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The Stetter reaction is an organic reaction involving the nucleophile catalyzed conjugate addition of an aldehyde to a Michael acceptor such as an enone.^[1] The reaction product is a 1,4-dicarbonyl compound. The active catalyst can be a combination of a thiazolium salt and a base (which forms an N-heterocyclic carbene in situ) or cyanide anion. It was found by Dr. Hermann Stetter in 1976.^[2]

Scheme 1. Stetter reaction overview

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.

Scheme 2. Stetter reaction mechanism

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

Scope

The Stetter reaction produces classically difficult to access 1,4-dicarbonyl compounds and related derivatives, such as 1,4-ketoesters and ketonitriles. Intramolecular aldol-type cyclizations of these products leads efficiently to cyclopentenones and related compounds.^[3] An example of the Stetter reaction is the preparation of 2,5-undecanedione from heptanal and 3-buten-2-one as shown below.^[4]

Scheme 3. Stetter synthesis of 2,5-Undecanedione

Just as with benzoin condensations the reaction can be carried out as an intramolecular asymmetric synthesis using persistent carbenic triazolium salts, exemplified by the synthesis of a hydrobenzofuranone shown below.^[5] The base in this reaction is KHMDS.^[6]

Scheme 4. Intramolecular asymmetric Stetter reaction

Variations

Several variations of the Stetter reaction have been developed since its discovery in 1973.

Asymmetric

The first asymmetric variant of the Stetter reaction was reported in 1996 by Enders et al, employing a chiral triazolium catalyst.^[7] Subsequently, Rovis and coworkers developed a family of related chiral triazolium catalysts that generated intramolecular Stetter products in high enantiomeric excess (82-97% ee).^[8]

Related

Baylis–Hillman reaction

References

1. ^ Review. Catalyzed Addition of Aldehydes to Activated Double Bonds - A New Synthetic Approach Stetter, H. Angewandte Chemie International Edition Volume 15, Issue 11, Pages 639 - 647 1976 Abstract
2. ^ http://careerchem.com/NAMED/Named-Rxns(Q-T).pdf
3. ^ Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407. doi:10.1002/0471264180.or040.04
4. ^ H. Stetter, H. Kuhlmann, and W. Haese Organic Syntheses, Coll. Vol. 8, p. 620; Vol. 65, p. 26 Article
5. ^ Asymmetric Synthesis of Hydrobenzofuranones via Desymmetrization of Cyclohexadienones Using the Intramolecular Stetter ReactionQin Liu and Tomislav Rovis J. Am. Chem. Soc.; 2006; 128(8) pp 2552 – 2553; Abstract
6. ^ The first step in this sequence is the oxidation of p-cresol by iodosobenzene diacetate in presence of 30 equivalents of ethylene glycol, the second step another oxidation this time of the hydroxyl group by Dess-Martin periodinane.
7. ^ Enders, D.; Breuer K.; Runsink, J.; Teles, J. H. Helv. Chim. Acta 1996, 79, 1899.
8. ^ Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298.

Category:Addition reactions Category:Carbon-carbon bond forming reactions Category:Name reactions