Synthesis of Piperidines via Intramolecular Hydride Transfer from α‐Amino sp3 Carbon Atoms to Ethenetricarboxylate‐Derived Fragments and Further Cyclization

The cyclization of amides derived from ethenetricarboxylic acid bearing tert‐amino groups has been examined. The amides were efficiently converted to piperidine derivatives (2‐piperidones) upon heating in a polar solvent (e. g., DMSO or DMF) via intramolecular hydride transfer and subsequent ring closure. The reaction was less efficient in the presence of a Lewis acid. The reactivity varies depending on the alkyl substituents of tert‐amino groups, probably due to steric effects. The hydride transfer/cyclization mechanism was investigated by DFT calculations. The reaction of the carboxylic acid and relatively bulky diamines such as diisopropyl‐substituted diamine in the presence of amide condensation reagents at 60 °C gave the piperidine derivatives in a one‐pot reaction. The reaction of the diisopropylamine substituted piperidine product with primary amines gave secondary amine‐substituted piperidines. Reaction of amides of ethenetricarboxylate bearing tert‐amino groups gave piperidines (2‐piperidones) upon heating in a polar solvent (e. g., DMSO or DMF) via intramolecular hydride transfer and subsequent ring closure. The reaction mechanism was investigated by DFT calculations. The reaction of the carboxylic acid and diisopropyl‐substituted diamine in the presence of amide condensation reagents gave the piperidine derivatives in a one‐pot reaction. The reaction of the diisopropylamine substituted piperidine product with primary amines gave secondary amine‐substituted piperidines.