Theoretical Insight into the Mechansim and Origin of Ligand-Controlled Regioselectivity in Homogenous Gold-Catalyzed Intramolecular Hydroarylation of Alkynes.

This work aims at understanding the mechanism and regioselectivity in ligand-controlled gold-catalyzed divergent intramolecular hydroarylation of alkynes reported by Jiang et al. ( J. Am. Chem. Soc. 2016 , 138 , 5218 - 5221 ). Focusing on a representative alkyne, N-propargyl-N-tosylaniline, we conducted a detailed computational study on the ortho- and para-position hydroarylation of the alkyne catalyzed by gold(I) catalysts with different ligands. Both the ortho- and para-position hydroarylation reactions are found to follow a similar three-stage mechanism: electrophilic cyclization, proton loss, and protiodeauration. The initial electrophilic cyclization was identified as the rate- and regiochemistry-determining step. With the flexible electron-deficient phosphite ligand, the ortho-position cyclization is identified as the energetically more favorable pathway, while with the rigid electron-abundant phosphine (Xphos) ligand, the dominant pathway turns to the para-position cyclization. The theoretical results are in good agreement with the experimental observations. The π-π interaction between alkynyl phenyl and the directing acylamino group are found to be mainly responsible for the observed ortho-selectivity, while a combination of favorable noncovalent CH···π interaction and steric repulsion between Xphos ligand and alkynyl group contributes to the observed exclusive para-selectivity. The present calculations provide deeper insight into the mechanism and origin of regioselectivity of the title reaction.