Metal-and Photosensitizer-Free Hydrodifluoromethylation of Unactivated Alkenes via Acetamide-Activated Difluoromethyl Aryl Sulfones

Abstract

Herein, we report a photocatalyst-and metal-free, visible-light-induced hydrodifluoromethylation of unactivated alkenes via an acetamide-mediated activation of difluoromethyl aryl sulfones, a class of bench-stable CF₂H reagents. The cooperative roles of acetamide, KF, and H₂O enable efficient CF₂H radical generation under blue-light irradiation in DMSO, affording hydrodifluoromethylated products in good yields with broad substrate scope and functional group tolerance. This protocol features tunable regioselectivity, furnishing both anti-Markovnikov and Markovnikov hydrodifluoromethylated products. Mechanistic investigations reveal the formation of an electron donor-acceptor (EDA) complex between acetamide and the difluoromethyl aryl sulfone, which, upon visible-light excitation, undergoes single-electron transfer (SET) followed by C-S bond fragmentation to generate CF₂H radicals under mild conditions. This work establishes a practical and sustainable strategy for direct CF₂H incorporation into complex molecular scaffolds and expands the synthetic potential of Hu reagents in fluorine chemistry and late-stage functionalizationGreen foundation1. This study presents a sustainable, photocatalyst-and transition-metal-free, visible-light-induced strategy for the hydrodifluoromethylation of unactivated alkenes using bench-stable difluoromethyl aryl sulfones. The reaction operates through an acetamide-mediated EDA activation that enables CF₂H radical generation without external photocatalysts, stoichiometric oxidants, or reductants, offering a mild, energy-efficient, and environmentally benign platform for installing the CF₂H motif. 2. The room-temperature conditions, tunable regioselectivity, broad functional-group tolerance, and compatibility with complex natural products, and pharmaceuticals make this protocol highly attractive for late-stage functionalization. Its metal-free, redox-neutral nature minimizes waste generation and aligns well with the core principles of green and sustainable chemistry. 3. Future efforts will focus on achieving hydrodifluoromethylation under aqueous or solvent-minimized conditions, and potentially enabling sunlight-driven radical generation, further advancing this transformation toward a greener, more scalable fluorination process.