Olefin‐Catalyzed Aromatic Bromination toward Biocompatible Tyrosine Modification

The chemical modification of biomolecules is an emerging technique for studying and manipulating biological mechanisms. Among these methods, catalysis offers advantages over stoichiometric strategies due to its ability to enhance selectivity, for example, spatiotemporal control, via catalytic turnover, and the modification of tyrosine recently attracts considerable attention due to its significant biological functions. However, catalyst-controlled aromatic halogenation is challenging under near-physiological conditions due to the lack of biocompatible catalysts, despite the potential of tyrosine bromination as an attractive biomolecular labeling technique. In this study, inspired by the bioorthogonal reactivity of cyclic olefins, we developed catalytic aromatic bromination via the transfer of a bromenium ion from olefins to aromatic substrates based on the in-situ generation of bromiranium ions as active species. Bifunctional cyclooctenes bearing a hydroxybenzyl group efficiently catalyzed the bromination of phenol derivatives, which was applicable in tyrosine modification. The substituent effects of the catalysts primarily affected the rate of the generation of bromiranium ions, which provided the kinetics enabling light-gated catalysis that could be activated in situ via the photochemical deprotection of the hydroxybenzyl group. Such olefin catalysis was compatible with aqueous conditions, enabling the bromination of peptides, and the Lewis-base catalysis of the olefins proceeded even under acidic conditions.