Highly diastereoselective four-component synthesis of polysubstituted 2-piperidinones with three and four stereogenic centers

Abstract

A novel four-component diastereoselective synthesis of polysubstituted 2-piperidinones is reported. The Michael addition–Mannich cascade of benzylidenemalononitriles or benzylidenecyanoacetates, dialkyl malonates, aromatic aldehydes and ammonium acetate in alcohols provides convenient access to alkyl (±)-5,5-dicyano-2-oxo-4,6-diarylpiperidine-3-carboxylates with three stereocenters in 66–92% or dialkyl (±)-2,4-diaryl-3-cyano-6-oxopiperidine-3,5-dicarboxylates with four stereocenters in 62–90%. The formation of products was highly stereoselective, with only one diastereomer formed. Ammonium acetate plays a dual role, acting as a base and as a nitrogen source. Structures of the synthesized compounds were confirmed by 1H NMR, 13C NMR, IR, elemental analysis and mass spectral studies. The formation of a single diastereomer was confirmed by singe-crystal X-ray diffraction studies.