Mechanism of Boron-Catalyzed N‑Alkylation of Amines with Carboxylic Acids

Mechanistic study has been carried out on the B­(C₆F₅)₃-catalyzed amine alkylation with carboxylic acid. The reaction includes acid-amine condensation and amide reduction steps. In condensation step, the catalyst-free mechanism is found to be more favorable than the B­(C₆F₅)₃-catalyzed mechanism, because the automatic formation of the stable B­(C₆F₅)₃-amine complex deactivates the catalyst in the latter case. Meanwhile, the catalyst-free condensation is constituted by nucleophilic attack and the indirect H₂O-elimination (with acid acting as proton shuttle) steps. After that, the amide reduction undergoes a Lewis acid (B­(C₆F₅)₃)-catalyzed mechanism rather than a Brønsted acid (B­(C₆F₅)₃-coordinated HCOOH)-catalyzed one. The B­(C₆F₅)₃)-catalyzed reduction includes twice silyl-hydride transfer steps, while the first silyl transfer is the rate-determining step of the overall alkylation catalytic cycle. The above condensation–reduction mechanism is supported by control experiments (on both temperature and substrates). Meanwhile, the predicted chemoselectivity is consistent with the predominant formation of the alkylation product (over disilyl acetal product).