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Synthesis 2006(24): 4167-4179  
DOI: 10.1055/s-2006-950337
PAPER
© Georg Thieme Verlag Stuttgart · New York

Synthesis and Regioselective N- and O-Alkylation of 1H- or 3H-[1,2,3]Triazolo[4,5-d]pyrimidine-5,7(4H,6H)-diones (8-Azaxanthines) and Transformation of Their 3-Alkyl Derivatives into 1-Alkyl Isomers

Rafiqul Islam, Tomohisa Nagamatsu*
Department of Drug Discovery and Development, Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry, and Pharmaceutica­l Sciences, Okayama University, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan
Fax: +81(86)2517926; e-Mail: nagamatsu@pheasant.pharm.okayama-u.ac.jp;
Further Information

Publication History

Received 5 July 2006
Publication Date:
02 November 2006 (online)

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Abstract

Several alkylating agents, for example alkyl halides and dimethyl sulfate, were employed in aprotic solvents under a variety of conditions for the alkylation of mono- and disubstituted 1H- or 3H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7(4H,6H)-diones, which were prepared by cyclization of the appropriate 5,6-diaminouracils with nitrous acid. The alkylation on the triazole ring in the presence of anhydrous potassium carbonate took place simultaneously at the 1- and 2-positions, with alkylation at the 2-position taking priority. Similar alkylation on the pyrimidine ring with an equivalent alkylating reagent took place only at the 4-position. The alkylation of 3,6-disubstituted derivatives at room temperature led to 5-O-alkylation accompanied by 4-N-alkylation, but at high temperature only 4-N-alkylation took place. Reaction of 3,4,6-trisubstituted derivatives with excess alkylating agent at high temperature leads to the formation of 1,4,6-trisubstituted derivatives with elimination of the 3-substituent.

Key words

8-azaxanthines - triazolopyrimidines - regioselectivity - alkylations - heterocycles