Direct Amidation of Tertiary <i>N</i> -Benzylamines

Protecting groups have become standard tools for mitigating chemoselectivity challenges in complex molecule synthesis, but the inefficiency inherent to standalone protecting group manipulations and the difficulties frequently encountered with protecting group cleavage from polyfunctional molecules are outstanding problems associated with their usage. Leveraging routinely used protecting groups as handles for desired functionalization steps would eliminate these drawbacks while retaining the important function of suppressing undesired reactivity. The chemistry reported herein achieves this goal by enabling the direct amidation of tertiary N-benzylamines under mild conditions, yielding medicinally important acrylamides as well as a variety of other amides with high yields and broad functional group tolerance. The method is easily implemented and we showcase its utility in the endgame synthesis of sensitive acrylamide Active Pharmaceutical Ingredients (APIs), including the KRAS^G12C inhibitor MK-1084.