α-C–H functionalization of glycine derivatives under mechanochemical accelerated aging en route the synthesis of 1,4-dihydropyridines and α-substituted glycine esters†

The emergence of accelerated aging reaction provided a safer, cleaner, and more sustainable technology for material manufacturing and biomass treatment but still underexploited in organic synthesis and medicinal chemistry. We report the first mechanochemical accelerated aging strategy for solvent-minimal (cascade) cross dehydrogenative coupling (CDC) reactions between glycine esters/amides and a range of nucleophiles, which features clean and convenient setup, ambient temperature, atmospheric oxidation, and feasibility, for multigram-scale synthesis. By virtue of these facts, the present method provided an expedient and sustainable alternative to synthesize biologically important α-glycine derivatives and functionalized 1,4-dihydropyridines including the precursor of the antioxidant AV-154 and calcium channel blocker analogs. Mechanistically, a pre-grinding of the reactants and silica gel/NaCl facilitated spontaneous oxidation of glycine esters/amides under open air without continuous energy input followed by a coupling reaction (and sequential transformations). Multiform green metrics calculation demonstrates that the current accelerated aging protocol meets many of the principles of green chemistry such as waste prevention, high atom economy, unnecessary solvent, and good energy efficiency.