Phosphite mediated molecular editing switch to -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 -C-H alkylation -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 -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 -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 -alkylation methods with smaller and more reactive electrophiles. This switch in site selectivity tuning the phosphite-mediated protocol resulted in sequential C-H difunctionalization of isoquinoline including regiodivergent , -dialkylations of isoquinolines.