Stetter Reaction

The Stetter Reaction is a 1,4-addition (conjugate addition) of an aldehyde to an a,β-unsaturated compound, catalyzed by cyanide or a thiazolium salt. This reaction competes with the corresponding 1,2-addition, which is the Benzoin Condensation. However, the Benzoin-Condensation is reversible, and since the Stetter Reaction leads to more stable products, the main product will be derived from 1,4-addition.

Some of the possible products are: 1,4-diketones, 4-ketocarboxylic acids and the corresponding nitriles.

Mechanism of the Stetter Reaction

The cyanide ion effects an umpolung of the normal carbonyl charge affinity, and the electrophilic aldehyde carbon becomes nucleophilic after deprotonation:

This in situ generated nucleophile reacts with the unsaturated compound:

The thiazolium salts may be converted into ylides by deprotonation. These ylides are comparable to the cyanide adducts in their ability to catalyze the Stetter Reaction effectively.

Recent Literature

Oxazolium Salts as Organocatalysts for the Umpolung of Aldehydes
V. K. R. Garapati, M. Gravel, Org. Lett., 2018, 20, 6372-6375.

Catalytic Activation of Carbohydrates as Formaldehyde Equivalents for Stetter Reaction with Enones
J. Zhang, C. Xing, B. Tiwari, Y. R. Chi, J. Am. Chem. Soc., 2013, 135, 8113-8116.

Enantioselective Stetter Reactions Catalyzed by Bis(amino)cyclopropenylidenes: Important Role for Water as an Additive
M. R. Khalkhali, M. M. D. Wilde, M. Gravel, Org. Lett., 2021, 23, 155-159.

Dynamic Kinetic Resolution of α-Keto Esters via Asymmetric Transfer Hydrogenation
K. M. Steward, E. C. Gentry, J. S. Johnson, J. Am. Chem. Soc., 2012, 134, 7329-7332.

Facile Synthesis of γ-Ketophosphonates by an Intermolecular Stetter Reaction onto Vinylphosphonates
A. Patra, A. Bhunia, A. T. Biju, Org. Lett., 2014, 16, 4798-4801.

Synthesis of α-Amido Ketones via Organic Catalysis: Thiazolium-Catalyzed Cross-Coupling of Aldehydes with Acylimines
J. A. Murry, D. E. Frantz, A. Soheili, R. Tillyer, E. J. J. Grabowski, P. J. Reider, J. Am. Chem. Soc., 2001, 123, 9696-9697.

Solvent-Free Synthesis of Alkylthiazolium-Based Ionic Liquids and their Use as Catalysts in the Intramolecular Stetter Reaction
A. Aupoix, G. Vo-Thanh, Synlett, 2009, 1915-1920.

D-Camphor-Derived Triazolium Salts for Enantioselective Intramolecular Stetter Reactions
Z.-Q. Rong, Y. Li, G.-Q. Yang, S.-L. You, Synlett, 2011, 1033-1037.

The First Asymmetric Intramolecular Stetter Reaction
D. Enders, K. Breuer, J. Runsink, Helv. Chim. Acta, 1996, 79, 1899-1902.

A Highly Enantio- and Diastereoselective Catalytic Intramolecular Stetter Reaction
J. Read de Alaniz, T. Rovis, J. Am. Chem. Soc., 2005, 127, 6284-6289.

Enantioselective Synthesis of Highly Substituted Fluoroalkylated Benzopyranones and 3-Coumaranones via N-Heterocyclic Carbene-Catalyzed Intramolecular Annulations
I. Barańska, K. Rafińska, Z. Rafiński, J. Org. Chem., 2023, 88, 14339-14344.

A Highly Enantio- and Diastereoselective Catalytic Intramolecular Stetter Reaction
J. Read de Alaniz, T. Rovis, J. Am. Chem. Soc., 2005, 127, 6284-6289.

NHC-Catalyzed Dual Stetter Reaction: A Mild Cascade Annulation for the Syntheses of Naphthoquinones, Isoflavanones, and Sugar-Based Chiral Analogues
R. N. Mitra, K. Show, D. Barman, S. Sarkar, D. K. Maiti, J. Org. Chem., 2019, 84, 42-52.

Synthesis of 2-Aryl Naphthoquinones by the Cross-Dehydrogenative Coupling Involving an NHC-Catalyzed endo-Stetter Reaction
A. Ghosh, A. Patra, S. Mukherjee, A. T. Biju, J. Org. Chem., 2019, 84, 1103-1110.