Engineering Isoquinoline-derived Directing Template for Distal C5-H Functionalization of Bicyclic Aza-arenes

Benzo-fused mono- and di-azines constitute privileged scaffolds in pharmaceuticals and functional materials; however, achieving site-selective remote benzocyclic C─H functionalization on these motifs remains a formidable challenge due to the lack of an ideal tethering site for directing group (DG) and the tendency of heteroatom to deactivate metal catalysts. Herein, we report a robust isoquinoline-based directing template that enables catalytic, site-selective C5─H functionalization of benzo-fused azines. The template recruits the substrate through reversible N-coordination, allowing the strong σ-donating isoquinolinyl arm to position the metal catalyst for precise activation of the remote C5─H bond. This design facilitates efficient alkenylation with a broad range of alkenes, which are otherwise inaccessible with conventional stoichiometric nitrile-based templates reported in the literature. Notably, this new class of directing template unlocks the unprecedented C5─H alkynylation, further demonstrating the pivotal role of structural tuning of the directing entity in facilitating diverse C5─H functionalization transformations. Various key intermediates have been intercepted by single-crystal X-ray diffraction, and complementary spectroscopic analyses to shed light on the mechanism of the catalytic cycle. The mechanistic study also discloses that the cooperativity exists between the directing template (DT) and the template chaperone (TC) in the catalytic cycle.