Baran Group Meeting Fischer Carbene Complexes in Organic Synthesis Ke Chen

1/31/2007

Ernst Otto Fischer (1918 - ) Other Types of Stabilized Carbenes:

German inorganic chemist. Born in Munich Schrock carbene, named after Richard R. Schrock, is nucleophilic
on November 10, 1918. Studied at Munich at the carbene carbon atom in an unpaired triplet state.
Technical University and spent his career
there. Became director of the inorganic Comparision of Fisher Carbene and Schrock carbene:
chemistry institute in 1964. In the 1960s,
discovered a metal alkylidene and alkylidyne
complexes, referred to as Fischer carbenes
and Fischer carbynes. Shared the Nobel Prize
in Chemistry with Geoffery Wilkinson in 1973,
for the pioneering work on the chemistry of
organometallic compounds.
Schrock carbenes are found with: Representatives:

Isolation of first transition-metal carbene complex: high oxidation states

CH2
early transition metals Ti(IV), Ta(V)
non pi-acceptor ligands Cp2Ta
CH2N2 Me
LiMe Me non pi-donor substituents CH3
(CO)5W CO (CO)5W
(CO)5W A.B. Charette J. Am. Chem. Soc. 2001, 123, 11829.
OMe
O

E. O. Fischer, A. Maasbol, Angew. Chem. Int. Ed., 1964, 3, 580. Persistent carbenes, isolated as a crystalline solid by Anthony J.
Arduengo in 1991, can exist in the singlet state or the triplet state.

Representative Fischer Carbenes:

W(CO)5 Cr(CO)5 Fe(CO)4 Mn(CO)2(MeCp) Co(CO)3SnPh3

Me OMe Ph Ph Ph NEt2 Ph OTiCp2Cl Me OMe

Foiled carbenes were defined as "systems where stabilization is

Fischer carbenes are found with : obtained by the inception of the facile reaction which is foiled by
the impossibility of attaining the final product geometry". They only
low oxidation state metals; exist in the singlet state.
middle and late transition metals Fe(0), Mo(0), Cr(0), W(0);
pi-electron acceptor metal ligands; Rolf Gleiter, Ronald Hoffman J. Am. Chem. Soc. 1968, 90, 5457 - 5460.
pi-donor substituents on methylene group such as alkoxy and Jean-Luc Mieusset and Udo H. Brinker J. Am. Chem. Soc. 2006, 128,
15843 - 15850.
amino groups.

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Baran Group Meeting Fischer Carbene Complexes in Organic Synthesis Ke Chen
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Advantages over regular carbenes 2. Excellent functional group compatibility - serving as blocking groups
- From fleeting intermediates to powerful reagents in organic synthesis.

1. Improved stability OTMS OMe Ph O

H
OMe BuLi, THF, -78 oC
Typical carbenes such as diphenyl carbene have lifetimes in the [Cr]
nanosecond regime. [Cr] Ph
Et 75 % Et

3 equiv of CH2CHCH2Li, THF [Cr] O

Most Fischer carbene complexes are stable to air and water and to -78 oC to RT, then SiO2
dilute acids and bases. Despite the high dipole moment of these
complexes (~ 4 - 5 Debye), most complexes can be purified by
71 % H
chromatography on silica gel with hexane as eluent and are usually Ph Et
the first compounds to elute. Identification of the fractions from the
column containing the carbene complex can simply be done by eye
on the basis of their color. The colors of complexes bearing alkoxy J. Barluenga. J. Am. Chem. Soc. 2002, 124, 9056 -9057.
groups as the heteroatom-stabilizing group tend to correlate with the
hybridzation of the carbon substituent of the carbene carbon. Those
3. Improved reactivity and selectivity
with sp3 carbons usually are yellow, those with sp2 carbons are
normally red and those with sp hybridized carbon substituents are
Cr(CO)5 Cr(CO)5
invariably an intense purple/black color. Cr(CO)5
RT, 3 h
MeO MeO MeO
70 %

92 : 8
O O O

MeO MeO MeO

thermal conditions: RT, 7 months, 54 % 70 : 30

AlCl3, 0.5 h , 50 % 95 : 5

W. Wulff. J. Am. Chem. Soc. 1990, 112, 3642.

[Link]

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Baran Group Meeting Fischer Carbene Complexes in Organic Synthesis Ke Chen
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Synthesis of Fischer carbene complexes: 2. Hegedus-Semmelhack approach

1. Standard Fischer route O
OK OR2
OLi OR2 C8K R1 Cl R2X
R1Li RX M(CO)6 K2[M(CO)5] (OC)5M (OC)5M
M(CO)6 (OC)5M (OC)5M
R1 R1
R1 R1 O
M = Cr, Mo, W
R3
R1 = alkyl, aryl, vinyl HN R1 NR3R4
HS R3
RX = R23O+BF4-, R2OSO3F
R4
R3, R4 = H, alkyl
O- NR3R4
SR3 NR3R4 TMSCl
(OC)5M NR3R4 (OC)5M
(OC)5M (OC)5M
R1 R1
R1 R1

This is the most direct and general approach to Fischer carbene M = Cr, W
complexes; R1 = alkyl, aryl, vinyl
Limitations are the availability of organolithium compound R2X = R23O+BF4-, R2OSO3F
and the alkylation reagent.
R3, R4 = H, alkyl

O R2 This strategy combining an organoelectrophile and a metal nucleophile

OLi O-NMe4+ O can be extended to the synthesis of aminocarbene complexes.
Me4N+Br- X R2
(OC)5M (OC)5M O
R1 R1 (OC)5M
R1 Recent reviews:
M = Cr, W
R1 = alkyl, aryl, vinyl W. D. Wulff, in Comprehensive Organometallic Chemistry II, ed.
R2 = Me, tBu R3OH A. W. Abel, F. G. A. Stone and G. Wilkinson, pergamon Press, Oxford, 1995, vol. 12, p. 469
L. S. Hegedus, ibid., vol. 12, p. 549.
X = Br, Cl
R3 = terpene, sugar skeletons OR3
(OC)5M
R1

This is the standard approach to optically active Fischer carbene

complexes bearing alkoxy substituents.

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Baran Group Meeting Fischer Carbene Complexes in Organic Synthesis Ke Chen
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Reaction pattern of carbene complexes: Pattern B: Bond formation via metal carbene anions
Part I: Ligand-centered OR OR
OMe OMe
(OC)5M (OC)5M
(OC)5Cr O
R R
pKa = 12 pKa = 25
C

H3C
OH O O
OC CO O R A E N CH3
1. nBuLi
OC Cr O 2. PhCHO Ph N N CH3
OC CO CR2 Nu N 3. HOAc / Ce(IV)
Ph
H B (OC)4Cr Ph
B 60 %, > 96 % de CH3
CH3
W. Wulff, J. Org. Chem., 1994, 6882.

Pattern A: Addition of nucleophiles OMe

OMe O
1. nBuLi
OMe (OC)5Cr (OC)5Cr (OC)5Cr
OMe - MeOH NHR
NH2R H 2. O
(OC)5Cr (OC)5Cr NHR (OC)5Cr
Ph OLi
Ph Ph

B. A. Anderson, J. Am. Chem. Soc., 1993, 115, 4602.

OMe O
(OC)5Cr OLi
THF, -80 oC to RT Ph Pattern C: Transformation of metal carbenes to metal carbynes
Li
Ph
O O
50 %
Cr(CO)5
J. Barluengal, J. Chem. Soc., Chem. Commun. 1993, 1068

OMe Ph
?
(OC)5Cr N N
MeO For reviews on reaction pattern of carbene complexes, see "Carbene Chemistry : From Fleeting
Ph Intermediates to Powerful Reagents", chapter 8.
Cr(CO)5

H. Fischer, Chem. Ber. 1980, 113, 193

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Reaction pattern of carbene complexes: Diels-Alder reaction of boroxycarbene complexes:

Part I: Ligand-centered
1. t-BuLi, Et2O F
Cycloaddition reactions: Br 2. Cr(CO)6, Et2O
(OC)5Cr O Ph
OMe B F
OMe N
[2 + 2] (OC)5W CH3 N N
OMe . Me
RT, 12 h 3. BF3 Et2O, RT
(OC)5W
H3CO
87 % [Link], -78 oC to RT
85%
CH3 K. L. Faron, J. Am. Chem. Soc. 1988, 110, 8727 -8729. 2. 3N HCl, THF, RT
95 %
[3 + 2]
TMSCHN2 F
OMe OMe (OC)5Cr O
hexanes, RT CHO B F
(OC)5W (OC)5W HBr, DCM, RT
4.5 h, 87 % N N
NH
85 %
H3C N O
O
CH3
W. D. Wulff, J. Am. Chem. Soc. 1986, 108, 5229 -5236.
[4 + 2] J. Barluenga. J. Am. Chem. Soc. 1998, 120, 2514 -2522.
H 3C H3C
N CH3 TBSO N CH3
Miscellaneous cases
O O
Ipc
OCH3 N
N Ph O B
Ph OLi (-) -Ipc2BCl, Et2O Ph
(OC)4Cr CH3 H
(OC)4Cr
DCM, RT, 12 h (OC)5W
80 %,single isomer -78 oC to RT
CH3O
Ph
CH3
OTBS
W. D. Wulff, J. Am. Chem. Soc. 1997, 119, 6438 -6439. J. Barluenga, J. Am. Chem. Soc,, 1996, 118, 6090 -6091. H2O2, NaOH
Intramolecular Pauson -Khand reaction: 83 %, > 99 % de

NH
(OC)5W Ph OH OH
(OC)5W [Co2(CO)8]
Ph
75 % O

Ph
J. M. Moreto. Angew. Chem. Int. Engl. 1991, 11,1470.

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Baran Group Meeting Ke Chen
1/31/2007 Fischer Carbene Complexes in Organic Synthesis

Reaction pattern of carbene complexes: OMe

OMe
Part II: Metal-centered DMF, 152 oC
(OC)5Cr H
1. Reaction with olefins 88 %, 97 % de
Fe Fe
OR1 OR1 OR1
(OC)5Cr (OC)4Cr (OC)4Cr R2
R2 R2
"The functionalized Ru Fischer-type
complexes are active in a variety of Cr(CO)5 Me H
THF, 100oC
olefin metathesis reactions, although Et
with significantly lower rates than the Olefin Metathesis Me OMe 55 % MeO
Cyclopropanation Et
corresponding carbon analogues."
favored
R, H. Grubbs, Organometallics. 2002, 21, 2153 -2164. H
H

General carbene complexes used in cyclopropanation reactions: Et Et

Cr R R
MeO MeO
Cp Cp Cr(CO)5 (CO)4 Cr(CO)4
R*Ph2P Cr(CO)5 Cr(CO)5
OC H
Fe H Fe H
OC OC CH2 OMe
Me OMe Ph OMe Me H
Me MeO Cr R MeO R
Et MeO
(CO)4 Et
W(CO)5 W(CO)5 Mo(CO)5 Cr(CO)4 Et
disfavored
Ph OMe Ph H Bu OMe J. Am. Chem. Soc. , 113, 23, 1991, 8916-8921
(leads to olefin (less stable )
metathesis product)
O O
Cr(CO)5
Suitable olefins: Cl o O
Alkyl R1 OMe intermediate 85 C,12 h
Alkyl A 85 % O
EWG R1 O
EWG EWG R2 R2
R1 R1, R2 = akyl, aryl
R1, R2 and R3 = alkyl
R3 requires stronger Chemtracts - Organic Chemistry. 17, 67 -71, 2004
R2
electrophilic metal carbenes

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Baran Group Meeting
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Reaction pattern of carbene complexes:

Part II: Metal-centered OMe O O OMe O O OH
ether, reflux
2. Benzannulation (Dotz reaction) Cr(CO)5 nPr
51 %
Cr(CO)5 Cr(CO)4

OMe - CO OMe O
M. F. Semmelhack, Tetrahedron, 1985, 5803.
+ CO

RS RL OTBS OCPh3
OMe OCPh3
RS TBSCl, hunig base
RL (OC)5Cr
Cr(CO)3
> 92 % d. e.
RS
OMe RL Cr(CO)4
O Cr(CO)3 W. D. Wulff, J. Am. Chem. Soc,, 1994, 116, 6449. OMe
OMe RS OMe
RL
OC Cr CO OTBS
minimization O O OMe
OC CO
of interaction MeO
Cr(CO)5
RL 35 %

O RS RL
TBSO
HO RS O O
Cr(CO)3 BnO
OMe Cr(CO)3
OMe EtO N
O O OMe OTBS
MeO

Suitable metal: Compatible substitution pattern:

fredericamycin A
Cr (metal of choice) Aryl carbenes with various substituents
Mo ( furan formation occasionally) O O OH OTBS
Naphthyl and heteroaryl carbenes BnO
W (favor 3 + 2 cycloaddtion) Vinyl carbenes bearing alkyl substituents N
Mg (low yields) EtO
Electron - neutral alkynes with various
substituents D. L. Boger, J. Am. Chem. Soc,, 1995, 11839.

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Baran Group Meeting Ke Chen
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Me
Reaction pattern of carbene complexes:
OMe Me O
Part II: Metal-centered MeO OMe
(OC)5Cr O

3. General Annulation of Fischer carbenes with alkynes and alkenes: CH3

Organometallics, 1990, 9, 3014 - 3015 13 % 10 %

OMe H
(OC)5Cr CO2Et
CH3
CO2Et
66 % OMe
J. Am. Chem. Soc. 1994, 116, 6719 - 6732 Bu

OMe O O
THF, 70 oC, 24 h
(OC)5Cr O OMe
Ph O CO, 73 %, d. r. = 3 :1
H
O O CH3 O CH3
J. Am. Chem. Soc. 1992, 114, 10665 - 10666 Ph
OMe
C 3H 7 Ph
(OC)5Cr O O O
CH3OMe
CH3 o OMe Ph O
THF, 105 C, 15h CH3 CH3 O
CH3
Ph OMe Ph OMe (OC)5Mo
48 % 18 % THF, 70 oC, 14 h, 40 %
Ph
Me
J. Am. Chem. Soc. 1991, 113, 5459 - 5461 CH3

J. Am. Chem. Soc. 1990, 112, 1645 - 1647

Ph
OMe Ph Ph
Me Me THF, 90 oC O O OEt
EtO Ph EtO Ph
(OC)5Cr
Me (OC)5Cr NMe2 3 Ph
71 %
TMSO OTMS MeO Me THF
Ph NMe2 NMe2
SiMe3
Ph Ph Ph
J. Barluenga, Org. Lett., 2006, 8, 2703 -2706. 64 : 36
Angew. Chem. 1999, 111, 1369

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State of art:
Group 6 metal carbenes in catalytic carbene transfer reactions

OMe OMe
(OC)5M L nM multi-faced
R R
chemistry
M = Cr, W M = Pd, Cu, Rh

stable, storable, less reactive reactive, unstable

NMe2 O
CO2Me
(OC)5Cr
2 mol %Pd(OAc)2, Et3N CO2Me

THF, reflux, 8 h, 80 % Daniel F. Harvey Jose Barluenga

Br

Br
M. A. Sierra, J. Am. Chem. Soc., 2001, 123, 851 -861.

1. [Cu(MeCN)4][PF6], DCM
O 2. DCM, Et2O
(OC)5Cr

MeCN O
J. Barluenga, Angew. Chem. Int. Ed., 2001, 40, 3392.
Cu PF6
Et2O
O William D. Wulff
Louis S. Hegedus