Stetter reaction

The Stetter reaction is a reaction used in organic chemistry to form carbon-carbon bonds through a 1,4-addition reaction utilizing a nucleophilic catalyst. While the related 1,2-addition reaction, the benzoin condensation, was known since the 1830s, the Stetter reaction was not reported until 1973 by Dr. Hermann Stetter. The reaction provides synthetically useful 1,4-dicarbonyl compounds and related derivatives from aldehydes and Michael acceptors. Unlike 1,3-dicarbonyls, which are easily accessed through the Claisen condensation, or 1,5-dicarbonyls, which are commonly made using a Michael reaction, 1,4-dicarbonyls are challenging substrates to synthesize, yet are valuable starting materials for several organic transformations, including the Paal–Knorr synthesis of furans and pyrroles. Traditionally utilized catalysts for the Stetter reaction are thiazolium salts and cyanide anion, but more recent work toward the asymmetric Stetter reaction has found triazolium salts to be effective. The Stetter reaction is an example of umpolung chemistry, as the inherent polarity of the aldehyde is reversed by the addition of the catalyst to the aldehyde, rendering the carbon center nucleophilic rather than electrophilic.

As the Stetter reaction is an example of umpolung chemistry, the aldehyde is converted from an electrophile to a nucleophile under the reaction conditions. This is accomplished by activation from some catalyst - either cyanide (CN⁻) or thiazolium salt. For the use of either catalyst, the mechanism is very similar; the only difference is that with thiazolium salts, the catalyst must be deprotonated first to form the active catalytic species. The active catalyst can be described as the combination of two contributing resonance forms - an ylide or a carbene, both of which portray the nucleophilic character at carbon. The thiazolium ylide or CN⁻ can then add into the aldehyde substrate, forming a cyanohydrin in the case of CN⁻ or the Breslow intermediate in the case of thiazolium salt. The Breslow intermediate was proposed by Ronald Breslow in 1958 and is a common intermediate for all thiamine-catalyzed reactions, whether in vitro or in vivo.

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