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Synthesis 2009(23): 4022-4026  
DOI: 10.1055/s-0029-1217030
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A New Route to Substituted Pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones and Facile Extension to 5,7(6H,8H) Isomers

Anjanette J. Turbiak, H. D. Hollis Showalter*
Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109-1065, USA
Fax: +1(734)6478430; e-Mail: showalh@umich.edu;
Further Information

Publication History

Received 27 May 2009
Publication Date:
12 October 2009 (online)

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Abstract

A new route to substituted pyrimido[5,4-e]-1,2,4-tria­zine-5,7(1H,6H)-diones is outlined. The synthesis proceeds via preformed hydrazone intermediates, which are then condensed with an activated chlorouracil to build up the entire molecular framework, followed by a reductive ring closure to provide the parent series. The route has been extended to the isomeric pyrimido[5,4-e]-1,2,4-triazine-5,7(6H,8H)-dione class via the use of methylhydrazine as hydrazine surrogate, followed by regiospecific alkylation of the N 8-H pyrimidotriazinediones with a range of alkyl and alkaryl substituents. This new methodology permits the generation of a wide range of compounds with variable substitution at the N¹, C³, and N8 positions for a heterocyclic scaffold with demonstrated pharmacological activity.

Key words

pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones - py­rimido[5,4-e]-1,2,4-triazine-5,7(6H,8H)-diones - heterocycles - hydrazones - cyclizations