A Facile One-Pot Synthesis of 3-Imidazolyl 1,2,4-Triazoles and 1,2,4-Oxa­diazolones

Abstract

5-(5-Aminoimidazol-4-yl)-1,2,4-triazol-3-ones were obtained under mild experimental conditions from 5-amino-4-(N-ethoxycarbonyl) cyanoformimidoyl imidazoles and hydrazine in a rapid one-pot reaction. When hydroxylamine hydrochloride was used, in the presence of base, the corresponding 1,2,4-oxadiazol-5-ones were isolated. An equally fast reaction occurred when 5-amino-4-(N-acetyl/benzoyl) cyanoformimidoyl imidazoles were combined with hydrazine to give 5-(5-aminoimidazol-4-yl)-1,2,4-triazoles.

heterocycles - cyclization - ring closure - imidazole - 1,2,4-triazole - 1,2,4-oxadiazole

References and Notes

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14

General Procedure for the Synthesis of 1,2,4-Triazolones 3
Hydrazine monohydrate (2.0 equiv) was added to a suspension of imidazole 2 (0.52-1.95 mmol) in DMF (for 3a and 3b, 2.0 mL) or EtOH (for 3c-f, 1.0-5.0 mL). The mixture was stirred at r.t. for 5-30 min (for 3a,b and 3d-e), and at 0 ˚C for 40 min (for 3c and 3f). The resulting suspension was filtered and washed with EtOH and Et₂O to give compounds 3 (78-99%). The structure of the products was confirmed by elemental analysis, ^¹H NMR and ^¹³C NMR spectroscopy.
5-[5-Amino-1-(4-methoxyphenyl)-1 H -imidazol-4-yl]-2,4-dihydro-3 H -1,2,4-triazol-3-one (3a)
Mp >316 ˚C (dec.). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 11.20 (s, 1 H), 7.42 (d, J = 8.7 Hz, 2 H), 7.39 (s, 1 H), 7.09 (d, J = 8.7 Hz, 2 H), 5.22 (s, 2 H), 3.81 (s, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 158.98, 155.64, 144.33, 137.91, 130.96, 127.36, 126.31, 114.85, 108.10, 55.52. Anal. Calcd for C₁₂H₁₂N₆O₂: C, 52.94; H, 4.44; N, 30.87. Found: C, 52.75; H, 4.60; N, 30.88. IR (mull): 3428, 3331, 3102, 1715 (CO), 1634 cm^-¹.

15

General Procedure for the Synthesis of 1,2,4-Oxadiazolones 4
A yellow suspension of 2 (0.29-1.85 mmol) in CH₂Cl₂ (for 4a, 15.0 mL) or in MeCN (for 4b-d, 3.0-5.0 mL) was added to a solution of hydroxylamine hydrochloride (for 4a, 3.0 equiv; for 4b-d, 2.0 equiv; for 4c, 1.2 equiv) in aq 1 M KOH (for 4a, 3.0 equiv) or to a solution of Et₃N (for 4b-d, 3.0 equiv) in MeCN. The mixture was stirred at r.t., and after 29-72 h the starting material was totally consumed. The light yellow solid was filtered and washed with EtOH, MeCN, and Et₂O to give compounds 4 in 17-99% yield. The structure of the products was confirmed by elemental analysis, ^¹H NMR and ^¹³C NMR spectroscopy.
3-[5-Amino-1-(4-methoxyphenyl)-1 H -imidazol-4-yl]-1,2,4-oxadiazol-5 (4 H )-one (4a) Mp 261-264 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 13.00-10.00 (br s, 1 H), 7.49 (s, 1 H), 7.42 (d, J = 8.7 Hz, 2 H), 7.11 (d, J = 8.7 Hz, 2 H), 5.46 (s, 2 H), 3.81 (s, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 159.54, 159.30, 155.30, 140.73, 132.66, 126.78, 126.75, 114.96, 103.15, 55.56. Anal. Calcd for C₁₂H₁₁N₅O₃: C, 52.75; H, 4.06; N, 25.63. Found: C, 52.85; H, 4.13; N, 25.57. IR (mull): 3414, 3317, 3128, 1787 (CO), 1633 cm^-¹.

16

General Procedure for the Synthesis of 5
A suspension of aminopiperidine or 1-amino-4-metilpiperazine (1.2-1.3 equiv) and imidazole 2 (0.98-1.20 mmol) in CH₂Cl₂ (0.5 mL) or EtOH (2.0 mL) was stirred at r.t.. After 45-50 min the yellow suspension evolved to a white solid precipitate that was filtered and washed with EtOH and Et₂O. The structure of the products obtained was confirmed by elemental analysis, ^¹H NMR and ^¹³C NMR spectroscopy.
Ethyl [5-Amino-1-(4-methoxyphenyl)-1 H -imidazol-4-yl](piperidin-1-ylimino)methylcarbamate (5a)
Mp 165-166 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 8.06 (s, 1 H), 7.38 (d, J = 8.7 Hz, 2 H) 7.38 (s, 1 H), 7.10 (d, J = 8.7 Hz, 2 H), 5.69 (br s, 2 H), 3.81 (s, 3 H), 3.98 (q, J = 7.2 Hz, 2 H), 2.50-3.50 (br s, 4 H), 1.50 (br s, 6 H), 1.20 (t, J = 7.2 Hz, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 162.35, 159.04, 149.28, 141.60, 130.05, 59.95, 55.55, 55.03, 26.69, 25.27, 14.28. Anal. Calcd for C₁₉H₂₆N₆O₃: C, 59.05; H, 6.78; N, 21.75. Found: C, 59.08; H, 6.68; N, 21.69. IR (mull): 3359, 3287, 3162, 3112, 3066, 1698 (CO), 1618, 1571 cm^-¹.

17

General Procedure for the Synthesis of 6 and 7
Acetic or benzoic anhydride (2.0 equiv) was added to a suspension of 1 (1.0-4.0 mmol) in MeCN (1.0-5.0 mL) at 0 ˚C, and the mixture was stirred at r.t. until the starting material was totally consumed (2-4 h). The bright yellow/orange solid was filtered and washed with MeCN and Et₂O to give compounds 6 and 7 in 13-99% yields. The structure of the products was confirmed by elemental analysis, ^¹H NMR and ^¹³C NMR spectroscopy.
5-Amino-1-(4′-fluorophenyl)-4-[( N- benzoyl)cyano-formimidoyl]-1 H -imidazole (7, R ^¹  = 4-FC ₆ H ₄ , R ^²  = Ph)
Mp 167-168 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 8.34 (br s, 2 H), 8.08 (d, J = 7.2 Hz, 2 H), 7.77 (s, 1 H), 7.64 (t, J = 7.2 Hz, 1 H), 7.55 (dd, J = 9.0, 4.8 Hz, 2 H), 7.54 (t, J = 7.2 Hz, 2 H), 7.44 (t, J = 9.0 Hz, 1 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 174.93, 160.06 (d, J = 243 Hz), 151.23, 138.60, 135.38, 134.74, 132.81, 131.57 (d, J = 3 Hz), 129.41, 128.51, 125.08 (d, J = 8 Hz), 122.51, 116.31 (d, J = 22 Hz), 112.14. Anal. Calcd for C₁₂H₁₁N₅O₃˙0.1H₂O: C, 64.51; H, 3.67; N, 20.90. Found: C, 64.40; H, 3.81; N, 20.86. IR (mull): 3342, 2232 (CN), 1629, 1603, 1529 cm^-¹.

18

General Procedure for the Synthesis of 8 and 9
Hydrazine monohydrate (2.0 or 1.2 equiv) was added to a suspension of imidazole 6 (0.78-1.36 mmol) or 7 in EtOH (1.5-2.0 mL) at 0 ˚C leading to a homogeneous solution. After 5 min a white solid precipitated out of solution and was filtered and washed with EtOH and Et₂O. The structure of the products was confirmed by elemental analysis, ^¹H NMR and ^¹³C NMR spectroscopy.
Characterization of 1-Methyl-4-(5-methyl-4 H -1,2,4-triazol-3-yl)-1 H -imidazol-5-amine (8c)
Mp >233 ˚C (dec.). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 13.15 (br s, 1 H), 7.20 (s, 1 H), 5.51 (br s, 2 H), 3.44 (s, 3 H), 2.23 (s, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 158.43, 152.03, 139.21, 141.98, 139.87, 131.61, 108.53, 29.76, 13.76. Anal. Calcd for C₈H₉N₅O˙0.1H₂O: C, 46.71; H, 5.71; N, 46.69. Found: C, 46.65; H, 5.86; N, 46.25. IR (mull): 3354, 3276, 3170, 3104, 2725, 1616, 1571 cm^-¹.
1-(4-Fluorophenyl)-4-(5-phenyl-4 H -1,2,4-triazol-3-yl)-1 H -imidazol-5-amine (9b)
Mp >250 ˚C (dec.). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 13.94 (br s, 1 H), 8.06 (dt, J = 6.6, 1.5 Hz, 2 H), 7.64 (dd, J = 9.0, 4.8 Hz, 2 H), 7.55 (s, 1 H) 7.43 (t, J = 9.0 Hz, 2 H), 7.48-7.40 (m, 3 H), 5.75 (br s, 2 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 161.48 (d, J = 244 Hz), 160.16, 152.27, 138.98, 131.58, 131.15, 128.65, 128.58, 127.11 (d, J = 9 Hz), 125.76, 116.58 (d, J = 23 Hz), 108.89. Anal. Calcd for C₁₇H₁₃N₆F˙0.1H₂O: C, 63.39; H, 4.13; N, 26.08. Found: C, 63.26; H, 4.18; N, 26.01. IR (mull): 3407, 3276, 3318, 3127, 1634, 1603, 1518 cm^-¹.