Biocompatible ultrafast thiol-acetalization enabled by triaryl carbenium ion-pair

Abstract

Dithioacetals are essential building blocks in organic synthesis, materials development, and drug discovery. Despite their utility, existing synthetic methods often depend on organic solvents and transition metal catalysis under harsh conditions, limiting their sustainability and biological compatibility. In this work, we present an ultrafast, triaryl carbenium ion-pair-catalyzed thiol-acetalization protocol in water. Using a variety of aldehydes, ketones and isatins with thiols as coupling partners, the reaction proceeds under mild, metal-free conditions to deliver thioacetals in excellent yields (up to 99%) and with broad substrate scope. The method tolerates diverse functional groups and enables late-stage functionalization of natural products, amino acid derivatives, and small-molecule drugs. Moreover, the thiol-acetalization proceeded efficiently with catalyst loadings as low as 1.0 mol% and was scalable to a gram level. Furthermore, the biocompatibility, mild conditions, and rapid features make this approach well-suited for potential use in bioconjugation and biomolecule derivatization.