Domino imino-aldol-aza-Michael and imino-aldol-aza-Michael-imino-aldol reactions: Diastereoselective synthesis of highly functionalized 2,6-disubstituted piperidines

Enolate mediated domino imino-aldol-aza-Michael and domino imino-aldol-aza-Michael-imino-aldol reactions of alpha-(aryl/alkyl)methylidene-beta-diketones with activated N-aryl aldimines (1.0 and 2.0 equiv., respectively) have been developed for the diastereoselective (de >99%) synthesis of two sets of highly functionalized 2,6-disubstituted piperidines. The reaction course follows an intermolecular imino-aldol reaction followed by an intramolecular aza-Michael reaction with 1.0 equiv. of imine; whereas another intermolecular imino-aldol reaction takes place when 2.0 equiv. of imine is present in the reaction medium. The formation of the piperidine derivatives has been explained by plausible reaction mechanisms. (C) 2021 Elsevier Ltd. All rights reserved.

Automated summary

Enolate mediated domino imino-aldol-aza-Michael and domino imino-aldol-aza-Michael-imino-aldol reactions have been developed for the diastereoselective synthesis of highly functionalized 2,6-disubstituted piperidines. The reaction mechanism involves an intermolecular imino-aldol reaction followed by an intramolecular aza-Michael reaction, depending on the presence of 1.0 or 2.0 equiv. of imine. The formation of piperidine derivatives is explained by plausible reaction mechanisms.