Synthesis of Ethyl Pyrimidine-4-carboxylates from Unsymmetrical Enamino Diketones and Their Application in the First Synthesis of Pyrimido[4,5-d]pyridazin-8(7H)-ones

Abstract

The reaction of unsymmetrical enamino diketones [RC(O)C(=CNMe₂)C(O)CO₂Et, where R = Ph, 4-MeC₆H₄, 4-MeOC₆H₄, 4-BrC₆H₄, 4-ClC₆H₄, 4-FC₆H₄, 4-O₂NC₆H₄, 2-thienyl, benzofuran-2-yl, and CF₃] with N-C-N dinucleophiles, such as benzamidine hydrochloride or 1H-pyrazole-1-carboxamidine monohydrochloride, afforded a series of ethyl 2,5-disubstituted pyrimidine-4-carboxylates in a chemoselective and highly chemo­selective manner (51-86%). Reaction of these two series of pyrimidines (R = Ph, 4-MeOC₆H₄, 4-FC₆H₄, and 2-thienyl) with hydrazine monohydrate under mild conditions led to 2,5-substituted pyrimido[4,5-d]pyridazin-8(7H)-ones in high yields (81-92%).

Key words

cyclizations - enones - ring closure - heterocycles - pyrimidines - regioselectivity

References

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Crystallographic data for compounds 4a, 6h, and 7a reported in this paper, have been deposited with the Cambridge Crystallographic Data Centre (CCDC Number 686848, 686847, and 687296, respectively). Copies of the data can be obtained, free of charge, on application to CCDC 12 Union Road, Cambridge CB2 1EZ, UK [Fax: [phone] or e-mail: [e-mail]].

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HYPERCHEM^TM Professional 7.52(2002), Hypercube, Inc.: 1115 NW 4th Street, Gainesville, FL 32601, USA.

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SHELXTL 6.14, Bruker AXS Inc.: Madison WI, 2003.