Insights into the Oxidative Palladium-Catalyzed Regioselective Synthesis of 3-Arylindoles from N-Ts-Anilines and Styrenes: A Computational Study

Palladium (Pd)-catalyzed intermolecular oxidative annulation represents as an attractive approach to regioselective synthesis of 2/3-arylindoles, but the unexpected regioselectivity remains to be one of the most challenging questions in this field. Herein, we present a systematically theoretical study on the Pd-catalyzed regioselective synthesis of 3-arylindoles from N-Ts-anilines and styrenes with the presence of oxidant, special ligand, and benzoquinone (BQ) additive. A refined mechanism, in which the single six-membered ring CMD-type transition state was involved in the C-H activation of styrenes, is obviously more energetically favorable than the proposed pathway associated with the [6-6] palladacyclic transition state in the experimental report (Youn et al., Angew. Chem. Int. Ed. 2017, 56, 1-6). The preferred reaction pathway consists of N-H deprotonation, CMD-type C-H bond activation of styrenes, carbopalladation, BQ-assisted beta-C-H activation, alpha-C-H bond activation, and reductive elimination. With BQ additive, the carbopalladation is the key step for controlling the regioselectivity, and the favorable Pd-O coordinating bond interaction between Pd and BQ as well as the less distortion degree of styrene in the C3-regioselective transition state determine the observed regioselectivity. The obtained computational insights should be valuable for understanding and rational design of the transition metal-catalyzed oxidative annulation reactions with special regioselectivity.