Photoinduced amine-mediated hydrodifluoroalkylation of 3-methyleneisoindolin-1-ones

Abstract

Difluoroalkyl groups are valuable motifs in medicinal chemistry; however, catalyst-free methods for their incorporation into heterocyclic scaffolds remain limited. Herein, we report a photoinduced amine-mediated hydrodifluoroalkylation of 3-methyleneisoindolin-1-ones under catalyst-free conditions. Preliminary mechanistic studies indicate that the reaction proceeds via halogen-bond-assisted activation of difluoroalkyl bromides, thereby facilitating efficient radical generation. This activation step concurrently generates an α-amino alkyl radical, a key reductant which drives radical polar crossover. It is further found that water increases yields significantly by acting as a proton shuttle. This mild, operationally simple protocol provides rapid access to difluoroalkylated isoindolinone derivatives with good functional-group tolerance.