Studies on the Conversion of Nucleoside H-Phosphonate Monoesters into the Corresponding H-Phosphonothioates

Abstract

We have recently reported t h a t reaction of nucleoside hydrogenphosphonates with coupling agents in pyridine, followed by dition of hydrogen sulfide, affords nucleoside H-phosphonodithioates as known that in the latter solvent activation of H-phosphonate monoesters with acyl chlorides yields the mixed anhydride of type 22 almost exclusively. Unfortunately, when nucleoside H-phosphonate 1 was treated with various amounts of pivaloyl chloride (PV-C1) in quinoline/acetonitrile (1 :4, v/v) followed by addition of hydrogen sulfide, the dithio H-phosphonate 3 was again the predominant product. Depending on the amount of coupling agent, the reaction afforded mainly 3 (3 equiv. of PV-C1) or a mixture of 3 and the starting material 1 (ratio -1 :1) when 1.1 equiv. of PV-C1 was used. The amount of the monothio H- phosphonate 5 was approximately the same in all reactions and constituted -10% of all nucleotidic material.