gem-Difluoromethylene Alkyne-Enabled Diverse C-H Functionalization and Application to the on-DNA Synthesis of Difluorinated Isocoumarins

Using gem-difluoromethylene alkynes as effectors, unprecedented diverse C-H activation/[4+2] annulations of simple benzoic acids are reported. The chemodivergent reaction outcomes are well-tuned by Rh/Ir-catalyzed system; in the Rh-III catalysis, 3-alkenyl-1H-isochromen-1-one and 3,4-dialkylideneisochroman-1-one skeletons are afforded in a solvent-dependent manner whereas difluoromethylene-substituted 1H-isochromen-1-ones are generated under the Ir-III-catalyzed system. Mechanistic studies revealed that unusually double beta-F eliminations and fluorine effect-induced regioselective reductive elimination are independently involved to enable distinct reaction modes for divergent product formations. Besides, synthetic application in both the derivatization of obtained diene products and the on-DNA synthesis of DNA-tagged difluorinated isocoumarin have been demonstrated, which manifested great potential for synthetic utility of the developed protocols.

Automated summary

This study reports unprecedented diverse C-H activation/[4+2] annulations of simple benzoic acids using gem-difluoromethylene alkynes as effectors. The outcomes of the chemodivergent reaction are well-tuned by Rh/Ir-catalyzed system, resulting in different skeletons depending on the solvent used. Mechanistic studies reveal the involvement of double beta-F eliminations and fluorine effect-induced regioselective reductive eliminations in enabling distinct reaction modes for divergent product formations.