One-pot five-component high diastereoselective synthesis of polysubstituted 2-piperidinones from aromatic aldehydes, nitriles, dialkyl malonates and ammonium acetate

A novel five-component diastereoselective synthesis of polysubstituted 2-piperidinones is reported. The Knoevenagel condensation–Michael addition–Mannich cascade of two equivalents of aromatic aldehydes, nitriles, dialkyl malonates and ammonium acetate or aqueous ammonia in alcohols provides convenient access to alkyl (3SR,4RS,6SR)-5,5-dicyano-2-oxo-4,6-diarylpiperidine-3-carboxylates with three stereocenters in 52–90% or dialkyl (2SR,3RS,4RS,5SR)-2,4-diaryl-3-cyano-6-oxopiperidine-3,5-dicarboxylates with four stereocenters in 38–88%. The formation of products was highly stereoselective, with only one diastereomer formed. Ammonium acetate or aqueous ammonia plays a role both as a catalyst and as a nitrogen source. 2,4,6-triaryl-3,3,5,5-tetracyanopiperidines were obtained as a side products in the reactions with nitro-substituted aldehydes or with ethyl and n-propyl cyanoacetates. A series of 14 2-piperidinones and piperidines was assessed for antimicrobial activity against a panel of five bacteria and two fungi; no significant activity was observed. Two side piperidines with nitro substituents in aromatic ring possess bacteriostatic action against S. aureus ATCC 43300 and A. baumannii ATCC 19606 at 32 ug/mL.