Thiol-Epoxy Click Chemistry: Neutral Quaternary Phosphonium-Promoted Weak Catalysis for Alkylation of Thiols

The thiol-involved ring-opening reaction of epoxides plays a critical role in organic synthesis and life sciences. However, achieving efficient, precise, and green thiolysis of epoxides under mild conditions remains a significant challenge, and the application in thiol-targeted alkylation in biological scenarios is even more restricted by harsh reaction conditions and a narrow substrate scope. Herein, we present a straightforward thiol-epoxy click chemistry that was catalyzed by neutral phosphonium salts under ambient conditions in solvent-free or aqueous systems. The protocol exhibits excellent orthogonality and substrate compatibility, achieving near-quantitative conversion of both common and more challenging substrates, including sterically hindered steroidal epoxides, tetrasubstituted epoxides, drug precursors, cysteine, and a thiosugar, into β-hydroxy thioethers. Moreover, the method demonstrated scalability to 10-g-scale synthesis with consistent efficiency and enabled catalyst recycling over seven cycles. Density functional theory (DFT) calculations reveal a synergistic catalytic process in which the phosphonium ion coordinates with the epoxide, while Cl– assists in thiol deprotonation. By eliminating the use of toxic reagents, transition metals, and harsh acidic or basic conditions, this method provides a green platform for drug synthesis, peptide conjugations, biomolecular modifications, etc. that leverage thiol alkylation as a pathway. This work validates the feasibility of “weak catalysis” in advancing sustainable organic chemistry and life sciences.