Palladium-Catalyzed C-H Thiolation of Phenylalanine-Containing Peptides via In Situ Imine Generation.

We report a palladium-catalyzed C-H thiolation of phenylalanine residues in peptides using diaryl disulfides. Key to this approach is an imine directing group generated in situ from the N-terminal Boc group, which obviates the need for an external auxiliary. The reaction features a broad substrate scope, good functional group tolerance, and scalability, delivering thioether-functionalized peptides in synthetically useful yields. Mechanistic studies suggest an imine-directed C-H activation followed by radical C-S bond formation. This auxiliary-free strategy, which relies on a substrate-derived imine as the directing group, provides a versatile platform for late-stage peptide modifications.