Synthesis of Isomeric Enamine Derivatives of Fused Cycloalkeno Thieno[2,3-d]pyrimidin-4(3H)-ones. Stereoelectronic Effect on the Regioselectivity

Abstract

A regioselective synthesis of enamine and enaminone derivatives of fused cycloalkeno thieno[2,3-d]pyrimidin-4(3H)-ones is reported. The enamine versus enaminone product in the condensation reaction with N,N-dimethylformamide dimethylacetal (DMFDMA) was shown to depend on the conformation of the cycloalkeno ring fused to the pyrimidinone moiety. The ring conformation and the stereoelectronic effect of the amidine α-protons were studied by X-ray crystallography. In deuterium exchange experiments, the amidine-ketene-N,N-acetal tautomerism was shown to be prohibited with larger (n = 3-4) ring systems consequently yielding the enaminone products.

Key words

regioselectivity - electrophilic additions - imines - ketones - tautomerism

References

• 1 Wähälä K, Lilienkampf A, Alho S, Huhtinen K, Johansson N, Koskimies P, and Vihko K. inventors; US Patent Appl.  A120050032778. 
• 2 Pindur U. N,N-Dimethylformamide Diethyl Acetal, In Handbook of Reagents for Organic Synthesis, Reagents, Auxiliaries and Catalysts for C-C Bond Formation   Coates RM. Denmark SE. Wiley; Chichester: 1999.  p.315-318  
• 3a Martin JC. Barton KR. Gott PG. Meen RH. J. Org. Chem.  1966,  31:  943 
• 3b Moltenini V. Hamilton MM. Mao L. Crane CM. Termin AP. Wilson DM. Synthesis  2002,  12:  1663 
• 3c Peterlin-Masic L. Mlinsek G. Solmajer T. Trampus-Bakija A. Stegnar M. Kikelj D. Bioorg. Med. Chem. Lett.  2003,  13:  789 
• 4a Olivera R. SanMartin R. Dominguez E. J. Org. Chem.  2000,  65:  7010 
• 4b Spivey AC. Diaper CM. Adams H. J. Org. Chem.  2000,  65:  5253 
• 4c Schenone P. Mosti L. Menozzi G. J. Heterocycl. Chem.  1982,  19:  1355 
• 4d Menozzi G. Mosti L. Schenone P. J. Heterocycl. Chem.  1987,  24:  1669 
• 4e Gopalsamy A. Yang H. Ellingboe JW. Tsou H.-R. Zhang N. Honeres E. Powell D. Miranda M. McGinnis JP. Rabindran SK. Bioorg, Med. Chem. Lett.  2005,  15:  1591 
• 5a Lin Y.-I. Lang SA. J. Heterocycl. Chem.  1977,  14:  345 
• 5b Dominguez E. Ibeas E. Martinez de Marigorta E. Kepa Palacios J. SanMartin R. J. Org. Chem.  1996,  61:  5435 
• 6a Spivey AC. Srikaran R. Diaper CM. Turner DJ. Org. Biomol. Chem.  2003,  1:  1638 
• 6b Porcheddu A. Giacomelli G. De Luca L. Ruda AM. J. Comb. Chem.  2004,  6:  105 
• 6c Gudmundsson KS. Johns BA. Org. Lett.  2003,  5:  1369 
• 6d Johns BA. Gudmundsson KS. Turner EM. Allen SH. Samano VA. Ray JA. Freeman GA. Boyd FL. Sexton CJ. Selleseth DW. Creech KL. Moniri KR. Bioorg. Med. Chem.  2005,  13:  2397 
• 7a Fossa P. Menozzi G. Dorigo P. Floreani M. Mosti L. Bioorg. Med. Chem.  2003,  11:  4749 
• 7b Bondavalli F. Bruno O. Lo Presti E. Menozzi G. Mosti L. Synthesis  1999,  1169 
• 7c Sircar I. Duell BL. Bristol JA. Weishaar RE. Evans DB. J. Med. Chem.  1987,  30:  1023 
• 8a Aoyama H. Nishio T. Hirabayashi Y. Hasegawa T. Noda H. Sugiyama N. J. Chem. Soc., Perkin Trans. 1  1975,  298 
• 8b Cohnen E. Dewald R. Synthesis  1987,  566 
• 8c Elghamry I. Synth. Commun.  2002,  32:  897 
• 8d Gabbutt CD. Hepworth JD. Heron BM. Pugh SL. J. Chem. Soc., Perkin Trans. 1  2002,  2799 
• 8e Gupton JT. Krumpe KE. Burnham BS. Dwornik KA. Tetrahedron  1998,  54:  5075 
• 9 Schuda PA. Ebner CB. Morgan TM. Tetrahedron Lett.  1986,  27:  2567 
• 10a Gompper R. Heinemann U. Angew. Chem., Int. Ed. Engl.  1981,  20:  296 
• 10b Molina P. Fresdena PM. J. Heterocycl. Chem.  1984,  21:  461 
• 11 Albright JD. Sheperd RG. J. Heterocycl. Chem.  1973,  10:  899 
• 12 Kantlehner W. Haug E. Speh S. Bräuner HJ. Liebigs Ann. Chem.  1985,  65 
• 13 Chenard BL. Welch WM. Blake JF. Butler TW. Reinhold A. Ewing FE. Menniti FS. Pagnozzi MJ. J. Med. Chem.  2001,  44:  1710 
• 14 Vetelino MG. Coe JW. Tetrahedron Lett.  1994,  35:  219 
• 15a Hermecz I. Bitter I. Horvath A. Toth G. Meszaros Z. Tetrahedron Lett.  1979,  27:  2557 
• 15b Hermecz I. Vasvasri-Debreczy L. Simon K. Pongor-Csakvari M. Meszaros Z. J. Chem. Soc., Perkin Trans. 1  1983,  369 
• 15c Hermecz I. Horvath A. Meszaros Z. De Vos C. Rodriguez L. J. Med. Chem.  1984,  27:  1253 
• 16a Yamazaki T. Takahata H. Ishikura M. Nagata M. Heterocycles  1978,  9:  1717 
• 16b Takahata H. Ishikura M. Yamazaki T. Chem. Pharm. Bull.  1980,  28:  220 
• 16c Takahata H. Ishikura M. Nagai K. Nagata M. Yamazaki T. Chem. Pharm. Bull.  1981,  29:  366 
• 17 Jeener J. Meier BH. Bachmann P. Ernst RR. J. Chem. Phys.  1979,  71:  4546 
• 18 Günther H. NMR Spectroscopy: Basic Principles, Concepts, and Applications in Chemistry   2nd ed.:  Wiley; Chichester: 1995.  p.333-334  
• 20a Csukonyi K. Lazar J. Bernath G. Hermecz I. Meszaros Z. Monatsh. Chem.  1986,  117:  1295 
• 20b Manhas MS. Amin SG. J. Heterocycl. Chem.  1992,  13:  903 
• 21 Kapustina MV. Kharizomenova IA. Shvedoov VI. Radkevich TP. Shipilova LD. Pharm. Chem. J.  1992,  26:  73 

19

Crystallographic data has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 643240 (3b), CCDC 643241 (3c), CCDC 643242 (3d), and CCDC 643243 (3e). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.