KOtBu-promoted facile and practical synthesis of various substituted piperidine-2,6-diones between methyl acetates and acrylamides via a Michael addition/intramolecular imidation cascade sequence has been disclosed. And reaction scale-up, further transformation of representative products, and preparation of bioactive molecules (e. g. Aminoglutethimide and Niraparib) were achieved in good yield using this newly developed method.

Abstract

Substituted piperidine-2,6-diones are privileged scaffolds in numerous bioactive molecules and their facile and practical preparation still remains unsolved. In this paper, a facile and practical approach for the construction of α-substituted and α,α-/α,β-disubstituted piperidine-2,6-diones from abundant methyl acetates and acrylamides under transition-metal free condition was disclosed. It features mild reaction condition, operational simplicity, and excellent functional group tolerance, delivering a wide range of piperidine-2,6-diones in moderate to good yield. Furthermore, the application potential was further demonstrated by reaction scale-up (5 kilo-gram scale) and bio-active molecule synthesis (Aminoglutethimide and Niraparib). Additional control experiments revealed that the radical process could be excluded from this reaction and a michael addition/intramolecular imidation cascade sequence was proposed based on the control experiments. All these results demonstrated its significant application potential both in academic and industrial production.