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 Ref|Stetter. 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.

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An example of the Stetter reaction is the preparation of 2,5-undecanedione from heptanal and 3-buten-2-one as shown below. Ref|Stetter2.

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.Ref|Liu. The base in this reaction is KHMDS Ref|cre.

References

# "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 [http://www3.interscience.wiley.com/cgi-bin/abstract/106580616/ABSTRACT Abstract]
# H. Stetter, H. Kuhlmann, and W. Haese Organic Syntheses, Coll. Vol. 8, p.620; Vol. 65, p.26 [http://www.orgsynth.org/orgsyn/pdfs/CV8P0620.pdf Article]
# "Asymmetric Synthesis of Hydrobenzofuranones via Desymmetrization of Cyclohexadienones Using the Intramolecular Stetter Reaction"Qin Liu and Tomislav Rovis J. Am. Chem. Soc.; 2006; 128(8) pp 2552 - 2553; [http://dx.doi.org/10.1021/ja058337u Abstract]
# The first step in this sequence is the oxidation of p-cresol by iodosobenzene diacetate in presence of 30 equivalents of ethanol, the second step another oxidation this time of the hydroxyl group by Dess-Martin periodinane. "ee" stands for enantiomeric excess