Copper-Catalyzed Enantioconvergent Nucleophilic Fluorination of Alkyl Electrophiles to Generate α-Fluoroamides

Despite the pharmaceutical significance of alkyl fluorides wherein a fluorine-bearing carbon is stereogenic, progress in the development of catalytic asymmetric methods for their synthesis has been limited; furthermore, the approaches that have been described to date predominantly employ electrophilic fluorinating agents (e.g., NFSI and Selectfluor) rather than more economical nucleophilic fluorinating agents (e.g., CsF and KF). Herein, we describe a method for the catalytic asymmetric synthesis of alkyl fluorides through copper-catalyzed enantioconvergent substitutions of racemic alkyl halides, specifically, fluorinations of α-haloamides by CsF, enabling carbon-fluorine bond formation with good enantioselectivity and in good yield under simple and mild conditions. We have applied this new process to a streamlined, catalytic asymmetric synthesis of a bioactive α-fluoroamide and to the synthesis of other classes of enantioenriched fluorinated compounds.