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

ABSTRACT 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 mechanochemical process were modulated and the differences with solution-based mechanistic pathways were disclosed. The selection of the most suitable method was driven by the physical state of both the reactants and the intermediates, while the physical state of the final 1,4-DHP directed the choice of the catalyst (Lewis vs Brønsted) and the type of work-up to recover the final products (by column chromatography vs precipitation in water). The results herein described are unprecedented in the arena of synthetic methods to access diversely substituted 1,4-DHPs, an N-heterocyclic scaffold relevant to both synthetic and medicinal purposes. GRAPHICAL ABSTRACT