Benign synthesis of therapeutic agents: domino synthesis of unsymmetrical 1,4-diaryl-1,4-dihydropyridines in the ball-mill

The solvent-free preparation of unsymmetrical N-aryl-5,6-unsubstituted-1,4-dihydropyridines (DHPs) by ball-milling was investigated. Three different mechanochemical domino reactions (one-pot/one step or stepwise) were studied, the process parameters underlying any modulated and differences with solution-based mechanistic pathways disclosed. selection most suitable method driven physical state both reactants intermediates, while final 1,4-DHP directed choice catalyst (Lewis vs Brønsted) type work-up to recover products (by column chromatography precipitation in water). results herein described are unprecedented arena synthetic methods access diversely substituted 1,4-DHPs, an N-heterocyclic scaffold relevant medicinal purposes.