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A study on the mechanism of the asymmetric intramolecular Stetter reaction is reported. This investigation includes the determination of the rate law, kinetic isotope effects and competition experiments. The reaction was found to be first order in aldehyde and azolium catalyst or free carbene. A primary kinetic isotope effect was found for the proton of the aldehyde. Taken together with a series of competition experiments, these results suggest that proton transfer from the tetrahedral intermediate formed upon nucleophilic attack of the carbene onto the aldehyde is the first irreversible step.The seminal example of the reversal of functional group polarity, the benzoin reaction, dates to 1832, when Wöhler and Liebig reported that cyanide catalyzes the formation of benzoin from two equivalents of benzaldehyde (eq. 1). 1,2 In 1943, Ukai et al showed that thiazolium salts catalyze the homodimerization of aldehydes in the presence of base. 3 A related Umpolung 4 transformation is the Stetter reaction, the conjugate addition of the aldehyde into a Michael acceptor. 5 Utilizing cyanide or thiazolylidene carbenes as catalysts, Stetter demonstrated that a variety of aromatic and aliphatic aldehydes are competent nucleophilic coupling partners with a wide range of α, β-unsaturated ketones, esters, and nitriles. 6 The ability to bring two different electrophilic partners together and form a new carbon-carbon bond enhances the potential utility of this transformation.Our group has developed chiral triazolinylidene carbenes and precursors, 1-3, for a variety of carbene mediated transformations. 7 We have shown that the carbenes derived from 1 and 2 are capable of inducing the cyclization of aromatic and aliphatic aldehydes to α,β-unsaturated esters, ketones, thioesters, amides, aldehydes, and nitriles. 8 Mechanistic insight into organocatalytic reactions is important for the development of general transformations. 11 To the best of our knowledge a detailed study probing the mechanism of the Stetter reaction has not been reported. In the absence of such a study the working model of the Stetter reaction is based on the Breslow mechanism for the thiamincatalyzed benzoin reaction. 12,13 The mechanism is closely related to Lapworth's mechanism for cyanide anion catalyzed benzoin reaction. 14 As with the cyanide catalyzed benzoin reaction, the thiazolinylidene catalyzed reaction is reversible. 15 The proposed catalytic cycle is as follows: the carbene I (Scheme 1), formed in situ by base deprotonation of the corresponding azolium salt, adds to the aldehyde to form II. A proton transfer event generates acyl anion equivalent III, termed the nucleophilic alkene or Breslow intermediate. Subsequent addition into the Michael acceptor forms a new carbon-carbon bond to generate IV. A second proton transfer event then provides V. Finally, collapse of this tetrahedral intermediate V to form Stetter product is accompanied by liberation of the active catalyst. As we strive to understand differences in catalysts and continue to ...

A highly enantioselective intramolecular Stetter reaction of aromatic and aliphatic aldehydes tethered to different Michael acceptors has been developed. Two triazolium scaffolds have been identified that catalyze the intramolecular Stetter reaction with good reactivity and enantioselectivity. The substrate scope has been examined and found to be broad; both electron rich and poor aromatic aldehydes undergo cyclization in high yield and enantioselectivity. The tether can include oxygen, sulfur, nitrogen and carbon linkers with no detrimental effects. In addition, the incorporation of various tethered Michael acceptors includes amides, esters, thioesters, ketones, aldehydes and nitriles. The catalyst loading may be reduced to 3 mol% without significantly affecting the reactivity or selectivity of the reaction.

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The use of N-heterocyclic carbenes as catalysts for organic transformations has received increased attention in the past 10 years. A discussion of catalyst development and nucleophilic characteristics precedes a description of recent advancements and new reactions using N-heterocyclic carbenes in catalysis.