Stetter reaction

The Stetter reaction is an organic reaction involving the nucleophile catalyzed conjugate addition of an aldehyde to a Michael acceptor such as an enone. The reaction product is a 1,4-dicarbonyl compound. The active catalyst can be a combination of a thiazolium salt and a base or cyanide].

Reaction mechanism
Key in the reaction mechanism is the conversion of the aldehyde carbonyl group from an electrophile to a nucleophile in an umpolung process. This is accomplished by deprotonation of the quaternary thiazolium salt 1 by base to the thiazolium ylide 2 which reacts in a nucleophilic addition with the aldehyde 3 to the tetrahedral intermediate 4. After a 1,2-rearrangement reaction of the methylene proton in 4 to oxygen the resulting carbanion 5 is able to react with enone 6 in a Michael reaction to adduct 7. A hydrogen migration takes place to 8 after which the thiazolium group is expelled generating the 1,4-diketone 9 and completing the catalytic cycle.



The Stetter reaction is related to the Benzoin condensation where the nucleophilic catalyst is a cyanide ion and the electrophile a carbonyl.

Scope
An example of the Stetter reaction is the preparation of 2,5-Undecanedione from heptanal and 3-buten-2-one in scheme 3.



Just as with benzoin condensations the reaction can be carried out as an intramolecular asymmetric synthesis and with persistent carbenic triazolium salts exemplified by the synthesis of a hydrobenzofuranone in scheme 4. The base in this reaction is KHMDS.