Preparation of 1,3-thiazines: Sulphur analogues of nucleic acid pyrimidine bases

Abstract

Sulphur analogues of uracil and thymine have been prepased, in which the N1 atom of the pyrimidine base has been replaced by a sulphur atom. A number of general synthetic methods are described for the synthesis of these 1,3-thiazines. The uracil analogues were prepared from the related 2-thio-1,3-thiazines, by acid hydrolysis of the 2-alkylthio derivative. 3,4-Dihydro-4-oxo-2-thio-2H-1,3-thiazine, its N-methyl and N-ethyl derivatives were obtained by cyclization of the addition compound resulting from the reaction of propiolic acid and the appropriate dithiocarbamic acid. The generality of this reaction, when propiolic acid is replaced with other acetylenic acids or their related esters, is discussed. The crystalline addition compounds obtained from dithiocarbamic acid and either propiolic acid or methyl propiolate were all shown by p.m.r, spectroscopy to have cis stereo-chemistry. The thymine analogues were prepared by an alternative route, which utilized the intramolecular cyclization of S-ethyl-N-(β-methoxymethacryloyl)dithiocarbamate to form 2-ethylthio-6-methyl-4-oxo-4H-1,3-thiazine, followed by acid hydrolysis of the 2-ethylthio group. Related intramolecular cyclization reactions of N-acyl-dithiocarbamates formed the 5-acetyl-, the 5-cyano-6-methyl-, the 5-cyano-6-ethyl-, and the 6-methyl-2-ethylthio-1,3-thiazine derivatives. A third approach involved the successful acid catalysed ring-opening-ring- closure of a. 4-oxo-2-thio-1,3-oxazine to the isomeric 2,4-dioxo-1,3-thiazine.