Catalyst-Free Synthesis of Phosphorothioates via P–S Coupling ­Reaction of Dialkyl Phosphites with Thiols

Abstract

A catalyst-free synthesis of phosphorothioates via a P–S cross-coupling reaction of thiols with dialkyl phosphites has been studied. With presented method, various phosphorothioates were obtained by the reaction of thiols with H-dialkyl phosphites in the presence of DMSO as both solvent and oxidant under transition-metal-free conditions. Mechanistic studies showed that the reaction proceeds with formation of a known disulfide intermediate via the oxidation of thiols in the presence of DMSO. Nucleophilic substitution of dialkyl phosphite with the disulfide intermediate gave phosphorothioate. The presented method is a convenient process for the synthesis of phosphorothioates under catalyst-free conditions.

Key words

phosphorothioates - thiols - H-dialkyl phosphites - coupling reaction - catalyst-free

Publication History

Received: 09 October 2022

Accepted after revision: 20 November 2022

Accepted Manuscript online:
20 November 2022

Article published online:
13 December 2022

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• 39 Synthesis of Phosphorothioates 3; General Procedure: Thiol (1 mmol) was added to a solution of dialkyl phosphite (2 mmol) in DMSO (2 mL). The reaction mixture was stirred for 12–24 h (Table 2) at 90 °C. EtOAc (20 mL) was added to the reaction mixture and the mixture was washed with NaOH (5%, 10 mL) and brine (10 mL). The organic phase was evaporated, and the pure product was obtained by flash on silica gel with n-hexane–EtOAc (9:1 to 6:4). All products gave satisfactory spectral data in accord with the assigned structures and literature reports (see the Supporting Information).