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

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.

heterocycles - nitriles - neighboring-group effect - imidazole - diaminomaleonitrile

References

1

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

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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).

12 Handbook of Chemistry and Physics   76th ed.:  Lide DR. CRC Press; Boca Raton: 1995. 

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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.

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