The Reaction of 5-Bromouracil Derivatives with Sulfur Nucleophiles, and a Novel Synthetic Route to 5-Sulfur-Substituted Uraciis and Nucleotides

1-Methyl-5-bromouracil (1) reacts with sodium hydrosulfide in dimehtyl sulfoxide at room temperature to give l-methyl-5-mercaptouracil (2, isolated as the disulfide 3) and 1-methyluracil (4). Deuterium-exchange studies are consistent with 1,4 addition of the reagent to 1, followed by tautomerization, to give two stereoisomeric ad-ducts which, after nucleophilic displacement of the bromine by another anion of the reagent, undergo trans elimination reactions leading to 2 and 4, respectively, Based on this mechanism, a useful, novel synthetic route was developed for the introduction of a 5-sulfur substituent into the pyrimidine ring of uracil derivatives via addition of methyl hypobromite to the 5,6 double bond, followed by reaction of the adduct with sodium disulfide. By use of this method, 3 was synthesized in 74% yield, and the disulfide of the nucleotide 5-mercapto-2′-deoxyuridine 5′-phosphate (15) was synthesized in an overall yield of 68%.