Cu(II)-Catalyzed Hydrofunctionalization of Unactivated Alkynes via π-Lewis Acid Activation

A copper(II)-catalyzed stereodivergent hydrooxygenation of electronically unactivated alkynes with carboxylic acids is reported. Regioselectivity and kinetic reactivity are facilitated by a bidentate auxiliary, and <i>syn</i>- or <i>anti</i>-stereoselectivity is controlled through the judicious tuning of reaction conditions. The method affords trisubstituted <i>E</i>- or <i>Z</i>-alkenes with an enol ester functionality in a highly selective manner. Beyond carboxylic acids, a variety of other OH- and NH-nucleophiles react smoothly to furnish enol ether, enamine, and alkylidene β-lactam building blocks. Mechanistic experiments and density functional theory (DFT) calculations shed light on the nature of π-Lewis acid activation with Cu(II) and support a catalytic cycle that features an inner-sphere nucleocupration mechanism via a six-membered transition state for <i>syn</i>-addition and a base-assisted outer-sphere nucleocupration mechanism for <i>anti</i>-addition.