Palladium‐Mediated Arylation of Lysine in Unprotected Peptides

A mild method for the arylation of lysine in an unprotected peptide is presented. In the presence of a preformed biarylphosphine‐supported palladium(II)–aryl complex and a weak base, lysine amino groups underwent C−N bond formation at room temperature. The process generally exhibited high selectivity for lysine over other amino acids containing nucleophilic side chains and was applicable to the conjugation of a variety of organic compounds, including complex drug molecules, with an array of peptides. Finally, this method was also successfully applied to the formation of cyclic peptides by macrocyclization. Defenses down: In the presence of a preformed biarylphosphine‐supported palladium(II)–aryl complex and a weak base, lysine amino groups in unprotected peptides underwent C−N bond formation at room temperature (see scheme). The process was applicable to the conjugation of a variety of organic compounds, including complex drug molecules, to peptides and was also successfully applied to the formation of cyclic peptides through macrocyclization.