Regioselective N ‐Benzotriazole Substitution Under Mechanochemical Conditions

Here, we present a simple and efficient method for synthesizing substituted benzotriazoles under mechanochemical conditions. Under optimal conditions, the coupling between 1,2,3‐benzotriazole and benzyl bromide occurs with 99% conversion and 17:1 regioselectivity within 30 min of neat milling. Using density functional theory calculations, we demonstrate that this reaction proceeds through a concerted S N 2 mechanism. Following this, various reaction environments were explored, which enable variable control over product regioselectivity. Notably, through the inclusion of tert ‐butoxide and phosphate salts, we were able to switch the reaction mechanism from this concerted pathway to a stepwise, S N 1‐type mechanism. We attributed this change in mechanism to the sodium and potassium counter‐ions stabilizing the deprotonated imidazole ion intermediates. We were then able to influence the equilibrium between these intermediates, and by extension, the regioselective outcome of the reaction via liquid‐assisted grinding. These levers for reaction control are unique to mechanochemistry, and underscores its potential advantages over solvothermal synthesis.