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Microwave Review 2004-08 Papers

Microwave Review 2004-08 Papers

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Mol Divers (2009) 13:71–193DOI 10.1007/s11030-009-9138-8
REVIEW
Controlled microwave heating in modern organic synthesis:highlights from the 2004–2008 literature
C. Oliver Kappe
·
Doris Dallinger
Received: 6 January 2009 / Accepted: 27 February 2009 / Published online: 21 April 2009© Springer Science+Business Media B.V. 2009
Abstract
Direct and rapid heating by microwave irradia-tion in combination with sealed vessel processing in manycases enables reactions to be carried out in a fraction of thetime generally required using conventional conditions. Thismakes microwave chemistry an ideal tool for rapid reac-tion scouting and optimization of conditions, allowing veryrapid progress through hypotheses–experiment–results iter-ations. The speed at which multiple variations of reactionconditions can be performed allows a morning discussionof “What should we try?” to become an after-lunch discus-sion of “What were the results?” Not surprisingly, there-fore, many scientists both in academia and industry haveturned to microwave synthesis as a front-line methodologyfor their projects. In this review, more than 220 publishedexamples of microwave-assisted synthetic organic transfor-mations from the 2004 to 2008 literature are discussed. Anadditionalca.500reactionschemesarepresentedintheElec-tronic Supplementary Material, providing the reader with anoverall number of ca. 930 references in this fast-moving andexciting field.
Keywords
Combinatorial chemistry
·
Enabling technol-ogies
·
High-temperature reactions
·
Microwave dielectricheating
·
Organic synthesis
Electronic supplementary material
The online version of thisarticle (doi:10.1007/s11030-009-9138-8) contains supplementary material, which is available to authorized users.C. O. Kappe (
B
)
·
D. DallingerChristianDopplerLaboratoryforMicrowaveChemistry(CDLMC)andInstitute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse28, 8010 Graz, Austriae-mail: oliver.kappe@uni-graz.at
1 Introduction
Heating chemical reactions by microwave energy continuesto be a popular theme in the organic and medicinal chemis-trycommunity. Since thefirstpublished reports on theuseof microwave irradiation to carry out organic chemical trans-formations by the groups of Gedye and Giguere/Majetichin 1986 [1,2], more than 4,000 articles have been published in this fast-moving and exciting field, generally referred toas microwave-assisted organic synthesis (MAOS) (Fig.1).In many of the published examples, microwave heating hasbeen shown to dramatically reduce reaction times, increaseproduct yields, and enhance product purities by reducingunwanted side-reactions compared with conventional heat-ing methods. The advantages of this enabling technology areexploited not only in organic and medicinal chemistry/drugdiscovery,buthavealsopenetratedrelatedfieldssuchaspoly-mer synthesis, material sciences, nanotechnology, and bio-chemical processes. At least in the field of organic synthesis,the use of microwave irradiation has become such a populartechnique that it might be assumed that, in a few years, mostsynthetic chemists will probably use microwave energy toheat chemical reactions on a laboratory scale.Today, several books [312], a number of special issues ofsyntheticchemistryjournals[1316]andanextensivecol- lection of review articles (>150, see Table1)[17203] cover MAOS from every conceivable angle. In 2004 our grouppublished a review article entitled “Controlled microwaveheating in modern organic synthesis” in
Angewandte Che-mie
[48] that currently is the most cited review in the field,having received 260 citations in 2008. The present reviewprovides an update of our original 2004 treatise coveringthe literature from April 2004 until the end of 2008. Sincemanyotherreviewarticles[1720]andbooks[312]already discuss the basic theory of microwave chemistry and
 123
 
72 Mol Divers (2009) 13:71193
01002003004005006007008009001000
   1   9   8   6   1   9   8   7   1   9   8   8   1   9   8   9   1   9   9  0   1   9   9   1   1   9   9   2   1   9   9   3   1   9   9  4   1   9   9   5   1   9   9   6   1   9   9   7   1   9   9   8   1   9   9   9   2  0  0  0   2  0  0   1   2  0  0   2   2  0  0   3   2  0  0  4   2  0  0   5   2  0  0   6   2  0  0   7   2  0  0   8
Fig. 1
Publications on microwave-assisted organic synthesis (1986–2008). Gray bars: Number of articles involving MAOS for sevenselected synthetic organic chemistry journals (
 J Org Chem
,
Org Lett 
,
Tetrahedron
,
Tetrahedron Lett 
,
Synth Commun
,
Synthesis
, and
Synlett 
;SciFinder Scholar keyword search on “microwave”). The black barsrepresent the number of publications (2001–2008) reporting MAOSexperiments in dedicated reactors with adequate process control (ca. 50 journals, full-text search: “microwave”). Only those articles dealingwith synthetic organic chemistry were selected
provideinformationonequipmentandprocessingtechniques(Table1), the focus of the current review is to highlight synt- heticapplicationsofMAOSpublishedduringthepast5years.The review is therefore mainly intended as a resource andinspiration for synthetic organic chemists in academia andindustry.
2 Literature survey
The present review article highlights selected examples of controlled microwave heating technology in organic synthe-sis published between April of 2004 and 2008. The term“controlled” here refers to the use of a dedicated microwavereactor for synthetic chemistry purposes (single- or multi-mode). Therefore, the exact reaction temperature
during theirradiation process
has been adequately determined in theoriginal literature source. In terms of processing techniques,preferenceisgiventotransformationsinsolutionphaseundersealedvesselconditions,sincethisreflectstherecenttrendinthe literature. Among the ca. 950 original publications thatappeared in 2008 describing microwave-assisted reactionsunder controlled conditions (Fig.1), a careful analysis dem-onstratesthatinca.90%ofthecasessealed-vesselprocessingin dedicated single-mode microwave instruments has beenemployed. Arecent survey has found thatas much as 30% of all published MAOS papers still employ kitchen microwaveovens [217], a practice unfavored by most scientific journalstoday.The focus of the following microwave literature survey ison modern synthetic methods of interest to organic/medic-inal chemists working in industry or academia. Because of the volume of the covered material, the information is
Table 1
Review articles and key references in microwave-assistedorganic synthesisMicrowave theory/dielectric1721 heatingMicrowave effects2232,204,205,209 Microwave reactors/equipment17,19,33 Technical reviews3440 General organic synthesis34,35,4156 Solvent-free conditions5766 Reactions on graphite supports67,68 Phase-transfer catalysis6971 Gaseous reagents72Green chemistry59,7384 Water as solvent73,8587,206 Ionic liquids77,8891 Passive heating elements204,207 Medicinal chemistry/drugdiscovery92106,111,117,145,147 Combinatorial chemistry107116,131 Parallel processing107,117119,124 Solid-phase synthesis120125 Polymer-supported reagents126131 Fluorous synthesis132134 Peptide synthesis135137,208 Enzymatic reactions138Carbohydrate chemistry139142 Organocatalysis209Transition-metal catalysis143155 Metathesis chemistry154,155 Multicomponent reactions132,156158 Heterocycles58,74,122,127,148,156,159174 Cycloadditions166,175177 Natural products178,179 Photochemistry180,181 Radiochemistry182186 Hyphenated methods180,181,187 Miscellaneous188194 Scale-up195199 Continuous flow processing200203 Energetic aspects33,37,210 Educational publications41,211,212 Internet resources213216
presented in a graphical-abstract format, with a minimum of additional information being discussed in the accompanyingtext.Thearrangementofchemistryexamplescloselyfollowsthe sequence used in our 2005 Wiley-VCH book, where theliterature from 2000 to 2004 was covered in a similar for-mat [11]. In addition to the ca. 220 schemes/references dis-cussedinthemainsectionofthisreviewarticle,anadditionalca. 500 examples are briefly mentioned in the text with the
 123
 
Mol Divers (2009) 13:71193 73
XR
1
R
1
R
1
R
2
BrR
2
C
2
H
4
(150 psi), [Pd]K
2
CO
3,
Bu
3
N, DMFMW, 125-150 °C, 60 min[Pd], K
2
CO
3
MW, 175 °C, 15 minX = I, BrR
1
= Me, OMe, COMe, NH
2
R
2
= Me, COMe, OMe, "naphthyl"14 examples(6-72%)
123
Scheme 1
Synthesis of asymmetrically substituted stilbenes
corresponding reaction schemes being provided in the Elec-tronic Supplementary Material.
2.1 Transition-metal-catalyzed carbon–carbon bondformation
2.1.1 Mizoroki–Heck reactionsNicholas Leadbeater and Chad Kormos from the Universityof Connecticut have disclosed a one-pot two-step Mizoroki–Heckcouplingstrategyforthepreparationofasymmetricallysubstituted stilbenes (Scheme1)[218]. In the first step, sty- renes
2
were synthesized selectively by employing ethene ascoupling partner using a gas-loading device. For aryl iodides(
1
) as coupling partners, 0.02mol% Pd using an ICP stan-dard and 125
C are required to obtain the coupled products
2
,whereasforarylbromides(
1
)0.5mol%oftheHerrmannscatalyst and 150
C are necessary. In the next step, styrenes
2
are coupled with aryl bromides using a 1:1 molar ratio andHerrmann’s catalyst in the same reaction vial to get stilbenes
3
. It has to be noted that the less reactive aryl halide has tobe used in the first coupling step in order to reduce the com-petitive symmetric stilbene formation and thus increase theproduct yield.Nicolas Lachance and co-workers form the Merck FrosstCentre for Therapeutic Research in Quebec have shown thatimines/enamines
6
canbeconverted
via
amicrowave-assistedintramolecular Mizoroki–Heck reaction to the correspond-ing azaindoles
7
in good yields (Scheme2)[219]. Several synthesis routes have been investigated, including the one-step reaction (route
A
) of aminopyridines
4
with ketones
5
or ketals as well as the one-pot two-step reaction (route
B
)leading to azaindoles
7
. Using either of the two strategiesa small library of 17 examples was synthesized employingchloro-, bromo-, and iodo-aminopyridines with toleration of sensitive groups such as ketones and esters.Intramolecular Heck couplings have also been used byVasudevan for the construction of cyclic sulfonamides(SchemeS1)[220], by Porco for the generation of indanes and related polycyclic scaffolds (SchemeS2) [221], by Vander Eycken for the synthesis of 3-benzazepines (Scheme S3)[222],andbyChrumaforthesynthesisofpolyfunctionalized1-aminoindanes (SchemeS4) [223].
NNN
A
MWXNH
2
XNHR
1
R
2
NHR
2
R
1
1. Condensation2. Heck reactionN ClNH
2
OEtOEt
B
R
1
OR
2
B
NNH+CondensationMW
4 567
Heck reactionMWX = Cl, Br, IPd(PPh
3
)
4
, pyridineMW, 160 °C, 20 min81%+16 related examples(12-95%)
Scheme 2
Synthesis of 4-, 5-, 6-, and 7-azaindoles
 123

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