Copper-Catalyzed Synthesis of 1,2,4-Triazoles via Sequential Coupling and Aerobic Oxidative Dehydrogenation of Amidines

Abstract

A convenient, efficient, and practical copper-catalyzed one-pot method for the synthesis of 1,2,4-triazoles has been developed via reactions of amidines. The procedure underwent sequential base-promoted intermolecular coupling (nucleophilic substitution) between two amidines and intramolecular aerobic oxidative dehydrogenation, and the inexpensive, convenient, and efficient method for the synthesis of 1,2,4-triazoles will attract much attention in academic and industrial research.

Key words

copper - aerobic oxidative - dehydrogenation - amidines - 1,2,4-triazoles

• References and Notes

• 1a DeSimone RW, Currie KS, Mitchell SA, Darrow JW, Pippin DA. Comb. Chem. High Throughput Screening 2004; 7: 473
• 1b Leeson PD, Springthorpe B. Nat. Rev. Drug Discovery 2007; 6: 881
• 2a Al-Masoudi IA, Al-Soud YA, Al-Salihi NJ, Al-Masoudi NA. Chem. Heterocycl. Compd. (N.Y.) 2006; 42: 1377
• 2b Huntsman E, Balsells J. Eur. J. Org. Chem. 2005; 3761
• 3a Larsen SD, DiPaolo BA. Org. Lett. 2001; 3: 3341
• 3b Stocks MJ, Cheshire DR, Reynold R. Org. Lett. 2004; 6: 2969
• 3c Balsells J, DiMichele L, Liu J, Kubryk M, Hansen K, Armstrong JD. III. Org. Lett. 2005; 7: 1039

For some reviews, see:
• 4a Stahl SS. Angew. Chem. Int. Ed. 2004; 43: 3400
• 4b Punniyamurthy T, Velusamy S, Iqbal J. Chem. Rev. 2005; 105: 2329
• 4c Shi Z, Zhang C, Tang C, Jiao N. Chem. Soc. Rev. 2012; 41: 3381
• 4d Campbell AN, Stahl SS. Acc. Chem. Res. 2012; 45: 851
• 4e Wendlandt AE, Suess AM, Stahl SS. Angew. Chem. Int. Ed. 2011; 50: 11062
• 5 Xiao Q, Wang W.-H, Liu G, Meng F.-K, Chen J.-H, Yang Z, Shi Z.-J. Chem.–Eur. J. 2009; 15: 7292
• 6a Tsang WC. P, Zheng N, Buchwald SL. J. Am. Chem. Soc. 2005; 127: 14560
• 6b Tsang WC. P, Munday RH, Brasche G, Zheng N, Buchwald SL. J. Org. Chem. 2008; 73: 7603
• 6c Jordan-Hore JA, Johansson CC. C, Gulias M, Beck EM, Gaunt MJ. J. Am. Chem. Soc. 2008; 130: 16184
• 7 Inamoto K, Saito T, Katsuno M, Sakamoto T, Hiroya K. Org. Lett. 2007; 9: 2931
• 8 Wasa M, Yu J.-Q. J. Am. Chem. Soc. 2008; 130: 14058
• 9a Mei T.-S, Wang X, Yu J.-Q. J. Am. Chem. Soc. 2009; 131: 10806
• 9b Neumann JJ, Rakshit S, Dröge T, Glorius F. Angew. Chem. Int. Ed. 2009; 48: 6892

For recent reviews on copper-catalyzed cross-couplings, see:
• 10a Kunz K, Scholz U, Ganzer D. Synlett 2003; 2428
• 10b Ley SV, Thomas AW. Angew. Chem. Int. Ed. 2003; 42: 5400
• 10c Beletskaya IP, Cheprakov AV. Coord. Chem. Rev. 2004; 248: 2337
• 10d Evano G, Blanchard N, Toumi M. Chem. Rev. 2008; 108: 3054
• 10e Ma D, Cai Q. Acc. Chem. Res. 2008; 41: 1450
• 10f Monnier F, Taillefer M. Angew. Chem. Int. Ed. 2009; 48: 6954
• 10g Surry DS, Buchwald SL. Chem. Sci. 2010; 1: 13
• 10h Rao H, Fu H. Synlett 2011; 745
• 10i Liu T, Fu H. Synthesis 2012; 44: 2805 ; and references cited therein

For selected papers, see:
• 11a Klapars A, Antilla JC, Huang X, Buchwald SL. J. Am. Chem. Soc. 2001; 123: 7727
• 11b Klapars A, Huang XH, Buchwald SL. J. Am. Chem. Soc. 2002; 124: 7421
• 11c Antilla JC, Klapars A, Buchwald SL. J. Am. Chem. Soc. 2002; 124: 11684
• 11d Okano K, Tokuyama H, Fukuyama T. Org. Lett. 2003; 5: 4987
• 11e Gujadhur RK, Bates CG, Venkataraman D. Org. Lett. 2001; 3: 4315
• 11f Gajare AS, Toyota K, Yoshifuji M, Yoshifuji F. Chem. Commun. 2004; 1994
• 11g Ma D, Zhang Y, Yao J, Wu S, Tao F. J. Am. Chem. Soc. 1998; 120: 12459
• 11h Ma D, Cai Q, Zhang H. Org. Lett. 2003; 5: 2453
• 11i Zhu L, Cheng L, Zhang Y, Xie R, You J. J. Org. Chem. 2007; 72: 2737
• 11j Rao H, Jin Y, Fu H, Jiang Y, Zhao Y. Chem.–Eur. J. 2006; 12: 3636
• 11k Guo X, Rao H, Jin Y, Fu H, Jiang Y, Zhao Y. Adv. Synth. Catal. 2006; 348: 2197
• 11l Jiang D, Fu H, Jiang Y, Zhao Y. J. Org. Chem. 2007; 72: 672
• 12a Wang C, Li S, Liu H, Jiang Y, Fu H. J. Org. Chem. 2010; 75: 7936
• 12b Lu J, Jin Y, Liu H, Jiang Y, Fu H. Org. Lett. 2011; 13: 3694
• 12c Xu W, Jin Y, Liu H, Jiang Y, Fu H. Org. Lett. 2011; 13: 1274
• 12d Xu W, Fu H. J. Org. Chem. 2011; 76: 3846
• 12e Xu H, Fu H. Chem.–Eur. J. 2012; 18: 1180
• 12f Wang X, Jin Y, Zhao Y, Zhu L, Fu H. Org. Lett. 2012; 14: 452
• 13a Brasche G, Buchwald SL. Angew. Chem. Int. Ed. 2008; 47: 1932
• 13b Ueda S, Nagasawa H. Angew. Chem. Int. Ed. 2008; 47: 6411
• 13c Saha P, Ramana T, Purkait N, Ali MA, Paul R, Punniyamurthy T. J. Org. Chem. 2009; 74: 8719
• 13d Wang H, Wang Y, Liang D, Liu L, Zhang J, Zhu Q. Angew. Chem. Int. Ed. 2011; 50: 5677
• 13e Wang Y.-F, Chen H, Zhu X, Chiba S. J. Am. Chem. Soc. 2012; 134: 11980
• 14 Ueda S, Nagasawa H. J. Am. Chem. Soc. 2009; 131: 15080
• 15a Häger I, Fröhlich R, Würthwein E.-U. Eur. J. Inorg. Chem. 2009; 2415
• 15b Wikstrom JP, Filatov AS, Rybak-Akimova EV. Chem. Commun. 2010; 46: 424
• 15c Kopylovich MN, Pombeiro AJ. L, Fischer A, Kloo L, Kukushkin VY. Inorg. Chem. 2003; 42: 7239
• 16 General Procedure for the Synthesis of Compounds 2a–s A 10 mL Schlenk tube was charged with a magnetic stirrer and DMSO (1.5 mL). For entries 1–5 in Table 2, aromatic amidine (1 mmol), Cu powder (0.1 mmol, 6.4 mg), and Cs₂CO₃ (2 mmol, 489 mg) were added to the tube. The mixture was stirred at 120 °C for 24 h under nitrogen atmosphere, and then the nitrogen atmosphere was changed into oxygen atmosphere (other conditions were kept). The following aerobic oxidative intramolecular formation of N–N bond was carried out at 120 °C for 48 h. The resulting mixture was cooled to r.t. and filtered, and the solid was washed with EtOAc (3 × 3 mL). The combined filtrate was concentrated by a rotary evaporator, and the residue was purified by column chromatography on silica gel using PE–EtOAc as eluent to give the desired target product. For entries 6–19 in Table 2, aromatic amidine (1.0 mmol), aliphatic amidine (0.5 mmol), Cu powder (0.1 mmol, 6.4 mg), and Cs₂CO₃ (3.0 mmol, 978 mg) were added to the tube. The mixture was stirred at 120 °C under nitrogen atmosphere, and additional aromatic amidine (2 × 0.5 mmol) was added to the resulting solution after 8 h and 16 h, respectively. The reaction was performed for a total 24 h under nitrogen atmosphere, and then the nitrogen atmosphere was changed into oxygen atmosphere (other conditions were kept). The following aerobic oxidative intramolecular formation of N–N bond was carried out at 120 °C for 48 h. The workup procedure was similar to that of entries 1–5 in Table 2. Data for three representative examples are given here. 3-Methyl-5-phenyl-4H-1,2,4-triazole (2f) ¹⁴ Eluent: PE–EtOAc (1:1); yield 64 mg (80%); white solid; mp 163–165 °C (lit.¹⁴ mp 163–165 °C). ¹H NMR (600 MHz, DMSO-d ₆): δ = 13.75 (s, 1 H), 7.95 (d, 2 H, J = 7.56 Hz), 7.44–7.33 (m, 3 H), 2.35 (s, 3 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 160.8, 154.3, 131.7, 129.3, 129.1, 126.2, 126.1, 12.5. ESI-MS: m/z = 160.3 [M + H]⁺; m/z = 182.2 [M + Na]⁺. 3-(4-Chlorophenyl)-5-cyclopropyl-4H-1,2,4-triazole (2o) ¹⁴ Eluent: PE–EtOAc (6:1); yield 85 mg (78%); white solid; mp 203–205 °C (lit.¹⁴ mp 202–203 °C). ¹H NMR (600 MHz, DMSO-d ₆): δ = 13.71 (s, 1 H), 7.91 (d, 2 H, J = 8.9 Hz), 7.57–7.40 (m, 2 H), 2.09–1.96 (m, 1 H), 1.06–0.80 (m, 4 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 160.2, 160.1, 133.7, 131.0, 129.2, 127.9, 8.6, 7.5. ESI-MS: m/z = 220.2 [M + H]⁺; m/z = 242.0 [M + Na]⁺. 4-(5-Methyl-4H-1,2,4-triazol-3-yl)pyridine (2q) ¹⁷ Eluent: PE–EtOAc (4:1); yield 56 mg (70%); white solid; mp 104–106 °C (lit.¹⁷ mp 207–209 °C). ¹H NMR (600 MHz, DMSO-d ₆): δ = 13.94 (s, 1 H), 8.81–8.55 (m, 2 H), 7.91 (d, 2 H, J = 3.4 Hz), 2.44 (s, 3 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 159.4, 154.8, 150.8, 139.1, 120.5, 12.2. ESI-MS: m/z = 161.2 [M + H]⁺; m/z = 183.1 [M + Na]⁺.
• 17 Lipinski CA, Lamattina JL, Oates PJ. J. Med. Chem. 1986; 29: 2154