Facile and Practical Synthesis of Substituted Piperidine‐2,6‐Diones Under Transition‐Metal Free Condition

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.