Synergistic Organoboron/Palladium Cocatalyzed Dehydrative Couplings of Azoles with Allylic Alcohols: A Combined Experimental and Computational Mechanistic Investigation

Abstract

In the presence of Pd(Xantphos) and an electron-deficient arylboronic acid cocatalyst, azoles such as pyrazoles, triazoles, tetrazoles, and purines undergo regioselective, dehydrative allylations with allylic alcohols. The boronic acid has a significant effect on both the rate and the regioselectivity of these reactions. Herein, a combined experimental and computational mechanistic study of the synergistic organoboron- and palladium-catalyzed allylation of azoles is described. Kinetic analysis and an evaluation of the effects of arylboronic acid substitution on the reaction rate point toward turnover-limiting ionization of the allylic alcohol, with Lewis acid activation by the boronic acid. Computational modeling of the reaction pathway with density functional theory indicates that allylic alcohol ionization is also the regioselectivity-determining step and that the resulting ion pair undergoes C–N bond formation through an outer-sphere mechanism. An unexpected observation of autocatalysis that emerged from the kinetic analysis motivated a study of the effects of additives, leading to the development of an improved protocol.