Synthesis and Rearrangements of Alkyl Phosphorothioates

Reaction of PSCl₃ with benzyl alcohol in triethyl phosphate followed by aqueous workup produces S-benzyl phosphorothioate, 2, while similar reaction of cyclohexanol produces O-cyclohexyl phosphorothioate. The S-benzyl ester is postulated to arise from rearrangement of either O-benzyl phosphorodichloridate, 5, or a hydrolysis product. Reaction of P¹-O-cyclohexyl P²-n-propyl 1-thiodiphosphate, 3, with BrCN in aqueous solutions buffered at pH 7.2 with lutidine or at pH 10.3 with triethylamine produces P¹-cyclohexyl P²-n-propyl diphosphate, 4, in essentially quantitative yield within 10 min. Similar reaction in H₂ ¹⁸0 produces exclusively [P¹-¹⁸O\4 with no indication of the presence of ¹⁸O at P². The reaction is postulated to involve the intermediate formation of P¹-O-cyclohexyl P²-n-propyl 1-thiocyanatodiphosphate, 9, by reaction of 3 with BrCN. 9 undergoes hydrolysis with displacement of SCN^-by H₂O, producing 4. Similar reaction of P¹~O-cyclohexyl 1-thiodiphosphate in H₂ ¹⁸O produces cyclohexyl [l-¹⁸O,2-¹⁸O\diphosphate in high yield, with approximately 50% ¹⁸O-enrichment at each position. This labeling pattern is postulated to arise from neighboring group participation by the terminal phosphoryl group. Initial reaction of P¹-O-cyclohexyl 1-thiodiphosphate produces the intermediate P¹-O-cyclohexyl 1-thiocyanatodiphosphate, 10. The latter is partitioned between two pathways, direct displacement of SCN^-by water to form cyclohexyl diphosphate and internal displacement of SCN^-by the neighboring phosphoryl group to form cyclohexyl cyclodiphosphate, 11, a highly reactive species which undergoes immediate hydrolysis to cyclohexyl diphosphate.