Stetter reaction of aldehydes

In the early 1970s, Stetter and coworkers succeeded in transferring the coneept of the thiazolium-eatalysed nucleophile acylation to the substrate class of Michael acceptors. The Stetter reaction, is widely used as a catalytic pathway for the synthesis of 1,4-bifunctional compounds such as 1,4-diketones, 4-ketonitriles, and 4-ketoesters. In 1996, the first asymmetric intramolecular Stetter reaction was reported by Enders and coworkers. Later, the Rovis group made remarkable contributions in terms of catalysts and substrate scope for the asymmetric intramolecular Stetter reaction. 

In 2009, a highly enantioselective intermolecular Stetter reaction of het-eroaiylaldehydes with nitroalkenes was developed by Rovis and coworkers.  

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An interesting application of the Paal thiophene synthesis was documented for the synthesis of a polystyrene-oligothiophene-polystyrene copolymer. In the Stetter reaction of aldehyde 13 and P-dimethylaminoketone 14, in situ generation of the a,p-unsaturated ketone preceded nucleophilic 1,4-conjugate addition by the acyl anion... 

An efficient high yielding synthesis of 3-substituted 2,3-dihydroquinolin-4-ones 90 was developed by using a one-pot sequential multi-catalytic process <06TL4365>. The scheme below shows the one-pot sequential multi-catalytic Stetter reaction of aldehyde 91 and a, (3-unsaturated esters 92, resulting in the formation of the desired dihydroquinolines 90. 

Unfettered by the bounds of common Michael acceptors with electron-withdrawing groups, the Glorius group have impressively demonstrated the Stetter reaction of aldehydes with tethered unactivated 1,1-disubstituted alkenes. The cyclization reaction generally proceeds smoothly to afford cyclic ketones with quaternary stereocenters in excellent yields with high enantioselectivity. Based on detailed DFT calculations, they proposed a concerted mechanism for this reaction the proton migration and C—C bond formation between the Breslow enolate and the alkene occur simultaneously (Scheme 7.23). 

In 2008, the Enders group presented the first synthetically useful NHC-catalyzed intermolecular Stetter reactions of aldehydes and chalcones in... 

Scheme 7.32 NHC-catalyzed asymmetric intermolecular Stetter reaction of aldehydes and Af-acylamido acrylates reported by Glorius.

The first asymmetric intermolecular Stetter reaction was developed by Enders et al. in 1989. In 2008, Enders and coworkers reported a new chiral triazolium carbene precatalyst with an N-benzyl substituent that catalysed the as3mimetric intermolecular Stetter reaction of aldehydes with chal-cones. The desired 1,4-diketones 39 were obtained in moderate to excellent yields and with moderate to good enantioselectivities (Scheme 20.19). 

In 1995, Ciganek [39] reported the thiazolium salt 31 catalyzed intramolecular Stetter reaction of aldehyde, affording corresponding 4-chromanones in up to 86% yield. In 1996, Enders et al. [40] developed the enantioselective version, using chiral triazolium salt 2 as the precatalyst. Various 4-chromanones were obtained in good yields with moderate enantiomeric excesses (Scheme 7.21). 

In 2011, Glorius and co-workers [61] first reported the Stetter reaction of aldehydes 54 with cyclopropenes 55. The acylation products 56 were obtained in moderate to good yield with excellent diastereocontrol (Scheme 7.41). 

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