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Synthesis 2009(21): 3589-3592  
DOI: 10.1055/s-0029-1216978
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Prompt Lithiation of 1-Dimethylsulfamoylthymine Used for the Synthesis of 1-Allyloxymethyl-6-(α,2,6-trifluorobenzyl)thymine

Yasser M. Lokshaa, Erik B. Pedersen*a, Andrew D. Bondb, Paolo La Collac, Barbara Seccic, Roberta Loddoc
a Nucleic Acid Centre, Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark
Fax: +4566158780; e-Mail: ebp@ifk.sdu.dk;
b Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark
c Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Microbiologia e Virologia Generale e Biotecnologie Microbiche, Università di Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy
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Publication History

Received 16 March 2009
Publication Date:
28 August 2009 (online)

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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)fluo-romethyl]-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.

Key words

antiviral agents - heterocycles - HIV - medicinal chemistry - sulfonamides

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