Aldrichimica Acta - Sigma-Aldrich

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n-heterocyclic Carbene Organocatalysts Organocatalysis has been an active field of research with over 2,000 publications in the past 10 years. Interest in this relatively new field derives from the many advantages of organocatalysis such as easy experimental procedures, reduction of chemical waste, avoidance of metal contamination in the product, and cost saving from not using expensive metals for the catalysis. Scheidt and coworkers have developed a series of N-heterocyclic carbene organocatalysts for various reactions. These catalysts are efficient, and the chiral ones have given rise to good enantioselectivities. In 2005, Audrey Chan and Karl A. Scheidt reported the transformation of unsaturated aldehydes into saturated esters in good yields by using as low as 5 mol % of an N-heterocyclic carbene catalyst. Ph O Ph OEt 72% O Ph H sigma-aldrich.com + R OH Ph OPh Reference: Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905. O I N N 708593 (5 mol %) PhOH (2 eq.) DBU, toluene O Ph O O Ph OR Ph O 56% 57% 77% For ordering or more information, please visit sigma-aldrich.com O Ph Recently, Phillips et al. reported the utilization of a chiral triazole for the enantioselective addition of homoenolates to nitrones affording γ-amino esters. This reaction is very versatile and tolerates electron-rich and electron-poor groups on the aldehyde. Using 20 mol % of the chiral triazole at –25 °C affords the desired products in good yields and selectivities. O H + O Ph N R H (20 mol %) CH2Cl2, Et3N, −25 °C then NaOMe/MeOH Reference: O O Phillips, E. H3CO M. et al. J. Am. Chem. OH Soc. 2008, H3CO 130, 2416. Ph N Ph Ph 70%, 93% ee O N N N 708542 Ph BF4 70%, 93% ee OH N Ph H3CO H3CO O Ph H3CO O R OH N Ph R = aryl, Cy 62–80% 81–93% ee O N N N 708542 N N N 708607 N N 708577 I BF 4 BF 4 N O N N N Ph 62%, 90% ee BF 4 708569 I N N 708593 N 708585 I N OH N Ph
discovering new reactions with n-heterocyclic Carbene Catalysis Mr. Eric M. Phillips Dr. Audrey Chan Professor Karl A. Scheidt Outline 1. Introduction 2. Acyl Anions 2.1. Stetter Reactions 2.2. Imine Additions 3. Oxidation Reactions 4. Homoenolates 4.1. b Protonation 4.2. Formal [3 + n] Cycloadditions 5. Enolate Chemistry 6. Elimination Reactions 7. Theoretical Calculations 8. Conclusions and Outlook 9. Acknowledgements 10. References and Notes 1. Introduction Inspired by advances in our understanding of biological processes, new reactions employing organic molecules as catalysts have grown significantly over the last two decades. 1 In the broadest of terms, the most successful of these catalysts can be classified either as Brønsted acids, 2,3 hydrogen-bond donors, 4–7 or Lewis bases. 8–11 Each of these catalytic manifolds activates substrates in biological settings and provides an inspiring blueprint to create smaller, synthetic versions of these impressive biocatalysts. Lewis base catalysis is presently an exciting area of research and encompasses a wide variety of strategies to initiate both established and new chemical processes. 12,13 An elegant and key biological transformation utilizes the cofactor thiamine, a coenzyme of vitamin B 1, to transform α-keto acids into acetyl CoA, a major building block for polyketide synthesis. In this process, a normally electron-deficient molecule (e.g., pyruvic acid) is converted into an intermediate that possesses electron density on the carbon atom that was initially part of the carbonyl system. These carbonyl or acyl anions are unusual since they have “umpolung” (reversed polarity) when compared to the initial keto acids. In 1954, Mizuhara and Handler proposed that the active catalytic species of thiamine-dependent enzymatic reactions is a highly unusual divalent carbon-containing species, 14 later on referred to as an N-heterocyclic carbene (NHC). An alternative description of the active thiamine cofactor employs the term zwitterion, which can be viewed as a resonance form of the carbene description. This unique cofactor accomplishes Eric M. Phillips, Audrey Chan, and Karl A. Scheidt* Department of Chemistry Center for Molecular Innovation and Drug Discovery Chemistry of Life Processes Institute, Silverman Hall Northwestern University 2145 Sheridan Road Evanston, IL 60208, USA Email: scheidt@northwestern.edu fascinating Lewis base catalyzed transformations by utilizing the lone pair of electrons at C-2. In the early 1960s, Wanzlick and co-workers realized that the stability of carbenes could be dramatically enhanced by the presence of amino substituents, and they attempted to prepare a carbene center at C-2 of the imidazole ring. 15,16 However, only the dimeric electron-rich olefin was isolated. Later on, Wanzlick’s group demonstrated that potassium tert-butoxide can deprotonate imidazolium salts to afford imidazol-2-ylidenes, which can be trapped with phenyl isothiocyanate and mercury salts. 17–19 However, Wanzlick’s group never reported the isolation of the free carbene. Following these results, Arduengo et al. isolated in 1991 a stable crystalline N-heterocyclic carbene by the deprotonation of 1,3-di(1-adamantyl)imidazolium chloride with sodium or potassium hydride in the presence of a catalytic amount of either potassium tert-butoxide or dimethyl sulfoxide. 20 The structure was unequivocally established by single-crystal X-ray analysis, and the carbene was found to be thermally stable, which stimulated extensive research in this field. The nature of the stabilization is ascribed to the steric and electronic effects of the substituents: The two adamantyl substituents hinder reactions of the carbene center with external reagents as well as prevent dimerization. In 1992, Arduengo et al. expanded this carbene class by successfully isolating the carbene from 1,3,4,5-tetramethylimidazolium chloride by treating the latter with sodium hydride and catalytic amounts of potassium tert-butoxide in tetrahydrofuran. 21 The successful isolation of carbenes with less bulky substituents demonstrates that electronic factors may have greater impact on the stability of the carbene than steric ones. Such electronic factors operate in both the π and σ frameworks, resulting in a “push-pull” synergistic effect to stabilize the carbene. π donation into the carbene from the out-of-the-plane π orbital of the heteroatoms adjacent to C-2 stabilizes the typical electrophilic reactivity of carbenes. The electronegative heteroatoms adjacent to C-2 provide additional stability through the framework of σ bonds, resulting in a moderation of the nucleophilic reactivity of the carbene (Figure 1). 22 The combination of these two effects serves to increase the singlet–triplet gap and stabilize the singlet-state carbene over the more reactive triplet-state one. The electronic properties of NHCs are a key determinant of the unique reactivity of these catalysts. Lewis bases are normally considered as single electron-pair donors. However, the singlet VOL. 42, NO. 3 • 2009 55
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