Docking on Azaarene Nitrogen for Phosphite Mediated Sequential Transportations: Switch to meta-C−H Alkylation of Isoquinolines

Direct meta-C−H alkylation of azaarenes largely remains an unsolved challenge and typically requires multi-step synthesis protocols to circumvent the inherent ortho/para-reactivity. Recent progress for direct meta-C−H functionalization has been reported, but alkylation remains elusive due to the low reactivity of alkyl halides compared to the other successful electrophiles. We developed a new approach to “dock” the alkyl groups on isoquinoline nitrogen for their phosphite-mediated migrations to C2 carbon for an overall ortho-C−H alkylation with complete recovery of the phosphite. Tuning the phosphite-mediated protocol to switch the site selectivity would expedite direct and diverse multi-C−H bond functionalization. Herein, we report a switch to meta-C−H alkylation via developing photochemical [1,3] migration of the alkyl group followed by rearomatization. This dock-ing strategy for dual nitrogen activation and C−H functionalization led to a net-zero carbon waste method. The docking and migration protocol works with primary, secondary, and all carbon tertiary alkyl halides, leading to unprecedented success with sterically demanding alkylations. The phosphite-mediated transportation of the alkyl group from nitrogen to ring carbon makes the nitrogen of the meta-alkylated isoquinoline product ready for dock again. Here, for the first time, we showed consecutive re-docking of different functional groups on the free isoquinoline nitrogen for their sequential regioselective migrations at ortho-position. The change in phosphite-mediated methods and the docking order led to derivatizations of the meta-alkylated iso-quinoline products, including regiodivergent multi-C−H alkylations of isoquinolines.