Prompt lithiation of 1-dimethylsulfamoylthymine used for the synthesis of 1-allyloxymethyl-6-(a,2,6-trifluorobenzyl)thymine

LOKSHA YM;PEDERSEN EB;BOND AD;LA COLLA P;SECCI B;LODDO, ROBERTA

2009-01-01

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Abstract

The 6-position of the uracil ring was activated for a lithiation reaction by condensing thymine with dimethylsulfamoyl chloride. X-ray crystallography was used to confirm the structure of the intermediate product 1- dimethylsulfamoylthymine, which was lithiated and subsequently treated with 2,6-difluorobenzaldehyde. The dimethylsulfamoyl group was removed by treatment with aq HCl and the alcohol was fluorinated with DAST. The fluoro-derivative was silylated and alkylated at the N1-position with bis(allyloxy)methane to give 1-allyloxymethyl-6-[(2,6-difluorophenyl)fluoromethyl]-5-methylpyrimidine-2,4(1H, 3H)-dione, which showed moderate activity against HIV-1. An attempt was also made to activate 5-methyl-2-(methylthio)pyrimidin-4(3H)-one with dimethylsulfamoyl chloride for a lithiation reaction. However, X-ray crystallography and subsequent reactions showed that the sulfamoylation had taken place on the oxygen at the 4-position.