Copper-Mediated Sequential C–N and N–N Bond Formation: Facile Synthesis of Symmetrical 1,2,4-Triazoles

Abstract

Via a one-pot process, catalyzed by Cu(OAc)₂, a series of 3,5-disubstituted 4H-1,2,4-triazoles was conveniently and efficiently synthesized by using low-toxicity, stable, readily available, inexpensive amidine hydrochloride.

Key words

1,2,4-triazoles - copper - amidine hydrochloride - N–N bond coupling - de-amine reaction

• References and Notes

• 1 Hull JW, Romer DR, Adaway TJ, Podhorez DE. Org. Process Res. Dev. 2009; 13: 1125
• 2 Sun J, Zhang A, Zhang J, Xie X, Liu W. J. Agric. Food. Chem. 2011; 60: 160
• 3 Haddadin MJ, Ghazvini Zadeh EH. Tetrahedron Lett. 2010; 51: 1654
• 4 Khanmohammadi H, Erfantalab M. Spectrochim. Acta, Part A 2012; 86: 39
• 5 Zhang J.-P, Zheng S.-L, Huang X.-C, Chen X.-M. Angew. Chem. Int. Ed. 2004; 43: 206
• 6 Zhang J.-P, Zhang Y.-B, Lin J.-B, Chen X.-M. Chem. Rev. 2011; 112: 1001
• 7a Ueda S, Nagasawa H. J. Am. Chem. Soc. 2009; 131: 15080
• 7b Yeung K.-S, Farkas ME, Kadow JF, Meanwell NA. Tetrahedron Lett. 2005; 46: 3429
• 8a Buscemi S, Vivona N, Caronna T. J. Org. Chem. 1996; 61: 8397
• 8b Holzer M, Dobner B, Briel D. Liebigs Ann. Chem. 1994; 895
• 9a Huntsman E, Balsells J. Eur. J. Org. Chem. 2005; 3761
• 9b Reichelt A, Falsey JR, Rzasa RM, Thiel OR, Achmatowicz MM, Larsen RD, Zhang D. Org. Lett. 2010; 12: 792
• 10a Yin P, Ma W.-B, Chen Y, Huang W.-C, Deng Y, He L. Org. Lett. 2009; 11: 5482
• 10b Wang L.-Y, Tseng W.-C, Lin H.-Y, Wong FF. Synlett 2011; 1467
• 11 Zhang J.-P, Lin Y.-Y, Huang X.-C, Chen X.-M. J. Am. Chem. Soc. 2005; 127: 5495
• 12 Xu H, Jiang Y, Fu H. Synlett 2013; 24: 125
• 13a Poulsen TB, Jørgensen KA. Chem. Rev. 2008; 108: 2903
• 13b Ma D, Cai Q. Acc. Chem. Res. 2008; 41: 1450
• 13c Zhang C, Tang C, Jiao N. Chem. Soc. Rev. 2012; 41: 3464
• 14a Daugulis O, Do H.-Q, Shabashov D. Acc. Chem. Res. 2009; 42: 1074
• 14b Díez-González S, Nolan SP. Acc. Chem. Res. 2008; 41: 349
• 14c Kumar MR, Park A, Park N, Lee S. Org. Lett. 2011; 13: 3542
• 15a Zhang Q, Zhang Z, Yan Z, Liu Q, Wang T. Org. Lett. 2007; 9: 3651
• 15b Zhang Z, Zhang Q, Sun S, Xiong T, Liu Q. Angew. Chem. Int. Ed. 2007; 46: 1726
• 15c Zhang Z, Zhang Q, Yan Z, Liu Q. J. Org. Chem. 2007; 72: 9808
• 15d Zhang Z, Zhang Q, Ni Z, Liu Q. Chem. Commun. 2010; 46: 1269
• 15e Zhang Z, Xue C, Liu X, Zhang Q, Liu Q. Tetrahedron 2011; 67: 7081
• 15f Zhang Z, Fang S, Liu Q, Zhang G. Adv. Synth. Catal. 2012; 354: 927
• 15g Bi J, Zhang Z, Liu Q, Zhang G. Green Chem. 2012; 14: 1159
• 16 See the Supporting Information for more information.
• 17a Arockiam PB, Bruneau C, Dixneuf PH. Chem. Rev. 2012; 112: 5879
• 17b Wu X.-F, Neumann H, Beller M. Chem. Rev. 2012; 113: 1
• 18a Schaefer FC, Hechenbleikner I, Peters GA, Wystrach VP. J. Am. Chem. Soc. 1959; 81: 1466
• 18b Rosenberg MG, Brinker UH. J. Org. Chem. 2003; 68: 4819
• 18c Oxley P, Short WF. J. Chem. Soc. 1949; 449
• 19 Ashley JN, Barber HJ, Ewins AJ, Newbery G, Self AD. H. J. Chem. Soc. 1942; 103
• 20a Bates CG, Saejueng P, Doherty MQ, Venkataraman D. Org. Lett. 2004; 6: 5005
• 20b Tye JW, Weng Z, Johns AM, Incarvito CD, Hartwig JF. J. Am. Chem. Soc. 2008; 130: 9971
• 20c Xu Z, Thompson LK, Miller DO. Inorg. Chem. 1997; 36: 3985
• 20d Op’t Holt BT, Vance MA, Mirica LM, Heppner DE, Stack TD. P, Solomon EI. J. Am. Chem. Soc. 2009; 131: 6421
• 21 Yang D, Fu H, Hu L, Jiang Y, Zhao Y. J. Org. Chem. 2008; 73: 7841
• 22a Neumann JJ, Suri M, Glorius F. Angew. Chem. Int. Ed. 2010; 49: 7790
• 22b Suri M, Jousseaume T, Neumann JJ, Glorius F. Green Chem. 2012; 14: 2193
• 23 General Procedure for the Synthesis of Compounds 2a–o: To a round-bottom flask (25 mL) equipped with a spherical condenser (40 cm length) were added amidine hydrochloride 1 (1.0 mmol), Cu(OAc)₂ (0.2 equiv), K₂CO₃ (2.0 equiv), 1,10-phenanthroline (0.1 equiv) and anhyd DMF (2.0 mL). Then the mixture was well stirred at 130 °C under an inert atmosphere. After cooling off, the mixture was filtered through a pad of celite eluting with CH₂Cl₂ (3 × 6 mL). The volatiles were removed under reduced pressure and the residue was purified by a short flash silica gel column chromatography to give compound 2. 2a: white solid; eluent: petroleum ether–EtOAc (3:1). Yield: 86%; mp 191–192 °C. ¹H NMR (400 MHz, CD₃OD): δ = 8.05 (d, J = 6.4 Hz, 4 H), 7.41–7.49 (m, 6 H). ¹³C NMR (100 MHz, CD₃OD): δ = 160.53, 131.02, 130.17, 129.89, 127.56. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₁N₃: 222.1026; found: 222.1026. General Procedure for the Synthesis of Compounds 2p: To a round-bottom flask (25 mL) equipped with a spherical condenser (40 cm length) were added acetimidamide hydrochloride 1p (94.5 mg, 1.0 mmol), benzimidamide hydrochloride 1a (0.5 equiv), Cu(OAc)₂ (37 mg, 0.2 mmol), K₂CO₃ (276 mg, 2.0 mmol), 1,10-phenanthroline (20 mg, 0.1 mmol) and anhyd DMF (2.0 mL). Then the mixture was well stirred at 130 °C under an inert atmosphere. The other two batches of benzimidamide hydrochloride 1a (0.5 equiv for each) were added to the mixture every 8.0 h. After 48 h (total reaction time), the reaction mixture was cooled, filtered through a pad of celite eluting with CH₂Cl₂ (3 × 6 mL). The volatiles were removed under reduced pressure and the residue was purified by short flash silica gel column chromatography to give compound 2p as a white solid; eluent: petroleum ether–EtOAc (2:1). Yield: 68%; mp 161–163 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.03 (d, J = 6.0 Hz, 2 H), 7.44 (d, J = 6.0 Hz, 3 H), 2.53 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 161.04, 155.71, 130.08, 129.73, 128.89, 126.44, 12.81. HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₉N₃: 160.0869; found: 160.0874. General Procedure for the Synthesis of Compounds 3a,b: To a round-bottom flask (25 mL) equipped with a spherical condenser (40 cm length) were added amidine hydrochloride 1s or 1t (1.0 mmol), Cu(OAc)₂ (0.2 equiv), K₂CO₃ (2.0 equiv), 1,10-phenanthroline (0.1 equiv) and anhyd DMF (2.0 mL). Then the mixture was well stirred at 130 °C under an inert atmosphere. After cooling off, the mixture was filtered through a pad of celite eluting with CH₂Cl₂ (3 × 6 mL). The volatiles were removed under reduced pressure and the residue was purified by a short flash silica gel column chromatography to give compound 3a or 3b. 3a: yellow solid; yield: 80%; mp 81–83 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.35 (d, J = 8.8 Hz, 2 H), 6.62 (d, J = 8.4 Hz, 2 H), 4.28 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 150.80, 133.67, 120.41, 114.33, 99.30. 3b: white solid; yield: 86%; mp 110–113 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.55 (d, J = 8.8 Hz, 2 H), 6.95 (d, J = 8.8 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 160.57, 134.47, 119.42, 116.63, 102.80.
• 24 Toth B. In Vivo 2000; 14: 299