Molecular editing of aza-arene C-H bonds by distance, geometry and chirality

Direct molecular editing of heteroarene carbon-hydrogen (C-H) bondsthrough consecutive selective C-H functionalization hasthe potential to grant rapid access into diverse chemical spaces, which is a valuable but often challenging venture to achieve in medicinal chemistry(1). In contrast to electronically biased heterocyclic C-H bonds(2-9), remote benzocyclic C-H bonds on bicyclic aza-arenes are especially difficult to differentiate because ofthe lack of intrinsic steric/electronic biases(10-12). Here we report two conceptually distinct directing templates that enable the modular differentiation and functionalization of adjacent remote (C6 versus C7) and positionally similar (C3 versus C7) positions on bicyclic aza-arenes through careful modulation of distance, geometry and previously unconsidered chirality in template design. This strategy enables direct C-H olefination, alkynylation and allylation at adjacent C6 and C7 positions of quinolines in the presence of a competing C3 position that is spatially similar to C7. Notably, such site-selective, iterative and late-stage C-H editing of quinoline-containing pharmacophores can be performed in a modular fashion in different ordersto suit bespoke synthetic applications. This Article, in combination with previously reported complementary methods, now fully establishes a unified late-stage 'molecular editing' strategy to directly modify bicyclic aza-arenes at anygiven site in different orders.

Automated summary

This study presents two distinct directing templates that allow for the differentiation and functionalization of remote and similar positions on bicyclic aza-arenes. This strategy enables site-selective C-H olefination, alkynylation, and allylation reactions on quinoline-containing compounds, and can be performed in a modular fashion in different orders.