Silicon-Catalyzed Mannich Reaction of Unactivated Amides

Significance

Kobayashi and colleagues report an unusual Mannich reaction between unactivated amides 1 and tosylimines 2, catalyzed by triisopropylsilyl triflate and triethylamine. The authors propose that the reaction proceeds via a catalytic formation of a silyl enol ether A from amide 1, which reacts with imine 2 to form intermediate B. The ammonium triflate salt then regenerates the silicon catalyst, affording product 3 and completing the cycle. Although the proposed silyl intermediate A was elusive by NMR spectroscopy, several indirect experiments provide support for the suggested catalytic cycle. For less reactive substrates, a metal co-catalyst (CuOTf) was found necessary, which presumably provides Lewis acid activation of imines 2 rather than forming a copper enolate from 1.