Metal-Free Access to <i>N</i> , <i>S</i> -Acetals via <i>N</i> -Acyliminium Borate Intermediate under Biocompatible Conditions

N,S-Acetals are important motifs in pharmaceuticals, natural products, and functional materials. Herein, we report a metal-free, aqueous-phase synthesis of N,S-acetals through [Ph3C]+[B(C6F5)4]−-catalyzed generation of highly electrophilic N-acyliminium borates from 3-hydroxyisoindolin-1-ones. This protocol proceeds at room temperature and physiologically relevant pH, exhibits broad substrate scope including sterically hindered and biologically relevant substrates, and enables site-selective cysteine modification of unprotected peptides and proteins. The N-acyliminium borate intermediate was directly characterized in solution, providing mechanistic support. This operationally simple method offers a general and efficient platform for thiol functionalization and late-stage peptide/protein modification.