Stetter Reaction - Mechanism

Mechanism

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 Breslow in 1958 and is a common intermediate for all thiamine-catalyzed reactions, whether in vitro or in vivo.

Once the nucleophilic aldehyde is formed, whether as a cyanohydrin or stabilized by a thiazolium ylide, the reaction can proceed down two pathways. The faster pathway is self-condensation with another molecule of aldehyde to give benzoin products. However, benzoin condensation is completely reversible, and therefore does not interfere with product formation in the Stetter reaction. In fact, benzoins can be used instead of aldehydes as substrates to achieve the same overall Stetter transformation, because benzoins can be restored to their aldehyde precursors under the reaction conditions. The desired pathway toward the Stetter product is the 1,4-addition of the nucleophilic aldehyde to a Michael-type acceptor. After 1,4-addition, the reaction is irreversible and ultimately, the 1,4-dicarbonyl is formed when the catalyst is kicked out to regenerate CN- or the thiazolium ylide.