Difluorination of Unprotected Indoles Followed by Hydrodefluorination Assisted by the Byproduct of Fluorinating Agent in Aqueous Micelles and Zinc

Unprecedented aqueous fluorine chemistry has been reported, involving a highly selective monofluorination of unprotected indoles via simultaneous difluorination-hydrodefluorination, all in water, This is achieved through a carefully engineered process, which utilizes a benign proline-based surfactant called PS-750-M in an aqueous micellar environment. In situ formation of the difluorinated indole and the N-(phenylsulfonyl)benzenesulfonamide byproduct are vital to the process, and extensive control experiments have indicated the significance of N-(phenylsulfonyl)benzenesulfonamide and zinc in the two-electron transfer process, leading to a highly selective transformation. Notably, the unique feature of this technology is the requirement for simultaneous zinc activation and zinc ion sequestering within the reaction medium, which can only be achieved through the use of zinc and a fluorinating source. The resulting synthetic methodology can selectively prepare a broad range of monofluorinated indoles, is easy to execute, and is greener than traditional 3-fluoro indole-forming reactions requiring toxic reaction medium or rare-earth metals.