Synthesis of α-Halophosphonates via Copper-Catalyzed Atom Transfer Radical Addition

Abstract α-Substituted alkylphosphonates and phosphates have broad utility in the pharmaceutical, agrochemical, and commodity chemical industries. Herein, we present the copper-catalyzed atom transfer radical addition (ATRA) of alkyl halides to alkenylphosphonates for the synthesis of α-halophosphonates enabled by 1,1′-azobis(cyclohexanecarbonitrile) (ACHN). Mechanistic investigations support that the diazo compound serves as an in situ reducing agent regenerating [Cu(I)] throughout the reaction and enabling high turnover numbers. Under the optimized conditions, a broad scope of radical precursors, including primary, secondary, and tertiary haloalkanes add to substituted vinylphosphonates in good to excellent yields. Product derivatization demonstrates the synthetic utility of the reaction.