Cascade reactions hetero-Michael

In fact, the only example of a simple hetero-Michael reaction under PTC conditions which does not involve a cascade process consists of an intramolecular aza-Michael reaction of conveniently 2-substituted indole compounds incorporating an a,p-unsaturated ester moiety at the side chain (Scheme 5.35)." This methodology shows up as a very straightforward and efficient method for building up the l,2,3,4-tetrahydropyrazino[l,2-u]indole... 

Hetero-Michael/aldol cascade reactions have been studied by several research groups using ort/zo-substituted benzaldehydes as functionalized reagents. In this context, different benzo-fused heterocyclic architectures have... 

Scheme 7.55 Hetero-Michael/Michael cascade reaction for the asymmetric synthesis of tetrahydrothiophenes and pyrrolidines.

Cascade Processes Initiated by Hetero-Michael Reactions... 

Synthesis of chiral heterocycles by domino organocatalytic processes has also been intensively studied. In particular, various benzo-fused heterocycles, such as chiral chromans, " thiochromanes, hydro-quinolines, dihydropyranes, or thiopyranes were investigated. These organocatalytic sequence were typically initiated by a hetero-Michael addition of a sulfur, oiqrgen or nitrogen nucleophile, which triggers the formation of an enolate/enamine that adds to the ortho electrophile terminating the cascade reaction. An elimination step or an additional cyclisation step follows (Scheme 8.25). 

Remaining in the field of hetero-Michael reaction, Gong et al. disclosed a four-component quadruple cascade reaction activation initiated by oxa-Michael addition of alcohol to acroleins providing an easy and direct access to highly functionalized chiral trisubstituted cyclohexene derivatives 170 (Scheme 2.54) [81]. 

The Michael-aldol cascade reaction of2-mercaptobenzaldehyde with a,/ -unsaturated A-acyl imides (293) (R = alkyl, Ar, hetero-Ar), giving rise to thiochromanes (294), has been attained using the thiourea derivative (295) as a chiral organocatalyst. The key factor here is the presence of the pyrazole moiety as H-bond acceptor, which facilitates the activation and contributes to a better organization of the transition state. 

A mechanism for the piperazine-catalyzed formation of 4//-chromenes is complex cascade of reactions, starting with piperazine acting as a base which activates malononitrile, promoting Knoevenagel condensation, and also formation of an enamine, followed by Michael condensation, proton transfer, intermolecular cycliza-tion via a nucleophilic addition of the enolate oxygen to the nitrile group (hetero-Thorpe-Ziegler), and finally hydrolysis and tautomerization. 

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