A Radical–Radical Relay Strategy for Nickel-Catalyzed Phosphination of Unactivated Alkyl Electrophiles with Chlorophosphines

Transition metal-catalyzed C–P cross-coupling of unactivated alkyl electrophiles remains a formidable challenge, primarily due to their sluggish oxidative addition and competing β-hydride elimination. Herein, we describe an unprecedented radical–radical relay strategy based on a nickel center, achieving efficient nickel-catalyzed cross-electrophile coupling of unactivated alkyl electrophiles with chlorophosphines. This attractive protocol enables the rapid assembly of unactivated alkyl phosphines by facilitating alkyl radical oxidative addition while entirely preventing β-hydride elimination. The reaction tolerates a wide range of unactivated alkyl electrophiles, including alkyl chlorides, sulfonates, bromides, and iodides. Additionally, the competitive coordination of phosphine products to the nickel catalyst is suppressed by employing chelating bidentate nitrogen ligands. Notable features of this method include a simple thermal catalytic system amenable to large-scale preparation, the use of commercially available reagents, good functional group compatibility, and successful late-stage modification of bioactive molecules, underscoring its synthetic utility in organic synthesis. Mechanistic investigations and DFT calculations suggest a nickel-catalyzed radical–radical coupling process, wherein oxidative addition of the chlorophosphines occurs preferentially due to a favorable energy barrier.