Boric Acid Promoted Base-Free Chan-Lam Amination Reaction: A Computationally Inspired Mechanistic Investigation

Cu^II-catalyzed oxidative coupling reactions based on Chan-Lam (CL) protocol have established themselves as one of most reliable and practical synthetic tools for the efficient formation of carbon-nitrogen/heteroatom bonds. Since decades this methodology has witnessed considerable development in its application scope, industrial uptake and fundamental mechanistic knowledge. Despite its successful application and popularity, the underlying mechanistic understanding remains underdeveloped and unexplored. Current theoretical investigation underpins the mechanism of CL-based amination reaction under base-free conditions employing the transmetalation by-product B(OH)₃ as promoter. The rate-determining transmetalation involves an energy span of 26.4 kcal mol^-1 with subsequent overall disproportionation and reductive elimination barrier of 25.4 kcal mol^-1, accompanying stable intermediates in comparison to the base-mediated CL amination. The aryl migration involves a unique six-membered transition state unlike similar transition-metal catalyzed transmetalation event. The Cu^I→Cu^II oxidative regeneration is facile in the presence of B(OH)₃ coordinated intermediates. The calculated results are in line with experimental kinetic studies and for the first time elucidates the mechanistic effect of inverting the organoboron: amine stoichiometry. Furthermore, Hammett studies involving substituted aryl boronic acid substrates reveals electron-rich substitution to entail lower transmetalation barrier. Overall, the boric acid stabilized copper intermediates are thermodynamically stable, allowing the amination to occur at improved time frame.