Silver(I)-Catalyzed A3-Coupling for the Regioselective Synthesis of 2-Chloro-(Phenylvinyl)imidazo[1,2- a ]pyridines and Late-Stage Drug Functionalization

Abstract

We report a silver(I)-catalyzed three-component A3-coupling strategy for the synthesis of 2-chloro-(phenylvinyl)imidazo[1,2-a]pyridines from 2-aminopyridines, terminal alkynes, and β-chlorovinyl aldehydes. The transformation proceeds under mild conditions with high regioselectivity, broad substrate scope, and excellent functional-group tolerance. Notably, retention of the vinylic C–Cl bond in the products provides access to structurally important chlorovinyl-substituted imidazo[1,2-a]pyridines. The retained chlorovinyl motif may offer potential value for further diversification and for the development of medicinal chemistry-oriented scaffolds and pharmacophores. The protocol is operationally simple and scalable, as demonstrated by gram-scale synthesis. Its synthetic utility is further highlighted through the late-stage functionalization of complex molecules, including Naproxen and Gemfibrozil, as well as the synthesis of amino acid-derived 2-chloro-(phenylvinyl)imidazo[1,2-a]pyridines. These results underscore the versatility of the protocol and its potential applications in medicinal chemistry, molecular diversification, and drug discovery.