Organocatalysis by N-Heterocyclic Carbenes Dieter Enders,* Oliver Niemeier, and Alexander Henseler Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany Received March 27, 2007 Contents achieved considerable attention.1 Beside their facile reaction course, selectivity, and environmental friendliness, new 1. Introduction 1 synthetic strategies are made possible. Particularly, the 2. Enzymes as Archetypes 1 inversion of the classical reactivity (Umpolung) opens up 3. Benzoin Condensation 2 new synthetic pathways.2 In nature, the coenzyme thiamine 3.1. Breslow Mechanism 2 (vitamin B1), a natural thiazolium salt, utilizes a catalytic 3.2. First Asymmetric Benzoin Condensations 3 variant of this concept in biochemical processes as nucleo- 3.3. Stable Carbenes 3 philic acylations.3 The catalytically active species is a 3.4. Asymmetric Benzoin Condensations 5 nucleophilic carbene.4 3.5. Crossed Benzoin Condensations 7 Carbenes belong to the most investigated reactive species 3.6. Intramolecular Crossed Benzoin 9 in the field of organic chemistry. As typical structural Condensations features, all carbenes are neutral and possess a bivalent 4. Stetter Reaction 10 carbon atom with an electron sextet. First evidence for the 4.1. Intermolecular Stetter Reactions 10 existence of carbenes is found in the pioneering work of Buchner and Curtius and Staudinger and Kupfer in the late 4.2. Intramolecular Stetter Reactions 11 19th and early 20th century.5 Because of their pronounced 4.3. Special Intermolecular Stetter Reactions 16 reactivity, carbenes could not be isolated until recently and − − 4.4. Stetter Paal Knorr Reactions 16 were regarded as reactive intermediates.6,7 4.5. Polymer-Supported Stetter Reactions 17 Since the first reports of stable nucleophilic carbenes by 4.6. Natural Product Synthesis 18 Bertrand and co-workers8 and Arduengo et al.9 in the late 5. a3 to d3 Umpolung 19 1980s and early 1990s, the broad application of N-hetero- 5.1. Cross-Condensation of Enals and Aldehydes 20 cyclic carbenes (NHCs) in organic synthesis has been or Imines impressively demonstrated. Beside their role as excellent 5.2. Protonation and Nucleophile Trapping 23 ligands in metal-based catalytic reactions,10 organocatalytic 5.3. Diels−Alder Reactions 25 carbene catalysis has emerged as an exceptionally fruitful 11 5.4. Cross-Condensation of Enals and 1,2-Diones 27 research area in synthetic organic chemistry. This review 5.5. Cross-Condensation of Enals and Enones 27 highlights the extensive applications and reaction pathways 5.6. Miscellaneous 29 of thiazol- (A), triazol- (B), imidazol- (C), and imidazolin- 2-ylidenes (D) as versatile synthetic methods (Figure 1). 6. Transesterification Reactions 30 7. Polymerization Reactions 33 2. Enzymes as Archetypes 8. Ring-Opening Reactions 36 8.1. Ring-Opening Reactions of Three-Membered 36 In nature, realms of complex biochemical reactions are Rings catalyzed by enzymes, many of which lack metals in their 9. 1,2-Additions 39 active site. Among them, nucleophilic acylation reactions are 9.1. 1,2-Additions to Aldehydes and Ketones 39 catalyzed by transketolase enzymes12 in the presence of 3 9.2. 1,2-Additions to Aldimines and Ketimines 43 coenzyme thiamine (1, vitamin B1). Inter alia, this coenzyme 10. Miscellaneous 43 is present in baker’s yeast and might serve as an example of 11. Conclusions 46 highly selective chemical reactions that are accomplished in vivo. In 1954, Mizuhara et al. found that the catalytic active 12. Acknowledgments 47 species of the coenzyme thiamine is a nucleophilic carbene 13. Note Added after ASAP Publication 47 (Figure 2).4 The biochemistry of thiamine-dependent en- 14. References 47 zymes has been studied in detail, resulting in broad applica- tions as synthetic tools.13 An X-ray structure of a thiamine-dependent transketolase 1. Introduction enzyme was determined by Schneider et al. after isolation In the investigation of efficient chemical transformations, from Saccharomyces cereVisiae in the 1990s and is shown the carbon-carbon bond-forming reactions play an outstand- in Figure 3.14 The thiamine cofactor is embedded in a narrow ing role. In this context, organocatalytic processes have channel in the center of the enzyme. From the complex surrounding of the heart of this enzyme, it seems to be * To whom correspondence should be addressed. Fax: +49 241 8092127. obvious that chemical reactions at the catalytically active E-mail: [email protected]. site in this channel proceed inevitably with high selectivities. 10.1021/cr068372z CCC: $48.50 © xxxx American Chemical Society Published on Web 10/23/2007 PAGE EST: 49.3 B Chemical Reviews Enders et al. Dieter Enders was born in 1946 in Butzbach, Germany. He studied Alexander Henseler was born in Bonn in 1979. He studied chemistry in chemistry at the Justus Liebig University Giessen and received his Dr. Cologne and Sheffield and received his diploma from the Universita¨t zu rer. nat. under the supervision of Professor D. Seebach in 1974. After Ko¨ln in 2006. As a scholarship holder of the RWTH Aachen Graduierten- postdoctoral studies at Harvard University with Professor E. J. Corey, he kolleg, he is now working on his Ph.D. in the research group of Professor returned to Giessen, obtaining his habilitation in 1979. In 1980 he moved D. Enders. His research studies focus on the development of new chiral to the University of Bonn as an associate professor, and in 1985 he moved N-heterocyclic carbene catalysts and their application in asymmetric to his present position as Professor of Organic Chemistry at the RWTH synthesis. Aachen University. His current research interests are asymmetric synthesis, new synthetic methods using organometallics, the stereoselective synthesis of biologically active compounds, and organocatalysis. He has been the recipient of many prizes, among them the Leibniz Prize (Deutsche Forschungsgemeinschaft), the Yamada Prize (Japan), the Max Planck Research Award (Max Planck Gesellschaft and Alexander von Humboldt Foundation), and the Emil Fischer Medal (Gesellschaft Deutscher Chemiker). Figure 1. General types of N-heterocyclic carbenes. Oliver Niemeier was born in 1976 in Leverkusen, Germany. He studied chemistry at the RWTH Aachen University, where he received his diploma degree in 2004. In 2006 he obtained his Ph.D. under the supervision of Professor D. Enders. His research was concerned with the development Figure 2. Coenzyme thiamine (vitamin B1). of novel chiral triazolium salts, their application in carbene-catalyzed intramolecular crossed benzoin cyclizations, and organocatalytic asym- In 1903, Lapworth postulated a mechanism for this reaction metric intramolecular aldol reactions. From May on, he is carrying out in which an intermediate carbanion is formed by hydrogen postdoctoral research at Imperial College London with Professor A. G. cyanide addition to benzaldehyde followed by deprotona- M. Barrett. tion.16 Here, the former carbonyl carbon features an inverted, The aim of many organic chemists is to develop synthetic nucleophilic reactivity. This intermediate “active aldehyde” catalysts that mimic this enzymatic system. Therefore, only exemplifies the “Umpolung” concept of Seebach and co- the actually catalytically active site, without the necessity workers.2 In 1943, Ugai et al. recognized that thiazolium of the huge enzyme proteins around it, is the goal, as well salts could also be used as catalysts in the benzoin condensa- as to use it efficiently and selectively in organic reactions. tion.17 In 1958, on the basis of the work of Lapworth, Breslow proposed a mechanistic model for the thiazolium 3. Benzoin Condensation salt-catalyzed benzoin condensation.18 In this mechanism, the catalytically active species is thiazolin-2-ylidene 3,a 3.1. Breslow Mechanism carbene compound, which is formed in situ by deprotonation The benzoin condensation catalyzed by N-heterocyclic of the thiazolium salt 2. The postulated catalytic cycle is carbenes has been intensively investigated. First investiga- shown in Scheme 1. tions date back to 1832 when Wo¨hler and Liebig discovered Breslow assumed that the thiazolium salt 2 is deprotonated the cyanide-catalyzed coupling of benzaldehyde to benzoin.15 at its most acidic position to form the thiazolin-2-ylidene 3, Organocatalysis by N-Heterocyclic Carbenes Chemical Reviews C Figure 4. Thiazolin-2-ylidene dimer. synthetic concept for the preparation of numerous R-hydroxy- ketones. Aliphatic aldehydes showed the best results with catalyst 10a, whereas for aromatic substrates, the thiazolium salts 10b or 10c were better catalysts (Figure 5).22,23 Figure 5. Thiazolium salts utilized by Stetter et al. Figure 3. Structure of the transketolase enzyme isolated from Saccharomyces cereVisiae. 3.2. First Asymmetric Benzoin Condensations As the product of the benzoin condensation is an R-hy- Scheme 1. Catalytic Cycle of the Benzoin Condensation as droxyketone 8, a new stereogenic center is formed. Conse- Proposed by Breslow quently, many chemists have tried to develop heterazolium- catalyzed asymmetric benzoin condensations and, later, other nucleophilic acylation reactions (Scheme 2). Scheme 2. Asymmetric Benzoin Condensation In 1966, Sheehan and Hunneman presented the first results of an asymmetric benzoin condensation utilizing the chiral thiazolium salt 11 as precatalyst.24 However, the enantiomeric excess of the synthesized benzoin was only 22%. Some years later, they were able to obtain enantiomeric excesses of up to 51% with modified