Hidden Role of Borane in Directed C–H Borylation: Rate Enhancement through Autocatalysis

The metal-catalyzed C–H borylation reaction is a robust and valuable method for the installation of boronate esters into simple organic substrates. The regioselectivity observed in early examples was governed by steric control; those systems were extended to include a number of approaches that override the natural selectivity to obtain directed C–H borylation. In spite of the array of catalysts and directing groups that are now known to achieve directed reactions, no comprehensive experimental and computational study of the mechanism has been reported to date. In this study, experimental and computational results have been used to provide a detailed study of the catalytic mechanism of amine-directed C(sp2)–H borylation. A notable result of the present study is the absence of inter- or intramolecular kinetic isotope effects at the functionalized C–H bond. The kinetic and computational data support a rate-determining reassociation of pinacolborane from the iridium catalyst to allow carbon–boron bond formation. An additional feature of note is the role of the boron source in the reaction. Computational analysis revealed the anticipated role of pinacolborane generated in the catalytic cycle. Based on this analysis, pinacolborane was examined as an additive, which overcame an induction period and provided an overall rate enhancement. Pinacolborane was found to serve as an autocatalyst in the transformation, a feature that can be utilized to improve the reactivity in directed C–H borylation reactions. The experimentally and computationally determined free energies of activation for the overall reaction are in agreement and provide valuable insights into substrate-directed C–H borylation reactions.