Unified Template Strategy for Editing Multiple Remote C–H Bonds

Through consecutive selective C–H functionalization at multiple sites, the direct molecular editing of heteroarene carbon-hydrogen (C–H) bonds has the potential to grant rapid access into diverse molecular space; a valuable but often challenging venture to achieve in medicinal chemistry. Contrasting with electronically-biased heterocyclic C–H bonds, remote benzocyclic C–H bonds on bicyclic aza-arenes are especially difficult to differentiate due to lack of intrinsic steric/electronic biases. Through careful consideration of distance and geometric parameters, we herein report a unified catalytic directing template strategy that enables the modular functionalization of chemically-similar and adjacent remote positions on bicyclic aza-arene scaffolds. Differentiated by using two structurally distinct catalytic directing templates, this method enables direct C–H olefination, alkynylation, and allylation at previously inaccessible C6 and C7 positions of quinolines, and is amenable to the iterative, modular, and late-stage C–H editing of quinoline-containing pharmacophores and pharmaceuticals. This report, in combination with our previous C5-selective template and other complementary methods, now fully establishes a unified ‘molecular editing’ strategy to directly modify aza-arene heterocycles at any given site.