Metal-catalyzed alkyne oxidation/CH functionalization: Effects of oxidant, temperature, and metal catalyst on chemoselectivity.

Gold-catalyzed intermolecular alkyne oxidation has attracted much synthetic attention, but mostly suffering undesired over-oxidation. Recent experiments demonstrated that over-oxidation could be dramatically suppressed in zinc(II)-catalyzed intermolecular alkyne oxidation/CH functionalization. By means of first-principle density functional theory calculations, we explored the mechanism of the M-catalyzed intermolecular alkyne oxidations (M = Zn(OTf)2 and Au+ PR3 ) as well as the effects of oxidants, temperature, and metal catalysts on chemoselectivity, in an effort to disclose the origin of the extraordinary chemoselectivity pertaining to zinc catalysis. Our calculations indicate that the Zn-catalyzed intermolecular alkyne oxidation/CH functionalization proceeds by a Friedel-Crafts alkylation mechanism rather than metal carbene insertion mechanism. The chemoselectivity of CH functionalization against over-oxidation in Zn catalysis, in comparison with gold catalysis, can be jointly controlled by four factors: (1) the use of less nucleophilic N-oxide, (2) the enhanced electrophilicity and carbocationic nature of the carbenic site in the α-oxo metal carbenoid intermediate, (3) enhanced steric repulsion to incoming oxidant exerted by bulky ancillary ligand in the close nearby of the carbenic site to disfavor intermolecular over-oxidation and (4) the large negative value of activation entropy in the intermolecular over-oxidation pathway, that jointly give rise to lower activation free energy for the intramolecular cyclization/CH functionalization pathway than for the intermolecular over-oxidation pathway. © 2018 Wiley Periodicals, Inc.