Visible-light-mediated histidine modification via C–H arylation

Histidine is a proteinogenic amino acid whose electron-deficient imidazole side chain plays key roles in enzymatic catalysis, proton transfer, and metal coordination. Consequently, site-selective histidine modification has emerged as a valuable strategy for the late-stage diversification of peptides and proteins. However, most reported methodologies rely on N-functionalization of the imidazole ring, which may alter its intrinsic biological properties, whereas direct C–H functionalization remains largely unexplored. Inspired by recent advances in visible-light-promoted Minisci-type reactions, we developed a photoinduced methodology for the selective C(2)-arylation of histidine derivatives under mild conditions. Preliminary results demonstrate the feasibility of this approach using diazonium salts bearing both electron-donating and electron-withdrawing substituents. To our knowledge, this is the first example of histidine arylation via direct C–H functionalization. Ongoing studies aim to improve reaction efficiency and expand the substrate scope toward the selective late-stage bioconjugation of histidine-containing peptides for applications in chemical biology and peptide engineering.