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.

Key words

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

References and Notes

• 1 For a recent review, see: Moulin A. Bibian M. Blayo A.-L. El Habnouni S. Martinez J. Fehrentz J.-A. Chem. Rev.  2010,  110:  1809 
• 2a Patel NB. Khan IH. Rajani SD. Eur. J. Med. Chem.  2010,  45:  4293 
• 2b Bayrak H. Demirbas A. Karaoglu SA. Demirbas N. Eur. J. Med. Chem.  2009,  44:  1057 
• 2c Isloor AM. Kalluraya B. Shetty P. Eur. J. Med. Chem.  2009,  44:  3784 
• 2d Bayrak H. Demirbas A. Demirbas N. Karaoglu SA. Eur. J. Med. Chem.  2009,  44:  4362 
• 3 Katica CR. Vesna D. Vlado K. Dora GM. Aleksandra B. Molecules  2001,  6:  815 
• 4a Demirbas N. Ugurluoglu R. Demirbas A. Bioorg. Med. Chem.  2002,  10:  3717 
• 4b Romagnoli R. Baraldi PG. Cruz-Lopez O. Cara CL. Carrion MD. Brancale A. Hamel E. Chen L. Bortolozzi R. Basso G. Viola G. J. Med. Chem.  2010,  53:  4248 
• 5 Abdel-Megeed AM. Abdel-Rahman HM. Alkaramany G.-ES. El-Gendy MA. Eur. J. Med. Chem.  2009,  117 
• 6 Alanine A. Anselm L. Steward L. Thomi S. Vifian W. Groaning MD. Bioorg. Med. Chem. Lett.  2004,  14:  817 
• 7a Mathew V. Keshavayya J. Vaidya VP. Giles D. Eur. J. Med. Chem.  2007,  42:  823 
• 7b Farooqui M. Bora R. Patil CR. Eur. J. Med. Chem.  2009,  794 
• 8 Borg S. Vollinga RC. Labarre M. Payza K. Terenius L. Luthman K. J. Med. Chem.  1999,  42:  4331 
• 9a Yeung K.-S. Farkas ME. Kadow JF. Meanwell NA. Tetrahedron Lett.  2005,  46:  3429 
• 9b Amarasinghe KKD. Maier MB. Srivastavab A. Graya JL. Tetrahedron Lett.  2006,  47:  3629 
• 9c Katritzky AR. Khashab NM. Kirichenko N. Singh A. J. Org. Chem.  2006,  71:  9051 
• 9d Bibian M. Blayo A.-L. Moulin A. Martinez J. Fehrentz J.-A. Tetrahedron Lett.  2010,  51:  2660 
• 10a Su Y. Jiang Z. Hong D. Lu P. Wang Y. Lin X. Tetrahedron  2010,  66:  2427 
• 10b Kurz T. Lolak N. Geffken D. Tetrahedron Lett.  2007,  48:  2733 
• 10c Yin P. Ma W.-B. Chen Y. Huang W.-C. Deng Y. He L. Org. Lett.  2009,  11:  5482 
• 10d Ueda S. Nagasawa H. J. Am. Chem. Soc.  2009,  131:  15080 
• 10e Wang Y. Miller RL. Sauer DR. Djuric SW. Org. Lett.  2005,  7:  925 
• 10f Lin S. Lang JrY.-iA. Lovell MF. Perkinson NA. J. Org. Chem.  1979,  44:  4160 
• 10g Saleem RSZ. Tepe JJ.
  J. Org. Chem.  2010,  75:  4330 
• 10h Perez MA. Dorado CA. Soto JL. Synthesis  1983,  483 
• 11a Temple C. Kussner CL. Montgomery JA. J. Org. Chem.  1965,  30:  3601 
• 11b Temple C. Kussner CL. Montgomery JA. J. Org. Chem.  1967,  32:  2241 
• 11c Okamura T. Kurogi Y. J. Med. Chem.  2002,  45:  3703 
• 11d Hosmane RS. Lim BB. Burnett FN. J. Org. Chem.  1988,  53:  382 
• 12a Alves MJ. Booth BL. Freitas AP. Proença MF. J. Chem. Soc., Perkin Trans. 1  1992,  913 
• 12b Booth BL. Dias AM. Proença MF. J. Chem. Soc., Perkin Trans. 1  1992,  2119 
• 12c Alves MJ. Booth BL. Proença MF.
  J. Heterocycl. Chem.  1994,  31:  345 
• 12d Booth BL. Coster RD. Proença MF. Synthesis  1988,  389 
• 12e Alves MJ. Booth BL. Carvalho MA. Pritchar d RG. Proença MF. J. Heterocycl. Chem.  1997,  739 
• 12f Al-Azmi A. Booth BL. Carpenter RA. Carvalho MA. Marrelec E. Pritchard RG. Proença MF. J. Chem. Soc., Perkin Trans. 1  2001,  2532 
• 12g Booth BL. Cabral IM. Dias AM. Freitas AP. Matos-Beja AM. Proença MF. Ramos-Silva M. J. Chem. Soc., Perkin Trans. 1  2001,  1241 
• 12h Carvalho MA. Esteves TM. Proença MF. Booth BL. Org. Biomol. Chem.  2004,  2:  1019 
• 12i Carvalho MA. Álvares Y. Zaki ME. Proença MF. Booth BL. Org. Biomol. Chem.  2004,  2:  2340 
• 13 Dias AM. Cabral IM. Vila-Chã AS. Proença MF. Synlett  2007,  1231 

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.