4 Compounds containing phosphorus and chromium, molybdenum, or tungsten

The only significant developments in this area since the publication of chapter 4.12.4.3.4 in
<1995COFGT(4)543> have involved compounds containing phosphorus and tungsten. Treat-
ment of cationic carbene complexes 215 with NaSCN <1994ICA(222)77> or isonitriles R2NC
<1998JOM(553)103> results in rearrangement to give 216 and 217, respectively, while with
sodium cyclopentadienide there is simple addition to give 218 <1996JOM(520)59>. Addition of
trimethylphosphine to tungstacyclopropene complex 219 gives 220 <1999OM3414>. In a remark-
able process, the phosphinidene complex Cp*P[W(CO)5]2 reacts with but-2-yne under thermal or
photochemical conditions to give 221 <2000JCS(D)2493>.
Cp Cp PPh2 Cp PPh2
+ PPh2 +
OC W – – SCN W R1 R2NC W R1
BF4 /PF6
Me3P –
R1 Me3P Me3P BF4
O O
215 216 217
Cp
PPh2 Cp* Cp* OC
OC W Ph Ph
R1 TMS W TMS W– + OC W P
Me3P ON ON PMe3 OC CO W(CO)5
Cp
218 219 220 221
4.12.4.3.5 Compounds containing phosphorus and manganese or rhenium

The only significant development in this area since the publication of chapter 4.12.4.3.5 in
<1995COFGT(4)543> is a report that the rhenium carbene complex 222 reacts with Me3P to
give 223 <1997JA5750>.
4.12.4.3.6 Compounds containing phosphorus and iron, ruthenium, or osmium

<1995COFGT(4)543> is a report that the ruthenium carbene complex 224 reacts with Me3P to
give 225 <1994OM971>.
+
Cp Cp Ph Ph PMe3
– Cp – Cp
OC Re OC Re + Ru Ru
OC PMe3 CO CO
OC
222 223 224 225
4.12.4.3.7 Compounds containing phosphorus and cobalt, rhodium, or iridium

Reaction of the cobalt complex 226 with ButCP results in insertion to give 227
<1994ICA(222)13>. Oxidation of the dinuclear rhodium complex 228 with oxygen in the
presence of silica gives 229 <1997OM1531>. Products from the interaction of CH2I2 with
RhI(CO)(PEt3)2 include 230 <1998ICA(280)99>.
O O But F3C CF3

P Cp CO
Cp# Co Co Cp# Co Cp#
Cp# Co Rh Rh
Ph2P Cp
O O
226 227
R
Cp# = C5Me4CH2CH2CH=CH2 228
+
Cp PPh2 PEt3
Rh
Rh O Et3P – I
F3C Rh
OC I
Cp R I
F3C
230
229
4.12.4.3.8 Compounds containing phosphorus and nickel, palladium, or platinum

The ylide Ph3P¼CHC(O)NMe2 coordinates to a variety of palladium compounds exclusively
through C rather than O or N to give products of the type 231 <1998JCS(D)1699>. Reaction of
PhS(O)CH2PdCl(PPh3)2 with Ph3P¼CH2 takes place with displacement of one Ph3P to give 232
<1994OM441>. Reaction of the bis(ylide) Ph3P¼CHC(O)CH¼PPh3 with PdCl2 first gives
233 <1998OM5887> but when this is heated it undergoes cyclopalladation to afford 234 whose
chemistry has been examined <1999IC2455>.
+ +
+ PPh3 PPh3
Ph3P CONMe2 PPh3
O Cl
+ – Cl –
–
PdLn S Pd – PPh3 O Pd Pd O
Ph
Cl
231 232 + + (ClO4–)2
PPh3 PPh3
233
Ph2 +
P+ PPh3
–
Pd O
Cl –
Cl (ClO4–)2
O Pd
+ +
Ph3P P
Ph2
234
The reaction of K+ [PtCl3 CH2¼CH2] with stabilized ylides to give products such as 235 has
been described <1996ICA(245)157> and the Pt(IV) anion PtCl5NH3 reacts similarly to give 236
<2002OM3744>. Reaction of Ph3P¼C¼C¼O with K+ [PtCl3 C2H4] or PtCl2(C2H4)2
followed by a range of nucleophiles leads to systems such as 237–239 <2000OM1373>. The
dinuclear platinum complexes 240 are found to exist predominantly in the isomeric 51 form 241
<1992JA4687> and when these compounds are treated with CO and then heated the 11
compounds 242 are produced with loss of the ketone R2CO <1994OM478>. The carbonyls in
242 may then be stepwise displaced by phosphines while retaining the 11 structure
<1994OM830>. Controlled peracid oxidation of the ButCH¼PButPt(PPh3)2 adduct gives the
oxide 243 <2003CC1092>.
COR Cl NH O
Cl 3
+ – Cl
+ – Cl + Pt – PPh3 Pt
Ph3P Pt
–
PPh3 Cl Cl NMe2
Cl Cl +
COR PPh3
COR
235 236 237
PPh2
+
+
PPh3 PPh3
R Pt Pt R
O MeO – Cl O
ButHN – Cl Pt •
Pt Cl – Ph2P
Cl – NHBut O
O +
+
PPh3 PPh3
239 240
238
Ph2 O
PPh2 P But
P
But
R Pt Pt R OC Pt Pt CO Pt
Ph2P
Ph2P Ph3P PPh3
242 243
241
4.12.4.3.9 Compounds containing phosphorus and copper, silver, or gold

Compounds of the type (RO)2P(O)CH2Cu and (R2N)2P(O)CH2Cu, formed by the treatment of
the corresponding methylphosphonates or phosphonamidates with BuLi followed by CuI, are
stable at room temperature and undergo palladium-catalyzed coupling with aryl iodides
<2001JGU172>. Treatment of Ph2PCH2PPh2+CH2CO2Me ClO4 with Ag(acac)Ph3P gives 244
whereas the corresponding oxide or sulfide Ph2P(¼X)CH2PPh2+CH2CO2Me ClO4 give the
bicyclic structure 245 <1995JCS(D)805>.
Ph2 Ph2
Ph3P +P ClO4–
P
Ph3P
Ag +
X PPh2
PPh2 Ag
O– Ag
O3Cl MeO
MeO2C O
PPh3
244 245
X = O, S
4.12.4.3.10 Compounds containing phosphorus and zinc, cadmium, or mercury

<1995COFGT(4)543> is a report that palladium-catalyzed reaction of (EtO)2P(O)CH2I with
PhZnCl results in formation of (EtO)2P(O)CH2ZnCl <2001JGU172>.
4.12.4.4 Group 13 and 14 Derivatives
4.12.4.4.1 Compounds containing phosphorus and aluminum

4.12.4.4.1 in <1995COFGT(4)543>.
4.12.4.4.2 Compounds containing phosphorus and gallium, indium, or thallium

4.12.4.4.2 in <1995COFGT(4)543>.
4.12.4.4.3 Compounds containing phosphorus and tin or lead

Reaction of Ph2P(S)CH2Li with Ph3SnCl, Ph2SnCl2, PhSnCl3, and SnCl4 has been used to
prepare, respectively, Ph3SnCH2P(S)Ph2, Ph2Sn[CH2P(S)Ph2]2, PhSn[CH2P(S)Ph2]3, and
Sn[CH2P(S)Ph2]4 <1994POL1705>. In contrast Ph2P(O)CH2Li reacts only once with Ph2SnCl2
to afford Ph2Sn(Cl)CH2P(O)Ph2 <1994POL1705>. The influence of a remote chiral auxiliary on
the stereoselectivity of deprotonation and stannylation of a phosphine–borane adduct to give
246 has been examined <2001JOC5566>, and the addition of a chiral heterocyclic anion to
(EtO)2P(O)C(¼CH2)SnPh3 to give 247 has been reported <2002TA233>. Reaction of Me3SnCH2I
and Ph3SnCH2I with BuLi followed by R2PCl has been used to prepare a range of products such
as Me3SnCH2P(menthyl)2, Ph3SnCH2P(menthyl)2, and Ph3SnCH2P(mesityl)2 <1999JCS(D)1867>.
Treatment of the zirconacycle 12 with Me2SnCl2 results in transmetallation to give
248 <1997CC1239>. Hydrostannylation of phosphaalkynes, RCP, using Ph3SnH results in
twofold addition to give RCH(SnPh3)PH(SnPh3) in 75–80% yield <1998EJI227>. Finally, the
bicyclic compound 28 described earlier in Section 4.12.1.3.9 contains a function of this type.
BH3 EtO O
H
H P(OEt)2
Ph2P N N
OBn
N SnPh3
Bu3Sn O Et Pri Sn P
Me2 Ph
OEt
246
247 248
4.12.4.5 Actinide Derivatives

in <1995COFGT(4)543>.
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Biographical sketch
Alan Aitken was born in the Dumfries and Galloway area of SW Scotland.
He studied at the University of Edinburgh where he obtained a B.Sc. in
1979 and his Ph.D. in 1982 under the direction of Dr I. Gosney and
Professor J. I. G. Cadogan. After spending two years as a Fulbright Scholar
in the laboratories of Professor A. I. Meyers at Colorado State University
he was awarded a Royal Society Warren Research Fellowship and moved
in 1984 to the University of St Andrews where he has been a Senior Lecturer
since 1997. His research interests are in the area of synthetic and mechani-
stic organic chemistry including asymmetric synthesis, synthetic use of
flash vacuum pyrolysis, heterocyclic chemistry, organophosphorus, and
organosulfur chemistry.
4.13
Functions Containing at Least One
As, Sb, or Bi with or without a
Metalloid (Si or Ge) or a Metal
E. FOUQUET and A. HERVÉ
Laboratoire de Chimie Organique et Organométallique,
Bordeaux, France
4.13.1 FUNCTIONS CONTAINING TWO ARSENIC, ANTIMONY,

OR BISMUTH GROUPS 576
4.13.1.1 Functions with Two Similar Elements: R12AsCR22AsR32, etc. 576
4.13.1.1.1 Arsenic functions 576
4.13.1.1.2 Antimony functions 579
4.13.1.1.3 Bismuth functions 580
4.13.1.2 Functions with Two Dissimilar Elements: R12AsCR22SbR32, etc. 580
4.13.2 FUNCTIONS CONTAINING ARSENIC, ANTIMONY, OR BISMUTH
AND A METALLOID (Si OR Ge) 581
4.13.2.1 Arsenic Derivatives 581
4.13.2.1.1 Arsenic and silicon functions 581
4.13.2.1.2 Arsenic and germanium functions 583
4.13.2.2 Antimony Derivatives 584
4.13.2.2.1 Stibines 584
4.13.2.2.2 Stiboranes 587
4.13.2.3 Bismuth Derivatives 588
4.13.2.3.1 Bismuth and silicon functions 588
4.13.2.3.2 Bismuth and germanium functions 590
4.13.3 FUNCTIONS CONTAINING ARSENIC, ANTIMONY OR BISMUTH, AND A METAL 590
4.13.3.1 Arsenic Derivatives 590
4.13.3.1.1 Arsenic and group 1 metals 590
4.13.3.1.2 Arsenic and group 14 metals 590
4.13.3.2 Antimony Derivatives 591
4.13.3.2.1 Antimony and group 1 metals 591
4.13.3.2.2 Antimony and group 14 metals 591
4.13.3.3 Bismuth Derivatives 591
4.13.3.3.1 Bismuth and group 1 metals 591
4.13.3.3.2 Bismuth and group 14 metals 591
575
576 Functions Containing at Least One As, Sb, or Bi with or without a Metalloid or a Metal
4.13.1 FUNCTIONS CONTAINING TWO ARSENIC, ANTIMONY,

OR BISMUTH GROUPS
4.13.1.1 Functions with Two Similar Elements: R12AsCR22AsR32, etc.
4.13.1.1.1 Arsenic functions
(i) Chloro derivatives

Bis(dichloroarsino)-, bis(chloroalkylarsino)-, and bis(chloroarylarsino)methane derivatives are
precursors of a wide range of bis(arsino)methane derivatives. Bis(dichloroarsino)methane 1a is
prepared in good yield by the reaction of arsenic oxide As2O3 with acetyl chloride and AlCl3 at
170 C followed by treatment with SOCl2 <1949CB152>. Acetyl chloride and AlCl3 are also used
as reagents to transform arsenic acids MeAsO(OH)2 and PhAsO(OH)2 into the corresponding
chloroarsines 2a and 2b <1949CB152> (Scheme 1).
Cl2As AsCl2 Cl(R)As As(R)Cl

1a: R = H 2a: R = Me
1b: R = Me 2b: R = Ph
Scheme 1
(ii) Hydride, alkyl, and aryl derivatives

Bis(dichloroarsino)methane 1a is a particularly useful substrate for the preparation of tetraalkyl and
tetraaryl derivatives. Thus, its reactions with methylmagnesium chloride and ethylmagnesium
chloride afford the corresponding tetramethyl and tetraethyl derivatives 3b and 3c
<1987CB1281>. Chloroarsine 1a is also reduced on treatment with LAH to give bisarsinomethane
3a (m.p. 91–96 C). An alternative method for the synthesis of alkyl and aryl derivatives 3 is the
reaction of chlorodialkyl- or chlorodiarylarsines with dialkyl- or diarylarsinomethylsodium and
lithium derivatives as exemplified by the synthesis of bis(diphenylarsino)methane 3 via the reaction
of diphenylchloroarsine Ph2AsCl with diphenylarsinomethyllithium 4. Symmetrical derivatives can
also be synthesized by the reaction of dialkyl- or diarylarsino sodium or lithium with 1,1-dichloro-
methane or 1,1-dichloroethane. Thus, arsine 3e is prepared by the reaction of (p-MeOC6H4)2AsLi
with 1,1-dichloromethane, while derivative 3f is formed by mixing Ph2AsNa with 1,1-dichloro-
ethane. Finally, symmetrical and unsymmetrical bisarsonium methyltrifluoromethanesulfonate salts
6 are prepared by the reaction of triphenylarsonium methyltrifluoromethanesulfonate salt 5 with a
small excess of triphenylarsine R3As (R = Ph, Et, Me) in acetonitrile at room temperature and are
isolated in yields ranging from 38% to 96% <1998ZN599> (Scheme 2).
R1
R23As AsR22
3a: R1 = R2 = R3 = H 3d: R1 = H, R2 = R3 = Ph
3b: R = H, R = R = Me 3e: R1 = H, R2 = R3 = p-MeOC6H4
1 2 3
3c: R1 = H, R2 = R3 = Et 3f: R1 = Me, R2 = R3 = H
+ + +
Ph2As Li Ph3As OTf Ph3As AsR3
4 5 R = Me, Et, Ph
6
Scheme 2
Functions Containing at Least One As, Sb, or Bi with or without a Metalloid or a Metal 577
(iii) Acid derivatives

Hydrolysis of (dichloromethane)arsine 1a readily affords the corresponding dimeric bisoxide 7,
which gives bisarsenic acid derivative 8 on further oxidation with H2O2 <1949CB152>. Methyl-
ene bis(phenylarsenic acid) 9a is prepared by the reaction of phenylarsenic oxide with dibromo-
methane, while methylene bis(methylarsenic acid) 9b is formed by mixing oxide 7 with
methyliodide <1970ZAAC120>. Bisphenylarsenic acid 9a can also be obtained by dephenylation
of compound 3d on treatment with LAH (Scheme 3).
As As (HO)2As As(OH)2 R(HO)As As(OH)R

O O O O O O
7 8 9a: R = Ph
9b: R = Me
Scheme 3
(iv) Amino derivatives

Reactions of chloroarsines of type 1 or 2 with nucleophiles open routes to various compounds.
Thus, compounds 1a and 2a react with secondary amines in Et2O at 30 C to lead to the
corresponding tetraamino and diamino derivatives 10 <1975JOM393> and 11
<1975ZAAC202>. Bis(dichloroarsine) 1a also reacts with primary amines, thus providing the
2,4,6,8-tetraaza-1,3,5,7-tetraarsadamantanes 12 oils. The chemistry of amino arsines and related
compounds has been reviewed <1982S173> (Scheme 4).
As
RN NR
RN Y Y
R2As AsR2 R(Me)As As(Me)R As N As As As
As R O O
10 11 N
RN R
13a: X = NMe,Y = O
R = NMe2, NEt2, NPr2n,NBun2, N, N R = Me, Et, Prn, Pri, Bun, But 13b: X = Y = S
12 13c: X = Y = NMe
Scheme 4
Tetramethylamino arsine (10; R = NMe2) undergoes AsN bond fission on reaction with nucleo-
philes. Thus, its reaction with 2-(methylamino)ethanol affords the cyclic arsenic derivative 13a
(45%, b.p. 155 C/0.01 mm Hg), while ethane-1,2-dithiol furnishes compound 13b (40%, b.p.
175 C/0.001 mm Hg). All these derivatives can be obtained directly from bis(dichloroarsino)methane
1a, as illustrated by the formation of compound 13c in 55% yield by the reaction of 1a with
1,2-bis(N-methylamino)ethane <1991ZAAC151>. Aminoarsines 10 (R = NMe2) and 11
(R = NMe2) also react with oximes of general form R1R2C¼N-OH to give the corresponding arsenic
oxide derivatives 14 and 15 in yields ranging from 75% to 100% <1992JPR716> (Scheme 5).
R2 R2
R1 R2 R1
O O O N HO O N
OH OH
Me As R1 O As Me As N O As
Me As R1 O As Me As OH N O As
OH
O O O N HO O N
R1 R2 R1
R2 R2
14 R1 = H, Me 16
15 17
R2 = H, Me, Ph
Scheme 5
It is interesting to note that when mixing with salicylaldoxime C6H4(OH)CH¼NOH, com-

pounds 10 and 11 react exclusively with the phenolic hydroxyl to afford the phenoxy derivatives
16 and 17 in 95% and 65% yields, respectively (Scheme 5).
(v) Radicals
X-ray irradiation of single crystals of methylene diarsenic acid 8 gives rise to a variety of radicals
in which the arsenic-centered radicals 18 and 19 have been identified by electron spin resonance
<1981HCA329> (Scheme 6).
HO OH HO OH
As As As As
HO O– O OH HO O O OH
18 19
Scheme 6
(vi) Cyclic compounds

Alkyl- and arylarsenic dichlorides react readily with malonic esters to afford the 1,3-dialkyl- and
1,3-diaryl-1,3-diarsacyclobutanes 20 in yields ranging from 10% to 75% <1976AG(E)56,
1978JCR252> (Scheme 7).
R1 R
R2OOC As COOR2 TMSO As OTMS
AsR
R2OOC As COOR2 But As But
But OTMS
R1 R
R1 = Me, Ph R2 = Me, Et, But R = Me, Et
22a: R = Me
20 21 22b: R = Et
Ph Ph
C
C(TMS)3
AsC(TMS)3 (TMS)3C As As C(TMS)3
As
C OMe
C C C
Ph Ph Ph Ph Ph Ph
23 24 25
Scheme 7
Alternatively, 1,3-diarsacyclobutanes 21 can be prepared by the photodimerization of the corres-

ponding arsoranes 22a and 22b, and are isolated in 86% (m.p. 94 C) and 95% (m.p. 123 C)
yields, respectively <1980ZAAC(470)144, 1980ZAAC(470)157>. Thermal dimerization of
cumulene 23, generated by the treatment of 24 with butyllithium in THF at 78 C, furnishes
diarsacyclobutane 25 (47%, m.p. 224 C). Other cyclic derivatives can be synthesized by the
reaction of chloroarsines with K2SN2: thus, compound 27 is formed from 26
<1987ZN(B)118>. Similarly, compound 28 is obtained from chloroarsine 1b by a double reaction
with K2SN2. Finally, reductive elimination of chlorine from bis(methylchloroarsino)methane by
sodium amalgam provides a convenient route to 1,2,4,5-tetramethyl-1,2,4,5-tetraarsacyclohexane
29 <1975ZAAC202> (Scheme 8).
Me
Me
Me As As
But But Me Me
But But As As N N As As
As As S
N N N N As As
Cl Cl S S Me Me
26 27 28 29
Scheme 8
4.13.1.1.2 Antimony functions
(i) Alkyl and aryl derivatives

A general route to groups flanked by two antimony atoms derives from the reaction of dialkyl- or
diarylstibino sodium or lithium with 1,1-dichloromethane. Thus, the treatment of diphenylmethyl-
stibine with sodium in liquid NH3 and subsequent reaction with 1,1-dichloromethane affords
bis(phenylmethylstibino)methane 30 (b.p. 130–168 C/0.01 mmHg) <1972JOM333>. Alterna-
tively, alkyl or aryl derivatives such as bis(dimethylstibino)methane 33, are formed by the reaction
of bis(dichlorostibino)methane 32, generated by dephenylation of bis(diphenylstibino)methane 31,
with alkylmagnesium chloride (MeMgCl) (Scheme 9).
Me Me
Sb Sb Ph2Sb SbPh2 Cl2Sb SbCl2 Me2Sb SbMe2
Ph Ph
30 31 32 33
Scheme 9
(ii) Thio derivatives

Tetrachlorodistibine 32 also reacts with dithioamides, dithioesters, or dithiophosphonates to furnish the
corresponding compounds 34–36 <1992ZAAC164>. Finally, reduction of antimony(V) chloride 37
occurs easily on treatment with sodium sulphide in methanol at room temperature, allowing isolation of
the stable asymmetric monosulfide 38 (40 %, m.p. 89–90 C) <1975JOM57> (Scheme 10).
S S S S S S
Sb Sb Sb Sb Sb Sb
R2N S S NR2 RO S S OR (RO)2P S S P(OR)2
2 2 2 2 2 2
34a: R = Me 35a: R = Et 36a: R = Me

34b: R = Et 35b: R = Pri 36b: R = Pri
S
Cl2(Ph)(Me)Sb Sb(Me)(Ph)Cl2 Ph(Me)Sb Sb(Me)Ph
37 38
Scheme 10
(iii) Cyclic compounds

Complex salts such as 39 are obtained by the reaction of tetrachlorodistibine 32 with the suitable
quaternary bromide salts and subsequent heating <1992ZAAC157>. The chloro-bridged polymeric
geminal C-centered distibine complex 41 is formed by mild thermolysis of (2-pyridyl) (SiMe3)2CSbCl2 via
elimination of TMSCl and a [2+2]-stereospecific cis-cycloaddition of stibaalkene 40 <1998CC575>.
Hexastibino-cage compound 43 is synthesized by the treatment of a DME solution of FeCl3 with 1 equiv.
of the diphosphastibolyl ring anion 42 (61%, m.p. 82 C) <1997CC305> (Scheme 11).
Finally, reaction of the phosphavinyl Grignard reagent [CyP¼C(But)MgCl(OEt)2] 44 with
SbCl3 leads to compound 46 (66%, m.p. 83–85 C) probably via a coupling and a subsequent
rearrangement of two molecules of the supposed intermediate 45 <2002MI1209> (Scheme 12).
2–
X Sb Sb X
CH2Cl2 2– X
X X
Cl2Sb SbCl2 + R4EBr Cl2BrSb SbBrCl2 2R4E+ 2R4E+
X
25 °C, –3 h 100–110 °C
32 39
X = Br, Cl
R4E = Et4N, Ph4P, Ph4As, Ph4Sb
TMS
N Cl
PhMe
TMS 50 °C, 4 h TMS Cl
TMS Sb Sb
N N Cl
SbCl2 SbCl N
TMS
40 41
But FeCl3 But Sb

P But P But
P DME, 25 °C,18 h P [4+2] But
P P Sb P
Sb Sb P Cycloaddition Sb
P P But
But But But
But
42 43
Scheme 11
But
SbCl3
Cl
Et2O, –78 °C Cy SbCl2 Sb Cl
CyP C(But)MgCl(OEt)2 P P
But
Cl2Sb t P Cy
Bu
Cy
44 45 46
Scheme 12
4.13.1.1.3 Bismuth functions

Bismuthinomethane derivatives are prepared analogously to their distibino counterparts. Thus,
bis(diphenyllbismuthino)methane 47 is obtained from Ph2BiNa by reaction with 1,1-dichloro-
methane <1980AG(E)723, 1985CB1039> (Scheme 13).
Ph2Bi BiPh2
47
Scheme 13
4.13.1.2 Functions with Two Dissimilar Elements: R12AsCR22SbR32, etc.

To the best of our knowledge, only compounds containing arsenic and antimony have been
prepared. A convenient approach to such compounds is illustrated by the reaction of stibino-
methyllithium, obtained from bis(diphenylstibino)methane 31 on treatment with PhLi, with
diphenylchloroarsine in THF to afford the derivative 48 in 23% yield <1983CB473,
1985CB2353>. Another example is the formation in 57% yield of the trifluoromethanesulfonate
salt 49 by the reaction of triphenylarsonium methyltrifluoromethanesulfonate 5 with triphenyl-
stibine in refluxing acetonitrile (Scheme 14).
+ +
Ph2As SbPh2 Ph3As SbPh3
48 49
Scheme 14
4.13.2 FUNCTIONS CONTAINING ARSENIC, ANTIMONY, OR BISMUTH

AND A METALLOID (Si OR Ge)
4.13.2.1 Arsenic Derivatives
4.13.2.1.1 Arsenic and silicon functions
(i) Arsines
(a) Chloroarsines. In general, chloroarsines containing an sp3-carbon flanked with one arsenic
and one silicon are prepared from arsenic trichloride and a silylated lithium or Grignard reagent.
Thus, bis(trimethylsilylmethyl)chloroarsine 50 is formed by the reaction of arsenic trichloride with
trimethylsilylmethylmagnesium chloride in a 1:1 molar ratio in THF <1991PS(57)1>. In a similar
fashion, arsenic trichloride reacts with bis(trimethylsilyl)methyllithium in Et2O to furnish chloro-
arsine 51 (m.p. 70–72 C, 61%) <1980JCS(D)2428>. Other derivatives can be obtained in the same
manner. Reaction of bis(diethylamino)chloroarsine with trimethylsilylmethylmagnesium chloride or
bis(trimethylsilyl)methylmagnesium chloride at 78 C, followed by aqueous work-up, readily
affords dichloro(trimethylsilylmethyl)arsines 52 (81%) and 53 <1991MI413-01, 1990POL319>.
Arsenic trichloride also reacts with silylated ketene acetals such as 54 in either THF or Et2O at
room temperature to quantitatively afford dichloroarsine 55 <1989TL349>. The final example is
the intramolecularly complexed dichloride 56 generated in 55% yield by mixing arsenic trichloride
with Pyr-20 C(TMS)2Li in Et2O at 80 C <1991CC1560> (Schemes 15 and 16).
TMS
TMS
AsCl TMS
TMS
AsCl TMS AsCl2
TMS TMS AsCl2 TMS
TMS
50 51 52 53
Scheme 15
TMS OTMS TMS TMS

N TMS
AsCl2
H OEt EtOOC AsCl2
54 55 56
Scheme 16
(b) Tertiary arsines, secondary and primary alkyl- or arylarsines. Tertiary arsine 57 is prepared
by the reaction of AsCl3 with an excess of trimethylsilylmethylmagnesium chloride in THF
(80%, m.p. 67–68 C). An alternative approach to 57 is the use of chloro derivative compound
58 in place of arsenic chloride. Under these conditions, compound 57 is obtained in 95% yield
<1990IC3502>. Chloro derivatives 52 and 50 are reduced by LAH in Et2O at 78 C to afford
the corresponding primary arsines 59 <1990POL319> and 60, respectively <1991PS(57)1>.
Finally, secondary arsine 61 is synthesized in 75% yield by metallation of phenylarsine with
sodium in liquid NH3 followed by a coupling reaction with TMSCH2Cl <1996OM84>
(Scheme 17).
TMS TMS
As O TMS
AsCl TMS AsH2 AsH TMS As(Ph)H
TMS O TMS
57 58 59 60 61
Scheme 17
(c) Cyclic arsines. Reaction of arsine 59 with triphenyl- or trimethylgallane in benzene at 55 C

gives the corresponding trimeric mono(arsino)gallanes 62a and 62b in quantitative and 85% yield,
respectively. However, its reaction with tris(trimethylsilylmethyl)gallane results in the formation
of the pentacyclic arsine 63 <1990POL319>. Bis[bis(trimethylsilyl)methyl]trimethylsilyl arsine
[(TMS)2CH]2AsTMS reacts with GaCl3 in a 1:1 ratio in pentane to give the six-membered ring
62c (67%, m.p. 180–184 C), whereas the use of a twofold excess of arsine affords the four-
membered ring 64 (80%, m.p. 101–108 C) <1986OM1266> (Scheme 18).
R1 R 1
R2 Ga R2 R2 R2
As As As As
2
R 1 1 R2 As As R
Ga Ga R1 Cl2Ga GaCl2
R 1 As R As
As As
R2 R2 R2 R2
62a: R1 = Me, R2 = CH2TMS
62b: R1 = Ph, R2 = CH2TMS 63 64
62c: R1 = l, R2 = CH2TMS
Scheme 18
(d) Miscellaneous. Finally, a derivative containing an As¼P double bond has been prepared.
Thus, reaction of chloroarsine 60 with (2,4,6-But3C6H2)PH2 in THF in the presence of excess
1,5-diazabicyclo[5.4.0]undec-5-ene affords phosphaarsene 65 as an orange crystalline solid
<1983CC881> (Scheme 19).
But But
As
P CH(TMS)2
But
65
Scheme 19
(ii) Arsoranes
Reaction of tris(trimethylsilylmethyl)arsine 57 with bromine provides the corresponding arsorane
66a (m.p. 118–120 C) <1958JA1336>. This arsorane is thermally unstable and, at 170 C, it
rearranges to the trivalent derivative 67, probably via the salt 68. Chloro derivative 66b is
prepared by the addition of arsenic trichloride in Et2O to a hexane/benzene solution of 57 and
isolated in 17% yield after recrystallization (m.p. 112–114 C) <1991PS(57)1> (Scheme 20).
TMS Br
As TMS +
As CH2 Br –
(TMSCH2)3AsX2 TMS TMS
66a: X = Br
66b: X = Cl 67 68
Scheme 20
(iii) Quaternary salts

A general method to prepare quaternary salts incorporating arsenic and silicon consists of
reaction of the corresponding trialkylarsine and trimethylsilylmethyl chlorides. Thus, reaction
of trimethylarsine with TMSCH2Cl in a sealed tube at 170 C gives the corresponding salt 69a. In
a similar fashion, salt 69b is formed in 79% yield by reaction of triethylarsine with trimethyl-
silylmethyl chloride. Compound 69c, used for silylcyclopropanation reactions, can also be
prepared by the treatment of methylenearsorane 70 with trimethylsilyl chloride in Et2O at
70 C under an inert atmosphere <1984TL4425> (Scheme 21).
+ –
R3As TMS, Cl Ph3As CH2
69a: R = Me 70
69b: R = Et
69c: R = Ph
Scheme 21
(iv) Ylides and cumulenes

All salts of the type 69 mentioned above react readily with BuLi to afford the corresponding ylides 71 in
high yields. The chemistry of arsenium ylides has been reviewed <1982AOC115> and several spectro-
scopic studies have been reported <1975CB2649, 1976CB473>. Such ylides also react with alkyl halide
electrophiles. Thus, ylide 71a reacts with methyl bromide to afford the corresponding salt 72. This latter
can again be converted into the ylide 71b. Finally, ylides such as 71c react with trimethylsilanol in a
desilylation reaction to lead to the corresponding (trialkylarsine)methylene Me3As¼CH2 and hexa-
trimethyldisiloxane <1967IC168>. A more esoteric example is the formation of the unstable arsorane
73 by dehydrohalogenation of the dichloroarsine 55 by DABCO <1989TL349> (Scheme 22).
+ – +
R13As TMS
– TMS Rt3As TMS, Br –
ClAs
R2 Me CO2Et
71a: R1 = Et, R2 = H 72 73
71b: R1 = Et, R2 = Me
71c: R1 = Me, R2 = H
Scheme 22
(v) Photoreactions
Photolysis of degassed toluene solutions of chloroarsine 53 in the presence of the electron-rich
olefin 75 furnishes the corresponding arsenic centered radical 74 characterized by its electron spin
resonance spectrum <1976CC623> (Scheme 23).
Et Et
N N
TMS TMS
N N
TMS As As TMS Et Et
74 75
Scheme 23
4.13.2.1.2 Arsenic and germanium functions

Reaction of ClGe(Me)2CH2Cl 76 (prepared in three steps from germanium tetrachloride) with
dimethylarsinolithium Me2AsLi in benzol affords 77 in 72% yield. The latter reacts with dimethyl-
arsino chloride to lead to derivative 78 (91%). Aminolysis of 78 with dimethylamine gives 79,
which can also be obtained by treatment of 78 with Me2NLi. Finally, compound 80 is formed by
the reaction of 78 with dimethyltrimethylsilylphosphine <1977JOM77> (Scheme 24).
Me2AsLi Me2AsCl
Cl(Me)2Ge Cl Me2As(Me)2Ge AsMe2 Cl(Me)2Ge AsMe2
Benzol, rt 91%
72% 78
76 77
HNMe2/Et2O
or LiNMe2
Me2N(Me)2Ge AsMe2
90%
79
78
Me3SiPMe2
Me2P(Me)2Ge AsMe2
70%
80
Scheme 24
4.13.2.2 Antimony Derivatives
4.13.2.2.1 Stibines
(i) Chlorostibines
Treatment of diphenyl(trimethylsilylmethyl)stibine (prepared from diphenylstibino chloride and
trimethylsilylmagnesium chloride) with HCl in chloroform led to dichlorostibine 81a.
<1995JOM117> Its bromide counterpart 81b is obtained in 79% yield from tris(trimethylsilyl-
methyl)stibine 86 by treatment with a twofold excess of antimony tribromide <1993JOM119>.
Use of a twofold excess of antimony tribromide affords the monobromide derivative 84. Reaction
of antimony trichloride with bis(trimethylsilyl)methylmagnesium chloride at 78 C in Et2O
affords compound 82 <1983POL291, 1984IC2582>. The later reacts with 2-(N,N-dimethyl-
aminomethyl)phenyllithium at 80 C to give the chiral chlorostibine 85 (96%, m.p. 80 C)
<2003IC1751> (Scheme 25).
TMS
TMS
TMS Sb Cl
TMS
TMS SbCl2 Sb Cl TMS
TMS SbBr N
TMS SbX2 TMS TMS
TMS
81a: X = Cl 82 83 84 85
81b: X = Br
Scheme 25
(ii) Tertiary stibines, secondary and primary stibines

Various stibines are prepared by the reaction of substituted alkyllithiums or Grignard reagents
with antimony trichloride. Thus, reaction of trimethylsilylmethylmagnesium chloride with SbCl3
in THF and subsequent hydrolysis affords tris(trimethylsilylmethyl)stibine 86 as a white solid
(74%, m.p. 64–65 C) <1958JA1336, 1992OM2163>. Tertiary stibine 87 (98%, m.p. 80–82 C) is
obtained in a similar fashion by reacting antimony trichloride with bis(trimethylsilyl)methylmag-
nesium chloride, while dimethyl-bis(trimethylsilylmethyl)stibine 88 (76%, b.p. 32 C/
2101 mmbar) is prepared by alkylation of dichlorostibine 82 with methylmagnesium iodide
in a 2:1 molar ratio <2002JOM33> (Scheme 26).
The preparation of stable primary and secondary stibines has been reported. Thus, addition of
dichlorostibine 82 in Et2O to LAH at 60 C affords the primary stibine 89a in 69% yield
<2001OM2666>. It can be noted that hydrides of main group 15 elements are important
compounds, frequently used as reducing agents <1998JOM297> or precursors for electronic
materials. However, many of them, such as RSbH2 (R = Me, Ph) and R2SbH (R = Me, Et),
decompose in minutes or hours at room temperature. By contrast, stibine 89a is stable at room
temperature in a sealed tube for weeks, and at 28 C it is stable indefinitely. Distibine 90 is
formed in 93% yield from the same reagents as 89a but in a ‘‘reverse addition’’ reaction
<2003OM576>. The mixed compound bis(trimethylsilyl)methylstibino chloride
(TMS)2CH(H)SbCl is postulated to be an intermediate in the formation of 90 via reaction of
(TMS)2CHSbCl2 with LAH and loss of H2. Similarly, primary stibine 89b is obtained in 51%
yield from the corresponding bromostibine 81b by treatment with LAH in tetraglyme
<1993JOM119> (Scheme 27).
TMS
TMS TMS TMS
Sb TMS
Sb TMS TMS SbMe2
TMS TMS TMS TMS
86 87 88
Scheme 26
LAH
Et2O, –60 °C (TMS)2CHSbH2 H H
TMS SbCl2 TMS Sb(H)Cl (TMS)2HC Sb Sb
(-HCl) CH(TMS)2
TMS TMS 90
(-Cl–) +H–
TMS SbH2
TMS SbH2
TMS
89a 89b
Scheme 27
In a similar fashion, the secondary stibines 91a (m.p. 14 C) and 91b are obtained in 66% and
45% yields by reacting the corresponding chlorides 83 and 84 with LAH <2002OM2584,
1993JOM119>. Stibine 89a reacts with methyl iodide/DBU with substitution of hydrogen by
methyl to give the corresponding tertiary stibine 92 <2003OM576>. Use of the reagents in a 1:1:1
molar ratio exclusively affords the secondary stibine 93 in 82% yield. Also distibine 90 reacts with
methyl iodide and DBU to furnish distibine 94 in 69% yield (Scheme 28).
R
TMS
Sb H TMS SbMe2 TMS Sb(H)Me
TMS Me Me
Sb
R TMS TMS (TMS)2HC Sb CH(TMS)2
91a: R = TMS 92 93 94
91b: R = H
Scheme 28
An efficient synthesis of the three unsymmetrical organoantimony compounds 95 from the

corresponding chloride has been reported <2003IC1751>. Unsymmetrical stibines are of parti-
cular interest due to the potential activity of antimony and bismuth compounds bearing three
different substituents as chiral reagents or catalysts for enantioselective synthesis. Thus, chloride
85 is reduced by LAH in Et2O to give the secondary unsymmetrical stibine 95a in 87% yield.
Treatment of 95a with n-butyllithium in THF at 80 C and subsequent crystallization gives
compound 95b (62%, m.p. 48–52 C). The latter is transmetallated with sodium t-butoxide in
the presence of TMEDA at 50 C and subsequent crystallization gives compound 95c (44%,
m.p. 65–70 C) (Scheme 29).
TMS
Sb TMS
R
N
95a: R = H
95b: R = Li
95c: R = Na
Scheme 29
(iii) Cyclic stibines

It is noteworthy that the heating of 89a to 110–120 C leads to the cyclic compound R4Sb4 96
<2001OM2666>. Distibine 90 is also used for the preparation of antimony homocycles. Con-
trolled removal of hydrogen is achieved when LAH is added to a solution of 90 in Et2O at room
temperature: tristibine 97 and tetrastibine 96 are formed and isolated in 11% and 12% yields,
respectively <2003OM576>. These two compounds can also be formed from chloride 82. Thus,
treatment of compound 82 with n equivalents (n = 3 or 4) of magnesium turnings in THF affords
the corresponding homocycle 97 (n = 3) or 96 (n = 4) in 88% yield <1992OM145,
1984JOMC27>. The three-membered ring compound 97 is also prepared by reacting chloride
82 with Li3Sb at 40 C (58%, m.p. 94–98 C) and by UV irradiation of its four-membered
counterpart 96 (quantitative yield) <1998OM5594>. Reaction of stibine 89a with antimony
trichloride in the presence of pyridine yields the polycycle 98 in 32%. Exposure to light leads to
photochemical ring contraction with formation of the tristibine 97. Finally, the bicyclic com-
pound 99 (2%, m.p. 152–153 C) is formed in low yield in an attempt to metallate distibine 94
with sodium t-butoxide in the presence of 18-crown-6.
Preparation of heterocyclic organoantimony derivatives has been described. Treatment of
chloride 82 with KOH in water/Et2O at 25 C and subsequent recrystallization affords the cyclic
stibane oxide 100 <1994ZN877> whereas its reactions with sodium chalcogenides furnish the
corresponding cyclic antimony chalogenides 101a, 101b, and 101c in 84%, 75%, and 70% yields,
respectively <1996ZN149> (Scheme 30).
R R
Sb R R
Sb
Sb Sb Sb
R R R
Sb Sb Sb Sb R Sb Sb Sb Sb R
Sb
Sb Sb Sb Sb
Sb Sb Sb Sb Sb
R R R R R R R R
96 97 98 99
R
O Sb R = CH(TMS)2
R
Sb O Sb X n
O Sb R
R
Sb O
R
101a: X = S, n = 2– 4
100 101b: X = Se, n = 2–3
101c: X = Te, n = 2–3
Scheme 30
The synthesis of several cyclic metal complexes of organoantimony ligands has also been
reported. Thus, complexes 102 (15%, m.p. 99 C) and 103 (70%, m.p. 138 C) are prepared by
reacting distibine 90 and cyclo [TMSCH2Sb]5 with W(CO)5THF <1998OM5594,
2001ZAAC1855> whereas complex 104 (69%, m.p. 159 C) is prepared by an insertion reaction
of Fe2(CO)9 in the three-membered ring 97. The ring–ring equilibria [(TMS)2CH]2Sb2S2/
[(TMS)2CH]3Sb3S3 and [(TMS)2CH]2Sb2Se2/[(TMS)2CH]3Sb3Se3 also react with W(CO)5THF
to form the corresponding complexes 105a <2002MI547> and 105b <2002JOM130> in quanti-
tative and 42% yields, respectively (Scheme 31).
W(CO)5 R R W(CO)5
R Sb Sb Sb
Sb R Sb Sb R
R Sb Fe(CO)4 X X R = CH(TMS)2
W(CO)5
Sb Sb Sb Sb Sb
R (OC)5W R R R W(CO)5
102 103 104 105a: X = S
105b: X = Se
Scheme 31
(iv) Miscellaneous
In analogy to dichloroarsine 60, dichlorostibine 82 reacts with (2,4,6-But3C6H2)PH2 in THF in the
presence of excess 1,5-diazabicyclo[5.4.0]undec-5-ene to afford the phosphastibene 106 <1983CC881>.
Finally, the preparation of the hexastibino-cage compound 107 has been reported. This com-
pound (41%, m.p. 203 C) is synthesized by the reaction of the potassium complex of diphos-
phastibolyl ring anion 42 with dimethylsilyl dichloride <2001JOM61> (Scheme 32).
Me Me
Si
But P But
But
Sb P
But But P Sb
– P
P But P
Sb But
P CH(TMS)2 But H
But
106 42 107
Scheme 32
4.13.2.2.2 Stiboranes
(i) Chloro- and bromostiboranes

Bromination of tertiary stibines affords the corresponding dibromostiboranes. Thus, reaction of stibine
89a with bromine in petroleum ether at 0 C furnishes dibromo-tris(trimethylsilylmethyl)stiborane 108
(m.p. 158–160 C) <1958JA1336>. In a similar fashion, addition of Br2 or I2 in Et2O at 0 C to a
solution of tertiary stibines 87 and 88 affords the corresponding trialkylantimony halides 108, 109a,
and 109b in 84% (m.p. 174 C), 61% (m.p. 149–151 C), and 98.5% (m.p. 116–118 C) yields,
respectively. Moreover, hydrolysis of stiborane 108 with a solution of potassium hydroxide in water
surprisingly gives the hydroxy bromide 110 (m.p. 120–123 C, 70%). This compound is also obtained in
72% yield by reacting dibromostiborane 109a with potassium hydroxide in water <2002JOM33>.
Similarly, pentavalent compounds 111b (92%, m.p. 164–165 C) and 111a are prepared in 92% yield by
the addition of iodide or bromide to the tristibine 86. Thermal decomposition of 111b gives the iodide
derivative 112 (91%) which, on further treatment with I2, furnishes bis(trimethylsilylmethyl)antimony
triiodide 113b <1992OM2163>. Bis(trimethylsilylmethyl)antimony tribromide 113a is quantitatively
formed by addition of excess Br2 to bromide 84 in petroleum ether at 20 C <1999JOM256>. Its
reaction with 2 equiv. of diphenyldithiophosphinate in refluxing CHCl3 affords tris(trimethylsilyl-
methyl)antimony bis(diphenyldithiophosphinate) 114 (m.p. 103 C) in 42% yield (Scheme 33).
[(TMS)2CH]3SbBr2 (TMS)2CH(Me)2SbX2 [(TMS)2CH]3Sb(OH)Br

108 109a: X = Br 110
109b: X = I
[TMSCH2]3SbX2 TMSCH2SbI2 [TMSCH2]2SbX3 [TMSCH2]3Sb(S2PPh2)2
111a: X = Br 112 113a: X = Br 114

111b: X = I 113b: X = I
Scheme 33
(ii) Alkylstiboranes
A general and versatile route to alkylstiboranes is the reaction of suitable lithium reagents with an
appropriate antimony derivative <1978CB2702>. Thus, reaction of stiborane 111b with methyl-
lithium (2 equiv.) in Et2O at 0 C affords stiborane 115 (78%, m.p. 51–53 C), while its reaction
with trimethylsilylmethyllithium (2 equiv.) gives pentakis derivative 116 (89%, m.p. 93 C)
<1978CB2702>. The same lithium reagent is used to convert the salt 117 (obtained by the reaction
of tristibine 86 with methyl iodide) into stiborane 118 (68%, m.p. 33 C). This salt also reacts with
methyllithium (2 equiv.) to afford stiborane 115 (78%). Similarly, stiborane 119 (83%, b.p. 65 C/
0.1 torr) is prepared by the reaction of trimethyldibromostiborane Me3SbBr2 (generated by bromi-
nation of trimethylstibine) with trimethylsilylmethyllithium. This lithiated reagent is also used to
transform tetramethyliodostiborane Me4SbI (obtained by the reaction of trimethyldibromostibor-
ane with methyllithium) to tetramethylstiborane 120 (37%, b.p. 68 C/5.5 torr) (Scheme 34).
[TMSCH2]3SbMe2 Sb(CH2TMS)5 [TMSCH2]3SbCH3I
115 116 117
[TMSCH2]4SbMe [TMSCH2]2SbMe3 TMSCH2SbMe4

118 119 120
Scheme 34
4.13.2.3 Bismuth Derivatives
4.13.2.3.1 Bismuth and silicon functions
(i) Chlorides
Trimethylsilylmethylbismuthino dichloride 121 is prepared in two steps from diphenylbismuthino
chloride. First, diphenylbismuthino chloride Ph2BiCl is transformed into diphenyl(trimethylsilyl-
methyl)bismuthine Ph2(TMSCH2)Bi by reaction with trimethylsilylmethylmagnesium bromide.
Then, substitution of the phenyl groups is achieved on treatment with gaseous HCl
<2002AG(E)2309>. The same reaction sequence allows the synthesis of chloride 122 (77%)
from diphenylbismuthino chloride and bis(trimethylsilyl)methylmagnesium chloride
<1999OM328>. Bismuthino chloride 123 is prepared in 93% yield by the reaction of bis(tri-
methylsilyl)methyllithium with bismuth trichloride in a 2:1 molar ratio <1999OM328>. Finally,
the chiral bismuthino chloride 124 is formed in 91% yield by reaction of 122 with 2-(Me2NCH2)-
C6H4Li in toluene at 80 C <2003IC1751> (Scheme 35).
TMS
TMS
TMS Bi TMS
TMS BiCl
Cl
BiCl2 TMS N
TMS BiCl2 TMS TMS
121 122 123 124
Scheme 35
(ii) Tertiary bismuthines, secondary and primary bismuthines

As with the arsenic and antimony derivatives, reaction of bismuth trichloride BiCl3 with tri-
methylsilylmethylmagnesium chloride in THF affords tertiary bismuthine 125 in 35% yield
<1958JA1336>. Dialkyl(trimethylsilylmethyl)bismuthines 126b and 126c are synthesized by the
reaction of dialkylbismuthinosodium with chloromethyltrimethylsilane <1988ZN(B)739,
2002AG(E)2309>. Primary and secondary stibines are also obtained from the corresponding
chlorides on treatment with LAH. Thus, chlorides 121 and 123 react with LAH in Et2O at
80 C to lead to trimethylsilylbismuthine 126a <2002AG(E)2309> and bis(trimethylsilyl)methyl-

bismuthine 127 (66%, m.p. 14 C), respectively <2002OM2584>. The latter decomposes at
room temperature to give the corresponding dibismuthine 128 (73%, m.p. 104 C) and 1 equiv.
of dihydrogen. Finally, chloride 123 reacts with sodium sulfide and disodium telluride in liquid
NH3 to afford di(bistrimethylsilyl)methylbismuth tellurides 129a (E = S, 88%, m.p. 87 C) and
129b (E = Te, 53%, m.p. 83 C), respectively <2002JOM130> (Scheme 36).
TMS
TMS TMS TMS
Bi BiH
TMS
TMS TMS BiR2 TMS
125 126a: R = H 127
126b: R = Me
126c: R = Ph
(TMS)2HC(H)Bi Bi(H)CH(TMS)2 (TMS)2HCBi E BiCH(TMS)2
128 129a: E = S
129b: E = Te
Scheme 36
(iii) Cyclic bismuthines

Cyclic bismuthines 130a and 131a are synthesized in 68% global yield by the reduction of chloride 123
with magnesium filings in THF at 35 C <1998AG(E)3175>. In solution, there is an equilibrium
between the two organobismuth rings. The equilibrium constant K = [R3Bi3]4/[R4Bi4]3 is 40.5 mol l1 in
C6D6 at 23 C. This equilibrium is shifted in favor of the four-membered ring when the solution is cooled.
Above 50 C, bismuthine 126a decomposes to furnish a mixture of the three-membered and the five-
membered ring compounds 130b and 132b in 90% global yield <2002AG(E)2309> (Scheme 37).
R
R Bi
R R
Bi Bi Bi
R Bi Bi R
Bi R
Bi Bi Bi Bi Bi
R R R R R
130 131 132

a: R = CH(TMS)2
b: R = CH2TMS
Scheme 37
Bis(trimethylsilyl)methylbismuthino chloride 123 also reacts with Na2[Fe(CO)4] to afford com-

pounds 133a (20%, m.p. 111–113 C) and 134a (14%, m.p. 84–86 C). Finally, reaction of the
ring–ring equilibrium 130b and 132b with W(CO)5THF affords the bismuthene complex 135b
(m.p. 95–96 C) <2002AG(E)2309> (Scheme 38).
R
Bi R R
Fe(CO)4 Fe(CO)4 Bi Bi
Bi R Bi
R Fe(CO)4 (OC)5W W(CO)5
133 134 135
a: R = CH(TMS)2
b: R = CH2TMS
Scheme 38
4.13.2.3.2 Bismuth and germanium functions

The germylated derivative 136 is synthesized from dimethylbismuthinosodium and chloromethyl-
trimethylgermane <1988ZN(B)739> (Scheme 39).
Me3Ge BiMe2
136
Scheme 39
4.13.3 FUNCTIONS CONTAINING ARSENIC, ANTIMONY OR BISMUTH, AND A METAL
4.13.3.1 Arsenic Derivatives
4.13.3.1.1 Arsenic and group 1 metals

Dialkyl- and diarylarsinomethyllithium derivatives can be prepared from the corresponding
bis(dialkylarsino)- and bis(diarylarsino)methanes as exemplified by the synthesis of diphenylarsi-
nomethyllithium 137 by the treatment of bis(phenylarsino)methane 3c (74%) with n-butyllithium
in THF at 40 C <1978TL4391>. An alternative approach for the preparation of 137 consists in
mixing diphenylarsinomethyl iodide with n-butyllithium or phenyllithium at 78 C with quanti-
tative yield <1982TL2301>. Finally, lithium derivatives 139 are formed almost quantitatively on
treatment of alkyldiphenylarsane oxides 138 with lithium diisopropylamide in THF at 40 C.
Lithium derivatives 139 readily react with organic halides or carbonyl compounds with CC
linkage. The resulting arsane oxides can be easily reduced to arsines <1977AG(E)53,
1977AG(E)709> (Scheme 40).
O
O Ph2As R
Ph2As Li Ph2As R Li
137 138 139
R = H, Et, Pr, Bun, CH2CH=CH2, Bn, Ph
Scheme 40
4.13.3.1.2 Arsenic and group 14 metals

Derivatives containing arsenic and tin such as diphenyl(tributylstannylmethyl)arsine 140 (73%)
are prepared by the reaction of tributylstannylmethyllithium Bu3SnCH2Li with diphenylchloro-
arsine Ph2AsCl <1982CB1810> or by the addition of tributyltin chloride to diphenylarsinophe-
nyllithium <1985CB2353>. A similar route is used to prepare lead derivatives. Thus, compound
142 is synthesized in two steps from tris(triphenyllead)methane. Treatment with 2 equiv. of
phenyllithium affords bis(triphenyllead)methyllithium Ph3PbCH2Li (98%), which reacts with
diphenylarsino chloride Ph2AsCl to give compound 141 in 65% yield. Addition of phenyllithium
and subsequent reaction with another equivalent of diphenylchloroarsine led to derivative 142 in
53% yield <1980TL2807>. Another example is the dimethylarsino trimethylstannylcyclopenta-
diene 143 prepared in 26% yield by the reaction of dimethylaminotrimethylstannane with
dimethylarsino cyclopentadiene in pentane at room temperature <1979JOM57> (Scheme 41).
Ph2As PbPh3 Ph2As PbPh3 AsMe2

Ph2As SnBu3 PbPh3 AsPh2 SnMe3
140 141 142 143
Scheme 41
4.13.3.2 Antimony Derivatives
4.13.3.2.1 Antimony and group 1 metals

Phenyllithium reacts with bis(diphenylstibino)methane in THF at 70 C to afford diphenylsti-
binomethyllithium 144 quantitatively <1978TL4391, 1983CB473, 1985CB2353>.
4.13.3.2.2 Antimony and group 14 metals

Dimethylstibinotrimethylstannylcyclopentadiene 145 is synthesized in 80% yield by following the
same procedure as described above for compound 143 <1979JOM57> (Scheme 42).
Ph2Sb Li SbMe2
SnMe3
144 145
Scheme 42
4.13.3.3 Bismuth Derivatives
4.13.3.3.1 Bismuth and group 1 metals

Diphenylbismuthinomethyllithium 146 is generated by following the same procedure as for its
arsino and stibino counterparts, i.e., by transmetallation of bis(diphenylbismuthino)methane with
phenyllithium in Et2O at 78 C <1980AG(E)723, 1985CB1039>.
4.13.3.3.2 Bismuth and group 14 metals

Reaction of dimethylbismuthinosodium with chloromethyltrimethyltin furnishes derivative 147
<1988ZN(B)739> (Scheme 43).
BiPh2 Li Ph2Bi SnBu3
146 147
Scheme 43
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Biographical sketch
Eric Fouquet was born in Lourdes (France). Agnès Hervé was born in Versailles (France).
He studied at Paul Sabatier University of She studied chemistry at the ‘‘Ecole Nationale
Toulouse, where he obtained a DEA in 1987. Supérieure de Chimie de Lille.’’ After spend-
He moved to Ecole Polytechnique in Palai- ing a year in Scotland (Edinburgh University),
seau where he obtained his Ph.D. in 1991 as an exchanged ERASMUS student, she
under the direction of Dr. Samir Z. Zard. He went back to Lille, where she was appointed
joined the group of Professor Michel Pereyre Ingenior in chemistry in 1999. The same year
in the Laboratory of Organic and Organome- she obtained a DEA. She joined the group of
tallic Chemistry in Bordeaux, where he got a Professor H.-J. Cristau in the Laboratory of
position of ‘‘Chargé de Recherche’’ at the Organic Chemistry at the ‘‘Ecole Nationale
CNRS, in October 1991. After spending a Supérieure de Montpellier’’ and obtained her
year (1994), as Postdoctoral Research Fellow, Ph.D. in 2003. During these three years, she
in the laboratory of Professor William was interested in the synthesis of new organo-
B. Motherwell at UCL (London), he went phosphorus compounds with potential biolo-
back to his former group in Bordeaux, where gical activity. She is currently in Bordeaux, as
he took up his present position as Professor in a Postdoctoral Research Fellow under the
Chemistry in September 2000. His scientific direction of Professor E. Fouquet, in the
interests include all aspects of organotin Laboratory of Organic and Organometallic
chemistry, in particular, the design of new Chemistry where she works on new organotin
organotin reagents for organic chemistry. He reagents and their application as radiotracers.
develops as well methodologies for the synth-
esis of condensed polyphenols (tannins) and
rapid chemistry for the introduction of short-
lived radiotracers such as 11C in bioactive
compounds.
4.14
Metalloid (Si, Ge, or B) Together
with Another Metalloid or Metal
N. G. BHAT
The University of Texas-Pan American, Edinburg, TX, USA
4.14.1 FUNCTIONS CONTAINING TWO METALLOIDS 596

4.14.1.1 Functions Bearing Two Silicons: R12C(SiR23)2, etc. 596
4.14.1.1.1 Formation of the SiCSi linkage 596
4.14.1.1.2 Changing the groups attached to the central methylene 599
4.14.1.1.3 Changing the ligands on silicon 600
4.14.1.2 Functions Bearing Two Germaniums: R12C(GeR23)2 602
4.14.1.2.1 Formation of the GeCGe linkage 602
4.14.1.2.3 Changing the ligands on germanium 602
4.14.1.3 Functions Bearing Two Borons: R12C(BR22)2, etc. 603
4.14.1.3.1 Formation of the BCB linkage 603
4.14.1.3.2 Changing the groups on the central methylene 604
4.14.1.3.3 Changing the ligands on boron 605
4.14.1.4 Functions Bearing a Silicon and a Germanium Group: R12CSiR23GeR33, etc. 605
4.14.1.4.1 Formation of the SiCGe linkage 605
4.14.1.4.3 Changing the groups attached to the metalloids 606
4.14.1.5 Functions Bearing a Silicon and a Boron Group: R12CSiR23BR32, etc. 606
4.14.1.5.1 Formation of the SiCB linkage 606
4.14.1.5.3 Changing the groups attached to the metalloids 611
4.14.1.6 Functions Bearing a Germanium and a Boron Group: R12CBR22GeR33, etc. 611
4.14.2 FUNCTIONS CONTAINING A METALLOID AND A METAL 611
4.14.2.1 Silicon and a Metal: R12CSiR23M, etc. 611
4.14.2.1.1 Silicon and a group 1 or group 2 metal: R12CSiR33Li, etc. 611
4.14.2.1.2 Silicon and a transition metal: R12CSiR23CuX, etc. 614
4.14.2.1.3 Silicon and a group 13 or group 14 metal: R12CSiR23SnR33, etc. 617
4.14.2.1.4 Silicon and other elements 619
4.14.2.2 Germanium and a Metal: R12CGeR23M 619
4.14.2.2.1 -Lithiogermylalkanes 619
4.14.2.2.2 Other -metallogermylalkanes 620
4.14.2.3 Boron and a Metal: R12CBR22M 620
4.14.2.3.1 -Lithioborylalkanes 620
4.14.2.3.2 Other -metalloborylalkanes 620
595
596 Functions Containing at Least One Metalloid (Si, Ge, or B)
4.14.1 FUNCTIONS CONTAINING TWO METALLOIDS
4.14.1.1 Functions Bearing Two Silicons: R12C(SiR23)2, etc.

The COFGT (1995) details the synthetic methods for the preparation of an sp3-hybridized
carbon connected to two silyl groups and either protons or carbon fragments. Recently, a
useful review on silenes has appeared <2002POL467>. A review describing the synthesis,
structure, and reactions of groups 1–3 containing bulky silicon-substituted alkyl groups has
been published <1995JOM89>.
4.14.1.1.1 Formation of the SiCSi linkage

In COFGT (1995), the different methods to form the SiCSi linkage are reported. The different
routes involve the quenching of a carbanion with a silyl electrophile, quenching a silyl anion with
a carbon electrophile, construction from silenes or disilenes, the generation of 1,1-bis(silyl)
alkanes through rearrangements involving silenes, hydrosilylation, and the synthesis of 1,1-bis(si-
lyl) alkanes via the replacement of functionality on the central methylene by either protons or
carbon fragments.
(i) Quenching a carbanion with a silyl electrophile

gem-Disilyl compounds 2 could also be prepared by the deprotonation of dihalotrimethylsilyl-
methane 1 with lithium diisopropylamide followed by silylation with trialkylsilyl chlorides
(Scheme 1) <1997JOM185>.
LDA RMe2SiCl
RMe2SiCHX2 RMe2SiCX2Li RMe2SiCX2SiMe2
1 2
X = Cl, R = Me, 90% X = Br, R = Me, 85%
= Cl, R = H, 74% = Br, R = H, 62%
= Cl, R = vinyl, 97% = Br, R = vinyl, 85%
Scheme 1
(ii) From silenes and silylenes

When the co-thermolysis of pivaloyltris(trimethylsilyl)silane with benzil was carried out in a
sealed tube at 140 C for 12 h, 1-[(t-butyl)bis(trimethylsilyl)methyl]-3,4-diphenyl-1-trimethyl-
siloxy-2-5,dioxa-1-silacyclopent-3-ene 3 was obtained in 67% yield (Equation (1)) <2003JOM1>.
Ph Ph
O O O
140 °C, 12 h
(Me3Si)3Si C C(CH3)3 + Ph C C Ph O O
67% Si ð1Þ
C OSiMe3
(CH3)3C
SiMe3
SiMe3
The reaction of a sterically hindered silylene 4 with isocyanides provided the first stable
silylene–Lewis base complexes 5 (Scheme 2) <1997JA1456>.
The photolysis of bis(trimethylsilyldiazomethyl)disilane 6 in t-butyl alcohol provided the
t-butyl alcohol adducts 7 and 8. The structures of these products revealed the stepwise formation of
asymmetric silenes as intermediates (Scheme 3) <1995JOM99>.
Functions Containing at Least One Metalloid (Si, Ge, or B) 597
Tbt Tbt 60 °C Tbt CN-R Tbt

Si Si Si: Si
THF or C6D6 C NR
Mes 100%
Mes Mes Mes
4 5
SiMe3
Me3Si
SiMe3
Tbt = Mes =
SiMe3
Me3Si
SiMe3
Scheme 2
N2 N2
Me3Si C (SiMe2)2 C SiMe3
hν (>300 nm) ButOH/benzene SiMe3 N C N

H SiMe3 N2 H SiMe3
C C C
+ ButOMeSi Si
Si SiMe3
N2 ButOMeSi Me
Me3Si Me Me Me
ButOH H
C C
Me3Si Si SiMe3 12% Si H
Me Me –N2 H
H
ButOMe2Si Si Si Me
Me
Me Me
ButOH –N2 (cis, trans mixture)
Me3Si Me
SiMe3 ..
H Me3Si Me
C C 58% + BuOMe2Si HC CH
tOMe Si Si SiMe3 CH CH Si SiMe3
Bu ButOMe2Si Si SiMe2OBut
2
Me OBut
Me Me
Scheme 3
1-[2,6-Bis(dimethylaminomethyl)phenyl]-1,2,2-tris(trimethylsilyl)silene) was prepared by the

treatment of (dichloromethyl)tris-(trimethylsilyl)silane with 2,6-bis(dimethylaminomethyl)phenyl-
lithium (molar ratio 1:2). The product is a crystalline compound, indefinitely stable at room
temperature. The reaction of trimethyl-substituted silene 9 with water or methanol led to the
addition of these nucleophiles to the siliconcarbon double bond, producing the silanol 10 and
the methoxysilane 11 respectively. The reaction pathway leading to these products was discussed
(Scheme 4) <2001JOM261>.
The silylated alcohol 12 was deprotonated with methyllithium in ether at low temperature. This
resulted in the elimination of lithium trimethylsilanoate to provide the transient silene 13, which
underwent readdition of lithium trimethylsilanoate to give the observed product 14 after silylation
with chlorotrimethylsilane (Scheme 5) <1996JOM181>.
(iii) Other routes

The reaction of 1-boraadamantane with 1-alkynylsilicon compounds led to adamantylbis(silyl)
compound 15 upon reaction with methanol (Scheme 6) <2001JOM51>.
A one-pot procedure for the transformation of the -silylated amide 16 to ,-disilylated amide
17 has been reported via the deprotonation of the -silylated amide with n-butyllithium followed
by silylation with trimethylsilyl chloride (Equation (2)) <2000T4467>.
NMe2
NMe2 OH SiMe3
H2O
SiMe3 Si CH
Et2O
Si C 67% SiMe3 SiMe3
Me3Si SiMe3 1h
Me2N
Me2N
9
10
1h MeOH
Et2O
84% reflux
Me2N
OMe SiMe
3
Si CH
SiMe SiMe3
3
Me2N
11
Scheme 4
SiMe3 Me3Si H
OH
Si C Me3SiOLi
Me3Si Si CH MeLi
Me3Si
SiMe3
12
13
Me3SiO Me3SiO SiMe3

ClSiMe3
Me3Si Si CH
Me3Si Si CH
Li
SiMe3
SiMe3
14
Scheme 5
SiMe3
B B
Pentane SiMe3
Me3Si SiMe3 +
–50 °C
MeOH pentane
MeO Me H
H SiMe3 O
SiMe3
B SiMe3
B
SiMe3
15
Scheme 6
BunLi
–78 °C CO SiMe3
CO SiMe3 N
Ph N Ph ð2Þ
Me3SiCl / THF, 1 h H
H 30% SiMe3
16 17
3,3-Bis(trimethylsilyl)propene reacted with iminium ions 18 generated in situ from secondary

amines by an aminomethylation–desilylation process, leading to (E)--aminovinylsilanes 19.
When a secondary amine with two secondary groups was used the reaction failed, probably due
to steric hindrance (Scheme 7) <2000JOM186>.
Me3Si
+ +
+ H2C NR1R2 Me3Si
NR1R2 Me3Si
Me3Si 18 NR1R2
Me3Si 19
Scheme 7
The synthesis of pure trimethyl-substituted -allenic amines 20 was achieved by the reaction of
1,1-bis(trimethylsilyl)-2-propyne with iminium ions, via an aminomethano desilylation process
(Scheme 8) <1996SC3351>.
+ Me3Si
+ Me3Si 49–67%
Me3Si R1R2N=CH2
NR1R2
Me3Si THF–H2O NR1R2
CF3COOH SiMe3
20
Scheme 8
Facile cleavage of Et2O occurred with [tris(trimethylsilyl)methyl]lithium in the presence of BX3

(where X = F, Cl, or Br) yielding ethyl tris(trimethylsilyl)methyl ether 21 instead of the expected
[tris(trimethylsilyl)methyl]boron dihalide; an analogous Et2O cleavage also occurred with AlCl3.
The sterically hindered ether formed was unreactive toward carbonoxygen bond cleavage by
HBr, BCl3, and Me3SiI (Equation (3)) <1995OM3098, 1995OM5695>.
Hexane/ether
(Me3Si)3CLi + BX3 (Me3Si)3COCH2CH3
X = F, 40%; Cl, 45%;
ð3Þ
Br, 64% 21
The photolysis of hexa t-butylcyclotrisilane in the presence of thiophene generated 2,2,6,6-tetra

t-butyl-2,6-disilabicyclo[3.1.0]hex-3-ene 22 as one of the products in 8% yield (Scheme 9)
<1995OM5695>.
R2
S
SiR2 hν S Si SiR2
+ + + +
R2Si SiR2 SiR2
R2Si SiR2 SiR2 SiR2
R = CMe3
49% 8% 10% 16%
22
Scheme 9
4.14.1.1.2 Changing the groups attached to the central methylene

In COFGT (1995), the preparation of 1,1-bis(silyl) alkanes through the manipulation of the
central group of an existing 1,1-bis(silyl)methane was outlined. The simplest route to such a
change would involve metallation followed by an electrophilic quench.
2-Methylpyridine was deprotonated with n-butyllithium followed by silylation with chlorotri-

methylsilane to afford the bis(silylated) product 23. The latter was reacted further with
n-butyllithium followed by treatment with chlorotrimethylsilane to produce the tris(trimethylsilyl)
compound (Scheme 10) <1995JOM89>.
BunLi / hexane
Me3SiCl / hexane
N Me N CH(SiMe3)2
23
Scheme 10
N-Methyl-3-(trimethylsilyl)propanamide was reacted with s-butyllithium and N,N,N0 ,N0 -tetra-

methylethylenediamine (TMEDA) and subsequent quenching with chlorotrimethylsilane gave the
silylated product 24 in 61% yield (Scheme 11) <1999JCS(P1)2433>.
Li+
O Li+ O- E O
CH3 BusLi CH3 E+ CH3
R2R1Si N R2R1Si N R2R1Si N
TMEDA
H H
R = R1 = CH3
24
R = CH3, R1 = Ph
E+ = Me3SiCl, 61%
= Me2PhSiCl, 83%
Scheme 11
The trimethyl-substituted silene was formed by the reaction of -bromotrimethylsilane with

n-butyllithium. The silene 25 in the presence of n-butyllithium was transformed into the corre-
sponding 1,3-disilacyclobutane 26 (Scheme 12) <2000JOM304>.
Me SiMe3
Me2Si C(SiMe3)2 BunLi BunLi Me Si C SiMe3

Me2Si C(SiMe3)2 Me2Si C(SiMe3)2
MeO Br Me3Si C Si Me
MeO Li 25
Me3Si Me
26
Scheme 12
4.14.1.1.3 Changing the ligands on silicon

In COFGT (1995), silicon-based substitution reactions on 1,1-bis(silyl)alkanes to generate new
systems are described. The most common process by which an existing 1,1-bis(silyl) alkane could
be functionalized is through the displacement of chlorine bound to silicon by a nucleophilic carbon.
A novel method for the deprotonation of a methyl group on silicon has been developed. The
demonstrated -lithiation protocol was based on intramolecular pyridyl group coordination to
stabilize the -silylcarbanion together with the inherent silicon -effect. It was found that the
deprotonation (ButLi/Et2O/78 C) occurred with 2-pyridyltrimethylsilane but not with other
related silanes such as phenyltrimethylsilane, 3-pyridyltrimethylsilane, and 4-pyridyltrimethylsilane.
It seemed that this deprotonation proceeded through the agency of the complex-induced proximity
effect (CIPE) of a 2-pyridyl group on silicon. 1H-NMR analysis of (2-pyridyldimethylsilyl)methyl-
lithium revealed the intramolecular coordination of a pyridyl group to lithium. The (2-pyridyl-
dimethylsilyl)methyllithium 27 was found to react with chlorosilanes to give the desired compounds
28 in excellent yields (Scheme 13) <2001JOC3970>. The results are outlined in Table 1.
ButLi Me3SiCl
Ph
Et2O 93%
N
N SiMe2Ph –78 °C, 30 min Si N Si SiMe3
Li Me Me Ph
27 28
Scheme 13
Table 1 The reaction of (2-pyridyldimethylsilyl) methyllithium with various silyl electrophiles

Nucleophile Electrophile Product Yield (%)
N Si Li Me3SiCl N Si SiMe3 93
Me2
Me Me
N Si Li PhMe2SiCl N Si SiMe2Ph 99
Me Me2
Me
N Si Li 2-PyrMe2SiH 63
N Si Si N
Me Me Me2 Me2
The platinum-catalyzed intramolecular hydrosilylation of a vinyl silane 29 was achieved in

heptane to produce the 1,3-disilacyclobutane derivative 30 (Equation (4)) <2001JOM127>.
H3C CH3
C(SiMe2H)3 Pt HMe2Si Si H
Si heptane, 60 °C C C
Me Me
86%
ð4Þ
HMe2Si Si CH3
29
H3C CH3
30
The addition of platinum catalyst to trisilyl-substituted amines 31 resulted in the formation of

intramolecular cyclization products 32. Unexpectedly, four-membered-ring products were formed
predominantly, rather than the thermodynamically more stable five-membered rings resulting
from endo-cyclization. The products were quite thermally stable and resisted reaction with BunLi
and BunLi/TMEDA. The trisilyl-substituted amine starting materials were prepared from lithium
bis(silyl)amides and chlorosilanes in high yields (Equation (5)) <1999OL423>.
Me Me
Me2Si H Pt cat. Si
THF RMe2Si N Me
N
RMe2Si SiMe2R Si
ð5Þ
31 Me Me
32
R = –CH=CH2, 97%
R = H, 59%
4.14.1.2 Functions Bearing Two Germaniums: R12C(GeR23)2

1,1-Bis(germyl)alkanes could be prepared by the formation of either one or both of the GeC
bonds or modification of the groups attached to either the germaniums or to the central carbon.
The different methods to generate an sp3-hybridized carbon connected to two germanium atoms
and either protons and carbon fragments are outlined in COFGT (1995).
4.14.1.2.1 Formation of the GeCGe linkage

In COFGT (1995), the formation of the GeCGe linkage via quenching of a carbanion with a
germyl electrophile, quenching a germyl anion with a carbon electrophile, and from germenes or
digermenes is described.
The reaction of 4-pentenoyl chloride with (trimethylgermyl)copper(I)-dimethyl sulfide and
trimethylsilyl chloride in dry THF at 78 C followed by work up with aqueous ammonium
chloride and ammonium hydroxide gave two products; the major product was shown to be an
amide (62%) 33 and the minor product was shown to be the gem-digermyl compound 34
(Equation (6)) <1995OM5011>.
O Me3GeCu·SMe2 O
Me3SiCl, THF, –78 °C OSiMe3
NH2 +
Cl NH4Cl GeMe3 ð6Þ
NH4OH, H2O GeMe3
33 (62%) GeMe3
34 (13%)
In the photochemical bis-germylation of C60 with 1,1,2,2-tetrakis(2,6-diethylphenyl)-1,2-diger-

mirane, a cycloadduct 35 was obtained in high yield for the first time. Spectroscopic analysis and
theoretical investigation confirmed that the product resulted from 1,4-cycloaddition. Control
experiments and laser flash photolysis experiments suggested that an exciplex intermediate was
responsible for the formation of the cycloadduct. The redox properties of the cycloadduct were
examined by differential pulse voltammetry (Equation (7)) <2000OL2671>.
Dep
High-pressure
mercury-arc Dep
lamp Ge
Dep2Ge GeDep2 + C60 C60
Dep = 2,6-diethylphenyl 61%, toluene ð7Þ
Ge
Dep
Dep
35

In COFGT (1995), the only method reported is the metallation of bis(trimethylgermyl)methane
with t-butyllithium and subsequent reaction with an electrophile. No further advances have
occurred in this area since the publication of chapter 4.14.1.2.2 in <1995COFGT(4)601>.
4.14.1.2.3 Changing the ligands on germanium

In COFGT (1995), the preparation of the 1,1-bis(germyl)alkanes by changing the ligands on
germanium present in 1,1-bisgermylalkanes is reported. No further advances have occurred in this
area since the publication of chapter 4.14.1.2.3 in <1995COFGT(4)601>.
4.14.1.3 Functions Bearing Two Borons: R12C(BR22)2, etc.

In COFGT (1995), systems containing two boryl groups and either proton or carbon fragments
bound to an sp3-hybridized carbon were reviewed. A useful review has appeared on highly Lewis
acidic bifunctional organoboranes <2000EJI2131>.
4.14.1.3.1 Formation of the BCB linkage

The formation of the BCB linkage through the hydroboration of terminal alkynes, internal
alkynes, vinylboranes, and through the quenching of a carbanion with a boryl electrophile is
outlined in COFGT (1995). In addition to hydroboration, vinylboranes have been boroborated to
give 1,1,2-trisborylalkanes.
(i) From diboration

The catechol-substituted diboranes reacted with the catechol-substituted borylacetylenes, in the
presence of [Pt(PPh3)2(C2H4)] or [Pt(PPh3)4], to give tetra- and hexaborylethane derivatives. When
[Pt(COD)2] was used as catalyst, the tetraborylethene was formed exclusively. Catalytic hydro-
genation of the tetraborylethene afforded the 1,1,10 ,10 -tetraborylethane which has been studied by
X-ray structure analysis <1999EJI1693>.
The insertion reaction of bis(pinacolato)diborane 36, [(Me4C2O2)BB(O2C2Me4), with various
diazoalkanes provided novel representatives of a new class of substituted C1-bridged bis(pinaco-
lato)diborane derivatives 37 in 75–78% isolated yields. The reaction was efficiently catalyzed by
Pt(PPh3)4 in toluene at 110 C. Single-crystal X-ray diffraction, GCMS, and NMR multinuclear
spectroscopies fully confirmed the structure and configuration of the new compounds (Equation (8))
<2002OM1870, 1995AG(E)809>.
R1 R2
R1 Pt(PPh3)4
O O Et2O, 0 °C/overnight C
B B + C N2 O B B O
O O 75%
R2 ð8Þ
O O
36
37
R1 = R2 = H
Diboration of the styrylboronate esters (E)-p-R-C6H4-CH¼CH-Bcat (R = H, MeO;

cat = 1,2-O2C6H4), with bis(catechol)diborane (B2cat2), in the presence of a variety of rhodium
phosphine catalysts gave the corresponding hydroborated products. The formation of the products
apparently involved regiospecific insertion of the vinylboronates into a rhodiumboron bond
followed by -hydride elimination, another regiospecific insertion of the 2,2-diboration, and a
2,1-hydrogen shift (Equation (9)) <2002JOM77>.
Bcat Bcat
Rh cat. Bcat Bcat
+ B2cat2 + Bcat + Bcat
Ar Bcat + + ð9Þ
Bcat Bcat
Ar Ar
Ar Bcat Ar
Bcat Ar Bcat
Bcat
(ii) From dihydroboration terminal alkynes

Dihydroboration of propargyl bromide with 9-BBN-H followed by the treatment of the adduct
with aqueous sodium hydroxide afforded the hydroxyl(cyclopropyl)borate complex (Equation
(10)) <2000TL4251>, which underwent efficient palladium-catalyzed cross coupling to produce a
variety of aryl- and vinylcyclopropanes in good-to-excellent yields <2000TL4251>.
OH
Br Br B
(9-BBN-H)2 NaOH (aq.) B
B + ð10Þ
H
THF rt, 1 h
reflux B
Trialkylsilanes or dialkylsilanes reacted rapidly with boron trichloride in the absence of ethereal
solvents or other nucleophiles to form unsolvated dichloroborane. If no substrate was present,
dichloroborane disproportionated to trichloroborane and two geometric isomers of chloroborane
dimer, which in turn yielded monochlorodiborane and, slowly but irreversibly, diborane. All of the
BH compounds in the mixture except diborane were highly active hydroborating agents. With
alkenes in the presence of sufficient boron trichloride, the products were alkyldichloroboranes.
These were free from detectable contamination by dialkylchloroboranes unless more than 1 mol of
hydride was present. Similar hydroboration of terminal acetylenes could be controlled to yield
either (E)-1-(dichloroboryl)alkenes or 1,1-bis(dichloroboryl)alkanes, each free from significant
contamination by the other. Alkyldichloroboranes with trialkylsilanes at 25 C produce alkyl-
monochloroboranes, detected by 11B-NMR. 1,1-Bis(dichloroboryl) alkanes similarly yielded
1,1-diborylalkane dimers. An alkylmonochloroborane could hydroborate a second alkene to form
a dialkylchloroborane. For this purpose, differing alkyl groups may be introduced in either order,
regardless of their relative steric properties. With 2 mol of trialkylsilane, alkyldichloroboranes were
converted to alkylborane dimers. Boron tribromide and its bromoborane derivatives behaved
similarly to the chloro compounds in the examples tested (Scheme 14) <1995OM4157>.
HO
O
BHCl2 BHCl2 BCl2 B
BCl2 HO O
n-Bu n-Bu n-Bu
n-Bu BCl2
B
O O
Scheme 14
(iii) Other route

Tetraalkynyltin compounds were reacted with triethylborane to provide 1,10 -spirobisstannols.
These provided carboranes 38 when reacted with boron halides. The intermediates prior to the
formation of carboranes were 3-borolenes bearing boryl groups in the 2,5-positions with the boryl
groups at the same side of the ring (Equation (11)) <1995JOM87>.
X
B
Et R1 R 1 BEt2
Et Et
+ 4BX3
Sn –2EtBX2 ð11Þ
–SnX4 R1 B R1
Et2B R1 R 1 Et
X
R1 = Et, Pr, Bu, and Pri 38
X = Cl
4.14.1.3.2 Changing the groups on the central methylene

According to COFGT (1995), the simplest method for adding functionality to the central
methylene was by direct deprotonation followed by an electrophilic quench.
The dihydroboration of trimethylsilylacetylene with diperfluorophenylborane followed by

thermal treatment provided 1,2-diborylethane derivative 39 (Scheme 15) <1995TL987,
1995AG(E)809>.
2HB(C6F5)2 B(C6F5)2
Me3Si C CH Me3SiCH2 CH
B(C6F5)2
– +
Heat
Me3Si Ph3C 2h
Ph3COMe Me3Si
(F5C6)2B B(C6F5)2 B(C6F5)2
O HC CH2
Me
(F5C6)2B
39
Scheme 15
4.14.1.3.3 Changing the ligands on boron

The route to the generation of 1,1-bis(boryl)alkanes was through the modification of ligands on
boron. In COFGT (1995), several such reactions have been demonstrated on bis(boryl)alkanes.
It has been discovered that diazomethane reacted with -iodo boronate ester to insert methy-
lene to give the corresponding gem-diboronate 40 in 83% yield which could be easily hydrolyzed
to the corresponding boronic acid 41 (Scheme 16) <2001OM3962>.
O CH2N2 O O O O
ICH2 B B CH2 B + B CH2CH2 B
O O O O O
40
HCl
HCl reflux
reflux
HO OH
HO OH B CH2CH2 B
B CH2 B HO OH
HO OH
41
Scheme 16
4.14.1.4 Functions Bearing a Silicon and a Germanium Group: R12CSiR23GeR33, etc.

The generation of systems containing both a silyl group and a germyl group attached to the same
sp3-hybridized carbon along with either hydrogen or carbon fragments is outlined in COFGT
(1995).
4.14.1.4.1 Formation of the SiCGe linkage

The formation of the SiCGe linkage has been outlined in COFGT (1995) by quenching a
carbanion with a germyl electrophile, quenching a carbanion with a silyl electrophile, quenching a
metalloid anion with a carbon electrophile, and hydrogermylation of silylallene.
It has been reported that a germanone 42 readily underwent intramolecular carbon–silicon
insertion in solution to give a mixture of stereoisomers 43 and 44 containing -trimethylsilyl-
germyl moieties (Equation (12)) <2002POL563>.
OSiMe3 OSiMe3
Tip H Me3Si Tip H
Me3Si Ge Ge
Tbt
Me3Si SiMe3 + Me3Si SiMe3
Ge O
Tip Tbt: R' ð12Þ
42 R' R' Me3Si SiMe3

Me3Si SiMe3
R' = CH(SiMe3)2 43 44
Tip: R' = CH(CH3)2

In COFGT (1995), metallation of the central carbon has been demonstrated by the deprotonation of
trimethylgermyl(trimethylsilyl)methane with t-butyllithium. The same intermediate could also be pre-
pared from the corresponding -chloro derivative through metal–halogen exchange with lithium metal.
Bis[2-pyridyl)bis(trimethylsilyl)-C,N]germanium(II) 45 was prepared by the reaction of lithiated
2-[bis(trimethylsilyl)methyl]pyridine and germanium(II) chloride–dioxane in ether at 78 C. The
structure of the product was confirmed by an X-ray diffraction study (Equation (13))
<1997OM2116>.
(Me3Si)2
C N
C(SiMe3)2 Et2O
+ GeCl2·C4H8O2 Ge
ð13Þ
N Li –78 °C N C(SiMe3)2
45
4.14.1.4.3 Changing the groups attached to the metalloids

According to COFGT (1995), one of the most frequently used transformations was the replace-
ment of a halogen by a carbon nucleophile, a reaction that has also been applied to 1-silyl-
1-germylalkanes. The alkoxide ligands on the metalloids have been replaced by both oxygen and
nitrogen ligands. The silyl(germyl)methane moiety has also been used as a ligand for transition
metals. No further advances have occurred in this area since the publication of chapter 4.14.1.4.3
in <1995COFGT(4)601>.
4.14.1.5 Functions Bearing a Silicon and a Boron Group: R12CSiR23BR32, etc.
4.14.1.5.1 Formation of the SiCB linkage

COFGT (1995) detailed the different methods to form the SiCB linkage by quenching a
carbanion with a boryl electrophile, quenching a carbanion with a silyl electrophile, hydrobora-
tion of vinyl silane, and borylboration of vinyl silane. Described below are the synthetic routes to
generate systems containing silicon to boron.
(i) Quenching a carbanion with a boryl electrophile

The reaction of boron halides with indenyllithium reagents was studied. In this case, the indenyl
moiety was readily transferred and bis(indenyl)boranes were formed (Equations (14) and (15))
<1997JOM361>.
SiMe3
Me3Si
Pentane, rt
2
+ PhBCl2 12 h B ð14Þ
Li+ 99%
Me3Si
SiMe3
Pentane, rt SiMe3
12 h +
+ Ph2BBr ð15Þ
97%
Li+ BPh2
BPh2 Me3Si
The stereocontrolled synthesis of 1-silyl-1-boryl-2-alkenes by gem-silylborylation of -chloro-

allyllithiums has been reported. The -chloroallyllithiums generated in situ from allylic chlorides
with lithium diisopropylamide (LDA) in tetrahydrofuran were reacted with (dimethylphenylsilyl)
(pinacolato)borane 46 to provide the corresponding gem-silylboryl reagents 47. The results are
summarized in Table 2 (Equation (16)) <2001AG(E)4283>.
Table 2 Synthesis of 1-silyl-1-boryl-2-alkenes from allylic chlorides

Allylic chloride Product Yield (%)
Cl B(OCMe2)2
82
SiMe2Ph
Cl
B(OCMe2)2
86
SiMe2Ph
Pr Cl Pr B(OCMe2)2
75
SiMe2Ph
Cl
B(OCMe2)2
Pr 79
Pr SiMe2Ph
Ph
Cl Ph B(OCMe2)2
75
SiMe2Ph
Cl
B(OCMe2)2
72
SiMe2Ph
Cl
B(OCMe2)2
73
SiMe2Ph
R1 R1
R2 Cl LDA R2 B(OCMe2)2
+ PhMe2Si B(OCMe2)2
10 min ð16Þ
R3 46 72–86% R3 SiMe2Ph
47
(ii) From hydroboration

Two methods for the synthesis of tris(hydridosilylethyl)boranes were explored. In the first
method, the chlorovinylsilanes 48 were reacted with lithium aluminum hydride in diethyl ether
solution followed by hydroboration with borane–methyl sulfide complex to give the correspond-
ing tris(hydridosilylethyl)boranes 49. In the second method, chlorovinyl silanes were hydrobo-
rated with borane–methyl sulfide complex followed by treatment with lithium aluminum hydride
in diethyl ether. The excess lithium aluminum hydride was removed by treatment with trimethyl-
silyl chloride (Schemes 17 and 18), <1999JOM115>.
H CH2 H CH2 R′
C C BH3.S(CH3)2 CH3
Excess LiAlH4 B
H Si R2 R′ CH
Cl Si R2 Et2O, 0 °C Toluene, 0 °C
R1 Si R2
R1 55% H
(Not isolated) R1
48
R′ = C2H4Si(R1)(R2)H
49
Scheme 17
R′ R′
H CH2 CH3 CH3
C B B
BH3.S(CH3)2 R′ CH Excess LiAlH4 R′ CH
Cl Si R2 Et2O, 0 °C
Toluene, 0 °C
Cl Si R2 H Si R2
R1 49%
R1 R1
R′ = C2H4Si(R1)(R2)H R′ = C2H4Si(R1)(R2)H
Scheme 18
Hydroboration of aliphatic vinyl silanes with the highly electrophilic bis-(pentafluorophenyl)

borane, HB(C6F5)2, gave predominantly the thermodynamically favored regioisomer with boron
and silicon on the same carbon. Thermodynamic product mixtures were obtained because
equilibration of isomers through boryl migration was facile in the products of hydroboration
with HB(C6F5)2. The 1,1-substituted isomers are the most stable by virtue of a ground-state
-silicon effect involving hyperconjugation between the trimethylsilyl group and the electrophilic
borane center. More complex thermal rearrangements were observed when aromatic vinyl silanes
were hydroborated with HB(C6F5)2. Experiments using 13C-labeled and para-substituted sub-
strates provided mechanistic information on these rearrangements, which appeared to be driven
by the formation of compounds that could be engaged in the ground-state -silicon interaction
(Scheme 19) <1998T15469>.
B(C6F5)2
(C6F5)2BH ∆
Me3Si ( )n Me3Si ( )n B(C6F5)2 ()
C6D6 Me3Si n
n = 0, 1, and 4
Scheme 19
Hydrocarbon reactions of dichloroborane–, monochloroborane–, and borane–dimethyl sulfide

with dichloromethylvinylsilane and trichlorovinylsilane were investigated. The first addition
appeared strictly regioselective in the -position to silicon, producing one chiral methine group
between silicon and dichloroborane in the compound formed 50. The second addition of borane–
or monochloroborane–dimethyl sulfide at the vinyl groups of dichloromethylvinylsilane and
trichlorovinylsilane also took place in the -position to silicon, forming a second chiral methine
group 51. In the case of borane–dimethyl sulfide the third addition occurred in the -position
owing to the steric hindrance to boron in tris[(dichloromethylsilyl)ethyl] borane 52 (Scheme 20)
<2000POL323>.
x=3 CH3
RCl2Si SiCl2R
Toluene RCl2Si B
10 °C, 6 h CH3
98% 52
Cl
x=2 RCl2Si CH3
XR Si + Hx BCl(3 – x ) SMe2 B Cl
Toluene RCl2Si
Cl 10 °C, 6 h CH3
97% 51
R = CH3, Cl
x=1 CH3
Toluene RCl2Si
10 °C, 6 h B Cl
93% Cl SMe2
50
Scheme 20
(Z)-1-Trimethylsilyl-1-alkenes 53, easily prepared by the hydroboration of the corresponding

1-trimethylsilyl-1-alkynes followed by protonolysis with acetic acid, readily reacted with dibromo-
borane–methyl sulfide complex in dichloromethane for 6 h. The resulting solution was then
treated with 1,3-propanediol in a 1:1 mixture of dichloromethane and n-pentane at 0 C for half
an hour to provide the corresponding gem-dimetalloalkanes 54 containing boron and silicon.
These -trimethylsilylalkylboronate esters were purified by vacuum distillation in high yields
(72–84%) and the structures of these novel intermediates were further confirmed by selective oxidation
with alkaline hydrogen peroxide to provide the corresponding alcohols 55 containing the trimethyl-
silyl group (Scheme 21) <2003TL6833>. Representative examples of boronate esters with an
-trimethylsilyl group are provided in Table 3.
SiMe3 SiMe3
R SiMe3 RCH2CH HO(CH2)3OH RCH2CH H2O2
C C RCH2CHSiMe3
H H B NaOH
BHBr2.SMe2 B SMe2 O O OH
53 Br Br 55
54
Scheme 21
(iii) Other routes

Addition of diarylstannylenes to an electrophilic carbine 56 furnished the corresponding
stannaethene 57. The X-ray structure analysis of the stannaethene revealed a strictly planar
environment of the tricoordinated tin and carbon atoms and a slight twisting of the tincarbon
double bond (Scheme 22) <1997JOM255>.
Several representative silylboranes, including B-(phenyldimethylsilyl) catecholborane, were pre-
pared and their reactivity was explored. The reaction of silylboranes with either vinyllithium or
lithium acetylide generated the corresponding silylborates, which rearranged upon treatment with
iodine producing the vinyl silanes and silylacetylide, respectively. The reaction of B-(phenyldi-
methylsilyl)catecholborane 58 with ethyl diazoacetate yielded ethyl(phenyldimethylsilyl) acetate
59 upon hydrolysis (Scheme 23) <1995OM3112>.
Table 3 Synthesis of gem-dimetalloalkanes containing boron and silicon

(Z)-1-Trimethylsilyl-1-alkene Product Yield (%)
n-C4H9 SiMe3 SiMe3

O
C C n-C4H9CH2CH B 84
H H O
n-C5H11 SiMe3 SiMe3

O
C C n -C5H11CH2CH B 82
H H O
n -C6H13 SiMe3 SiMe3

O
C C n -C6H13CH2CH B 78
H H O
Cl(CH2)3 SiMe3 SiMe3

O
C C Cl(CH2)3CH2CH B 72
H H O
(CH3)3C SiMe3 SiMe3

O
C C (CH3)3CCH2CH B 74
H H O
CH3CH2CHCH3 SiMe3 SiMe3

O
C C CH2CH B 80
H H CH3CH2CHCH3 O
Me3Si B Me3Si B :SnR"2 Me3Si B

C C C C C SnR''2
C B Me3Si B
Me3Si B Me3Si
57
56
R" = 2-But-4,5,6-Me3C6
Scheme 22
O N2CHCO2Et O
CO2Et –N2
PhMe2Si B – H2O
O B + O CO2Et PhMe2SiCH2CO2Et
O THF N2
PhMe2Si O B 30 min
0 °C, 3 h SiMe2Ph
59
58
Scheme 23

As described in COFGT (1995), the only method described for the manipulation of functionality on the
central methylene of -borylsilylalkanes is through deprotonation followed by electrophilic quench. No
further advances have occurred in this area since the publication of chapter 4.14.1.5.2 in
<1995COFGT(4)601>.
4.14.1.5.3 Changing the groups attached to the metalloids

As indicated in COFGT (1995), ester exchange provided a simple route to the manipulation of the
functionality on boronic acids. A carbonboron bond may be formed by the displacement of an
alkoxide ligand, such as the reaction of an allyl Grignard reagent with -trimethylsilyl-B-methoxy-
borolane.
The cyclic compounds 60 containing boron and silicon were prepared by reacting 2,3-diborata-
1,3-butadiene with dichloromethylsilane followed by treatment with boron trichloride (Scheme 24)
<2002JOM262>.
HH H Me Cl Me
Me3Si SiMe3
C C H Si SiMe3
BCl3 H Si SiMe3
Cl2SiHMe C C
H C C
B B Me3Si H
B B Me3Si
B B
Dur Dur Dur Dur
Dur Dur
60
Dur =
Scheme 24
4.14.1.6 Functions Bearing a Germanium and a Boron Group: R12CBR22GeR33, etc.

In COFGT (1995), very little work was reported concerning systems containing both boron
and germanium on the same sp3-hybridized carbon. One example was the hydroboration of
dimethyl(divinyl)germane with borane–methyl sulfide complex, which resulted in a mixture
of regioisomers as evidenced by the alcohols produced upon oxidative work-up. No further advances
have occurred in this area since the publication of chapter 4.14.1.6 in <1995COFGT(4)601>.
4.14.2 FUNCTIONS CONTAINING A METALLOID AND A METAL
4.14.2.1 Silicon and a Metal: R12CSiR23M, etc.

According to COFGT (1995), the most important route for the preparation of 1-metallo-
1-silylalkanes is deprotonation. This has been most generally performed when the resultant
carbanion is stabilized by, for example, aryl, allyl, or carbonyl groups. Two useful reviews have
appeared recently on organometallic compounds in <1995JOM101> and <2001T2065>.
4.14.2.1.1 Silicon and a group 1 or group 2 metal: R12CSiR33Li, etc.

In COFGT (1995), different methods have been outlined to synthesize -lithiosilylalkanes from
-lithiosilylalkanes involving deprotonation, addition of organolithium to vinyl silane, halogen-
lithium exchange, transmetallation, sulfur–lithium exchange, -sodio- or -potassiosilylalkanes,
-magnesiosilylalkanes involving halogen–magnesium exchange, addition of a Grignard reagent
to vinyl silane, transmetallation, and rearrangement.
(i) By deprotonation of alkyl silanes and allyl silanes

The generation of [bis(2-pyridyldimethylsilyl)methyl]lithium was easily accomplished by the
deprotonation of [bis(2-pyridyldimethylsilyl)methane] using n-butyllithium in diethyl ether. The
bis(2-pyridyldimethylsilyl)methyl]lithium thus generated was found to react with a variety of
aldehydes and ketones to give the corresponding vinyl silanes in extremely high yields with
complete stereoselectivities <2000OL1299>.
The formation of benzocyclobutenol derivatives by intramolecular cyclizations of o-acylbenzyl-
lithiums is described. Treatment of o-(trialkylsilylmethyl)phenyl ketones with LDA followed by the
quenching of the corresponding 1-trialkylsiloxy-2-(trialkylsilyl) benzocyclobutenes provided the
desired products in good yields. Subsequently, o-acyl-m-methoxybenzyllithiums were found to work
well in cyclizations to benzocyclobuten-1-ol derivatives. The reaction of 2-benzoyl-3,4,5-trimethoxy-
benzyllithium, generated in situ by deprotonation of 6-methyl-2,3,4-trimethoxybenzophenone with
LDA, and subsequent treatment with chlorotrimethylsilane afforded the corresponding 1-(trimethyl-
siloxy) benzocyclobutene. Cyclization of 2-pivaloyl-3-methoxybenzyllithiums, generated in situ from
t-butyl-2-methyl-6-methoxyphenyl ketones upon deprotonation with LDA, proceeded spontaneously
at 78 C to give the corresponding benzocyclobuten-1-ols. The results of thermal isomerization of
these 1-trimethylsiloxy-2-(trialkylsilyl) benzocyclobutenes were also described <1999JOC3557>.
Both (Z)- and (E)-allylic silanes were prepared with high stereoselectivity by copper-mediated
substitution of allylic carbamates by organometallic reagents. The reaction of alkylmagnesium reagents
with (E)-allylic carbamates provides (Z)-allylic silanes, whereas both alkylmagnesium and alkyllithium
reagents react with (Z)-allylic carbamates to afford (E)-allylic silanes. Because the Grignard reagents
are often more facile to prepare than alkyllithium species, these reagents are the optimal nucleophiles
for the synthesis of both (Z)- and (E)-allylic silanes. This method also allows readily available
nonracemic allylic carbamates to be converted to chiral, nonracemic (Z)- and (E)-allylic silanes with
high stereoselectivity <2000JOC1601>. The selective deprotection of acetals with trimethylsilylmethyl-
magnesium chloride to the corresponding diols has been achieved <2000JOC4694>. The organo-
mercury compounds containing the bulky silyl ligands have been prepared <1996JOM143>.
Treatment of a tetrahydrofuran solution of t-butyldimethylsilyldihalomethyllithiums with
p-MeOC6H4CHO or n-butanal followed by an addition of HMPA and benzaldehyde gave the
corresponding 1,3-diol monosilyl ether in 83% or 45% yield, respectively. The use of oxirane in
place of aldehyde as the first electrophile followed by addition of benzaldehyde provided 1,4-diol
monosilyl ether <1996T503>.
The reaction of 1-triphenylsilyl-2-propenyllithium with ethylene oxide afforded an adduct, a
lithium salt of 3-triphenylsilyl-4-penten-1-ol, which regenerated an allyllithium species, 3-lithio-
5-triphenylsiloxy-1-pentene via anionic rearrangement of a silyl group from carbon to oxygen in
the presence of HMPA. This allylic lithium compound could be trapped in one pot by various
electrophiles to provide the corresponding adducts as regioisomeric mixtures. A successive addi-
tion of epoxides, aldehydes, and HMPA to 1,3-bis(triphenylsilyl)-2-propenyllithium gave 1,4-diol
monosilyl ethers in one pot with high regioselectivity <1998TL2575>. Reactions of aliphatic
ketones with lithium trimethylsilyldiazomethane in the presence of excess olefins afforded methy-
lenecyclopropanes in moderate-to-good yields <1999T3687>.
Allylation of the radical generated from -silyl--phenylselenoacetic esters with various allyl-
tributyltin substrates led to good yields of the corresponding homoallylsilanes. A study on the
nature of the radical thus generated was performed using comparative allylation rates with
electronically different allyltributyltin compounds. Finally, these homoallylsilanes were converted
into the corresponding homoallylic-1,2-diols after reduction of the ester function and oxidation of
the CSi bond <1995T12097>. The preparation of -(alkoxy)silylacetic esters has been achieved
<1995T12083>. LDA treatment of 2-silylated benzamides afforded 2-fluorosilylated aceto-
phenones in a general process likely driven by complex-induced proximity effect (CIPE)-facili-
tated -silyl carbanion formation and rearrangement; oxidation (H2O2) of the products gives
2-hydroxyacetophenones and catechols <1996TL2915>.
The synthesis of 2-substituted allylic alcohols from esters has been achieved by the reaction of
trimethylsilylmethylmagnesium chloride with esters <1996JOC9617>. The enantioselective synth-
esis of (2-substituted-2-hydroxyethyl)allylsilanes by cerium-mediated trimethylsilylmethylmagne-
sium chloride addition on the ester group of optically active -hydroxy esters. The reaction of
ester acetals with trimethylsilylmethylmagnesium chloride to afford the alcohol acetals has also
been achieved <1997TL3861>. An efficient synthesis of substituted vinylcarbamates, from
benzylcarbamates via the Peterson olefination was described <1997TL1851>.
Reactions of aliphatic ketones with lithium trimethylsilyldiazomethane in the presence of excess
olefins afforded methylenecyclopropanes in moderate-to-good yields. The multiplicity of the
alkylidene carbene intermediate in the reaction has been revealed to be a singlet <1999T3687>.
The reaction of -ketoaldehyde acetals with lithium trimethylsilyldiazomethane afforded 2-cyclo-
pentenones via the 1,5-carbon–hydrogen insertion of alkylidene carbene in high-to-moderate
yields <2000TL6859>.
Treatment of 1-[axial]-(trimethylsilylethynyl)cyclohexan-1-ol with dicobalt octacarbonyl results

in a conformational ring flip such that the bulky dicobalt-alkyne cluster moiety now occupies the
favored equatorial site. However, when a 4-t-butyl substituent is present, the coordinated alkynyl
group retains its original axial or equatorial position. Complexation of trans-[diaxial]-1,4-bis(tri-
phenylsilylethynyl)cyclohexane-1,4-diol brings about a chair-to-chair conformational inversion
such that both cluster fragments now occupy equatorial sites. In contrast, cis-1,4-bis(triphenyl-
silylethynyl)-cyclohexane-1,4-diol reacts with Co2(CO)8 to yield the twist-boat conformer in which
the two axial hydroxyl substituents exhibit intra-molecular hydrogen bonding. Likewise, the
corresponding reaction of cis-1,4-bis(trimethylsilylethynyl)cyclohexane-1,4-diol with Co2(CO)8
leads to a twist-boat, but in this case, the molecules are linked through inter-molecular hydrogen
bonds. Eight of these cobalt clusters have been characterized by X-ray crystallography, and the
potential participation of twist-boats in synthesis is discussed <2001JOC8585>. t-Butyldimethyl-
silyldibromomethyllithium acted as a dibromomethylene dianion synthon in the reaction with
aldehydes followed by 1,3-rearrangement of silyl group from carbon to oxygen <1996T503>. The
hydroxymethylating reagent [dimethyl(phenylthiomethyl)silyl]methylmagnesium chloride adds to
a sugar aldehyde with high selectivity to give stable syn-product <1995SL1069>. Treatment of
allyldiphenylsilanol with 2 equiv. of n-butyllithium in the presence of HMPA provided silylallyl-
lithium 61 bearing an oxide anion on the silicon atom. The reaction of silylallyllithium with
different electrophiles was also investigated (Scheme 25) <1997TL5189>.
OH 2BunLi OLi OH
OH
SiPh2 SiPh2 E+ SiPh2 + E
THF/HMPA SiPh2
45–48%
–45 °C Li
30 min E
61
Scheme 25
(ii) By nucleophilic addition

N,N-Dimethylbenzamide was reacted with dimethylphenylsilyllithium to provide the correspond-
ing -silyllithium 62 and gave deuterated -silylamine 63 on quenching with D2O. The reaction of
-silyllithium with alkyl halides provided the corresponding -silyl alkylated products 64 (Scheme
26) <1998CC713>.
NMe2
SiMe2Ph
D
63
68%
D2O (90% D)
NMe2 NMe2
NMe2
PhMe2SiLi SiMe2Ph SiMe2Ph
O THF Li MeI E
or
–78 °C to –20 °C Br
1.5 h THF 64
62
E = Me 54%
E = allyl 63%
Scheme 26
(iii) Another route

Starting from the lithium alkyl 65, the bis[(diphenyl)(piperidinomethyl)silyl]methyl]metal com-
pounds 66 containing metals such as magnesium, cadmium, gallium, palladium, and mercury
were synthesized in different solvents (toluene and tetrahydrofuran) by metathesis reactions, using
the corresponding metal(II) halides (Equation (17)) <2002JOM149>.
CH3 N
Ph Ph Li Ph
Si
2 Si 2ButLi Si MX2
Ph Ph M Ph
N n-pentane Ph N CH3 Si
–90 °C to rt Ph ð17Þ
N
2
THF
65
66
–90 °C to rt
M = Mg, Ga, Pd, Cd, and Hg
4.14.2.1.2 Silicon and a transition metal: R12CSiR23CuX, etc.

According to COFGT (1995), there have been many reports of systems containing both silicon
and a transition metal (including zinc) bound to the same carbon together with either protons or
carbonyl groups. They have been prepared mainly by the reactions of transition metal complexes
with an -silylmethyl anion, by the reaction of an -metallomethyl transition metal with a silyl
electrophile, and changing the groups attached to the central methylene or to the metal.
The zirconium–silene complex 67 was formed from dicyclopentadienyl chloride and dimethyl-
phenylsilyllithium, which reacted with diphenylacetylene to provide the silazirconacyclopentene
68 (Scheme 27) <2000JOM304>.
Ph Ph
Ph Me PhC CPh
Si THF, –78 °C Ph
Cp2ZrCl2 + 2Me2PhSiLi Si
Cp2Zr Cp2Zr Me
67 68
Scheme 27
The (trimethylsilyl)ethylene–titanium alkoxide complex 69 was generated from trimethyl(vinyl)-

silane with titanium tetraisopropoxide and isopropylmagnesium chloride. The preformed
alkene–titanium complex reacted with aldehydes to form the corresponding -silyl alcohol 70.
The reaction was believed to go through oxatitancycles (Scheme 28) <2000JOC6217>.
Me3Si
Me3Si RCHO Ti(OPri)2
Me3Si
+ Ti(OPri)4 + PriMgCl O
Et2O Ti(OPri)2 Et2O, –50 °C
–50 °C 69
2h R
E+
R = C7H15 E = H 63%
o -C6H11 H 87% Me3Si E
" D 85% OH
" I 87%
R
But H 66%
70
Ph H 34%
Scheme 28
The reaction of Cp2Ti(CH2SiMe3)2 with bis(trimethylsilyl)acetylene in toluene formed

tris(trimethylsilyl) titanacyclobutene 71. Unlike other titanacyclobutenes, which underwent inser-
tion with carbonyl compounds, this reagent converted carbonyl compounds to the corresponding
alkenylsilanes (Equation (18)) <1995TL3619>.
SiMe3
SiMe3 Me3Si SiMe3

Ti Ti SiMe3
ð18Þ
SiMe3 PhMe, 80 °C
quantitative yield
SiMe3
71
A variety of cyclobutanedione derivatives, including squaric esters, reacted with dicyclopenta-

denyltitanocene to afford the corresponding methylenation products 72. With certain mixed-
substituted substrates the reaction proceeded preferably at a ketonic carbonyl rather than a
vinylogous ester (Scheme 29) <1995TL6001>.
PrOi O
SiMe3
SiMe3 PrOi SiMe3
Me3Si SiMe3 PrOi
Ti Ti SiMe3 O
SiMe3
PhMe, 100 °C PhMe, 25 °C PrOi O
SiMe3
72
(62%, 1/1 (Z )/(E ))
Scheme 29
Treatment of dibromomethyltrialkylsilanes with butylmagnesium bromide in the presence of a

catalytic amount of manganese(II) chloride provided (E)-1-trialkylsilyl-1-pentenes with high
stereoselectivity in good yields. The reaction proceeded through -silylmanganese intermediate
73 (Scheme 30) <1997TL3275>.
(R1CH2)3MnMgBr Br 25 °C H
THF Mn–CH2R1 2h R3Si
R3SiCHBr2 R3SiCH CH2R1 R3SiCH
Mn C C
0 °C CH2R1 57–95%
2h R1CH2 H R1
73
Scheme 30
A convergent route to allylzirconocene reagents 74 by the insertion of a silyl-substituted

carbenoid such as trimethylsilylchloromethyllithium reagent (LiCH(SiMe3)Cl) into vinylzircono-
cene chlorides was reported (Scheme 31) <1999TL9353>.
Me3Si Li ZrCp2Cl
Cl
Cp2ZrHCl
H Cl
R1C CH Cp2Zr Me3Si R1
THF R1
20 °C –78 to –40 °C
74
1h
73% NaHCO3 (aq.)
Me3Si R1 + Me3Si R1
11%
89%
Scheme 31
A variety of aromatic aldehydes were converted to the corresponding vinyl silanes in a one-pot
procedure involving the addition of (trimethylsilylmethyl)lithium to the aldehyde followed by
treatment with Cp2TiCH2AlMe2Cl (‘‘Tebbe’s reagent’’). Halide and alkoxide substituents were
tolerated, and (E)-vinyl silanes were formed exclusively in good yield <2001TL1411>. An
efficient synthesis of silylketenes via an unusual rhodium-mediated Wolff rearrangement involving
-silylrhodium species has been reported <1999CC1199>. Trimethylsilylmethyllithium has been
utilized in the synthesis of -ketosilanes via the reaction with (Z)-1-bromo-1-alkenylboronate
esters <2000TL6541>. Mixed diorganozincs underwent selective transfer of the alkyl grouping in
a 1,4-fashion to various Michael acceptors <1997JCS(P1)3117>. Highly enantioselective addition
of mixed diorganozincs to aldehydes to provide the corresponding chiral alcohols has been
investigated <1997JOC7895>.
The generation of (2-PyMe2Si)2CHLi was easily accomplished by the deprotonation of
(2-PyMe2Si)2CH2 using n-BuLi in Et2O. Thus, the generated (2-PyMe2Si)2CHLi was found to
react with a variety of aldehydes and ketones to give the corresponding vinyl silanes in
extremely high yields with complete stereoselectivities <2000OL1299>. Tris(trimethylsilyl)-
methyllithium has been prepared from tris(trimethylsilyl)methane by reaction with methyl-
lithium <1998TL4745>.
The compound {(Me3Si)2CHSiMe2CH2}2 has been prepared and metallated with MeLi to give
the chelated lithiate ion [CH2SiMe2C(SiMe3)2LiC(SiMe3)2SiMe2CH2], which was isolated as
its [Li(TMEDA)2] salt (TMEDA = N,N,N,N-tetramethylethylenediamine). The potential of this
salt as a source of the very bulky dicarbanionic ligand {(Me3Si)2CSiMe2CH2}2 was demon-
strated by its reaction with HgBr2 in THF to give the chelated mercury compound
[CH2SiMe2C(SiMe3)HgC(SiMe3)2SiMe2CH2]. The crystal structures of the salt and the mercurial
compound were determined <1996OM1651>.
The reaction of dipentylzinc with (E)-trimethylsilylpropenal in the presence of chiral catalyst
provided allylic alcohol 75 in 70% yield and 92% ee. The reaction of allylic alcohol 75 with butyl
vinyl ether and N-bromosuccinimide in dichloromethane afforded the bromoacetal 76 in 88%
yield. The nickel-catalyzed cyclization proceeded smoothly with diethylzinc and lithium iodide to
provide the -trimethylsilyl zinc reagent 77 (Scheme 32) <1995TL231>.
SiMe3
Br
Pent
BuO
Me3Si OH NBS, CH2Cl2
75 O
Pent OBu
76
Et2Zn, Lil
Ni(acac)2 cat.
THF, 40 °C
SiMe3
XZn CH
O
Pent OBu
77
Scheme 32
It has been demonstrated that vinyl silanes were highly reactive and their reactions with zincated
hydrazones were shown to be highly regioselective. The reaction was shown to proceed through
-zincated silicon species 78, which could undergo reaction with electrophiles (Scheme 33)
<1997TL7099>.
NMe2 NMe2
N N
H ZnBr
i. ButLi BuLi
R1 ii. ZnBr2 R1
R2 R2
NMe2
N NMe2 NMe2
N N
ZnBu
+ +
SiR3 SiR3 E
R1 SiR3
R1
R1
R2
R2 Zn–Bu R2 E
78
Scheme 33
Silylketenes bearing a range of substituents (alkyl, alkenyl, aryl, heteroaryl) were prepared by
an unusual rhodium-mediated Wolff rearrangement of the corresponding silyldiazo ketone and
the reaction was shown to proceed through an -silylrhodium species <1999CC1199>. Metal-
lated epoxides (epoxysilanes, epoxynitriles, and epoxystyrene) inserted efficiently into the zirco-
nacyclohexane containing an -trimethylsilyl group (Scheme 34) <2000TL5275> via a 1,2-
metallate rearrangement to afford the corresponding substituted alkenes 79.
–
O Li+ OLi
R1 Li C6H13 Me3Si
R1 R1 H
C6H13 SiMe3 O
ZrCp2 SiMe C6H13
ZrCp2 3
R2 ZrCp2
R2 R2
–
Li+ R1
Me3Si H C6H13
R1
C6H13 SiMe3
R2
Zr-O
R2 Cp2 ZrCp2
LiO
79
Scheme 34
4-t-Butylcyclohexanone was treated with (trimethylsilylethynyl)lithium and subsequent hydro-

lysis yielded two alkynols that were readily separable by column chromatography. The isomers
with axial and equatorial alkynyl groups, respectively, formed in a 5:2 ratio. Each alkynol was
stirred at room temperature for 24 h with an equimolar quantity of dicobalt hexacarbonyl to give
the corresponding dicobalt hexacarbonyl clusters 80 and 81 (Scheme 35) <2001JOC8585>.
4.14.2.1.3 Silicon and a group 13 or group 14 metal: R12CSiR23SnR33, etc.

The most common methods for the preparation of compounds containing a silicon and a group
13 or 14 metal bound to the same carbon along with either protons or carbon atoms have been
through transmetallation from easily accessible -lithio or -magnesiosilylalkane derivatives.
R
RC CLi OH
O
Et2O, –78°C
OH + R
H2O
R = Ph R = Me3Si
R = Me3Si R = Ph3Si
R = Ph3Si Co2(CO)8
Co(CO)3 OH
R Co(CO)3 Co(CO)3
+ Co(CO)3
OH R
80 81
R = Ph R = Me3Si
R = Me3Si R = Ph3Si
R = Ph3Si
Scheme 35
The 1-hydroxy-3,3-heterobimetallic compound 82 containing tin and silicon was acetylated with
acetic anhydride in pyridine, which underwent palladium-catalyzed hydrogenolysis of the result-
ing allylic acetate to the corresponding alkenes 83 containing gem-heterobimetallic species with tin
and silicon (Scheme 36) <1996T7221>.
SnBu3 SnBu3 SnBu3

OH OAc Pd2(DBA)3
Ac2O, DMAP
pyridine PPh3, HCOOH
Me3Si R rt R Me3Si R
Me3Si Et3N
12 h dioxane
82 98% 83
heat, 3 h
99%
Scheme 36
The gem-distannane containing a siloxy group was metallated with n-butyllithium and reacted
with benzaldehyde to provide 3-(t-butyldimethylsilyl)-3-(tributylstannyl)propanol 84 exclusively
(Equation (19)) <1998JOC1773, 1995TL9345>.
Bu3Sn
OSiMe2But Bu3Sn
BunLi, –78 °C to 0 °C, THF OH
SnBu3
ð19Þ
PhCHO, 65% ButMe2Si
84
A variety of ferrocene-containing organotin compounds 85 and 86 has been synthesized by

employing the (dimethylsilyl)methylene group as a spacer between the ferrocene units and tin
(Equations (20) and (21)) <2000OM430>.
Me Me Me Me
Si MgCl Si SnPh3
2Ph3SnCl
Fe Fe
THF, reflux ð20Þ
Si overnight Si
MgCl SnPh3
Me Me 63%
Me Me
85
Me Me Me Me
Si Cl Si SnMe3
2Me3SnNa, NH3, –78 °C
Fe Fe ð21Þ
Si Si SnMe3
Cl
Me Me Me Me
86
Starting from vinyl triflates, the corresponding allylsilanes were prepared using a cross coupling with
tris[(trimethylsilyl)methyl]aluminum catalyzed by palladium(0) <1997T15853>. The compounds con-
taining -silylindium, aluminum, and gallium have been prepared <1997ZAAC883, 1996CB1425,
1997CB417, 1998EJI1661, 1998EJI355, 1999JCS(D)2385, 1999ZAAC2095>. The preparation of com-
pounds containing -silyltitanium species has also been reported <1995TL6001, 2001AG(E)2890>.
The reaction of tetrakis[bis(trimethylsilyl)methyl]digallane with 1,10 -ferrocenedicarboxylic acid afforded
orange-red crystals of the macrocyclic compound in 84% yield <2000OM1128>.
The tris(phenylthiomethyl)silanes 87 were prepared by the reaction of (phenylthiomethyl)-
lithium with the corresponding chlorosilanes. The reductive carbonsulfur bond cleavage was
achieved through metallation using an electron-transfer reagent such as lithium p, p0 -di-t-butyl-
biphenylide (LiDBB). The reaction was effective in replacing thiophenyl groups of tris(phe-
nylthiomethyl)silanes with lithium to give the corresponding tris(lithiomethylsilanes) 88, which
were derivatized with tri-n-butyltin chloride to the corresponding tris(tri-n-butylmethyl)stannanes
89 (Scheme 37) <2000OM4223>.
R R
R Cl 3LiCH2SPh SPh 6LiDBB Si Li 6Bu3SnCl R
Si Si SnBu3
Si
–40 °C to rt –40 °C –78 °C to rt
Cl Cl
THF PhS SPh THF Li Li THF
6h 62–81% SnBu3 SnBu3
87 88
89
Scheme 37
4.14.2.1.4 Silicon and other elements

In COFGT (1995), the systems in which the silicon and the group 15 and 16 elements (selenium,
tellurium, arsenic, and antimony) attached to an sp3-carbon are covered in chapters 4.13 and 4.08.
A study of the scope of the catalytic hydrogenation and hydrosilylation of chiral exomethylene-
substituted cyclopentanes and cyclohexanes utilizing the organolanthanide precatalysts
Cp2LnCH(SiMe3)2 (Cp = C5Me5; Ln = Sm, Yb) was undertaken. Both reaction types were
sterically driven and lead to the cis-diastereomer as the major product. Additionally, the hydro-
silylation was regiospecific, the silane being placed exclusively at the terminal position of the
double bond <1996JOM275>. The -trimethylsilylsamarium species has been used in the efficient
regiospecific synthesis of pyrrolizidine and indolizidine skeletons <1996JA707, 1996JA9295>. It
has been reported that the lanthanide metallocenes such as Cp2LnCH(SiMe3)2 (Ln = Sm and Nd,
Cp = C5Me5 and C5Me4) catalyzed the regiospecific intermolecular addition of primary amines to
acetylenic, olefinic, and diene substrates <1996OM3770>.
4.14.2.2 Germanium and a Metal: R12CGeR23M

There have been many reports on the generation of -metallogermylalkanes from the trans-
metallation of the corresponding -lithio derivatives as described in COFGT (1995). No further
advances have occurred in this area since the publication of chapter 4.14.2.2 in <1995COFG(4)601>.
4.14.2.2.1 a-Lithiogermylalkanes
As reported in COFGT (1995), deprotonation of to the germyl group with LDA provides the
most efficient route to these systems. The other route includes the addition of an organolithium
reagent to a vinylgermane. No further advances have occurred in this area since the publication of
chapter 4.14.2.2.1 in <1995COFGT(4)601>.
4.14.2.2.2 Other a-metallogermylalkanes

As outlined in COFGT (1995), the transmetallation of an -lithio derivative provided a rapid entry
into other -metallogermylalkanes. A further route to -metallogermylalkanes was achieved by the
displacement of the halide of (halomethyl)trimethylgermanes with anionic iron and tungsten com-
plexes resulting in the generation of the -metallogermylalkanes. No further advances have
occurred in this area since the publication of chapter 4.14.2.2.2 in <1995COFGT(4)601>.
4.14.2.3 Boron and a Metal: R12CBR22M

According to COFGT (1995), the most readily available derivatives are the -lithioorganoboranes.
4.14.2.3.1 a-Lithioborylalkanes
In COFGT (1995), the preparation of compounds containing a carbon bound to a lithium, a
boron, and either hydrogen or carbon atoms has been described by deprotonation, by halogen–
metal exchange, or by transmetallation.
The preparation of tris(ethylenedioxyboryl)methane 90, the reagent for the only known homo-
logation of aldehydes and ketones under nonacidic conditions, was improved by avoiding the
difficult isolation of the intermediate tris(dimethoxyboryl)methane and by direct crystallization of
tris(ethylenedioxyboryl)methane 90 (Scheme 38) <1995T11219>.
R' O
H2O
O O R' R' CHO
BunLi
HC B Li+ –CH B
R B O NaBO3
CH2Cl2 / THF R O 1 h, rt R
O O
3 2
R = Ph(CH2)3; R' = H 85%
90 R = R' = –(CH2)5– 65%
Scheme 38
The condensation of dimesitylboron-stabilized carbanions with a variety of aromatic aldehydes

followed by in situ oxidation at low temperature, is a unique, highly stereoselective process
yielding predominantly erythro-1,2-diols <1996T1085>.
4.14.2.3.2 Other a-metalloborylalkanes

The other -metalloborylalkanes have been prepared by -haloalkylboronic esters as indicated in
COFGT (1995). Rearrangements have been implicated during the preparation of a number of
cyclic organotin compounds containing an -boryltin moiety.
In the preparation of novel organoborane Lewis acids via a selective boron–tin exchange process,
the attack by a boron halide on an organotin substrate could be viewed as passing through a
transition state containing boron and tin attached to an sp3-carbon <1998EJI761>. Stannylated
allenes 91 have been prepared by 1,1-organoboration of 2 equiv. of bis(trimethylstannyl)ethyne with
1 equiv. of triethylborane or ferrocenyldimethylborane (Scheme 39) <1996JOM169>.
Boryl substitution on an olefin activated the olefinic double bond toward addition of an
organozinc reagent. Addition of an allylic zinc reagent 92 to an alkenylboronate 93 thus took
place smoothly to afford a variety of gem-zincio/boryl species 94. Theoretical studies with density
functional calculations on the reaction pathway revealed that the reaction proceeded via zincio-
ene reaction rather than a bora-Claisen rearrangement (Scheme 40) <2001OL3137>.
Me3Sn C C SnMe3 Me3Sn BEt2 Me SnC CSnMe3 Et

3 Me3Sn
Et3B C C C C C
Et Me3Sn SnMe3
Me3Sn C
Me3Sn BEt2
91
Scheme 39
R3
R3 O
R1 ZnBu O E+ R3 O
B
+ B O B
O 36–48 h 82–96% O
R2 R1 R2 ZnBu 1 2
R R E
92 93
94
Scheme 40
Functionalized mixed alkyl(trimethylsilylmethyl)zinc reagents added efficiently to a wide vari-

ety of Michael acceptors in high yield and with exclusive 1,4-regioselectivity, without the need for
transition metal catalysis. The trimethylsilylmethyl group behaved as a nontransferable group,
and in no cases was transfer of this group observed <1998T1471>. The addition reaction of
-boryl carbanions to aldehyde was studied. Terminal alkenes and 1,2-alkanediols were obtained
in high yields by the addition of [(Me2C)2O2BCH2]Cu(CN)ZnI from Knochel’s (dialkoxyboryl)-
methylzinc reagent. The reaction provided a simple procedure for the olefination or the hydroxy-
methylation of aldehydes <1996T915>.
The bis(1,3,2-benzodioxaborolyl)dicobaltatetrahedrane was shown to catalyze the trimerization
of the diborylacetylene 95, thus verifying the catalytic cycle with cobalt octacarbonyl. The
diborylacetylene was allowed to react with a catalytic amount of cobalt octacarbonyl to provide
the corresponding addition product 96 (Equation (22)) <2000EJI1177>.
Co2(CO)8
O O O
CH2Cl2 O
B B
B B
O O rt, 20 h
O C O ð22Þ
reflux, 2 h
95 C
45%
(OC)3Co Co(CO)3
96
A novel class of organometallic complexes containing 1,1-bimetallics of boron and zirconium

has been reported <1996JST291>. The use of gem-borazirconocene alkanes in the regioselective
synthesis of -allenic boronic esters has been demonstrated (Scheme 41) <1995JOC486>.
ZrCp2Cl
R1 HZrCp2Cl CuCN, 10 mol.% O O
O B
B R1 O CH2
B Br
O CH2Cl2 R1 C
O
rt toluene/CH2Cl2
35–87% R2CHO
97
OH
R1
R2
Scheme 41
gem-Borazirconocenes readily added across Michael acceptors in the presence of CuBrSMe2,

to afford the 1,4-addition products 98 in good-to-excellent yields. In the case of cycloalkenones
diastereomers were produced, with the anti-product favored. The selectivity with cyclopentenone
was high (9:1), while with cyclohexenone it was less (3:1). In this context, gem-borazirconocene
alkanes could be regarded as -hydroxyl anion equivalents (Equation (23)) <1995TL1805>.
ZrClCp2 CuBr.SMe2, 10 mol.% EWG
+ EWG
R R
NaHCO3 (aq.)
B B
62–94%
O O O O
EWG = electron ð23Þ
withdrawing groups
such as ketones and esters
98
Reaction of acid chlorides and gem-borazirconocene alkanes produced enol borates by the
rearrangement of -bora ketones. Reaction of the enol borates with NBS occurred with complete
regioselectivity to give the corresponding unsymmetrical -bromo ketones <1995TL5665>. Some
unusual chemistry involving boron migrations that resulted from the juxtaposition of boron
and zirconium in the same molecule has been described <1995JOC4316>. The synthesis of
1,1-bimetallics of boron and zirconium via the hydrozirconation of the corresponding unsaturated
boronates has been reported <1996JST291>.
In the diboration of allenes catalyzed by palladium complexes and organic iodides, the genera-
tion of the palladium-allyl species with the boryl attached to the central carbon of the -allyl
group has been shown <2001JA761>. In the facile titanium-catalyzed dehydrogenative borylation
of ethylene, -boryltitanium species have been shown to be the intermediate <1995JA6615>.
Treatment of -chloroalkylboronic esters with CrCl2 in the presence of LiI and TMEDA gener-
ated -boryl radicals, which added to ,-unsaturated esters in a 1,4-fashion under mild condi-
tions in excellent yields <1998SL253>. Synthetically useful (E)-1-alkenylboronic esters were
prepared stereoselectively from aldehydes with one-carbon extension by using a geminal dichro-
mium reagent derived from a dichloromethylboronic ester chromium(II) chloride and lithium
iodide <1995SL963>.
ACKNOWLEDGMENTS
The author is grateful for the financial support provided by the Robert A. Welch Foundation of
Texas (grant no. BG-1387) and the NIH-MBRS funding (grant no. NIH NIGMS 2S06GM08038-32)
while preparing this chapter.
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Biographical sketch
Narayan G. Bhat was born in Navilgon, India. He studied at Karnatak

University, India, where he obtained a B.Sc. in 1976 and an M.Sc. in
1978. He obtained his Ph.D. in 1982 from Pune University, India (for
the work carried out at the National Chemical Laboratory, Pune, India)
under the direction of Dr. G. H. Kulkarni. After spending eight years
(1982–1990) as a Postdoctoral Research Associate in the laboratory of
Professor Herbert C. Brown, 1979 Nobel Laureate in Chemistry, at
Purdue University, West Lafayette, Indiana, USA, he joined in 1990
Ethyl Corporation, Baton Rouge, LA. After working at the Indian
Institute of Science as an Assistant Professor of Chemistry and as an
Instructor of Organic Chemistry at the University of Nebraska, Lincoln,
he joined the University of Texas-Pan American, Edinburg, Texas in
1996 as an Assistant Professor of Chemistry. Currently, he is an Associ-
ate Professor of Chemistry and his scientific interests include all aspects
of organic chemistry, in particular organoborane chemistry, selective
organometallic syntheses, and bioorganometallic chemistry. Currently,
his research activities at the University of Texas-Pan American are
supported by the Robert A. Welch Foundation of Texas and the
National Institute of Health.
4.15
Functions Containing Two Atoms
of the Same Metallic Element
A. P. SADIMENKO
University of Fort Hare, East London, South Africa
4.15.1 FUNCTIONS CONTAINING TWO GROUP 1 METALS 627

4.15.2 FUNCTIONS CONTAINING TWO GROUP 2 METALS 628
4.15.3 FUNCTIONS CONTAINING TWO TRANSITION METALS 629
4.15.3.1 Introduction 629
4.15.3.2 Functions Containing Two Sc, Y, or La Atoms 629
4.15.3.3 Functions Containing Two Ti, Zr, or Hf Atoms 629
4.15.3.4 Functions Containing Two V, Nb, or Ta Atoms 629
4.15.3.5 Functions Containing Two Cr, Mo, or W Atoms 630
4.15.3.6 Functions Containing Two Mn, (Tc), or Re Atoms 631
4.15.3.7 Functions Containing Two Fe, Ru, or Os Atoms 632
4.15.3.8 Functions Containing Two Co, Rh, or Ir Atoms 650
4.15.3.9 Functions Containing Two Ni, Pd, or Pt Atoms 657
4.15.3.10 Multidecker Sandwich Complexes of Transition Metals 658
4.15.3.11 Functions Containing Two Cu, Ag, or Au Atoms 659
4.15.3.12 Functions Containing Two Zn, Cd, or Hg Atoms 660
4.15.4 FUNCTIONS CONTAINING TWO Al, Ga, In, OR Tl ATOMS 661
4.15.5 FUNCTIONS CONTAINING TWO Sn OR Pb ATOMS 661
4.15.6 FUNCTIONS CONTAINING TWO LANTHANIDE OR ACTINIDE ATOMS 661
4.15.1 FUNCTIONS CONTAINING TWO GROUP 1 METALS

The species [(5-Cp)K]1 has a classical zigzag polymeric structure <1997OM3855>. Crystal-
lization of [((5-3,5-Me2C6H3)5C5)Li(THF)2] from toluene leads to the species with an infinite
chain one-dimensional structure containing alternating [((5-3,5-Me2C6H3)5C5)Li] and
[(THF)Li((5-3,5-Me2C6H3)5C5)Li((5-3,5-Me2C6H3)5C5)Li(THF)]+ moieties in a manner similar
to the formation of the polydecker complexes <2003JCS(D)2658>. Such extended structures are
observed in the solid state of the cyclopentadienyls of lithium, sodium, and potassium
<1997OM3855>, 1,2,4-tris(trimethylsilyl)cyclopentadienyl)potassium <2001JCS(D)1128>, as
well as in the solvated complexes such as [(THF)K(-5-Cp*)]x <2002JOM(649)252>,
[(DME)Na(-5-Cp)]x <2002JCS(D)896>, and [Li(5-C5(CH2Ph)5)2(C6D6)] <1996OM4702>.
Tetranuclear species of composition [(PMDETA)K{-CH(SiMe3)2}K{-CH(SiMe3)2}-
K{-CH(SiMe3)2}K(PMDETA)] is an example of compounds with KCK frameworks
<2000OM4030>. The ligand CH2(SiMe3)(SiMe2OMe) with t-butyllithium in pentane gives 1
<2003OM2505>. The latter reacts with potassium t-butylate in hexane and then with diethyl
ether to yield 2. With NaCH2Ph in ether, the starting ligand produces 3. The behavior of the ligand
CH2(SiMe3){SiMe(OMe)2} in the reaction with t-butyllithium in pentane is different and the
product is 4.
627
628 Functions Containing Two Atoms of the Same Metallic Element
SiMe3 H SiMe3 H SiMe3

H
O O O C Na
C Li C Na
Li SiMe2 Na SiMe2 K SiMe2
O C O C O O
C
Me Me Et2 Me
8 ∞ ∞
1 2 3
H SiMe3 Li
Li C C
OMe
O Si
Me Me ∞
4
1-Aza-1,3-diene with excess lithium in ether gives N,N-dilithium-hexa-1,5-diene-1,6-diamide

<2003AG(E)2253>. If the same reaction is run in THF under ultrasound, species 5 is formed.
Prolonged treatment finally gives 6.
Ph H H Ph
Me Me THF
THF THF
Pri Li(OEt2)2 Li Pri Li
N N
N
(Et2O)2Li Pri Pri
Li Li
N C Ph
H
C Ph Me
H
Me
6
4.15.2 FUNCTIONS CONTAINING TWO GROUP 2 METALS

Three-coordinate homoleptic organomagnesium compounds are rare, among them [(2,6-Et2Ph)2Mg]2
<2001IC6004> and [t-Bu2Mg]2 <2003OM2458>. They contain the -C skeletons in their dimeric
structures. Organomagnesium species [(5-Cp)Mg(Me)(OEt2)]2 when reacted with acetylenes
RCCH (R = Ph, Fc) yield the cubic tetramers 7 (R = Ph, Fc) <2003OM1793>. When 7
(R = Ph) is dissolved in THF, the dimer 8 with the bridging acetylide moieties results.
η5-Cp
Mg CCR
CPh
η5-Cp
RCC Mg O C
(η5-Cp)Mg Mg(η5-Cp)
RCC Mg η5-Cp C
O
PhC
Mg CCR
η5-Cp
7 8
Functions Containing Two Atoms of the Same Metallic Element 629
4.15.3 FUNCTIONS CONTAINING TWO TRANSITION METALS
4.15.3.1 Introduction
This has been discussed in detail in COFGT (1995).
4.15.3.2 Functions Containing Two Sc, Y, or La Atoms

No substantial new data is available for inclusion since the publication of COFGT (1995).
4.15.3.3 Functions Containing Two Ti, Zr, or Hf Atoms

Interaction of [(5-Cp)2ZrMe2] with [CPh3][B(C6F5)4] gives unusual dinuclear cationic species with
the bridging methyl group, [{(5-Cp)2ZrMe2}2(-Me)][B(C6F5)4] <1996JMOC67, 2001JA223,
2003JOM(677)10>. Rearrangement of the species [(5-Cp*)2Ti(2-Me3SnC¼CSnMe3)] followed
by elimination of the SnMe3 groups gives a dinuclear complex 9 without any signs of the
titanium–titanium interaction <2000ACR119, 2003AG(E)1794>. These and similar species pos-
sess dynamic behavior <1997AG(E)606, 1998JA6952, 2002OM2254, 2002OM2627>.
CSnMe3
C
(η5-Cp*)2Ti Ti(η5-Cp*)2
C
Me3SnC
9
The reaction of [(5-C5H4SiMe3)(H)Zr(-H)2Zr(H)(5-C5H4SiMe3)] yields among the other

products cluster 10 where the assembly between the two zirconium sites is realized in an 5:1
mode <1999OM2933>.
(η5-C5H4SiMe3)2
Zr
H
H
SiMe3
(η5-C5H4SiMe3)2Zr Zr(H)(η5-C5H4SiMe3)2 (B(C6F5SiPr3i )4)
H
10
4.15.3.4 Functions Containing Two V, Nb, or Ta Atoms

Terminal Me3SiCH2 groups of the species 11 enter stepwise substitution with protic agents
<1996OM5502>. Phenols substitute one of such groups and produce a series of compounds
12 (Ar = C6HPh4-2,3,5,6, C6HPh2-2,6-Me2-3,5, C6HPh2-2,6-t-Bu2-3,5, C6H2-Ph-2-t-Bu2-4,6,
C6H2(1-Np)-2-t-Bu2-4,6) <1999OM3016>.
SiMe3 SiMe3
C C
(Me3SiCH2)2Ta Ta(CH2SiMe3)2 (Me3SiCH2)(ArO)Ta Ta(CH2SiMe3)2
C C
SiMe3 SiMe3
11 12
4.15.3.5 Functions Containing Two Cr, Mo, or W Atoms

Species [(5-Cp)(OC)Mo(-PR2)(-Cl)Mo(CO)(5-Cp)] (R = Cy, Ph, OEt) containing the double
molybdenum–molybdenum bond can be reduced with LiBHEt3, Na(Hg), or KBH(i-Bu)3 to yield
the anions of the respective alkali metals 13 (R = Cy, Ph, OEt) <2003OM1983>. The latter possess
an interesting reactivity pattern. Thus, the derivative 13 (R = Cy) reacts with methyl iodide to
give the neutral complex 14 containing the bridging methyl group. Me3OBF4 gives rise to the
methoxycarbyne compound 15, where the triple bond between molybdenum atoms is retained.
Addition of allyl chloride leads to 16. The other possible ways of reacting the Mo2 or W2
compounds of similar nature is oxidative addition of the cyclopentadienyl ligand to generate species
of the type 17 (M = Mo, W; R = Me, Ph, EtO; X = CH2, O) and the PX bond addition to afford
18 (M = Mo, W; R2PXPR2 = dppm, dmpm, (EtO)2POP(OEt)2) <1997OM354, 1997OM624,
1997OM1378, 1997OM2581>. Among the compounds with the bridging carbonyl groups,
there are [(5-Cp)2W2(-X)(-CO)(CO)2(-dppm)](PF6) (X = F, Cl) <1999OM4509>. Species
[(5-Cp)2Mo2{-OP(OEt)2}{-P(OEt)2}(CO)2] reacts with HCC(Tol-p) to give a mixture of iso-
meric products 19 and 20 <2003OM2741>. One more example includes the representative of the
species with a bridging methylene group, [(5-Cp)2W2{-C(OMe)¼CH2})(-CH2)(CO)2(-dppm)]+
<2002OM1177>. One of the products of interaction of [(5-Cp)Cr(CO)2(SPR2)] (R = Ar) is the
compound 21 containing two bridging carbonyl groups <2002OM5287, 2003OM1657>.
–
R2 Cy2
P P
(η5-Cp)Mo Mo(η5-Cp) (η5-Cp)(OC)Mo Mo(CO)(η5-Cp)
Me
OC CO
13 14
Cy2
Cy2
P P
(η5-Cp)Mo Mo(η5-Cp) (η5-Cp)(OC)Mo Mo(CO)(η5-Cp)
C CH2
OC COMe
15 16
X
R2P PR2 R2P X
O
H C
(OC)2M M(CO)(η5-Cp) (η5-Cp)(OC)M M(CO)(η5-Cp)
P
R2
17 18
(OEt)2
O P
(EtO)2P P(OEt)2 HC O
H
C
(η5-Cp)(OC)Mo Mo(CO)(η5-Cp) (η5-Cp)(OC)Mo Mo(CO)(η5-Cp)
C
C R
R P
19 (OEt)2
20
O O
C Cr C
S
Cr Cr
P
R2
21
Complex [W2(COT)(NMe2)4] <1996OM992> reacts with neopentanol, isopropanol, and t-butanol

to yield [W2(COT)(OR)4] having the structural arrangement 22 <2002JCS(D)4077>. With lighter
alcohols (methanol, ethanol, and n-propanol), [W2(COT)(NMe2)4] forms compounds of higher
nuclearity [W2(COT)(OR)4]2 (R = Me, Et, Prn) containing the [W2(-5,5-COT)(-OR)(OR)2]
<2003JOM(684)269>.
(RO)2W W(OR)2
22
Alkynyl complexes of chromium tend to produce di-, tri-, and tetranuclear clusters containing
bridging cyclobutenylidene ligands <1996OM3723, 1998EJI1225>. The vinylidene complexes of
chromium [(OC)5Cr¼C¼C(R1)(R2)] (C(R1)(R2)¼CMe2, C(CH2)5, C(Me)(Et), C(Me)(tBu)) on
warming give the dinuclear species 23 with the same set of R1 and R2 <2003JOM(677)46>.
Among the representatives of this group of complexes, it is interesting to mention [(5-Cp)-
Mo(-SiMe3)3(-1, 2-C¼C(R)H)Mo(5-Cp)](BF4) <2001OM1230>. 1,8-Nonadiyne reacts
with [(5-C5H4R)2Mo2(CO)6] (R = H, COMe, COOEt) <1996OM4182> to yield clusters 24
and 25 (R = H, COMe, COOEt) <1999OM3164, 2000OM5032>. Tris(isopropylsilyl)bis(pentalene)
dimolybdenum has a sandwich structure, where the molybdenum–molybdenum bond length falls
into the range of those for triple and quadruple molybdenum–molybdenum bonds
<1998OM1934, 1999OM1087>. Alkyl and aryl aldehydes with [W2(OCH2tBu)6(Pyr)2] give
[W2(-CHR)(O)(OCH2tBu)6(Pyr)] (R = Alk, Ar) <2000OM884>.
R2
C HC C(CH2)5C CH
R1
C
(η5-C5H4R)Mo Mo(η5-C5H4R)
(OC)5Cr Cr(CO)4 (CO)2 (CO)2
23 24
HC C-(CH2)5-C CH
(η5-C5H4R)Mo Mo Mo Mo(η5-C5H4R)
(CO)2 (CO)2 (CO)2 (CO)2
(η5-C5H4R) (η5-C5H4R)
25
4.15.3.6 Functions Containing Two Mn, (Tc), or Re Atoms

The complex [Re2Me4(-dppm)2] on reaction with carbon monoxide produces the di--methylene
compound [Re2(-CH2)2(CO)4(-dppm)2] <2003JOM(671)166>. Decarbonylation of [(OC)5-
ReCCRe(CO)5] gives species 26 with no rhenium–rhenium interaction <1997JOM(541)423>.
Cluster 27, however, contains the rhenium–rhenium bond. Complex cation [(5-Cp*)-
(OC)2Re(3-CH2CCH)]+ with pyridine forms the rhenacyclobutadiene species [(5-Cp*)-
(OC)2Re(3-CH2C(Pyr)¼CH)], which tends to isomerize to yield the allene of composition
[(5-Cp*)(OC)2Re(3-CH2¼CH(Pyr)] <1998JA722>. A cation containing the t-butyl
substituent in the alkyne framework, [(5-Cp*)(OC)2Re(3-CH2CCBut)], with 4-(dimethylami-
no)pyridine gives at the first stage the rhenacyclobutadiene, but isomerization of the product
takes another route—to the alkyne species [(5-Cp*)(OC)2Re(3-NC5H4NMe2CH2¼C¼CBut)].
A number of similar propargyl derivatives with aldehydes give the 1-2,5-dihydro-3-furyl-based

clusters <1996JA530>. They enter into alkoxycarbonylation reactions <1996JA9279,
1996JOC3245, 1997JOC1986, 1997TL5209>, oxidative carbonylation <1998OM2683>, and
other reactions.
(OC)5Re
CRe(CO)5
C C C Re(CO)4
(OC)4Re Re(CO)4 H
C Re
(CO)4
(OC)5ReC
26 27
4.15.3.7 Functions Containing Two Fe, Ru, or Os Atoms

Complex 28, when reacted with aryl(silyl)phosphanes, ArP(H)(SiMe3), gives products 29
(Ar = 2,4,6-R3C6H2, R = Me, Pri, But, CF3) containing bridging isophosphaalkyne ligands. With
ButP(H)SiMe3, however, the product is 30 <1997ZN(B)655>. The mesityl complex 29 can be
oxidized by sulfur or selenium to produce 31 (X = S, Se). It can also be methylated using methyl
triflate to yield 32 and subsequently reduced by sodium borohydride to afford 33. Anionic species 34
(R = Ar) possess ambidentate reactivity <1996OM1535, 2001JOM(627)255>. One reactivity
pattern is electrophilic attack at the iron site with a partial negative charge accompanied by
replacement of the bridging carbonyl moiety, and another direction is the electrophilic attack at
the oxygen site of a carbyne framework. In the latter case, reaction of Et3OBF4 with 34 (R = o-, m-,
and p-MeC6H4, -C10H7, p-MeO-, p-Br-, and p-ClC6H4) yields the products 35 with the same set of
substituents R <2003JOM(676)80>. Clusters with the bridging isocyanide moiety are exemplified
by [(5-Cp)2Fe(CO(COOR)(-CNMe2)2]+ <2000JOM(612)18>. Interaction of the carbon nucleo-
philes with [(5-Cp)2Fe2(-CX)(-CO)(CO)2](SO3CF3) (X = SMe, N(R)Me; R = Me, CH2Ph)
<1997JCS(D)4665, 1997JCS(D)4671> is the reaction of formation of carbon–carbon bonds.
Thus, the acetonitrile complexes [(5-Cp)2Fe2{-CN(Me)R}(-CO)(CO)(AN)](SO3CF3) (R = Me,
CH2Ph, Xyl) insert acetylenes followed by the acetonitrile displacement, to yield the vinyliminium
compounds [(5-Cp)2Fe2{-1:3-C(R2)¼CHC¼N(Me)R1}(-CO)(CO)](SO3CF3) (R1 = Me,
XCH2Ph, Xyl; R2 = SiMe3, Me, Bun, Tol, Ph, H) <2003OM1326>. In sharp contrast, the reaction
with methyllithium gives the product of rearrangement of the acetonitrile ligand [(5-Cp)2Fe2-
{-CN(Me)R}(-CO)(CO)(CH2CN)](SO3CF3) <2002JOM(649)64>. Treatment of the -amino-
carbyne complex [(5-Cp)2Fe2{-CN(Me)Xyl}(-CO)(CO)(NCBut)](SO3CF3) <1996JOM(509)19,
2000JOM(606)163> by p-tolylacetylide followed by triflic acid gives [(5-Cp)2Fe2{-1:3-
C(p-Tol)¼C¼C(But)}N(H)CN(Me)Xyl}(-CO)(CO)](SO3CF3) <2003JOM(684)37>.
+
SMe PAr
C C
(η5-Cp)(OC)Fe Fe(CO)(η5-Cp) (η5-Cp)(OC)Fe Fe(CO)(η5-Cp)
C C
O O
28 29
P(H)But P(X)Mes
C C
(η5-Cp)(OC)Fe Fe(CO)(η5-Cp) (η5-Cp)(OC)Fe Fe(CO)(η5-Cp)
S C
Me O
30 31
P(Me)Mes P(H)Mes
H
C C
(η5-Cp)(OC)Fe Fe(CO)(η5-Cp) (OTf) (η5-Cp)(OC)Fe Fe(CO)(η5-Cp)
C C
O O
32 33
O –O EtO
C SeR C SeR C SeR
(OC)3Fe -Fe(CO)3 (OC)3Fe Fe(CO)3 (OC)3Fe Fe(CO)3
34 35
Methoxinitrido clusters [Ru3(CO)9(3-CO)(3-NOMe)] experience thermolytic cleavage of the NO

bond and produce, in particular, the hexanuclear species [Ru6(CO)6(-CO)2(4-NH)(-OMe)2]
<1996JCS(D)1707>. This cluster also gives rise to heterometallic carbonyl clusters
<1999JOM(577)323>. Ruthenium clusters with a bridging methylene group include
[(5-Cp)2Ru2(-CH2)(CO)2(SiR3)(H)] (SiR3 = SiMe3, SiEt3, SiPrn3, SiMe2Ph, SiPh3, Si(OMe)3)
<1996OM4162> as well as the product of the reaction of [(5-Cp*)RuCl]4 with Mg(CH2SiR3)2,
36 (SiR3 = SiEt3, SiMe2Et, SiMe2Ph) <1999OM1904>. The reaction of [H4Ru4(CO)12]
with dimethylphenylphosphine in the presence of Me3NO gives two products, one of
which, [(OC)7Ru4(-CO)2(-H)2(PMe2Ph)4], contains two bridging carbonyls
<2003ICC675>. The reaction of [Ru3(CO)10(-dppm)] with di-t-butylphosphine gives
[(3-H)(-H)Ru3(-CO)(CO)4(-dppm)(-PBut2)2] <1996JOM(526)145>. With diphenylpho-
sphine, [Ru3(-CO)(CO)6(-PPh2)2(3-CH2Ph)] is the main product <1999ICC128>. Cluster
anion [HRu3(CO)11] with tricyclohexylphosphine gives [Ru3CO)4(PCy3)2(-H)(-CO)2] in two
isomeric forms <1999ICC247>. Complex 37 <1996JOM(512)11, 1997ICA(262)109> with
LiBHEt3 forms the methylene-bridged cluster 38 <1999OM3008>. The A-frame complex 39
reacts with different salts to yield 40 (X = Cl, Br, I, SH, S( p-Tol), SiPr, N3) <1999OM4244>.
Species [(-H)2(Os3(CO)9L] (L = PEt3, PEt2Ph, PPh3, PPriPh2, PCy3) with diazomethane give
[(-H)2Os3(CO)9(PPh3)(-CH2)] <2000OM761>. One of the products of interaction of 2,2,6,6-
tetramethyl-3,5-heptanedionate (L) with [Os3(CO)12] is [Os4(-H)(-CO2)L(CO)13] containing
a unique CO2 ligand <2001JCLS421>. Another unique situation is realized in the product
of interaction of [Os7(CO)19(AN)2] with 1,10 -bis(diphenylphosphino)ferrocene where the
2-CO-bridged cluster [Os7(CO)17(4-2CO)(AN)(-dppf)] is the product <1999ICC498>.
Me2 Me2
Si Si
H2
C H2
O
(η5-Cp*)Ru C C
Ru(η5-Cp*)
Ru Ru Ru Ru
Cl SiR3 C C
OC O CO OC O CO
36 37 38
2+
Ph2P PPh2 Ph2P PPh2
O O
C C
(AN)2Ru Ru(AN)2 XRu RuX
C C
O O
Ph2P PPh2 Ph2P PPh2
39 40
The diiron carbyne species of composition [(5-Cp)(OC)Fe(-CO)(-CR)Fe(CO)(5-Cp)](BBr4)

(R = Ph, p-Tol) and [(5-C5H4SiMe3)(OC)Fe(-CO)(-CR)Fe(CO)(5-C5H4SiMe3)](BBr4) (R = Ph,
p-Tol, p-CF3C6H4) react with nucleophiles like NaSR0 (R0 = Et, Ph, o-Tol) in THF at low tem-
peratures to yield [(5-Cp)(OC)Fe(-CO)(-C(R)SR0 )Fe(CO)(5-Cp)] (R = Ph, p-Tol; R0 = Et, Ph,
p-Tol), or Na[M(CO)5(CN)] (M = Cr, Mo, W) to produce [(5-Cp)(OC)Fe(-CO)(-CPh)-
Fe(N¼C¼M(CO)5)(5-Cp)] (M = Cr, Mo, W) <2000OM3498, 2000OM3784, 2001OM4092>.
Complexes [(OC)2Fe(-8-COT)(-C(R)(OEt))Fe(CO)2] (R = Ph, p-Tol, p-CF3C6H4) with
HBF4 in Et2O at low temperature give [(OC)2Fe(-8-COT)(-CR)Fe(CO)2](BF4) <2003OM1816>.
The product, where R = p-CF3C6H4, when reacted with NaSR (R = Et, p-Tol) gives the neutral
dinuclear complex [(OC)2Fe(-8-COT)(-C(p-CF3C6H4)(SO2R))Fe(CO)2] (R = Et, p-Tol). Reaction
of [(OC)2Fe(-8-COT)(-C(R))Fe(CO)2](BF4) with NaBH4 gives [(OC)2Fe(-8-COT)(-
C(R)(H))Fe(CO)2] (R = Ph, p-Tol, p-CF3C6H4). With [NaM(CO)5(CN)] (M = Cr, Mo, W), they
give rise to [(OC)2Fe(-8-COT)(-C(R)(N¼C¼M(CO)5)Fe(CO)2] (R = Ph, o-Tol, o-C6H4CF3;
M = Cr, Mo, W).
Clusters of the type [Ru6C(CO)17] are active in hydrogenation reactions <2001JCS(CC)2624>.
A pentaruthenium carbide system was also developed <1998JCS(D)1253>. The silica-supported
clusters [Ru6C(CO)16SnCl3] and [Ru6C(CO)16SnCl2] are catalysts <2001AG(E)1211>. Another
cluster of this kind is [Ru6C(CO)16]2 <2001JCLS273>. They form nanostructures, and the
mixed palladium–ruthenium complexes are efficient as catalysts <1999JCS(CC)1571,
2000AG(E)1131, 2000JCS(CC)1955, 2001AG(E)4638>, especially when immobilized by
silica <2001JCS(D)3295>. An illustrative example is the reaction of [Ru3C(CO)14]2 with
[PtCl2(AN)2] in the presence of silica to afford [Ru5PtC(CO)18] and [Ru12PtC2(CO)32(AN)]
<2003EJI1325>. The pentaosmium analog [Os5C(CO)15] is a popular starting agent for prepara-
tion of the heteronuclear clusters <1996JCS(D)2887, 1996JOM(524)211, 1997JCS(D)2445,
1997JCS(D)2705>.
The reaction of 41 with a solution containing low-valent titanium ions, previously speculated
<1997AG(E)2234, 1997AG(E)2380>, leads to the formation of three new clusters containing
three iron atoms, 42–44 <1999OM534>. The ethynyl cluster 43 is the result of reduction of the
carbonyl moiety, the other two may result from the rearrangement of the CCO group and
subsequent protonation.
O 2–
C CH2
C
C
(OC)3Fe Fe(CO)3 (OC)3Fe Fe(CO)3
Fe C Fe
(CO)3 O (CO)3
41 42
OTi(THF)4
–
CH C
C C
Fe Fe
(CO)3 (CO)3
43 44
Species 45 <1997JOM(527)247, 1998ICA(291)178, 1998ICC257> undergoes isomerization to

46 <1998JCS(CC)1815, 2000OM5696, 2001JCS(D)341>. The thiolate species [Fe2(CO)6{-
O¼CC(Ph)¼CH2}(-SC6F5)] on reaction with diphenylphoshinomethane gives 47–49
(isomers), as well as 50 <2003JOM(672)22>.
H Ph Ph
Ph H H
H H H
(OC)3Fe Fe(CO)3 (OC)3Fe Fe(CO)3 (OC)2Fe Fe(CO)2
P P S
Ph2 Ph2 C6F5
Ph2P PPh2
45 46
47
Ph Ph H
Ph
S H O
H S S
(OC)2Fe (OC)2Fe (OC)2Fe
Fe(CO)2 Fe(CO)2 Fe(CO)2
Ph2P PPh2 Ph2P PPh2 Ph2P PPh2
48 49 50
Interaction of [PPh4][HFe3(CO)11] with diphenylacetylene in the presence of methyl iodide gives 51

<2002JOM(642)107>, which rearranges at room temperature to the main product 52. Prolonged
reflux with excess diphenylacetylene and methyl iodide yields the trinuclear anionic cluster 53. In
excess methyl iodide only and at room temperature, the product is 54 <2003JOM(678)117>. Cluster
[(-H)Os3(CO)9(PPh3)(-2-CH¼CH2)] is known <1996OM4930, 1998OM3087>. Related exam-
ples include [Os3(CO)10(3-2-C2R2)] (R = Me, Ph) <1998ICA(274)82> and [Ru3(CO)8(-dppm)(3-
2-C2(COOMe)2] <1998JOM(552)109>.
Ph
Ph Ph Ph
H
– –
O
H O
51 52
Ph Ph Ph Ph
H –
Fe(CO)3 O H
Me
53 54
The complex [(5-Cp)(OC)(-CH2)(-CO)Ru(CO)(5-Cp)] is a convenient precursor for the

coupling of alkynes <1997OM5572>. This is not a property for the cluster [(OC)2Ru(-CO)
(-dppm)2Ru(CO)2], which reacts with alkynes in a traditional manner to yield the alkynyl,
alkenyl, and vinylidene species without coupling <1999ICC197, 2000JOM(593)77>. Complex
[(OC)2Ru(-CH2)(-dppm)2Ru(CO)2] <2001OM1882> at elevated temperatures causes formation
of the uncoordinated PhCCC(Ph)¼CH2 on interaction with phenylacetylene
<2003ICA(350)101>. At lower temperatures the formation of complex 55 is observed. The
same product follows from [(OC)2Ru(-CO)(-dppm)2Ru(CO)2] and phenylacetylene in toluene.
In more polar media, the process is stepwise and can be governed by the amount of phenyl-
acetylene added. First formed is the alkynyl-bridged product 56, then the product with an
alkynyl bridge and alkenyl side group follows 57 and finally the alkylidene bridge is added
replacing the carbonyl bridge 58.
Ph2P PPh2 Ph2P PPh2

O O
C C
(OC)2Ru Ru(CO)2 (OC)HRu Ru(CO)
C
Ph H
CPh
Ph2P PPh2 Ph2P PPh2
55 56
Ph2P PPh2 Ph2P Ph PPh2

O
C C
(OC)(CH2=C(Ph))Ru Ru(CO) (OC)(CH2=C(Ph))Ru Ru(CO)
C C
CPh CPh
Ph2P PPh2 Ph2P PPh2
57 58
Clusters [HRu3(CO)9(3-2, 2, 1-CCBut)] enter substitution reactions with phosphorus

donors and acetonitrile <1996ICA(241)71, 1996JOM(516)65, 1999JCS(CC)1499,
1999JCS(D)479, 1999JOM(589)239, 2000OM2330>. Reactions of the osmium analogs containing
the CCR group (R = H, Me, Ph, CMe2OH) with a variety of two-electron donor ligands
were also documented <1996OM3916>. Thermolysis of 59 with the diphosphine ligand in
methylene chloride in the presence of Me3NO gives a mixture of products 60 and 61
<2003OM1953>. If thermolysis is conducted in DCE, 62 is the additional product. A product
similar to 60 but containing the CCTol-p moiety can be prepared from the relevant ruthenium
cluster <1997JCCR25> and the diphosphine ligand <2003OM1953>. The cationic species 63
(R = H, Me) does not contain ruthenium–ruthenium bonds <2002JCS(CC)2174>.
Ph Ph2 Ph
P
O
(OC)3Ru Ru(CO)3 Ru Ru(CO)3
H P H
O CO
Ru Ph2 Ru
(CO)3 (CO)3
59 60
O
Ph Ph Ph
+P 2 P
O
OC O
–
Ru Ru(CO)3 (OC)2Ru Ru
OC H (CO)2
P H PPh2
O Ph2 Ru Ph Ph
(CO)2 Ru
(CO)3
61 62
(η5-C5H4R)(OC)2Ru Ru(CO)2(η5-C5H4R)
2(η
+Ru(CO) 5-C H R)
5 4
63
Complexes containing bridging polyynediyl moieties acquire substantial interest because of their
efficiency in transmission of the electronic effects between the redox active metal sites
<1996AG(E)414, 1996MC200, 1996OM477>, rich reactivity pattern involving functionalizations,
oligomerization, and metal core enhancement <1996CJC2349, 1997JCLS293>, and possible appli-
cations in materials chemistry <1996ICA(247)99, 1997OM4882, 1997OM5988>. Alkynes react with
[Fe3(CO)12] to yield the ferrole-type complexes 64 (R1 = R2 = Et; R1 = Me, R2 = Et; R1 = Ph,
R2 = Et; R1 = R2 = Ph; R1 = Me, R2 = NEt2; R1 = R2 = CH¼CHNMe2;
R1 = R2 = CH¼CHS) <1997JCLS407>. The same structural principles apply to [(5-
Cp)2Ru3(-CO)2(C2(CF3)2)2(C2Ph2)] <1996JCS(D)975>. Thermal degradation of complexes 64
gives 65 with the same set of R1 and R2 groups <1999JOM(573)139>. Similarly unusual
transformations are known for the products of the coordinated diynes with carbenes and their
metal fragment condensation <1996OM2855, 1997JCS(CC)483>. In a related transformation the
allenylidene iron complex in methanol is converted to 66 <1997JCS(D)1851>and still other
examples exist <1997JOM(533)31, 1997JOM(533)45>. The ruthenium analogs of ferrole com-
plexes follow from [Ru3(CO)12] and 1,4-diphenylbuta-1,3-diyne <1996ICA(250)129>. Reaction of
isopropenylacetylene with [Fe3(CO)12] gives the open cluster 67 among the isomeric products
<2002JCS(D)1448>. Triruthenium clusters possess a remarkable ability to activate hydrocarbon
substrates <1996JCS(D)975, 2002EJI1009, 2003JA9910>. The nido-ruthenacyclopentadiene com-
plexes [{(5-Cp*)Ru(-H)}3(CH¼CMeCR¼CH) (R = H, Me) on thermolysis give a mixture of
the product of dehydrogenation 68 (R¼H, Me) and then 69 (R = H, Me) <2003OM2196>. In
the formation of 64, the Ru3 core is partially cleaved but further on it is restored followed by the
CC bond cleavage. Osmacyclopentadiene cluster 70 originating from [Os3(CO)12] and dipheny-
lacetylene is characterized by rapid ligand substitution reactions occurring at the Os(CO)4 moiety
<1999OM5518>.
(CO)2 R1 R2 C(Ph)H
Fe
OC H
R1 R2 (OC)3Fe
(OC)3Fe
R2
(OC)2Fe
R2 R1
O O
OC
Fe R1
Fe Fe(CO)3
(CO)2
(CO)3
66
64 65
η5-Cp*
(CO)3 (CO)3 Me Ru
Fe Fe H
H
H2C C C Fe(CO)4 (η5-Cp*)Ru Ru(η5-Cp*)
C C
Me H O
R
67 68
R
Ph Ph Os(CO)4
(η5-Cp*)Ru Ru(η5-Cp*)
Ru H (OC)2
Os Os(CO)3
η5-Cp*
C
H Ph Ph
69 70
1-Ethynylcyclohexanol with [Fe3(CO)12] gives [Fe3(CO)9(-CO)(3-2-1,2-HCCC6H11OH)],

[Fe3(CO)9(-CO)(3-2-1,2-C¼CC6H10)], and other products <2001JCS(D)1485>. Related
examples on alkynol clusters were systematized <1999MI1>. Thus, 1-phenyl-1-propyn-2-ol reacts
with [Fe3(CO)12] to yield 71, which further reacts with methanol to give 72 <1997JCS(D)1851>.
The product of interaction of alkynol MeCCC(H)(Et)OH with [Fe3(CO)12], 73, experiences

further transformation to the hydrido-acetylide cluster 74 <2000JCS(D)989>. Species [(5-
Cp)2Fe2(-CN(Me)(Me2C6H3-2,6))(-CO)(CO)(ButCN)](OTf) reacts with p-tolyl acetylide and
then triflic acid to give [(5-Cp)2Fe2(-1:3-C(4-MeC6H4)¼C¼C(But)N(H)CN(Me)-
(Me2C6H3-2,6))(-CO)(CO)](OTf) <2003JOM(684)37>.
C(Ph)H OMe
C
C O CH
(OC)3Fe Fe(CO)3 (OC)3Fe C
OC Fe C(Ph)H
(CO)3 Fe
(CO)3
71 72
CMe
C
CMe
C (CO)3
Fe Fe(CO)3
MeC
(OC)3Fe Fe(CO)3 C
Fe
(CO)2
H (CO)3Fe
Fe 2
(CO)3
Fe
73 (CO)3
74
Thermolysis of dimethylaminopropyne with [Ru3(CO)12] gives the product 75 along with 76

<2003JOM(671)137>. Trimethylsilylpropargyl alcohol under conditions gives 77 along with 76. If
the latter reaction is run in MeOH/KOH medium with subsequent acidification, species 76 becomes
the main product which is formed along with 78. Similar complexes include [(-H)Ru3(CO)9{CHCH-
C(OMe)}] <2000JOM(609)169>, [(-H)Ru3(CO)8(PPh3)(3-3-HCCHCOH)] <1998ICC134,
1999JCS(D)2777>, [(-H)Ru3(CO)9(3-3-C12H17)] <1998JCS(D)751>, [(-H)Ru3(CO)9(3-3-
C12H19)] <1996JOM(510)37>, and [(-H)Ru3(CO)9(3-3-HCCPhCH)] <1996OM4100>. A typical
propargyl structure in the ruthenium chemistry is characterized by the -1:2 coordination mode of
this three-electron-donor ligand 79 <1996OM164, 1997OM1159, 1997OM1476, 1998JA3243,
2000JOM(593)465, 2000OM3179, 2002ICC82>. Another option is the five-electron -2:3 arrange-
ment <1998JA1938>. The alkynyl cluster [Ru3(-H)(3-C2CPh2(OH))(CO)9] contains the hydroxyl
group <1998CRV2797>. Propargyl alcohol HCCC(Ph2)(OH) with [Ru3(CO)10(AN)2] forms first
80, then on thermolysis eliminates the carbonyl ligand to afford 81 <2000JCS(D)881>. The latter can
be protonated in three ways—by HBF4 to give 82, by HBF4 in the presence of diphenylphosphino-
methane to yield 83, and using a combination of K(BHBu3s)/HBF4 to afford 84. Protonation of the
products of interaction of alkynols with [Ru3(CO)12], 80 (but CRPh, R = Me, Ph, instead of CPh2) by
tetrafluoroboric acid include 84 as well as species 85 and 86 <1998POL2937, 2000JCS(D)4390>. The
range of clusters originating from HCCC(H)(OH)Me may be supplemented by the tetra-, penta-,
hexa-, and heptaruthenium compounds <1998JCS(D)3391>. Complexes of the type 81 tend to
produce the alkene–alkyne species and this process is usually catalyzed by the oxide supports
<2001JCS(D)46, 2002ICA(334)131>. Protonation of the alkynol complex 87 is followed by elimina-
tion of water to yield 88 <1996JOM(508)39>. Interaction of HCCC(Me2)OH with [Os3(CO)12]
leads to 89, which can be dehydrated to form the alkene–alkyne complex 90. Propargyl alcohols
HCCCR2OH (R = H, Me, Ph) with [(5-Cp)(AN)Ru(-CH2)(-CO)Ru(CO)(5-Cp)] yield the
allylidenes [(5-Cp)(OC)Ru(-1:3-C(C(R2OH)CH¼CH2)(-CO)Ru(5-Cp)] (R = H, Me, Ph)
<2003ICA(354)29>. The products when reacted with tetrafluoroboric acid are dehydrated and the
2-butadienyl complexes {[(5-Cp)(OC)Ru(-2:3-CR2¼CCH¼CH2)(-CO)Ru(5-Cp)](BF4)
(R = H, Me, Ph)} result.
H NH2
H C C H
C H
C H
C C
(OC)3Ru Ru(CO)3
Ru
(CO)3
H (OC)3Ru Ru(CO)3
Ru H
(CO)3
75 76
H CSiMe3
H C
C CH2OH
C C
(OC)3Ru Ru(CO)3
Ru
(CO)3
(OC)3Ru H
Ru(CO)3
H Ru
(CO)3
77 78
H C(Ph2)OH
CC(Ph)2OH
R12C C C C
C CR2 O
C
LnRu RuLn (OC)3Ru Ru(CO)3 (OC)3Ru Ru(CO)3
Ru H
Ru
(CO)3 (CO)3
79 80 81
C(Ph)2 C(Ph)2 C(Ph)2

C C C
C C C
(OC)3Ru Ru(CO)3 (OC)2Ru Ru(CO)3 (OC)3Ru Ru(CO)3
H OH Ph2P OC H
Ru Ru H Ru
(CO)3 (CO)3 (CO)3
PPh2
82 83 84
(CO)3 (CO)3 CPh2

Ru C Ru C
C C
C(Me)(Ph)
(OC)3Ru OC (OC)3Ru
Ru Ru
(CO)3 (CO)3
Ru Ru(CO)3 Ru Ru(CO)3
(CO)2 (CO)2
85 86
C(Me2)OH H Me
H CMe2 CC(Me2)OH
C C C C C C CH2
C
O O
C C
C
(OC)3Os Os(CO)3 (OC)3Os Os(CO)3 (OC)3Os Os(CO)3
(OC)3Os Os(CO)3
H
Os Os H
Os Os
(CO)3 (CO)3 (CO)3 (CO)3
87 88 89 90
The conjugated diyne PhCCCCCH2OH with [H2Os3(CO)10] gives the product of intramolecular
cyclization 91 <1999JCS(D)2511> containing the 2-coordinated 2-benzylfuran <2001OM3854,
2003OM3455>. If the starting diyne used is PhC(O)CCCCPh, the product of cyclization is 92,
where the furan ring reveals aromaticity but coordination is fulfilled in the 3-manner, in which the
exocyclic carbon site participates. The final product of the reaction of HOMe2CCCCCCMe2OH is
the trinuclear cluster 93 <2003OM3455>. [H2Os3(CO)10] also reacts with 1,4-diphenylbuta-1,3-diyne
to yield [Os3(-H)(CO)10(3-3:1:3-Ph(C)C9H6)], where the product experiences ring-closure and for-
mation of the fused five- and six-membered ring ligand, interacting with the osmium triangle via the
pseudo-allylic route <2003JOM(683)313>. The product can be decarbonylated to give [Os3(-H)-
(CO)9(3-3:1:3-Ph(C)C9H6)].
PhCH2 Ph
O CCMe2OH
O HOMe2C C
Ph
C C

H H
Os Os Os
(CO)3 (CO)3 (CO)3
91 92 93
Dimethyl- and diphenylacetylene react with [Ru3(CO)9(-CO)(3-C¼C¼CPh2) to give

[Ru3(CO)9(3-C(R)C(R)C2Ph2)] (R = Me, Ph) and [Ru4(CO)12(4-C(Ph)C(Ph)CCCPh2]
<2001JCS(D)46>. A related cluster is [Ru3(3-C(OCH2CH¼CH2)CHCCPh2OC(O)(-dppm)-
(-CO)(CO)6] <2001AJC319>. [Ru2(CO)6(PPh2)(-1, 2-CCBut)] experiences intermolecular
coupling to yield [Ru4(CO)8(-PPh2)2(ButCCCCBut)] <1996OM5269>. The reaction with the
-1, 2-CCPh derivatives is followed by the formation of the tetranuclear clusters <1998OM2936>.
The dialkynyl complex [Ru2(CO)6(-PPh2)(-1, 2-CCCCBut)] gives among other products
[Ru4(CO)9(-PPh2)2(4-1, 2, 2, 1-CCC¼C(But)CCCCBut)] <1998OM2477>. Similarly,
[Fe2(CO)6(-PPh2)(-1, 2-CCPh)] gives [Fe4(CO)8(-PPh2)2(4-2, 2, 2, 2-PhCCCCPh)]
<1997AG(E)2668, 1997JCS(CC)1883, 1998OM2970, 1999JCS(D)13>. Examples of coordinated
1,3-diynes can be found, e.g., [Ru3(CO)10(3-2-C2Ph(CCPh))] <1996AJC155>, [Ru3(CO)8(dppm)-
(3-2-C2Ph(CCPh))] <1997JOM(536)93>, and others <1996JCLS109, 1996JCS(D)1551,
1997OM4276, 1998JOM(558)197, 2000JCS(D)2939, 2001AJC325>. The reaction of 1,4-diphenyl-
buta-1,3-diyne with [Ru3(CO)12] in THF in the presence of Me3NO gives [(OC)3Ru(-2,
5-C(CCPh)¼C(Ph)-C(CCPh)¼CPh)Ru(CO)3] <1996ICA(250)129>. The same reaction
but in benzene and in the absence of an initiator gives [(OC)3Ru(-2, 5-C(Ph)C(CCPh)-
C(CCPh)CPh)Ru(CO)3] <1997JOM(536)339>. Thermolysis where 1,4-bis(ferrocenyl)buta-
1,3-diyne participates is similar <1996RCB1200>. 1,6-Bis(trimethylsilyl)hexa-1,3,5-triyne with
[Os3(CO)10(AN)2] gives cluster 94 <1999JOM(578)103>. The products of interaction of the same
alkyne with [Ru3(CO)12] are different and can be formulated as 95 and 96. Cluster 96 further interacts
with [Co2(CO)8] to produce the heterodimetallic species 97 containing two homonuclear metal
cluster counterparts. The same reaction run at room temperature leads to [Ru3(CO)10(3-2-
C2(CCSiMe3)2)] and [Ru4(CO)12(4-2-C2(CCSiMe3)2)] <1999JOM(578)55>. Similar struc-
tures based on triiron cores are known <2000JOM(604)150>. The osmium homolog of the latter is
known <1998JOM(565)279> and is illustrated as 94. Among the products of the ruthenium clusters
with diynes, [Ru3(3-C5H5NMe)(-3-PhCH¼CCCPh)(-CO)2(CO)6] <1998MI1> may be
mentioned. The cluster [Os3(3-2-FcCCCCFc)(CO)10] <2000OM2411> reacts with water
to give [Os3(-H)(3-3-FcCH¼CCCFc)(CO)9] and [Os3(-OH)(3-3-FcCH¼CCCFc)-
(CO)9] <2000OM4090>. Similar products are formed between thienyl diyne and [Os3(CO)10)(AN)2]
<2000JCS(D)4015>. The result of the coupling reaction is the cluster [Ru3(-NS(OMePh))(-3-
PhCH¼CCCPh)(CO)9] <1997JOM(549)275>. The [Ru3(-H)(-2-3,5-Me2pz)(CO)10] complex
reacts with 2,4-hexadiyne to yield among the other products cluster 98 <2001ICC57>. Cluster
[(5-Cp*)(OC)2FeCCCCFe(CO)2(5-Cp*)] with Fe2(CO)9 gives a mixture of 99 and 100
<1998JOM(565)49, 2000JCS(CC)1285>.
Me3Si SiMe3 Me3Si

SiMe3 Me3Si SiMe3
C C C
C C C
C C C
C C C
C C C
O C C C
(OC)3Ru
C (OC)3Ru Ru(CO)3
C C
(OC)3Os Os(CO)3
C C
Os C Ru C Ru Ru
(CO)3 (CO)3 (CO)3 (CO)3
Me3Si SiMe3
96
94 95
(OC)3Co Co(CO)3 Me
(Me)HC C
C C C C
Ru(CO)3
C SiMe3
Me3Si C (OC)2Ru CO
Me
C C Ru
N (CO)2
(OC)3Ru Ru(CO)3 Ru
N
(CO)3
Ru Ru Me
(CO)3 (CO)3 98
97
Fe(CO)2(η5-Cp*) C CC CFe(CO)2(η5-Cp*)
(η5-Cp*)(OC)2Fe
C C
C C C (OC)3Fe Fe(CO)3
O
Fe CO
(OC)3Fe Fe(CO)3 (η5-Cp*)
99 100
The tetrairon clusters [(5-C5H4R)Fe4(3-CO)4] (R = H, Me) of the cubane type when treated with
lithium aluminum hydride, give the acetylene clusters 101 (R = H, Me) <1998JA9135>. They enter
into oxidation reactions with ammonium hexafluorophosphate and silver tetrafluoroborate to yield
the cationic clusters, where the butterfly-type framework is retained <2002IC6726>.
H
C
C
(η5-C5H4R)Fe H Fe(η5-C5H4R)
Fe
η5-C5H4R
Fe
HC CH
η5-C5H4R
101
The reaction of [(Cp*)(OC)2FeCCCCH] with [Ru3(CO)12] leads to a mixture of cluster

compounds 102–105, <2003JOM(670)2>. Thermolysis of the heterodimetallic complex
[Os3(CO)10(-H)(-3-C(¼CHPh)CCW(O)2(5-Cp*)] gives products 106 and 107, both with the
--2 coordination mode of the acetylene ligand <1999OM1675>. The reaction of [H4Ru4(CO)12]
with 1,4-dialkynes RCCCCR (R = Me, SiMe3, Ph) gives a mixture of tetranuclear clusters 108
and 109, and the dialkyne with R = Ph additionally produces the trinuclear allenylidene 110
<2000JCS(D)4527>. Similar reactions of 1,3-dialkynes are known <1999JOM(589)213>.
C CFe(CO)2(η5-Cp*)
C CFe(CO)2(η5-Cp*) O
C C C C CFe(CO)2(η5-Cp*)
C C
(OC)3Ru Ru(CO)3
C C
H H H
Ru
(CO)3
(OC)3Ru Ru(CO)3
102 103
C CFe(CO)2(η5-Cp*) H
C C CFe(CO)2(η5-Cp*)
C C CFe(CO)2(η5-Cp*) C C
HC C (η5-Cp*)(OC)2FeC C
C
H
CH (OC)3Ru Ru(CO)3
(OC)3Ru Ru(CO)3
104 105
η5-Cp*
O
W
(CO)3 O
H (CO)3
Os Os
(OC)4Os C H (OC)3Os C H
C C
Os Os
(CO)3 (CO)3
H H
Ph Ph
106 107
RH2C R RHC CHR

C C C C
C
O O
(OC)3Ru C Ru(CO)3 (OC)3Ru C Ru(CO)3
Ru Ru
C (CO)2 C (CO)2
O O
Ru Ru
(CO)2 (CO)2
108 109
PhH2C Ph
C C C
H
(OC)3Ru Ru(CO)3
Ru
(CO)3
110
[Ru3(CO)9(2-NCPh2)(2-H)] reacts with HCCCH2CCSiMe3 to give variously coordi-

nated triruthenium clusters 111–113 <2000OM5424>. The ruthenium cluster based on
2-aminopyridine reacts with MeCCCCMe to yield 114. With an excess of the dialkyne,
cluster 115 is formed, both being examples of alkyne–alkene complexes <2001OM4973,
2003ICA(350)215>. Another illustration of the coupling reactions of the coordinated ligands
pertains to the allenylidene complex 116. With phenylacetylene, it experiences dehydration
followed by the formation of 117 (R1 = Ph, R2 = H, R3 = Ph). With trimethylsilylacetylene, the
first step is the coupling reaction leading to 118 and the second is dehydration to afford 117
(R1 = R3 = Me3Si, R2 = H) <1999JOM(589)239>. MeCCCCMe with [Os3(CO)10(AN)2]
gives [Os3(CO)9(-CO)(3-2:3-1, 1, 3-MeC2C2MeOC5Me2)Os3(-CO)(CO)9] and other
clusters <2001JOM(635)119>. Cluster [Os3(CO)10(-2-2-C5H4N)(-H)] reacts with 1,4-bis(ferro-
cenyl)butadiyne to yield isomers 119 and 120 <2001JOM(637)514, 2001OM5225>.
H2 H
C C CSiMe3 C C CPh
H2C
C PhHC
(OC)3Ru (OC)2
Ru(CO)3 Ru Ru(CO)3
N
N Ru
(CO)3
CPh2 Ph
111 112
H
C Me N NH
CPh N NH O
PhHC Me C
C O
C (OC)2Ru Ru(CO)2
(OC)2Ru Ru(CO)3 (OC)2Ru Ru(CO)2 MeC
C Ru CO
N MeHC C Ru CO (CO)
Ru C CMe
(CO)2
(CO)3 C C
MeC C
Ph CMe
113 114 CHMe
115
CPh2 R3 H
C R2C C C
C CPh2 CPh2
C (Me3Si)HC C
HC C C
(OC)3Ru Ru(CO)3 (CO)3 (CO)3
Ru Ru
R1C
H OH (OC)3Ru
Ru Ru(CO)3
(CO)3 (OC)3Ru Ru(CO)3 O
H
116 117 118
Fc H
N Fc C C
Fc +
C C Fc
C
C C H
(OC)3Os Os(CO)3
(OC)3Os Os(CO)3
N Os –
(CO)3
Os
(CO)3
119 120
Interaction of a fourfold excess of hexamethyl Dewar benzene (L) with [Os3(CO)10(AN)2] first
gives [Os3(CO)10(4-L)], then, under reflux, the product of decarbonylation, [(-H)2Os3(CO)9-
(-3-CH(C6Me5)], which can be thermally or photochemically transformed to 121
<2003OM2361>. The cyclotetradeca-1,8-diyne (C14H20) complexes, for example, [Os3(CO)10(3-
2-C14H20)2], 122 <1999OM880> further react with [Os3(CO)10(AN)2] to yield derivatives
[{Os3(CO)10}2(3, 3-2, 2-C14H20)], with the ligand in photochemical conditions to give
[Os3(CO)9(-4-C14H20)2], and with the ligand in Me3NO/AN to afford [Os3(CO)9(3-3-
C4H10)2] <2003OM2990>. In excess ligand or on reaction of the products with complex 122,
more spacious complexes are formed that are likely to play a role in materials chemistry.
Cyclodeca-1,8-diyne reacts with [Os3(CO)10(AN)2] to give cluster 123 possessing a branched
reactivity pattern <1999OM880>. On thermolysis, 123 is converted into 124. In excess
[Os3(CO)10(AN)2] it gives species 125, and on photochemical decarbonylation, product 126
is afforded. [Fe3(CO)12] in this reaction behaves differently and forms the cluster product 127,
which on thermolysis undergoes unusual rearrangements to the 4-cyclobutadienyl, 128, and
5-cyclopentadienyl, 129, derivatives respectively. Ruthenium and osmium clusters containing
1,3-cyclohexadiene are characterized by either the 4- or 2-2:2 coordination mode
<1996JCS(D)2165>. [Os4(CO)9(RCCR)(6-C6H6)] (R = Me, Ph) reacts with Me3NO and
1,3- or 1,4-cyclohexadiene to afford [{Os4(CO)8(RCCR)(6-C6H6)}2(2-2:2-L)] (R = Me, Ph;
L = C6H8-1,3, C6H8-1,4) <2003ICC1291>.
Me
Me
Me
Et
Me
OC CO
(CO) 2 Os
Os (OC)3Os Os(CO)3
(OC)3Os Os(CO)3
C CO
H O
121 122
Nucleophilic attack of diphenylphosphine on the allenyl species [Fe2(CO)6(-PPh2)(-1:2-

(H)C¼C¼CH2)], 130, gives [Fe2(CO)6(-PPh2)(-1:2-CH3C¼CH(PPh2)]
<1996JCS(CC)1545, 1997OM3221>. Diphenylphosphinomethane produces [Fe2(CO)6(-
PPh2)(-1(P):1(C)-2(C)-Ph2PCHPPH2(H)C¼CCH3)] and an iron–carbon-bridged phos-
phinomethanide complex <1996OM5302, 1997OM297>. Trialkylphosphites give
[Fe2(CO)6(-PPh2)(-1:2-CH3C¼CCH(PO(OR)2)] (R = Me, Et, Prn) <1997OM4251>.
Complex 130 reacts with P(NR2)3 (R = Me, Et, Prn) to yield the zwitterionic derivatives 131
(R = Me, Et, Prn) <1999OM679> in accord with the reaction course of the same starting
reagent with primary amines <1998OM3331>. However if species 130 is treated first with
HBF4 and then with P(NMe2)3, a mixture of the vinylidene-bridged complex, 132, and the
dimetallacyclobutene, 133, results <1999OM679>. Under HBF4 alone, species 130 isomerizes
into the acetylide complex 134. Complexes 131 (R = Me, Et, Prn) slowly decarbonylate into
135 (R = Me, Et, Prn). Thermolysis of 132 (R = Me) gives the same product, 136 (R = Me).
For 131 (R = Et, Prn), however, the products are 136 (R = Et, Prn) and 137 (R = Et, Prn).
The structure of these complexes is similar to those of [Fe2(CO)5(-PPh2)(-1:2-
(NuC(O)CH2)C¼CH2)] (Nu = OR, NHR, Alk) <1996OM2688, 1997OM1186, 1997OM3221,
1998JOM(569)39, 1998OM2953>. Complexes 137 also resemble analogous iron alkenyls
<1997JOM(527)247>. Complex 130 on reaction with triphenylphosphine gives an analog
where, instead of the P(NR2)3 moiety, there is a PPh3 group carrying the partial positive
charge <1999OM679>. The product reacts with P(NEt2)3 to produce 131 (R = Et). On
thermolysis, it gives an analog of 136 with P(NR2)3/PPh3 substitution. The latter reacts with
P(NEt2)3 to give 136 (R = Et). Reactions with isocyanides were also studied <1999OM3178>.
Bis(phenylene)butatriene Fe2(CO)6 complexes are of interest <1996OM1511>. Species 130 with
t-butylisocyanide gives a mixture of 137 and 138 <1999OM3178>. The latter is decarbonylated to
give 139.
(CO)3
Os
(OC)3Os Os(CO)4
(OC)4Os Os(CO)3
(CO)3
Os Os
(CO)3 (OC)4Os Os(CO)3
(OC)3Os Os(CO)3
123 H
Os
124 (CO)3
125
(OC)3 Os(CO)3
Os Os(CO)3 (OC)3Fe Fe(CO)3
Fe(CO)3
Fe
(CO)3
126 127 128
–
O
C
Fe Fe
OC
–
129
+P(NR
2)3
(Me2N)3P+ Me
CH2 C
C H C
C CH2
HC
C
(OC)3Fe Fe(CO)3 (OC)3Fe– (OC)3Fe – Fe(CO)3
Fe(CO)3
P P P
Ph2 Ph2 Ph2
130 131 132
+
P(NR2)3
(Me2N)3P+ Me CH3 C
C H
C C C CH2
C
– –
P P P
Ph2 Ph2 Ph2
133 134 135
+ t
(Me2N)3P H Bu N O
C C C+ Me C CH2
ButHN CH2
O C CH2 C C C
–
P P P
Ph2 Ph2 Ph2
136 137 138
ButHN
C CH2
O CH2
C
(OC)2Fe Fe(CO)3
P
Ph2
139
Cluster 140 <1997JCS(D)2937> has an interesting reactivity pattern manifested in reactions with
molecular hydrogen, olefins, and cyclopentadiene <1997JCLS293>. Its reaction with buta-1,3-diene
gives 141 containing a bridging benzene in the form of cyclohex-3-en-1-yne <1999JOM(573)134>.
The related system is [Ru5(2, 3-C2)(-SMe2)(-PPh2)2(CO)13] <1997JCS(D)371>.
(CO)2
Me Ru
S MeS PPh2
Ph2P
C C (CO)2
(OC)3Ru (CO)2 (CO)2 Ru
Ru (OC)2Ru Ru(CO)2
Ru
Ru C
P Ru(CO)2
MeS Ph2 (CO)2
C CH
Ru P S
(CO)2 Ph2 Me H2C CH
C
H
140 141
Heterogeneous precursors for the catalytic transformations of benzene and arenes are adsorption
complexes of these ligands with transition metals <2001JCLS139, 2001SSCI18> and homogeneous
catalytic precursors are cluster complexes, e.g., [(6-C6H6)4Ru4H4Cl2] <1997JOM(539)163> and other
similar species <1996JCS(D)2395>, where the bonding mode of the arene ligands is predominantly -2,
2, 2. The -1, 1, 1 is observed, in particular, in the adsorption complex of benzene with ruthenium
<1998JVST(A)1017>. In the species [{(5-Cp*)Ru}3(-H)3(3-3, 3-C6H6)]2+ <1997JA625>,
the mode is different. Cluster complexes [(6-C6Me6)2(6-C6H6)Ru3-(2-H)2(2-OH)(3-O)]+
and [(6-C6M6)2(6-C6H6)Ru3(3-H)3(3-O)]+ are efficient catalysts of the hydrogenation of arenes
<2001JOM(621)103>. Successive carbonylation of [Ru3(CO)6(-CO)(3-5, 3, 3-C10H8)] leads
first to [Ru3(CO)8(3-5, 2, 1-C10H8)] and then to [Ru2(CO)5(2-5, 3-C10H8)] <2001OM359>.

Excess acenaphthylene with [Os3(CO)10(AN)2] gives [Os3(CO)10(-H)(-2-C12H7)], which on
thermolysis transforms into [Os3(CO)9(-H)2(3-2-C12H6)] <2002IC5525, 2003JOM(683)421>.
The product of thermolysis reacts with acenaphthylene to produce four clusters: [Os4(CO)12-
(4-2:2-C12H6)], [Os2(CO)6(-4-C24H12)], [Os3(CO)9(-H)(3-4-C24H13)], and [Os2(CO)5(-4-
C24H12)(2-C12H8)].
Pyrolysis of clusters containing phenyl-substituted P-ligands often leads to the appearance of
benzyne ligands through the stages of o-metallation and cleavage of the phosphorus–carbon bond
<2001JCLS139>. [Ru3(CO)10(dppe)] in benzene on heating produces clusters 142 and 143
<2002ICC414>. Bonding of the six-electron benzyne ligand occurs in a 4-4 manner. Cluster 143
is characterized by the 1, 2-3 coordination mode of the three-electron C6H5 moiety. The reactivity
of the o-metallated derivative 144 is receiving much attention <1998JCS(D)1097, 2000ICC553,
2000JOM(616)157, 2000OM5623, 2001JCLS5, 2001JOM(625)112, 2003JOM(681)237>. Large
clusters of osmium are [Os6(CO)14(-H)(-CO)(AN)(Pyr)(-2-C5H4)] <1997JCS(D)4357> and
[Os6CO)14(-CO)(-H)(-1:2-C9H8N3)] <1998JCS(D)1939>. MeCCCCMe with
[Os3(CO)10(AN)2] gives [Os3(CO)9(-CO)(3-2:3-1, 1, 3-MeC2C2MeOC5Me2)Os3(-CO)(CO)9]
and other clusters <2001JOM(635)119>. One of the products of interaction of [Os3(-H)-
(-OH)(CO)10] with 1-naphthol is 145 <2003JOM(687)203>.
P PPh2
PhP PPh2
(OC)3Ru Ru(CO)
(OC)4Ru
CO
(OC)3Ru Ru(CO)2 Ru(CO)2
(OC)3Ru
142 143
Ph
P CH2
Os(CO)3 O
PPh2
(OC)3Os Os(CO)3
(OC)3Os Os(CO)2
H
H Os H
(CO)3
144 145
The triple-decker complex 146 is assumed to be formed via the sandwich 147. These two species
follow simultaneously from the corresponding 2,3-dihydro-1,3-diborole and [(5-Cp)Fe(4-COD)]
<1996CEJ487>. A mixture of 1,4,2-diphosphastibolyl and 1,2,4-triphospholyl anions with
[RuCl2(PPh3)3] gives an isomeric mixture of antimony-containing sandwiches
<1997JCS(D)2183>. In excess [(5-Cp*)Ru(AN)3](PF6), the triple-decker 148 results.
η5 -Cp*
Fe(η5-Cp) Fe(η5-Cp) Ru
Et Et
BEt BEt P
Et P
Et B Me B Me Sb
Et Et
Fe( η5-Cp) Ru
η5 -Cp*
146 147 148
Activation of 1-methylpyrrole using triosmium clusters gives among the others zwitterionic
product 149 <1997OM1735>.
NMe
+
(OC)4Os Os(CO)3
– H
Os
(CO)3
149
Quinoline and tetrahydroquinoline react with [M3(CO)12] (M = Ru, Os) to give [(-H)(-2-
C9H6N)M3(CO)10] (M = Ru, Os), the product of oxidative addition of the C(2)H bond of the
quinoline ring to [M3(CO)12]. The same type of products, 150 (R1 = R2 = H; R1 = Me, R2 = H;
R1 = H, R2 = Me), results from the derivatives of quinoline and [Os3(CO)10(AN)2]
<1996OM1979, 1998OM415, 1998POL2975, 2002OM1508> but products 151 (R1 = R2 = H;
R1 = Me, R2 = H; R1 = H, R2 = Me) are also formed in minor amounts. At elevated tempera-
tures, decarbonylation of 150 (R1 = R2 = H; R1 = Me, R2 = H; R1 = H, R2 = Me) takes place,
and the result is 152 (R1 = R2 = H; R1 = Me, R2 = H; R1 = H, R2 = Me), the process being
reversible. Complexes 152 (R1 = R2 = H; R1 = Me, R2 = H; R1 = H, R2 = Me) enter hydroge-
nation with LiEt3BH to give 153 (R1 = R2 = H; R1 = Me, R2 = H; R1 = H, R2 = Me). Proto-
nation of 153 (R1 = R2 = H; R1 = Me, R2 = H; R1 = H, R2 = Me) by triflic acid gives 154
(R1 = R2 = H; R1 = Me, R2 = H; R1 = H, R2 = Me), and further hydrogenation/protonation
sequence gives 155 (R1 = Me, R2 = H). A similar process occurs when 152 (R1 = R2 = H)
interacts with R1Li [R1 = Me, Bun, But, PhCH2, Ph, vinyl, C2(CH2)3Me, CH2CN, CMe2CN,
CHS(CH2)2S, CH2COOBut] or R1MgBr (R1 = Me, CH2¼CHCH2MgBr) to yield 156 [R1 = Me,
Bun, But, PhCH2, Ph, vinyl, CH2¼CHCH2, C2(CH2)3Me, CH2CN, CHS(CH2)2S, CH2COOBut,
R2 = R3 = R4 = H] and on protonation 157 with the same set of substituents as in 156
<1998JA12818, 2000JOM(593)226>.
R2
R1 R1
R2 R1
R2
N N N
H H
Os Os Os H
(CO)4 (CO)4 (CO)3
150 151 152
R1 HH
H R1 HH
H R1 H H
R2 R2 H
– R2
N N H
N H
Os H Os H Os H
(CO)3 (CO)3 (CO)3
153 154 155
R1 R2 R1 H R
2
H R4
R4 R3 R3
H
–
N N
(OC)3Os Os(CO)3 (OC)3Os Os(CO)3
H Os(CO)3 H Os(CO)3
156 157
5,6-Benzoquinoline complex 158 is reactive toward triphenylphosphine to yield 159

<1998OM415, 1999OM3519>. Thermolysis of 159 gives 160. Complex 158 with LiEt3BH and
then CF3COOH gives 161 and with LiMe2CCN/CF3COOH, 162. With n-butyllithium/
CF3COOH, a mixture of products is obtained, 163–165.
N N
H
(OC)3Os Os(CO)3 (Ph3P)(OC)3Os Os(CO)3
H Os Os
(CO)3 (CO)4
158 159
H
N H N
(Ph3P)(OC)2Os Os(CO)3 (OC)3Os Os(CO)3
H Os H Os H
(CO)3 (CO)3
160 161
CMe2CN
H
H
N Bun N
H Os H Os H
(CO)3 (CO)3
162 163
n
Bu
Bun
N N
H Os H Os
(CO)3 (CO)3
164 165
Cluster 166 upon thermolysis in the presence of [Os3(CO)10(AN)2] rearranges into 167
<1996JOM(513)27> containing along with nitrogen-coordination, the 2-coordination via the
vinyl group.
H N
N (OC)3Os
H
H H
H (CO)3
Os
Os
(CO)3 Os(CO)4
(OC)3Os Os(CO)3
(CO)3 Os
Os
H (CO)3 H Os
H (CO)
4
166 167
4.15.3.8 Functions Containing Two Co, Rh, or Ir Atoms

In the [Co4(CO)12] structure, three of the carbonyl ligands are bridging between the cobalt atoms
<1999JOM(573)60>. In the clusters [(5-Cp)3Co3(-CO)2(2-CH2)] and [(5-Cp)3Co3(3-CO)(3-
NNCH2)], the bridging methylene moieties have a dynamic behavior <2001JOM(617)561>. Bridging
carbonyls are contained in [Co4(-dppm)2(-CO)3(CO)5], [Co4(-CO)3(CO)6(6-C6H6)]
<2001AJC277>, [Co4(3-AsPh)(4-2, 2, 1-As4Ph4)(-CO)2(CO)8], and the product of its thermo-
lysis, [Co4(3-AsPh)2(4-2, 1-As2Ph2)(-CO)(CO)9] <2001JOM(625)245, 2003CCR(241)273>.
Clusters [((5-Cp)Co)3(3-S)(3-CS)] on reaction with RI or ROTf (R = Me, Et) are converted into
the cationic species [((5-Cp)Co)3(3-S)(3CSR)]+ <2003ICA(354)54>. Dibenzothiophene with
[Co4(CO)12] or [Co2(CO)8] forms cluster 168 <1999OM5721>. The product reacts with
[Cr(CO)3(AN)3] to yield the 6-benzene complex 169. Species 169 also results from the reaction of
benzothiophene with [Co4(CO)12]. In [Rh4(CO)12], the carbonyl groups are fluxional, and mutual
exchange of the terminal and bridging carbonyls is not accompanied by energy changes for the
complexes in solution <1996ICA(252)311, 2003OM3448>. Clusters [MoIr3(-CO)3(CO)8(5-Cp)]
enter the ligand substitution reaction with isocyanides to yield [MoIr3(-CO)3(CO)8nLn(5-Cp)]
(L = CNBut, CNC6H3Me2-2,6; n = 1–3) L <2003JOM(678)72>. [Mo2Ir2(-CO)3(CO)7(5-Cp)2]
reacts with t-butyl isocyanide to give a single product of composition [Mo2Ir2(-
CO)2(CO)6(CNBut)2(5-Cp)2]. Species with the Rh2(-CH2)2 units deserve mentioning
<1998JOM(554)155>. Anionic carbide cluster [Co13C2(CO)24] is known <2003ICA(350)187>.
S Co
Co
O O
C C
(OC)2Co Co(CO)2 (OC)2Co Co(CO)2
CO CO
C Co C Co
O (CO)2 O (CO)2
168 169
The carbene complexes of rhodium(I), trans-[RhCl(¼CR2)(Sb(Pri)3)2] on thermolysis give

the dinuclear species 170 (X = X0 = Cl) <2000CEJ4471>. The bridging Sb(Pri)3 ligand can be
replaced by carbon monoxide or t-butyl isocyanide. The chloride ligands can be substituted by
acetylacetonate moieties <1999AG(E)1609, 2002CEJ309> to yield 170 (X = X0 = 2-acac). With
various acetylacetonates, the products of incomplete (170, X = Cl, X0 = 2-acac) and complete sub-
stitution follow. With sodium bromide or iodide, the products are 170 (X = X0 = Br, I)
<2003JCS(D)1495>. Mixed acetylacetonato–carboxylato species of the type 170 are other illustrations.
Dinuclear complex [(2-acac)2Rh2(-CPh2)2(-PPh3)] is also known <2000AG(E)3909>. The dirho-

dium species [(acac)Rh(-PMe3)(-CPh2)2Rh(acac)] and [ClRh(-PMe3)(-CPh2)2RhCl] contain not
only the CPh2 bridge but trimethylphosphine ligand, which is a rarity <2000AG(E)3909,
2002AG(E)2301>. [Rh6(CO)14(, 3-Ph2P(CH¼CH2)] contains the framework where two adjacent
rhodium atoms are bonded to the double bond of the vinyl group <2003JCS(D)2468>.
Pr3i
Sb
X Rh Rh X′
C
Ph2
C
Ph2
170
Interaction of [Rh4(CO)12] with alkynes in an atmosphere of carbon monoxide or carbon mon-

oxide/hydrogen leads to two types of complexes, one of which, 171, contains the CRh2 functional
groups <1999OM417, 1999OM1542, 1999OM3457>. Ethylene reacts with [(dfepe)2Ir2(-H)3(H)] to
give the -1:3-coordinated dinuclear complex 172 <1999OM5717>. Several rhodium complexes
contain metal–2-acetylide interactions <1996OM506, 1998OM2553>. Phosphaalkynes PCR
(R = But, Ad) with the rhodium dimer 173 give the triple-decker products 174 (R = But, Ad)
<1999OM4838>.
R
C
(OC)3Rh Rh(CO)3 (dfepe)Ir IrH(dfepe)
C H
R′
172
171
η5-Cp
F3CC CCF3 Rh
R CF3
(η5-Cp)Rh Rh(η5-Cp)
P
CF3
O (η5-Cp)(OC)Rh
173 174
The iridium dimer [Ir2Me(CO)(-CO)(dppm)2](OTf) reacts with CO, SO2, PR3, CNR (L) to
rearrange its bridging moiety to [Ir2H(L)(CO)2(-CH2)(dppm)2](OTf) <1998OM2553, 1999JA2613,
1999JA3666>. With alkynes, the bridging methylene normally forms vinylcarbenes <1996CJC2289,
1996OM506, 1996OM1042, 1997OM2297>. The cationic species [MeIr(-dppm)2(-CO)Ir(CO)]
with acetylenes R1CCR2 (R1 = R2 = Me, Et, Prn; R1 = Me, R2 = Et; R1 = Me, R2 = Ph) finally
form cluster structures 175 <1999OM1629, 1999OM2177, 1999OM4134>. The same starting
complex with acetylene gives 176 <1997ICA(259)213, 1998JA4047, 1999OM4134>, and similar
complexes are found in organoruthenium and -osmium chemistry <1996OM272, 1998JA4047>.
R +
H Ph2P CH2 PPh2
H C
C C(R')H
C
OC Ir Ir CO Me(OC)Ir Ir(CO)
Ph2P PPh2 H
Ph2P PPh2 Ph2P PPh2
175 176
Electrochemical oxidation of [(5-Cp)3Co3(3-CPh)2] gives the cationic cluster [(5-Cp)3Co3(3-

CPh)2]+ <2003POL3413, 2004ICA(357)533, 2004JOM(689)146>. With halogens, the starting cluster
gives the adducts [(5-Cp)3Co3(3-CPh)2(-Cl)](PF6)AN, [(5-Cp)3Co3(3-CPh)2(-Br)](SbF6), [(5-
Cp)3Co3(3-CPh)2(-I)](SbF6)CH2Cl2, and [(5-Cp)3Co3(3-CPh)2(-I)](I3) <2004ICA(357)1236>.
[Co3(3-CR)(-(AsMe2)2O)(CO)3] (R = Cl, Me) and [Co2(-C2(COOMe)2)(-(AsMe2)2O)(CO)4]
<2000JCS(D)395>react with hydrogen sulfide to yield the bisdimethylarsine sulfide bridges
<2003JOM(681)102>. Alkynes with [Co2(CO)8] typically form species 177. Excess amounts of
alkynes give 178 <1999OM206>. Complex 177 (R1 = Ph, R2 = H) with excess ethynylbenzene in
the presence of trimethylamine N-oxide forms 179 <1999OM215> and 180 <1999OM197>. The
cyclic tetrayne, C20H8, with [Co2(CO)8] gives the double addition product 181 <1999JOM(578)91>.
The structure of the cluster containing the propargyl moiety, [(ButCC)3C(Co2(CO)6)2]+, was
determined <1998AG(E)161>. Bis(diphenylphosphino)acetylene with Co2(CO)8 gives 177
(R1 = R2 = PPh2) and in excess [Co2(CO)8] species 182 is formed <1999ICC450>. The product of
cluster formation of alkynediol 183 dehydrates by the cyclization pathway to yield 184
<1997OM2152>. Other routes of dehydration are possible <1999OM4552>. When bromoalkynes
take part in the cluster formation, they couple to form coordinated diynes <2001JOM(634)74>. The
other route for the transformation of coordinated alkynols, alkene–alkynes, and diynes is cyclization
leading to the facile synthesis of metallacyclopentadiyne cobalt complexes <1999JCS(CC)2503,
2000AG(E)2732, 2001JOM(635)119>.
O
R Ph
R1 R2 R R O
Ph
(OC)3Co Co(CO)3 (OC)2Co Co(CO)2 (OC)2Co Co(CO) Ph

C
177 R R O
R
178 179
(CO)3
R1 R2 Co
Co(CO)3
(OC)3Co
R2
R1
Co (OC)3Co
(CO)2 Co
(CO)3
180 181
O
C O
(OC)2Co Co(CO)2 HOH2CC CH2OH

C
Ph2P O PPh2 (η5-Cp)Co Co(η5-Cp) (η5-Cp)Co Co(η5-Cp)
OC Co OC Co
(OC)3Co Co(CO)3 (η5-Cp) (η5-Cp)
182 183 184
[(5-Cp*)(OC)2FeCCCCH] reacts with [Co2(CO)8] and [(5-Cp)Mo(CO)]2 to yield 185

(M = Co(CO)3, Mo(CO)(5-Cp)) <1997JCS(CC)1557, 1999JCS(CC)101, 2003JOM(670)2>. Excess
[Co2(CO)6] leads to a 1:2 adduct 186. [(5-Cp*)(OC)2FeCCCCFe(CO)2(5-Cp*)] with
[Co2(CO)8] gives 187 <1999OM4684>. 1,8-Nonadiyne reacts with [Co2(CO)8] to yield cluster 187
<1999OM3164>. [Co4(CO)12] and the corresponding diyne give cluster 188 <2002JOM(656)57>.
Related examples can be found elsewhere <1996ICA(243)109, 1999JOM(578)155>.
(OC)3Co Co(CO)3
(η5-Cp*)(OC)2FeC CC CH (η5-Cp*)(OC)2FeC CC CH
M M (OC)3Co Co(CO)3
185 186
Me2
H2C C
NMe
(OC)2Co C
Me2
HC C(CH2)5C CH C
OC
Co Co Co Co
(CO)3 (CO)3(CO)3 (CO)3 (OC)3Co Co(CO)3
187 Co
(CO)3
188
The 3-bromocarbyne species 189, on reaction with [Au(P(p-Tol)3)]2(-CC)n (n = 2–4) catalyzed

by Pd(PPh3)4/CuI, gives the cluster-capped chain structures 190 (n = 2–4) <2003JOM(670)170>. One
of the products, 190 (n = 3), with TCNE yields the adduct 191. [(3,30 -Dimethylbutyne)Co2(CO)6]
reacts with chelating diphosphine ligands (dppm, dppe) to yield clusters 192 (L2 = dppm, dppe).
With monodentate ligands, clusters 193 (L = CO, PPh3) result <1999OM3859>. Bis(t-butylsulfonyl)-
ethyne with [Co2(CO)8] gives cluster 194 <1999OM4275>. The product reacts with various
sulfides and produces 195 (R1 = p-Tol, R2 = Me; R1 = R2 = PhCH2, Et, THT (tetrahydrothiophine)).
Me3Si(CC)3SiMe3 with [Co2(CO)6(dppm)] in benzene gives cluster products 196 and 197
<1999OM3885>. These species further react with [(5-Cp)RuCl(PPh3)2] to give the products of
substitution of the trimethylsilyl groups by the (5-Cp)RuCl(PPh3)2 moiety. 1,3,5-
(OC)3M P(PPh2)(CC)3C6H3 (M = Mo, W) react with [Co2(CO)8] to yield 198 (M = Mo,
W) <1999OM2565>. The same type of reaction was applied to [H{CC-p-C6H4}n]4 (n = 1, 2,
3) <1998C533, 1998JCS(CC)2661>.
PPh2 PPh2
Ph2P Co(CO)2 Ph2P Co(CO)2 Co(CO)3

(OC)2Co CBr (OC)2Co C (C C)n C Co(CO)2
Co(CO)3 Co(CO)3 (OC)2Co PPh2
Ph2P
189 190
PPh2
Co(CO)2 C(CN)2 H
Ph2P
(OC)3Co C (C C)2 C Co(CO)2
(OC)2Co Co(CO)2
Co(CO)2 C C Co(CO)3
PPh2 (NC)2C L L
Co(CO)2
Ph2P
192
191
H
ButSO2 SO2But ButSO2 SO2But
(OC)2Co Co(CO)3
(OC)3Co Co(CO)3 (OC)2Co Co(CO)2
L
194 SR1R2 SR1R2
193
195
(CO)2
C Co
Co(CO)2
Me3SiC C C C Me3SiC C C C
Co(CO)2
Ph2P Co(CO)2 C
C
PPh2
CSiMe3
196 197
M(CO)5
Ph2P
(OC)3Co Co(CO)3
(CO)3
Co
Co(CO)3
Ph2P PPh2
Co
Co (CO)3
(CO)3
M(CO)5 M(CO)5
198
The reactivity studies of the complexes containing the Co3 framework were extended to alkynes
capped by other transition metal moieties. Thus, 189 when reacted with [(5-
Cp)(OC)3WCCCCAuPPh3] gives 199 (MLn = W(CO)3(5-Cp)) <2003JOM(683)398>. Inter-
action with [Me3SiCCCAuP(p-Tol)3] gives 199 (MLn = SiMe3), and subsequent reaction
with sodium methoxide and then [AuClP(p-Tol)3] affords 199 (MLn = AuP(p-Tol)3).
PPh2
Ph2P Co(CO)2
(OC)2Co CC CC CMLn
Co(CO)3
199
Organometallic clusters containing cyclopentadienyl, indenyl, and fluorenyl ions allow addi-
tional insight on the behavior of the short-lived ligands <1996CRV1077, 1997OM2160>.
9-((Trimethylsilyl)ethynyl)-9-fluorenol with [Co2(CO)8] forms cluster 200 <1999OM3372>. Pro-
tonation of the latter using HBF4 gives the cationic species 201, and interaction of 200 with
diphenylphosphinomethane gives the complex 202. The product of protonation of the latter by
HBF4 is 203. The 1-(trimethylsilyl)-2,3-diphenylindenol cluster 204 prepared in a similar man-
ner can be protonated to give the indenyl cationic complex 205. Further combination with
diphenylphosphinomethane/HBF4 gives 206 and 207. Tetraphenylcylopentadienone and
2,5-diethyl-3,4-diphenylcyclopentadienone give rise to clusters 208 (R = Ph, Et) and 209
(R = Ph, Et), respectively.
HO HO
C C C
+
(OC)3Co Co(CO)3 (OC)3Co Co(CO)3 Me3SiC Co(CO)2
PPh2
C C Co
SiMe3 SiMe3 (CO)2 P
Ph2
200 201
202
Ph
Ph
Ph
OH Ph
C C C
+
+
Me3SiC Co(CO)2 Me3SiC Co(CO)3 Me3SiC Co(CO)3
PPh2 Co Co
Co (CO)3
(CO)2 P (CO)3
Ph2
203 204 205
Ph
Ph
Ph R
Ph
OH
Ph
R
OH C Ph C
C
+
Me3SiC Co(CO)2 Me3SiC Co(CO)3 Me3SiC Co(CO)3
PPh2
Co Co Co
(CO)2 P (CO)3 (CO)3
Ph2
207 208
206
Ph
R Ph
C R
+
Me3SiC Co(CO)3
Co
(CO)3
209
Cluster complexes 210 (R1 = H, R2 = Me; R1 = Me, R2 = H; R1 = H, R2 = Ph; R1 = Ph,

R = H) follow from [(5-Cp)Co(C2H4)2] and a variety of 1-alkenylbenzenes
2
<1996JOM(516)187, 1996OM5622>. The products when treated with molecular hydrogen in

the presence of palladium/charcoal catalyst give species 211 with the same set of R1 and R2
<1999JOM(573)22>. The triple-decker complex of cobalt, 212, possesses an interesting reactivity
pattern with respect to the polycyclic hydrocarbons <1998CEJ1982, 1999JOM(579)139>.
For example, the product of reaction of 212 with triphenylene is 213 where the threefold
4-coordination mode of three cobalt sites is realized <2003ICA(350)625>. The structure of this
product and some other related complexes was described in detail <1998AG(E)155,
2000CEJ3686, 2002AG(E)1211>.
H H R2
R2 H
R1 H R1
(η5-Cp)Co Co(η5-Cp) (η5-Cp)Co Co(η5-Cp)
Co Co
(η5-Cp) (η5-Cp)
210 211
η5-Cp*
Co
η5-Cp*
Co
η5-Cp*
Co
Me
Co Co
η5-Cp* η5-Cp*
212 213
2-Methylthiophene with [(5-Cp*)IrH2(-H)2IrH2(5-Cp*)] in the presence of t-butylethylene

produces cluster 214 <1999OM134>. Pyrrole in these conditions gives 215, along with trace
amounts of 216. Some other examples are interesting with regard to the problem of desulfuriza-
tion, e.g., the benzothiophene-derivatized cluster 217 <1997POL3115> and other clusters
<1999OM1786>.
Me
H MeN
Me
S
H
(η5-Cp*)Ir Ir (η5-Cp*) (η5-Cp*)(H)Ir Ir(η5-Cp*)
H
214 215
MeN
+
S
H
–
(η5-Cp*)Ir Ir (η5-Cp*) (η5-Cp*)Co Co(η5-Cp*)
216 217
2,3-Dihydro-1,3-diborole derivatives react with [(C2H4)2RhCl]2 to yield dimers 218

(R1 = R2 = Me, R3 = MesCH2; R1 = Et, R2 = R3 = Me; R1 = Me, R2 = But, R3 = Me)
<1998JOM(571)107, 2001JOM(619)7>. Pure 1,3-diborolyl sandwich 220 (R1 = Me, R2 = But,
R3 = Me) can be prepared from 219 (R1 = Me, R2 = But, R3 = R4 = Me), methyllithium, and
the 1,3-diborole ligand <2001JOM(619)7>. The by-product of this reaction is the triple-decker
species 221 (R1 = Me, R2 = But, R3 = Me).
R1 R2
B H R1 R2 R1 R2
B H B H
3
B2 R 3 3
R 1
R B R B2 R
R1 R2 R1 R
R1 R2 Rh Rh Rh
B H
2
R 1 R R1 R2
B2 R3 B H B H
R1 R 3 3
B2 R B2 R
Rh-Cl 2 R 4 R1 R R1 R 2
218 219 220 221
4.15.3.9 Functions Containing Two Ni, Pd, or Pt Atoms

Cationic species Pt2+ with methane experiences dehydrogenation to give the carbene cluster
Pt2CH2+<2000CPL53>. The product forms a 1:1 adduct with ammonia, Pt2C+NH3
<2003JA3676>. The nickel(0) complex [Ni(ButCCCMe2OH)2] can be trimerized to yield the product
222 followed by the evolution of two alkyne molecules. A related example is the dinuclear species 223
<1996OM2314, 1999OM4942>. Nickelocene reacts with methyllithium and diphenylacetylene to yield,
in particular, species 224 <1996JOM(519)69, 1998JOM(566)217, 2000JOM(593)245,
2000JOM(613)37>. Nickelocene with methyl- or phenyllithium and bis(trimethylsilyl)acetylene gives
[(5-Cp)Ni(-2:2-Me3SiCCSiMe3)Ni(5-Cp)], [(5-Cp)Ni(-2:2-PhCCSiMe3)Ni(5-Cp)], and
[((5-Cp)Ni)4(, -2:2:2:2-Me3SiCCCCSiMe3)Ni(5-Cp)] <2003ICA(350)520>.
HOMe2CC
CBut CMe2OH
C H2
CMe2OH N Ph
C Ni C
Ni
Ni
Ni CBut C N (η5-Cp)Ni CPh
Ni HOMe2CC CMe2OH H2
C C
ButC CBut CMe2OH CCMe 2OH Ni
CCMe2OH η5-Cp
222 223 224
Dinuclear platinum(II) acetylides of the A-frame type, 225 (R = Ph, C6H4Et-4, C6H4Ph-4,
C6H4OMe-4, C6H4OEt-4) are luminescent materials <1998OM2590>. Reaction of
[XPt(PEt3)2C(X) = PMes] (X = Cl, Br) with [Pt(PEt3)4] gives the dinuclear complexes 226
(X = Cl, Br, I) <1999OM258, 2003EJI1843>. The product with X = Cl with methyl iodide yields
species 227, with [PtCl2(PEt3)2] to provide 228, and with [W(CO)5(THF)] to afford 229.
[Cl(Ph3P)Ni{P(N(SiMe3)2)C(PPh3)}] reacts with [(Ph3P)2Ni(C2H4)] to yield 230 <1998OM1569>.
+
Ph2P CR PPh2
C
Pt Pt
C C
RC Ph2P PPh2 CR
225
(Et3P)2PtX Pt(PEt3)Cl Pt(PEt3)Cl2

I(Et3P)2Pt P
C
C Cl(Et 3P)2Pt C
P
Pt(PEt3)2
Pt(PEt3)2 PMe
226 227 228
PPh3
W(CO)5
C
P (Ph3P)ClNi NiCl(PPh3)
Cl(Et 3P)2Pt C P
Pt(PEt3)2
N(SiMe3) 2
229
230
Complex 231 is stable in its zwitterionic arrangement <1997JOM(530)187>. The product of

interaction of [Pd(PPh3)2Cl](PF6)2 with [Pd2(DBA)3] and 2-trimethylsiloxy-1,3-butadiene in the
presence of triethylamine, or of ligand exchange of [(Ph3P)Pd(-1,3-butadiene)(-Cl)Pd(PPh3)](PF6)
<1996JCS(CC)825> with 2-trimethylsiloxy-1,3-butadiene formulated as 232, is also stable in
its zwitterionic form <1999JOM(574)142>. Reaction of trans-[Pd(PPh3)2Cl(1-C(R)¼C¼CH2)]
or trans-[Pd(PPh3)2Cl(1-CH2CCR)] (R = H, But, Ph, SiMe3) with [Pt2(DBA)3] gives the
binuclear species 233 <2001JA3223>. In the case of R = Ph, the bridging iodide and phenylsulfide
complexes were prepared. The complex with R = Ph adds electrophilic agents ECl to yield 234
(E = H, MeCO).
–Pd(PPh –O
3)Cl RC C CH2
(Ph3P)Pd Pd(PPh3) (Ph3P)Pd Pd(PPh3) (Ph3P)Pd Pd(PPh3)

+ +
Cl Cl Cl
231 232 233
E
C
C CH2
(Ph3P)Pd Pd(PPh3)
Cl
234
The complexes -5:5-(2-benzyl-1,3,4,5-tetramethyl-2,3-dihydro-1,3-diborolyl)(3-allyl)(4-

1,5-hexadiene)dinickel and -5:5-[2-(2,4,6-trimethylbenzyl)-1,3,4,5-tetramethyl-2,3-dihydro-
1,3-diborolyl](3-allyl)(4-1,5-hexadiene)dinickel may serve as the representative triple-decker
complexes <2001ZN(B)73>.
4.15.3.10 Multidecker Sandwich Complexes of Transition Metals

Using a combination of the laser-vaporization and flow tube reactor techniques, the whole range
of benzene sandwiches and multideckers was synthesized for all of the first row transition metals
<1999OM1430>. For scandium, titanium, and vanadium <1997JPC(A)8207, 1999OM1430>,
ordinary multideckers with parallel benzene rings follow. For iron, cobalt, and nickel
<1997JCP3492, 1999OM1430>, the structures are more irregular and may include arrangements
235–237.
M
M
M M M
M M
M M
235 236 237
4.15.3.11 Functions Containing Two Cu, Ag, or Au Atoms

Among the trinuclear copper(I) acetylides, there are complexes 238 (R1 = R2 = Ph, But,
C6H4NO2-4, C6H4Ph-4, C6H4OMe-4, C6H4NH2-4, n-C6H13; R1 = C6H4OMe-4, R2 = C6H4OEt-
4; R1 = C6H4OMe-4, R2 = C6H4NO2-4), 239 (R = Ph, But, C6H4NO2-4, C6H4Ph-4, C6H4OMe-4,
C6H4NH2-4, n-C6H13), 240, and 241 (R1 = Ph, R2 = C6H4Et-4; R1 = Ph, R2 = C6H4OMe-4;
R1 = Ph, R2 = C6H4Ph-4; R1 = Ph, R2 = C6H4NO2-4; R1 = R2 = Ph; R1 = C6H4F-4, R2 = Ph;
R1 = C6H4Me-4, R2 = Ph; R1 = C6H4OMe-4, R2 = Ph), as well as the complexes of the type 238
but containing bridging ligands, bis(diphenylphosphino)alkyl and arylamines <1996JCS(D)2335,
1996JCS(D)3283, 1997JCS(CC)963, 1997OM1772, 1997JPP(A)75, 1998CCR(171)17,
1998OM3293, 1999JOM(578)3>. Analogs of 238 also exist where R1 and R2 are replaced
by the (OC)Re(bpy) moieties <1998JCS(CC)777>. Cluster 242 is the product of interaction
of [Cu(AN)4](PF4) and [Au(CCC6H4OMe-4)] in methylene chloride <1996JCS(CC)2067>.
Reaction of trimethylsilylacetylene with [Cu2(dppm)2(AN)2]2+ in the presence of n-butyllithium
in THF gives the tetranuclear complex 243 <1996AG(E)1100>. The dinuclear species 244 is also
of interest in materials chemistry <1996JCS(D)2889>. The alkene–alkyne complexes of copper
may contain oxygen donor ligands <2001IC6167>.
+
R
C
R +
C C But +
Ph2 C
Ph
P Cu P 2 C
Ph2 C
Ph2 Ph2
P Cu P Ph2
Ph2P Cu Cu PPh2 P Cu P
Ph2P PPh2 Ph2P Cu Cu PPh2
C Ph2P Cu Cu PPh2
Ph2P PPh2
C Cl
R′
238 239 240
R13P R2
C +
PR3 Ph3P CC6H4OMe-4
Cu C PPh3
R2
C Cu C
4-MeOC6H4C
C Cu
C Cu C Cu
Cu
PR13
Cu C PPh3
Cu C
C
R13P R2
CR2
Ph3P CC6H4OMe-4
241 242
2+
Ph2 Ph2 Ph
P P C
Ph2
P
PPh2 C
Cu Cu
C
P C (MePh2P)2Cu Cu(PPh2Me)
PPh2
Ph2 Cu Cu
C
Ph2P PPh2
Ph
243 244
Silver acetylide forms a number of double salts, e.g., Ag2C2mAgX (X = F, ClO4, NO3, and others)
as well as acetylides with six to nine silver atoms <1998AG(E)630, 1998JCS(CC)339, 1999JA3136,
2000JA7608, 2001AG(E)1130, 2001JA1501, 2001JA7594, 2001JCS(CC)807, 2002AG(E)4135,
2002JCLS63, 2002JCS(CC)2682, 2002NJC513>. Some illustrative examples include
[Ag2C2]6CHF2COOAg, [Ag2C2]5CF3SO3Ag2MeCN2H2O, and [Ag2C2]8CF3SO3Ag2EtCN3H2O
<2003JOM(670)235>. Silver(I) acetylides 245 (R = Ph, C6H4OMe-4, C6H4NO2-4) and
246 (R = Ph, C6H4NO2-4) <1996POL1853> as well as the analog of 245 (R = Ph)
where instead of the diphenylphoshinomethane, the (Ph2P)NPrn chelating ligand is used,
<1997OM2032> possess interesting photochemical properties. Oligomeric and polymeric
gold(I) acetylides deserve attention <1996IC2490, 1996JCS(CC)181, 1996JCS(D)3411,
1996JCS(D)3699, 1996JCS(D)4227, 1996OM1734, 1997AG(E)1179, 1997OM3541,
1998JCS(CC)1055>. Species 247 (R = n-C6H13, Ph, C6H4OMe-4) serve as an illustration
<1996OM1734>.
R R
C C
C C
Au Au
+
R Ph2P PPh2
C
R +
C C
Ph2 Ph2
P Ag P C
Ph2 Ph2
P Ag P Ph2P PPh2
Ph2P Ag Ag PPh2
Ph2P PPh2 Au Au
C Ph2P Ag Ag PPh2
C C
Ph2P PPh2
C C C
R R R
245 246 247
The tetrameric pentafluorophenyl copper, [Cu(C6F5)]4, can be prepared using the appropriate
Grignard reagent and copper(I) chloride in ether <2003OM3526>. On recrystallization from
toluene, [Cu(C6F5)]4(2-toluene)2] can be prepared. The latter contains one short and one long
CuCu diagonal distance.
4.15.3.12 Functions Containing Two Zn, Cd, or Hg Atoms

No substantial new data is available for inclusion since the publication of COFGT (1995).
4.15.4 FUNCTIONS CONTAINING TWO Al, Ga, In, OR Tl ATOMS

Tetralkyldialuminum methylene-bridged species 248 are chelating Lewis acids <1998ZAAC937>,
for example, with respect to nitrate 249 and nitrite 250 anions <1998EJI921>. Species 248, when
reacted with sodium azide in acetone in the presence of 18-crown-6, gives 251, and under the same
conditions but with sodium acetate yields 252 <1999JOM(579)18>. A similar trend is observed
for the methylene-bridged tin compounds <1997OM5716>. The recent structural determination
of [Al2(CD3)6] should be noted <2000OM4398>. 3,30 -Bis(triphenylsilyl)-2,20 -dihydroxy-1,10 -
binaphthyl with Al2Me6 gives 253 <2003OM2318>.
–
H2 –
C
H2
R2Al AlR2 C
R2Al AlR2
H2 O O
C N O
N
R2Al AlR2
O O
248 249 250
–
H2
C
((Me3Si)2HC)2Al Al(CH(SiMe3)2)2 [Na(18-crown-6)(O-CHMe2)]+
N N N
251
– Me Me
H2
C Al AlMe2
Al(CH(SiMe3) 2)2 [Na(18-crown-6)(O-CHMe2)]+ R O O
((Me3Si)2HC)2Al
O O
Me
252
253
4.15.5 FUNCTIONS CONTAINING TWO Sn OR Pb ATOMS

Anionic complexes [(5-Cp)5Pb2] and [(5-Cp)9Pb4] <1998CSR225> as well as [(5-Cp)2Pb]1
<1998IC163> are examples of the nontransition metal polydecker species.
4.15.6 FUNCTIONS CONTAINING TWO LANTHANIDE OR ACTINIDE ATOMS

Multidecker structures for the rare-earth metals include [(5-Cp*)Sm]2(-8, 8-C8H8)]
<1998JA9555>. A general synthetic scheme for these complexes includes interaction of metal
trichloride in THF followed by potassium cyclopentadienide <1999OM1460>. Complexes 254
and 255 were prepared this way. At elevated temperatures and reduced pressures, both 254 and
255 transform into 256 (M = Eu, Yb). ButCP reacts with scandium atoms to yield the triple-
decker species 257 <1997JCS(CC)481>. Metal-vapor synthesis also allowed formation of the
mixed ligand triple-decker scandium species 258 <1996JA7630>.
P
P
P
P P
η5-Cp* η5-Cp* η5-Cp* P
Yb(THF) Eu(THF)2 M Sc Sc
P P
P P
P P
Sc
Sc
Yb(THF) Eu(THF)2 M P
P P
η5-Cp* η5-Cp* η5-Cp* P
P
P
254 255 256 257 258
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Biographical sketch
Alexander P. Sadimenko was born in Rostov-on-Don in 1951. He

studied at Rostov State University, where he obtained his M.Sc. in
1973 and Ph.D. in 1976 under the guidance of Professor O. A. Osipov.
In 1976–1987 he worked as Lecturer, Senior Lecturer, and Associate
Professor at Rostov State University, 1987–1991 as Associate Professor
at Addis Ababa University, 1991–1994 as Associate Professor and
Professor at National University of Lesotho, and 1994 till date, Professor,
Head of the Department, and Head of Directorate of physical and earth
sciences at the University of Fort Hare. His scientific interests include all
aspects of organometallic chemistry of the heteroaromatic ligands, in
particular, materials chemistry aspect.
4.16
Functions Containing Two Atoms
of Different Metallic Elements
A. P. SADIMENKO
University of Fort Hare, East London, South Africa
4.16.1 FUNCTIONS CONTAINING AT LEAST ONE GROUP 1 METAL 673

4.16.2 FUNCTIONS CONTAINING AT LEAST ONE GROUP 2 METAL (AND NO GROUP 1
METALS) 674
4.16.3 FUNCTIONS CONTAINING AT LEAST ONE TRANSITION METAL (AND NO GROUP 1
OR 2 METALS) 674
4.16.3.1 Two Different Transition Metals 674
4.16.3.1.1 Two genuine transition metals (Ti and Pt) 674
4.16.3.2 A Genuine Transition Metal Linked to a Late Transition, i.e., Group 11 (Cu, Ag, Au)
or 12 (Zn, Cd, Hg) Metal 687
4.16.3.3 Two Late Transition Metals 689
4.16.3.4 A Transition Metal and a Group 13 or 14 Metal 689
4.16.3.5 A Transition Metal and Other Metals 689
4.16.4 FUNCTIONS CONTAINING AT LEAST ONE GROUP 13 METAL
(AND NO GROUP 1, 2, OR TRANSITION METAL) 690

The general principle of synthesis of multidecker anions is to react sandwich complexes of tin or
lead with the alkali metal complexes of crown or cryptand ligands <1999OM1148>. Among
the products are [(5-Cp)2Pb(-5,5-Cp)Na(15-crown-5)], [(5-Cp)2Pb(-5,5-Cp)Pb(-5,
5-Cp)Cs(18-crown-6)], and others. Interaction of [(5-Cp)2Pb] and [(5-Cp0 )Na(THF)]
(Cp0 = 2-tetrahydrofurfurylcyclopentadienyl) in toluene is a nucleophilic 1:1 stacking addition
leading to the triple-decker [{(5-Cp)2Pb(-5-Cp0 )Na}0.5THF] <2000JCS(D)2247>.The reaction
between [(5-Cp)PbCl] and [(5-Cp0 )K(THF)] (the meaning of Cp0 is the same as above) mixed in
THF in a ratio of 1:2 proceeds differently and yields [{(5-Cp)2Pb(-5-Cp)K}2THF] not containing
the Cp0 -group <2003OM2528>. Similar structure but with a differing coordination mode of
the cyclopentadienyl ligands is observed for [{(2-Cp)2Mn(-2:5-Cp)K(THF)}0.5THF]
<2001JCS(CC)1956>.
The reaction of N,N0 -bis(2-pyridylethyl)-1,2-bis-2,4,6-trimethylphenylimino)ethane-1,2-diamine
or N,N0 -bis(diphenylphosphino-3-propyl)-1,2-bis(2,4,6-trimethylphenylimino)-ethane-1,2-diamine
with n-butyllithium and [(4-COD)PdMeCl] followed by methyllithium in THF gives the dimer
[(THF)4Li4Me8Pd2] with the structure 1 <2003JOM(681)24>. Similar cluster compounds are
known <1999ZAAC1904, 2000JPS(A)4764, 2001OM4221>. Starting with the dinuclear complex
[(acac)Pd(oxam)Pd(acac)] in the presence of phenyllithium in THF, complex 2 can be prepared
<2003JOM(681)24>. Interaction of (Et8-calix-pyrrole)[Li(THF)]4 with [SmCl3(THF)3] gives
species with the Li(-Me)2Sm moiety <200OM817>.
673
674 Functions Containing Two Atoms of Different Metallic Elements
THF
Li
Me Me
Me Pd Me
(THF)Li Li(THF) (THF)2Li Pd Li(THF)2
Me Pd Me
Me Me
Li
THF
1 2
The lanthanide (II) compounds containing the alkali metal cyclopentadienyl moieties are
stable <1997OM2963, 1998M8650, 2000JA10533, 2001OM3323, 2001OM4565, 2002JOM(647)61>.
The reaction of [(5-Cp*)2M(THF)2] (M = Sm, Eu, Yb) with KCH(SiMe3)2 gives complexes 3
(M = Sm, Eu, Yb) <2003OM129>, where the lanthanide site is characterized by the oxidation
number 2+. Compounds [(5-Cp*)2M(THF)2] (M = Sm, Eu, Yb) react first with sodium hydride
and phenyl silane and then an additional equivalent of phenyl silane to yield complexes 4
(M = Sm, Eu, Yb).
Me Me Me Me
(THF)2 THF
Me Me Me K Me Me Me K
Me Me
M Me M Me
Me Me
Me THF Me
Me Me
SiH3
CH(SiMe3)2
n n
3 4
4.16.2 FUNCTIONS CONTAINING AT LEAST ONE GROUP 2 METAL (AND NO

GROUP 1 METALS)
No substantial new data are found after the publication of COFGT (1995).
4.16.3 FUNCTIONS CONTAINING AT LEAST ONE TRANSITION METAL (AND NO

GROUP 1 OR 2 METALS)
4.16.3.1 Two Different Transition Metals
4.16.3.1.1 Two genuine transition metals (Ti and Pt)

5
[( -C5H4SiMe3)2Ti(CCFc)2] with [Pd(PPh3)4] (Fc = ferrocenyl) gives the heterotetranuclear
cluster [(5-C5H4SiMe3)2Ti(CCFc)2Pd(PPh3)2] <1999OM4119>.
The reaction between [(5-Cp)2V] and [Co2(CO)8] gives the heterodinuclear complex [(5-Cp)2-
V-Co(CO)4] <1999OM2452>.
A MoW complex containing the diphenylphosphinomethane (DPPM) bridge and the
four-electron donor -1:2-CNR ligand is known <1997OM1378>. The other example is
[(OC)3(5-Cp)Mo(-Cy)W(5-Cp)(CO)3] (Cy = cyclohexyl) <1999JOM(578)155, 2000JOM(607)137>.
Complex [Fe(CO)4(2-C2H2)] reacts with [(5-Cp)(OC)2WCPh] to yield 5 (M = Fe, R = Ph,
L = 5-Cp) <2003JOM(681)250>. Complex 5 (M = Os, R = Ph, L = 5-Cp) was prepared
similarly. On decarbonylation, these compounds readily provide 6 (M = Fe, Os; R = Ph,
L = 5-Cp). Compound [(5-Cp)2Mo2{-OP(OEt)2}{-P(OEt)2}(CO)2] reacts with [Fe2(CO)9]
and one of the products is 7 <2003OM2741>. Oxidative addition of molecular chlorine or
iodine to [MoRu(CO)6(-DPPM)2] gives [(OC)2Mo(-X)(-CO)(-DPPM)2Ru(CO)2[Mo(CO)4X3]
<2003ICC1175>.
Functions Containing Two Atoms of Different Metallic Elements 675
R R
C C (EtO)2P O
(OEt)2
P
L(OC)2W M(CO)4 L(OC) 2W M(CO)3 (η5-Cp)(OC)Mo Mo(η5-Cp)
5 6
Fe CO
(CO)3
7
Species [(5-Cp)2Mo2Ir2(-CO)3(CO)7] with diphenylacetylene yields [(5-Cp)2Mo2Ir2(-CO)4-

(CO)4(4-2-PhC2Ph)]. The latter with t-butylisocyanide affords [(5-Cp)2Mo2Ir2(-CO)4(CO)3-
(CNBut)(4-2-PhC2Ph)] <2003JOM(682)41>.
[Ru3(CO)12] reacts with [(5-Cp*)(OC)3WCH2CCPh] and gives the mixed-metal -allenyl
product 8 <1996ICA(243)109>. Complexes [Ru4(CO)13(-PNR2)] (R = Pri, Cy) under reflux
with [(5-Cp*)W(O)2(CCPh)] form the heteronuclear clusters 9 and 10 <1999JOM(577)126>.
Cluster 8 reacts with HBF4OEt2 to yield species 11 containing the tungsten–fluorine bond.
[Ru3(CO)12] and [(5-C5R5)WRu3(CO)8(C2Ph)] (R = H, Me) at elevated temperatures give
[(5-C5R5)WRu4(5-C)(CO)12(-CPh)] and [(5-C5R5)WRu5(6-C)(CO)14(-CPh)] (R = H, Me)
<2001OM215>. Both these clusters are hydrogenated to [(5-C5R5)WRu4(5-C)(CO)11(-CPh)
(-H)2] (R = H, Me) and [(5-Cp*)WRu5(6-C)(CO)13(-CPh)(-H)2]. The structure of the species
[(5-Cp)(OC)3Ru2Mo(3-1-CC)Ru(CO)2(5-Cp)] <1998JCS(CC)1805> was later reformulated as
[3-1-{(5-Cp)(OC)2MoC-C}Ru3(CO)5(5-Cp)3] <2003JOM(672)17>.
H2C Ph
η5-Cp*
W
C CPh C C O
O
(OC)3Ru Ru PNR2
(OC)3Ru Ru(CO)3 (CO)3
(OC)3 Ru Ru
(CO)2
C
(η5-Cp*)W(CO)2 O
8 9
Ph
(CO)3
C C
Ph H W(η 5-Cp*)F
(OC)3Ru (OC)3Ru Ru
C C O
O
Ru W(η5-Cp*) O
(CO)3 Ru
Ru O (OC)3
R2NP (CO) Ru(CO)2
2 P
Ru
(CO)2 NR2
10 11
Mixed-metal clusters <1998JOM(559)157, 1999JOM(582)252, 1999OM3164, 2000JOM(616)140,

2000OM5032, 2001JOM(628)123, 2001NJC939, 2002OM5066> readily enter the metal
exchange reactions. Thus, linked clusters 12 (R = COOEt, Ph) with Na[Mo(CO)3(C5H4R0 )]
(R0 = H, COMe, COOEt, CO-p-C6H4COOMe) give a set of heterometallic species 13
(R = COOEt, R0 = H, COMe, COOEt, CO-p-C6H4COOMe; R = Ph, R0 = COOEt)
<2003JOM(676)55>. Clusters 13 (R = COOEt, R0 = COMe, CO-p-C6H4COOMe) react with
Na[Mo(CO)3(5-Cp)] and produce 13 (R = COOEt, R0 = H) and 14 (R = R0 = H; R = H,
R0 = COMe, CO-p-C6H4COOMe, R = R0 = COMe). Reaction of the clusters 15 (M = Mo, W) with
Ph2PCCBut gives the following products: 16 (M = Mo, W), 17 (M = W), and 18 (M = Mo, W)
<1999JOM(573)180>.
R R
CO O O CO
(OC)3Co Mo C C Mo Co(CO)3
Co CO CO Co
(CO)3 (CO)3
12
R R
CO CO
CO
(OC)3Co Mo R' R Mo Mo R'
Co CO CO Co CO
(CO)3 (CO)3
13 14
MeOOC
COOMe
MeOOC COOMe
PPh2
(η5-Cp)(OC)2M Co(CO)3 (η5-Cp)(OC)2M Co(CO)3
But
15 16
OMe
MeOOC CBut
C
O MeOOC COOMe
(η 5 -Cp)(OC)M Co(CO)2
(η5-Cp)(OC)2M Co(CO)2
P
Ph2 PC CBut
17 18
The 3-CCo2M (M = Cr, Mo, W, Fe, Ni, Ru) and C2CoM (M = Mo, W) clusters are normally
made using the metal-exchange approach <1997POL2387, 1997POL3067, 1997POL3273>.
Thus, cluster 19 reacts with Na[(5-C5H4R)Mo(CO)3] (R = H, COMe, COOEt) to give the
metal-exchange products 20 and 21 (R = H, COMe, COOEt) <1999OM3164>. Cluster 22 with
[Co2(CO)8] gives 23, whose assignment is based on spectral characteristics <1996ICA(245)143,
1996POL4117, 1998JOM(568)157, 1998JOM(570)71> and X-ray structural determination
<1999OM3164>.
HC C(CH2)5C CH HC C(CH2)5C CH
Co Co Co Co Co Co Co Mo(η 5-C5H4R)
(CO)3 (CO)3(CO)
( )3 (CO)3 (CO)3 (CO)3(CO)3 (CO)2
19 20
HC C-(CH2)5-C CH HC C(CH2)5C CH
Co Mo Co Mo(η5-C5H4R) (η5-C5H4R)M o Mo(η 5-C5H4R)

(CO)3 (CO)2 (CO)3 (CO)2 (CO)2 (CO)2
(η -C5H4R)
5
21 22
HC C-(CH2)5-C CH
(η 5 -C5H4R) Mo Mo Co Co
(CO)2 (CO)2 (CO)3 (CO)3
(η -C5H4R)
5
23
Anionic carborane complex [(5-Cp*)Co(Et2C2B3H4)]– with [Mo(CO)4Cl(-Cl)]2 gives triple-

decker and tetradecker species 24 [MLn=Mo(CO)4, M0 Ln0 =Co(5-Cp*), R1 = R2 = R3 = H,
R4 = R5 = Et] and 25 [MLn¼M00 L00 n¼Co(5-Cp*), M0 ¼Mo(CO)2, R1 = R2 = R3 = H,
R4 = R5 = Et], respectively <1998IC102>. Compound 25 [MLn¼M00 L00 n¼Co(5-Cp*),
M0 ¼Mo(CO)2, R1 = R2 = R3 = H, R4 = R5 = Et] is the only product of the interaction of
[(5-Cp*)Co(Et2C2B3H4)]– and [Mo(CO)4Br(-Br)]2 but the triple-decker species is not formed
<1998IC102>. The reaction of the same cobalt precursor with [W(CO)4Br(-Br)]2 gives the
tungsten analog of 24 [MLn¼W(CO)4, M0 L0 n¼Co(5-Cp*), R1 = R2 = R3 = H,
R4 = R5 = Et]. Complex 24 [MLn¼Mo(CO)4, M0 L0 n¼Co(5-Cp*), R1 = R2 = R3 = H,
R4 = R5 = Et] with phenyllithium in the presence of trimethyloxonium tetrafluoroborate in
toluene gives 24 [MLn¼Mo(CO)4, M0 L0 n¼Co(5-Cp*), R1 = PhCH2,
2 3 4 5 5 –
R = R = R = R = Et]. nido-[( -Cp*)Co(Et2C2B3H4)] , and CpTaCl4, Cp*TaCl4, and
CpNbCl4 yield the triple deckers 24 [MLn¼Co(5-Cp*); M0 L0 n¼MXX0 (5-C5R5) (M = Ta,
R = H, Me, X = X0 = Cl; M = Mo, R = H, X = X0 = Cl); R1 = R2 = R3 = H; R4 = R5 = Et]
as the main products. Upon reaction with an alkylating or arylating agent, complex 24
[MLn¼Co(5-Cp*); M0 L0 n¼MXX0 (5-C5R5) (M = Ta, R = H, X = X0 = Cl);
1 2 3 4 5
R = R = R = H; R = R = Et] undergoes the following transformations: with Me2Zn or
AlMe3 to 24 [MLn = Co(5-Cp*); M0 L0 n = MXX0 (5-C5R5) (M = Ta, R = H, X = Me,
X0 = Cl); R1 = R2 = R3 = H; R4 = R5 = Et], with MeLi or MeMgBr to 24 [MLn¼Co(5-Cp*);
M0 L0 n = MXX0 (5-C5R5) (M = Ta, R = H, X = X0 = Me); R1 = R2 = R3 = H; R4 = R5 = Et],
with Zn(CH2Ph)2 to 24 [MLn¼Co(5-Cp*); M0 L0 n¼MXX0 (5-C5R5) (M = Ta, R = H,
X = PhCH2, X0 = Cl); R1 = R2 = R3 = H; R4 = R5 = Et], under PhCH2MgBr to 24
[MLn¼Co(5-Cp*); M0 L0 n = MXX0 (5-C5R5) (M = Ta, R = H, X = X0 = PhCH2);
R = R = R = H; R4 = R5 = Et], with Np2Mgdioxane to 24 [MLn = Co(5-Cp*);
1 2 3
M0 L0 n = MXX0 (5-C5R5) (M = Ta, R = H, X = ButCH2, X0 = Cl); R1 = R2 = R3 = H;

R4 = R5 = Et], and with NpLi to 24 [MLn¼Co(5-Cp*); M0 L0 n¼MXX0 (5-C5R5) (M = Ta,
R = H, X = X0 ¼ButCH2, X0 = Cl); R1 = R2 = R3 = H; R4 = R5 = Et]. Treatment of 24
[MLn¼Co(5-Cp*), M0 L0 n¼TaCl2(5-Cp), R1 = R2 = R3 = H; R4 = R5 = Et] with N-bromo-
or N-iodosuccinimide gives 24 [MLn¼Co(5-Cp*); M0 L0 n¼TaCl2(5-Cp); R1 = R2 = R3 = Cl,
Br; R4 = R5 = Et] <2000OM2200>. Reaction of the anionic sandwich 26 [MLn¼Co(5-Cp*),
R1 = R2 = R3 = H, R4 = R5 = Et] taken as its lithium salt with [(5-Cp*RuCl]4 gives the triple-
decker species 24 [MLn = Ru(5-Cp*), M0 L0 n¼Co(5-Cp*), R1 = R2 = R3 = H, R4 = R5 = Et]
<1997JOM(536)115>. Sandwich nido-[(5-Cp*)Ir(2,3-Et2C2B3H5)] enters the reaction of bridge
deprotonation with n-butyllithium, and further treatment with [(5-Cp*)IrCl2]2 leads to the triple-
decker species 24 [MLn¼M0 L0 n¼Ir(5-Cp*), R1 = R2 = H, R3 = Cl, R4 = R5 = Et]
<1996IC7027>. The heterobimetallic cobalt–iridium analog 24 [MLn¼Ir(5-Cp*),
M0 L0 n¼Co(5-Cp*), R1 = R2 = H, R3 = Cl, R4 = R5 = Et] derives from the anionic nido-
[(5-Cp*)Co(Et2C2B3H4)]– and [(5-Cp*)IrCl2]2.
MLn
R4
BR3
BR2
R5 B1
R
M' –
MLn R4 MLn
R4 BR 3 R4
BR3 BR3
2 5
BR2
BR R B BR2
R5 B R1 R5 B
R1 M'Ln' M''L''n R1
24 25 26
The reaction of [M(CO)5(1-DPPM)] (M = Cr, Mo, W) with [Pt(CH2CH2)(PPh3)2] leads to

the formation of the heterodinuclear complexes [(OC)4M(-CO)(-DPPM)Pt(PPh3)] (M = Cr,
Mo, W) <2003JOM(684)216>. With CF3NC, p-MeC6H4SO3CH2NC, (PPh3CH2NC)(PF6), the
complexes with the bridging isocyanide moiety, [(OC)4M(-C¼NR)(-DPPM)Pt(PPh3)]
(M = W, R = CF3; M = Cr, Mo, W, R = CH2SO2C6H4Me-p; M = W, R = (CH2PPh3)(PF6)).
For isocyanides PhCH2NC, CyNC, and (EtO)2POCH2NC, complexes containing terminal iso-
cyanide ligand result [(RNC)(OC)3W(-CO)(-DPPM)Pt(PPh3) (R = CH2Ph, Cy, CH2PO(OEt)2).
Interaction of [M(CO)5(1-(Ph2PNHPPh2)] (M = Mo, W) gives species 27 (M = Mo, W)

<1999OM248>. The products react with p-tosylmethylisonitrile to yield 28 (M = Mo, W).
On protonation using HBF4, the cationic species 29 (M = Mo, W) evolves. Further interaction
of the tungsten complexes with 2,6-xylylisonitrile and benzylisonitrile gives the substitution
products 30 (R = 2,6-xylyl, benzyl).
H H
N N
Ph2P PPh2 Ph2P PPh2
(OC)4M Pt(PPh3) (OC)4M Pt(PPh3)

C C
O
27 N(CH2)SO2C6H4Me-p
28
H H
N N
Ph2P PPh2 Ph2P PPh2
(OC)4M Pt(PPh3) (OC)3(RNC)M Pt(PPh3)

C C
NH(CH2)SO2C6H4Me-p NH(CH2)SO2C6H4Me-p
29 30
Reaction of [(5-Cp)(Mn(CO)2(¼C¼C(Ph)H)] with [Pt(PPh3)2] gives the mixed metal dinuclear

cluster 31 (L = PPh3), which can be converted into 32 (L2 = DPPM) by a ligand substitution reaction
with diphenylphosphinomethane. Interaction of the manganese–platinum cluster with [Fe2(CO)9]
gives rise to the tetranuclear iron–platinum cluster 32 and a couple of trinuclear manganese–iron–
platinum clusters, 33 and 34 <1996JOM(524)81, 1998RCB531, 1999JOM(577)238>.
Ph
H
Ph H C
C
(η 5-Cp)(OC)Mn PtL2 (dppm)Pt Fe(CO)3
Fe Fe
O (CO)3 (CO)3
31 32
Ph Ph
H H
C C P(=O)Ph2
C C PPh2
CO
(η 5-Cp)(OC)Mn Pt (η 5-Cp)(OC)Mn Pt
PPh2 CO
C C
O Fe P O Fe
(CO)2 Ph2 (CO)3
33 34
Electrophilic carbyne manganese and rhenium complexes of composition [(5-Cp)

(OC)2MCPh](BBr4) (M = Mn, Re) react with [Fe2(-CO)(-SeBun)(CO)6]–, [M3(CO)11]2–
(M = Ru, Os), or [Fe4(CO)13]– to yield various trimetal bridging carbyne species <2000OM72,
2001OM2226, 2002CCR(231)109, 2002OM2764>. The manganese carbyne complex [(5-Cp)

(OC)2MnCPh](BBr4) with [(Ph3P)2N][Rh(CO)4] gives the tetranuclear and pentanuclear clus-
ters 34 (M = Mn) and 35 (the presence of the chlorine bridge is due to the contaminants in the
rhodium reagent) <2003OM4369, 2004ICA(357)864>. Rhenium analog also forms 34 (M = Re)
but together with a tetranuclear cluster 36 <2003OM4369>.
(η5-Cp) (η5-Cp)
OC M CO Ph Ph OC Mn CO Ph
C C C
(OC)2Rh Rh M(η5-Cp) (η5-Cp)(OC)Mn Rh Rh Mn(η5-Cp)(CO)
C C C
C O O C Cl O
Ph Ph
34 35
C
(CO)2
(η5-Cp)Re Rh Rh(CO)
OC
Rh C C
(CO)2 O O
36
Cluster [(4-C¼C)Fe2Ru2(5-Cp*)2(CO)10] formally illustrated as 37 reacts with -chloropropionic

acid via the route of addition to the ruthenium–ruthenium bond to yield the -hydrido--carboxylato
complex [(4-C¼C)(-H)(-1:1-MeCHClCOO)Fe2Ru2(5-Cp*)2(CO)8] <2003OM3055>. The
same starting complex on irradiation with diphenylphosphinomethane and diphenylphosphinoethane
gives the products of ligand substitution, [(4-C¼C)Fe2Ru2(5-Cp*)2(CO)8(-Ph2P(CH2)nPPh2)]
(n = 1, 2). The product with n = 1 is protonated by HBF4OEt2 to yield [(4-CCH)Fe2Ru2-
(5-Cp*)2(CO)7(DPPM)](BF4), which can be schematized in an abbreviated form as 38. The latter
can be reduced using NEt4BH4, and the reaction is followed by transformation of the tetranuclear
cluster to the trinuclear species [(3-CCH)FeRu2(5-Cp*)(CO)5(DPPM)], while the reaction with
diphenylsilane gives [(3-HCCH)FeRu2(5-Cp*)(CO)5(DPPM)] formally depicted as 39.
+
H Fe H H
C C C C
Fe Fe
C Fe Ru Fe Ru
C
Ru Ru
Ru Ru H
37 38 39
Species 40 considered in the previous chapter further reacts with [Ru3(CO)12] to give the mixed-
metal ruthenium–osmium cluster 41 <1999JOM(578)103>.
Me3Si SiMe3
C C Me3Si SiMe3
C C C
C
C C C C
O C C
C
(OC)3Ru Os(CO)3
(OC)3Os Os(CO)3
Os Os Os
(CO)3 (CO)3 (CO)3
40 41
The lithium salt of C5H5BMe– with [(5-Cp*)Fe(acac)]x gives [(5-Cp*)Fe(6-C5H5BMe)]

<1996OM5236> along with [Fe(5-Cp*)2] and [Fe(6-C5H5BMe)2]. Further reaction of this
sandwich with [(5-Cp*)Fe(AN)3] or [(5-Cp*)Ru(AN)3](CF3SO3) (AN = acetonitrile) gives
the stacking cationic products 42 (M = Fe, Ru; n = 1). With [(5-Cp*)M(MeNO2)x]2+
(M = Rh, Ir), 42 (M = Rh, Ir; n = 2) is formed. Interaction of [(4-COD)Rh(6-C5H5BMe)]
with [(4-COD)Rh(solv)x]+ gives the triple-decker species [(-6-C5H5BMe){Rh(4-COD)}2]+
(solv = CH2Cl2, MeNO2) <1996OM5236>. The scope of the triple-decker species was broadened
to [(5-Cp*)Fe(-6-C5H5BMe)MLn]2+ (M = Co, Ln = 5-Cp*; M = Rh, Ir, Ln = 5-Cp;
M = Ru, Ln = C6H6, 1,3,5-C6H3Me3, C6Me6) <2002JOM(649)136>.
2+
η5-Cp*
Fe
B Me
M
η5-Cp*
42
The effect of the presence of two or more different metals in the heteronuclear clusters is
attractive in homogeneous catalysis <1998MI1, 1999MI1>. An example is the application of the
clusters [HMCo3(CO)12] (M = Fe, Ru) <1996JMRC689> in ligand substitution chemistry by the
phosphine ligands. On reaction with cyclohexylphosphine, the iron complex gives 43, while
the ruthenium analog provides 44 <1999OM4908>. They both slowly transform into 45
(M = Fe, Ru) along with [MCo2(3-PCy)(CO)9] in methylene chloride.
(CO)3 (CO)2(PCy2H)
Fe Ru
O O
C C
(OC)3Co Co(CO)2(PCyH2) (OC)3Co Co(CO)3
H H
C Co C Co
O (CO)2 O (CO)2
43 44
(CO)2
OC Co
(OC)2
Co
(OC)2Co M(CO)3
Co
OC
(CO)2
P
Cy
45
The methylene-bridged species 46 <1999JA2613> can be protonated by triflic acid at 80 C

to yield 47, where the methylene group has been transformed to the methyl moiety strongly bound
to osmium but retaining weak bonding to the rhodium site <2003OM2638>. As the temperature
is increased to 40 C, the dication is transformed to another dicationic species 48 with two
bridging carbonyls. Upon warming to room temperature, the latter experiences transformation to
a monocationic heterodinuclear complex 49. The methylene-bridged iridium–ruthenium and
rhodium–ruthenium species are of interest in terms of their activity in Fischer–Tropsch catalysis
<2001OM88, 2002OM3228>. Thus, the rhodium–ruthenium complex 50 <2002OM3228> under-

goes loss of the bridging carbonyl in the presence of trimethylamine N-oxide to yield 51
<2003OM2944>. The latter interacts with a number of acetylenes RCCR0
(R = R0 = COOMe, CF3, COOEt; R = Me, R0 = CH(OEt)2, CH2OH) to yield [RhRu(CO)3-
{-1:1-C(R)¼C(R0 )CH2)(-DPPM)2](CF3CO3), of which the one with R = R0 = COOMe was
decarbonylated in the same manner to afford 52 (R = COOMe) <1999OM4134, 2003OM2944>.
Complex [RhRu(OTf)(CO)2{-1:1-C(COOMe)¼C(COOMe)(-DPPM)2] enters the reaction
with diazomethane to give the mixed-bridged derivative 53 (R = COOMe) <2003OM2944>.
[(OC)Rh(-DPPM)2Ir(CO)2(Me)](CF3SO3)] on reaction with phosphines gives [(R0 R2P)Rh-
(-DPPM)2(-CO)2Ir(CO)(Me)](CF3SO3) (R = R0 = Me, OPh; R = Me, R0 = Ph; R = OMe,
R0 = Ph) <1999OM1629>. Reaction of ethylene with [HIrRu3(CO)12] gives the ethylidyne cluster
[HIrRu4(CO)15(4-CMe)] where the hydrocarbon is coordinated to the four ruthenium atoms via
the carbon site <1999ICCC60>.
+ 2+
Ph2P PPh2 Ph2P PPh2

H2
H C
(OC)Rh Os(CO)2 (OC)Rh Os(CO)2
Ph2P PPh2 Ph2P O PPh2

O
46 47
2+ +
Ph2P O PPh2 Ph2P Me PPh2

O
(Me)Rh Os(CO)2 Rh Os
TfO
Ph2P PPh2 Ph2P O PPh2
O
48 49
+ +
Ph2P PPh2 Ph2P PPh2
(OC)Rh Ru(CO)2 (OC)Rh Ru(CO)2
Ph2P PPh2 Ph2P PPh2

O
50 51
+
R
R
H
Ph2P PPh2 Ph 2P PPh2
H
(OC)Rh Ru(CO)2 (OTf)Rh Ru(CO) 2
Ph2P PPh2 Ph2P PPh2
52 53
Refluxing [Os3Rh(-H)3(CO)12] in toluene in the presence of a hydride acceptor (4-vinylphenol)

gives [Os3Rh4(-1,1,1-PhMe)(CO)13] <2003AG(E)1935>, a rare coordination mode. The
dianionic cluster [Os5C(CO)14]2– reacts with [(5-Cp*)RhRh(5-Cp*)]2+ and forms the
mixed-metal osmium–rhodium cluster 54 <2003ICC733>. A related cluster is [Os5PdC(CO)12-
(-CO)2(PPh3)2] <1998JCLS417>.
(OC)3Os Rh(η5-Cp*)
(OC)3Os Os(CO) 3 CO
C
(OC)3Os Os
(CO)2
54
The iron complex [(5-Cp*)(OC)2FeCCCCH] reacts with [(OC)3CoMo(5-Cp)(CO)] to

yield 55 <1999JCS(CC)101, 1999OM4684, 2003JOM(670)2>. Interaction of the species similar
to 55, where instead of the Mo(CO)(5-Cp) moiety there is the Co(CO)3 group, with [Fe2(CO)9]
leads to the elimination of the Co(CO)4 moiety and formation of 56. Cluster 57 with [Fe2(CO)9]
forms a mixture of products 58 and 59 <1998CRV2797>. Thermolysis of 56 after a complicated
chain of rearrangements gives cluster 60. The related example is [(5-Cp*)FeCo2Ru(CO)10(4-
C2H)] <1998JA11071>. Two moles of [(5-Cp)Co(PPh3)2] interact with [(OC)2Fe(PPh3)2(2CSC)]
to yield the mixed-metal cluster 61 <1998JOM(551)139> and with [(OC)2Fe(PPh3)2(2-SCNR)] to
produce 62 (CX, CY = CO, CNR) <1999JOM(573)109>. Reaction of [Fe2(CO)9(-CO)(3-2-
C¼C(C6H10))] and [Co3(CO)9(3-CCH2(C6H10OH))] with ethynylcyclohexanol leads to the
formation of [Co2Fe(CO)6(-CO)(3-7-(C6H9)CC(H)C(H)C(H)(C6H10))] <2001JCS(D)1485>.
Clusters [(5-Cp)3Co3(3-S)(3-CNR)] when treated with [Fe(CO)2(PPh3)2(2-SCX)] give the
heterotrinuclear products [((5-Cp)Co)2Fe(CO)2(PPh3)(3-S)(3-CX)] (X = S, SR+, NR;
R = Me, Et) <1998JOM(551)139, 1999JOM(573)109>. Cluster 62 interacts with RI or ROTf
(R = Me, Et) to produce the cationic species 63 with Y = +SR. This reaction can be reverted
using R0 O– (R = H, Me, Et) <2003ICA(354)54>.
(η 5-Cp*)(OC)2FeC CC C
(η5-Cp*)(OC)2FeC CC CH
(OC)3Fe Co(CO)3
(OC)3Co Mo(η 5-Cp)(CO)
55 (OC)3Fe
56
(OC)3Co Co(CO)3
O C C
(OC)3Co Co(CO)3
C C C H
(η 5-Cp*)(OC)2FeC CC CH (η 5-Cp*)(OC)2Fe Fe Co(CO)3
C Co
(OC)3Co Co(CO)3 O C (CO)3
O
57 58
(CO)3
Co H
H (η 5-Cp*)Fe C Fe(η 5 -Cp*)
C
O C C Co(CO)3 C C
C C Co
(CO)3Co Co (CO)2 Co
Co (CO)3 (CO)3
(η 5-Cp*)(OC)Fe Co (CO)3
(CO)2 Co
Fe
(CO)3 (CO)3
C 60
O
59
R
S Y +
C C S
C
(η5-Cp)Co (η5-Cp)Co
(η5-Cp)Co
Fe(CO)2(PPh3) Fe(CO)(CX)(PPh3)
(η 5-Cp)Co (η5-Cp)Co Fe(CO)2(PPh3)
(η5-Cp)Co
S S
61 62 S
63
The ferrocenyl derivatives R2Si(CCFc)2 (R = Me, Ph) with excess [Co2(CO)6] give species
64 (R = Me, Ph) and 65 (R = Me, Ph) <1999JOM(573)36>, manifesting the role of ferroce-
nylethynyl complexes as templates for long-range electronic communication <1996ICA(247)99,
1996OM3935, 1997CRV637>.
Fc Fc
(OC)3Co
Co(CO)3
R2Si Co(CO) 3 R2Si
Co(CO)3
(OC)3Co
(OC)3Co Fc Fc
64 65
Homogeneous cluster 66, when reacted with [Fe(CO)5] at elevated temperatures in acetone,
forms the mixed-metal complex 67 <1999OM3372>. The same type of reaction relates clusters 68
and 69. The analogous structure [CoFe(CO)6(HC¼C¼CR2)] is known <1998OM4992>.
Ph
Ph
Ph
HO OH Ph
C C C C
(OC)3Co Co(CO)3 (OC)3Co Fe(CO)3 Me 3SiC Co(CO)3 Me3SiC Fe(CO)3
C C Co Co
SiMe3 (CO)3 (CO)3
SiMe3
66 67 68 69
Sandwich 70 reacts with [(2-C2H4)2RhCl] to give the tetranuclear product 71 formulated as a

penta-decker species with two central bridging chlorine atoms <1999EJI1685>. Excess 2-vinyl-
pyridine with [Os3Rh(-H)3(CO)12] gives product 72 <2003ICC174>.
η 5-Cp*
Ru(η5-Cp*) Ru
Me
BMe Me
BMe
Me B Me Me B Me
Me
Me
RhCl 2
70 71
N
(OC)3Os
H
OC Rh H
(OC)3Os Os(CO) 3
H Os H
(CO)3
72
The mixed cluster [PtRu5(CO)15(6-C)(-CO)] <2000JCS(CC)937> enters ligand-substitution

reactions <2003IC3111>. With dimethylphenylphosphine, it gives [PtRu5(CO)14(PMe2Ph)(6-C)
(-CO)] and [PtRu5(CO)13(PMe2Ph)2(6-C)(-CO)], both retaining the structure of an octahedral
Ru5Pt cluster with the carbide site in the center of the base. Trimethylphosphine also gives two
substitution products, while with Me2S only the product of monosubstitution is obtained. A
similar structure was observed for [PtRu5(CO)13(DPPM)(6-C)(-CO)] <1998OM3020>. The
cluster [PtRu5C(CO)16] reacts with methanolic potassium hydroxide to give the dianionic species
[PtRu5C(CO)15]2– <2003JCS(D)2651>. The product obtained as the (Ph4P+)2 salt, when reacted
with [Au(PPh3)Cl] in the presence of thallium hexafluorophosphate, leads to [PtRu5C-
(CO)15(AuPPh3)2], similar in structure to that of [Ru6C(CO)16(AuPR3)2] (R3 = Ph3, MePh2)
<1996JOM(518)121>. With [Pt(4-COD)Cl2] in the presence of silica, [Pt2Ru4C(CO)13(4-cod)]
follows <2003JCS(D)2651> with the structural arrangement similar to that in
[Pt2Ru10C2(CO)28]2– <2003EJI1325> and [PtRu5C(CO)11(2-dppe)(3-2,2,2-C60)]. The
Ru = Pt clusters are active catalysts of hydrogenation <2001AG(E)4638>. [PtRu5(CO)16(6-C)]
when reacted with [Pt(PBut3)2] and [Pd(PBut3)2] gives [PtRu3(CO)6(6-C)M(PBut3)] (M = Pt, Pd)
and [PtRu3(CO)6(6-C)M(PBut3)2] (M = Pt, Pd) <2003JOM(682)113>.
The iron–platinum-bridged Ph2PNHPPh2 isonitrile complexes have received attention
<1998EJI495>, e.g., [(OC)3Fe(-CNR)(-dppa)Pt(PPh3)]. The mixed-metal complex [(OC)3Fe-
(-CO)(-DPPM)Pt(PPh3)] reacts with PO(OEt)2CH2NC to give the product with the isocyanide
bridge, [(OC)3Fe(-C¼NCH2PO(OEt)2)(-DPPM)Pt(PPh3)] <2003JOM(684)216>.
The ferrocenyl species [(5-Cp)Fe(5-C5H4)CH¼N(CH2)2NMe2] reacts with Na2[PdCl4] in the
presence of sodium acetate trihydrate in methanol to yield the mixed-metal cluster 73
<1999JOM(577)292>. With triphenylphosphine in benzene, the latter gives 74, and with addi-
tional triphenylphosphine in deuterochloroform it gives 75.
H H NMe2 H NMe2
C N C N C N
Pd NMe2 Pd Cl Pd(PPh3)2Cl
Fe Cl Fe PPh3 Fe
73 74 75
An interesting class of multinuclear complexes results when two different transition metals
interact through the cyclopentadienyl ligand in a 5:1 manner, e.g., ferrocenyl platinum com-
plexes <1996JOM(511)47>. Trimethylstannylruthenocene and 1,10 -bis(trimethylstannyl)rutheno-
cene react with [(4-COD)PtCl2] in THF to yield 76 and 77, respectively <1999JOM(574)66>.
Using ligand-exchange reactions, a series 78 (X = Cl, Br, NCS) was prepared. On reaction with
acetylenes, RCCR (R = COOMe, COOEt), some of the species 78 give 79 (X = Cl,
R = COOMe; X = Br, R = COOMe; X = Cl, R= COOEt).
Pt(PEt3)2X
Pt(η4-COD)Cl Pt(PEt3)2X H
Pt(η4-COD)Cl
R R
Ru Ru Ru Ru
Pt(η4-COD)Cl
76 77 78 79
Reaction of [(5-Cp)(OC)2RuCH2CCPh] with [Pt(PPh3)2(C2H4)] gives 80 <2000OM3179,

2002ICC82>. A similar complex [(5-Cp)(OC)2Ru(-1:2-CH¼C¼CH2)Pt(PPh3)2] enters a
simple ligand substitution reaction with t-butyl isonitrile to yield [(5-Cp)(OC)2Ru(-1:2-
CH¼C¼CH2)Pt(PPh3)(ButNC)] <2000JOM(593)465>. Hydration reaction is a nucleophilic
process <2000ICA(307)1>. Reaction of [(5-Cp)(OC)2Ru(-1:2-CPh¼C¼CH2)Pt(PPh3)
(ButNC)] with the electrophilic agent, (p-Tol)SO2N¼C¼O, is a [3 + 2]-cycloaddition reaction
affording 81 <2000JOM(593)465>. [(5-Cp)(OC)2Ru(-1:2-CH¼C¼CH2)Pt(PPh3)2] reacts
with [Au(PPh3)]+ (R = Ph, H) and forms the 3-allyl complexes <2000JCLS233>. The
Pt(PPh2)2 diphenylbutadiyne complex with [Fe(CO)5] or [Ru3(CO)12] gives [Pt2M(PhC2C2Ph)
(CO)5(PPh3)2] (M = Fe, Ru) <1998OM775>.
O
H2C ToNs
C CPh
Ph
(η5-Cp)(OC)Ru Pt(PPh3) 2 η5-Cp)(OC)Ru
( Pt(PPh3)(Bu t NC)
80 81
[Rh2Co2(CO)12] reacts with alkynes to yield [Rh2Co2(CO)10(4,2-R1CCR2)]

<2002JOM(650)181>. The reaction of the same cluster with a series of dialkynes where the
alkyne groups are separated, HCCH2O-R-OCH2CCH (R = C6H4-1,4-(C(O))2,
(C(O)CH2)2, (C(O)CH)2, (C(O))2CH2,(C(O))2, leads to the linked clusters 82 with the same set
of R groups <2003JOM(681)275>. Compounds [M(CO)4(2-alkyne)] are used to obtain the
alkyne-bridged heterometallic species of iron, ruthenium, or osmium and cobalt, rhodium, or iridium
<2000OM2766>. [RhIr(CO)3(DPPM)2] oxidatively adds MeOCH2I to yield [RhIr(CH2OMe)(I)
(CO)(-CO)(DPPM)2] <2000OM854>. Methyl triflate causes iodine abstraction and formation of
[RhIr(CH2OMe)(CO)(-CO)(DPPM)2](CF3SO3).
(CO)2 (CO)2
OC Co Co OC
(OC)2 (OC)2
Rh Rh
(OC)2Rh CCH2OROCH2C (OC)2Rh
C C
H H
OC OC
Co Co
(CO)2 (CO)2
82
Triplatinum dicationic clusters [Pt3(3-CO)(-DPPM)3](PF6)2 react with [Ir(CO)4]– and

[Re(CO)5]– to yield the mixed-metal species, e.g., 83 <1997POL3861, 1998OM2433>. Product
83 decarbonylates to yield 84 and then 85. Similarly, with H[Ru(CO)4]–, cluster 86 is formed,
which slowly transforms to 87 <1999OM3737>. The reaction of [Pt(DPPM)2]Cl2 with
(PPN)[Ir(CO)4] gives cluster 88 <1999OM2162>. o-Bis(phenylethynyl)benzene with [Pt2Ru4-
(CO)14(CO)18] gives [Pt2Ru4(CO)14(5-C6H4(C2Ph2)2)] with two PtRu2 triangles <1999ICC1>.
The rhodium and iridium dimers [(4-COD)M(-Cl)]2 (M = Rh, Ir) react with the anionic
platinum complexes A[cis-Pt(C6F5)2(CCR)2] (A = PPh3Me, R = Ph; A = NnBu4, R = But,
SiMe3) to yield 89 (R = But, SiMe3), 90 (R = Ph, But, SiMe3), and 91 <1999OM4344>.
+
(CO)4
Ir CO +
O
C Ir
Ph2 Ph2 CO
P P Pt
Ph 2 Ph Ph2
P Pt P 2 Pt P
Ph2
Pt P P Pt CO
Ph2
P Pt P
Ph2 C Ph2
O P
Ph2 84
83
+ (CO)4 +
O Ru
C Ph2
Pt
Ph2 Ph2 P
CO Ph
P Pt P Ph2 P 2
Ph2 P Pt H
Ir P Ph2
P Pt Pt P
Ph2 C PPh2 P Pt
O Ph2
P P
Ph2 Ph2
85 86
+
O (CO)3 O
C Ru C O
Ph2 C
Ph2 Ph2
P Ph2 P
Ph2 P P
P Pt H Pt
Ph2
Pt P Ph2P PPh2
P Pt Ru Ru
Ph2 H (CO)3 (CO)2
P
Ph2
87 88
η4-COD
Rh
C CR C CR C CSiMe3
(C6F5)2Pt Cl (C6F5)2Pt Rh(η4-COD) (C6F5)2Pt
C CR C CR Ir(η4-COD)
Me3SiC C
Rh 90
η4-COD 91
89
The palladium 3-allenyl complex [(C6F5)(Ph3P)Pd(3-(But)C¼CH2)] reacts with

[Pt(PPh3)2(C2H4)] to yield the binuclear mixed-metal product 92 <1998JA1938>. Palladium
dimer [Pd(-Cl)(3-C3H5)]2 interacts with A[cis-Pt(C6F5)2(CCR)2] (A = PPh3Me, R = Ph;
A = NnBu4, R = But, SiMe3) to yield the heterodinuclear cluster [cis-Pt(C6F5)2-
(-CCR)2Pd(3-C3H5)]– (R = Ph, But, SiMe3) <1996OM4537>. Similar transformations are
known <1997AG(E)606, 1998JA6952, 1998OM4578>.
(PPh3)2Pt
C
t-BuC CH2
Pd(C6F5)(PPh3)
92
4.16.3.2 A Genuine Transition Metal Linked to a Late Transition, i.e., Group 11 (Cu, Ag, Au)
or 12 (Zn, Cd, Hg) Metal
Reaction of [(5-C5H4SiMe3)2Ti(CCSiMe3)2CuSC6H4CH2NMe2-2)] with organic nucleophiles
(R) gives [(5-C5H4SiMe3)2Ti(CCSiMe3)2CuR], where the ethynyl moiety is coordinated to the
copper(I) site in an 2 fashion <1996IC2476, 1996JA4817, 1996SL1>. Titanocene [(5-C5H4Si-
Me3)2Ti(CCR)2] (R = But, SiMe3) and MX (M = Cu, X = SCF3, SEt, SC6H4CH2NMe2-2;
M = Ag, X = COOMe, COOPh, NO3) give products 93 with the relevant sets of R, M, and X
<1997OM4776, 1999OM598>. Products 93 (MX = CuSC6H4CH2NMe2-2, R = But, SiMe3;
R = But, AgX = AgOCOMe, AgOCOPh, AgONO2; R = SiMe3, AgX = AgOCOMe, AgOCOPh,
AgONO2) react with LiR0 (R0 = Me, C6F5, C6H2(CF3)3-2,4,6) or Mg(C6H2Ph3-2,4,6)Br to pro-
duce 93 (R = SiMe3, MX = CuC6F5, CuC6H2(CF3)3-2,4,6, CuC6H2-Ph3-2,4,6, AgC6H2(CF3)3-
2,4,6, AgC6H2-Ph3-2,4,6, AgMe; R = But, CuC6H2-Ph3-2,4,6, CuMe, AgMe). Species 94
(R = SiMe3, MX = AgMe) tends to lose free silane at 10 C and form 95. The arrangement
of the silver-containing part of this heterotetranuclear complex is similar to that in [AgCCR]n
<1996OM639>. Similar examples are described in numerous sources, e.g., <1996JCS(CC)2043,
1996JOM(514)219, 1996JOM(515)57, 1997OM4970>. Species 93 (R = But, MX = CuMe) on
reaction with [(5-C5H4COOH)2Fe] may lose one methane molecule (reactant ratio 1:1) or two
such molecules (reactant ratio 2:1) to yield 96 and 97, respectively <1999OM5725>. Interaction
of 93 (R = Me3Si, MX = CuMe) with the product 96 gives an analog of 97 where half of the
molecule contains t-butylethynyl and half trimethylsilylethynyl moieties. Another product formed
in this reaction is [(5-C5H4SiMe3)2Ti(CCSiMe3)(CCCu)]2 <1999JPRC1>. Copper (I) acet-
ate and benzoate species <1998MI2> are among the related examples. Complexes 93 (M = Cu,
Ag; X = OTf, BF4, ClO4) with Lewis acids, e.g., methyl cyanide, phenyl cyanide, and THF, form
complexes of the types 98 and 99 <1996IC2476>. Species 98 (L = NCMe X = BF4) with
Ph3PAuCN gives 100 <2000OM749>. Reaction of 93 (M = Ag, X = BF4) with Ph3PAuCN
leads to the formation of the neutral complex 101, while reaction of 93 (M = Cu, X = CN)
with [Cr(CO)5(THF)] gives 102.
CR CR
C C
5
(η -C5H4SiMe3)2Ti MX (η5-C5H4SiMe3)2Ti MR'
C C
CR CR
93 94
CSiMe3
C
(η5-C5H4SiMe3)2Ti Ag
C C
C C
Ti(η5-C5H4SiMe3)2
Ag
C
C
Me 3Si
95
CBut
C
(η5-C5H4SiMe3)2Ti CuOOC
C
Fe
CBut
COOH
96
CBut
C
(η5-C5H4SiMe3)2Ti CuOOC
C
Fe ButC
CBut
C
Ti(η5-C5H4SiMe3)2
COOCu
C
t
Bu C
97
CR CR
C C X
(η5-C5H4SiMe3)2Ti Cu L X (η5-C5H4SiMe3)2Ti Ag
C C L
CR CR
98 99
CSiMe3 Me3SiC
C C
(η5-C5H4SiMe3)2Ti Cu N=C-Au-C=N Cu Ti(η5-C5H4SiMe3)2 (OTf)

C C
CSiMe3 Me3SiC
100
CSiMe3
C F.BF3
(η5-C5H4SiMe3)2Ti Ag
C N CAu(PPh3)
CSiMe3
101
CSiMe3
C
(η5-C5H4SiMe3)2Ti CuC N Cr(CO)3
C
CSiMe3
102
Examples of the trinuclear 103 and pentanuclear 104 (M = Cu, X = PF6; M = Ag, X = SbF6)
complexes are remarkable, since these compounds do not contain metal–metal bonds
<1999CEJ745, 2003AG(E)1794>. Dianionic cluster [Fe3(CO)9(CCO)]2– with [Re(CO)5]– gives
[Fe3(CO)9CCRe(CO)5]– <1996OM3916>.
(OC)5Re Re(CO)5
(OC)5Re Re(CO)5
(SbF6) M X
Au(PPh)3
(OC)5Re Re(CO)5
103 104
Reaction of [Ru3(-H)(3-C2CPh2(OH))(CO)9] with K(BHBus)3 and then [AuCl(PPh3)] gives

the heterohexanuclear Au3Ru3 cluster 105 <1996OM394, 1999ICC453>. Similar cases were
analyzed <1997JOM(545)207>.
PPh3
Au (CO)3
Ph3PAu AuPPh3
Ru
(OC)2Ru Ru(CO)3
O
C C
HC
O
CPh2
105
Heteropolynuclear clusters can be prepared by oxidizing homonuclear species with copper (I),
silver (I), and gold (I) salts <1999CCR(193)619>. Thus, the reaction of [(5-Cp)3Co3(-CPh)2]
with silver acetate and silver nitrate yields [(5-Cp)3Co3(3-CPh)2(-AgX)] (X = CF3COO, NO3)
<2004JOM(689)146>. When silver tetrafluoroborate or silver hexafluorophosphate in acetonitrile
are used, the adduct has the composition [(5-Cp)3Co3(3-CPh)2(-Ag(AN)]+.
Cationic species PtAu+ generated from the respective metal alloy dehydrogenates methane to
produce the mixed cluster of composition [PtAuCH2]+ <2003JA3676>. The product appeared to
be an efficient mediator of the coupling reaction between methane and ammonia to produce
hydrogen cyanide and molecular hydrogen.
4.16.3.3 Two Late Transition Metals

No new substantial data are found since the publication of COFGT (1995).
4.16.3.4 A Transition Metal and a Group 13 or 14 Metal

4.16.3.5 A Transition Metal and Other Metals


(AND NO GROUP 1, 2, OR TRANSITION METAL)
The titanium–aluminum carbide clusters are stable <2000AG(E)3263, 2001OM3209,
2002JA11486> including [(5-Cp)Ti(-Me)(-NPMe3)(4-C)(AlMe2)3] <2001OM1175>. The
reaction mixture consisting of [(5-Cp)2ZrMe2], (CPh3)(B(C6F5)4), and excess trimethylaluminum
gives the heterodinuclear cationic cluster [(5-Cp)2Zr(-Me)2AlMe2]+ containing two bridging
methyl groups <2000MCP581, 2003JOM(677)10>. The other aluminum-containing anions
following from CH activation are the result of an interaction between trimethylaluminum and
[(5-Cp*)CrCl2]2 <2003OM1992>. They have the composition [{(5-Cp*)Cr}4(-Cl)3(-CH2)4-
AlMe] [(Me2Al)(3-O)(AlCl2Me)(AlMe2Cl)].
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Biographical sketch
Alexander P. Sadimenko was born in Rostov-on-Don in 1951, studied at

Rostov State University where he obtained his M.Sc. in 1973 and Ph.D.
in 1976 under the guidance of Professor O. A. Osipov. In 1976–1987
worked as Lecturer, Senior Lecturer, and Associate Professor at Rostov
State University, 1987–1991 as Associate Professor at Addis Ababa
University, 1991–1994 as Associate Professor and Professor at National
University of Lesotho, 1994 up to now Professor, Head of the Depart-
ment, Head of Directorate of Physical and Earth Sciences at the Uni-
versity of Fort Hare. His scientific interests include all aspects of
organometallic chemistry of the heteroaromatic ligands, in particular,
materials chemistry aspect.
4.17
Functions Incorporating
Two Halogens or a Halogen
and a Chalcogen
D. J. St. JEAN, Jr. and G. A. MOLANDER
4.17.1 DIHALO FUNCTIONS: R2C¼C(Hal)2 696

4.17.1.1 Difluoro Alkenes 696
4.17.1.1.1 Elimination reactions 696
4.17.1.1.2 Reactions involving organometallics 698
4.17.1.1.3 Wittig-type reactions 700
4.17.1.1.4 Thermal methods 701
4.17.1.2 Dichloro Alkenes 703
4.17.1.2.1 Wittig and related reactions 703
4.17.1.2.2 Reactions involving dichlorocarbene 704
4.17.1.2.3 Elimination reactions 705
4.17.1.2.4 Miscellaneous reactions 705
4.17.1.3 Dibromo Alkenes 707
4.17.1.3.1 Wittig-type reactions 707
4.17.1.3.2 Miscellaneous routes 712
4.17.1.4 Diiodo Alkenes 713
4.17.1.4.1 Wittig and related reactions 713
4.17.1.4.2 Reactions involving organometallics 713
4.17.1.4.3 Miscellaneous routes 714
4.17.1.5 Mixed Halo Derivatives 715
4.17.1.5.1 Fluoro halo alkenes 715
4.17.1.5.2 Chloro halo alkenes 718
4.17.1.5.3 Bromo halo alkenes 719
4.17.2 FUNCTIONS INCORPORATING A HALOGEN AND A CHALCOGEN:
R2C¼C (Hal)(Chalc) 720
4.17.2.1 Halogen and Oxygen Derivatives 720
4.17.2.1.1 -Fluorovinyl ethers 720
4.17.2.1.2 -Chlorovinyl ethers 721
4.17.2.1.3 -Bromo- and -iodovinyl ethers 722
4.17.2.2 Halogen and Sulfur Derivatives 723
4.17.2.2.1 Fluorovinyl sulfides, sulfoxides, and sulfones 723
4.17.2.2.2 Chlorovinyl sulfides, sulfoxides, and sulfones 724
4.17.2.2.3 -Bromo- and -iodovinyl sulfides, sulfoxides, and sulfones 726
4.17.2.3 Halogen and Selenium or Tellurium Derivatives 727
695
696 Functions Incorporating Two Halogens or a Halogen and a Chalcogen
4.17.1 DIHALO FUNCTIONS: R2C¼C(Hal)2
4.17.1.1 Difluoro Alkenes

Difluoroalkenes can be synthesized using a number of well-defined synthetic procedures. These
methods have been organized into those involving elimination reactions, the use of organome-
tallics (i.e., additions, substitutions, and Pd-catalyzed cross-couplings), reactions using Wittig-type
reagents, thermal reactions, and miscellaneous routes.
4.17.1.1.1 Elimination reactions
(i) Eliminations involving metals in the zero oxidation state

Exposing trifluoromethyl ketones 1 to Mg(0) (with catalytic amounts of I2) results in the formation of
an enolate that can be trapped as its trimethylsilyl (TMS) enol ether 2 (see Figure 1) <1999CC1323>.
Jeong and co-workers reported that 2,3-diaryl-1,1-difluoro-1,3-butadienes 3 (see Equation (1)) could
also be debromofluorinated with Mg(0) to yield difluoro alkenes, presumably through a cyclic transi-
tion state <2001SC2261>. Also utilizing Mg(0), 2-bromo-1,1,1-trifluoroundecane 4 was converted to
1,1-difluoroundeca-1-ene 5 <2002JOC8430, 1996TL3223>.
O OTMS
F3 C R F2C R
1 2
R = Ph, 91%
R = p-MeOC6H4, 89%
R = C6H11, 62%
Figure 1
R1
R1
F
F
F3C Mg (1.5 equiv.), I2 (cat.)
Br Ether, reflux
ð1Þ
R2
R2
3 R1 = R2 = H, 81%
R1 = H, R2 = CH3, 60%
R1 = Cl, R2 = H, 72%
Zinc dust has also been shown to be an efficient reductant for this process. Zinc readily eliminated
Cl2 from 6 (Zn, EtOH, 60 C, 80%) <2000T3539> and ClF from 7 (Zn, DMF, 85%)
<1995CC1969> (see Figure 2).
F3C
C9H19CH(Br)CF3 C9H19CH=CF2 ClF2C CFCl2 BnO CO2Et
Cl
4 5 6 7
Figure 2
Functions Incorporating Two Halogens or a Halogen and a Chalcogen 697
(ii) Elimination reactions utilizing organometallics

Because of their high basicity, organometallic bases have been extensively used to generate
1,1-difluoroalkenes. Organolithiums, especially n-BuLi, are often used to mediate the elimination
of HF from trifluoromethylated compounds. Some representative examples of eliminations using
n-BuLi are shown in Table 1.
Table 1 Eliminations using BunLi to produce 1,1-difluoroalkenes

Substrate Product Reagents Yield (%) References
HOCH2CF3 PMBOCH¼CF2 i.NaH, PMBCl 32 <2002BMCL2353>
ii.BunLi
ROCH2CF3 ROCH¼CF2 BunLi 100 <2001TL6377>
R=(CH3)CH¼CH2
MEMOCH2CF3 MEMOC(SnBu3)¼CF2 BunLi 70 <1995TL9201>
Bu3SnCl
MEMOC(TMS)¼CF2 BunLi TMSCl 79 <1995TL9201>
MEMOCH¼CF2 BunLi NH4Cl 88 <1995TL9201>
(Me2N)2CHCF3 (Me2N)2C¼CF2 BunLi NH4Cl <1997JOC1576>
O F
Cl HOCH2CH(Ph)¼CF2 BunLi 70 <1995CC1857>
Ph F
O F
Cl
HOCH2CH(Bn)¼CF2 BunLi 75 <1995CC1857>
Bn F
OH OLi
BunLi <1999OS151>
F3C CF3 F3C CF2
Lithium diisopropylamine (LDA) has also been used to produce various 1,1-difluoroalkenes.
LDA has been used to make stannane 8 <2000SL963, 1996TL5975>, highly reactive organo-
metallics 9 <1999CC2183, 1995T10289>, vinyl iodide 10, and substituted 1,1-difluoro alkene 11
in high yields <1996SL371, 2000SL963> (see Figure 3). In addition to n-BuLi and LDA,
Grignard reagents have also been shown to defluorinate allylic acetates <1999IJ193>.
OCONEt2 OCbse OCbse OEt

OH
F2C SnBu3 F2C M F2C I F2C
8 9 10 11
M = Li, Mg
O
Cbse = OTBDPS
N
Pri
Figure 3
(iii) Miscellaneous elimination reactions

Certain imines have also been shown to undergo elimination of HX to form difluoroalkenes with
either K2CO3 <2002JCS(P2)1033> or t-BuOLi <2001TA1303> (Equations (2) and (3)).
CF3 CF2
K2CO3
N DMF, ∆ N ð2Þ
Ph Ph
OH OH
CF2Br ButOLi CF2 ð3Þ
–78 °C
N CO2Et quantitative N CO2Et
A variety of other bases have been shown to promote the formation of 1,1-difluoroalkenes via
an elimination pathway. Table 2 provides some stereotypical examples of these elimination
reactions.
Table 2 Miscellaneous eliminations to form 1,1-difluoroalkenes

RCF2OCF(CF3)C(O)F RCF2OCF¼CF2 Na2CO3 <2000JFC(106)13>
R¼C(CF3)(F)OC3F7
F 3C F 3C CF3 CF
CF3 CF F 3
F 3
F F CF2 KF, <2000JFC(104)239>

CF3
F F F
F
CF3CH2PPh2 F2C¼CHPPh2 t-BuOK 75 <1999JFC(97)109>

ClF2CCHIF F2C¼CIF hydrated lithium <1997JFC(83)171>
dibromoplumbite
(TMSF2C)2 F2C¼CFTMS cat. TBAF <1997JA1572>
TMSCH2C=CF2 (i) NaH, CF2Br2
TMSCH2CH(CO2But)
CO2Et (ii) TFA 80 <1996TL5401>
CO2Et
(iii) NaOH
(BrCF2)2CH2 BrF2CCH¼CF2 KOH, 60 C 89 <1997S1481>

35 mmHg
TMS(CH2)2CF2Br TMSCH2CH¼CF2 DBU 70 <1995OS225>
4.17.1.1.2 Reactions involving organometallics
(i) Addition reactions

A number of nucleophilic addition reactions involving metallated difluoroethylenes have been
reported. Organolithiums, organocuprates, and Grignard reagents have been used in nucleophilic
additions involving a wide array of electrophiles (Table 3).
In addition to the organometallics shown in Table 3, Qing and co-workers have shown that
CF3CFBr2 adds to chiral Garner aldehyde 12 in 54% yield with exquisite diastereoselectivity
using Zn dust and catalytic amounts of AlCl3 <1999JCS(P1)3345>. Cuprate 13 added across bis-
trifluoromethylacetylene 14 and, after coupling with I2, yielded fluorinated 1,3-pentadiene 15 in
high yield <1995JFC(72)49>. Burton and co-workers also reported that fluorinated allyl iodide
16 reacted with an eclectic variety of electrophiles in good yield using copper metal
<1998JOC2887> (see Figure 4).
Table 3 Addition of organometallics that produce 1,1-difluoroalkenes

Nucleophile Electrophile Product Yield (%) References
X
O OH X
F2 C X = F, 65a
Li PhO PhO <2000JFC(102)43>
CF2 X = Cl, 32a
X = F, Cl
X
OH
F2 C O
Li X = F, 69a
CF2 <1999CC2535>
X = F, Cl X = Cl, 76a
X
Cl OH
F2C CF2
Li PhCHO Ph 96 <1998JCS(P1)2541>
Cl
TES CF2
TESCl Cl 89 <1998JCS(P1)2541>
O
Cl
HO
R CF2 70 <2000CC2339>
R
R = (CH2)2CO2Et
F
OH
F2C But O But
Li CF2 100b <1999JFC(99)127>
F
OR
RO
F2C Cl
Cu CF2 76 <1996TL5975>
R = CONEt2
OCbsec OH
F2C CbseO
CH3CHO 87 <1999CC2183>
MgBr
CF2
a b c
BF3OEt2 was also used. Isolated as mixture of diastereomers. Cbse = N-[2-(t-butyldiphenylsilyloxy)ethyl-N-isopropylcarbamate.
CHO CF3
F CF3 CF2I
NH F2C F3C CF3 I F2C
O Cu F
F2C
12 13 14 15 16
Figure 4
(ii) Cross-coupling reactions

Fluorinated organozincs have been proven to be excellent partners in Pd-catalyzed cross-coupling
reactions. Zinc reagent 17 (along with derivatives 22 and 23) has been used in cross-coupling reactions
to construct fluorovinylsalicylic acid derivatives (18 and 19) <1995JFC(74)67>, difluorostyrene
derivatives 20 <1997JOC7758>, -bromo-,-difluorostyrenes 21 <1998JOC1714>, and
functionalized protoporphyrins <1999CPB1326, 2000H383, 2000JFC(103)99> in good yields. Bur-

ton has developed a convenient one-pot approach to the synthesis of -chloro-,-difluorostyrenes
<2002TL6979> and ,,-trifluorostyrenes <2002TL2731> using vinylzinc reagents 22 and 23. This
procedure provides a cost-efficient route to these frameworks and is reported to proceed smoothly at
room temperature (rt).
Borane derivatives such as 24 have also been used in cross-coupling reactions, however, only
with moderate success <2002CL282, 1997CC1537, 2001BJC971>. Percy and co-workers, while
probing the reactivity of difluoroenol carbamates 25 (R = I) with arylboronic acids in Suzuki–
Miyaura cross-couplings, have reported that this class of compounds also underwent Stille
couplings in good yields to form 26 <2000SL963>.
Finally, both 2,2-difluorovinylzirconocene 27 and gem-difluorohomoallenyl bromide 28
have been demonstrated to undergo palladium-catalyzed cross-coupling reactions to form
1,1-difluoroalkenes <1999TL7261, 1996TL8799, 2001OL2213> (see Figure 5).
CF2 CF2
X
ZnBr
F2C
CO2Me CO2Me
H R
OAc OAc
17 18 19 20
(X = Br, 44%) R = alkyl, Ar
(X = I, 71%) (48–92%)
Br CF2
ZnBr BR2 OCONEt2
F2C F2C F2C
X R R
R
X = Cl, 22
21 24 25
X = Br, 23
R = CH3, OCF3, R = alkyl R = H, I, SnBu3
(77–93%)
TIPS
OCONEt2 ZrCp2X
C CF2
F2C F2C
R H
Br
26 27 28
R = Ar, allylic, vinyl
(44–83%)
Figure 5
(iii) Substitution reactions

Sodium thiophenoxide cleanly displaces bromide ion in bromodifluoromethyl alkenes
(BrCF2CH¼CHR) via an SN20 displacement to yield fluorinated allylic sulfides in moderate-to-
high yields (52–100%) with good regioselectivities (100:1 to 1:6). <2001JFC(107)89> Other
nucleophilic organometallics have been shown to be equally as useful (Table 4).
Of particular synthetic importance is the work by Nemoto and co-workers. This method
involved the use of 1-bromo (or acetoxy)-1,1-difluoroallyl derivatives in catalytic -allyl Pd
reactions <2000CPB885, 1995TL6305>.
4.17.1.1.3 Wittig-type reactions

In addition to the thorough review of Wittig reactions that form 1,1-difluoroalkenes presented in
chapter 4.17.1.2.2 in COFGT (1995) <B-1995COFGT(4)729>, Burton has written a number of
reviews concerning the reactivity of fluorinated ylides <1996CRV1641, 1999JFC(100)177>.
Table 4 Substitution reactions that form 1,1-difluoroalkenes

CF3C(CO2Et)¼NPh CF2¼C(CO2Et)NPh(Et) Et2Zn 80 <1996TL2045>
CF3(Ph)C¼CH2 CF2¼C(Ph)CH2CH3 CH3Li 90 <1995TL5003>
F 2C S
Li
CF3(Ph)C¼CH2 Ph S S 90 <1995TL5003>
S
CF3(Ph)C¼CH2 CF2¼C(Ph)CH2N(i-Pr)2 LDA 90 <1996JCS(P1)1409>

CF3C(F)¼C(H)NMe2 CF2¼C(F)CH-(Ph)(NMe2) PhMgBr 87 <1999TL2985>
E-(n-hex)CH¼CHCF2Br (n-hex)(n-BuLi)-CHCH¼CF2 BunLi, 20 C 96 <1997TL5989>
E-(n-hex)CH¼CHCF2Br (n-hex)(TMS)-CHCH¼CF2 TMS-Li CuCN 75
4 mol.% Pd0
CH2¼CHCF2Br (CO2Et)2(CH3)C-CH¼CF2 (CO2Et)2CCH3 97 <2000CPB885>
Na
Serafinowski and co-workers successfully converted a ketone to a 1,1-difluoroalkene using a

Wittig reagent generated in situ from dibromodifluoromethane (CF2Br2) and hexamethylpho-
sphorus triamide (HMPT) in good overall yield (69–74%) <1996T7929, 2000T333>. Yamazaki
and co-workers have also utilized this method to difluoromethylenate 2-keto arabinoside 29
<1997SL669>. Yamazaki and co-workers have also reported that -substituted ketones could
be difluoromethylated to form difluoroalkenes 30 <2001OL743>. The combination of bromodi-
fluoromethyl[tris(dimethylamino)]phosphonium bromide and zinc using sonication has also been
reported <1997S225>. Nicolaou and co-workers have used diethyl(difluoromethyl)phosphonate/
n-BuLi in dimethoxyethane (DME) to convert an aromatic ketone to the difluoro derivative 31,
albeit in low yield <2000MI972> (see Figure 6).
O
Ph O CF2
O OMe
O R1
TBSO R3
O OMe R2 OTBS CF2
OMe
29 30 31 OMe
(EtO)2P(O)CHF2
R1 = CH3, R2, R3 = H, 83% ButLi, then ∆
R1 = Ph, R2 = CH3, R3 = H, 90% 20%
Figure 6
4.17.1.1.4 Thermal methods

McCarthy and co-workers have reported a procedure that involved conversion of a carboxylic
acid to sulfoxide 32. Heating these sulfoxides neat at 160–200 C resulted in the formation of the
desired fluorinated alkenes 33 <1996TL3223>.
Exposure of sodium carboxylates 34 to high temperatures resulted in decarboxylation. The
resulting anion then eliminated NaF to yield the desired difluoroalkene 35. Thermally induced
extrusion of substituted aromatic carboxylates 36 has also been reported <1998JFC(89)31>.
This procedure has been used to make large amounts (>50 g) of difluorinated -halovinyl ethers.
Shoichet and co-workers have also reported the thermolysis of various trimethylsilyl esters
<1997JOC7844>.
Perhaps more synthetically useful is the decarboxylation of ,-difluoro--lactones 38
<1995JOC5378, 1998JFC(88)41>. Exposure of fluorinated hydroxy acids 37, available from
bromodifluoroacetate and various ketones via a Reformatsky reaction, to benzenesulfonyl
chloride followed by careful work-up produced the desired difluoro oxetanones 38. Heating these
lactones neat, or in solvent, yielded the 1,1-difluoroalkenes 39 in near quantitative yields.
Chen and co-workers have shown that the elimination of HBr from bromofluoroalkene 40
produced difluororalkene 41 in high yield, although the reaction proceeded using harsh conditions
(carbon, 300 C/1 mmHg, 86%) <1997S1481>. Pyrolysis of fluorinated acid fluoride 42 also
produced difluoroalkene 43, but again required very harsh conditions <1999JFC(94)65>. Finally,
while elucidating an anomalous elimination of HCl, Dolbier and co-workers also reported that
the thermolysis (650 C) of 2-chloro-1,1-difluoroethane produced relatively small amounts of 1,1-
difluoroethylene <2002TL8075> (see Figure 7).
F
F
170 °C CF2
SMe
neat
O 64%
32 33
O F OCF2CF2CO2M
F
ONa RO CF2
RO
CF3 R1
34 35 36
R = alkyl R1 = H, or NO2
M = Na or K
O
HO
O R1
CO2H 100–180 °C
R2 F R 1 F CF2
R2
R 1 F R2 F
37 38 39
R1, R2 = Et, 98%
R1, R2 = Ph, 88%
R1 = Ph, R2 = Me, 90%
R1 = Ph, R2 = Bn, 100%
BrCF2CH2CFBr BrCF2CH=CF2
40 41
F CF3 F2 O CF2 F O
2
F C O C O
O (CF2)3 F F O (CF2)3 F
O F CF3 F CF3
42 43
Figure 7

A large number of research groups have reported the synthesis of 1-tert-butyldimethylsilyloxy-2,2-
difluoroethylene derivatives 44. These methods include the reaction of trifluoromethyltrimethyl-
silane 45 with TMS-ketone 46 <1999SL432>, electrochemical reduction of trifluoromethyl ketone
47 <1998TL3741>, and nucleophilic addition of tert-butyldimethylsilyllithium followed by a
subsequent rearrangement <1998JCS(P1)1215>. These reactive silyl enol ethers have been utilized
to form fluorinated 1,3-diketones via a Lewis-acid catalyzed aldol <2001JOC4543>.
Shen and co-workers have reported an elegant protocol for the formation of functionalized 1,1-
difluoroalkenes <2001JFC(109)141>. In this procedure, 2,2-difluoro-1-tosyloxyvinyl anion 48
reacted with ethoxycarbonylvinylphosphonate 49 to yield a stabilized anion that can react further
with aldehydes to form gem-difluoropenta-1,4-dienes 50 in good overall yields (75–96%). Friedel–

Crafts addition using AlCl3, p-xylene, and 2,3,3-trifluoropropenol 51 has also been reported
<1999JOC1366>. Burton and co-workers reported a convenient procedure to access tetrafluor-
oallene 53 by allowing anion 52 to warm to rt <1995JFC(75)83>. It should be noted that the
elimination of LiF proceeded smoothly, with only trace amounts (2%) of tetrafluoropropyne 54
being formed under optimized conditions. Finally, Huang and co-workers demonstrated that aryl
thiols added to 1,1-difluoroallene 55 to produce 1,1-difluoro substituted sulfides 56 in good yields
(61–94%) <1995JFC(70)5> (see Figure 8).
OTBDMS O O
F2C R CF3SiMe3 Ph TMS F3C Ph

R = Ph, Bn
44 45 46 47
CF3 CO2CH3 OTs CO2Et
H OTs F2C
P(O)(OEt)2
R = Ar R
48 49 50
HO
F3C
CF2 F2C C CF2 F3C F F2C C CH2
F2C
Li
F
51 52 53 54 55
F2C
H SR
R = Ar
56
Figure 8
4.17.1.2 Dichloro Alkenes

Because of the structural similarity with difluoroalkenes, a number of similar transformations
have been reported to construct 1,1-dichloroalkenes. Also, just as for difluoroalkenes, these
transformations can be conveniently grouped into categories that include the Wittig-type reaction
of carbonyls using PPh3 and CCl4, reactions involving dichlorocarbenes, elimination reactions,
and miscellaneous routes.
4.17.1.2.1 Wittig and related reactions

One of the most synthetically useful routes to 1,1-dichloroalkenes is the reaction of carbonyl
compounds with a PPh3/CCl4 mixture. In the late 1990s and early 2000s, a large number of
research groups have used this method to form a wide range of dichloroalkenes. As displayed in
Table 5, this procedure has been shown to work well for -ketoesters, amides, formates, lactones,
ketones, and succinimides. Ketones and aldehydes readily underwent the dichloromethylenation
at low temperatures (CCl4, rt), whilst amides, lactones, and esters required higher temperatures
(refluxing tetrahydrofuran (THF)). In certain cases, however, ketones have required the use of
higher temperatures (Table 5, last entry).
Table 5 Formation of 1,1-dichloroalkenes by reaction of triphenylphosphine and carbon tetrachloride with

various carbonyl compounds
Substrate Product Conditions Yield (%) References
(n-Bu)NTsCHO (n-Bu)NTsC¼CCl2 PPh3,CCl4 99 <2000SL1402>
THF, 60 C
(Ph)NTsCHO (Ph)NTsC¼CCl2 81 <2000SL1402>
(Bz)NTsCHO (Bz)NTsC¼CCl2 96 <2000SL1402>
RNTsCHO RNTsC¼CCl2 97 <2001MI369>
R¼CH2CH¼CH2
O CCl2
87 <2000SL1402>
MenthylO H MenthylO H
TMS CHO
TMS
CCl2
TMS CHO PPh3,CCl4 Mg 53 <1999JOM(578)144>

CCl2
CoCp TMS
CoCp
CHO
Fe C=CCl2 4 equiv. PPh3 85 <2000SC1569>
Fe
2 equiv. CCl4
O
R CCl2
R
O
N O
Ac N PPh3,CCl4 96 <1998CL1237>
Ac THF, reflux 78 <1998CL1237>
R = Bn
R = Me 75 <1998CL1237>
R = Pri
O
R1 CCl2
N R2 R1
N R2
O PPh3, CCl4 31 <1995JHC783>
O 39 <1995JHC783>
R1 = H, R2 = Bn
R = H, R2 = (CH2)2p-Tol
O
CCl2
R1 CO2R2
R 1 CO2R2 PPh3, CCl4, 62 <2002SC2821>
R1 = Ph, R2 = Me
CH2Cl2 65 <2002SC2821>
R1 = Tol, R2 = Me
O
CCl2
R R2
1 PPh3,CCl4 88 <2000S109>
1 2
R = R = pentyl R 1 R2 THF, 60 C 89 <2000S109>
R1 = R2 = fluorenyl
4.17.1.2.2 Reactions involving dichlorocarbene

Nenajdenko and co-workers reported a preparation of 1,1-dichloroalkenes from various ketones
via the corresponding hydrazones <2002JCS(P1)883>. Exposure of the hydrazone to catalytic
amounts of CuCl in CCl4 led to good yields of chlorinated alkenes (Table 6). The mechanism
of this reaction has been thoroughly studied <2000T6557>. Additionally, dichlorocarbene was
also added to thioketone 57 to produce 2,2-dichlorothiirane 58. This compound subsequently
underwent desulfurization upon standing to give 1,1-dichloroalkene 59 <1999HCA946> (see
Figure 9).
Table 6 Formation of 1,1-dichloroalkenes using cat. CuCl
R1 CCl4 CCl2
NNH2
CuCl (cat.) R1 R2
R2

p-Tol Me 65 <2002JCS(P1)883>
p-ClC6H4 Me 82 <2002JCS(P1)883>
Ph Me 57 <2002JCS(P1)883>
p-MeOC6H4 Me 70 <2002JCS(P1)883>
p-NO2 C6H4 H 84 <2000T6557>
Cl
Cl Cl
S
S
Cl
57 58 59
Figure 9
4.17.1.2.3 Elimination reactions

Metals in the zero oxidation state have been extensively used to produce 1,1-dichloroalkenes.
During their synthesis of lennoxamine, Koseki and Nagasaka used a zinc/AcOH mixture to open
trichloromethyl lactone reductively (60 and 61) in 90% yield <1995CPB1604>. A variety of 3,3,3-
trichloropropyl acetates 62 readily underwent elimination using zinc dust to produce dichloroalk-
enes 63 in high yields <2000TL4007>. Additionally, Rao and co-workers used zinc metal to
synthesize 1,1-dichloro-2,2-difluoroethylene 65 in 80% yield <2000T3539>. Zinc dust has also
been shown to form TMS silyl ketene acetal 67 in good yield from trichloromethyl ester 66
<2001TL1313>. Despite the apparent generality of this method, Guirado and co-workers
reported that exposing trichloromethylamides 68 to zinc metal did not form the desired dichlor-
oalkene 71, rather the partial reduction product 69 was formed. This problem was solved by first
reacting amides 68 with PCl5 to yield chlorides 70, which can be electrochemically reduced to
form 71 in good-to-excellent yields <2001T4925> (see Figure 10).
Like zinc, indium readily eliminated Cl-OR from functionalized trichloromethyl carbinols to
produce dichloroalkenes. Although the reduction of trichlorocarbinols with indium metal yielded
a mixture of products (30% after 18 h at 150 C), reaction of the corresponding acetate, mesylate,
or tosylate produced the chlorinated alkene in excellent yields (Table 7).
CrCl2 has also been shown to be an efficient reductant <2001CC4925>. Using CrCl2, trichloro-
methyl derivatives 72 has been converted to dichloroalkene 73 in near quantitative yield.
1,1-Dichloroalkenes, like difluoroalkenes, can be constructed by elimination with various bases.
Trichloroethyl carbamate 74 reacts with excess lithium diisopropylamide (LDA) to yield dichlor-
ovinyl carbamate 75 in 90% yield <2002OL2193>. Back and Minksztym reported that allylic
selenides 76 could be constructed by elimination of HCl from the trichloromethyl derivatives
using t-BuOK at 10 C in excellent yields <1997CC1759>. Lastly, ,-dichlorocyclobutanones
77 undergo photocycloelimination to yield 1,1-dichloroalkenes 78 in acceptable yields
<1999CJC1245> (see Figure 11).
4.17.1.2.4 Miscellaneous reactions

A polychloromethane–titanocene (II) system has been used to construct dichloroalkenes from
a variety of ketones. Reaction of titanium complex 79 with ketones in CCl4 resulted in
good yields of the dichloroalkenes 80 <1999T2475>. The Ramberg–Bäcklund rearrangement
has also been used to construct 1,1-dichloroalkenes <1998T1901>. Using this rearrangement,
Raj and co-workers reported that trichloromethyl sulfones 81 underwent base-induced
O
O CCl2 COOH
OMe OMe OAc
Cl3C
CCl3 R CCl2
R
OMe OMe
60 61 62 63
R = Bui, 93%
R = But, 92%
R = C6H11, 88%
R = Ph, 86%
R = CH3CH2Ph, 85%
OTMS
Cl3C CF2Cl Cl2C CF2 Cl3CO2Me Cl2C
OMe
64 65 66 67
O OH O OH O Cl O
R N CCl3 R N CHCl2 R N CCl3 R N CCl2

H H H H
68 69 70 71
R = Ph, 90%
R = p-NO2C6H4, 88%
R = p-MeC6H4, 72%
R = But, 70%
Figure 10
Table 7 Formation of 1,1-dichloroalkenes using indium
R2O CCl2
In, DMF
R1 CCl3
H 150–160 °C R1 H

Ph Ac 76 <2002TL5993>
Ph Ms 93 <2002TL5993>
Ph Ts 94 <2002TL5993>
p-MeOC6H4 Ms 92 <2002TL5993>
p-ClC6H4 Ts 95 <2002TL5993>
1,5,-diazabicyclo[5.4.0]undec-5-ene (DBU) rearrangement to give 1,1-dichloroalkenes 82 in excel-

lent yields <2000TL1501>. Also, imine 83 reacted with diphenyldiazomethane at 65 C to yield 84
in 70% yield <1999EJO1541>.
Additionally, while studying the conjugate addition/elimination of unsaturated-TMS esters,
Cunico and Zhang reported the synthesis of 3,3-dichloro-1-(trimethylsilyl)-2-propenone 86 by
hydrolysis of 85 (MeOH, H2O) <1995T9823>. Bis-alkylation of malonate derivatives with 87 has
been used to construct symmetrical 1,1-dichloroalkene 88 <2000JOC8532>. Finally, Masuda and
co-workers reported the preparation of 1,1-dichloroalkenes from alkynes via hydroboration
<1995JCS(P1)2955>. Treatment of the dialkylborane with a copper(II) chloride in the presence
of water produced the 1,1-dichloroalkene 89 in excellent yield (see Figure 12).
OMs O O
Ph CCl3 Ph CCl2 Cl3C O N(Pri)2 Cl2C O N(Pri)2
72 73 74 75
R1 R2 Cl O
R1 Cl
PhSe Cl R1 Cl
R3 R2 Cl
R2 Cl
76 77 78
1,
R R3 = H, R2 = Bun, 90% R1, R2 = Ph, 40%
R1, R2 = Bun, R3 = H, 92% R1 = CH3, R2 = CH2OBz, 60%
R1, R3 = H, R2 = C6H13, 92% R1 = H, R2 = CH2OBz, 65%
Figure 11
X X
CCl2
Cp2Ti[P(OEt)3]2
R1 R2 SO2CCl3 CCl2
79 80 81 82
R1, R2 = Ph, 22% X = CH2, 92%
R1 = Me, R2 = naphthyl, 66% X = O, 88%
R1, R2 = (CH2)4CH3, 58%
Ph
CO2Me N OEt O
Cl3C N Ph CCl2 Cl3C Cl2C
TMS TMS
H
83 84 85 86
Cl Cl R R Cl
Cl Cl
E E E E CCl2 via C
H H BR2
Br Br
87 88 89
E = CO2Me, 75% R = Bun, 83%
R = But, 96%
Figure 12
4.17.1.3 Dibromo Alkenes

As expected, methods used to construct other 1,1-dihaloalkenes have been reported to be
successful for 1,1-dibromo derivatives as well. The most common method involves the use of
PPh3 and CBr4. Other miscellaneous methods have also been reported.
4.17.1.3.1 Wittig-type reactions
(i) Using PPh3 and CBr4

Since the seminal reports of Ramirez and co-workers <1962JA1745> and Corey and Fuchs
<1972TL3769>, the dibromination of carbonyl compounds using PPh3 and CBr4 has become
a common practice. The high functional group tolerance and typically high yields make this
reaction especially amenable to natural product synthesis. Table 8 shows some stereotypical
examples of this method, although the list is by no means comprehensive.
Table 8 Formation of 1,1-dibromoalkenes using triphenylphosphine and carbon tetrabromide with various
carbonyl compounds
H OPMBa
OPMB
HMPT 95 <1997CL1193>
O
CBr2
O O Br2C CBr2 25 C, 15 h 92 <1998S1362>
BnO CHO CBr2

O BnO
OMe O
BnO
OMe CH2Cl2, 0 C 87 <1999EJO471>
OBn BnO
OBn
Cl CHO Cl CBr2
CO2Et CH2Cl2 10 C 95 <1999SC3125>

CO2Et
Cl N
Cl N
SEM
SEM
O
CBr2
H
O
O NEt3 CH2Cl2 91 <2000JA9099>
OBn
OBn
OTBDMS
OTBDMS
O
CBr2
R
N H R
N H CH2Cl2, 60 C 92 <2000SL1402>
Ts
Ts
R = CH2CH=CH2
TESO OR CHO -
CBr2
PMBO OR
>94 <2001JA4161>
R = TBDMS
O O
O CBr2
H
H CH2Cl2, 0 C to
76 <2001EJO1619>
rt 2.5 h
CHO CBr2
NEt3 >54 <2001JOC4904>
NHt-BOC
NHt-BOC
RO CHO RO
CBr2
O O CH2Cl2, 20 C 92 <2002T2351>
R = TBDPS
Table 8 (continued)
Br2C
O O
OHC O N N
NH CH2Cl2 63 <1999SL1124>
O TBDPSO
TBDPSO
Br Br
Br Br
O
CHO O CBr2 CH2Cl2, 20 C >80 <2002CEJ2116>
O
O
O
O
O O
O O CH2Cl2, rt 86 <2002T4955>
O
CHO O
CBr2
O
CBr2
OMe
H () OMe CH2Cl2, 0 C, 1 h 85 <2002OL2517>
6 H ()
O 6
O
OHC
Cl Br2C CH2Cl2 0 C, 4 h 80 <2002JA10396>
Cl
O
CBr2
R
R
CH2Cl2 >21 <2003JOC1339>
But
But
R= TMS
S
S
S O CH2Cl2 >92 <1999OL1249>
S CBr2
a
PMB = p-Methoxybenzyl.
Kerr and co-workers reported that aldehyde 90 failed to react under standard conditions.
Reacting this aldehyde with excess amounts of these reagents (3.6 equiv. PPh3 and 1.8 equiv.
CBr4) produced not only the 1,1-dibromoalkene, but also removed the dioxolane to give ketodi-
bromide 91 <1996T7391>. However, there exists a successful report of the dibromination of this
aldehyde without deprotection <1995CC457>.
While investigating the conversion of p-methoxybenzyl (PMB) ether to the corresponding alkyl
bromides using CBr4 and PPh3, Yadav and Mishra reported that PMB-aldehyde 92 was con-
verted to the bromide 93 using an excess of reagents (4:2 PPh3/CBr4), with simultaneous removal
of the PMB ether. The PMB ether can be removed selectively (2:1 PPh3/CBr4) <2002TL5419>. In
certain cases, PPh3 can be difficult to remove using standard methods. Sciotti and co-workers
reported using polystyrene supported PPh3 for Wittig-type reactions. This modification to the
original procedure allowed for easy separation of the sometimes recalcitrant phosphine, and
produced the desired olefin in good yield (94 and 95) <2002BMCL2121> (see Figure 13).
Finally, Martin and co-workers have investigated the reaction of simple ,-epoxy aldehydes with
PPh3 and CBr4. They reported that exposing aldehydes 96 to the reaction conditions does not provide
the desired 1,1-dibromoalkene 98 directly; rather an intermediate bromohydrin 97 (see Scheme 1) was
formed. The formation of this bromohydrin was reported to proceed with complete stereo- and
regioselectivity. This bromohydrin could be converted into the desired 1,1-dibromo alkene upon
exposure to n-Bu4NF tetra-n-butylammonium fluoride (TBAF) <2001JOC7231>.
O CBr2 O
O
O ( ) ( )
H PMBO CHO Br
H 8 8
CBr2
90 91 92 93
F O F O
O O
OHC N H N H
N Br2C N
O O
94 95
Figure 13
O
O R OH O
CBr2
PPh3, CBr4 TBAF
R CBr2 R
H CH2Cl2 H H
Br
96 97 98
R = n-C13H27 (83%) R = n-C13H27 (90%)
R = n-C6H13 (82%) R = n-C6H13 (91%)
Scheme 1
(ii) Using PPh3 and CBr4 and Zn metal

Since the original discovery by Corey and Fuchs that the addition of zinc dust removed the
requirement for excess amounts of Ph3P, this reaction has become a valuable addition to the
organic chemist’s repertoire <1972TL3769>. Similar to the CBr4 and PPh3 system, this mixture
exhibits high functional group tolerance and is typically very high yielding.
Parsons and co-workers reported that aldehyde 99 is cleanly converted to 1,1-dibromoalkene
100 <1995SL255>. Also, ,-unsaturated aldehydes undergo dibromination in excellent yield
<2002JMC2651>. For example, 3,3-dimethylacrolein 101 was converted into gem-dibromodiene
102 in high yield <2001OL1713, 2002SL743>. Cyclopropanes are also stable under these condi-
tions <2001AG(E)603>. Cyclopropane 103 was cleanly converted to the gem-dibromide 104 in
good yield (72%) <2002CEJ3195>. Unlike cyclopropanes, epoxides sometimes undergo deleter-
ious side reactions. Rather than delivering the expected product 106, 105 produced aldehyde 107
(60%), a product derived from rearrangement of the epoxide. Formation of 106 (99% yield) could
be achieved using hexamethylphosphorus triamide (HMPT) in place of triphenylphosphine
<1995JA7379> (see Figure 14).
Br Br TMS TMS
O
Br
H CO2Me H CO2Me Br
O
Br CHO
Br
99 100 101 102 103 104
OHC Br
Br
CHO Br
O
O Br
105 106 107
Figure 14
Lièvre and co-workers reported a procedure to dibrominate aldoses. Exposing substituted

aldoses to an excess of dibromomethylenetriphenylbromophosphorane (4 equiv.) in hot 1,4-
dioxane produced modest-to-good yields of the desired 1,1-dibromoalkene <2002TL1847>
(Equation (4)).
Br
TrO
O OH Br
OH Ph3P+CHBr2 Br–
TrO
Zn ð4Þ
HO 1,4 dioxane, ∆ OH
(90%)
6 Examples (44–77%)
This combination of reagents is also compatible with various protection groups. Dioxolanes, as
well as methyl acetals, have been shown to be stable to these conditions (108 to 109 and 110 to
111) <2000TA4761, 2002OL3847>. When t-butyldimethylsilyl (TBDMS) ether 112 was exposed
to a Zn, CBr4, and PPh3 mixture, 113 (see Figure 15) was formed in 83% yield <2001JA765>.
Triisopropyl silyl (TIPS) groups are also stable to these conditions <2001TL3175>.
OHC OTBDMS
Br
O O O O O
MeO2C CHO MeO2C Br
OMe
108 109 110
Br OTBDMS OTBDMS
OTBDMS
Br O TBDMSO Br
TBDMSO CHO
OMe Br
111 112 113
Figure 15
(iii) Using Ph3PCHBr2 and t-BuOK

Although esters or lactones are not reactive toward the standard CBr4 and PPh3 mixture, the
combination of bromomethylenetriphenylphosphorane and t-BuOK cleanly transformed lactone
114 to the desired 1,1-dibromoalkene 115 in good yield, although the reaction required refluxing
THF <2001TL7265>. The mechanism of the reaction has also been studied <2001TL7265>. This
combination of reagents is exceedingly reactive toward aldehydes. For example, piperidine 116
was converted to the corresponding 1,1-dibromide 117 (see Figure 16) in high yield at rt in only
10 min <2002OL1955>.
Br
O O O
BnO BnO Br N
H H N t-BOC
t-BOC Br
O O O O
CHO
Br
114 115 116 117
Figure 16
4.17.1.3.2 Miscellaneous routes
(i) Rearrangements
McNelis and co-workers have reported a creative method for the formation of 1,1-dibromoalk-
enes <2002OL3847, 1996T10267> via the rearrangment of bromoalkynes (Equation (5)). Bro-
moalkynol derivative 118 has been demonstrated to undergo a rearrangement in the presence of
2.2 equiv. of N-bromosuccinimide (NBS) in high yield.
Br
HO HO
HO 2.2 equiv. NBS O
O O
(74%) O ð5Þ
O
HO O OH O
Br
Br
118
(ii) Using organometallics

Similar to 1,1-dichloroalkenes, indium metal can also be used to form 1,1-dibromoalkenes (Table 7).
Exposing tribromomethyl carbinols 119 to indium metal results in quantitative elimination of Br-OMs
to form the desired dibromides 120 <2002TL5993>. Dabdoub and co-workers reported that stannane
121, produced via hydrozirconation of the corresponding tributylstannylacetylene, reacted with NBS
to form 1,1-dibromoalkenes 122 in good yields <2001JA9694>. Also, Normant and co-workers
demonstrated that bis-metallic species 123 reacted smoothly to give the corresponding gem-dibromide
<1995TL7451>. Finally, ,-bis-indium derivatives, such as 124, react with NBS to produce 1,1-
dibromides in high yields <1999JOC7537> (see Figure 17).
But But
Br Br O M1 O In
MsO R Sn(C4H9)3 R Br
R1 CBr3 Pr M2 Pr In
H R1 H H ZrCp2Cl H Br
119 120 121 122 124
123
R = Ph, 96% R = CH2OBn, 81% M = Metal (65%)
R = p-ClC6H4, 95% R = C6H11, 70% Li, Mg, or Zn
R = p-MeOC6H4, 97%
Figure 17
(iii) Using hydrazones

The synthesis of functionalized ,-dibromostyrenes utilizing catalytic amounts of CuCl and
aromatic hydrazones has been reported (Equation (6)) <2001S2081>. This reaction not only
produced the desired 1,1-dibromoalkenes in high yield, but it is reported to be air- and moisture-
insensitive. The mechanism of this reaction has been studied <2002JCS(P1)883>.
Ar CBr4, CuCl (cat.) Ar Br

N
NH3 aq, DMSO, rt
H NH2 H Br
Ar = p-ClC6H4, 84% ð6Þ

Ar = o-ClC6H4, 77%
Ar = o-FC6H4, 92%
Ar = p-CF3C6H4, 57%
Ar = o-CF3C6H4, 81%
4.17.1.4 Diiodo Alkenes

Unlike other symmetrical 1,1-dihaloalkenes, there exist relatively few examples of this functional
group transformation. These relatively few reports can be conveniently grouped into three
categories: Wittig and related reactions, reactions using bis-organometallic species, and miscella-
neous routes.
4.17.1.4.1 Wittig and related reactions

In the total synthesis of gambierol, Yamamoto and co-workers reported the successful conversion
of an advanced intermediate aldehyde into the corresponding 1,1-diiodoalkene using a PPh3-CI4
mixture <2003JA46>. Not only did this reaction proceed in high yield (>92%), but this example
also illustrates the high functional group tolerance associated with this transformation.
The combination of phosphonium salt 125 with base also provides a method for the conversion
of aldehyde to 1,1-diiodoalkenes. 126 Was shown to react with 125 in the presence of n-BuLi
(THF, 0 C) to give 127 in 58% yield <1999T15071>. Michel and Rassat also reported this
reaction worked well with a weaker base (t-BuOK) to give the desired products 128 in 80%
yield <1999TL8579>. It is important to note that 128 was not formed when reacted with the ylide
derived from CI4 and PPh3 (see Figure 18).
H I R= , 80%
I N
Ph3 P+CHI I– O
2, R I t-BOC
I
125 126 127 128 R= , 80%
N
Figure 18
4.17.1.4.2 Reactions involving organometallics
(i) Organoindiums
Phenylacetylene reacts cleanly with 1 equiv. of (allyl)3In2I3 to form an intermediate ,-bis-
indium intermediate, 129. This organometallic can be reacted with either I2 or LiI (5 equiv., 65–
74%) to produce desired diiodide 130 in good yield <1999JOC4095, 1997JOC2318>. The
mechanism of this transformation has been studied <1997JOC2318>. Klaps and Schmid also
reported the successful transformation of acetylene derivatives to 1,1-diiodoalkenes 131 (see
Figure 19) using the combination of allyl bromide and indium metal with sonication
<1999JOC7537>, a method that can also be used to synthesize 1,1-dibromo alkenes (see
Section 4.17.1.3.2).
Ph I
Ph In X I
I
In RO I
X
129 130 131
R = Bn, 64%
R = Ac, 48%
R = TBDMS, 76%
Figure 19
(ii) Miscellaneous organometallics

Similar to indium, gallium can also be used to convert terminal acetylenes to 1,1-diiodoalkenes.
Exposing acetylene 132 to (allyl)3Ga2Br3 in the presence of Hunig’s base yielded an intermediate
gem-digallium species 133 that reacted with I2 to give 134 in high yield <2002CL172>. Bis-
metallic species 135 not only reacts with electrophilic bromine to form a 1,1-dibromoalkene (see
Section 4.17.1.3.2), but was also converted to the 1,1-diiodo derivatives 136 (see Figure 20) upon
exposure to a small excess of iodine <2001JA9694>. González-Nogal and co-workers reported
that exposure of mixed bis-organometallic 121 to I2 produced diiodides 137 in 78% yield
<2001JOC1961>.
Ph Ph
GaLn I
Ph ButPh2Si Cu ButPh2Si I
H GaLn I
SnBu3 I
132 133 134 135 136
R Sn(C4H9)3 R I
H ZrCp2Cl H I
121 137
R = Bun, 78%
R = C6H13, 84%
R = Ph, 87%
R = CH2OBn, 84%
R = CH2OH, 72%
Figure 20
4.17.1.4.3 Miscellaneous routes

In 1999, Kirschning and co-workers reported the use of polymer-supported iodinating reagent 138
<1999OL2101>. Using this reagent, acid 139 was transformed to lactone 140 in 57% yield. Along
the same lines, bis(sym-collidine)iodine(I) hexafluorophosphate 141 has been reported to form
1,1-diiodoalkenes in certain cases <1995TL2619>. For example, iodoacetylene 142 was cleanly
converted to the cyclic diiodoalkene 143 in 75% yield (see Figure 21).
I
OAc HO I O
O O
I (collidine)2I+PF6
N+Me3 I–
HO2C I I
OAc
138 139 140 141 142 143
Figure 21
Various rearrangements have also been reported to be efficient routes to 1,1-diiodoalkenes.

Exposing alkynols 144 and 146 to I2 and [(hydroxy)(tosyloxy)iodo]benzene (HTIB) cleanly
produced 145 and 147, respectively (Scheme 2) <1996T10267>. This rearrangement has also
been shown to work with alkynols derived from xylose <1999TL7193>.
Finally, Eguchi and co-workers reported that 4-hydroxycyclobutenone 148 underwent a ring
expansion to form diiodoalkene 149 in the presence of iodobenzene (IBD) and I2 <1995TL5539>
(see Figure 22).
I I I I
O I
HO I2/HTIB O HO I2/HTIB
I
85% 100%
144 145 146 147
Scheme 2
O
EtO O EtO I
I
EtO EtO I
OH
O
148 149
Figure 22
4.17.1.5 Mixed Halo Derivatives
4.17.1.5.1 Fluoro halo alkenes
(i) 1,1-Fluoro-chloro alkenes

As expected, transformations that form symmetrical 1,1-dihalo alkenes can be used to construct
1,1-fluorochloroalkenes. For example, Wittig-type reactions have been used to construct unsym-
metrical dihaloalkenes. Exposing aldehydes to fluorotribromo-methane in the presence of PPh3
and Zn metal cleanly forms the desired alkenes 150 <1999TL827>.
Elimination reactions can also be utilized to form mixed 1,1-dihaloalkenes. The structure 151
readily undergoes a zinc-mediated reduction to give 152 in 75% yield <2000T3539>. This
elimination can also be accomplished with KOH in 78% yield ((E):(Z) = 1.2:1) <1997T17127>.
Elimination of HF from 153 with t-BuOK produced 154 in 55% yield <2002JFC(115)83>
((E):(Z) = 4:1). Finally, exposure of 1-chlorotrifluoroethylene 155 to phenyllithium results in
formation of 156 in 48% yield <2002JFC(113)211> (see Figure 23).
Cl F F F F
F F F F F Cl F
F Cl F
F Ph
R F PhS H PhS Cl Cl F F
Cl
Cl
150 151 152 153 154 155 156
R = Ph
26/74 (Z )/(E )
R = p-MeOC6H4
R = PhCH2CH2
Figure 23
Nenajdenko and co-workers have reported a novel two-step approach to 2-chloro-2-fluorostyr-

enes from aromatic aldehydes (Equation (7)) <2003EJO302>. After transformation to the corre-
sponding hydrazones, reaction with catalytic amounts of CuCl in the presence of CFCl3 provides
the desired mixed halo-alkenes in moderate yield.
H2N F Cl
N CFCl3
Ar R CuCl Ar R
R = p-ClC6H4, 78%, (E )/(Z ) 2.6/1 ð7Þ

R = p-BrC6H4, 68%, (E )/(Z ) 2.4/1
R = p-MeOC6H4, 43%, (E )/(Z ) 4/1
R = Ph, 62%, (E )/(Z ) 2.8/1
R = p-IC6H4, 55%, (E )/(Z ) 2.5/1
(ii) 1,1-Fluorobromo alkenes

Not surprisingly, many of the same methods used to prepare 1,1-fluorochloroalkenes can be
used to construct the 1,1-fluorobromo derivatives. Wittig-type reactions have been used to
convert various aldehydes to the desired unsymmetrical 1,1-dihaloalkenes. Simple aromatic
aldehydes react with PPh3, CFBr3, and Zn to produce the desired dihaloalkenes. Benzaldehyde
and p-nitrobenzaldehyde are converted to the desired alkenes using this protocol, although the
latter required the use of cupric sulfate <1999TL827, 2001TL9127>. Using these conditions,
when 157 was exposed to (bromofluoromethylene)triphenylphosphorane 158, bromofluorovi-
nyl derivative 159 was produced in 75% yield <2000JMC1180, 1998JMC3078>. While inves-
tigating Pd cross-coupling reactions, Burton and co-workers also reported that aromatic
aldehydes 160 formed the desired halogenated alkenes 161 <2002TL2877> using CFBr3 and
PPh3. Burton and co-workers also studied the isomerization of these fluorobromoalkenes
using various conditions.
Elimination reactions can also be used to construct 1,1-bromofluoroalkenes. Exposing acid 162
to NaHCO3 (or Bu4N+OH) resulted in the formation of 163 in near quantitative yield
<2001CCC1508, 1997BSF741> (see Figure 24).
Br F F Br
O O
H H
H O
O
FBrC=PPh3 O
O X
OTBS O X
OTBS O
157 158 159 160 161

X = H, o-Cl, p-MeO
p-F, m-NO2
Br Br F
HO2C F
Br
162 163
Figure 24
Kuroboshi and co-workers have reported two stereoselective syntheses of (E)-1,1-bromo-

fluoro alkenes <1995TL6271, 1998BCJ2903>. When 164 was treated with lithium (2,2,6,6-
tetramethyl)piperidide at 98 C, the (E)-isomer 165 was formed with very high selectivity
(Equation (8)). Additionally, when acetate (or tosylate) 166 was exposed to the combination of
EtMgBr and diisopropylamine (DIPA), the (E)-isomer 167 was again preferentially formed
(Equation (9)).
F
F
LITMP, –98 °C F
R
R CF2Br
Br
164 ð8Þ
165
R = p-MeOC6H4, 87%, (E )/(Z ) 92/8

R = p-Tol, 78%, (E )/(Z ) 91/9
H
OAc(OTs) EtMgBr–DIPA Br
R CF2Br –98 °C R
F
166 167
ð9Þ
R = naphthyl, 81%, (E )/(Z ) >99/1
R = p-NCC6H4, 89%, (E )/(Z ) 91/9
R = p-MeOC6H4, 84%, (E )/(Z ) >99/1
R = CH2CH2Ph, 80%, (E )/(Z ) 33/67
Other bases have also been used to produce 1,1-bromofluoroalkenes via an elimination path-
way. While studying enantioselective aldol reactions, Iseki and co-workers reported that zinc
metal effectively dehydrobrominated 168 in the presence of trimethylsilyl chloride (TMSCl) to
form bromofluoroketene silyl acetal 169 <1999T2225>.
Other specialized routes to 1,1-bromofluoroalkenes have been reported. Friedel–Crafts addition
using AlCl3, p-xylene, and allyl bromide 170 yielded 171 in 66% yield as a mixture of (E):(Z)
isomers 1999JOC1366. Finally, reaction of vinyl stannane 172 with bromine resulted in regiospe-
cific bromination to give 173 <1996JFC(52)37> (see Figure 25).
Br
OTMS F F F F
O F H
F F
EtO
Br2FC OEt F Bu3Sn TES Br TES
Br F2BrC H
168 169 170 171 172 173, 92%

62/38 (E )/(Z )
Figure 25
(iii) 1,1-Fluoroiodo alkenes

Similar transformations used to form 1,1-diiodoalkenes can be adapted to form mixed halo
alkenes. Many of the reactions used to construct this functional group involve the formation of
the stabilized anion, shown generically as 174. For example, exposing vinylsilanes 175 to KF in
the presence of I2 resulted in the stereospecific formation of the desired 1,1-fluoroiodo alkene 176
in high yield <2002JFC(113)211, 1996TL7237> (see Figure 26).
R F F F F F
R Li H R H I
174 175 176
R = SiEt3
R = SiPhMe2
Figure 26
Along these lines, Davis and Burton have demonstrated that (Z)-,-difluorostyrenes can be
converted to (E)-,-difluoro--iodostyrenes in one of two ways (Table 9) <1997JOC9217>.
Reaction of the organolithium or an intermediate organostannane with I2 results in good yields of
the desired alkenes.
Table 9 Lithiation conditions to form 1,1-fluoroiodoalkenes
Method 1:
F F F F
i. Bu3SnCl ii. LITMP, –78 °C iii. I2
Ar H Method 2: Ar I
i. BunLi, –100 °C ii. I2, –100 °C
R Method Yield (%)

p-MeOC6H4 1 87
p-MeOC6H4 2 85
C6H5 2 83
p-EtO2CC6H4 1 77
p-EtO2CC6H4 2 39a
m-ClC6H4 1 85b
a b
LITMP was used rather than n-BuLi. One-pot procedure.
Additionally, organolithium 177 can also be quenched with I2 to form iodoalkene 178 in 63%
yield <1997T14749, 1996TL5183>. Vinylsilane 179 can be deprotonated with n-BuLi at low
temperatures and reacted with I2 to give 180 exclusively as the (E)-isomer <1997JOC1064>.
Trifluorovinyllithium, available from 1,1,1,2-tetrafluoroethane, reacts with I2 to give the iodotri-
fluoroethylene in high yield <1996CC49>. Analogously, stannane 181 reacted cleanly with I2 to
give the desired vinylsilane 182 in high yield <1996T37> (see Figure 27).
OMEM OMEM
I H F I F F F F F
Li
F O F SiEt3 F SiEt3 Bu3Sn SiEt3 I SiEt3
F O
177 178 179 180 181 182

(100% (E ))
Figure 27
4.17.1.5.2 Chloro halo alkenes

There exist relatively few examples from the late 1990s and early 2000s of this functional
group. Normant and co-workers have reported a general procedure for the formation of 1,1-
bromochloro alkenes form ketones <2000S109> (Scheme 3). Nucleophilic addition of
LiCBr2Cl to ketones and acetylation, followed by exposure of acetate 183 to EtMgBr, pro-
duced the mixed dihalo alkenes 184 in very high yield. Normant also reported that organo-
metallic species 185 could be quenched with either NBS or I2 to give, in good yields, 186 and
187, respectively (Scheme 4) <1996S1499>. Additionally, organometallic 188 reacts with I2 or
NBS to give the corresponding mixed halogenated alkenes 189 and 190 (see Scheme 5)
<1995TL3687>.
Mixed dihaloalkenes can also be formed via a hydroboration pathway, a procedure that can
also be used to form 1,1-dichloro- and 1,1-dibromoalkenes (Table 10) <1995JCS(P1)2955>.
O Cl Br
AcO CBr2Cl EtMgBr
R1 R2 R1 R2 –95 °C R2
R1
183 184
R1, R2 = –CH2(CH2)2CH2–, 89%

R1 = R2 = C5H11, 81%
Scheme 3
But But But

O Br O M1 O I
NBS I2
Pr Cl Pr Cl Pr Cl
186 185 187
Scheme 4
Cl NBS Cl I2 Cl
R Br R Li R I
189 188 190
R = C5H11, 68% R = C5H11, 84%
R = C6H5, 60%
Scheme 5
Table 10 Formation of dihaloalkenes using hydroboration and

copper (II) salts
i. HBR2 R1 X1
R1 X1
ii. Cu(II)X22 H X2
R1 X1 Copper salt Yield (%) (Z)/(E)

n
Bu Br CuCl2 82 100% Z
Bun I CuCl2 85 99:1
But Cl CuBr2 84 1:99
But Br CuCl2 72 99:1
4.17.1.5.3 Bromo halo alkenes

McNelis and co-workers have reported the rearrangement of bromopropynyl alcohols to form
bromoiodo alkenes. Carbinols 191, 192 (see Scheme 6), and 195 undergo this rearrangement in the
presence of I2 and HTIB ([(hydroxy)(tosyloxy)iodo]benzene) to produce 193, 194, and 196 (see
Figure 28), respectively <1995SC1223, 1996T10267, 1996SC4091>. Marchand and co-workers
have also reported a rearrangement of this type <1995T11673>.
Br Br
Br I
O I
HO I2/HTIB O HO I2/HTIB
Br
100% 100%
191 193 192 194

193 (2° Carbon shift): 194 194/193, (9/1)
(3° Carbon shift), (4/1)
70/30 (Z )/(E )
Scheme 6
OH Ph
Ph Ph Br
Br
Ph O I
195 196
Figure 28
4.17.2 FUNCTIONS INCORPORATING A HALOGEN AND A CHALCOGEN:

R2C¼C (Hal)(Chalc)
4.17.2.1 Halogen and Oxygen Derivatives
4.17.2.1.1 a-Fluorovinyl ethers

As demonstrated earlier <B-1995COFGT(4)667>, displacement of halogens in alkyl and alkenyl
halides remains an effective method for the preparation of -fluorovinyl ethers. While investigat-
ing the Claisen rearrangement of allyl fluorovinyl ethers, Tellier and co-workers reported that
potassium alkoxide 197 reacted quickly at low temperatures with trifluorovinylsilane to give 198
in high yield <1998TL5041>. This alkoxide 197 has also been shown to react with bromotri-
fluoroethylene 199 by an analogous addition/elimination pathway to produce 200. The (E)-isomer
was the major product in all cases <2000EJO1933, 2001TL2665, 1999JFC(94)27>. Unsaturated
ketone 201 underwent two addition/elimination reactions with either phenoxide or methoxide to
provide olefin 202 <2000JCS(P1)1529> (see Figure 29).
R1 R2 Oalkyl
R1 R2 R1 R2 Br H Br
F2C F O via
F F
OK F O H
Br
TMS F
199 200
197 198, (E ) = major
R1 = R2 = alkyl
F
C2F5 CF3
C2F5 OR
RO
F3C CF3
F 3C CF3
O
O
201 202
R = C6H5 or Me
Figure 29
Elimination reactions have also been used to construct -fluoroenol ethers. Aromatic diol 203
was dialkylated with BrCF2CF2Br, then subjected to zinc-mediated reduction to produce
enol ether 204 in fair yield on relatively large scale <2000JFC(104)109>. Heating acid fluoride
205 resulted in a rearrangment to form alkene 206 <1999JFC(94)65>. Finally, exposure of
TMS-carboxylate 207 to high temperature in the presence of KF resulted in extrusion of CO2
to form 208 <1997JOC7844> (see Figure 30).
F CF3
F O F (CF2)2 F
O
F F F RO F
HO OH F ROCFCOSi(CH3)3 O O
F O Ar O CF3 F F 207
F
203 204 205 206 F (CF2)2 F
R = alkyl O
F O
208
Figure 30
4.17.2.1.2 a-Chlorovinyl ethers

Like other -halovinyl ethers, the addition of alkoxides to trichloroethylene remains an effective
way to construct -chlorovinyl ethers. Some stereotypical examples of this method are shown in
Table 11.
Table 11 Displacement reactions involving trichloroethylene

ROH ROCCl¼CCl2 KH, CHCl¼CCl2 >59 <2001TL6987>
R = alkyl >57 <2001TL6987>
R = Ar
OH KH, CHCl¼CCl2 77 <1998JOC7037>

OCCl=CCl2
SPh
SPh
PMPa O R PMP O R
O O
OH OCCl=CCl2
KH, CHCl¼CCl2 81
87 <2002TL1973>
R = CH2CH=CH2 <2002TL1973>
R = CH2CH2CH=CH2
OH
CCl=CCl2
Pri Pri
Pr i Pri
KH, CHCl¼CCl2 81 <2000JOC6966>
Pri
Pri
a
PMP = p-methoxyphenyl.
-Chlorovinyl ethers can also be formed under phase transfer conditions (PTC). Ketones 209
react smoothly with trichloroethylene (TCI) in aqueous base using PTC to give enol ethers 210
<2000T6083>. Simple alkyl alcohols have also been shown to react with dichloroacetylene under
PTC to provide the corresponding -chlorovinyl ethers 211 in good yield <1997BSB809>.
Yu and Jin have reported the convenient synthesis of -halovinyl ethers from the correspond-
ing alkynes <2000JA9840>. Exposing 212 to TMSCl (0.99 equiv.) and MeOH (0.99 equiv.)
resulted in formation of 213 in 97% yield (see Figure 31). It is important to note that the reaction
with TMSCl is not only faster than using commercially available solutions of HCl, but gave better
selectivity. Using TMSCl, they were able to carefully monitor the amount of HCl in solution, and
since TMSOMe is volatile, neither work-up nor column chromatography was necessary. Direct
HCl addition (LiCl/HOAc) to an alkyne has also been demonstrated to produce -chlorovinyl
ethers <1998AG(E)1253>.
O Cl Cl Me OR
Ph R
H O Me OR
R O Cl H Cl
R Ph Cl
209 210 211 212 213
R = Me, 70% R = (–)-Menthol
R = Ph, 75% R = Me, 73%
R = Et, 80%
R = Bu, 83%
R = C6H13, 87%
R = C8H17, 80%
R = C10H21, 75%
Figure 31
4.17.2.1.3 a-Bromo- and a-iodovinyl ethers

Jin and co-workers have published a convenient preparation of both bromo- and iodo vinyl
ethers. Using TMSBr (or TMSI), Yu and Jin were able to form these unstable ethers in
quantitative yield, without the need for column chromatography (Table 12) <2000JA9840>.
Table 12 Formation of -halovinylethers using TMS-X

Me OR
Me OR
Br
TMSBr 99 <2000JA9840>
H
TMSI 97 <2000JA9840>
R = (–)-Menthol
R = (–)-Menthol
OMe OMe TMSBr 89 <2000JA9840>

TMSI 91 <2000JA9840>
H Br
OR
OR TMSBr 99 <2000JA9840>
TMSI 99 <2000JA9840>
H Br
R = cyclohexyl
Additionally, when peroxide 214 was reacted with N-iodosuccinimide (NIS), -iodovinyl ether
215 was formed in 91% yield <1999JCS(P1)3345> (see Figure 32).
C3H7 SnBu3 C3H7 I
MeO O O OAc MeO O O OAc
214 215
Figure 32
4.17.2.2 Halogen and Sulfur Derivatives
4.17.2.2.1 Fluorovinyl sulfides, sulfoxides, and sulfones

Wittig-type reactions have proven to be an efficient way to construct -fluorovinyl sulfoxides and
sulfones. Trifluoromethylated phosphonate 216 reacted with Grignard reagents to form fluorovi-
nyl sulfones 217, after elimination of the phosphoric acid anion (Equation (10)) <2002OL2083>.
PhO2S O RMgX F3C SO2Ph

F
(EtO)2(O)P CF3 –P(O)(OEt)2 R F
216 217
R = p-FC6H4, 73% ((E ) only) ð10Þ
R = p-ClC6H4, 75% ((E ) only)
R = o-Tol, 83% ((E ) only)
R = m-Tol, 66% ((E ) only)
R = p-Tol, 58% ((E ) only)
R = o-CH3OC6H4, 72% ((E ) only)
Chiral sulfoxide 218 has also been reported to olefinate aldehydes to provide vinylsulfoxides
219 in both good yield and selectivity <2001EJO911> (Equation (11)). Fluorovinyl sulfones can
also be synthesized using phosphonate 220. Phosphonate 220 will also react with both alde-
hydes and ketones to give the desired sulfones 221 in high yield, albeit with moderate selectivity
(see Figure 33).
O O R1 O
: i. LDA, THF :
Ph P S 2 S
Ph p-Tol R p-Tol
ii. R1R2CO
F F
218 219
R1 = R2 = H, 82% ð11Þ
R1 = Me, R2 = H, 91%, (E )/(Z ) 8/92
R1 = But, R2 = H, 57%, (E )/(Z ) <2/98
R1 = Ph, R2 = H, 85%, (E )/(Z ) 80/20
R1 = p-Tol, R2 = H, 86%, (E )/(Z ) 94.5/5.5
R1 = Ph, R2 = Me, 18%, (E )/(Z ) 52/48
R SO2Ph
–
[PhSO2CFPO(OEt)2]
F
Ph
220 221
R = H, 100%, (E )/(Z ) 1/1

R = CH3, 92%, (E )/(Z ) 2/1
Figure 33
Similar to 1,1-dihaloalkenes, elimination reactions provide a viable route to -fluorovinyl

sulfides, sulfoxides, and sulfones. Exposing 151 to KOH resulted in dehydrofluorination to
form 222. This sulfide 222 can be oxidized with 3-chloroperoxybenzoic acid (MCPBA) to produce
the corresponding vinyl sulfone <2000T3539, 1998TL6529>. Furata and Hiyama reported that
223 reacted with zinc to yield the expected olefin in high yield <1996TL7983>. Carbonate 224
readily eliminated in the presence of NaOH (1.5 equiv.) to form vinylsulfone 225 in quantitative
yield <2001TL4861, 1998BCJ1939>. It is important to note that this elimination failed when
sulfide 226 was used, resulting only in decomposition.
Like -halovinyl ethers, -fluorovinyl sulfides can be prepared by the reaction of metallated
thiophenoxides with trifluoroethylene <1997T17127>. Vinyl sulfide 152 was produced via an
addition/elimination process when fluorotrichloroethylene was exposed to sodium thiophenoxide
(see also Table 11). By an analogous pathway, lithium thiophenoxide reacted with 227 to give
vinyl sulfide 228 <1999JFC(97)109>.
Other miscellaneous preparations of this functional group have been reported. Exposure of
vinylsilane 229 to CsF resulted in cross-coupling with S-phenylbenzenethiosulfonate to afford
230 in excellent yield <2002JFC(118)99>. Lastly, Fuchigami and co-workers have reported the
synthesis of allenes 231 by NaOMe-mediated rearrangement of the corresponding alkyne
<2001TL3009, 2002T5877> (see Figure 34).
O O
HO
F Cl F Cl Br SMe O O O O
F Cl H F SO2Ph
PhS H PhS Cl Ph(CH2)4 F SO2Ph SPh
F
F F
151 222 223 224 225 226
O O
SiPh2Me SPh F
F Cl F PPh2 F PPh2
F F Ar
PhS F F H PhS H
152 227 228 229 230 231
63%, (E )/(Z ) = ~1/1 83%, (E )/(Z ) = 90/10 50–70%
Figure 34
4.17.2.2.2 Chlorovinyl sulfides, sulfoxides, and sulfones

Like the corresponding -fluoro derivatives, -chlorovinyl sulfoxides can be synthesized using
Wittig-type reactions. 232 readily reacted with a variety of aldehydes to provide -chlorovinyl
sulfoxides 233 in good yields <1996TA3513> (Table 13).
Table 13 Wittig-type reactions to form -chloro

vinylsulfoxides
Cl H H O
MeO p-Tol i. n-BuLi :
P S S
MeO R p-Tol
O O ii. RCHO
:
Cl
232 233
R Yield (%) (Z):(E)

Ph 85 1.2:1
p-BrC6H4 92 6:1
p-NO2C6H4 78 100:0
Me 63 2.2:1
Phosphine oxide 234 also reacts with a large variety of aldehydes to form -chlorovinyl
sulfones 235 in good yield with high selectivity <1997T10527> (Table 14).
Table 14 Wittig-type reactions to form -chlorovinyl sulfoxides

O O H O
i. LDA
Ph P S S
R1 R2 R1
Ph ii. R2CHO
Cl Cl
234 235
R1 R2 Yield (%) (Z):(E)

Me Ph 75 >98:2
Me p-ClC6H4 70 >98:2
Me p-MeOC6H4 71 >98:2
Me Bun 63 4.7:1
Ph H 72 –
Ph Prn 70 97:3
p-tolyl Ph 60 >98.2
Elimination reactions also provide a convenient procedure for the preparation of -chlorovinyl
sulfides and sulfoxides. Reaction of 236 with dimsylsodium resulted in the formation of 237
<2001TL9241, 2000T5113>. Thiol 238 (Mes = 1,3,5-trimethylphenyl) reacted cleanly with tri-
chloroethylene, in the presence of KH, via an addition/elimination pathway to give 239
<2001JOC6400, 1995JOC7690>.
Not only has Jin and co-workers reported a general procedure for the formation of -halovinyl
ethers using TMS-X (see Sections 4.17.2.1.2 and 4.17.2.1.3), but he also reported a modified
procedure for the formation of -halovinyl sulfides <2001TL3771>. Acetylenic sulfide 240
reacted cleanly with TMSCl and MeOH to give the expected vinyl sulfide in quantitative yield.
HCl gas has also been successfully used to convert a substituted alkyne 241 to the corresponding
-chlorovinyl sulfide 242 in 82% yield (single isomer) <2001JOC5237>.
Percy and co-workers have reported that organolithium 243 reacted with a variety of electro-
philes including S-phenyl benzenethiosulfonate, which delivered vinyl sulfide 244 in 93% yield
<1998JSC(P1)2541>. Additionally, 245 has been reported to undergo a Pummerer rearrangement
in the presence of acetyl chloride to yield 246 <1997JOC8031>. Finally, Suma and Asokan have
reported that exposure of 247 to the Vilsmeier reagent (POCl3, dimethylformamide (DMF))
resulted in the formation of -chlorovinyl sulfides 248 <1996SC847> (see Figure 35).
O
OAc O H3C(CH2)3 SPh alkyl SCH3
Ph S p-Tol
S p-Tol : SR
Ph 240 241
:
Cl H 3C Cl SCH3
SCH2Mes
236 237 R = H, 238
(90%, (Z ):(E ) 4:1) R = ClC=CHCl, 239, 71% alkyl Cl
242
:
F Cl O S NHCbz O S O Cl
F Cl S NHCbz p-Tol
p-Tol
Cl R Ar SMe Ar SMe
F Li F SPh H R
243 244 245 246 247 248
R = CF3, CF2H Ar = Ph, 70%
Ar = p -Tol, 68%
Ar = p-ClC6H4, 60%
Figure 35
4.17.2.2.3 a-Bromo- and a-iodovinyl sulfides, sulfoxides, and sulfones

Alkynyl sulfides provide an efficient route to -bromo and iodovinyl sulfides. In 2001, Jin and
co-workers published a general procedure for the formation of -halovinyl sulfides. Jin showed that
a variety of acetylenic sulfides react with TMS-X to produce the desired -halovinyl sulfides in high
yield without the need for purification <2001TL3771> Table 15. Additionally, sulfide 250 was
formed in good overall yield when acetylenic sulfide 249 was exposed to ZnX2 <1997JOC6326>.
Table 15 Synthesis of -halovinylsufides using TMS-X

Substrate Product Reagents Yield (%)a References
n-Pr SPh
n-Pr SPh
TMSBr 99b <2001TL3771>
H X
TMSI 99 <2001TL3771>
X = Br
X=I
R SPh
R SPh
H X TMSBr 99 <2001TL3771>
TMSI 99 <2001TL3771>
R = (CH2)2Ph, X = Br
R = (CH2)2Ph, X = I
SPh
SPh
TMSBr 99 <2001TL3771>
H X
TMSI 99b <2001TL3771>
X = Br
X=I
a b
All products were isolated as a single isomer unless otherwise indicated. (E)/(Z) 20/1.
The reaction of organometallic species with electrophilic bromine (or iodine) also provides a
potential route to these uncommon functional groups. For example, stannane 251 has been shown
to react with I2 to provide vinylsulfone 252 in 88% yield <1996JA4284>. Also, vinyl tosylate 253
was converted in good yield into the corresponding -bromovinyl sulfide upon addition of MgBr2
<2001SL371>. Reaction of vinylzirconium species 255 with I2 produced vinyl sulfoxide 256 in
good overall yield <2000T8921>. Treatment of lithium dianion 257 with I2 produced diiodide 258
in 48% yield (see Figure 36). Finally, formation of -iodovinyl sulfides can also be accomplished
using cuprates <1995TL3605>.
Hexn SnBu3 Hexn I Ph SMe Ph SMe

H S* X S*
S* = chiral sulfoxide H SO2CF3 H SO2CF3 H OTs H I
249 250 251 252 253 254
X = Cl, 83%
X = Br, 75%
X = I, 87%
Ph SOPh Ph SOPh Li Li I I
S S S S
H ZrCp2Cl H I But But But But
255 256 257 258
R = SOPh, 68%
R = SOp-Tol, 69%
Figure 36
The addition of bromine to alkenes or alkynes has also been shown to lead to -bromovinyl
sulfides and sulfones. Addition of bromine to 259, followed by exposure to base (NEt3) resulted in
formation of vinyl bromide 260 <1997SL1043, 1995TL3605>. Also, Yoshimatsu and co-workers
demonstrated that ethyl enol ether 261 reacted with bromine to give vinyl bromide 262 in high
yield <1999CPB1497>. Finally, Braga and co-workers demonstrated that the bromination of
acetylenic sulfides could be accomplished using Amberlyst A-26 in its perbromide form 263, to
form -bromovinyl sulfides efficiently <2000SC407> (see Figure 37).
Br N+(Me)3Br3–
PhS CF3 PhS CF3
S Ph S Ph
O2 O2
H OEt Br OEt
259 260 261 262 263
Figure 37
4.17.2.3 Halogen and Selenium or Tellurium Derivatives

The reaction of organometallics with electrophilic halogens provides an efficient method for the
preparation of -halovinyl chalcogens. Dabdoub and co-workers reported that the hydrozircona-
tion of telluroalkynes produced a vinyl zirconium species that cleanly reacted with I2 or NBS to
produce telluroalkenes (Table 16) <1998T2371>.
Table 16 Formation of -halovinyl tellurium compounds

using vinylzirconium reagents
R TeC4H9 R TeC4H9
H ZrCp2Cl H X
R Reagents Yield (%) E:Z

n
Pr I2 80 90:10
Bun I2 77 86:14
C6H13 I2 80 80:20
Ph I2 81 95:5
C3H7 NBS 80 55:45
C6H13 NBS 77 56:44
Dabdoub and Baroni also reported that stannane 264 reacted with either NBS or I2 to give the
corresponding iodide 265 <2000JOC54>. It has also been demonstrated that ethynylselanyl-
benzene 266 undergoes hydrostannation with tributyltin hydride to yield 267. When exposed to
I2, 267 produced iodoalkenes 268 in high yields <1997SC225, 1997SC2407> (see Figure 38).
R SnBu3 R I R SnBu3 R I
PhSe H
H TeBu H TeBu H SePh H SePh
264 265 266 267 268
R = H, 56% R = Ph, 84%
R = Bun, 92% R = p-ClC6H4, 82%
R = C6H13, 85% R = p-Tol, 85%
R = Ph, 81%
Figure 38
Alkynyl chalcogens have also been converted to the corresponding alkenes by a number of
methods. Braga and co-workers have reported that a broad range of acetylenic selenides react
with HX to yield 1-halo-1-selenolalkenes (Table 17) <1996T9687>.
Table 17 Addition of HX to acetylenic selenides
HX Bun SeMe
Bun SeMe
X
HX Yield (%) Z:E

HCla 75 4.2:1
HClb 78 4.1:1
HClc 84 12.8:1
HBra 74 10.8:1
HBrb 76 14.1:1
HIa 80 2.6:1
HIb 85 2.6:1
a
Reaction performed in benzene/HOAc (3:1)/ aq. HX. b Reaction
performed in CHCl3/aq HX in the presence of catalytic amounts of HgCl2
(5.0 mol. %). c Reaction performed in benzene with saturated, dry HX.
Alkynylseleniums 269 have also been demonstrated to undergo bromination with Br2 to form
270 in good yield <2001SC3027>. This has also been demonstrated with perbromide resins
<2000SC407>. Additionally, 271 was cleanly hydrochlorinated using a mixture of LiCl and
HOAc to produce 272 <2000S1819>.
Finally, 273 has been successfully used in Wittig-type reactions with a variety of aldehydes
<2001PS(172)173> (see Figure 39).
Br SePh R1 SeR2 Cl
R SePh R1 SeR2 PhSe
R Br H Cl Cl
269 270 271 272 273

R = CH3, 72% R = 1 Prn, R2 = CH3, 84%, 100% (Z )
R = Ph, 78%
R1 = Bun, R2 = Et, 82%, 100% (Z )
R = p-Tol, 80%
R = THPOCH2, 55% R1 = C6H11, R2 = Me, 70%, 100% (Z )
Figure 39
ACKNOWLEDGMENTS
The superb information collecting skills of Mrs. Cherie St. Jean are gratefully recognized.
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Biographical sketch
David J. St. Jean, Jr. was born in Alexandria, Professor Gary Molander was born in Cedar
VA. in 1977. He received a B.A. degree with Rapids, IA, USA. He received his B.S. degree
distinction from Goucher College, Towson, at Iowa State University in 1975 working with
MD, in 1999. During his time at Goucher, Professor R. C. Larock. He entered the grad-
he was an NSF funded research assistant at uate chemistry program at Purdue University
UCLA with Professor R. Kaner, as well as a in 1975, obtaining his Ph.D. degree in 1979
research associate at Goucher with Professor under the direction of Professor H. C. Brown.
D. Horn. From there, he moved to the Uni- He joined Professor B. Trost’s group at the
versity of Pennsylvania, where he is currently University of Wisconsin, Madison as a
pursuing a Ph.D. in organic chemistry under National Institutes of Health postdoctoral fel-
the direction of Professor G. Molander. His low in 1980, and in 1981 he accepted an
interests include synthetic organic chemistry appointment at the University of Colorado,
with emphasis on the development of novel Boulder, as an assistant professor of chemis-
stereoselective C¼C bond forming reactions try. He was promoted to Associate Professor
using organometallic reagents as well as meth- in 1988 and Professor of Chemistry in 1990.
ods driven total synthesis. In 1999 he joined the faculty at the University
of Pennsylvania, and in 2001 was appointed
Allan Day Professor of Chemistry. His
research interests focus on the development
of new synthetic methods for organic synth-
esis and natural product synthesis. A major
area of research has also been the application
of organolanthanide reagents and catalysts to
selective organic synthesis.
4.18
and Another Group Other Than a
Halogen or a Chalcogen
C. V. STEVENS and B. VANDERHOYDONCK
Ghent University, Ghent, Belgium
4.18.1 HALOGEN AND NITROGEN DERIVATIVES 736

4.18.1.1 gem-Amino Halo Alkenes 736
4.18.1.1.1 By addition of halide 736
4.18.1.1.2 By amination 740
4.18.1.1.3 By electrophilic attack 742
4.18.1.1.4 Other methods of alkene formation 743
4.18.1.2 gem-Halonitroalkenes 745
4.18.1.2.1 By halogenation 745
4.18.1.2.2 By nitration 746
4.18.1.3 Diazonium and Diazo Derivatives 747
4.18.1.4 Iminophosphorane, Sulfimide, and Metallonitrene Complexes 747
4.18.2 DERIVATIVES OF PHOSPHORUS AND OTHER GROUP 15 ELEMENTS 748
4.18.2.1 -Haloalkenylphosphorus Derivatives 748
4.18.2.1.2 From fluorinated alkenes 750
4.18.2.1.4 Other methods of alkene formation 755
4.18.2.2 -Haloalkenyl Derivatives of Arsenic, Antimony, and Bismuth 757
4.18.3 DERIVATIVES OF SILICON AND OTHER GROUP 14 ELEMENTS 757
4.18.3.1 -Haloalkenylsilicon Derivatives 757
4.18.3.1.2 By silylation of -haloalkenyllithium and -haloalkenylmagnesium species 757
4.18.3.1.4 By halogenation of -silylalkenyl metal derivatives 763
4.18.3.1.5 By addition of alkyl halides to alkynyl silanes 769
4.18.3.2 -Haloalkenylgermanium Derivatives 770
4.18.3.3 -Haloalkenyl Derivatives of Tin and Lead 771
4.18.4 DERIVATIVES OF BORON AND OTHER GROUP 13 ELEMENTS 773
4.18.4.1 -Haloalkenylboron Derivatives 773
4.18.4.1.1 By ligand exchange and by halogenation reactions 773
4.18.4.1.2 By hydroboration of haloalkynes 774
4.18.5 DERIVATIVES OF LITHIUM AND OTHER GROUP 1 AND GROUP 2 METALS 775
4.18.5.1 -Haloalkenyllithium Derivatives 775
4.18.5.1.1 -Fluoroalkenyllithium compounds 776
4.18.5.1.2 -Chloroalkenyllithium compounds 776
4.18.5.1.3 -Bromoalkenyllithium compounds 777
4.18.5.1.4 -Iodoalkenyllithium compounds 777
4.18.5.2 -Haloalkenylmagnesium Derivatives 777
735
736 Functions Incorporating a Halogen and Another Group Other Than a Halogen or a Chalcogen
4.18.6 DERIVATIVES OF THE TRANSITION METALS 778

4.18.6.1 By Transmetallation Reactions 778
4.18.6.2 From Alkenyl Halides 779
4.18.6.3 From Alkynes 780
4.18.1 HALOGEN AND NITROGEN DERIVATIVES
4.18.1.1 gem-Amino Halo Alkenes

Although Ghosez and Marchand-Brynaert have reviewed the synthesis of -haloenamines twice
<B-1976MI418-01, 1988OSC(6)282>, they did not include those compounds in which the
electron pair is involved in further functionality, such as enamides. This chapter focuses on
-haloenamines as well as compounds bearing further functionalization on nitrogen following
the same structure as used by Smith <1995COFGT(4)789>. The transformations reviewed by
Smith are briefly summarized and further updated concentrating on the period 1995–2003.
4.18.1.1.1 By addition of halide

The most common method to synthesize -chloroenamines starts from tertiary amides, using phos-
gene as a chlorination agent and triethylamine as base <1988OSC(6)282>. This general method is
successfully applied to prepare a wide variety of N,N-dialkyl -haloenamines. Similarly, Breitenmoser
and Heimgartner prepared -chloroenamines from the corresponding thioamides using phosgene and
DABCO as base (Equation (1)) <2002HCA885>. Compared to the use of the amides directly,
treatment of the thioamides with phosgene leads to better yields <1996HCA527>.
S i. COCl2, toluene Cl
cat. DMF
N CO2R N CO2R
ii. DABCO, THF ð1Þ
R = Me, Et
Prompted by the hazards associated with the use of large amounts of phosgene as well as the
ban on phosgene in many laboratories, Ghosez and co-workers re-examined the synthesis of
-disubstituted -chloroenamines <1998T9207>. -Chloroenamine 3 is successfully prepared
using di- or triphosgene, which are easier to manipulate and to store (Scheme 1). The best results
are obtained with 2 equiv. of diphosgene at room temperature or 3 equiv. of triphosgene in
refluxing dichloromethane. In both cases the formation of 1 was accompanied by that of a minor
product 2. However, both compounds lead to enamine 3 upon treatment with base. Holmes and
co-workers prepared -chloroenamine 3 as well as the corresponding bromo derivative with oxalyl
chloride or oxalyl bromide, respectively, followed by treatment with triethylamine <1997CC1067>.
O Cl – OCO2CCl3
(COCl2)n Cl +
+
NMe2 NMe2 + NHMe2
–
CH2Cl2 Cl
1 2
Et3N
Cl
NMe2
3
n = 2, 75%
n = 3, 65%
Scheme 1
Functions Incorporating a Halogen and Another Group Other Than a Halogen or a Chalcogen 737
Using phosphorus oxychloride and phosphorus oxybromide, Ghosez and co-workers successfully
prepared a large variety of -chloro- and -bromoenamines, respectively, which were thermally stable
and were purified by distillation (Equation (2)). The bromination reactions take place more rapidly
than the corresponding chlorination reactions. Besides, in the presence of a catalytic amount of
dimethylformamide (DMF), the chlorination and the bromination is reported to proceed much faster
<1998T9207>. Following a similar method using phosphorus pentachloride instead, 2-azabutadiene
4 has been prepared from N-benzyldichloroacetamide in 63% yield <2001RJGC143>. This pro-
cedure has been extended to the preparation of polymer bounded -haloenamines 5 by treating
immobilized tertiary amides with phosphorus halide and triethylamine <2003WOP0320684>.
O i. OPX3, CH2Cl2 X
R R cat. DMF R R
N N
ii. NEt3, CH2Cl2 ð2Þ
R R R R
Distil
46–95% X = Cl, Br
Cl Cl
N N
Cl
polymer
4 5
1,2-Dichloro-1,2-diaminoethenes 8 are prepared from Vilsmeier reagent 6 and a bulky base

(Scheme 2). Vilsmeier reagent 6, generated from N-methylformanilide and oxalyl chloride or
phosphorus oxychloride, is deprotonated leading to the aminochlorocarbene 7. The carbene subse-
quently reacts with another molecule of compound 6 yielding the 1,2-dichloro-1,2-diaminoethenes 8.
When N,N-diisopropylethylamine (DIPEA or Hünig’s base) is used, these dimers are formed optimally.
The dimers 8 are unstable compounds that decompose slowly on storage, especially when electron-
donating groups are present (R = Me, MeO) <1996CC1395, 1998JCS(P1)1619, 2002S2426>.
R R
H
(COCl)2 or OPCl3
CHO
N N Cl
R = H, F, Cl, Br, Me, OMe Cl Me
Me
50–85%
6
DIPEA
Me
R
Cl N R 6
R N Cl N Cl
Me Me
8 7
Scheme 2
Due to their mode of reactivity, -haloenamines bearing a basic nitrogen atom are usually
found in a mixture of (E)- and (Z)-isomers, equilibrating via the keteniminium halide. This
property is used in the preparation of the fluoro, bromo, and iodo derivatives from the readily
available chlorides (Scheme 3) <1977NJC369, 1979CC1180>. A fluoro derivative can be alter-
natively prepared, adding potassium hydrogen difluoride to N,N-diethyl-1-propynamine
<1977NJC369>. The -fluoroenamine is isolated in a 9:1 (E):(Z) ratio, though slow isomeriza-
tion shifts the ratio to 10:1 in favor of the (Z)-isomer during storage in chloroform.
R NR2
R F
KF
50–80%
R NR2 R CH2Br2 R NR2

NR2 Cl
R Cl R R = Me, 78% R Br
KI
40–73%
R NR2
R I
Scheme 3
The direct dihalogenation of ynamines has been described only once. Ishihara and co-workers
treated N,N-dibutyltrifluoropropynamine with bromine, furnishing the ,-dibromoenamine
quantitatively (Equation (3)). Fluorine NMR analysis showed that the ,-dibromoenamine
was a mixture of two isomers in a ratio of 78:22. The use of other solvents—such as dichloro-
methane, tetrahydrofuran, diethyl ether, and dioxane—led to similar results, though the ratio of
the isomers was slightly varied (78–84:22–16) <2001JFC(108)229>. -Phosphorylated -halo-
enamines are accessible via the reaction of an ynamine with phosphorus pentachloride. Trostyanskaya
and co-workers synthesized compounds 10 and 11 upon treatment of salt 9 with Et4NI or SO2,
respectively (Scheme 4) <1996ZOR1054>. The addition of phosphorus pentachloride is reported
to be a stereoselective anti-addition solely yielding (E)--chloroenamines. (E)--haloenamides
have been prepared by hydrohalogenation of ynamides using magnesium halide salts. The reac-
tion is highly regio- and stereoselective when performed in wet dichloromethane. The proposed
source of hydrogen halide is its in situ generation from the magnesium halide salt and traces of
water present in the reaction mixture (Equation (4)) <2003OL1547>.
N(Bun)2
Br2
F3C N(Bun)2 Br
Br
Molecular sieves (4 Å) ð3Þ
CF3
CH3CN, rt
99%
Cl
Et4NI Cl2P NEt2
R = Me 10
PCl5 R Cl
R NEt2 PCl6 56–77%
Cl3P NEt2
R = Me, Et, Pr i
9
SO2 R Cl
Cl2P NEt2
O
11
Scheme 4
R2 MgX2 R2 C(O)R3
N
R1 N
C(O)R3 CH2Cl2 R1 ð4Þ
X
37–99%
X = Cl, Br, I
Further functionalization at the -position can be accomplished employing the appropriate

-functionalized amide <B-1976MI418-01>. Trichlorovinylamines may be prepared by action of
tributylphosphine on trichloroacetamides (Equation (5)) <1960JA903, 1973OSC(5)387>. Alter-
natively, N,N-disubstituted acetamides with the nitrogen atom linked to at least one aromatic
substituent yield -phosphorylated -chloroenamines with cis(P, N) configuration when treated
with phosphorus pentachloride (Equation (6)) <1999RJGC1377>. Further, reacting N-(fluoro-
acetyl)trichloroacetamide with phosphorus pentachloride leads to the formation of the correspond-
ing acetimidoyl chloride, which upon treatment with 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) or
on heating at elevated temperatures affords the gem-chlorovinylenamide (Equation (7))
<2002JFC(117)107>.
O NEt2
Bu3P, 85–95 °C Cl
Cl ð5Þ
Cl3C NEt2
Distil, 69–74 °C Cl
O Cl
3 equiv. PCl5 –
NR1R2 NR1R2 PCl6
+
benzene PCl3
30–77%
ð6Þ
R1 = Ph, 4-CH 3–C6H4, 4-NO2–C6H4

R2 = Me, Et, Pr i, Ph, Bz, CH2CH CH2
O O Cl O
i. PCl5
F F
N CCl3 ii. DBU or ∆ in POCl3 N CCl3 ð7Þ
H H
62%
(Z )/(E ) 3/1
Primary -haloenamines have been prepared by addition of hydrogen halides across acetonitrile
derivatives bearing electron-withdrawing groups (Scheme 5). Hydrogen chloride, bromide, or iodide
successfully adds to the potassium salt of tricyanomethanes in very high yields (93–98%)
<1963CB3230>, as does the corresponding addition of hydrogen chloride to dicyanomethane deri-
vatives <1963CB1035, 1970TL1937>. Secondary -chloroenamines are prepared by an unusual
reaction path involving a thermolysis of 2,2-dicyanovinylazides (Scheme 6) <1967AG(E)959>.
R R R NH2
HX
K CN NH2 X
NC NC NC X
X = Cl, Br, I
R = CN, CO2Et, CONHPh
Scheme 5
NC R NC NC NHR
∆ HCl
NR
NC N3 NC NC Cl
R = H, Me, Ph
34–74%
Scheme 6
4.18.1.1.2 By amination
The addition of nitrogen nucleophiles to unsaturated halides also leads to the formation of
-haloenamines. Dimethyl- and diethylamine both add to dichloroalkyne, which is prepared in
situ from trichloroethene prior to the addition of the amine <1987S76>. In addition, heterocyclic
nitrogen nucleophiles add to dichloroalkyne yielding the corresponding -chloroenamines as well.
The reaction of benzimidazole with trichloroalkene in dimethylformamide furnishes the adduct 12
as the (E)-isomer in rather poor yield (Equation (8)). Benzimidazoles bearing an alkyne substi-
tuent at the 2-position give better results, although the addition requires more forcing conditions
in the case of 2-(2-triisopropylsilylethynyl)benzimidazole <2002OL4543>. Similarly, alkenes 13
and 14 are obtained using carbazole <1988LA595> and imidazole <1989BAP123> as nitrogen
nucleophiles, respectively. Further, N-aryl formamides add to dichloroethyne, which is generated
from trichloroethene upon reaction with sodium hydroxide in the presence of tetra-n-butylammo-
nium hydrogen sulfate (TBAHS) as a catalyst. The reaction affords a mixture of the -chloro-
enamidine and an azacyclic compound (Equation (9)) <2002SL1703>. Usually, this type of
reaction affords the (E)-isomer, which is explained by assumption of anti-addition across the
triple bond.
i. NaH or KH, DMF N

N 50–60 °C R
R N
N ii. Cl2C CHCl, rt Cl
H Cl ð8Þ
R = H (35%) 12
= C CPh (94%)
= C CTIPS (70%)
Cl
O Cl
50% NaOH R R R R
R Cl N N N
N H + + N N N
H Et2O, C6H12, TBAHS Cl
Cl Cl R ð9Þ
R = C6H4 65% 30%
4-CH3-C6H4 52% 42%
4-Cl-C6H4 44% 32%
4-MeO-C6H4 70% 25%
When a functional group capable of stabilizing the developing negative charge is present,
monohaloalkynes may also be employed. Aziridine, for example, adds to methyl bromopropiolate
in methanol, affording enamine 15 <1984CHE1231>. -Bromoenammonium salt 16 is prepared
by reaction of -bromopropynones with N,N-dimethylhydrazine in acetonitrile at 20 C. The
structure of the compound was established by X-ray analysis <1999RCB1516>.
N Br
N N N NMe2NH2
Cl Cl MeO2C
Cl Cl Br ROC Br
13 14 15 16
(yield: 80%) (yield: 60%) (yield: 78%) R = Ph, 2-thienyl
(yield: 45–69%)
An alternative approach makes use of an addition–elimination reaction of a nitrogen nucleo-

phile with a ,-difluoro ,-unsaturated ester. Starting from compound 17, Shi and co-workers
isolated the corresponding gem-difluoroindolylalkene in excellent yield (Equation (10)). Unlike
similar ,-difluoro ,-unsaturated carbonyl compounds, which lead to exhaustive substitution
of two fluorine atoms, only one fluorine is substituted owing to the presence of the electron-
donating silyl group. To explain the formation of only the (Z)-isomer, Shi and co-workers
proposed an intramolecular coordinative interaction between the silicon and fluorine atom
<2000JOC627>.
F SiMe3 SiMe3 F SiMe3

Indole, n-BuLi F
F Nu N
THF, –78 °C CO2Et ð10Þ
CO2Et F CO2Et
94%
17 Nu = indolyl
Several perfluorinated alkenes also allow the synthesis of -fluoroenamines. Perfluoro-2-

methylpent-2-ene <1995JFC(73)267> and perfluoro-3-methylpent-2-ene <1998JFC(88)169> are
both found to react in good yield with amines via a fluoride-ion-catalyzed isomerization of the
double bond. However, using morpholine or bis(perfluoro-p-tolyl)amine, perfluoro-2-methylpent-
2-ene affords a mixture of the corresponding -fluoroenamine as well as the internal substitution
product (Scheme 7) <1996ZPK103>. The -fluoroenamines are reported to hydrolyze slowly to
the corresponding amide by exposure to the air.
C2F5 C2F5
HNEt2
F NEt2
NEt3 C2F5 C2F5
Et2O, 0 °C
Et2O, 0 °C F F
90%
R1 = CF3
R2 = F
CF3 O C2F5
C2F5
Morpholine CF3
CF3 N + N
R1 C3F7
1
R = F; R2 = CF3 F O CF3
R2
R1 = F
R2 = CF3
N(SiMe3)Et2 CF3 CF3

N(SiMe3)Et2
Et2O, rt F NEt2
C3F7 C3F7
Et2O, rt
F 98% F
Scheme 7
Furthermore, monosubstitution of gem-dihaloalkenes with amines is successfully applied preparing

-haloenamines. Coe and co-workers allowed diethylamine to react with perfluorinated diene 18,
giving a mixture of the four possible isomers (Equation (11)). Only the major isomers 19 and 20 were
isolated and fully characterized <2001JCS(P1)552>. Treatment of polyhalogenated 2-nitro-1,3-buta-
diene 21 with amines leads to replacement of the terminal chlorine in the trichlorovinyl group or of
bromine in the bromodichlorovinyl group (Equation (12)) <1997RJOC1632, 2000RJOC877>.
CF3 CF3 CF3 CF3

F NEt2
F F
CF3 CF3 CF3 NEt2 CF3 F
5 equiv. HNEt 2
F 19
F
Et2O, rt ð11Þ
CF3 F
59% F CF3 F CF3
18 F NEt2
F3C F3C
CF3 NEt2 CF3 F
20
R1 Cl R1 Cl
HNR2
X NR2
R2 R2
X = Cl, Br
NO2 Cl NO2 Cl
ð12Þ
21
R1 = benzotriazol-1-yl, 3,5-dimethylpyrazol-1-yl
R2 = arylamino, 3,5-dimethylpyrazol-1-yl
Finally, gem-haloaminoalkenes have been prepared using a Michael-type addition followed by

a subsequent elimination. Coe and co-workers report the addition of dimethylamine to ketone 22
(Scheme 8) <2000JCS(P1)1529>. The addition product 23 is noted to be more reactive than
starting material 22, so that a second Michael-type addition leads to the corresponding gem-
haloaminoalkene. Before, Schroth and co-workers isolated gem-chloropyrrolidinoalkenes from
,-dichloroalkenylarylketones. According to them, -keto -haloenamines are configurationally
unstable. This instability is attributed to a lowering of the barrier to rotation about the double
bond by donor–acceptor interactions, rather than to any tendency to form a ketenimine
<1982S199>.
CF3 O CF3 O
HNMe2 Me2N
C2F5 CF3 C2F5 CF3
Et2O, –20 °C
CF3 F F
22 23
36% HNMe2
CF3 O
Me2N
C2F5 CF3
F NMe2
Scheme 8
4.18.1.1.3 By electrophilic attack

Electrophilic halogenation, in which the multiple bond participates as a nucleophile, is not well
documented since enamines direct such substitution into their 2-position. However, halogenation of
1-diethylamino-2-phthalimidostyrenes with chlorine and bromine furnishes -haloenamides 24 via a
2-substitution in good yields (68–95%) <1967CB1087>. An unusual example of 1-bromination has
been observed with perfluoro-N-bromodimethylamine affording the corresponding 3-bromoallene 25
from 1,1,3-tris(hexafluorodimethylamino)propadiene in high yield <1973JCS(P1)1066>.
O
Et2N N (F3C)2N N(CF3)2
O
X (F3C)2N Br
25
R 24
X = Cl, Br
Minière and Cintrat prepared ,-diiodoenamide 26 via iododestannylation of the correspond-

ing stannylenamine with 2 equiv. of iodine (Scheme 9). Compound 26 was reported to be too
unstable to be purified, but the purity of the crude compound was reported to be higher than 90%
<2001S705>. Employing a titanacycle, Sato and co-workers successfully prepared diiodide 27 by
iodinolysis in good yield (Equation (13)) <2003OL67>.
Ts Ts
Ts (SnMe3)2 N Bn 2 equiv. I2 N Bn
H N
Bn Pd(PPh3)4 Me3Sn SnMe3 CH2Cl2, –78 °C I I
THF, 50 °C 26
92%
Scheme 9
Ts Ts Bn
N Bn N
4 equiv. I2 I
Ti(OPri)2 ð13Þ
Et2O, –50 °C I
Bun Bun
Bun 65% Bun
27
4.18.1.1.4 Other methods of alkene formation

This section covers methods using reactants bearing already the heteroatom functionality. McNab
and Morrow treated Meldrum’s acid with phosgeniminium chloride affording the corresponding
chlorodimethylaminomethylene derivative in satisfactory yield (Equation (14)) <2002MI125>.
Trichloroacetimidoyl chlorides react with triethylphosphite yielding a 2.1:1 mixture of compound
28 and the -chloroenamide, respectively (Equation (15)). Starting from trifluoroacetimidoyl
fluoride, only the corresponding compound 28 and no -fluoroenamide is formed
<1999RJGC1879>.
O Cl O NMe2
Me Me
O N O Cl ð14Þ
+
O O Cl Cl CHCl3 O O
60%
CO2Me MeO2C CO2Me

1 equiv. P(OEt)3 N PO(OEt)2
Cl N (EtO)2OP N
Cl +
toluene Cl ð15Þ
CCl3 CCl3
distil Cl
28
(yield: 37%)
Drach and co-workers have prepared N-trichlorovinylbenzimidoyl chloride and -benzylideneamine

by 1,2- and 1,4-elimination of hydrogen chloride <1975JOU119, 1976JOU2252, 1980JOU1762>.
The elimination method was also implemented by Anders et al. (Scheme 10). Pyridinium chloride 29 is
prepared from thionyl chloride, trichloroacetaldehyde, and pyridine in acetonitrile in very good yield
(80%). The electron-withdrawing trichlorovinyl group of N-(trichloroethenyl)pyridinium chloride
activates the pyridinium moiety allowing nucleophilic addition. Tributylphosphine, benzylmagnesium
bromide, and triisopropylphosphite all add to the C4 position, exclusively <1999JOC3113>.
Diphenylethyne is fluorinated with methyl 3-azidotetrafluoropropionate in a closed vessel and
at high temperature, furnishing the corresponding -fluoroenamide in poor yield (Equation (16)).
The mechanism of the reaction is believed to involve intermediate formation of an N-substituted
azirine followed by a phenyl and fluoride shift <2002RJGC1289>. Shevchenko and co-workers
Cl
Cl
N Cl
P(Bun)3 Cl
CH2Cl2, 0 °C P(Bun)3
91%
Cl Cl Cl Cl Cl
Pyr BnMgBr Cl
Cl
Cl3C N N N
EtOH, rt Et2O, –78 °C Cl
Cl
71% 73% Bn
29
P(OPri)3
CH2Cl2, –78 °C
80% Cl
Cl
N
Cl
P(O)(OPri)2
Scheme 10
reported an unusual reaction of methylene diphosphine and 5,5,5-trifluoro-4-(trifluoromethyl)pent-

3-en-2-one leading to a novel type of zwitterionic compound containing an -fluoro enamine
functionality (yield: 27%) (Scheme 11). The detailed structure of the enamine was solved by X-ray
analysis and is remarkable since it contains two oppositely charged phosphorus atoms with
different coordination numbers <2002CC120>. Performing this reaction with the corresponding
nitrile, a polyfluorinated triene (yield: 49%) was isolated instead together with a fluorine-
substituted ylide in a 1:1 ratio (Scheme 11). In the NMR spectra, a fast interconversion between
possible steric isomers has been observed; however, the central double bond always retains its
trans configuration <2003EJI54>.
F O
N3CF2CF2CO2Me
Ph Ph Ph
N CF2CO2Me ð16Þ
CH2Cl2, 170 °C H
Ph
20%
F F
(Et2N)2P P F
H
F3C O
R = C(O)CH3
F NEt2
F3C Et2O
(Et2N)2P
R –15 °C
+
F3C
(Et2N)2P
NEt2
20 °C
F3C
R = CN F (Et2N)2P PFNEt2
NC F3C
CN + CN
F CF3
CF3
NEt2
Scheme 11
4.18.1.2 gem-Halonitroalkenes
Barrett reviewed the preparation and synthetic utility of 1-heterosubstituted nitroalkenes covering
ether, thioether, halogen, and nitro substituents <1991CSR95>. Based on the structure used by
Smith <1995COFGT(4)789>, this chapter aims to extend and update that work.
4.18.1.2.1 By halogenation
The reactions outlined in this section are those in which the halogen is added at a nitro-containing
compound as an electrophilic species.
gem-Fluoronitroalkenes are very rare in the literature. (E)-1,2-difluoro-1,2-dinitroethene 30 has
been prepared by fluorination of 1,1,2,2-tetranitroethane and subsequent elimination of
dinitrogen tetraoxide <1991JOC537>. More general, fluorination of the dianion of 1,1,3,3-
tetranitropropane followed by alcohol-induced elimination leads to a series of alkyl -fluoro-
-nitroacrylate esters 31 <1989BAU635>.
F
NO2 NO2
O2N RO2C
F F
30 31
(yield: 92%) (yield: 40–45%)
An important method of preparation of -bromo- or -chloronitroalkenes is from nitroalkenes

by dihalogenation and subsequent elimination (Scheme 12). Using this method, Trukhin and
co-workers prepared -bromonitroalkene 32 in excellent yield <1996RJOC458> and its
(Z)-configuration was supported by proton NMR and UV spectral data <1998RJOC59>.
Bromination of nitroalkene 32 in refluxing chloroform and subsequent treatment of the tribromo
compound with potassium hydroxide in ethanol furnishes the corresponding (E)-,-dibromo
nitroalkene (yield: 50%) <1998RJOC1061, 1999RJGC803>. gem-Bromo nitroalkene 33 was
obtained by direct bromination of 2-nitrovinylfuran in the presence of activated carbon, followed
by dehydrobromination using pyridine <2000WOP0153283>. Botata and co-workers reported
the first preparation of -phosphorylated gem-halonitroethene 34. Nitrovinylphosphonate is
halogenated in glacial acetic acid with bromine or chlorine furnishing the corresponding dihalide
that readily undergoes dehydrohalogenation on silica gel or upon storage. Both gem-haloni-
troethenes are isolated as the (Z)-configuration, exclusively <1995RJGC141, 1998RJGC384>.
gem-Halonitroalkenes are reported to be configurationally stable under normal conditions. How-
ever, upon irradiation, 2-bromo and 2-chloro-2-nitrostyrene isomerize substantially from the (Z)-
to the (E)-configuration, giving a mixture composed of 60–80% (E) for the chloro derivative but
only 10–20% (E) for the bromo compound <1976JOC2112>.
NO2 X2 X NO2 Base NO2
R R X R X
R = alkyl, aryl
X = Cl, Br
Scheme 12
NO2 NO2
O NO2
Br (RO)2(O)P
Br Br
Cl X
32 33 34
(yield: 93%) R = CH2CH2Cl
X = Cl (50%)
= Br (78%)
To synthesize -chloro--nitrostyrene derivatives, Kim and co-workers developed an interesting

method applying hydrogen chloride in the presence of oxone (2KHSO5KHSO4K2SO4)
(Equation (17)). The authors tentatively proposed a mechanism involving the addition of hypochlor-
ous acid to the nitroalkene, followed by dehydration of the chloronitroalcohols. Hypochlorous acid is
formed in situ by oxidation of hydrogen chloride. Due to the reaction of hypochlorous acid with
unreacted hydrogen chloride, chlorine is probably generated causing some side reactions such as
ring chlorination or addition to the double bond of the produced -chloro--nitrostyrenes.
m-Chloroperbenzoic acid (MCPBA) was also successfully utilized as oxidant, but showed no
advantages over oxone in terms of yields and ease of separation. Further, it is notable to report
that nitroolefins having a substituent at the -position such as p-chloro--ethyl--nitrostyrene
decomposed almost quantitatively to p-chlorobenzaldehyde <1997SC1885>.
OH
HCl, DMF
NO2 NO2 NO2 ð17Þ
R R R
oxone, rt – H2O
Cl Cl
42–85%
Using N-halosuccinimides (NXSs) in benzene-chloroform, the halogenation proceeds directly

without the elimination step provided that the alkene is activated by an electron-donating group.
Chlorine, bromine, or iodine can be introduced with equal efficiency yielding the 2-halo-2-
nitro-enamines 35 <1985JOC1547>. An alternative route to 2-chloro-2-nitroenamine 36 includes
the condensation of chlorinated nitroacetone with aniline in the presence of titanium tetrachloride
<1977AP(310)30>. Finally, compound 37 has been prepared by addition of iodine to 1-ferrocenyl-
2-nitroethene in sodium methoxide <1969BCJ3270>.
R22N NO2
NO2 NO2
R1 PhHN Fe I
X Cl
35 36 37
X = Cl, Br, I (yield: 30%)
(yield: 30–90%)
4.18.1.2.2 By nitration
When heavily substituted or polyhalogenated, alkenes have been nitrated with nitric acid or
nitrogen oxides. Compound 38 is prepared from 1H-perchloro-1,3-butadiene by the action of
concentrated nitric acid <1991JOU48>. Nechai and co-workers employed a mixture of nitric and
phosphoric acid (10:1) to nitrate 1,1,3,4-tetrachloro-1,3-butadiene in order to synthesize 1,3-
dinitro-1,2,4,4-tetrachloro-1,3-butadiene (Equation (18)) <1998MI75>. Treatment of these multi-
functional compounds with strongly basic amines results in the substitution of the two terminal
chlorine atoms leading to the corresponding dinitrodienediamines <2000RJOC650>.
Cl Cl Cl Cl
HNO3 /H2PO4 (10:1) NO2
Cl Cl ð18Þ
Cl NO2 Cl
Dihaloalkynes are also suitable precursors for the preparation of the corresponding gem-
halonitroalkenes. Nitrotriiodoethene 39 has been prepared from diiodoethyne in variable yield
with nitrous acid in an excess of ethereal iodine <1900CB2190>. The addition of nitrogen dioxide
to dichloroethyne furnishes compound 40 in unspecified yield and geometry <1943CB88>.
Cl Cl
NO2 I NO2 NO2
Cl
Cl Cl I I Cl Cl
38 39 40
(yield: 49%) (yield: 40–70%)
4.18.1.3 Diazonium and Diazo Derivatives

Even though the aryldiazo derivatives of alkenes are stable and isolated as colored solids, the alkyldiazo
equivalents are much less stable and are only used as reactive intermediates <1979JCS(P1)249>.
Arylhydrazones of chloral spontaneously lose hydrogen chloride and lead to haloalkenyldiazo
compounds upon treatment with bromine or chlorine in unspecified yields (Equation (19))
<1931JCS1088>. More recently, Tyurin and co-workers found that 1-aryl-2-alkenyldiazene oxides
furnish the corresponding chlorohydrazones in quantitative yield when treated with hydrogen
chloride. Arylhydrazones, obtained from 1-aryl-2-(2-phenylethene)diazene oxides, undergo elimina-
tion of hydrogen chloride affording gem-chlorodiazoalkene in unspecified yield and in a 1:2 (E):(Z)
ratio (Scheme 13). Heating the mixture of isomers in acetonitrile for 15 h results in the isolation of
the (E)-isomer only <1994MC220, 1995IZV928, 1995IZV924, 1995IZV917>.
Cl Cl
X2
N N
Cl NPh Cl NPh ð19Þ
–HX
X
X = Cl, Br
Cl
N O HCl H 2O N R2
R1 N N Ph N
R 1 NHR2
R2 Et2O, rt CH3CN Cl
Cl
95–100% R1 = Ph
R2 = 2,4,6-Br3C6H2, 4-NO2C6H4
Scheme 13
4.18.1.4 Iminophosphorane, Sulfimide, and Metallonitrene Complexes

A variety of iminophosphoranes <1979JGU1947> and sulfimides <1976JOU782> have been
prepared by the reaction of -haloenamines with phosphorus or sulfur halides, respectively
(Scheme 14). Following an alternative approach, Rozinov and co-workers prepared compound
41 with unspecified configuration by treatment of acetaldoxime with phosphorus pentachloride in
benzene <1997RJGC483>. Further, compounds 42 were obtained in high yields by the addition
of triphenylphosphite <1972T5149> or phosphorus tribromide <1979JGU1947> across the
cyanide triple bond of -bromomalononitrile derivatives. Similarly, molybdenum and tungsten
chlorides have been added across 1,1-dicyanobis(trifluoromethyl)ethane furnishing compounds 43
<1986CB3150>.
NC N PBr3
PBr5 NC X
X = Br
NC NH2
NC X
X = Cl
SCl2 or SOCl2 NC N SCl2
NC X
Scheme 14
PCl6 F3C Cl
N R1 N PR32 F3C N MCl4
Cl3P PCl3
Cl R3 Br NC Cl
41 42 43
(yield: 41%) R1 = alkyl, CN M = W, Mo
R2 = OPh, Br
R3 = CN, CO2Et
4.18.2 DERIVATIVES OF PHOSPHORUS AND OTHER GROUP 15 ELEMENTS
4.18.2.1 a-Haloalkenylphosphorus Derivatives

Despite the substantial number of reported syntheses of -haloalkenylphosphorus species, only a
few proceed by direct condensation with carbonyl compounds. The first reaction of this type was
described by Seyferth and Marmor, who successfully applied the Wadsworth–Emmons reaction.
Treatment of the anion of tetraethyldichloromethanediphosphonate with pivaldehyde or acetone
gives high yields of -chlorophosphonoalkenes, but fails with benzophenone (Scheme 15)
<1973JOM(59)237>. Employing diethyltrichloromethylphosphonate, a one-pot procedure allows
the synthesis of -chloroalkenylphosphonates via the intermediate formation of lithium tetraethyl
chloromethanediphosphonate (Scheme 15) <1994JOC4548, 1997JCS(P2)967>. Feasson and
co-workers developed an electrochemically induced Wadsworth–Emmons synthesis of -chloro-
,-unsaturated phosphonates with a similar yield and stereoselectivity compared to the ones
obtained by the chemical procedure (lithiated base/low temperature) (Equation (20))
<1999S981>.
P(O)(OEt)2
[(EtO)2P(O)]2CCl2 BuLi R1CHO
R1 Cl
Major isomer
[(EtO)2P(O)]2CClLi
BuLi R2COR3
R1, R2 = alkyl, aryl R2 P(O)(OEt)2

(EtO)2P(O)CCl3 Et2O
–78 °C R3 = alkyl
R3 Cl
(E ) and (Z )
Scheme 15
P(O)(OEt)2
e–/Mg*, DMF, rt R1CHO
[(EtO)2P(O)]2CCl2 [(EtO)2P(O)]2CCl
Magnesium anode R1 Cl ð20Þ
Carbon felt cathode Major isomer
R1 = alkyl, aryl
Savignac and co-workers synthesized gem-chlorophosphonoalkenes in generally high yields

(56–95%) from the anion derived from chloromethanediphosphonate using lithium diisopropyl-
amide (LDA) as a base (Scheme 16) <1986JOM(304)283>. Analogously, gem-fluorophospho-
noalkenes have been prepared starting from fluoromethanediphosphonates (Scheme 16)
<1986JCS(P1)1417, 2003OL2267>. Since the anion of fluoromethanediphosphonate is formed
in situ when treated with n-butyllithium, fluorodibromomethylphosphonate was also successfully
applied to obtain gem-fluorophosphonoalkenes (Scheme 16) <1998TL4477>. When treated with

lithium bis(trimethylsilyl)amide (LiHMDS) and benzaldehyde at 110 C, fluorophosphonate 44
furnishes a 1:1 mixture of the gem-fluorophosphonoallene and the corresponding Wadsworth–
Emmons product (Equation (21), see also Scheme 28) <1998T15541>. Finally, the condensation
of chlorinated phosphonoacetate 45 with paraformaldehyde gives gem-chloro(phosphono)ethene
in good yield (Equation (22)) <2000PJC1123>.
P(O)(OR)2
[(EtO)2P(O)]2CHCl
LDA R1 X
R1CHO
Major isomer
BuLi
[(RO)2P(O)]2CHF [(RO)2P(O)]2CXLi
R2COR3
X = F, Cl
BuLi
R = Et, Pri
R2 P(O)(OR)2
(EtO)2P(O)CFBr2 THF R1, R2 = alkyl, aryl
–78 °C
R3 = alkyl R3 X
(E ) and (Z )
Scheme 16
F F F Ph
P(O)(OEt)2 P(O)(OEt)2
i. LiHMDS, THF
+
ii. PhCHO C5H11 ð21Þ
C5H11 OH C5H11
44 Ph
(yield: 30%)
i. KOH, H2O, EtOH P(O)(OEt)2

EtO2C P(O)(OEt)2
Cl ii. (CH2O)n, EtOH Cl ð22Þ

cat. piperidine
45
72%
A similar condensation using the Wittig reaction instead is only reported twice. Bisphosphonium
ylide 46 undergoes condensation with perfluoro acid fluorides <1983JA650> as well as with alkyl
and aryl aldehydes (Scheme 17) <1985JA2811>. When alkyl aldehydes are used, the condensation
reaction is (E)-selective, but gives alkenes in a (Z)-selective manner with aryl aldehydes.
+
P Bun3
RCHO R F
+ (E ) > (Z )
F P+ Bun3 RfCOF P Bun3
–
F
+
Rf F P Bun3 ArCHO
46 +
Ar P Bun3
F
(Z ) > (E )
Scheme 17
Substituting a phosphonate unit by a trimethylsilyl group, gem-halophosphonoalkenes can be

formed by the Peterson olefination (Scheme 18). Savignac and co-workers synthesized several
-fluoroalkenylphosphonates in generally high yields using both aldehydes and ketones. The
reaction with aliphatic aldehydes shows no stereochemical control, whereas aromatic and hetero-
aromatic aldehydes give rise to the formation of mainly the (E)-isomer (up to an 8:2 (E):(Z)
ratio). The reaction with ketones is dependent on steric factors and the corresponding (Z)-isomers
are produced as main products. Particularly noteworthy is the fact that the condensation with
cyclic ketones (2-methylcyclohexanone, ()-carvone, isophorone, and -tetralone) only results in
the formation of the (Z)-isomer. The influence of different trialkylsilyl groups on the stereose-
lectivity of the reaction was also examined. Increasing the steric bulk of the trialkylsilyl group,
carbonyl compounds leading to mainly the (E)-isomer show a decrease in (E):(Z) ratio. By
contrast, the size of the trialkylsilyl group has no influence upon the (E):(Z) ratio when the
(Z)-isomer is the main product. Substituting the fluorine atom by a chlorine atom has no effect on
the stereochemistry. The authors proposed a closed transition state to explain the results of their
study <1996T14199, 1996TL1783, 1996JFC(80)59>.
P(O)(OEt)2
(EtO)2P(O)CFBr2 R1CHO
R1 X
TMSCl, BuLi TMS

THF, –78 °C (EtO)2(O)P Li
X R2COR3
X = F, Cl R2 P(O)(OEt)2
(EtO)2P(O)CCl3 47
R3 X
Scheme 18
The utility of the Peterson olefination using esters as substrates has been reported only once.
Generally, esters are not reactive enough to react with anion 47 (see Scheme 16); however, applying
trifluoroacetic esters permits the synthesis of -fluoro--trifluoromethyl--alkoxyvinylphosphonates
48 with high (E)-selectivity (yield: 32–91%) <2001JFC(108)69>. Ylide acylation results in products
that exist preferentially or exclusively in the enol form, e.g., enol ether 49 <1993JOC1531>.
Treatment of anion 47 with carbon dioxide at 60 C gives gem-fluorophosphonoalkene 50 in
unspecified yield after a [1,3]-migration on warming to room temperature <1997T6391>. A different
approach for the synthesis of -chloroalkenylphosphonates starts from an acylphosphonate and
makes use of the Vilsmeier reagent (DMF/POCl3). This procedure leads exclusively to the formation
of the (Z)-isomer in moderate yield (Equation (23)) <2000PS(158)179>.
F3C P(O)(OR2)2 R P Ph3 LiO P(O)(OEt)2
R1O F EtO Br Me3SiO F

48 49 50
R1 = Et, Pr n, Pri, Bun, Bui R = MeCO2, EtO
R2 = Et, Pri
O P(O)(OEt)2
DMF, POCl3
H3C P(O)(OEt)2 ð23Þ
CH2Cl2, 30 °C OHC Cl
55%
4.18.2.1.2 From fluorinated alkenes

Although the success of these reactions is strongly dependent on experimental conditions, several
-trifluorovinylphosphorus derivatives have been prepared by action of trifluorovinyllithium or
trifluorovinylmagnesium on phosphorus(III) halides <1969JA1934, 1988BAU1686>. Analogously,
several gem-difluorophosphonoalkenes have been prepared in unspecified yields from the

corresponding -fluoroalkenyllithium derivatives (Equation (24)) <1997HAC467>. Brisdon and
co-workers significantly improved this method by treating 1,1,1,2-tetrafluoroethane with 2 equiv. of
n-butyllithium followed by phosphorus(III) chlorides in a one-pot reaction (Equation (25)).
Utilizing 1-chloro-2,2,2-trifluoroethane, this procedure was further extended to the formation of
1-chloro-2,2-difluorovinyl-containing phosphines <1999JCS(D)427, 2001JFC(112)35>.
F I i. Mg, Et2O, –40 °C F PR2R3
R1 F ii. R2R3PCl, Et2O, –80 °C R1 F

ð24Þ
R1 = CF3, SF5
R2 = OMe, OEt, Pri
R3 = OMe, OEt, NEt2, Pri
i. 2 equiv. n-BuLi
THF or Et2O, –78 °C
CF3CH2X PRm(CX=CF2)nCl3–m –n
ii. PRmCl3–m, –100 °C ð25Þ
X = F, Cl R = Ph, Pri
24–80%
A second route to -fluorovinylphosphorus compounds consists of the action of a phosphor-

us(III) species on a polyfluoroalkene. When treated with triisopropylphosphite, an Arbusov
reaction on iodotrifluoroethane furnishes the corresponding 2-iodo-1,2-difluoroethenylphospho-
nate as the (E)-isomer <1981PS(10)127>. In order to prepare the corresponding phosphonium
salts and phosphine oxide, Hanamoto and co-workers synthesized -fluorovinyldiphenyl-
phosphine by action of lithium diphenylphosphide on 1,1-difluoroethene. Careful temperature
control is necessary to avoid the formation of 1,1-bis(diphenylphosphinyl)ethene (Scheme 19)
<1999CC151, 2000JCS(P1)103>. Further, a number of phosphorus(III) species have been
successfully added to perfluoroalkenes. Dimethylphosphine and tetramethyldiphosphine react
with hexafluoropropene in the dark (Scheme 20) <1975JCS(P1)702>. Phosphonium salts are
isolated when perfluoroalkenes are treated with tertiary phosphines <1979JA3689,
1996JFC(80)149>, and reaction of perfluoroalkenes with phosphites results in the corresponding
phosphonates (Scheme 20) <1988CZ69, 1996JFC(80)149, 2001PS(176)201>.
P Ph2Me I
F
MeI
91%
F LiPPh2 PPh2 Ph2IOTf P Ph3OTf
F THF – toluene F cat. CuCl F

–60 °C 82%
86%
H2O2
84%
P(O)Ph2
Scheme 19
Michael addition of phosphites to perfluoromethacrylate esters furnishes gem-fluorophosphono

,-unsaturated carbonyl compounds. An Arbusov reaction is not observed; however, the major
products being the corresponding P-fluorophosphoranes isolated as single, unspecified isomers
(Scheme 21) <1976BAU853, 1976BAU873>. Alternatively, treating the -phenylsulfonyl
,-difluoroalkene with triethylphosphite does proceed via an Arbusov reaction, furnishing the
F PMe2 F P R3F
F3C F Me2PH or Rf F
Me4P2 R3P
R = alkyl, Ph
Rf = CF3
F F
Rf F i. Bun3 P
P(OR)3 ii. BF3 OEt2
F P(O)(OR)2 F P Bun3 BF4
Rf F Rf F
R = Et, TMS
Scheme 20
corresponding -fluoroalkenylphosphonate (Scheme 21) <1999MI768>. A similar addition–elim-

ination reaction is observed adding sodium diethylphosphite to 2-[(trimethylsilyl)methyl]-substi-
tuted 3,3-difluoropropenoate (Scheme 21). The reaction stops at the stage of the substitution of
one fluorine owing to the presence of the electron-donating silyl group. Additionally, an intra-
molecular coordinative interaction between fluorine and silicon is proposed to control the transi-
tion-state conformation leading to the (E)-isomer, exclusively (see also Equation (10))
<2000JOC627>.
F3C PF(OMe)3
P(OMe)3 MeOOC F
85%
R1 F R1 P(O)(OEt)2
P(OEt)3
R2 F PhO2S F
R2 = COOR, SO2Ph R1 = Me, Et, Pr, C6H11, Ph

HP(O)(OEt)2,
NaH
88%
TMS F
EtOOC P(O)(OEt)2
Scheme 21
Although there are several methods to obtain (E)--fluorovinylphosphonates, there is a paucity

of routes for the preparation of (Z)--fluorovinylphosphonates. A palladium-catalyzed displace-
ment of iodine by diethylphosphite furnishes gem-fluorophosphonoalkenes with retention of
stereochemistry <1993TL7197>. Utilizing this method, Zhang and Burton developed a kinetic
separation method for the stereoselective preparation of 1-fluorovinylphosphonates from (E):(Z)
mixtures of 1-bromo-1-fluoroalkenes (Scheme 22). (E)-1-bromo-1-fluoroalkenes react significantly
faster than the (Z)-isomers, leading to a reaction mixture that contains both 1-fluoro-
vinylphosphonate with a 95:5 (E):(Z) ratio and pure (Z)-isomer of the starting material that
could be readily recovered. The isomerically pure (Z)-1-fluorovinylphosphonates are prepared via
phosphorylation from the (Z)-1-bromo-1-fluoroalkenes at higher temperatures. However, at these
higher temperatures a competitive reduction becomes significant <2001JFC(112)47>.
P(O)(OEt)2
Br HP(O)(OEt)2 F
+
Pd(PPh)4, NEt3 R F
R F R Br
35 °C (E ):(Z ) 95:5
(E ) and (Z )
R = alkyl, aryl
HP(O)(OEt)2
Pd(PPh)4, NEt3, 70 °C
F F
+
R P(O)(OEt)2 R H
(Z ) only
Scheme 22
Alkene 1,2-diphosphonates have been prepared as (E):(Z) mixtures by double reaction of

phosphites with polyfluoroalkenes <1988BAU1686>. Starting from perfluoroepoxide 51, a 1:2
(E):(Z) mixture of bisphosphonate 53 is obtained when reacted with diethyl(trimethylsilyl)pho-
sphite (Scheme 23). The reaction proceeds via an ylide, which spontaneously leads to the forma-
tion of phosphonate 52 <1997HAC59>.
F3C O F 2 equiv. TMSOP(OEt)2 F3C OTMS (EtO)2(O)P F

P OEt
C6F5 F –CO, –FSiMe3 C6F5 OEt C6F5 F
51 –FP(O)(OEt)2 52
78% TMSOP(OEt)2
(EtO)2(O)P P(O)(OEt)2
C6F5 F
53
Scheme 23
Direct halogenation of vinyl phosphonates followed by elimination is reported to afford
-haloalkenyl phosphonates. Hägele and Dolhaine performed the halogenation with chlorine,
bromine, and their diatomic interhalogen compounds, including those with iodine (Scheme 24). The
,-dihaloethanes are produced in an anti-Markovnikov fashion, with the more electrophilic
halogen geminal to the phosphorus atom. The elimination furnishes the gem-halo(phosphono)-
ethenes in 30–82% yield <1977PS(3)47>. Kobayashi and William successfully extended this
method for the synthesis of gem-bromophosphonoalkenes bearing a substituent at the -position
(Equation (26)). The gem-bromophosphonoalkenes were isolated in good yield and the stereo-
selectivity was varied from quite high to moderate depending on the -substituent and the
stereochemistry of the substrates <2002OL4241>. The same sequence has also been applied to
(Z)-1-propenylphosphonic acid, giving only the (Z)-isomer of 1-bromo-1-propenylphosphonic
acid. Starting from (E)-1-propenylphosphonic acid, a mixture of both the (E)- and (Z)-isomer is
obtained <1995JOC74>. Proving the generality of this procedure, gem-halophosphonamidoaldehydes,
predominantly in the (Z)-enol form 54, were prepared from the corresponding 2-ethoxyvinyl-
phosphonamide <1992JGU1222>. Similarly, 2-(alkylthio)-1-bromovinylphosphonate 55 has been
prepared from the corresponding vinyl phosphonate <1987JCS(P1)1275>.
P(O)(OEt)2 X–Y P(O)(OEt)2 NaOAc P(O)(OEt)2
(AlCl3) X Y or NH3 Y
30–82%
X = Cl, Br
Y = Cl, Br, I
Scheme 24
P(O)(OEt)2 i. Br2, CH2Cl2, 10 °C P(O)(OEt)2
R ii. NEt3, CH2Cl2, 40 °C R Br ð26Þ

R = Me, Ph, C5H11
O
P N O P(O)(OEt)2
2
HO X RS Br
X = Cl, Br, I R = Et, p-tolyl

54 55
Addition of phosphorus species has been observed with alkynes and alkenes. Phosphorus
pentachloride reacts via an electrophilic attack with (alkylthio)chloroethynes, affording predomi-
nantly (Z)-(-chlorovinyl)-tetrachlorophosphoranes (Scheme 25) <1991JGU983>. D’yachkova
and co-workers performed the addition of phosphine oxides across (alkylthio)chloroethynes in the
presence of potassium hydroxide leading to (Z)-1-chloro-2-(alkylthio)vinylphosphine oxides in
good yield (Scheme 25) <2001RJGC1717>. Upon irradiation, phosphorus tribromide was added
to bromoalkynes leading to 1-dibromophosphino-1,2-dibromoalkenes in a 20:1 (E):(Z) ratio. The
regioselectivity of the addition is not absolute, giving rise to small amounts of the other regioi-
somer (Equation (27)) <1995RJGC956>.
R1S PCl4
PCl5 Cl Cl
C6H6 73–92% (Z )
87–95%
R1S Cl
R1 = Et, Pr n HP(O)R 2
2
2
KOH P(O)R2
Dioxane
78–85% R1S Cl
2
R = CH2CH2Ph
Scheme 25
PBr3, hν Br PBr2 Br PBr2

R Br +
79–89% R Br Br R ð27Þ
R = Me, But (E )/(Z ) 20/1 (<10%)
Heating 1,1-dichloroethene in the presence of compound 56, which is a precursor of a terminal

phosphinidene complex (PhP!M), results in the formation of phosphirane 57 through a [2+1]-
cycloaddition. When subjected to a palladium-catalyzed ring opening, a gem-chlorophosphinoethene
complex is formed that can be oxidized with trimethylamine N-oxide (Scheme 26) <2000JOC652>.
Applying a nickel-catalyzed Arbusov reaction, Beletskaya and co-workers obtained 1-bromo-

2-butoxyvinylphosphonate from the corresponding dibromide and triethylphosphite (Scheme 27).
The phosphonate is initially formed as an isomeric mixture. However, distillation at 120–150 C leads
to isomerization and only the (Z)-isomer is isolated <1999TL569>. Utilizing a Pd-catalyst and
dimethylphosphite, the gem-bromophosphonoalkene is only formed as a side product (Scheme 27)
<2000OL3873>.
M P Ph
COOMe
M
COOMe Cl Cl
Cl 56 Pd(PPh3)4 P
Ph
P
Cl Toluene, 110 °C Ph M 70% Cl
M = W(CO)5
80% 57
i. MeOH, 60%
ii. Me3NO, 60%
O
OMe
P
Ph
Cl
Scheme 26
P(O)(OEt)2
P(OEt)3 R Br
NiBr2 R = OBun
Br 74%
R Br
HP(O)(OMe)2
P(O)(OMe)2 P(O)(OMe)2
Pd(OAc)2
+
DPPF, THF R
R Br
(yield: 24%) (yield: 41%)
R = cyclohexyl
Scheme 27
4.18.2.1.4 Other methods of alkene formation

When treated with n-butyllithium, (E)-chloroenyne 58 reacts with chlorodiphenylphosphine lead-
ing to the formation of the (E)-isomer of the corresponding gem-chlorophosphonoalkene in good
yield (Equation (28)). Noteworthy is the fact that under the same conditions, attempted conver-
sions of (Z)-chloroenyne and (E)-1-chlorohept-1-ene into -chlorophosphonoalkenes were unsuc-
cessful <1995TL3687>. Hammond and co-workers prepared gem-fluorophosphonoallenes from
-fluorophosphonoalkynes upon treatment with tetra-n-butylammonium fluoride (TBAF)
(Scheme 28). The allenes are thermally stable and were easily purified by chromatography
<2000JOC227>.
Cl i. BuLi, –100 °C Cl
C5H11 ii. Ph2PCl, –100 °C C5H11 PPh2 ð28Þ

70%
58
TBAF P(O)(OEt)2
F THF, –80 °C
R1 = TIPS, 75%
P(O)(OEt)2
R1
TBAF, E
F
THF, –78 °C C5H11 P(O)(OEt)2

E = H2O, PhCHO 2
R
R1 = C5H11
R2 = H (40%, 41% de)
= PhCHOH (72%)
Scheme 28
Otaka and co-workers reported the synthesis of -fluorophosphonoalkenes via an organocopper-

mediated reduction of gem-difluorophosphonoalkenes. Although the butylcopper reagent
gives the reduction product as well as the Michael adduct (24%), conjugate addition is not
detected using methylcopper reagents (Equation (29)) <2000CC1081>. An unsaturated fluoro-
analog of adenine has been prepared by elimination of hydrogen fluoride using 1,5-diazabicyclo[4.3.0]-
non-5-ene (DBN) as base (Equation (30)) <1997T5389>. Arylsulfonylglycyl chlorides spontaneously
lead to gem-chloroalkenylphosphorus compounds in excellent yield when treated with triphenyl-
phosphine (Scheme 29). Although the mechanism of the reaction is not established, a cyclic
oxaphosphorane has been suggested as an intermediate <2001T9873>. Finally, reacting
2,4-di-t-butyl-6-methylphenylphosphonous dichloride with chloroform in the presence of LDA leads
to trichlorovinylphosphine 59 in poor yield (Equation (31)). Careful temperature control is necessary to
minimize the formation of side product <1996HAC23>.
F F
F
P(O)(OEt)2 2.5 equiv. Me2Cu(CN)Li2
ROOC P(O)(OEt)2
LiBr, LiCl, THF, –78 °C ð29Þ
ROOC
92%
R = Et, (2S)-bornane-[10.2]-sultam
F P(O)(OEt)2
F
Ade P(O)(OEt)2 DBN
F ð30Þ
Br THF, rt Ade Br
21%
Ade = adenine
RSO2 Cl PPh3 RSO2 Cl RSO2 P(OH)Ph3

N N N
H THF or Et2O H PPh3 H
O O Cl
94–95%
R = Ph, 4-alkyl-C6H4
Scheme 29
But But But

CHCl3 Cl
But PCl2 But P Cl + But P
LDA Cl
Cl Cl Cl ð31Þ
59
25% (–120 °C) 1% (–120 °C)
5% (–78 °C) 13% (–78 °C)
4.18.2.2 a-Haloalkenyl Derivatives of Arsenic, Antimony, and Bismuth

Very little work on the -haloalkenyl derivatives of arsenic, and less on those of antimony and
bismuth, has been reported. Lewisite 60 is generally a mixture of several compounds with the
trans isomer being the predominant one. The geminal isomer 61 has been reported by Smith and
co-workers <1995MI1541, 1999JPO95> as one of the components of the mixture.
AsCl2 AsCl2
Cl Cl
60 61
gem-Arsinofluoroalkene 62 was prepared by action of dimethylarsine on 2,3-dichlorotetrafluoro-

propene in good yield <1968JOM(12)133>. In a similar fashion to the phosphorus derivative
previously described (see Section 4.18.2.1.2), trifluorovinylmagnesium iodide <1961MI110> and
1-chloro-2,2-difluorovinyllithium <2000JOM(616)96> react with arsenic, antimony, and bismuth
trihalide affording the corresponding tris(trihalovinyl) species 63 in moderate yield.
F
F
Cl AsMe2
X X
F M
F3C F
F
62 F X F
(yield: 52%) 63
M = As, Sb, Bi
X = F, Cl
4.18.3 DERIVATIVES OF SILICON AND OTHER GROUP 14 ELEMENTS

Although silicon and germanium are often classified as metalloids while tin and lead are metals,
the synthesis of their covalent derivatives resembles one another so closely that they are con-
veniently dealt with in one section.
4.18.3.1 a-Haloalkenylsilicon Derivatives

The Peterson olefination, commonly encountered in gem-fluorophosphonoalkene chemistry, is
rarely represented in the synthesis of silylalkenes. Bis(trimethylsilyl)bromomethyllithium reacts
with aldehydes affording gem-bromosilylalkenes in good yields, the (Z)-isomer being preferred
for more bulky alkyl groups (Scheme 30) <1977JOM(142)39>. Analogously, treatment of
bis(trimethylsilyl)fluoro(tributylstannyl)methane with n-butyllithium followed by addition of an
aldehyde furnishes -fluoroalkenylsilanes in moderate to good yields. The stereoselectivity of the
reaction depends on the substituent R. However, for most aldehydes studied, the (Z)-isomer was
predominantly formed. Interestingly, 3-phenylpropanal and perfluorobenzaldehyde lead to the
(E)-isomer instead with high to very high selectivity, respectively (Scheme 30) <1999TL7375,
2000BCJ1685>.
4.18.3.1.2 By silylation of a-haloalkenyllithium and a-haloalkenylmagnesium species

This is the most general method for the preparation of gem-fluorosilylalkenes, although it has
also been applied to the synthesis of -chloro- and -bromoalkenes. Only one iodo derivative
has been prepared by this method. Seyferth reviewed the use of organomagnesium compounds
SiMe3
M = Li R Br
RCHO
R = alkyl, vinyl
52–78%
(Z ):(E ) 1:1 to 3:1
(Me3Si)2CXM
i. BuLi, –78 °C
X = F, Br
ii. RCHO, –98 °C
SiMe3
51–98%
M = SnBu3
R F
R = Ph, Ar, (E )-PhCH CH (Z ):(E ) 1:1 to 3:1
= 4-MeO– C6H4 (Z ):(E ) 85:15
= Ph(CH 2)2 (Z ):(E ) 7:93
= C6F5 (Z ):(E ) 1:99
Scheme 30
in the preparation of trifluorovinylsilanes <1962MI129> (see also <1968JOC472> and refer-

ences cited therein). More recently, a lithium derivative, prepared by metal–halogen exchange
at low temperature, was used to prepare trifluoroethenylsilane in good yield (Equation (32))
<1996T37, 2002JFC(113)211>. Burton and co-workers <1996CC49> prepared trifluorovinyl
silane from 1,1,1,2-tetrafluoroethane via a dehydrofluorination/metallation sequence using
trimethylsilyl chloride and 2 equiv. of n-butyllithium at low temperature (Scheme 31). Employ-
ing 3 equiv. of base, trifluorovinyl silane undergoes further reaction in situ with n-butyllithium
affording the -fluorohexenyl silane (Scheme 31) <2000TL971>. To prepare silane 64, (E)-1,2-
difluoroethenyl silane was synthesized via reduction of trifluoroethenyl silane and subsequent
isomerization of the (Z)-isomer by ultraviolet light and a catalytic amount of diphenyl disulfide.
Next, (E)-1,2-difluoroethenyl silane was treated with LDA and trimethylsilyl chloride furnishing
silane 64 in poor yield (Scheme 32) <1996T37>. Stepanov and co-workers developed an
electrochemical silylation of fluoroalkenes with an excess of chlorotrimethyl silane. While the
vinyl silanes are prepared in good yield from trifluorobromoethene and 1,2-difluoro-1,2-dichlor-
oethene, hexafluoropropene leads to the corresponding gem-fluorosilylpropene in only poor
yield (Equation (33)) <1998T257, 2000MI190>.
i. BuLi, –100 °C (X = Cl)

F X or MeLi, –78 °C (X = Br) F SiR3
F F ii. PhMe2SiCl (X = Cl) F F

ð32Þ
or Et3SiCl (X = Br)
X = Cl, Br
77% (X = Cl)
88% (X = Br)
i. 2 equiv. BunLi
Et2O, –78 °C F SiMe3 1 equiv. BunLi F SiMe3
CF3CH2F
ii. Me3SiCl F F Et2O, –78 °C Bun F
70% 82%
Scheme 31
F SiEt3 LiAlH4 F SiEt3 hν (254 nm) SiEt3
F F THF, 0 °C F cat. PhSSPh F F

87%
Me3SiCl, LDA
THF, –78 °C
25%
Me3Si SiEt3
F F
64
Scheme 32
F X Excess Me3SiCl F SiMe3
R F Stainless steel cathode R F ð33Þ

Sacrificial Zn or Al anode
X = F, Cl, Br CH3CN or DMF
R = F, Cl, CF3
Hanamoto and co-workers prepared vinyl silane 65 from 1,1-difluoroethene upon nucleophilic
displacement of fluoride by diphenylmethylsilyllithium (yield: 56%) <1999CC2397>. Sequential
lithiation and silylation of (E)-1-bromo-1,2-difluoro-2-(1-naphthyl)ethene at 130 C gives -fluoro-
alkenyl silane 66 with retention of configuration and in excellent yield (96%) <1995TL6271,
1998BSJ2903> while using a similar sequence, gem-fluorosilylalkenes 67 (yield: 40%)
<1995JCS(P1)2681, 2001CCC1508>, 68 (yield: 60–71%) <1996TL5183, 1997T14749>, and 69
(yield: 51%) are obtained in only moderate yields <2000USP6159956, 2001USP6207846>.
F
SiPh2Me F SiMe3
SiMe3
F F
65
66 67
SiMe2R
SiR3 F
MEMO F
F PhO
O
F
R = Me, Et R = 4-Cl-C6H4
68 69
gem-Chloro- and gem-bromosilylalkenes have also been prepared by metallation and subsequent
silylation. Treatment of 1,1-dibromo-2,2-diphenylethene with n-butyllithium followed by addition of
dimethylsilyl chloride furnishes the -bromoalkenylsilane in 56% isolated yield (Scheme 33)
<1995JA3298>. Deprotonation of bromomethylenecyclobutane by LDA and trapping the anion
with trimethylsilyl chloride leads to the formation of the corresponding gem-bromosilylalkene
(Scheme 33) <1999JOC1529>. In addition, alkenes 70 <1999JA7039> and 71 <1995TL3687>
have been prepared with a very high stereoselectivity from the corresponding (E)-chloroalkenes
using n-butyllithium as base at 100 C (yield: 63–85%). Shimizu and co-workers
<1987BSJ777> reported a nonstereoselective synthesis of gem-bromo- or gem-chlorosilylalkene

isomers 72, gem-halosilylenolethers 73, as well as ketene acetals 74 in moderate-to-good yield
(23–84%). Similar to the synthesis of trifluorovinylsilane (see Scheme 31), -chloroalkenylsilane 75
has been prepared from 1-chloro-2,2,2-trifluoroethane using only 2 equiv. of n-butyllithium (yield:
89%) <1998JCS(P1)2541>.
Ph SiHMe2
X = Br i. BuLi, –100 °C
R = Ph ii. Me2SiHCl Ph Br
56%
R X
R Br
LDA, Me3SiCl
THF/Et2O SiMe3
X= H
R = (CH2)3 –107 °C
33% Br
Scheme 33
SiMe3 R1 SiMe3 F SiMe3

R
Cl R2 X F Cl
70 R = (E )-C8H17CH CH X = Cl, Br 75
71 R = C5H11C C
= PhC C 72 R1, R2 = H, Me, Ph
73 R2 = Me3SiO
74 R1 = MeO, R2 = Me3SiO
A rare example of the silylation of -iodoalkenyllithium species is demonstrated by the synth-

esis of -iodoethenylsilane 76 from iodoethene in poor yield (20%). The best results are obtained
with 3 equiv. of LDA as base at 100 C. Lithium–iodine exchange from 1,1-diiodoethene gives
less satisfying results <1998OM5390>. Although no base is used, the procedure reported by
Bardin and co-workers should also be mentioned here. Perfluoroalkenyl silanes are obtained from
the corresponding iodides or bromides, applying tris(diethylamino)phosphine as condensing agent
at room temperature (Equation (34)). This method is also applicable for the preparation of
trichloroethenyl silane 77 from tetrachloroethene in 66% isolated yield <1995SC2425>.
SiMe3 Cl SiMe3
I Cl Cl
76 77
R X Me3SiCl R SiMe3
F F P(NEt2)3, rt F F
ð34Þ
R = F, X = Br (85%)
R = (CF3)2CF, X = I (77%)
This section deals with those reactions in which a halogen atom is introduced by electrophilic
attack on an unsaturated silane. The introduction of chlorine (reviewed by Seyferth
<1962MI129>) and bromine is most abundantly documented, whereas only some examples of
iodination have been reported. The single example of fluorination encloses the addition of nitryl
fluoride to bis(trimethylsilyl)ethyne affording compound 78 in 50% yield <1986S132>. The
bromination of vinyl silane followed by elimination has been successfully applied affording
-bromovinylsilane 79 <1988OSC(6)1033>, while derivative 80 has been prepared in unspecified
yield from trimethylsilylethyne by addition of SF5Br across the triple bond <2002USP6479645>.
Bromination of alkynyl silanes has been shown to afford a range of (E)-1,2-dibromosilyl alkenes
81 in generally good yields (42–83%) <1989JOM(372)183, 2001JCS(P1)154, 2001SC3027>. 1,2-
Dibromovinylsilane 81 (R = H) has also been isolated in 20% yield from a mixture formed when
dibromodifluoromethane is added to trimethylsilyl ethyne in the presence of an equimolar
mixture of ammonium persulfate and sodium formate <1998T14189>.
O2N SiMe3 SiMe3 Br SiMe3
Me3Si F R Br R Br
78 79 (R = Br) R = H, alkyl, aryl

80 (R = SF5) = SiMe3, SePh
81
Sato and co-workers prepared a gem-bromosilylallene from the corresponding enantiopure

propargylstannane upon treatment with N-bromosuccinimide (NBS) as brominating agent
(Equation (35)) <2001TL6323>. Further, reacting compound 82 with thionylbromide at 0 C
affords the corresponding gem-bromosilylallene in good yield. It is worth noting that the synthesis
of the gem-chloro derivative was not successful since applying thionyl chloride leads to substitu-
tion of the hydroxyl group by chlorine (Equation (36)) <1996AG(E)1986>. Although not
introducing bromine by electrophilic attack, reaction of alkyne tosylates or mesylates with
CuBr/LiBr affording gem-bromosilylpropadienes is most appropriately listed in this section.
The transformation displays a very high stereoselectivity and proceeds, depending on the sub-
strate, in poor-to-good yield (Equations (37) and (38)) <1996JOC9631, 2002JA15255>.
Bu NBS Bu Br
SiMe3
THF ð35Þ
Bu3Sn SiMe3
80% 86% ee
SiPr3i
R R
OH Br
SiPr3i SOBr2
R R
Et2O, Pyr, 0 °C ð36Þ
R R
R 88% R
R = Pr3i SiC C
82
OTs
CuBr.Me2S, LiBr
O O SiMe3
N SiMe3 THF, 60 °C N ð37Þ
t-BOC t-BOC Br
(4R,3R) (4R,aR): 75%, >99% de
(4R,3S) (4R,aS): 70%, >99% de
OMs
CuBr.Me2S, LiBr
SiMe3
NH SiMe3 THF, –78 °C NH
Mts = 2,4,6-(CH3)3-C6H2SO2 Br ð38Þ
Mts Mts
(4S,3R) (4S,aR): 30%, >99% de

(4S,3S) (4S,aS): 20%, >99% de
Iodine has been incorporated in a variety of ways. Barluenga and co-workers reported a
mercury(II)-catalyzed addition of iodine to phenyl(trimethylsilyl)ethyne affording gem-iodosilyl-
alkenes (Equation (39)) <1987JCS(P1)1017>. Employing bis(pyridyl)iodonium(I)tetrafluoro-
borate (IPy2BF4) as iodine source, the same group developed a method for the homocoupling of
alkynyl silanes in excellent yield. The reaction only furnishes gem-iodosilyl alkenes when, at low
temperatures, t-butyldimethylsilyl alkynes are applied since trimethylsilyl-protected alkynes lead to
iodoalkynes upon reaction with IPy2BF4/HBF4. Related aliphatic alkynyl silanes fail to couple
under the same conditions (Scheme 34) <1997JA6933>. Starting from phenylthio(t-butyldimethyl-
silyl)ethyne, this procedure gives rise to the formation of heterocyclic -iodoalkenyl silane 83 in
unspecified yield (Scheme 34) <1998AG(E)3136>.
I2, HgX2 X SiMe3

Ph SiMe3
50–54%
ð39Þ
Ph I
X = Cl, OAc
R1
SiMe2But
IPy2BF4, HBF4 I
CH2Cl2, –80 °C
R1 = 4-R2–C6H4 R2
90–98% R2 = H, CH3, But, Cl
R1 SiMe2But
IPy2BF4, HBF4
CH2Cl2, –80 °C
SiMe2But
R1 = PhS
S
I
SiMe2But
SPh
83
Scheme 34
Finally, several gem-iodosilyl alkenes have been successfully prepared via an electrophilic
cyclization strategy. Iodocyclization of the 4-pentynyl sulfide followed by an oxidation using
3-chloroperoxybenzoic acid (MCPBA) proceeds cleanly to give the five-membered ring adduct
with (E)-geometry in quantitative overall yield. Bromocyclization using bromine was not success-
ful (Equation (40)) <1995JOC6468>. Yao and Larock obtained the substituted -pyrone in
excellent yield of a single isomer treating the trimethylsilyl-substituted 2-(1-alkynyl)benzoate
with ICl (Equation (41)) <2003JOC5936>. -Iodoalkenyl silane 84 is formed from the corre-
sponding 4-alkynylcyclobutenone via an ionic rearrangement when iodine and iodobenzene
diacetate are employed (Equation (42)) <1995TL5539>.
O SiMe3
SiMe3 i. I2, CH2Cl2, rt O
S I
Ph S ð40Þ
ii. 2.5 equiv. MCBPA
100%
O
CO2Me
1.2 equiv. ICl
O ð41Þ
CH2Cl2, rt
SiPr3i 96% SiPr3i
I
O
EtO O EtO SiMe3
I2, PhI(OAc)2
SiMe3 CH3CN, –15 °C ð42Þ
EtO EtO I
OH O
68%
84
4.18.3.1.4 By halogenation of a-silylalkenyl metal derivatives

This section covers methods for the preparation of mainly gem-iodosilylalkenes involving the
replacement of a metal atom on an alkenylsilane by an iodine atom. In addition to iodine,
bromine and chlorine have also been introduced in this way. However, methods for the incor-
poration of fluorine are still lacking.
Hydroalumination and subsequent bromination or iodination of alkynylsilanes lead to (E)-gem-
bromosilylalkenes in good yield (Scheme 35) <1999CPB1108, 2001OM2109, 2001CL554>. Using
this sequence, (1(E),3(E))-1-iododienyl silane 85 has been prepared from the corresponding
vinyl(trimethylsilyl)ethyne, but undergoes spontaneous isomerization to the (1(Z),3(E))-isomer
on standing (yield: 82%) <1998TL4219>. Similarly, the synthesis of bis(-bromovinylsilane) 86
has been reported as part of an organic synthesis preparation in good yield (75%)
<2002JA9366>. It is worth noting that (E)--chloro- or bromoalkenylsilanes, and (E)--iodoalk-
enylsilanes may be isomerized to their (Z)-isomers by reaction with a catalytic amount of bromine
under UV irradiation or treatment with t-butyllithium (5 mol.%), respectively <1981JOC1292>.
Bu2iAlH R SiMe3 Br2 or NBS R SiMe3

R SiMe3
hexane or Et2O or I2
AlBu2i X
X = Br, R = 8-Br-naphthyl 59%

X = I, R = 2-Br-C6H4CH2 59%
X = Br, R = (Z )-(2-Br-C6H4)CH CH 97%
Scheme 35
SiMe3
Br
I
C6H13 Me3Si
SiMe3
Br
85 86
Negishi and co-workers reported a trans-hydroalumination of !-trimethylsilyl-substituted alky-

nyl alcohols by their sequential treatment with Me3Al (or Et3Al), which acts as a metallating
agent for the hydroxy group, and diisobutylaluminum hydride (DIBAL-H). The authors propose
a nonstereoselective, though regioselective addition followed by a chelation-controlled stereo-
isomerization step, which is supported by the fact that the (E)- to (Z)-isomerization is not
observed in the absence of the hydroxy group (Scheme 36) <1997TL3829>. Stannylmetallation
of silylated prop-2-ynoic acid furnishes the -silylalkenyltin derivative without butyl ligand
transfer from the stannylcuprate to the triple bond and with absolute regioselectivity. Subsequent
treatment with iodine leads to the (E)-3-iodo-3-(trimethylsilyl)prop-2-enoic acid with retention of
configuration and in moderate yield (Scheme 37) <1998TL4277>. Analogously, iodinolysis of the
corresponding gem-silylstannyl alkene has been performed to prepare (E)-1-iodo-1-(trimethylsi-
lyl)-1-hexene in 69% yield <2001SL403>. Yamaguchi and co-workers obtained (Z)--iodoethenyl
silane 87 as one stereoisomer by trapping an -silylalkenylgallium derivative, which is involved
in a Friedel–Crafts -silylethenylation of aromatic hydrocarbons with trimethylsilylethyne
(Scheme 38) <1999BCJ1445>.
i. Me3Al or Et3Al AlR22 SiMe3

SiMe3 CH2Cl2, rt
R1 n
n SiMe3 n AlR2
OH
ii. DIBAL-H OAlR32 O
CH2Cl2, rt R1 R1
R2 = Bui, Me or Et
I2, THF
R3 = Me or Et
R1 = H, n = 0 (65%, >98% Z )
SiMe3
= H, n = 1 (65%, >98% Z )
= H, n = 2 (70%, >96% Z ) n I
= CH 3, n = 1 (74%, >98% Z ) OH
R1
Scheme 36
i. Bu3Sn(Bu)CuLi
LiCN, THF, –78 °C HOOC SiMe3
HOOC SiMe3
ii. H2O, –78 °C SnBu3
55%
I2, Et2O, rt
51%
HOOC SiMe3
Scheme 37
i. 3 equiv. GaCl3
CH2Cl2, –78 °C SiMe3
+ SiMe3
ii. 9 equiv. MeLi GaMe2
79% I2, THF, 0 °C
SiMe3
87
Scheme 38
Titanium-catalyzed hydrozincation of 1-(trimethylsilyl)-1-octyne has been performed with zinc

hydride, generated in situ from zinc(II) iodide and lithium hydride. Reacting the organozinc
compound with iodine affords the (E)-gem-iodosilyl alkene with good regioselectivity (Equation
(43)) <1995JOC290>. Further, electrophilic iodination of the vinylzirconium species, prepared by
hydrozirconation using Schwartz reagent (Cp2Zr(H)Cl), gives the corresponding -iodovinyl silane
(Equation (44)) <2001OL3281>. Trost and Pinkerton prepared vinyl halides via a ruthenium-
catalyzed three-component coupling. Applying this method on (trimethylsilyl)ethyne and methylvinyl
ketone leads to the trisubstituted gem-bromosilyl alkene with complete stereoselectivity and in mod-
erate yield (Equation (45)) <2000TL9627, 2002JA7376>.
i. ZnI2, LiH, THF

cat. Cp2TiCl2 C6H13 SiMe3 C6H13 SiMe3
C6H13 SiMe3 + ð43Þ
ii. I2, THF I I
70% 91:9
i. Cp2Zr(H)Cl I
THF, 55 °C I
RO SiMe3 RO RO
ii. I2, CH2Cl2, rt +
SiMe3 SiMe3 ð44Þ
R = Bn 87% 97:3
R = SiPh2But 82% 92:8
[CpRu(CH3CN)3]PF6 SiMe3
+ SiMe3
SnCl4, LiCl, acetone, 60 °C ð45Þ
O O Br
49%
Tetrasubstituted alkenes may be prepared by carbometallation of alkynylsilanes. trans-Carbo-

alumination of !-trimethylsilyl-substituted alkynyl alcohols and subsequent iodination furnishes
gem-iodosilyl alkenes in moderate yield. Initially, the syn-carboaluminated alkenes are formed,
which are further thermally isomerized via an aluminacycle to give exclusively or predominantly
the anti-isomers (Equation (46), see also Scheme 36). It is important to note that the hydroxyl
group is necessary for the isomerization to occur <1997JOC784>. Takahashi and co-workers
reported the carbozirconation of silylated alkynes with allylic compounds <1995T4519> or
chloroformate <2000JA3228> followed by iodinolysis affording the corresponding -iodoalkenyl-
silanes in good yield and with high isomeric purity (>96%) (Scheme 39).
i. 3 equiv. Me3Al
n
SiMe3 1 equiv. Cp2ZrCl2, CH2Cl2 SiMe3
OH ii. ∆ I
n
iii. I2, CH2Cl2
OH ð46Þ
n = 1: 77%, >98:2 (Z ):(E )
n = 2: 59%, >97:3 (Z ):(E )
n = 3: 60%, >88:12 (Z ):(E )
n = 4: 54%, >60:40 (Z ):(E )
R1 R1
R2 OR3 I2
SiMe3 SiMe3
Cp2ZrBu2, PMe3
R1 = C6H13, Ph R2 ZrCp2OR3 72–94% R2 I
R2 = H, C3H7
R3 = Et, allyl, Ph
R1 SiMe3
i. Cp2ZrEt2
R1 = Bu Bu Bu
ii. ClCOOEt
SiMe3 I2 SiMe3
EtOOC EtOOC
57%
ZrCp2Cl I
Scheme 39
Performing the iodination of the zirconacyclopentadienes in the presence of Cu(I)Cl, the

preparation of diiododienes 88 has been improved in terms of preventing the formation of the
monoiodinated compounds <1997TL4099>. Carbozirconation–halogenation of 1,6-enyne 89
leads to the (E)-configuration (X = I) or to an unspecified mixture of stereoisomers (X = Br) of
cyclic gem-halosilylalkenes 90 in poor yield <2002JOM(643–644)324>.
SiMe3 SiMe3
R1 SiMe3 X
I
Ph2Si Ph2Si
I X
R2
3
R
88 89 90
R1 = Me, Bu X = Br (41%)
R2, R3 = Me, Ph = I (14%)
(yield: 57–73%)
1,4-Diiodopenta-1,4-diene 91 has been prepared as a single regio- and stereoisomer from a

monosubstituted allene and 1-(trimethylsilyl)octyne via an intermediate titanacycle (Scheme 40)
<1998CC271>. Further, halogenation of titanacyclopentadienes, prepared from two alkynes
utilizing Ti(OPri)4/PriMgCl (1:2) reagent, furnishes 1,4-dihalobuta-1,3-dienes in generally good
yields (Equation (47)). This procedure does not require any additives such as Cu(I)Cl, which
is a notable advantage for the titanacyclopentadiene route in comparison with the zirconacyclo-
pentadiene route <1998JOC10060, 1999AG(E)1604, 2002AG(E)3023>. Employing the same
method, but using 1,7-bis(trimethylsilyl)hepta-1,6-diynes instead, affords cyclic diiodo-1,4-
dienes 92 <1998JOC10060, 1999JA10420, 1999JAP(K)11246566, 1999CC1543, 2002CEJ4734,
2003OL365>. Homo-coupling product 93 is formed in 65% yield when isopropylmagnesium
chloride is added to a mixture of 1,5-bis(trimethylsilyl)penta-1,4-diyne and 2 equiv. of
titanium(IV)isopropoxide <2002CC820>. In addition, a mixture of hexenyne and allyl bromide
affords the corresponding -iodoalkenyl silane when Ti(OPri)4/PriMgCl (1:2) reagent is added,
followed by iodine (Scheme 41) <2000JA11244>. When 1,5-bis(trimethylsilyl)penta-1,4-diyne and
3,4-dichlorobut-1-ene are employed, compound 94 is produced in 64% yield <2001JA4857>.
Similarly, an indium-mediated allylation of trimethylsilylethyne followed by quenching with NXS
has been reported leading to 1-halo-1-(trimethylsilyl)penta-1,4-dienes in good yield (Scheme 41)
<1999JOC7537>.
PriO
SiPhMe2 Me3Si OPri
SiMe3 Ti(OPri) 4 Ti
+
C6H13 2 equiv. Pr iMgCl SiPhMe2
C6H13
54% I2
Me3Si I
I
C6H13
SiPhMe2
91
Scheme 40
i. Ti(OPri)4 SiMe3
SiMe3 R3 2 equiv. Pr iMgCl R1
X
+
R1 R2 ii. X2, –78 °C X
R2
R3
R1 = H, Me, C6H13, CH(OEt)2, CO2But X = I: 63–85% ð47Þ
R2 = H, Me,
R3 = SiMe3, C6H13, C2H4OBn
R 1, R2 = H X = Br: 51%
R3 = SiMe3
SiMe3 Me3Si SiMe3 SiMe3

X Me3Si I
R1 I I
R2 X I I
n I
SiMe3 Me3Si SiMe3 94
92 93
X = I, n = 1, R1, R2 = CH2OMe (86%)

R1, R2 = H (75%)
n = 2, R1, R2 = H (89%)
X = Br, n = 2, R1, R2 = H (78%)
i. Ti(OPri)4, Me2But SiO SiMe3

i
2 equiv. Pr MgCl
I
ii. I2
73%
R SiMe3 + Br
i. In, THF
Ultrasound
SiMe3
ii. NXS, 0 °C
X
X = Br (67%)
= I (68%)
Scheme 41
Sato and co-workers <1995TL4261, 1996TL1253, 2003OL523> reported the cyclization of

!-silylated enynes to give the titanacyclopentenes, which, upon addition of iodine, lead to the
corresponding -iodosilyl alkenes (Scheme 42). Montchamp and Negishi conducted similar
cyclizations, though using a trimetallic reagent system (Et2Zn/ClTi(OPri)3/PriMgCl) that is cata-
lytic in titanium <1998JA5345>. Further, carbotitanation–iodination of 2,7-enynylcarbonate 95
and subsequent elimination of ethylcarbonate anion provides the corresponding gem-iodosilyl alkene
(Equation (48)) <1997AG(E)851>. The sequence was successfully extended to an annulation
method using N-propyl 6-(trimethylsilyl)hex-5-ynaldimine instead of an enyne (Equation (49))
<1996CC533>.
SiMe3
I
i. Ti(OPri)4 BnO
BnO
R = H2C C(CH3)– 2 equiv. PriMgCl
ii. I2 I
87%
(E )/(Z ) 26/74
SiMe3
BnO
BnO i. Ti(OPri)4,
R 2 equiv. PriMgCl
(E )/(Z ) >95/5 ii. I2 SiMe3
R=H 79% I
BnO
BnO I
Scheme 42
SiMe3 SiMe3
i. Ti(OPri)4, 2 equiv. Pr iMgCl I

ð48Þ
OCOOEt ii. I2
80%
95
SiMe3 SiMe3

ð49Þ
Prn ii. I2 Prn
N N
75% H
Sato and co-workers also reacted titanacyclopropenes, formed from alkynes upon treatment
with Ti(OPri)4/PriMgCl (1:2), with alkynes <1999JA7342>, carbonyl compounds <1995TL3203,
1996TL7275, 1997TL4619>, or imines <1995TL5913, 2003OL2145>. Subsequent iodinolysis of
the intermediate titanacyclopentenes furnishes dienes, allyl alcohols or allyl amines, respectively,
in good yield (Scheme 43). Following the same method, dienyne 96 has been transformed into the
corresponding cyclic -iodoalkenylsilane with absolute regioselectivity (Equation (50))
<1996TL1253>. Intramolecular reaction of the titanacyclopropene moiety with an ester and
subsequent iodinolysis furnishes the corresponding -methylidenecyclopentanone in good yield
(Equation (51)) <1996JA2208>. Finally, applying an alkynyl carbonate as carbonyl compound
instead, Sato and co-workers <1998TL7947> synthesized an -methylidenelactone in good yield
and with retention of absolute stereochemistry (Equation (52)).
SiMe3
SiMe3
C6H13
I R1
I
I
R2 OH
R3 i. R3
R3 = (CH2)2OBn ii. I2 i. R2CHO 61% R1 = CH2OTHP
ii. I2
R2 = Et
64%
71% R1 = C6H13
R1 SiMe3 R2 = c-C6H11
Ti
PriO OPri
O
i. O
i.PrnCH=NBn CHO
ii. I2
ii. I2
76% 62%
1 SiMe3
R = C6H13
SiMe3
= CH2OTHP
C6H13 Me2ButSiO I
I = CH2OSiButMe2
Bn HO O
Prn N
H O
88% de
Scheme 43
SiMe3
i. Ti(OPri)4, 2 equiv. Pr iMgCl
SiMe3 ii. PhCHO I
BnO BnO OH
BnO iii. I2 BnO ð50Þ
66% Ph
96
(E )/(Z ) 57/43
SiMe3 O SiMe3
i. Ti(OPri)4, 2 equiv. Pr iMgCl
I ð51Þ
COOPri ii. I2
67%
SiMe3 O SiMe3
O ð52Þ
OCOOEt ii. I2
TrO
79%
TrO
Tr = trityl
4.18.3.1.5 By addition of alkyl halides to alkynyl silanes

This section covers transition metal-catalyzed and radical-initiated additions of alkyl halides to
silylated alkynes. Notable is the consistent reversal of selectivity between perfluoroalkyl transfer
(trans-selective) and alkyl transfer (cis-selective), regardless of the method of catalysis.
Perfluorobutyl iodide has been added to trimethylsilyl ethyne in the presence of zinc metal as
a catalyst via a single electron transfer (SET) mechanism. The reaction affords the gem-
iodosilyl alkene in good yield and excellent regioselectivity, but only with moderate stereo-
selectivity (Equation (53)) <2000JOC8763>. With the aid of a palladium(0) catalyst
(Pd(PPh3)4) <1986CL1895> or iron pentacarbonyl <1984TL303>, perfluoroalkyl groups
have been transferred to trimethylsilyl alkynes as well, furnishing (E):(Z) mixtures of
-iodoalkenylsilanes in good yields. Zhang and Lu reported the first preparation of a gem-
chlorosilylalkene via a metal-catalyzed addition. They performed an intramolecular palladiu-
m(II)-assisted enyne cyclization reaction providing the corresponding lactone (Equation (54))
<1996TA1923>. Finally, copper-catalyzed trifluoromethylthiolation of trimethylsilyl ethyne
gives a mixture containing both isomers of 2-chloro-1-trifluoromethylthio-2-trimethylsilyl
ethene (Equation (55)) <1999MI161>.
C4F9I C4F9 SiMe3

SiMe3
Zn, CF3COOH I ð53Þ
CH2Cl2, rt
(E )/(Z ) 67/33
73%
SiMe3 O SiMe3
O Pd(OAc)2 Cl
O
O LiCl, AcOH, rt
Cl ð54Þ
C5H11 C5H11
(E )-isomer: 45%, >99% de

(Z )-isomer: 28%, >99% de
ClSCF3 F3CS SiMe3 F3CS SiMe3

SiMe3 + ð55Þ
Cu Cl SCF3
A catalytic amount of triethylborane in water has been used to initiate radical addition of
perfluorohexyliodide to trimethylsilyl ethyne at room temperature. The reaction affords prefer-
entially the (E)-isomer of the gem-iodosilyl alkene together with a minor dimeric compound
(Equation (56)) <1998SL1351>. On the contrary, a (Z)-specific addition of alkyl iodides to
trimethylsilyl alkynes is observed when a solution of triethylborane in hexane is applied. The
(Z)-specificity is believed to be due to postaddition isomerization since (E)--iodoalkenyl silanes
are reported to isomerize into the corresponding (Z)-isomers when treated with a solution of
triethylborane in hexane <1994TA961, 1995BCJ625>.
C6F13 SiMe3
C6F13I C6F13 SiMe3 SiMe3
SiMe3 +
Et3B, H2O I ð56Þ
I
58% 21%
(E )/(Z ) 61/39
Weavers and co-workers have used and optimized a benzoyl-peroxide-initiated radical cycliza-
tion to prepare exocyclic gem-iodosilyl alkenes, predominantly as (E)-isomers. The authors
reported that high concentrations of initiator are required and portionwise addition of initiator
is beneficial for the course of the reaction (Equation (57)) <1995T4665, 1995T11257>. Analo-
gously, radical addition of halotrichloromethane to the double bond of compound 97 followed by
cyclization leads to the exocyclic gem-halosilyl alkene (Equation (58)) <1997TL2919>. Finally, in
the presence of benzoyl peroxide or 2,20 -azobisisobutyronitrile (AIBN) and at elevated tempera-
ture, iodomethyltriflone adds regioselectively across trimethylsilylethyne affording the corre-
sponding gem-iodosilylalkenyl sulfone in excellent yield (Equation (59)) <1995JA3272>.
SiMe3 I
SiMe3
H
I (PhCO2)2
n n O
Benzene or EtOAc O ð57Þ
O O
reflux H
88% (n = 1)
86% (n = 2)
X SiMe3
R2 R2 SiMe3
CXCl3
O
Cl3C
R1 O (PhCO2)2 or AIBN ð58Þ
Toluene, reflux R1 R2
97 R2
R1 = H, CH3 X = Cl, Br
71–88%
R2 = H, CH3, (CH2)5
CF3SO2CH2I F3CSO2 SiMe3

SiMe3
(PhCO2)2 or AIBN I ð59Þ
benzene, 100 °C
(E )/(Z ) 12/88
99%
4.18.3.2 a-Haloalkenylgermanium Derivatives

The preparation of gem-germylhaloalkenes closely follows that of the corresponding silicon
compounds, but far fewer examples are known. Trifluorovinyllithium reacts with triphenylgerma-
nium bromide, furnishing the corresponding trifluorovinylgermanium derivative. Further -func-
tionalization by displacement of fluoride has also been reported (Scheme 44) <2002IC4748>.
Using tris(dialkylamino)phosphine instead of a lithium base, reaction of iodotrifluoroethene with
triethylgermanium chloride leads to trifluorovinyltriethylgermane <1995SC2425>. -Chloroalk-
enylgermanes 98 and 99 have been prepared in very poor yields from the corresponding
,-dichloroalkenes upon treatment with divalent germanium compounds (germylenes GeR2)
<1996JOM(521)387, 1997OM5127>.
i. 2 equiv. BuLi
Et2O, –78 °C F GePh3 LiAlH4, NaOMe F GePh3
CF3CH2F
ii. Ph3GeBr F F or RLi R F
71% 64–93%
R=H
= MeO
= Me, Bu, Bu t, Ph
Scheme 44
GeR2Cl GeR1R2Cl
Cl Cl
R = CH(SiMe3)2
98 R1 = 2,4,6-CH3–C6H2
R2 = 2,4,6-CH(SiMe3)2 –C6H2
99
Bromination of vinylgermanes, followed by base-induced elimination, has been used to produce

gem-bromogermyl alkenes such as compound 100 <1984TL3221>. Electrophilic bromination of
the corresponding germylalkyne affords exclusively the (Z)-isomer of gem-bromogermyl alkene
101 (yield: 55%). It was suggested that this rare example of syn-addition of bromine across an
alkyne is caused by specific stereoelectronic properties of the germyl substituent
<2001JOM(627)1>. Negishi and co-workers reported the hydroalumination <1997TL3829>
and carboalumination <1997JOC784> of germyl alkynes. Subsequent iodination of the alumina-
cycles furnishes the corresponding -iodoalkenylgermanes with high stereoselectivity and in good
yields (Scheme 45, see also Equation (46) and Scheme 36).
GePh3 Ph GeR3
Br Br Br
100 R = –OCH2CH2N
101
GeMe3
i. Me3Al I
ii. DIBAL-H OH
>98% (Z )
65%
iii. I2
GeMe3
OH
i. Me3Al, Cp2ZrCl2
ii. ∆ GeMe3
iii. I2 73%
I
OH
>95% (Z )
Scheme 45
4.18.3.3 a-Haloalkenyl Derivatives of Tin and Lead

-Fluorovinyltin compounds have been prepared in high yield by a low-temperature reaction of tin
halides with trihalovinyllithium, generated from 1,1,1,2-tetrafluoroethane <1996CC49, 1997CC139,
2002IC4748> or 1-chloro-2,2,2-trifluoroethane <1998JCS(P1)2541, 2000JOM(616)96> and 2 equiv.
of n-butyllithium (Scheme 46). Deprotonation of (E)-1,2-difluoro(trialkylsilyl)ethene and subsequent
treatment with tributyltin chloride has been used to prepare (Z)--fluorovinylstannane 102
<1996T37, 2003JFC(119)21>. Starting from (Z)-1,2-difluoro(tributylstannyl)ethene instead, the
stereoselective synthesis of the corresponding (E)-bisstannane is described in 76% yield
<2002OL1483>. Similarly, compounds 103 <1996TL5183, 1997T14749>, 104 <1995TL3687>,
and 105 <2001CCC1508> were obtained from the corresponding monohalogenated alkenes in
good yields. The preparation of -iodoethenylstannane 106 has been reported treating iodoethene
with 3 equiv. of LDA followed by tributyltin hydride at 100 C <1998OM5390>.
2 equiv. BuLi F Li R3SnCl F SnR3

CF3CH2X
THF, –78 °C F X F X
R = Ph, X = F (86%)
R = Bu, X = Cl (95%)
Scheme 46
SnBu3
F F MEMO R SnBu3
F
R3Si SnBu3 Cl
O
102 103 104
R = Me (yield: 84%) (yield: 90%) R = C6H5 (yield: 63%)
R = Et (yield: 68%) R = C5H11 (yield: 87%)
SnBu3 SnBu3
F I
106
(yield: 40%)
105
(yield: 48%)
Burton and co-workers reported a stereospecific conversion of a wide range of vinyl silanes to
the corresponding vinylstannanes applying tributyltin chloride in the presence of 2 equiv. of
potassium fluoride. When bis(tributyltin) oxide is used as electrophile, only catalytic potassium
fluoride (5–10%) is needed to complete the conversion (Equation (60)) <1996TL1921,
1997JOC1064, 2002BCJ2497>. -Fluoroalkenylphenylsulfones have also been used to prepare
-fluoroalkenyltin derivatives. Treating 2,2-disubstituted fluorovinylsulfones with 2 equiv. of
tributyltin hydride and a radical initiator leads to -fluorovinylstannanes with retention of
configuration. On the contrary, 2-monosubstituted analogs equilibrate to mixtures of (E)- and
(Z)-isomers (Equation (61)) <1994JOC8034, 1995OS216, 1996T45, 2002OL2083>.
R1 SiR 33 Bu3SnCl or (Bu3Sn)2O R1 SnBu3
R2 F KF, DMF, rt or 80 °C R2 F
69–92% ð60Þ
1 = H,
R F
R2 = H, F, I, Ph, alkyl, CF2 CF
R3 = Me, Et
R1 SO2Ph 2 equiv. Bu3SnH R1 SnBu3
R2 F AIBN, C6H6 R2 F
ð61Þ
76–98%
R1 = H, CH3, CF3, SiMe3
R2 = alkyl, aryl
Bis(tributyltin)copper lithium has been added to ethyl 3,3-difluoro-2-methoxyprop-2-enoate via

an addition–elimination mechanism affording the corresponding (E)-gem-fluorostannyl alkene in
good yield (Equation (62)) <1995JOC6608>.
EtOOC F (Bu3Sn)2CuLi EtOOC SnBu3
THF, –78 °C
ð62Þ
MeO F MeO F
81%
Monohalogenation of gem-distannyl alkenes affords -fluoroalkenylstannanes by replacement

of one stannyl group. Iodine or NBS at low temperatures has been successfully applied, although
iodine always gives some gem-diiodoalkene. N-Chlorosuccinimide (NCS) chlorinates only on
heating. Upon UV irradiation or thermolysis, the bromo and iodo compounds both isomerize
to the less crowded isomer (Scheme 47) <1983JOM(256)37, 1986OM1991, 1998TL481>.
R SnMe3 R SnMe3 SnMe3

I2, NBS or NCS UV
SnMe3 –78 °C to 50 °C X or heat R X

40–87%
R = alkyl, Ph
X = Cl, Br, I
Scheme 47
Finally, triphenyllead chloride reacts with trifluorovinyllithium leading to (trifluorovinyl)tri-

phenyllead 107 that was isolated as a solid in 77% yield <2002IC4748>.
F PbPh3
F F
107
4.18.4 DERIVATIVES OF BORON AND OTHER GROUP 13 ELEMENTS
4.18.4.1 a-Haloalkenylboron Derivatives
4.18.4.1.1 By ligand exchange and by halogenation reactions

Generating trifluorovinyllithium from 1,1,1,2-tetrafluoroethane using t-butyllithium as a base,
Brauer and Pawelke attached a trifluorovinyl group to dimethylaminobis(trifluoromethyl)borane
in quantitative yield. The corresponding trimethylamine borane, which is prepared by alkylation
with methyliodide in the presence of potassium hydroxide, reacts with hydrogen fluoride furnish-
ing fluoroborate 108 (Scheme 48) <2000JOM(604)43>. Analogously, (E)- and (Z)--fluoro-
alkenylboron derivatives have been prepared with retention of configuration from the
corresponding organolithium compounds upon reaction with trimethylborate and subsequent
treatment with potassium hydrogen difluoride and hydrogen fluoride in aqueous methanol
(Scheme 49) <2001ZAAC(627)2499>. UV irradiation ( > 280 nm) of (E)--fluoroalkenyltri-
fluoroborates dissolved in acetone gives rise to partial conversion to the corresponding (Z)-isomer
(Scheme 49) <2002ZAAC(628)721>. Further, Frohn and Bardin reported the synthesis of
difluoroboranes by defluoridation of the fluoroborate salts with retention of stereochemistry
and in very good yield (Scheme 49) <2001JOM(631)54>.
i. ButLi, Et2O, –78 °C F B(CF3)2 NHMe2

B(CF3)2NMe2 + CF3CH2F
ii. H2O, –78 °C F F
89%
i. MeI, KOH, Et2O
51%
ii. HF, NEt3, 200 °C
F B(CF3)2F NHMe3
F F
108
Scheme 48
R BF3 K
F F
hν (λ > 280 nm)
acetone (E )/(Z ) 31/69
R = C4F9
F Li i. B(OMe)3 F BF3 K
R F ii. K(HF2), HF R F
43–72% (Z ) or (E )
BF3, –40 °C
CH2Cl2 or CFCl3
80–90% F BF2
R F
(Z ) or (E )
Scheme 49
Because of the relatively good electrofugal-leaving ability of tetracoordinate boron anions

compared to protons, halogenation of vinylboronates and subsequent elimination is limited.
However, bromination of gem-diboroalkene leads to bromodeboronation affording the corre-
sponding gem-bromoboroalkene 109 <1974JOM(69)53>. Addition of bromine to an activated
alkyne containing a boron atom stabilized by B–N bonds leads to adduct 110 in 57% yield
<1989JGU2040>. Finally, radical addition of perfluorohexyliodide to ethynylboronate proceeds
regioselectively and furnishes one unspecified isomer of the functionalized -iodoalkenylboronate
in moderate yield (Equation (63)) <1996SL377>.
O
B O Br B(NMe2)2
Br EtO Br
109 110
O
i. hν, Toluene, 0 °C B O
ð63Þ
B(NPr2i )2 + C6F13I
ii. Pinacol C6F13 I
40% One isomer
4.18.4.1.2 By hydroboration of haloalkynes

The hydroboration of a wide variety of 1-haloalkynes, substituted with t-butyl, cycloalkyl, or
n-alkyl chains, using dialkylboranes (dicyclohexylborane or 1,1,2-trimethylpropylcyclohexyl-
borane) has been extensively investigated. The products were obtained as (Z)-isomers by
exclusive cis-hydroboration and were described as being relatively stable <1967JA5086,
1972S555>. More recently, a highly regio- and stereoselective (except for R = CH2OCH3)
hydroboration of 1-haloalkynes with 9-BBN-H has been reported. In the presence of
5 mol.% of dicyclohexylborane, the reaction is remarkably accelerated and furnishes the
(Z)-gem-haloboroalkenes in quantitative yields (Equation (64)). The halogen may be chlorine,
bromine, or iodine and the reactivity increases in that order. It is also worth mentioning that in
contrast with the previously reported procedures, the 1-haloalkynes may also be substituted
with a phenyl moiety <1997SC567>.
9-BBN-H BR22
R1 X
5 mol.% (c-hex)2BH R X
THF, 4 h, rt
ð64Þ
R1 = Bun, Ph, (CH2)3Cl, CH2OCH3
R2 = bicyclo[3.3.1]nonyl
X = Cl, Br, I
4.18.5 DERIVATIVES OF LITHIUM AND OTHER GROUP 1 AND GROUP 2 METALS

Derivatives of lithium and other group 1 and group 2 metals, and -haloalkenyl metals, in
general, exhibit ambiphilic behavior concerning their reactivity and have been described as
alkylidene carbenoids (Scheme 50). -Metallated vinyl halides readily behave as ordinary
organometallic nucleophiles at sufficiently low temperatures demonstrating their carbanionic
reactivity (pathway A). Examples of their preparation and nucleophilic behavior are to be
found in other sections of this chapter (especially for silicon, see Section 4.18.3.1; for phosphorus,
see Section 4.18.2, and for the transition metals, see Section 4.18.6.1). Further, the surprising
reaction of metallated vinyl bromides with alkyllithium compounds proves the electrophilic
character of the -haloalkenyl metals (pathway B) <1993JOC546>. Finally, the intramolecular
shift of a -aryl, cyclopropyl, or hydrogen substituent (known as the Fritsch–Buttenberg–
Wiechell rearrangement) of thermolabile -lithiated vinyl halides (pathway C) and the cyclopro-
panation reaction with -alkyl-substituted -haloalkenyl metals (pathway D) are both features of
carbene-type reactivity <1952HOU(E19b)85>. Reviews of fluorinated vinyl organometallic spe-
cies <1994T2993> and -heteroatom-substituted 1-alkenyllithium reagents, in general,
<1998AG(E)430> have been published.
R1 M
R2 X
+
A, E D,
B, R3Li C, ∆
R1 E R1
R2 X R2
R1 M
R1 R2
R2 R3
Scheme 50
4.18.5.1 a-Haloalkenyllithium Derivatives

-Haloalkenyllithium derivatives are usually generated quantitatively in solution under inert
conditions at low temperatures and allowed to react further without isolation. The greater
s character of the CH bond compared with alkanes as well as the presence of a halogen atom
increases the acidity of the geminal proton, allowing deprotonation by using alkyllithium reagents
(n- or t-BuLi) or lithium amides (LDA or LITMP). Lithium–halogen exchange and, to a much
lesser extent, lithium–metal exchange (see Section 4.18.5.1.1 for example) have also been
reported as suitable methods to prepare -haloalkenyllithium derivatives. With vinyl fluorides
and vinyl chlorides, deprotonation is faster than lithium–halogen exchange, whereas the rate
of lithium–halogen exchange increases when going from chlorine to iodine <1993JA5430,
1998AG(E)430>.
Routes of thermal decomposition are hard to predict but often include elimination of a
potential leaving group in the -position or an intramolecular rearrangement (Fritsch–Buttenberg–
Wiechell rearrangement; see Scheme 50, pathway C). These reactions may be suppressed by low
temperatures, and -chloro, fluoro, and alkoxy groups are commonly found in carbenoids
<1993JA5430, 1995JCS(P1)2681, 1998AG(E)430, 1998OM5390>.
4.18.5.1.1 a-Fluoroalkenyllithium compounds

Kvicala and co-workers prepared -fluorovinyllithium derivatives employing metallation or
lithium–halogen exchange with n-butyllithium at 100 C (Equation (65)). The influence of
several -substituents on the stability of 1-fluoro-1-lithioalkenes was studied using low-temperature
19
F NMR spectroscopy. It was noticed that a fluorine cis to lithium stabilizes the carbanion
more than a phenyl group, while hydrogen and silyl groups show no stabilizing effect. This is
illustrated by the observation that only products of decomposition of (E)-1,2-difluoro-
2-(dimethylphenylsilyl)-1-lithioethene are observed, whereas the corresponding (Z)-isomer is
rather stable even at 90 C. Further, it is worth mentioning that lithium–chlorine exchange
as well as metallation employed on (E):(Z) mixtures of -substituted -fluorolithioalkenes
proceed with different rates for both isomers <1995JCS(P1)2681, 2001CCC1508,
2002JFC(113)211>.
R1 X 1.6 equiv. BuLi R1 Li
R2 F THF, –110 °C R2 F
ð65Þ
X = H, Cl, Br, I
R1 = F, Ph
R2 = H, F, Ph, SiPhMe2
Trifluorovinyllithium has also been prepared from 1,1,1,2-tetrafluoroethane using 2 equiv. of

n- or t-butyllithium as base and is reported to be stable for several hours at 78 C. Decomposi-
tion in THF is much more rapid than in diethyl ether and the compound is less stable when the
concentration is higher. Attempts to prepare -fluorovinyllithium derivatives from 1,1,1-trifluoro-
ethane and 1,1,1,3,3,3-hexafluoropropane with n-butyllithium were unsuccessful. <1996CC49,
1999JFC(99)127>. Finally, -fluoroalkenyllithium compounds have been prepared from the
corresponding vinylstannanes by lithium–tin exchange (Equation (66)) <2003S209>.
F3C SnBu3 BuLi F3C Li
R F THF, –78 °C R F ð66Þ
R = 4-CH3–C6H4, 4-Cl–C6H4, 4-MeO–C6H4
4.18.5.1.2 a-Chloroalkenyllithium compounds

The metallation of 1-chloro-2,2-diarylethenes using n-butyllithium at low temperatures has been
reviewed <1990JOM(400)19>. An X-ray crystal structure analysis of a THFTMEDA complex of
1-chloro-2,2-bis(4-chlorophenyl)-1-litioethene 111 reveals that the CCl bond is distinctly elon-
gated with respect to that in the nonlithiated compound, while the CLi bond is shorter than
expected. The C–Li bond is bent toward the axis of the alkene CC bond, whereas the CCl
bond adopts a position at an angle to the double bond significantly smaller than the 120 angle at
sp2-hybridized carbon atoms <1993AG(E)1032>. Nelson and Brammer performed a computa-
tional study of (E)- and (Z)-1-chloro-1-lithiostyrenes 112 and obtained similar results. The general
observation that the most stable carbenoids generally carry the metal atom cis to the most bulky
group, especially where that group is an aryl ring, has been explained by an agostic bonding
between lithium and an ortho-proton of the aryl moiety, rather than -complexation with lithium
<2002HAC263>.
Cl
Li Ph Li
Cl R Cl
R = H, CH3
112
Cl 111
The preparation of 1-chloro-2,2-difluorovinyllithium from 1-chloro-2,2,2-trifluoroethane is

analogous to the formation of trifluorovinyllithium (see Section 4.18.5.1.2). The upper limit for
the stability of 1-chloro-2,2-difluorovinyllithium is reported to be 50 C in hexane
<1997JFC(85)151, 1998JCS(P1)2541, 1999JFC(99)127>.
4.18.5.1.3 a-Bromoalkenyllithium compounds

Compared to the corresponding fluoro and chloro species, gem-bromolithioalkenes have not been
as intensively studied. Metallation of monobromoalkenes with butyllithium may lead to competi-
tion from lithium–bromine exchange, affording nonhalogenated products. Lithium amides may
provide alternative bases in difficult cases. Hence, Gilbert and co-workers added bromomethyle-
necyclobutane to a mixture of LDA and trimethylsilyl chloride at 107 C (see also Scheme 33)
<1999JOC1529>.
Owing to the high reaction rate, even at low temperatures, lithium–bromine exchange is
particularly suitable for generating unstable -haloalkenyllithium derivatives. Jones and co-workers
treated 1,1-dibromo-2,2-diphenylethene with 1 equiv. of n-butyllithium at 100 C to prevent
rearrangement (see also Scheme 33) <1995JA3298>.
4.18.5.1.4 a-Iodoalkenyllithium compounds

Rodriguez and co-workers reported the sole example of the preparation of 1-iodo-1-lithioethene.
The best results are obtained employing the metallation method with 3 equiv. of LDA in THF.
The solution of 1-iodo-1-lithioethene readily begins to decompose after 5 min at 100 C leading
to the formation of 1-lithioethyne. However, the anion has been successfully trapped by various
electrophiles (see Sections 4.18.3.1.2 and 4.18.3.3 for further details). Applying the lithium–iodine
exchange reaction from 1,1-diiodoethene instead, only large amounts of decomposition product
were isolated <1998OM5390>.
4.18.5.2 a-Haloalkenylmagnesium Derivatives

Carbenoid 113 has been prepared by Boche and co-workers from 9-(dibromomethylene)fluorene
using n-octylmagnesium bromide at 30 C. The THF complex of compound 113 was isolated as
a single crystal and the structure was elucidated by X-ray analysis. Comparable results as for
-chloroalkenyllithium 111 (see Section 4.18.5.1.2) were obtained, being characteristic for the
carbenoid nature of 113 <1994CC1393>. Further, Grignard reagents 114 have been prepared
from the corresponding perfluoroalkenyl iodides in diethyl ether <1997HAC467>.
MgBr F MgI
Br R F
R = SF5, CF3
114
113
4.18.6 DERIVATIVES OF THE TRANSITION METALS

Many reports of -haloalkenyl derivatives of transition elements mainly concentrate on ligand
modification. Hence, chemistry of direct relevance to organic synthesis is largely limited to copper
and the group 12 elements, especially zinc. There are no reports of -haloalkenyl derivatives of
the lanthanide and actinide elements. A review of fluorinated vinyl organometallic reagents has
been published <1994T2993>.
4.18.6.1 By Transmetallation Reactions

Metal exchange between metal salts and lithium carbenoids is the most general route to
-haloalkenyl transition metals. A variety of -chloroalkenyl species have been prepared, some
of which were surprisingly stable (Equation (67)) <1972AG(E)473, 1982JFC(20)699,
1990JOM(400)19>. Brisdon and co-workers developed a one-pot synthesis of perfluorovinylmetal
derivatives (yield: >90%) reacting the corresponding metal halides with 1,1,1,2-tetrafluoroethane
in the presence of n-butyllithium at low temperatures (Scheme 51). The majority of these com-
plexes are thermally stable, although decomposition does occur in the presence of water
<1997CC139, 1999JOM(582)301, 2001JFC(112)35>. Analogously, using 1-chloro-2,2,2-trifluoro-
ethane instead, the corresponding gem-chlorodifluorovinyl transition metals have been prepared
in poor (Ni: 36%)-to-good (Pd, Au, Hg: 60–88%) yields (Scheme 52) <2000JOM(616)96,
2001JFC(112)35>. Anilkumar and Burton modified this procedure allowing the synthesis of
chloro(-halodifluorovinyl)zinc at room temperature (15–20 C). Treatment of zinc(II) chloride
and 1,1,1,2-tetrafluoroethane <2002TL2731> or 1-chloro-2,2,2-trifluoroethane <2002TL6979>
with LDA in THF furnishes the corresponding gem-fluoro- (yield: 73%) or gem-chlorovinylzinc
(yield: 91%) derivative, respectively.
R1 Li MXn R1 MXn –1
R2 X THF or Et2O R2 X
ð67Þ
M = Ti, Cr, Fe, Cu, Zn, Ag, Hg
R1, R2 = H, F, Cl, Ph, alkyl, Rf
X = F, Cl, Br
Pt(PBu3)2(CF=CF2)2
Pt(PBu3)2(CF=CF2)Cl Mn(CO)5(CF=CF2)
0.5 equiv.
Pt(PBu3)2Cl2 Mn(CO)5Br
Pt(PBu3)2Cl2
FeCp(CO)2(CF=CF2)
FeCp(CO)2I
BuLi
CF3CH2F CF2CF Li
Et2O, –78 °C TiCp2X2
0.5 equiv. TiCp2(CF=CF2)X

TiCp2X2 X = F, Cl
HgCl2 0.5 equiv.
HgCl2
Hg(CF=CF2)Cl TiCp2(CF=CF2)2
Hg(CF=CF2)2
Scheme 51
Pd(PBu3)2(CCl=CF2)2
0.5 equiv. Ni(PBu3)2(CCl=CF2)2

0.5 equiv.
Ni(PBu3)2Cl2
Pd(PBu3)2Cl2
BuLi Au(PPh3)Cl
CF3CH2Cl CF2CCl Li Au(PPh3)(CCl=CF2)
Et2O, –78 °C
0.5 equiv.
HgCl2
HgCl2
Hg(CCl=CF2)Cl
Hg(CCl=CF2)2
Scheme 52
Transmetallation is not restricted to lithium carbenoids only. Brisdon and co-workers prepared
chloro(chlorodifluorovinyl)mercury by treatment of mercury(II) chloride with the tin-containing
compound acting as transfer reagent of the chlorodifluorovinyl group (Scheme 53)
<2000JOM(616)96, 2001JFC(112)35>.
i. BuLi, Et2O, –78 °C F SnBu3 HgCl2 F MR

CF3CH2Cl
ii. Bu3SnCl, –78 °C F Cl or AuCl(PPh3) F Cl
EtOH
84% M = Hg, Au
R = Cl, PPh3
Scheme 53
4.18.6.2 From Alkenyl Halides

Generally, transmetallation reactions using lithium carbenoids have the disadvantage of requiring
low temperatures causing difficulty when carried out on a large scale. To overcome this problem,
Burton and co-workers treated a variety of fluorinated alkenylbromides <1993JA5430> and
halogenated vinyl iodides <1997JOC9217, 2000TL8045, 2002TL6979> with metallic zinc in
polar aprotic solvents (Equation (68)). Further, metal–bromine exchange has been performed
utilizing lithium tributylzincate (R13ZnLi) <1993JOC4897> or bis(trimethylsilyl)mercury
<1971TL1879> affording compounds 115 and 116, respectively.
R1 X M R1 MX
R2 Y DMF or DMA R2 Y
M = Zn, Cd ð68Þ
X = Br, I
Y = F, Cl, Br
R1, R2 = H, F, Ph, Rf
1
R2 ZnR 2Li F HgSiMe3
R3 X F F
115 116
R1 = Bun, Bus, But
R2, R3 = Ph, alkyl
X = Cl, Br
Metal anions react with polyfluoroalkenes by net addition–elimination or by allylic substitution

followed by rapid fluoride ion migration producing -fluoroalkenyl metal species (Equation (69))
<1989CC1159, 1998RJOC1435>. -Chlorovinylosmium species 117 have been prepared from
tetrachloroethene by osmium–chlorine exchange in 71% yield <2000OM4344>. Similarly, chloro-
vinylcobaloxime complexes 118 (dmgH = dimethylglyoximate) are formed when tetra- or trichloro-
ethene is treated with cobalt(II) acetate or cobalt(II) chloride and dimethylglyoxime (yield: 45%)
<2002CC234, 2002IC393>. Starting from chlorotrifluoroethene, Cowie and co-workers synthesized
diiridium complex 119 (dppm = 1,2-bis(diphenylphosphino)methane, py = pyridine) as a bright
yellow powder in 89% yield <2002OM5172>. As an intermediate of a rhodium-mediated reduction
of perfluorinated propene, alkenylrhodium derivative 120 has been isolated in unspecified yield
<2002AG(E)2745>. Braun and co-workers <2002JCS(D)2213> obtained fluorovinylnickel com-
plexes 121 from fluorinated vinyl halides upon treatment with bis(1,5-cyclooctadienyl)nickel in the
presence of triethylphosphine. The (Z)-isomers of palladium and platinum complexes 122 have been
successfully prepared when the corresponding N-(2,2-dichlorovinyl)imine and phosphino metal
complexes are heated in toluene at 50 C <2003EJI514>. Finally, -bromoalkenylpalladium 123
is formed in unspecified yield via cleavage of the CS bond of 2,5-dibromothiophene. Structure 123
has been confirmed by X-ray crystallography <1999JOM(588)268>.
R1 X M(CO)n R1 M(CO)n
R2 F THF R2 F
ð69Þ
M = Mn, FeCp, Co, Re
X = F, Cl
R1, R2 = F, Ph, CF2CF, Rf
Cl Os(CO)2(PPh3)2Cl Co(dmgH)2py F Ir2(CO)2(dppm)2CH3Cl
Cl Cl Cl Cl F F CF3SO–3
117 118 119
F Rh(PEt3)3 F Ni(PEt3)2Y M(PPh3)2Cl

Ph
F3C F F X N Cl
121 Ph 122
120
X = F, Br M = Pd (yield: 66%)
Y = Br, I = Pt (yield: 79%)
(Me3P)2Pd
Pd(PMe3)2Br
S
Br
123
4.18.6.3 From Alkynes

-Haloalkenyl metal compounds have been prepared from metalloalkynes or from 1-haloalkynes.
The addition of hydrogen chloride to a bis(ethynyl)platinum complex affords gem-chlorovinyl-
platinum compound 124 <1976JA6046>. An example of the second mode of addition is provided
by compound 125 formed by reaction of chloroethyne with cobal(I)oxime in unspecified yield
(Equation (70)) <2002IC393>.
Cl
Pt(PPhMe2)2
Cl
124
Co(dmgH)2 Co(dmgH)2py Co(dmgH)2py

Cl +
Pyr (pH = 9) Cl Cl ð70Þ
125 (3:1)
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Biographical sketch
Christan Stevens was born in Gent, Belgium Bart Vanderhoydonck was born in Genk,
and obtained a Master’s degree as Bioengineer Belgium and obtained a Master’s degree as
in chemistry at Ghent University in 1988. He Bioengineer in chemistry at Ghent University
obtained a Ph.D. in 1992 at Ghent University in 2000. He is preparing a Ph.D. dissertation
under the direction of Prof. Norbert De under the direction of Prof. Christian Stevens
Kimpe on the chemistry of halogenated imi- on the chemistry of phosphonoazadienes. His
nes. He researched at the University of South- scientific interests include heterocyclic chemis-
ern California at Los Angeles (USC) under try, organophosphonate chemistry, and com-
the guidance of Prof. Charles McKenna. He putational chemistry. Apart from chemistry,
then moved as a NATO Research Fellow to he likes reading, squash, and enjoys playing
the Florida Center for Heterocyclic Chemistry guitar.
to do postdoctoral work on the benzotriazole
methodology (1992–1993) with Prof. Alan
R. Katritzky. He spent a short postdoctoral
period with Prof. Miguel Yus (University of
Alicante, Spain) and did further postdoctoral
work with Prof. Norbert De Kimpe at Ghent
University, Belgium. In 1995, he got a perma-
nent position as Research Leader of the
National Fund for Scientific Research at
Ghent University, became a guest professor
in 1998, and a professor in 2000 at the same
university. His scientific interests include het-
erocyclic chemistry and synthetic methodol-
ogy in general, organophosphonate chemistry,
and chemical modification of renewable
resources. He was laureate of the Royal Flem-
ish Society of Engineers in 1989 and laureate
of the Belgian Royal Academy of Sciences
in 1992.
4.19
Functions Bearing Two Chalcogens
D. C. ONICIU
Esperion Therapeutics, Pfizer Global Research and Development,
Ann Arbor, MI, USA
4.19.2 FUNCTIONS CONTAINING TWO OXYGEN ATOMS, R12C¼C(OR2)2, etc. 790
4.19.2.1 Ketene Acetals, R12C¼C(OR2)2 790
4.19.2.1.1 From carboxylic acids, esters, and chlorides 790
4.19.2.1.2 From ortho-esters and analogs 793
4.19.2.1.3 From -haloacetals and analogs 793
4.19.2.1.4 From cycloaddition reactions of , -unsaturated ketones and esters 793
4.19.2.1.5 By reduction–elimination in !-keto esters 794
4.19.2.1.6 From diazoalkanes 795
4.19.2.1.7 From ketenes 796
4.19.2.1.8 From gem-dihalogenoalkenes and analogs 796
4.19.2.1.9 From oxazoles and isoxazoles 798
4.19.2.1.10 By miscellaneous rearrangements and cycloadditions 798
4.19.2.1.11 By miscellaneous transformations 801
4.19.2.2 Other Related Ketene Derivatives, R12C¼COR2OX, etc. 801
4.19.2.2.1 Ketene silyl acetals, R12C¼COR2OSiR33 801
4.19.2.2.2 Ketene silyl acetals, R12C¼COSiR23OSiR33 804
4.19.2.2.3 Boryloxy derivatives, R12C¼COR2OBR33 804
4.19.3 FUNCTIONS CONTAINING OXYGEN AND SULFUR, R12C¼COR2SR3, etc. 805
4.19.3.1 Dicoordinated Sulfur Derivatives, R12C¼COR2SR3 805
4.19.3.1.1 From monothiocarboxylic acids and esters or thioesters 805
4.19.3.1.2 By alkeneation methods 806
4.19.3.1.3 By elimination methods 807
4.19.3.1.4 By miscellaneous methods 808
4.19.3.2 Tricoordinated Sulfur Derivatives, R12C¼COR2S(O)R3 810
4.19.3.3 Tetracoordinated Sulfur Derivatives, R12C¼COR2SO2R3 810
4.19.4 FUNCTIONS CONTAINING OXYGEN AND EITHER SELENIUM
OR TELLURIUM, R12C¼COR2SeR3, etc. 810
4.19.5 FUNCTIONS CONTAINING TWO SULFUR ATOMS, R12C¼C(SR2)2, etc. 810
4.19.5.1 Two Dicoordinated Sulfur Atoms, R12C¼C(SR2)2 810
4.19.5.1.1 From dithiocarboxylic acids and derivatives 810
4.19.5.1.2 By double bond formation via elimination 812
4.19.5.1.3 By alkeneation methods 812
4.19.5.1.4 From gem-dihalogeno alkenes and analogs 819
4.19.5.1.5 By miscellaneous methods 819
4.19.5.2 One Dicoordinated and One Higher Coordinated Sulfur Derivatives, R12C¼SR2S(O)nR3 822
4.19.5.3 Two Tricoordinated Sulfur Atoms, R12C¼C[S(O)R2]2 823
4.19.5.4 One Tricoordinated and One Tetracoordinated Sulfur, R12C¼CS(O)R2S(O)2R3 824
4.19.5.5 Two Tetracoordinated Sulfur Atoms, R12C¼C[S(O)2R2]2 824
4.19.6 FUNCTIONS CONTAINING SULFUR AND EITHER SELENIUM OR TELLURIUM,
R12C¼CSR2SeR3, etc. 825
4.19.6.1 Dicoordinated Sulfur Derivatives 825
4.19.6.1.1 Selenium derivatives 825
4.19.6.1.2 Tellurium derivatives 827
4.19.6.2 Tri- and Tetra-coordinated Sulfur Derivatives 828
789
790 Functions Bearing Two Chalcogens
4.19.7 FUNCTIONS CONTAINING SELENIUM AND/OR TELLURIUM,

R12C¼C(SeR2)2, etc. 828
4.19.7.1 Selenium Derivatives 828
4.19.7.2 Tellurium Derivatives 829
4.19.1 INTRODUCTION
The review covers compounds containing a double bond in which one carbon atom is connected
to two chalcogen atoms. Articles published from 1996 through August 2003 were reviewed using
Beilstein. Compounds whose chalcogen atoms are part of a heterocycle are generally treated by
Comprehensive Heterocyclic Chemistry and therefore have been excluded in this review. However,
some cases where a synthetic method was considered general are described, especially if one of the
reactants bears the double bond and one chalcogen. Also, compounds containing OH, SH, or the
chalcogen substructure that display coordination to a metal ion are not included in this review.
4.19.2 FUNCTIONS CONTAINING TWO OXYGEN ATOMS, R12C¼C(OR2)2, etc.
4.19.2.1 Ketene Acetals, R12C¼C(OR2)2

This section describes compounds in which the two oxygen atoms of the acetal are further
connected to carbon atoms.
4.19.2.1.1 From carboxylic acids, esters, and chlorides

Earlier literature showed that the disadvantage of the formation of ketene acetals from esters is
due to the carbon versus oxygen regioselectivity. Intramolecular reactions could occur more
successfully when the molecular geometry favors the attack of the carbonyl group to the double
bond of a nucleophilic olefin as in the condensation of derivative 1 with dimethyl barbituric acid,
when the tetracyclic hetero-Diels–Alder cycloadduct 2 was produced as a single diastereomer cis
(Scheme 1) <1997SL1155>. A typical example is the reaction of azulene 3 with dicyclo-
hexylcarbodiimide (DCC) in benzene at room temperature for 1 h (Scheme 2). Two reaction
products are formed: the benzazulene ketene acetal 4 in 43% yield and the azulene 5 in 12%
yield <1997JCCS265>.
O O
O
N N
O N N
N O
O N O O
N H OH
O
N
S N N H
N N S
S
1 2 (cis 92%)
<1997SL1155>
Scheme 1
Acyl ketenes can be obtained in situ from carboxylic acids possessing a strong electron-
withdrawing group in the -position <2002JOC8975>. Methyl malonic monoester 6a was treated
with 1 equiv. of DCC to generate in situ acyl ketene 6b. The reaction was performed in the
Functions Bearing Two Chalcogens 791
O O O
O O
O
DCC, benzene
+
O rt, 1 h
O
N N N
O O
3 4 (43%) 5 (12%)
<1997JCCS265>
Scheme 2
presence of a large excess of nucleophilic olefins such as cyclopentadiene and ethyl methyl ether,
with the idea that a [2+2]-cycloaddition would occur between the acyl ketene formed in situ and
the olefin to form a cyclobutanone derivative. Ketene acetal 8 was formed instead by a [4+2]-
cycloaddition reaction of the acyl ketene with a second DCC molecule 7 (Scheme 3)
<2002JOC8975, 2001OL3733>.
O
OH O N
DCC, CH2Cl2
DCC C
O + NC N O O N
Me rt, 1 h
O O O 59%
EtO
6b 7 8
6a
<2002JOC8975>
Scheme 3
Diethyl malonate 10 was reacted with -difluoroketones in the presence of sodium carbonate
in dioxane at 60 C to produce the appropriate ketene acetals <1996S1363>. Thus,
7-chloro-4,4,5,5,6,6,7,7-octafluoroheptane-2-one 9 was treated under these conditions to produce
derivative 11 with a trans–trans stereochemistry (Scheme 4).
O OH
F F O O O O
F F O Na2CO3
Cl + F O
O Dioxane, F F
F F
F F O i. 60 °C, 1 h
ii. 60 °C, 10 h Cl F
F F
9 10 11
<1996S1363>
Scheme 4
Similarly, perfluoro-3-methylpent-2-ene 12 reacted with 1 equiv. of bidentate nucleophiles such

as diethyl malonate 10 in the presence of 2 equiv. of sodium hydride in diethyl ether to produce
2-F 13 and 4-F 14 pyranes by intermolecular cyclization (Scheme 5) <1998JFC(88)169>.
Diethyl malonate 10 also reacted with the -alkynylmethanesulfonic acid 15 as shown in Scheme 6,
in the presence of 1,2-bis(diphenylphosphino)ethane, sodium hydride, and a palladium catalyst in
tetrahydrofuran at room temperature to produce a dihydrofuran derivative 16 <2002CCC1421>.
F F
F F F F
F F F O F O
O F
O F F NaH, TDA-1 F F
O + F F O + F O
Et2O, 1 h, F
O F F F
F F F F 0 °C to rt, 16 h, F O O F O O
reflux, 30 min, F F F F
10 12 71% combined yield 13 (66%) 14 (33%)
<1998JFC(88)169>
Scheme 5
F
F F
O 1,2-Bis(diphenyl- O
S
O O phosphino)ethane,
O O
+ NaH, Pd, THF O
O
F rt, 24 h
O O O
F F
15 10 16
<2002CCC1421>
Scheme 6
Photodecarbonylation of 1,3-bis(ethylenedioxyl)-2-indanone 17 in THF solution led to bisketal

18 in 48% yield (Scheme 7) <2002TL7063>. Benzocyclobutanedione 19 was also formed by
irradiation in tetrahydrofuran, while by irradiation in crystal the latter was the only product.
Also, Meldrum’s acid and analogs reacted with oxygen nucleophiles to give ketene acetals
<1996LA1673, 1999H833>.
O O
O O O
O hν O H+/H2O
+ O
O O O
–CO
O O O
O
17 18 19
<2002TL7063>
Scheme 7
Acid chlorides have also been used as starting material for ketene acetals. Thus,
2-cyclopentadienyliden-1,3-dioxolane 22 was prepared as shown in Scheme 8 from cyclopentadiene
21 and 2-chloroethyl chloroformate 20 <1997SC3385>. The reaction was carried out with 2 equiv.
of sodium cyclopentadienide and KOH.
O O
O
KOH, CH3CN
Cl +
Cl O rt, 1 h
82%
20 21 22
<1997SC3385>
Scheme 8
Cyclization of o-acyloxy benzoyl chlorides with triethylamine in refluxing toluene led to the
preparation of a new class of compounds: 2-alkylidene-benzo-[1,3]dioxin-4-ones <2001TL5231>.
For instance, the cyclohexanoic acid derivative 23 produced the acetal 24 in 58% yield, and
derivatives with asymmetrical substitution at the ketene acetal double bond were obtained as
(Z)/(E) mixtures (Scheme 9).
O
O
Cl Et3N, toluene O
O
110 °C, 15 h O
O
58%
23 24
<2001TL5231>
Scheme 9
4.19.2.1.2 From ortho-esters and analogs

Earlier literature referred often to this reaction, but only one entry was found in the period
reviewed here. Triethoxymethane 26 was reacted with ethyl 2,3,4,5-tetrafluorobenzoylacetate 25
to give the corresponding diethoxyacetylate 27 <1998JMC4273>. The reaction occurred in
refluxing acetic anhydride (Scheme 10).
O O
O O
Ac2O F
F O O
O +
130 °C, 4 h
O O F F O
F F O
F
F
25 26 27
<1998JMC4273>
Scheme 10
4.19.2.1.3 From a-haloacetals and analogs

-Bromoaldehydes are often protected as 1,2-benzenedimethyloxy acetals because of the facile
elimination of the protecting group. Such acetals underwent bromine -elimination to afford
ketene acetals. The bromine elimination in compound 28 was achieved by treatment with
potassium t-butoxide in THF and subsequent heating for 1 h to obtain product 29 as a solid
(Scheme 11) <2001JOC305, 2001TL3183>.
O
O Br ButOK
THF/heat 1 h O
O
89–95%
28 29
<2001TL3183>
Scheme 11
4.19.2.1.4 From cycloaddition reactions of a, b-unsaturated ketones and esters

,-Unsaturated systems react with allylic alcohols to produce ketene acetals. The recent exam-
ples refer to the synthesis of some polycycles containing ketene acetal systems. As an example,
cumarone 30 treated with 2-methyl-3-buten-2-ol 31, in the presence of cerium(IV) ammonium
nitrate in acetonitrile at 0 C, produced the ketene acetal 33 in 21% yield along with the major
product 32 (Scheme 12) <1999JNP1627>.
OH
OH
O O O
CAN, acetonitrile O
+ OH
+
0 °C, 1 h
OH O O
O O
30 31 32 (45%) 33 (21%)
<1999JNP1627>
Scheme 12
Intramolecular [2+4]-hetero-Diels–Alder cycloaddition of pyrazole 34 produced cycloadduct

35 as a single cis-diastereomer in 84% yield. The reaction was carried out in acetonitrile in the
presence of ethylene diammonium diacetate (Scheme 13) <1997SL1155>.
N O N O
O H
Acetonitrile O
N
N N
reflux, 36 h
N H
S 84% S
34 35
<1997SL1155>
Scheme 13
4.19.2.1.5 By reduction–elimination in w-keto esters

Compound 36 (obtained by the condensation of 5-methylthio-2-benzoyl-pyrrole with
spiro[2,5]-5,7-dimethyloctane-4,8-dione in the presence of NaH) underwent an acid-catalyzed
rearrangement in refluxing toluene/methanol (10:1) to produce tetrahydro-2H-oxocine 37 in
46% yield <1999H833>. The same compound was obtained by treatment with DIBALH in
toluene at rt for 7 h followed by acidic work-up, which proves indirectly a two-step mechanism
to produce the oxocine ring in 37 consisting of reduction of the benzoyl group followed by ring
closure under acidic conditions (Scheme 14) <1999H833>.
S
S DIBALH, N
N toluene
O O
0–25 °C, 7 h
O O 46% O
O
O O O
36 37
<1999H833>
Scheme 14
In a similar example, the formation of pyrano-pyridine 39 by thermolysis of sulfolene 38 was

explained by an electrocyclic ring closure involving the carbonyl function of an ester group
<2002T3655>. Sulfolenes of type 38 were converted by thermal extrusion to terminally substi-
tuted dienes having either the (E)- or (Z)-configuration (Scheme 15).
O O
S 1,2-Dichlorobenzene
O Cl N O
Cl N 200 °C, 12 h
O
O N 80%
N
38 39
<2002T3655>
Scheme 15
4.19.2.1.6 From diazoalkanes

Meldrum’s acid derivatives 40 reacted with diazoalkanes 41 in dichloromethane and ether at 30 C
to produce the enolized Meldrum’s acid methoxydioxinones 42 (Scheme 16) <1997TL6689>. The
compounds underwent [4+2]-cycloreversion at room temperature to the corresponding
methoxycarbonyl ketenes and ketones, showing their susceptibility to nucleophilic agents.
O
O CH2Cl2 / Et2O
O O + CH2N2 O
–30 °C, 10 min
O 87% O O
40 41 42
<1997TL6689>
Scheme 16
-Carboxyl diazomethanes of type 43 underwent a similar intramolecular reaction to produce

methoxyfuro[3,4-d]isoxazoles 44 as described in Scheme 17 <1996H1165>. The reaction was
performed in the presence of Rh2(OAc)4 by heating in dichloroethane for 2 h.
O O
Rh2(OAc)4,
N O
N N 1,2-dichloroethane
O N
reflux, 2 h, O O
O O 68% O
43 44
<1996H1165>
Scheme 17
Similarly, dimethyl diazomalonate 46 generated a carbonylcarbene in the presence of bis(acetyl-

acetonato)copper(II) as a catalyst <2000HCA966>. This carbene reacted in situ with 1,3-dioxepins
45 to produce polycyclic structures 47. Treatment of vinyl acetals with dimethyl diazomalonate
(dmdm) or ethyl acetodiazoacetate produced 2-alkoxy-substituted dihydrofuranes. Several research
groups investigated the reaction of enol ethers with diazodicarbonyl compounds and proposed
different mechanisms. The authors have considered the product distribution versus the nature of the
diazocarbonyl compound and have established that according to the literature findings ethyl
diazoacetate yielded mainly cyclopropanes and rarely rearrangement products, while dmdm
afforded addition–elimination and rearrangement products. Ethyl acetodiazoacetate produced

2-alkoxy-substituted dihydrofuranes and rearrangement products. The rearrangement products
occur via structures possessing two chalcogens (Scheme 18) <2000HCA966>.
O
O Cu(acac)2 O O
+ N–
N O O
O O benzene
+
O reflux, 12 h O
O O O O O
O
45 46 47
<2000HCA966>
Scheme 18
4.19.2.1.7 From ketenes

Ketenes are commonly generated by a photo-Wolff rearrangement from the corresponding
diazoketones, and they readily react with various nucleophiles. For instance, by treating ketenes
48 with alcohols such as 49, ketene acetals such as 50 were produced (Scheme 19)
<2001JOC5016>. Similar reactions could also lead to ring closures with the formation of
2-alkoxyfurans <1998AG(E)1540>.
O
C
Acetonitrile OH
+ OH
rt
O
48 49 50
<2001JOC5016>
Scheme 19
Carbomethoxypivaloyl ketene 51 (an -oxoketene generated by flash vacuum pyrolysis of the

corresponding furan-2,3-dione) underwent hetero-Diels–Alder reaction across the ketene carbonyl
moiety to produce the [4+2]-cycloaddition adduct dioxinone 52 in 87% yield (Scheme 20)
<2001T6757>.
O O O O
O O
C C
O O O O O
+ rt, 4 h
O O 74% O
O O
51 51 52
<2001T6757>
Scheme 20
4.19.2.1.8 From gem-dihalogenoalkenes and analogs

1,1-Dialkylthio alkenes or -keto ketene (S),(S)-acetals 53 were reacted with substituted phenols
54 to produce ketene acetals such as 55 integrated in polycycles (Scheme 21). The reactions were
performed in refluxing acetonitrile for 30 min to 1 h <1996SC4289>.
The same substrate 53 was reacted with hydroxyl-indolin-2-ones 56 <2000SC1257>, and
spiro-ketene acetals 57 were obtained (Scheme 22).
O O
NH2 N N
Acetonitrile
+ O O
OH reflux, 33 h
S S
49%
53 54 55
<1996SC4289>
Scheme 21
O
O O
OH O
Et3N / dioxane
+ O
O
reflux, 13 h
N O O S S 85%
H O
N
H
56 53 57
<2000SC1257>
Scheme 22
Dienophile tetracyanoethylene 58 was reacted with ethanol under heating at 70 C for only
4 min in the presence of urea, and diethoxymethylene-malononitrile 59 was produced in 58%
yield <2002JCS(D)1687>. This compound and similar structures described within this reference
were used as bridging ligands in the preparation of coordination polymers with antiferromagnetic
properties (Scheme 23).
N N N
Urea O
+
OH
70 °C, 4 min O
N N 58% N
58 59
<2002JCS(D)1687>
Scheme 23
Dicyanoketene acetal 60 was prepared similarly as 59 (Scheme 24) and was used for copoly-
merization with styrene, divinylbenzene, or ethylene glycol dimethylacrylate, to produce poly-
meric dicyanoketene acetals utilized as recyclable -catalysts in monothioacetalization or CC
bond-forming reactions of acetals <1998TL5799, 2000CPB1010, 1996BCJ195>.
N
N N
Et3N N O
+ OH
rt, 6 h
N N O
41%
58 60
<1996BCJ195>
Scheme 24
4.19.2.1.9 From oxazoles and isoxazoles

Isoxazole derivatives such as 61 produced ketene acetals of type 62 <1997T10433> (Scheme 25).
Derivatives 61 were prepared from 4-aryl-isoxazolin-4-ones and 1,2-bromoethane in acetonitrile in
the presence of triethylamine as a catalyst. The N-alkylated products were obtained along with
derivatives 61, which generated the corresponding N,O-ketene acetals by heating with sodium
methoxide in methanol (not shown).
Et3N, O
acetonitrile
O
Br reflux, 1 h,
N 88%
O N
O
61 62
<1997T10433>
Scheme 25
5-Alkoxyoxazole 63 underwent a tandem Diels–Alder–retro-Diels–Alder reaction sequence with

the acetylenic dienophile 64 with elimination of acetonitrile to produce 2-alkoxyfuran 65 (Scheme
26) <2000AJC749>.
O O O O Toluene O
+
N O reflux, 3 h O
46% O
O
63 64 65
<2000AJC749>
Scheme 26
4.19.2.1.10 By miscellaneous rearrangements and cycloadditions

It has been shown earlier that isomerization of 2,2-dialkoxymethylenecyclopropane derivatives of
type 66 (Scheme 27) and 68 (Scheme 29) produced dialkyl ketene acetals. Compound 66 isomer-
ized to a dimethylene ketene acetal 67 upon prolonged heating above 120 C, and further
reactions evidenced the high reactivity toward electron-deficient olefins <1996S1380>.
O O Benzene-d6
O O
150 °C, 6 h
66 67
<1996S1380>
Scheme 27
Methylenecyclopropanone ketal 68 reacted with diquinene 69 (Scheme 28) in acetonitrile at

80 C following an intermolecular [3+2]-cycloaddition pathway with the formation of two
adducts 70 and 71 in a ratio of 2:1 and practically quantitative yield <1998EJO257>. The two
O O
O
O O
O CD3CN
O O + +
80 °C, 38 h O O O
O
O ca. 100% O O
O O O
68 69 70 ratio 2:1 71
<1998EJO257>
Scheme 28
O O O O
+ CD3CN
O O O +
80 °C, 4 h N N
N O O O O
O O
O O
68 72 73 74
<1998JOC1694>
Scheme 29
acetals hydrolyzed to the corresponding esters while attempting separation on column chromato-
graphy. Similar hetero [3+2]-cycloaddition reactions of dipolar trimethylenemethane have also
been reported, such as the reaction of ketal 68 with O-alkyloxime 72 (Scheme 29)
<1998JOC1694>. The reaction occurred similarly in acetonitrile at 80 C with the formation of
both isomers 73 and 74 in a ratio of 30:70 and 81% yield.
Dipolar trimethylenemethane 68 was also reported to react with active methylene compounds,
such as acetylacetone 75, to produce the end-product 76 (Scheme 30) and with methylene
disulfone 77 to produce the end-product 78 (Scheme 31). The reaction proceeds via ionic
alkylation of the active methylene substrate under neutral, mild conditions <2001SL(S)1030>.
O O O O
CD3CN
O O + 80 °C, 26 h
40% O O
68 75 76
<2001SL(S)1030>
Scheme 30
Alkylidenecyclopropanone acetals such as 79 (Scheme 32) are versatile precursors of dipolar

trimethylenemethane (TMM), which was generated by their mild thermolysis. When possessing a
terminal diylophile the compounds underwent intramolecular [3+2]-cycloadditions in acetonitrile
within 9–32 h <2000CL664>. The regioselectivity and diastereoselectivity of the products were
dependent on the electron demand of the terminal diylophile and was not affected by the alkylide-
necyclopropanone ring that behaves as a ketene acetal in these reactions. The mechanism does not
O O
O CD3CN
O O + O S
S O 60 °C, 8 h O O
O 75% S S
O O
68 77 78
<2001SL(S)1030>
Scheme 31
O O
O
O O CD3CN O O
O
H H
80 °C, 16 h
80%
79 80
RO OR RO RO OR
RO OR
X X
X X RO
or
<2000CL664>
Scheme 32
necessarily obey the endo rule of cycloaddition, being either concerted, or stepwise single-electron
transfer (SET). The concerted pathway was stereochemically more defined and the products
obtained were of the type 80. When exomethylene acetals were obtained instead of structures with
two chalcogens, the mechanism was ascribed to a SET intermolecular reaction.
Diazoketone 81 generated fulvenone 82 by mild photolysis via the cyclopentadienyl radical.
Two molecules of fulvenone 82 underwent an addition reaction to produce the derivative 83 in
33% yield (Scheme 33) <2001JOC7420>. The reaction was performed in hexanes by photolysis
with 300 and 350 nm light for 6 min in the presence of TEMPO and maleic anhydride. Two other
dimers were isolated in 4% and 6% yields, respectively (not shown).
O
+N N– hν, 6 min O
C O
TEMPO
33% O
maleic anhydride
81 82 83
<2001JOC7420>
Scheme 33
Furandione 84 was subjected to flash vacuum pyrolysis at 400 C and subsequent reaction with
pyridine at 40–100 K, followed by heating at room temperature <1996JA12598>. Compound 85
was then isolated in 70% yield (Scheme 34), proving that dipivaloyl ketene was the intermediate
produced by pyrolysis, while pyridine activated the cycloaddition reaction between two molecules
of this ketene.
O O
O
O O
Pyridine, 400 °C
O O
77 K to rt
O O 70% O
84 85
<1996JA12598>
Scheme 34
4.19.2.1.11 By miscellaneous transformations

Adamantylketene dimethyl acetal 87 was prepared quantitatively by desulfurization of
2,2-dimethoxythiirane 86 by treatment with triphenylphosphine (Scheme 35) <2001OL2455>.
The stable thiirane 86 was obtained in the reaction of adamantanethione with dimethoxy carbene,
which in turn was generated by thermolysis of 1,1-dimethoxy-5,5-dimethyl-oxadiazoline.
S O
O
Ph3P O
O
Quantitative
yield
86 87
<2001OL2455>
Scheme 35
4.19.2.2 Other Related Ketene Derivatives, R12C¼COR2OX, etc.
4.19.2.2.1 Ketene silyl acetals, R12C¼COR2OSiR33

The silylation of ester enolates 88 to give ketene acetals 89 is still widely used in the original
Ireland version, although numerous other variations are available. The method entails the
deprotonation of an ester with a strong base in hexane/THF at 78 C and subsequent trapping
of the ester enolate with a silyl derivative, usually with high yields (Scheme 36) <2001JOC7464,
2000CPB1577>.
LDA, THF O
O
+ Si Cl
–78 °C O
O Si
93%
88 89
<2000CPB1577>
Scheme 36
When two enolizable groups are present in the molecule, i.e., a 1,3-dicarbonyl system, it was
shown that competitive reactions could occur <2001EJO3657>. For example, when ethyl cyclo-
pentanone-2-carboxylate 90 was silylated with trimethylsilyl chloride in the presence of LDA in
THF, the reaction took place at both carbonyl sites, and two reaction products were formed: the
1,3-bis-(trimethylsiloxy)-1,3-diene 91, in which both the ester enolate and the keto enolate reacted
with the silylating agent, and silyl enol ether 92 where only the ketone group was silylated leaving
the ester group intact (Scheme 37).
LDA, Pr2i N Si Si
O O O
Si THF/hexanes O Si +
+ O
O Cl
O 0 °C, 3 h
O O
90
91 92
<2001EJO3657>
Scheme 37
When isopropyl cyclohexanone-2-carboxylate 93 and its 5-substituted analogs were silylated in

the same manner, the reaction occurred at both terminal carbon atoms of the 1,3-dicarbonyl
system, generating only products of type 94 (Scheme 38). The same outcome was found for
cycloheptanoate derivatives. For all compounds in this series yields were reported to be over 90%
<2001EJO3657>.
Si
LDA, Pr2i N O
O O
THF/hexanes
Si O
O + 0 °C, 3 h
Cl
96% O
Si
93
94
<2001EJO3657>
Scheme 38
Cyclohexanone-derived bis-(trimethylsiloxy)-1,3-dienes were regioselectively prepared by using

various silylating systems <2000SL497>. Ethyl cyclohexanone-2-carboxylate 95 was treated with
triethylamine–TMSCl in benzene at room temperature to produce the thermodynamically favored
silyl enol ether 96 (Scheme 39). This compound was treated with LDA for 1 h at 78 C, then
reacted with TMSCl with warming to rt, whereupon 1,3-bis-(trimethylsiloxy)1,3-diene 97 as a
single stereoisomer was obtained in good yield. Reaction of compound 95 with 2 equiv. of
triethylamine-TMSOTf at 20 C gave silyl enol ether 96 rather than diene 97. The difference
was explained by the base strength of triethylamine, too low for the deprotonation of both the
methylene group adjacent to the double bond and the one adjacent to one carbonyl group. The
Lewis acid TMSOTf enhances the acidity of a ketone and deprotonation of a neighboring
methylene is not possible. Also, the activation described here may not be sufficient for the
deprotonation at 20 C of a methylene group adjacent to a double bond, as in compound 96.
Addition of acetyl chloride to diene 97 in the presence of a catalytic amount of TMSOTf occurred
1,4- at the conjugated system to produce derivative 98.
,-Unsaturated esters and acids react with silyl halides to afford silyl dienol ethers. Such an
example is the synthesis of compound 100 starting from 1,3-dioxin-4-one 99 (Scheme 40).
Compound 99 was treated with a base (LDA or KHMDS) at 78 C in THF followed by
addition of TMSCl. The isolated yields were in the range of 50–80% <2001JOC3548>.
Silyl vinyl ketene acetals 102 obtained from trans-but-2-enoic acid (tiglic acid) and its esters 101
were obtained in conditions similar to the ones described above (Scheme 41) <1995TL9465,
2001JOC4293, 2002BMC1249>. The reaction product was isolated as an inseparable mixture of
isomers (Z) and (E) in about 2:1 ratio.
Me3Si
O O O O
OEt TMSCl, Et3N
OEt
C6H6, 20 °C
90% 96
95
83% LDA, –78 °C

TMSCl, THF
Me3Si
O OEt
O O O O
OSiMe3
OEt Cl
TMSOTf,
CH2Cl2, –78 °C 97
98
70%
<2000SL497>
Scheme 39
O O LDA or KHMDS
O
+ TSMCl Si
Si
O Cl
THF, –78 °C to rt O O
50–80%
99 100
<2001JOC3548>
Scheme 40
O LDA, THF
MeI Si
O
+ Si
O Cl –78 °C to rt
63% O
101 102 (Z )/(E ) = 70/30
<2001JOC4293>
<1995TL9465>
Scheme 41
Esters 103 treated with LHMDS in the presence of 1.3 equiv. of DMPU followed by the
addition of t-butyldimethylsilyl triflate gave O,O-silyl ketene acetals 104 as mixtures of (Z)
(major) and (E) (minor) isomers (Scheme 42) <1998TL3157>. When the 2-butenoic system was
terminally substituted with a methoxy group, the stereochemistry of the double bond was
preserved <1998AJC421>. For cyclohexadiene systems such as 105 (Scheme 43) only the (Z)-iso-
mer 106 was formed <2000BMC253>.
F3C S
O
S LHMDS, DMPU O
+ O
O Si O
O O THF, –78 °C Si
S
103 104
<1998TL3157>
Scheme 42
O O
O
LDA, THF/hexanes Si
+ Si
Cl O
–78 °C, 1 h
O O 100%
106
105
<2000BMC253>
Scheme 43
Other silyl derivatives used besides halides and triflates were: triethyl silane <1997CL1245>,
t-butyldimethyltrifluoromethanesulfonyloxysilane <1998TL3157>, and t-butyldiphenylchloro-
silane <1997TL6689>.
4.19.2.2.2 Ketene silyl acetals, R12C¼COSiR23OSiR33

Silyl enol ethers are stable and isolable synthetic equivalents of enols and enolates, and they have
been often used instead in various reactions, such as enantioselective protonation <2000JA8120>.
For this purpose, bis-silylated enol ethers 108 were prepared from 2-arylcarboxylic acids 107 by
treatment with LDA and excess triethylchlorosilane in THF at 0 C with isolated yields of about
90% (Scheme 44). A similar reaction was reported for cycloalkylcarboxylic acid 109 to obtain
compound 110 (Scheme 45) <2001JOC7464>.
Si
LDA, THF O
OH Si
+
O Cl 0 to –20 °C, 2.5 h O
Si
92%
107 108
<2000JA8120>
Scheme 44
O
OH O Si
LDA
+ Si Cl
>70% O
Si
109 110
<2001JOC7464>
Scheme 45
4.19.2.2.3 Boryloxy derivatives, R12C¼COR2OBR33

There are no reports on boryloxy derivatives in the time period reviewed, as disclosed by a
Beilstein substructure search.
4.19.3 FUNCTIONS CONTAINING OXYGEN AND SULFUR, R12C¼COR2SR3, etc.
4.19.3.1 Dicoordinated Sulfur Derivatives, R12C¼COR2SR3
4.19.3.1.1 From monothiocarboxylic acids and esters or thioesters

Thiol ester enolates, enethiolates, and thiono esters have been reacted with electrophiles to afford
ketene monothioacetals. Ketene-O-silyl monothioacetals were prepared from the corresponding
thiol esters as their dioxa analogs described above (see Section 4.19.2.2). Thioisobutyric acid
S-phenyl ester 111 was reacted with allyl-chloro-dimethylsilane to produce the silylketene
monothioacetal 112 in over 90% yield (Scheme 46) <1999TL2183>.
Cl S O
S Si
+
Si
O 93%
111 112
<1999TL2183>
Scheme 46
In a first stage, enethiolization of the thionoester was performed in the presence of a strong base
such as LDA at low temperature usually in THF as a solvent, then in a second stage an alkyl or silyl
halide was added. Most used in chemical synthesis are the O-silylated derivatives. The stereochemistry
of the silyl thioketene acetals is determined by the solvent and chelating agents. A series of thioester
enolates, e.g., 113, was treated with trimethylchlorosilane to produce trimethylsilyloxy-thioesters
such as 114 (Scheme 47) <2001JOC697>. Similarly, dienolates 116 were obtained from 115 (Scheme
48) as a mixture of isomers (Z):(E) in a ratio of 1:1 <2001CL1080>.
LDA, THF Si
S O
+ Si Cl
O –78 to 20 °C S
91%
113 114
<2001JOC697>
Scheme 47
O LDA, THF Si
O
S + Si Cl
–78 °C S
78%
115
116
<2001CL1080>
Scheme 48
Thioesters 117 were refluxed in chlorobenzene for 8 h and thioketene acetal 118 was obtained in
80% yield (Scheme 49) <2001S924>. The reaction was assumed to proceed by a [3,3]-sigmatropic
shift followed by a 1,3-H+ shift and enolization. When the coumarin and phenoxy rings were
substituted with electron-withdrawing groups, the yields were in the range of 50%, while sub-
stitutions with one or two alkyl groups afforded yields of up to 85%.
O S
O S 1,2-Dichlorobenzene
O
reflux, 8 h
80% O
O O
118
117
<2001S924>
Scheme 49
4.19.3.1.2 By alkeneation methods

In the time period reviewed here, there is only one report on Peterson alkeneation to convert
aldehydes and ketones to the corresponding ketene O,S-diacetals <1999CEJ2270>. Aromatic and
aliphatic aldehydes and ketones were treated at 78 C in THF with lithio-phenoxy(phenylthio)
(trimethylsilyl)methane (Scheme 50). The ketene-O,S-acetals (119 and 120) were obtained in
almost quantitative yields with poor (E) to (Z) selectivity for aromatic carbonyl compounds
and no selectivity for the aliphatic ones.
Phenanthroline
O TMEDA, s-BuLi O
Si THF/cyclohexane S
O S +
S +
–78 °C to warm up, 2.5 h O
then rt, 20 h
119 (65%) 120 (32%)
<1999CEJ2270>
Scheme 50
There are quite a few reports on alkeneation reactions using carbon disulfide and activated
methylene compounds. Thus, carbon disulfide reacted with ethyl acetoacetate and 2-bromoetha-
nol in dimethylformamide in the presence of potassium carbonate at room temperature
<2000IJC(B)147>. Both the oxathiolane 121 and the dithiolane 122 were obtained in a ratio of
2.4:1 (Scheme 51).
O O
S S
O O K2CO3, DMF
Br S O
HO + C + + O
S O rt, 5 h O S
O O
121 (47%) 122 (20%)
<2000IJC(B)147>
Scheme 51
When reacting carbon disulfide and 2-bromoethanol with acetylacetone in the same conditions,
the ratio between oxathiolane 123 and dithiolane 124 was about the same (Scheme 52).
Deoxybenzoins 125 reacted similarly with carbon disulfide and methyl iodide to produce
2-(alkylthio)isoflavones in a single step at room temperature <2002TL6113>. The reaction was
performed in a THF/water two-phase system by treatment of the three reactants with aqueous
sodium hydroxide in the presence of tetrabutylammonium hydrogen sulfate as a catalyst. Iso-
flavone 126 was obtained in 87% yield (Scheme 53). When allyl and benzyl bromide were used
instead of methyl iodide, the yields were over 96%.
O O O O
K2CO3, DMF
O O S
Br + + C +
HO S
5 h, rt O S S S
123 (58%) 124 (18%)
<2000IJC(B)147>
Scheme 52
O OH O
O
NaOH, TBAHS
+ MeI THF/water
+ S C S
rt,
O
O 87% O O S
125 126
<2002TL6113>
Scheme 53
4.19.3.1.3 By elimination methods

By electroreduction of an -haloacyl halide in the presence of sulfide anions generated in the
anodic compartment, one can obtain [1,3]oxathiolan-5-one derivatives. When a layer of solid
sodium thiosulfate was placed on the diaphragm in the anodic side, H2S was generated in the
anodic compartment, which reacted with electrogenerated bases to give sulfide anions. Anodic
elimination of bromine in 2-bromo-2,2-diphenylacetyl bromide led to the formation of oxathiolane
127 in 21% yield (Scheme 54) <1996T1259>, along with 2,2-diphenylacetic acid bromide 128.
Ph O
O Ph
H2S Ph O
Br O
S +
Br Ph Ph Br
Ph
Ph Ph
127 (21%) 128
<1996T1259>
Scheme 54
Elimination of methyl sulfide and subsequent cyclization in -hydroxy--oxo-dithioacetals

led to the formation of oxathiolane systems <2002JOC1595>. An example is the synthesis of
furo-azepine derivative 130 (Scheme 55). It is known that treatment of thioketals with
dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) causes the carbon–sulfur bond to
become labile upon methylthiolation. N-Substituted azepan-2-one (lactam) 129 was treated with
DMTSF in dichloromethane at low temperatures to afford the cyclic aminofuran 130 in 56%
yield. An alkylthiosulfonium salt was first generated, which dissociated into a thionium ion and
methyl sulfide. Further, the thionium ion underwent a DMTSF-induced cyclization followed by
acetic acid elimination to furnish aminofuran 130.
Elimination–cyclization reactions occurred in perfluoro derivatives such as 131 (Scheme 56)
<2000RCB1749>. The reaction took place in the presence of BF3NEt3 in refluxing chloroform
with formation of oxathiole 132.
Sulfenyl chloride 133 was reacted with benzo[1,3]dioxol-5-ol 134 in chloroform, and benzo-
xathiole 135 was formed in 85% yield by hydrochloric acid elimination (Scheme 57)
<2001RCB1255>.
S i. DMTSF, CH2Cl2
OH
–40 °C to 0 °C, 4.5 h S
S
ii. Et3N, CH2Cl2, 0 °C O
O N
N 56%
O
O
129 130
<2002JOC1595>
Scheme 55
O CF3
.
BF3 NEt3
O CF3
S CHCl3
CF3 61 °C S CF3
F 61%
131 132
<2000RCB1749>
Scheme 56
O O O O CF3
O CHCl3
S +
F3 C Cl O O S O
HO 20 h
F O
85%
133 134 135
<2001RCB1255>
Scheme 57
4.19.3.1.4 By miscellaneous methods

Thiirane-2-carboxylic ester 136 underwent decomposition by irradiation in benzene/cyclohexane
to afford oxathiole 137 among other products (Scheme 58) <1996LA1295>.
S S O
O O
O Benzene S
O O
cyclohexane + +
O C
2 h, hν O
136 137
<1996LA1295>
Scheme 58
Vinyl thiirane 138 reacted with heterocumulenes to produce oxathiolanes, dithiolanes, and
thiazolidines regio- and enantioselectively by a palladium-catalyzed cyclization reaction per-
formed in THF at 5 psi and 50 C <2001JOC3502>. When the reaction was performed with
ketenes as reactants, oxathiolanes were preferentially obtained. The reaction of vinyl thiirane 138
with diphenyl ketene produced oxythiolane 139 regioselectively, probably because of steric factors
(Scheme 59).
Trimethylsilylmethylthio-1,3-indanthione 140 is a precursor of an alkylidene–thiocarbonyl-ylide
that could be generated in situ by its treatment with fluorides (CsF, LiF, AgF, or TBAF). The
ylide thus formed is a 1,3-dipolar reagent that could react with reactive hetero-dipolarophiles such
dppp, THF
Pd2(dba)3.CHCl3
S +
O O
24 h, 50 °C
81% S
138
139
<2001JOC3502>
Scheme 59
as aldehydes and ketones <1996CPB653>. The reaction showed complete regiospecificity when
heterodipolarophiles are aromatic aldehydes. By reacting 140 with tolualdehyde the ketene
O,S-diacetal 141 was obtained in 44% yield (Scheme 60), while the reaction with benzaldehyde
occurred in 71% yield.
R
O
CsF, 100–140 °C O
S
O 1h O
+
S Acetonitrile
R S
O Si rt, 20 h O
140 141 R = Me (44%)

R = H (71%)
<1996CPB653>
Scheme 60
Ketene dithioacetals were reacted with alcohols and phenols to give oxathiolanes. Compound
142 produced O,S-diacetal 143 (Scheme 61) <2000IJC(B)147>, while compound 144 afforded
oxepine derivative 145 (Scheme 62) <1996SC4289>.
S ButONa
Benzene
S OH O
+ HS
89%
O O S
142
143
<2000IJC(B)147>
Scheme 61
O O N
NH2 Acetonitrile
+ O
reflux O
OH S
S S
144 145
<1996SC4289>
Scheme 62
4.19.3.2 Tricoordinated Sulfur Derivatives, R12C¼COR2S(O)R3

There is only one report on this class of compounds in the period reviewed <1999JCR(S)610>.
A series of compounds of this type were prepared by reacting sulfonyl propenones of the type 146
with aryl hydrazones and aldoximes in refluxing methanol, in the presence of chloramine-T (Scheme
63). When aldoximes were the reagents, 2-isoxazolines of the type 147 were obtained. The reaction is a
1,3-dipolar cycloaddition where the aldoxime acts as a bifunctional olefin.
O Chloramine-T, Ph O
OH methanol O
S Ph N O
+ S
O
O O 3 h, reflux O
Cl O N
Cl
146 147
<1999JCR(S)610>
Scheme 63
4.19.3.3 Tetracoordinated Sulfur Derivatives, R12C¼COR2SO2R3

A Beilstein search for the period 1996 to August 2003 did not reveal any entry in this class.
4.19.4 FUNCTIONS CONTAINING OXYGEN AND EITHER SELENIUM

OR TELLURIUM, R12C¼COR2SeR3, etc.
One entry was revealed in a Beilstein substructure search.
Benzeneselenyl chloride reacted with enolized dihydrofuran-2-one 148 and the condensation
product thus obtained was derivative 149 (Scheme 64) <2000BMCL1893>.
O Cl
O i. LDA O
Se Se
ii. Benzeneselenenyl chloride
+ O
149
148
<2000BMCL1893>
Scheme 64
4.19.5 FUNCTIONS CONTAINING TWO SULFUR ATOMS, R12C¼C(SR2)2, etc.
4.19.5.1 Two Dicoordinated Sulfur Atoms, R12C¼C(SR2)2
4.19.5.1.1 From dithiocarboxylic acids and derivatives

Ketene dithioacetals are usually generated from a dithiocarboxylic acid or ester by -deprotona-
tion of the corresponding anion and subsequent addition of an electrophile. The method is similar
to the one described in Section 4.19.2.1.1 for ketene diacetals. A typical example is presented in
Scheme 65 for the reaction of cyclopentanedithio-carboxylate 150 and iodomethane to produce
dithioacetal 151 <1997CC1011>.
Deprotonation could be performed with strong bases such as LDA, LiHMDS, or sodium
ethoxide in ethanol. When the dithiocarboxylate is activated by the presence of an -oxo
group, the deprotonation was performed with potassium carbonate in DMF <2002SC2369>.
S LDA S
S MeI S
98%
150 151
<1997CC1011>
Scheme 65
Compound 152 was prepared in low yield (13%) by disproportionation of diphenylmethyldithio-

carboxylic acid. The deprotonation was performed with BunLi in THF at 78 C, and was followed
by treatment with trimethylchlorosilane at 20 C (Scheme 66) <1996CB663>. Similarly, by depro-
tonation of dimethyltin derivative 153 with LiHMDS in THF/hexane at 20 C followed by
treatment with iodine at room temperature, derivative 154 was obtained (Scheme 67)
<1996CB663>.
1.6 M BuLi, Me3SiCl,

HS Ph HS Ph THF, hexane Ph S Ph
+
S Ph S Ph i. –78 °C, 15 min Ph S Ph
ii. rt, 2 h
152
13%
<1996CB663>
Scheme 66
Ph
Ph S Sn S 1 M LiHMDS, iodine S S
S THF, hexane
Ph S Ph
Ph S Ph
Ph i. –20 °C, 30 min, 20 °C, 2 h Ph
ii. rt, 3 h
154
153
<1996CB663>
Scheme 67
Thioacyl thioketene 155, subjected to flash vacuum pyrolysis, produced thioacyl thioketene 156
by a 1,3-shift of the phenyl group onto the alkylthio group with a subsequent loss of an S-alkyl
thiophenol (Scheme 68) <1996TL4805>.
S
C Vacuum pyrolysis S
S S 800–1000 °C S
S
155 156
<1996TL4805>
Scheme 68
Cyclic dithiocarboxylic ester 157 was converted with a 63% yield into the corresponding ketene
dithioacetal 158 by reaction with 0.5 N sodium hydroxide in the presence of benzyltriethylammo-
nium chloride, followed by treatment with iodomethane (Scheme 69) <1996JPR516>.
,-Unsaturated dithiocarboxylic ester 159 reacted with maleic acid dimethyl ester in the presence
of lithium perchlorate in diethyl ether at room temperature in two days to produce ketene
dithioacetal 160 in 39% yield (Scheme 70) <1996OPPI103>.
0.5 N NaOH
N benzyltriethyl- N
ammonium chloride
+ MeI
H2N H2N
N S S 63% N S S
H
157 158
<1996JPR516>
Scheme 69
O O
O O
S Lithium perchlorate
O Et2O S O
S + O S
rt, 2 days
O 39%
159 160
<1996OPPI103>
Scheme 70
4.19.5.1.2 By double bond formation via elimination

This section comprises preparations of ketene dithioacetals from compounds containing hydroxyl
and halogen groups that allow for the elimination of water and hydrogen halide, respectively.
In the case of alcohols, the leaving group is on the thioacetal carbon. Bis(diarylmethylene)-
alcohol 161 was converted into thioacetal 162 through TsOH-catalyzed dehydration in 85% yield
(Scheme 71) <2000JOC5514>. Elimination of hydrogen halide occurred at the -carbon to the
dithioacetal carbon. Hydrogen fluoride was eliminated in the reaction of carbon disulfide and
tetramethylammonium fluoride with 2-H-heptafluoropropane (Scheme 72) <1997JFC(82)29>,
and was trapped as fluorodithioformate FCS 2 , which was added to 2-H-heptafluoropropane
with subsequent dimerization of the addition intermediate. The reaction product thus obtained
was bis-dithioacetal 163.
O
O
S S
S S TsOH
benzene S
S
OH
reflux 1 h
85%
O O
161 162
<2000JOC5514>
Scheme 71
4.19.5.1.3 By alkeneation methods

This section refers to the condensation of a carbonyl compound or its equivalent with a dithio-
acetal anion in particular. Wittig, Horner–Wittig, Horner–Emmons, and Peterson-type reactants
are widely used. In this chapter the reaction of carbon disulfide with active methylene compounds
was also included.
F3C
F CF3
S
+ S Me4NF
C S
F3C CF3 S F3C
75 °C, 9 days
CF3
73%
163
<1997JFC(82)29>
Scheme 72
(i) Peterson alkeneation

In the 1990s, the Peterson alkeneation was widely used in the synthesis of ketene dithioacetals
<2001JMC4379, 2001NN995, 1998JMC821>. 2-(Trimethylsilyl)-1,3-dithiane 164 is a precursor of
dithiane carbene, which was produced by treating lithio- 164 with tosylhydrazide in HMPA–THF
solution at 70 C. The carbene thus formed was reacted with 3,3-dimethylcyclopropene dicarbox-
ylate derivative 165 at 70 to 0 C to produce dithianylidene 166 (20% yield) and the dithioacetal
adduct of succinic acid derivative 167 (57% yield) (Scheme 73) <1997T9269>.
O O
O Tosyl azide S O
S S
HMPA–THF O
Si + +
O
S –70 °C, 1.5 h S S S S
O
0 °C, 2 h
O
164 165 166 (20%) 167 (57%)
<1997T9269>
Scheme 73
(ii) The reaction of carbon disulfide with active methylene compounds

The reaction of active methylene compounds with carbon disulfide and alkyl halides in basic
conditions was earlier treated under Section 4.19.5.1.1 as it was considered to involve a dithio-
carboxylic acid. Classifying the reaction under an alkeneation reaction would be more suitable,
because the alkanedithioic acid A (Scheme 74) formed by addition of carbon disulfide to the
active methylene group is readily deprotonated by the base to form the corresponding dianion B,
which could be isolated as a salt <1996CB663>.
S S–
SH S–
(A) (B)
O O Et3N, DMSO O O
+ S C S + MeI
O O rt, 5 h O O
50%
S S
168
<2001JCS(P2)1534>
Scheme 74
The current reports are focused on replacing strong bases as methanolic potassium hydroxide or
alkyllithium derivatives used in earlier reports <1996ZN(B)399, 1996LA953, 1996JST177,
1997S949, 1999MI57> with milder reagents. Among the new methods, the reaction of Meldrum’s
acid with carbon disulfide and triethylamine followed by alkylation of the thus formed dianion with
iodomethane in DMSO produced derivative 168 in 50% yield (Scheme 74) <2001JCS(P2)1534>.
2-Pyrazolin-5-one derivatives were reacted with carbon disulfide and dihalides in a one-pot
procedure using triethylamine and DMSO (Scheme 75) <2001SC3175>. The reaction was com-
pleted in a shorter time and with improved yields (89.7% for compound 169) compared to earlier
methods. Similar results were obtained in a one-pot procedure when using sodium ethoxide
in ethanol (Scheme 76) <1998JCR(S)162>. 2-Pyrazolin-5-ones could also be treated with
carbon disulfide and various alkyl bromides or their acetals under phase-transfer catalysis
conditions to produce the corresponding ketene dithioacetals 170. Deprotonation was achieved
in a liquid/solid phase combination of benzene and anhydrous potassium carbonate and
tetrabutylammonium bromide as a catalyst <1997H451>. 4,4-Dibromo-1-phenyl-pyrazolidine-
3,5-dione 171 and malononitrile were reacted in similar one-pot conditions using potassium
carbonate, tetrabutylammonium bromide as a catalyst, and dioxane as a solvent to produce
dithioacetal 172 (Scheme 77) <2000PS(160)159>.
N
S Et3N, DMSO S
N C Br N
N + + Br
S
rt, 2.5 h S
O
O 89.7%
<2001SC3175> 169
Scheme 75
N
N
N EtONa
N + S C S MeI
+
O
O S
S
170
<1998JCR(S)162>
Scheme 76
N
O K2CO3, TBABr, O
N N S Br dioxane S
+ C N N
S + S
HN Br HN
60 °C, 40 min N
O O
40 °C, 6 h
171 56% 172
<2000PS(160)159>
Scheme 77
Ketene dithioacetals resulting from acetylacetic acid esters and analogs are important building
blocks for heterocyclic synthesis and therefore their preparation was intensively studied.
Comparative preparations are reported for ketene dithioacetals 173 of ethyl acetylacetate
<1997T17151>. The reaction presented in Scheme 78 was performed by two methods: (a) in
the presence of potassium carbonate in DMF at room temperature, and (b) by absorption of the
components on a mixture of alumina and potassium fluoride at room temperature.
Method (a) showed higher yields than method (b). Later, it has been shown that potassium fluoride
alone, without activation or solid support, could be used to promote these reactions at room
O O
K2CO3
O O S O
C DMF
+
S + Br Br
O rt, 7 h S S
69%
173
<1997T17151>
Scheme 78
temperature <1999JCR(S)492>. Among the solvents studied, DMF was found to be the solvent
of choice in terms of higher conversions after 2 h and better isolated yields, while dioxane, THF,
and acetonitrile showed poor conversions even after prolonged contact of the reagents (20 h).
Yields were also dependent on the nature of the alkyl halide. As an example, 1,3-indanedione
reacted with carbon disulfide and benzyl chloride as shown in Scheme 79 to afford derivative
174 in 60% yield, while when using butyl bromide the reaction product was formed in 79%
yield <1999JCR(S)492>.
O Ph
O
Cl KF, DMF S
+ Br + S C S +
8h S
O 60% O Ph
174
<1999JCR(S)492>
Scheme 79
Sodium hydride in DMF was used for the weakly activated malononitrile compound 175
<1999JPR552>. The adduct 176 was obtained in 53% yield (Scheme 80). Similarly,
3-(2-chlorophenyl-3-oxo)-propionitrile 177 was treated with iodomethane and carbon disulfide
in the presence of sodium hydride in a mixture of THF and DMSO, to produce bis-methylsulfanyl-
acrylonitrile 178 in 92% yield (Scheme 81) <1996F407>. Other weakly activated methylene
compounds required stronger reaction conditions. 2-Cyano-thioacetamide (Scheme 82)
<1997JCS(P1)3285> and ethyl cyanoacetate (Scheme 83) <1997BMCL651, 1997JCS(P1)3285,
2002SC3509> were reacted with alkyl halides and carbon disulfide using sodium ethoxide as a base
to produce compounds 179 and 180, respectively. Carboxylic acid esters were treated with LDA at
78 C to generate their lithium enolates in order to react with carbon disulfide to further produce
derivative 181 (Scheme 84) <1997JMC2363>, while 2,5-dioxo-cis-octahydropentalene 182 required
potassium t-butoxide in DMSO or DMF at 0 C to produce compound 183 (Scheme 85)
<1996PS(113)263>.
CN CN
CN NaH, DMF CN
+ S C S + MeI
S
0–20 °C, 1.5 h
H 53% H S
175 176
<1999JPR552>
Scheme 80
Dimethyl sulfate has been used as an alkylating agent instead of alkyl halides. The reactions were
performed at room temperature in the presence of sodium hydride in acetonitrile and compounds
such as 184 were produced with yields in the range of 70–80% (Scheme 86) <1999PS(148)235>.
O S
Cl NaH, THF
DMSO S
+ S C S + MeI
N –5 °C, 2 h Cl
O 92% N
178
177
<1996F407>
Scheme 81
N
NaOEt
NH2
N EtOH
+ S C S + MeI S NH2
S
reflux, 20 min
S S
20%
179
<1997JCS(P1)3285>
Scheme 82
N
O NaOEt S C
C Br
S C S + N + Br
O 0 °C S O
O
180
<1997BMCL651>
Scheme 83
O
O LDA, THF
+ S C S+ MeI O
O –78 °C to rt
20 h S S
85%
181
<1997JMC2363>
Scheme 84
S
H DMSO S
H
Br ButOK
O O + S C S + Br
O O
10 °C, 2 h
H
28% H
182
183
<1996PS(113)263>
Scheme 85
O NaH CN
O S O O acetonitrile
S S O
NC + C +
O S O 0.5 h, 20 °C
S O
11 h, 5 °C
74%
184
<1999PS(148)235>
Scheme 86
Competitive C- versus O-alkylation has been reported in a few instances <1996TL809,

1997H451>. Bicyclo[3.1.0]-hexan-2-one 185 gave ketene dithioacetal 186 in only 9% yield,
while the major product is the xanthate 187 obtained in 60% yield (Scheme 87) <1996TL809>.
O
OH O
O LDA, THF
(CH2)5 O + S C S + MeI
0 °C
H H (CH2)4CH3
O
185
S S
S O O
O S O O S O
O O
S +
(CH2)5 O (CH2)5 O
H H (CH2)4CH3 H H (CH2)4CH3
O O
186 (9%) 187 (60%)
<1996TL809>
Scheme 87
(iii) Horner–Emmons and Wittig–Horner reactions

There are limited examples of the use of the Horner–Emmons–Wadsworth procedure in the
synthesis of ketene dithioacetals <1996S285, 1998JCS(P1)9, 2002TL7159>. Dithianylphospho-
nates could be readily prepared by condensation of the carbanion obtained from 1,3-dithiane and
dialkyl chlorophosphate. Recently, several thioacetals of formylphosphonates 188 were studied
and compared, and a one-pot procedure for the preparation of ketene dithioacetals was described
<1997BSF891>. Yields were dependent on the nature of the carbonyl compound, being in the
range of 90% for products derived from cyclohexanones and cyclooctanone, and 33% for
derivative 189 obtained from the more sterically hindered bornan-3-one (Scheme 88). In a typical
procedure, a substrate such as ketone 190 was treated with LDA in THF at a low temperature,
and the enolate thus formed was treated with 1,3-dithiane and diethyl chlorophosphate to afford
derivative 191 in 77% yield (Scheme 89) <2002TL7159>.
H2O,
O S
O THF
P S
+ S
O O rt, 2–4 h
Li S 33%
189
188
<1997BSF891>
Scheme 88
O LDA
S
(EtO)2POCl S
S THF
+
O Si S –78 °C to rt
77% O Si
190 191
<2002TL7159>
Scheme 89
Phosphonoketene dithioacetals such as 193 (Scheme 90) are useful reagents in the synthesis of
thioallenes by the Horner–Emmons–Wittig synthesis. As they have no substituent at the -position to
phosphorus, there are many possibilities for functionalization at this position and the compounds
could be widely used in organic syntheses. As an example, compound 193 was prepared by reacting
dithiane with triethyl phosphonoacetate 192 in dichloromethane in the presence of dialkylaluminum
chloride or ethylaluminum dichloride as catalyst. The former was preferred due to better yields and
simplicity of manipulation <1996JOC8132>. The compound was further functionalized by deproto-
nation with 2,2,6,6-tetramethylpiperidide in THF at 78 C followed by treatment with an aldehyde
to produce allylic alcohol thioacetal adducts 194. Treatment of compounds such as 194 with potassium
t-butoxide in THF at room temperature afforded a mixture of both head-to-head 195 and head-to-tail
196 dimers in a ratio of 77:23 (195/196). t-Butyl substitution instead of isopropyl to the alcohol
changed the ratio of the dimers in favor of the head-to-tail dithioacetal derivative.
O OEt O (CH3)2CHCHO
OEt
P S (Me/Et)2 AlCl S P LDA or LTMP
OEt + OEt
S –78 °C to rt, –78 °C, 1.5 h
COOEt S H
4–12 h 86%
192 16–82% 193
S
O ButOK
O
S P S
O THF + S
S S
rt, 6 h
S OH S S S
Total yield 55%
195 196
194 ratio 77:23
<1996JOC8132>
Scheme 90
Esters of dithiolphosphoric acid are Wittig and Wittig–Horner reagents commonly used in
the synthesis of ketene dithioacetals, and preparations are described in several publications
<1998JOC1268, 1999TL5997, 2000EJO51, 2001EJO933>. In general, deprotonation of these
reagents occur at low temperatures and in the presence of strong bases, especially alkyllithium
derivatives. In a typical example (Scheme 91) <1997H263> the dithiolphosphoric ester 197 was
treated with BunLi at 78 C to produce the dithiolylphosphonate anion that underwent further
addition to the ketone 198 in moderate-to-high yields to give compound 199. Cyclophanes 201
obtained by similar olefination using bis-dithiolphosphonic ester 200 are interesting for their redox
behavior upon oxidation (Scheme 92) <2000JCS(P1)2719>. The Wittig–Horner reaction of ketones
with 2-methoxyphosphinyl-1,3-benzodithiole 202 (Schemes 93 <1997CC2325> and 94
<2000CC295, 2001JOC713, 2002M1055>) produced compounds (203 and 204) with interesting
redox properties. This chemistry is used intensively in the synthesis of sulfur-rich analogs
of tetrathiafulvalene derivatives like 204 that have interesting electronic properties including para-
magnetic and semiconducting electrical behavior <1996JOC3650, 1997JOC870, 1998JOC1268,
1999TL3271, 1999TL5997, 2000EJO51, 2000EJO1199, 2001EJO933, 2002JACS14227>.
BuLi, THF,
S O
hexane S
P O S S S
+ S S
S O O –78 °C S
S
O 47%
197 199
198
<1997H263>
Scheme 91
(CH2)12
S (CH2)12 S BuLi S
S
S hexane
S O THF
S S S
O + S
P O
15 min, –78 °C, S S
O
O O P O
O then 1 h
15%
200 201
<2000JCS(P1)2719>
Scheme 92
O S O Base S
+ P O
S O 91% S
202 203
<1997CC2325>
Scheme 93
O
BuLi, THF
S O hexane S S
P O +
S –78 °C to rt S S
O
O 20 h
98%
202 204
<2002M1055>
Scheme 94
4.19.5.1.4 From gem-dihalogeno alkenes and analogs

Vinylic halide displacement was reported for the preparation of ketene dithioacetal derivatives of
perfluoroisobutene and its 1,1-dichloro analog (Scheme 95) <1999JFC(94)37>. The reaction was
performed in THF at 78 C by mixing excess dihaloalkene with equimolar amounts of aromatic
thiol and diethylisopropylamine, affording perfluorinated ketene dithioacetals 205. Substitution
with electron-withdrawing groups in aromatic thiols increased the yields, but
2-aminobenzenethiol gave only a benzothiazole derivative.
4.19.5.1.5 By miscellaneous methods

The examples of this section are of more theoretical than preparative interest, and have been
reported in connection mainly with mechanistic studies. Ketene dithioacetals of type 206 were
F3C CF3 SH DIPEA F3C S

THF
+
F F –78 °C, 30 min F3C S
68%
205
<1999JFC(94)37>
Scheme 95
obtained in good yields by reacting lactones with 1,3-dithiols in the presence of trimethylaluminum
in dichloromethane at room temperature <2001TL7163, 2002JA10101>. The reaction of 3-methyl-
tetrahydropyran-2-one with propane-1,3-dithiol occurred with ring-opening and afforded com-
pound 206 (Scheme 96) <2002JA10101>.
OH
O AlMe3
+ HS SH
0 °C to reflux
O
20 h S S
90%
206
<2002JA10101>
Scheme 96
In the reaction of (benzenesulfanyl)phenylacetylene 207 with thiophenol at 154 C in the

presence of AIBN, two unsymmetrical ketene dithioacetal species, 208 and 210, were isolated
along with thioderivative 209 and thiophene 211 (Scheme 97) <1999T12227>. The product
distribution was considered as the evidence of a mechanism via a vinyl radical followed by
hydrogen abstraction in competition with -fragmentation. The higher yield in product 208
compared to 210 showed that alkanesulfanyl radical addition to the alkyne triple bond was a
nonreversible process, whereas arenesulfanyl radicals added under a reversible mechanism.
S Ph
SH AIBN
+ 30 min, 154 °C
207
Ph
Ph S Ph
S Ph S Ph
+ + + S
S Ph Ph S S Ph S Ph
Ph Ph
208 (27%) 209 (24%) 210 (13%) 211 (6%)
<1999T12227>
Scheme 97
Diaryl ketenes and P2S5 in pyridine produced thioketenes as transient species only, and the
isolated products were dimers or other heterocycles, such as 214 (Scheme 98) <1996JOC7326>.
Compound 213 was separated only as a mixture with compound 212 in a ratio of 7:4 (213/212).
P2S5
pyridine S S
+
21 h, heating S S
C
O
212 (17%)
S
S +
S
S S
213 (30%) 214 (7%)
<1996JOC7326>
Scheme 98
Dicyanohexatriyne and tetrathiafulvalene underwent a [2+2]-cycloaddition with subsequent

opening of the cyclobutene ring (Scheme 99) <1999EJO2491>. Initially, a 3,3,4,4-tetrathiasub-
stituted cyclobutene intermediate was formed by the cycloaddition of one of the terminal triple
bonds with the thiafulvalene central double bond. The intermediate was stabilized by subsequent
electrocyclic ring opening to generate the butadiene derivative 215.
N S
N S
S
S Toluene S
+ S
S 48 h, rt
S
40%
N
N
215
<1999EJO2491>
Scheme 99
1,3,4,6-Tetrathiapentalene-2,5-diones were reacted with esters of alkyl- and cycloalkyl-

carboxylic acids in a multistep preparation (Scheme 100) <1996JOC3987>. The ketone derivative
was treated with a Grignard reagent and the intermediate was trapped with an organotin
compound such as Cl2SnBu2 at 78 C to produce an organotin thiolate 216. Without further
purification, thiolate 216 was reacted with an ester in a Me3Al-promoted coupling synthesis to
afford product 217. Other Lewis acids were also utilized instead of Me3Al, and good results were
obtained with TiCl4 and Me2AlCl, while with BF3OEt2 only trace amounts of product 217 were
obtained.
Systems of type 219 were synthesized starting from 1,3-dithiolium cation salts 218 and ketones.
The trifluoroborate of salt 218 was reacted with anthrone in the presence of sodium ethoxide in
ethanol at room temperature (Scheme 101) <1998CEJ2580>. For other cations such as iodine,
pyridine in refluxing acetic acid was used.
NaOMe
O Cl2SnBu2
S O S S S
O Me3Al
S + Bu2Sn O S
S S
S S
S O S O
216 217
<1996JOC3987>
Scheme 100
R R
S S
R Sodium ethoxide
S+ ethanol
SMe +
S rt
R X–
O O
218 219
<1998CEJ2580>
Scheme 101
4.19.5.2 One Dicoordinated and One Higher Coordinated Sulfur Derivatives, R12C¼SR2S(O)nR3
Oxidative methods are widely used for the preparation of higher coordinated sulfur derivatives.
Although often mixtures of tri- and tetra-coordinated species are formed, there were reports of
highly selective oxidations. For example, vinyl 1,3-dithiane (obtained by treatment of trimethylsilyl-
1,3-dithiane with BunLi and acetone as described earlier) underwent oxidation with sodium
metaperiodate in methanol/water at 0 C to produce sulfoxide 220 in 70% yield as a mixture of
diastereoisomers in a syn/anti ratio of 1:6 (Scheme 102) <1998T14581>.
NaIO4
H 2O O
S S methanol S
16 h, 0 °C S
74%
220
<1998T14581>
Scheme 102
Ketene dithioacetals could also be oxidized to S-monoxides by treatment with 1 equiv. of MCPBA,
when (E)-isomers were preferentially formed <1997CC1011>. The ketene dithioacetal derived from
diethyl malonate was reacted with MCPBA in dichloromethane at 0 C to produce 221 (Scheme 103)
in a high yield, but no indication about stereoselectivity was reported <1997JHC1773>.
O O
O MCPBA,
S O CH2Cl2 O O
S O 0 °C S S
O O
221
<1997JHC1773>
Scheme 103
Tetracoordinated sulfur derivatives are obtained with stronger oxidizing agents than the ones
used for tricoordinated ones <2002JMC1176, 1996S285>. In the time frame considered in this
review, almost all references with this substructure derive from -thiomethyl-substituted thio-
phenes. Methylsulfonyl derivative 223 was obtained by treatment of thiophene 222 with hydrogen
peroxide (Scheme 104) <1999JMC1849>. Thiophenesulfonamides were obtained from thio-
phenes via thiophene sulfonyl chlorides <1996BMCL2651> in the following reaction sequence:
bromothiophenes were treated with BunLi, the anions quenched with sulfur dioxide and further
oxidation of the resultant sulfinates with N-chlorosuccinimide produced the thiophene sulfonyl
chlorides 224 (Scheme 105). Alternative chlorosulfonation using chlorosulfonic acid at low
temperature was reported for 3-benzylthiophene only. Treatment of thiophene sulfonyl chlorides
with amines produced thiophenesulfonamides.
N aq. 30% H2O2 H2N N

H2N AcOH
N
S 14 days S S
N S O
O
222 223
<1999JMC1849>
Scheme 104
Cl
ClSO3H, POCl3, PCl5 O S
CH2Cl2 O
S –5 °C, 30 min S
rt, overnight
78%
224
<1996BMCL2651>
Scheme 105
Phenylsulfonyl-acetophenones reacted with a mixture of elemental sulfur and malononitrile

in dry DMF containing a catalytic amount of anhydrous Et3N to furnish the corresponding
2-amino-4-aryl-5-phenylsulfonylthiophene-3-carbonitriles 225 in good yields (Scheme 106)
<1997MC687>.
Ph CN
Ph O
DMF, Et3N
+ S + CH2(CN)2
Reflux, 6 h PhSO2 S NH2
PhSO2
68%
225
<1997MC687>
Scheme 106
4.19.5.3 Two Tricoordinated Sulfur Atoms, R12C¼C[S(O)R2]2

A series of p-tolylsulfinyl dienophiles were synthesized and their behavior in Diels–Alder reactions
was studied <1997TA409>. Enantiomerically pure dienophile 227 was prepared in two steps from
(S,S)-bis-p-tolylsulfinylmethane 226 with a 73% overall yield by deprotonation of 226 with BunLi
in THF and reaction with diethyl oxomalonate at 78 C, followed by dehydration of the
addition product at room temperature under Mitsunobu conditions (DEAD, PPh3 in pyridine/
dichloromethane) (Scheme 107).
PPh3, DEAD
pyridine, CH2Cl2
S S S S
O O rt, 2 h O O
OH 73%
O O O O
O O O O
226 227
<1997TA409>
Scheme 107
Oxidation of furan-2-one 228 performed with MCPBA at room temperature in dichloro-

methane provided the bis-methylsulfinyl derivative 229 in 90% yield (Scheme 108)
<2000IJC(B)897>.
S O S O
S S
MCPBA, CH2Cl2
O rt O
O 90% O
228 229
<2000IJC(B)897>
Scheme 108
4.19.5.4 One Tricoordinated and One Tetracoordinated Sulfur, R12C¼CS(O)R2S(O)2R3

A Beilstein search did not reveal any examples reported in the literature in the period discussed here.
4.19.5.5 Two Tetracoordinated Sulfur Atoms, R12C¼C[S(O)2R2]2

Ketene dithioacetal 230 reacted with dimethyldioxirane in acetone at room temperature to yield
84% of methylsulfonyl derivative 231 (Scheme 109) <1999JPR552>. Trimerization of phenyl
phenylethynyl sulfone 232 in the presence of (COD)2Ni is an example of a Diels–Alder reaction
with an inverse electron demand. Because of the slowness of the cyclotrimerization step, a
nucleophilic dienophile 234 was formed that had time to interact with the nickel adduct of
233 to ultimately produce 235 as the major product (Scheme 110) <1998T1169>. Compound
233 was generated by a 1,4-addition to the conjugated double bond system of Ni–diene 234
followed by reductive elimination of Ni(0).
N N
Dimethyldioxirane
acetone N
N O
S 24 h, rt S
O
84%
H S H S
O O
230
231
<1999JPR552>
Scheme 109
(COD)2Ni O
aq. HCl Ph S O Ph Ph
O
THF S O
Ph S Ph +
16 h O
O Ph Ph O S Ph
232 O
233
O Ph Ph
Ph O S Ph
Ph O
S O +
S Ph
O Ph Ph S
O Ph O
O
234 (15%)
235 (69%)
<1998T1169>
Scheme 110
4.19.6 FUNCTIONS CONTAINING SULFUR AND EITHER SELENIUM

OR TELLURIUM, R12C¼CSR2SeR3, etc.
4.19.6.1 Dicoordinated Sulfur Derivatives
4.19.6.1.1 Selenium derivatives

Selenothioic acid S-alkyl esters were treated with triethylamine and Cd(OAc)22H2O in methanol
in the presence of alkyl, allyl, and benzyl halides to afford ketene selenothioacetals in moderate
yields <1996CL877>. An example is shown in Scheme 111, where selenothioic acid ester 236 was
reacted with methyl iodide to afford selenothioacetal 237 in 50% yield. The reactivity of ester 236
toward Zn and Cd is different. When the reaction was performed in the presence of
Zn(OAc)22H2O, the starting ester 236 was recovered in 39% yield along with 18% of compound
237 (Scheme 111). The results were explained by the high affinity of selenocarbonyl compounds
toward cadmium salts than other Lewis acids with higher affinity to carbonyl compounds
<1996CL877>. In the absence of alkyl halide, only substituted diselenide 239 was obtained
(Scheme 112).
i. Cd(OAc)2.2H2O
Et3N, MeOH
65 °C, 3 h
Se
50%
S + I S
ii. NBu4NF, THF Se

0 °C, 30 min
236 62% 237
+
Se– NBu4
238
<1996CL877>
<2000CL368>
Scheme 111
Cd(OAc)2.H2O, Et3N S
Se Se
methanol
S Se
S + Se
236
236
239
<1996CL877>
Scheme 112
An alternative method to ketene selenothioacetals was reported later by the same authors
<2000CL368>. Ammonium eneselenolates generated ketene selenothioacetals in high yields
when reacted with alkyl halides. Selenothioic acid S-ester 236 was reacted with tetra-n-butyl-
ammonium fluoride in THF at room temperature in the presence of methyl iodide. Intermediate
selenolate 238 reacted with methyl iodide to produce ketene selenothioacetal 237 in higher yield
(Scheme 111). The deprotonation with ammonium fluoride was applied to -monosubstituted and
unsymmetrically substituted selenothioic acid esters, when both (E)- and (Z)-isomers were obtained.
The lack of stereoselectivity is explained by the fast reaction rates for both the deprotonation and the
addition of electrophile. When the alkyl halide was added 30 min after the mixing of selenothioic acid
S-ester with tetra-n-butylammonium fluoride, (Z)-isomers were obtained predominantly ((E):(Z) of
1:6 to 1:19). Similar reactions were described in more recent reports (Scheme 113) <2001JOC8101>
showing that exclusive formation of the (Z)-isomers depended upon thermodynamic characteristics of
the intermediate ammonium selenolates, which were kinetically generated as stereoisomeric mixtures.
Only (Z)-isomers were obtained when the reaction time to generate selenolates was extended to
1.5–2 h, leaving time for the (E) species to convert to the (Z)-isomers. Further treatment with alkyl
halide provided exclusively the (Z)-ketene selenothioacetal 241.
Bu4NF
Se Se
THF
+ MeI
S S
1.5 h, 0 °C
51%
240
241
<2001JOC8101>
Scheme 113
The reaction of selenothioic acid esters with trialkyl phosphites in toluene at 85 C was carried
out for 10 min and generated ketene acetals along with -phosphoryl sulfides <1999CL105>. The
product distribution was reported to be strongly dependent on the nature of the ester. For
derivative 236 the reaction with trimethyl phosphite generated predominantly -phosphoryl
sulfide 242 and only small amounts of selenoacetal 237, while for selenothioacetic acid S-butyl
ester and triethyl phosphite the products were formed in equimolar amounts (Scheme 114).
Other trivalent phosphorus compounds were used and the product distribution was
discussed <2000JCS(P1)917>. It was shown that dimethyl phenylphosphonite and mainly
methyl diphenylphosphinite produced the ketene selenoacetals in higher yields, as shown in
Scheme 115.
Ketene dithioacetals reacted with activated methylene compounds and freshly prepared sodium
selenide to produce selenophenes in moderate-to-good yields <2003SL855>. First, the ketene
dithioacetal was heated with freshly prepared sodium selenide at 50 C in DMF, and then
chloroacetyl chloride was added followed by potassium carbonate to produce compound 243 in
32% yield (Scheme 116).
O R
Se P R
2 R Toluene S
S + O P S +
R 6 h, 110 °C Se
236 237 (3%)

242 (75%)
R = OMe, OEt
<1999CL105>
Scheme 114
R O
Se P R
2 Toluene S
S + O P S +
110 °C, 10 min Se
236 237 (30%)

242 (42%)
R = Ph
<2000JCS(P1)917>
Scheme 115
O O O
Na2Se, K2CO3
O DMF
+ Cl
S S 50 °C, 5 h S
Se
32% O
243
<2003SL855>
Scheme 116
4.19.6.1.2 Tellurium derivatives

The only examples of tellurium derivatives in this class are thienotelluroles <1997H1891> and
dithienoheteroepines <1997H1899>. Syntheses are described for thieno[2,3-b]-, thieno[3,4-b]-, and
thieno[32-b]-telluroles 247 (Scheme 117). Dithienoheteroepines 250 were prepared as displayed in
Scheme 118.
TMS
TMS
S TBAF
S DIBAL-H S i. ButLi, Et2O, –80 °C TMS S
Br M
NBS M
Br Br ii. (PhSO2)2Se or TeCl4
90%
245 246 247
244
M = Se, Te
<1997H1891>
Scheme 117
DIBAL-H i. ButLi, Et2O, –80 °C

S S S M S
70% ii. (PhSO2)2Se
S S
Br Br Br Br or TeCl4
30–65% 250
248 249
M = Se, Te
<1997H1899>
Scheme 118
4.19.6.2 Tri- and Tetra-coordinated Sulfur Derivatives

Tellurophene 253 is the only compound belonging to this class <2000JOC5413>. It was obtained
from benzo[c]-tellurophene 251 via the lithio derivative 252 prepared by treatment with BunLi at
low temperature. Derivative 252 was further treated with toluenesulfonic anhydride to yield
tellurophene 253 in 61% yield (Scheme 119).
Li SO2C6H4Me-p
BunLi
Te Te Te
(p -MeC6H4SO2)2
Li 61% SO2C6H4Me-p
251 252 253
<2000JOC5413>
Scheme 119
4.19.7 FUNCTIONS CONTAINING SELENIUM AND/OR TELLURIUM,

R12C¼C(SeR2)2, etc.
4.19.7.1 Selenium Derivatives

Dendralenes bearing the 1,3-selenole moiety were prepared as described in Scheme 120
<2001JOC7757>. The selenium-containing template 255 was treated with phosphonate 256 in
the presence of NaH in THF at room temperature to produce derivative 257 in 67% yield.
S O
P O
S O
Se O Se O S
N 256 Se
Se +
Se O S
254 NaH, THF, 0.5 h Se
255 67% O
257
<2001JOC7757>
Scheme 120
Diselenadithiafulvalenes were also obtained as described in Section 4.19.5.1.3 for tetrathiafulva-

lenes via the Me3Al-promoted reactions of organotin selenolates with esters <1996JOC3987>.
Diselenole derivative 259 was obtained by treating 2 mol. of isolable and stable 2-(1,3-
dimethylimidazolidinio)diselenocarboxylate 258 with 1 mol. of diethyl acetylenedicarboxylate
(Scheme 121) <2000JA9120>. Even when the ratio between reactants is 1:1, only the bis-adduct
259 was obtained.
O O
O O
Se– N O
N+ CH2Cl2 Se
+ O
O O
Se 0.5 h N Se
N
O O O
67% O
258
259
<2000JA9120>
Scheme 121
4,5-Dimethyl-2-methylseleno-1,3-diselenolium salts 260 are useful building blocks for diselenols

such as 261 (Scheme 122) <1998T13257, 2002JOC4218>. The reaction occurred by heating the
reagents in pyridine/acetic acid with a yield of 86%.
Se Se
O Pyridine,
O– acetic acid
F3C Se+
S Se
+ O 16 h,
O
Se
60–70 °C O
260 86% 261
<1998T13257>
Scheme 122
4.19.7.2 Tellurium Derivatives

Tellurole derivatives were synthesized starting from tellurole dialdehyde 262 (Scheme 123)
<2002OL2581>. By condensation with malononitrile or with carboxymethyl phosphorane, tell-
uroles were obtained in moderate to high yields (63% for 263). This compound was used in the
synthesis of the first 1,3-ditellurole-containing radialene-type tetrathiafulvalene derivative.
O S
PPh3 O
O S
S O
O Te
Te O
O POCl3 Te O S
+ NaH
Si N Te
Si Te O
Te O 63% S
O
S
262
O
O O
263
<2002OL2581>
Scheme 123
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Biographical sketch
Daniela Carmen Oniciu received her M.S. in organic chemistry and che-
mical engineering from the University ‘‘Polytechnica’’ of Bucharest
(Romania). After completing a three-year industrial training, compulsory
in the communist times, she worked as a Senior Scientist in medicinal
chemistry (radioimmunochemistry) at the Institute of Endocrinology in
Bucharest. Later on, as a Scientist at the Department of Organic Chem-
istry of the University ‘‘Polytechnica’’ of Bucharest, she received her
Ph.D. in 1992 with a thesis focused on nitrogen-centered free radicals.
Her postdoctoral experience was gained with Alan Katritzky at the Uni-
versity of Florida and Hiizu Iwamura at the University of Tokyo. In
1998, she joined the Alchem Laboratories in Alachua, Florida, as Direc-
tor of Chemistry, working in pharmaceutical research and development.
Since February 2001 she is Director of Chemical R&D at Esperion
Therapeutics, Inc. in Ann Arbor, MI, which has become a Division of
Pfizer Global Research and Development in February 2004. Her research
interests encompass broad areas, among them heterocyclic chemistry, the
chemistry of free radicals, and medicinal chemistry, with emphasis on
pharmaceuticals to treat cardiovascular disease.
4.20
Functions Containing
a Chalcogen and Any Group
Other Than a Halogen or
a Chalcogen
B. BESSIERES
Université Joseph Fourier, Grenoble, France
4.20.1 FUNCTIONS CONTAINING A CHALCOGEN AND A NITROGEN FUNCTION 836

4.20.1.1 Functions Bearing Oxygen and Nitrogen 836
4.20.1.1.1 Ketene hemiaminal derivatives 836
4.20.1.1.2 Other nitrogen derivatives 839
4.20.1.2 Functions Bearing Sulfur and Nitrogen 840
4.20.1.2.1 Dicoordinate sulfur derivatives 840
4.20.1.2.2 Tetracoordinate sulfur derivatives 846
4.20.1.2.3 Functions bearing selenium with nitrogen 846
4.20.2 FUNCTIONS CONTAINING A CHALCOGEN AND A PHOSPHORUS,
ARSENIC, OR ANTIMONY 847
4.20.2.1.1 Elimination reaction 847
4.20.2.1.2 Addition to alkynes 847
4.20.2.1.3 Addition to ketenes 848
4.20.2.1.4 Condensation reaction 848
4.20.2.1.5 Enolization of -carbonylphosphorus compounds 849
4.20.2.1.6 Metal-catalyzed coupling reaction 849
4.20.2.1.7 Cycloaddition reactions 850
4.20.2.2.1 Condensation reaction 850
4.20.2.2.2 From 1-lithio-1-phosphorylated alkenes and allenes 851
4.20.2.2.3 From ketene dithioacetals 852
4.20.2.2.4 Functions bearing selenium and tellurium 852
4.20.3 FUNCTIONS CONTAINING A CHALCOGEN AND A METALLOID 853
4.20.3.1.1 Oxygen and silicon or germanium 853
4.20.3.1.2 Oxygen and boron 858
4.20.3.2 Functions Bearing Sulfur, Selenium, or Tellurium 859
4.20.3.2.1 Sulfur and silicon or germanium 859
4.20.3.2.2 Selenium or tellurium together with silicon or germanium 864
4.20.4 FUNCTIONS CONTAINING A CHALCOGEN AND A METAL 866
4.20.4.1 Oxygen Functions 866
4.20.4.1.1 Lithium 866
4.20.4.1.2 Tin 867
4.20.4.1.3 Copper 869
4.20.4.1.4 Transition metals 869
4.20.4.2 Sulfur Functions 870
835
836 Functions Containing a Chalcogen and Any Group Other Than a Halogen or a Chalcogen
4.20.4.2.1 Lithium 870

4.20.4.2.2 Tin 871
4.20.4.2.3 Magnesium 872
4.20.4.2.4 Zinc 872
4.20.4.3 Selenium Functions 872
4.20.1 FUNCTIONS CONTAINING A CHALCOGEN AND A NITROGEN FUNCTION
4.20.1.1 Functions Bearing Oxygen and Nitrogen
4.20.1.1.1 Ketene hemiaminal derivatives

The main method to synthesize ketene hemiaminals 2 is by O-alkylation of amide enolates
(Equation (1)):
O OR
i. Base
R3 R1 R3 R1
N
ii. RX
N ð1Þ
R2 R2
1 2
Neier and co-workers prepared a series of N-butadienyl-O-silyl hemiaminals by deprotonation

of the amides 3 in a mixture of THF/HMPA at 78 C (Table 1). Trapping of the resulting
enolate with TBDMS-Cl gives the (Z)-N,O-ketene hemiaminals 4. <1999CEJ3162, 1996S1239>.
The yields, as shown in Table 1, are very high. Although silylation with trimethylsilyl chloride
is also feasible, the corresponding acetals are less easily formed and are more sensitive to
hydrolytic cleavage.
Table 1 The synthesis of O-silyl ketene hemiaminal from amide
O OTBDMS
R1 R2 R1 R2
N LDA / THF-HMPA N
–78 °C/ TBDMS-Cl
3 4

i
Pr Me 98 <1996S1239>
Pri Bn 97 <1996S1239>
Pri CH¼CHCH3 98 <1996S1239>
Bn Et 98 <1996S1239>
p-BrCH2C6H4 Et 96 <1996S1239>
Anthranylmethyl Et 70 <1996S1239>
Bz Me 98 <2000HCA2712>
The same reaction can be applied to imides (R1 = Bz, Table 1), with a similar efficiency
<2000HCA2712>.
In studies on the enantioselectivity of enolate formation, Vedejs and co-workers deprotonated
a series of arylamides 5 with s-butyllithium followed by addition of trimethylsilyl chloride
(Table 2). The assignment of the geometry of 6 was based on an upfield shift of the SiMe3
protons in the (Z)- versus the (E)-isomer <2000JA4602, 1995JA891>.
Functions Containing a Chalcogen and Any Group Other Than a Halogen or a Chalcogen 837
Table 2 Geometry of O-silyl ketene hemiaminal
R1 R1 Ar
i. BusLi NR2
NR2 NR2 +
Ar ii. TMSCl Ar R1
O OTMS OTMS
5 (Z )-6 (E )-6
Ar R1 R (Z)/(E)
i
Ph Cyclopentyl Pr 4.7:1
Me Me 1:1.6
MeO
Ph Me Me 2.1:1
The generation of the amide enolate can also be accomplished using unusual procedures.
Thus, deprotonation of the 2-fluoro-2-phenylthiopropionamide 7 by germyl anion followed
by quenching with a silyl triflate gives a mixture of O-silyl ketene hemiaminal (E)/(Z)-8
(Equation (2)) <1998SL37>. Semi-empirical molecular orbital calculations reveal that the
(E)-enolate is thermodynamically more stable than the (Z)-enolate, in accordance with the
experimental data.
i. Et 3GeNa OTBDMS OTBDMS

F Me
THF/HMPA, –30 °C Me + F
PhS CONEt2 NEt2 NEt2
ð2Þ
ii. TBDMSOTf, –78 °C F Me
7 8 (E )/(Z ) 97/3
Another unusual enolate formation is the electroreductive defluorination of trifluoroacetic acid

derivatives <1999JOC6717>. Thus, when trifluoroacetamide 9 was electrolyzed in anhydrous
acetonitrile at 0 C using a carbon anode and a lead cathode, in the presence of chlorotriethyl-
silane, ketene hemiaminal 10 was obtained in 54% yield (Equation (3)).
OSiEt3
O +2e–, 0 °C, 2.0 F mol–1
F
Et3SiCl NPh2 ð3Þ
F3C NPh2
F
9 10
The enolization of N,N-dimethylacetamide with 2.5 equiv. of boron triflate gives the doubly
borylated enolate 11 in 98% yield <2002JA10759> (Equation (4)).
O B(c-Hex)2
c-Hex2BOTf, Et3N O
Me2N CDCl3, 0 °C B(c-Hex)2 ð4Þ
Me2N
11
Other methods to access the ketene hemiaminal function 13 do not start from amides. For
example, Furukawa and co-workers used -oxothio ester 12 and amines as starting materials
<1999SC599>. This reaction is limited to primary amines (Table 3). When secondary amines
are used, reactions are very slow and yields are very low.
The N,S-acetals 14 (obtained from the ketene dithioacetals; see Section 4.20.1.2.1) undergo
facile displacement with sodium methoxide in refluxing methanol to afford the corresponding
N,O-acetals 15 in good yields <2000JOC1583> (Equation (5)).
Table 3 The synthesis of ketene hemiaminal from -oxothio ester
R1 OEt NEt3 R1 OEt

+ R2NH2
OH S MeCN, rt O NHR2
12 13
1 2
R R Yield (%)
Me Me 84
Me Pr 99
Me Ph 98
But Pr 99
Ph Me 67
Ph Pr 99
p-MeOC6H4 Pr 96
H SMe H OMe
NaOMe
Ar HN MeOH, ∆ Ar HN ð5Þ
O N O N
14 15
The particular enediamine 16 can also react with sodium methoxide to give the N,O-acetal in
66% yield (Equation (6)) <1996KGS699>.
O 2N NMe2 MeONa O2N OMe
NC NH2 66% NC NH2 ð6Þ

16
Similarly, lactim ethers or lactim sulfides react with ketene dithioacetals in refluxing methanol
for 2 days to afford ring-opened product (Equation (7)) <1997JCS(P1)2421>.
( )n
N SMe
O2N SMe O2N NHCH2CH2(CH2)n CO2Me
+ or
SMe ( )n ð7Þ
OMe
N OMe
n = 1, 2, 3
Wentrup and co-workers generated iminopropanedienones by flash vacuum thermolysis (FVT)

from substituted Meldrum’s acid derivatives <1997JOC4240>. In the case of compound 17, the
generated ketene 18 is in equilibrium with the ketimine 19. Chemical evidence was obtained by
trapping the intermediate with methanol at 77 K giving the N,S-acetal 20 and N,O-acetal 21
(reaction run on a 1.9 mmol scale, Scheme 1).
O
O PriN
PriHN FVT PriN C C O
MeS 600 °C
MeS SMe
O
17 18 19
+ MeOH
PriHN O PriHN O
MeS OMe MeO SMe

19% 58%
20 21
Scheme 1
The isoxazole ring can be reduced by Raney-Ni to give enamine derivatives. In the case of the
3-methoxyisoxazole 22, the N,O-hemiaminal derivative is obtained in 94% yield (Equation (8))
<1995ACS53>.
OMe O NH2
Raney-Ni
N OMe
O 94% ð8Þ
NHCOMe NHCOMe
22
Oxazolidinethione and the acyclic thionocarbamate analogs can lead to N,O-hemiaminals after
S-alkylation followed by sulfur extrusion (Table 4) <2000H827>.
Table 4 Sulfur extrusion from oxazolidine-2-thione and thionocarbamates

R1 R2
R1 R2 R1 R2
PhCOCH2Br Sealed tube O NH
O NH O N
O
Et3N/DMF/120 °C Ph
S S
Ph
O
1 2
R R Yield (%) References
Et Ph 48 <2000H827>
CH2CH2 52 <2000H827>
97 <2000H827>
H 2C CH2
Oxygen nucleophiles can also add to alkynylamines. Thus, acetic acid reacts with the ynamine
23 to give the conjugated N,O-hemiaminals 24 (Equation (9)) <1995C72>.
R2
R1 R1 N
N O AcOH
AcO
ð9Þ
R2
H O
H
23 24
4.20.1.1.2 Other nitrogen derivatives
(i) N-Oxide derivatives

Ciganek and co-workers reported the addition of dimethylhydroxylamine and N-hydroxypiper-
idine to ethoxyacetylene <1995JOC5795>. The N-oxide derivatives 25 were obtained in good
yields after 3 days at room temperature (Equation (10)).
O–
+NR
R2NOH + HC COEt 2 R = Me, CH2(CH2)3CH2
H2C ð10Þ
OEt
25
(ii) Imino derivatives

Condensation of acid chlorides and N-TMS-imine affording the azadiene 26 was reported by
Panunzio and co-workers <1997JOC8911, 2000EJO2379, 2000OL1077>. After filtration of the crude
reaction mixture over Celite, an aliquot was analyzed by NMR, showing that it contained essentially
pure azadiene (Equation (11)). This crude mixture was directly utilized in Diels–Alder cyclization.
H R X X R
+ NEt3 N
N ð11Þ
TMS O Cl TMSO
26
Ghosez and co-workers reported the synthesis of such azadienes from the same starting material as well
as from acylimidates 27 (Equation (12)) or directly from aldehydes 28 (Equation (13)) <1995T11021>.
O R4 OR1
R1O CHR3R4 TBDMSOTf, NEt3 R3 R2
N ð12Þ
N
R2 TBDMSO
27
H i. LiHMDS R2 R1
O N
R1 ii. NEt 3, R2CH2COCl TBDMSO ð13Þ
28
(iii) Isocyanate derivatives

Ghosez and co-workers also prepared the 1-silyloxy-alkenyl isocyanate 29 by reaction of an acid
chloride, silver isocyanate, and t-butyldimethylsilyl triflate in the presence of triethylamine
(Scheme 2). This one-pot method avoids the isolation and purification of the intermediate acyl
isocyanate, a procedure that always leads to extensive decomposition <1997BSF989>.
O O
Cl C C
AgOCN N TBDMSOTf, NEt3 N R = H, 49%
O R = Me, 72%
R O TBDMSO
R R
29
Scheme 2
4.20.1.2 Functions Bearing Sulfur and Nitrogen
4.20.1.2.1 Dicoordinate sulfur derivatives
(i) 1-Amino-1-thioalkenes
These compounds have the general formula 30 and are normally known as ketene N,S-acetals.
R1 SR3
R2 NR24
30
The synthesis of this system is realized according to four main routes:

(i) displacement of an alkylthio group of a 1,1-bis(alkylthio)alkene;
(ii) S-alkylation of a thioamide;
(iii) addition of a thiol to nitrile group; and
(iv) addition of a carbanion to an isothiocyanate
In addition, a number of rather singular and nongeneral methods will be reported under ‘‘miscellaneous.’’
(a) Reaction of amines with 1,1-bis(alkylthio)alkenes. 1,1-Bis(alkylthio)alkene 31, whose synth-
esis is discussed in Chapter 4.19, reacts with a wide range of amines (Equation (14)).
X SR1 X SR1
+ R2R3NH
Y SR1 Y NR2R3
ð14Þ
31
As this reaction involves the initial attack at C-1 of the dithioacetal 31 (it is a conjugate addition/
elimination on an activated double bond), the ease of reaction will depend on the electron-withdrawing
abilities of X and Y. Furthermore, a limited number of dithioacetals 31 are used in this reaction.
Singh and co-workers have developed an access to 2-oxo-ketene-N,S-acetals by condensation of
1 equiv. of the lithium salt of the aromatic amine (either an aniline or a pyridine derivative) on the
S,S-ketal at room temperature. If 2 equiv. of amines are used, the N,N-ketal is obtained (see Chapter 4.21).
All the N,S-ketals thus obtained exist as a single (E)-stereoisomer, based on IR and NMR data. For
example, the N–H stretching vibration at 3330–3350 cm1 indicates an intramolecularly associated
hydrogen <1997JCS(P1)3561, 2003JOC3966>. Representative examples are listed in Table 5.
Table 5 Displacement of methylthio group by lithio amides

H Ar
O SMe O N
R1 SMe
+ Ar-NH– Li+
R1 SMe
R2 R2
R1 R2 ArNH2 Yield (%) References

Ph H p-ClC6H4NH2 82 <1997JCS(P1)3561>
Ph H 92 <1997JCS(P1)3561>
N NH2
p-MeOC6H4 H 93 <1997JCS(P1)3561>
N NH2
p-ClC6H4 H 90 <1997JCS(P1)3561>
N NH2
2-Furyl H 88 <1997JCS(P1)3561>
N NH2
NH2
Ph H 70 <1997JCS(P1)3561>
N
NH2
p-MeOC6H4 H 70 <1997JCS(P1)3561>
N
NH2
2-Furyl H 62 <1997JCS(P1)3561>
N
Ph H 0.5 equiv. 68 <2003JOC3966>
H2N NH2
Ph H 0.5 equiv. 75 <2003JOC3966>
H2N NH2
Ph H 0.5 equiv. 85 <2003JOC3966>

NH2
NH2
(Bis-methylthio-methylene)malonitrile 32 is another of the dithioacetals used as precursor of

N,S-acetals (Table 6). Compound 32 and the appropriate amine are refluxed in an alcoholic
solvent (ethanol or isopropanol) for several hours <2003JMC1229, 1999JMC1235,
1997JMC3601>, and sometimes a catalytic amount of piperidine is added <2002SC3509>.
Table 6 Displacement of methylthio group by amines
NC SMe NC NHR
+ RNH2
NC SMe NC SMe
32
Amine Solvent Yield (%) References

4-Methoxyaniline EtOH 70 <2003JMC1229>
Ethylamine EtOH 61 <2003JMC1229>
N
H2N PriOH 63 <1999JMC1235>
( )3
CO2Et
H2N O
EtOH/piperidine(catalytic) 90 <2002SC3509>
N
Me N Ph
Me
Yang and co-workers have improved the reaction for weakly nucleophilic arylamines (Equation
(15)). The best yields are obtained in acetonitrile with a catalytic amount of the ion exchange resin
Amberlite IRA-93 <1998SC3965>.
NC SMe CH3CN, IRA-93 NC NH NO2

+ O2N NH2 ð15Þ
NC SMe 92%
NC SMe
The same reactivity is observed for nitro-activated dithioacetal 33 (Equation (16)). The sub-
stitution is realized by reaction with an amine, either neat <1999JMC730>, in ethanol
<1998JMC3239>, or in acetonitrile <1996T9509>.
SMe NHR
+ RNH2
O 2N SMe O2N SMe ð16Þ
33
Sizov and co-workers reacted amines with -fluoro vinyl sulfides to obtain the product of
fluorine substitution (Equation (17)) <2002IZV938>.
R1S EWG1 14 Examples RS EWG1

+ NH2R2
55–85%
F EWG2 R2HN EWG2 ð17Þ
EWG = CO2Me, CF3, CN; R1 = Bn, Bu; R2 = aryl
The nitrogen source can also be a lactim ether <1997JCS(P1)2421>. In this case, the reaction
was carried out in dioxane/water to give 65% of the product (Equation (18)).
O2N SMe O2N NHCH2CH2(CH2)n CO2Et

+ ð18Þ
N OEt 65%
SMe SMe
(b) S-Alkylation of a thioamide anion. Treatment of a thioamide with a base in the presence of
an electrophile produces the S-alkylated product (Table 7) <1998HCA1207, 2000PJC1101>.
Table 7 S-Alkylation of a thioamide
O S R3X/K2CO3 O NR1R2
Ph NR1R2 acetone or THF Ph SR3
R1 R2 R3X Yield (%) References

Ph H MeI Quantitative <1998HCA1207>
Bn H MeI 83 <1998HCA1207>
Bn Bn MeI 89 <1998HCA1207>
Ph H BrCH2CH2CO2Et 41 <2000PJC1101>
The -hydroxy-N,N-dimethylthioamides 34 were deprotonated with LDA at 40 C, and alkyla-

tion of the dianions by allylic halides occurred only at the sulfur atom to give the allylic N,S-acetals
35 (Scheme 3) <1997T17253>. Such allylic acetals are prone to thio-Claisen rearrangement and
were not isolated, but they were characterized by NMR. Similar thioamides bearing an enantiopure
-sulfinyl group were prepared by the group of Metzner <2001JOC7841>.
OH S
OH S i. LDA, –40 °C OH S Thio-Claisen
R1 NMe2
R
R1 NMe2 ii. R R1 NMe2
Br
34 35 R
Scheme 3
(c) Addition of thiol to a nitrile group. Addition of a thiol to a nitrile group in the presence of
triethylamine leads to the formation of the expected N,S-acetals in moderate-to-good yields
<1995S635, 1996S1325>. The compounds are obtained as an inseparable mixture of (Z)/(E)
isomers (Table 8).
Table 8 Addition of thiol to nitrile
O O H2N
CN Et3N/EtOH SR2
R1 NH + R2SH R1 NH
2–4 days
CO2Et CO2Et

Me Et 83 <1995S635>
Bu Et 72 <1995S635>
Bu CH2CH2OAc 60 <1995S635>
Bu Ph 86 <1995S635>
Bu Bn 86 <1995S635>
Bu p-MeOC6H4 91 <1995S635>
Bu p-FC6H4 67 <1995S635>
Duncia and co-workers reacted substituted thiophenols on 1,1,2,2-tetracyanoethylene 36 and

1,2-dicarboethoxy-1,2-dicyanoethane 37 to produce the di-addition product in low yields
(Equations (19) and (20)) <1998BMCL2839>.
SH CN NH2
NC CN NaOH/water/acetone
+ S Ar
Ar S ð19Þ
CO2Me NC CN 36%
NH2 CN
36
SH EtO2C NH2
EtO2C CO2Et Et3N/ THF
+ S Ar
12% Ar S ð20Þ
NH2 NC CN
NH2 CO2Et
37
(d) Addition of a carbanion to an isothiocyanate. Bremner and co-workers reacted diversely

substituted (o-halogeno(cyanomethyl))pyridines with phenyl isothiocyanate in the presence of
sodium hydride, followed by quenching with methyl iodide, to obtain the N,S-acetals. The latter
cyclize to the thienopyridine at rates depending on relative substitution and reaction conditions
<1998S1095>. One example is presented in Equation (21).
CN
NHPh
70 °C
SMe
CH2CN 37% N Cl
i. NaH/DMSO
+ PHN=C=S ð21Þ
N Cl ii. MeI
100 °C CN
20%
NHPh
N S
The same method was used by Kirsch and co-workers <2002TL257>, by Papageorgiu and
co-workers <1998JMC3530>, and by Rudorf and Uhlig <1995JPR29> to prepare N,S-acetals,
which are precursors of heterocycles. Wentrup and co-workers used only malononitrile and
modified the isothiocyanate (Table 9) <2002JOC1084>.
Table 9 Addition of activated methylene on isothiocyanate
R1 R2
i. Base
R1 R2 + ArN=C=S
ii. RX
ArHN SR
R1 R2 Ar RX Yield (%) References

CN CO2Et (p-CF3)Ph MeI 61 <1998JMC3530>
CN CO2Et Ph MeI 87 <2002TL257>
Ac CO2Et Ph MeI 97 <2002TL257>
CN CN Ph MeI 91 <2002TL257>
Bz Bz Ph MeI 58 <2002TL257>
CN CN Me MeI 39 <2002JOC1084>
CN CN Et MeI 60 <2002JOC1084>
PhSO CN Ph MeI 61 <1995JPR29>
PhSO CN Ph BnBr 65 <1995JPR29>
p-MePhSO CN Ph BnBr 40 <1995JPR29>
PhS CN Ph MeI 74 <1995JPR29>
PhS CN Ph BnBr 51 <1995JPR29>
PhSO Bz Ph MeI 32 <1995JPR29>
p-MePhSO Bz Ph BnBr 35 <1995JPR29>
p-MePhS Bz Ph MeI 51 <1995JPR29>
Lithiated allenes were also reacted with isopropyl isothiocyanate at 100 C to produce, after
quenching of the resulting thiolate with methyl iodide, the enamines which rearrange to the fully
conjugated compounds upon heating (Scheme 4) <1997TL6905>.
Me
Me H
Me H i. Pr iN=C=S 65 °C
C Me
C
ii. MeI Me SMe Me
Me Li
Pri N N SMe
Me
Scheme 4
(e) Miscellaneous preparations of 1-amino-1-thioalkene. Morel and Berrée reacted 5-aminothia-

zolium salts 38 with electron-deficient alkenes via 1,3-cycloadditions. Depending on the reaction
conditions (solvent, base) and dipolarophiles used, the ketene N,S-acetals were obtained in good
yields <1995T7019>. One selected example is shown in Equation (22).
MeS BnHN
Cl SMe
S CN Me2N
+ THF/NEt3
N NHBut +
Bn 90% ButNHC(S) CN ð22Þ
NC
NMe2 CN
38
Reduction of isothiazolium salts 39 with sodium borohydride gives the N,S-acetals in good
yields (Equation (23)) <2002JOC5375>.
SR2
NaBH4/EtOH Ar SR2
X–
N+ 86–96% S NHR1 ð23Þ
Ar S R1
39
By analogy with the displacement of a methylthio group by an amine in S,S-acetals, an amine

can substitute the 1-chloro group of diene 40 <2001PS221> (Equation (24)).
Cl SR1 Cl SR1
Cl R2NH2 Cl
Cl NHR2 ð24Þ
Cl NO2 8 Examples, Cl NO2
12–84%
40
(ii) 1-Nitro-1-thioalkenes
This class of compounds is mainly obtained by the method of Barrett, via the condensation of
alkyl- or arylthionitromethanes with an aldehyde in the presence of a base (Equation (25)). The
nitro-alcohols thus obtained are further dehydrated by treatment with methanesulfonyl chloride
and a base to give the nitroalkenes <1995JCS(P1)1009, 1995JOC6431, 1999JCS(P1)937,
2002S2296>. In the case of nitro(phenylthio)methane, the base used is potassium t-butoxide,
whereas for the tolyl derivative, butyllithium is used.
NO2 i. Base NO2
+ RCHO
SAr ii. MsCl, NR3 R SAr ð25Þ
Ar = Ph, Tol
Barrett and co-workers also prepared the chiral, camphor-derived nitroalkenes 41 for
asymmetric induction purposes <1999JOC5818>.
R
S
SO2NR2 NO2
41
The reaction of 2-nitrothiophene with pyrrolidine in ethanol and in the presence of silver nitrate
for 10 days at 0 C gave a salt that was methylated to give nitroalkene in 52% yield (Equation (26))
<1997HCA2329>.
i. EtOH, AgNO3 NO2

+ N
S NO2 N ii. MeI ð26Þ
SMe
52%
4.20.1.2.2 Tetracoordinate sulfur derivatives

The synthesis of these compounds results mainly from the condensation of tosylmethyl isocyanide
(TosMIC) on aldehydes, in DME, using potassium t-butoxide as base <1995HCA1837,
1998T9033>. The formamide obtained can be converted to the isonitrile by reaction with
POCl3 (Scheme 5).
SO2Tol SO2Tol SO2Tol

ButOK/DME POCl3
+ RCHO
NC R NHCHO R NC
Scheme 5
One example of a sulfone derivative from trichloroacetylamino compound 42 is reported by a

Russian group <1997ZOR1594> (Equation (27)).
H H
Cl3C N Cl i. ArSO2Na Cl3C N SO2Ar
O CCl3 ii. Et3N O CCl2

ð27Þ
42 Ar = Ph: 67%, Ar = Tol: 62%
4.20.1.2.3 Functions bearing selenium with nitrogen

There are only two examples of this system. Kato and co-workers alkylated selenoamide 43 with
iodomethane to give the ketene (Z)-azaselenoacetal 44 in 87% yield (Equation (28))
<1998SL619>. It is noteworthy that when allyl bromide was used as the electrophile, only
C-alkylation occurred.
Se SeMe
i. MeLi, 0 °C
O N ii. MeI O N
O O ð28Þ
87%
43 44
Back and co-workers reacted 1-phenylselenoethyne with pyrrolidine to obtain a mixture of

2- and 3-addition products (Equation (29)) <1998JOC7908>.
Ts
Ts SePh
Ts SePh + H + H
N
N N ð29Þ
SePh
66% 32%
4.20.2 FUNCTIONS CONTAINING A CHALCOGEN AND A PHOSPHORUS,

ARSENIC, OR ANTIMONY

Seven different reactions have been used to produce these systems: elimination reactions, addition
to alkynes, addition to ketenes, condensation reactions, enolizations, metal-catalyzed coupling
reactions, and cycloaddition.
4.20.2.1.1 Elimination reaction

Treatment of compound 45 with iodotrimethylsilane resulted in the formation of methyl iodide,
fluorotrimethylsilane, and the unexpected vinylic derivative 46 (Scheme 6) <1997CB279>. The
expected trimethysilyloxycarbonyl derivative was probably formed and decarboxylated together
with the loss of fluorotrimethylsilane.
CO2Me O O SiMe3
Me3SiO F
TMSI F –CO2
Me3SiO CF3 CF2
P(OSiMe3)2 –MeI Me3SiO –TMSF (Me3SiO)2P F
P(OSiMe3)2
O O
O
45 46
Scheme 6
4.20.2.1.2 Addition to alkynes

Reaction of amino(imino)phosphines 47 with alkoxyalkynes gives the phosphorus-containing
1-alkoxyallenes in modest-to-good yields (Equation (30)) <1995ZOR488>. The reaction works
well in pentane, whereas the yields decrease dramatically when methylene chloride or acetonitrile
are used as solvent.
R1 OR3
Me3Si R1 Pentane, rt C
N P NSiMe3 + OR3
4–6 d R2 P NHTMS
Me3Si R2
N(TMS)2
47 ð30Þ
1=
R R2 = H, R3 = Et, 70%
R1 = H, R2 = Me, R3 = Me, 100%
R1 = R 2 = Me, R3 = Et, 30%
The same group reported the reaction of P-halophosphaalkenes 48 with alkoxyalkynes.

Similarly, the alkoxyallenes are formed in good yields <2000ZOR1624> (Equation (31)).
R1 OR3
R1 Hexane, rt C
X P CSiMe2 + OR3 ð31Þ
40–60 min R2 P CH(SiMe3)2
R2 8 examples, X
48 70–100%
Another Russian group reacted silylphosphine 49 with terminal alkoxy acetylenes

<1998IZV1792>. Unlike the reaction with internal alkynes (see Section 4.20.3.1.1), the reac-
tion proceeds at room temperature in acetonitrile and gives the -alkoxyvinylic phosphine in
good yields (Equation (32)).
Heat OR
Ph2PSiMe3 + H OR
70 °C PPh2
49 ð32Þ
R = Me, 77%
R = Et, 68%
R = Bu, 72%
4.20.2.1.3 Addition to ketenes

Reaction of iron complexes 50 with ketenes afford the adduct 51 in good yields (Table 10)
<2000JCS(D)4379, 2000ZAAC1831>. Those compounds are solids and are purified by recrys-
tallization. The antimony derivative with a methyl substituent is thermolabile and is only
observed as a mixture by NMR and could not be purified.
Table 10 Addition to ketenes
R R
+ C O Ph
Fe E(SiMe3)2 Ph Fe E
OC OC OSiMe3
CO CO SiMe3
E = P, As, Sb
50 51
E R Yield (%) References

P Ph 89 <2000JCS(D)4379>
As Ph 73 <2000JCS(D)4379>
Sb Ph 70 <2000JCS(D)4379>
Sb Cyclohexyl 76 <2000ZAAC1831>
Sb Me Only characterized by NMR <2000ZAAC1831>
4.20.2.1.4 Condensation reaction

Treatment of dialkyl phosphites with 2 equiv. of base in the presence of chloro- or bromoacetyl
chloride provides the enol phosphonate in good yield. The reaction was run at 100 C, for 5 s
<1995JOC5209>. No epoxide resulting from the internal substitution of chloride by the oxoanion
was detected (Scheme 7).
O O
RO KHMDS (2 equiv.)
2 P H + X
RO Cl –100 °C, THF
5s
O O
O– O O O–
X P(OR)2 P(OR)2 O P(OR)2
X P(OR)2
X O
P(OR)2 P(OR)2
P(OR)2 P(OR)2
O O
O O
R = Et, 72%
R = Bn, 71%
Scheme 7
4.20.2.1.5 Enolization of a-carbonylphosphorus compounds

-Ketophosphonates, obtained by an Arbuzov reaction between an acid chloride and a phosphite,
exist partly in the enolized structure. They can also be easily enolized by a base in dichloromethane
or THF. The enolate thus obtained can be trapped with acetic anhydride <1997TL1663> or a
sulfonyl fluoride <1999TL5337>. If a common triflating agent (Tf2O, N-phenyltriflimide) is used,
the enol triflate is obtained in low yield (0–34%). Results are summarized in Table 11.
Table 11 Enolization of -ketophosphonate
O R4
O
i. Base, solvent
R2 R2
(R1O) 2P (R1O)2P
4X
ii. R
O R3 O R3
R1 R2, R3 R4 X Base Yield (%) References

Me H, H Ac2O Et3N/rt 7 <1997TL1663>
Me Me, H Ac2O Et3N/rt 48 <1997TL1663>
Me Et, H Ac2O Et3N/rt 55 <1997TL1663>
Me Ph, H Ac2O Et3N/rt 74 <1997TL1663>
Me 4-MeOC6H4, H Ac2O Et3N/rt 57 <1997TL1663>
S
Me H Ac2O Et3N/rt 67 <1997TL1663>
Et H, H C4F9SO2-F DBU/45 C 82 <1999TL5337>

Et Ph, H C4F9SO2-F DBU/45 C 41 <1999TL5337>
Et Me, Me C4F9SO2-F DBU/45 C 80 <1999TL5337>
Et Me, Et C4F9SO2-F DBU/45 C 72 <1999TL5337>
Ketophosphonate 52 exists in the fully enolized form (as determined by NMR) and protonates
the methylenephosphorane to give compound 53 as the (E)-isomer in 63% yield (Scheme 8)
<1999S1056>.
OH O
(MeO)2P OMe
O
Ph3MePO O
Ph3P=CH2
(MeO)2P OMe
Toluene, 0 °C
O
63%
O O 53
(MeO)2P OMe
O
52
Scheme 8
4.20.2.1.6 Metal-catalyzed coupling reaction

Beletskaya and co-workers have prepared -alkoxyvinylphosphines <1995TL4121> and -alkoxy-
vinylphosphonates <1999TL569> by nickel- and palladium-catalyzed cross-coupling reactions.
Vinyl phosphines 54 are obtained by palladium-catalyzed coupling between a trimethylsilyl
phosphine and -alkoxyvinyl halide (Equation (33)).
PdCl2, 1 mol.% EtO

RP(H)SiMe3 + BrC(OEt)=CHR1 CHR1 ð33Þ
3 Examples, R(H)P
80–90% 54
The corresponding vinyl phosphonates are either accessed via nickel-catalyzed cross-coupling
of a vinylic halide and a trialkyl phosphite or by palladium-catalyzed cross-coupling of a vinylic
halide and a dialkyl phosphite in the presence of a base. The palladium-catalyzed reaction
requires milder conditions than the nickel one (temperature in the range 20–100 C versus
120–160 C; see Scheme 9).
O
H Br NiBr2, 5 mol.%, (EtO)3P, 80% H P(OEt)2
H OEt or H OEt
Pd(PPh3)4, 2 mol.%, NEt3, (EtO)2POH, 92%
Scheme 9
4.20.2.1.7 Cycloaddition reactions

Evans and co-workers have used the Diels–Alder reaction to produce -phosphonato dihydro-
pyrans <2000JA1635>. The reaction is catalyzed by chiral bis(oxazoline) copper(II) complexes,
and gives the dihydropyrans with high regio- and enantioselectivity. One example is displayed in
Equation (34).
O O 2OTf –
Me Me
N N
+ But But
Cu2+ ð34Þ
(MeO)2P O OEt (MeO)2P O OEt
10 mol.%, CH2Cl2, –78 °C
O O
endo/exo 99/1
99% ee

A smaller range of reactions has been used to produce this system, compared to their oxygenated
analogs: condensation reaction, from 1-lithio-1-phosphorylated alkenes and allenes, and from
ketene dithioacetals.
4.20.2.2.1 Condensation reaction

Sheng and Jiang have developed a novel base-catalyzed olefination method <2000S99>. This
variation of the Knoevenagel condensation uses N-tosyl imine 55 instead of a carbonyl compound
(Table 12). The reaction is carried out in THF at 70 C for 2 min, and the olefins are obtained in
good yields as the (E)-isomer.
Mikolajczyk and co-workers used this new reaction as well as the classical Knoevenagel
condensation to produce vinyl phosphonate 56, with the advantages of the new reaction (better
yield, reaction time considerably reduces) outlined in Scheme 10 <2002TL3061>.
Table 12 Knoevenagel-type condensation

O O
O O NTs (EtO)2P SPh
+ NaH 20 mol.% + TsNH2
(EtO)2P SPh
R
R
55
R Yield (%)
Ph 77
4-MeC6H4 85
4-MeOC6H4 76
4-ClC6H4 74
4-FC6H4 87
2-Furyl 81
PHCHO, piperidine
Benzene, reflux, 4 h
60%
O O O O
(MeO)2P S (MeO)2P S
p-Tol p-Tol
Ph
PhCH=NTs, NaH 20 mol.% 56
THF, 70 °C, 2 min
75%
Scheme 10
4.20.2.2.2 From 1-lithio-1-phosphorylated alkenes and allenes

Minami and co-workers have treated several phosphonoketene dithioacetals 57 with LITMP at
78 C in THF. The resulting vinyllithium anion undergoes facile elimination of thiolate to give
the thioethynylphosphonates 58 and 62 or the thioethynylphosphine oxide 59. These are then
subjected to nucleophilic attack of the thiolate to induce 1,2-migration of the thio group after
hydrolysis (Scheme 11) <1996JOC8132>.
O
O
H+ H PR22
S PR22
(CH2)3 S S
SLi
O O
R1S PR22 LiTMP R 1S PR22 R2 = OEt, 58 R2 = OEt, 50%, 60
2 = Ph,
R 59 R2 = Ph, 47%, 61
R1S H R 1S Li
57 O
O
H+ H P(OEt)2
EtS PR22 + EtSLi
50%
EtS SEt
62 63
Scheme 11
The same group also treated phosphonoketene dithioacetals 64 with LiTMP at 78 C in THF.
In this case, the vinyl anion neither rearranged nor eliminated a thiolate anion as in the case of 58
and 59. Instead, it could be quenched with various electrophiles, e.g., a disulfide giving 65
(Equation (35)) <1998JOC6239>. It is important to note that elimination of the thiolate anion
can be prevented by inverse addition, i.e., by adding LiTMP to a mixture of the phosphonoketene
dithioacetal and the electrophile.
O O
S P(OEt)2 i. LiTMP S P(OEt)2
ii. MeSSMe ð35Þ
S H S SMe
76%
64 65
Similarly, phosphorylated allenes can be treated by LDA in THF at 78 C to furnish the
anion that can be condensed with various electrophiles (Table 13) <1998PS1, 2000PS265>.
Table 13 Condensation with 1-lithio-1-phosphorylated allenes
H R1 E R1
i. LDA, –78 °C
• •
R2P R2 ii. EX, –78 °C to rt R2P R2
O O
R R1 R2 EX Yield (%) References

MeO Me Me PhSCl 60 <2000PS265>
Ph Me Me PhSCl 55 <2000PS265>
MeO –(CH2)5– MeS(O)Cl 59 <2000PS265>
MeO Me Me CCl3S(O)Cl 65 <2000PS265>
MeO Me Me Me3SiOSO2Cl 50 <2000PS265>
Ph Me Me Me3SiOSO2Cl 48 <2000PS265>
MeO Me Me MeSCl 65 <1998PS1>
MeO Me Me MeS(O)Cl 72 <1998PS1>
MeO Me Me MeS(O)2Cl 65–70 <1998PS1>
4.20.2.2.3 From ketene dithioacetals

As discussed in Section 4.20.1.2.(i).(a), bis(alkylthio)alkenes 66 bearing electron-withdrawing
groups (whose synthesis is discussed in Chapter 4.19) can react with phosphorus nucleophiles to
provide the desired products (Equation (36)) <1997TL5201>.
NC SMe
NC SMe 3 equiv. (RO)2P(O)H
2 equiv. NaH/ THF R P(OR)2 ð36Þ
R SMe
3 examples, 91–99% O
66 R = CN, CO2Et
4.20.2.2.4 Functions bearing selenium and tellurium

Midura and Mikolajczyk have synthesized -phosphorylvinyl selenide 68 from sulfoxide precur-
sor 67. Deprotonation of 67 with butyllithium at 78 C provides an anion that could be captured
by phenylselenyl bromide. Subsequent elimination of sulfenic acid upon heating in benzene at
80 C for 4–5 h affords the selenides in high yields (Scheme 12) <1995TL2871>.
Treatment of alkynylphosphonates with organocuprates and subsequent capture of the inter-
mediate vinylcopper compounds with several electrophiles gives the trisubstituted vinylphospho-
nates. When phenylselenyl bromide and phenyltelluryl iodide were used, the corresponding vinyl
selenide 69 and vinyl telluride 70 were obtained (Scheme 13) <1999JOC2950>. In the case of
69, the 1-bromo-substituted phosphonate was obtained in considerable amount as a side product.
O O O O O
(EtO)2P STol i. BuLi/–78 °C (EtO)2P STol ∆ (EtO)2P SePh
ii. PhSeBr PhSe
R R R
3 examples, 72–92%
67 68
Scheme 12
O
PhSeBr (EtO)2P Bun
40%
O PhSe Me
O
(EtO)2P Bun 69
(EtO)2P Bun + Me2CuMgBr2
Cu Me
PhTeI O
(EtO)2P Bun
80%
PhTe Me
70
Scheme 13
As discussed earlier, phosphorylated allenes can be deprotonated with LDA at low tempera-
tures. Quenching of the resulting nucleophile with phenylselenyl bromide affords vinyl selenide 71
<2000PS265> (Equation (37)).
H PhSe
i. LDA, –78 °C •
•
(MeO)2P ii. PhSeCl, –78 °C to rt (MeO)2P ð37Þ
O O
50%
71
4.20.3 FUNCTIONS CONTAINING A CHALCOGEN AND A METALLOID
4.20.3.1.1 Oxygen and silicon or germanium

This class of compounds with general formula 72 are formally the enol ethers of the correspond-
ing acyl silanes 73.
O
R1 OR3
R1
SiR3
R2 SiR3 R2
72 73
(i) Preparation from vinyl ether carbanions

This method is most widely used to generate compounds 74 (Table 14). Nevertheless, access to the
vinylic carbanion can be realized starting from different substrates.
The main method consists of deprotonation of a vinyl ether with an alkyllithium, usually at low
temperatures, and subsequent quenching of the resulting anion with a chlorosilane
<2002JA10101, 2001JOC2842, 1999HCA561, 1999TL5523>. Alternatively, hexamethylcyclotri-
siloxane can be utilized as demonstrated in the last entry of Table 14 <2000OL3221>.
Table 14 Deprotonation of vinyl ethers

R1 OR2 i. Base R1 OR2
H ii. R3MCl MR3
74
R1 R2 Base R3MCl Yield (%) References

t
CH(Bn)(CH2CH2OH) Me Bu Li/0 C Me3SiCl 72 <2002JA10101>
CH2 O
n
N O Bu Li/()-sparteine/0 C Me3SiCl 84 <2001JOC2842>
CH2CH2CH2 ButLi/78 C PriHSiCl 75 <2000OL3221>

CH2CH2 ButLi/78 C PriHSiCl 71 <2000OL3221>
H Bu ButLi/78 C PriHSiCl 72 <2000OL3221>
N
H Et Unspecified Ge 86 <1996JOM(508)255>
Cl
H Et ButLi/78 C ButMe2SiCl 82 <1999HCA561>

OH
Me BunLi/40 C Me3SiCl 62 <1999TL5523>
CH2CH2CH2 ButLi/78 C (Me2SiO)3 68 <2000OL3221>
This method has also been used to prepare the only germanium derivative reported
<1996JOM(508)255>. These results are summarized in Table 14.
As expected, the size of the chlorosilane is of importance in the silylation of a bulky lithium
anion (Equation (38)) <1995T2673>.
i. BuLi/–78 °C SiR3
OAm
ii. R3SiCl OAm
ð38Þ
TMSCl, 69%
TBDMSCl, 0%
The vinyllithium intermediate can also be generated from ,-unsaturated acetals. Thus,
treatment of 1,1-diethoxybut-2-ene with 2 equiv. of Schlösser’s base at 100 C promotes a
1,4-elimination leading to 1-ethoxybuta-1,3-diene (Scheme 14). Further metallation generates
the vinylic anion that reacts with electrophiles <1999S1841>.
OEt BuLi/ButOK, 2 equiv. M TMSCl SiMe3

OEt
OEt THF/–100 °C OEt 80% OEt
Scheme 14
Percy and co-workers <2001TL6377, 1995T10289> and the team of Ishihara and Funabiki
<1998JCS(P1)2413> have generated 76 from 2-fluoroethyl ethers 75. The dehydrofluorination/
metallation step is realized by treating 75 with at least 2 equiv. of base in THF at 78 C and
quenching the intermediate vinyllithium with trimethylsilyl chloride. Results are summarized in
Table 15.
Table 15 Dehydrofluorination/metallation of 2-fluoroethyl ethers
OR OR OR
Base/ THF Rf Rf
TMSCl
RfF2C Li SiMe3
–78 °C
F F
75 76
Rf R Base Yield (%) References

F CONEt2 LDA 69 <1995T10289>
F BunLi 90 <2001TL6377>
OBn
F BunLi 78 <2001TL6377>
F BunLi 90 <2001TL6377>
CHF2 Ts BunLi/DMPU 79 <1998JCS(P1)2413>

CF3 Ts BunLi/DMPU 64 <1998JCS(P1)2413>
Halogen–lithium exchange has also been used to generate the vinylic anion that reacts with
TMSCl to afford the condensation product in 97% yield (Equation (39)) <2000JA9840>.
Me OR i. ButLi, –78 °C Me OR
(R = (–)-menthol)
ii. TMSCl ð39Þ
Br SiMe3
97%
Allenic ethers derived from carbohydrates have also been metallated and the resulting
allenyllithium condensed with TMSCl <2001S1377, 2000TA3131>. One example is given in
Equation (40).
O O O O
O i. BunLi/–50 °C O
O O ð40Þ
ii. TMSCl
O 95% O O
O
H2C C H 2C C
H SiMe3
(ii) Preparation from acyl silanes

The enolization of acyl silanes has been used by several groups. Treatment of acyl silane 77 by
Hünig’s base in the presence of trichlorosilyl triflates (Equation (41)) gives a mixture of (E) and
(Z) enolates <1998JOC9517>.
O Cl3SiOTf/Pr2iNEt OSiCl3
Me Me
PhMe2Si Pentane/0 °C PhMe2Si ð41Þ
44%
77 (Z )/(E ) 9/1
The geometry of the acyl silane silyl enol ether can also be controlled depending on the deprotona-
tion conditions <2002T6815>. Most interesting is the use of the phosphonium diylide prepared from
dibenzyldiphenylphosphonium bromide that gives geometrically pure (E)-isomers (Scheme 15).
OSiMe3
LDA/25 °C TMSCl
R (E )/(Z ) 82–99/1–18
THF/HMPA SiMe3
O + – OSiMe3
Ph3P(CHPh)2 TMSCl (E ) only
R R
SiMe3 THF SiMe3
OSiMe3
LDA/–78 °C TMSCl (E )/(Z ) 10–11/89–90
SiMe3
THF
R
Scheme 15
Another Japanese group reports the thermal isomerization of 1,2-bis[tris(trimethysilyl)silyl-

carbonyl]alkanes 78 <2001JA8400>. The formation of 79 is best explained by assuming the
formation of an intermediate silene, followed by an oxa-Cope rearrangement (Scheme 16).
O OSiMe3 OSiMe3
R1 R1 R1
Si(SiMe3)3 200 °C Si(SiMe3)2 Si(SiMe3)2
Si(SiMe3)3 20 h Si(SiMe3)2 O
R2 R2 R2
O OSiMe3 Si(SiMe3)3
78 79
R1 = R2 = H, 94%
R1 = R2 = (CH2)4, 94%
Scheme 16
(iii) Addition to ynol ethers

Kochetkov and co-workers report the addition of diphenyl(trimethylsilyl)phosphine 80 to alkoxy-
acetylenes 81 <1998IZV1792>. Reacting equimolar amounts of 80 and 81 without solvent gives a
mixture consisting of (E)-(2-alkoxy-2-trimethylsilylalkenyl)phosphine 82, and (Z)-(2-alkoxyalkenyl)-
phosphine 83 in a 5/1 ratio. In the presence of solvents, compound 83 becomes the major product
(Equation (42)).
Heat Ph2P OEt Ph2P OEt

Ph2PSiMe3 + R OEt +
70 °C R SiMe3 R H ð42Þ
80 81 82 83
Denmark and Dixon used Ito’s silastannation procedure to generate compound 85. Thus,
palladium-mediated reaction of ethoxy acetylene with silylstannane 84 gives 85 in 88% yield
(Equation (43)) <1998JOC6167>.
Pd(OAc)2 (6 mol.%) EtO

EtO + ButMe2Si–SnMe3
ButMe2Si SnMe3
NC ð43Þ
84 85
88%
(iv) Addition of silyllithium

Addition of tris(trimethylsilyl)silyllithium to ketenes gives the oxygen anions 86 that rearrange to
silicon-based anion 87. Hydrolysis or quenching with TMSCl gives the corresponding vinyl silanes
in good yields (Scheme 17) <1999JOM(574)50>.
Ph OSiMe3
H2 O
R Si(SiMe3)2
H
Ph Ph O– Li+ Ph OSiMe3 R = Ph, 78%
C O + (Me3Si)3SiLi R = Me, 67%
R R – Si(SiMe )
R Si(SiMe3)3 3 2
Ph OSiMe3
Li+
TMSCl R Si(SiMe3)2
86 87
SiMe3
R = Ph, 74%
R = Me, 69%
Scheme 17
Phenyldimethylsilyllithium adds to cyclobutenone in a 1,2-fashion, followed by immediate ring

opening. The resulting lithium enolate was trapped with acetic anhydride to give 88 (Scheme 18)
<2001JA6441>.
O SiMe2Ph SiMe2Ph SiMe2Ph

THF/–78 °C LiO LiO Ac2O AcO
PhMe2SiLi +
5 min
Ph Ph 87% Ph
Ph
88
Scheme 18
(v) Peterson olefination

Moeller and co-workers used a two-step TPAP oxidation–Peterson olefination to synthesize
silylated enol ethers 90 from alcohols 89 (Equation (44)) <2001T5183>.
OMe
OMe
i. TPAP/NMO R2 R1
R2 R1
ii. (Me3Si)2CHOMe/BunLi R2 ( )n TMS ð44Þ
R2 ( )n
OH –78 °C to rt
OMe
89 90
(vi) Oxidation of a CB bond

Soderquist and León report one example of oxidation of the CB bond of the hydroboration
product of phenyl(trimethylsilyl)alkyne. Oxidation with 2 equiv. of triethylamine N-oxide gives
styrene derivative 91 in 91% yield (Equation (45)) <1998TL3989>.
O
H O B
i. 9-BBN-H
Ph SiMe3 ð45Þ
ii. Me3N-O
Ph SiMe3
91%
91
4.20.3.1.2 Oxygen and boron

Few examples of this system appear in the recent literature. Snieckus and co-workers metallated
dihydropyran derivative 92 and condensed the resulting vinyllithium with trimethyl borate.
Boronic acid derivative 93 was obtained in 90% yield after hydrolysis and was not purified before
use in Suzuki coupling (Equation (46)) <1998JOC1514>.
OCONEt2 OCONEt2
i. ButLi, 4 h, –78 °C
ii. B(OMe)3, 16 h, –78 °C O B(OH)2 ð46Þ
O
92 93
The vinyllithium anion can also be generated by treatment of an allylic acetal with
Schlösser’s base. The butadienyllithium 94 thus obtained is condensed with triisopropyl borate
to give, after hydrolysis, the boronic acid 95. Owing to its instability, 95 was isolated as the
boronate 96 after esterification with pinacol or 2,2-dimethylpropane-1,3-diol (Scheme 19)
<2002OL1275>.
OEt M
i. B(OPr i)3
BunLi/ButOK
OEt OEt ii. H2O
94
O O
B(OH)2 B
HO OH = or
OEt HO OH
OEt OH OH HO OH
95 96
Scheme 19
Finally, one preparation of vinylborinates 98 was reported by Soderquist from B-alkyl

derivatives of 9-BBN 97. Thus, reaction of 97 with -methoxyvinyllithium leads to the
quantitative formation of stable ‘‘ate’’ complexes 98, whose reaction with boron trichloride
gives rise to the formation of the corresponding neutral vinyl borinates (Equation (47))
<1997TL6639>.
OMe
R OMe
B O R
Li R B O Li B O
BCl3
ð47Þ
97 98
6 examples
4.20.3.2 Functions Bearing Sulfur, Selenium, or Tellurium
4.20.3.2.1 Sulfur and silicon or germanium
(i) Condensation by a Peterson reaction

Barton and co-workers prepared the vinylic sulfone 101 by a Peterson olefination <1995AJC407>.
Sulfide 99 is dialkylated with TMSCl and treated with BuLi to give the phenyl bis(trimethylsilyl)-
methyllithium anion, which reacts with formaldehyde to give vinyl sulfide 100. Further oxidation
with MCPBA gives the corresponding sulfone 101 quantitatively (Scheme 20).
i. BunLi/TMSCl SiMe3 i. Bu nLi SPh MCPBA SO2Ph

PhSCH3 PhSH
nLi/TMSCl 99%
ii. Bu SiMe3 ii. HCHO SiMe3 SiMe3
81%, two steps 65%
99 100 101
Scheme 20
(ii) Anion reactions

While -metallation of aryl thioalkenes is usually best realized using 1 equiv. of ButLi or LDA in
THF at 78 C, the group of Cabiddu and Fattuoni employed 2 equiv. of BunLi at 0 C to obtain
the dimetallated product directly <1998T14095>. Thus, the ortho,alpha-dilithiated intermediate
is generated, and can be quenched with chlorotrimethylsilane or dichlorodimethylsilane
(see Scheme 21).
Me3Si
Me3SiCl S
Li 60%
S 2BunLi S SiMe3
Li Me2SiCl2
S
30%
Si
Scheme 21
Allenyl sulfones can similarly be metallated with BuLi at 78 C followed by quenching the
allenyllithium with TMSCl to give the -silylallenyl sulfones (Equation (48)) <1995RTC51>.
R1 H i. Bu nLi, –78 °C R1 SiMe3

C C
ii. TMSCl, –78 °C ð48Þ
R2 SO2Tol R2 SO2Tol
8 examples,
33–100%
Masson and Fromont obtained silylated keteneimines from S-methyl -(trimethylsilyl)ethane-

imidothioate 102. Upon lithiation with 2 equiv. of n-butyllithium at 78 C followed by warming
to 5 C, imidothioester 102 was converted to the silylated ketenimine 103. Reaction with PhSCl
(2 equiv.), PhS(O)Cl (1 equiv.) and the less reactive PhS(O)2Cl gave, respectively, the sulfanyl-,
sulfinyl-, and sulfonyl ketenimines (Scheme 22) <1999T5405>.
The monolithiation has also been performed using MeLi at 78 C to obtain the -silyl
vinylsulfoximine in good-to-excellent yields (Equation (49)) <1996JCS(P1)1673>.
Li
NPh 2BunLi NPh
PhSCl Me3Si
Me3Si Me3Si
SMe –78 °C SMe C NPh
H PhS
102
–78 °C to +5 °C
PhS(O)Cl Me3Si
Me3Si
C NPh
C NPh
Ph(O)S
H
103
+ MeS– Li+ Me3Si

PhS(O)2Cl
C NPh
Ph(O)2S
Scheme 22
Ph O
Ph O i. MeLi/–78 °C S
S TolSO2N R
TolSO2N R ii. TMSCl
SiMe3 ð49Þ
R = Ph, 58%
R = Me, 68%
R = Pr, 98%
Alternatively, -vinyllithium sulfide or sulfone anion can be obtained by a lithium–halogen

exchange reaction. The reaction is realized using either ButLi at 78 C <2001TL3771> or BunLi
at room temperature <1997SL595>. The results are summarized in Table 16.
Table 16 Lithium–halogen exchange
R1 SR2 i. RLi R1 SR2
Br ii. TMSCl SiMe3
R1 R2 RLi Yield (%) References

n
Ph Me Bu Li/rt 60 <1997SL595>
n
C5H11 Me BunLi/rt 71 <1997SL595>
Cyclohexyl Me ButLi/78 C 86 <2001TL3771>
Knochel and co-workers realized the lithium–magnesium exchange of -bromo vinyl sulfone
104 with PriMgBr in THF at 40 C. The vinyl Grignard reagent formed can react with diverse
electrophiles, and gives 82% of the silyl derivative 105 (Scheme 23) <2002T4787>.
SO2Ph SO2Ph SO2Ph

PriMgBr/ THF/–40 °C Me3SiCl
Ph Br Ph MgBr 82% Ph SiMe3
104 105
Scheme 23
Zhong and Guo obtained the zirconocene complex 106 via hydrozirconation of trimethylsilyl
acetylene derivatives. The organometallic compounds further react with sulfinyl chloride in THF
at 40 C to afford the vinyl sulfoxides 107 in high yields (Scheme 24) <2001SC615>.
R SiMe3 R SiMe3
R SiMe3 Cp2Zr(H)Cl R1S(O)Cl
H ZrCp2Cl 6 examples, H S(O)R1
75–84%
106 107
Scheme 24
(iii) Addition to alkynes

One of the simplest ways to access this system involves trimethylsilyl acetylene derivatives as the
starting material. Thus addition of alkyl- or arylsulfenyl chloride to the triple bond gives the
vinylsulfur compounds 108 <1996JOC1817>, that can be further oxidized to the sulfoxide 109
using MCPBA <2001EJO1643>. The results are summarized in Table 17.
Table 17 Addition of sulfenyl chloride to trimethylsilyl acetylenes
CH2Cl2 R1 SiMe3 R1 SiMe3

R1 SiMe3 + R2SCl MCPBA
–78 °C
Cl SR2 Cl SR2
O
108 109

a
Ph Ph 86 <1996JOC1817>
CH3(CH2)5 Ph 95a <1996JOC1817>
TMSO(CH2)3 Ph 91a <1996JOC1817>
Ph TMSCH2CH2 70b <2001EJO1643>
Bun TMSCH2CH2 62b <2001EJO1643>
H TMSCH2CH2 53b <2001EJO1643>
a b
Yield of sulfide. Yield after oxidation (two steps).
Moriarty and co-workers investigated the reactivity of the hypervalent iodine reagent
PhI(SCN)2, prepared in situ from PhICl2 and lead(II) thiocyanate in dichloromethane at 0 C,
with alkynes. In the case of the trimethylsilyl acetylene derivative, the dithiocyanated product 110
was obtained in 91% yield (Equation (50)) <2001TL553>.
PhICl2/Pb(SCN)2 Ph SCN
Ph SiMe3
CH2Cl2/0 °C NCS SiMe3 ð50Þ
91%
110
Titanacyclopentadienes, synthesized from alkynes and titanium tetra-isopropoxide, can react

with benzene disulfide or other sulfur electrophiles. In the case of trimethylsilyl acetylene, reaction
with thiocyanogen affords butadiene 111 in 56% yield, which cyclizes to dithiin 112 upon
treatment with Bun4NF or SmI2 (Scheme 25) <1999AG(E)1604>.
SiMe3 T(OPri)4 (SCN)2

Me3Si Ti SiMe3
PriMgCl PriO OPri
n
Bu4NF or
Me3Si SiMe3 Me3Si SiMe3
NCS SCN SmI2 S S
56%
111 112
Scheme 25
Isobe and co-workers have developed a hydrosilylation of acetylenic compounds in the

presence of platinum(II) <1997T5103> or cobalt(III) complexes <1998TL2609, 1999TL6927>.
The yield is quantitative with the pre-complexed cobalt derivative. The regioselectivity is
extremely high with phenyl thioacetylenes, whereas it is much less selective with other groups
(Equation (51)).
SPh H
O Et3SiH O SiEt3
AcO AcO
Cat.
SPh
AcO AcO
Na2PtCl6 (0.5 mol.%), 75%

ð51Þ
Co2(CO)8 (5 mol.%), 88%
(OC)8Co2
SPh
O
AcO (20 mol.%), 99%
AcO
Two more examples of the addition of sulfide groups to trimethylsilyl acetylene, catalyzed by
transition metal complexes, were reported. The addition of dibutyl disulfide to a terminal alkyne
is catalyzed by RhH(PPh3)4 and trifluoromethanesulfonic acid, no reaction being observed in the
absence of either reagent. The addition is stereoselective, giving the (Z)-isomer <2001OL763>.
Several examples are reported, and in the case of trimethylsilyl acetylene, the addition product is
obtained in 64% yield (Equation (52)).
RhH(PPh3)4/(p-MeOC6H4)3P Me3Si
+ (BunS)2 SBun
Me3Si n ð52Þ
CF3SO3H/acetone reflux SBu
64%
Alkyne can also be carbothiolated with thioesters in the presence of a platinum(0) catalyst. The
reaction takes place in toluene, under reflux, with 5 mol.% of platinum tetrakis(triphenylphos-
phine), whereas no reaction occurs with palladium tetrakis(triphenylphosphine) (Equation (53))
<2001JA5108>.
O Pt(PPh3)4 Me3Si
+ Me3Si Ph
Toluene ð53Þ
p-BrC6H4S Ph p-BrC6H4S
75%
(iv) Elimination reactions

Benzotriazole derivative 113 reacts with hexamethyldisilathiane in the presence of TMSOTf or
cobalt dichloride to afford the corresponding thioacyl silane. The latter can be trapped with
dienes via cycloaddition reactions. In the special case of 113, use of TMSOTf as a Lewis acid gives
a mixture of vinyl sulfides 114 and 115 (Equation (54)) <2000JOC9206>.
Bt SMe (Me3Si)2S Me3Si SiMe3 SiMe3

+
Bu SiMe3 TMSOTf S MeS ð54Þ
113 114 115
Chloroalkyl dithioketals rearrange to -silyl vinyl sulfides when treated with alumina in
refluxing petroleum ether (Equation (55)) <2001TL7779>.
R1S SiMe2R3 SR1

Al2O3/petroleum ether
( )n
R2S ( )n Reflux R3Me2Si SR2
Cl
ð55Þ
R1 = R2 = Me, R3 = Me, n = 1, 95%
R1, R2 = CH2-CH2-CH2, R3 = Me, n = 1, 100%
R1, R2 = CH2-CH2-CH2, R3 = Bu, n = 1, 98%
(v) From epoxides

-Silylepoxystannane 116 is attacked at the -position by lithium phenyl sulfide to give the
intermediate lithium alkoxide 117. Surprisingly, instead of undergoing the Peterson elimination
to give the -stannylated vinyl sulfide, the only product isolated was the -silylated vinyl sulfide
118 resulting from elimination of HOSnBu3 (Scheme 26) <2001TL8993>.
SPh SiMe3
SiMe3 PhS– Li+ H2O
SnBu3 SiMe3
O 0 °C or rt LiO SnBu3 NH4Cl or NaHCO3 SPh
116 117 118
Scheme 26
(vi) From thiirane S-oxide

Schwan and co-workers have shown that thiirane S-oxides 119, when treated with a base, can lead
to the sole formation of elimination products 120 and 121 instead of the possible desulfurization
product <1995JA184, 2000SUL111>. Results are summarized in Table 18.
Table 18 Opening of thiiran S-oxide
1 O O
R3Si i. Base/ THF/–78 °C 1
R3Si S R2 S
S O Bn + Bn
ii. BnBr
R2
R2 R13Si
119 120 121
Yield (%)
R1 R2 Base 120/121 References
Et H LDA 18/49 <1995JA184>
Et H LiN(TMS)2 58/0 <1995JA184>
Et H KN(TMS)2 36/15 <1995JA184>
Ph H LiN(TMS)2 36/0 <1995JA184>
Me Bu LiN(TMS)2 57/0 <1995JA184>
Me2But Bu LiN(TMS)2 54/0 <1995JA184>
Et H MeLi–LiBr 46/23 <2000SUL111>
(vii) From acyl silanes

Bonini and co-workers have reported that acyl silanes containing a hydrogen atom to the
carbonyl can be transformed stereoselectively into (Z)--silyl-enethiols. The thionation is per-
formed at low temperatures with hydrogen sulfide and hydrogen chloride, followed by neutraliza-
tion of the ethereal solution with sodium bicarbonate (Table 19) <1999SL486, 1996T4803,
1996JCS(P1)2803>.
Table 19 Thionation of acyl silanes

O i. H2S / HCl SH
R R
SiMe2Ph ii. NaHCO 3 SiMe2Ph
R Yield (%) References

(CH2)2CO2H 75 <1999SL486>
(CH2)4CO2H 86 <1999SL486>
(CH2)6CO2H 85 <1999SL486>
CH2Cl 87 <1996T4803>
(CH2)2Cl 100 <1996T4803>
(CH2)8Br 100 <1996T4803>
(CH2)10Br 96 <1996T4803>
4.20.3.2.2 Selenium or tellurium together with silicon or germanium

The small number of reported syntheses of these compounds can be divided into two main classes:
addition to substituted alkynes and reaction of selenium-stabilized anions.
(i) Reaction of selenium-stabilized anions

-Bromo vinyl selenides can be treated with BunLi at 0 C to give the intermediate vinyllithium,
which reacts with electrophiles. While the reaction was unsuccessful with TMSCl, (Me3Si)2 reacts
at 65 C (Scheme 27) <1997SL595>.
C5H11 SePh C5H11 SePh (Me3Si)2 C5H11 SePh

BunLi
H Br Hexane H Br H SiMe3
Scheme 27
(ii) Addition to alkynes

The group of Murai and Kato has studied the reaction of selenoamides 122 with organolithium reagents.
While reaction with 2 equiv. of the nucleophile gives the unsymmetrical ketone, reaction with 1 equiv. of
trimethylsilyl acetylide gives the conjugated ketone 123 (Table 20) <1998TL4329, 2001OL1993>.
Table 20 Addition of acetylide to selenoamides

Se
O SeMe
R N + Me3Si Li
R SiMe3
122 123
R Conditions Yield (%) References
i) TMEDA/Et2O, 3 h 78 <1998TL4329>
Me ii) MeI, 3 min
4-MeOC6H4 i) MeOTf, 30 s 72 <2001OL1993>
ii) RLi, 1.5 h
4-BrC6H4 i) MeOTf, 30 s 64 <2001OL1993>
ii) RLi, 1.5 h
Bn i) MeOTf, 30 s 54 <2001OL1993>
ii) RLi, 1.5 h
Carbamotelluroate 124 adds to acetylenes under irradiation. The addition proceeds via forma-
tion of carbamoyl and PhTe radicals formed by homolytic cleavage of the carbamoyl-CTe
bond. The carbamoyl radical adds to the triple bond and the vinylic radical thus formed is
trapped by the tellurium radical (Equation (56)) <2001OL2085>.
O O TePh
+ SiMe3 hν
Me2N TePh Me2N ð56Þ
35% SiMe3
124
Renaud and co-workers have reported examples of radical-mediated [3+2] annulation from
homopropargylic phenyl selenides. The homolytic cleavage of the CSe bond is realized by
irradiation with a sun lamp. The generated radical reacts with methyl acrylate to give a vinylic
radical that couples with the PhSe radical (Equation (57)) <1999EJO477>.
O
O But O
But O SiMe3
+ Sun lamp/80 °C Me
SiMe3
Me CO2Me O ð57Þ
O 79%
SePh SePh
CO2Me
Sonoda and co-workers have shown that the carbotelluration of alkynes could be realized by
photoinduced or radical addition of di-alkyl tellurides on triple bonds. When tellurides having one -But
group are used, the addition is regio- and stereoselective, and gives the vinylic telluride 125 in
62% isolated yield <1998TL5511>. When 2 equiv. of acetylides are used, the divinylic telluride
126 is obtained in 86% yield <1998PS637>.
Me3Si Me3Si SiMe3
Te
But Te But
But But
125 126
Trimethylsilyl acetylenes can also undergo hydrozirconation or hydromagnesiation followed by

metal–selenium exchange to access this system. Thus hydrozirconation of acetylenes yields the
zirconium complexes. Reaction with aryl selenyl bromides at 60 C gives the vinyl selenides in good
yields (Table 21) <1998SC4165>. The same kind of silylated acetylenes are hydromagnesiated with
Grignard reagents in the presence of titanium catalyst. The -silyl vinyl Grignard further reacts with
selenyl bromide to afford the -selenyl vinyl silanes 127 in good yields <2002S1347>.
Table 21 Hydrometallation followed by metal–selenium exchange
R SiMe3 R SiMe3
R SiMe3 “Metal” ArSeBr
H M H SeAr
127
R ‘‘Metal’’ conditions Ar Yield (%) References

C6H13 Cp2Zr(H)Cl THF, rt Ph 85 <1998SC4165>
C6H13 Cp2Zr(H)Cl THF, rt Tolyl 87 <1998SC4165>
CH3OCH2 Cp2Zr(H)Cl THF, rt Ph 80 <1998SC4165>
Ph Cp2Zr(H)Cl THF, rt Ph 81 <1998SC4165>
Bu BuiMgBr/Et2O Cp2TiCl2 (5 mol.%) Ph 81 <2002S1347>
Bu BuiMgBr/Et2O Cp2TiCl2 (5 mol.%) Tolyl 78 <2002S1347>
Hexyl BuiMgBr/Et2O Cp2TiCl2 (5 mol.%) Ph 82 <2002S1347>
Bn BuiMgBr/Et2O Cp2TiCl2 (5 mol.%) Ph 72 <2002S1347>
Bn BuiMgBr/Et2O Cp2TiCl2 (5 mol.%) Tolyl 68 <2002S1347>
4.20.4 FUNCTIONS CONTAINING A CHALCOGEN AND A METAL
4.20.4.1 Oxygen Functions

A wide variety of vinyl ethers bearing a metal at C-1 have been prepared. Some are stable and have
been isolated and characterized. Others are reactive intermediates and have the reactivity and
stability that can be expected for organometallics. This subject was reviewed in the corresponding
section of COFGT (1995), as well as in Friesen’s review <2001JCS(P1)1969> dealing with the
preparation and reactivity of -metallated vinyl ethers, covering the period from 1951 to 1996.
Thus, lithium and tin are the more important metals as described below.
4.20.4.1.1 Lithium
Most of the reactions generating 1-oxyalkenyllithiums have been reported by Kennewell,
Westwood and Westwood in COFGT (1995) <1995COFGT(4)879> and involve either the direct
metallation of a vinyl ether with a strong base at low temperatures or halogen–metal exchange of
-halogenovinyl ethers with butyllithium at 78 C (Scheme 28).
R1 OR RLi R1 OR
Low temperature R2 Li
R2
R1 OR BunLi or ButLi R1 OR
R2 X Low temperature R2 Li
Scheme 28
Nevertheless, a few nonclassical methods are also reported. Percy and co-workers prepared
lithium enol carbamate 129 by dehydrofluorination of 128 as well as by tin–lithium exchange of
vinylstannane 130 (Equations (58) and (59)) <1996TL8233>.
OCONEt2 OCONEt2
LDA 2 equiv./ THF/0 °C
F F
Li ð58Þ
F Inverse addition
F F
128 129
OCONEt2 OCONEt2
BunLi/ THF/–78 °C
F F
SnBu3 Li ð59Þ
F F
130 129
Tius and Harrington prepared lithio allene 131 by deprotonation of the corresponding allene by
butyllithium in THF between 78 C and 30 C <2001JA8509>. This chiral reagent allows high
asymmetric induction in the condensation step.
O O
Li
•
H
H
131
Treatment of crotonaldehyde diethyl acetal with Schlösser’s base at 95 C readily gives the
-metallated 1-ethoxy butadiene (Equation (60)) <2002OL1275>.
OEt BuLi–ButOK Li
ð60Þ
OEt –95 °C OEt
4.20.4.1.2 Tin
The main route to 1-alkoxyvinylstannanes consists of transmetallation with the corresponding
lithium compound. The vinyllithium is obtained by direct metallation or by halogen–lithium
exchange (Table 22).
Table 22 Preparation of 1-trialkylstannyl-1-alkoxyalkanes from vinyllithium
OR1 R3Li OR1 R34SnX OR1
R2 Li SnR34
R2 = H, halogen
Vinyl ether R3Li Tin halide Products Yield (%) References
Me O((–)-menthol) Me O((–)-menthol)
ButLi Me3SnCl 98 <2000JA9840>
Br SnMe3
OEt SnBu3
BunLi- ButOK Bu3SnCl 64 <2001JCS(P1)437>
OEt OEt
O O SnBu3
TIPSO TIPSO
t
Bu Li Bu3SnCl 78 <2001JOM(621)77>
TIPSO TIPSO
OTIPS OTIPS
O O SnBu3
O O
t
Bu Li Bu3SnCl 89 <2001JOM(621)77>
O O
OTIPS OTIPS
O O SnBu3
O O
ButLi Bu3SnCl 33 <2001JOM(624)172>
O O
OTIPS OTIPS
Other routes to these compounds are less versatile. Barbero and Pulido have added tributyl-
stannyllithium to the intermediate ketene 133 obtained from the BHT esters 132 (Scheme 29).
The enolates are further trapped with phenyldimethylchlorosilane to give the -stannylvinyl
ethers 134 in good yields <2001SL827>.
Murai and co-workers have generated stannylmethyllithium by treatment of the corresponding
iodide with ButLi at 50 C in diethyl ether. Exposure to carbon monoxide, followed by quenching
the resulting enolate as a silyl ether resulted in the formation of 135 in good yield (Equation (61))
<1999JOM(574)171>.
O OSiMe2Ph
BuLi R1 i. Bu3SnLi, –78 °C
R1 R1
OBHT • O ii. PhMe2SiCl, –78 °C to rt SnBu3
–78 °C
R2 R2 R2
132 133 134
Scheme 29
R I i. ButLi 2.2 equiv., –50 °C OSiEt3

ii. CO, 1 atm, –78 °C R
SnBu3 SnBu3
iii. Et3SiOTf, –78 °C to rt
ð61Þ
135
R = H, 88%
R = Et, 88%
Vinylstannanes could be prepared by noncatalyzed as well as by palladium-catalyzed carbostanny-

lation of alkynes. Shirakawa and Hiyama reported the palladium-catalyzed stannylation of diverse
alkynes <1999JOM(576)169>. In the case of ethoxyacetylene, the reaction is highly regioselective
(Equation (62)).
Ph
[PdCl(π-C3H5)]2/ligand SnBu3
Ph SnBu3 + EtO ð62Þ
THF/50 °C/5 h
H OEt
55%
Lébl and co-workers have studied the catalyzed and noncatalyzed carbostannylation of alkynes
<2001JOM(625)86>. As summarized in Table 23, the expected -alkoxyvinylstannanes 136 are
obtained as the minor products.
Table 23 Carbostannylation of alkoxyalkynes

R
R OEt
Ph3SnH
+
EtO SnPh3 R SnPh3
OEt
136 137
% %
R Catalyst (136) (137) References
H None 0 100 <2001JOM(625)86>
Bu None 3 80 <2001JOM(625)86>
H Pd(PPh3)4 30 70 <2001JOM(625)86>
Bu Pd(PPh3)4 54 46 <2001JOM(625)86>
Dussault and co-workers have prepared -alkoxyvinylstannane by photooxygenation of allylic

-alkoxystannanes <1999JCS(P1)2189>. Instead of the expected dioxolane, the hydroperoxide
was generated (Equation (63)). Alternatively, the alcohol could be obtained after reduction
(Equation (64)).
OAc O2, sensitizer OOH OAc

ð63Þ
C5H11 SnBu3 42% C5H11 SnBu3
OMOM O2, sensitizer OH SnBu3

ð64Þ
C5H11 SnBu3 39% C5H11 OMOM
4.20.4.1.3 Copper
-Lithiated vinyl ethers can be transmetallated with copper bromide–methyl sulfide complex
(Equation (65)) <2002CC426> or copper cyanide (Equation (66)) <2001JA3369> at low tem-
peratures to give the corresponding vinylcopper that further reacts or rearranges.
2–, 2Li+
R
O Li O Cu R
RLi/CuBr.Me2S ð65Þ
TBSO –40 °C TBSO
OTBS OTBS
O i. ButLi O
ð66Þ
ii. CuCN, LiCl
Br )2CuCNLi2
Alkoxyalkynes can undergo silylcupration. In the case of 138, the product of -addition 139 is
formed exclusively <1997JA125> (Equation (67)).
O O Cu(SiMe2Ph)CNLi2
+ (PhMe 2Si)2CuCNLi2
Ph Ph SiMe2Ph ð67Þ
138 139
Similarly, stannylcupration of alkoxyalkyne 140 leads to the vinylcuprate 141 (Equation (68))
<1997JA3878>.
Bu3Sn Cu-SnBu3
C8H17O + (Bu3Sn)2CuCNLi2
H OC8H17 ð68Þ
140 141
4.20.4.1.4 Transition metals

A number of transition metal complexes are known, with diverse access routes and stabilities. Only
one example of a gold complex prepared and isolated by Raubenheimer and co-workers is highlighted
here (Scheme 30) <2002OM3173>. The Fischer carbene was deprotonated at 78 C and the
resulting vinyl ether condensed with the Ph3PAu+ electrophile. The gold complexes can be purified
by low temperature (15 C) column chromatography. In the case of chromium and tungsten, the
metal can be decoordinated by treatment with a stronger coordinative ligand such as Ph3P.
OR BuLi/ THF OR OR Li+

Ph3PAuCl
(OC)5M (OC)5M (OC)5M
CH3 –78 °C CH2
–
CH2
Li+
AuPPh3
OR –78 °C to rt Ph3PAu OR PPh3 Ph3PAu OR
(OC)5M M(CO)5 Et2O
CH2
M = Cr, Mo, W
Scheme 30
4.20.4.2 Sulfur Functions
4.20.4.2.1 Lithium
As with the oxygen compounds described earlier, most of the methods reported to access these
systems have been reviewed in COFGT (1995) <1995COFGT(4)879> and involve either a direct
metallation of a vinyl sulfide or a halogen–lithium exchange (Scheme 31). These compounds
are only reaction intermediates and are obviously not isolated.
R1 SR RLi R1 SR
Low temperature
R2 R2 Li
R1 SR BunLi or ButLi R1 SR
R2 X Low temperature R2 Li
Scheme 31
Results are summarized in Table 24.
Table 24 -Lithiation of vinylsulfur compounds

Starting material Conditions Product References
Ph SMe Ph SMe
1.5 BuLi, rt <1997SL595>
Br Li
C5H11 SMe C5H11 SMe

1.5 BuLi, rt <1997SL595>
Br Li
S S
2 BuLi, 0 C <1998T14095>
Li Li
TolS
TolS O Li
2 BuLi, 78 C O <1999TL5957>
OH
OLi
BuLi-ButOK Li Li <2000JA5052>
ButS SBut ButS SBut
S ButLi, 78 C S <2001TL3771>
I Li
4.20.4.2.2 Tin
In contrast to the lithium compounds, the tin analogs are stable and isolable compounds.
Surprisingly, the most obvious route to this system (reaction of the -lithiovinyl sulfides described
in the previous section with a stannyl chloride) is seldom used (Equations (69) and (70))
<2001TL3771, 1996JA4284>.
i. ButLi/ THF/–78 °C
SMe SMe ð69Þ
ii. Bu3SnCl
I SnBu3
Bu3SnH, heat SO2CF3

n
C8H13 SO2CF3 n
ð70Þ
25 °C, 98% C8H13 SnBu3
Thus, the main route is the palladium-catalyzed hydrostannylation of alkynes, although non-
catalyzed reactions are reported (Equation (71)) <1995TL3605, 1997JOC6326>. The regioselec-
tivity of this noncatalyzed hydrostannylation implies that the reaction proceeds via conjugate
addition of the hydride.
O
O
Bu3SnH, PhH, rt R S
R S Tol
Tol
SnBu3 ð71Þ
R = H, 88%
R = Bu, 85%, (Z )/(E ) 7.5/1
The palladium-catalyzed hydrostannylation is performed in an apolar solvent (benzene,

toluene) with palladium tetrakis(triphenylphosphine) as the catalyst. The reaction is generally
highly regio- and stereoselective. Results are summarized in Table 25.
Table 25 Palladium-catalyzed hydrostannylation of alkynes
R1 SR2
R33SnH, [Pd(PPh)4]
R1 SR2
SnR33
R1 SR2 R3 (Z)/(E) Yield (%) References
O
SPh Bu 0/1 <1998AG(E)1724>
O
C8Hn13 SO2CF3 Bu 1.7/1 80 <1996JA4284>

C8Hn13 SO2CF3 Ph 1/1.5 82 <1996JA4284>
Ph 0/1 35 <2000JA5052>
ButS SBut
Bu Sp-Tol 0/1 <2002JOC8166>
Shirakawa and co-workers have also reported and studied the mechanism of the palladium-
catalyzed allylstannation of alkynes. The reaction is regioselective both in the allylic and alkynic
moieties (Equation (72)) <2000OL2209>.
SnBu3 Pd2(dba)3 SnBu3

Ph SO2p-Tol + Me
Toluene, 50 °C ð72Þ
Me Ph SO2p-Tol
74%
Hydrozirconation of alkynylstannanes followed by reaction with sulfinyl chloride affords (Z)-

-stannyl unsaturated sulfoxides in good yields with isomeric purities more than 96% (Scheme 32)
<2000JOM(603)249>.
Cp2Zr(H)Cl R SnR13 R2SOCl R SnR13

R SnR13
THF H ZrCp2Cl 9 Examples, H SOR2
63–81%
Scheme 32
4.20.4.2.3 Magnesium
Knochel and co-workers showed that bromine–magnesium exchange in the vinyl sulfone 142 takes
place in THF at 45 C in 1 h, affording the Grignard reagent (Equation (73)) <2002T4787>.
SO2Ph SO2Ph
PriMgBr
THF, –45 °C ð73Þ
Ph Br Ph MgBr
142
4.20.4.2.4 Zinc
Jin and co-workers showed that -bromovinyl sulfides 143 could be metallated with t-butyl-
lithium to form 144, followed by transmetallation with anhydrous zinc chloride to give the zinc
compounds 145 <2002OL691>.
Alkyl SMe
X
143 X = Br
144 X = Li
145 X = ZnCl
4.20.4.3 Selenium Functions

Metallation of the -bromovinyl selenide 146 is realized with n-butyllithium at ambient temperature
(Equation (74)). The resulting vinyllithium is further reacted with electrophiles <1997SL595>.
Br Li
BunLi
R SePh rt R SePh ð74Þ
146 R = Ph, C5H11
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Biographical sketch
Bernard Bessieres was born in 1970. He studied at the University of

Rennes (France), where he obtained his Ph.D. in 1996 under the direc-
tion of Professor M. LeCorre, on the asymmetric synthesis of cyclopro-
pane amino acids. After ten months of military service, he spent one
year in the group of Professor G. Molander, then at the University of
Colorado, Boulder and nine months in the group of André Mann, at the
University of Strasbourg (France). Since September 1999, he is Maiˆtre
de Conferences in chemistry at the Université Joseph Fourier, in Greno-
ble. His scientific interests are in the field of organic synthesis, particu-
larly of boronated compounds and the development of methodology for
accessing such compounds.
4.21
Nitrogen and No Halogen or
Chalcogen
G. L. PATRICK
University of Paisley, Paisley, UK
4.21.1 FUNCTIONS CONTAINING TWO NITROGENS, R32C¼CNR12NR22, etc. 879

4.21.1.1 Ketene Aminals, R32C¼CNR12NR22 879
4.21.1.1.1 From ketene dithioacetals and ketene N,S-acetals 879
4.21.1.1.2 From thioamides, thioureas, and isothioureas 882
4.21.1.1.3 From vinylidene dihalides, ,,-trihaloethanes, and chloro enamines 884
4.21.1.1.4 From -amino--(trihalomethyl)vinyl esters and ketones 886
4.21.1.1.5 From ketene acetals 886
4.21.1.1.6 From imino esters and ketene N,O-acetals 886
4.21.1.1.7 From enamines 888
4.21.1.1.8 From nitriles 889
4.21.1.1.9 From cyanamides 889
4.21.1.1.10 From carbodiimides 890
4.21.1.1.11 From halo alkynes 891
4.21.1.1.12 From ynamines 891
4.21.1.1.13 From acetylides 891
4.21.1.1.14 From enylidene systems 892
4.21.1.1.15 From amidines and amidinium salts 892
4.21.1.1.16 From tricyanomethanide, dicyanoacetates, dicyanothioacetates, and dicyanoacetamides 893
4.21.1.1.17 From amides and other carboxylic acid derivatives 893
4.21.1.1.18 From miscellaneous ‘‘head group’’ synthons 893
4.21.1.1.19 From ring opening of pyrimidines 893
4.21.1.1.20 From ring opening of imidazoles and imidazolidinediones 894
4.21.1.1.21 Miscellaneous syntheses from ring systems 895
4.21.1.1.23 By modification of other ketene aminals 897
4.21.1.1.24 By combinatorial synthesis 907
4.21.1.2 Derivatives of Ketene Aminals 908
4.21.1.2.1 -Amido enamines, R42C¼C(NR12)(NR2COR3), -formamido enamines,
R32C¼C(NR12)(NR2CHO), and -thioamido enamines, R42C¼C(NR12) (NR2CSR3) 908
4.21.1.2.2 -Alkoxycarbonylamino enamines, R32C¼C(NR12)(NHCO2R2) 911
4.21.1.2.3 -Ureido enamines, R32C¼C(NR12)(NHCONR22) 912
4.21.1.2.4 N-Acylated -ureido enamines 912
4.21.1.2.5 gem-Diureido alkenes, R22C¼C(NHCONR12)2 912
4.21.1.2.6 -Thioureido enamines, R32C¼C(NR12)(NHCSNR22), and -isothioureido enamines,
R32C¼C(NR12)(NH(C¼NR2)SR) 912
4.21.1.2.7 -Cyanamino enamines, R22C¼C(NR12)(NHCN) 913
4.21.1.2.8 -Sulfonylamido enamines, R32C¼C(NR12)(NHSO2R2) 913
4.21.1.3 Derivatives Bearing at Least One NRX Function 914
4.21.1.3.1 -Hydrazino enamines, R42C¼C(NR12)(NR2NR32) 914
4.21.1.3.2 gem-Dihydrazino alkenes, R32C¼C(NR1NR22)2 915
877
878 Functions Containing at Least One Nitrogen and No Halogen or Chalcogen
4.21.1.3.3 Derivatives of -hydrazino enamines 915

4.21.1.3.4 -Hydroxylamino enamines and -alkoxyamino enamines, R32C¼C(NR12)(NHOR2) 917
4.21.1.3.5 -Thiophosphoramido enamines, R52C¼C(NR12)(NR2)PO(OR3)(SR4) 918
4.21.1.4 Derivatives Bearing One NY or NZ Function and One NR2 Function 918
4.21.1.4.1 -Alkylideneamino enamines, R32C¼C(NR12)(N¼CR22) 918
4.21.1.4.2 -Aminoalkylideneamino enamines, R42C¼C(NR12)(N¼CR2NR32),
R32C¼C(NR12)(N¼CXNR22) 919
4.21.1.4.3 -Diaminomethyleneamino enamines, R32C¼C(NR12)(N¼C(NR22)2) 920
4.21.1.4.4 -Bis(methylthio)methyleneamino enamines, R22C¼C(NR12)(N¼C(SMe)2) 920
4.21.1.4.5 -Azo enamines, R32C¼C(NR12)(N¼NR2) 920
4.21.1.4.6 -Azido enamines, R22C¼C(NR12)N3 920
4.21.1.4.7 -Isocyano enamines, R22C¼C(NR12)NC 921
4.21.1.4.8 -Phosphimino enamines, R32C¼C(NR12)(N¼PR23) 921
4.21.1.4.9 -(N,N0 ,N0 -Triphenylphosphorimidic triamido) enamines, R2C¼C(NHPh)
(N¼P(NHPh)3) 921
4.21.1.4.10 gem-Amido nitro alkenes, R22C¼C(NR1COPh)(NO2) 921
4.21.1.4.11 gem-Alkoxycarbonylamino nitro alkenes, R32C¼C(NR1CO2R2)(NO2) 922
4.21.1.5 Derivatives Bearing One NY Function and One NRX Function 922
4.21.1.5.1 gem-Acylhydrazino azido alkenes, R22C¼C(NHNHCOR1)N3 922
4.21.1.6 Derivatives Bearing Two NY Functions 922
4.21.1.6.1 gem-Alkylideneamino isocyanato alkenes, R22C¼C(NCO)(N¼CR12) 922
4.21.1.6.2 gem-Dithioureido alkenes 922
4.21.1.6.3 gem-Bisazo alkenes, R22C¼C(N¼NR1)2 922
4.21.1.6.4 gem-Azido phosphazido alkenes, R2C¼C(N¼N–N¼PPh3)N3 922
4.21.1.6.5 gem-Diazido alkenes, R2C¼C(N3)2 923
4.21.1.6.6 gem-Dinitro alkenes, R2C¼C(NO2)2 923
4.21.1.6.7 gem-Arylazo nitro alkenes, R2C¼C(NO2)2(N¼NAr) 924
4.21.1.6.8 gem-Aminoalkylideneamino nitro alkenes, R32C¼C(NO2)2(N¼CR1NR22) 924
4.21.1.6.9 gem-Dimethoxazonyl alkenes, R2C¼C(NO¼NOMe)2 924
4.21.1.6.10 gem-Imino phosphimino alkenes, R32C¼C(N¼PR13)(N¼CR22) 924
4.21.1.6.11 gem-Diphosphazido alkenes and gem-diphosphimino alkenes, R22C¼C(N¼NN¼PR13)2,
R22C¼C(N¼PR13)2 924
4.21.1.6.12 gem-Disulfoximido alkenes, R22C¼C(N¼SOR12)2 924
4.21.2 FUNCTIONS CONTAINING ONE NITROGEN AND ONE PHOSPHORUS,
R32C¼CNR12PO(OR2)2, R32C¼CNR12PR22, etc. 925
4.21.2.1 Derivatives Bearing a Phosphino Function 925
4.21.2.1.1 -Phosphino enamines, R22C¼C(PPh2)NHR1 925
4.21.2.1.2 gem-Amido phosphino alkenes, R32C¼C(NHCOR1)PR22 925
4.21.2.2 Derivatives Bearing a Phosphonium Group 925
4.21.2.2.1 -Trialkylphosphonio enamines, R32C¼C(NR12)P+R23 925
4.21.2.2.2 gem-Carboxyamino phosphonio alkenes and gem-chlorocarbonylamino phosphonio alkenes,
R2C¼C(NHCO2H)P+Ph3 and R2C¼C(NHCOCl)P+Ph3 926
4.21.2.2.3 gem-Amido phosphonio alkenes, R22C¼C(NHCOR1)P+Ph3 926
4.21.2.2.4 gem-Alkoxycarbonylamino phosphonio alkenes, R22C¼C(NHCO2R1)P+Ph3 928
4.21.2.2.5 gem-Phosphonio ureido alkenes, R22C¼C(NHCONR12)P+Ph3 928
4.21.2.2.6 gem-Arylchloromethyleneamino phosphonio alkenes, R22C¼C(N¼C(Cl)Ar)P+R13 928
4.21.2.2.7 gem-Aminochloromethyleneamino phosphonio alkenes, R32C¼C(N¼C(Cl)NR12)P+R23 928
4.21.2.2.8 gem-Phosphonio tetrazol-1-yl alkenes 928
4.21.2.3 Derivatives Bearing a Metallophosphino Function 929
4.21.2.3.1 -Metallophosphino enamine 929
4.21.2.4 Derivatives Bearing a PPhX Group 929
4.21.2.4.1 Enamine derivatives bearing a PPhNHN¼CR2 group 929
4.21.2.4.2 Enamine derivatives bearing a PR1PR2NR32 group 929
4.21.2.5 Derivatives Bearing a Phosphinoyl or Thiophosphinoyl Group 930
4.21.2.5.1 -Phosphinoylenamines, R32C¼C(NR12)POR22 930
4.21.2.5.2 gem-Amido diphenylphosphinoyl alkenes, R22C¼C(NHCOR1)POPh2 930
4.21.2.5.3 gem-Methoxycarbonylamino diphenylphosphinoyl alkenes and gem-alkoxycarbonylamino
diphenylphosphinoyl alkenes, R22C¼C(NHCO2R1)POPh2 930
4.21.2.5.4 gem-Diphenylphosphinoyl ureido alkenes, R22C¼C(NHCONR12)POPh2 931
4.21.2.5.5 -Thiophosphinoylenamines, R32C¼C(NR12)P(¼S)R22 931
4.21.2.5.6 Derivatives bearing a diphenylphosphinoyl group and an N¼C(X)Ar group,
Cl2C¼C(N¼C(X)Ar)POPh2 931
4.21.2.6 Derivatives Bearing a Phosphonyl Group, POXR 931
4.21.2.6.1 gem-Amido phosphonoyl alkenes, R32C¼C(NHCOR1)POXR2 931
4.21.2.6.2 gem-Phosphonoyl ureido alkenes 932
4.21.2.7 Derivatives Containing a Dialkoxy Phosphoryl Group 932
4.21.2.7.1 -Phosphorylenamines, R32C¼C(NR12)PO(OR2)2 932
4.21.2.7.2 gem-Formamido phosphoryl alkenes, R22C¼C(NHCHO)PO(OR1)2 935
4.21.2.7.3 gem-Amido phosphoryl alkenes, R32C¼C(NHCOR1)PO(OR2)2 935
4.21.2.7.4 gem-Alkoxycarbonylamino phosphoryl alkenes, R32C¼C(NHCO2R1)PO(OR2)2 938
4.21.2.7.5 gem-Phosphoryl ureido alkenes, R32C¼C(NHCONR12)PO(OR2)2 939
4.21.2.7.6 gem-Diphenylphosphinoylamino phosphoryl alkenes, R22C¼C(NHPOPh2)PO(OR1)2 939
4.21.2.7.7 gem-Phosphorylamino phosphoryl alkenes, R42C¼C[NR2PO(OR3)2][PO(OR1)2] 939
Functions Containing at Least One Nitrogen and No Halogen or Chalcogen 879
4.21.2.7.8 gem-N-Phosphorylamido phosphoryl alkenes, R42C¼C[N(COR1)PO(OR2)2][PO(OR3)2] 940

4.21.2.7.9 gem-Alkylideneamino phosphoryl alkenes, R32C¼C(N¼CR12)PO(OR2)2 940
4.21.2.7.10 gem-Alkylideneamino phosphoryl alkenes bearing a heteroatom X at the vinyl position,
R32C¼C(N¼CXR1)PO(OR2)2, R22C¼C(N¼CX2)PO(OR1)2 941
4.21.2.7.11 gem-Isocyano phosphoryl alkenes, R22C¼C(NC)PO(OR1)2 942
4.21.2.7.12 gem-Isocyanato phosphoryl alkenes, R22C¼C(N¼C¼O)PO(OR1)2 942
4.21.2.8 Derivatives Bearing a PS(OR)2, PO(OR1)(NR22), POX2, or PO(OR1)(SR2) Group 943
4.21.2.8.1 -Thiophosphorylenamines 943
4.21.2.8.2 gem-Amido phosphoramidoyl alkenes, Cl2C¼C(NHCOPh)PO(OMe)(NR2) 943
4.21.2.8.3 gem-Phosphoramidoyl ureido alkenes, R42C¼C(NHCONR1R2)PO(OR3)NR1R2 943
4.21.2.8.4 -Phosphorodiamidoylenamines, R32C¼C(NR12)PO(NR2)2 943
4.21.2.8.5 gem-Amido phosphorodiamidoylalkenes, R32C¼C(NRCOR1)PO(NR2)2 943
4.21.2.8.6 gem-Alkoxycarbonylamino phosphorodiamidoyl alkenes, R42C¼C(NR1CO2R2)PO(NR3)2 943
4.21.2.8.7 gem-Phosphorodiamidoyl ureido alkenes, R2C¼C(NHCONHAr)PO(NHAr)2 944
4.21.2.8.8 gem-Aminobenzylideneamino phosphorodiamidoyl alkenes,
R22C¼C(N¼C(NR12)Ph)PO(NR12)2 944
4.21.2.8.9 gem-Difluorophosphoryl ureido alkenes 944
4.21.2.8.10 gem-Arylchloromethyleneamino dichlorophosphoryl alkenes,
R2C¼C(N¼C(Cl)Ar)POCl2 944
4.21.2.8.11 gem-Dihalophosphoryl isocyanato alkenes, R2C¼C(NCO)POX1X2 944
4.21.3 FUNCTIONS CONTAINING ONE NITROGEN AND ONE METALLOID,
R32C¼CNR12SiR23, etc. 944
4.21.3.1 Nitrogen and Silicon Derivatives, R32C¼CNR12SiR23 944
4.21.3.1.1 -Silylenamines 944
4.21.3.1.2 gem-Isocyanosilyl alkenes 946
4.21.3.1.3 gem-Isothiocyanato silyl alkene 946
4.21.3.1.4 gem-Aminoborylamino silyl alkenes, PrCH¼C(TMS)N(R)B(X)NMe2 946
4.21.3.1.5 gem-Amidosilylalkenes, PhCH¼C(TMS)NHCOR 946
4.21.3.1.6 gem-Lithioamino silyl alkenes, RCH¼C(TMS)NLiAr 946
4.21.3.1.7 gem-Diazonium silyl alkenes, R22C¼C(SiR13)N+2 947
4.21.3.2 Nitrogen and Boron Derivatives, R32C¼CNR12BR22 947
4.21.4 FUNCTIONS CONTAINING ONE NITROGEN AND ONE METAL, R22C¼CNR12M, etc. 947
4.21.4.1 Group 1 and 2 Metals, R22C¼CNR12Li, etc. 947
4.21.4.2 Transition Metals, R22C¼C(NR12)PdX, etc. 947
4.21.4.2.1 Palladium and platinum 947
4.21.4.2.2 Copper 948
4.21.4.2.3 Chromium, molybdenum, and tungsten 948
4.21.4.2.4 Manganese 949
4.21.4.2.5 Iron 950
4.21.4.2.6 Rhenium 950
4.21.4.3 Other Metals 950
4.21.4.3.1 Tin 950
4.21.1 FUNCTIONS CONTAINING TWO NITROGENS, R32C¼CNR12NR22, etc.
4.21.1.1 Ketene Aminals, R32C¼CNR12NR22

Ketene aminals 2 are tautomeric with amidines but are less stable. Therefore, ketene aminals
reported in the literature either contain stabilizing electron-withdrawing groups at the -position
or contain tertiary amino groups that prevent the formation of the amidine tautomer. Ketene
aminals of the former type often have low energy barriers to rotation about the formal double
bond such that geometrical isomerism is not observed unless other factors such as intramolecular
hydrogen bonding are present. A large variety of methods have been reported for the synthesis of
ketene aminals <1995COFGT(4)967>. Several of these have continued to be used since the 1990s
in particular the use of ketene dithioacetals or ketene N,S-acetals.
4.21.1.1.1 From ketene dithioacetals and ketene N,S-acetals

The reaction of ketene dithioacetals 1 with two or more equivalents of amine remains a popular
method for the synthesis of ketene aminals 2 (Equation (1)) <2000MI307, 1994JPR357,
1983EUP0092647, 1997HCA273, 1988EUP0286153>.
X1 SMe HNR1R2 X1 NR1R2
X2 SMe X2 NR1R2 ð1Þ

1 2
The reaction rate depends on the strength of the electron-withdrawing group(s) at the
-position as well as the strength of the attacking amine. Ketene dithioacetals bearing two ester
groups, e.g., 3, do not normally react with amines. However, the 5-bis(methylthio)methylene
derivative of Meldrum’s acid 4 reacts with 2 equiv. of 2,2-dimethylpropylamine to give the ketene
aminal 5 <2002JOC2619>.
Mixed ketene aminals are obtained by reacting ketene dithioacetals with 1 equiv. of an amine,
isolating the intermediate ketene N,S-acetal 6, then substituting the second alkylthio group with a
different amine <2003USP6525069, 2002JOC2619, 1999MI93, 1999JMC1235, 1995BMC279,
1997HCA273, 1993EUP547517, 1994EUP591891, 1996USP5521177, 1988EUP0286153,
1992JMC2327>. In certain cases, the second substitution may prove difficult and it is necessary
to oxidize the ketene N,S-acetal prior to the second substitution <1993EUP547517,
1994EUP591891, 1996USP5521177>. For example, reaction of the ketene N,S-acetal 7 with
t-butylamine proved unsuccessful. Prior oxidation of the ketene N,S-acetal with m-chloroperben-
zoic acid, then reaction with t-butylamine was more successful giving the desired ketene aminal 8
in 43% yield <1999JMC1235>. Mercuric oxide and mercuric chloride have also been used in the
reaction of a ketene N,S-acetal with an amine to aid the second substitution <1997JOC4240>.
Mixed ketene aminals containing a -nitro group are obtained from the ketene dithioacetal 9
and are of particular interest to the pharmaceutical industry. The histamine antagonist agent
ranitidine 10 has been used for many years as an antiulcer agent and can be synthesized by a
variety of ways using the ketene dithioacetal 9 (e.g., <1996EUP0697411, 1997USP5696275>).
One of these methods involves the intermediate 11 which can in turn be synthesized from 9
<1993PHA143>.
An interesting alternative approach to the synthesis of ranitidine and nizatidine 15 has been the
use of the thiazolidine 12, which can also be viewed as a ketene N,S-acetal. Treatment of 12 with
methylamine results in the formation of the thiol 11, which can be alkylated in situ with the alkyl
halides 13 or 14 to give ranitidine or nizatidine, respectively <1998WOP9811081,
1997USP5672724>.
O O
X1 SMe O SMe O NHCH2But NR1R2
X1
X2 SMe O SMe O NHCH2But X2 SMe
3 (X1 = X2 = CO2Me) O O
4 5 6
9 (X1 = H; X2 = NO2)
1 = H; X2 = COMe)
21 (X
24 (X1 = ArCO; X2 = CHO)
NC CN NC CN
N But N O2N NHMe2.Cl

MeS N N N
H H H S
MeHN N O
H
CO2Me CO2Me
7 8 10
O2N CHNO2 X
N
SH HN S Me2N X Me2N
MeHN N
O S
H
11 12 13 14
The ketene dithioacetal route has been used to introduce the -nitroketene aminal moiety into other
structures with a variety of pharmacological activities including histamine antagonists <1998MI187,
1998MI177, 1994AP455, 1996AP87, 1995AP349, 1994MI308, 1994JMC57, 1996USP5541335,
1992CPB2432>, structures having dual histamine H2 and gastrin receptor antagonist activity
<1997CPB116>, adrenoreceptor antagonists <1994AP661>, 3 adrenergic receptor agonists
<2001BMC379, 2001BRP2356196>, acetylcholinesterase inhibitors <1994JMC689, 1992JMC1102>,
structures having potassium ion channel opening activity <1992JMC2327, 1999WOP9958497,
1993BMC999>, analgesics <1993JMC2373>, and insecticides <1997MI7, 1994MI119, 1993MI31,
1993MI41, 1989USP4806553, 1995EUP0649845, 1988EUP0302389>. The ranitidine dimer 16 has
also been synthesized <1997BMC3045>.
The ketene diothioacetal 9 has also been treated with ammonia to synthesize the ketene aminal
17 as an important synthetic intermediate for heterocycles. The yield was 45%, but optimization
of the reaction conditions improved the yield to 77% by increasing pressure and lowering the
temperature of the reaction <1997C280>.
A general disadvantage in using reagent 9 is the fact that the substitution reactions with amines
produce volatile and bad smelling methylmercaptans (MeSH). To address this problem, the
ketene dithioacetal reagent 18 has been successfully used in the synthesis of ranitidine and
ranitidine analogs <1995PHA12>. An alternative method of avoiding the release of methanethiol
into the atmosphere has been reported, whereby the ketene N,S-acetal 19 was treated with silver
nitrate to form the keteneimine 20 with precipitation of silver methylmercaptide. The ketenimine
was then treated in situ with methylamine to give ranitidine in high yield <1986BRP2169600>.
O2N NO2
S CHNO2
Me2N Me Me
S S N S
N N NHMe MeHN N O O N NHMe
H H H
15 Cl–
16
NO2
H NH2 H SCH2Ph
Me2N S
O 2N NH2 O2N SCH2Ph O N SMe
H
17 18 19
Me2N S N C CHNO2
O
20
Intermediary ketene N,S-acetals can be obtained in better purity and yield using lithiated amino
salts without the problem of ketene aminals being present as a result of disubstitution
<2000JOC1583>. For example, heating the -oxoketene dithioacetal 21 with aniline resulted in a
mixture of starting material, ketene N,S-acetal, and ketene aminal, which was difficult to separate. In
contrast, the reaction proceeded in 80–90% yield at room temperature using the lithio salt of aniline.
Lithiated amino salts have also proved advantageous in the synthesis of mixed ketene aminals from
ketene N,S-acetals, and in the synthesis of ketene aminals 2. DBU has also been used to advantage in
the synthesis of ketene N,S-acetals from ketene dithioacetals and amines <1995BMC279>.
Reaction of ketene dithioacetals with diamines gives ketene aminals containing a diaza hetero-
cyclic ring 22 <2000MI307, 1995PS87, 1994BMC1107, 1997MI7>. An alternative method of produ-
cing such compounds via the mixed ketene aminal 23 has also been described <1995BMC279>.
The reaction of ketene dithioacetals bearing an aldehyde group at the -position 24 has been
studied under various conditions <1995PS87>. The nature of the solvent, the amine, the level of
amine present, and the experimental conditions determines the selectivity of the reaction. Reac-
tion at the acetal carbon forms ketene aminals or ketene N,S-acetals, and is under thermodynamic
control, whereas reaction at the aldehyde group to form imines is under kinetic control. In
general, more basic nucleophilic aliphatic amines are sufficiently reactive to overcome the
high-energy barrier to acetal attack, especially if the reaction is carried out over long time periods
or with a high-enough temperature. With more weakly basic amines such as aromatic amines, the
imine is formed, possibly reversibly. However, under vigorous conditions such as refluxing DMF,
aromatic amines react at the acetal carbon.
The reaction of isothiocyanates with active methylene compounds, followed by reaction with an
alkyl halide, is an alternative method of generating ketene N,S-acetals, which can then be converted
to ketene aminals on reaction with amines (Scheme 1) <2000WOP027805, 1995EUP760362>.
R1
X1 N NC NHR1
Y
X2 N NC N OH
H
R2
22 23
R1NCS X NHR1 RX X NHR1 R2R3NH X NHR1

X Y
Base
Y S– Y SR Y NR2R3
Scheme 1
This procedure has advantages over using a ketene dithioacetal. For example, ketene N,S-acetal
(6; X1 = H, X2 = NO2, NR1R2 = NHMe) is an important intermediate in the synthesis of
histamine antagonists such as ranitidine and nizatidine. Its synthesis from the ketene dithioacetal
9 results in a product that is contaminated with starting material and the ketene aminal 25. Better
results are obtained via the isothiocyanate route, using methyl isothiocyanate and the carbanion
of nitromethane. The reaction has been optimized such that it is suitable for large-scale prepara-
tions. The preferred solvent is dimethyl sulfoxide with a co-solvent such as water. A metal
alkoxide is preferred as base and the intermediate 26 can be methylated in situ with methyl iodide
or dimethyl sulfate to give the required ketene N,S-acetal 24 in 66% yield <1985BRP2160204>.
4.21.1.1.2 From thioamides, thioureas, and isothioureas

Ketene aminals have been synthesized from isothiocyanates via thioamides (Scheme 2)
<1998WOP9850344>. The reaction of the thioamide with amines was carried out in the presence
of a desulfurizing agent, for instance mercuric oxide or N-ethyl-N0 -(3-dimethylaminopropyl)car-
bodiimide hydrochloride (EDC, a water-soluble carbodiimide). This method has also been used in
the development of a combinatorial synthesis of ketene aminals (see Section 4.21.1.1.24).
X
O2NHC
Y
9 (X = Y = SMe)
25 (X = Y = NHMe)
26 (X = S– ; Y = NHMe)
R1NCS Z NHR1 R2R3NH Z NHR1

Z CN
NEt3 EDC or
NC S NC NR2R3
HgO
Scheme 2
In the above reaction sequence, an isothiocyanate was reacted with an active methylene
compound to give a thioamide that was subsequently treated with the second amine. Alterna-
tively, the isothiocyanate can be treated first with the amine and the active methylene compound
added later. Thus, reaction of an isothiocyanate with an amine gives a thiourea, which can then
be alkylated to an isothiourea. Reaction of the isothiourea with an active methylene compound

such as nitromethane then gives the ketene aminal (Scheme 3) <1988EUP0302389>.
R3-NCS S MeI SMe CH3NO2 CHNO2

NHR1R2
2R1N
R NHR3 R2R1N NR 3
R2R1N NHR3
Scheme 3
This method has been used in the synthesis of a series of structures 27 having insecticidal
activity <1994MI119, 1993MI41, 1993MI31>.
An alternative method of obtaining the required isothiourea intermediate is demonstrated in
the synthesis of nizatidine 15 illustrated in Scheme 4 <1984BRP2134521>, whereby the amine 28
is treated with reagent 29 to give the isothiourea 30.
CHNO2
X (CH2)n N3 NHR1
R
N
27
S
NH2 N NMe
Me2N N S Me2N HN 15
SMe S SMe CH3NO2
S 2-butanol
28 MeN SMe 30
29
Scheme 4
Treatment of the thiourea 31 with methyl iodide generates N,N,N0 N0 -tetramethylmethylthio-

formamidinium iodide 32, which reacts with the carbanions of active methylene compounds to
give ketene aminals 33 (Scheme 5) <1995COFGT(4)967>. Similar starting materials have been
used for the synthesis of diaza heterocyclic ketene aminals, but despite the fact that these methods
were useful in synthesizing ketene aminals containing ester groups at the -position, they have not
been used in the 1990s.
X1
+ CH– Na+
Me2N NMe2 MeI Me2N NMe2·I– X2 X1 NMe2
C C + MeSH + NaI
S SMe X2 NMe2
31 32 33
Scheme 5
It has been found that heating tetramethylthiuram disulfide 34 with the ylide 35 resulted in
decomposition of the disulfide to form the thiourea 31, which then reacted with the ylide to form
the ketene aminal 36 in 33% yield (Scheme 6) <1993T6411>. However, this reaction was not
observed with ylides bearing an ester group.
+ –
Ph3P CHCN NC NMe2
Me2N S S NMe2 ∆ Me2N NMe2 35
C C
S S S H NMe2
34 31 36
Scheme 6
4.21.1.1.3 From vinylidene dihalides, a,a,a-trihaloethanes, and chloro enamines

The reaction of amines with vinylidene dichlorides 37 is another popular method of synthesizing
ketene aminals <1995COFGT(4)967, 1994CB2013, 1993MM916, 1994JPR29, 1993ZOR885,
1995ZOR1816, 1997ZOR1715, 1999ZOR1809>. Vinylidene dihalides have an advantage over
ketene dithioacetals in that they are more reactive to amine substitution, allowing the synthesis
of ketene aminals containing -substituents that are weakly electron withdrawing. Normally,
4 equiv. of amine are used since 2 equiv. are required to neutralize the 2 equiv. of hydrogen
chloride released in the reaction. However, it is possible to use 2 equiv. of the amine if 2 equiv.
of a tertiary amine (e.g., triethylamine) are added. Alternatively, sodium hydroxide can be used.
Thus, reaction of the vinylidene dichloride 37; X1 = X2 = CN with 2 equiv. of hexamethylene-
diamine in the presence of 2 equiv. of sodium hydroxide successfully resulted in the formation of
the first example of an aliphatic poly(enamino nitrile) 38. Similar attempts to synthesize the
polymer 39 were less successful. This was attributed to the weaker nucleophilic nature of the
aromatic diamine 40 <1993MM916>.
Reaction of vinylidene dichlorides with diamines gives ketene aminals containing a diaza
heterocyclic ring 41 <1995COFGT(4)967, 2000ZOR676>.
Under carefully controlled conditions, it is possible to synthesize the intermediate chloro
enamine intermediate, then react it with a different amine to produce a mixed ketene aminal
<1995COFGT(4)967, 1990EUP0381130, 1993MI41>. It is possible to carry out this synthesis
without isolating the intermediate chloro enamine. For example, 1,1-dichloro-2-nitroethene (37:
X1 = H; X2 = NO2) was treated with an equivalent of amine in the presence of triethylamine or
sodium carbonate to give the chloro enamine 42. This was then treated in situ with an excess of a
second amine to give the mixed ketene aminal 43 <1990EUP0381130>. In the same publication,
it was shown that identical products could be obtained using 1,1,1-trichloro-2-nitroethane 44 as
reagent and generating the vinylidene dichloride in situ by dehydrohalogenation with a base. The
amines could then be added in either order.
The selectivity of the substitution reaction for the vinylidene dihalide over halides at other
positions has been demonstrated <1997ZOR1715, 1996CJC2331>. For example, the reaction
of trichloroethylene 45 with lithium diethylamide/diethylamine under mild conditions gave the
mono-substituted chloro enamine 46. Further reaction with excess diethylamine and heating
gave the ketene aminal 47 <1996CJC2331>. Reaction of the chlorinated butadiene 48 with
aliphatic amines gave the ketene aminal 49 where only the gem-vinylidene halides were
substituted, while reaction with less basic aromatic amines gave ketene aminals 50
<2000ZOR676>. It is known that the ¼CCl2 group is a hard electrophilic center. Thus,
hard nucleophiles such as aliphatic amines preferentially attack the ¼CCl2 group while softer
nucleophiles such as aromatic amines are capable of reacting at the soft electrophilic center
(¼CCl) as well.
NC CN NC CN
X1 Cl O
X2 Cl N NH O
NH NH (CH2)6– H2N NH2
n H
37 38 n 40
39
Et Het Et Het
H Cl NO2
N N
X1 N Cl
(CH2)n Cl
X2 N O2N Cl O2N NRMe
H
41 42 43 44
Cl NEt2 NEt2 O2N Cl O2N NR1R2 O2N NHAr

Cl
Cl Cl Cl Cl NEt2 O2N (Cl)C Cl O2N (Cl)C NR1R2 O2N (Cl)C NHAr
Cl Cl NHAr
45 46 47 48 49 50
Chloro enamines can be generated from starting materials other than vinylidene dichlorides,
then converted to ketene aminals. For example, amides can be treated with phosgene to produce
chloro enamines, which are subsequently converted to mixed ketene aminals
<1995COFGT(4)967>. This method allows the synthesis of mixed ketene aminals without
electron-withdrawing substituents at the -position. Other halogenating agents have also been
used such as phosphorus pentachloride or thionyl chloride in an aprotic solvent. A base such as
pyridine or triethylamine is present to trap the by-product HCl <1988EUP0302389>.
An alternative method of generating chloro enamines is to react activated methylene
groups with N,N-dimethyldichloromethyleneaminium chloride 51 in the presence of
triethylamine. The chloro enamines 52 obtained can then be converted to mixed ketene aminals
where one of the amino functions must be the dimethylamino group (Scheme 7) <1993BSB129,
1993JCS(P2)911>.
Me2N Me2N X
Me + Cl X Et3N X R1R2NH
N C + C C C C
Cl Cl Y R2R1N Y
Me Y
51 52
Scheme 7
When X and Y are strongly electron withdrawing (e.g., CN), the chloro enamine is formed
easily. With weaker electron-withdrawing groups such as esters, the presence of triethylamine is
required along with stronger reaction conditions. This also holds true for vinylogous structures.
Thus, alkylidenemalononitriles 53 and alkylidenecyanoacetates 54 reacted with 51 in the presence
of triethylamine to give the (Z)-isomer of the -chlorodienamines 55 and 56, respectively, whereas
alkylidenemalonates 57 failed to react. Reaction of the -chlorodienamine 58 with secondary
amines resulted in the formation of ‘‘push–pull’’ dienes 59 with inversion of configuration.
Reaction of 58 with 1,2-bis(methylamino)-ethane resulted in substitution of both the chloro and
the dimethylamino groups to give the heterocyclic diene 60.
R1 X Me CN Me CN Me Me CN
R1 X
Cl Cl Me2N N
Y CN CN CN
Me Y N
R2N H Me2N H R2N H H
Me
53 (X = Y = CN) 55 (X = Y = CN) 58 59 60
54 (X = CN; Y = CO2Et) 56 (X = CN; Y = CO2Et)
57 (X = Y = CO2Et)
Normally, vinylidene chlorides or chloro enamines are used for the synthesis of ketene aminals,
but other vinylidene dihalides have been reported as starting materials <1995COFGT(4)967>.
The reactions of the vinylidene difluoride 61 with various nucleophiles have been studied
<1994T11637>. Reaction with 4 equiv. of aniline gave the ketene aminal 62 in 88% yield. The
mixed ketene aminal 63 was also prepared by reacting the difluoride with 2 equiv. of diethylamine,
then 2 equiv. of aniline. Using 2 equiv. of amine was found to be superior to using 1 equiv.
of amine in the presence of a base such as n-butyllithium or triethylamine.
It has also been reported that reaction of the phenyl trifluoroethyl ether 64 with 3 equiv. of
lithium diethylamide afforded the ketene aminal 65 in 28% yield, presumably via a vinylidene
difluoride <1995HAC45>.
Treatment of the vinylidene dibromide 66 with amines using water as a solvent can give amides
67, ketene aminals 68, or amidines 69 depending on the amine used <2002T9925>.
The mixed vinylidene dihalide 70 was treated with 5 equiv. of primary amine to give the ketene
aminals 71 in 53–61% yield <1995ZOR1816>.
O O PhO F PhO NEt2

Ph F Ph NR1R2 F
F H NEt2
Bun F Bun NR3R4
61 1 = R3 = H; 65
62 (R R2 = R4 = Ph) 64
63 (R1 = H; R2 = Ph; R3 = R4 = Et)
Br NR1R2 NR1R2 NHR
Br O NR1R2 NR
O2N O2N O2N O2N
66 67 68 69
Cl RN NHR
OHC(Cl)C
Br Cl NHR
70 71
4.21.1.1.4 From b-amino-b-(trihalomethyl)vinyl esters and ketones

Reaction of -amino--(trichloromethyl)vinyl esters 72 with primary amines resulted in replace-
ment of the trichloromethyl group to form ketene aminals 73. Similar results were obtained using
the starting materials 74a–74c <1965JPR239>. The reaction of the vinyl ester 72 with ethylene-
diamine gave the bis-adduct 75. In contrast, the reaction of vinyl aliphatic ketones 76 with
ethylenediamine led to substitution of both the trichloromethyl and amino groups to give
imidazolidines 77 <2000IZV1245, 1999MC206>. The reaction was found to be slow at room
temperature with poor-to-moderate yields. However, the experimental conditions were not opti-
mized. In contrast, similar reactions carried out on aliphatic -amino--(trifluoromethyl) vinyl
ketones 78 gave diazepines 79 or imidazolidines 80 where substitution of the trifluoromethyl
group did not take place <1998IZV2305>.
4.21.1.1.5 From ketene acetals

Ketene acetals can be converted to ketene aminals <1995COFGT(4)967>. However, the method
offers no advantages over the use of ketene dithioacetals or vinylidene dihalides since the ketene
acetals are less reactive. As a result, there have been no reports of ketene acetals being used in the
synthesis of ketene aminals since the 1990s.
4.21.1.1.6 From imino esters and ketene N,O-acetals

Imino esters and their salts are tautomers of ketene N,O-acetals and can be converted into ketene
aminals <1995COFGT(4)967, 1994MI137>. For example, the imino ester hydrochloride 81 was
treated with ammonia or ammonium acetate to generate the ketene aminal 82, which was further
reacted in situ to form a range of heterocycles <1999MI313, 1994AP33>.
Imino ester hydrochlorides can be converted to their free bases that exist as the ketene
N,O-acetal tautomer. These can then be converted to ketene aminals <1995JHC1679>. For example,
the imino ester hydrochloride 81 was converted to its ketene N,O-acetal tautomer as a mixture of
(Z)- and (E)-isomers, 83 and 84, then treated with benzylamine to give the ketene aminal 85 as the
(E)-isomer <1994AP85>.
NC CCl3 NC NHR
MeO2C NH2 MeO2C NH2

72 73
H
R1 CCl3 NC NCH2 H CCl3 H N
R2 NH2 MeO2C NH2 R NH2 R N

O O H
2
74a (R1 = CN; R2 = COPh) 75
76 77
b (R1 = COPh; R2 = CO2Et)
c (R1 = R2 = CO2Et)
H CF3 R CF3 F3C H CN

R N
R NH2 N NH HCl.HN OEt
O HN
O 81
78 79 80
CN
CN CN CN
HN NH2
H2N NH2 H2N OEt EtO NH2 85
82 83 84 Ph
Imino ester hydrochlorides can be obtained from nitriles. Thus, the imino ester hydrochlorides 87
were obtained from nitriles 86 and converted to the ketene aminals 88 (Scheme 8) <1994AP225>.
R R R
EtOH EtOH
HCl NH3
O O O
CN
H2 N OEt H2N NH2
Cl–
86 87 88
Scheme 8
A series of indolin-2-one ketene aminals 91 were synthesized from the hydroxyindole salt 89 via
the ketene N,O-acetal 90 (Scheme 9) <1998KFZ5>. This was considered a superior route to one
that produced similar compounds by reacting an enamine with N,N-dimethylacetamide diethyl
acetal (see Section 4.2.1.1.7).
MeO H2N
CN
NH2 NR1R2
CN HCl 1° and 2°
CN CN
N O– MeOH amines
N O N O
Cl Cl Cl Cl Cl Cl
+
Et3NH
89 90 91
Scheme 9
The ketene aminal 92 was generated in 92% yield from the reaction of methylamine with the
ketene N,O-acetal. Structure 93 was synthesized in 42% yield from the reaction of ketene
dithioacetal 94 with 1 equiv. of ethanolamine in the presence of TsOH. The yield was low since
the ketene aminal 95 was also formed in 27% yield <2002MI121>.
NHMe O SMe NHCH2CH2OH

O2N NHCH2CH2OH O2N N O2N SMe
H O2N NHCH2CH2OH
92 93 94 95
4.21.1.1.7 From enamines

The indole structure 96 was reacted with the diethyl acetal of dimethylacetamide 97 to give the
dienediamine 99 as shown in Scheme 10 <1994KFZ48>. The reaction involves the loss
of dimethylamine from the indole, and the resulting intermediate then reacts with a ketene
N,O-acetal intermediate 98 to give the ketene aminal observed.
Me2N Me2N
OEt OEt
NMe2 NMe2
Me OEt –NHMe2
+
N OEt Me2N OEt N OEt N OEt
Et Et Et
BF4– BF4– BF4–
96 97 98
Me2N
NMe2
+NHMe2
N OEt
Et BF4–
99
Scheme 10
In a similar manner, the reaction of the indolin-3-ones 100 with malononitrile resulted in the
formation of the ketene aminals 101 in 71–75% yield. The same reaction also took place with
the pyrrolin-4-ones 102 resulting in the analogous structures 103 in 77–87% yield
<1995KFZ22>.
O O EtO2C O EtO2C O
CN CN
NR1R2 NR1R2 NR1R2 NR1R2
N N Me N Me N
H H H H
NH2 NH2
100 (R1 = R2 = Me) 101 (R1 = R2 = Me) 102 (R1 = R2 = Me) 103 (R1 = R2 = Me)
(R1, R2 = (CH2)5) (R1, R2 = (CH2)5) (R1, R2 = (CH2)5) (R1, R2 = (CH2)5)
The reaction is thought to occur as shown in Scheme 11. Thus, malononitrile replaces the
dialkylamino group to form a salt 104, which then dissociates to the hydroxy heterocycle 105
and the free amine (NHR1R2). The product of the reaction is achieved when the amine adds to
one of the nitrile groups. However, this is not an easy process and usually a nitrile group has
to be activated (e.g., by conversion to an imino ester) for amine addition to take place. It is
therefore proposed that activation occurs intramolecularly involving the hydroxy group on the
heteroaromatic ring to form the ketenimine 106. The amine then reacts rapidly and irreversibly
with the ketenimine to form the amidine 107, which tautomerizes to the observed product.
1 2
O CH2(CN)2 O– H2NR R OH O NH
CN CN C
NR1R2
N N CN N CN N CN
H H H H
104 105 106
OH NH O
NR1R2 CN
NH2
N CN N
H H
NR1R2
107
Scheme 11
The amino substituent (NR1R2) on the starting material must be tertiary or else this reaction is
not observed. When R1 or R2 is hydrogen, it is thought that intramolecular hydrogen bonding
with the carbonyl oxygen stabilizes the molecule. The route illustrated in Scheme 11 is supported
by the fact that the salt 104 can be isolated with short-time heating, and then subsequently
converted to the ketene aminal by further heating. Acidification of the salt 104 also allows the
isolation of the dicyanovinyl structure 105.
4.21.1.1.8 From nitriles

Ketene aminals are not normally obtained directly from nitriles. However, the reaction is
possible if one of the nitrile groups can be activated intramolecularly as described in the
previous section. Thus, the vinylidine dinitriles 108 and 109 were treated with a range of
primary amines to give the ketene aminals 110 and 111, respectively. Deacetylation takes place
during the reaction to give the hydroxyl group that is necessary for the activation of the nitrile
group.
Treatment of tetracyanoethylene 112 with a large excess of n-butylamine at room temperature
resulted in substitution of two cyano groups and generation of the ketene aminal 113 in 63% yield
<1996BCJ195>.
4.21.1.1.9 From cyanamides

Cyanamide and monosubstituted cyanamides react with activated methylene compounds in the
presence of nickel acetylacetonate to give ketene aminals <1995COFGT(4)967>. Further work
has shown that the reaction of cyanamide with ethyl acetoacetate in the presence of Ni(acac)2
(15 mol.%) gives the ketene aminal 114a in 76% yield while reaction of cyanamide with ethyl
benzoylacetate under the same conditions gives the ketene aminal 114b in 56% yield
<1993IZV419>.
EtO2C OAc OAc EtO2C O O

CN CN CN CN
NH2 NR2R3
Me N CN N CN Me N N
H H H H
NHR1 NHR1
108 109 110 111
O
NC CN NC NHBu R NH2
NC CN NC NHBu EtO NH2

O
112 113 114a (R = Me)
b (R = Ph)
These structures can also be synthesized via the N-benzoyl derivatives 115 followed by metha-
nolysis in the presence of sodium methoxide (Scheme 12).
MeONa
PhCONHCN O Ph O
MeOH
Ni(acac)2 R HN R NH2
RCOCH2CO2Et O –20 °C
R = Me, Ph EtO NH2 EtO NH2

O O
115 114
Scheme 12
4.21.1.1.10 From carbodiimides

Ketene aminals have been prepared previously from carbodiimides <1995COFGT(4)967>. The
reaction between the carbodiimides 116 and the active methylene compound 117 resulted in
formation of the ketene aminals 118 in 63–66% yield <1994S249>.
R2O2S R2O2S NHR1

R1 N C N R1
R2O2S R2O2S NHR1
116 117 118
A synthesis leading to the preparation of the antiulcer agents ranitidine and niperotidine has
been reported that involves reaction of the carbamate 119 with a diamine to give the bis-urea 120.
Treatment of 120 with triphenylphosphine/bromine in the presence of a base leads to the bis-
carbodiimide 121, which can be treated with nitromethane in the presence of sodium hydride to
give the bis-ketene aminal 122 (Scheme 13) <1992USP5118813>.
PPh3/Br2
O O O or SOCl2
R H2Nn(H2C) S S (CH2)nNH2 or SO2Cl2
N OAr RHN N (CH2)n S S (CH2)n HN NHR
H H NEt3
119 120
NaH
CH3NO2 CHNO2 CHNO2
RN C N (CH2)n N C NR DMSO
S S (CH2)n
RHN N (CH2)n S S (CH2)n HN NHR
H
121 122
Scheme 13
4.21.1.1.11 From halo alkynes

Chloro alkynes containing an electron-withdrawing substituent react with secondary amines to
give ketene aminals containing one electron-withdrawing substituent at the -position and iden-
tical tertiary amino groups <1995COFGT(4)967>. As such, the method is quite restricted in its
utility and has not been used since the 1990s.
4.21.1.1.12 From ynamines

Ynamines with an electron-withdrawing substituent react mainly with secondary amines to
give ketene aminals containing one electron-withdrawing substituent at the -position, and
two tertiary amino groups which may or may not be identical <1995COFGT(4)967>. One of
the amino groups is obviously dictated by the ynamine used. The method has not been used
since the 1990s.
4.21.1.1.13 From acetylides

Reaction of acetylides 123 with the guanidinium salt 124 gave orthoamides 125, which on treatment
with acidic methylene compounds gave the dienes 126 (Scheme 14) <2002ZN(B)399, 1998JPR408>.
X
R NMe2
Me2N NMe2 NMe2
– THF Y X
R C C Na + R C C NMe2 NMe2
Cl–
NMe2 NMe2 Y
123 124 125 126
Scheme 14
The orthoamide 127 was obtained in a similar fashion and reacted with acidic methylene
compounds to give the dienes 128.
Me2N NMe2 Me NMe2

NMe2
X
H2C C C NMe2
OMe Y OMe
127 128a (X = CN; Y = CO2Me)
b (X = Y = CO2Me)
The metal complexes 130 were synthesized in good yield (64–67%) from the reaction of
deprotonated tris(dimethylamino)prop-1-yne 129 with metal complexes, followed by abstraction
of a dimethylamido group using BF3 etherate (Scheme 15) <1996OM1139>.
–
– NMe2 NMe2 BF3·OEt2 NMe2
(CO)5M(THF) + C C C NMe2 (CO)5M C C C NMe2 (CO)5M C C C
NMe2 NMe2 NMe2
M = Cr, W 129 130
Scheme 15
Metal complexes 131 were synthesized in a similar fashion in 36–42% yield from the acetylide
132.
NMe2 NMe2
(CO)5M C C C C C C C C C C NMe2
NMe2 NMe2
131 M = Cr, W 132
4.21.1.1.14 From enylidene systems

The metal complexes 135 were obtained in good yield from the reaction of the ynamine
134 with metal complexes 133 at room temperature <1998OM1511>. The reaction involves
insertion of the electron-rich alkyne into the terminal C¼C bond of the metal complex
(Scheme 16).
NEt2
NMe2 Me C C NEt2
134
(CO)5M C C C C C (CO)5M C C C Me
NMe2
Me2N NMe2
133a (M = Cr)
b (M = W)
NEt2
(CO)5M C C C C C NMe2
Me NMe2
135a (M = Cr)
b (M = W)
Scheme 16
Such compounds are seen as having potential nonlinear optical properties. The related metal
complex 136 was synthesized in low yield from the reaction of dimethylamine with the metal
complex 137 that was generated in situ and could not be isolated. The metal complexes 138 were
synthesized by a similar reaction, involving the quantitative addition of dimethylamine to the
metal complexes 133 <1996OM1139>.
NMe2 NMe2 NMe2

(CO)5W C C C C C NMe2 (CO)5W C C C C C C C (CO)5M C C C NMe2
NMe2
136 NMe2 137 138a (M = Cr) NMe2
b (M = W)
4.21.1.1.15 From amidines and amidinium salts

The ketene aminal 139 was synthesized in 90% yield from the amidinium salt 140 on reaction with
sodium hydride, dimethylamine, and B(OMe)3 <2000JPR256>.
The amidine 141 has been reduced with lithium using THF as solvent and ultrasound to
give the dilithio salt of the tetraaminoethane 142 in quantitative yield. The reaction of 142
with akyl halides proceeded quantitatively to give the ketene aminals 143 <1996CB39,
1998MI183>.
NMe2
NMe2
(Me2N)2HC NMe2 Me2N Cl
NMe2
139 140
Li Li
ArN NAr ArN NAr ArRN NRAr
PhMeN NMePh PhMeN NMePh PhMeN NMePh
141 142 143
4.21.1.1.16 From tricyanomethanide, dicyanoacetates, dicyanothioacetates, and dicyanoacetamides

The reagents specified react with amines to give ketene aminals and have been reported as useful
alternatives to using ketene dithioacetals when the ketene aminal to be synthesized bears a
primary amino group <1995COFGT(4)967>. However, no reports of their use have been pub-
lished since the 1990s.
4.21.1.1.17 From amides and other carboxylic acid derivatives

Tertiary amides and other carboxylic acid derivatives can be converted into ketene aminals using
Ti(NMe2)4 <1995COFGT(4)967>. Despite the fact that the method seems useful in generating
ketene aminals without electron-withdrawing substituents at the -position, there have been no
reports of its use since the early 1970s.
4.21.1.1.18 From miscellaneous ‘‘head group’’ synthons

A variety of reagents have been used in the past as ‘‘head group’’ synthons for the synthesis of
ketene aminals. These include N,N,N1,N1-tetramethylmethylthioformamidinium iodide, alkox-
ytris(dimethylamino)methanes <1995COFGT(4)967>, tetramethylurea diisopropyl acetal,
tetramethylchloroformamidinium chloride <1995COFGT(4)967>, as well as specific aminals,
ortho-esters, and amide acetals <1995COFGT(4)967>. However, no reports of these have been
given in the 1990s. The lack of interest in ‘‘head group’’ synthons is due presumably to the
inevitable restrictions that these methods place on the amino groups which can be added to ketene
aminals.
4.21.1.1.19 From ring opening of pyrimidines

Pyrimidines 144 bearing an electron-withdrawing substituent at the 5-position and a chloro
substituent at the 6-position are prone to nucleophilic attack and ring opening, resulting in ketene
aminals where one of the amino groups is primary and one of the -substituents is cyano
<1995COFGT(4)967>.
This method has been rarely used for the synthesis of ketene aminals. However, a further
example of this method has been reported <1996CHE699> involving fission of the pyrimidine
rings 145 under acid conditions to give ketene aminals 146. Previously, a dialkylamino substituent
was thought necessary for such reactions, but it has been shown that the reaction is possible with
aniline substituents.
Nitration of the 2-methyl-4,6-dihydroxypyrimidines 147 with nitric acid/sulfuric acid, followed

by dilution with water, resulted in generation of the ketene aminal 148 in 80% yield. The
dihydropyrimidine 149 has been identified as an intermediate <2001ZOR766>.
N NR1R2 N NR1R2
NC NH2
N N
X NO2 O2N NR1R2
Cl Cl
144 145 146
NO2
Me N OH C N OH
O2N NH2 O2N
N NO2
R N
O2N NH2 NO2
OH OH
R = H,NO2
147 148 149
4.21.1.1.20 From ring opening of imidazoles and imidazolidinediones

Imidazoles can be quaternized at the N-3 position with methyl iodide then ring-opened in the
presence of a basic catalyst to give ketene aminals. Thus, the nucleoside 150 was methylated to
give the quaternary salt 151 in quantitative yield. Treatment with 1 equiv. of base resulted in the
ketene aminal 152 <1995MI367>.
Similar results were obtained when the imidazoles 153 were treated with alkyl iodides to
give the quaternary salts 154 in 50–90% yields, then treated with aqueous sodium hydroxide
to give the ketene aminals 155 in 55–60% yield <1997MI14>. It has also been reported that
the reaction intermediate 157 may be formed during the reaction of the imidazole 156 with
ethyl chloroformate in aqueous sodium bicarbonate <1997CPB75> (see also Section
4.21.1.2.1(v)).
1,1-Diamino-2,2-dinitroethylene 158 (also known as FOX-7) is of interest as an explosive.
Previous attempts to synthesize this compound from the vinylidene di-iodide 159 were
unsuccessful despite the fact that other ,-dinitroketene aminals could be synthesized in
this fashion. However, the compound was successfully synthesized from 2-methylimidazole
160. Nitration of 2-methylimidazole 160 with sulfuric acid and nitric acid resulted in
precipitation of the dinitro imidazolidinedione 161, which on standing at room temperature
decomposed with the loss of nitric oxides to the ketene aminal 162 in 15% yield. Addition of
162 to water and neutralization by aqueous ammonia to pH 8–9 resulted in dissolution and
ring cleavage to form the insoluble 1,1-diamino-2,2-dinitroethylene 158 in 87% yield
<1998T11525>.
It is believed that the mechanism leading to 161 involves oxidation of 2-methylimidazole 160 to
give structure 163, which is then nitrated twice in the ring to give 164. The electron-withdrawing
effects of both the keto and the nitro groups then activate the methyl group to nitration resulting
in the formation of 161 <1998T11525>.
The advantage of having electron-withdrawing substituents on the imidazole ring was further
demonstrated by the finding that structure 162 can also be obtained in 67% yield from the
nitration of the imidazolidinedione 165. This structure can be synthesized in turn from acetami-
dine HCl and diethyl oxalate in 64% yield <1998T11525>.
I Me
Me
CO2Et CO2Et N CO2Et
N N OHC
N N HN
O NH2
O NH2 O NH2
Ph3CO
Ph3CO Ph3CO
O O
O O O O
150 151 152
CHO
NC NH2 NC NH2 NC NH2
N NMe EtO2C N NHMe
N NAr R N NAr OHC N NHAr
NC NHMe NC NHMe
R
I
153 154 155 156 157
H H
N O 2N N O O2N N O
O2N NH2 O2N I
Me NO2
O2N NH2 N O2N N O2N N O
O2N I H NO2 H
158 159 160 161 162
H H H
N O N O Me N O
Me Me NO2
N N MeO N
H H NO2 H O
163 164 165
4.21.1.1.21 Miscellaneous syntheses from ring systems

Ketene aminals have been synthesized by the ring opening of various heterocycles
<1995COFGT(4)967>, but these methods have limited synthetic utility. The following are more
recent examples.
(i) From 2-trichloromethylchromones

The reaction of 2-trichloromethylchromones 166 with ethylenediamine at room temperature gave
2-phenacylideneimidazolidines 168 in 63–94% yields. The reaction can be carried out with or
without ethanol as solvent. The probable mechanism involves nucleophilic attack on the C(2)
atom of the chromone system resulting in pyrone ring opening and formation of an intermediate
enamine 167. Intramolecular replacement of the trichloromethyl group then takes place (Scheme 17)
<1999MC206>. The same products can be obtained by reacting relevant -amino--(trihalo-
methyl) vinyl ketones with amines (Section 4.21.1.1.4), but the reaction times are longer and the
yields are lower (25–40%).
The cyclic system 169 also reacted with ethylenediamine to give the imidazolidine 170.
R3 O R2 R2
R2 R1 R3 R1 R3
(NH2CH2)2
H
CCl3 N
R1 O CCl3
OH O NH(CH2)2NH2 OH O HN
166 167 168
Scheme 17
O
H
N
NH2
O CCl3 O HN
169
170
(ii) From isoxazolones

The reaction of 2-phenylisoxazolone 171 with secondary amines resulted in the formation of
ketene aminals 172 that exist predominantly as the amidine tautomer <1992AJC2037>. The
malonamide 173 was also formed as a product and the ratio of products depended on the solvent,
temperature, and nature of the base. With primary amines, only the malonamide product was
observed. The ketene aminal product is thought to be formed as shown in Scheme 18.
Ph
O
N NR2
O CO2Et
PhHN
CO2Et EtO2C NHPh CONEt2
O
171 172 173
Ph Ph H Ph
N R2NH N NR2 N NR2 –CO2 PhN NR2 PhHN NR2
O O O
CO2Et CO2Et CO2Et CO2Et CO2Et
O O O H
Scheme 18
(iii) From isothiazoles

Desulfurization of the nitroisothiazole structure 174 with triphenylphosphine results in ring
opening and the formation of the highly reactive ketene imine intermediate 175. This was trapped
by the addition of thiobenzoic acid to give the adduct 176, which hydrolyzed on work-up to give
the thioamide 177 in 75% yield (Scheme 19) <1998HCA2388>.
PPh3
CH2Cl2 O2N NHPh O2N NHPh
PhHN NO2 N2, 0 °C NPh
PhCOSH –PhCOOH
Ph N C C PhN NHPh PhHN NHPh
N –Ph3PS NO2 NHPh S +H2O
Ph N S
S
Ph O
Ph
174 175 176 177
Scheme 19
Trapping the intermediate 175 with amines resulted in the formation of ketene aminals 178 in
good yields (72–93%). This reaction did not occur in the presence of aniline and 4-methoxyani-
line, and the reaction products obtained were those that would be obtained in the absence of an
amine (i.e., the quinoxaline N-oxide 179). Addition of thiophenol to the reaction mixture resulted
in the formation of the thioimidate 180 in 62% yield. However, adding aliphatic thiols failed to
trap the intermediate, and only structure 179 was formed along with decomposition products.
Addition of 4-nitrophenol was thought to occur in a similar fashion to give 181. However, this
product decomposed on work-up and could not be fully characterized <1998HCA2388>.
O 2N NHPh O NHPh O2N NHPh O2N NHPh

N
PhN NHPh O PhN NHPh PhN NHPh
NR2 SPh O
N NHPh
178 180 181
179
O2N

A variety of procedures has been used for the synthesis of specific ketene aminals. These include
the synthesis of the allyl cation 182 from pentachlorocyclopropane <1994CC2517>, and the
synthesis of 1-phospha-1,3-butadienes 183 and 184 from the reaction between the metallopho-
sphaalkene 185 and disubstituted alkynes <1996OM123, 1994ZN(B)1693>.
The ketene aminal 186 can be obtained in 90% yield by dehydrofluorinating the saturated
diamine 187 with BunLi in diethyl ether <1997JOC1576>.
NMe2
ButHN NHBut
C NMe2
OC Fe NMe2 NMe2
ButHN NHBut Fe OC Fe
OC P NMe2 OC Ph OC P
182
O NMe2
R CO2Me CO2But
183a (R = CO2Me) 184 185

b (R = Me)
c (R = H)
F NMe2 F NMe2
F
F NMe2 F NMe2
186 187
4.21.1.1.23 By modification of other ketene aminals
(i) Introduction of -substituents

Ketene aminals have nucleophilic properties and can be elaborated to introduce groups at the
-carbon by electrophilic substitution <1995COFGT(4)967>. Both nitrogen groups are generally
tertiary and there must necessarily be a hydrogen at the -position. The other -substituent is not
crucial to the success of the reaction.
Reaction of ketene aminals 188 with alkyl or aryl isothiocyanates gave keto aminals with
-thioamido substituents 189 <2001MI1763, 1995JHC1679, 1995MI73, 1994MI137,
1997HCA273, 1996SC1187> while reaction of monoacyl ketene aminals 190 with benzoyl
isothiocyanate gave the corresponding structures 191. In these examples, the ketene aminals
contained a primary or secondary amino group.
The reaction of the ketene aminal 192 with alkyl or aryl isothiocyanates gave either the
monothioamido-substituted ketene aminal 193a or the disubstituted product 194a depending on
the amount of isothiocyanate used. Similarly the amido-substituted ketene aminals 193b and 194b
were obtained on reaction of 192 with alkyl or aryl isocyanates. It should be noted that the ketene
aminal 192 reacted explosively with phenyl isocyanate in the absence of solvent and that reactions
were consequently carried out in THF. The monosubstituted amido ketene aminal 193b was
obtained quantitatively when an equimolar amount of phenyl isocyanate was used, while the
disubstituted product 194b was obtained quantitatively with 2 equiv. of reagent. Treatment of the
monosubstituted product 193b with phenyl isocyanate yielded the disubstituted product 194b in
98% yield, allowing the possibility of introducing two different amido groups. With less reactive
aliphatic isocyanates, longer reaction times and higher reaction temperatures were required to
complete the reaction and less selectivity was observed. The reaction of 192 with a bifunctional
isocyanate 195 resulted in the formation of the polyamide polymer 196 <1999JPS(A)3079>.
The reaction of the ketene aminal 197 with ,-unsaturated acyl isothiocyanates 198 has been
achieved in acetone to give ketene aminals 199 bearing an acyl thioamide substituent at the
-position <1998HCA718>. Yields varied from 59% to 87%.
O
S NH2 Ph S
NR1R2 R4HN NR1R2 HN NH2
R3 NR1R2
X NR3R4 X NR3R4 O R3 NR1R2
O
188 (X = CN, CO2Et, NO2) 189 (X = CN, CO2Et, NO2) 190 191
X O O
NMe2 NMe2 RHN NMe2 R
N N
RHN NMe2 OCN R NCO H H
NMe2 RHN NMe2
X X Me2N NMe2
192 193a (X = S) 194a (X = S) 195 196
b (X = O) b (X = O)
NHMe O
R C C S
S C N C C R H H HN
O2N NHMe H H NHMe
O
197 198 199 O2N NHMe
The reaction of ketene aminals 200 with enamines 201 allows the synthesis of conjugated ketene
aminals 202 bearing a vinylic substituent at the -position (Equation (2)) <1993BSB645>. The
reaction is carried out in the presence of p-toluenesulfonic acid in an inert atmosphere and with
heating.
TsOH NR4R5
NR4R5 R1 NR32
+ ∆ R1
–HNR32 NR4R5 ð2Þ
NR4R5 R2
R2
200 201 202
In a similar fashion the conjugated ketene aminals 203 and 204 can be obtained from the
reaction of 200 with enamines 205 and 206, respectively. The reaction of ketene aminal 207 with
the enamine 208 gave the diene 209 in 43% yield <1994AP85>.
In the above reactions, vinyl substitution is possible since the amino group can be lost from the
enamine moiety. The reaction of the ketene aminal 210 with the vinylidene dichloride 211 can be
viewed in a similar light. In the presence of triethylamine, the conjugated ketene aminal 212 is
obtained as a result of a chloride ion being lost from the vinylidene dichloride moiety
<1993JCS(P2)911, 1993TL1779>.
Michael additions are possible at the -position of ketene aminals. Thus, the ketene aminal
hydrochloride salt 213 reacted with acrylonitrile in THF and triethylamine to give the ketene
aminal 214 in 92% yield <1995T7161>.
The -chloro-substituted ketene aminal 215 reacted with carbon disulfide in the presence of
triethylamine to give the disulfide 216 in 30–41% yield <1995SUL73>. The presence of triethyl-
amine is crucial to this reaction and no product is detected in its absence. The proposed
mechanism is shown in Scheme 20. Addition of carbon disulfide gives the betaine structure
217, which cyclizes to give the thiiranthione 218 which in turn undergoes dehydrochlorination to
give the dithiolactone 219. This structure is highly strained and decomposes to give the diradical
220. Hydrogen abstraction by the more reactive vinyl carbon site, followed by dimerization of the
resulting dithiocarboxyl radical 221 gives the final product 216.
NR1R2
NR1R2 NR2 NR2 NC NH2
NR1R2
NR1R2 R2N NHCH2Ph
( )n R2N ( )n
203 204 205 206 207
NMe2 NC NHCH2Ph
NMe2 NC Cl NMe2
NC
Ph NH2
NMe2 NC Cl NMe2
O Ph
NC Cl
O
208 209 210 211 212
NC
NH2 NH2
NEt2 Et2N NEt2
HCl
O NH2 O NH2
Cl NEt2 Et2N S S NEt2
O O
S S
213 214 215 216
S Cl NEt2 S S
CS2 –Cl– NEt2 NEt2
215 –
S H NEt2 S S
H NEt2 NEt2
217 218 219
NEt2 H NEt2
NEt3
S NEt2 S NEt2 216
S S
220 221
Scheme 20
1,1-Bis(methylamino)-2-nitroethene 222 is strongly polarized due to the influence of the amino

groups and the -nitro group. As a result, it readily undergoes reactions with electrophiles at the
-position. Thus, reaction with the aldehydes 223 and 224 led to the condensation products 225
and 226, respectively, in 78% and 58% yields. Similar reactions occur using the ketene aminals
227 and 228. Thus, the ketene aminal 227 reacts with 223 and 224 to give -substituted ketene
aminals in 33% and 70% yields, respectively, while the ketene aminal 228 reacts with the same
aldehydes to give -substituted products in 80% and 46% yields, respectively. The ketene aminal
229 also reacts but the initial condensation products are not isolable and react further to produce
heterocyclic structures <1997ZOR1044, 1999CHE286>.
Ketene aminals 230 have been treated with formaldehyde or chloral hydrate in the presence of
triethylamine to give the allylic alcohols 231a. If the reaction is carried out in the presence of a
primary or secondary amine instead of triethylamine, allylic amines 231b are obtained. In a
similar fashion, the presence of a thiol in the reaction mixture results in thioethers 231c
<1990EUP0392560>.
The fluorinated ketene aminal 232 reacts with 1 equiv. of an alkyllithium at room temperature
such that one fluorine substituent can be substituted with an alkyl group to give the mono-
alkylated products 233. These structures are converted to -fluoroacetamides 234 when a hydro-
lytic work-up is used <1997JOC1576>.
The reaction of the ketene aminals 235 and 236 with acetylenedicarboxylate in methanol gave
the ketene aminals 237 and 238, respectively, in 29% and 68% yield <1991BCJ2118>. When the
reaction was carried out on 236 using acetonitrile as solvent, the ketene aminal 239 was obtained
in 62% yield, a reaction which is thought to occur by a [2+2]-cycloaddition followed by ring
opening. Apart from structure 235, ketene aminals bearing an NH group gave heterocyclic
products arising from further cyclization of the initial reaction product.
NHMe O O O O
Me H H Me
O2N NHMe NHMe NHMe
Me O O Me
O O O NO2 NHMe O NO2 NHMe
222 223 224 225 226
N H
NHCH2CH2OH N O2N NR1R2
O2N N O2N N
O2 N NHCH2CH2OH H NR3R4
H
O
227 228 229 230
O2 N N R1R2 F2C C(NMe2)2

H
232 N
3 4
R5 NR R O2NHC
RFC C(NMe2)2
Y N
5 233 H
231a (Y = OH; R = H or CCl3)
b (Y = NR6R7; R5 = H or CCl3) RFHC CONMe2 235
5
c (Y = SR or SAr; R = H or CCl3) 234
O O O
CO2Me MeO2C MeO2C
H
N MeO2CHC N MeO2CHC N O2NHC N
O2NHC
N O2N N O2N N MeO2C N
H
O O O
236 237 238 239
(ii) Deacylation
,-Diacylketene aminals have been monodeacylated to give -acylketene aminals using methanol
in the presence of Co(OAc)24H2O <1995COFGT(4)967>. The deacylation of the ketene aminal
240 has also been carried out using trifluoroacetic acid in dichloromethane. The ester group is
first hydrolyzed then decarboxylation takes place. The resulting product was the cyanoacetami-
dine trifluoroacetate 241, which can be tautomerized by treatment with base or buffer to give the
ketene aminal 242 <1998WOP9850344>.
(iii) From ketene aminals via iminopropadienones

The bisaminomethylene derivative of Meldrum’s acid 243 can be converted to the iminopropa-
dienone 244 by flash vacuum thermolysis, then treated with secondary amines to give ketone
aminals bearing a -amido substituent 245 <2002JOC2619>. The initial addition of the amine is
to the C¼O group to form an amidoketenimine, which can be detected by NMR and IR
spectroscopy. A second molecule of amine then adds more slowly to give the observed products.
The products are actually obtained as the amidine tautomers but these tautomerize on distillation
to give the ketene aminals.
NC NR2R3 NC NR2R3 NC NR2R3
ButO2C NHR1 NR1 NHR1
240 241 242
O O
O NMe2 R 22N NR22
O C C C NR
O NHR NHR1
O
243 244 245 (R2 = Me, Et)
(iv) From cycloaddition reactions

The ,-difluoroketene aminal 246 undergoes a [2+2]-cycloaddition reaction with ethyl propio-
late to give a cyclobutene product 247, which undergoes electrocyclic ring opening to give the
ketene aminal 248 in 66% yield (Scheme 21) <1999JOC5599>. The cyclobutene structure is stable
at temperatures below 15 C.
F H
F NMe2 F EtO2C NMe2
Hexane
+ H CO2Et F
F NMe2 60 °C Me2N NMe2
NMe2CO2Et F
246 248
247
Scheme 21
The reaction of 246 with dimethyl acetylene dicarboxylate gives the analogous cyclobutene
structure 249 at low temperatures. However, on warming no diene 250 is observed, with poly-
merization taking place instead.
F CO2Me
F MeO2C NMe2
F
Me2N NMe2
NMe2CO2Me F CO2Me
249 250
(v) Dehydrohalogenation and subsequent reactions

Dehydrohalogenation of the diene structure 251 using DABCO in THF results in the formation
of the butatriene 252, which undergoes polar additions with a variety of electrophilic and
nucleophilic compounds leading to ketene aminal derivatives <1993JCS(P2)911, 1993TL1779>.
Thus, bromination of 252 gives the dibromo structure 253. Treatment of 252 with HX gives
structures 254a–254c, treatment with sodium ethoxide in ethanol gives 254d, treatment with
secondary amines gives 254e, and treatment with benzoyl chloride gives 255. Attempts to carry
out cycloaddition reactions with 252 proved unsuccessful.
O
H NMe2 NC NMe2 Br NMe2 H NMe2 Ph NMe2
NC C C C C NC NC NC
NMe2 NC NMe2 NMe2 NMe2 NMe2
NC Cl NC Br NC X NC Cl
251 252 254a (X = Cl)
253 255
b (X = Ac)
c (X = SPh)
d (X = OEt)
e (X = NR2)
(vi) Hydrolysis of -amido enamines

The N-benzoyl derivatives 256a,b were treated with sodium methoxide in methanol to generate
the ketene aminals 257 <1993IZV419>.
(vii) Modification of -isocyano groups

Treatment of the ketene aminal 258 with hydrazoic acid resulted in the modification of the
isocyano group to a tetrazole 259 in 57% yield <1994JPR29>.
O Ph O H H
R HN R NH2 N PO(OEt)2 N PO(OEt)2
O
EtO NH2 EtO NH2 N NC N N
O O H H N N
N
257
256a (R = Me) 258
259
b (R = Ph)
(viii) Alkylation of amino groups

Ketene aminals 260 reacted with the thioether 261 when heated at 80 C, resulting in N-alkylation
and the formation of the antiulcer agents 262 <1983EUP0092647>.
NH2 Me Me CHNO2
O2NHC N S N S
Me SMe Me NR1R2
NR1R2 O O N
H
260 261 262
(ix) Substitution of amino groups

The explosive 1,1-diamino-2,2-dinitroethene 263 (also known as FOX-7) reacts as a ‘‘push–pull’’
alkene and undergoes transamination reactions via an addition–elimination mechanism when
treated with a variety of amines (predominantly primary amines). Either one or both of the
amino groups can be replaced to give the mixed ketene aminal 264 and the ketene aminal 265,
respectively. With the diamines 1,2-diaminoethane and 1,3-diaminopropane, it is possible to get
the cyclic products 266 and 267, respectively, when a solvent is used. However, when the reaction
is carried out in neat 1,2-diaminoethane, the heterocyclic product 268 is formed instead in 25%
yield <2002JCR(S)257>.
H
O2N NH2 O2N NHR O2N NHR O2N N O 2N HN O2N N
O2N NH2 O2N NH2 O2N NHR O2N N O 2N HN O2N N

H
263 264 265 266 267 268
Transamination reactions have also been reported for the ketene aminal 269. Treatment with
3 equiv. of a strongly basic amine such as ammonia, methylamine, or morpholine in aqueous
medium resulted in mono-amination products 270, which precipitated from solution in low-to-
moderate yield. The dimethylamino moiety was selectively replaced. Reaction of 269 with a large
excess of amine such as dimethylamine or morpholine, on the other hand, resulted in the bis-
amination products 271 in low yield (12–18%). Under these conditions, the mono-aminated
product did not precipitate and so reacted further. Reaction of 269 with diamines allowed the
formation of ketene aminals containing a diazaheterocyclic ring 272 in reportedly high yields.
Reaction of 269 with piperazine resulted in the formation of two products—the diazabicyclohep-
tane derivative 273 obtained in 7% yield, and the bisvinylpiperazine 274 obtained in 32% yield
<1996CHE699>.
H
NC NH2 NC NH2 NC NR1R2 NC N (CH )
2 n
O2N NMe2 O2N NR1R2 O2N NR1R2 O2N N

H
269 270 271 272 (n = 1, 2)
NC NH2
O2N N
NC N
N NO2
O2N N
H2N CN
273 274
Ketene aminals containing benzotriazolyl groups 275 have been synthesized. The benzotria-
zolyl group is a good leaving group and the reaction of 275 with 1 equiv. of aromatic,
arylaromatic, or heterocyclic amine was investigated and found to result in substitution of
one benzotriazolyl residue leading to the mixed ketene aminals 276 in 70–95% yields. The
reaction did not proceed satisfactorily with aliphatic amines and tarring took place. Reaction
of the mixed ketene aminals 276 with a further equivalent of amine resulted in the substitution
of the second benzotriazolyl residue and formation of the ketene aminals 277 in 40–70%
yields. The same products were synthesized directly from 275 in 25–50% yields using 2 equiv.
of amine. Reaction of 275 (X = Cl) with 1 equiv. of various diamines resulted in the formation
of ketene aminals containing diazaheterocyclic rings 278 and 279 in 55% and 75% yields
<1997ZOR1541>.
When the amine involved was a p-substituted aniline (alkyl or alkoxy substituent), the first
substitution took place as described above to give structures 280. Reaction with various primary
and secondary amines then resulted in substitution of one of the terminal chlorines rather than
the second benzotriazolyl group to give the substitution products 281 in 47–92% yield. These
results were explained by proposing that the C4 atom of the trichlorovinyl fragment is more
susceptible to attack by hard bases. In the case of the mixed ketene aminal bearing aniline itself,
reaction with another molecule of aniline results in substitution of the second benzotriazolyl
group, whereas reaction with the harder base piperidine results in substitution of the chloro
substituent <2000ZOR910>.
N N
N N
ClXC CCl N ClXC CCl N
O2N N O2N NR1R2

N
N
275 (X = Br, Cl) 276 (X = Br, Cl)
H H
ClXC CCl NR1R2 Cl2C CCl N Cl2C CCl N
O2N NR1R2 O2N N O2N N

H H
277 (X = Br, Cl) 278 279
N N
Cl N Cl N
CCl N CCl N
X R3R2N
O2N NH O2N NH
R R
280 (X = Cl or Br; 281
R = OR1 or R1)
The reaction of the triazolyldienes 282 with 1 equiv. of an aliphatic, heterocyclic, or aromatic
amine was also investigated and found to result in transamination of one of the azolyl moieties
leading to mixed ketene aminals in high yields (85–95%) <1997ZOR1715>.
Reactions of the bis(pyrazolyl)dienes 283 gave different products depending on the amine used
<1997ZOR1715, 2000ZOR910>. Reaction with 1 equiv. of an amine such as diethylamine,
morpholine, or p-toluidine resulted in mixed ketene aminals, but in lower yields (35–50%)
compared to the triazolyldienes. However, reaction with piperidine led to substitution of a
terminal chlorine to give structure 284. With excess amine, the reaction was nonselective and
tarring took place. The reaction of 283 with anilines was also investigated. Reaction with 1 equiv.
of an aniline resulted in substitution of one of the pyrazole substituents to give the mixed ketene
aminals 285. Reaction of the resulting mixed ketene aminals with diethylamine or piperidine
resulted in substitution of a terminal halogen substituent as described above to give products 286
in 63–78% yields, whereas reaction with the less basic anilines resulted in tarring
<2000ZOR910>.
Me Me Me Me
Cl N N
CCl N Cl N N N Cl N Cl N
X CCl N CCl N CCl N CCl N
Me Me Me 1R2RN Me
O2N N X Cl X
O2N N Me O2N N Me O2N NH O2N NH
N N
N N
Me Me
R R
282 283 284 285
286
(x) Ketene aminals via dithiolates

Ketene aminals can be converted to bis(dialkylamino)carbenium dithiocarboxylates, which
undergo further reactions to give modified ketene aminals. For example, the ketene aminals
287a–287c were treated with elemental sulfur in benzene in the presence of triethylamine
to give the bis(dialkylamino)carbenium dithiocarboxylates 288a,b in 70–97% yield
<1995HAC45>.
X NR2
S NR2 S NR2
=
H NR2
S NR2 S NR2
287a (R = Et; X = Cl) 288a (R = Et)
b (R = Pr; X = Cl) b (R = Pr)
c (R = Et; X = OPh)
Reaction of the dithioate 288a with methyl iodide gave the carbenium salt 289, which
reacted at the sulfur atom with a range of soft nucleophiles such as Grignard and organo-
lithium reagents to give the ketene aminals in near-quantitative yield 290 (Scheme 22). The
order of the synthetic steps can be reversed, such that the dithioate is first treated with a
nucleophile to give the salts 291, which can then be treated with methyl iodide to give 290 in
84–94% yield. Reactions of 288a with 1.2 equiv. of ButLi, followed by treatment with methyl
iodide gave a mixture of the ketene aminals 292 and 293 in moderate yield, whereas reaction
of 288a with 2 equiv. of ButLi followed by methyl iodide gave a 56:44 mixture of 292 and 293
in 89% yield <1998CL321>.
I– +
S NEt2
RLi or
MeI RMgX
MeS NEt2
S NEt2 RS NEt2
289
S NEt2 MeS NEt2
RS NEt2
288a RLi or 290
MeI
RMgX
MS NEt2
291; M = Li or MgX
Scheme 22
The mechanism proposed involves a single electron transfer process from ButLi to 288a to
produce a pair of radicals 294. Combination of the radical pair and methylation produces 292,
whereas disproportionation of the radical pair produces 295 and isobutene. Structure 295 could
then be lithiated to give 296, which would react twice with methyl iodide to produce the observed
product 293. The ratio of products is dependent on the solvent used and the metal ion. For
example, treatment of 288a with 2 equiv. of ButMgCl in ether gave only 292 as the product
<1998CL321>.
The reaction has been used to synthesize large crystalline water-soluble compounds. Thus,
reaction of 288a with the hexabromide 297, followed by reaction with 6 equiv. of methyl iodide
gave structure 298 bearing 6 ketene aminal moieties in 61% yield <2001CL768>.
RS NEt2 S NEt2 HS NEt2 MS NEt2

R
MeS NEt2 MS NEt2 MS NEt2 MS NEt2
292 (R = But ) 296
294 295
293 (R = Me)
Me NEt2
Et2N NEt2 S
NEt2
S
Br MeS S SMe
NEt2
NEt2 S
Br Br
S NEt2
Br Br Et2N
SMe S SMe
S
Br
Et2N
S Et2N NEt2
297
NEt2 Me
298
The salt 289 has been treated with a variety of nucleophiles such as lithium enolates, lithium
diethylamide, and sodium thiolates to give the products 298a–298c. Reaction with sodium
sulfide in water gave the trisulfide 299 quantitatively, while reaction with trialkyl phosphites
resulted in an Arbuzov reaction and formation of the phosphorylated products 298d
<1997TL5013>.
Reduction of the salt 288a with more than 2 equiv. of lithium naphthalenide produced the
ethene-1,1-dithiolate 300, which was converted to the ketene aminal 301 in 73% yield on
treatment with methyl iodide. The reduction was also feasible using LiEt3BH and the product
301 was obtained in 85% yield following treatment with methyl iodide. Reaction of 300 with
1,2-dibromoethane gave the 1,3-dithiolane 302 in 77% yield while treatment of 300 with carbon
disulfide followed by methyl iodide gave the trithiocarbonate derivative 303 in 92% yield
<1998HAC703>.
RS NEt2 S S NEt2
MeS NEt2 MeS NEt2

298a (R = CH2COR; 92–95%) 2
b (R = NEt2; 90%) 299
c (R = SR; 95–98%)
d (R = PO(OR)2; 88–95%)
S NEt2 MeS NEt2 S NEt2 MeS2CS NEt2
S NEt2 MeS NEt2 S NEt2 MeS2CS NEt2
300 301 302 303
(xi) Modification of -substituents

Treatment of the ketene aminals 304 with diethyl azodicarboxylate (DEAD) in DMF led to the
formation of isothiazoles 305 in 44–97% yields (Scheme 23). On dissolving in DMSO the
isothiazoles unexpectedly ring-opened and isomerized to give the ketene aminals 306 in 61–96%
yields <1997HCA273>. The rate of isomerization depended on the polarity of the solvent and did
not occur in methylene chloride.
O2N NHR2 R2HN NO2 R3 S NO2

DEAD DMSO
H
R3 N NHR1 DMF R1
N N N NHR2
S
S NHR1
304 305 306
R3
Scheme 23
The isomerization rate was slowed if R3 was electron withdrawing, or if R1 and R2 were
aromatic rings with an electron-donating group at the para position. A proposed mechanism is
shown in Scheme 24 <1997HCA273>.
O
R2HN N O R2HN NO2
1
N N R N N
305 R1 S S 306
R3 R3
Scheme 24
Treatment of the ketene aminal 307 with DEAD led to intractable mixtures. However, treat-
ment with bromine gave the ketene aminal 308 <1997HCA273>.
S S
PhHN NHMe N NHMe
O2N N O2N N
307
308
4.21.1.1.24 By combinatorial synthesis

A combinatorial synthesis of ketene aminals has been reported which involves the reaction of
isothiocyanates with active methylene compounds (see also Section 4.21.1.1.2)
<1998WOP9850344>. Various solid supports are reported to be feasible including polystyrene,
polyethylene glycol, and polyethylene glycol attached to polystyrene, polyamides, polysacchar-
ides, and silicates. In the case of a polystyrene resin, a Wang or a Rink linker can be used. The
reaction sequence involves acylation of hydroxyl groups on the linker with a cyanoacetic acid
derivative 309 (preferentially an anhydride generated in situ) (Scheme 25). The resulting resin-
bound cyanoacetate 310 is then treated with an excess of an aromatic or aliphatic isothiocyanate
in NMP, DMF, or THF in the presence of a base such as diisopropylethylamine or DBU to give a
resin-bound thioamide 311. Treatment with the coupling agent EDC and a primary or secondary
amine gives the resin-bound ketene aminal 312. The use of condensing agents alone or in the
presence of a catalyst such as pyridinium tosylate or the salt of a tertiary amine is also reported
for this step. Cleavage conditions depend on the type of resin and linker used in the synthesis. For
example, trifluoroacetic acid was used with polystyrene resins having a Wang or a Rink linker.
The resulting products were ketene aminals bearing a -cyano substituent 313.
O O O
CN CN CN CN
OH O O O
X R1NCS EDC Cleavage
CN base R1HN S R2R3NH R1HN NR2R3 R1HN NR2R3
O
309 310 311 312 313
Scheme 25
It was also possible to carry out certain modifications on the resin-bound ketene aminal before
release—such as acylation of an NH group using an activated carboxylic acid derivative, or
treatment with isocyanates, isothiocyanates, or sulfonyl chlorides to give carboxamides, ureas,
thioureas, or sulfonamides, respectively.
4.21.1.2 Derivatives of Ketene Aminals
4.21.1.2.1 a-Amido enamines, R42C¼C(NR12)(NR2COR3), a-formamido enamines,

R32C¼C(NR12)(NR2CHO), and a-thioamido enamines, R42C¼C(NR12) (NR2CSR3)
It is usual to obtain -amido enamines by procedures similar to those used for the synthesis of
ketene aminals. Starting materials such as ynamines, N-acyl ketenimines, isothioureas, and
N-acylated ketene N,S acetals have been described previously <1995COFGT(4)967>.
(i) Formylation of ketene aminals

Formylation of ketene aminals has been carried out using sodium hydride to abstract a proton
from the ketene aminal, then adding formic acetic anhydride to give the N-formylated ketene
aminal <1993MI41>. For example, formylation of the ketene aminal 314 was carried out using
sodium hydride and formic acetic anhydride to give the N-formylated ketene aminal 315 in 24%
yield <1994MI119>.
OHC
NHMe NMe
O2NHC O2NHC
N Cl N Cl
Me N Me N
314 315
(ii) Acylation of ketene aminals

The preparation of a demethylnitenpyram affinity column 316 has been reported, whereby the
ketene aminal 317 was linked to EDC-activated agarose (Scheme 26) <1996MI1669>.
An intramolecular acylation of ketene aminals has been reported. Reaction of the ketene
aminals 318 with methyl iodide in the presence of a base such as silver oxide or potassium
carbonate gave the thioimidates 319 in 63–77% yield (Scheme 27). Desulfurization of 319 with
mercuric acetate produced an unexpected rearrangement reaction resulting in acylation of one of
the amino groups of the ketene aminal. The resulting N-acylated ketene aminals 320 were
obtained in 46–85% yields <1993HCA2817, 1997HCA273>.
HO2C(CH2)5HN
EtHN O
Aminohexanoic Cl H
acid agarose C O C (CH2)5 N
Me2HN (CH2)3 N
Et N C N (CH2)3NHMe2
Cl
Cl EDC
N N NH2
Cl O2N
O
H H 317
N N N C (CH2)5 N
O2N
316
Scheme 26
O2N NHR CH3I O2 N NHR O 2N NHR O 2N NHR

Hg(OAc)2
H3C
R1
OCHN NHR DMF R1 OCN NHR DMF S NHR NC RN COR1
S SMe AcOHg N
318 319 R1 320
O
Scheme 27
(iii) From amidines and formamidines

The persubstituted oxalic amidine 321 was reduced with lithium using THF as solvent and
ultrasound to give the dilithio salt of the tetraaminoethane 322 in quantitative yield. Reaction
with methyl benzoate gave the monobenzoylated structure 323, which was treated in situ with
an alkyl halide to give structures 324 in 59–61% yield. The dibenzoylated structure 325 was
obtained in 76% yield by reacting 322 with the stronger electrophile—benzoyl chloride
<1998MI183>.
Li Li Ph O Li Ph O
COPh COPh
ArN NAr ArN NAr ArN NAr ArN NRAr ArN NAr
PhMeN NMePh PhMeN NMePh PhMeN NMePh PhMeN NMePh PhMeN NMePh
321 322 323 324 325
The formamidines 326 were treated with methyl iodide to give the amidinium salts 327 then
converted to the -amido enamine 328 by reaction with 2 equiv. of silver acetate in dry acetoni-
trile (Scheme 28) <1999JCS(P1)2821>.
+ I–
NMe2 NMe2
NMe2 NMe2
MeI 2MeCO2Ag O O
H3C X H3C XMe
Me N Me HN
N N
Ph O Ph O Ph
Ph
326 (X = S or Se) 327 (X = S or Se) 328
Scheme 28
The reaction mechanism is thought to feature formation of an O-acylamidinium salt inter-

mediate 329, followed by acetate-induced deprotonation of the amidinium moiety leading to
intermediate 330, and finally intramolecular capture of the acetyl residue by the enamine moiety
previously generated (Scheme 29).
NMe2
2 MeCO2Ag H NMe2 O
O N
327 O 328
N Me H3C O Ph
Ph
329 330
Scheme 29
The nature of the metal counterion and the heteroatom of the incoming nucleophile greatly
influences the reaction. For example, the yield is much lower when potassium acetate is used
instead of silver acetate. It was also demonstrated that the formamidines 326 could be converted
directly to 328 by treatment with silver acetate in dry acetonitrile (Scheme 30).
AcOAg
NMe2
2 MeCO2Ag H NMe2 O NMe2 O
H3C X
O O 328
HN
N Me N Me
Ph
AgX Ph Ph
326 (X = S or Se)
Scheme 30
(iv) From cyanamides

The N-benzoyl derivatives 330a and 330b were synthesized from the reaction of benzoyl cyana-
mide 331 with ethyl acetoacetate and ethyl benzoylacetate, respectively, in the presence of a
Ni(acac)2 catalyst <1993IZV419>.
(v) From ring opening of imidazoles

Treatment of the imidazole 332 with ethyl chloroformate in aqueous sodium bicarbonate at room
temperature resulted in a complex mixture of products, which included the -formamido enamine
333, isolated as a mixture of (E)- and (Z)-isomers in 20% yield <1997CPB75>.
O Ph Me
O NC N
R HN EtO2C NH N CHO
Ph
O
HN C N MeHN N
EtO NH2 NC NHMe
O Me
330a (R = Me) 331 332 333

b (R = Ph)
(vi) Ring opening of isothiazoles

Desulfurization of the nitroisothiazole structure 334 with triphenylphosphine resulted in ring open-
ing and the formation of the highly reactive intermediate ketene imine 335, which was trapped by
the addition of benzoic acid to give the unstable adduct 336. Intramolecular N-acylation of 336 as
shown in Scheme 31 resulted in the -amido enamines 337 in 67% yield <1998HCA2388>.
PPh3
PhHN NO2 CH2Cl2 O2 N NHPh O2N NHPh
N2, 0 °C NPh RCO2H
Ph N C C PhN NHPh PhHN NPh
Ph N S N
–Ph3PS NO2 NHPh
Ph O O O O
Ph
334 335 R 336 337
Scheme 31
(vii) Ring opening of thiazines

Reaction of the thiazine 338 with ammonia in dry ether resulted in ring opening and formation of
the -thioamido enamine 339 <1997ZOB1195>. The nature of the solvent is important and if the
reaction is carried out in alcoholic ammonia, a different product is obtained. The reaction is not
generally useful in producing -thioamido enamines since reaction with primary or secondary
amines results in thiazines where the chloro group is substituted by the amine. However, this
appears to be the first reported example of -thioamido enamines.
(viii) Miscellaneous
The N-formylketene aminal 340 has been reported, but no details of its synthesis were given
<1990EUP0381130>.
Cl NHMe
O NH2 O2NHC
N
C S N
Ph H HN
H2N OHC
S
Ph S
O N
338 339 340
Br
4.21.1.2.2 a-Alkoxycarbonylamino enamines, R32C¼C(NR12)(NHCO2R2)

There has only been one reported instance of the synthesis of an -alkoxycarbonylamino enamine
prior to 1996 <1995COFGT(4)967>. Three other reports have now appeared in the literature.
Compounds of this nature were isolated as by-products arising from ring opening of the
imidazole 332 referred to above (Section 4.21.1.2.1). Thus, the -alkoxycarbonylamino enamines
341 and 342 were isolated in 2% and 7% yields, respectively <1997CPB75>.
EtO2C NH NHMe OHC NH NHMe
NC N CO2Et NC N CO2Et
Me Me
341 342
-Alkoxycarbonylamino enamines have also been prepared by the ring opening of pyrimi-
dines. Thus, pyrimidine 343 was nitrated with nitric acid and sulfuric acid to give the 5,5-
dinitrodihydropyrimidine 344 which was heated with anhydrous methanol or ethanol to give
the -alkoxycarbonylamino enamines 345 in 45% yield <2001ZOR766>.
A more general method for preparing -alkoxycarbonylamino enamines has been reported,
whereby ketene aminals 346 are deprotonated with sodium hydride, then acylated with a carbo-
nate to give a range of structures having general formula 347. Ketene aminals containing a
diazaheterocyclic ring have also been reacted in this way to give structures 348
<2003USP6538013>.
O OH
NO2
HN N NO2 O2N NHCO2R YHC YHC O YHC O
O2N
Me N OH OH O2N NH2 R2R1N NHR R2R1N N OR RN N OR
NO2 R
343 344 345 346 347 348

(R = Me, Et) (Y = CN, NO2) (Y = CN, NO2) (Y = CN, NO2,
CH2CN, CH2NO2)
4.21.1.2.3 a-Ureido enamines, R32C¼C(NR12)(NHCONR22)

-Ureido enamines have been synthesized from ketene aminals, an oxazin-6-one, and an imino
ester <1995COFGT(4)967>. More recently, it has been reported that heating ketene aminals
349 with various disubstituted ureas 350 in DMF gave the -ureido enamines 351 in low yield
(3–11%) <1999HCO203>. These were shown by X-ray crystallography and NMR to exist as the
(Z)-isomers, stabilized by intramolecular hydrogen bonding. In contrast, the reaction of (349
R = Et) with monosubstituted ureas gave -ureido enamines which existed as a mixture of
(E)- and (Z)-isomers.
NC NH2 O NC NH2
O
RO2C NH2 H2N NR1R2 RO2C HN
NR1R2
349 350 351
4.21.1.2.4 N-Acylated a-ureido enamines

N-Acylated -ureido enamines have been synthesized by the reaction of an N-acylketenimine with
carbodiimides, as well as by a Curtius rearrangement of an acyl azide <1995COFGT(4)967>. Further
examples of the latter technique have been reported, whereby the acyl azide 352 was treated with
aromatic amines to give the N-acylated -ureido enamines 353 in 22–49% yield <1998MI990>.
H
O N Ar
NC O NC
C N3 NH
N C C N C C
H NH H NH
NC NO2 NC NO2
O O
Cl Cl
352 353
4.21.1.2.5 gem-Diureido alkenes, R22C¼C(NHCONR12)2

There has only been one instance of a gem-diureido alkene synthesis <1995COFGT(4)967> with
no syntheses reported in the 1990s.
4.21.1.2.6 a-Thioureido enamines, R32C¼C(NR12)(NHCSNR22), and a-isothioureido enamines,

R32C¼C(NR12)(NH(C¼NR2)SR)
The persubstituted oxalic amidine 354 has been reduced with lithium using THF as solvent and
ultrasound to give the dilithio salt of the tetraaminoethane 355 in quantitative yield. Quenching of
the dilithio salt with 2 equiv. of phenyl isocyanate gave the dilithium salt 356 which on treatment
with methyl iodide gave the isothiourea derivative 358 in 92% yield. Alternatively, treatment of
356 with methanol gave the thiourea 357 in 95% yield. When methyl isothiocyanate or benzoyl
isothiocyanate are used instead of phenyl isothiocyanate, the starting amidine 354 is recovered as
the major product after an aqueous work-up. This synthesis has been used to produce a variety of
macrocylic structures such as 359 <1998MI1803>.
The -thioureido enamine 360 has been proposed as a reaction intermediate in the synthesis of
a thiouracil from ketene aminals and acyl isothiocyanates <1998HCA718>.
Li NPh NPh Li
Li NHPh NHPh
Li
S S S S
ArN NAr ArN NAr ArN NAr ArN NAr
PhMeN NMePh PhMeN NMePh PhMeN NMePh PhMeN NMePh
354 355 356 357
S S
NPh NPh
MeS SMe EtO2C NH2
ArN NAr S
S S
H HN
PhN NPh HN R
PhMeN NMePh ArN NAr
358 PhMeN NMePh 360
359
4.21.1.2.7 a-Cyanamino enamines, R22C¼C(NR12)(NHCN)

A specific synthesis of the sodium salt of -cyanamino enamine 361 has been reported, involving
the reaction of malononitrile with sodium dicyanamide at an elevated temperature and in the
presence of an aprotic dipolar solvent to give the product in 55–80% yield <1994EUP611751>.
This represents an improvement over the previous synthesis which involved the reaction between
sodium cyanamide and 1-amino-1-ethoxy-2,2-dicyanoethylene 362 – a reaction which only pro-
ceeded in modest yield (28%). Moreover, the previous synthesis required the prior synthesis of
the required ketene-N,O-acetal, whereas the more recent synthesis involves the use of commer-
cially available reagents. In a later report <1995WOP9503282>, it was revealed that the
-cyanamino enamine 361 could be prepared by reacting a dialkyl cyanimidocarbonate 363
with an alkali metal salt of malononitrile to give the alkali metal salt of the ketene-N,O-acetal
364. Immediate reaction with ammonia in a polar solvent and with heating furnished 361. If
diethyl (N-cyanimido)-carbonate (363; R = Et) is used, both reactions can be carried out in the
same reaction vessel using ethanol as solvent.
The -cyanamino enamine 365 has been reported as a by-product of the decarboxylation
reaction of the bis-triazole 366 <1999JOC6756>.
Na EtO2C CO2Et
NC
NC NH2 NC NH2 RO NC NCN N N N
N PhHN NHCN N N
NC NCN NC OEt RO CN NC OR N N
NHPh Ph Ph
Na
361 362 363 364 365 366
4.21.1.2.8 a-Sulfonylamido enamines, R32C¼C(NR12)(NHSO2R2)

-Sulfonylamido enamines have been synthesized from the ketene dithioacetal 367 (Scheme 32). The
ketene dithioacetal was treated directly with a primary cycloalkylamine to give the intermediate ketene
N,S-acetals 368. An alternative method was used to introduce isopropylamine, whereby the ketene
dithioacetal was treated with hydrogen peroxide to give the oxidized intermediate 369 in 41% yield,
then substituted with isopropylamine to give the corresponding ketene-N,S-acetal 368. Treatment
of the ketene-N,S-acetal 368 with the sodium salts of various sulfonamides 370 then gave the
-sulfonylamido enamines 371 in 25–78% yield <1998JMC3239, 1997EJM453>.
R1HN O O
S
NH2
R2NH2
R1HN O O CHNO2
CHNO2 EtOH N 370
CHNO2 S
N NHR2
MeS SMe MeS NHR2 Dioxane/DMF H
367 368 1 equiv. NaOH N 371
H 2O2 R2NH2
AcOH MeOH
CHNO2 R2 = CHMe2 or cycloalkyl
Me
MeS S
O
369
Scheme 32
4.21.1.3 Derivatives Bearing at Least One NRX Function
4.21.1.3.1 a-Hydrazino enamines, R42C¼C(NR12)(NR2NR32)

-Hydrazino enamines have been proposed as intermediates in the synthesis of heterocycles, and
a small number of references report the isolation of -hydrazino enamines from a variety of
methods similar to those used in the synthesis of ketene aminals <1995COFGT(4)967>.
(i) From ketene N,S-acetals and ketene dithioacetals

Examples of the use of ketene N,S-acetals and ketene dithioacetals as starting materials for
-hydrazino enamines have been reported previously <1995COFGT(4)967>. A further example
involves the reaction of the ketene dithioacetal 372 with the primary amine 373 to give the ketene
N,S-acetal 374a. Treatment of 374a with hydrazine then resulted in the formation of the
-hydrazino enamine 374b in 93% yield <1992JMC3141>.
CHNO2
O2N SMe Me2N Me2N
S S
O NH2 O N X
SMe H
372 373 374a (X = SMe)
b (X = NHNH2)
The ketene dithioacetal 372 has also been the starting point for the synthesis of the -hydrazino
enamines 375 and 376. In both cases, the ketene dithioacetal was reacted first with the relevant
amine to produce an intermediate ketene N,S-acetal, that was then treated with the hydrazine
<1989USP4806553>.
Cl CHNO2
Me CHNO2
N N N N NHNMe2
N NHNMe2 N H
H S N Me
375 376
Other examples of the reaction of ketene N,S-acetals with hydrazines have been reported
<1988EUP0302389>.
(ii) From vinylidene dihalides

The -hydrazino enamines 377–379 were synthesized from 1,1,1-trihalogeno-2-nitroethanes via
vinylidene dihalides <1990EUP0381130>.
(iii) Transamination of ketene aminals

The reaction between 1,1-diamino-2,2-dinitroethene 380a and hydrazine is reported to give the
-hydrazino enamine 381b by means of a transamination process <2002JCR(S)257>.
NHNMe2 NHMe NHNH2

O2NHC O2NHC O2NHC
X
RN Me2NN HN
(O2N)2C
NH2
N N N
X Cl
377 (X = H, Cl; 378 379 380a (X = NH2)

R = H, Me) b (X = NHNH2)
4.21.1.3.2 gem-Dihydrazino alkenes, R32C¼C(NR1NR22)2

Reported syntheses of gem-dihydrazino alkenes are rare <1995COFGT(4)967> and there have
been no instances since the 1990s.
4.21.1.3.3 Derivatives of a-hydrazino enamines
(i) N-Acylated hydrazino enamines

N-Acylated hydrazino enamines have been obtained by acylation of the parent -hydrazino
enamines with acetic anhydride, methyl chloroformate, or methyl isocyanate. They have also
been obtained by treating imino esters with arylcarbonylhydrazines <1995COFGT(4)967>.
More recently, it has been shown that it is possible to introduce substituents into the -position
of N-acylated hydrazino enamines since the C-2 position is more nucleophilic than the amino
groups. Thus, the N-acylated hydrazino enamines 381 react with an equimolar amount of phenyl
isothiocyanate in dry DMF at room temperature to give the propenethioamides 382
<1999JHC1183>.
Treatment of the N-acylated hydrazino enamine 381b with diethyl acetylenedicarboxylate is
thought to involve a Michael-type reaction, whereby the -carbon of the enamine reacts with the
alkyne to give the proposed N-acylated hydrazino enamine intermediates 383. However, these
intermediates have not been isolated since they cyclize to heterocycles <1995H1479>.
S EtO2C CO2Et
NHNHCOR1 PhHN NHNHCOR1 NHNHCOR1
R2 NH2 NH2
R2 EtO2C NH2
381a (R2 = CN) 382 (R2 = CN, CO2Et) 383
b (R2 = CO2Et)
The trans-isomer of the epoxy imidate 384 reacts with carbazates (H2NNHCOR) to give epoxy
acylamidrazones 385, which can then be converted to the N-acylated -hydrazino enamines 386
by heating in methanol, or by heating in acetone in the presence of triethylamine (Scheme 33)
<2001S2435>.
R1 CN Br N(Bu)4 R1 CN R3CONHNH2 R1 CN
ROH OR H O N
H O CN H O
NHCOR3
HN H2N
384 385
MeOH or NC NH2
acetone/NEt3
R1 NHNHCOR3
O
386
Scheme 33
The proposed mechanism involves a rearrangement where the driving force is furnished by the
possibility of intramolecular H-bonding between the oxirane and the acylamidrazone substituent
(Scheme 34).
R1 CN NC NH2
NC NH2
H O NH2
H N R1 N R1 N NHCOR2 386
N HO H N O H
R2OC COR2
Scheme 34
(ii) Hydrazones of -hydrazino enamines

Only one synthesis of the hydrazone of an -hydrazino enamine has been reported previously
<1995COFGT(4)967>. A further example has now been published <1999MI97>. The reaction
of ethyl cyanoacetate with the thiourea structure 387—synthesized as shown in Scheme 35—
resulted in the formation of the -hydrazino enamine 388 with concurrent formation of a thiazole
ring. A yield of 82% was obtained.
Ph
Ph N
PhHN
SCH2COPh NC S
HN NH2 i. PhN=C=S
HN N EtO2C NC HN N
S DMF KOH
S
HN Me
ii. PhCOCH2Br HN Me EtO2C HN Me
387 388
Scheme 35
Structure 388 was further reacted with a range of nitrogen-containing nucleophiles to build
different heterocyclic structures at the -position. Thus, reaction with hydrazines gave the
pyrazoles 389, reaction with hydroxylamine hydrochloride gave the isoxazole-5-one 390, and
reaction with urea or thiourea gave the pyrimidines 391.
Ph Ph Ph
Ph N Ph N Ph N
S S NH2 S
HN N HN N N HN N
N N
X
N O N HN Me
R HN Me HN Me
O O OH
389 390 391 (X = O, S)
The thiazole derivative 392 was also synthesized and treated with malononitrile and ethyl
cyanoacetate to give the condensed products 393a and 393b, respectively, in 79–82% yield. These
were in turn treated with hydrazine hydrate or phenylhydrazine to give the pyrazolo[3,4-d]thiazoles
394 and 395, respectively.
H Ph
OH OH
N N N N
Ph N CN Ph N CN
Ph N NH2 Ph N NH2
S S
NH2 S NH2 S
HN N NC HN N
HN N HN N
S N N
HN Me X HN Me N N
HN Me Ph HN Me
X X
392 393a (X = CN) 394a (X = NH2) 395a (X = NH)

b (X = CO2Et) b (X = OH) b (X = O)
4.21.1.3.4 a-Hydroxylamino enamines and a-alkoxyamino enamines, R32C¼C(NR12)(NHOR2)
(i) From ketene dithioacetals and ketene N,S-acetals

The (E)-isomer of the -alkoxyamino enamine 399 was synthesized by reacting the ketene
dithioacetal 397 with a primary amine 396 to give the intermediate ketene N,S-acetal 398 in
57% yield, then converting 398 to the final product in 64% yield by reaction with O-methyl-
hydroxylamine (Scheme 36) <1989USP4806553>.
CHNO2
Cl MeS SMe Cl Cl
Me 397 Me CHNO2 NH2OMe Me CHNO2
N N N N N N
NH2 N SMe N NHOMe
396 398 H 399 H
Scheme 36
The -alkoxyamino enamine 400 and the -hydroxylamino enamines 401 and 402 were simi-
larly prepared <1989USP4806553, 1993EUP563686>.
(ii) From vinylidene dihalides

It has been reported that the -alkoxyamino enamine 403 was synthesized from 1,1,1-trihalo-
geno-2-nitroethane via a vinylidene dihalide in a similar manner to ketene aminals
(Section 4.21.1.1.3) <1990EUP0381130>.
F3C F Cl NHMe
O O O2NHC
Me CHNO2
N NHEt NHEt MeON
N
O N NHOMe S
H Cl
Cl H HNOH H HNOH
N
400 401 402 403
(iii) From thioureas and isothioureas

The -alkoxyamino enamine 404 was prepared via the thiourea/isothiourea route normally used
for the synthesis of ketene aminals (Scheme 37) (Section 4.21.1.1.2) <1988EUP0302389>.
NHMe
HN O2NHC
NHMe NMe
MeO MeNCS NaH CH3NO2 N
S MeS
NCH2Ar MeI NCH2Ar MeO
N
MeO MeO
404 N
Scheme 37
4.21.1.3.5 a-Thiophosphoramido enamines, R52C¼C(NR12)(NR2)PO(OR3)(SR4)

A patent has described the synthesis of -thiophosphoramido enamines 405 by treating ketene
aminals 406 with sodium hydride to deprotonate the secondary amino group, then adding a
phosphonochloridethiolate 407 <1995EUP684247>.
R5 OR1 R5
OR1
N P SR2 NH
NC(Y)C NC(Y)C Cl P SR2
O
NR3R4 NR3R4 O
405 407
406
4.21.1.4 Derivatives Bearing One NY or NZ Function and One NR2 Function
4.21.1.4.1 a-Alkylideneamino enamines, R32C¼C(NR12)(N¼CR22)

The thiazolidines 408 were methylated with trimethyloxonium tetrafluoroborate to give the
nitrilium salts 409, which were reacted with sodio diethyl malonate to give a mixture of
products, one of which was the -methyleneamino enamine 410 obtained in low yield
(0–11%) <1993H55>. Reaction with sodio ethyl acetoacetate failed to give a similar type of
product.
S NY S NY S NY
N N N CO2Et
CN C
MeHN CO2Et
NMe BF
4
408 409 410 (Y = Me, Et, CH2Ph)

The mechanism proposed for the formation of 410 is shown in Scheme 38. The reaction does
not appear to have much synthetic utility. However, it does appear to be the first reported
synthesis of an -alkylideneamino enamine.
S NY S NY
EtO2C
H
EtO2C N N 410
C CO2Et
MeN CO2Et
N
CH3
Scheme 38
4.21.1.4.2 a-Aminoalkylideneamino enamines, R42C¼C(NR12)(N¼CR2NR32),

R32C¼C(NR12)(N¼CXNR22)
-Aminoalkylideneamino enamines have been synthesized from a variety of starting materials
including a ketene aminal, an iminium perchlorate, acetals and enamines, and ketene N,S-acetals
<1995COFGT(4)967>.
(i) From ketene N,S-acetals

Further examples of the use of ketene N,S-acetals have been reported, whereby the ketene
N,S-acetals 411 were treated with formamidine acetate 412 in the presence of sodium hydroxide
and ethanol to give the -aminoalkylideneamino enamines 413 in 62–86% yields <1997AF35>.
H2N H
EtO2C SMe NH EtO2C N
NC NHR H2N H NC NHR

411 412 413
(ii) From ketene aminals

The reaction of ketene aminals 414 with the diethyl acetal of DMF (Me2NCH(OEt)2) led to
the mono-amidines 415 in high yield (97–98%) <1996CHE699>. Under the same conditions, the
di-amidine 416 was obtained in 97% yield from the ketene aminal 417.
Treatment of the diamidine 416 with benzylamine resulted in a mixture of transamination
products (418–420) obtained in low yield. The same reaction carried out on (415; R1 = R2 = Me)
gave 418 and 419 <1996CHE699>.
NMe2 NMe2
NC NH2 NC N NC N NC NH2
O2N NR1R2 O2N NR1R2 O2N N O2N NH2

NMe2
414 (NR1R2 = NMe2, NHMe) 415 416 417
NMe2 NMe2
NC NHCH2Ph NC N NC N
O2N NHCH2Ph O2N NHCH2Ph O2N NH2

418 419 420
4.21.1.4.3 a-Diaminomethyleneamino enamines, R32C¼C(NR12)(N¼C(NR22)2)

Only one synthesis of an -diaminomethyleneamino enamine has been reported
<1995COFGT(4)967> and none since the 1990s.
4.21.1.4.4 a-Bis(methylthio)methyleneamino enamines, R22C¼C(NR12)(N¼C(SMe)2)

Only one synthesis of an -bis(methylthio)methyleneamino enamine has been reported
4.21.1.4.5 a-Azo enamines, R32C¼C(NR12)(N¼NR2)

-Azo enamines have been synthesized from a pyrazole ring system and from a dimeric bipyrazole
structure <1995COFGT(4)967>. Further examples of the latter synthesis have been reported
<1994CB1729>, whereby the dimeric bipyrazoles 421 were treated with Pb(OAc)4 in methanol to
give the azo-substituted enamines 422.
EtO2C NHAr EtO2C NHAr
N H2N N
H2N N N
N N
H2N N NC N
EtO2C NHAr EtO2C NHAr
421 422
4.21.1.4.6 a-Azido enamines, R22C¼C(NR12)N3

Synthesis of -azido enamines has been reported starting from gem-diazido alkenes, N-alkyl-5-
phenylisoxazolium fluoroborates, -chloro enamines, and ketene N,S-acetals <1995COFGT(4)967>.
An attempt to synthesize the azido enamine 425 from the norprolinate 424 proved unsuccessful and
gave the geminal diazide 423 instead (Scheme 39) <2002HCA885>.
i. COCl2 /toluene i. COCl2/toluene

ii. DABCO ii. DABCO
N3 N3 S iii. NaN3 / THF N3
CO2Me iii. NaN3 / THF CO2Me CO2Me
N N N
423 424 425
Scheme 39
This was attributed to the strained nature of the chloriminium chloride intermediate 426, which
prefers to undergo addition of a second chloride ion to relieve the strain of the double bond
exocyclic to a four-membered ring and to give the geminal dichloride 427. Subsequent substitu-
tion with azide ions produces the observed product. Thus, the alternative mechanism via the
chloro enamine 428 cannot take place.
Cl–
Cl Cl Cl Cl
CO2Me CO2Me CO2Me
N N N
426 427 428

4.21.1.4.7 a-Isocyano enamines, R22C¼C(NR12)NC

Only one synthesis of an -isocyano enamine has been reported <1995COFGT(4)967> and none
since the 1990s.
4.21.1.4.8 a-Phosphimino enamines, R32C¼C(NR12)(N¼PR23)

-Phosphimino enamines have been synthesized from ketene aminals, an -azido enamine, and a
bisphosphimino alkene <1995COFGT(4)967>, but there have been no reports of syntheses since
the 1990s.
4.21.1.4.9 a-(N,N0 ,N0 -Triphenylphosphorimidic triamido) enamines, R2C¼C(NHPh)

(N¼P(NHPh)3)
The synthesis of only one -(N,N0 ,N0 -triphenylphosphorimidic triamido) enamine has been
reported <1995COFGT(4)967> with none since the 1990s.
4.21.1.4.10 gem-Amido nitro alkenes, R22C¼C(NR1COPh)(NO2)

Methods for the synthesis of gem-amido nitro alkenes have been reported for the first time.
(i) From nitrooxazoles

Ring opening of the nitrooxazole 429 with nucleophilic amines affords gem-amido nitro alkenes
430 in 70–98% yields (Scheme 40) <1999T13809, 1998JOC6050>. The mechanism involves a
three-step hetero-domino process involving the oxazolone 431 and the corresponding ring-opened
product 432 as key intermediates. A mixture of isomers is usually obtained.
O Ph O
NO2 N O NO2
N HNR1R2 N HN NO2
H N
CHCl3 Ph H
Ph H O NR1R2 Ph
O rt OH NR1R2 R2R1N H
H 430
429 432
431
Scheme 40
(ii) From azlactones

Unsaturated azlactones 433 have also been used to synthesize gem-amido nitro alkenes. The
azlactones are converted in two steps to dichloro -acylamino carboxylic acids 434, which
are then reacted with sodium nitrite in the presence of sodium hydrogen carbonate. A
chloro group is substituted by a nitro group, then decarboxylation takes place to give the
gem-amido nitro alkenes 435 in 50–60% yields (Scheme 41) <1997ZOB1046>. The stereo-
chemistry of the products has been determined with the nitro group being trans to the
aromatic ring.
Ph NaNO2
N Ar NHCOPh Ar NHCOPh NaHCO3
Ar H2O Cl2
O Cl Cl
H CO2H H CO2H
H O
433 434
Ar NHCOPh –CO2 Ar NHCOPh Ar NHCOPh

Cl NO2 Cl NO2
H CO2H H H NO2
435
Scheme 41
4.21.1.4.11 gem-Alkoxycarbonylamino nitro alkenes, R32C¼C(NR1CO2R2)(NO2)

The carbamate 436 was isolated as a low-yield by-product (5%) from the reaction of nitrostyrene
437 with ethyl [(4-nitrobenzenesulfonyl)oxy]carbamate. The main product was the aziridine 438
<1998T6169>. Although this method is not suitable for the synthesis of gem-alkoxycarbonyla-
mino nitro alkenes, this is the first synthetic example of a compound containing this functional
group.
4.21.1.5 Derivatives Bearing One NY Function and One NRX Function
4.21.1.5.1 gem-Acylhydrazino azido alkenes, R22C¼C(NHNHCOR1)N3

gem-Acylhydrazino azido alkenes have been involved as intermediates in heterocyclic synthesis
but have not so far been isolated <1995COFGT(4)967>.
4.21.1.6 Derivatives Bearing Two NY Functions
4.21.1.6.1 gem-Alkylideneamino isocyanato alkenes, R22C¼C(NCO)(N¼CR12)

gem-Alkylideneamino isocyanato alkenes have been reported on only one occasion and not since
the 1990s <1995COFGT(4)967>.
4.21.1.6.2 gem-Dithioureido alkenes

Only one example of a gem-dithioureido alkene has been reported in the 1970s
<1995COFGT(4)967>.
4.21.1.6.3 gem-Bisazo alkenes, R22C¼C(N¼NR1)2

The syntheses of some gem-bisazo alkenes were reported mainly in the late 1970s and early 1980s
<1995COFGT(4)967>. Yields were poor and no further syntheses have been reported.
4.21.1.6.4 gem-Azido phosphazido alkenes, R2C¼C(N¼N–N¼PPh3)N3

Only one example of a gem-azido phosphazido alkene has been reported in the 1980s
<1995COFGT(4)967>.
4.21.1.6.5 gem-Diazido alkenes, R2C¼C(N3)2

gem-Diazido alkenes have been synthesized from vinylidene dichlorides by treatment with sodium
azide <1995COFGT(4)967>. A further report on the synthesis of the diazide 439 from the
vinylidene dichloride 440 has been published <1993JCR(S)162>.
NO2 NO2 NO2

Ph
N
Ph NHCO2Et Ph
CO2Et
436 437
438
N3 Cl
NC N3 NC Cl
439 440
4.21.1.6.6 gem-Dinitro alkenes, R2C¼C(NO2)2

gem-Dinitro alkenes have been synthesized by a number of methods, which include the nitration
of alkenes and alkanes with nitric acid or dinitrogen tetroxide, thermal extrusion of N2O4 from
nitro alkanes, thermal or acid/base-catalyzed dehydrations of dinitro alkanols, base-catalyzed
extrusions, generation from dinitromethane and from diazo compounds <1995COFGT(4)967>.
Further syntheses have been reported since the 1990s.
(i) From dinitroalkanols

The acid-catalyzed dehydration of the dinitro alkanol 441 to form the dinitro alkene 442 in situ
has already been described <1995COFGT(4)967>.
NO2 NO2
HO NO2 NO2
441 442
In a similar manner, the potassium salt of 441 was dehydrated to form 442, which was then
reacted in situ with trinitromethane to form the hexanitroisobutene anion 443 (Scheme 42)
<1999ZOR1581>.
K NO2
NO2 NO2 K NO2 O2N NO2
HC(NO2)3 HC(NO2)3
HO NO2 NO2 –HNO2 O2N NO2 –HNO2 O2N NO2

NO2 NO2
442 K
443
Scheme 42
(ii) From diazo compounds

The reaction of diazo compounds with CI(NO2)3 to give dinitroalkenes has been described
previously <1995COFGT(4)967>. More recently, the reaction of cyanodinitroethoxycarbonyl-
methane 444 with phenyldiazomethane resulted in the formation of 1,1-dinitro-2-phenylethene
445 amongst other products. This contrasts with the reaction of 444 with diazomethane or
diazoethane where triazole rings were formed <1993ZOR61>. Treatment of the oxadiazoles
446 with phenyldiazomethane (PhCHN2) gave a mixture of products, which included the dinitro-
alkene 445 obtained in 20–23% yield <1999ZOR1581>.
NC NO2 NO2 N O
C NO2
EtOCO NO2 Ph NO2 Ph N R
NO2
444 445 446 (R = Cl, CO2Et)
4.21.1.6.7 gem-Arylazo nitro alkenes, R2C¼C(NO2)2(N¼NAr)

Very few syntheses of alkenes containing gem-nitro and arylazo groups have been reported
4.21.1.6.8 gem-Aminoalkylideneamino nitro alkenes, R32C¼C(NO2)2(N¼CR1NR22)

The reaction of the imidazole structure 447 with p-toluidine in aqueous methanol resulted in ring
opening and formation of the gem-imino nitro alkene 448 in 80–90% yield <1994H1511>.
NO2 HN NO2
N Me Me NH N
Me
N H NO2
O2N
448
447
4.21.1.6.9 gem-Dimethoxazonyl alkenes, R2C¼C(NO¼NOMe)2

The synthesis of a gem-dimethoxazonyl alkene was reported in 1969, with no further examples
<1995COFGT(4)967>.
4.21.1.6.10 gem-Imino phosphimino alkenes, R32C¼C(N¼PR13)(N¼CR22)

The synthesis of two gem-imino phosphimino alkenes was reported in 1972, but there have been
no further examples <1995COFGT(4)967>.
4.21.1.6.11 gem-Diphosphazido alkenes and gem-diphosphimino alkenes,

R22C¼C(N¼NN¼PR13)2, R22C¼C(N¼PR13)2
There have been no reported syntheses of gem-diphosphazido alkenes or gem-diphosphimino
alkenes since the one reported method published in 1985 <1995COFGT(4)967>.
4.21.1.6.12 gem-Disulfoximido alkenes, R22C¼C(N¼SOR12)2

A synthesis of gem-disulfoximido alkenes was reported in 1983 <1995COFGT(4)967>, but no
further syntheses have been published.
4.21.2 FUNCTIONS CONTAINING ONE NITROGEN AND ONE PHOSPHORUS,

R32C¼CNR12PO(OR2)2, R32C¼CNR12PR22, etc.
4.21.2.1 Derivatives Bearing a Phosphino Function
4.21.2.1.1 a-Phosphino enamines, R22C¼C(PPh2)NHR1

-Phosphino enamines have been synthesized from dihalo alkenes, halo enamines, and ketimines
<1995COFGT(4)967>. A further example of the synthesis of these compounds from halo enamines
has been reported. Thus, the chloro enamine 449 was treated with diphenylphosphine (Ph2PH) at
room temperature in the presence of 5 mol.% PdCl2(PPh3)2 as a catalyst to give the phosphino
enamines 450 in 70–84% yield <1999TL573>. Benzene was used as solvent and triethylamine was
present as a base. The carbon–halogen bond in 449 is very reactive due to the effect of the
-dialkylamino group. The reaction can also be carried out using diphenyltrimethylsilylphosphine
(Ph2PSiMe3) with 5 mol.% PdCl2(PPh3)2 as a catalyst to give the same products without the need of
additional purification, though prolonged reaction times are required for completion.
R1 X R1 PPh2
R2 NEt2 R2 NEt2
449 (R1 = Me, H; 450

R2 = Me, TMS;
X = Cl, Br)
4.21.2.1.2 gem-Amido phosphino alkenes, R32C¼C(NHCOR1)PR22

The synthesis of a gem-amido phosphino alkene was reported in 1979, but no further examples
have been published <1995COFGT(4)967>.
4.21.2.2 Derivatives Bearing a Phosphonium Group
4.21.2.2.1 a-Trialkylphosphonio enamines, R32C¼C(NR12)P+R23

-Trialkylphosphonio enamines have been rarely synthesized with the only example involving an
-halo enamine as starting material <1995COFGT(4)967>. An alternative method of synthesis
has now been reported (Scheme 43) <1993ZOB80>. The reaction of the isocyanate 451 with
triphenylphosphine resulted in phosphorylation to give an intermediate 452 that contains a labile
hydrogen atom at the -position. This favors easy dehydrochlorination to form an alkene.
Moreover, the resulting chloride ion reacts with the isocyanate group to form a reactive chloro-
carbonylamino (NHCOCl) group. The observed products 453 can be isolated in 87–96% yield.
Hydrolysis of (453; R1 = R2 = Cl) gave the trialkylphosphonio enamine 455 in 95% yield.
i. H2O
R1 Cl R1
+
P Ph3Cl
– R1 + –
P Ph3 Cl ii. NaClO4
PPh3
Cl CH Cl CH
R2 N C O R2 N C O R2 NHCOCl
451 452 453
+ R1
+
P Ph3 ClO4–
R1 P Ph3 ClO4– –CO2
R2 NHCO2H R2 NH2
454 455
Scheme 43
4.21.2.2.2 gem-Carboxyamino phosphonio alkenes and gem-chlorocarbonylamino phosphonio

alkenes, R2C¼C(NHCO2H)P+Ph3 and R2C¼C(NHCOCl)P+Ph3
The synthesis of the gem-chlorocarbonylamino phosphonio alkene 453 was described in Section
4.21.2.2.1 (Scheme 43). Hydrolysis of 453 resulted in the gem-carboxyamino phosphonio alkene 454
as an intermediate which spontaneously decarboxylated to give structure 455.
4.21.2.2.3 gem-Amido phosphonio alkenes, R22C¼C(NHCOR1)P+Ph3

gem-Amido phosphonio alkenes have been synthesized from gem-amido carboxyalkenes,
N-trichloroethylamides, and N-tetrachloroethylamides, and by modification of gem-amido phos-
phonio alkenes <1995COFGT(4)967>.
(i) From gem-amido carboxy alkenes

Further examples of the conversion of gem-amido carboxy alkenes 456 to gem-amido phosphonio
alkenes 457 have been reported <1993ZOB87>. The reaction involves chlorination of the alkene,
followed by treatment with triphenylphosphine <1995COFGT(4)967>. The required starting
materials are in turn prepared by hydrolysis of unsaturated azlactones 458.
Ar
+ –
CO2H P Ph3Cl N
Ar NHCOR Ar NHCOR R O
O
456 457 458
(ii) From N-fluoroacetyltrichloroacetamide

Reaction of N-fluoroacetyltrichloroacetamide 459 with phosphorus pentachloride gave N-tri-
chloroacetylfluoroacetimidoyl chloride 460 in 82% yield, which was treated with an equivalent
of an arylphosphine to give the gem-amido phosphonio alkenes 461 as a mixture of isomers
((E)/(Z) 6:1) (Scheme 44) <2002JFC107>.
O Cl PArAr'2 Cl
O PCl5 O PArAr'2
FHC
F HN F N HN COCCl3
CCl3 CCl3
459 460 461a (Ar = Ar' = Ph; 77%)
b (Ar = Ph, Ar' = 4-MeOC6H4; 86%)
Scheme 44
(iii) From N-tetrachloroethylamides

gem-Amido phosphonio alkenes have previously been synthesized from N-tetrachloroethylamides
<1995COFGT(4)967>. A further example has been reported whereby the N-tetrachloroethyl-
amide 462 was synthesized in 68% yield by the reaction of the isocyanate 463 with cyanomethyl-
enetriphenylphosphorane 464, then treated with 1.5 equiv. of triphenylphosphine to give the
gem-amido phosphonio alkene 465 in 92% yield <1997ZOB391>. The reaction involves nucleo-
philic substitution by the triphenylphosphine, followed by dehydrochlorination.
Similar treatment of the N-tetrachloroethylamide 466 with 1.1 equiv. triphenylphosphine gave
the gem-amido phosphonio alkene 467 in 85% yield <2002ZOB226>.
Cl PPh3 Cl
Cl3C O Cl Cl2C O
HN NC
Cl3C PPh3 HN
PPh3 N C O PPh3
NC NC
463 464
462 465
Cl PPh3 Cl
Cl3C O Cl2C O
HN HN
CHCl2 CHCl2
466 467
(iv) By modification of gem-amido phosphonio alkenes

It is possible to introduce a chlorine substituent into the -position of structure 457. However,
chlorination of 457 itself does not take place under mild conditions. -Substitution can be
carried out by first converting 457 to the imidoyl chloride 468. This compound then reacts
easily with chlorine to give an intermediate 469 that undergoes dehydrochlorination to give the
imidoyl chloride 470. Subsequent hydrolysis then gives the -chloro analog 471 (Scheme 45)
<1993ZOB87>.
PPh3 Cl Cl PPh3 Cl Cl PPh3 Cl

PCl5 Cl2 –HCl
457 R Cl R R
Ar N Ar N Ar N
Cl Cl Cl
468 469 470
i. H2O
ii. NaClO4 Cl PPh3 ClO4–
Ar NHCOR
471
Scheme 45
The gem-amido phosphonio alkene 472 was chlorinated by reaction with phosphorus pen-
tachloride to give the hexachlorophosphonium chloride 473 in 95% yield. Hydrolysis gave the
gem-amido phosphonio alkene 474 in 80% yield <1998ZOB167>.
PPh3 Cl PPh3 Cl PPh3 Cl

Cl2C Cl2C Cl Cl2C
HN COMe N HN COCCl3
CCl3
472 474
473
The reaction of the gem-amido phosphonio alkene 475 with 2-aminopyridine resulted in
substitution of the -chloro group to give the gem-amido phosphonio alkene 476 in 51–63%
yield <1993ZOB642>. This is in contrast with the reaction of 475 with benzamidine where 1,3,5-
triazines are formed. In the latter case, the greater basicity of benzamidine causes elimination of
HCl from 475, which deactivates the -carbon to nucleophilic attack and leads to a different
reaction.
4.21.2.2.4 gem-Alkoxycarbonylamino phosphonio alkenes, R22C¼C(NHCO2R1)P+Ph3

Compounds of this nature have been rarely reported <1995COFGT(4)967>. However, it is
possible to synthesize such compounds 477 in 80–95% yield by reaction of the chlorocarbonyla-
mino compound 453 with alcohols <1993ZOB80>.
4.21.2.2.5 gem-Phosphonio ureido alkenes, R22C¼C(NHCONR12)P+Ph3

In a similar vein, few examples of these structures exist <1995COFGT(4)967>. However, gem-
phosphonio ureido alkenes 478 are available in 35–96% yield by treating the chlorocarbonyl-
amino compound 453 with ammonia or amines <1993ZOB80>. In the same paper, it was
demonstrated that a range of gem-phosphonio ureido alkenes could be obtained by the reaction
of triphenylphosphine with the carbodiimide 479 to give the reactive intermediate 480, which
was then treated with water, alcohols, or amines to give various gem-phosphonio ureido alkenes
481. Treatment of 480 with triphenylphosphine gave the diphosphorylated urea derivative 482 in
64% yield.
Cl NHCOR NH2 + +
R1 P Ph3ClO4– R1 P Ph3ClO4–
N NHCOR
H PPh3 Cl– R2 NHCO2R3 R2 NHCONR4R5
Cl H PPh3 Cl–
475 (R = Ph, p-MeC6H4) 476 (R = Ph, p-MeC6H4) 477 478
+ +
Cl P Ph3 ClO4– P Ph3 ClO–4
Cl2C CH Cl2C CH Cl2C NHCONH CCl2
Cl3C CH + +
N C NCHClCCl3 N C NCHClCCl3 HN C NHR P Ph3 P Ph3
Cl O ClO4– ClO4–
479 480 482
481
4.21.2.2.6 gem-Arylchloromethyleneamino phosphonio alkenes, R22C¼C(N¼C(Cl)Ar)P+R13

gem-Chloroarylideneamino phosphonio alkenes have been previously synthesized by treating
the appropriate gem-amido phosphonio alkenes with PCl5/POCl3 or with PCl5
<1995COFGT(4)967>. Further examples have now been reported <1993ZOB87>, whereby
gem-amido phosphonio alkenes 483 were converted to the gem-arylchloromethyleneamino
phosphonio alkenes 484 in 86–93% yield on treatment with phosphorus pentachloride. Further
reaction with chlorine under mild conditions gives an intermediate that spontaneously loses HCl
to give the analogous structures 470 with a -chloro substituent (Scheme 45). Structure 473 was
similarly prepared <1998ZOB167>.
4.21.2.2.7 gem-Aminochloromethyleneamino phosphonio alkenes, R32C¼C(N¼C(Cl)NR12)P+R23

The reaction of triphenylphosphine with the carbodiimide 479 gave the reactive intermediate 480
(Section 4.21.2.2.5) <1993ZOB80>.
4.21.2.2.8 gem-Phosphonio tetrazol-1-yl alkenes

The gem-arylchloromethyleneamino phosphonio alkenes 484 were treated with sodium azide to
give the phosphonium salts 485 containing a tetrazole ring. These compounds were not char-
acterized but were treated with sodium perchlorate to give the perchlorates 486 in 83–95% overall
yield <1995ZOB955>.
+ – +
P Ph3 Cl
– PPh3 ClO4
P Ph3 Cl PPh3 N3
Ar Ar
Ar NHCOAr Ar N C Ar Ar N Ar N
Cl N N N N
483 N N
484
485 486
4.21.2.3 Derivatives Bearing a Metallophosphino Function
4.21.2.3.1 a-Metallophosphino enamine

Reaction of the metallophosphaalkene 487 with azo compounds resulted in the condensation of a
ring methyl substituent with the bis(dimethylamino)methylene group to give the metallopho-
sphino enamine 488 (Scheme 46) <1994PS325>.
E
N N
E
CH2 NMe CH
NMe2 E = CO2Et NMe2 2
OC Fe OC Fe P C OC Fe P OC Fe P C NMe2
P C t C
OC CO2Bu OC OC OC
NMe2 N NMe2 N NMe2 N
COPh E N E E E
HN E HN E
487 488
Scheme 46
4.21.2.4 Derivatives Bearing a PPhX Group
4.21.2.4.1 Enamine derivatives bearing a PPhNHN¼CR2 group

The aminophosphaalkene 489 reacts with disubstituted diazo compounds at 20 C to give the
tricoordinated phosphorus compounds (490–492) via a Staudinger-type reaction <1993BSB719>.
These compounds decompose at room temperature.
NMe2 NMe2 NMe2 NMe2

Me C H2C C H2C C H2C C
P P NH CO2R P NH Ph P NH R1
Ph Ph N Ph N Ph N
CO2R Ph R2
489 490 (R = Me, Et) 492
491
4.21.2.4.2 Enamine derivatives bearing a PR1PR2NR32 group

The reaction of the methylidenephosphane 493 with the C-amino-substituted ethylidenepho-
sphane 494 afforded the unsymmetrical 1,2-diphosphane 495 as a mixture of two diastereomers
(due to the formation of two new asymmetric centers at the P atoms) in 64% yield (Equation (3))
<1997JOC7605>. The reaction is the first example of a type II ene reaction between phosphaalk-
enes with different substitution patterns.
Ph Ph N(TMS)2
(TMS)2N H P P P
P C + CH2TMS ð3Þ
TMS NMe2 NMe2
493 494 495
4.21.2.5 Derivatives Bearing a Phosphinoyl or Thiophosphinoyl Group
4.21.2.5.1 a-Phosphinoylenamines, R32C¼C(NR12)POR22

-Phosphinoylenamines were reported in 1972 but have not been reported since
<1995COFGT(4)967>.
4.21.2.5.2 gem-Amido diphenylphosphinoyl alkenes, R22C¼C(NHCOR1)POPh2

The synthesis of gem-amido diphenylphosphinoyl alkenes from N-tetrachloroethylamides was
reported in the 1970s <1995COFGT(4)967>. A further synthesis has recently been reported.
Thus, reaction of N-fluoroacetyltrichloroacetamide 496 with phosphorus pentachloride gives
N-trichloroacetylfluoroacetimidoyl chloride 497 in 82% yield, which reacts with an equivalent
of ethyl diphenylphosphinite to give the gem-amido diphenylphosphinoyl alkene 498 as a mixture
of isomers ((E)/(Z) 4:1) in 60% yield (Scheme 47) <2002JFC107>.
O Cl POPh2
O PCl5 Ph2P(OEt) FHC
O
F HN F N HN COCCl3
CCl3 CCl3
496 497 498
Scheme 47
4.21.2.5.3 gem-Methoxycarbonylamino diphenylphosphinoyl alkenes and gem-alkoxycarbonylamino

diphenylphosphinoyl alkenes, R22C¼C(NHCO2R1)POPh2
gem-Methoxycarbonylamino diphenylphosphinoyl alkenes were reported in the 1970s
<1995COFGT(4)967>. More recently, the fluorinated gem-alkoxycarbonylamino diphenylpho-
sphinoylalkenes 501 were synthesized by treating the -hydroxy urethane 499 with chlorodiphe-
nylphosphine to give the phosphorylated urethanes 500. Treatment with base (triethylamine,
diazabicyclooctane, or 1 N NaOH) resulted in dehydrofluorination to give the gem-alkoxycarbo-
nylamino phosphoryl alkenes 501 (Scheme 48) <1999ZOB1299>. The use of diazabicyclooctane
as a base gave better results than triethylamine.
F OH F POPh2 F POPh2
F O Ph2PCl F O Base O
F2HC(F2C)n HN F2HC(F2C)n HN HN
NEt3 F2HC(F2C)n
OMe OMe OR
499 500 501a (n = 3; R = Me; 45%)
b (n = 5, R = Et; 66%)
Scheme 48
4.21.2.5.4 gem-Diphenylphosphinoyl ureido alkenes, R22C¼C(NHCONR12)POPh2

gem-Diphenylphosphinoyl ureido alkenes were reported in 1984 but have not been reported since
<1995COFGT(4)967>.
4.21.2.5.5 a-Thiophosphinoylenamines, R32C¼C(NR12)P(¼S)R22

-Thiophosphinoylenamines were reported in 1972 but have not been reported since
<1995COFGT(4)967>.
4.21.2.5.6 Derivatives bearing a diphenylphosphinoyl group and an N¼C(X)Ar group,

Cl2C¼C(N¼C(X)Ar)POPh2
The derivatives described in the title were reported in 1978 but have not been reported since
<1995COFGT(4)967>.
4.21.2.6 Derivatives Bearing a Phosphonyl Group, POXR
4.21.2.6.1 gem-Amido phosphonoyl alkenes, R32C¼C(NHCOR1)POXR2

The synthesis of gem-amido phosphonoyl alkenes has been reported, starting from an acyl-
aminophosphinic ester as well as from N-tetrachloroethylamides <1995COFGT(4)967>.
Structures of this nature have now been synthesized from the azlactone 502, which was first
hydrolyzed then chlorinated to give the N-acylated amino acid 503 (Scheme 49)
<1993ZOB1259>. This was then treated with diethyl phenylphosphonate to give the gem-
amido phosphonoyl alkene 504. The reaction involves an Arbuzov rearrangement reaction,
followed by decarboxylation and elimination of chloride ion. The phosphonoyl alkene 504 under-
goes intramolecular cyclization when heated with phosphorus pentachloride to give the cyclic
structure 505. Hydrolysis of this structure with water, methanol, or aniline gives the phospho-
noylalkenes 506 in 75–90% yield.
PhHC O Cl CO2H P(O)(OEt)Ph

CO2H
H2O PhHC Ph Cl2 PhHC Cl Ph PPh(OEt)2 PhHC Ph
N O HN HN
HN
O O O
Ph
502 503 504
PhHC Ph O P(O)(X)Ph
PCl5 P HX PhHC Ph
N O HN
O
Ph
505 506 (X = OH, OMe, NHPh)
Scheme 49
Various cinnamic acid derivatives 507 obtained by the Erlenmeyer synthesis have been treated
in this way to give dichlorinated adducts <1999GEP19801952, 2000PS209, 1998AG(E)2851> in
near-quantitative yield. Since the latter were unstable to heat and light, they were treated
immediately with different phosphonites (R3P(OR2)2) to give the (E)-isomers of the phosphonoyl
alkenes 508 in 10–35% yield. The corresponding phosphinic acids 509 were prepared from 508 in
good yields (over 80%) by transesterification with halogenotrimethyl silane at room temperature
followed by saponification of the trimethylsilyl ester.
4.21.2.6.2 gem-Phosphonoyl ureido alkenes

A gem-phosphonoyl ureido alkene was synthesized in 1984, but no further instances have been
reported <1995COFGT(4)967>.
4.21.2.7 Derivatives Containing a Dialkoxy Phosphoryl Group
4.21.2.7.1 a-Phosphorylenamines, R32C¼C(NR12)PO(OR2)2

-Phosphorylenamines have previously been synthesized by a variety of methods
<1995COFGT(4)967>.
(i) From halo enamines

Halo enamines have been treated with triethyl phosphite by the Arbuzov reaction to give
-phosphorylenamines in good yield <1995COFGT(4)967>. Further work has been reported
whereby the chloroenamine 510 reacts with triethyl phosphite without a catalyst to give the product
511 in 15 min in quantitative yield <1999ZOR452, 1999TL569>. The same product was synthe-
sized in 82% yield by a palladium-catalyzed cross-coupling of diethyl hydrogen phosphite with 510
in the presence of 2 mol.% of dichlorobis(triphenylphosphine)palladium and triethylamine.
O OR2 O OH
H CO2H H P H P
Ph R3 R3
HN NHCOPh NHCOPh
O
R1 R1 R1
507 508 509
Me Cl Me P(O)(OEt)2
Me NEt2 Me NEt2
510 511
(ii) From tertiary amides

Tertiary amides have previously been converted to -phosphorylenamines via iminium esters or
iminium chlorides <1995COFGT(4)967>. A novel route has now been described which gives a
highly stereoselective synthesis of (E)-vinylphosphonates and has the advantage of being a short,
one-pot reaction <2000HAC512>. Tertiary amides 512 are mixed with phosphorus oxychloride
(POCl3) to form Vilsmeier reagents, which are reacted with an equimolar amount of the phosphite
(EtO)2P(O)H to form the vinylphosphonates 513 in 35–50% yield (Equation (4)).
O O Et3N (excess) Ph NR 22
+ R1Cl
(EtO)2POR1 + PhH2C NR22 + Cl P Cl H P(OEt)2 ð4Þ
Cl –HNEt 3.OP(O)Cl2
(R1 = H, Et) O
512 (R2 = Me, Et)
513
A plausible pathway for this reaction is shown in Scheme 50 where the Vilsmeier reagents act
in the form of an iminium chloride 514. The phosphorus atom of diethyl phosphite then attacks
the electrophilic central carbon of 514 with elimination of HOP(O)Cl2 to give intermediate 515,
which then eliminates HCl to give the product. The observed stereochemistry is thought to arise
from a least-crowded, most-stable conformation of the intermediate 515.
H
Cl (EtO)2POR1 Cl
CH2Ph CHPh
POCl3 NEt3 NEt3 (E )-513
512 R2N R2N
OP(O)Cl2 – Et NH.OP(O)Cl P(O)(OEt)2 – Et NH.Cl
3 2 3
514 515
Scheme 50
It should be noted that the reaction proceeds in low yield (2–3%) using the amide 516. The
transition state leading to 515 is sterically congested and the presence of four relatively large
groups attached to the central carbon atom would make the formation of 515 difficult.
In the absence of triethylamine, the intermediate 515 reacts further with another mole of
phosphite to give the corresponding biphosphonate 517. It is possible to use various tertiary
amides to give a range of biphosphonates 518, which can then be reacted with aldehydes under the
conditions of the Wittig–Horner reaction to furnish the vinylphosphonates 519 and 520 in 30–47%
yield (Equation (5)) <1999HAC271>. It has also been observed that the (Z)-isomer 520 can be
converted to the (E)-isomer 519 in boiling ethyl acetate.
O O CH2Ph
(EtO)2P C NMe2
PhH2C N
P(OEt)2
O
516 517
i. NaH
O H R4 NR2R3 H NR2R3
ii. R4CHO
(EtO)2P C NR2R3 +
–(EtO)2P(O)ONa H P(OEt)2 R4 P(OEt)2 ð5Þ
P(OEt)2
O O
O
518 (E )-519 (Z )-520
(iii) From active methylene compounds and diethyl phosphorocyanidate

Reaction of diethyl phosphorocyanidate 521 (DEPC) with diethyl malonate and ethyl cyano-
acetate in the presence of zinc chloride and triethylamine resulted in selective addition of the
active methylene group to the cyano group of DEPC to give the -phosphorylenamines 522
<1994CPB1919>. A variety of Lewis acids was used to increase the electrophilicity of the cyano
carbon atom, with zinc chloride giving the best results. The addition of molecular sieves to the
reaction with diethyl malonate to give 522a dramatically increases the yield from 22% to 66%.
With methyl cyanoacetate, the yield of 522b—obtained as a single isomer—is lower at 43–49%,
and it is believed that this may be due to the Lewis acid being coordinated with the cyano group
of the cyanoacetate as well as DEPC. The stereochemistry was confirmed by 13C NMR with the
ester group being (E) to the phosphoryl group. This can be rationalized by proposing a reaction
intermediate 523 that is fixed by chelation of the zinc metal with the ester carbonyl oxygen atom
rather than the nitrile nitrogen atom, followed by a proton shift to give the product. In contrast,
treatment of enolizable methyl acetoacetate and acetylacetone with DEPC gave enol phosphates
524 as a result of nucleophilic displacement on the phosphorus atom of DEPC.
O MeO2C NH2 OMe O

R
(EtO)2P CN H (EtO)2P
O O O
R P(OEt)2
ZnCl
O (EtO)2P N Me X
O
521 522a (R = CO2Me) 523 524 (X = OMe, Me)
b (R = CN)
(iv) From -phosphoryl-,-unsaturated carboxylic acids

-Phosphoryl-,-unsaturated carboxylic acids 525 were prepared as shown in Scheme 51 as a
mixture of isomers, then the mixture was treated with diphenylphosphoryl azide at about 0 C to
give the acyl azide 526 <1994USP5321153>. The acyl azide was diluted with toluene and
warmed to 90 C to effect a Curtius rearrangement. The incipient isocyanate 527 was then
trapped in situ with an alcohol to produce urethanes 528a, which on deprotection give the
-phosphorylenamines 528b.
TFA
1 CO2R2 R1 CO2R2
CO2R2 R1CHO R CH2Cl2 R1 CO2H (PhO)2P(O)N3
+
TiCl4 sieves NEt3
PO(OMe)2 THF/CCl4 PO(OMe)2 HO PO(OMe)2 PO(OMe)2
525
R1 CON3 Heat R1 NCO R4OH R1 NHR3

Curtius
PO(OMe)2 PO(OMe)2 PO(OMe)2
rearrangement
526 527 528a (R3 = CO2R4)
b (R3 = H)
Scheme 51
(v) From bromonitroethenylphosphonate 529

Bromonitroethenylphosphonate 529 reacts with 1 equiv. of benzylaniline to form the adduct 530
in 73% yield, which can be dehydrobrominated in the presence of pyridine to give the
-phosphorylenamine 531 in 55% yield <1997ZOB160>.
Br Br PO(OR)2 PO(OR)2
CHPO(OR)2 O2NHC
O 2N O2N NPhCH2Ph NPhCH2Ph
529 (R = CH2CH2Cl) 530 531
(vi) From a ‘‘head group’’ synthon

The (dialkylamino)methylphosphonate 532 can be viewed as a head group synthon for the
synthesis of -phosphorylenamines. Deprotonation using butyllithium, and subsequent reac-
tion with diisopropyloxalate or ethyl-N,N-diethyloxamate resulted in the formation of the
3-(dialkylamino)-3-phosphono pyruvates and pyruvamides 533. Depending on the nature of
the amino substituent, these can primarily exist as the (E)-enamine tautomer 534
<1996HCA895>. Thus, when the amino substituent is diethylamino, the -phosphorylena-
mines are formed in 60% and 61% yield for Z = NEt2 and PriO, respectively. For other
amines, a mixture of the tautomers 533 and 534 are formed, the latter being present both in
the (E) and (Z) configuration.
Related to this, reaction of the aldehyde 535 with 532 gave the -phosphorylenamine 536 in
84% yield <1989EUP300387>.
O O
PO(OEt)2 Z PO(OEt)2 Z PO(OEt)2 O2N Cl O2N Cl
Me Me
NR1R2 O NR1R2 HO NR1R2 NMe2
CHO
532 533 (Z = NEt2, PriO) 534 535 536 PO(OEt)2
4.21.2.7.2 gem-Formamido phosphoryl alkenes, R22C¼C(NHCHO)PO(OR1)2

gem-Formamido phosphoryl alkenes have been synthesized from the reaction of aldehydes with
tetraethyl formamidomethylenediphosphonate, as well as from oxazolines <1995COFGT(4)967>.
The first of these methods was used more recently to synthesize a range of gem-formamido
phosphoryl alkenes 538 from tetramethyl formamidomethylenediphosphonate 537 in 42–85%
yield (Equation (6)) <1996MI281>. The products (538; R = Me,Ph) were obtained as a mixture
of (E)- and (Z)-isomers, which could be separated by chromatography.
i. NaH
ii. RCHO RHC
HN
NHCHO ð6Þ
OHC P(O)(OMe)2
537 538 (R = H, Me, Ph)
4.21.2.7.3 gem-Amido phosphoryl alkenes, R32C¼C(NHCOR1)PO(OR2)2

These structures have previously been synthesized from a variety of starting materials such as
azlactones, amides and oxophosphonates, N-tetrachloroethylamides, and N-trichloroethylidene
amides <1995COFGT(4)967>.
(i) From azlactones and cinnamic acids

The synthesis of gem-amido phosphoryl alkenes from azlactones has already been described
<1995COFGT(4)967>. Further work has been reported on this approach <1993ZOB1259>.
Thus, the azlactones 539 were ring-opened by treatment with water to give the ,-unsaturated
carboxylic acids 540 that were then treated with chlorine to give the dichlorinated adducts 541.
Treatment of 541 with triethyl phosphite gave the amido phosphoryl alkenes 542 in 30–90% yield
(Scheme 52).
R2R1C O Cl CO2H P(O)(OEt)2

CO2H
H2O R2R1C Cl2 R2R1C Cl R3 P(OEt)3 R2R1C R3
R3
N O HN HN
HN
O O O
R3
539 540 541 542
Scheme 52
The reaction with triethyl phosphite is thought to proceed as shown in Scheme 53,
whereby an Arbuzov rearrangement reaction takes place to give the first intermediate 543,
which then undergoes decarboxylation and elimination of the chloride ion to give the observed
product.
Cl P(O)Et2 –H+ Cl P(O)Et2

P(OEt)3 –Cl–
541 R2R1C CO2H R2R1C 542
–EtCl NHCOR3 –CO2 NHCOR3
543
Scheme 53
In general, this route has been used for aromatic derivatives. For example, the (E)-phosphoryl
alkenes 544 have been obtained from cinnamic acid derivatives 545 <1996GEP19519983,
1998CHIR564, 1996SC777>.
H P(O)(OR)2 H CO2H
Ph Ph
Ar HN Ar HN
O O
544 545
The phosphoryl alkenes 542 can be converted to the corresponding phosphonic acids 547 by
treatment with 2 equiv. of phosphorus pentachloride to give the cyclized structures 546, followed by
hydrolysis with excess water in acetone to give the products 547 in 50–84% yield (Scheme 54)
<1993ZOB1259>. Attempts to hydrolyze 542 directly in acid solution resulted in a mixture of
compounds and proved unsatisfactory.
R2R1C Cl O H2O
P(O)(OEt)2 2PCl5 P(O)(OH)2
P acetone
R2R1C R3 R2R1C R3
N O
HN HN
O R3 O
542 546 547
Scheme 54
(ii) From acid chorides or -oxophosphonates

The reaction of primary amides with an -oxophosphonate to give gem-amido phosphoryl
alkenes has already been reported <1995COFGT(4)967>. This procedure has recently been
used to synthesize a variety of gem-amido phosphoryl alkenes including the (Z)-methylenamido
phosphonate 548, the latter being obtained in typically poor yield (11%) <1999OL387>
(Equation (7)).
BnOCONH2
O PhH
N(H)Cbz
reflux
ð7Þ
P(O)(OMe)2
P(O)(OMe)2
548
A different method of introducing an amido group has now been described which results in
better yields <2002JOM404>. The necessary oxophosphonates 549 are generated from the
Arbuzov reaction of acid chlorides with trimethyl phosphite (Scheme 55). These are then
converted to the -oximinophosphonates 550. The oximinophosphonates are converted to the
oxime acetates 551 that are then reduced in situ with metallic iron to cause rupture of the weak
NO bond and formation of an iminyl radical 552. A second electron transfer leads to the
iminyl anion 553 which is captured by acetic anhydride to give the enamides 554 in 71–89%
yield from the oximinophosphonate 550. The substituent R can be alkyl or aromatic. If the
reaction is carried out with heating, the imide 555 is obtained. For example the imide (555;
R = Ph) was obtained in 54% yield in this manner. However, heating also makes side reactions
more likely and when R = CH2Ph, the main product was 3-phenylpropionitrile isolated in 55%
yield—arising from -scission of the iminyl radical 552. It was found that carrying out the
reduction at a lower temperature of 50–60 C minimized side reactions and maximized the yield
of 554. The products obtained were a 1:1 mixture of (E)- and (Z)-isomers, which are thought to
be in equilibrium under the mildly acidic conditions used in the reaction. The method has been
recommended as a practical and flexible means of accessing gem-amido phosphoryl alkenes
using cheap and readily available starting materials and reagents, and involving no toxic or
hazardous components.
O HON AcON
P(OMe)3 NH2OH Ac2O
RCH2COCl P(O)(OMe)2 P(O)(OMe)2 P(O)(OMe)2
R R AcOH R
549 550 551
N N P(O)(OMe)2 P(O)(OMe)2
Fe Ac2O Ac2O
e– R e– R R NHAc R N(Ac)2
552 553 554 555
Scheme 55
(iii) From aldehydes and amides

It has already been recorded that the Arbuzov reaction of the N-tetrachloroethylamides 556 with
triethyl phosphite gives the phosphonates 557, which can be dehydrochlorinated in the presence of
triethylamine to give the gem-amido phosphorylamide 558 <1995COFGT(4)967>.
The phosphonate (557; R = Me) has also been obtained by the route shown in Scheme 56
(R = Me) and similarly converted to the gem-amido phosphoryl amide (558; R = Me) in 60%
yield in the presence of triethylamine <1998IZV1810>.
Cl PO(OEt)2 PO(OEt)2
Cl3C R Cl3C R Cl2C R
HN HN HN
O O O
556 557 558
R
H 2N OH (EtO)2PCl
O base NEt3
O Cl3C R
Cl3C 557 558
HN
H
O
Scheme 56
(iv) From N-fluoroacetyltrichloroacetamide

Reaction of N-fluoroacetyltrichloroacetamide 559 with phosphorus pentachloride gave N-tri-
chloroacetylfluoroacetimidoyl chloride 560 in 82% yield, which was then treated with an equiva-
lent of triethyl phosphite to give an equimolar mixture of the gem-amido diphenylphosphinoyl
alkene 562 and its isomer 561 (Scheme 57). The latter is formed by the Arbuzov reaction and is
converted to 562 by an irreversible prototropic isomerization on heating. Thus, vacuum distilla-
tion of the mixture led to the complete rearrangement of 561 into 562, which was obtained as a
mixture of isomers ((E)/(Z) 5:1) in 64% yield. The pure (E)-isomer of 562 was isolated by
fractional crystallization of the isomer mixture <2002JFC107>.
O Cl PO(OEt)2 PO(OEt)2
O PCl5 O P(OEt)3 O ∆ FHC
F HN F N F N HN COCCl3
CCl3 CCl3 CCl3
559 560 561 562
Scheme 57
Reaction of the imidoyl chloride 560 with the hydrophosphoryl compound [(EtO)2P(O)H] in
the presence of triethylamine also resulted in the formation of 562, which was identified
by NMR of the reaction mixture. A similar reaction with diphenyl phosphite resulted in
the formation of 563 and the bisphosphonate 564. The former was identified by NMR of
the reaction mixture, while the latter crystallized from the mixture in 35% yield
<2002JFC107>.
(v) Modifications of gem-amido phosphoryl alkenes

Treatment of the gem-amido phosphoryl alkene 565 with chlorotrimethylsilane has been reported
to generate the N-silylated product 566 in equilibrium with the isomer 567. Neither of these
structures was isolated since they are thermally unstable and distillation results in loss of the TMS
group and cyclization to a heterocycle <1998IZV2101>.
PO(OPh)2 PO(OPh)2
FHC FH2C PO(OPh)2
HN COCCl3 HN COCCl3
563 564
PO(OEt)2 PO(OEt)2 PO(OEt)2

Cl2C Ph Cl2C Ph Cl2C Ph
HN TMSN N
O O OTMS
565 566 567
4.21.2.7.4 gem-Alkoxycarbonylamino phosphoryl alkenes, R32C¼C(NHCO2R1)PO(OR2)2

gem-Alkoxycarbonylamino phosphoryl alkenes were synthesized in the 1980s by the alcoholic
hydrolysis of isocyanato or chlorophosphoryl groups <1995COFGT(4)967>. A further synthesis
has been reported following the route shown in Scheme 56 (R = OEt) to give the gem-alkox-
ycarbonylamino phosphoryl alkene (558; R = OEt) <1998IZV1810>.
The fluorinated gem-alkoxycarbonylamino phosphoryl alkenes 570 were synthesized by treating
the -chloro urethane 568 with trialkyl phosphites in an Arbuzov reaction to give the phosphory-
lated urethanes 569, Treatment of 569 with base (triethylamine, diazabicyclooctane or 1 N NaOH)
resulted in dehydrofluorination to give the gem-alkoxycarbonylamino phosphoryl alkenes 570
(Scheme 58) <1999ZOB1299>. The use of diazabicyclooctane as base gave better results than
triethylamine.
F Cl F PO(OR)2 F PO(OR)2
F O P(OR)3 F O Base O
F2HCF2CF2C HN F2HCF2CF2C HN F2HCF2CF2C HN
OMe OMe OMe
568 569 570 (R = Et, Pri;
39%, 48%)
Scheme 58
An attempt to dehydrofluorinate the trifluoromethyl analog 571 to give 572 under similar
reaction conditions was unsuccessful. Prolonged heating is reported to be successful but no
experimental details were given <1999ZOB1299>.
A procedure for synthesizing gem-alkoxycarbonylamino phosphoryl alkenes 528a by means of
a Curtius rearrangement has already been described above (Scheme 51) <1994USP5321153>.
4.21.2.7.5 gem-Phosphoryl ureido alkenes, R32C¼C(NHCONR12)PO(OR2)2

Two methods of synthesizing gem-phosphoryl ureido alkenes were reported in the 1970s and
1980s <1995COFGT(4)967>. One of these methods involved the reaction of the vinyl isocyanate
573 with aniline. A related method has been reported, whereby the saturated isocyanate 574 is
treated with a variety of aliphatic and aromatic amines to give the ureas 575. Treatment of 575
with morpholine results in dehydrochlorination and the generation of gem-phosphoryl ureido
alkenes 576, two of which were isolated and characterized. With longer reaction times, a cycliza-
tion reaction takes place to give the heterocyclic structures 577 <1993PS125>.
F PO(OEt)2 F PO(OEt)2
F O O
F HN F HN
OMe OMe
571 572
PO(OEt)2 PO(OEt)2 PO(OEt)2 PO(OEt)2 (EtO)2OP

N
Cl3C Cl3C O Cl2C O
N C O N C O HN HN N NHR
O O
NHR NHR
573 574 575 576a (R = 4-Me-C6H4; 21%) 577
b (R = 4-NO2-C6H4; 25%)
4.21.2.7.6 gem-Diphenylphosphinoylamino phosphoryl alkenes, R22C¼C(NHPOPh2)PO(OR1)2

The only reported synthesis of a gem-diphenylphosphinoylamino phosphoryl alkene was in 1988
<1995COFGT(4)967>.
4.21.2.7.7 gem-Phosphorylamino phosphoryl alkenes, R42C¼C[NR2PO(OR3)2][PO(OR1)2]

gem-Phosphorylamino phosphoryl alkenes have been synthesized from benzoylhydrazones and
halotricyanomethanes <1995COFGT(4)967>. Treatment of 2,2,2-trihaloacetimidoyl chlorides
with trialkyl phosphites also gave gem-phosphorylamino phosphoryl alkenes
<1995COFGT(4)967>. In a similar fashion, 2,2-dihaloacetimidoyl chlorides have now been
converted to the title compounds. Thus, the imidoyl chloride 578 reacts with 2 equiv. of triethyl
phosphite to give the (Z)-isomer of the gem-phosphorylamino phosphoryl alkene 581 in 35%
yield (Scheme 59). The reaction involves an aza-Perkow type mechanism via the reactive inter-
mediates 579 and 580, and is highly stereoselective. When the reaction is carried out with an
equivalent of triethyl phosphite, NMR studies show that the product 581 is still formed along
with formation of the phosphorylated azabutadiene 582, the latter resulting from the dehydro-
chlorination of intermediates 579 and 580 <2001ZOB157>.
O
Cl2HC
HN CH2Ph
PCl5 Cl PO(OEt)2
72% P(OEt)3
Cl Cl PO(OEt)2 H N CH2Ph
P(OEt)3 P(OEt)3 –EtCl
Cl2HC Cl2HC Cl2HC (EtO)2OP
N CH2Ph N CH2Ph N CH2Ph 581
578
–HCl H PO(OEt)2
579 580
Cl N CHPh
582
Scheme 59
An attempt to dehydrofluorinate the trifluoromethyl analog 583 to give 584 in the presence of a
basic catalyst proved unsuccessful <1999ZOB1299>.
F PO(OEt)2 F PO(OEt)2
F O O
F2HC(F2C)2 HN P OEt F2HC(F2C)2 HN P OEt
OEt OEt
583 584
4.21.2.7.8 gem-N-Phosphorylamido phosphoryl alkenes,

R42C¼C[N(COR1)PO(OR2)2][PO(OR3)2]
The imidoylphosphonate 585 was treated with triethyl phosphite in an Arbuzov reaction to give
the heterocyclic compound 586, which was detected by NMR. This structure is unstable and ring-
opens to form the bisphosphorylated enamine 587 and the azadiene 588, which were also detected
by NMR but not isolated. When structure 585 is treated with triethylphosphine or triphenyl
phosphite, a different reaction course took place since dealkylation is not possible (see Section
4.21.2.7.10) <1991PS95>.
(EtO)2OP
PO(OEt)2 CCl3 PO(OEt)2 PO(OEt)2
Cl3C O N Cl2C Cl2C OPO(OEt)2
P(OEt)3
N N COPh N
Ph O
Ph (EtO)2OP Ph
585 586 587 588
In a similar fashion, the trichloroacetimidoyl chloride 589 was treated with triethyl phosphite to
give the imidoylphosphonate 590 and the trichlorovinylphosphoroamidate 591 in approximately
equal amounts (Equation (8)). Reaction of the mixture with a second mole of triethyl phosphite
resulted in further reaction of 590 through the unstable phosphorane 592 to give the dipho-
sphorylated isomers 593 and 594 (Scheme 60) <1999ZOB1966>. Fractional distillation resulted in
the isolation of 593 in 14% yield. A better method of obtaining 593 was to react the imidoyl
chloride 589 with diethyl hydrogen phosphite to isolate structure 590 in 41% yield, then react 590
with triethyl phosphite to give structure 593 in 50% yield <1999ZOB1966>.
Cl PO(OEt)2 Cl Cl
Cl3C O P(OEt)3 Cl3C O O
N + Cl N
N ð8Þ
OMe OMe (EtO)2OP OMe
589 590 591
(EtO)2OP PO(OEt)2
P(OEt)3 CCl3 PO(OEt)2
590 N Cl2C + Cl2C OMe
P(OEt)3 N CO2Me N
MeO O (EtO)2OP OPO(OEt)2
592 593 594
Scheme 60
4.21.2.7.9 gem-Alkylideneamino phosphoryl alkenes, R32C¼C(N¼CR12)PO(OR2)2

A limited number of gem-alkylideneamino phosphoryl alkenes have been synthesized from
imidoyl chlorides and from N-acylamides. Thus, dehydrochlorination of the 2,2,2-trichloroacet-
imidoyl chloride 595 with base gave the azadiene 596, which reacted with triethyl phosphite to give
the product 597 in 34% yield <1995COFGT(4)967>. When the azadiene analog 598 is treated
with triethyl phosphite, the reaction is less selective since the electron-donating influence of the
methyl group is capable of directing the attack of triethyl phosphite to other electrophilic centers,
resulting in a mixture of products. However, analysis of the mixture by NMR indicated the
presence of the gem-alkylideneamino phosphoryl alkene 599 <2001ZOB159>.
The formation of a gem-alkylideneamino phosphoryl alkene 582 was also observed by NMR as
one of the products formed when the imidoyl chloride 578 was treated with 1 equiv. of triethyl
phosphite (Scheme 59). The same product was synthesized independently by treating the imidoyl
chloride 578 with triethylamine to give the dichloroazadiene 600 in 88% yield, then reacting 600
with 2 equiv. of triethyl phosphite. However, the final product could not be obtained in an
analytically pure form and contained about 25 mol.% of other unidentified products
<2001ZOB157>.
Me PO(OEt)2
Cl Cl Cl Cl PO(OEt)2 Me Cl Cl
Cl3C Cl N ClHC
N CH2Ph Cl N Cl N Cl N Ph N CHPh
Ph Ph Ph
595 596 597 598 599 600
A new synthetic method involves the use of iminebiphosphonates 602 obtained in 40–92% yield
from the condensation reaction of aminomethyldiphosphonate 601 with a range of aromatic,
heteroaromatic, and ,-unsaturated aldehydes (Scheme 61) <2000T6319>. The iminebipho-
sphonates 602 were olefinated by the Wadsworth–Emmons reaction using a range of aliphatic,
aromatic, and heteroaromatic aldehydes to give the alkylideneamino phosphoryl alkenes 603 in
30–80% yields.
i. Base
(EtO)2(O)P (EtO)2(O)P H P(O)(OEt)2
R1CHO ii. R2CHO
NH2 N
(EtO)2(O)P (EtO)2(O)P CHR1 R2 N
R1
601 602 603
Scheme 61
A variety of bases can be used in the reaction. However, it was found that the mild base
caesium carbonate in THF/PriOH provided good yields when aliphatic, aromatic, or heteroaro-
matic aldehydes were used. Further advantages included shorter reaction times, the ability to
carry out the reaction at room temperature, and an easy work-up procedure. NMR studies
demonstrated that the (E)-isomers were formed. The conjugated products 604 and 605 were
also obtained in good yield using the relevant aldehydes.
4.21.2.7.10 gem-Alkylideneamino phosphoryl alkenes bearing a heteroatom X at the vinyl position,

R32C¼C(N¼CXR1)PO(OR2)2, R22C¼C(N¼CX2)PO(OR1)2
As mentioned in Section 4.21.2.7.8, the reaction of 585 with triethyl phosphite gives the gem-
alkylideneamino phosphoryl alkene 588 as one of the products <1998IZV2101>. Treatment of
the imidoylphosphonate 585 with triethylphosphine or triphenyl phosphite results in a different
reaction course from the one involving triethyl phosphite. An unstable heterocycle 606 is formed
as before, but ring opening is accompanied by the loss of R3PO to form the azadienes 607 and
608. These were detected by NMR spectroscopy of the reaction solution but were not isolated.
In a similar fashion, reaction of the trichloroacetimidoyl chloride 589 with excess triethyl
phosphite resulted in a mixture of compounds that included the diphosphorylated isomer 594,
which was identified by NMR but not isolated (Scheme 60) <1999ZOB1966>.
Treatment of the gem-isocyano phosphorylalkene 609 with halogens results in the formation of
the dihalogenated products 610 <1994JPR29>.
The gem-isocyano phosphoryl alkene 611 reacts with primary amines to give the adduct 612
<1994JPR29>.
H P(O)(OEt)2 H P(O)(OEt)2
N N
R2 R1
Ph
O2N 604 605 (R1 = Aromatic / heteroaromatic;
R2 = Me, Ph)
(EtO)2OP
CCl3 Cl PO(OEt)2 PO(OEt)2 PO(OEt)2
N Cl2C OPO(OEt)2 Cl2C Cl Cl2C Cl2C X
PR3
N N NC N
Ph O
Ph Ph X
606 (R = Ph, OPh) 607 608 609 610 (X = Cl; 81%)
(X = Br; 74%)
EtS PO(OEt)2 EtS PO(OEt)2
EtS NC EtS N CHNHR
611 612 (R = Et; 48%)

(R = 4-Me-C6H4; 48%)
4.21.2.7.11 gem-Isocyano phosphoryl alkenes, R22C¼C(NC)PO(OR1)2

The gem-isocyano phosphoryl alkene 609 has been synthesized by the rearrangement of
1-formylimino-2,2,2-trichloroethanephosphonate via a formimide chloride intermediate
<1991PS95>. A more convenient method of obtaining this structure is to treat the phosphono
trichloroethaneformamide 613 with phosphorus pentachloride to form 614, which is dehydroha-
logenated by the subsequent addition of base. The desired product 609 is obtained in 83% yield
<1994JPR29>.
The vinylic chlorides in 609 can be substituted with a variety of nucleophiles. Thus, reaction
with secondary amines gives the ketene aminals 616. It is also possible to isolate the intermediate
monoamino derivatives 615 as crude products in high yield. Reaction of 609 with primary amines
results in cyclizations and the formation of heterocyclic products. Treatment of 609 with nucleo-
philes such as ethylenediamine, cysteamine, ethanedithiol, and ethanethiol resulted in the corre-
sponding gem-isocyano phosphoryl alkenes (617a–617c, 618). Alternatively, reaction of 609 with
propylenediamine led to a cyclic heterocyclic structure <1994JPR29>.
PO(OEt)2 PO(OEt)2 R2N PO(OEt)2 R 2N PO(OEt)2 X PO(OEt)2 EtS PO(OEt)2

Cl3C Cl3 C
HN CHO N C Cl Cl NC R 2N NC Y NC EtS NC
H
613 615 616 (R = Me; 73%) 617a (X = Y = NH; 64%) 618 (66%)
614 b (X = S; Y = NH; 61%)
c (X = Y = S; 70%)
4.21.2.7.12 gem-Isocyanato phosphoryl alkenes, R22C¼C(N¼C¼O)PO(OR1)2

A limited number of gem-isocyanato phosphoryl alkenes were synthesized in the 1970s and 1980s
from various isocyanates <1995COFGT(4)967>. However, no other syntheses have been
reported.
4.21.2.8 Derivatives Bearing a PS(OR)2, PO(OR1)(NR22), POX2, or PO(OR1)(SR2) Group
4.21.2.8.1 a-Thiophosphorylenamines
An -thiophosphorylenamine was synthesized in 1971 from a dialkylthiophosphonate and an
ynamine, but no other synthesis has been reported since <1995COFGT(4)967>.
4.21.2.8.2 gem-Amido phosphoramidoyl alkenes, Cl2C¼C(NHCOPh)PO(OMe)(NR2)

A synthesis of gem-amido phosphoramidoyl alkenes from azlactones was reported in 1982, but no
further syntheses have been published <1995COFGT(4)967>.
4.21.2.8.3 gem-Phosphoramidoyl ureido alkenes, R42C¼C(NHCONR1R2)PO(OR3)NR1R2

A few gem-phosphoramidoyl ureido alkenes were synthesized from isocyanates in the 1980s, but
no further syntheses have been reported <1995COFGT(4)967>.
4.21.2.8.4 a-Phosphorodiamidoylenamines, R32C¼C(NR12)PO(NR2)2

A synthesis of -phosphorodiamidoylenamines from imino chlorides and an alkoxy phosphorus
diamine was reported in 1985, but no further reports have appeared in the literature concerning
the syntheses of these compounds <1995COFGT(4)967>.
4.21.2.8.5 gem-Amido phosphorodiamidoylalkenes, R32C¼C(NRCOR1)PO(NR2)2

The first example of structures of this type has recently been reported. Reaction of N-fluoroace-
tyltrichloroacetamide 619 with phosphorus pentachloride gave N-trichloroacetylfluoroacetimidoyl
chloride 620 in 82% yield, which reacted with an equivalent of the diamidophosphite 621 to give
the gem-amido phosphorodiamidoyl alkene 622 as a mixture of isomers ((E)/(Z) 3:1) (Scheme 62).
Crystallization gave the pure (E) isomer in 48% yield <2002JFC107>.
O Cl
PCl5 (Et2N)2P(OEt) PO(NEt2)2
O O FHC
F HN F N 621 HN COCCl3
CCl3 CCl3
619 620 622
Scheme 62
4.21.2.8.6 gem-Alkoxycarbonylamino phosphorodiamidoyl alkenes,

R42C¼C(NR1CO2R2)PO(NR3)2
The first example 624 of this type of structure was synthesized in 78% yield by the base-catalyzed
dehydrochlorination of the trichloromethyl compound 623. The latter was synthesized from an
aldehyde and urethane as shown in Scheme 63 <1998IZV1810>.
O OH PO(NEt2)2 PO(NEt2)2
Cl3C Cl3C OEt Cl3C OEt Cl2C OEt
H OEt HN (Et2N)2PCl HN NEt3 HN
H2N O base O O
623 624
O
Scheme 63
4.21.2.8.7 gem-Phosphorodiamidoyl ureido alkenes, R2C¼C(NHCONHAr)PO(NHAr)2

gem-Phosphorodiamidoyl ureido alkenes were synthesized in the 1980s from isocyanato
dichlorophosphoryl reagents <1995COFGT(4)967>. No further reports have appeared on their
synthesis.
4.21.2.8.8 gem-Aminobenzylideneamino phosphorodiamidoyl alkenes,

R22C¼C(N¼C(NR12)Ph)PO(NR12)2
The synthesis of gem-aminobenzylideneamino phosphorodiamidoyl alkenes from dichloropho-
sphoryl reagents was described in 1982 <1995COFGT(4)967>. No further syntheses have been
reported.
4.21.2.8.9 gem-Difluorophosphoryl ureido alkenes

A gem-difluorophosphoryl ureido alkene was synthesized in 1989 from the reaction of a gem-
difluorophosphoryl isocyanato reagent with aniline <1995COFGT(4)967>. No further examples
have been published.
4.21.2.8.10 gem-Arylchloromethyleneamino dichlorophosphoryl alkenes,

R2C¼C(N¼C(Cl)Ar)POCl2
gem-Arylchloromethyleneamino dichlorophosphoryl alkenes were synthesized in 1982 from gem-
amido phosphoryl alkenes <1995COFGT(4)967>. No further examples have been reported.
4.21.2.8.11 gem-Dihalophosphoryl isocyanato alkenes, R2C¼C(NCO)POX1X2

A few examples of gem-dihalophosphoryl isocyanato alkenes being synthesized from isocyanates
were reported in the 1980s <1995COFGT(4)967>. However, no further examples have appeared
in the literature.
4.21.3 FUNCTIONS CONTAINING ONE NITROGEN AND ONE METALLOID,

R32C¼CNR12SiR23, etc.
4.21.3.1 Nitrogen and Silicon Derivatives, R32C¼CNR12SiR23
4.21.3.1.1 a-Silylenamines
A variety of synthetic methods for generating -silylenamines have been reported previously
<1995COFGT(4)967>, with the most promising approach being the use of cyanohydrins.
Further examples have appeared since the 1990s.
(i) From cyanohydrins and nitriles

N,N-Bis-silylated -silylenamines 626 have been synthesized in 68–82% yield by the reductive
silylation of silylated cyanohydrins 625 with lithium and chlorotrimethylsilane at 0 C, using
hexamethylphosphoramide as solvent <1995COFGT(4)967>. The use of HMPA as cosolvent is
important to the success of the reaction. Further work has shown that it is possible to carry out
this reaction by electroreduction, thus removing the need for lithium and lowering the quantity of
HMPA required <1996OM1604>. The reaction can be carried out at room temperature with
trimethylsilyl chloride in THF in the presence of 1 equiv. of HMPA (instead of 4 in the chemical
process) in an undivided cell equipped with an aluminum-made sacrificial anode. After 4.4 faraday
are passed through the reaction mixture, the enamines 626 are obtained in comparable yields to
the chemical route. The products are obtained as mixtures of the (E)- and (Z)-isomers with the
former predominating.
Removal of the N-silyl groups can be achieved in quantitative yield by treatment with dry
hydrogen chloride in ether, or with chlorotrimethylsilane in methanol to give structure 627. The
enamine obtained slowly isomerizes to the iminium salt 628.
Studies into the electrochemical reductive silylation of nitriles have been carried out
<1997MI503>. In the case of nitriles bearing at least one -hydrogen (RR1CHCN), a mixture
of products is obtained which includes the enamines 626, presumably formed from an intermedi-
ate N-silylketenimine 629. In contrast to the reaction on O-silylated cyanohydrins, the major
isomer is (Z) rather than (E).
OTMS TMS TMS TMS R1

R1 C CN R2R1C R2R1C R2R1HC C N
R2 N(TMS)2 NH2.HCl NH.HCl R2 TMS
625 626 627 628 629
The reductive silylation of cyanotrimethylsilane in THF with lithium, chlorotrimethylsilane,

and HMPA gave principally the saturated products 630a,b along with trace amounts (5% yield)
of the unsaturated product 631 <1993O1378>. The same products were obtained from the
electrochemical reductive silylation of cyanotrimethylsilane, with the -silylenamine obtained in
8% yield <1994OM3711>. Electrochemical reductive silylation of dimethylcyanamide gave the
-silylenamine 632 as a by-product in 5% yield.
(ii) From silylated alkynes

The -silylenamine 633 was reported as a minor product (26% yield) in the reaction between the
silylated alkyne 634 and dimethylamine <1992CB2051>.
TMS SiMe2CH2R TMS N(TMS)2 Me2N N(TMS)2 OEt OEt

N (CO)5Cr TMS (CO)5Cr
TMS TMS (TMS)2N TMS (TMS)2N TMS
NMe2
630a (R = H) 631 632 633 TMS
b (R = TMS) 634
(iii) From the iminium salt 636

Reaction of tris(trimethylsilyl)silyllithium 635 with the iminium salt 636 led to a mixture of the
silylenamines 637 and 638 in 50% and 13% yields, respectively <1999EJI21>.
TMS Cl Cl CH3 Cl NMe2 TMS NMe2

TMS Si Li C C N C C
TMS H H H CH3 H Si(TMS)3 H Si(TMS)3
635 636 637 638
(iv) Miscellaneous syntheses

Addition of ammonia to the silylated alkynyl chromium complex 639 in THF generated a mixture
of chromium complexes 640a and 641 with the latter predominating (5% versus 78%)
<1993CB2535>. With diethyl ether as solvent, no enamine is formed at all. Reaction of 639
with dimethylamine in diethyl ether gave the enamine 640b in 27% yield <1993OM2556>.
Modification of the reaction conditions allows this compound to be prepared in 52% yield
when the reaction is carried out as a one-pot process in pentane <1999AG(E)1285>.
The enamine 640b was heated in THF at 5055 C and converted to a mixture of the chelated
tetracarbonylchromium complex 642 and the aminomethylene complex 643 in poor yield (17 and
20% yield, respectively) <1993TL5875>.
OEt OEt NH2 OEt

(CO)5Cr (CO)5Cr NR2 (CO)5Cr (CO)4Cr Me H
EtO N
TMS Me2N Cr(CO)5
TMS TMS TMS TMS
639 640a (R = H) 641 642 643
b (R = Me)
4.21.3.1.2 gem-Isocyanosilyl alkenes

Only three examples of gem-isocyanosilylalkenes have been reported in the literature. All three
were synthesized from a vinylidene isocyanide <1995COFGT(4)967>.
4.21.3.1.3 gem-Isothiocyanato silyl alkene

One example of a gem-isothiocyanato silyl alkene was synthesized from an isocyanide in 1982
<1995COFGT(4)967>. No further examples have been reported.
4.21.3.1.4 gem-Aminoborylamino silyl alkenes, PrCH¼C(TMS)N(R)B(X)NMe2

Three examples of gem-aminoborylamino silyl alkenes were synthesized in 1982
<1995COFGT(4)967>. No further examples have appeared in the literature.
4.21.3.1.5 gem-Amidosilylalkenes, PhCH¼C(TMS)NHCOR

The silyl acid 644 was treated with diphenylphosphoryl azide (DPPA) at 0 C to give an acyl azide
that was converted to a vinyl isocyanate at room temperature. The styryl Grignard reagent 645
was added to give a 1:1 mixture of the vinyl silane 646 and its isomer 647 that could be separated
by chromatography (Equation (9)) <2000TL3735>. The yield of each isomer was only 9%.
Ph Ph
i. DPPA, NEt3, 0 °C
Ph CO2H ii. PhMe, rt, 0.5 h Ph HN H HN
O + O
H TMS iii. Et2O, –78 °C H TMS Ph TMS ð9Þ
644 Ph
646 647
BrMg
645
4.21.3.1.6 gem-Lithioamino silyl alkenes, RCH¼C(TMS)NLiAr

The reaction of the lithium trimethylsilylmethyl compound 648 with the isocyanide 649 resulted in
the insertion of the isocyanide into the LiC bond of 648 to give the lithium 1-azallyls 650
<2001JCS(D)2409, 2000ZAAC1081, 1998CCC201> in 62% yield. In a similar fashion, the lithio
structure 651 was treated with the isocyanides 649 and 652 to give the lithium 1-azallyls 653, 654,
respectively, in 82% and 70% yields.
CH3
H CH3
Li C TMS
N C
TMS H3C N Li
TMSHC
CH3
TMS
648 649 650
Me Me
Me Me Me Me
H Me But N
N N
But N C N Li
Li C Ph Me N Li
N PhHC N
TMS PhHC N
TMS MeMe
Me Me TMS MeMe
651 652 653 654
4.21.3.1.7 gem-Diazonium silyl alkenes, R22C¼C(SiR13)N+

2
gem-Diazonium silyl alkenes have not been isolated. However, they have been formed in solution
and identified by NMR. Thus, protonation of the acetate 655 with superacid FSO3HSbF5(1:1)/
SO2 at less than 75 C resulted in the formation of five major ions, which included the (Z)- and
(E)-isomers of the gem-diazonium silyl alkene 656 <1993JCS(P2)1387>. These ions were also
formed when the acetate 655 was treated with the less acidic superacid FSO3H/SO2. The (Z)
isomer of the diazonium ion 658 was identified by NMR following protonation of the acetate 657
with superacid FSO3HSbF5(1:1)/SO2 <1993JCS(P2)1387>.
Me Me
SiPr3i HO SiPr3i Me2Si TMS MeO Si TMS
MeO2C MeO2C
N2 MeO N2 N2 HO N2
655 656 657 658
4.21.3.2 Nitrogen and Boron Derivatives, R32C¼CNR12BR22

Only one synthesis of these structures has been reported involving the addition of trialkylboranes
to ynamines <1995COFGT(4)967>.
4.21.4 FUNCTIONS CONTAINING ONE NITROGEN AND ONE METAL,

R22C¼CNR12M, etc.
4.21.4.1 Group 1 and 2 Metals, R22C¼CNR12Li, etc.

Functions containing one nitrogen along with lithium, sodium, or magnesium were reported
previously <1995COFGT(4)967>. However, no further work has been reported.
4.21.4.2 Transition Metals, R22C¼C(NR12)PdX, etc.
4.21.4.2.1 Palladium and platinum

Palladio enamines have been synthesized previously from isocyanides <1995COFGT(4)967>.
Further work has now appeared on this approach. Thus, the palladium complex 659 synthesized
as shown in Scheme 64 was treated with 1 equiv. of t-butyl isocyanide, resulting in an insertion–
migration reaction of the isonitrile into the PdC bond of 659 to give the palladio imine 660, which
tautomerizes to the palladio enamine—a process driven by the formation of an intramolecular
hydrogen bond <1993OM4899>. Structure 659 fails to react with carbon monoxide or ethylene and
the success of the reaction with the isonitriles is possibly due to the ability of the isocyanide to
displace PPh3 in the preliminary stage of the insertion in a position cis to the PdC bond. The yield
of 661 is variable (from 30–80%) depending on the solvent used and the concentration of the
reagents.
But
N
O PPh3 Ph C Ph
Pd(PPh3)4 ButNC
Cl Cl Pd CH2 Cl Pd CH2
Ph O –PPh3 O
PPh3 PPh3
659
O H
O NBut
CH2 Ph NBut
+PPh3
Ph Pd PPh3
Ph3P Cl Pd PPh3
Ph3P Cl
660 661
Scheme 64
More recently, it has been reported that the reaction of benzylpalladium complexes 662 with
t-butyl isocyanide yields imidoyl complexes that exist in solution as equilibrium mixtures of the
corresponding imine 663 and enamine 664 tautomers <1999OM5225, 1995OM2151>. The equili-
brium constant is markedly affected by the electronic effect exerted by the substituents (Y) on the
phenyl ring, but the effect of the metal fragment is less pronounced and is dominated by steric
factors. Both tautomeric forms can also be found in the solid state.
Reaction of 664 (X = Cl, Y = CF3, R = Me) with the chelating phosphine 1,2-bis-(dimethyl-
phosphino)ethane afforded the cationic complex 665, which was found to exist only in the
enamine form both in solution and the solid state.
H NHBut H NHBut
PR3 Me
NBut
PR3 P Me
X Pd CH2 Y Y CH2 Pd Pd
Pd PR3 X
PR3 PR3 X P
R3P X Me Me
Y Y
662 663 664 665
4.21.4.2.2 Copper
A copper-substituted enamine was reported in 1992 <1995COFGT(4)967> but no further reports
have been published.
4.21.4.2.3 Chromium, molybdenum, and tungsten

Molybdenum- and tungsten-substituted enamines have been proposed as reaction intermediates
while a tungsten-substituted enamine has been isolated from the reaction of a tungsten complex
with an ynamine <1995COFGT(4)967>.
The reaction of chromium and tungsten vinylidene complexes 666 with imines 667 has recently
been studied (Scheme 65) <2001JOM165>. Analogous studies using iron vinylidene complexes
were reported previously <1995COFGT(4)967> and have been used as the first stage of a method
to produce -lactams. It is believed that the imine uses the lone electron pair on nitrogen to form
a bond to the -carbon of the vinylidene ligand to form the zwitterion 668. Ring closure may or
may not take place resulting in the 2-azetidin-1-ylidene metal complex 669.
M(CO)5
R1 R3 R1 M(CO)5
+ N R1
C M(CO)5 N R2
R1 R2 R4 R1 N R2 R1
R3 R3 R4
666 667 R4
668 669
Scheme 65
The vinylidene chromium complex 670a was treated with the imine 671a to give the zwitterionic
chromium complex 672 in 23% yield relative to Cr(CO)6. The complex could be crystallized and
was stable in the solid state at room temperature. When dissolved in a nonpolar solvent, the
zwitterion cyclized slowly over the period of a week to the 2-azetidin-1-ylidene chromium complex
673. Cyclization was faster in polar solvents or with heating.
Reaction of the vinylidene chromium complex 670a with the imines 674 gave the analogous
zwitterions 675 in 11% and 21% yields relative to Cr(CO)6, but substitution products 676 were
also obtained to a lesser extent (7.5 and 3.4%). These latter compounds were also formed if the
zwitterions 675 were heated in solution, rather than the 2-azetidin-1-ylidene chromium complexes.
Reaction of the imine 671b with the vinylidene chromium complex 670a or the vinylidene
tungsten complex 670b gave the adducts 677a and 677b in 14% (relative to Cr(CO)6) and 61%
yields, respectively, neither of which underwent cyclization.
The mechanism is thought to involve a rapid but reversible addition of the imine to the
vinylidene metal complex. Whether the adduct obtained cyclizes to a 2-azetidin-1-ylidene metal
complex or not depends on the relative rates of cyclization versus dissociation back to starting
materials. Strongly electrophilic vinylidene complexes and strongly nucleophilic imines give rise to
adducts such as 672, which are stable with respect to dissociation and which can undergo
cyclization. In contrast, the adducts 675 and 677 dissociate back to starting materials on heating.
Decomposition of the vinylidene metal complex takes place with loss of the vinylidene ligand,
allowing addition of the imine to form pentacarbonyl(imine)metal complexes such as 676.
The above reaction was not observed if the imine contained an NH group. For example, the
reaction of 670a with the imine 678 gave mainly the metal complex 679 with no sign of the
zwitterion adduct. The reaction of N-unsubstituted imines with vinylidene metal complexes is
thought to involve the same initial addition reaction as with N-substituted imines, but the adduct
formed rapidly rearranges by deprotonation/reprotonation.
Cr(CO)5
Me Cr(CO)5
Me N
R1 R3 N Me X
C M(CO)5 N Me N Me Me
1 R4 Ph Ph H
R Me
H 674a (X = S)
670a (M = Cr; R1 = Me) 671a (R3 = Ph; R4 = H) 673
672 b (X = O)
b (M = W; R1 = Ph) b (R3 = OMe; R4 = Me)
Me Cr(CO)5 R1 M(CO)5 (CO)5Cr

(CO)5Cr N
R1 N Me N O
Me N N
MeO H
X X Me O
675a (X = S) 676a (X = S) 677a (M = Cr; R1 = Me) 678 679
b (X = O) b (X = O) b (M = W; R1 =Ph)
4.21.4.2.4 Manganese
A manganese-substituted enamine was reported in 1979 <1995COFGT(4)967> but no further
reports have been published.
4.21.4.2.5 Iron
A few reports of relevant iron complexes were published in the 1970s and 1980s
<1995COFGT(4)967> but there have been no subsequent publications.
4.21.4.2.6 Rhenium
A rhenium-substituted enamine was reported in 1975 <1995COFGT(4)967> but no further
reports have been published.
4.21.4.3 Other Metals
4.21.4.3.1 Tin
The synthesis of a stannylenamine from a diamine has been reported previously
<1995COFGT(4)967>. Acyclic stannylenamines have been reported to be extremely unstable as
far as the enamine moiety is concerned. However, a new and efficient synthesis has been reported
<2001S705>, which involves the hydrostannation of ynamines. Thus, the ynamine 680a was
reacted with Bu3SnH in the presence of PdCl2(PPh3)2 to give a 71% yield of a mixture of the
(E)- and (Z)-enamines 681 and 682 in an (E)/(Z) ratio of 3:2 (Equation (10)).
Bu3SnH Tos Tos

Tos
PdCl2(PPh3)2 Me3Si N Bn + H N Bn
R N
Bn
ð10Þ
THF, 60 °C H SnBu3 Me3Si SnBu3
680a (R = TMS)
681 682
b (R = H)
The unprotected ynamine 680b was also reacted with Bu3SnSiMe3 in the presence of Pd(PPh3)4
to give the stannylenamine 682 as the pure (Z)-isomer in 91% yield, making this route comple-
mentary to the hydrostannation of the silylated enamine. The ynamine 680b was treated with a
variety of other stannous reagents (R3SnX; X = H, Bu3Sn, Me3Sn) by this method to give other
enamines 683 in good yields (65–92%) with exclusively cis addition of the stannyl reagents. In the
case of the reagent (R3SnH), a significant amount of side product 684 was also formed but could
be removed by chromatography. Structure 683 (X = Me3Sn, R = Me) was iodinated to give the
-iodo enamine 685 in 64% yield.
It has also been reported that the condensation of primary aliphatic and aromatic amines with
acylstannanes 686 is a versatile and easy method of synthesizing imidoylstannanes 687
<1993S981>. One of these structures 688 was converted to the stannous enamine 689 in 78%
yield as shown in Equation (11).
Tos Tos Tos

H N Bn H N Bn H N Bn O NR2
R3Sn H I SnMe3 R1 SnBu3 R1 SnBu3

X SnR3
683 684 685 686 687
TfOSiMe3 Me3Si
Bu
N Et3N Me N Bn
ð11Þ
SnBu3 SnBu3
688 689
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Biographical sketch
Dr. Patrick graduated in chemistry at Glasgow University and received

a Carnegie scholarship to carry out his Ph.D. studies with Professor
D. J. Robins and Professor G. W. Kirby on the biosynthesis of gliotoxin.
He spent several years in the pharmaceutical industry working as a
radiochemist and development chemist before returning to academia as
a medicinal and organic synthetic chemist, working with Professor
J. B. Stenlake and Dr. W. Sneader at Strathclyde University, then
Professor L. Mander at the Australian National University. After a
temporary lecturing post at Leeds University, he accepted his current
post at Paisley University where he is course leader in medicinal chem-
istry. Dr. Patrick has a keen interest in scientific writing and has written
several undergraduate textbooks on medicinal chemistry and organic
chemistry.
4.22
Phosphorus, Arsenic, Antimony
or Bismuth, and No Halogen,
Chalcogen or Nitrogen
P. BAŁCZEWSKI, J. DRABOWICZ, A. SZADOWIAK,
_
R. ZURAWIŃSKI, P. KIEŁBASIŃSKI, and M. MIKOŁAJCZYK
Polish Academy of Sciences, Łódź, Poland
4.22.1 DIPHOSPHORUS FUNCTIONS—R12C¼C(PR22)2, etc. 958

4.22.1.1 Acyclic Bisphosphino Alkenes 958
4.22.1.2 Mixed Acyclic Cyclic (3–6-Membered) Bisphosphino Alkenes 961
4.22.1.2.1 Three-membered rings 961
4.22.1.2.2 Four-membered rings 962
4.22.1.2.3 Five-membered rings 963
4.22.1.2.4 Six-membered rings 966
4.22.1.3 Cyclic (3–6-Membered) Bisphosphino Alkenes 967
4.22.1.4 Alkali Metal Salts of Bisphosphino Alkenes 969
4.22.1.5 Transition Metal Complexes of Bisphosphino Alkenes 970
4.22.2 FUNCTIONS CONTAINING ONE PHOSPHORUS AND EITHER ARSENIC, ANTIMONY
OR BISMUTH, R12C¼C(PR22)AsR32, etc. 973
4.22.3 FUNCTIONS CONTAINING ONE PHOSPHORUS AND A METALLOID,
R12C¼C(PR22)SiR33, etc. 973
4.22.3.1 Silicon Derivatives 973
4.22.3.1.1 Acyclic compounds 973
4.22.3.1.2 Acyclic cyclic compounds (3–7 membered) 975
4.22.3.1.3 Acyclic cyclic metal complexes and salts 983
4.22.3.2 Germanium Derivatives 987
4.22.3.3 Boron Derivatives 987
4.22.4 FUNCTIONS CONTAINING PHOSPHORUS AND A METAL,
R12C¼C(PR2)M, etc. 987
4.22.4.1 Main Group Metals 988
4.22.4.1.1 Group 1 metals 988
4.22.4.1.2 Group 2 metals 991
4.22.4.1.3 Group 13 metals 992
4.22.4.1.4 Group 14 metals 993
4.22.4.2 Transitional Metals (Groups 3–12 Metals), R12C¼C(PR22)PdX2, etc. 996
4.22.4.2.1 C¼C-Bonded compounds 996
4.22.4.2.2 P- and C¼C-Bonded compounds 999
4.22.4.2.3 C¼C- and C¼C-Bonded compounds 1001
4.22.4.2.4 P-, C¼C-, and C¼C-Bonded compounds 1002
4.22.4.2.5 P- and C¼C-Bonded compounds 1004
4.22.4.2.6 C¼C-Bonded compounds 1005
4.22.4.2.7 PCC-Bonded compounds 1006
957
958 Functions Containing at Least One Phosphorus, Arsenic, Antimony or Bismuth
4.22.4.2.8 P- and PCC-Bonded compounds 1007

4.22.4.2.9 -Half sandwich compounds 1007
4.22.4.2.10 Metallocenes 1013
4.22.5 FUNCTIONS CONTAINING TWO ARSENIC, ANTIMONY OR BISMUTH FUNCTIONS,
R12C¼C(AsR2)2, etc. 1039
4.22.6 FUNCTIONS CONTAINING TWO DISSIMILAR COMBINATIONS OF ARSENIC,
ANTIMONY OR BISMUTH, R12C¼C(AsR22)SbR34, etc. 1040
4.22.7 FUNCTIONS CONTAINING ARSENIC, ANTIMONY OR BISMUTH WITH A
METALLOID, R12C¼C(AsR22)SiR33, etc. 1040
4.22.8 FUNCTIONS CONTAINING ARSENIC, ANTIMONY OR BISMUTH AND A METAL,
R12C¼C(AsR22)M 1042
4.22.1 DIPHOSPHORUS FUNCTIONS—R12C¼C(PR22)2, etc.

This class of compounds is subdivided into: (i) acyclic bisphosphino alkenes in which neither
phosphorus is included in a ring, (ii) mixed acyclic, cyclic bisphosphino alkenes in which one
phosphorus is a part of a ring and the second one is ‘‘acyclic,’’ and (iii) cyclic bisphosphino
alkenes in which both phosphorus are included in a ring.
Transition metal complexes of bisphosphino alkenes are metalloorganic compounds with at
least one phosphorus atom bound to a metal.
4.22.1.1 Acyclic Bisphosphino Alkenes

Hydrophosphinylation of alkynes and ketenes with diaryl or dialkylphosphines was previously
reviewed as one of the general methods for the synthesis of the title compounds via CP bond
formation <1995COFGT(4)1021>. It has been further extended by Schmidbauer and co-workers on
alkadiynes and allenes <1995CB365>. Thus, hydrophosphinylation of 1,2-bis(diphenylphosphino)-
ethyne 1 and 1,4-bis(diphenylphosphino)butadiyne 5 with diphenylphosphine 2 led to the formation of
1,1,4,4-tetrakis(diphenylphosphino)butatriene 3 in 33% yield and 1,1,4,4-tetrakis(diphenylphosphino)-
1,3-butadiene 6 each as the exclusive reaction product, respectively (Scheme 1).
PPh2 PPh2
ButOK
Ph2P C C PPh2 + Ph2PH Ph2P C C C C PPh2
1 2 3
Y
i. Me2S CH2
ii. S8 Ph2P Y
PH2P C PPh2
C
Y
PPh2
Y
4; Y = 2e, S
PPh2 PPh2
t
Bu OK
Ph2P C C C C PPh2 + Ph2PH Ph2P C CH CH C PPh2
5 2 6
i. Me2S CH2 Y
ii. H2O2 or S8 or Se Ph2P Y
Ph2P CH PPh2
C
Y
PPh2
Y
7; Y = 2e, O, S, Se
Scheme 1
Functions Containing at Least One Phosphorus, Arsenic, Antimony or Bismuth 959
Both products 3 and 6 were modified on treatment with dimethylsulfonium methylide to give
new cyclopropyl derivatives (4: Y = 2e) and (7: Y = 2e). Further reaction of (4: Y = 2e) with
elemental sulfur gave the corresponding tetrasulfide (4: Y = S) and the reaction of (7: Y = 2e)
with H2O2, elemental sulfur and selenium afforded the corresponding tetrachalcogenides 7
[Y = O, S, Se].
In contrast to the potassio derivatives of diphenylphosphines, lithium phosphides were also
employed in the reactions with 1,1,2-trichloroethene and perchloroethene to give tris- and tetra-
kis(diphenylphosphino)ethenes as ligands for platinum group metals <2002MI137>.
The first synthesis of diphosphinoketenimine 10 was formally carried out by the coupling
reaction of the transient diphenylphosphino carbene [(Ph2P)2C:] with phenyl isocyanide to give
the manganese (I) complex 8 followed by UV/Vis irradiation to liberate 10 from the metallic
fragment 9 <1998OM3835> (Scheme 2).
Ph Ph Ph Ph
PhNC I
OC P ∆ OC P hν Ph2P
Mn C I Mn C C NPh C C NPh
OC P OC P Ph2P
CO CO 10
Ph Ph Ph Ph
8 9
Scheme 2
The unsymmetrical dimer 11 obtained from the ketenimine 10 as a result of a unique, reversible
dimerization involving a new type of [2+3]-cycloaddition reaction <2000AG1891,
2000AG(E)1821> was further selectively oxidized with 1–3 equiv. of H2O2 to give mono- 12,
di- 13 or tri- 14-oxidized forms <2002CEJ3872> (Scheme 3).
Heating the compounds 12 and 13 in toluene afforded monomeric keteneimines 10 and/or 16
while the fully P-oxidized compound 14 decomposed instantaneously to the keteneimine 15 before
its isolation. The new ketenimines 10 and 16 behaved as 1,3-dipoles toward a variety of dipolar-
ophiles (alkynes, RNCO, RNCS), allowing the synthesis of five- and six-membered phospha-
heterocycles.
Another class of bisphosphinoalkenes are bis(dichlorophosphino)alkenes represented by 19.
This heterocyclic compound was synthesized by the condensation reaction of the benzene solution
of PCl3 with N-(dichlorophosphinomethylene)pyridinium ylide 18 obtained from the pyridinium
halide 17 <1996PSS(112)121> (Scheme 4).
Ethylidenebisphosphonates are extremely useful compounds in organic synthesis. Tetraethyl
ethylidenebisphosphonate 20 (R = Et) (Scheme 5), synthesized by the method of Degenhardt
<1986JOC3488>, was utilized in hydroxylation and epoxidation reactions <1995JOC7080> in
Michael addition reactions <2001T1837, 1995PSS(103)125>, as well as in transesterification reac-
tions to tetramethyl ester 20 (R = Me) using trimethoxymethane <1995PSS(103)125> and
to tetrakis(trimethylsilyl) ester 20 (R = TMS) using bromotrimethylsilane <1995JOC7080>. A
slightly modified version of Degenhardt’s protocol was also utilized for the synthesis of 20
R = Et <2002MI1991>. Bromotrimethylsilane itself or with collidine and p-toluenesulfonic acid
were also used to convert the tetraethyl ester 20 (R = Et) to the corresponding phosphonic
tetraacid 20 (R = H) <1995PSS(103)125, 2001T1837, 1995JOC7080, 1998MI687> (Scheme 5).
This acid was also obtained by the dehydration reaction under basic conditions (NaOH) of the
corresponding 1-hydroxy-1-methylbisphosphonic tetraacid <1998IZV1784>. Tetrabenzyl ethylide-
nebisphosphonate 20 (R = C6H5CH2) was also synthesized <2002SC211>.
A new methylenebisphosphonic cyclic ester 21 was prepared by condensation of the corre-
sponding unsubstituted cyclic bisphosphonate with formaldehyde in the presence of diethylamine
followed by dehydration with Amberlite IR 120 (H+) <1998MI1093>.
2-Substituted methylenebisphosphonates and their analogs were also synthesized. For instance,
tetraethyl allenebisphosphonate 24 was prepared from diethyl 3-hydroxy-methylbut-1-yne-phos-
phonate 23 and diethyl chlorophosphite in 77% yield <1996MI171>. Ebetino and co-workers
synthesized the bisphosphinic triacid 22 (R = H) from the corresponding triethyl ester 22
(R = Et) upon treatment with bromotrimethylsilane and water (99% yield). The 2-substituted
triethyl ester 22 (R = Et) was obtained upon treatment of the corresponding unsubstituted
triethyl ester with dimorpholinomethyl-3-pyridine in 41% yield <1996PSS(109)217>. Wiemer and

co-workers synthesized the bisphosphonate 25 possessing three isoprenoid units in the phospho-
nate chain using a classical method involving the selenylation/oxidation elimination sequence for
the introduction of the double bond to P <1998MI687>. Another 2-substituted bisphosphonate
26 was synthesized in 55.5% yield in the Knoevenagel reaction of the corresponding
,-unsaturated aldehyde and tetraethyl methylenebisphosphonate in the presence of titanium
tetrachloride and N-methylmorpholine <2001MI257>.
Ph Ph
Crystallization P PPh2
Ph2P Ph2P
C C NPh
Ph2P ∆, Ph-Me Ph2P
N NPh
10 Ph
11
H2O2
Ph Ph O
P PPh2
∆, Ph-Me Ph2P
16 + 10
Ph2P
N NPh
Ph
12
H2O2
Ph Ph O
P PPh2
Ph2P ∆, Ph-Me Ph2P
2 C C NPh
Ph2P Ph2P
N NPh
O 16 O Ph
13
H2O2
Ph Ph O
O O
P PPh2
Ph2P Ph2P
C C NPh
Ph2P Ph2P
N NPh
O O Ph
15
14
Scheme 3
2Et3N, C6H6 PCl3

+ PCl3
+ Et3NH+Cl– +
Et3NH+Cl–
N N N
Et3NH+X– PCl2
R CH2 R CH2 CH PCl2 R CH2
X– Cl2P
17 18
19 R = H, C6H5, C6H4NO2-p
Scheme 4
O O O
O OR
P(OR)2 P P
O Me
P(OR)2 O
P P(OR)2
O N
O O
O
20 21 22
O
O Et3N, CH2Cl2,
HO –70 to 25 °C P(OEt)2
P(OEt)2 + (EtO)2P Cl
77% P(OEt)2
O
23 24
O O
P(OEt)2 i–iii
P(OEt)2
P(OEt)2 P(OEt)2
O O
25
i. NaH, THF, 25 °C, 80 min; ii. C6H5SeBr, THF, 0 °C, 3 h;

iii. H2O2, THF, H2O, AcOH, 0 °C, 130 min
H
O
P(OEt)2
H
P(OEt)2
O
ButMe2SiO O
SiMe2But
26
Scheme 5
4.22.1.2 Mixed Acyclic Cyclic (3–6-Membered) Bisphosphino Alkenes
4.22.1.2.1 Three-membered rings

Majoral and co-workers synthesized new three-membered phosphirene systems 30 using zirco-
nium chemistry <1998CC1171> (Scheme 6). Thus, treatment of the acetylenic phosphine
oxide 27 with the zirconocene [Cp2Zr]-28 followed by reaction with alkyl (R = Me) or aryl
(R = Ph) dichlorophosphines gave 30. It should be emphasized that the phosphoryl group
played a key role in stabilization of the intermediate zirconacyclopropene 29 which was fully
characterized.
P
O O
ZrCp2 RPCl2
Ph2P Ph + [Cp2Zr] Ph2P
Ph2P Ph
Ph
O
27 28 29 30
Scheme 6
A mixture of the phosphirene 33 and the 1,2-diphosphete 34 was obtained by treatment of

P-phenyl-N-(2,4,6-tri-t-butylphenyl)phosphinimine 31 with 1-ethoxy-2-diisopropylphosphino-
ethyne 32 in 20% and 28% yields, respectively <1996ZOR443> (Scheme 7).
Et2O/C6H6 = 1:1,
7 days, 20 °C
Ph P N + Pr2i P C C OEt
31 32
N
N N
P
+
Ph P P Ph
Pr2i P OEt
Pr2i P OEt
33 34
N N
P P
MeI
+
Pr2i P OEt Pr2i P OEt
Me
I–
35 36
Scheme 7
P-t-butyl protected phosphirene 35 underwent methylation at the trivalent phosphorus to give

the corresponding phosphonium iodide 36 <1995ZOR400>.
4.22.1.2.2 Four-membered rings

Starting from the phosphonium bromide 37, two basic four- and five-membered frameworks
(38a–38c) and 43 were synthesized <1996CEJ221> (Scheme 8). Thus, the reaction of 37 with
phosphorus trichloride gave the di-P-chloro derivative 38a (R1 = R2 = Cl), while the reaction
of 37 with dichlorophenylphosphine afforded the di-P-phenyl derivative 38b (R1 = R2 = Ph).
Didechlorination of 38a (R1 = R2 = Cl) with tri-n-butylphosphine afforded the new five-
membered system 39. Replacement of phosphorus trichloride by dichlorophenylphosphine
in the reaction of 37 afforded the 4-membered structure 43, which was converted with the
triphenylphosphine/phosphorus trichloride system to the five-membered mono-P-chloro deri-
vative 38c. Addition of elemental selenium to 38b and 43 gave the corresponding selenides 41
and 42, respectively. The bis(triflate) and bis(tetrachloroaluminate) of 40 were also synthe-
sized in the methylation reaction of 39 with methyl triflate (pathway viii) and in the reaction
of 38c with aluminum trichloride (pathway ix), respectively <1996CB1083>.
R2
P P
+ +
ix Ph3P PPh3
40
viii 78%
+ R1 R2 R1 R2
Ph3P PPh3 P P P P
i (ii) iii
90% + 90% +
Ph Ph3P PPh3 Ph3P PPh3
37
Ph Ph
38 39
v a R1 = R2 = Cl
iv b R1 = R2 = Ph
c R1 = Cl; R2 = Ph Se Se R2
R1
Se P P
Ph3P Ph Ph3P Ph
P vi P
+
Ph3P PPh3
+ +
Ph PPh3 Ph PPh3 Ph
43 42 41
i. PCl3, PPh3, Et3N, CH2Cl2, 3 days (R1 = R2 = Cl); ii. PhPCl2, Ph3P, Et3N, CH2Cl2, 3 d (R1 = R2 = Ph);
+ +
iii. Bu3nP, Et3NCl–, 3 h; iv. PhPCl2, Et3N, CH2Cl2, 15 h; v. PCl3, PPh3, Et3NX–, CH2Cl2, 5 h
(R1 = Ph, R2 = Cl); vi. Se, CH2Cl2, 5 d; vii. Se, CH2Cl2, 3 d (R1 = R2 = Ph); viii. CF3SO3Me (2 equiv.),
CH2Cl2, 30 min (R2 = Me); ix. AlCl3, CH2Cl2, –78 °C, 10 min (R1 = Cl, R2 = Ph)
Scheme 8
4.22.1.2.3 Five-membered rings

In this section acylic, cyclic bisphosphino alkenes possessing one or two endo-phosphorus
atoms in the five-membered ring in addition to the exocyclic phosphino group will be
discussed. The benzophospholide moiety was also used as a five-membered cyclic fragment
of bisphosphino alkenes.
1-(Trialkylphenyl)-2-dibromophosphino-4-methylphospholes 45 (R = Me, Pri) were synthe-
sized from arylphospholes 44 through the site-phosphorylation reaction with PBr3
<2000JCS(P1)1495, 2002JOM(643-644)32> (Scheme 9). One or two PBr bonds in 45 were
further replaced by PO or PN bonds in reactions with alcohols (methanol) or secondary
amines (diisopropylamine, morpholine) to give, after hydrolysis or oxidation, a variety of
organophosphorus compounds such as phosphonic amides, H-phosphinic amides, and H-phos-
phinates.
Thus, the substitution reaction of one PBr bond by either oxygen or nitrogen gave the
compounds 46 and 47, while the substitution of two PBr bonds by two nitrogen atoms
followed by oxidation gave the second set of compounds 48 and 49. It is noteworthy that the
exocyclic P-moiety in 48 underwent a selective monooxidation to give 49a with the phosphole
phosphorus atom remaining mostly unoxidized. Oxidation of both P leading to 49b occurred
only in 14% yield. Interestingly, for R = But in 44, the phosphorylation with PBr3 took place at
the position 3 of the phosphole moiety. Phosphorus tribromide was also used for cyclization of
bisphosphonium dibromide 50 providing the bicyclic derivative 51 in 78% yield <1995BSF280>
(Equation (1)).
PBr3, Pyr, CHCl3

P 63 °C, 48 h P PBr2
R R R R
R R
44 R = Me, Pri 45
Br O H
R1OH, Et 3N, 78 °C, 1 h, C6H6
P H2O P
or R22NH, C6H6, 26 °C, 1 h P OR1(NR22 ) P OR1(NR22)
45
R R R R
R R
46 47
H2O2, CHCl3 Y2
NR22 0 °C, 1 h NR22
P P
2 R22NH, benzene, 1 h P NR22 P NR22
45 Y1
R R R R
R R
48 49a Y1 = 2e, Y2 = O
b Y1 = Y2 = O
Scheme 9
+
Ph2P +
Ph2P
Cl
PBr3, Et3N, CH2Cl2, 1 h
2Br– P– Br– ð1Þ
78%
Cl +
+ Ph2P
Ph2P
50 51
2-Phosphino-1-phosphaindenes 53 and their disulfides 54 were prepared from the reaction of

2-phosphino-1-zirconaindenenes 52 and dichlorophosphines (R = Ph, But) followed by addition
of elemental sulfur <1997CC279> (Scheme 10).
H H H
RPCl2 S8
S
Zr PPh2 P PPh2 P PPh2
Cp2 R R S
52 53 54
Scheme 10
1-Dichlorophosphino-2-phosphaindolizines 56 were synthesized from 17 or directly from 19 via

the intermediate 55 from a intramolecular cyclocondensation <1996PSS(112)121> (Scheme 11) in
acetonitrile solution.
PCl3, Et3N,
+ MeCN Et3N
N N + N N
PCl2 –Et3NHCl– R
R CH2 R CH2 PCl2 R PCl2
H P P
Cl2P
X– Cl
17 19 55 56
MeCN
2 56 R=Ph N N
–PCl 3 N N +
Ph P Ph Ph P Ph Cl–
P P P P
Cl
58
57
R2 R2 R2
2 N N Cl N + PCl3
N PCl2 N P
P P P
59 R2 = H, Me 60
Scheme 11
In the case of R = Ph, the initially formed 56 underwent disproportionation to form 57, which
exists in equilibrium with 58. If N-alkyl groups in 17 were replaced by the N-amino group,
moisture-sensitive 1,2,3-diazaphospholo [1,5-a] pyridines 59, being in equilibrium with 60, were
formed in acetonitrile solution upon treatment with 2 equiv. of PCl3 and 5 equiv. of Et3N at
0–5 C <1995S173>.
Mathey and co-workers synthesized other acyclic bicyclic structures 64, 66, and 67 possessing
the exocyclic phosphonate and phosphonamide moieties. They utilized the [4+2]-cycloaddition
reaction of diethyl ethynylphosphonates and phosphonamides 63 and 65 with transient 2-phenyl-
phosphole 62, in equilibrium with 1-phenylphosphole 61 at 140 C <1996JOC3531>
(Scheme 12).
Ph
i
90% P
Ph P(O)(OEt)2
140 °C 64
P Ph P
Ph
Ph
ii +
61 62 P
Ph P P(O)(NEt2)2 P(O)(NEt2)2
66 (54%) 67 (18%)
i. Ph P(O)(OEt)2 63, 150 °C, 3 h

ii. P(O)(NEt2)2 65, 145 °C, 15 min
Scheme 12
Thus, both diethyl 2-phenylethynylphosphonate 63 and its corresponding phosphonamide gave

only one regioisomer 64, while unsubstituted ethynylphosphonamide 65 afforded two regio-
isomers 66 and 67. Dimorpholinyl 2-phenyl-ethynylphosphonamide also gave only one regio-
isomer.
Bisphosphino alkene fragments are also present in the phospholide structures 68–70.
In contrast to alkali metal naphthalenides, only one phosphonium moiety was cleaved in
reactions of bis(phosphonio)benzo[c]phospholide 68 with magnesium to give new phospholide
structures 69 and 70 (Equation (2)) <1999EJI1169>.
Ph3P+ Ph3P+ Ph2P+
Mg
– PX– – P + – P + Ph3P
– PhMgX ð2Þ
Ph3P+ Ph2P
68 X = Cl, Br 69 70
4.22.1.2.4 Six-membered rings

The 1,4-azaphosphinine system 76 was synthesized by the chlorination of 74 with phosphorus
pentachloride via the isolable intermediate salt 75 <1999ZOB833> (Scheme 13).
Cl H
PCl5, C6Cl6, 25 °C +
Me2N N CH CH2 Me2N N CH CHP(O)Cl2 Me2N N PCl2 PCl6–
–HCl
C(O)Me C(Cl) CH + – H P(O)Cl2
PCl3 PCl6
74 75
76
Scheme 13
Schmidpeter and co-workers elaborated the synthesis of two cyclic systems 80 and 81 from the
corresponding amine 77 and the phosphorane 78, respectively. Both reagents were condensed with
(Z)-olefin 79 in the presence of pyridine. Further reactions of 80 and 81 with elemental sulfur gave
the corresponding derivatives containing the P(S)Cl moieties <1996ZN(B)1761> (Equation (3)).
Cl2P PCl2
N +
Ph3P PPh3 79
Ph
77 Pyridine Cl Y Cl
P P
or ð3Þ
+
Cl2P PCl2 Ph3P PPh3
PPh3 80 Y = N–Ph
78 81 Y = C PPh3
Acyclic, cyclic bisphosphino alkenes involving a six-membered phosphinine moiety as the cyclic
unit were represented in the review period 1995–2003 by the slowly decomposing 84 and stable 85
obtained in the reaction of organozinc derivative of the phosphinine 82 and its pentacarbonyl-
tungsten complex 83, respectively, with excess of PCl3 <1996OM802> (Equation (4)).
PCl5, THF, –60 °C

I
P NMe2 P PCl2
Zn
ð4Þ
X Me N X
2
82 X = 2e 84 X = 2e
83 X = W(CO)5 85 X = W(CO)5
1,2-Dihydrophosphinine 87a was obtained on treatment of 86 with excess of methyllithium

followed by protonation. Since both substrate and products were air sensitive, the compound 87a
was converted to the stable disulfide 87b (Equation (5)) <1996OM1597>.
i. 3MeLi, THF
ii. H+
P PMe2 P PMe2 ð5Þ

Y
Me Y
86 87a Y = 2e
1/8S8
b Y=S
Mathey and co-workers prepared 2,6-diphenylphosphino-phosphinine 91 upon heating the

1,3,2-diazaphosphinine 88 with 2 equiv. of the alkyne 89 <1996JA11978>. This highly regiose-
lective reaction proceeded step by step via the 1,2-azaphosphinine 90 with extrusion of two
molecules of t-butylnitrile (Scheme 14).
But But But Ph Ph Ph

i 89, ∆ , toluene
N N –ButCN N –ButCN
P P PPh2 Ph2P P PPh2
88 90 91
i. Ph2PC CPh (89), ∆, toluene
Scheme 14
Another 2-diphenylphosphino-phosphinine 94 was synthesized by Mathey and co-workers via

organopalladium insertion into the 2-carbonbromine bond of the phosphinine 92 followed by
reaction with diphenyl(trimethylsilyl)phosphine 93 <1995S717> (Equation (6)).
Ph2P TMS 93
Pd(DBA)2, toluene
80 °C, 2 h
ð6Þ
P Br P PPh2
Ph Ph
92 94
The delocalized carbanion 95 belongs formally to the group of cyclic bisphosphino alkenes and is
obtained on treatment of dimethylphosphino-4,5-dimethylphosphinimine 86 with methyllithium
(Equation (7)) <1996OM1597>.
3MeLi Li+
86 –
ð7Þ
P PMe2
Me
95
4.22.1.3 Cyclic (3–6-Membered) Bisphosphino Alkenes

In this section syntheses of bisphosphino alkenes containing both the phosphorus atoms in the ring
will be discussed. In the review period a very limited number of new methods have been reported.
These include syntheses of three-, four-, five-, and six-membered rings and their combinations.
Yoshifuji and Toyota synthesized three-membered methylenediphosphirane 97 from the
1,3-diphosphaallene 96 and dichlorocarbene <1996PSS(109-110)613> (Equation (8)).
Cl Cl
CCl2
P C P P P ð8Þ
96
97
Mathey and co-workers synthesized a wide range of 2-phosphinophosphinines 99, 100, and 102
by simple conversions of 2-(dibromophosphino)-4,5-dimethylphosphinine 98 <1996OM1597>.
The PBr2 moiety in 98 was converted to the corresponding P(alkyl, aryl or alkynyl)2, P(MeO,
BunS or Et2N)2 and PH2 groupings upon reactions with organolithiums, hetero(O,S,N)-nucleo-
philes and LiAlH4, respectively. The reaction of 98 with alkynes gave the phosphirene 99 in 55%
yield (Equation (9)). The latter was converted to 1,2-dihydrophosphete 100 in 75% yield upon
reaction with the accompanying 98 (Equation (10)). The reaction of 98 with the titanacyclobutene
101 yielded the expected four-membered ring derivative 102 in 80% yield (Equation (11)).
i. AlCl3, CH2Cl2
ii. PhC CPh
iii. Bun3P
55%
ð9Þ
P PBr2 P P Ph
98
Ph
99
Ph Ph
P P
Bun3P, CH2Cl2 ð10Þ
98 + 99
75% P P
100
Ph Ph
Toluene, –20 °C, 10 min
98 + Ph
Cp2Ti 80%
P P ð11Þ
101 Ph
102
(1-Diazo-2-oxoalkyl)silanes 103 existing in equilibrium with 1-diazo-2-silyloxy-1-alkenes 104,

when treated with 1,2,3(3)diazaphospholes 105, gave [3+2]-cycloadducts 106, which underwent
thermolysis in a sealed tube at 80 C to afford tricyclic P-heterocycles 107 with extrusion of
nitrogen <1999EJO2633> (Scheme 15).
R1C C SiR3
O N2
1 OSiR3
103 Ac R R3SiO R1 Ac
3
R N 80–100 °C
CH2Cl2, 20 °C N N N
+ N Ac N P N N P P N
–N2
1 P
R N
C N2 105
R3 H R3 H H R3
R3SiO
104 106 107
Scheme 15
Starting from 1,2-bis(lithiophenylphosphino) benzene 108 and tetrachloroethylene 109, both the
expected dibenzotetraphosphafulvalene 110 and its strain free six-membered ring isomer 111 were
obtained <1997BSF853> (Equation (12)).
Ph Ph Ph Ph
PPhLi Cl Cl P P P P
+ +
ð12Þ
PPhLi Cl Cl P P P P
Ph Ph Ph Ph
108 109 110 111
Alkyl-substituted 2-(3,4-dimethyl-phosphol-1-yl)phosphinines such as 114 were synthesized

in 75% yield in the condensation reaction of 2-bromo-3-methyl-phosphinine 112 with
3,4-dimethylphospholyllithium 113 in the presence of the nickel complex. Elemental sulfur
was added to the phosphole phosphorus in 114 to give the corresponding sulfide 115. 2,6-
Bis-(3,4-dimethyl-phosphol-1-yl)phosphinines, such as 118, were obtained in the reaction of
113 with 2,6-dibromo-3,4-dimethyl-phosphinine 116 in 50% yield in the presence of palla-
dium complex. Replacement of lithium in 113 by tin in 1-trimethylstannyl-3,4-dimethyl-
phosphole 117 gave the monobromo phosphinine 119 in 50% yield <1999BSF910>
(Scheme 16).
–P
i ii
+ Li+
75% 65%
P Br P P P P
S
112 113 114 115

i. (DPPE)NiCl2, THF, 6 h
ii. S8, toluene, 2 h, 70 °C
Li+
–P
113, Pd(DBA)2
THF, 3 h, 30 °C
50%
P P P
118
Br P Br
Me3Sn P 117, Pd(DBA)2
116
50% Br P P
119
Scheme 16
4.22.1.4 Alkali Metal Salts of Bisphosphino Alkenes

Only one product of this type has been reported in the review period. The product 120 underwent
reduction with alkali metals (Li, Na) to give the dimetallated species 121 (Equation (13))
<1999EJI1169>.
+
PPh3 PhP– Li
Li
P Ph – P Li+
–PhLi ð13Þ
PPh3 PPh2
120 121
4.22.1.5 Transition Metal Complexes of Bisphosphino Alkenes

Mononuclear 124 and dinuclear 125 cyclometallated complexes were prepared on treatment of the
palladium chloride-bridged complex 122 of 1,3,4,5-trimethyl-2-phenylimidazole with various
amounts of 1,1-bis(diphenylphosphino)ethene 123 (Scheme 17) <2000EJI2055>.
+
Ph2
Cl P
Pd Ph2P Pd PF6– ii
Me 2
i Me
N N + N N P
75% Ph2 91%
Ph2P
122 123 124
Ph2 Ph2
P P N N
Me
Pd Pd
Me
N N Cl Cl
i. NH4PF6, acetone
ii. Acetone, 25 °C 125
Scheme 17
Thus, treatment of 122 with 123 in a 1:1 molar ratio gave the dinuclear complex 125 while
treatment of 122 with 123 in a 1:2 molar ratio in the presence of ammonium hexafluorophosphate
afforded the mononuclear complex 124 in 75% yield.
Other mononuclear cyclic palladium complexes of this type with 1,1-bis(diphenylphosphino)
ethene were also synthesized <2002NJC1425, 2002OM1304>.
The chromium complex 127, prepared by treatment of the bisphosphine 126 with chromium
hexacarbonyl, was deprotonated with methyllithium and the resulting carbanion was acylated
with acyl chlorides 128 (R = Ph or p-tolyl). The intense green color of the chromium complex
129 indicated that the aromatic ring was converted into a quinonoid system (Scheme 18)
<1995MI120>.
Ph2 Ph2
Ph2P P P OC(O)Ph
i
Ph + Cr(CO)6 (OC)4Cr Ph (OC)4Cr
Ph2P 38% Ph
P P
Ph2 Ph2
126
127 129
i. MeLi, RCOCl 128, Et2O, benzene
Scheme 18
New homo- and heterobimetallic complexes of Ni(II), Pd(II), and Pt(II) with 1,1,2-tris(di-
phenylphosphino)ethene (3P) and 1,1,2,2-tetrakis(diphenylphosphino)ethene (4P) were synthe-
sized and characterized. The complexes of Pd(II) and Pt(II) showed a square planar geometry
while complexes [Ni(3P)Cl4] and [NiPt(3P)Cl4] had a tetragonal geometry around nickel
<2002MI137>.
The stable 1-pentacarbonyltungsten complex of 4,5-dimethyl-2-dichlorophosphinophosphinine
85 was earlier described <1996OM802>. Starting from 2-dibromophosphino-4,5-dimethylphos-
phinine and ethanol in the presence of triethylamine, Mathey and co-workers prepared the
phosphinine derivative 130, which turned out to be a powerful bridging ligand able to stabilize
metalmetal single and triple bonds between low-valent transition metal centers
<1997CB(R)843>. Thus, the reaction of 130 with Mn2(CO)10 yielded the corresponding
MnMn complex 131 (Equation (14)). Reaction of 130 with [Fe2Cp2(CO)4] under UV irradiation
similarly yielded the FeFe-bridged complex 132 (Equation (15)).
Xylene, reflux, 2–3 h

OEt + Mn2(CO)10 OEt
P P 50% P P
OEt OEt ð14Þ
(OC)4Mn Mn(CO)4
130 131
hν, THF, –80 °C, 3–4 h OEt

130 + [FeCp(CO)2]2 P P
60% ð15Þ
OEt
Cp(CO)Fe Fe(CO)Cp
132
A clean addition of 2-diphenylphosphino-4,5-dimethylphosphinine occurred at the

MoMo triple bond of [Mo2Cp2(CO)4] to give the MoMo single-bonded complex 133
(Equation (16)).
THF, 25 °C, 10 min Ph

Ph + [MoCp(CO)2]2 P P
P P 80% Ph ð16Þ
Ph
Cp(CO)2Mo Mo(CO)2Cp
133
When the phosphino group in 133 was replaced by the P(OEt)2 group [or P(OAr)2], the
thermolysis of the resulting 134 occurred to give the Mo2Cp2(CO)2 triple-bonded complex
135.
The MoMo triple bond of the latter readily added two molecules of CO to reform 134 or one
molecule of t-butyl isocyanide to give the new complex 136 (Scheme 19).
The benzophospholide anion 137, with an excess of Ni(CO)4, formed the complex 138 in 40%
yield after recrystallization from THF/diethyl ether <1999EJI1169> (Equation (16a)).
∆, –2CO, xylene
OEt reflux, 6 h OEt
P P P P
OEt CO, 8 bar OEt
toluene, 25 °C Cp(CO)Mo Mo(CO)Cp
Cp(CO)2Mo Mo(CO)2Cp
134 135
ButN C
toluene, 25 °C
OEt
90 % P P
OEt
Cp(CO)Mo Mo(CO)Cp
C
N
t
Bu
136
Scheme 19
PPh2 Ph2P Ni(CO)3
Ni(CO)4
– P Li+ – P Li+
–2CO ð16aÞ
PPh2 Ph2P Ni(CO)3
137 138
Gudat and co-workers discovered that cationic 1,3-bis-triphenylphosphonio-benzophospholide

68 reacted selectively with an excess of sodium borohydride to give the neutral compound 139 via
cleavage of the PPh3 moiety <2000CC1637> (Scheme 20). Treatment of the latter with different
chromium carbonyls afforded new complexes 140 and 141. These reactions showed that 139
behaved like a phosphine-like -donor/-acceptor ligand in (P)-complexes and like a phosphaar-
ene ligand in -complexes.
+
PPh3
ii
– P
+
PPh3
Cr(CO)3
i
– P Cl– – P 140
+ +
PPh3 PPh3 iii
– P Cr(CO)5
68 139
+
PPh3
i. NaBH4, THF, 24 h, rt; ii. [(cyclooctene)Cr(CO)5], THF, 6 h, rt;
iii. [(naphthalene)Cr(CO)3], THF, 6 h, rt 141
Scheme 20
4.22.2 FUNCTIONS CONTAINING ONE PHOSPHORUS AND EITHER ARSENIC,

ANTIMONY OR BISMUTH, R12C¼C(PR22)AsR32, etc.
Although no important progress has been made in this area since 1995, it is worth noting that
some new products of interest appeared in the literature. The condensation of the organozinc
reagent 142 with AsCl3 gave 2-(dichloroarsino)-4,5-dimethylphosphinine 143 from which the
corresponding P-(phosphinine) pentacarbonyltungsten derivative was obtained <1996OM802>
(Equation (17)).
I Me2
AsCl3
N ð17Þ
P Zn P AsCl2
N
Me2
142 143
The cycloaddition–cycloreversion sequence was utilized by Le Floch and co-workers for the
synthesis of the arsinine 145 from the 1,3,2-diazaarsinine 144 and 1-diphenylphosphino-2-phenyl-
ethyne <1997OM4089> (Equation (18)).
Ph Ph
Ph2P C C Ph, 120 °C, 12 h
N N 50% ð18Þ
As Ph2P As PPh2
144 145
The 2-phosphinostibole 147 was produced in the reaction of the 2-phosphinozirconaindene 146
with PhSbCl2 <1997CC279> (Equation (19)).
PhSbCl2
Zr PPh2 Sb PPh2 ð19Þ

Cp2 Ph
146 147
4.22.3 FUNCTIONS CONTAINING ONE PHOSPHORUS AND A METALLOID,

R12C¼C(PR22)SiR33, etc.
After 1995, many methods leading to this class of compounds possessing one of the three
metalloids (Si, Ge, or B) appeared in the literature in contrast to the previous review period in
chapter 4.22.3 <1995COFGT(4)1021> where no representative protocol was reported. The
majority of methods reviewed here concern the synthesis of compounds with P, Si-functions,
three of them concern P, Ge-compounds, and just one deals with the synthesis of a compound
with P, B-functions. In all the cyclic P, Si-compounds, the phosphorus is included in the ring
while the Si is mostly acyclic. Complexes with metals as well as mono and dianions of the title
P, Si-compounds were also reported.
4.22.3.1 Silicon Derivatives
4.22.3.1.1 Acyclic compounds

Treatment of the vinyl phosphine oxide 148 with LDA at low temperatures in the presence of
trimethylsilyl chloride afforded a mixture consisting of the silylation product 149 (major) and a
minor addition product 150 <1998TL1637> (Equation (20)).
O O O NPr2i
LDA, TMSCl
Ph2P Ph2P + Ph2P
Ph Ph Ph ð20Þ
TMS TMS
148 149 150
Similarly, the phosphine oxide 151 upon treatment with LDA in the presence of trimethylsilyl
chloride gave 152 <1999JCS(P1)1807> (Equation (21)).
i. LDA
O O
ii. TMSCl, –78 °C, 7 h
Ph2P Ph2P
71% ð21Þ
O O TMS O O
151 152
In this case, no addition product of LDA to the double bond was detected. The reaction could
be performed at much lower temperature (78 C) most probably due to a better stabilization of
the intermediate vinyllithium by the neighboring acetal oxygen than by the phenyl group in 148.
The vinylphosphonates 153 and 155 were also readily lithiated at the -position to the phos-
phorus atom by LDA or LITMP. The resulting 1-lithiovinylphosphonates were trapped with silyl
or germyl chlorides to give 1-functionalized phosphonates 154 and 156 <1998JOC6239>
(Equations (22) and (23)).
O O
i. LITMP
RS P(OEt)2 RS P(OEt)2
ii. ECl, THF
RS H RS E
ð22Þ
153 154a E = TMS, RR = (CH2)2 (81%)
b E = SiPh3, RR = (CH2)2 (69%)
c E = GeMe3, RR = (CH2)2 (78%)
d E = TMS, R = R = Et (64%)
O i. LDA O
ii. EX, THF
P(OEt)2 P(OEt)2
ð23Þ
EtO EtO E
155 156a E = TMS (96%)
b E = SiButMe2 (75%)
Further transformations at the 2-position of 1-silylated vinylphosphonate 156 were also inves-
tigated. Thus, the Michael addition reaction of lithium ethyl mercaptide to 156 gave 157 as a
mixture of (E)/(Z) isomers in a ratio 3.8:1 (Equation (24)).
O
EtSLi, THF, –78 °C, rt P(OEt)2
156 ð24Þ
EtS TMS
157
Elimination of ethanol from 158 with catalytic amounts of EtONa in THF afforded the
unsubstituted 159 in 80% yield (Equation (25)).
O O
P(OEt)2 EtONa (0.2 equiv.), THF P(OEt)2
ð25Þ
80%
EtO TMS TMS
158 159
Alkynes and alkynylphosphonates were also employed in the synthesis of the title compounds.
Takaki and co-workers reported hydrophosphination of the alkyne 160 in the presence of
catalytic amounts (15 mmol.%) of the ytterbium imine complex 161 to give only one product
(E)-162 in quantitative yield <2001TL6357> (Equation (26)).
i. 161, THF, rt, 4 h
ii. H2O2 Ph TMS
Ph C C TMS + Ph2PH
100% H PPh2
O
160 162 ð26Þ
Ph
N
Yb
Ph Ph
161
The addition reaction of PX13 (X1 = Cl, Br) to 1-silylated or 1-germylated alkynes (163a,b)
afforded 1-silyl- or 1-germyl-1-phosphino alkenes (164a,b) <1996ZOB1637> (Equation (27)).
Me3X2
PX13 + Me3 X2 C COR C C(X1)OR
X1 = Cl, Br
X12P ð27Þ
163a X2
= Si 164a,b
b X2 = Ge
The reactions of PCl3 with both types of alkynes (163a,b) were performed either neat or in
acetonitrile in 5–30 days at 20–50 C (X2 = Si, R = Me, Et, Bun) or in 12–72 h at 20 C (X2 = Ge,
R = Me, Et). The reactions of 163a with PBr3 were carried out in methylene chloride at 20 C and
were completed within 3 h while the reactions of PBr3 with 163b were completed within 10–15 min
at 30–40 C. The addition reaction of PBr3 to 1-trimethylsilylethyne was also performed under
photochemical conditions (30 min, neat) to give the corresponding addition product in 90% yield,
as a mixture of (E)/(Z) (95:5) isomers <1995ZOB1046>.
Gil and Oh reported addition of the organocopper (I) reagent 166 to 1-alkynyl phosphonate
165 followed by the capture of the resulting 1-phosphonyl-2,2-di-n-butylvinylcopper intermediate
with trimethylsilyl chloride to give diethyl 1,2,2-trisubstituted vinyl phosphonate 167 with stereo-
selectivity retained from vinylcopper intermediates <1999JOC2950> (Equation (28)).
O
i. Bun2CuLi2I 166
O (EtO)2P Bun
ii. TMSCl, 30 min, rt
(EtO)2P C C Bun ð28Þ
82%
TMS Bun
165 167
Deprotonation of allylphosphonates 168 upon treatment of an excess of LDA at 70 C in the

presence of trimethylsilyl chloride resulted in the formation of the lithiated intermediates 169, on
acidic hydrolysis gave the corresponding phosphonates 170 in quantitative yields
<1996JCS(P1)931> (Scheme 21).
When treated with various aldehydes at 70 C, the lithio reagent 169b, surprisingly led to
phosphorus analogs of -lactones 172b via the intermediate 171b. Aromatic aldehydes (R3 = aro-
matic) gave exclusively 172b in 80–92% yields, while aliphatic aldehydes (R3 = aliphatic) afforded
mixtures of 172b in 7–30% yield of the Peterson olefination products.
4.22.3.1.2 Acyclic cyclic compounds (3–7 membered)

In this section are described the syntheses of compounds possessing P, Si-functionality with the
phosphorus built into three-, four-, five-, six-, and seven-membered rings. Syntheses of trifunc-
tional compounds with P, Si, and metal functions, such as metal complexes and anions, will be
discussed in the next section.
O O
LDA, THF, –70 °C
(EtO)2P TMSCl, –70 °C (EtO)2P TMS
+
– Li
R1 R1
R2 R2
168 169a R1 = H, R2 = Ph
b R1 = Me, R2 = Me
i. R3CH=O, H3O+, –70 °C

THF, –70 °C
ii. HCl
O O O
EtO
P TMS (EtO)2 P TMS (EtO)2P TMS
O Li O
1
R
R3 R3
Me Me Me Me
R2
172b 171b 170a R1 = H,
R2 = Ph
b R1 = Me, R2 = Me
Scheme 21
Silylated aryl-substituted phosphirenes 175 were formed at 10 C via LiCl elimination from
carbenoids 174 obtained from 173 via Cl/Li exchange with n-butyllithium <1996PSS(109-110)613>
(Scheme 22).
Cl
BunLi TMS
CCl2 THF C Li(THF)3 C
Ar P Ar P Ar P
C(TMS)2 –LiCl C
C(TMS)2 TMS
173 174 175
Scheme 22
Zirconacyclopentadienes 176a,b (R = Ph, Bun) reacted with PCl3 in dichloromethane to give

1-chlorophosphirenes 177a,b <1999OM4205> (Scheme 23). The latter were also synthesized from
the corresponding titanacyclopropene complex using a metallacycle transfer reaction
<1998OM1677>. In the case of the methyl-substituted derivative 176c (R = Me) when PBr3
was used as a reagent, the five-membered metathesis reaction product, i.e., 1-bromophosphole
178c, was formed within 15 min at 35 C instead of the expected 1-bromophosphirene.
R R
R TMS
PCl3
+ RC C TMS
TMS Zr
TMS R = Ph, Bun P
Cp2
Cl
176a R = Ph 177a,b
b R = Bun
c R = Me
PBr3
TMS TMS
P
R = Me
X
178c (X = Br)
Scheme 23
In contrast, the metathesis reaction of 176c with PCl3 gave a mixture of 1-chloro- 178 and
1-cyclopentadienyl- 179 phospholes, which turned out to be unstable during purification
<1999OM2491> (Equation (29)). Analogous chlorostiboles, chlorobismoles, and chloroarsoles
were earlier described as thermolabile compounds as well <1988JA2310, 1994JA1880>.
PCl3,
THF
+
TMS Zr TMS TMS P TMS TMS P TMS
Cp2 ð29Þ
Cl
176c 178 (X = Cl)

179
Treatment of a mixture of 178 and 179 with calcium in THF afforded dimeric bis(tetrahy-
drofuran-O)dicalciumbis[3,4-dimethyl-2,5-bis(trimethylsilyl)-1-phosphacyclopenta-2,4-dienide]-
cyclopentadienide chloride, as an example of trifunctional compound containing P-, Si-, and
Ca-functions.
While addition reactions of Grignard reagents and organolithium compounds to phosphinines
<1967AG(E)87, 1974TL4501, 1977TL407> and 1,3,5-triphosphinines <2003AG(E)1863> are
known, the analogous reaction with 1,3-diphosphinines remained unknown until 2003. Regitz
and co-workers <2003S1526> discovered that although 1,3-diphosphinines decomposed on treat-
ment with n-butyllithium (78 C to room temperature), the reaction with methylmagnesium
bromide at 40 C led to the formation of isomeric Dewar-benzenes 181a and 181b in a ratio of
14:1 in 83% yield. When the reaction temperature was raised to 120 C for 4 days, the same
products were obtained in a 5:2 ratio in 20% yield still favoring 181a (Equation (30)).
TMS But
TMS P But But But
CH3MgBr, THF P P
+
P P P ð30Þ
But But But TMS But
But
180 181a 181b
The photolysis of pentafluorophenyl isocyanide in the presence of [bis(diisopropylamino)phos-

phino](trimethylsilyl)diazomethane 182 yielded 3-trimethylsilyl-1,2-azaphosphetine 183 in 4%
yield <1989JFC73> (Equation (31)).
F F
F N C Pr2i N N2 F F
n-pentane
+ Pr2i N
Pr2i N P C TMS 4%
F F P N F ð31Þ
F 182 F
TMS NPr2i
183
Flash vacuum pyrolysis (FVP) of 184 provided evidence for the existence of equilibrium between
the two intermediate phosphacyclobutadienes 185a and 185b, which further gave t-butylphos-
phaalkyne 186 and 1-trimethylsilylphosphaalkyne as phosphorus-containing products <2001S463>
(Scheme 24). The reaction of 184 with 186 gave 1,3-diphosphinine 187 in 71% yield.
Very rare and thermally rather unstable 2-phosphino-2H-phosphirene 188 rearranged after 3 h
at room temperature to 15,23-diphosphete 189. Photochemical rearrangement of 188 afforded a
mixture of 189 (87%), 190 (3%), and 191 (10%).
Irradiation of the diphosphete 189 gave the isomeric 1,2-dihydrodiphosphete 190 in 69% yield
<1999CEJ274> (Scheme 25).
An attempt to isolate 188 as the more stable thiophosphoranyl derivative or the BH3 adduct
resulted in the formation of the corresponding new diphosphete derivatives 192 and 193.
The same adducts were also obtained directly from 189 <2001S463> (Scheme 26).
But But TMS But TMS

TMS
FVP, 700 °C/10–7 mbar
P
P P
But But But
184
ButC P 186 185a 185b
toluene, 8 h, 20 °C
71%
But P But
P
But
TMS
187
Scheme 24
TMS
R2P TMS R2P
rt, 3 h
P P
But But
188 189
hν, 254 nm
hν, 254 nm 69%
TMS
PR2
RP
P
+ 189 + 190 RP
TMS But But
191 R = Pr2i N 190
Scheme 25
+ TMS
S8 R2P
51% ( 90%) S P
–
S But
192
188 and 189
+ TMS
BH3 R2P
87% ( 95%) – P
H3B But
193
+ TMS
W(CO) 5THF R2P
75% – P
R = Pr2i N (OC) 5W But
194
Scheme 26
Moreover, 189 reacted at room temperature with pentacarbonyl tungsten to afford the
1-complex 194 as orange crystals <1995JA10785>. Analogous complexes of 189 with diiron
nonacarbonyl were also obtained in 48% yield and further reactions of 189 with MeOTf, Se
(1 and 2 equiv.), TMS2O2 (2 equiv.), W(CO5)THF/TMS2O2, 2TCBQ (tetrachloro-o-benzoquinone)
and MeOTf/TCBQ were also investigated <1996AG2386, 1997JA9720>.
The nitrogen analog of 188, i.e., the 2-phosphino-2H-azirine 195, showed completely different
behavior than its phosphorus counterpart. In the reaction with borane at room temperature the
five-membered heterocycle 196 was formed in 76% yield <1997CEJ1757> (Equation (32)) instead
of the expected nitrogen analog of 193.
+ TMS
R2P TMS R2P
BH3.Me2S, toluene, rt
–B
N 76%
H Ph ð32Þ
N
Ph H
H
195 196
Deprotonation of both (1-bromo-2-thiophen-3-yl-vinyl)trimethylsilane 197a (X = H) and its

bromo derivative 197b (X = Br) with t-butyllithium followed by the condensation with dichloro-
phenylphosphine and cyclization afforded the phosphole derivative 198 (Equation (33)). In the
analogous reaction [1-bromo-2-(4-bromothiophen-3-yl)vinyl]trimethylsilane was also used
<1997H1891>.
TMS
ButLi, Et2O, –80 °C TMS
Br + PhPCl2 P
S X S ð33Þ
Ph
197a X = H 198
b X = Br
Maas and co-workers described thermal extrusion of nitrogen from the 1,2,4-diaza-phosphole
derivative 199 to give 2,3-dihydro-1,3-oxaphospholes 200 in one of the competing reaction path-
ways <1997CB(R)779> (Scheme 27).
Mes Mes
R1 Toluene, Mes O
Ph P 110 °C Ph P SiR3 SiO2/air Ph P SiPr3i
OSiR3 –N2 10%
Ph Ph Ph
N N O O
R1
199 201c
200
1 = But; R = SiPh But (83%)
aR 3 2
b R1 = But; R3 = SiMe2But (74%)
c R1 = Me; R3 = SiPr3i (4%)
Mes = 2,4,6-Me3-C6H2 d R1 = 4-MeOC6H4; R3 = Pr3i (27%)
Scheme 27
During chromatographic work-up 200c was oxidized with the oxygen in air to the cyclic
phosphinoxide 201c.
Triphosphabishomoprismanes (203a and b) and 204 were synthesized by Diels–Alder reaction
of 2,4,6-tri-t-butyl-1,3,5-triphospha-Dewar-benzene 202 with the corresponding acetylene deriva-
tives (Scheme 28) <1999S1363>. In solution, 203a slowly rearranged even at room temperature to
the corresponding triphosphasenobullvalene 205. This rearrangement was enhanced by irradiation
with the Hg-high-pressure lamp (Equation (34)).
But
But Et2O, 0 °C, 2 h P
But P But But
R1 C C TMS P
P R
P P But
202 R1
203a R1 = TMS (80%)

b R1 = Ph, TMS (69, 5%)
TMS C C But
1
–2 (CH2)7 P
But
TMS C C P
Et2O, 0 °C, 2 h P TMS
But
73.4% But
P
But (CH2)7
P
P
But
TMS
204
Scheme 28
But
P
hν P P
203a ð34Þ
But
TMS But TMS
205
Märkl and Dorsch showed that the 1,3-azaphosphinine 206 underwent the Diels–Alder
cycloaddition/cycloreversion reaction sequence with the diacetylene 207 under high pressure
(8 kbar) to give the corresponding phosphinine 208 in 58% yield <1995TL3839> (Equation (35)).
Ph Ph TMS
C
C
N
+ TMS C C C C TMS ð35Þ
–PhCN
Ph P Ph 58% Ph P TMS
207
206 208
The analogous approach utilizing a [4+2]-cycloaddition/cycloreversion sequence involving the

concomitant loss of one or two nitrile groups and using 1,3,2-diazaphosphinines or 1,2-azaphos-
phinines under normal pressure was widely developed by the group of Mathey. This approach
enabled various syntheses of 2-trimethylsilyl or 2,6-bis(trimethylsilyl)phosphinines as well as
silylated tripodal ligands, silacalixphosphinines and other systems. Thus, mono- 210 or bissily-
lated phosphinines 212 and 213 were obtained from 1,3,2-diazaphosphinine 88 in one or two
[4+2]-cycloaddition-cycloreversion sequences using 2 equiv. of the same 209 or 1 equiv. each of
two different silylated alkynes 209 and 211 <1997OM4089> (Scheme 29).
These thermally promoted reactions were also utilized in a slightly modified manner for the
synthesis of the so far unknown tripodal ligands <2000EJI2565>. One of such new ligands 215,
was synthesized starting from the triyne 214, 3 equiv. each of 1,3,2-diazaphosphinine 88 and
trimethylsilylacetylene 211 (Equation (36)).
TMS C C C10H9Fe 209

C10H9Fe
toluene, 2 h, 125 °C
N N N
P P TMS
88 210
HC C TMS 211
toluene, 1 h, 95 °C 209, xylene, 15 h
70%
150 °C, 60%
C10H9Fe FeH9C10 C10H9Fe
TMS P TMS TMS P TMS

212 C10H9Fe = ferrocenyl 213
Scheme 29
But But
H
i. N N 88 (3 equiv.) Me2
P
Me2Si SiMe2 ii. TMS C CH 211 (3 equiv.) Si P TMS
SiMe2 H Me2 P TMS
35% Si
ð36Þ
Me Me Me2Si P TMS
Me
214 215
Some of the tripodal ligands obtained were then complexed with [W(CO)5THF] to afford
1-W(CO)3 complexes.
The utility of the new process was demonstrated further by the synthesis of silacalix-[n]-phosphi-
nines <1999CEJ2109, 1999PSS(144-146)251>. The best results were obtained when 216 was treated
with 1 equiv. of diyne 217 under high-dilution conditions to give 218 (n = 3) in 20% yield (Equation (37)).
This strategy was also extended to the synthesis of 220 (n = 4) (Equation (38)).
Ph Ph
Me2 P Me2
Me2 Me2 Si Si
Ph Si P Si Ph Ph Ph
i
P P
(–2ButCN) Ph Ph
P P Si ð37Þ
Me2
N N Ph Ph
But But
216 218
i. Toluene, 110–115 °C, 7–8 days, Me2Si(C C Ph)2 217
Ph Ph i. Toluene, 110–115 °C Me Ph Ph Me
Ph Me Si P Si Me Ph
7–8 days
+ 216
Me2Si P SiMe2 P P
–2ButCN
ð38Þ
Ph Me Si P Si Me Ph
Me Me
Ph Ph
Ph Ph
219 220
The same method was applied to the synthesis of analogous but more flexible macrocycles
having different cavity sizes <2001JOC1054>.
The neutral gold(0) complexes of 220 were obtained and found out to be particularly stable
<1999AG(E)3194>. Other silacalix-[3]-phosphinine-based macrocycles with SiOSi spacers
and their cationic complexes with group 11 metal centers (Cu, Ag, Au) were also synthesized
<2002EJI2034>.
Other homogenic 2,6-bis(trimethylsilyl)phosphinines obtained from 88 were also reported
<1996JA11978>. Mixed 2-diphenylphosphino-6-trimethylsilylphosphinine was synthesized from
88, 1,2-bis(diphenylphosphino)acetylene and (trimethylsilyl)acetylene in two [4+2]-cycloaddition-
cycloreversion steps in 70% yield (toluene, 1 h, 40%) <1997OM4089>. Further examples of
reactions involving 88 and bisacetylenes containing a heterocyclic (furan, thiophene, phosphinine,
phosphole, phosphaferrocene) fragment as a central unit were also described <1999OM4205>.
The cycloaddition/cycloconversion sequence was adapted for the combination of the silylated
acetylenes and t-butylphosphaethyne 186 to afford azadiphosphabarrelenes 221 <1998EJO2039>
(Equation (39)).
P
i. R1 C C TMS But
But But ii. P C But 186 But
TMS
N N –2ButCN P
P N
ð39Þ
88 R1
221 a R1 = TMS (53%)

b R1 = Ferrocenyl (67%)
c R1 = H (75%)
While thermolysis of the barrelenes 221a and 221b in refluxing toluene led exclusively to the
starting material as the retro-Diels–Alder reaction product, the thermolysis of 221c under the
same reaction conditions furnished the 1,3-diphosphinine 222 unambiguously identified as its
tungsten complex 223 (Scheme 30).
(CO)5
Toluene W(CO)5THF
W
100 °C, 3 h P 25 °C, rt P
221c
20% 85%
But P TMS But P TMS
222 223
Scheme 30
Seven-membered phosphabenzocycloheptenes 225 and 226 were synthesized in a multistage

reaction consisting of the metallation of the (Z),(Z)-butadiene derivative 224, condensation of the
resulting lithium species with dichlorophenylphosphine and finally cyclization, in 12 and 28%
overall yield, respectively. The corresponding P-oxide 226 was further reduced back to 225
<1999CPB1108> (Scheme 31).
i. ButLi, Et2O, –80 to –20 °C

ii. PhPCl2, 6.5 h
+ 226
12%
Br Br TMS P TMS
224 Ph
225
i
P TMS
Ph O
i. SiHCl3, 80 °C, benzene, 1 h
226
Scheme 31
4.22.3.1.3 Acyclic cyclic metal complexes and salts

This section describes syntheses of three-, five-, and six-membered compounds with the endo-P and
exo-Si atoms and possessing various coordination modes to the metal: 1(P), 5 in silylated phosphole
anions; 5 in half-sandwich phosphabenzene complexes; 5, 5 in 1,10 -diphosphametallocenes; 6, 6 in
-sandwich complexes of phosphabenzene as well as ionic compounds such as alkali metal mono-
anions and dianions of phosphabenzene derivatives. The tungsten(0) azaphosphirene complex 227
was converted upon heating with silylated acetylenes to phosphirene complexes 228a,b with a con-
comitant extrusion of benzonitrile <1999ZAAC102> (Equation (40)).
(OC)5W CH(TMS)2 (OC)5W CH(TMS)2

R C C OEt
P P
–PhCN
N
ð40Þ
Ph EtO R
227 228a R = Me
b R = Ph
The 7-phosphanorbornadiene derivative 229 with excess of trimethylsilylacetylene 211 gave the
silylated phosphirene 230 which dimerized in the presence of Pd(0) catalyst to 1,2-dihydro-
1,2-diphosphinine 231 <2000CC1137> (Scheme 32).
(OC)5W (CH2)2CO2Et
P HC C TMS 211
110 °C, toluene, 20 h (OC)5W (CH2)2CO2Et
CO2Me P
62%
TMS
CO2Me
230
229
Pd(PPh3)4
toluene, TMS TMS ButOK, TMS TMS
85 °C, 16 h P P THF, rt P P
(OC)5W W(CO)5 (OC)5W – W(CO)5
70%
EtO2C(CH2)2 (CH2)2CO2Et K+ (CH2)2CO2Et
231 232
EX
TMS TMS
P P
(OC)5W W(CO)5
X (CH2)2CO2Et
233a EX = TsCl; X = Cl (77%)

b EX = HCl; X = H (54%)
c EX = PhCH2Br; X = PhCH2 (46%)
Scheme 32
Treatment of 231 with t-BuOK in THF induced a clean dealkylation to give the monoanion
232, which was then transformed to PCl, PH and P-alkyl derivatives (233a–233c)
<2002OM336> (Scheme 32). All transformations were done in the coordination sphere of
pentacarbonyl tungsten, which was known to increase the kinetic stability of P¼P double bonds.
Finally, an interesting thermal contraction of the ring size was observed in the dibenzyl
6-membered derivative 234, which on heating to 180 C, gave the 5-membered phosphole 236
via the transient diphosphinine 235 (Scheme 33).
TMS TMS i TMS TMS ∆, 180 °C TMS TMS

P P P P P
(OC)5W W(CO)5 (OC)5W
(OC)5W CH2Ph
CH2Ph CH2Ph CH2Ph CH2Ph
234 235 236
i. ∆, 180 °C, 8 min
Scheme 33
The 2,5-disilylated phospholyl anion 238 gave the silylated P-functionalized phosphole 240,
phosphaferrocene 242, or 1,10 -diphosphaferrocene 243 upon treatment with halides 239 (X = Cl,
Br), the ionic complex 241 or FeCl2, respectively <1999OM4205> (Scheme 34). The anion 238
was synthesized from the P-chloro derivative 237 with excess lithium in THF.
i ii
–
RMe2Si SiMe2R X=Cl or Br RMe2Si SiMe2R
P RMe2Si P SiMe2R P
Cl Li+
238 R1
237
240
R1 = Cl, CN, CO2Et

[Fe( η 6
Cp)( η6 C6H5C3H7)] +
FeCl2, THF, rt
[PF6]– 241, THF, rt
RMe2Si SiMe2R
P
Fe Fe
RMe2Si SiMe2R RMe2Si SiMe2R

P P
242 243
R = Me C C
i. Li, THF, rt, 2 h

ii. R1(CH2)2X 239, –80 °C to rt, 3 h
Scheme 34
2,20 -Bis(trimethylsilyl)-1,10 -diphosphaferrocene was obtained in a similar way from

3,4-dimethyl-1-phenyl-2-trimethylsilyl phosphole via the PPh bond cleavage with lithium in
THF to give the corresponding lithium phospholide followed by the reaction with FeCl2
<1996BSF541>.
Similarly, 2,20 ,5,50 -tetrakis(trimethylsilyl)-3,30 ,4,40 -tetramethyl-1,10 diphosphaferrocene was
obtained from 1-phenyl-2,5-bis(trimethylsilyl)-3,4-dimethylphosphole and its dynamic solution
behavior was investigated <1997PSS(130)203>.
Using the above method involving condensation of the phospholide anion with metal halide,
other diphosphametallocenes were obtained. Thus, Nief and co-workers synthesized divalent
thulium THF complex 245 using more reactive potassium 2,5-bis(trimethylsilyl)-3,4-dimethylphos-
pholide 244 in the reaction with TmI2 <2002CC1646> (Equation (41)).
TMS
– TmI2 (THF)3 P
2 TMS TMS
P Et2O, 25 °C
K+ TMS
TMS Tm THF ð41Þ
244
P
TMS
245
An interesting synthesis of the 1,10 -diphosphazirconocene 246 with bulky TMS substituents,
investigated as a co-catalyst in propylene polymerization, was also demonstrated <1998JMOC155>.
TMS
P
TMS
Zr Cl
TMS Cl
P
TMS
246
Silylated phosphinine-phosphole-based and phosphinine-phosphaferrocene-based tridentate

ruthenium complexes 248 and 250 were synthesized from the corresponding precursors 247
and 249, respectively, and [Rh(COD)Cl]2 <1999OM4205>. The bimetallic (Fe, Rh) complex
250 was notable for its triple 1 (P-Rh) and 5-ferrocene coordination modes (Equations (42)
and (43)).
Cl
Me Me Me Me
Me Si Me i Me Si Me
Si Si
P P
P P
P Rh P
TMS TMS ð42Þ
TMS Cl TMS
Cl
247 248
i. 1/2 [Rh(COD)Cl]2, CH2Cl2, 15 min
Me Fe Me Me Fe Me
Me Si Me i Me Si Me
Si Si
P P
P P
P Rh P ð43Þ
TMS TMS
TMS Cl TMS
249 250
i. 1/2 [Rh(COD)Cl]2, CH2Cl2, 15 min
The phosphinine moieties in both ligands were obtained again utilizing [4+2]-cycloaddition–
cycloreversion sequence which was discussed in the previous section (4.22.3.1.2).
The most effective route to 2-silylated phosphinine iron complexes 252 turned out to be
condensation of the (COD)2Fe prepared in situ with the phosphinine 251. The three-component
reaction of stoichiometric amounts of Fe(g), COD, and 251 was much less effective (20% yield)
<1996OM2713> (Equation (44)).
–50 to 20 °C
(COD)2Fe + TMS
85% P
P TMS
Fe ð44Þ
251
252
The use of bulky 2,6-bis(trimethylsilyl) phosphinines 253 yielded 6-ionic complexes

(255a–255d) upon reaction with the ruthenium complex 254 and AgBF4 in THF
<2001OM3304> (Equation (45)).
R2 R1 R2 +
BF4–
AgBF4, THF
1 2
R R 60 °C
+ TMS R2
P
TMS P TMS
Ru Ru TMS
253 Cl
ð45Þ
254
255a R1 = R2 = R3 = H (70%)
b R1 = R3 = Me; R2 = H (75%)
c R1 = R2 = Me; R3 = H (84%)
d R1 = R3 = TMS; R2 = H (79%)
Starting from macrocycles 256 and 258 containing two phosphinine rings, dianions 257 and 259
with PP bonds were formed as a result of successive one-electron chemical and electrochemical
reductions <2001JA6654> (Equations (46) and (47)).
2 [Na(2.2.2)]+
Me Me Me Me Me Me
Ph Si Me i. 2C10H8Na, Ph Si Me
O Si Ph THF, rt O Si Ph
ii. [2.2.2] – P
P
P 35% P – ð46Þ
Ph Si Ph Si
Me O Si Ph Me O Si Ph
Me Me Me Me
Me Me
256 257
TMS TMS
C10H8Na THF
THF, rt TMS
2 P – P Na THF
+ +
Na P – ð47Þ
TMS THF THF TMS
TMS
258 259
The intermediate radical monoanions were detected by EPR. The dianion 257, as a cryptand
[2.2.2] complex, was obtained from the initially formed THF complex.
The reaction between vapors of chromium and 2-trimethylsilyl-3-methylphosphabenzene 260
using a metal vapor synthesis technique produced an extremely air-sensitive yellow oil containing
two nonseparable isomers of bis(2-trimethylsilyl-3-methylphosphabenzene (261a and 261b) in
40% and 60% yields, respectively <2000MI561> (Equation (48)).
TMS TMS
P
P
Cr + Cr + Cr
ð48Þ
P TMS
P P
260
TMS TMS
261A 261B
4.22.3.2 Germanium Derivatives

More progress in this field has been recently made in comparison with the previous review period
(before 1995) where no examples were reported in the literature.
Thus, the synthesis of a few acyclic compounds with the P, Ge functions has already been
mentioned in the previous section (4.22.3.1.1) devoted to the synthesis of analogous P, Si
compounds.
Moreover, bis-(2,5-di-t-butyl)-1,10 -diphosphagermanocene was synthesized from the corre-
sponding lithium 2,5-di-t-butylphospholide and GeI2 in an analogous manner to other
1,10 -diphosphametallocenes <1999CC1273>.
It is worthy to note that although bicyclic structures 262 and 263 were not synthesized, their
unexpected thermodynamic stability was calculated <1996OM3070>.
HP GeH HP GeH2
H2Ge PH HP GeH2
262 263
4.22.3.3 Boron Derivatives

Only one product of this type, represented by three examples (266a–266c), has been reported.
Thus, hydroboration of 1-alkynylphosphonates (264a–264c) with pinacolborane 265 in methylene
chloride gave, after workup, the kinetic products (266a–266c) <2001TL8059> (Equation (49)).
The latter could be isomerized to place boron at the C2 position (thermodynamic product) by
extended heating or by use of PdCl2 catalyst.
O
O O R P(OEt)2
(EtO)2P C C R + H B
O H B O ð49Þ
264a R = n-C5H11 265 O
b R = Cl(CH2)3
c R = Ph
266a–c
4.22.4 FUNCTIONS CONTAINING PHOSPHORUS AND A METAL,

R12C¼C(PR2)M, etc.
Significant progress in this field has been made since 1995. Many interesting compounds with
different metal coordination modes have appeared in the literature and they will be reviewed here.
Until 1995, compounds containing an alkali or alkaline earth metal attached to the -carbon of a
phosphino alkene are unknown with the exception of few aromatic compounds, e.g., lithium
2,6-diphenylphospholide <1995COFGT(4)1021>.
4.22.4.1 Main Group Metals
4.22.4.1.1 Group 1 metals

Compounds containing only lithium, sodium, and potassium will be reported below and com-
pounds with heavier members of the family (Rb, Cs) are yet to be synthesized.
Müller and Fenstel reacted the tris(phosphinomethyl)-substituted alcohol 267 with an excess
of BunLi in toluene at room temperature to afford the unknown, symmetrically substituted
tris(dimethylphosphino)trimethylenemethane dianion 268, which crystallized with
[Li3OC(CH2PMe2)3]2+ as a counterion <2001CC1024> (Equation (50)).
–
2
H PMe2
BunLi
PMe2 5 equiv. PMe2
.3Li+. Me2P
2 Me2P Me2P H ð50Þ
HO PMe2 O– PMe2
H PMe2
267 268
The X-ray structure of the latter showed that each lithium was coordinated to one of the
phosphino groups and to a methylene carbanionoid carbon of an adjacent dianion. Thus, the
lithium is tetra-coordinate, being bonded to one oxygen, two phosphorus, and one carbon
atom.
Wang and co-workers synthesized 1-lithioethenylphosphine oxides 270 in the regioselective
manner from the corresponding 1-iodoethenyl phosphine oxides 269 and utilized in the alkenyla-
tion of aldehydes and ketones <1999JOC1650> (Equation (51)).
R R
ButLi, THF, 30 min

O O
–78 °C ð51Þ
Ph2P Ph2P
I Li
R R
t
269 R = Bu , H 270
Other lithio derivatives with a defined stereochemistry, i.e., 2-lithio-3,4-dimethylphospholes 271

and diethyl 1-lithio-2-ethoxyethenylphosphonate 272, were synthesized and reacted with electro-
philes <1996BSF33, 2002PSS(177)1953>. Other systems were reviewed earlier in Section
4.22.3.1.1.
O
P(OEt)2
X P Li
Ph EtO Li
271 272
X = H, Br
The lithium salts 274 and 276 were prepared on treatment of 273 and 275 with ButLi and
BunLi, respectively. Silylation of the resulting fluorenyllithium occurred at the carbon to the
phosphorus <2002EJI678> (Equations (52) and (53)).
But But But But

P N P N
H 2ButLi, –78 °C Li
97% ð52Þ
Li
273 274
But
But N
P H
BunLi, –78 °C
85% ð53Þ
P H
But N
But
Li
275 276
Similarly, cyclopentadienyl, indenyl, and fluorenyl potassium salts 278 were synthesized by
deprotonation of 277 with PhCH2K in yields exceeding 95% (Equation (54)).
Rn
But
PhCH2K, –78 °C Rn P
NEt2
>95%
P ð54Þ
But NEt2 K
277 278
RnCp = Me4Cp, ButCp, indenyl, fluorenyl
The synthesis of dilithium derivative 280 of asymmetrically substituted cyclopentadienyl ansa

ligand was also reported in 93% yield starting from lithium or potassium cyclopentadienide 279
<2001OM71> (Equation (55)).
SiMe2Cl
i. –MCl Me Me
PPh2
ii. 2BunLi Si PPh2
Li2 ð55Þ
93%
M
279 M = Li, K 280
The first crystallographically characterized alkali metal phospholide was lithium tetramethyl-
phospholide 281 obtained from the reaction of the corresponding P-chlorophosphole with an
excess of lithium and TMEDA in THF at room temperature via the 1,10 -bisphospholyl inter-
mediate <1989AG(E)1367>. This method was applied to the synthesis of sodium 283 and
potassium 284 phospholides via the cleavage of one or two PP bonds of the phosphole tetramer
282 possessing two 1,10 -bisphosphole units <1996AG(E)1125> (Scheme 35).
P
Li
N N
281
Ph P Ph
P
Ph P Ph
P
Na /DME K /DME / THF
282
Ph 2–
P P P
Ph Ph
P
Na(DME) Na(DME)
Ph Ph THF K K THF
P
P Ph P P Ph
Ph
283 2trans-[K([18]crown-6)(THF)2]+ ·2 THF

284
Scheme 35
The potassium P-cyclopentadienide 286, obtained from 1-cyano-3,4-dimethylphosphole 285 in

90% yield, underwent the migration of the 2,3,4,5-tetramethyl-1-cyclopentadienylidene substitu-
ent from phosphorus to the -carbon atom to give three possible isomers of the Cp-substituted
phospholide 287 on heating at 140 C overnight in THF <2001OM5513> (Scheme 36).
2 CpLi(K)
or CpLi then BunLi 140 °C, THF –
+ + P
P P K K
H
CN
–
285
286 287
Scheme 36
Finally, it is worthwhile to mention the synthesis of some other specific alkali metal phospho-
lides. For instance, a sterically crowded potassium 2,5-di-t-butyl-3,4-dimethylphospholide was
synthesized from the corresponding Ph-substituted phosphole <2002CC1646>, and lithium ben-
zophospholide anion obtained from bis(phosphonio)benzo[c]phospholide 68 and lithium naphtha-
lenide <1999EJI1169>.
Schmützler and co-workers synthesized sodium phenyl-substituted di- and tri-phospholides 290
and 291 in the reaction of the phosphaalkene 288 with an excess of sodium. Phenyl phosphaa-
cetylene 289, detected by 31P-NMR (31P = 31.8 ppm) as an intermediate with a half-life of
7 min, gave a 1:1 mixture of 290 and 291 after 16 h <1996JOM(512)141> (Scheme 37).
Ph
Ph P Ph
TMSO P – P
Na, DME, 40 min 16 h + –
C P [PhC P]
Ph TMS –(TMS)2 O P P
289 Ph Ph
[Na(DME)]+
288 [Na(DME)3]+
291
290
Scheme 37
Six-membered derivatives of phosphinines and group 1 metals are known. An interesting

polymeric structure 293 was obtained in the reduction reaction of 4,40 ,5,50 -tetramethyl-
2,20 -biphosphinine 292 with sodium/naphthalene in dimethoxyethane at room temperature
<2001AG(E)4476> (Equation (56)). In this structure two sodium cations are bound to the
two P atoms of one molecule and in an 2-fashion to a PC bond in the second molecule of
the ligand. Although the interactions of sodium cations and the reduced ligand are mainly
electrostatic in nature, the polymeric structure 293 may be formally qualified to the group of
metallophosphinoethenes. The reaction of 292 with the lithium/naphthalene system in the
presence of cryptand [2.2.1] yielded only the monomeric complex.
+
Na
2C10H8Na, DME P P
+ +
P P Na Na
+
292 Na
P P
Na+ ð56Þ
P P
Na+ Na+
Na+
P P
+
Na
293
The -C-Li bonding was observed in 2-lithio-P-pentacarbonyltungsten phosphinines 295a,b

which were obtained via the iodine–lithium exchange from 2-iodo derivatives 294a,b on treatment
with n-butyllithium at 100 C. The 2-lithio complexes could be detected at this temperature by
31
P-NMR spectroscopy but decomposed thermally at 70 C. The lithiation of P-uncoordinated
2-iodophosphinines did not occur <1996OM794> (Equation (57)).
R R
R n
Bu Li, –100 °C R
P I P Li ð57Þ
W(CO)5 W(CO)5
294a R = H 295a,b
b R = Me
Treatment of dimethylphosphino-4,5-dimethylphosphinine 86 with methyllithium led to the

intermediate delocalised carbanion 95 which was characterized by 31P-NMR <1996OM1597>
(Equation (7)).

Before 1995 compounds containing the group 2 metals were already known, and more com-
pounds with Mg, Ca and even heavier Ba have since emerged. Based on the limited data, it seems
that these compounds are unstable in a monomeric form and tend to adopt more stable dimeric
structures. No examples with Be and Sr were reported. Thus, the phosphinine Grignard reagent
297 was synthesized in 19% yield from the corresponding 2-iodo phosphinine 296 as one of the
three products identified. It decomposed slowly at room temperature (Equation (58))
<1996OM794>.
Mg
19% ð58Þ
P I P MgI
296 297
The reaction of the barium salt 298 with diphenylbutadiyne 299 yielded the dimeric complex
300 with a unique three-center two-electron BaCBa bond. The coordination sphere of barium
contained phospholide, tetrahydrofuran, and alkenide moieties. The latter bridged two barium
atoms with BaC bond lengths of 2.881 and 3.071 Å <1998JA6722> (Equation (59)).
Ph
Ph Ph
TMS THF Ph
P Ba
Ba P ð59Þ
[(TMS)2P]2Ba + Ph C C C C Ph
298 299 Ph THF TMS
Ph Ph
Ph
300
The dimeric structure 301 containing the phospholide calcium moieties was also synthesized
<1999OM2491>.
TMS
TMS THF THF

TMS
Ca
P Ca Cl TMS
Ca Cl Ca
TMS P
TMS
THF THF
TMS
P
TMS
301

Only Ga- and Tl-containing compounds have been synthesized so far. Compounds of indium are
still unknown.
5-Phospholylgallium 303 was the first synthesized monomeric polyhapto compound between a
phospholyl ligand and a main group metal (with the exception of alkali metal complexes)
<1999AG(E)1646> (Scheme 38). It was obtained in the condensation of gallium(I) bromide
with the lithium phospholide 302 at 78 C in 70% yield as the main product. Further reaction,
with the chromium pentacarbonyl-cyclooctene complex 304, afforded yellow crystals of the
bimetallic complex 305 in 80% yield.
The yellow polymeric structure of the thallium phospholide 307 possessing the thallium
5-bonded to both sides of the phospholyl ring as revealed by X-ray analysis, was obtained via
the lithium cleavage of 1-phenyl phosphole 306 followed by the lithium/thallium exchange with
thallous(I) ethoxide <2001OM3884> (Equation (60)).
But
But
GaBr + LiP P Ga + Cr(CO)5

70% 80%
t 304
Bu
But
302 303
t
Bu
OC CO
P Ga Cr CO +
OC CO
But
305
Scheme 38
i. Li
ii. ButCl
iii. TlOEt, THF
Tl ð60Þ
P P
Ph
306 307

Two representatives (Si, Ge) of the group 14 elements are metalloids and have already been
mentioned in Section 4.22.3. Two remaining metallic elements (Sn, Pb) of this group are presented
below.
Collignon and co-workers carried out a stereoselective and convenient synthesis of
(E)-1-triphenylstannyl or (Z)-1-tri-n-butylstannyl-1-alkenylphosphonates 309 and 310 using a
‘‘tin-Peterson-like’’ reaction <1995SC1921> (Scheme 39). Thus, the key reagent diethyl distan-
nyllithio methylphosphonate 308, was easily prepared via distannylation of diethyl methylpho-
sphonate with tri-n-butyl- or triphenyltin chloride. Subsequent reaction of 308 with aromatic or
aliphatic aldehydes at 70 C showed a regioselectivity depending on the substituent R1 in the
stannyl group SnR13. Actually, with aromatic aldehydes, the triphenylstannyl group led predomi-
nantly to the (E)-309 isomer, while in contrast the tri-n-butylstannyl group favored the formation
of the (Z)-310 isomer.
O
2
(EtO)2P R
R1 = Ph3
1 Ph3Sn H
O SnR 3
R2CHO/–70 °C 309
(EtO)2P C Li
1 O
SnR 3
(EtO)2P H
308 R1 = Bun
n 2
Bu3Sn R
310
Scheme 39
1-Lithiovinylphosphonates obtained via lithiation of vinylphosphonates 153 with lithium tetra-

methylpiperidide were trapped with stannyl chlorides to give 311 <1998JOC6239>
(Equation (61)).
O O
RS P(OEt)2 i. LITMP RS P(OEt)2

ii. R13SnCl
1 ð61Þ
RS H RS SnR3
153 311a R1 = Ph; RR = (CH2)2 (69%)

b R1 = Bun; R = Et (83%)
LiTMP – lithium tetramethylpiperidide
Wrackmeyer and co-workers described 1,1-organoboration of stannylethynylphosphines

<1994PSS(91)229>. The reaction of 312 with 1 equiv. of Et3B gave selectively the (Z)-alkene
313a, and in the presence of excess of Et3B the bis(alkenyl)phosphine 314a was formed. Treat-
ment of 312 with bulky Pri3B afforded only 314b even with a large excess of the borane. The
analogous set of reactions was carried out with the alkyne 315. Thus, the reaction of 315 with an
excess of Et3B gave quantitatively the stannole 316a, while the reaction with Pri3B gave a 2:1
mixture of the stannole 316b and the 1-stanna-4-bora-2,5-cyclohexadiene 317b (Scheme 40).
Me3Sn BR2
Me3Sn BR2
R3B R3B
Ph P(C C SnMe3)2 Ph P Et
R = Et Et
312 Ph P R
Me3Sn BR2
SnMe3 314a R = Et
313a R = Et b R = Pri
Ph2P BR2 Ph2P Pri
R3B
Me2Sn(C C PPh2)2 Me2Sn + Me2Sn B R
315
R
Ph2P Ph2P Pri
316a R = Et 317b R = Pri

b R = Pri
Scheme 40
Streubel and co-workers reported the first example of the competitive formation of the
tungsten 1-1-phosphaallene 320 and 1H-phosphirene 321 complexes obtained by thermal
decomposition of the 2H-azaphosphirene complex 227 in the presence of triorganostanny-
l(ethoxy)acetylenes 318 (R = Me, Ph). The reaction proceeded via the intermediate formation
of the zwitterionic products 319, which were regarded as common precursors of the final
products 320 and 321. The analogous Mo(CO)5 derivatives were also obtained <1998CC1761,
1999ZAAC102> (Scheme 41).
Another use of alkynylstannanes was the reaction of 1-tri-n-butylstannyl-2-phenylethyne with
3,4-dimethyl-1-phenylphosphole 61 at 150 C which afforded 2-stannyl-1-phosphanorbornadiene
322 (Y = 2e) in 90% yield. Mild oxidation of the latter gave the corresponding phosphine oxide
322 (Y = O). More drastic oxidation (K2O2, 15% in toluene, 80 C) induced the oxidative
cleavage of the PCH2 bridge and insertion of oxygen to give the strain-released phosphinate
derivative 323 <1998EJO2683> (Scheme 42).
(OC)5W CH(TMS)2 (OC)5W CH(TMS)2

Heat
P + R3Sn C C OEt –P +
–PhCN
318 C C OEt
C N
R3Sn
Ph
319
227
(OC)5W (OC)5W
OEt CH(TMS)2
P C C + P
(TMS)2CH SnR3
C C
R3Sn OEt
320 321
Scheme 41
i. 150 °C Ph O
Ph
n
ii. [O] [O]
+ PhC C SnBu 3 P P
P
Y O n
Ph SnBun3 SnBu3
61 322 Y = 2e, O, S 323
Scheme 42
The synthesis of 322 (Y = 2e), its oxidation and sulfurization (Y = 2e and Y = O) are men-
tioned in the patent literature <1999WOP9947530>. Although some 2-stannylphosphinines have
already been described in the literature before 1995, Mathey and co-workers prepared the
phosphinines 325a,b by a variation of the organomagnesium route, used previously for the
large scale synthesis of silyl and polysilylphosphines <1995S717, 1992BSF291> (Equation (62)).
R R
R R1 R R1
Mg, THF, rt, 2 h
+ Me3SnCl
70% ð62Þ
P Br P SnMe3
324a R = Me, R1 = H 325a,b

b R = H, R1 = Me
The iodo-Grignard reagent 297 treated with chlorotriphenylstannane also gave the Ph analog
of 325a <1996OM794>.
2-Lithio-1-pentacarbonyltungsten phoshinines 294a,b were also utilized in Li/Sn transmetalla-
tion reactions with chlorotriphenylstannane to give the corresponding 2-stannyl derivatives
326a,b in 4% and 48% yields, respectively <1996OM794> (Equation (63)). The stannyl com-
pounds was found to be much more stable than their lithio-congeners.
R R
R R
Ph3SnCl, –90 to –100 °C
P Li P SnPh3 ð63Þ
W(CO)5 W(CO)5
294a R = H 326a R = H (4%)
b R = Me b R = Me (48%)
Bickelhaupt and Teunissen used organozinc reagents 327 for the transmetallation reaction with
various tin chlorides. The reaction of 327 with chlorotriphenylstannane gave the known phenyl
analog 325a while the reaction with dichlorodimethylstannane gave diphosphinine stannane 328
<1996OM802> (Scheme 43).
Me2SnCl2 (MeCN)W(CO)5
R ZnI R Sn R P Sn P
Me2 Me2
(CO)5W W(CO)5
327 328 329
Scheme 43
The pentacarbonyltungsten complex 329 was also synthesized from 328 and (acetonitrile)pen-
tacarbonyltungsten.
Bis[2,5-di-(t-butyl)]-1,10 -diphosphaplumbocene and tinocene were synthesized in a standard
way from the corresponding lithium phospholide and MX2 (M = Pb, Sn) <1999CC1273>.
4.22.4.2 Transitional Metals (Groups 3–12 Metals), R12C¼C(PR22)PdX2, etc.
4.22.4.2.1 s C¼C-Bonded compounds

In the case of trifunctional 1-P-1-heterosubstituted alkenes involving additional coordination to a
transition metal through a double bond, preference will be given to a heteroatom and not to the
metal in the discussion below. Thus, for instance, the synthesis of 1,10 -diphosphaferrocene will be
discussed in this chapter, while synthesis of the TMS-substituted 1,10 -diphosphaferrocene has
already been mentioned in Section 4.22.3.
Organocopper phosphinine 330 and its pentacarbonyltungsten complex 332 were synthe-
sized by Bickelhaupt and Teunnissen via transmetallation reactions of the respective phos-
phinines 82 and 83 with copper(I) salts (Equation (64) and Scheme 44). Both organocopper
phosphinines 330 and 332 were obtained at 60 C to 80 C and found to be unstable at
higher temperatures. For instance, the compound 332 decomposed completely at room
temperature within 6 h <1996OM802>. In an alternative approach, the complex 332 was
obtained by the reaction of 331 with highly reactive metallic copper(0) prepared in situ
(Scheme 44).
CuCN(LiBr)2, –80 °C
I
NMe2 ð64Þ
P Zn P Cu
Me2N
82 330
Transmetallation of organozinc phosphinines 327 and 82 with silver salts (AgNO3 or THF-
soluble AgBr2LiBr) was carried out with limited success since the resulting organosilver
derivatives 333 are unstable at room temperature as their Cu analogs <1996OM802> (Scheme
45).
Organomercury phosphinines 334 and 335 were synthesized in a similar manner starting from
organozinc phosphinines 327 and 83 via transmetallation of organozinc phosphinines 327 and 83
with HgCl2 <1996OM802> (Equations (65) and (66)).
CuCN(LiCl) 2, –60 °C
I
NMe2
P Zn P Cu
(CO)5W N W(CO)5
Me2
83 332
Cuo
P I
W(CO)5
331
Scheme 44
AgNO3, DMF
P ZnI P Ag(L)
327 333
AgBr(LiBr)2, THF
I
NMe2 L–coordinated solvent
P Zn
Me2N
82
Scheme 45
HgCl2
ð65Þ
P ZnI P Hg P
327 334
HgCl2
I
NMe2 Hg
P Zn P P ð66Þ
(OC)5W N W(CO)5 W(CO)5
Me2
83 335
Mathey and co-workers regioselectively inserted palladium(0) and nickel(0) complexes 337 and
338 into the CBr bond of 2,6-dibromophosphinines 336 opening a versatile route to
-functionalized phosphinines 339 and 340. The new complexes obtained were solids, fully
characterized by spectroscopic methods and X-ray analysis <1995S717> (Scheme 46).
Recently, the P/Zr chemistry has been developed intensively by the group of Majoral. For
instance, treatment of the alkynylphosphinine 343 with the zirconocene 341 in benzene at 80 C
led to the formation of a phosphinozirconaindene 344 as a result of the regioselective insertion of
the CC triple bond into a ZrC bond of the transient benzene zirconocene 342 <1997CC279>
(Scheme 47). Addition of elemental sulfur to 344 afforded the corresponding sulfide 345 which
was analyzed by X-ray diffraction. The insertion reaction mentioned above was also extended to
bis(alkynyl)phosphines.
Ph2
P
Pd (DBA) 337 Br
P 40 °C, 10 min, toluene Me
Ph2
R = Br Br
Br P Pd
R
Ph2P PPh2
Me
Ph2
P Ph 339
Br P Br Ni 338, 25 °C, toluene R
P Ph Me
336 Ph2
R = Br, Me Br
Br P Ni
Ph2P PPh2
340
Scheme 46
C6H6, 80 °C, 6 h Ph2P C C R 343

[ ZrPh2Cp2 ] Cp2Zr Cp2Zr
342
341
R R
S8
– +
Zr PPh2 Zr PPh2
Cp2 Cp2 S
344 345
Scheme 47
Many other examples of reactions involving 342 and 344 also came from the group of Majoral and
have recently been reviewed <2002TCC53>. Various cycloaddition reactions involving 2-phosphi-
nozirconaindene 344 were also described: [3+1]-cycloaddition with azides and [3+2]-cycloadditions
with aldehydes, alkynes, and heterocumulenes (CO2, CS2, RN¼C¼NR, RNCO, RNCS) to give
18 electron zirconate complexes of type 345. Moreover, practical applications of multiple [3+2]-
cycloadditions involving 344 and dendrimers with terminal or internal aldehyde groups were shown to
exemplify the utility of this kind of phosphorus-zirconium chemistry. Finally, syntheses of
2-zirconaphosphinines and 2-phosphabenzyne-zirconocene dimers were also described.
In 2003 Majoral and co-workers published further examples of the addition of diazoalkanes 346
(R = CO2Et, TMS) to 344 to give the corresponding zirconates 347 <2003NJC675> (Equation (67)).
R R
H R Toluene, 25 °C
+
82–86% – +
Zr PPh2 N2 Zr PPh2
Cp2 Cp2 N ð67Þ
346 N
344 CHR
347
Fischer and co-workers reported the addition of various phosphines to the allenylidene (penta-
carbonyl) chromium complexes 348, which occurred at the C giving the ylide complexes 349
<1995JOM(490)221> (Equation (68)).
–
R CH2Cl2 (OC)5Cr R
(OC)5Cr C C C + PR12R2 + C C C ð68Þ
R R12R2P R
348 349
The stability of the resulting complexes 349 depended on the nature of substituents. In some cases
they could be isolated (R = C6H4NMe2-p, R1 = R2 = Me, 76% yield). At room temperature they
rearranged to the PCr allenylphosphine complexes (R = C6H4NMe2-p, R1 = R2 = H) followed
by isomerization to PCr alkynylphosphine complexes (R = C6H4NMe2-p, R1 = H, R2 = 2,4,6-
C6H2Me3) or they underwent [2+2]-cyclodimerization at the C to cyclobutane derivatives.
Reaction of the 1,3-diphosphacyclobutane-2,4-diyl-2-ide 350 with chromium or tungsten hex-
acarbonyl afforded the red anionic complexes 351 (M = W, Cr) by the formal insertion of CO
into the four-membered ring. These complexes further reacted with electrophiles such as
[Me3O][BF4] in methylene dichloride or TMSCl in THF to afford the neutral complexes 352
and 353 showing almost planar P2C3 backbone <2002CEJ2188> (Scheme 48).
TMS TMS Li(THF)n+
– M(CO)6
P P P P
M = W, Cr –
C
Li(THF)n+ O
M(CO)5
350 351
TMS
P P
352 M = Cr, R = Me, TMS

RO M(CO)5 353 M = W, R = Me
Scheme 48
4.22.4.2.2 s P- and p C¼C-Bonded compounds

Mays and co-workers reported the thermolysis reaction of the complex 354 (R = Me, CO2Me) in
n-heptane at 70 C furnished in each case a mixture of axial and equatorial complexes 355 in a 7:3
ratio <1996JOM(508)137>. The opposite reaction occurred when the reaction mixture containing
both isomers 355 was purged with CO at 20 C (Equation (69)).
R R R
C Co(CO)3 – CO, 70 °C C Co(CO)3 C Co(CO)3
+
CO, 20 °C OC CO OC CO
(OC)3Co Co(CO)2R1 Co C H2C Co C
OC CO ð69Þ
354 R1 = Ph2PCH CH2 H2C CH PPh2 HC PPh2
CO
355 axial, major 355 equatorial, minor
The reaction of 356 (R = Me, CO2Me) with cis-1,2-bis(diphenylphosphino)ethene possessing

three binding centers (double bond and two P atoms) proceeded in a different way to give the
complex 357, in which coordination to a second phosphorus atom was more favorable than to the
double bond as in the compound 355 (Equation (70)).
R R
cis-Ph2PCH CHPPh2
C Co(CO)3 C Co(CO)3
THF, 10 min, reflux
Ph2P
R = Me, CO2Me CO
(CO)3Co Co(CO)3 OC Co C
CO ð70Þ
H C CO
356
PPh2
C
H
357
Mays and co-workers also reported the synthesis of the complex 359 in which the vinyl
phosphine acted as a -1:2 four-electron ligand to a bimetallic fragment <1999CC2455>
(Equation (71)). The complex 359 was obtained as a result of the multistage reaction by treatment
of the anionic species 358 with acryloyl chloride.
Ph2 O Ph2
P – P
Cl
(OC)2CpMo MoCp(CO)2 (OC)2CpMo MoCp(CO)2
ð71Þ
358 359
The thermal reactions of diphosphine-substituted dinuclear cobalt carbonyl complex 360 with
an excess of the electron donor ligands (PPhMe2, PPh2H, P(OMe)3 or ButNC) in refluxing
toluene gave mixtures of mono- and di-substituted complexes of the type 361 in combined yields
ranging from 35% to 50%. The mixtures were readily separated by column or thin layer
chromatography <1998ICA186> (Equation (72)). For instance, the reaction of 360 with
PPhMe2 gave the red-brown complex 361a (L = CO, L0 = PPhMe2) and the dark green complex
361b (L = L0 = PPhMe2) in 9.8% and 40% yield, respectively.
H
H
H
H PPh2 PPh2
CO
CO PPhMe2
Co(CO)2 L(OC)Co Co(CO)L′
(OC)2Co
H
Ph2 P ð72Þ
Ph2 P
H H
H
H
360 361
361a L = CO, L′ = PPhMe2 (9.8%)

b L = L′ = PPhMe2 (40%)
Treatment of an inseparable mixture of two monosubstituted isomeric complexes 362 and 363
with triphenylphosphine in refluxing toluene for 1 h yielded the green complex 364 in 78% yield
<2001JCS(D)1269> (Scheme 49).
Treatment of 365 with trimethyl phosphite under the same reaction conditions gave a mixture of
two compounds of which the minor 366a was isolated in 12% yield. The analogous reaction was
carried out with PPhMe2 to give the complex 366b (L = PPhMe2) in 8% yield (Equation (73)).
O L, toluene
H C SPh 110 °C, 1 h
Ph2P
8–12% OC Co(CO)L
Co(CO)2 ð73Þ
Co L(OC)Co SPh
(CO)L PPh2
365 366 a L = P(OMe)3 (12%)

b L = PPhMe2 (8%)
H
H
OC
H
Co(CO)2
PPh3 H
PhS Co PPh2 toluene
(CO)P(OMe)3
110 °C, 1 h Ph2P
362 OC Co(CO)2PPh3
78%
+ P(OMe)3(OC)Co SPh
OC SPh
364
Co(CO)2
H
Co PPh2
H (CO)P(OMe)3
363
Scheme 49
When the osmium complex 367 was reacted with diphenylacetylene in toluene at room tem-
perature, the new yellow complex 368 was formed within 4 h and isolated in 49% yield
<2003OM2087> (Equation (74)).
H
Pr3i P Cl H H PPr2i
H H PhC CPh ClPh2Sn
Os Os + C6H6 + cis-PhCH CHPh ð74Þ
H H 49%
H H
Pr3i P SnPh3 PPr3i
367 368
The formation of 368 was a result of multiple complex reactions with the participation of
radical-like species as intermediates.
4.22.4.2.3 s C¼C- and p C¼C-Bonded compounds

The binuclear complex 369 reacted with PPh2H and PPhH2 to afford new complexes of the type
(370a,b) (pathways i and ii) <1996CC1545>. The complex 370a (pathway i) was formed by the
1,3 addition of PPh2H across the allene fragment while the complex 370b (pathway ii) was formed
via the 1,3-addition of both PH bonds of PPhH2 across 2 equiv. of the allene fragment
(Equation (75)).
γ H
PPhR
β C γ α
H α C H H3C β C
i or ii H
C C
(OC)3Fe Fe(CO)3 (OC)3Fe Fe(CO)3 ð75Þ

P 370a R = H
Ph2 b R = Fe2(CO)6(µ-PPh2)R1
369 R1 = { µη1: η 2-(Me)C=CH}
i. PPh2H, Et2O; ii. PPhH2, Et2O
The mixed-metal cluster 371 reacted with the redox-active 2,3-bis(diphenylphosphino)maleic

anhydride 372 at 80 C to afford the new blue–green zwitterionic cluster 373 in 30–45% yield as
the initially observed substitution product. This product upon prolonged heating overnight
gradually produced the brown–green cluster 374 <2003OM1383> (Scheme 50).
H
C CO
CpNi Co CO
O
CO O O
Co O O
OC CO O
CO CO
CO
– CO
371 – CO Co
∆ Ph2P Co Ph2P +
+ Ph2P +
30–45% 33% PPh2
O CH
Ph2P PPh2 CH
Ni Co CO
Ni Co CO Cp
Cp CO
CO
O O O
372 373 374
Scheme 50
4.22.4.2.4 s P-, s C¼C-, and p C¼C-Bonded compounds

The phosphinoalkyne coupling reaction of the alkyne mixed-metal tungsten–cobalt or molybdenum–
cobalt complexes led to the formation of new complexes possessing various combinations of
- and -bonding to a double bond and phosphorus (Equation (76) and Scheme 51). Thus, the
coupling of the alkyne-bridged MoCo complexes 375 with phosphinoalkynes was largely deter-
mined by the nature of the substituents of both the reactants and led to the formation of the
complexes (376a–376c) <2000JCS(D)3331> (Equation (76)).
R
R1
R1 R2
Ph2P R2
+ Ph2PC CR
Cp(OC)2Mo Co(CO)3 Cp(OC)Mo Co(CO)2 ð76Þ
375 376a R = R2 = But, R1 = H

b R = Ph, R1 = R2 = CO2Me
c R = Ph, R1 = H, R2 = But
Ph Ph2P
R1 R2 H H
i
Ph2P But + Ph But
Cp(OC)2W Co(CO)3
Cp(OC)W Co(CO)2 Cp(OC)2W Co(CO)2
377
378 (7%) 379 (28%)
R1 = H, R2 = But
ii iii
(OC)4Fe
But P Ph2
H H
Ph2P
But Ph But
O
Cp(OC)W Co(CO)2 Cp(OC)2W Co(CO)2
380 (41%) 381 (41%)
i. Ph2PC CPh, 110 °C, C6H5Me; ii. Ph2PC CBut, 110 °C, C6H5Me; iii. Fe2(CO)9, 60 °C
Scheme 51
On the other hand, coupling of the alkyne-bridged W–Co complex 377 with
1-diphenylphosphino-2-phenylethyne afforded a mixture of the regioisomeric complexes 378
and 379 with the CC double bond coordinated to cobalt. The 31P-{1H} NMR spectrum of
378 showed a peak at = 56.9 ppm with satellites due to coupling to 183W [JP–W = 54 Hz]
indicating that the phosphorus is bound to tungsten rather than to cobalt, while the 31P-{1H}
NMR spectrum of 379 showed a singlet due to the uncoordinated diphenylphosphino group at
= 17.1 ppm.
The reaction of 377 with 1-diphenylphosphino-2-t-butylethyne afforded the complex 380. The
source of the oxygen at the P(O) group was uncertain but could either be a carbonyl group,
molecular oxygen or water. The anticipated reactivity of the pendant diphenylphosphino group in
379 was realized during its reaction with Fe2(CO)9 in THF to give the complex 381 in 41% yield
<2000JCS(D)3331> (Scheme 51).
The heterobimetallic complexes 382 underwent a thermal reaction with Ph2PCl via the initial
PCl bond cleavage and coupling of the resulting diphenylphosphide unit with an alkyne in
one of the four different ways to give the complexes 383 (R1 = H, R2 = Ph or R1 = R2 = H or
R1 = R2 = CO2Me), 384 (R2 = Ph or Me or H), 385 (R2 = Ph or Me), or 386
<1995JCS(D)3049> (Scheme 52). The direction of coupling depended mainly on the nature
of the alkyne substituents.
R2
R1 R2 CR1 Ph2 P CH
Ph2 P R2
Ph2PCl, ∆ C
OC C Cp + Cp Cl +
Cp(OC)Mo W(CO)2Cp Mo W W Mo
C Cp Cl CO Cl Cp
O P
Ph2
382 383 384
R2 CO2Me
Ph2P CH
Ph2P CO2Me
C
Cp Cl
+ Mo W + Cp(OC)W Mo(CO) Cp
Cl Cp
P Cl
Ph2
385 386
Scheme 52
The iron–cobalt phosphido-bridged complex 387 was subjected to the reaction with symme-
trical and unsymmetrical alkynes to give initially the products containing five-membered ferra-
cycle as a result of a regioselective insertion of CO and alkyne into a CoP bond
<2000JOM(601)271>. For instance, treatment of 387 with symmetrical 1,2-bis(methoxycarbony-
l)ethyne afforded the five-membered 388 in 27% yield and the decarbonylation product 389 in
24% yield (Scheme 53). The direct conversion of the green-brown complex 388 into the red
complex 389 was achieved only in 5% yield.
The new, well-characterized complex 390 is an example of a new class of ditungsten complexes
and was obtained under photolytic reaction conditions <1995JCS(D)1597>.
Ph2
P
(OC)4Fe Co(CO)3
O CO2Me
387
C CO2Me CO2Me
Ph2P
THF, 40 °C Ph2P
+ +
3h CO2Me
(OC)3Fe (OC)3Fe Co(CO)3
CO2Me Co(CO)3
388 389
CO2Me THF, 60 °C, 18 h

5%
Scheme 53
CO2Me
Ph2 P
CO2Me
W W
Cl CO
390
4.22.4.2.5 s P- and s C¼C-Bonded compounds

On treatment of the cationic 2-complex 391 with Et2NLi, the tungstencarbon double bond
migrated into the exo-CC position to give the new neutral complex 392 <1996JOM(520)59>
(Equation (77)).
PPh2
PPh2 Et2NLi
W BPh4 W
–[BPh4]Li, Et2NH C ð77Þ
OC C Me OC
OC OC CH2
391 392
Deprotonation with Et3N also gave the same complex <1995JOM(491)283>. In the absence of
Na[BPh4], a base-induced carbonyl carbene coupling reaction afforded 3-phosphinoketene com-
plexes <1995CB289>.
Reaction of the neutral vinylidene complexes 393 (R = H, CH3, C6H5) with chlorodiphenyl
phosphine (R1 = Ph) afforded the neutral complexes 394. Analogously, the reaction of chloro-di-
t-butyl phosphine (R1 = But, R = H) with 393 (R = H) gave rise to the bulky complex 394
(R1 = But, R = H). The formation of the metallacyclopropane rings was rationalized by nucleo-
philic attack of chlorophosphine on the C of the vinylidene followed by chloride–carbon
monoxide exchange <2000OM5281> (Equation (78)).
W + R12PCl W
C Cl ð78Þ
OC C CHR
CHR NO P
NO
R12
393
394
Addition of diphenylphosphine to the molybdenum alkynyl complex 395 afforded a mixture of

the (E)/(Z) addition products 396 in 52% yield <2001JOM(633)125> (Equation (79)).
PPh2H, Me3NO, MeCN

Mo C Mo CO2Me ð79Þ
C 52%
Cl C C
OC CO2Me
OC CO OC P H
Ph2
395 396
A large number of various platinum complexes differing in structure and metal coordination to
the CC double bond were also prepared based on the 2-coordinated alkynylphosphine complex
397 <2002JCS(D)226>. The regiospecific addition of hydrogen chloride in benzene formed the
tetra-coordinate 1-vinyl-Pt(II) complex 398 from which the new platinum complex 399 contain-
ing a three-membered methylenephosphaplatinacycle fragment was obtained via the reversible
dissociation of the chloride ion (Scheme 54).
+
Cy2 PPh2 Cy2 C 6D 6 Cy2
P P Cl P PPh2
HCl –Cl–
Pt Pt PPh2 Pt
P P CD2Cl2 P Me
Cy2 Me Cy2 +Cl– Cy2
H Me H
397
398 399
Scheme 54
On treatment of the 2-alkynylphosphine complex 400 with HCl (1 equiv.) in diethyl ether, the
penta-coordinate nickel(II) complex 401 was prepared as a thermally sensitive red solid
<2001OM980> (Scheme 55). Subsequent reactions with carbon dioxide or carbon disulfide
gave the corresponding zwitterionic insertion products 402.
Cy2 Me Cy2 Cy2

Cl
P P Cl P Y Y
HCl, Et2O CY2
Ni Ni PPh2 Ni +
100% Y = O,S – PPh2
P P P
Cy2 PPh2 Cy2 Cy2
400
H Me H Me
401 402
Scheme 55
Wenger and co-workers studied regioselective insertion reactions of unsymmetrical phosphinalk-

ynes to the yellow 5-membered phosphanickelacycles 403 (R3 = Et3 or R3 = PhBn2) and obtained
new complexes 404 possessing 3-membered alkenylphosphanickelacycles <2001OM2864> (Scheme
56). Depending on susbstituents R and R1, the dimeric structure 405 or four-membered alkenylpho-
sphanickelacycle 406 could be prepared upon further heating of 404.
4.22.4.2.6 p C¼C-Bonded compounds

2
Pure -complexation was observed in the platinum complex of the allenylphosphonium salt 407
prepared from the 2-coordinated platinum alkynylphosphine complex 397 by methylation with
methyl iodide <2001JCS(D)226> (Equation (80)).
Ph2
P Br
1
PPh2 R C C PPh2
Ni
PR3
Ni
Br PPh2
P R3 R1
404
403
R = Et, a R3 = Et3, R1 = Me
R1 = CO2Me b R3 = PhBn2, R1 = Me or Ph
Ph2
P Br
Ph2
Ni PPh2 CO2Me P
Br
Ni
PPh2 PPh2
MeO2C Ni
1
Br P R
Ph2
406
405
Scheme 56
Me
Cy2 Cy2 H +PPh
PPh2 2
P P
MeI
Pt Pt
ð80Þ
P P
Cy2 Me Cy2
H H
397
407
Kirchner and co-workers synthesized 4-butadiene amido complexes through migration and
NH activation of the PPh2NHPh ligand. Thus, treatment of the cationic complex 408 with
various alkynes (R = Ph, Bun, CH2Ph) resulted in the formation of the corresponding com-
plexes 409 in 43–88% yields <2003OM1771> (Equation (81)). The starting complex 408 was
obtained in the reaction of [RuCp(CN)3]PF6 with 1 equiv. of PPh2NHPh at 100 C in 92%
yield. In a similar manner cyclic complexes with 1,6-heptadiyne and 1,7-octadiyne were
obtained.
+ +
H
Ru Ru NPh
HC CR R
H3CCN PPh2NHPh
R
ð81Þ
43–88%
NCCH3 H
408 PPh2
H
409
4.22.4.2.7 p PCC-Bonded compounds

2
Cationic -phosphinocarbene complexes 410 reacted at 78 C with alkyl isonitriles (R = Me,
But) to provide tungstenaphosphabicyclo[1.1.0]butanone complexes 411. Besides the description
of the complexes as bicyclic systems, the canonical form 412 possessing a planar 3-allylic
arrangement may be considered <1998JOM(553)103> (Equation (82)).
PPh2 PPh2
PPh2
MeNC
W BF4 W C Tol BF4 W C Tol BF4
OC MeNC MeNC ð82Þ
C C
Me3P Tol C
Me3P Me3P
O O
410 412
411
4.22.4.2.8 s P- and p PCC-Bonded compounds

The -1-phosphabutadienyl Fe complex 414 with the phosphorus additionally 1-bonded to
3
another metal (W) was synthesized by Mathey and co-workers on prolonged heating of the
-phosphido complex 413 in boiling toluene, as the only representative of this new class of
compounds till now <2001JOM(617-618)748> (Equation (83)).
∆, 110 °C, toluene

overnight
Fe(CO)2Cp ð83Þ
63% P Fe(CO)Cp
P
Ph W(CO)5 (OC)5W Ph
413 414
4.22.4.2.9 p-Half sandwich compounds
(i) 4-Phosphole compounds

Mathey and co-workers described functionalization of 1-phenyl-3,4-dimethylphosphole 415 in
which the dienic phosphole system and the lone pair of the phosphorus were protected with iron
carbonyl groups <2001JOM(624)105> (Scheme 57).
Fe(CO)3 Fe(CO)3
Fe(CO)3
i. LDA CH2 CH2
ii. CuCl2 S8, toluene
2 2
20%
P P P
Ph Fe(CO)4 Ph Fe(CO)4 Ph S
415 416 417
Scheme 57
The first stage involved a selective deprotonation of the 3-methyl group in 415 followed by
oxidative coupling of the resulting lithium derivative with CuCl2 to give the dimer 416. The
P-protecting iron carbonyl moieties were cleanly removed by treatment with elemental sulfur in
refluxing toluene to give 417. Total decomplexation of the remaining iron carbonyl group
Fe(CO)3 was achieved with CAN in a dichloromethane/isopropanol mixture. The lithium
derivative of 415 also reacted with various electrophiles (MeI, TMSCl, benzophenone,
p-chlorobenzaldehyde, (E)-cinnamaldehyde) to afford the corresponding expected adducts.
(ii) 5-Phosphinocyclopentadienyl compounds

Half sandwich titanium and zirconium complexes 419 were prepared in moderate yields through
transmetallation reactions starting from trimethyltin derivatives 418 and TiCl4 or ZrCl4
<2002EJI678> (Equation (84)).
But
But
P NEt2 Rn P
i
+ MCl4(THF)2 NEt2
–Me3SnCl ð84Þ
Rn 25–38%
M
SnMe3 Cl
Cl
Cl
418 Rn = Me4, But i. Toluene, 80 °C/5 h 419 M = Ti, Zr
The titanium P-chloro complex 421 was prepared via deprotonation of 420 with Et3N followed
by reaction with TiCl4 (Scheme 58) <2002EJI678>. This half sandwich complex was further
transformed into the constrained complex 422 as a mixture of two diastereoisomers.
But But
But P
t TiCl4/Et3N, –78 °C Cl But NHLi/Et3N But
Bu
t –Et3NHCl –LiCl, –Et3NHCl P
Bu P
89% Ti Cl
Cl Cl Ti
Cl N
420 Cl
Cl
But
421
422
Scheme 58
(iii) 5-Phosphacyclopentadienyl compounds

In this section will be described compounds in which a metal (Mn, Co, Ph, Ir, U) is coordinated
to one phosphacyclopentadienyl (phospholide) ring and at the same time either to small molecules
[CO, BH4, Ph3P, (MeO)3P] or to the second ring other than cyclopentadienyl (THF, COD,
cyclooctatetraenyl, cyclobutadienyl). Accordingly, phosphacymantrenes (metal = Mn) will be
mentioned here but metallocenes (a metal coordinated to two cyclopentadienyl rings) will be
summarized in the following sections.
Starting from 1-(20 -pyridyl)-3,4-dimethylphosphole 423, Mathey and co-workers synthesized
the phosphacymantrene 424 using the two-step reaction depicted in Equation (85)
<1997JOM(548)17>.
P
i. ButOK, THF, 80 °C, 4 h
ii. BrMn(CO)5, toluene, 110 °C, 1 h
P
ð85Þ
N Mn(CO)5
424
423
In an approach to chiral phosphacymantrenes, the novel chiral and enantiomerically pure

phosphole 425 with two ()-menthyl groups at the 2- and 5-positions of the phosphole ring
was utilized. This compound was submitted to the known reaction with lithium to give the new
chiral lithium phospholide 426 followed by the thermal reaction with manganese carbonyl to
afford 427 <2001OM1014> (Scheme 59).
R* P R*
Mn2(CO)10, xylene
–
Li (excess) reflux
R* P R* THF R* P R*
85%
Li+
Ph Mn(CO)3
425 R* = (–)-Menthyl 426 427
Scheme 59
A known approach to unsubstituted phosphacymantrenes was applied by Mathey and

co-workers <1999OM5688> to the synthesis of 2-functionalized compounds. Thus, the thermal
reaction of 1-phenyl-2-ethoxycarbonyl-3,4-dimethylphosphole 428 with 0.5 equiv. of Mn2(CO)10
gave 429 in 50–70% yield (Equation (86)).
Mn2(CO)10, xylene
140 °C, 1.5 h
(OC)3Mn
CO2Et CO2Et ð86Þ
P P
Ph 429
428
An important finding was that a replacement of one carbonyl group on manganese by

triphenylphosphine enhanced the sensitivity of phosphacymantrenes toward electrophilic substi-
tution, for example, the Vilsmeier formylation. Usually, phosphacymantrenes do not undergo the
Friedel–Crafts alkylation.
The McMurry coupling (TiCl4/3 equiv., Zn/6 equiv., THF, reflux) of 2-acetyl- and 2-benzoyl-
3,4-dimethylphosphacymantrenes enabled modification of the side chain of phospholyl rings in
bis(phosphacymantrenyl)ethenes <2002OM2635>.
Similarly, Mathey and co-workers <2003OM1340> synthesized phosphacymantrenyl carbe-
nium ion using AlCl3 in CH2Cl2 at 0 C which enabled further modification of the pendant
2-phosphole substituents in alkylation of ferrocene as well as alkylation of electron-rich arenes
such as anisole and 1,3-dimethoxybenzene.
Starting from (2,5-di-t-butylphospholyl)dicarbonyl cobalt 431, Mathey and co-workers
obtained a range of cobalt phospholyl complexes <1997OM2049>. The complex 431 was synthe-
sized as a red liquid by thermolysis of the bisphosphole 430 with Co2(CO)8 (7 h, 97 C, C7H16) in
80% yield (Equation (87)).
But But But P But

P Co2(CO)8
P 80% ð87Þ
t t
Bu Bu Co
OC CO
430 431
Thermolysis of 431 with trimethyl phosphite resulted in replacement of one CO group

in 90% yield. Photolysis of 431 with COD or 1,3-cyclohexadiene afforded orange solids of
2,5-di-t-butylphospholyl (COD) cobalt 432 in 90% yield and the analogous 2,5-di-t-
butyl(1,3-cyclohexadiene) cobalt in 70% yield, respectively. Instead of the expected pyridines,
the yellow cyclobutadiene complex 433 was obtained in the thermolysis reaction (3 d, sealed tube,
120 C) of 432 with a large excess of phenylacetylene in propionitrile (Equation (88)).
But P But
But P But
PhCH CH
EtC N
Co
Co ð88Þ
Ph Ph
432 433
Photolysis of 431 in the absence of donor ligands gave the doubly bonded complex 434 in
70% yield as deep green microcrystals. Ethyl diazoacetate reacted with the latter exclusively at
the Co¼Co bond to give the carbene complex 435 as a mixture of isomers in 85% yield
(Scheme 60).
But P But But P But

hν , C5H12, N2 N2CHCO2Et
431
70% 85%
Co Co
OC CO OC CHCO2Et
t Co Co
Bu
P
But
But P But
434
435
Scheme 60
The plumbocene 436 was converted to new rhodium and iridium complexes 437 on treatment
with the corresponding metal halides (M = Rh, Ir) complexed to COD <1999CC1273>
(Equation (89)).
P But But P But

But
Pb [MCl(COD)]2 M
But
M = Rh, Ir ð89Þ
P
But 437
436
Mixed 2,3,4,5-tetramethylphospholyl and 3,4-dimethyl-2,5-bis(trimethylsilyl)phospholyl/

cyclooctatetraenyllanthanide (Sm, Nd) complexes were prepared by Visseaux and co-workers by
metathesis of the corresponding phospholyl potassium salts with cyclooctatetraenyllanthanide
halide precursors.
Treatment of 438 or 439 with potassium phospholide gave the first mixed cyclooctatetraenyl-
phospholyl uranium complex 440, the structure of which was determined by X-ray analysis
<2002JOM(643/644)209> (Scheme 61). Other uranium complexes containing the phospholyl
moiety were also obtained.
-
U(COT)(BH4)2(THF)
P H
438 K+
O U H B H
–KBH4 or
[U(COT)(BH4)(THF)2] [BPh4] H
–KBPh4
439 P
440
Scheme 61
(iv) 6-Phosphinobenzene compounds

Most compounds of this type constitute di- or tri-carbonyl chromium(0) complexes which were
first ortho-lithiated and then phosphinylated. For instance, (+)-(R)-tricarbonyl chromium(0)
complexes 441 were deprotonated with lithium tetramethylpiperidide (LiTMP) at 78 C for
1 h. Subsequent reaction with chlorodiphenylphosphine afforded the phosphino modified chro-
mium complexes (442a,b) <2002T4617> (Equation (90)).
R R
i. LiTMP
(OC)3Cr ii. Ph2PCl (OC)3Cr
OMe R = Me, PhCH2 OMe
96–97% ee
But But PPh2 ð90Þ
(+)-(R)-441 442
a R = Me, 88% (96% ee)

LiTMP – lithium tetramethylpiperidide b R = PhCH2, 91% (97% ee)
Overman and co-workers reported highly diastereoselective lithiation of the dicarbonyltriphe-

nylphosphinochromium(0) oxazoline complex 443 <2002AG(E)3884> (Scheme 62).
CO
CO
Ph3P
Cr
i. BusLi, Et2O, –78 °C O
ii. Ph2PCl
59%
CO N
CO But
Ph3P PPh2
Cr
O 444 18:1 dr
CO
N CO
t
Bu Ph3P
Cr PPh2
i. BunLi, Et2O, TMEDA, –78 °C
443 ii. Ph2PCl O
81%
N
But
445 50:1 dr
Scheme 62
The lithiation of 443 with s-butyllithium at 78 C followed by quenching with dichlorophenylpho-
sphine produced diastereoisomers 444 and 445 in an 18:1 ratio, while the use of n-butyllithium in the
presence of TMEDA at 78 C provided 445 and 444 in a 50:1 ratio and in 81% yield.
Two other chiral tricarbonyl chromium(0) complexes 446 and 447 were prepared in a similar
manner via ortho-lithiation with s-butyllithium and t-butyllithium in Et2O in 50% and 25% yields,
respectively. One of the three carbonyl groups could be replaced by PPh3 using the Hg-lamp
<1995JOM(503)143>.
Me
PPh2 R NMe2
N
R OCH2OMe Me
(OC)3Cr PPh2
(OC)3Cr
Me
446 447
Another method of synthesis of phosphinylated tricarbonyl chromium(0) complexes involves the

reduction of the phosphine oxides 448 to phosphines 449 carried out with polymethyl hydrosiloxane
(PMHS) in the presence of titanium tetraisopropoxide in THF <1997SL1453> (Equation (91)).
P(O)Ph2 PMHS PPh2
E Ti(OPri)4, THF, ∆ E
ð91Þ
Cr(CO)3 Cr(CO)3
448 449 E = TMS (74%)

SnMe3 (93%)
A number of 16e ruthenium complexes were synthesized by Valerga and co-workers

<2002OM5334>. It was found that the unstable complexes 450 (R = Ph, Pri) were rearranged to
18e sandwich species 451 on standing in fluorobenzene with trace amounts of oxygen (Equation (92)).
+ +
B Ar4– B Ar4–
O2 (traces)
Ru Ru ð92Þ
R2PhP PPhR2 R
450 P
R
Ar - 3,5-(CF3)2C6H3 451
Two other interesting 6-ruthenium complexes (452a,b), both of yellow color, were synthesized
in 91% and 76% yields, respectively, in which only one P was coordinated to an arene 6-C6H3
moiety derived from one of the biaryl rings <1997OM3735>.
R1 R1
Ru
R2P
R2P
O O
Me Me
452 a R1 = Me, R = 3,5-Bu2t C6H3

b R1 = CH2TMS, R = 3,5-Bu2t C6H3
(v) 6-Phosphabenzene compounds

1,4-Phosphaboratabenzenes found to be new and good six--electron ligands toward transition
metals and replacements of Cp groups of metallocenes. The synthesis of these systems was first
reported by Nöth and Berger in 1983 <1983JOM(230)33>; however, this coordination chemistry
remained unexplored until 2003 when Ashe III and co-workers <2003OM910> synthesized
1,4-dihydro-4-(diisopropylamino)-2,6-dimethyl-1-phenyl-1,4-phosphaborin 453. The P-phenyl
group of the latter was easily cleaved and the reaction of 453 with lithium powder in diethyl
ether gave a deep red solution of the -coordinated anion of the 1,4-phosphaboratabenzene 455.
This conversion caused the characteristic downfield shift from 31P = 11.5 ppm 453 to
31P = 38.5 ppm 455. Further reaction of 455 with [Cp*RuCl]4 afforded deep yellow crystals of
the Ru(II) complex 456. Similarly the reaction of the 1,4-phospaborin 453 with Mn2(CO)10 in
xylene at 140 C afforded the pale yellow Mn complex 454 (Scheme 63).
Mn2(CO)10
Ph P B NPr2i P B NPr2i
453 Mn(CO)3
Li 454
– [Cp*RuCl]4
P B NPr2i P B NPr2i
Ru
455
Cp*
456
Scheme 63
Zenneck and co-workers synthesized the binuclear complex 458 starting from the 1-pentacarbonyl
chromium complex of 2-chloro-4,5-dimethylphosphinine 457.
Although the yields of the product exceeded 80%, solution of 458 was found to be extremely
air sensitive and could be stored only for a few hours at rt even in the absence of oxygen
<1996OM2713> (Equation (93)).
Cr(CO)5
P
[(COD)2Fe], –40 °C Cl
83%
P Cl ð93Þ
Fe
Cr(CO)5
457
458
4.22.4.2.10 Metallocenes
(i) Phosphino metallocenes

The most widely used method for introduction of a phosphino group to a metallocene still remain
lithiation/phosphinylation protocols. Before 1995, lithiation and so called ortho-lithiation/phos-
phinylation procedures were applied only to ferrocene and its derivatives. After 1995 these
procedures have been further developed. New modifications, applications to syntheses of other
metallocenes (e.g., ruthenocenes and osmocenes) as well as asymmetric lithiations will be briefly
mentioned below.
(a) CH/CLi exchange. This group of methods includes new ortho-lithiation, ortho-dilithiation,
stepwise lithiation and dilithiation/phosphinylations as well as diastereo- and enantioselective
deprotonation reactions.
Most of the new procedures and modifications still concern phosphino ferrocenes. Homochiral
compounds of this type can be prepared either via resolution of racemic precursors for instance:
<1982ACR395, 1988PAC7, 1992CRV857> or via introduction of chiral ‘‘directed metallation
group’’ auxiliaries <1996C86, 1996AG(E)1475> or by asymmetric ortho-lithiation. In the latter
method, Snieckus and co-workers <1996JA685, 1996JOC1172> used the complex of n-BuLi and
()-sparteine while Uemura and co-workers used the complex of n-BuLi and (+)-1(R),2(R)-bis(di-
methylamino)]cyclohexane <1996JOC1172>. Jendralla and Paulus <1997SL471> reported a mod-
ification of enantioselective deprotonation of the diamido ferrocene 459a by twofold asymmetric
ortho-lithiation with the n-BuLi/()-sparteine complex followed by addition of Ph2PCl to afford
enantiomerically pure monophosphine 459b after a single recrystallization. Treatment of the latter
with the same complex gave enantiomerically pure C2-symmetric diphosphine 459c with 86–94% de,
while the rac-459b furnished a mixture of 459c and 459d in a ratio of 1:1.
When the s-BuLi/()-sparteine complex was used, the meso-diphosphine 459d was obtained
with 92% de.
The diamides 459b were also synthesized and used as catalysts by Snieckus and co-workers
<2000OL629>.
R2
R1
Fe R5
R4
R3
R1 R2 R3 R4 R5
459 a CONPr2i H H CONPr2i H

b CONPr2i PPh2 H CONPr2i H
c CONPr2i PPh2 PPh2 CONPr2i H
d CONPr2i PPh2 H CONPr2i PPh2
It was reported that the diastereoselectivity of the ortho-lithiation of chiral 1,10 -bis(oxazolinyl)ferro-
cenes (460a,b) could be controlled by temperature, solvents, and/or lithiating agents <1996TL6137>.
Thus, monolithiation of 460 with butyllithiums (n, s, t) in Et2O followed by treatment with Ph2PCl
favored (R)-461 while the use of THF led to (S)-461 (see Scheme 64 for the use of BusLi). Dilithiation
with s-BuLi or t-BuLi in Et2O led to (R,S)-462. The step-by-step lithiation at different temperatures with
s-BuLi in Et2O gave (R,R)-462 while s-BuLi in THF afforded (S,S)-462 as the major product.
PPh2
R O O
N R R
i. BusLi, Et2O i. BusLi, THF
ii. Ph2PCl ii. Ph2PCl
N N
Fe O Fe Fe
O
R R O
N
R
N
O N
PPh2
(R )–461a 81% 460a R = Pri
b 70% b R = But (S )–461a 72%
b 71%
Scheme 64
R O R O
Ph2P
N N N
Ph2P Fe Ph2P Fe Fe
R O
R O R O
Ph2P
N
N N
Ph2P Ph2P
O
(R),(S)– 462 (S),(S)– 462
R
(R),(R)– 462
The known diastereoselective ortho-metallation was applied in a double fashion by Schwink

and Knochel <1998CEJ950> for the -(N,N-dimethylamino)alkyl ferrocene and ruthenocene
to afford the dilithium derivatives 463 (M = Fe, Ru) which were further treated with Ph2PCl
to give 464 (M = Fe, Ru) in moderate chemical yield (29–54%) and with 98% ee. The latter
reacted quantitatively with stoichiometric amounts of Pd(MeCN)Cl2 in toluene to give, in the
case of ferrocene, the C2-symmetrical complex 465 (R = Ph, M = Fe) and in the other cases
(M = Ru), mixtures of less symmetrical coordination isomers (Scheme 65).
R NMe2 R NMe2 R NMe2
Li PPh2 Ph2
P
Ph2PCl Pd(MeCN)2Cl2
M M M PdCl2
29–57% 100%
Li PPh2 P
Ph2
R NMe2 R NMe2 R NMe2
463 464 M = Fe; R = Me, n-C5H11, Ph, 2-Naphtyl 465 M = Fe; R = Ph

M = Ru; R = Ph
Scheme 65
There were also reported other stereoselective ortho-lithiation/ Ph2PCl phosphinylation reactions of
the following compounds: (R) and (S)-N,N-dimethyl-1-ferroceno(n-propyl-n-pentyl)amines 466
<2003OM618, 2002TA1687, 1996JOC1172, 1995TA2495>, bis-(dimethylamino)ferrocenes 467
<1996TL25, 1998TL5523>, N,N-diisopropyl-ferrocenecarboxamide 468 <1996JA685>,
1,10 -bis[(S)-2-(4R-oxazolinyl)]ferocenes 469 <1995TL7263, 1996TL6137>, monooxazolinylferrocenes
470 <1995SL79> and their substituted analogs 471 <1997JOM(545-546)381, 1995SL74>, 4-(meth-
oxymethyl-2-[2-trimethylsilyl,diphenylphosphinyl)-ferrocenyl]-1,3-dioxane 472 <2002OM4552>,
trans-(2R,5R)-2,5-dialkyl-1-(ferrocenylmethyl)pyrrolidines 473 <2002JOC4209>, (RC,SP)-
[5-cyclopentadienyl][5-4-N,N-(dimethylamino)-3-diphenylphosphino)-4,5,6,7-tetrahydro-1H-
indenyl]iron(II) 474 <2002OM1766>, (R)-[amino-o-bromophenylmethyl]ferrocene 475
<2002CEJ843>, (E)-benzoylferrocene[(S)-1-amino-2-methoxymethylpyrrolidine]-hydrazone
476 <2000EJO2839>, 1,2-(-exo-dimethylaminotetramethylene)-ferrocene 477
<2001JOC1560>, (1S,2S)-N-ferrocenylmethyl-N-methyl-1-methoxy-1-phenylprop-2-ylamine 478
<2001JOC8912>, (S)-N-ferrocenylmethyl-3,5-dihydro-4-H-dinaphth[2,1-c:10 ,20 -e]azepine 479

<1999TA4369>, (R)-()-ferrocenyl-t-butyl sulfoxide 480 <1998T7301, 2003JOC3679>, (R) or (S)-
ferrocenyl p-tolyl sulfoxide 481 <1998JOC3511, 2003JOC3679>, (S)-1,10 -(1-N,N-dimethylaminopro-
pane-1,3-diyl)ferrocene 482 <1996JOM(508)195>. (Arrows indicate sights of phospinylation.)
H R NMe2 O
NMe2 R NPr2i
Fe Fe Fe
NMe2
466a R = H(49%) 467a R = n-C5H11 (55–57% 468 (82%, 90% ee)

b R = Me (93%, 2 steps) b R = Ph overall 3 steps)
c R = Et (59% from RC c R = Et (55%)
32% from SC)
d R = Bun (44% from R )
e R = Ph
R
O
O O
N
N N
Fe Fe R Fe E Pri
R
O
469a R = Pri (60%) 470a R = Pri (77%)s 471a E =Me (72%)

b R = But (43%) b R = Bu (58%) b E = PhSe (53%)
c R = Ph(55%) c E = TMS (75%)
d R = Me (25%)
e R = PhCH2(56%)
f R = But (51%)
NMe2
R H
O
N
O
Fe R1 OMe Fe R Fe
472a R1 = TMS (29%) 473a R = Me (27%) 474 (71%)

b R1 = Ph2P (37%) b R = Et (10%)
R1R2N Br Ph Me2N
N N
Fe Fe MeO Fe
475a R1 = R2 = Me (88%) 476 (89%) 477 (96%)

R1 = R2 = Me [33% for
(3,5-xylyl)2PCl]
b R1 = R2 = CH2CH2 (64%)
c R1 = (R )-PhCH(Me); R2 = Me (41%)
d R1 = (S )-PhCH(Me); R2 = Me (58%)
e R1 = Me2NCH2CH2; R2 = Me (41%)
f R1 = R2 = Prn (53%)
g R1 = R2 = Bun (46%)
h R1 = R2 = Bui (36%)
Me But
N
N S
O
Fe O Ph Fe Fe
Me
478 (97%) 480 (82%)

479 (no yield given)
p-Tol
H NMe2
S O
..
Fe Fe
R2
481 (57%) 482a R1 = PPh2
b R2 = PPh2 (2'–44%, 3'–6%
4'–5%, 5'–7%)
Gusev and co-workers synthesized 1,10 -bis(diphenylphosphino)osmocene 484, the missing com-
pound along the iron triad (Fe, Ru, Os). It was prepared in 25–30% yield via the double lithiation
procedure of the osmocene 483 followed by the reaction with chlorodiphenylphosphine
<2003OM913> (Equation (94)).
PPh2
i. BunLi/TMEDA
ii. Ph2PCl
Os Os
25–30% ð94Þ
PPh2
483 484
Hansen and Johannsen described the regioselective ortho-lithiation of the azaferrocene 485
(Me = Fe) and the azaruthenocene 485 (M = Ru) with n-BuLi at 0 C <2003JOC1266>. The
resulting racemic anions were quenched with chlorodiphenylphosphine to afford new azametallo-
cenes 486 (M = Fe, Ru) (Equation (95)).
N N
PPh2
BunLi,
i. 1.2 equiv. THF, 0 °C
ii. 1.2 equiv. Ph2PCl, 0 °C
M M
ð95Þ
485 486 M = Fe (41%)

M = Ru (35%)
A clean removal of the chiral sulfoxide auxiliary from 487 by treatment with t-BuLi generated
optically pure anion 488 which was stable at low temperatures and quenched with chlorodiphe-
nylphosphine to give the optically pure azaferrocene 489 (Scheme 66). The same reaction
sequence was also performed with the opposite diastereomer (SS, SP).
.. O
N S N N
p-Tol – PPh2
2.5 equiv. ButLi 1.2 equiv. Ph2PCl
THF, 0 °C THF, 0 °C
Fe Fe Fe
487 (SS,RP) 488 489 (RP)
Scheme 66
(b) C–Hal/C–Li exchange. Various diphenylphosphino-substituted ferrocenes were obtained

as a result of a combination of the ortho-lithiation (LDA) and/or the Br/Li exchange followed by
the reaction with chlorodiphenylphosphine <1999MI576>. For instance, the ortho-lithiation of
one of the cyclopentadienyl rings in 1,10 -dibromoferrocene 490 gave 1,10 -dibromo-2,5-bis(diphe-
nylphosphino)ferrocene 491 as one of the reaction products. Further reaction of the latter with
BunLi followed by phosphinylation with Ph2PCl afforded 1,2,3,10 -tetrakis(diphenylphosphino)fer-
rocene 492 (Scheme 67).
Br Br PPh2
Ph2P PPh2 Ph2P PPh2
i. LDA i. BunLi
ii. Ph2PCl ii. Ph2PCl
Fe Fe Fe
Br Br Ph2P
490 491 492
Scheme 67
Knochel and co-workers <2002CEJ843> reported another interesting example of the double
Br/Li exchange/diphosphinylation reaction facilitated by the presence of the phenyl ring to give
products in high chemical yield (91–92%) and with d.r.’s of 95–96/4–5.
The dimethylamino group facilitated the exchange of bromine and iodine for lithium in (R)-
1-bromo(iodo)-2-(dimethylaminomethyl)ferrocenes. Subsequent reaction of the lithium deriva-
tives formed with Ph2PCl gave the corresponding (R)-products in 80% (I) and 81% (Br) yields
<2001JOC8912>. The same lithiation–phosphinylation sequence was also reported for the
C2-symmetrical 3,5-dihydro-4H-dinaphtho[2,1-c:10 20 -e]azepine subunit as the chirality inducing
fragment <1999TA4369>.
The I/Li exchange enabled by the oxazolinyl ferrocene 493 and leading to 494 was also
described (Equation (96)) <2002JOC4684>.
O O
R R
N i. BunLi N
R ii. Ph2PCl R
Fe I Fe PPh2
ð96Þ
493
494a R = Me (73%)
b R = Bu (31%)
(c) C-p-TolS(O)/C–Li exchange. Kagan and co-workers <1998JOC3511, 2000EJO2893>

synthesized 1,2-disubstituted ferrocenes 497 (ee 98%) starting from the BH3-protected phos-
phine 495 which in turn was obtained via the LDA ortho-lithiation/phosphinylation sequence in
57% yield. Modification of the CP-2 position was achieved in a subsequent step in which t-BuLi
attacked the sulfinyl sulfur to generate a new chiral 2-lithium species 496. The latter was further
trapped with electrophiles (R2X = ClCO2Me, Cy2PCl) to give 497 after removal of the borane in
refluxing diethylamine (Imamoto method) (Scheme 68).
BH3 BH3
PPh2 p-Tol PPh2 PPh2
S O Li i. ButLi, –78 °C R2
.. ii. R2X
ButLi, –78 °C iii. Et2NH
Fe Fe Fe
495
496 497a R2 = COOMe (64%)
b R2 = (C6H11)2P (19%)
Scheme 68
The lithioferrocene 496 was also condensed with TMSCl at 78 C to give the TMS sub-
stituted analog of 497 (R2 = TMS) <2002JOC7982>. Another example of the p-tolylsulfinyl
group/Li exchange in the aryl substituted ferrocenes followed by reactions with either Ph2PCl
or Ph2P(O)Cl in 16–81% yield has recently been reported by Johannsen et al. <2003JOC1258>.
(d) Other methods. Various ferrocenyl polyphosphines (499, 500 and 501), were synthesized by
Broussier and co-workers from 1,2-bis(diphenylphosphino)-3,4,5-trimethylcyclopentadienyl-
lithium 498 utilizing the classical ferrocene synthesis <1998JOM(561)85> (Scheme 69).
The diphosphine 499 and the tetraphosphine 500 were further oxidized with H2O2 to the
corresponding diphosphinoyl and tetraphosphinoyl ferrocenes. All three polyphosphines (499,
500 and 501), were treated with chromium tetracarbonyl to give complexes of the type 502
possessing two phosphorus bound to Cr (Equation (97)). The tungsten analog of 502 was also
obtained.
PPh2
i. FeCl2
ii. –
Li+
Fe PPh2
67%
499
PPh2
PPh2
1
PPh2 2 FeCl2 PPh2
– Li+ Fe PPh2
83%
498 PPh2
500
i. FeCl2 PPh2
PPh2
ii. –
+
Li PPh2
Fe
63%
PPh2
501
Scheme 69
Ph2
PPh2 P
M(CO)4
M(CO)4L2 P
Fe PPh2 Fe Ph2
M = Cr, L2 = NBD (85%) ð97Þ
M = W, L2 = PIP (88%)
499 502
NBD—norbornadiene
PIP—piperidine
In a similar way, Otero and co-workers prepared the ansa complexes 504 in the reaction of
MCl4(THF)2 (M = Ti, Nb) or MCl4 (M = Zr or Hf) and the corresponding dilithiated ansa
derivative 503 <2002EJI2470, 2002JOM(655)63> (Equation (98)).
PPh2
Me2
Si PPh2
Me Cl
MCl4 + Li2 Si M
– 2 LiCl Me Cl
55–74% ð98Þ
503
504 M = Ti, Zr, Hf
The reaction of the complexes 504 with 2 equiv. of MeMgCl led to the replacement of chlorine
by methyl to give 505 <2002EJI2470> (Equation (99)).
PPh2 PPh2
+
Me Me B(C6F5)3 Me Me
–
Si Zr Si Zr Me B(C6F5)3
Me Me Me ð99Þ
505 506
Methyl abstraction from 505 gave the cationic species having the proposed structure 506. The
insertion reaction of the isocyanide unit into the ZrMe bond of 505 gave the corresponding
2-iminoacyl complex 507 <2002EJI2470> (Equation (100)).
PPh2 PPh2
Me Me Me Me
2,6-Me2 C6H3NC
Si Zr Si Zr
Me 60% N R
Me Me C ð100Þ
Me
505 507
The two niobocene imides 509, 511 <2002EJI2470> and the dichloride 512
<2002JOM(655)63> were also prepared (Equation (101)–(103)).
PPh2
NBut
Me Cl
Cl Cl THF
503 + Nb Si Nb
Cl N –LiCl Me
–2Pyr NBut ð101Þ
N
63%
508 509
PPh2
PPh2 508, THF Cl

2 Li Nb
72% NBut
ð102Þ
PPh2
510
511
PPh2
NbCl4(THF)2 Cl
510 Nb ð103Þ
74%
Cl
PPh2
512
The synthesis of P-chiral diphosphines based on ferrocenyl and bisferrocenyl frameworks has
recently been reviewed <2001JOC759>. Two novel ligands 514 and 516 were synthesized later
and employed in the palladium-catalyzed allylic substitution (Equation (104) and (105)).
Fe
Ph OMe
P
H3B
i. 1,1′-dilithioferrocene P
..
ii. Et2NH
Fe Ph
Fe ð104Þ
Ph
.. P
513
Fe
514
Ph
P R
i. Cu, heat Ph
I O
ii. Cl3SiH, Et3N, toluene .. P
R
iii. BH3, THF, separation
iv. Et2NH
R ..
P
Fe Fe ð105Þ
Ph
Fe
(RP,R )-515
R = 1-Naphthyl
(SP,S,S,SP)-516
The first (S,S)-514 was obtained via nucleophilic attack of 1,10 -dilithioferrocene on the enan-
tiopure methyl phosphinite (R)-513 occurring with inversion of configuration at the phosphorus
(Equation (104)). The second bisferrocenyl ligand (SP, S, S, SP)-516 was synthesized from 515
after the Ullmann coupling in four steps involving reduction of the P(O) group to the correspond-
ing P(III) compound and purification via the bisborane complex (Equation (105)).
(e) Complexes with metals. 1,10 -Bis(diphenylphosphino)octamethyl ferrocene 517, when
reacted with AuCl(tht) (tht = tetrahydrothiophene) in a 1:2 ratio, afforded the complex in
which one AuCl unit was coordinated to each phosphino group <1995IC3465>. The ratio 1:1
led to the tri-coordinate Au(I) monomer complex 518 in which the Au was trigonal planar
(Equation (106)).
Ph2
PPh2 P
AuCl(tht)
Fe Fe AuCl
ð106Þ
PPh2 P
Ph2
517 518
Kagan and co-workers <1996JOM(511)193> reported the asymmetric synthesis of the chiral
tetradentate ligand 519 which easily formed with ruthenium(II) dichloride and copper(I) triflate
the Ru(II) and Cu(I) complexes (520, 521 and 522), respectively (Scheme 70).
Fe
N N
PPh2 Ph2P
Fe
519
ii
56%
iii
84%
N Cl N
Ru (II)
CpFe Cl FeCp
P P
Ph2 Ph2
520 N N
Cu (I)
CpFe OTf FeCp
PPh2 P
Ph2
i. H2NCH2CH2NH2, EtOH, ∆
521
ii. RuCl2(DMSO)4, CHCl3, ∆
iii. CuOTf, CH3CN, rt
N N
Cu (I)
CpFe OTf FeCp
P Ph2P
Ph2
522
Scheme 70
Novel chiral cyclopentadienyl-ferrocenyldiphenylphosphine bidentate ligands 523 were pre-

pared by Hidai and co-workers <1997OM3091>. The (S,S)-523 was further deprotonated with
s-BuLi and then treated with [Rh(CO)2Cl]2 in a 2:1 ratio in THF to give the rhodium complex 524
(Equation (106a)).
Me H Me H
i. BusLi
H Cp ii. [Rh(CO)2Cl]2, THF, rt, 12 h Cp
66%
Ph2P OC Rh P
Ph2 Fe ð106aÞ
Fe
(S,S)-523 524
The lithium salt of the diastereomer (R,R)-523 produced with [RuCl2(PPh3)3], orange crystals
of the Ru complex 525 (Equation (107)). Hydrolytic cleavage of the dihydrooxazole ring was
utilized by Stepnicka for the synthesis of (SP)-2-(diphenylphosphino)ferrocenecarboxylic acid in
two steps <2002NJC567>. The structures of the corresponding phosphine oxide and ruthenium
complexes were studied by X-ray crystallography. The same author described syntheses of rac-2-
(diphenylphosphino, diphenylphosphinoyl and diphenylthiophosphinoyl) ferrocenyl methanols
<2002NJC1389>.
H Me H Me
Cp H Cp
PPh3
BusLi
i. Ru
PPh2 ii. RuCl2(PPh3)3 P Cl
Fe Fe Ph2 ð107Þ
75%
(R,R )-523 525
The reaction of RuCl2(PPh3)3 with 1,10 -bis(diphenylphosphino)ruthenocene (dppr) in CH2Cl2

gave dark green crystalline complex 526 in 80% yield <1997JOM(527)133>.
Ph2
P
Cl
Ru Ru PPh3
Cl
P
Ph2
526
Similarly, the reaction of RuCl(Cp)(PPh3)2 with dppr in refluxing benzene gave the analogous
complex in 91% yield without triphenylphosphine bound to ruthenium <1999JOM(575)171>.
1,2-Ferrocenediylazaphosphinines constitute a completely new family of planar chiral ferro-
cenes. Their complexes with Mo, W, Re, Pd, and Mn were obtained <2003OM1475>.
Kagan and co-workers synthesized several enantiopure phosphinoferrocenes 527 as substrates
for cationic complexes 528 useful in hydrogenation <2000EJO2885, 2001WOP0138336>
(Equation (108)).
CH2PR2 +
PR2
PPh2 [Rh(COD)2]X P Rh(COD)

Fe Fe Ph2 X–
X = BF4 ð108Þ
X = PF6
527 528
For instance, when R = C6H11, X = PF6, the corresponding complex 528 was obtained in 80%
yield.
Chung and co-workers <2003OM618> prepared P-functionalized chiral imidazolium salt 529
and its rhodium complex 530. The starting salt 529 was synthesized with retention of configura-
tion via the ortho-lithiation/phosphinylation sequence <1970JA5389> of the corresponding chiral
ferrocenylamine followed by replacement of the dimethylamino group by 1-methyl imidazole. The
reaction of 529 with the dimeric rhodium complex afforded the complex 530 in 34% yield
possessing two carbene ligands coordinated to the rhodium center (Equation (109)).
Me Me
N + N
i. ButOK, [Rh(COD)Cl]2,
N 70 °C N
Me 2 Me ð109Þ
Fe PPh2 ii. AgBF4 Fe P Rh+
I– Ph2
34%
BF4–
529 530
Cationic rhodium complexes (531a,b) were also prepared from the corresponding oxazolinyl
ferrocenes and [Rh(COD)2]BF4, whereas neutral rhodium complexes (532a,b) required the use of
[Rh(CO)2Cl] (THF, rt, 14 h, 85% yield) <1997JOM(545-546)381>.
O R' O R'
N R N R
BF4
Fe P Rh(COD) Fe P Rh Cl
Ph2 Ph2
CO
a R = Pri, R′ = H
531 b R = Ph, R′ = Ph 532
The novel C2-symmetric diphosphine ligand 533 containing carboxylic ester groups
was obtained by Ikeda and co-workers <1996TL7994> from 1,10 -bis(diphenylphosphino)-
2,20 -bis(oxazolinyl)ferrocene. On mixing 533 with 1 equiv. of dichlorobis(acetonitrile)palla-
dium(II), the P,P-chelate with Pd(II), 534 was formed in 97% yield (Equation (110)). The orange
1:1 complex of 534 with CH2Cl2 was formed by crystallization from CH2Cl2/n-hexane.
COOMe
COOMe Ph2
P
PPh2 PdCl2(MeCN)2
Fe PdCl2
Fe PPh2 ð110Þ
P
Ph2
COOMe
COOMe
533 534
In a similar way, two other phosphino ferrocenes with carboxylic acid-derived functionality
were obtained <2001JOM(637-639)845>. Phosphino bound palladium (M = Pd) and platinum
(M = Pt) complexes 535 were prepared based on the reaction of Kumada’s ferrocene-based ligand
with MX2 (X = Cl, Br) <1980BCJ1138>. In the case of palladium they isomerized to the more
stable (P,N)-complexes 536 (Equation (111)).
Me Me
Me Me
NMe2 NMe2
N N
Ph2 P Pd X
P M = Pd Ph2 ð111Þ
Fe M Fe X
P
Ph2 PPh2
535 (M = Pd, Pt) 536

Other examples of stable P,N- or transiently formed P,N- and P,S-ferrocene Pd complexes 537
were also reported <1996JOM(508)209, 2003OM1255>.
L2
Ph P
Pd Ph2 Fe
Ph
537 L2 = SPh, N = CHPh
Togni and Barbaro prepared a new chiral phosphine ligand 538 based on ferrocene
<1995OM3570>. It was obtained by the reaction of N,N-dimethyl-(S)-1-[(R)-2-(diphenyl phos-
phino)ferrocenyl]ethylamine with cyclohexylphosphine in acetic acid in 47% yield. This rare
example of tridentate ligand was ideal to form cationic d8-metal complexes (539a–539d) in
which the metal (Pd or Ni) was held in a rigid coordination environment (Equation (112)).
Fe Fe
Me P Me Me P Me
(X–)n
PPh2 Ph2P Fe P M P Fe
Ph2 Ph2
L ð112Þ
538 539
539 a M = Pd, L = Cl, (X–)n = PF–6 (64%, orange)

b M = Pd, L = MeCN, (X–)n = (PF–6)2 (62%, purple)
c M = Pd, L = MeCN, (X–)n = (BF4–)2 (82%, purple)
d M = Ni, L = MeCN, (X–)n = (ClO4–)2 (70%, deep purple)
The methoxycarbonylation reaction of ethene catalyzed by bis(aquo)palladium(II) com-

plexes with 1,10 -bis(diphenylphosphino)ferrocene and 1,1-bis(diphenylphosphino)octamethyl
ferrocene in the presence of p-toluenesulfonic acid was studied using high-pressure NMR
<2003OM2409>.
Gusev and co-workers <2003OM913> treated 1,10 -bis(diphenylphosphino)osmocene 484
with PdCl2(PhCN)2 and PdCl(Me)(COD) and obtained new Pd complexes 540 and 541.
These complexes were further reacted with halide scavengers (AgOTs, AgOTf, NaB[3,5-
(CF3)2C6H3]4) to give complexes possessing a new OsPd bond. For instance, treatment of
540 with silver triflate in acetonitrile afforded the complex 542. The X-ray analysis revealed a
strong OsPd bonding interaction (2.84 Å) and an additional PdN interaction (1.885 Å)
(Scheme 71).
Novel aminophosphine ligands 543 were prepared based on ferroceno- and trans-decalin back-
bones for enantioselective transition metal (Pd) catalysis <2002M991>.
PPh2 PPh2
PdCl2(PhCN)2 Cl
Os Os Pd
Cl
PPh2 PPh2
484 540
AgOTf
[PdCl(Me)(COD)]
MeCN
(OTf)2
PPh2 PPh2
Cl
Os Pd Os Pd NCMe
Me
PPh2 PPh2
541 542
Scheme 71
PPh2
R2 Fe
R1
543 R1R2=(=O); R1 = H; R2 = OH, NMe2
Synthesis of homogeneous chiral 1,10 -bis(diphenylphosphino) ferrocene derivatives as well as

silica-supported chiral ligands for stereoselective hydrogenation reactions was reported
<2000NJC597>.
Togni and co-workers synthesized dendrimers containing chiral ferrocenyl diphosphines and
applied them to asymmetric catalysis <1998JA10274, 2001CJC1762>. Several patents have also
appeared in this field and are dealing with: preparation of silylated ferrocenediphosphine ligands,
silica-gel and organic polymeric-bound derivatives and polymeric iridium and rhodium complexes
<1996EP729969>, preparation of ferrocenyldiphenylphosphine derivatives as ligands for metal
complexes (Pt, Rh, Pd, Ru, Ir) <1997JP09059290>, synthesis of optically active metallocenyl
phosphines <1996WOP9616971>.
(ii) Phosphametallocenes
(a) New methods and modifications. One of the methods of synthesis of phosphaferro-
cenes is the reaction of phospholes with dicyclopentadienyltetracarbonyl diiron in boiling
xylene. The reported yield remained, however, low and in the range of 20–30%. The perfor-
mance of such reactions under CO pressure in toluene as in the case of 544 gave the
phosphaferrocene 545 in a slightly better yield of 50% as a result of an accompanying [1,5]-
sigmatropic shift of the phosphinine moiety around the phosphole ring <1997CB(R)843>
(Equation (113)).
CO, 10 bar
toluene
160 °C, 1.5 h
P P + [FeCp(CO)2]2 P P
50% ð113Þ
Fe
544
545
Another method involved the PP diphosphole precursors which were reacted with penta-
methylcyclopentadienylsamariums 546 and 548 to afford new samarium complexes 547 and 549
possessing different coordination modes of samarium to the heterocyclopentadienyl ring
(Equations (114) and (115)) <2001OM3884>.
P
Toluene Cp*Sm
2[Cp*Sm(Et
2 2O)] + P P 2 P SmCp*2 ð114Þ
546
547
But But But
Toluene
2[Cp*Sm] + P P P ð115Þ
Cp*Sm
2
548
But But But
549
The dimeric structure 551 in which the unsubstituted phospholyl ligands, – bonded to the
two samarium atoms, were obtained by the condensation of the samarium etherate 546 with the
thallium phospholide 550 (Equation (116)).
P
Toluene
[Cp*2Sm(Et2O)] + Tl Cp*2Sm SmCp*2
–Tl ð116Þ
P P
546 550 551
By modification of the side chain of the phospholyl ring, the alcohol 552 could be converted to
the cationic fulvene-like species (E)-553. In the absence of a nucleophile the latter isomerized
to the thermodynamically more stable (Z)-553 <1998CEJ2148> (Scheme 72). Both (E)- and
(Z)- forms constitute synthetically valuable intermediates as electrophiles.
Thus, the reaction (E)-553 with nucleophiles (Nu = OH, PPh2 or P(C6H11)2) yielded the
corresponding products 554a with retention of configuration, while the (Z)-553 gave the products
554b with inversion of configuration in comparison with the starting alcohol 552.
(iii) Enantiopure phosphametallocenes

In the review period, interest in the synthesis of chiral phosphametallocenes has increased. Several
planar chiral phosphaferrocenes have been resolved in enantiomerically pure forms
<1997TA2607, 1997CB1771, 1997OM2862, 1998EJI1163, 1998OM773, 1998JOC4168,
1999OM5444, 2000OL3695, 2000JA9870, 2001TA533>.
OH + +
Me H H Me
Me
H
P P P
HBF4
Fe Fe Fe
–H2O
552 (E )-553 (Z )-553
NuH –H+ –H+ NuH
Nu Nu
Me H
H Me
P P
Fe Fe
554a 554b
Scheme 72
Ganter and co-workers reported an efficient method (94% yield, >99% ee) for resolution of the
racemic 555 via diastereomeric aminals formed from 555 and (R),(R)-1,2-di(N-methylamino)-
cyclohexane using column chromatography over silica gel <1997TA2607>.
Fu and Qiao synthesized other enantiopure planar chiral phosphaferrocenes 556 (X = OH,
PPh2) via reduction (LAH) of the corresponding aldehyde to alcohol 556 (X = OH) and reported
its resolution by chiral HPLC followed by one-pot chlorination with (COCl)2 and condensation
with Ph2PK <1998JOC4168>.
CHO
P X
P
Fe Fe
555 556 (X = OH, PPh2)
The phosphoferrocene 557 containing the chiral pinene-fused cyclopentadienyl ligand was
synthesized from the corresponding dimeric iron carbonyl complex and P-t-butylphosphole
<2000T17>. Introduction of the aldehyde function in the second position to the P was
achieved by the Vilsmeier reaction. The diastereomeric aldehydes obtained in a ratio of 2:1
were separated via the respective aminals derived from (R),(R)-1,2-di(N-methylamino)cyclo-
hexane.
Fe
557
Planar-chiral phosphaferrocene-oxazolines 558 (R1 = H) a new class of P,N-ligands were

synthesized by the reaction of the corresponding trifluoroacetylated monophosphaferrocene
with the dianion of the relevant amino alcohol (R = Pri, But) followed by separation of diaster-
eomeric oxazolines by column chromatography <2000OL3695>. Phenyl substituted phospha-
ferrocenes 558 (R1 = Ph) were also obtained in 46% (R = Ph) and 47% (R = Pri) yields
<2002OL3699>.
P N
R1 R
Fe
558 R = Pri, But, Ph

R1 = H, Ph
Starting from the novel enantiomerically pure phosphole 559 with two ()-menthyl groups at
the 2- and 5- positions of the phosphole ring, the corresponding chiral monophosphaferrocene
561 was obtained via the chiral lithium phospholide 560 in 84–85% yields, respectively
<2001OM1014> (Scheme 73).
R*
+ P
Li
Li (excess)
–
THF i R*
R* P R* R* P R* Fe
85%
Ph
560
559
561
R* = (–)-Menthyl i. [( η 6-mesitylene)FeCp]+[PF6]–
(2 equiv.), THF
Scheme 73
The first NMR studies of two atropoisomeric diastereoisomers of monophosphaferrocene with

four ()-menthyl groups have recently been conducted <2003OM1783>.
The latter protocol was applied to synthesis of the 3,4-dimethylphospholyl analog of ferrocifen
(a ferrocenyl analog of tamoxifen, a drug used in the treatment of hormone-dependent breast
cancers) <2003TL2749>.
The chemistry of other chiral heterometallocenes including enantiomerically pure phospha-
ferrocenes was reviewed up to 2001 by Ganter <2001JCS(D)3541>.
(iv) Metal complexes

Starting from 3,4-dimethylphosphaferrocene 562, new neutral and cationic rhodium complexes
563 and 564 as well as iridium complexes 565 and 566 were prepared <1999OM807>
(Scheme 74).
P
CH2Cl2, rt
P Rh P
n = 3, 80%
n Cl
P
563
[Rh(COD)Cl]2
Fe
+
P
NaBF4, CH2Cl2, rt –
P Rh P BF4
562 (=P) n = 4, 80%
P
[Ir(COD)Cl]2/NaBF4
80% CH Cl , 40 °C, 15 min 564
2 2
+
+
P
H2, 15 bar, MeOH, 30 min H P
Ir BF4– Ir BF4
–
75%
P P H P
P P
565 566
Scheme 74
Mathey and co-workers described the P,N-chelating properties of the new ligand 2-(20 -pyri-
dyl)phosphaferrocene 567 <1997JOM(548)17>. With soft transition metals they synthesized new
neutral tungsten 568 and cationic copper(I) complexes 570 (Scheme 75).
+
W(CO)5 ( THF) 120 °C –
THF, 25 °C toluene, 20 h Cu(MeC N)4+ BF4
Fe Fe
82%
Fe Fe BF4–
95%
Pyr Pyr
P P P N
P N
Cu
567 W
W(CO)5 (CO)4 L L
568 569
570 L = MeCN 69%
L = Ph3P
Scheme 75
It was interesting to note that on prolonged heating of the complex 568 in refluxing toluene, it
converted to the chelate 569 with loss of one molecule of CO. Both copper(I) complexes possessed
a low stability which precluded analysis by means other than NMR.
The reaction of the phosphaferrocene 571 with an excess of the tungsten pentacarbonyl
THF complex gave the new bimetallic complex 572 as a mixture of two diastereoisomers,
where both P and N atoms are separately complexed by two W(CO)5 moieties <2002EJI1657>
(Equation (117)).
W(CO)5
N
P O
Fe W(CO)5
W(CO)5.THF or
O Mo(CO)5.(MeCN) 572
P N
Fe ð117Þ
O
571
P N
Fe M
(CO)4
573 M = W
M = Mo
In this reaction, a minor compound 573 (M = W) was also formed as a mixture of two
diastereomers. However, the reaction of 571 with the molybdenium complex afforded exclusively
the chelate derivative 573 (M = Mo).
Looking for new P,P-chelate ligands, Ganter and co-workers <1999OM5444> synthesized the
cyclopentadienides 574 in the condensation reaction of racemic 3,4-dimethyl-2-formylphospha-
ferrocenes with cyclopentadiene in the presence of pyrrolidine.
The cyclopentadienide 574 (R = H) was further complexed with ruthenium complex
[Ru(PPh3)2Cl2] to give two diastereomeric half-sandwich complexes (575a,b) as red crystals in
63% yield and a 95:5 isomer ratio. The diastereomeric purity of the analogous Cp* complex 576
exceeded 98% <2001OM1614> (Equation (118)). From the cyclopentadienide 574a (R = H) and
FeCl2, the corresponding ferrocene ligand was obtained and further complexed with the moly-
bdenum carbonyl to give the new Mo-complex 577.
PPh3 Cl
P P Ru P Ru
Cl PPh3
[Ru(PPh3)3Cl2]
Fe Fe + Fe
ð118Þ
R5 R5 R5
574 R = H or Me 575a R = H 575b R = H

576 R = Me
The bis(dihydrogen)ruthenium complex 578, when treated with 2-phenyl-3,4-dimethylpho-

sphaferrocene, gave the new ruthenium(II) complex 579 in 90% yield <2001IC3034>
(Equation (119)).
A new concept for P,N and P,P chelate ligands with planar chirality was presented by Ganter
and co-workers <1997OM2862>. They used the phosphaferrocenes 580 (n = 1, 2) and reacted
them separately with [Cp*RuCl]4 (Scheme 76).
Fe
P CO
CO
Fe Mo
CO
P CO
Fe
577
Ph
PCy3
Ph H H
P Ru
PCy3 H H
H H P
Cy = C6H11 PCy3 ð119Þ
Ru + Fe Fe
H H
PCy3
578 579
Me2
( ) N
n
NMe2 Cp*
P P
Ru
Fe + [Cp*RuCl]n Fe Cl
n=2
581
580
Me2N
NMe2 Cp*
Cp*
Ru Ru
P Cl P Cl
P P
Fe NMe2 Me2N
n=1
Fe + Fe
582
583
Scheme 76
The complexation reaction of 580 (n = 2) gave the desired complex 581 as an orange red
powder in quantitative yield simply by evaporating the solvent. Completely different results
were obtained in the reaction of the ligand 580 (n = 1) with the same ruthenium complex and
the two isomeric complexes 582 and 583 were obtained. The P,P palladium complex with
(PhCN)2PdCl2 was also obtained from 580 (n = 1) in which NMe2 was replaced by OPPh2.
Hayashi and co-workers described the synthesis of a new chiral phosphinomethyl-phosphafer-
rocene ligand utilizing chiral lithium ()-2,5-dimenthylphospholide <2001OM3913>. The ligand
behaved either as a monodentate ligand in the complex 584 (with a free phosphaferrocene) or a
bidentate ligand in the complex 585 depending on the ratio of the phosphino-phosphaferrocene/
MCl2(COD)2 (M = Pt, Pd).
R*
R* R*
Fe Cl
Cl M P
Cl
R* Fe
Ph2P Pd Cl
Ph2P
Ph2P
Fe R* 585 M = Pd, Pt
R* R* = (–)-Menthyl
584 cis/trans
(v) Diphosphametallocenes
In the previous review period (until 1995), only 1,10 -diphosphaferrocenes were synthesized as
representatives of phosphametallocenes. Both 1,10 -diphosphaferrocenes and monophosphaferro-
cenes have usually been obtained from phospholes by two different procedures: (i) the lithium
induced cleavage of a P-substituent and subsequent reaction of the resulting lithium phospholide
with iron(II) halides or arene(cyclopentadienyl) iron derivatives; (ii) thermal sigmatropic shift of
the P-substituent followed by the reaction of the resulting intermediate 2H-phosphole with iron
complexes <1978JOM(156)C33, 1979JCS(D)1552, 1984JOM(263)55, 1997JOM(548)17>. The
reaction of phospholide anions with various metal halides was also used for the synthesis of
other diphosphametallocenes. 1,3-Diphosphaferrocene was also synthesized for the first time.
(a) Modifications and ring functionalizations of 1,10 -diphosphaferrocenes. 1,10 -Diphospha[2]fer-
rocenophane 588 with a tilt angle of 20 C was synthesized as a single isomer by Mathey and co-
workers by adaptation of the classical cleavage of the two PPh bonds of the diphosphole 586
with lithium (4 equiv.) followed by the reaction of the resulting diphospholide 587 with FeCl2
<2001OM1499> (Scheme 77).
Several Si-, S-, and Sn-substituted diphosphaferrocenes were prepared starting from 2-substi-
tuted (R = CN, SMe, SnMe3, TMS) 1-phenyl-3,4-dimethylphospholes via the usual PPh bond
cleavage by potassium in DME (R = CN) or lithium in THF (R = SMe, SnMe3, TMS) to give
the corresponding phospholides followed by the reaction with FeCl2 <1996BSF541>.
A mixture of meso and rac diastereoisomers of diphosphaferrocenes was similarly obtained in
23% yield <1998OM2996>. 1,10 -Diphosphaferrocenes can be easily functionalized via electro-
philic substitution reactions. Earlier studies by Mathey and co-workers showed that 1,10 -dipho-
sphaferrocenes underwent an easy functionalization via the Friedel–Crafts acetylation with the
acetyl chloride/AlCl3 system <1987NJC585, 1990JOM(400)149>. Zakrzewski and co-workers
<1998OM5880> showed that diphosphaferrocenes could also be monoacetylated with
succinic anhydride and AlCl3 (2 h) in dichloromethane in 80% yield. The acetoacetylated
1,10 -diphosphaferrocene was further synthesized by Zakrzewski and co-workers in the Friedel–
Crafts-type reaction of 3,30 ,4,40 -tetramethyl-1,10 -diphosphaferrocene with ketene in the presence
of Lewis acids (BF3 or AlCl3) <2001OM4448>.
2–
Li (4 equiv.)
THF, 2.5 h
2 Li+
P P
P P
Ph
Ph
586 587
FeCl2, AlCl3 (0.3 equiv.)

P
Fe THF, 0 to 25 °C, 45 min
588 (>30%)
Scheme 77
Functionalization of the delocalized CC double bond in 3,30 ,4,40 -tetramethyl-1,10 -diphosphafer-
rocene was also achieved by carboxylation with the CO2AlCl3 system following a similar procedure
applied to ferrocene to give the corresponding 2-carboxylic acid derivative <2002JOM(642)143>.
Probably the first example of 1,3-diphosphaferrocene 590 was synthesized on treatment of
ferrous chloride with a mixture of the anions [C3ButP2] 589, [C2ButP3] and [C5Me5] by a
modified procedure to give a mixture of four cross-products from which pale red crystals of 590
were isolated and analyzed by X-ray <1996JOM(512)141> (Equation (120)).
But But
P P
– + FeCl2 + –
But P But But P But
[Na(DME)3]+ Li+ Fe ð120Þ

589
590
(vi) 1,10 -Diphosphametallocenes other than 1,10 -diphosphaferrocenes

After 1995, preparations of numerous 1,10 -diphosphametallocenes (M = Ge, Sn, Pb, Ti, Zr, Hf, Tm,
Sm, Nd) were reported. Some of them were synthesized according to the usual protocol applied for
1,10 -diphosphaferrocenes. For instance, 2,5-di(t-butyl)phospholyl sandwich complexes containing
group 14 elements (M = Ge, Sn, Pb) were synthesized by reactions of the corresponding halides
MX2 (M = Sn, Pb, X = Cl; M = Ge, X = I) and the THF complex of lithium 2,5-di-(t-butyl)pho-
spholide <1999CC1273>. Syntheses of other metallocenes utilized the same type of condensation
reaction with various modifications of the starting materials. For instance, 2,5-dimenthyl and
2,5-dicyclohexyl 1,10 diphospharuthenocenes 593 [R = ()-menthyl, cyclohexyl] were synthesized by
two methods involving the condensation of the COD complexed ruthenium dichloride with:
(i) lithium phospholide 591 in THF (69% yield), (ii) P-stannylphosphole 592 in EtOH (79% yield)
<2002OM3062> (Scheme 78).
RuCl2(COD)n, THF
– + R P R
Li
R R 69%
P
591
Ru
RuCl2(COD)n, EtOH
R P R 79% R P R
SnBu3n
592 593
Scheme 78
The first NMR studies of two atropoisomeric diastereoisomers of diphospharuthenocene with

two ()-menthyl substituents at each ring have been recently reported <2003OM1783>.
Several C2-symmetric bis(phospholyl) adducts of group 4 metals (594, M = Ti, Zr, Hf), includ-
ing the first example of the 5-phospholyl hafnium complex 594 (M = Hf), were synthesized and
structurally characterized. These complexes underwent rac/meso isomerization in a process that
was accelerated by polar Lewis bases. The bases probably facilitated the isomerization by
stabilizing ring-slipped intermediates 595 <2001OM3453> (Equation (121)).
Ph
P
MCl2Ln
Ph
595 L = THF, PMe3
P Ph P Ph
i. ButOK, 140 °C
ii. MCl4 (0.5 equiv.), THF Cl Cl
+
M M
P M = Zr, Hf Cl Cl
ð121Þ
Ph
Ph
P P Ph
594 meso 594 rac
Several other dichlorodiphosphazirconocenes of the structure (2,5-R2C4H2P)2ZrCl2

(e.g., R = H, Ph, But, TMS) were also synthesized and used as catalysts of propylene polymer-
ization using methylaluminoxane as co-catalyst.
Modification of the metal coordination sphere of the octamethyl-1,10 -diphosphazirconocene
dichloride 596 was demonstrated by Mathey and co-workers in syntheses of three new complexes
(597–599) by trapping the transient 14e 1,10 -diphosphazirconocene with CO and alkynes (Scheme
79) <2002OM259>.
CO
CO (1 atm)
Zr
CO
597
P
Cl TMS
Mg/THF TMS C C TMS
Zr Zr
P Cl
TMS
598
596 Me C C Me
Zr
599
Zr = octamethyl-1,1′-diphosphazirconocene
Scheme 79
1,10 -Diphosphatitanocenes were synthesized by Hollis and co-workers according to the

modified procedure <1988CC770> via tin salts outlined in Equation (122) <2002CC2996>.
According to this procedure the chiral phosphatitanocene 600 was obtained from
3,4-dimethyl-1-phenylphosphole in a multistep reaction in 63–75% yield.
P Ph
i. ButOK, 140 °C
ii. Me3SnCl, THF
iii. TiCl4 Cl
Ti ð122Þ
63–75% Cl
P
Ph
P
Ph
600
Hollis and co-workers <2003OM1432> showed further the first example of a low-valent
phosphatitanocene, a structural analog of the zirconocene 596. They applied Mathey’s and
co-workers’ <2002OM259> reduction conditions using magnesium under an atmosphere of CO
at 40 C to produce the titanocene dicarbonyl analog of 597.
Condensation of thulium diiodide in THF with two molar excess of the potassium 2,5-di-
t-butyl-3,4-dimethylphospholide afforded a dark blue-green solid of structure 601 established by
X-ray analysis <2002CC1646> (Equation (123)).
But
P
– TmI2(THF)3, Et2O, 25 °C
2 But But But
P Tm ð123Þ
THF
K+
But
P But
601
Nief and co-workers synthesized unsolvated bis(phospholyl)neodymium(III) and samarium(III)

chlorides 603 (Ln = Nd, Sm) in the reaction of 2,3,4,5-tetramethylphospholyl potassium with the
THF solvated neodymium and samarium trichlorides 602 (Ln = Nd, Sm) in 57% and 63% yields,
respectively <1999EJI1041> (Scheme 80). Crystallization of the samarium complex 603
(Ln = Sm) from diethyl ether gave a polymeric ether solvate 604 which was characterized by
X-ray crystallography. The triply bridging chlorine atoms (between the Sm and K atoms) were
responsible for the polymeric chain that linked the organosamarium residues.
P
P
2 C4Me4PK Et2O
LnCl3(THF)x Cl
Ln Sm P
Ln = Nd, Sm Ln = Sm
602 K Cl
Cl Cl
P K
OEt2
603 604
Scheme 80
(vii) Metal complexes

1,10 -Diphosphaferrocene upon treatment with 2 equiv. of rhenium carbonyl/trimethylamine
N-oxide afforded the dirhenium complex 605 in 80% yield <2002JOM(645)268> (Equation (124)).
P (OC)9Re2 P
2Re2(CO)10 /Me3NO
Fe Fe
ð124Þ
80%
P (OC)9Re2 P
605
On the other hand, it was shown by Zakrzewski and co-workers <1998OM5880> that the
monoacetylated 1,10 -diphosphaferrocene 606, when treated with 1 equiv. of W(CO)5THF under
photochemical conditions, gave a mixture of the products in which the W(CO)5 moiety was
coordinated to either P(10 ) or P(1) in a 7:1 ratio. With two or more equivalents of
W(CO)5THF, the bis-W(CO)5 adduct 607 was obtained in 88% yield (Equation (125)).
O O
OH OH
O O
P (OC)5W P
W(CO)5THF ð125Þ
(2 equiv.)
Fe Fe
P (OC)5W P
606 607
The reaction of octaethyldiphosphaferrocene 608 with Pd(DBA)2 yielded a green complex 609
<200OM4899> (Equation (126)). The reaction of 608 with Ni(COD)2 gave the complex of
analogous structure which was too oxygen sensitive to be isolated.
R R
P
R R Pd(DBA)2, THF
P
rt, 30 min P
R Fe R Fe P Pd Fe
ð126Þ
P
R R
P
608 R = Et 609
The neutral octaethyl and octapropyldiphosphaferrocene ligand 608 (R = Et, Prn) reacted with
gallium chloride at rt to afford cationic gallium complexes <2002NJC1378> (Equation (127)).
R
R R
R GaCl4–
P
R R
P
GaCl3, CH2Cl2, 25 °C + Cl
R Fe R R Fe R Ga ð127Þ
R Cl
R P
R R
P
R
608 R = Et, Prn R
Theoretical studies showed that bonding of the phosphaferrocene ligand to the [GaCl2]+
fragment involved the lone pairs of phosphorus and contribution of the PFe bond. The starting
ligands 608 (R = Et, Prn) were prepared by condensation of the corresponding lithium phospho-
lides (2 equiv.) with FeCl2 (1 equiv.) in THF.
1,10 -Diphosphazirconocene 610 (M = Zr) obtained in 80% yield as a 63:37 mixture of racemic
and meso-isomers <2000JA11737> was used for the synthesis of the binap complex with rhodium
bound with phospholyl phosphorus. In a similar way C2-symmetric bis(phospholyl)hafnium
adduct (M = Hf) was obtained in 25% yield after recrystallization from pentane/Et2O
<2001OM3453>. The bent relationship between the two phospholyl rings in the complex 610-
rac allowed the synthesis of the new bidentate molybdenium complex 611 <2001OM3453>
(Equation (128)).
Ph Ph
P P
(CO)4Mo(NBD) (OC)4Mo
MCl2 MCl2 ð128Þ
M = Zr; 97%
P P
Ph NBD - norbornadiene Ph
610-rac 611
4.22.5 FUNCTIONS CONTAINING TWO ARSENIC, ANTIMONY OR BISMUTH

FUNCTIONS, R12C¼C(AsR2)2, etc.
No further advances have occurred in this area since the publication of chapter 4.22.5 in 1995
<1995COFGT(4)1021>.
4.22.6 FUNCTIONS CONTAINING TWO DISSIMILAR COMBINATIONS OF ARSENIC,

ANTIMONY OR BISMUTH, R12C¼C(AsR22)SbR34, etc.
No further advances have occurred in this area since the publication of chapter 4.22.6 in COFGT
(1995) <1995COFGT(4)1021>.
4.22.7 FUNCTIONS CONTAINING ARSENIC, ANTIMONY OR BISMUTH WITH A

METALLOID, R12C¼C(AsR22)SiR33, etc.
The reaction of zirconocene dichloride with 2 equiv. of n-butyllithium and 1-trimethylsilylpropyne
yielded a yellow 1,1-bis(cyclopentadienyl)-3,4-dimethyl-2,5-bis(trimethylsilyl)zirconacyclopenta-
2,4-diene 612. The metathesis reaction with AsCl3 yielded nearly quantitatively 1-chloroarsole
613 without chlorocyclopentadienyl exchange as in the case of the corresponding 1-chlorophos-
pholes <1999OM2491> (Scheme 81).
AsCl3, THF
78% MeLi
TMS TMS TMS TMS Et2O TMS TMS
Zr As As
Cp2 88%
Cl Me
612 613 614
Scheme 81
The AsCl/AsMe conversion of 613 to 614 was carried out with MeLi <2001OM3884>. Earlier,
Nief and Mathey reported the instability of chloroarsoles 613 <1993POL19>. The reduction of the latter
with distilled calcium gave the dimeric trifunctional (As, Si, Ca) complex 615 (Equation (129)).
TMS
As
TMS THF THF
TMS
Ca Cl
Cl As Ca
Ca
Cl ð129Þ
TMS THF TMS
THF
As
TMS
613 615
The silylated arsolylthulium(II) complex 617 was obtained by Nief and co-workers in the
condensation reaction of 2 equiv. of potassium 2,5-bis(trimethylsilyl)-3,4-dimethylarsolide 616
and a THF complex of TmI2 in diethyl ether <2002CC1646> (Equation (130)).
TMS
As
TmI2(THF)3, Et2O, 25 °C
– TMS
TMS TMS Tm
As TMS THF ð130Þ
K+
As
TMS
616 617
Silylated arsinines (618a,b) were prepared by Le Floch and co-wokers from the 1,3,2-diazarsinine
and silylated alkynes by the cycloaddition–cycloreversion sequence in 40% yield (Equation (131))
<1997OM4089>.
R1C CR2 (2 equiv.)
toluene, ∆ R2 R2
40%
N N
As R1 As R1 ð131Þ
618a R1 = TMS, R2 = H; 90 min, 95 °C

b R1 = R2 = TMS; 12 h, 125 °C
The Sn/As metathesis reaction of the stannacyclohexadiene 619 with AsCl3 gave 1-chloroarsacy-
clohexadiene 620 from which 2-trimethylsilyl-1-arsanaphthalene 621 was prepared (Scheme 82)
<2001OM2109>.
DBU, pentane
AsCl3, pentane –78 °C
93% 79%
Sn TMS As TMS As TMS
Me2
Cl
619 621
620
Scheme 82
Condensation of various aromatic acyclic dibromo- or monobromo derivatives with dichloro-

phenylarsine in the presence of strong and bulky bases led to formation of new 7- and
5-membered rings in bicyclic systems 622 and 624, respectively, as a result of a multistage reaction
consisting of metallation and cyclization. Thus, treatment of (Z,Z)-1-(bromophenyl)-4-(2-bromo-
phenyl)-1-trimethylsilyl-1,3-butadiene 224 in the presence of ButLi with dichlorophenylarsine gave
7-membered 5-phenyl-6-trimethylsilyl-5H-5-arsabenzocycloheptene 622 <1999CPB1108>
(Equation (132)). The reaction of 1-bromo-2-(3-bromothiophen-2-yl)vinyl]trimethylsilane 623
with the same arsine in the presence of ButLi afforded 4-phenyl-5-trimethylsilyl-4H-1-thia-
4-arsapentalene 624 <1997H1891> (Equation (133)). Analogously, 6-phenyl-5-trimethylsilyl-
6H-1-thia-6-arsapentalene was prepared from (Z)-1-bromo-2-thiophen-3-yl-vinyl)trimethylsilane
or (Z)-[1-bromo-2-(2-bromothiophen-3-yl]trimethylsilane <1997H1891>.
i. ButLi, Et2O, –80 to –20 °C

ii. PhAsCl2
28% ð132Þ
Br Br TMS As
Ph TMS
224 622
i. ButLi, Et2O, –80 °C

S TMS S
ii. PhAsCl2
TMS
Br As ð133Þ
Br
Ph
623 624
As far as chiral Sb(III) compounds are concerned, only a few examples of Sb-chiral stibafluor-
enes and triarylstibines with hydroxycarbonyl and amino groups are reported. The first example
of a resolution of ()-1-phenyl-2-trimethylsilylstibindole 625 was presented by Kurita and
co-workers <2000CC191>. They separated a mixture of diastereomeric Pd (II) complexes 627
having the bimetallic PdSb bonding, on treatment of racemic 625 with 0.5 equiv. of
di--chlorobis{(S)-2-1[1-(dimethylamino)ethyl]phenyl-CN}palladium(II) 626 (Scheme 83). It
resulted in a coordination of Sb to Pd to give quantitatively a 1:1 mixture of complexes 627 which

were separated chromatographically on silica gel. Decomplexation to give optically pure ()-628
and (+)-628 was carried out with triphenylphosphine.
Me
Me
CH2Cl2, 5 min, rt
+ N
Me 100%
Sb TMS Pd
Ph Cl
(±)-625 (S)-626
Me Sb TMS
Me i. Separation Ph
N ii. PPh3, CH2Cl2 628 (–)-SSb
Pd Me rt, 30 min
Ph +
100%
TMS Sb
Sb TMS
627 SC,RSb
+ Ph
SC,RSb
628 (+)-RSb
Scheme 83
4.22.8 FUNCTIONS CONTAINING ARSENIC, ANTIMONY OR BISMUTH AND

A METAL, R12C¼C(AsR22)M
Further progress has been made in the synthesis of new trifunctional compounds containing As,
Si, and a metal. Some of these methods have already been reviewed earlier (Section 4.22.7).
Thus, dimeric 3,4-dimethyl-2,5-bis(trimethylsilyl)-1-arsacyclopentadienyl-bis(tetrahydrofuran-O)
calcium chloride 615 was synthesized as the trifunctional (As, Si, Ca) calcium arsolide derivative
from 1-chloro-3,4-dimethyl-2,5-bis(trimethylsilyl)arsole (Equation (129)) <1999OM2491>.
2,20 ,5,50 -Tetra(trimethylsilyl)-3,30 ,4,40 -tetramethyl-1,10 -diarsathuliumocene 617 was another
example of a trifunctional (As, Si, Tm) reagent (Equation (130)) <2002CC1646>. Ashe, III and
co-workers synthesized a (As, Si, Mo) trifunctional complex converting 2-trimethylsilyl-1-arsa-
naphthalene to the dark red tricarbonyl molybdenum compound 629 which in the X-ray analysis
showed that the metal was 6-bound to the C5As ring <2001OM2109> (Equation (134)).
Py3Mo(CO)3, Et2O.BF3
Mo(CO)3
97% ð134Þ
As TMS As TMS
621 629
Treatment of 2-(diphenylarsino)-N,N-dimethylaminomethylferrocene 630 with n-butyllithium in

diethyl ether followed by reaction of the resulting monolithium derivative with diphenylchloro-
arsine gave 2,5-bis(diphenylarsino)-N,N-dimethylaminomethylferrocene 631 <2001MI1496>
(Equation (135)). The reaction of the dilithio compound derived from 631 with 2 equiv. of
diphenylchloroarsine afforded 2,5,10 -tris(diphenylarsino)-N,N-dimethylaminomethylferrocene.
CH2NMe2 CH2NMe2
AsPh2 Ph2As AsPh2
i. BunLi,
Et2O
ii. Ph2AsCl
Fe Fe ð135Þ
630 631
Nief and Ricard synthesized the samarium complex 633 from bis(pentamethylcyclopenta-
dienyl)samarium and the As–As precursor 632 <2001OM3884> (Equation (136)). In the new complex
one arsolyl ring was coordinated to both samarium in a :1, 5 fashion, whereas the other was only
1-bonded to one samarium.
Toluene
2 [Cp*Sm]
2 + As As 2 Cp2*Sm ð136Þ
As 2
632 633
Bis(6-arsenine)titanium 634a and bis(6-arsenine) vanadium 634b in addition to the earlier

known bis(6-arsenine) chromium 634c were obtained by Elschenbroich and co-workers
<1999OM1495> by means of a metal–ligand vapor co-condensation technique employing an
electron beam heated metal evaporation source (Equation (137)).
As
2 C5H5As (gas) + M (gas) M
ð137Þ
As
634a M = Ti
bM=V
c M = Cr
The 6-As tricarbonylchromium complex 635 and the 1-As pentacarbonyl complex 636 were
also prepared. The Cr(CO)5 moiety was easily displaced by THF, demonstrating the liability of
the 1 coordination. The competition reaction of the Cr vapor with C6H6 and C5H5As showed
that the 6-arsenine complexes were strongly favored <1999OM1495> (Scheme 84).
Cr(CO)5
100 °C, Bun2O n-Hexane
C5H5As + Cr(CO)6 As As Cr(CO)5
–3CO
Cr Cr
(CO)3 (CO)3
635 636
Scheme 84
The novel enantiomerically pure organoantimony-6-arenechromium complex 638 possessing a

C-chiral amine moiety was prepared from (S)-(-methylbenzyl)dimethylamine via ortho-lithiation
of its chromium complex 637 <2002CPB1404> (Equation (138)).
Me Cr(CO)3 Cr(CO)3
Cr(CO)6
H H
Bun2O/ THF Me i, ii Me
NMe2
(S)
NMe2 NMe2 ð138Þ
Sb(p -Tol)2
637 638
i. ButLi; ii. p -Tol2SbBr, Et2O
Kirchner and co-workers investigated reactions of the half-sandwich ruthenium complex 639
with triphenylphosphine, arsine, stibine, and bismuthine <2002JOM(649)55>. In the first three
cases the RuP, RuAs and RuSb coordination dominated while in the case of bismuthine the
competitive 6-arene coordination was favored due to the weakest RuBi interaction in the series
P>As>Sb>Bi. Thus, the reaction of 639 with 1 equiv. of BiPh3 gave a mixture of two com-
pounds, 640 and 641 (Equation (139)). The compound 640 could not be isolated from the reaction
mixture in pure form and 641 was synthesized independently by reaction of 639 and 0.5 equiv. of
BiPh3 in 86% yield.
+ PF6–
Ru
+ PF6– BiPh2
640
BiPh3 (1 equiv.)
Ru + ð139Þ
MeCN NCMe 2+
2PF6–
NCMe
639
Bi
Ru Ru
641
The same authors <2002JOM(649)55> carried out the thermolysis of the complex 642 in
nitromethane at 80 C for 6 h and isolated the complex 643 in 65% yield (Equation (140)).
2+
MeNO2, 80 °C, 6 h
Ru Ru Ph Ru
65% ð140Þ
MeCN SbPh3 MeCN Sb
NCMe Ph3Sb
Ph
642 643
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Biographical sketch
Piotr Bałczewski was born in Łódź, studied at Józef Drabowicz was born in Działosyzn,
the Technical University of Łódź and partly at Poland in 1946, studied at the University of
the Center of Molecular and Macromolecular Łódź, where he obtained an M.Sc. in 1969. He
Studies (CM&MS), Polish Academy of has been employed since at the Centre of
Sciences (PAS), Łódź, where he obtained a Molecular and Macromolecular Studies, Pol-
B.Sc., M.Sc. Engrng. in 1979 and his Ph.D ish Academy of Sciences in Łódź. He obtained
in 1985, both under the direction of Professor his Ph.D. under the supervision of Professor
M. Mikołajczyk. In the meantime 1979–1982 M. Mikołajczyk from the Institute of Organic
he did part-time studies at the Institute of Chemistry, PAS in 1975 and habiliation from
Organic Chemistry, PAS, Warsaw. After the University of Łódź in 1987. He did his
spending 1989–1991 in the laboratories of postdoctoral studies at the University of
Professor J.A. Joule, Manchester, England, Tsukuba, Japan, working with Professor
he returned to CM&MS, Łódź, where he S. Oae (1976–1977) and worked as a Research
made his habilitation in 1997. Subsequently, Associate with Professor J. C. Martin at Van-
he received a position of a docent in 1999 and derbilt University (Nashville-USA (1989–
(2001–) took up his present duties as Head of 1900)). Since 1988 he has been a Professor at
Laboratory of Metallo- & Metalloidoorganic the Department of Heteroorganic Chemistry,
Chemistry, CM&MS, PAS. Since 2002 he has CMMS PAS. Since 2002 he has simulta-
also been a Professor of Pedagogical Univer- neously been teaching at the Pedagogical Uni-
sity of Cze˛stochowa. His scientific interests versity of Czestochowa. He is an author or
include heteroatom (mainly phosphorus) and co-author of over 120 publications, including
organometallic chemistry, in particular, appli- one book and several book chapters, among
cation in total synthesis of biologically active them in ‘‘Houben-Weyl’’ and the Patai series.
compounds, free radical and carbanion chem- His scientific interests include chemistry and
istry, mechanistic aspects of organic reactions. stereochemistry of heteroorganic compounds,
synthetic methodology, and asymmetric
synthesis.
Aldona Szadowiak was born in Łódź, studied _

Remigiusz Zurawiński was born in Łódź,
at Technical University of Łódź, where she Poland in 1961. He obtained an M.Sc. in
obtained an M.Sc. in 1999. Since then she chemistry from the Technical University of
has been working at the Centre of Molecular Łódź in 1985. He has been employed since at
and Macromolecular Studies, Polish Academy the Center of Molecular and Macromolecular
of Sciences. She is completing her Ph.D. thesis Studies, Polish Academy of Sciences, where he
under the direction of Professor P. Bałczewski. received his Ph.D. in 1997 under the direction
Her scientific interests include stereochemistry of Professor M. Mikołajczyk. He spent seven
of organophosphorus compounds and free months as a postdoctoral fellow in Labora-
radical chemistry. In particular, she is inter- toire de Chimie de Coordination du CNRS,
ested in the heteroatom transfer addition reac- Toulouse, France, working with Professor
tion of heterosubstituted phosphonates and R. Chauvin and one year at the University of
related compounds. Tokyo, Japan, in the laboratory of Professor
T. Kawashima. He presently holds a position
of Assistant Professor at the Department of
Heterooraganic Chemistry, CMMS PAS. His
research interests include total synthesis of
biologically active compounds, synthesis of
new chiral ligands for asymmetric catalysis,
and application of enzymes in the synthesis
of chiral heteroorganic derivatives.
Piotr Kiełbasinski was born in Łódź, Poland Marian Mikołajczyk was born in Kłodawa,
in 1948, studied at the Technical University of Poland and studied chemistry at Technical
Łódź, where he obtained an M.Sc. in 1970. He University (TU) in Łódź, where he obtained
has been employed since at the Center of his Ph.D. in 1963 under the guidance of Pro-
Molecular and Macromolecular Studies, Pol- fessor J. Michalski. In 1967 he did habilita-
ish Academy of Sciences, where he obtained tion. From 1960 to 1963 he worked in the
his Ph.D. under the supervision of Professor Institute of Organic Synthesis of the TU in
M. Mikołajczyk in 1977 and habilitation in Łódź. In 1964 he moved to the Institute of
2000. He did his postdoctoral studies in the Organic Chemistry of the Polish Academy of
University of Nijmegan, The Netherlands, Sciences (PAS) in Łódź. After spending one
working with Professor B. Zwanenburg year (1968/1969) in the Max-Planck Institute
(1977–1978). He presently holds a position of of Experimental Medicine, Göttingen, in the
Associate Professor at the Department of Het- group of Professor F. Cramer he returned to
eroorganic Chemistry, CMMS PAS. He is an Łódź. Since 1974 he has been Professor of
author or co-author of over 60 publications, Organic Chemistry in the Centre of Molecular
including one book and several book chap- and Macromolecular Studies of PAS in Łódź
ters, among them in ‘‘Houben-Weyl’’ and the and Head of the Department of Heteroor-
Patai series. His scientific interests include ganic Chemistry and from 1991 director of
chemistry and stereochemistry of organosulfur the Centre. His scientific interests are in the
and organophosphorus compounds and appli- area of phosphorus and sulfur chemistry,
cation of enzymes in the synthesis of chiral organic chemistry, biocatalysis, and stereo-
heteroorganic derivatives. chemistry. He has received numerous awards,
including the State Award, M. Skłodowska-
Curie Award of PAS, A. von Humboldt
Research Award and honorary doctorate
from the P. Sabatier University (Toulouse)
and Technical University (Łódź). He is a
member of PAS and the Deutsche Akademie
der Naturforscher, Leopoldina.
# 2005 Published by Elsevier Ltd Comprehensive Organic Functional Group Transformations 2

4.23
Metalloid (Si, Ge, or B) and No
Halogen, Chalcogen, or Group 15
Element; Also Functions Containing
Two Metals
S. J. COLLIER
Albany Molecular Research, Inc., Albany, NY, USA
4.23.1 FUNCTIONS CONTAINING TWO METALLOIDS 1056

4.23.1.1 Functions Bearing Two Silicons—R12C¼C(SiR23)2, etc. 1056
4.23.1.2 Functions Bearing Two Borons—R12C¼C(BR23)2, etc. 1072
4.23.1.3 Functions Bearing Two Germaniums—R12C¼C(GeR23)2, etc. 1075
4.23.1.4 Other Functions—R12C¼CSiR23BR32, etc. 1075
4.23.1.4.1 Functions containing one silicon and one boron 1075
4.23.1.4.2 Functions containing one silicon and one germanium 1080
4.23.1.4.3 Functions containing one boron and one germanium 1081
4.23.2 FUNCTIONS CONTAINING A METALLOID AND A METAL 1081
4.23.2.1 Silicon Functions—R12C¼CSiR23M 1081
4.23.2.1.1 Functions with one silicon and one group 1 metal 1081
4.23.2.1.2 Functions with one silicon and one group 2 metal 1082
4.23.2.1.3 Functions with one silicon and one transition group metal 1082
4.23.2.1.4 Functions with one silicon and one group 13 or group 14 metal 1089
4.23.2.2 Boron Functions—R12C¼CBR23M 1094
4.23.2.3 Germanium Functions—R12C¼CGeR23M 1094
4.23.3 FUNCTIONS CONTAINING A GROUP 1 METAL—R2C¼CLiM 1095
4.23.4 FUNCTIONS CONTAINING A GROUP 2 METAL (AND NO GROUP 1
METAL)—R2C¼CMgXM, etc. 1095
4.23.5 FUNCTIONS CONTAINING A TRANSITION METAL (AND NO GROUP 1 OR GROUP 2
METAL)—R2C¼CTiM, etc. 1095
4.23.6 FUNCTIONS CONTAINING A GROUP 13 OR GROUP 14 METAL
(AND NO GROUP 1, 2, OR TRANSITION METAL)—R2C¼CA1M, etc. 1096
4.23.7 OTHER METAL DERIVATIVES 1098
1055
4.23.1 FUNCTIONS CONTAINING TWO METALLOIDS
4.23.1.1 Functions Bearing Two Silicons—R12C¼C(SiR23)2, etc.

1,1-Disilyl alkenes have been studied in detail and many methods for their preparation have been
reported. Previously reviewed methods include the hydrosilylation of alkynyl silanes; treatment of
silyl alkynes with metallosilyl species; diboration of disilylalkynes; photo chemical rearrangement
of alkynyl disilanes; displacement of halogen by a silyl group, via metal–halogen exchange;
various reactions of tris(TMS)methyllithium with electrophiles; base-mediated reactions of diha-
lodisilyl methanes; cleavage of 1,2-disilabut-3-enes with halogen; various reactions of silirenes;
reactions of siliranes with alkynes and the catalytic disilylation of alkynes. 1,1-Disilyl allenes have
been prepared through the treatment of silyleneynes with Li and TMSCl; silylcupration of
silylpropargyl halides; rearrangement of alkynyl disilanes; propargylic deprotonation of silyl
alkynes followed by treatment with silyl halides and the polysilylation of butynoic acid with
TMSCl and BuLi <1995COFGT(4)1043>.
The hydrosilylation approach has found continued use for the preparation of 1,1-disilyl alkenes,
and several different catalysts have proven effective for the regioselective hydrosilylation of silylalk-
ynes, generally favoring 1,1-disilylalkene products 1 over 1,2-disilylalkenes 2 (Scheme 1). For
example, organolanthanide and group 3 metallocene complexes have been studied for the hydro-
silylation of a wide range of 1-silyl alkynes with PhSiH3 (Scheme 1) <2002JOM(647)225>.
Increasing the steric bulk of the silyl group on the alkyne was found to increase the selectivity of
the reaction, but use of a more sterically demanding catalyst required higher reaction temperatures
and/or times. Under these more forcing conditions, yields of the required product were lowered due
to competing hydrogenation and isomerization reactions. The mechanism of the reaction and the
steric and electronic effects of substituents on the alkyne unit have been discussed in some detail,
but generally the regioselectivity is controlled by the electronics of the alkynyl silane. Terminal
alkynes are incompatible with these catalyst systems due to the acidity of the alkynic proton. The
use of Pt on carbon as a catalyst for the addition of a range of silanes has also been reported
<2002JOM(645)1>, although formation of products of type 2 was favored over type 1. With
terminal alkynes, 1,2-disilyl alkenes were formed exclusively, and the reaction failed with bis-
(TMS)ethyne due to the steric and/or electronic deactivation of the alkyne function by the two
TMS groups. Other catalysts including (Cp*)RuH3(PPh3) <2002OL2825> and Pt(CH2CHSi-
Me2)2O + PBut3 <2002JOC2645> also catalyze similar hydrosilylations.
SiPh3 Ph3Si
Cat.
R1 SiR23 + HSiPh3 +
27–84% R1 SiR23 R1 SiR32
1 2
R1 = n-octyl, EtCHMeCH2, C6H11, Ph, Ph(CH2)2;

2
SiR3 = SiMe2H, SiPri2H;
Cat. = Cp*2YMe.THF, [Cp2TMSYMe]2; [Cp2TMSLuMe]2
Ratio = 1:1 to exclusively 1
Scheme 1
The effect of different catalysts on the regioselectivity of hydrosilylation of cis- and trans-1,4-
bis(TMS)-3-buten-1-ynes 3 and 4 has been studied (Scheme 2). Four kinds of regio- and
stereoisomers 5–8 can be obtained with high selectivities with the correct choice of catalyst and
3 or 4. Some examples are given in Table 1. Other catalysts were also examined and in some
cases gave highly selective reactions, although extended reaction times were often required
<1997CL623, 2000JOM(609)130>. During studies on the formation of arylchromium complexes
of alkynes containing remote phenylsilyl hydride groups, intramolecular hydrosilylation was
noted, although the reaction was catalyzed by platinum residues left over from the substrate
preparation <1997OM5048>. Chiral 1,1-disilylallenes have been prepared in low to very low
yields and very low ee through the hydrosilylation of 1,4-bis(TMS)buta-1,3-diyne with diphenyl-
silane using chiral nickel complexes <2000JOM(603)116>.
SiR3
TMS R3Si
C
TMS
TMS TMS TMS
1.1 equiv. HSiR3 TMS
3 5 6
0.5 mol.% cat.
OR
80 °C, heat
TMS R3Si
TMS
TMS R3Si TMS
TMS TMS
4 7 8
Scheme 2
Table 1 Product ratios from hydrosilylation of (3) and (4)

Product ratio
Eneyne HSiR3 Catalyst Time 5 6 7 8 Yield (%)
3 HSiMe2Ph H2PtCl66H2O 2h 96 4 0 0 73
4 HSiMe2Ph H2PtCl66H2O 3h 0 93 0 7 100
3 HSiMe2Ph RhH(CO)(PPh3)3 19 h 0 0 95 5 98
4 HSiMe2Ph RhH(CO)(PPh3)3 19 h 10 0 9 81 96
3 HSiMePh2 RhH(CO)(PPh3)3 24 h 4 0 0 96 99
In contrast to intermolecular transition metal-catalyzed hydrosilylation, the Lewis acid-cata-

lyzed intramolecular hydrosilylation of alkynes gives trans hydrosilylation products (Scheme 3).
Silyl alkynes bearing a tethered silyl hydride function (e.g., 9 and 10) generally give cyclic disilyl
alkenes (e.g., 11–13) with a range of ring sizes via endo–trans addition catalyzed by AlCl3
<2000JOC8919>. The intramolecular trans-vinylsilylation of a silyl alkyne can also be effected
in high yield using EtAlCl2 (Equation (1)) <1999JA3797>. Treatment of 1-TMS-ethyne with
allyltrimethylsilane in the presence of HfCl4 gives the allylsilylation product 14 via the cationic
intermediate 15 (Scheme 4) <1997JA6781>. The silylcupration of silyl alkynes provides inter-
mediate 1-silyl-1-cuproalkenes (e.g., 16) via syn addition (Scheme 5). These intermediates can
be quenched with electrophiles to give the corresponding alkene derivatives 17 and 18
<2001JOC1961>.
TMS
HR1R2Si Cat.
TMS SiR1R2
3
0 °C to rt
9 CH2Cl2
11
R1 = R2 = Me, 96%
R1 = R2 = Pri, 89%
R1 = R2 = Ph, 30% + 35% 9
R1 = Me; R2 = Ph, 86%
Cat. AlCl3 Cat. AlCl3

CH2Cl2 TMS CH2Cl2
TMS n
Si n = 0, 36%
Me2 SiMe2H n = 1, 54%
Si
n = 2, 42% Me2 TMS
12 10
13
Scheme 3
TMS
EtAlCl2 (0.5 equiv.) TMS
ð1Þ
CH2Cl2, rt, 1 day TMS
TMS 85%
TMS
HfCl4 (0.5 equiv.) Cl4Hf –
TMS +
TMS H + H
TMS
CH2Cl2, 0 °C TMS
65%
15 14
Scheme 4
i. (PhMe2Si)2CuCNLi2
TMEDA
ii. aq. NH4Cl [Cu] SiMe2Ph SiMe2Ph
TMS TMS
TMS TMS 45% TMS TMS
16 17
i. (ButPh2Si)2CuLi ButPh2Si
O
ii. aq. NH4Cl
TMS TMS O
42%
18
Scheme 5
The geminal disilylation of alkynes and alkenes has also been used to prepare disilylalkenes.
Ortho-bis(dimethylsilyl)carborane–bis(triphenylphosphine)platinum complexes 19 react with
1-hexyne to give the 1,1-disilylated product 20 (R1 = Bun, R2 = H), but 1-phenylethyne gave
products of type 21 (Scheme 6) <1999OM1818, 2000OM1216>. Complex 19 was a poor
catalyst for the reaction of free ortho-bis(dimethylsilyl)carborane 22 with alkynes, due to the
strength of the PtSi bond, but the related bis(triethylphosphine)nickel carborane complex 23
catalyzed the 1,1-disilylation of both alkynes and monosubstituted alkenes by 22. In some cases,
low levels of 1,2-disilylation products were also observed <2000OM1722>. The mechanisms of
the above reactions with alkynes and alkenes have been discussed <2000OM1722>. The nickel-
catalyzed intermolecular disilylation of 1,4-bis(TMS)buta-1,3-diyne 24 with tetramethyldisilane
gives mixtures of silole 25 and 1,4-disilacyclohexa-2,5-diene 26 (Equation (2)) <1995OM1089>.
Furthermore, cyclic disilane 27 reacts with alkynes to give cyclic disilylation products 28
in the presence of Pd catalysts (Scheme 7) <1999OM3792>. When diyne 24 was used, a cyclic
tetrasilylbutatriene 29 was obtained (Scheme 7). The Pd(OAc)2/1,1,3,3-tetramethylbutylisocya-
nide-catalyzed high-pressure intramolecular bis-silylation of cyclic silylalkyne 30 (M = Si) gave 31
(M = Si) (Equation (3)) <1995BCJ2981>. However, 1,1,2,2-tetrakis-TMS-ethene could not be
prepared through the analogous intermolecular bis-silylation of bis(TMS)ethyne with hexamethyl-
disilane. The Ru-catalyzed silylation of ethene with bis(disubstituted-silyl)alkenes gives low yields
of 1:1 disilylethene adducts, along with mixtures of 2:1 adducts and further reduced species
<2000OM5750>.
Me2 Me2
Si Si R2 SiMe2H
M(L)2
Si
Me2 Si R1 SiMe2H
Me2
22
21
19 M(L)2 = Pt(PPh3)2
23 M(L)2 = Ni(PEt3)2
R1 Me2 R1
19 Si R2 22 R1
OR
54% Si R1 Cat. 23 R2
R2 Me2 R2
R1 = Bun;
20
R2 = H
Alkynes: Alkenes:
R1 = Bun; R2 = H: 71% R1 = p -MeOC6H4; R2 = H: 52%
R1 = Ph; R2 = TMS: 62% R1 = Me(CH2)5; R2 = H: 45%

R1 = TMS; R2 = TMS: 66% R1 = Ph; R2 = H: 76% (stochiometric 23)
Scheme 6
TMS TMS TMS

HMe2SiSiMe2H Me2
TMS Si
NiCl2(PEt3)2
TMS TMS +
Si TMS ð2Þ
24 TMS TMS Me2
Si TMS
Me2
25 26
R1 R2 TMS TMS
Et2Si SiEt2 C C
Et2Si SiEt2 Et2Si SiEt2
R1 R2 24
Cat. PdCl2(PPh3)2 Cat. PdCl2(PPh3)2

BCl3 TMS TMS 66%
TMS TMS Si TMS TMS
Si Me2 Si
Me2 Me2
28 27
R1 = Ph; R2 = H; 74% 29
R1 = Bun; R2 = H; 93%
1 = Ph; R2 = Ph;
R 67%
R1 = Ph; R2 = CCPh; 79%
Scheme 7
Cat. Pd(OAc)2
Me2 Me2 But Me2 Me2

NC M M
M M
ð3Þ
PhMe, 5000 bar M M
Me2M MMe2 Me2 Me2
110 °C
30 31
M = Si, Ge
An extension of the above approach involves the reaction of 3,4-benzo-1,1,2,2-tetraethyl-

1,2-disilacyclobut-3-ene 32 in the presence of catalytic Ni(PEt3)4 to give a transient intermediate
o-quinodisilane-nickel complex 33. In the presence of terminally unsubstituted alkenes cyclic
benzodisilacyclopentenes 34 are formed in low-to-moderate yield, accompanied by a range of
by-products, depending upon the alkene used (Scheme 8) <1995OM114>. The reaction of 32 with
alkynes gives cyclic benzodisilacyclopentenes 35 and disilacyclohexadiene 36 under similar con-
ditions (Scheme 8) <1995JOM(499)35>. Use of bis(TMS)ethyne led to a more complex reaction
mixture, with trans-silylation products 37 and 38 accompanying 35 and 36 <1996OM1101>. The
mechanisms of the above reactions have been discussed in detail. When some of the above
reactions were run in the presence of silyl hydrides, competing hydrosilylation of the alkynes
was noted.
R1
R1 i. +
Et2 i. + Et2 Et2
Si R1 TMS Si R1 Si R1
R2 SiEt2
+
SiEt2
Si R2 Si TMS Si TMS
Et2 Et2 Et2
32
34 35 36
21–29% 10–58%
R1 = H; R2 = Ph, (CH2)3Me, H:7–52%
R1 = Ph, (CH2)3Me, TMS
R1 = R2 = Ph:55%
Et2 Et2 Et2 Et2

SiEt2 Si Si Si Si
Ni(PEt)2
SiEt2 Si Si Si Si
Et2 Et2 Et2 Et2
33 37 38
i. Cat. Ni(PEt3)4, 150 °C, 24 h, heat
Scheme 8
1,1-Organoboration of 1,2-disilyl alkynes containing one or more hydrosilane units gives 1,1-
disilyl-2-boryl alkenes containing novel SiHB bridges. The treatment of alkyne 39 (R1 = Me)
with triallylborane gave 40 under mild conditions (Scheme 9) <1999AG(E)124>. Compound 40
contains a novel SiHB bridge, confirmed through 1H, 11B, and 29Si NMR and IR, and can
undergo further reaction between the SiH moiety and the C¼C double bonds of the allyl unit.
Thus, 41 can be formed via intramolecular hydrosilylation, which proceeds under remarkably
mild conditions in the absence of any catalyst. It is thought that the SiHB bridge may be a
prerequisite for such a mild reaction. With 41 (R1 = Me), still further rearrangement occurred
during attempts to distil, yielding 42 after a 1,1-deorganoboration–1,1-organoboration sequence,
whereas 41 (R1 = H) did not undergo further reaction. In contrast, much more forcing conditions
were required to perform the analogous reaction using BEt3, to give 43.
H H
Et2B SiMe2 SiMe2R1 All2B SiMe2 AllB SiMe2
ii. i.
SiMe3 SiMe2R1 R1 = Me, H SiMe2R1
R1 = Me R1 = Me, H
SiMe2H
43 39 40 41
R1 = Me
All = allyl
SiMe2
All2B TMS
i. BAll3, rt, 0.5–1 h; ii. BEt3, CHCl3, reflux,10 h 42
Scheme 9
When poly(silyl alkynes) such as 44 are treated with triethylborane, 2-silylsilole derivatives
such as 45 and polysiloles such as 46 are often isolated after a protracted reaction under some-
what forcing conditions via a series of annulations giving discrete silole intermediates (Equation (4))
<1999JOM(577)82>. The 1,1-hydroboration of 1,2-disilyl alkynes can also give 1,1-disilyl alkenes
via a silyl migration; thus, the treatment of 1,2-bis(TMS)ethyne with 6-aza-nido-decaboranes gives
1,1-hydroboration resulting in the corresponding 9-[2,2-bis(TMS)alkenyl]-6-aza-nido-decaboranes
in good yields (84–90%) <1995CB947>.
Me2 Me2 Me Me2

2
Me2Si Si SiMe2 Si Si Si
BEt3 Me2Si TMS Me2Si SiMe2
Me3Sn +
Very Slow B Me3Sn TMS ð4Þ
Et Et
SnMe3 TMS quant. Et Et BEt2
44 45 2:3
46
A new approach to 1,1-disilyl alkenes involves a ruthenium-catalyzed ring-closing reaction of

,!-bis(vinylsilyl) compounds and a range of cyclic 1,1-disilylethenes have been prepared in
good-to-high yield with excellent regioselectivities using this method (Table 2) <1998CC699>.
Only small amounts of intermolecular coupled products were observed, although when the
chain length of the aliphatic spacer between the silyl groups was 10 methylene units, the
opposite regioselectivity was observed, giving the (E)-1,2-disilyl alkene product. Two catalyst
precursors, [RuCl(CO)(PPh3)3(H)] or Werner’s hydride, [RuCl(CO)(PPri3)2(H)], were found to
be effective for this transformation, and generally the latter is more active. The mechanism of
the reaction is of some note, as it does not proceed via a Grubbs-type ring-closing metathesis, as
this would not give the observed 1,1-disilyl alkene. An intramolecular insertion—-elimination
mechanism—is thought to operate, resulting in a disproportionation of the ,!-bis(vinylsilyl)
species. The intermolecular self-disproportionation of vinyltrimethylsilane 47 has also been stu-
died (Equation (5)), and the regioselectivity of the reaction is often poor, leading to mixtures of 48
and 49. It is thought that the regioselectivity is controlled by the direction of insertion of the
second alkene unit into the RuSi bond of the initial Ru–vinylsilane intermediate. In a related
reaction, heating of the stable bis(2-vinyltrimethylsilane)Cp*Rh complex at 140 C in the
presence of excess vinyltrimethylsilane 47 gave 80% conversion of 47 to 48 (28%) and 49
(72%) after 1 week. Slow degradation of the Rh complex was noted as the reaction proceeded
<1999JA4385>.
Table 2 Cyclic 1,1-disilylalkenes via Ru-catalyzed ring closing of dienes

Starting material Product Catalysta Conditions Yield (%)
Me2 Me2
Si Si
Si
A PhMe, 80 C; 24 h 87 (glc)
Si
Me2 Me2
Me2 Me2
Si Si
Me2Si O O
O O SiMe2
O A THF, 100 C; 15 h 75 (isolated)
Me2Si O
O SiMe2 O
Si Si
Me2 Me2
Me2 Me2
Si Si
Si
B THF, 60 C; 24 h 83 (isolated)
Si
Me2 Me2
Me2 SiMe2
Si
SiMe2 A PhMe, 80 C; 25 h 97 (glc)
Si
Me2
Me2Si SiMe2
(H2C)10
(H2C)10 B PhMe, 110 C; 42 h 76 (isolated)
Me2Si SiMe2
a
Catalyst A = [RuCl(CO)(PPh3)3(H)]; catalyst B = [RuCl(CO)(PPti3)2(H)].
H i or ii TMS TMS
+
TMS –C2H4 TMS TMS
47 48 49 ð5Þ
i. Cat. RuCl(CNC6H4-4-NO2)(PPh3)3(H), PhMe, 100 °C, 20 h. Products: 48:6%; 49:42%

ii. Cat. RuCl(CO)(PPh3)3(H) + MeCN, PhMe, 100 °C, 20 h. Products: 48:35%; 49:6%
The ‘‘acyclic diene polycondensation’’ (ADPOL) of divinyl-substituted silanes and siloxanes 50 to

give poly(silylene-vinylenes) and poly(siloxylene-vinylenes) 51 has been reported (Scheme 10)
<1997TL3777>. The process is catalyzed by Ru or Rh complexes and proceeds via splitting of a
vinylic CH bond (nonmetathetical conversion), as opposed to cleavage of the CC double bond
(metathesis). In general, cyclic and linear oligomers are initially formed during the ADPOL, but
with divinylsiloxanes 50 (R = Me2SiOSiMe2), dimers 52, 53, and 54 can be formed under mild
conditions in varying ratios, depending upon the catalyst used (Scheme 10).
Rh or Ru cat. Me
R R O
R R R= Si Si Si
x y
Me Me2 Me2
50 51
Me2Si SiMe2 Me2 Me2 Me2 Me2 Me2 Me2

O O Si Si O Si Si Si Si
O Si Si O O
Me2Si SiMe2 Me2 Me2
52 53 54
Cat.: [RhCl(COD)]2; [RhH(CO)(PPh3)3]; [RuHCl(CO)(PPh3)2]; [RuCl2(PPh3)3]; [RuCl2(CO)3]
Scheme 10
A range of polycylic 1,1-disilyl alkenes can be prepared through the intramolecular oligomerization of
macrocyclic poly(disilyl alkynes) 55 (Scheme 11). The reaction is mediated by transition metal complexes
such as Co2(CO)8 and (MeCp)Mn(CO)3 and is often performed under photochemical conditions. The
nature and ratios of the products formed is dependent on the amount and type of catalyst used and the
conditions employed, as well as the structure of the precursor. This method has been applied to a range of
poly(disilylalkynes) and examples of some of the products obtained are given in Scheme 11
<1996CL1053, 1998BCJ41, 1998BCJ1705, 2000BCJ2129, 2000BCJ1461>. Many of these compounds,
such as 56, were derivatized to their polyanionic polylithium, sodium, or potassium salt derivatives
(Equation (6)), which were characterized using X-ray crystallography among other techniques.
SiMe2 Me Me2Si n SiMe2 Me2Si SiMe2

Me2Si 2
Si Me2Si SiMe2
Me2Si SiMe2 C C
Me2Si Si
Me2
n Si Si n
SiMe2 Si Si
Me2 Me2
Me2 Me2
Me2
Si Si (CH2)n n = 1; m = 3 n = 1; m = 3
n = 2; m = 3
Me2 n = 2; m = 3
m
Me2 Me2 Me2 Me2
Si Si Me2 Me2
Si Si Si Si
55 Me2Si SiMe2
Me2Si SiMe2 Me2Si SiMe2
Me2Si SiMe2 Me2Si SiMe2 Me Si SiMe2

2
Si Si Si Si
Me2 Me2 Me2 Me2 Me2Si SiMe2
n = 1; m = 4
n = 1; m = 4 n = 1; m = 4
56
Scheme 11
Me2 Me2 2–
Si Si
Hexane
Li/THF or PhMe Me2Si SiMe2
56
100% –THF Me2Si SiMe2
ð6Þ
Si Si
Me2 Me2
[Li2(THF)n]2+
The preparation of 1,1-disilyl alkenes from 1-halo-1-silylalkenes has also found synthetic utility
<2000JPR(342)804>. Treatment of 1-iodo-1-silyl alkene 57 with ButLi, and trapping of the resulting
vinyl anion with TMSCl gave the 1,1-disilylalkene 58 (Equation (7)). 1-Bromo-1-chlorosilyl alkene 59
was subjected to magnesium–halogen exchange, in an attempt to prepare ,-silylenevinylene poly-
mers, but the major products were cyclic 1,1-disilyl alkenes 60 and 61 in a high combined yield
(Scheme 12) <1995PP501>. Interestingly, high temperature pyrolysis of 61 in a vertical flow
nitrogen system induced rearrangement to give disilacyclopentene 62 in 25% yield (Scheme 12). The
mechanism for this rearrangement has been discussed in some detail <1995JA11695>.
I i. ButLi, Et2O TMS

TMS ii. TMSI TMS
ð7Þ
50% Br
Br
57 58
Me2
Mg, THF 61 only Si
Me2Si SiMe2
+ Me2Si SiMe2
ClMe2Si Br Si 600 °C Si
Me2 Me2
59 60 61 62
20–21% 66–71% 25%
Scheme 12
The base-induced dehydrobromination of 1-bromo-1,1-disilylethanes 63 (prepared from

dibromo derivative 64) gives high yields of the corresponding 1,1-disilylethenes 65 (Scheme 13)
<2001CL956, 2002CEJ1730>. 1,1-Bis(TMS)-1,1-dibromomethanes 66 (R1 = R2 = TMS) also
react with aldehydes in the presence of excess CrCl2 to give a wide range of 1,1-bis(TMS)alkenes
67 in variable yields (Scheme 14 and Table 3) <1997JCS(P1)2279>. The reaction proceeds
under mild conditions and tolerates even enolizable aldehydes. Dichlorodisilylmethanes
68 have been used to prepare a wide range of C-substituted 1,1-disilylalkenes 69 via allylcopper
species 70. The allylcopper species 70 were prepared through an initial lithium halogen
exchange, followed by treatment with a vinylmagnesium bromide in the presence of CuCN2LiCl,
as shown in Scheme 15. After formation of 70, quenching with electrophiles gave -adducts
69 exclusively, with no evidence of -addition. Suitable electrophiles include alkyl and allyl
halides, aldehydes and ketones, acid chlorides and water, and in some cases improved results
were obtained by using TMSCl as an additive. Propargyl electrophiles gave the corresponding
allenylated product. Selected examples are given in Table 4 <2002TL2399>.
R1 R2 Me3MgLi R1 R2 DBU (2 equiv.) R2 R1 R2 Yield 65 (%)

Br Br Me Br DMF,
R1 Ph2MeSi TMS 98
64 63 90 °C, 8 h 65 Et3Si Et3Si 98
ButMe2Si TMS 85
TMS TMS 83
PhMe2Si PhMe2Si 97
Ph2MeSi Ph2MeSi 89
PhMe2Si Et3Ge 85
Scheme 13
CrCl2 TMS
RCHO + Br2CTMS2 R
DMF TMS
66 67
Scheme 14
Table 3 1,1-Bis(TMS)alkenes via CrCl2-mediated reaction of alde-

hydes with bis(TMS)dibromomethane
R Yield (67)(%) R Yield 67(%)
Ph 84 MeO2C(CH2)4 64
CH3(CH2)7 78 NC(CH2)6 70
Cy 79 MeCO(CH2)10 58
But 28 Ph 84
Me
73 38
Me
PhCH2 39
Electrophile (2 equiv.)
Ph2MeSi SiMePh2 Ph2MeSi SiMePh2
Ph2MeSi SiMePh2 i, ii Additive (3 equiv.)
R1
Cu R3
Cl Cl
–78 °C to 0 °C R1
R2 R2
68
70 69
i. BunLi (1 equiv.), THF, –78 °C, 5 min.

ii. R 1CH=CR2MgBr (1.1 equiv.), CuCN.2LiCl (1.1 equiv.), –78 °C to 0 °C, 0.5 h
Scheme 15
Table 4 Formation of 1,1-disilylalkenes via allylcopper intermediates

1
R R2 Electrophile R3 Yield 69 (%)
H H MeI Me 73
Br
H H 86
H H Br C 60
H H PhCHO CH(OH)Ph 69
O OH
H H Ph
53
Ph Ph
Ph
O OH
H H 64
O O
O
Ph H CH3COCl 73
H Ph PhCHO CH(OH)Ph 83
Me H H3O+ H 78
O
Me H PhCOCl 73
Ph
1,1-Bis-silylated allenes 71 can be synthesized in acceptable yields from phosphonoalkenes 72

through treatment with LDA and quenching with TMSCl (Equation (8)) <1995JOM(487)89>.
Disilylketenes 73 have been prepared from quenching of transient lithium ynolates 74 (prepared
through carbonylation of lithio TMSdiazomethane with CO) with a silyl halide or pseudohalide
(Scheme 16). In no case was reaction observed at the oxygen function <1996JA7634>. Subse-
quent reaction with organolithium reagents results in attack at the C¼O function to give an
enolate, which undergoes Peterson type elimination to give silylalkynes <1996SL635>. The
treatment of disilylketenes 73 with KOBut in the presence of HMPA results in selective mono-
desilylation to regenerate the silylethynolate 74. When unsymmetrical disilylketenes bearing one
TMS group were used, selective removal of the less bulky TMS group was observed. However,
when larger silyl groups were present at both positions, the desilylation was less selective. As
would be expected, quenching with silyl halides results in reformation of the disilylketenes
<2002SL1329>.
OP(O)(OEt)2 Me3Si N(TMS)2

LDA, TMSCl
N(TMS)2 C
Me
71–74% Me3Si R
R ð8Þ
72 71
R = CH=CH2, C(Me)=CH2, CH=CMe2, Ph
R3MX Yield 73 (%)

TMS CO (1 atm.) R3MX TMS Et3SiOTf 85
N2 TMS OLi C O Pr3i SiCl 62
Li –78 °C, 2 h R3M ButMe2SiOTf 76
74 Me3GeBr 43
73
Bu3SnCl 85
Scheme 16
Di-t-butylsilylene 75 can be prepared through the photolysis of hexa-t-butylcyclotrisilane 76, or

1,1-di-t-butyl-trans-2,3-dimethylsilirane 77 (Scheme 17). Excess 75 undergoes a stepwise reaction
with bis-TMS-butadiyne 24 to give bicyclic disilyl alkene 77 <1999EJI2301>. In contrast,
dimesitylsilylene 78, prepared from 79, reacted with 24 to give 80 as a mixture of cis and trans
isomers (Equation (9)). Bis(TIPS)silylene 81, obtained through pyrolysis of tris(TIPS)silane 82,
inserts into bis(TMS)ethyne to give 1,1-bis(TIPS)-2,3-bis(TMS)-1-silacycloprop-2-ene 83 in 80%
yield (Scheme 18) <1999OM3921>. Bis(silacyclopropenes) 84 can be prepared through the
thermolysis of bis(silacyclopropanes) 85 in the presence of bis-TMS-ethyne at 60 C (Equation (10)).
Heating of 84 resulted in rearrangement to various products, including disilabenzvalenes and
(But)2
Si
(But)2Si Si(But)2
76 24 TMS
75
hν Bu2t Si TMS Si(But)2 Si(But)2
46% 2 (But)
32% 2Si
(But)2 75 TMS
Si 77
Me Me
77
Scheme 17
disila(Dewar benzene) depending upon the substituents. Similar products could be obtained
through treatment with AgBF4 at room temperature <1997JA3629, 2000JA3775>.
TMS
TMS
hν 24
TMS2SiMes2 Mes2Si Mes2Si SiMes2
79 78 ð9Þ
TMS
TMS
80
17% trans
11% cis
TMS TMS
Pr3i Si
(Pr3i Si)3SiH Pr3i Si Pr3i SiH
Si + Si +
225 °C, 2.5 h Pr3i Si 80% Pr3i Si
82 TMS TMS
2,2,4-trimethylpentane
81 83
Scheme 18
TMS
R TMS TMS R
TMS
Si Si Si Si
TMS ð10Þ
R 60 °C R
43–61% TMS
85 R = Ph, Et, Me 84
Hindered 2-silylsilacyclopropenes 86, which are air stable and can be handled without
special precautions, have been prepared through the photorearrangement of alkynyl disilanes
87 (Scheme 19). Interestingly, pyrolysis of 86 (R = Ph, Ar = 2,6-(MeO)2C6H3) in the absence
of traps with continuous removal of the eliminated alkyne gave a 3-trimethylsilyl-1,2-
disilacyclobutene 88 in 28% yield along with 53% recovered 86 <2003OM2436>. Similarly,
irradiation of the aryl alkyne 89 in CH2Cl2 gives an intermediate silacyclopropene 90, which
can be trapped with acetone to give cyclic 1,1-disilyl alkene 91 (Scheme 20). Running the
reaction in benzene in the presence of MeOH gave intramolecular cyclization product 92 in
25% yield, along with other products (Scheme 20) <2001MI1202>. Studies on the thermolysis
of several 1-aryl-3-phenyl-1,2-bis(TMS)silacycloprop-2-enes 93 showed that the outcome of the
reactions is somewhat dependent upon the nature of the aryl group (Equation (11)). The
mechanisms of these transformations have been discussed in some detail. Further studies on
the high-temperature pyrolyses of 93 in the presence of alkynes have also been discussed and
the reactions of the silacyclopropenes with diphenyl methyl silane also gave disilyl alkene
derivatives <1995OM1204>. Irradiation of 1-aryl-4-(pentamethyldisilanyl)buta-1,3-diynes 94
(R1 = Ar) gives an intermediate excited triplet-state silacyclopropene 95, which undergoes
photoaddition with MeOH to give disilylalkene derivatives 96 and 97, or with aldehydes or
ketones to give dihydrooxasiloles 98 and 99 (Scheme 21) <1995MI988>. The analogous
reactions of 1,4-bis(pentamethyldisilanyl)butadiene 94 (R1 = SiMe2TMS) gave similar results,
although 4% of a 2:1 adduct was also obtained in the reaction with methanol
<1996OM2182>.
R = Ph
Ph TMS
Ar Ar Ar = 2,6-(MeO)2C6H3
hν Si
R SiAr2TMS Ar Si Si Ar
Hexane, rt
R TMS – Ph TMS Ar Ar
87 86 28% 88
R = Ph, Ar = Mes
R = TMS, Ar = Mes
R = Ph, Ar = 2,6-(MeO)2C6H3
Scheme 19
Me2
TMS SiMe2TMS Si
hν MeOH hν
SiMe2 TMS
O PhH CH2Cl2
OH OH
92
89 90
25%
Me2CO
TMS
SiMe2
O
OH
91
35%
Scheme 20
TMS TMS
Ph TMS Ph TMS
∆
Si H + H + TMS
TMS Ar Me2Si Si Si Si
Ar
TMS Ar H Ar
93 ð11Þ
Ar = Mes: 49% 28% 0%
Ar = o -Tol: 7% 58% 5%
Ar = p -Tol: 11% 36% 9%
Highly reactive silamethylene species have also been used to prepare geminal disilyl alkenes. For
example, the gas-phase high-temperature vacuum thermolysis of bis(TMSdiazomethyl)disilane 100
gives an intermediate 1,4-disilabutadiene 101 which can reversibly cyclize to give disilacyclobutene
102 (Scheme 22). Treatment of the pyrolysate with 4-methyltriazolinedione provides the bicycle 103,
whereas oxygen exposure gave 104. Yields were invariably low <1995JOM(499)99>.
The thermolysis of anthracene complex 105 generates 1,2-di-t-butyl-4,4-bis(TMS)-4-silamethy-
lenecyclopropene 106 with elimination of anthracene (Scheme 23). This rearranges to silacyclo-
butadiene 107 which, in the presence of ButOH, gives silacyclobutenes 108 and 109
<1997JA3405>. Silamethylenes such as 110 can also be generated through the pyrolysis of
acyltris(TMS)silanes 111 and can be trapped through [2+2]-cycloaddition reactions with alkynes
(Scheme 24). With hindered acyl substituents formation of the two possible [2+2]-regioisomeric
cyclic 1,1-disilyl alkenes 112 and 113 occurs, although 113 undergoes rearrangement to the
allene derivative 114 (or can undergo further reaction with the alkyne to give 2:1 adducts). With
R1 SiMe2TMS
94
R1 = Ar, 300 nm
hν
R1 = SiMe2TMS, 254 nm
R1
R1
TMS O
TMS R1
Me
SiMe2 Me R2 TMS
R2 O Me2Si
O R2 Si
hν, 6 h
DCM, N2 Me2
98 99
95
hν, 24 h
MeOH, N2
R1
R1
TMS MeO
SiMe2
H SiMe2
MeO H TMS
96 97
R1 R2 Yield 98 (%) Yield 99 (%) R1 Yield 96 (%) Yield 97 (%)
Ph Me 16 1 Ph 13 17
p-MeOC6H4 Me 9 0.5 1-naphthyl 25 25
p-NO2C6H4 Me 35 0 p-MeOC6H4 13 12
SiMe2TMS Me 48 0 SiMe2TMS 12 18
SiMe2TMS H 35 18
Scheme 21
Me2Si SiMe2
TMS TMS
102
R = Me Me
TMS TMS
O N O
N2 N2 Me2Si SiMe2 Me2Si SiMe2
∆ N N
N N
RMe2Si Si Si SiMe2R RMe2Si SiMe2R R = Me
Me2 Me2 O N O
Me
100 101
103
10%
O2
O
Me2Si SiMe2
RMe2Si SiMe2R
104
R = Me: 13%; Ph: 6%
Scheme 22
But
But
But But TMS TMS TMS H OBut TMS

Si ButOH ButO Si TMS TMS Si
TMS Si TMS +
PhMe Si But
TMS TMS But But But But But
220 °C H
108 109
106 107
105 75% 25%
Scheme 23
OTMS OTMS
O TMSO
TMSC ≡ CH (TMS)2Si R (TMS)2Si R
Si(TMS)2 +
R Si(TMS)3 PhH, 24 h R
TMS H H TMS
140 °C
111
(sealed tube) 110 112 113
R = But, Ad 42–49%
OTMS
(TMS)2Si R
C
H TMS
114
33–38%
Scheme 24
less hindered acyl substituents, no disilyl alkenes are formed <1996OM5759>. Reaction of 111
(R = But, Ad) with bis(trialkylsilyl)ethynes gives silylated silacyclopropene derivatives 115 in
good yields without the formation of the allenes observed with monosubstituted silyl ethynes
(Equation (12)) <2000OM4921>. However, the reactions of 111 (R = But, Ad) with diynes 24
give the silene [2+2]-cylcoadducts 116 at 120 C, but at 160 C 2-oxa-1-silacyclopentene deriva-
tives 117 were observed (Scheme 25). It was later shown that heating of 116 at 160 C causes
rearrangement to 117 in very high yield <2002CL364>.
R2R3MeSi SiMeR2R3
111 + R2R3MeSi SiMeR2R3
12 h, heat TMS Si
R1 = But, Ad; OTMS ð12Þ
160 °C TMS R1
R2 = Me, Ph; (sealed tube)
115
R3 = Me, Ph 74–87%
O R1
OTMS (TMS)2Si
(TMS)2Si R1 TMS
111 + 24
12 h, heat 12 h, heat TMS
TMS TMS
120 °C R1 = But, Ad 160 °C TMS
116 (sealed tube) (sealed tube) 117
86–97% 92–93%
Scheme 25
Cyclobutenedione monoacetals 118 react with excess bis-TMS-ethyne to give 2-[1-(TMS)alk-

ylidene]-4-cyclopentene-1,3-diones 119 in variable yields (Equation (13)). The reaction is catalyzed
by Lewis acids and proceeds via a novel cationic 1,2-silyl migrative ring opening and subsequent
5-exo-trig ring closure. Yields varied widely depending upon the substituents on the cyclobute-
nedione, equivalents of alkyne, and the amount and type of Lewis acid used <1997JOC1292>.
O
R1 O Lewis acid, 0 °C R1 TMS
+ TMS TMS
OEt 13–85% TMS
R2 R2
OEt O ð13Þ
118 119
Lewis acid = BF3.OEt2, TiCl4, SnCl4
R1 = Me; R2 = OEt, Me, Ph
R1 = Ph, PhCC; R2 = OEt
Several isolated syntheses of 1,1-disilyl alkenes or their complexes have been reported and these
are briefly mentioned here for completeness. Aluminum 1-aza-allyl complexes 120 form air- and
moisture-sensitive adducts 121, when treated with THF (Equation (14)). The reaction is reversible
and removal of the THF ligand at low pressure regenerates complex 120 <1999OM2256>.
Treatment of [Li(Si(TMS)3(THF)3] with 2 equiv. of 2,6-dimethylphenylisonitrile in the presence
of a slight excess of TMEDA gives the 4-aryl(lithio)amino-1-aza-2-silacyclobut-3-ene derivative
122, which, when quenched with TMSOTf, gives cyclic 1,1-disilyl alkene 123 (Scheme 26)
<1999AG(E)501>. In a related series of reactions, LiC(TMS)3(THF)2 reacts with aryl nitriles
to give 1,1-disilyl alkenes 124 (Equation (15)) <1998TL4745>. 1,3,5-Triazine reacts with
LiC(TMS)3(THF)2 to give air- and moisture-sensitive 3-lithio-7,7-bisTMS-1,3,5-triazaheptatriene
in 56% yield <1997CC2091>. The pyridyl ruthenium complex 125 reacts with bis-TMSethene to
give an equilibrium mixture of 125 and -silylvinylidene complex 126 (Equation (16))
<2002OM3285>. Biphenylene 127 undergoes an Rh-catalyzed reaction with bis-TMS-ethene to
give 9-(bis(TMS)methylidene)fluorene 128 in high yield (Equation (17)) <2001OM5745>. The
thermolysis of tetrakis(TMS)tetrahedrane at 260 C in tetracosane is reported to yield the
1,1-disilylalkenes tetrakis(TMS)vinylacetylene and tetrakis(TMS)butatriene in varying ratios
depending upon reaction time <2002JA13819>. The combination of equimolar amounts of Ru
complex 129, NaB[C6H3(CF3)2]4, and bisTMS-ethyne gives a four-coordinate Ru–vinylidine
complex 130 (Equation (18)) <2000OM1967>.
TMS TMS
N THF Ph N AlClR
Ph AlClR THF ð14Þ
0.01 mbar, 4 h TMS TMS
TMS TMS 85–89%
120 R = Me, Cl 121
2 equiv. ArNC TMS TMS

TMEDA Ar TMSOTf Ar
[Li(Si(TMS)3(THF)3] TMS TMS
Pentane N Si N Si
(TMEDA)Li N TMS TMS N TMS
–80 °C to rt Pentane
57% Ar –40 °C to rt Ar
Ar = 2,6-Me2C6H3 75% 123
122
Scheme 26
[LiC(SiMe3)3(THF)2] + R CN TMS
Et2O ð15Þ
20 °C TMS N TMS
Li(THF)
R = H: 89%; F: 12%; Br: 88%; OMe: 70%; But: 81%
124
PCy2 PCy2
Cl Cl TMS
N Ru NCMe + TMS TMS N Ru C
Cl ClCH2CH2Cl Cl TMS ð16Þ
PCy2 PCy2
125 126
TMS TMS
10 mol.% [(dtbpm)RhCl]2
+ TMS TMS
C6D6, 125 °C, 37 h ð17Þ
95%
127 (dtbpm = bis(di-tert-butylphosphino)methane) 128
B[C6H3(CF3)2]4
MeBu2t P
PBu2t Me NaB[C6H3(CF3)2]4 NO
TfO Ru NO + Ru
TMS TMS
C ð18Þ
MeBu2t P C6H5F MeBut2P TMS
TMS
129
130
4.23.1.2 Functions Bearing Two Borons—R12C¼C(BR23)2, etc.

The study and preparation of 1,1-diboryl alkenes has been developed significantly since the
publication of COFGT (1995), and several new approaches to these systems have been discov-
ered. Previously reported routes to these systems include diboration of alkynes and addition of
tris(dialkoxyboryl)methyllithium to aldehydes and ketones <1995COFGT(4)1043>.
Diboration of alkynes has been further developed and certain transition metal complexes have been
found to catalyze the reaction. Thus, the diboration of 1-boryl alkynes 131 using bis(pinacolatoborane)
proceeds in high yield in the presence of a Pt catalyst 132 (prepared from Pt(PPh3)4 and bis(pinaco-
latoborane)) to give the expected trisboronated alkene 133 (Equation (19)) <2002OM4533>.
1,2-Bis(catecholboryl)ethyne also undergoes diboration in the presence of Pt catalysts, including
(PPh3)2Pt(C2H4) <1996AG(E)1501> and Pt(COD)2, <1999EJI1693> to give the tetraboryl alkene
134 (Equation (20)). The hydroboration of boryl alkynes has now also been shown to be an effective
approach to 1,1-diborylalkenes. Based on electronic effects, it is predicted that the hydroboration of
boryl alkynes should preferably give the geminal-substituted products, and in most cases, this is what is
observed. For example, hydroboration of boryl alkynes 135 with bis(pentafluorophenyl)borane gives
diboryl alkenes 136 in good yields with high (>95%) regioselectivity (Equation (21)) <1998OM3557>.
Similarly, catecholborane performed regioselective hydroboration of boryl alkyne 137 to give
1,1-diboryl alkene 138 with only a small amount of the isomeric 1,2-diboryl alkene observed
(Equation (22)) <2001EJI373>. In a related reaction, 1-(dichloroboryl)-4,4-dimethyl butyne 139
(prepared in situ from the corresponding lithium acetylide and BCl3) is hydroborated with HBCl2
(prepared in situ from BCl3 and Me3SiH) to give the bis(dichloroboryl)alkene 140. This could be
further elaborated through transhalogenation using BI3 followed by reaction with 3-hexyne to yield a
1,3-dihydro-1,3-diborapentafulvene 141 (Scheme 27) <2002ZN(B)1125>.
(Ph3P)3Pt(BPin)2 O O
O O O 132 O B B O
B
B R +
B ð19Þ
O O O 80 °C, overnight O B R
O
131 86–87%
Pin = pinacol
R = Ph, Bun 133
[(PPh3)3Pt(C2H4)]
or
O O
O O O O Pt(COD)2 O B B O
B B + B B
O O O O PhMe, 40 °C, reflux O B B O ð20Þ
24 – 48 h O O
50–70%
134
[HB(C6F5)2]2 (C6F5)2B R
(C6F5)2B R
Hexane, 25 °C (C6F5)2B ð21Þ
135
65–90%
136
R = But, Ph, C6F5
O
BH O
O O O B H
B H
O THF, 80 °C, 4 h O B H ð22Þ
137 86% O
138
I
But BCl2 But Et
Me3SiH 2BI3 But BI2 Et2C2 B
But BCl2
BCl2 BI2 H B Et
139 I
140 84.5% 141
37.7% 73.3%
Scheme 27
Terminal alkenes can also give 1,1-diboryl alkenes through a metal-catalyzed geminal dehy-
drogenative diborylation reaction. Thus, treatment of vinylanisole with bis(pinacolato)diboron in
the presence of 5 mol.% trans-[Rh(Cl)(CO)(PPh3)2] gives the 1,1-diboryl alkene 142 in good yield
and high selectivity, although the reaction required 5 days to reach completion (Equation (23))
<2003CC614>. The Rh-catalyzed boration of styrylboronates gives geminal diborylstyrene deri-
vatives <2002JOM(652)77>. 1,1-Bis(diethylboryl)prop-1-ene was observed by 11B NMR as an
intermediate in the complete hydroboration of diethyl(prop-1-ynyl)borane with tetraethyldibor-
ane, ultimately giving carborane products <1995CC1691>. 1,1-Bis(trimethylstannyl)isobutene
undergoes tin–boron exchange when treated with bis(1-dichloroborylethyl)chloroborane to give
1,3,5-trichloro-2-isopropylidene-4,6-dimethyl-1,3,5-triboracyclohexane <1995AG(E)681>.
O
O O trans-[Rh(Cl)(CO)(PPh3)2] B O
B
B B O ð23Þ
O O 3:1 PhMe:MeCN
MeO O
5 days
83%
MeO
(2 equiv.)
142
Another new approach to 1,1-diboryl alkenes 143 involves the treatment of 1-halo-1-lithioalk-
enes 144 (prepared through lithiation of the precursors 145) with diboranes 146, 147, and 148
(Scheme 28 and Table 5). The reaction proceeds through initial transmetallation of the lithium for
the boron species, followed by 1,2-migration of the second boron group. Yields vary from
moderate to good <2001AG(E)790, 2002T6381>. Use of 148 gave low yields of 143 due in
part to its low solubility, and bis(catechol)diboron was not effective in this reaction. The synthetic
utility of these species has been investigated <2002T6381>.
R1 X R1 X R1 X R1 BR23
+ R32B-BR32
R2 X R2 Li R2 B–R 23 R2 BR23
BR32
145 144 143
O O O O O O
B B B B B B
O O O O O O
146 147 148
Scheme 28
Table 5 Formation of 1,1-diboryl alkenes from 1-halo-1-lithioalkenes

Precursor (R32B)2 Product Yield (%) References
Br BR23
91 <2001AG(E)790>
146
H BR32 <2002T6381>
Cl BR32
<2001AG(E)790>
146 89
Cl BR32 <2002T6381>
Cl BR32
82 <2001AG(E)790>
H 146 BR32 <2002T6381>
n-Hex n-Hex
Cl BR32
H BR23 <2001AG(E)790>
146 48
<2002T6381>
n-Hex n-Hex
Br BR32
<2001AG(E)790>
Br 146 BR32 65
OCH2OCH2CH2OMe
<2002T6381>
OCH2OCH2CH2OMe
Br BR23
147 >99 <2002T6381>
Br BR23
Br BR23
148 15 <2002T6381>
Br BR23
Ph BR32
Ph Br
146 Ph BR32 40 <2002T6381>
Ph Br
4.23.1.3 Functions Bearing Two Germaniums—R12C¼C(GeR23)2, etc.

The chemistry of 1,1-digermyl alkenes has remained little explored. Previous methods of their
preparation include the addition of GeCl4 to germylalkynyl ethers: eliminations of tris(trialk-
ylgermyl)ethanol or -acetates or reactions of propynoyl chlorides with lithium trialkylgermanium
<1995COFGT(4)1043>.
The Pd(OAc)2/1,1,3,3-tetramethylbutylisocyanide-catalyzed high-pressure intramolecular bis-
germylation of cyclic germyl alkyne 30 (M = Ge) gave 31 (M = Ge) (Equation (3)).
<1995BCJ2981>. Ortho-bis(dimethylgermyl)carborane 149 reacts with Ni(PEt3)4 to give the
1,3-digermyla-2-nickela-carboranylene 150 (Scheme 29). Compound 150 catalyzes the
1,1-bis(germylation) of 1-hexyne by 149 to give the 1,1-bisgermylalkene 151 (R = Bu) in reason-
able yield (Scheme 29) <2001CC1730>, although many other alkynes gave 1,2-bisgermylation
products <2002OM3922>. Stoichiometric amounts of 150 react with 1-octene to give the
1,1-bisgermylation product 151 (R = C6H13) (Scheme 29) <2002OM3922>.
Me2 Bu H Me2
Ge GeMe2H cat. 150 Ge H
Ni(PEt3)4
Ni(PEt3)2
Ge GeMe2H PhMe, 25 °C Ge R
Me2 Me2
14 h 62%
150 149 R = Bu 151
Scheme 29
4.23.1.4 Other Functions—R12C¼CSiR23BR32, etc.

This section covers those functions containing borylsilyl-, germylsilyl-, and borylgermylalkenes.
4.23.1.4.1 Functions containing one silicon and one boron

Previously reported routes to these systems include hydroboration and diboration of silyl alkynes
and the reaction of geminal vinylsilyllithium species with boron halides. Allene derivatives have
been prepared from 3-lithiated-1-silyl propynes and trialkylborates, and ketene derivatives from
1-silyl-2-alkoxyethynes with boron halide derivatives <1995COFGT(4)1043>.
The regiospecific hydroboration of TMS alkynes has continued to be a useful route to 1-boryl-
1-silylalkenes. The preparation of (Z)-2-(1-TMS-1-alkenyl)-1,3,2-dioxaborinanes 152 from TMS
alkynes can be achieved using BHCl2Me2S or diisopinocampheylborane to give intermediates 153
or 154 respectively, followed by treatment with propanediol (Scheme 30) <2000TL8027>.
R TMS R TMS BHIpc2 BHCl2.SMe2 R TMS

HO(CH2)3OH
R TMS
B O BIpc2 BCl3/hexane BCl2
MeCHO
O
(excess) 154 153
70–84%
152
HO(CH2)3OH
–2HCl
65–75%
R = Bun, Bus, But, n-pentyl, n-hexyl, (CH2)3Cl
R TMS
B O
O
152
Scheme 30
However, use of BHBr2Me2S resulted in protodesilylation of the product. Nickel-catalyzed

hydroboration of 1-TMS-ethyne with catecholborane gave the 1,1-silylborylalkene 155 with
high selectivity (>98%) in moderate yield (Equation (24)). In contrast, the uncatalyzed reaction
of neat catecholborane and TMSethyne gave a 1:1 mixture of 1-boryl-1-silylalkene 155 and its
1,2-isomer <2000MI765>.
TMS
O 1% NiCl2(DPPE)
TMS H + HB O B
O THF, rt O ð24Þ
50%
155
The hydroboration of 1-alkynylchlorodimethylsilanes 156 with tetraethyldiborane has been

studied in some depth. With 156 (R = Bun), both cis and trans hydroboration adducts 157 and
158 are formed in nonconstant ratios (Equation (25)). However, trans-1,2-hydroboration is not
mechanistically likely, and it is thought that 158 forms via the twofold hydroboration of 156
(R = Bun) followed by dehydroboration, leading to the observed cis and trans isomers. Increas-
ing the steric bulk of the R group slows the rate of reaction, and with 156 (R = But)
forcing conditions are required to achieve hydroboration and only the cis product 157 is seen.
Subsequent reaction of 157 with a range of N- and C-lithiated azoles was explored and
zwitterionic adducts prepared <1999JOM(584)98, 2000JOM(602)45>. The hydroboration of a
range of 1-silyl alkynes with 9-BBN has been studied in some detail <2000JOM(602)45,
2003JOM(669)72>. With alkylsilylalkynes hydroboration was rapid and highly selective,
whereas with chlorodialkylsilylalkynes, the reaction required more forcing conditions. With
1-chlorosilyl-2-TMS-ethyne, the regioselectivity of the reaction is low and isomerization of the
initial cis adducts occurs giving all four cis and trans 1,1- and 1,2-hydroboration products
<2003JOM(669)72>.
BHEt2 R H H R
R S iMe2 +
Cl Cl Cl
Si BEt2 Si BEt2
156 Me2 Me2
ð25Þ
157 158
R = Bun
R = Bun
R = But, quantitative
Triallylborane possesses unique reactivity among triorganoboranes due to permanent allylic

rearrangement, and it is significantly more reactive than triethylborane in reactions with 1-silyl
alkynes. In some cases, 1,2-allylboration competes with 1,1-allylboration, although in most cases
the latter is dominant, particularly in polar solvents. For example, 159 (R = H) gives 160, 161,
and 162 in a 2:1:1 ratio (Scheme 31). Compound 162 results from the rapid rearrangement of 163
BAll3 All2B SiR13 R13Si H R13Si H

R13Si R2 + +
All = allyl All H All2B All All BAll2
159 160 161 163
All R13Si
R1 = Me, R2 = H: 160:161:162 = 2:1:1
B
R1 = R2 = Me: 160 only SiR13
B
R1 = Me, R2 = Ph: 160:161 = 2:1
All
R1 = Me, R2 = Ph: 160:161 = 1:1
164 162
Scheme 31
and undergoes further, slow rearrangement to bicycle 164. With 159 (R = Me), 160 is formed
exclusively. Increasing the size of the silane substituents decreases the reactivity of the alkyne,
and with 159 (R1 = R2 = Ph) no reaction is observed even after prolonged heating
<1999JOM(580)234>.
Heterocycles containing the 1-boryl-1-silylalkene unit can also be prepared through reactions of
polyalkynyl silanes with triallylborane <2002JOM(657)146>. The outcome of the reactions is
somewhat dependent on the nature of the terminal substituent on the alkyne units of 165 as well
as the reaction temperature. Examples are given in Scheme 32. As the size of the terminal
substituent increases, more forcing conditions are required to achieve reaction. It was also
found that 166 underwent thermal rearrangement to 167. The reactions of more complex
polyalkynyl silanes with triallylborane were also studied and bis(TMS-ethynyldimethylsilyl)ethyne
and tetrakis(TMS-ethynyl)silane gave similar cyclic 1-boryl-1-silyl alkynes to those in Scheme 32,
along with silole derivatives <2002JOM(657)146>. The allylboration of enediynes has also been
studied and competition between 1,1 and 1,2-allylboration is observed. The (Z)-enediyne 168 gave
mainly products of 1:1 reaction with triallylborane, 169 (Scheme 33) <2002CEJ1537>. In con-
trast, the (E)-enediyne 168 reacts with triallyl borane to give all five possible isomeric mono and
diallylboration adducts 170 and 171 formed via either 1,1- or 1,2-allylboration or a combination
of these modes of addition (Scheme 33).
R2
R1MeSi
R2
165
BAll3
All = allyl
Heat
Me
R2 All R2 All
Ph HSi Ph All BAll2
1MeSi
R1MeSi B All R B
All2B All TMS TMS
Si
All Me2
R2 All R2
166 167
R1 = R2 = Me R1 = R2 = Me R1 = H; R2 = Ph R1 = Me; R2 = TMS
R1 = H, Me; R2 = But
R1 = H, Me; R2 = TMS
Scheme 32
Platinum-catalyzed diboration of TMS alkynes may also give 1,2-diboryl-1-silylalkenes. For

example, treatment of bis-TMS-ethyne with bis(pinacolato)diboron in the presence of
(Ph3P)2Pt(C2H4) or (Ph3P)2Pt(boryl)2 gives diborated alkene 172 (Equation (26)). However, the
reaction is somewhat complicated and metathetical byproducts are observed. The analogous
reaction with 1,4-bis-(TMS)butadiyne 24 initially gave the diborated product 173, which slowly
underwent further reaction to give the tetraborated derivative 174 (Scheme 34) <1996OM5137>.
Metathetical by-products were also observed. However, when 24 was treated with bis(catechol)-
diboron under similar conditions, intermediates of type 173, were not observed and work-up of
the reaction gave a range of products. These and related reactions are discussed in further detail
<1996OM5137>.
R
1 TMS
R1
BAll2 BAll2
BAll3 BAll3
R2 R2
(Z )-isomer (E )-isomer
TMS All = allyl TMS
169 TMS 170

168
R1 = TMS, R2 = All;
R1 = TMS, R2 = All;
R1 = All, R2 = TMS
R1 = All, R2 = TMS
+
1
R
BAll2
R3
2
R
All2B
R4
171
R1 = TMS, R2 = All, R3 = TMS, R4 = All;

R1 = TMS, R2 = All, R3 = All, R4 = TMS;
R1 = All, R2 = TMS, R3 = TMS, R4 = All
Scheme 33
Pt cat. (Pin)B B(Pin) (Pin)B B(Pin)

TMS TMS + [(Pin)B]2 + (Pin)B TMS + TMS B(Pin) +
TMS TMS TMS B(Pin)
Pin = Pinacol
172
ð26Þ
(Pin)B B(Pin)
Pt cat. (Pin)B B(Pin)
24 + [(Pin)B]2 TMS
TMS TMS
(Pin)B B(Pin)
Pin = Pinacol TMS
173 174
Scheme 34
1-Halo-1-lithioalkenes 175 (prepared through lithiation of the precursors 176) react with
silylboranes 177–181 to give 1-boryl-1-silylalkenes 182 (Scheme 35) and selected examples
are given in Table 6. The reaction proceeds through initial transmetallation of the lithium for
the boron species, followed by 1,2-migration of the silyl group. Yields (from dihaloalkene) vary
from moderate to good although with sterically demanding silane substituents, reactions with
disubstituted carbenoids can be very poor <2001AG(E)790, 2002T6381>.
Using a similar method, 1-boryl-1-silylallenes 183 can be prepared from lithioalkynes 184,
which contain a leaving group - to the triple bond (Scheme 36). Selected examples are
given in Table 7. The mechanism proceeds through transmetallation of the lithium atom
with boron, followed by 1,2-migration of the silyl group from the charged intermediate with
elimination of the -leaving group. When 3-mesyloxyalkynes 184 (X = OMs) are used, the
R1 X R1 BR32
R1 X R1 X
+ R32 B SiR43
R2 BR32 R2 SiR43
R2 X R2 Li –
177–181 R43Si
176 175 182
O O O
B SiMe2Ph B SiPh3 O O
B SiPh2Me B TMS B SiMe2Ph
O O O O O
177 178 179 180 181
Scheme 35
Table 6 1-Boryl-1-silylalkenes from 1-lithio-1-haloalkenes

Precursor 176 R32B-SiR43 Product 182 Yield (%)
Br BR32
177 84
Br SiR43
178 <1
179 <1
180 67
181 78
Br BR32
177 81
H SiR43
178 60
179 62
180 45
181 72
Cl BR32
177 75 (E only)
Cl SiR43
Cl BR32
H SiR43
177 49 (1/1 E/Z)
n-Hex n-Hex
1/1 (E )/(Z )
Br BR23
Br 177 SiR43 45
OCH2OCH2CH2OMe OCH2OCH2CH2OMe
reaction can be accelerated and the yield increased through the addition of TMSCl, due to
coordination of TMSCl with the mesyloxy leaving group. Overall yields are moderate. Optically
active 3-mesyloxyalkynes 184 (X = OMs) give enantioenriched allenes, although some racemiza-
tion is noted <2003OL225>.
BuLi
R2 R2 R2 SiMe2Ph
R1 or LDA 177 – R2 SiMe2Ph
H R1 Li R1 B(OCHMe2)2 C
X X X R1 B(OCHMe2)2
Li
184
183
Scheme 36
Table 7 Synthesis of 1-boryl-1-silylallenes

Precursor Product Yield (%)
Me
Me SiMe2Ph
Me
C 77
AcO
Me B(OCHMe2)2
SiMe2Ph
C
B(OCHMe2)2 53–60
AcO
Ph
H SiMe2Ph
C 41–52
Cl (+/–)
Ph B(OCHMe2)2
(+/–)
Me
H SiMe2Ph
C 51–75
MsO (+/–) Me (+/–) B(OCHMe2)2
Me H H SiMe2Ph
C
Cl Me B(OCHMe2)2 75 (>74% ee)
S, >99% ee
n-Pent H H SiMe2Ph
C
Cl n-Pent B(OCHMe2)2 67 (70% ee)
S, >99% ee
Although strictly outside of the scope of this review, partially reduced 2-silylborabenzene
derivatives which contain the 1-silyl-1-borylalkene unit have been prepared through treatment
of dihydroboratabenzene with LDA followed by quenching with TMSCl <1997OM926> or
through the transmetallation of silylated 1-stannacyclohexa-2,4-dienes with BCl3
<1996OM1315, 1997JOC8286>.
4.23.1.4.2 Functions containing one silicon and one germanium

Previously reported routes to 1-germyl-1-silylalkenes include halogermylation of silyl alkynes with
germanium tetrachloride, or halosilylation of germyl alkynes with silicon tetrachloride. The
insertion of germanium dibromide into 1-bromo-1-silyl alkenes has also proved effective, as has
the transmetallation of lithiosilyl alkenes with germyl halides. 1-Germyl-1-silylalkenes have been
prepared through the propargylic deprotonation of silyl alkynes followed by quenching with
trialkylgermyl chlorides or, conversely, deprotonation of germylalkynes followed by quenching
with silyl chlorides <1995COFGT(4)1043>. Several alternative routes to 1-germyl-1-silylalkenes
have now been reported.
The treatment of 1-bromo-1-germyl-1-silylethane 63 (R1 = SiMePh2; R2 = GeEt3) with DBU

induces dehydrobromination to give 1-germyl-1-silylalkene 65 (R1 = SiMePh2; R2 = GeEt3) in
high yield (Scheme 13) <2002CEJ1730>. The Pt-catalyzed hydrogermylation of 1-TMS-
alkynes 185 with trimethylgermane gives 1:3 ratio of (Z)-1-germyl-1-silylalkenes 186 and
isomeric (E)-1-germyl-2-silylalkenes 187 (Equation (27)) <1995JCS(P1)3>. A new route to silyl-
substituted germacyclopropenes has been reported. The 1,1-bis(trialkylsilyl)-1-germacycloprop-
2-enes 188 are formed in good yield through reduction of bis(trialkylsilyl)dichlorogermanes 189
with molten potassium in the presence of bis-TMS-ethyne, without solvent (Equation (28))
<2002AG(E)1598>. 1-Germyl-1-silylketenes 73 (MR3 = GeMe3) can be prepared through
quenching lithium ynolate 74 with Me3GeBr (Scheme 16) <1996JA7634>.
Me3GeH
Cat.H2PtCl6.6H2O TMS H HO(CH2)4 TMS
HO(H2C)4 TMS + ð27Þ
Me3Ge (CH2)4OH Me3Ge H
185
186 187
K, TMS TMS R3Si SiR3

R3Si SiR3
Ge Ge
Cl Cl
TMS TMS ð28Þ
189 188
R3Si = Pr3i Si, Bu2t MeSi
4.23.1.4.3 Functions containing one boron and one germanium

The only route to these species previously reported is the hydroboration of germyl alkynes. No
further synthetic approaches have been reported since COFGT (1995).
4.23.2 FUNCTIONS CONTAINING A METALLOID AND A METAL
4.23.2.1 Silicon Functions—R12C¼CSiR23M
4.23.2.1.1 Functions with one silicon and one group 1 metal

Previously reviewed methods of preparing 1-lithio-1-silylalkenes include the silylcupration of
lithioalkynes, lithium–halogen exchange of 1-halo-1-silylalkenes and transmetallation of
1-stannyl-1-silylalkenes. 1-Lithio-1-silylallenes have been prepared through the lithiation of
TMS-propynes <1995COFGT(4)1043>. Of these, only lithium–halogen exchange has found
continued use during the 1990s. The synthetic utility of 1-lithio-1-silylalkenes has been demon-
strated in the preparation of heavy atom heterocycles <2001OM2109>. For example, lithiation
of iodoalkene 190 with ButLi gives 191, which readily undergoes cis/trans isomerization
(Scheme 37). Further treatment of 191 with Me2SnCl2 gives a 1,4-dihydrostannanaphthalene.
A wide range of benzoheteroepines was obtained using similar methods, although in this case, a
bromine–lithium exchange was employed (Scheme 38) <1999CPB1108>. Quenching of the
dilithium species 192 with electrophilic metal reagents gave the corresponding heteroepines 193
<1999CPB1108>.
TMS TMS
I Bu tLi
Li Me2SnCl2
Br Li Sn TMS
Me2
190
191
Scheme 37
ButLi MX2 or MX4

Br TMS
Br Li Li TMS M
TMS
192 193
M = SiMe2, GeMe2, SnMe2, PPh,
AsPh, SbPh, BiPh, S, Se, Te
Scheme 38
4.23.2.1.2 Functions with one silicon and one group 2 metal

Previously reported routes to these systems include Ni-catalyzed addition of MeMgBr to silyl
alkynes: hydromagnesiation or carbomagnesiation of silyl alkynes and transmetallation of 1-silyl-
1-bromoalkenes <1995COFGT(4)1043>. There have been no significant developments in the
preparation of the title compounds.
4.23.2.1.3 Functions with one silicon and one transition group metal
(i) Functions with one silicon and one group 4 metal

1-Titano-1-silylalkenes have previously been prepared via transmetallation of 1-lithio-1-silylalk-
enes and carbotitanation of silyl alkynes <1995COFGT(4)1043>. However, during the 1990s, the
chemistry of group 4 1-metallo-1-silylalkenes including titanium and zirconium species has under-
gone significant development and new approaches have been discovered. Hydrotitanation of
silylalkynes 194 (M = Si) with tris(aryloxy)titanium (IV) hydrides, stabilized as their PMe3
adducts 195, proceeds via syn addition to the triple bond with some degree of stereospecificity
giving 196 (M = Si) and sometimes 197 (M = Si) (Equation (29)) <1995OM4601>. Tris(TMS)-
titanocyclobutene 198 is a mild and effective reagent for the conversion of a wide range of
carbonyl groups to alkenyl silanes and it is prepared in high yield through the treatment of
bis(TMSmethyl)titanocene 199 with 1,2-bis(TMS)ethyne at 80 C (Equation (30))
<1995TL3619>. Titanium aryloxide 200 reacts with 1-TMS-6-hepten-2-yne 201 in the presence
of 2 equiv. of BunLi to form a bicyclic 1-titano-1-silylalkene 202 (Equation (31)) <2003CC18>.
Chiral 1-titano-1-silylallenes 203 can be prepared through treatment of optically active propargyl
alcohol derivatives 204 with Ti(OPri)4 and 2 equiv. of PriMgCl with an excellent degree of chiral
transfer (Equation (32)) <1998TL4555>.
MMe3 R
(ArO)3 TiH PMe3 + Me3M R (ArO)3 Ti + (ArO)3 Ti
–PMe3 R MMe3
195 194 H H
ð29Þ
Ar = 2,6-(Pri)2C6H3 M = Si, Sn 196 197
M = Si; R = H, 3:1 196:197

M = Si, Sn; R = Ph: 196 only
TMS
Cp TMS TMS TMS Cp
Ti Ti TMS
Cp TMS 80 °C Cp ð30Þ
TMS
199 198
(ArO)2TiCl2
200 TMS
2BunLi ArO
Ti ð31Þ
64% ArO
TMS
201 Ar = 2,3,5,6-Ph4C6H1
202
TMS Ti(OPri)4 X
R1 2PriMgCl (PriO)2Ti R1
R2 C
X TMS R2
203 ð32Þ
204
X = OP(O)(OEt)2; R1 = Bu; R2 = H: 204 = 96.7% ee; 203 = 85% ee
X = OCO2Et; R1 = (CH2)3CHMe2; R2 = Me: 204 = 97.2% ee; 203 = 85% ee
The 2-bis(TMS)ethyne complexes of Cp2Ti, 205, offer an excellent route to the unstable free
titanocene through elimination of the ethyne ligand. The free metallocene 206 undergoes
reaction with 1-TMS-4-phenylbutadiyne to give bimetallic bicycle 207 via an intermediate
cyclocumulene (Scheme 39) <1995OM2961>. In a more complex example, reaction of 205 with
tetrakis(TMS-alkynyl)silane gave tetracyclic bimetallic species 208 (Scheme 39)
<2000OM1198>. The treatment of meso-1,2-ethylene-1,10 -bis(5-tetrahydroindenyl) titanocene-2-
TMS-ethyne complexes 209 with CO2 can lead to regiospecific insertion reactions to give titanofur-
anone complexes 210 in good yields, with retention of the 1-titano-1-silylalkene unit (Equation (33))
<1998EJI1495>. However, several related titanocene-2-TMS-2-phenylethyne complexes contain-
ing other modified cyclopentadienyl ligands gave only insertion into the silicon substituted carbon
and 1-titano-1-silylalkene derivatives were not obtained. Treatment of 211 with acetone also gave
an insertion product, oxatitanocycle 212 (Equation (34)) <1995JOM(501)179>.
TMS
Cp2Ti
TMS
205
TMS – TMSCCTMS
TMS TiCp2 Ph
Si TMS Cp2Ti
Si 4 Ph TMS
TMS Cp2Ti TiCp2
Cp2Ti
TMS TMS
206 207
208
Scheme 39
R CO2 O O
Ti
Ti ð33Þ
R
TMS TMS
R = TMS, Ph 210
209
O
TMS TMS
Me Me R
Cp2Ti Cp2Ti ð34Þ
R = Ph, Bun O
R
211 212
1,5-Disilyl-3,4-dialkyltitanocyclopentadienes (e.g., 213) can be prepared through the reaction of

free titanocene (in this case prepared from Cp2TiCl2 and Mg) with 2 equiv. of alkyne, although
formation of titanocyclopropenes 214 competes as the size of the alkyne substituents increases
(Equation (35)) <1995JOM(501)179>. It was also found that 214 undergoes ring expansion with
further TMS alkynes to give titanocyclopentadienes 213 and 215 (Equation (36)), although
hindered alkyl substituents inhibit the ring expansion. Factors affecting the ratios of isomers
such as 213 and 215 have been discussed, and it was found that 215 is the kinetic product of the
reaction, with rearrangement to the thermodynamically more stable symmetrical 213 occurring
over time <1995JOM(501)179>. Several other 2-silyltitanocyclopentadienes have been prepared
under similar conditions <1995JOM(503)221, 1998CEJ1852, 1995CB967>.
TMS
TMS
R
Cp2TiCl2 + Mg + TMS R Cp2Ti + Cp2Ti
–MgCl2
R R
TMS ð35Þ
214 213
R = But R = Me
R = Prn 30:70 214:213
TMS TMS
TMS R R
+ TMS R Cp2Ti + Cp2Ti
Cp2Ti
R TMS
R TMS R ð36Þ
214 213 215
R = Bun
R = Ph 48:52 213:215
1-Zircona-1-silylalkenes were not discussed in the previous review <1995COFGT(4)1043>, but

in recent years there has been much activity in this area and several protocols for the preparation
of these species are now available. The main focus has been on the preparation of zirconacyclo-
pentadiene derivatives, although other 1-zircona-1-silylalkenes have been reported. Treatment of
eneyne 216 with Cp2ZrBu2 gave the 2-TMS-zirconacyclopentene 217 (Equation (37)), which was
used as an intermediate to the corresponding cyclic stannane derivative 218 <1995TL3725>.
Zirconocene alkene complexes are much less robust than the well-known zirconocene–alkyne
complexes, and alkene displacement is generally facile. However, complexation with benzocyclo-
butadiene gives a much more stable system, presumably due to the unfavorable liberation of an
antiaromatic compound upon displacement. The zirconium alkene complex 219 reacted with
TMS-ethyne gave the tricyclic 1-zircona-1-silylalkene 220 (Equation (38)) <2002OM5685>.
O O O O O O
Bu2Sn(OMe)2
74% ð37Þ
TMS
Zr Sn TMS
TMS Cp2 Bu2
216 217 218
Me3P
Cp2Zr + TMS H TMS
Zr ð38Þ
Cp2
219
220
As in the titanium series, reactive-free zirconocene can be generated from stable zirconocene–2-
alkyne complexes. These complexes also undergo a range of insertion reactions to give 1-zircona-
1-silylalkene derivatives. When treated with acetone, zirconocene–alkyne complexes 221 initially
give zirconadihydrofurans 222, which rearrange to the thermodynamically more stable isomer
223 (Scheme 40), although with 221 (R = TMS) the product is unstable and prone to the
reversion to the starting materials <1995JOM(501)189>. Alkyl vinyl ketones also insert into
zirconocene–alkyne complexes, although the outcome is somewhat dependent on both the Cp
ligand on the zirconocene and the ketone fragment. Thus, rac-1,2-ethylene-1,10 -bis(5-tetrahy-
droindenyl)zirconocene complex 224 reacts with methyl vinyl ketone to give the 1,4-insertion
product 225 in high yield (Scheme 41), but gives 1,2-insertion complex 226 with mesityl oxide
<2002OM3360>. Nitrous oxide inserts into 2-alkyne-stabilized zirconocenes 227 to give an
intermediate azoxy species 228 which eliminates N2 to give oxazirconacyclobutenes 229 in
quantitative yield (Scheme 42) <1998ICA399>. Treatment of 230 with benzoxazole, ben-
zothiazole, thiazole, and dimethylthiazole all give analogous ring-expanded products 231 via
insertion of the zirconocene unit into the heterocyclic ring (Equation (39)) <1996CB297>.
Benzaldehyde azine inserts into the ZrC bond of zirconocene–alkyne complexes to give a
1-zircona-2-azacyclopent-4-ene <1998OM4429>.
R TMS
TMS TMS R
Acetone
Cp2Zr Cp2Zr Cp2Zr
–THF O O
THF
R
221 222 223
R = TMS, But R = But R = But
Scheme 40
TMS TMS
TMS
O TMS O
TMS
Zr
Zr Zr
O
O
TMS
225 224 226
Scheme 41
TMS TMS TMS

N2O (0.7 atm) R
(Cp*)2Zr (Cp*)2Zr (Cp*)2Zr R
Pyr Heat or PhH N N –N2 O
R
O
227 228 229
R = Ph, cyclopentyl
Scheme 42
R1
TMS TMS
R2 N
Cp2Zr + Cp2Zr N
Pyr R2 X X
R1 R2
2
230 R
ð39Þ
231
R1 = TMS, But, R2 = Fused benzene ring; X = O

R1 = TMS; R2 = Fused benzene ring; X = S
R1 = TMS; R2 = Me; X = S
R1 = TMS; R2 = H; X = S
Zirconacyclopentadienes have attracted much interest in recent times and many examples of
2-silylzirconacyclopentadienes have been reported. Polymeric 2-silylzirconacyclopentadienes 232
have been obtained in quantitative yield through the reaction of free zirconocene (generated in
situ) with ethynyldisilane 233 (R = Me) (Scheme 43). Heating of the polymer led to depolymeriza-
tion followed by intramolecular coupling with 1,2-migration of the silyl group, ultimately giving
zirconacycle 234. Use of 233 (R = TMS) led to formation of 234 directly <2000CL1082>. The
intermolecular reaction between zirconocene and silyl alkynes has been used in the preparation of
symmetrical 2,5-disilylzirconacyclopentadienes 235 (Equation (40)) <1999OM2491, 1999OM4205>.
Use of more sterically demanding ligands on the zirconocene unit can promote the formation of the
unsymmetrical zirconacyclopentadienes <2002ICA(334)17>. As with titanocyclopentadienes
(Equation (36)), the unsymmetrical 2,4-disilyl species are generally the kinetic products, and these
rearrange to give the thermodynamically more stable symmetrical 2,5-disilyl species
<1998CEJ1852>. The intramolecular cyclization of di(TMS-alkynyl) ether 236 with Cp2ZrBu2
gives the ring fused zirconacyclopentadienes 237 (Scheme 44) <2002CEJ4734>. Transmetallation
with CuCl gave the corresponding bis(1-TMS-1-cuproalkene) species 238 which was trapped in situ
with a divinyl iodide to give cyclooctatetraene derivative 239 (Scheme 44). Use of shorter linkers
between the TMS-alkyne units can result in more complex reaction mixtures due to the increased
ring strain of any potential fused products <1995T4359>. Zirconacyclopentenes 240 react with
bis(butynyl)diphenylsilane to give 1-(diphenylbutynylsilyl)zirconacyclopentadiene 241, which under-
went rearrangement to give 242 upon heating (Scheme 45) <1997JA12842>.
Me2
R R Si
Me2Si SiMe2 Cp2ZrCl2 Me2 R
∆ SiMe2
Si
n Si
Bu Li
R R Me2 Zr Cp2Zr
Cp2 n
R
233 232 234
R = Me R = Me, TMS
Scheme 43
i. BuLi R R
ii. TMS R
Cp2ZrCl2
TMS
Zr TMS ð40Þ
R = Me, Ph, Bun Cp2
235
A range of macrocyclic polyzirconacyclopentadienes have been prepared via the cyclooligomeriza-

tion of bis(silylalkynes) with zirconocene <1995JA7031, 1998JA3271, 1998JOC3673, 2000JA10345,
2001JA2683, 2002CEJ74> (Equation (41)). Due to the reversibility of the zirconocene–alkyne cou-
pling, initially formed oligomeric zirconacyclopentadiene species are converted to the thermodynamic
product, which is the smallest strain-free ring that can form. With linear dialkynes, trimers 243 are
TMS
I
O
TMS I TMS TMS
TMS TMS TMS
Cp2ZrBu2 CuCl, DMPU Cu TMS
O ZrCp2 O O O
Cu
O TMS TMS TMS TMS
236 237 238 239
Scheme 44
Et Et
SiPh2 SiPh2
Et SiPh2 Et
2
(R1C5H4)2Zr (R1C5H4)2Zr (R1C5H4)2Zr Et
R2 THF, rt R 2
R2 R2 R2 R2
240 241 242
1 = H,
R R2 = Ph, Et
R1 = But, R2 = Ph
Scheme 45
generally obtained, with competing tetramer formation noted at higher concentrations

<1995JA7031>. With nonlinear dialkynes, dimers 244 could be obtained. Selected examples are
given in Equation (41). Macrocycles in which the zirconocene units are linked via the silyl moieties
have also been prepared using the same technique <1995JA5365, 1998JA1193>.
Cp2 Cp2
Zr TMS Zr
TMS TMS TMS
Linker
Linker
r
Lin
ke
TMS Linker TMS + Cp2Zr OR

ke
Lin
TMS TMS
Linker
Cp2Zr ZrCp2 TMS TMS
Zr
TMS TMS Cp2
243 244
82–99% 66–91%
Linker = ; ; 243 only

N N N N
n
n = 1– 4
N Ph OMe
Linker = ; ; 244 only
OMe
Ph N
Racemic (gives only

RR and SS) 244
ð41Þ
(ii) Functions with one silicon and one transition metal (not including a group 4 metal)
1-Cupro-1-silylalkenes have been prepared from silyl alkynes and organocopper–magnesium halide
species and several different transmetallations are also known. 1-Zinco-1-silylalkenes have been
prepared through organozincation of silyl alkynes and 1-zinco-1-silylallenes have been prepared
through transmetallation of lithium species <1995COFGT(4)1043>. Tungsten carbyne complexes
245 can undergo a carbyne–carbonyl coupling reaction when treated with acetonitrile, to give the
1-tungsto-1-silylketene complex 246, although the reaction is reversible and 246 can only be
obtained pure in the solid state (Equation (42)) <1999JOM(587)233>. 1-Rutheno-1-silylalkene
247 was prepared from 1-bromo-1-silylalkene 248 (presumably via 249) and can be considered
to be an example of a 1-silaallene that is stabilized by both metal ligation and interaction with a
metal hydrogen bond (Scheme 46) <1995JA3298>. Alkynes have been found to undergo
intramolecular insertion into the PdC bond of (iminoacyl)palladium complexes 250, preferably
in the presence of AgPF6, to give 1-pallado-1-silylalkenes 251 and 252 (Scheme 47)
<1998OM4335>. As reported previously <1995COFGT(4)1043>, 1-zinco-1-silylallenes 253 are
accessible via propargylic deprotonation of silyl alkynes 254 and subsequent transmetallation
with ZnBr2 (Equation (43)). The bimetallic reagents thus formed were found to add to -chiral
imines with high diastereoselectivity <2000JOC6553>. Compound 253 (R = Cl) was obtained
through treatment of a mixture of 1-silyl-3-chloropropyne and ZnBr2 with LDA at low tempera-
ture, and its reactions studied <2001EJO3295, 2002EJO1385>. An example of a 1-mercuro-
1-silylalkene 255 has been prepared through the carbomercuration of 1-TMS-alkyne 256 using a
tethered allylic silane (Equation (44)). The (Z)-alkene 255 was formed exclusively via net syn
addition of mercuric chloride and the allylic moiety to the alkyne <1997JOC8595>.
Cp* TMS
Cp* + MeCN W
W TMS OC
OC C
CO –MeCN ð42Þ
N C O
Me
245
246
i. BunLi, –70 °C
Cy3P Cp* Cy3P Cp*
Ph Br ii. Cp*(PCy3)RuCl Ph Ru Ph Ru
H
Ph SiMe2H Cy = cyclohexyl Ph SiMe2H Ph Si
Me2
248
249 247
Scheme 46
TMS TMS R
C R N TMS
N AgPF6 TMS
Et3P R N Et3P
Et3P Et3P + Pd
Pd + Pd N
Cl PEt3 Pd Cl PEt
Cl PEt3 3 R
Cl PEt3
R = Me, C≡CPh
250 251 252
Scheme 47
i. BusLi
R ii. ZnBr2 R TMS
TMS C ð43Þ
254 ZnBr
R = Me, Pr 253
TMS TMS ClHg TMS

HgCl2
Me
50% ð44Þ
Me
256 255
4.23.2.1.4 Functions with one silicon and one group 13 or group 14 metal
Previously reported methods of preparing 1-alumino-1-silylalkenes include the hydroalumination
or carboalumination of silyl alkynes <1995COFGT(4)1043>, both of which have found contin-
ued use. Hydroalumination of dialkynes 257 (with or without a benzene linker) with di(t-butyl)-
aluminum hydride offers a facile method for the synthesis of 1-silyl-1-aluminoalkenes. The
reaction proceeds via cis addition of the aluminum hydride to each alkyne group to give
((Z),(Z))-dienes 258 (Scheme 48) <2000JOM(608)54>. Heating of 258 gave a stepwise rear-
rangement when the benzene linker was present to give the thermodynamically more stable
((E),(Z))-isomer 259, then ((E),(E))-isomer 260, although, in the absence of the benzene linker,
only mixtures of uncharacterized products were obtained. Extension of this method to 1,2,4,5-
tetrakis(TMS-ethynyl)benzene 261 gave either bis- or tetra-hydroaluminated products 262 and
263, respectively (Scheme 49), depending on the equivalents of aluminum hydride used
<2002JOM(664)110>. Carboalumination of eneynes 264 with Et3Al in the presence of catalytic
Cl2ZrCp2 gives aluminocycles 265 (Equation (45)) <1998TL2503>. 1-TMS-ethyne undergoes a
formal insertion into the AlN bond of dimeric pyrazolatoaluminum dihydride or dichloride, 266
(R = H or Cl) (Scheme 50). With 6 equiv. of TMS-ethyne compound 266 (R = H) gives the
TMS
But2Al H
t
TMS TMS + 2 Bu2 AlH
40–63% H AlBu2t
257 TMS
(Z ),(Z )
258
AlBu2t AlBu2t
TMS H TMS H
H AlBu2t H TMS
TMS Bu2t Al
(E ),(Z )
(E ),(E )
259
260
Scheme 48
TMS TMS TMS AlBu2t

TMS TMS AlBu2t
But2 Al
+ 2 Bu2t AlH + 4 Bu2t AlH TMS

TMS
AlBu2t
TMS But2 Al TMS

Bu2t Al TMS TMS TMS
261 263
262
Scheme 49
aluminocycle 267 <2000AG(E)3099>, whereas treatment of 266 (R = Cl) with 2 equiv. of TMS-
ethyne gives the dichloroaluminum species 268 in high yield <2001OM3299>. The remaining
chloride ligands on the aluminum center allow for further elaboration <2002EJI1056>. The
reactions are thought to proceed via initial dissociation of the dimeric pyrazolatoaluminum
dihydride, 266, with subsequent reaction with the TMS-alkyne.
Et3Al TMS
TMS cat. Cl2ZrCp2
n AlEt ð45Þ
n n = 1, 2
264 265
But But
But H But H
6 TMS N N 2 TMS
N R R N
2 TMS Al Al TMS
N Al R N N R N Al
R=H R = Cl
But t But Cl Cl
But Bu
TMS 268
TMS 266
267
Scheme 50
Previously reported methods of preparing 1-stannyl-1-silylalkenes include the hydrostannyla-

tion of silyl alkynes or the transmetallation of 1-lithio-, 1-magnesio-, or 1-titano-1-silylalkenes
with trialkylstannyl halides. The organoboration of 1-silyl-2-stannylalkynes also gives 1-stannyl-
1-silylalkenes via stannyl migration. 1-Silyl-1-stannylallenes were prepared by the BuLi-mediated
addition of trialkystannyl chlorides to terminal alkynes <1995COFGT(4)1043>.
Of these, the organoboration of 1-silyl-2-stannylalkynes has found the most extensive use in
recent times. For example, the reaction of 1-trihalostannyl-2-TMS-alkynes 269 with BEt3 gives the
organoboration products 270 (Equation (46)), although these slowly decompose due to the weak
SnC bond <2002JOM(646)125>. In a more complex example, treatment of tris(1-silyl-2-stanny-
lalkyne) 271 with BEt3 gave 272 in 55% yield, via a series of 1,1-organoboration reactions
(Scheme 51) <1995CC399>. The initial organoboration products are (Z)- and (E)-isomers, 273
and 274, but due to the reversibility of the organoboration the equilibrium is shifted toward the
(Z)-isomer 273 by further irreversible organoboration reactions, finally giving 272.
BEt3 X3Sn Et
X3Sn TMS
TMS BEt2 ð46Þ
X = Cl, Br
269 270
This approach has been used extensively to prepare stannole and silole derivatives, including
2-silylstannoles, 2-stannylsiloles, and fused derivatives <1999ICA(296)26, 1998JOM(562)207,
1999JOM(577)82, 2002JOM(649)232, 1995JOM(503)289>. 2-Plumbylstannoles have also been
prepared this way <1995JOM(503)289>. In some cases, other products containing the 1-silyl-
1-stannylalkene function have been isolated. For example, 1,4-stannabora-2,5-cyclohexadiene 275
was obtained along with the expected stannole derivative 276 through the treatment of dialky-
nylstannane 277 with BEt3 (Equation (47)) <2002JOM(649)232>. 1-Stannyl-2-silylalkynes also
react with triallylborane to give 1-silyl-1-stannylalkenes, although in some cases 2-stannylsiloles
were obtained. Thus, treatment of 1,1-bis(TMS-ethynyl)dimethyltin 278 with triallylborane gave
an initial reversible 1,1-allylboration, followed by intramolecular 1,2-allylboration to give 1-silyl-
1-stannylalkene 279, which rearranged to 280 upon heating (Scheme 52) <2002JOM(657)146>.
In contrast, 1-(TMS-ethynyl)-1-(trimethylstannylethynyl)dimethylsilane gave a 2-stannylsilole
derivative. 1-Propyl-1-boratetralins 281 (n = 2) react with 1-TMS-2-trimethylstannylethyne to
Me3Sn Et Me3Sn BEt2

Me2Si SnMe3
Me2 BEt3 Me2Si BEt2 Me2Si Et
H Si SnMe3 Me2 +
Me2 Me2
H Si SnMe3 H Si SnMe3
Me2Si SnMe3
Me2Si SnMe3 Me2Si SnMe3
271 273 274
Me3Sn Et Me3Sn Et
Me3Sn Et
Me2Si BEt Me2Si B
H H
Si Et Si Et
Me2Si Me2 SnMe3 Me2 SnMe3
272
SnMe3
Scheme 51
give ring enlarged 1-silyl-1-stannylalkene derivatives 282 with >95% selectivity via a 1,1-organo-
boration reaction (Scheme 53) <1996MI215>. The ring expansion is highly selective and gives
the (Z)-product with the silyl and boryl groups in cis positions. However, boraindane 281 (n = 1)
gave adduct 283, again via a 1,1-organoboration (Scheme 53) <1998MI515>.
TMS
TMS Et TMS
BEt3 Et
X2Sn X2Sn B Et + X2Sn
BEt2
TMS Et TMS
TMS
ð47Þ
275 276
277
Me2
Si
X= N ; (9-borabicyclo[3.3.1]nonyl)-TMS-amino
Si
Me2
TMS All TMS All

TMS
BAll3 ∆ Me2Sn B
Me2Sn Me2Sn BAll
All = allyl All
TMS All TMS
TMS
278 279 280
All = allyl
Scheme 52
Ph
R1
SnMe3
n + B
B >95% B 25 °C, 24 h TMS
SnMe3 R1 = H, n = 2 Pr TMS >85%
Pr Pr
TMS 281 R1 = Ph, n = 1 SnMe3
283
282
Scheme 53
The hydrostannylation of silyl alkynes has found continuing use as an approach to the 1-silyl-
1-stannylalkene motif. Bis(hydrostannylation) of 1-TMS-1,4-pentadiyne by H2SnBu2 gave stanna-
cycle 284 (Equation (48)) <1996OM1315>. In contrast, an efficient hydrosilylation of stannyl
alkynes to give 1-silyl-1-stannylalkenes has remained elusive. The use of organolanthanide cata-
lysts gave either no reaction or complex product mixtures <2002JOM(647)225>. The stannylme-
tallation of alkynoic acid 285 has been studied, and optimal results were obtained when higher-
order cuprates such as Bu3Sn(Bu)CuLi and LiCN were used as reagents, giving 1-silyl-1-stanny-
lalkenes 286, with poor conversions noted with stannylaluminum, stannylmagnesium, and stan-
nylzinc reagents (Equation (49)) <1998TL4277>. The silylcupration of TMS-ethyne provides
intermediate 1-cupro-1-silylalkene 287 (MR13 = TMS), which gives 288 (MR13 = TMS,
R2 = Bu) upon treatment with Bu3SnCl (Scheme 54) <2001JOC1961>. Similarly, stannylcu-
pration of TMS-ethyne has been achieved (Scheme 54), although the reaction is reversible, and
quenching of the intermediate 1-cupro-1-silylalkene 289 with Me3SnCl gave the expected 1-silyl-
1,2-bisstannylalkene 290 <2001JOC1961>.
TMS TMS
H2SnBu2
SnBu2 ð48Þ
67%
284
TMS Bu3Sn(Bu)CuLi, LiCN Bu3Sn OH

OH
then H2O TMS O ð49Þ
O
286
285
(ButPh2Si)2CuCNLi2 [Cu] SiButPh2 R23SnCl Bu3Sn SiButPh2

R13M
MR13 = TMS, SnBu3 R13M 97% R13M
287 288
MR13 = TMS; R2 = Bu: 97%

MR13 = SnBu3; R2 = Me: 75%
MR13 = SnBu3; R2 = Bu: 88%
Bu3Sn(R)CuCNLi2 [Cu] SnBu3 Me3SnCl Me3Sn SnBu3

TMS
R = Me, Bu TMS 72% TMS
289 290
Scheme 54
A new approach to 1-silyl-1-stannylalkenes is the transmetallation of organozirconium species

by organotin alkoxides as demonstrated by the transformation of 217 to 218 using Bu2Sn(OMe)2
(Scheme 37) <1995TL3725>. The driving force for the reaction is the formation of a strong
ZrO bond, and organotin halides performed less well in similar reactions. Vinylation of
2-methylphenol 291 using TMS-ethyne in the presence of the SnCl4–Bu3N reagent leads to an
intermediate -TMS--trichlorostannylstyrene 292, which can be trapped using MeLi then Ac2O
to give the -TMS--trimethylstannylstyrene 293 (Scheme 55) <1998SL1317>. Bis(TMS-alky-
nyl)manganese species 294 are thermally stable but highly reactive and undergo quantitative
reaction with Me3SnCl to give d6 trans-alkynylvinylidine manganese complex 295 (Equation (50))
<2001OM3122>.
OH HC ≡ CTMS O i. MeLi OAc

SnCl4–Bu3N TMS ii. Ac2O TMS
SnCl3 55% SnMe3
291 292 293
Scheme 55
PMe2 TMS
Me2P Me3SnCl Me2P PMe2 SnMe3
Mn M TMS Mn
Me2P
Me2P PMe2 TMS ð50Þ
PMe2 TMS
294 295
M = Li, Na
The treatment of 1-silyl-3-phenylpropynes 296 (M = Si, Ar = Ph) with (trialkylstannyl)dialk-

ylamines at high temperatures (140–160 C) gives 1-stannyl-1-silylallenes 297 (M = Si, Ar = Ph)
(Scheme 56) <1995MI1369>. With pentafluorophenyl-substituted silyl alkynes 296 (M = Si,
Ar = C6F5), the reaction proceeds at a much lower temperature, due to the significant increase
in the acidity of the propargylic methylene protons. With the isomeric 1-phenyl-3-silylpropynes
298 (M = Si, Ar = Ph), even higher temperatures are required to achieve reaction, and bisstan-
nylation occurs to give 1-silyl-1,3-distannylallenes 299 (M = Si, Ar = Ph) (Scheme 56). Increasing
the temperature of the reaction 296 (M = Si, Ar = C6F5) to 170–210 C also gives 1-silyl-1,3-dis-
tannylallenes 299 (M = Si, Ar = C6F5) (Scheme 56). The thermal isomerization of [-(silyloxy)-
propargyl]stannane 300 was reported to give a good yield of the [-(silyloxy)allenyl]stannane
301 via a 1,3-sigmatropic rearrangement (Equation (51)) <1997JOC8955>. 1-Silyl-1-stannyl-
ketene 73 (R3M = Bu3Sn) can be prepared from lithium ynolates 74 through quenching with
Bu3SnCl (Scheme 16) <1996JA7634>.
Me3Sn Ar Me3SnNEt2 Ar Me3SnNEt2 Me3Sn SnMe3

C Me3M C
Me3M H –HNEt2 –HNEt2 Ar MMe3
296
Ar = Ph: 140–160 °C Ar = C6F5
297 M = Si, Sn, Ge 170–210 °C 299
Ar = C6F5: rt
Me3SnNEt2 Me3Sn SnMe3

MMe3
C
Ar
Ar MMe3
298
299
M = Si, Sn; Ar = Ph
Scheme 56
OTMS 200 °C TMS OTMS

TMS C
10 min ð51Þ
SnPr3i Pr3i Sn
300 301
4.23.2.2 Boron Functions—R12C¼CBR23M

The only previously reviewed boron functions are 1-boryl-1-stannylalkenes, and these were
prepared through the hydro- and organoboration of stannyl alkynes <1995COFGT(4)1043>.
Continuing with this approach, allylboration of bis(alkynyl)stannanes 302 with triallylborane
gave heterocycles 303, via an initial 1,1-allylboration of one of the alkynes, followed by an
intramolecular 1,2-allylboration of the second alkyne unit (Scheme 57) <2002JOM(649)232,
2002JOM(657)146>. Rearrangement of 303 to 304 occurred upon heating. 1-Boryl-1-zirconaalk-
ene 305 was prepared through the hydrozirconation of 1-TMS-2-(pinacolboryl)ethyne 306 with
Cp2ZrClH (Equation (52)), and this was used as an intermediate in a highly stereocontrolled
formal synthesis of rac-chokol A and G <1996TL2735>.
Me Me All Me All Me2

∆ Si
BAll3 X2Sn BAll X2Sn B X = N(TMS)2; N
X2Sn
All = allyl Si
All Me2
Me All Me
Me
303 304
302
Scheme 57
O
O Cp2ZrClH TMS B O
TMS B ð52Þ
O THF, 30 min ZrCp2Cl
306 305
4.23.2.3 Germanium Functions—R12C¼CGeR23M

This class of compounds was reported as being poorly documented in COFGT (1995). 1-Stannyl-
and 1-alumino-1-germylalkenes can be prepared through the hydrostannylation or hydroalumina-
tion of 1-germylalkynes. 1-Stannyl- or 1-plumbyl-1-germylalkenes have been prepared through
the sequential transmetallation of 1,1-distannyl or diplumbyl alkenes with MeLi, then Me3GeCl
<1995COFGT(4)1043>. This area of chemistry has remained little explored, although new
approaches to 1-alumino- and 1-stannyl-1-germylalkenes have been reported. Trimethylgermyl-
substituted homopropargyl alcohol 307 gives cyclic 1-alumino-1-germylalkene 308 when treated
with AlMe3 and Cp2ZrCl2 (Equation (53)). Syn-methylalumination occurs initially, but reversal of
the stereochemistry occurs upon heating to give 308 <1997JOC784>. 1-Germyl-1-stannylallenes
have been prepared in direct analogy with 1-silyl-1-stannylallenes (Scheme 56) <1995MI1369>.
Thus, the treatment of 1-germyl-3-phenylpropynes 296 (M = Ge, Ar = Ph) with trialkylstannyl-
dialkylamines at high temperatures gives 1-stannyl-1-germylallenes 297 (M = Ge, Ar = Ph)
(Scheme 56). As before, replacement of the phenyl group of 296 with a pentafluorophenyl
moiety allows the transformation to occur at ambient temperature, and increasing the reaction
temperature to 170–210 C gives 1-germyl-1,3-distannylallenes 299 (M = Ge, Ar = C6F5)
<1995MI1369>.
i. Me3Al
Cp2ZrCl2 Me GeMe3
GeMe3 ii. Heat
ð53Þ
AlMe
OH >80% by NMR
O
307 308
4.23.3 FUNCTIONS CONTAINING A GROUP 1 METAL—R2C¼CLiM

Previously reported methods of preparing 1,1-dilithioalkenes include lithium–halogen exchange of
1,1-diiodoalkenes and transmetallation of 1,1-dimercurioalkenes. Dilithioallenes have been pre-
pared through the treatment of 3-hydroxy-3-TMS-prop-1-ynes with 2 equiv. of alkyllithiums.
1-Lithio-1-stannylalkenes can be prepared through transmetallation of 1,1-distannylalkenes.
1-Plumbyl-1-lithioalkenes can be prepared through the transmetallation of 1-stannyl-1-plumby-
lalkenes or 1,1-diplumbylalkenes. There have been no significant developments in the preparation
of these species since COFGT (1995) <1995COFGT(4)1043>.
4.23.4 FUNCTIONS CONTAINING A GROUP 2 METAL (AND NO GROUP 1

METAL)—R2C¼CMgXM, etc.
Previously reviewed methods of preparing 1,1-dimagnesioalkenes include the organomagnesiation
of propargylic alcohols. Use of eneynes gives 1,1-dimagnesioallenes. 1-Magnesio-1-stannylalkenes
have been prepared through transmetallation of 1-lithio-1-stannylalkenes and through magne-
sium–halogen exchange of 1-iodo-1-stannylalkenes. 1-Magnesio-1-zincoalkenes have been pre-
pared through treatment of 1-magnesio-propargylic alcohol derivatives with allylzinc reagents
<1995COFGT(4)1043>. There have been no significant developments in the preparation of these
species since COFGT (1995).
4.23.5 FUNCTIONS CONTAINING A TRANSITION METAL (AND NO GROUP 1 OR

GROUP 2 METAL)—R2C¼CTiM, etc.
Several of the title functions have been previously reviewed. 1-Zircona-1-aluminoalkenes and
1-titano-1-aluminoalkenes have been prepared by the treatment of alkynylalanes with either
Cp2ZrCl(Me) or Cp2TiCl(Me). Similarly, cyclic 1-stannyl-1-zirconaalkenes have been prepared
from 1-stannylalkynes containing an !-alkene group and Cp2ZrCl2. 1,1-Dizincoalkenes have been
prepared from an allylzinc bromide and either prop-2-ynol methyl ether or 1-zincoprop-2-ynol as
its zinc bromide salt. Dimercuration of alkynes and alkenes gives 1,1-dimercurioalkenes as does
treatment of 1,1-diborylalkenes with mercuric chloride <1995COFGT(4)1043>.
There have been few developments in this field, although some new functionalities have been
reported. 1,1-Dititanoethenes 309 have been prepared from organotitanium oxide species 310 and
ketones under thermal or photochemical conditions, via a hydride–vinylidine intermediate 311
(Scheme 58) <1998CC691>. Reaction times were significantly longer under photochemical
conditions. In direct analogy with the hydrotitanation of silyl alkynes, treatment of 1-trimethyl-
stannyl-2-phenylethyne 194 (M = Sn, R = Ph) with stabilized tris(aryloxy)titanium(IV) hydrides
195, gives 1-stannyl-1-titanoalkenes 196 (M = Sn, R = Ph) through stereospecific syn addition to
the triple bond (Equation (29)) <1995OM4601>. 1,1-Dipalladoalkenes have also been reported.
The vinylidene complex 312 was prepared through the reaction of [Pd2Cl2(DPPM)2]
(DPPM = bis(diphenylphosphinomethane)) with bis(methylthio)ethyne in the presence of
HBF4OEt2 (Equation (54)) or via a stepwise reaction using other Lewis acids <1995OM4257>.
A 1,1-dipalladoalkene was also obtained through the double insertion of Pd(PPh3)4 into a vinyl
dichloride species 313 (Scheme 59). The product was found to be fluxional in solution due to
nondissociative intramolecular flipping of a PPh3 ligand, but subsequent treatment with DPPM
led to derivative 314 <2003EJI514>.
Me H H O H H CHR1R2
Heat O
H
or hν R1 R 2
TiCp* TiCp* TiCp*
Cp*Ti Cp*Ti Cp*Ti
O O O
Ti 1 = R2 = Me, Ti
Ti R Ph
O Cp* O O Cp* O O Cp* O
R1 = Ph, R2 = Me, Et
310 46–77% 309
311
Scheme 58
MeS SMe
Ph2P PPh2 Ph2P PPh2
MeS SMe
Cl Pd Pd Cl
Cl Pd Pd Cl ð54Þ
HBF4.OEt2
Ph2P PPh2 65% Ph2P PPh2
312
Cl
Ph3P Cl
Cl Pd Ph3P
2Pd(PPh3)4 Pd
Ph Ph PPh3
PPh3 Ph
N Cl N Pd
Ph PhMe, 110 °C Cl N Pd
Ph Ph3P
49% Ph Ph3P Cl
313
2DPPM –3PPh3
Ph2
P Pd PPh2
Ph
N P Pd PPh2
DPPM = bis(diphenylphosphino)methane Ph Ph2
314
Scheme 59
4.23.6 FUNCTIONS CONTAINING A GROUP 13 OR GROUP 14 METAL

(AND NO GROUP 1, 2, OR TRANSITION METAL)—R2C¼CA1M, etc.
Previously published methods of preparing 1,1-dialuminoalkenes include the hydro- and carbo-
alumination of alanylalkynes. 1,1-Dithallyl alkenes have been prepared from alkynes and
thallium(III) acetate. 1,1-Distannyl alkenes have been prepared through the hydrostannylation,
sometimes photolytic, of stannyl alkynes; the addition and subsequent rearrangement of
1-boryl-2-stannyl alkenes to stannyl alkynes; treatment of 1,1-dibromoalkenes with stannyl-
lithium reagents; carbostannylation of trichlorostannyl alkynes; and heating of 1,1,1-tristannyl-
2-phenoxyalkanes. 1-Plumbyl-1-stannylalkenes have been prepared through transmetallation of
1,1-distannylalkynes with MeLi then Me3PbCl, which may also give 1,1-diplumbylalkenes,
depending upon the conditions <1995COFGT(4)1043>.
Bis(tributylstannyl)acrylates 315 can be prepared through the regioselective hydrostannylation
of 3-trimethylstannylacetylenic esters 316 under free radical conditions using Bu3SnH/AIBN in
the absence of a co-solvent (Equation (55)) <1998TL479>. In contrast, Pd-catalyzed hydrostan-
nylation of 316 gave only the unwanted 1,2-distannyl derivative. The subsequent reactions of
these species have been explored <1998TL481, 1998TL485, 1998TL489>. In direct analogy to the
silylcupration of silyl alkynes, silylcupration of stannyl alkynes gives 1-stannyl-1-cuproalkene
intermediates 287 (MR13 = SnBu3), which when quenched with trialkylstannyl halides give the
expected 1,1-distannylalkenes 288 (MR13 = SnBu3) (Scheme 54) <2001JOC1961>. The treatment
of N-(2,4,6-triisopropylbenzenesulfonyl)pyrroline with ButLi then (Me3Sn)2CuCNLi2, followed
by quenching with MeI and HMPA gave 4,4-bis(trimethylstannyl)-1-(2,4,6-triisopropyl-
benzenesulfonyl)-but-3-eneamine as a by-product <2001JOC531>. A range of ,-bis(trimethyl-
stannyl)styrenes 317 have been prepared by the organometal trapping of intermediates in the
vinylation of phenols or anilines with ethyne in the presence of SnCl4–Bu3N reagent (Scheme 60)
<1998SL1317> The initial intermediates can be trapped with MeLi and after treatment with
Ac2O (for phenols) or TFAA (for anilines) the moisture-sensitive bis(stannyl)styrenes can be
obtained, often in good yields. 2,6-Bis(distannylvinylation) of 4-substituted phenols has also been
achieved using modified conditions <1997CC1663>.
O O
R13SnH, cat. AIBN
OMe OMe
Bu3Sn Heat, 90 °C
R13Sn SnBu3
ð55Þ
316 315
R1 = Bu: 71%
R1 = Ph: 43%; 1/1 (E )/(Z )
i. MeLi O
XH HC ≡ CH X ii. Ac2O
Me/CF3 X
SnCl4–Bu3N SnCl3 or TFAA
SnMe3
R R
SnCl3 R
SnMe3
317
X = O; R = 4-MeO, 4-F, 2-F, 2-OTBDMS, 4-Cl, 2-Me, 2-Cl, 2-I-4-But: 47–89%

X = NH; R = H, 2-Me, 4-Me: 69–73%
Scheme 60
The organoboration of distannyl alkynes has been used extensively to prepare 1,1-distanny-
lalkenes. The treatment of 1,2-distannylalkynes with triallylborane at 40 C results in a
reversible 1,1-organoboration with migration of a stannyl group to give 1,1-distannylalkenes
318 in quantitative yield (Equation (56)) <2000ICA169>. 1-Propyl-1-boraindane 319
reacts with bis(trimethylstannyl)ethyne to give ring enlarged 1,1-bis(trimethylstannyl)alkene
derivatives 320 or both 320 and 321 via a 1,1-organoboration reaction (Scheme 61)
<1996MI215, 1998MI515>. Compounds 320 and 321 undergo further ring expansion with
excess bis(trimethylstannyl)ethyne to give 1,1-bis(trimethylstannyl)allenes 322 and 323
(Scheme 61). The reaction of 1-propylboratetralin 319 (n = 2) with bis(trimethylstannyl)ethyne
was originally expected to give a ring expanded product <1996MI215>, but further investiga-
tion determined that the product was 324. Compound 324 reacted with further bis(trimethyl-
stannyl)ethyne to give 325 (Scheme 61) <1998MI515>. Similar reactions were reported with
dialkyl- and cycloalkyl(N-azolyl)boranes and unsymmetrical cycloalkanylboranes
<1997JOM(541)97>.
SnMe3
–40 °C Me3Sn BAll2
BAll3 + ð56Þ
rt Me3Sn
SnMe3 All = allyl
318
1,1-Distannylallenes 297 (M = Sn) and 299 (M = Sn) have also been prepared by stannylation
of 1-stannyl-3-arylpropynes 296 (M = Sn) with Me3SnNEt2 (Scheme 56), in direct analogy
with the stannylation of 1-silyl-3-arylpropynes (Section 4.23.2.1.4) <1995MI1369>. The thermal
decomposition of ethoxyethynyl(trimethyl)tin 326 was monitored by 31Sn NMR and the
major component was thought to be bis(trimethystannyl)ketene 327, along with other by-products
(Equation (57)) <1999ZN(B)705>. 2-Stannyl- and 2-plumbylstannoles have been prepared from
1-(dialkylchlorostannyl)-2-diethylborylalkenes and trimethylstannyl and trimethylplumbylalkynes
<1995JOM(503)289>.
n Me3Sn SnMe3
n=1 Pr SnMe3
R1 + Me3Sn SnMe3 Pr B
B B SnMe3
Pr R1 R1
n
319
320 321
R1 = H, Ph, n = 1
R1 = H, Ph R1 = H
R1 = H, n = 2
Me3Sn SnMe3
n=2 Me3Sn SnMe3
SnMe3
Me3Sn
Pr SnMe3
B C B SnMe3
SnMe3 SnMe3
SnMe3
Pr SnMe3 C
SnMe3 B Pr SnMe3
324
R1 323
322
Me3Sn SnMe3
R1 = H, Ph
SnMe3
B
Me3Sn
C SnMe3
Me3Sn
Pr
325
Scheme 61
Bu3Sn
Bu3Sn OEt C O
CD3C6D5 Bu3Sn ð57Þ
326
100 °C 327
60% by 31Sn NMR
4.23.7 OTHER METAL DERIVATIVES

No examples, not already covered in other sections of this chapter, were found, as was the case in
COFGT (1995) <1995COFGT(4)1043>.
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2003OM2436 J. Ohshita, N. Honda, K. Nada, T. Iida, T. Mihara, Y. Matsuo, A. Kunai, A. Naka, M. Ishikawa,
Biographical sketch
Steven Collier was born in York, England, and attended the University
of Liverpool where he obtained a B.Sc. (Hons) in Chemistry with Indus-
trial Chemistry in 1994. He studied heterocyclic ortho-quinodimethanes
under the direction of Dr. Richard C. Storr, subsequently receiving his
Ph.D. in 1998. After holding temporary positions as a process develop-
ment chemist at Zeneca Specialties and Glaxo-Wellcome, Steve spent
2½ years at Ultrafine (UFC Ltd.), carrying out contract research and
development rising to the position of Project Team Leader. In 2001 he
joined the Chemical Development Department of Albany Molecular
Research, Inc., where he is currently involved in the process develop-
ment and scale-up of biologically active compounds. His scientific
interests include many aspects of organic and process chemistry, parti-
cularly the applications of high throughput reaction screening, statistical
Design of Experiment (DOE) and laboratory automation in process
development.
4.24
Tri- and Dicoordinated Ions,
Radicals, and Carbenes Bearing
Two Heteroatoms (RX2C+, RX2C,
RX2C, X2C:)
A. J. ARDUENGO and D. ŢAPU
University of Alabama, Tuscaloosa, AL, USA

4.24.2 CATIONS 1104
4.24.2.1 Cation Centers with Pendant Group 15 Elements 1104
4.24.2.2 Cation Centers with Pendant Group 16 Elements 1104
4.24.3 ANIONS 1105
4.24.3.1 Anion Centers with Pendant Group 14 Elements 1105
4.24.4 RADICALS 1106
4.24.4.1 Radical Centers with Pendant Group 14 Elements 1106
4.24.4.2 Radical Centers with Pendant Group 15 Elements 1107
4.24.5 CARBENES 1107
4.24.5.1 Stable Singlet (Nucleophilic) Carbenes 1108
4.24.5.1.1 Nucleophilic N,N-carbenes: general synthetic methods 1108
4.24.5.1.2 Diaminocarbenes and other aminocarbenes 1109
4.24.5.1.3 Nucleophilic P,E-carbenes (phosphinocarbenes) 1110
4.24.5.2 Electrophilic Carbenes 1111
4.24.5.2.1 Electrophilic carbenes with pendant group 13 elements 1111
4.24.5.3 Cationic Carbene Adducts 1112
4.24.5.3.1 Carbocations with pendant group 1 elements 1112
4.24.5.3.8 Carbocations with pendant transition metals 1117
4.24.5.3.9 Carbocations with pendant lanthanide and actinide elements 1119
4.24.5.4 Anionic Carbene Adducts 1120
4.24.5.4.1 Carbanions with pendant group 14 elements 1120
4.24.5.5 Triplet Carbenes (as Analogs for Radicals) 1121
1103
1104 Tri- and Dicoordinated Ions, Radicals, and Carbenes Bearing Two Heteroatoms
4.24.1 INTRODUCTION
In order to continue the article of William M. Horspool in COFGT (1995)
<1995COFGT(4)1071>, who gave an early overview of the wide variety of carbon species
bearing two heteroatomic substituents, the results in this field are updated for this chapter.
Because the understanding of carbene chemistry has advanced dramatically since the 1990s, a
special emphasis is placed on the carbene section.
4.24.2 CATIONS
4.24.2.1 Cation Centers with Pendant Group 15 Elements

The stable ionic salt 1 was obtained in nearly quantitative yield via reduction of CF3SSCF3 by
two single-electron transfer steps. This salt was found to be stable up to its melting point
<2000JCS(P1)2183>.
CF3SSCF3
Me2N NMe2 Monoglyme Me2N NMe2
–
2SCF3 ð1Þ
Me2N NMe2 –20 °C to rt Me2N NMe2
N2, 0.5 h
1
Bis(diethylamino)carbenium dithiocarboxylate 2 was methylated with methyl iodide to form the

carbenium salt 3 quantitatively <1997TL5013>.
Et2N S Et2N S
X– X = I, BF4
Et2N S Et2N SMe
2 3
An unexpected cationic product, 4, was obtained from the reaction of INPPh3 with thallium in
THF suspension (Equation (2)) <2002ZAAC428>.
PPh3
N N=PPh3
THF O –
I ð2Þ
C4H8O + 12 INPPh3 + 10 Tl
–8 HNPPh3 Ph3P=N N=PPh3
–10 Tll I
4
For other examples of carbocations flanked by two nitrogen atoms see Sections 4.24.5.3.1 and
4.24.5.3.4.
4.24.2.2 Cation Centers with Pendant Group 16 Elements

In addition to the fission of CC bonds, which was reviewed by Horspool
<1995COFGT(4)1071>, another method of synthesis of cations flanked by two oxygen atoms,
is the protonation of carboxylic acid and their derivatives. For example, the reaction of formic
acid in the superacidic system HF/MF5 (M=As, Sb) led to dihydroxy carbenium hexafluorome-
tallates 5. Under inert conditions, they are stable at 40 C for some weeks <1996ZAAC1404>.
Similarly, the reaction of oxalic acid in HF/SbF5 afforded, dependent on the reaction tempera-
ture, different products. At 75 C, monoprotonation to HO(O)CC(OH)2+SbF6 6 occurred,
whereas at 40 C salt 7 was formed <1999ZAAC1479>.
Tri- and Dicoordinated Ions, Radicals, and Carbenes Bearing Two Heteroatoms 1105
OH HO OH HO OH
– – –
HC+ MF6 + SbF6 + + (SbF6 )2
OH O OH HO OH
5 6 7
An ion of the type represented by salt 9 can be prepared by the reaction of 8 with trimethylox-
onium tetrafluoroborate (Me3O+BF4) in dichloromethane under reflux for 20 h (Equation (3))
<1999JA10644>. Akiba and co-workers formulated structure 9 not as an isolated carbocation,
but rather as the first example of a structurally characterized 10-C-5 hypervalent carbon 9a.
MeO OMe
O OMe MeO OMe
MeO OMe MeO OMe MeO OMe
–
Me3O+BF4 ð3Þ
CH2Cl2
B2F7– B2F7–
8 9 9a
In addition to the methods reviewed by Horspool <1995COFGT(4)1071>, oxidation can also

be used as a synthetic approach to the cations bearing two sulfur atoms. Thus, iodine was used to
convert 10 into bicyclic dication 11 in almost quantitative yield <1997CC2325>.
( )n ( )n
S S S S
S S S S
( )n ( )n
10 n = 1, 2 11
4.24.3 ANIONS
4.24.3.1 Anion Centers with Pendant Group 14 Elements

One example of an anion bearing silicon and phosphorus was reported in 2000. The salt 12 was
prepared in 56% yield by the reaction of Me2P-CH(SiMe3)-C6H3-3,5-Me2 and n-butyllithium/
TMEDA. In the solid state, this salt consists of solvent-separated ion pairs <2000ZN(B)1114>.
SiMe3
PMe2
[Li(TMEDA)2]+
12

Weiss and co-workers reported an example of a carbanion bearing two nitrogen atoms. They
obtained 14 in 75% yield from the cyclic salt 13 in the presence of 2,20 -bipyridine <1998AG(E)344>.
N N N – N
+ + + +
–
H H 2OTf OTf–
H
13 14
Compound 15 is an example of an anion flanked by two phosphorus atoms. It was obtained by

the deprotonation of CH2(Ph2P¼NSiMe3)2 with MN(SiMe3)2 (M = Na, Li) in toluene
<2000IC4981>. Excess n-butyllithium was used to deprotonate tris(phosphine oxide),
{Ph2P(O)}2CHCH2P(O)Ph2, to give the dianion 16, the first example of a formal 1,2-dicarbanion
stabilized by phosphorus <2002CC2532>.
H O
Ph Ph O
Ph P P Ph Ph2P PPh2
N N M+
Me3Si SiMe3 H PPh2
O
15 16
In Section 4.24.3.1 one example of a carbanion flanked by silicon and phosphorus is described.
The asymmetrically substituted iminium salt, [Et3PNAsPh3]Br, reacted in the presence of
potassium hydride with acetonitrile to form an anionic center 17 bearing two pendant arsonium
cations and a cyano group stabilizing the anionic center <1998ZAAC1341>.
+
Ph3As
CN
Ph3As+ Br–
17

The formation of anions flanked by two sulfur atoms is a common step in many synthetic
strategies. Typically, a dithioacetal is treated with a base at low temperature to afford the
corresponding anion. As Horspool pointed out, both substitution and changes in the oxidation
level of the sulfur do not affect the efficacy of this reaction <1995COFGT(4)1071>. Cyano-
substituted anion 18 was prepared by one-pot reaction using stepwise trifluoromethylsulfonation
of acetonitrile. Deprotonation of CH3CN with 3 equiv. of butyllithium followed by the treatment
with 2 equiv. of trifluoromethylsulfonylfluoride afforded the methanide 18. It was isolated as a
caesium salt <1998HAC565>.
SO2CF3
NC Cs+
SO2CF3
18
4.24.4 RADICALS
4.24.4.1 Radical Centers with Pendant Group 14 Elements

Radical 20 was the first isolated and X-ray characterized alkyl radical bearing two heteroatoms,
which was not stabilized by the conjugation with adjacent unsaturated bonds. It was prepared in
15% yield by the reaction of 19 with a twofold excess of Et3GeLi in THF <1999JA8118>.
R2
O
Si
R2Si SiR2 Ad = Adamantyl
(Me3Si)3Si Ad
R = SiMe3
Ad
19 20
4.24.4.2 Radical Centers with Pendant Group 15 Elements

The crystalline 1,3-diphosphacyclobutane-2,4-diyl 22 was readily available from 21 by halogen–
metal exchange in the presence of n-butyllithium and subsequent t-BuOH addition
<1999AG(E)3028>.
Cl H
Mes P P Mes Mes P P Mes
SiMe3 SiMe3 Mes = 2,4,6-Bu3t C6H2
21 22
4.24.5 CARBENES
Since the discovery, in 1991, of stable nucleophilic carbenes, these compounds have become
important as ligands in organometallic chemistry and modern homogeneous catalysis. Carbene
complexes of late transition metals such as ruthenium and palladium possess the highest catalytic
activities in olefin metathesis and Heck-type reactions. These nucleophilic carbenes have devel-
oped as catalysts in their own right, even in the absence of transition metals. The chemistry of
these nucleophilic carbenes is rapidly growing and forms a convenient framework that can serve
to organize this chapter. Adduct formation of nucleophilic carbenes with electrophiles leads to a
cation (at least formally) at the former carbene center (e.g., carbenium ions arise from the
protonation of carbenes). Similarly, electrophilic carbenes form carbanion centers upon reaction
with nucleophiles (e.g., chloride addition to dichlorocarbene produces the trichloromethyl anion)
(Scheme 1).
R R R R
+ E+ E + Nu– Nu
R R R R
Scheme 1
With cationic electrophiles or anionic nucleophiles, the relationships described above are
conceptually simple. A complexity arises in cases where the electrophile or nucleophile is
neutral. To overcome this complexity carbene adducts of neutral electrophiles and nucleo-
philes are viewed as their charge separated zwitterionic structures. For strongly nucleophilic
carbenes or strongly electrophilic carbenes this reliance on zwitterionic structures for classifi-
cation has added validity because the substituents on these carbenes favor charge-separated
structures (Scheme 2).
R R R R
–
+ E E + Nu Nu+
R R R R
Scheme 2
The chemistry described in this section is organized along these conceptual lines. Advances in
the chemistry of carbenes are used as entry and reference points for the cationic and anionic
carbon centers that conform to the substituent constraints of this chapter. In general, the ease of
handling and widespread availability of nucleophilic carbenes has led to greater productivity than
from the less stable and difficult to handle electrophilic carbenes.
4.24.5.1 Stable Singlet (Nucleophilic) Carbenes
4.24.5.1.1 Nucleophilic N,N-carbenes: general synthetic methods

The ylidenes A and B are monomeric nucleophilic carbenes derived from imidazoles and triazoles.
With only one exception (R = mesityl), all related CC saturated (imidazolinylidene) carbenes C
dimerize to the corresponding diaminocarbene dimer D.
The electronic structure of the stable carbene center of an imidazol-2-ylidene A or triazol-
2-ylidene B can be simplified to a strongly bent singlet carbene model (1A1) in which the carbene
carbon is approximately sp2 hybridized. The two substituents and a lone pair of electrons occupy
the three sp2-hydrid orbitals, and a formally vacant p-orbital remains at carbon.
R R R R R
N N N N N N
N N N N N
R R R R R
A B C D
(i) Carbenes from imidazolium and triazolium ions via deprotonation

The deprotonation of imidazolium ions with a strong base such as sodium or potassium hydride
proceeded smoothly in the presence of catalytic amounts of potassium t-butoxide or DMSO
(Equation (4)) <1991JA361>. The first isolated imidazol-2-ylidene 23 proved to be remarkably
stable both in the solution and in the solid state. Carbene 23 melts at 240 C without decomposi-
tion. A solution of the 1,3-bis(1-adamantyl)imidazol-2-ylidene in THF-d8, sealed under a few
atmospheres of CO, has shown no decomposition or change after 7 years at room temperature
<2002UP001>.
Ad Ad
N THF N
H + NaH
N DMSO anion ð4Þ
N
Cl (cat.)
Ad Ad
23
Deprotonation with sodium hydride or potassium amide occurred quickly and quantitatively
in liquid ammonia providing imidazol-2-ylidenes, but the method is unsuitable for imidazolin-
2-ylidenes, which react with ammonia <1996MI1627, 1996MI772>.
(ii) Carbenes from imidazolethiones via reduction

A different approach to the alkyl-substituted nucleophilic carbenes was introduced by Kuhn and
co-workers. This original synthetic strategy relied on the reduction of imidazol-2-thiones 24 with
potassium in boiling THF (Equation (5)) <1993S561>.
R R
Me N Me N
K, THF, ∆
S
N N
ð5Þ
Me Me
R R
24 R = Me, Et, Pr i
(iii) Carbenes via -elimination

1,2,4-Triazol-5-ylidene 26 was obtained at 80 C and 0.1 mbar by -elimination of methanol from
the corresponding 5-methoxytriazole 25 in the solid state (Equation (6)) <1995AG(E)1021>.
Ph Ph
Ph N H 80 °C 0.1 mbar, Ph N
N N OMe –MeOH N N ð6Þ
Ph Ph
25 26
4.24.5.1.2 Diaminocarbenes and other aminocarbenes
(i) Cyclic diaminocarbenes

Using the methods outlined in Section 4.24.5.1.1, a broad variety of imidazol-2-ylidenes (27–30)
were prepared. They are stable and show no tendency to dimerize <1991JA361, 1993S561,
1994JA6641, 1992JA5530, 1997JA12742>.
R R1 Ph Mes
N Me N Ph N Cl N
N Me N Ph N Cl N
R R1 Ph Mes
27 28 29 30
R = Ad, Mes, Tol, R1 = Me, Et, Pri Mes = Mesityl
p-ClPh, Me, But, Ad = Adamantyl
In general, imidazolin-2-ylidenes were unstable and dimerized rapidly. In 1995, Arduengo and
co-workers succeeded in synthesizing imidazolin-2-ylidene 31 by the deprotonation of an imida-
zolinium salt (Equation (7)) <1995JA11027>.
Mes Mes
N THF N
H + KH
–KCl, –H2 ð7Þ
N N
Cl–
Mes Mes
31
Diisopropyl-3,4,5,6-tetrahydropyrimid-2-ylidene 32 was prepared in 40% yield by deprotona-

tion of the corresponding tetrahydropyrimidinium salt with NaN(SiMe3)2. The melting point of
this stable diaminocarbene is close to ambient temperature <1999CC241>.
Hahn and co-workers showed that a stable nucleophilic benzannulated imidazole carbene
33 could be synthesized under Kuhn’s reductive conditions from the corresponding
N,N0 -bis(2,2-dimethylpropyl)benzimidazol-2-thione, which was prepared in a three-step procedure
from o-phenylenediamine <1999MI1931>.
But
Pri
N N
N N
Pri
But
32 33
(ii) Acyclic diaminocarbenes

Bis(diisopropylamino)carbene 34, the first stable acyclic carbene, was prepared by Alder by the
deprotonation of N,N,N0 ,N0 -tetra-isopropylformamidinium chloride with lithium dimethylamide
in THF (Equation (8)) <1996AG(E)1121>. A year later, another two examples were reported
<1997CC1513>.
Pri Pri
Pri N LDA Pri N
H– ð8Þ
Pri N Cl THF Pri N
Pri Pri
34
(iii) Other aminocarbenes

The same synthetic routes described in Section 4.24.5.1.1 were used to prepare a number of stable
aminocarbenes containing a weaker -donor substituent, e.g., aryloxy 35, arylsulfido 36, or
sulfido 37 groups <1997LA365, 1998JA11526>.
Pri Me
Pri N Me N
Pri
O But S But Me Pri
N
But But
Me S
35 36 37
The (amino)(aryl)carbenes 39 were isolated at room temperature in almost quantitative yields

by the deprotonation of the corresponding iminium salts 38 Equation (9)) <2001SCI1901>.
F 3C F3C
KH
H3C H3C
N –H2 N
R + C R ð9Þ
H CF3 CF3
38 R = But, Ad, Pri 39
4.24.5.1.3 Nucleophilic P,E-carbenes (phosphinocarbenes)

Bertrand and co-workers have used with great success photochemically induced loss of nitrogen
from diazo compounds to prepare systems that can be formulated as carbenes where the
‘‘carbene’’ center is flanked by at least one phosphorus 40.
X X
+ –
P C P C X = SiR3, PR3, Ar
40a 40b
Preparation of (phosphino)(silyl)carbenes was previously reviewed by Horspool in Section

4.24.5.4.1<1995COFGT(4)1071>. A broad range of (phosphino)(alkyl)- and (phosphino)(aryl)-
carbenes were prepared by photolysis of their diazo precursors <2000SCI834, 2002AG(E)2835,
2003JA124>. The influence of the steric and electronic properties on the structure and stability of
these carbenes was studied experimentally and theoretically. Carbene 41 was stable for weeks at
room temperature both in the solution and in the solid state <2000SCI834>.
F3C
Pri
P
Pri
CF3
41
Stable (amino)(phosphino)carbenes 43 were generated cleanly at 78 C by the deprotonation

of the corresponding phosphinoiminium salt 42 with the lithium salt of hexamethyldisilazane
(Equation (10)). Their stabilities were dependent on the nature of the substituents at phosphorus.
All compounds were stable for days at temperatures below 20 C <2002JA6806>.
–
X
R2P + Pri LiHMDS R2P Pri
C N C N ð10Þ
H Pri –78 °C Pri
R = c-Hex2N, Pr2i N, Ph, But
42 43 X = CF3SO3
Recently, it was shown that (amino)(phosphino)carbene 44 can be transformed into

(amino)(phosphonio)carbene 45, which undergoes nucleophilic substitution reactions at the carbene
center. A variety of carbenes such as 46 and 47 were synthesized starting from a single carbene
precursor (Scheme 3) <2003SCI1223>.
But Pri MeOTf Me Pri

TfO
P N But P N
But C Pri –30 °C t C Pri
Bu
44 45
2,6-Me2C6H3SLi Pri
S N
–78 °C C Pri
45 46
Pri
2-ButC6H4OK
O N
–78 °C C Pri
But
47
Scheme 3
4.24.5.2 Electrophilic Carbenes
4.24.5.2.1 Electrophilic carbenes with pendant group 13 elements

No diborylcarbene has been isolated yet. However, borylmethyleneboranes 48 <1983AG(E)877>
and 49 <1995AG(E)1340> were employed as their synthetic equivalents as experimentally
demonstrated by the trapping reactions (see Section 4.24.5.4).
But R R = Me, Et, Neopentyl

B B R2
TMS R2 B R1 = 2,3,5,6-Me4C6H
But
B R 1 R2 = CR=C=C(SiMe3)2
TMS
48 49

Diazotetracyanocyclopentadiene 50 <1966JA4055>, diazotetrakis (trifluoromethyl)cyclopentadiene
51 <1983JA3563, 1984TL405>, and diazo(1,4-diethoxycarbonyl-2,3-dicyano)cyclopentadiene
52 <1994JPR145> have been used as thermal precursors to reactive electrophilic carbene intermedi-
ates. These carbenes are strongly electrophilic in character and were used to synthesize a variety of
ylides (see Section 4.24.5.4).
CN CF3 CO2C2H5
NC F3C NC
N2 N2 N2
NC F3C NC
CN CF3 CO2C2H5
50 51 52

Sheppard and Webster used diazodicyanoimidazole 53 to form a reactive electrophilic carbene
that attacked the halogen of arylhalides to form a fairly stable series of chloronium, bromonium,
and iodonium ylides <1973JA2695>.
NC N
N2
NC N
53
4.24.5.3 Cationic Carbene Adducts
4.24.5.3.1 Carbocations with pendant group 1 elements

Arduengo developed a one-pot synthesis of imidazolium ions that allows the production of various
substituted imidazolium ions that are not accessible by conventional routes (Equation (11))
<1991USP5077414>.
R1
R1
–
R4 H2N
O H R4 N
O + HX H
H –3H2O
R3 O R3 N X
–
H2N ð11Þ
R2
–
R2
R1, R2 = hydrocarbyl or substituted hydrocarbyl

R3, R4 = H, hydrocarbyl or substituted hydrocarbyl
X = anion
Another source for imidazolium ions was reported from the oxidation of imidazol-2-thiones
(Equation (12)) <1998AG(E)1963>.
Ph Ph
Ph N Ph N
CH3COOH
S + 3H2O2 H ð12Þ
Ph N –2H 2O Ph N –
HSO4
Ph Ph
Carbene 54 reacted with 1,3-dimesitylimidazolium salt 55 to form the bis(carbene)proton

complex 56. These complexes were the first structurally characterized species with a CHC
three-center four-electron interaction (Equation (13)) <1995JA572>.
Mes Mes Mes Mes
H N N H H N N H
THF –
: + H H
N N H N X– N ð13Þ
H X– H H
Mes Mes Mes Mes
54 55 56
X = PF6, CF3SO3
Dimeric nucleophilic carbene–alkali metal adducts were characterized for lithium, sodium, and
potassium. Bis(t-butyl)imidazol-2-ylidene or tetrahydropyrimid-2-ylidene reacted with alkali
metal (2,4,6-trimethyl)phenolates or bis(trimethylsilyl)amides to give the alkoxy-bridged lithium
dimer 57 <1996MI001> and amido-bridged dimer 58 <1999CC241>.
A lithium-cyclopentadienyl derivative 59 was reported for an imidazol-2-ylidenes <1999CL1021>.
TMS
But Ar But Pri R R Pri
TMS TMS
N – O – N N N N
+
– – – But
+ Li Li + M M + Li
N
N O N N N +
N
But Ar But Pri R R Pr
i N
But
57 58 59
Ar = 2,4,6-Me3C6H2 M = Li, Na, K; R = TMS

Reaction of 1,3-dimethylimidazol-2-ylidene with polymeric BeCl2 resulted in the formation of the
cationic 3:1 adduct 60 <1995JOM(501)C1>. Imidazol-2-ylidenes reacted with diethylmagnesium
to afford the corresponding 1:1 adducts 61 <1993JOM(462)13>.
Me
Me N R
+ –
N 2– Cl N – Et
N
+ Be + Mg
N Cl Me N Et
Me R
Me
+ N
Me N
R = Ad, Mes
60 61
Imidazol-2-ylidenes formed a variety of 2:1 or 1:1 adducts of type 62 <1997MI002> or 63

<1998OM3375> with magnesium, calcium, strontium, and barium.
R
R N
+ Me
N 2–
N Me
+ M N –
R + M
N N(SiMe3)2
R Me N
N(SiMe3)2
Me
62 63
M = Ca, Sr, Ba
M = Mg, Ca, Sr, Ba
R = Me, But
The Cp* ligands in these complexes bind in different modes depending on the metal. For Ca,
Sr, and Ba both C5Me5 rings were 5-coordinated to the metal. In the case of magnesium, one
cyclopentadienyl ring was 5-bound; the other exhibited a ‘‘slipped geometry’’. The stability of these
complexes decreased from calcium to barium.

The first nucleophilic carbene group 13 element complex to be isolated was the imidazol-2-ylidene-
alane complex 64 (Equation (14)) <1992JA9724>. Since then, a large number of carbene group
13 element complexes were reported and some are summarized in Equation (14). It was suggested
that the imidazole fragment in these complexes has an electronic structure that is intermediate
between those of the free carbene and imidazolium ion.
E R1 R2 X References
B Me Me H 1993CB 2041
R1 R1 Et Me H 1993CB 2041
R2 N R2 N
EX3 Al Pri Me H 1993CB 2041
EX3 Mes H H 1992JA9724
R2 N R2 N ð14Þ
Pri Me Me 1996CC2683
R1 R1 Ga Pri Me Me 1996CC2683
64 In Pri Me Cl 1997JCS(D)4313
Pri Me Br 1997JCS(D)4313
Pri Me H 1998CC869
The reaction of phosphinosilyl ‘‘carbene’’ 65 with AlCl3, GaCl3, or InCl3 in ethyl ether at 25 C
affords 1:1 adducts 66 (Equation (15)) <1994AG(E)578>. A related adduct was obtained from
the reaction of 65 with BEt3. This triethylborane adduct is stable in solution for several weeks at
20 C or for 24 h at room temperature <1993CC1354>.
(R2N)2P ECl3 (R2N)2P –

C ECl3
Me3Si Me3Si ð15Þ
65 66
R = cyclo-C6H11 E = Al, Ga, In

There are known adducts of all the elements in this group. Heterocumulenes such as carbon
dioxide, carbon disulfide, phenylisothiocyanate, or diisopropylcarbodiimide reacted with
imidazol-2-ylidene and 1,2,4-triazol-5-ylidene to give the corresponding zwitterions 67 and 68 in
good yields <1999ZN(B)427, 1999ZAAC851, 1999ZN(B)434, 1994ZN(B)1473, 1997CC627>.
Pri Ph
Me N X Ph N Y
+ –
C + C –
N X N N
Me Z
Pri Ph
67 68
X = O, S, NPri Y = S; Z = S, NPh
2-Methylimidazolium salt 70 was isolated as an intermediate in the reaction of 1,3-bis(mesityl)-

imidazolin-2-ylidene 69 with methyl iodide (Scheme 4) <1997JA12742>.
Carbene adducts with (semi)metals of group 14 are known with main group element in oxidation
state II or IV. Pentacoordinate silicon derivatives 71 and 72 formed when imidazol-2-ylidenes were
treated with dimethyl- or diphenyldichlorosilane or tetrachlorosilane <1995CB245>. Compound
73 is an example of a tricoordinated silicon derivative <1999CC755>.
Mes Mes Mes

Mes
N N 69 N
N
+ CH3I CH3 H
CH2 +
N N or KH N
I N I
Mes Mes Mes
Mes
69 70
Scheme 4
R R
–
N Cl Cl
1 N N N
+ Si R1 +
–
Si Cl +
–
Si
N R Cl
Cl N Cl N N
R R
71 72 73
R1 = Ph, Me R = Me, Et, Pri
The germanium(II) and tin(II) halides 74 <1993IC1541> and 75 <1995CB245> were obtained
starting from imidazol-2-ylidenes and GeI2 or SnCl2. A pentacoordinated tin adduct 76 was
obtained from imidazol-2-ylidenes and diphenyldichlorostannane <1995CB245>. Plumbene–
imidazole carbene complex 77 [Ar=2,4,6-(Pri)3C6H2] was generated in the reaction of an imidazol-
2-ylidene with a bis(aryl)-lead(II) compound <1999CC1131>.
Mes R R Pri
N – N – N Cl N
– –
+ Ge + Sn + Sn Ph + Pb
N I N Cl N Ph N Ar
I Cl Cl Ar
Mes R R Pri
74 75 76 77
R = Me, Et, Pri
Phosphinosilylcarbenes also react with germanium(II) or tin(II) compounds with putative

formation of similar adducts that undergo subsequent rearrangements <1992IC3493>.

Adducts of imidazol-2-ylidenes with pnictinidenes 78 were generated by the reaction of free
carbenes with cyclopolyphosphines (PPh)5 and (PCF3)4 and cyclopolyarsines (AsPh)6 and
(AsC6F5)4 (Equation (16)) <1997CL143, 1997IC2151>.
R1 R1 R1 R2 R3 E Yield (%)
R2 N R2 N
(ER3) n Me Me Ph P 79
E
Mes H Ph P 67 ð16Þ
R2 N R2 N R3 Mes H CF3 P 90
R1 R1
Mes H Ph As 45
78 Mes H C6F5 As 61
Phosphoranide 80 has been obtained in 100% yield by the reaction of 1,3-bis(mesityl)imidazol-

2-ylidene 79 with phenyltetrafluorophosphorane (Equation (17)) <1997JA3381>.
Mes Mes
N F
F N F F
+ P
+ F P 100% ð17Þ
N F N F F
Mes Mes
79 80
The phosphino-imidazolium salt 81 was the product of the reaction between 1,3-diisopropyl-
4,5-dimethylimidazol-2-ylidene and chlorodiphenylphosphine <1999ZAAC729>. Imidazol-2-
ylidene 30 reacts with pnictogen pentafluorides (EF5; E=P, As, Sb) or Sb(CF3)3 to give the
corresponding adducts 82 <2000M251> or 83, respectively <1999ZAAC1813>.
Pri Mes Mes

Me N Ph Cl N Cl N
P X– EF5 Sb(CF3)3
Me N Ph Cl N Cl N
Pri Mes Mes
81 82 83
X = Cl, AlCl4 E = P, As, Sb

A variety of imidazolium chalcogenides 84 was obtained from imidazol-2-ylidenes and elemental
chalcogens (Equation (18)) <1999MI1931, 1993CB2047, 1993ZN(B)973, 1993HAC409>. Similar
adducts were reported for 1,2,4-triazol-5-ylidene with oxygen, sulfur, and selenium
<1995AG(E)1021>.
Yield
R R1 E (%)
R R
R1 R1 Me Me Se 84
N En N
E Et Me Se 88
R1 N R1 N Pri Me Se 85
ð18Þ
R R Me Me Te 91
84 Et Me Te 90
Pri Me Te 94
Mes H Te 100
Mes Cl Te 100
By the reaction of 1,3-diisopropyl-4,5-dimethyl-imidazol-2-ylidene with SOCl2 and SCl2, hyper-

valent sulfur adducts 85 and 86 were formed in 30% and 66% yield, respectively (Equation (19))
<1996CB1579>.
Pri Pri
Me N Me N
ECl2 –
ECl2 ð19Þ
Me N Me N 85 E = S
Pri Pri 86 E = SO
By the oxidation of a 2-telluroimidazoline with iodine, a TeI2 adduct of carbene was obtained
in 87% yield <1996ZN(B)295>. This latter reaction is analogous to the oxidation of an imidazol-
2-thione by bromine or chlorine that was reported by Arduengo and Burgess in 1977 (Equation (20))
<1977JA2376>.
Me Me
N N X
X2
S S– ð20Þ
N N X
Me Me
X2 = Br2, Cl2

A reverse ylide, 87, formed from the reaction of a 1,3-di(1-adamantyl)imidazol-2-ylidene with
iodopentafluorobenzene (Equation (21)) <1991JA9704>.
Ad Ad F F
N N
+ IC6F5 I F ð21Þ
N N
Ad Ad F F
87
Similarly, 1,3-dimesitylimidazol-2-ylidene reacted with 2-iodoimidazolium salt 88 giving the

symmetrical compound 89 in 69% yield (Equation (22)) <1994JA3625>.
Mes Mes Mes Mes
H N N H H N N H
+ I I
H N X– N H H N X– N H ð22Þ
Mes Mes Mes Mes
88 89
X = I, BPh4
A stable adduct 90 was obtained in 62% yield by the reaction of iodine with 1,3-diethyl-4,5-
dimethylimidazol-2-ylidene (Equation (23)) <1993CC1778>.
Et Et
Me N Me N
I2 –
I I ð23Þ
Me N 62% N X–
Me
Et Et
90
Sulfuryl chloride reacted with 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene to form chloroi-

midazolium salt 91 (Equation (24)) <1994CC2283>.
Pri Pri
Me N Me N
ClSO2Cl
+ Cl ð24Þ
–
Me N Me N SO2Cl
Pri Pri
91
4.24.5.3.8 Carbocations with pendant transition metals

Carbene complexes of many metals of the periodic table are known. Access to these compounds is
mainly based on three different synthetic routes: (i) the complexation of the free, pre-isolated
carbene; (ii) the in situ deprotonation of carbene precursors (carbenium ions); and (iii) the
cleavage of electron-rich olefins (Scheme 5). Less general methods, mainly of importance in
special cases, will be mentioned at the end of this chapter.
R
R1 N (a) [MXLn]
H
Y N –HX R R R
R1 N R1 N N R1
R (c) MLn + 1
1/2
MLn
R Y N –L N N
R1 R1
R1 N (b) MLn + 1 R R
R
Y N –L
R
Scheme 5
(i) The use of an isolated carbene has the advantage that a large variety of metal precursors,
without special requirements regarding the ligand sphere and the oxidation state, can be used for
the preparation of carbene complexes.
Imidazol-2-ylidenes and triazol-2-ylidenes react with a broad variety of organometallic precursors
to afford the corresponding complexes after the replacement of a two-electron donor from the metal
center. Carbenes can cleave dimeric metal complexes with bridging ligands such as halides, carbon
monoxide, or acetonitrile. Metal precursors such as [(4-COD)MCl]2 or [Cp*MCl2]2 (M=Rh, Ir)
<1996MI1627, 1996MI772, 1977OM2472>, [(6-cymene)RuCl2]2 <1996MI1627, 1996MI772,
1999OM3760>, [Rh(CO)2Cl]2 <1996MI772>, [Cp*RuCl]4 <1999JA2674>, or M[N(SiMe3)2]3
(M=Y, La) <1997OM682> form these kind of complexes.
Most phosphine complexes are simple to exchange against carbenes even below room temperature
<1999AG(E)2416, 1999JA2674, 1999TL2247, 1998AG(E)2490, 1997OM2209, 1999OM4584>.
Starting with bis(tri-o-tolylphosphine)palladium(0), the bis(carbene)palladium(0) complex 93 was
obtained in quantitative yield (Scheme 6) <2000JOM(595)186>.
R R R R
N Pd-[P(o-Tol)3]2 N 92 N 2 N
PdP(o-Tol)3 Pd
N –P(o -Tol)3 N –P(o -Tol)3 N N
R R R R
92 R = mesityl, But, Pr i, cyclohexyl 93
Scheme 6
From carbonyl complexes such as [M(CO)6] (M=Cr, Mo, W), [Fe(CO)5], or [Ni(CO)4], one or
two molecules of carbon monoxide were easily displaced by carbenes <1996MI1627,
1993JOM(459)177, 1996AG(E)2805, 1994JOM(470)C8>. Exchange of a coordinated solvent
such as THF <1994AG(E)1733, 1994JA7927, 1997OM2209, 1999JOM(572)177> or acetonitrile
<1993JOM(459)177> afforded other stable carbene–metal complexes. Olefins <1994JA4391>,
amines <1994JOM(480)C7>, or other anionic ligands <1999JA2329> were also subject to ligand
exchange under certain conditions.
(ii) An advantageous method to prepare carbene–metal complexes employed the in situ depro-
tonation of the ligand precursors. This is the method of choice for carbenes that are not too stable
and are difficult to handle. A basic ligand such as hydride <1968JOM(12)42, 1972CB529>,
acetate <1995AG(E)2371, 1998JOM(557)93, 1997OM2209, 1999OM4082, 1999JOM(575)80>,
or alkoxide <1997JOM(532)261> of a metal precursor can deprotonate the carbenium salt.
Wanzlick, for example, used Hg(OCOCH3)2 for the synthesis of a mercury bis-carbene complex
94 (Equation (25)) <1968AG(E)141, 1971AX(B)2276>.
Ph Ph Ph
N N N
2 + H + Hg(OAc)2 + Hg +
ð25Þ
N ClO4– –2AcOH N N
Ph Ph Ph 2ClO4–
94
Basic silver(I) oxide <1999OM4325, 1998OM972> or 5-cyclopentadienyl anions

<1999OM529> have also served as the base to deprotonate the imidazolium salts.
Imidazolium 95, benzimidazolium, triazolium, and tetrazolium salts were deprotonated in situ
by Brônsted basic metallate anions upon heating (Equation (26)) <1968JOM(12)42,
1970AG(E)739, 1972CB529, 1969AG(E)916, 1976ZN(B)1070>. In these reactions, the metal of
the base functioned simultaneously as the carbene acceptor.
Me Me
N N –
–
+ H [HCr(CO)5] + Cr(CO)5 ð26Þ
N –H2 N
Me Me
95
Alternatively, an external base can be used to deprotonate the carbenium salt in situ. Triethy-
lamine <1997CB1253>, potassium t-butoxide <1996CB1483>, a phosphazene base at 0 C
<1998IC5412>, and n-butyllithium <1995JOM(490)149, 1996AG(E)310> were used to generate
the desired carbene in situ. This method led to different products as compared with the use of
metal salts with basic anions.
(iii) Imidazolin-2-ylidene complexes were prepared by the reaction of the corresponding
electron-rich olefin dimers with mononuclear or bridged dinuclear organometallic fragments
<1988JOM(358)185>. For example, heating tetraaminoethylene 96 in refluxing toluene in the pre-
sence of iron pentacarbonyl produced the corresponding bis(carbene)iron complex 97 (Equation (27)).
R R R
N N N –
2Fe(CO)5 ∆ 2
+ + Fe(CO)4
N N –2CO N ð27Þ
R R R
96 97
In addition to these three common methods, other specialized reactions have led to the
preparation of carbene complexes with different metals. Vapor-phase co-condensation of group
10 metals with imidazol-2-ylidene is a straightforward, but limited, method to obtain two-
coordinate homoleptic metal–carbene complexes (Equation (28)) <1999OM3228>.
But But But
N N 2– N
Co-condense
+ M(at) + M + ð28Þ
N –196 °C N N
But But But
M = Ni, Pd, Pt
Ligand-transfer reactions from one metal complex to another have been reported
<1998OM993, 1999OM2145, 1970AG(E)739, 1999CM1237, 1999OM1216>. For example, a
carbene may be transferred from group 6 metal carbonyl complexes to another transition metal
ion (Equation (29)) <1999OM2145>.
R R
N N Cl
M(CO)5 + (PhCN)2PtCl2 Pt Cl
N
ð29Þ
N CO
R M = W, Mo, Cr R
R = Et, Benzyl, 4-pentenyl
The metalla–Ugi reaction was used to prepare various carbene adducts of chromium, tungsten,
molybdenum <1994ICA(222)275>, and platinum <1982ZN(B)1044>. Aminoimidazolin-2-ylidene
complex 98 was obtained in a one-pot, four-component condensation reaction (Equation (30))
<1994ICA(222)275>.
H
ButHN N
+
[M(CN)(CO)5]– + ButNC + PhCHO + PhNH3 M(CO)5
ð30Þ
–H2O Ph N
M = W, Mo, Cr Ph
98
4.24.5.3.9 Carbocations with pendant lanthanide and actinide elements

Tetramethylimidazol-2-ylidene replaced the THF molecule in [(5-C5R5)2SmII(THF)] to form mono-
and biscarbene adducts 99 <1994JA7927>. Similar adducts were prepared for ytterbium
<1994AG(E)1733>. A seven-coordinate carbene adduct of Eu(III) 100 was prepared from dionato
precursors [Eu(thd)3] (thd=2,2,6,6-tetramethylheptane-3,5-dionate) <1994JA7927>. Treatment of
UO2Cl2(THF)3 in THF with 2 equiv. of 1,3-dimesitylimidazole-2-ylidene or 1,3-dimesityl-4,5-dichlor-
oimidazole-2-ylidene yields monomeric uranylcarbene complexes 101 <2001CC1348>.
Me Me MesMes
Me Me N R N O Cl N R
N 2
Sm Eu(thd)3 U
N n Me N R N Cl O N R
Me
Me Me Mes Mes
Mes = Mesityl
n = 1, 2 R = H, Cl
99 100 101
4.24.5.4 Anionic Carbene Adducts
4.24.5.4.1 Carbanions with pendant group 14 elements

Berndt found that carbene 102 reacted with germylenes or stannylenes at room temperature
to form the corresponding germaethenes <1999HAC554, 1987AG(E)798> or stannaethenes
(Equation 31) <1987AG(E)546, 1997JOM(530)255, 1999HAC554>.
But But
TMS B :ER2 TMS B R
–) E+
TMS TMS B R ð31Þ
B
But But ER2 = Ge[N(SiMe3)2]2, Sn[CH(SiMe3)2]2,
102 103 Sn(2-But-4,5,6-Me3C6H)2

The reaction of 102 with triphenylarsane or triphenylphosphane at 20 C leads to the ylide 104 or
105 (Equation (32)) <1984AG(E)826>.
But But But

B TMS B :EPh3 TMS B
TMS But EPh3
B TMS B TMS B ð32Þ
TMS
But But
104 E = As
102 105 E = P
Irradiation of 51 in the presence of 1-adamantyl nitrile afforded a stabilized nitrilium ylide 106
(Equation (33)) <1984TL405>.
CF3 CF3
F3C F3C
+ hν
N2 NC-Ad N C Ad
ð33Þ
F3C F3C
CF3 CF3
51 Ad = Adamantyl 106

The in situ generated electrophilic carbene 51 was used to synthesize a variety of ylides such as
dimethylsulfonium 107, carbonyl, and thiocarbonyl 108 <1983JA3563>.
CF3 CF3
F3C F 3C
S(CH3)2 X N(CH3)2
F3C F 3C
CF3 CF3 N(CH3)2
X = O, S
107 108

The electrophilic carbenes described in Sections 4.24.5.2.2 and 4.24.5.2.3 were used to produce
halonium ylides 109 and 110 by their irradiation in the presence of haloarenes <1966JA4055,
1983JA3563, 1994JPR145, 1973JA2695>.
CF3 CO2C2H5
F3C NC
X C6H4CH3(p) X C6H5
F3C NC
CF3 CO2C2H5
X = Cl, Br X = Cl, Br
109 110
4.24.5.5 Triplet Carbenes (as Analogs for Radicals)

Remarkably stable radicals have been prepared <1985JA718>. Known examples of the most
stable carbon centered radicals bear no heteroatoms at the radical center, although remote
heteroatomic substitution is critically important. Because there are no direct -heteroatoms
on these radicals, they do not strictly fall into the subject matter for this chapter and thus will
not be discussed in detail. Triplet carbenes can be regarded as a type of geminal diradical.
Remarkable strides have been made in the synthesis of stable triplet carbenes. As with the stable
carbon radicals, heteroatomic substitution for triplet carbenes has proved important, but again at
positions remote to the carbene center. Nonetheless, new stable triplet carbenes in the present
context for completeness and continuity will be mentioned briefly. In their attempts to prepare a
hindered divalent species completely unreactive toward external reagents, Zimmmerman and
Paskovich generated triplet diphenylcarbenes <1964JA2149>. These carbenes were not stable
enough to be isolated, but they exhibited unusual chemical properties. For example, a solution of
hexachloro(diphenyl)carbene 112 at room temperature did not react with the parent diazo
compound 111 to give azine, but dimerized to give tetrakis((2,4,6-trichlorophenyl)ethylene) 113
in 70–80% yield (Equation (34)).
Cl N2 Cl Cl Cl Cl 2 Cl
hν
ð34Þ
–N2
Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl
111 112 113
Tomioka and co-workers generated stable triplet carbene by using bulky substituents and
studied their reactivity (for reviews on persistent triplet carbenes see <1997ACR315,
B-1998MI2005>). The Tomioka group recently generated triplet di{9-[10-(2,6-dimethyl-4-t-
butylphenyl)-anthryl]} carbene 114 by the photolysis of a precursor diazomethane. The half-life
of the carbene is 1 week in the solution at room temperature <2003JA14664>. None of these
triplet carbenes bear heteroatoms at the carbene center, but their remarkable stabilities make
them worthy of a brief mention in this chapter.
Me Me Me Me
.
But C But But . C . But
.
Me Me Me Me
114
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Biographical sketch
Anthony J. Arduengo III was born in Tampa, Daniela Ţapu, was born in Roman, Romania,
Florida, in 1952. He studied chemistry at the in 1976. She received her B.S. in 1998 from
Georgia Institute of Technology, receiving his The Alexandru Ioan Cuza University, Iasi.
B.S. in 1974 and Ph.D. in 1976. After begin- She studied for a year at the Technische Uni-
ning his career with DuPont, he moved to the versität Braunschweig in connection with the
University of Illinois, Urbana, as a member of Socrates scholarship she was awarded. She
the Organic Faculty. From 1984 to 1998, he received her Master’s degree in 2000. She is
worked as a member of the research staff at currently a Ph.D. student at the University of
DuPont, advancing to Research Leader/ Alabama, Tuscaloosa, where she has held
Research Fellow. Professor Arduengo cur- Atotech and University of Alabama Graduate
rently holds the Saxon Chair in Organic Council Fellowships.
Chemistry at the University of Alabama. Tus-
caloosa, and is adjunct professor of chemistry
at the Technische Universität Braunschweig,
Germany. His research interests include unu-
sual bonding arrangements, main group ele-
ment chemistry, and various aspects of
applied chemistry.

Comprehensive Organic Functional Group Transformations II - V 4 (Carbon With Two Heteroatoms, Each Attached by A Single Bond)

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Professor Richard J. K. Taylor

Richard Taylor is currently Professor of Organic Chemistry at the

Janine Cossy did her undergraduate and graduate studies at the

Chris Ramsden was born in Manchester, UK in 1946. He is

Keith Jones was born in Manchester. He studied at Cambridge

Professor Gary Molander was born in Cedar Rapids, Iowa. He

Ray Jones started his chemistry career as an undergraduate

Eric F. V. Scriven is a native of Wales, UK. After working at

The following additional notes apply:

REAGENTS, SOLVENTS, ETC.

Part I: Tetracoordinated Carbon Functions Bearing Two

4.01 Dihaloalkanes, R1R2C(Hal)2, Pages 1-26, J. L. Méndez-Andino

4.17 Functions Incorporating Two Halogens or a Halogen

4.18 Functions Incorporating a Halogen and Another

4.19 Functions Bearing Two Chalcogens, Pages 789-833,

4.20 Functions Containing a Chalcogen and Any Group

4.21 Functions Containing at Least One Nitrogen and No

4.22 Functions Containing at Least One Phosphorus,

4.23 Functions Containing at Least One Metalloid (Si, Ge,

4.01.1 GENERAL METHODS 2

4.01.1 GENERAL METHODS

4.01.2.1 Difluoroalkanes from Alkanes

IF5 /Et3N–3HF, CH2Cl2, 4 h, rt F

4.01.2.2 Difluoroalkanes from Dihaloalkanes

Cl Cl SbF5, HF, 145 °C, 10 h F F

F Cr2O3, HF, 350 °C, 8–10 h F

Cl Porous-CaF2, 100 °C, 1 h F

Geminal difluorocyclopropanes having an electron-withdrawing group are accessible by treat-

4.01.2.3 Difluoroalkanes from Trihaloalkanes

N TDAE, DMF, –20 °C to rt, 1.5 h N

-Bromo-,-difluoroallyl derivatives undergo nucleophilic substitution reactions in the pre-

The fluoride ion-promoted alkylation of 2,2-difluoro-2-trimethylsilylacetates with a variety

4.01.2.4 Difluoroalkanes from Alkenes

Table 1 Reaction of n-hexyl 2-trimethylsilyl-2,2-difluoroacetate with various electrophiles

Entry Substrate Method Product Yield (%)

OH DAST, CH2Cl2, –70 °C, 0.5 h F

n-C6H11 F n-C6H11 F ð19Þ

4.01.2.5 Difluoroalkanes from Alkynes

4.01.2.6 Difluoroalkanes from Difluorocarbene

FSO2CF2CO2TMS + F– FSO2CF3COO– + TMSF

FSO2CF3COO– CF2: + SO2 + CO2 + F–

Difluorocarbene formation is catalyzed by fluoride under nitrogen atmosphere. This method

O TFDA, 0.01 equiv. NaF, 105 °C, 2 h F

TFDA, NaF, diglyme, 120 °C, 1 h Ph I

An alternative difluorocarbene source is 10,10-difluorobicyclo[4.3.1]deca-1,3,5-triene, which has

hν (>280 nm), 55 h, triglyme F F

4.01.2.7 Difluoroalkanes from Aldehydes and Ketones

Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-FluorTM) is an alternative reagent having

O Deoxo-Fluor, 0.2 equiv. HF, CH2Cl2, 16 h, rt F F

4.01.2.8 Difluoroalkanes from Imines

Ph IF5/Et 3N–3HF, EtOAc, 1 h, rt Ph

4.01.2.9 Difluoroalkanes from Dithianes

BrF3, CFCl3, 0 °C, 1–2 min F F

S BrF3, CFCl3, 0 °C, 1–2 min

4.01.3.1 Dichloroalkanes from Alkanes

4.01.3.2 Dichloroalkanes from Dihaloalkanes

O THF, –78 °C TBDMSO

Cl THF, ether, pentane OH

Cl THF, ether, pentane OH

Cl THF, ether, pentane OH

4.01.3.3 Dichloroalkanes from Trihaloalkanes

1.10 V vs. SCE O OH