Selective Ni-Catalyzed Cross-Electrophile Coupling of Heteroaryl Chlorides and Aryl Bromides at 1:1 Substrate Ratio

Abstract

Nickel-catalyzed cross-electrophile coupling (XEC) reactions of (hetero)aryl electrophiles represent appealing alternatives to palladium-catalyzed methods for biaryl synthesis, but they often generate significant quantities of homocoupling and/or proto-dehalogenation side products. In this study, an informer library of heteroaryl chloride and aryl bromide coupling partners is used to identify Ni-catalyzed XEC conditions that access high selectivity for the cross-product when using equimolar quantities of the two substrates. Two different catalyst systems are identified that show complementary scope and broad functional-group tolerance, and time-course data suggest that the two methods follow different mechanisms. A NiBr₂/terpyridine catalyst system with Zn as the reductant converts the aryl bromide into an arylzinc intermediate that undergoes in situ coupling with 2-chloropyridines, while a NiBr₂/bipyridine catalyst system with tetrakis(dimethylamino)ethylene as the reductant uses FeBr₂ and NaI as additives to achieve selective cross-coupling.