Ligand-Enabled Cu-Catalyzed Deoxyalkynylation of α-Unfunctionalized Alcohols with Terminal Alkynes

Despite the widespread utility of transition metal-catalyzed cross-couplings in organic synthesis, the coupling of unactivated alkyl electrophiles remains challenging due to sluggish oxidative addition and competing side reactions. Here, we describe a general and practical copper-catalyzed radical deoxyalkynylation of α-unfunctionalized alcohols through a synergistic combination of Barton-McCombie deoxygenation and copper-catalyzed radical cross-coupling. Key to the success of this method lies in not only the development of rigid anionic multiple N,N,N-ligand to exert remarkable selectivity of highly reactive unactivated alkyl radicals, but also the selection of one suitable oxidant to suppress Glaser homocoupling and other side products. This method provides a complementary approach for the cross-coupling of unactivated alkyl halides, which face notable difficulties in reaction initiation and bond formation under mild thermal conditions, especially the tertiary variants. This protocol not only exhibits a broad scope with respect to both coupling partners, covering alkyl- and (hetero)aryl alkynes, as well as α-unfunctionalized primary-, secondary-, and tertiary- alcohols with good functional group compatibility, but also facilitates the late-stage functionalization of a series of important natural and bioactive complex molecules.