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.