Enantioselective rapid assembly of bis-heterocycles by sequential palladium-catalyzed aza-Heck cyclization coupling reaction

A highly efficient palladium-catalyzed enantioselective aza-Heck-catalyzed cyclization coupling reaction of alkyne-tethered oxygen- and nitrogen-centered nucleophiles is reported. This protocol enables versatile access to chiral isoindolinone-linked benzofuran and indole bis-heterocyclic derivatives bearing a quaternary stereogenic center in good yields with high enantioselectivities. A sterically demanding, electron-rich (S)-(+)-1,1'-Bi-2-naphthol (BINOL)-derived phosphoramidite ligand provides excellent control over both chemoselectivity and enantioselectivity. Density functional theory calculations were used to elucidate the reaction mechanism and the origin of enantioselectivity. Moreover, these bis-heterocycles exhibited promising antimicrobial activity.