(Methyl)thianthrenium Salt Enabled Monoselective -Methylation and -(-Methyl) Labeling: Late-Stage Functionalization of Arylamides.

Herein, we report a practical and efficient approach for the monoselective -methylation of arylamide substrates using (methyl)thianthrenium triflate as an effective methylating agent. This strategy enables late-stage selective -monomethylation of structurally complex bioactive molecules with excellent efficiency and selectivity. Notably, the protocol facilitates monoselective -(-methyl) incorporation, providing access to isotopically labeled compounds of pharmaceutical interest for drug discovery and development. The versatility and broad applicability of this approach are demonstrated through the successful synthesis of marketed drugs such as enzalutamide and apalutamide. Its operational simplicity, versatility, selectivity, and scalability make this protocol an efficient tool for late-stage diversification and isotope labeling of amide-based scaffolds.