Synlett 2005(16): 2429-2432  
DOI: 10.1055/s-2005-872700
LETTER
© Georg Thieme Verlag Stuttgart · New York

New and Efficient Synthesis of Imidazo[4,5-b]pyridine-5-ones

Magdi E. A. Zaki, M. Fernanda Proença*, Brian L. Booth
Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
e-Mail: fproenca@quimica.uminho.pt;
Further Information

Publication History

Received 12 July 2005
Publication Date:
21 September 2005 (online)

Abstract

1-Aryl-5-amino-4-cyanoformimidoyl imidazoles 1 were reacted with methyl cyanoacetate, under mild experimental conditions, leading to 3-aryl-6,7-dicyanoimidazo[4,5-b]pyridine-5-ones 5, isolated after neutralization of their ammonium salts 4. A reaction intermediate, imidazole 3d, the precursor of the bicyclic structure 5d, could be isolated under carefully controlled experimental conditions and was shown to cyclize to imidazo[4,5-b]pyridine-5-one (4d, isolated as the DBU salt) after reflux in ethanol, in the presence of DBU.

    References

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  • 8a Alves MJ. Booth BL. Freitas AP. Proença MF. J. Chem. Soc., Perkin Trans. 1  1992,  913 
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  • 8d Booth BL. Coster RD. Proença MF. Synthesis  1988,  389 
  • 8e Alves MJ. Booth BL. Carvalho MA. Pritchard RG. Proença MF. J. Heterocycl. Chem.  1997,  739 
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  • 8i Carvalho MA. Álvares Y. Zaki ME. Proença MF. Booth BL. Org. Biomol. Chem.  2004,  2:  2340 
  • 9a Dias AM. Cabral IM. Proença MF. Booth BL. J. Org. Chem.  2002,  67:  5546 
  • 9b Zaki ME. Proença MF. Booth BL. J. Org. Chem.  2003,  68:  276 
  • 12 Handbook of Chemistry and Physics   76th ed.:  Lide DR. CRC Press; Boca Raton: 1995. 
  • 15 Gordon AJ. Ford RA. In The Chemist’s Companion: A Handbook of Practical Data, Techniques and References   John Wiley and Sons; New York: 1972.  p.62 
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1

Address: School of Chemistry, University of Manchester, Manchester M60 1QD, UK.

10

Compounds 4: a solution of 5-amino-1-aryl-4-cyano-formimidoyl imidazole (0.4-1.2 mmol) in MeCN (3-5 mL) and DMF (1-3 mL) was combined with methyl cyanoacetate (1.4-2.4 molar equiv) and the mixture was stirred in an ice bath for 5-8 h. After standing at -10 °C for 1-8 d, the solid suspension was filtered and washed with Et2O. A second crop of the same product could be recovered from the mother liquor after concentration on the rotary evaporator. The structure of the products obtained was confirmed by elemental analysis, 1H NMR and 13C NMR spectroscopy. Characterization of 4a: 1H NMR (300 MHz, DMSO-d 6): δ = 8.42 (s, 1 H), 7.69 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 8.4 Hz, 2 H), 7.20 (s, 4 H), 2.35 (s, 3 H). 13C NMR (75 MHz, DMSO-d 6): δ = 168.14, 151.2, 142.26, 136.34, 132.66, 124.60, 123.61, 118.90, 114.12, 113.52, 92.65, 20.57. Anal. Calcd for C15H9N5O·NH3·1.5 H2O: C, 56.42; H, 4.70; N, 24.33. Found: C, 56.56; H, 4.61; N, 26.08. IR (nujol mull): 2239 (w), 2211 (m), 1598 (m), 1585 (w).

11

Compounds 5: a solution of the ammonium salt of 3-aryl-6,7-dicyano-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridine (ca. 0.35 mmol) in EtOH (3 mL), H2O (5 mL) and AcOH (1-1.5 mL) was stirred at r.t. Turbidity gradually developed and after 30 min the solid was filtered and washed with EtOH and Et2O. Characterization of 5a: 1H NMR (300 MHz, DMSO-d 6): δ = 13.2-13.8 (br s, 1 H), 8.95 (s, 1 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.42 (d, J = 8.4 Hz, 2 H), 2.40 (s, 3 H). 13C NMR (75 MHz, DMSO-d 6): δ = 162.44, 148.28, 147.54, 138.47, 131.21, 130.25, 129.99, 124.24, 115.12, 114.39, 112.75, 91.16, 20.60. Anal. Calcd for C15H9N5O·0.2 H2O: C, 64.61; H, 3.37; N, 25.13. Found: C, 64.77; H, 3.62; N, 24.76. IR (nujol mull): 2231 (s), 1603 (s), 1576 (m), 1519 (s), 1493 (s).

13

Compound 3d: a solution of 5-amino-4-cyanoformimidoyl-(4′-fluorophenyl)imidazole (0.10 g, 0.44 mmol) in MeCN (2 mL) and Et2O (20 mL) was combined with methyl cyanoacetate (0.06 g, 0.60 mmol) while the reaction mixture was kept stirring in an ice bath. The solution was allowed to stand at -10 °C for 24 h, when the solvent was partially removed in the rotary evaporator. Addition of EtOH (10 mL) led to an orange solid that was filtered and washed with Et2O to give 3d (0.05 g, 0.16 mmol, 36%). Characterization: 1H NMR (300 MHz, DMSO-d 6): δ = 7.77 (s, 1 H), 7.60 (dd, J = 9.0 Hz, J = 4.8 Hz, 2 H), 7.46 (t, J = 9.0 Hz, 2 H), 7.18 (s, 2 H), 3.77 (s, 3 H). 13C NMR (75 MHz, DMSO-d 6): δ = 162.46 (d, J = 245.0 Hz), 163.01, 148.41, 137.00, 129.14 (d, J = 9.5 Hz), 122.79, 117.01 (d, J = 23.2 Hz), 116.53, 115.27, 52.60. Anal. Calcd for C15H10N2F: C, 57.88; H, 3.24; N, 30.64. Found: C, 57.61; H, 3.55; N, 22.46. IR (nujol mull): 2219 (m), 2202 (m), 1707 (s), 1629 (s), 1541 (s).

14

Calculations were done on an inspection version of Chem3D Ultra 8.0.

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Tuberculosis Antimicrobial Acquisition & Coordinating Facility, Southern Research Institute, Birmingham, Alabama, USA.