Phosphite mediated molecular editing <i>via</i> switch to <i>meta</i> -C–H alkylation of isoquinolines: emergence of a distinct photochemical [1,3] N to C rearrangement

The isoquinoline core is present in one of the largest subsets of bioactive natural products. The multifunctional isoquinoline core exerts diverse bioactivity, resulting in the development of numerous isoquinoline-based drugs and molecules that are currently under clinical trials. We developed a new approach for phosphite-mediated [1,2] alkyl migration for an overall <i>ortho</i>-C-H alkylation <i>via N</i>-alkylation of isoquinoline. Tuning the phosphite-mediated protocol to switch the site selectivity would expedite direct and diverse multi-C-H bond functionalization. We report a new approach starting with a simple <i>N</i>-alkylation of isoquinoline with sterically and electronically diverse alkyl bromides for their phosphite-mediated photochemical [1,3] N to C rearrangement followed by a rearomatization sequence that leads to <i>meta</i>-C-H (C4) alkylation. Combined experimental and computational studies unveiled the emergence of an unprecedented C-N bond cleavage pathway from the singlet excited state of the enamine-type intermediate. Our radical bond-cleavage pathway favors substituted alkyl group migration that complements the recently successful <i>meta</i>-alkylation methods with smaller and more reactive electrophiles. This switch in site selectivity <i>via</i> tuning the phosphite-mediated protocol resulted in sequential C-H difunctionalization of isoquinoline including regiodivergent <i>ortho</i>, <i>meta</i>-dialkylations of isoquinolines.