Synthesis of 6-substituted 1-alkoxy-5-alkyluracils

Synthesis of 6-substituted 1-alkoxy-5-alkyluracils 2a-c have been achieved from readily accessible 2-alkyl-3,3-di(methylthio)acryloyl chlorides 4a,b in high overall yields. Treatment of 4a,b with silver cyanate followed by reaction of the resulting isocyanates 5a,b with an appropriate alkoxyamine afforded N-alkoxy-N'[2-alkyl-3,3-di(methylthio)acryloyl]ureas 6a,b in 85-88% yields. Cyclization of 6a,b in acetic acid containing methanesulfonuic acid followed by oxidation with 3-chloroperoxybenzoic acid gave high yields of 1-alkoxy-5-alkyl-6-(methylsulfonyl)uracils 9a,b. Nucleophilic addition-elimination reaction of 9a,b with sodium azide, phenylthiol, or phenylselenol produced 6-azido-1-butoxythymine (2a, 98%), 5-ethyl-1-(2-phenoxyethoxy)-6-(phenylthio)uracil (2b, 95%), or 5-ethyl-1-(2-phenoxyethoxy)-6-(phenylselenenyl)uracil (2c, 91%).