4.1.2. Experimental Procedure for the Synthesis of Triazole Compounds 1–26
A solution of the corresponding 1-(azidomethyl)benzene derivative (3 mmol) with the corresponding ethynylbenzene derivative (2 mmol) in DMF/H2O (9:1, 50 mL) was heated at 60 °C for 2–4 h in the presence of CuSO4·5H2O (0.25 mmol) and sodium ascorbate (0.25 mmol). Then the reaction mixture was poured onto brine, and the aqueous phase was extracted three times with Ethyl Acetate. The collected organic phases were washed with brine and dried over anhydrous Na2SO4. Filtration and removal of the solvent under vacuum afforded a residue that was purified on column chromatography, using silica gel as stationary phase and a mixture of Hexanes:Ethyl Acetate (1:1; 4:6; 3:7) as mobile phase.
1-benzyl-4-phenyl-1H-1,2,3-triazole (1): yield, 52%, white solid, m.p. 127–129 °C; 1H NMR (400 MHz, CDCl3): δ 7.71 (dd, J = 7.3, 1.3 Hz, 2H), 7.58 (s, 1H), 7.33–7.16 (m, 8H), 5.44 (s, 2H); 13C NMR (100 MHz, CDCl3): 148.1 (C), 134.6 (C), 130.5 (C), 129.0 (CH), 128.7 (CH), 128.6 (CH), 128.0 (CH), 127.9 (CH), 125.6 (CH), 119.5 (CH), 54.1 (CH2); HR ESMS m/z 236.1183 (M + H+). Calc. C15H13N3: 235.11.
1-(2-methylbenzyl)-4-phenyl-1H-1,2,3-triazole (2): yield, 65%; 1H NMR (400 MHz, CDCl3): δ 7.76 (dd, J = 7.0, 1,2 Hz, 2H), 7.51 (s, 1H), 7.37 (td, J = 7,0, 1,2 Hz, 2H), 7.31–7.16 (m, 5H), 5.56 (s, 2H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3): 148.0 (C), 137.0 (C), 132.5 (C), 131.1 (CH), 130.6 (CH), 129.4 (C), 129.2 (CH), 128.8 (CH), 128.1 (CH), 126.7 (CH), 125.7 (CH) 119.2 (CH), 52.6 (CH2), 19.0 (CH3); HR ESMS m/z 250.1339 (M + H+). Calc. C16H15N3: 249.13.
1-(3-methylbenzyl)-4-phenyl-1H-1,2,3-triazole (3): yield, 43%; 1H NMR (400 MHz, CDCl3): δ 7.71 (dd, J = 7.0, 1.3 Hz, 2H), 7.59 (s, 1 H), 7.30–7.25 (m, 2H), 7.22–6.98 (m, 7H), 5.38 (s, 2H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3): 147.9 (C), 138.8 (C), 134.5 (C), 130.5(C), 129.3 (CH), 128.8 (CH), 128.6 (CH), 128.6 (CH), 127.9 (CH), 125.5 (CH), 124.9 (CH), 119.5 (CH), 54.0 (CH2), 21.1 (CH3); HR ESMS m/z 250.1347 (M + H+). Calc. C16H15N3: 249.13.
1-(4-methylbenzyl)-4-phenyl-1H-1,2,3-triazole (4): yield, 55%; 1H NMR (400 MHz, CDCl3): δ 7.70 (dd, J = 7.0, 1.2 Hz, 2H), 7.54 (s, 1H), 7.32–7.07 (m, 7H), 5.42 (s,2H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3): 148.1 (C), 138.6 (C), 131.6 (C), 130.6 (C), 129.7 (CH), 128.7 (CH), 128.1 (CH), 128.0 (CH), 125.6 (CH), 119.4 (CH), 54.0 (CH2), 21.1 (CH3); HR ESMS m/z 250.1342 (M + H+). Calc. C16H15N3: 249.13.
1-(2-methoxybenzyl)-4-phenyl-1H-1,2,3-triazole (5): yield, 52%; 1H NMR (400 MHz, CDCl3): δ 7.78 (dd, J = 7.0, 1.2 Hz, 2H), 7.68 (s, 1H), 7.40–7.18 (m, 5H), 6.96–6.90 (m, 2H), 5.57 (s, 2H), 3.86 (s, 3H); 13C (100 MHz, CDCl3): 157.2 (C), 147.7 (C), 130.8 (C), 130.3 (CH), 128.7 (CH), 127.9 (CH), 125.7 (CH), 123.0 (C), 121.0 (CH), 119.7 (CH), 110.8 (CH), 55.5 (CH2), 49.2 (CH3); HR ESMS m/z 266.1296 (M + H+). Calc. C16H15N3O: 265.12.
1-(3-methoxybenzyl)-4-phenyl-1H-1,2,3-triazole (6): yield, 63%; 1H NMR (400 MHz, CDCl3): δ 7.80 (dd, J = 7.0, 1.2 Hz, 2H), 7.67 (s, 1H), 7.43–7.38 (m, 2H), 7.33–7.25 (m, 3H), 6.92–6.83 (m, 2H), 5.54 (s, 2H), 3.79 (s, 3H); 13C (100 MHz, CDCl3): 160.2 (C), 148.2 (C), 136.1 (C), 130.5 (C), 130.2 (CH), 128.8 (CH), 128.1 (CH), 125.7 (CH), 120.2 (CH), 119.5 (CH), 114.2 (CH), 113.6 (CH), 55.3 (CH2), 54.2 (CH3); HR ESMS m/z 266.1297 (M + H+). Calc. C16H15N3O: 265.12.
1-(4-methoxybenzyl)-4-phenyl-1H-1,2,3-triazole (7): yield, 50%; 1H NMR (400 MHz, CDCl3): δ 7.80 (dd, J = 7.1, 1.3 Hz, 2H), 7.64 (s, 1H), 7.4 (dt, J = 7.1, 1,2 Hz, 2H), 7.34–7.24 (m, 3H), 6.93–6.90 (m, 1H), 6.84–6.83 (t, 1H), 5.50 (s, 2H), 3.81 (s,3H); 13C NMR (100 MHz, CDCl3): 159.9 (C), 148.1 (C), 130.6 (C), 129.6 (CH), 128.7 (CH), 128.1 (CH), 126.6 (C), 125.7 (CH), 119.3 (CH), 114.5 (CH), 55.3 (CH2), 53.7 (CH3); HR ESMS m/z 266.1294 (M + H+). Calc. C16H15N3O: 265.12.
1-(2-chlorobenzyl)-4-phenyl-1H-1,2,3-triazole (8): yield, 67%, white solid, m.p. 86–88 °C; 1H NMR (400 MHz, CDCl3): δ 7.75 (dd, J = 8.2, 1.4 Hz, 2H), 7.69 (s, 1H), 7.38 (dd, J = 8.0, 1.2 Hz, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.15–7.25 (m, 4H), 5.65 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 148.2 (C), 133.5 (C), 132.6 (C), 130.5 (C), 130.3 (CH), 130.3 (CH), 130.0 (CH), 128.8 (CH), 128.2 (CH), 127.7 (CH), 125.8 (CH), 119.8 (CH), 51.5 (CH2); HR ESMS m/z 270.0798 (M + H+). Calc. C15H12ClN3: 269.07.
1-(3-chlorobenzyl)-4-phenyl-1H-1,2,3-triazole (9): yield, 59%, white solid, m.p. 108–110 °C; 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.4, 1.2 Hz, 2H), 7.62 (s, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.24–7.29 (m, 4H), 7.11 (dt, J = 6.8, 1.8 Hz, 1H), 5.48 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 148.6 (C), 136.7 (C), 135.1 (C), 130.6 (CH), 130.5 (C), 129.1 (CH), 128.9 (CH), 128.4 (CH), 128.2 (CH), 126.1 (CH), 125.8 (CH), 119.6 (CH), 53.6 (CH2); HR ESMS m/z 270.0798 (M + H+). Calc. C15H12ClN3: 269.07.
1-(4-chlorobenzyl)-4-phenyl-1H-1,2,3-triazole (10): yield, 65%, white solid, m.p. 141–144 °C; 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J = 7.2 Hz, 2H), 7.59 (s, 1H), 7.30 (t, J = 7.4 Hz, 2H), 7.20–7.26 (m, 3H), 7.14 (d, J = 8.4 Hz, 2H), 5.43 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 148.4 (C), 134.8 (C), 133.3 (C), 130.4 (C), 129.4 (CH), 129.4 (CH), 128.9 (CH), 128.3 (CH), 125.7 (CH), 119.5 (CH), 53.5 (CH2); HR ESMS m/z 270.0798 (M + H+). Calc. C15H12ClN3: 269.07.
1-(2-bromobenzyl)-4-phenyl-1H-1,2,3-triazole (11): yield, 47%,white solid, m.p. 100–103 °C; 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.0 Hz, 2H), 7.71 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.25 (t, J = 7.8 Hz, 2H), 7.14 (m, 2H), 5.65 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 148.2 (C), 134.3 (C), 133.3 (CH), 130.4 (C), 130.4 (CH), 130.3 (CH), 128.8 (CH), 128.3 (CH), 128.2 (CH), 125.8 (CH), 123.4 (C), 119.8 (CH), 53.9 (CH2); HR ESMS m/z 314.0293 (M + H+). Calc. C15H12BrN3: 313.02.
1-(3-bromobenzyl)-4-phenyl-1H-1,2,3-triazole (12): yield, 64%, white solid, m.p. 96–99 °C; 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.4, 2H), 7.62 (s, 1H), 7.42 (t, J = 7.8, 1H), 7.39 (s, 1H), 7.33 (t, J = 7.4, 2H), 7.25 (t, J = 7.4, 1H), 7.16 (m, 2H), 5.46 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 148.5 (C), 137.0 (C), 132.1 (CH), 131.1 (CH), 130.8 (CH), 130.4 (C), 128.9 (CH), 128.4 (CH), 126.6 (CH), 125.8 (CH), 123.2 (C), 119.6 (CH), 53.5 (CH2); HR ESMS m/z 314.0293 (M + H+). Calc. C15H12BrN3: 313.02.
1-(4-bromobenzyl)-4-phenyl-1H-1,2,3-triazole (13): yield, 65%, white solid, m.p. 153–155 °C; 1H NMR (400 MHz, CDCl3): δ 7.73 (dd, J = 8.3, 1.2 Hz, 2H), 7.59 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.25 (tt, J = 7.4 Hz, 1.2, 1H), 7.12 (d, J = 8.4, 2H), 5.47 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 148.4 (C), 133.7 (C), 132.4 (CH), 130.4 (C), 129.7 (CH), 128.8 (CH), 128.3 (CH), 125.7 (CH), 123.0 (C), 119.4 (CH), 53.6 (CH2); HR ESMS m/z 314.0293 (M + H+). Calc. C15H12BrN3: 313.02.
4-(1-benzyl-1H-1,2,3-triazol-4-yl)aniline (14): yield, 34%, brownish solid, m.p. 180–181 °C; 1H NMR (300 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.42–7.28 (m, 5H), 5.57 (s, 2H); 13C NMR (75 MHz, DMSO-d6): δ 148.9 (C), 147.6 (C), 136.2 (C), 128.7 (CH), 128.0 (CH), 127.8 (CH), 126.1 (CH), 119.3 (CH), 118.4 (C), 114.0 (CH), 52.8 (CH2); HR ESMS m/z 251.1297 (M + H+). Calc. C15H14N4: 250.12.
4-(1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)aniline (15): yield, 25%, brownish solid, m.p. 131–133 °C; 1H NMR (400 MHz, CDCl3): δ 7.78 (d, 8.8 Hz, 2H), 7.32 (s, 1H), 7.23–7.05 (m, 4H), 6.59 (d, J = 8.8 Hz, 2H), 5.44 (s, 2H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 148.4 (C), 146.6 (C), 137 (C), 132.8 (CH), 131.1 (CH), 129.4 (CH), 129.1 (CH), 126.9 (CH), 126.7 (CH), 121.1 (C), 118.1 (CH), 115.3 (CH), 52.4 (CH2), 19.1 (CH3); HR ESMS m/z 265,1453 (M + H+). Calc. C16H16N4: 264.14.
4-(1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl)aniline (16): yield, 42%, brownish solid, m.p. 128–129 °C; 1H NMR (300 MHz, DMSO-d6): δ 8.30 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.27 (t, J = 7.8 Hz, 1H), 7.20–7.08 (m, 3 H), 6.60 (d, J = 8.8 Hz, 2H), 5.54 (s, 2H), 5.22 (s, 2H), 2.23 (s, 3H); 13C NMR (75 MHz, DMSO): δ 149.1 (C), 147.6 (C), 137.9 (C), 136.1 (C), 128.7 (CH), 128.6 (CH), 128.4 (CH), 126.1 (CH), 124.9 (CH), 119.2 (CH), 118.3 (C), 113.9 (CH), 52.8 (CH2), 20.9 (CH3); HR ESMS m/z 265,1453 (M + H+). Calc. C16H16N4: 264.14.
4-(1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)aniline (17): yield, 58%, brownish solid, m.p. 130–132 °C; 1H NMR (300 MHz, DMSO-d6): δ 8.23 (s, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 8.7 Hz, 2H), 5.52 (s, 2H), 5.21 (s, 2H), 2,29 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 148.6 (C), 147.6 (C), 137.3 (C), 133.1 (C), 129.2 (CH), 127.8 (CH), 126.1 (CH), 119.1 (CH), 118.3 (C), 113.9 (CH), 52.6 (CH2), 20.5 (CH3); HR ESMS m/z 265,1453 (M + H+). Calc. C16H16N4: 264.14.
4-(1-(2-methoxybenzyl)-1H-1,2,3-triazol-4-yl)aniline (18): yield, 52%, brown solid, m.p. 166–167 °C; 1H NMR (400 MHz, MeOD): δ 7.94 (s, 1H), 7.49 (d, J = 8 Hz, 2H), 7.32 (td, J = 8, 4 Hz, 1H), 7.19 (dd, J = 8, 4 Hz, 1H), 7.00(d, J = 12 Hz, 1H), 6.93 (td, J = 8, 1 Hz, 2H), 6.73 (d, J = 8 Hz, 2H), 5.55 (s, 2H), 3.85 (s, 3H); 13C NMR (100 MHz, MeOD): δ 158.6 (C), 149.3 (C), 149.1 (C), 131.2 (CH), 130.7 (CH), 127.5 (CH), 124.3 (C), 121.7 (CH), 120.8 (C), 120.5 (CH), 116.2 (CH), 111.8 (CH), 55.8 (CH3), 50.2 (CH2); HR ESMS m/z 281,1404 (M + H+). Calc. C16H16N4O: 280.13.
4-(1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)aniline (19): yield, 20%, brown solid, m.p. 103–105 °C; 1H NMR (400 MHz, MeOD): δ 8.05 (s, 1H), 7.51 (d, J = 8 Hz, 2H), 7.30–7.22 (m, 1H), 6.92–6.85 (m, 3H), 6.73 (d, J = 8 Hz, 2H), 5.53 (s, 2H), 3.75 (s, 3H); 13C NMR (100 MHz, MeOD): δ 161.8 (C), 150.2 (C), 149.7 (C), 138.5 (C), 131.4 (CH), 128.0 (CH), 121.4 (CH), 121.3 (C), 120.9 (CH), 116.6 (CH), 115.3 (CH), 114.8 (CH), 56.0 (CH2), 55.0 (CH3); HR ESMS m/z 281,1397 (M + H+). Calc. C16H16N4O: 280.13.
4-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)aniline (20): yield, 38%, brown solid, m.p. 132–134 °C; 1H NMR (400 MHz, MeOD): δ 8.01 (s, 1H), 7.50 (d, J = 8 Hz, 2H), 7.30 (d, J = 8 Hz, 2H), 6.92 (d, J = 8 Hz, 2H), 6.74 (d, J = 8 Hz, 2H), 5.50 (s, 2H), 3.77 (s, 3H); 13C NMR (100 MHz, MeOD): δ 161.4 (C), 149.9 (C), 149.4 (C), 130.6 (CH), 128.8 (C), 127.7 (CH), 121.1 (C), 120.3 (CH), 116.4 (CH), 115.4 (CH), 55.7 (CH3), 54.5 (CH2); HR ESMS m/z 281,1404 (M + H+). Calc. C16H16N4O: 280.13.
4-(1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (21): yield, 39%, brown solid, m.p. 112–115 °C; 1H NMR (400 MHz, MeOD): δ 8.03 (s, 1H), 7.52 (d, J = 8 Hz, 2H), 7.44 (dd, J = 8, 4 Hz, 1H), 7.36–7.26 (m, 2H), 7.22 (d broad, J = 8 Hz, 1H), 6.74 (d, J = 8 Hz, 2H), 5.68 (s, 2H); 13C NMR (100 MHz, MeOD): δ 150.0 (C), 149.6 (C), 134.8 (C), 134.5 (C), 131.6 (CH), 131.5 (CH), 131.1 (CH), 128.8 (CH), 128.0 (CH), 121.2 (CH), 121.1 (C), 116.6 (CH), 52.5 (CH2); HR ESMS m/z 285,0912 (M + H+). Calc. C15H13ClN4: 284.08.
4-(1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (22): yield, 40%, brownish solid, m.p. 143–144 °C; 1H NMR (400 MHz, MeOD): δ 8.12 (s, 1H), 7.53 (d, J = 8 Hz, 2H), 7.40–7.33 (m, 3H), 7.29–7.24 (m, 1H), 6.75 (d, J = 8 Hz, 2H), 5.58 (s, 2H); 13C NMR (100 MHz, MeOD): δ 150.1 (C), 149.6 (C), 139.2 (C), 135.7 (C), 131.5 (CH), 129.6 (CH), 129.0 (CH), 127.7 (CH), 127.4 (CH), 120.9 (C), 120.6 (CH), 116.4 (CH), 54.0 (CH2); HR ESMS m/z 285,0908 (M + H+). Calc. C15H13ClN4: 284.08.
4-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (23): yield, 71%, brownish solid, m.p. 164–166 °C; 1H NMR (400 MHz, MeOD): δ 8.09 (s, 1H), 7.52 (d, J = 8 Hz, 2H), 7.39 (d, J = 8 Hz, 2H), 7.33 (d, J = 8 Hz, 2H), 6.75 (d, J = 8 Hz, 2H), 5.58 (s, 2H); 13C NMR (100 MHz, MeOD): δ 150.3 (C), 149.8 (C), 135.9 (C), 135.6 (C), 130.9 (CH), 130.3 (CH), 127.9 (CH), 121.2 (C), 120.8 (CH), 116.5 (CH), 54.3 (CH2); HR ESMS m/z 285,0903 (M + H+). Calc. C15H13ClN4: 284.08.
4-(1-(2-bromobenzyl)-1H-1,2,3-triazol-4-yl)aniline (24): yield, 52%, brown solid, m.p. 133–134 °C; 1H NMR (300 MHz, MeOD): δ 8.04 (s, 1 H), 7.63 (dd, J = 7.9, 1.2 Hz, 1 H), 7.51 (d, J = 8.7 Hz, 2 H), 7.34 (td, J = 7.5, 1.2 Hz, 1H), 7.24 (td, J = 7.5, 1.7 Hz, 1H), 7.17 (dd, J = 7.5, 1.7 Hz, 1H), 6.73 (d, J = 8.7, 2H), 5.68 (s, 2H); 13C NMR (75 MHz, MeOD): δ 149.8 (C), 149.6 (C), 136.0 (C), 134.3 (CH), 131.5 (CH), 131.4 (CH), 129.3 (CH), 127.8 (CH), 124.4 (C), 121.1 (CH), 120.9 (C), 116.4 (CH), 54.9 (CH2); HR ESMS m/z 329,0402 (M + H+). Calc. C15H13BrN4: 328.03.
4-(1-(3-bromobenzyl)-1H-1,2,3-triazol-4-yl)aniline (25): yield, 73%, brownish solid, m.p. 134–135 °C; 1H NMR (300 MHz, DMSO-d6): δ 8.35 (s, 1 H), 7.60–7.52 (m, 2H 1H), 7.40–7.29 (m, 2H), 7.49 (d, J = 9 Hz, 2 H), 6.60 (d, J = 9 Hz, 2H), 5.61 (s, 2H), 5.24 (s, 2H); 13C NMR (75 MHz, DMSO): δ 148.6 (C), 147.7 (C), 138.8 (CH), 131.0 (2 x CH), 130.6 (CH), 126.9 (CH), 126.2 (CH), 121.8 (C), 119.4 (C), 118.1 (C), 113.9 (CH), 52.0 (CH2); HR ESMS m/z 329,0402 (M + H+). Calc. C15H13BrN4: 328.03.
4-(1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)aniline (26): yield, 88%, brownish solid, m.p. 169–170 °C; 1H NMR (300 MHz, C3D6O): δ 8.08 (s, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 9 Hz, 2H), 6.66 (d, J = 9 Hz, 2H), 5.58 (s 2H), 4.71 (s, 2H); 13C NMR (75 MHz, C3D6O): δ 148.3 (C), 148.2 (C), 135.7 (C), 131.7 (CH), 129.9 (CH), 126.3 (CH), 121.5 (C), 119.7 (C), 118.5 (CH), 114.2 (CH), 52.4 (CH2); HR ESMS m/z 329,0402 (M + H+). Calc. C15H13BrN4: 328.03.