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

<A NAME="RG22405ST-1">1</A>

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

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<A NAME="RG22405ST-10">10</A>

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).

<A NAME="RG22405ST-11">11</A>

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).

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<A NAME="RG22405ST-13">13</A>

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).

<A NAME="RG22405ST-14">14</A>

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

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<A NAME="RG22405ST-17">17</A>

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