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%).

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

References

<A NAME="RM03208SS-1A">1a</A> Nargund LVG. Badiger VV. Yarnal SU. Eur. J. Med. Chem.  1994,  29:  245 

<A NAME="RM03208SS-1B">1b</A> Ouf NH. Amr A. El-G E. Fayed AA. Monatsh. Chem.  2008,  139:  281 

<A NAME="RM03208SS-1C">1c</A> Tafi A. Bernardine C. Botta M. Corelli F. Andreini M. Martineli A. Ortore G. Baraldi PG. Fruttarolo F. Borea PA. Tuccinardi T. J. Med. Chem.  2006,  49:  4085 

<A NAME="RM03208SS-1D">1d</A> Orjales A. Mosquera R. López B. Olivera R. Labeaga L. Núñez MT. Bioorg. Med. Chem.  2008,  16:  2183 

<A NAME="RM03208SS-1E">1e</A> Danel K. Pedersen EB. Nielsen C. J. Med Chem.  1998,  41:  191 ; and references therein

<A NAME="RM03208SS-2A">2a</A> Brown DJ. In Comprehensive Heterocyclic Chemistry   Vol. 3:  Katritzky AR. Rees CW. Pergamon; Oxford: 1984. 

<A NAME="RM03208SS-2B">2b</A> Undheim K. Benneche T. In Comprehensive Heterocyclic Chemistry II   Vol. 6:  Katritzky AR. Rees CW. Scriven EF. Pergamon; Oxford: 1996. 

<A NAME="RM03208SS-2C">2c</A> Martins MAP. Frizzo CP. Moreira DN. Zanatta N. Bonacorso HG. Chem. Rev.  2008,  108:  2015 

<A NAME="RM03208SS-2D">2d</A> Martins MAP. Cunico W. Pereira CMP. Sinhorin AP. Flores AFC. Bonacorso HG. Zanatta N. Curr. Org. Synth.  2004,  1:  391 

<A NAME="RM03208SS-3A">3a</A> Jones RG. Whitehead CW. J. Org. Chem.  1955,  20:  1342 

<A NAME="RM03208SS-3B">3b</A> Krapcho AP. Maresch MJ. Helgason AL. Rosner KE. Hacker MP. J. Heterocycl. Chem.  1993,  30:  1597 

<A NAME="RM03208SS-4">4</A> Bradshaw JS. Huszthy P. Izatt RM. J. Heterocycl. Chem.  1994,  31:  1047 

<A NAME="RM03208SS-5">5</A> Riley TA. Hennen WJ. Dalley NK. Wilson BE. Robins RK. Larson SB. J. Heterocycl. Chem.  1987,  24:  955 

<A NAME="RM03208SS-6">6</A> Jones RG. J. Am. Chem. Soc.  1956,  78:  159 

<A NAME="RM03208SS-7A">7a</A> Kuderna JG. Skiles RD. Pilgram K. J. Org. Chem.  1971,  36:  3506 

<A NAME="RM03208SS-7B">7b</A> Mátyus P. Szilágyi G. Kasztreiner E. Rabloczky G. J. Heterocycl. Chem.  1988,  25:  1535 

<A NAME="RM03208SS-8">8</A> Treu M. Jordis U. Lee VJ. Molecules  2001,  6:  959 

<A NAME="RM03208SS-9">9</A> Rosa FA. Machado P. Rossatto M. Vargas PS. Bonacorso HG. Zanatta N. Martins MAP. Synlett  2007,  3165 

<A NAME="RM03208SS-10">10</A> Rosa FA. Machado P. Vargas PS. Bonacorso HG. Zanatta N. Martins MAP. Synlett  2008,  1673 

<A NAME="RM03208SS-11">11</A>

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]].

<A NAME="RM03208SS-12">12</A> Farrugia LJ. J. Appl. Crystallogr.  1997,  30:  565 

<A NAME="RM03208SS-13">13</A> Dewar MJS. Zoebisch EG. Healey EF. Stewart JJP. J. Am. Chem. Soc.  1985,  107:  3902 

<A NAME="RM03208SS-14">14</A>

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

<A NAME="RM03208SS-15">15</A> Echevarría A. Elguero J. Llamas-Saiz AL. Foces-Foces C. Schultz G. Hargittai I. Struct. Chem.  1994,  5:  255 

<A NAME="RM03208SS-16">16</A> Perrin DD. Armarego WLF. In Purification of Laboratory Chemicals   Pergamon; Oxford: 1998. 

<A NAME="RM03208SS-17">17</A>

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

<A NAME="RM03208SS-18">18</A> Farrugia LJ. J. Appl. Crystallogr.  1999,  32:  837