Sequential paired electrolysis-enabled synthesis of antifungal-active gem-difluoroalkenes via electrochemical halogen atom transfer

Abstract

Fluorine-containing compounds, particularly gem-difluoroalkenes—recognized as bioisosteres of carbonyl groups—hold crucial value in pharmaceuticals, agrochemicals, and functional materials, as they can modulate drug molecules’ lipophilicity, pK_a, and bioavailability. Alkyl halides, indispensable building blocks in organic synthesis, serve as alkyl radical precursors; however, generating alkyl radicals from unactivated alkyl halides typically relies on costly photocatalysts, posing a notable challenge. This work presents a practical electrochemical method for the deiodinative gem-difluorovinylation of unactivated primary, secondary, and tertiary alkyl iodides. Operating under mild, transition-metal-free, and sacrificial-anode-free conditions, it integrates electrochemical halogen-atom transfer (e-XAT) with convergent paired electrolysis. The method exhibits broad substrate applicability and excellent compatibility with complex functional groups, enabling late-stage diversification of natural products, biomolecules, and pharmaceuticals. Additionally, glycoside-derived halides were used to synthesize gem-difluoroalkene derivatives; their antifungal activity was evaluated, with several active compounds identified, and preliminary mechanistic studies were conducted.