Michael-Stetter reaction

What is Michael-Stetter reaction?

In 1973, Stetter et al. first reported a reaction that is now commonly known as the Michael-Stetter reaction. It involves the nucleophilic conjugate addition of an aldehyde to an electron-deficient alkene, resulting in the formation of a 1,4-bifunctional compound.

This reaction is also occasionally referred to as the Stetter condensation, or Stetter reaction and is analogous to the well-known Michael addition, thus also called the Michael-Stetter reaction.

Michael-Stetter reaction - general reaction scheme - Stetter condensation - Stetter reaction
Michael-Stetter reaction
  • R1, R3, R4 = H, alkyl, aryl
  • R2 = H, alkyl
  • X = COR, CO2R, CN, NO2, SO2R, etc. (see list of acronyms)

Thiazolium, imidazole, and triazolium can catalyze this reaction in a similar way. The addition of a catalyst to the aldehyde is thought to convert the carbonyl group into an acyl anion equivalent, which then adds to an α,β-unsaturated compound such as a ketone, ester, or nitrile to form the 1,4-dicarbonyl compound. This reaction typically exhibits high enantioselectivity and diastereoselectivity, especially in the presence of a chiral triazolium salt.

Furthermore, the intramolecular reaction can produce tertiary ether, thioether, and quaternary stereocenters with very high enantioselectivity.

However, the catalytic activity of thiazolium and triazolium salts is generally low for the Michael-Stetter reaction because the addition of the acyl anion equivalent to the α,β-unsaturated compound produces a relatively stable adduct, making it difficult for the thiazolium or triazolium salt to cleave from the adduct efficiently and resume another catalytic cycle.

The application of the Michael-Stetter reaction is broad and extends to the preparation of 1,4-bifunctional molecules from aldehydes.

References

Stetter, H. and Schreckenberg, M. (1973), A New Method for Addition of Aldehydes to Activated Double Bonds. Angew. Chem. Int. Ed. Engl., 12: 81-81. https://doi.org/10.1002/anie.197300811

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