Iron-Electrocatalytic MHAT Enables C–F Bond Activation of CF3 Alkenes: Access to Stable Keto and Enol Isosteres

Abstract

Iron-catalyzed metal hydride hydrogen atom transfer (MHAT) is a powerful strategy for hydrofunctionalization of alkenes, where reactive Fe–H is generated from a hydride donor through an oxidative process. Here, we report an iron-electrocatalytic MHAT reaction based on reductive generation of Fe–H directly from protons. Using an iron porphyrin catalyst and urea as the proton source, this protocol enables the selective C–F bond activation of CF3 alkenes to furnish gem-difluoroalkenes with a broad substrate scope under mild conditions. Mechanistic studies support the generation of proton-derived Fe–H intermediates, followed by MHAT and C–F bond cleavage. Removing the iron catalyst switches the reaction to a distinct pathway, selectively furnishing CF2H alkenes. Together, these complementary pathways provide independently accessible fluorinated isosteres of the keto and enol tautomeric states, which exhibit enhanced anti-inflammatory activity with distinct biological profiles in representative bioactive scaffolds. This work establishes the reductive model for iron-catalyzed MHAT reaction while providing a new strategy for the design and evaluation of carbonyl bioisosteres in medicinal chemistry.