2.1.3. General Procedure for the Synthesis of 3–5
To a solution of the corresponding amidinium salt (1.5 equiv) in dry EtOH (10–45 mL), NaOMe (1 equiv) in 10 mL of dry EtOH was added. The suspension was stirred at room temperature for 1 h. Then, the solid formed was filtered on Celite. Octanoic hydrazide (2 equiv) was added to the liquid layer and the mixture was stirred under reflux for 46–49 h. After cooling the reaction mixture, solvent was removed in vacuo. The residue was dissolved in CH2Cl2 and washed with water (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed in vacuo. The obtained residue was purified by MPLC using cyclohexane/EtOAc (3 : 1) as eluent, except for compound 5 where cyclohexane/EtOAc (3 : 1 to 4 : 1) was used.
3-Heptyl-5-phenyl-1H-1,2,4-triazole (
3
). Compound 3 was prepared from benzamidine hydrochloride hydrate (857 mg, 5.5 mmol), octanoic hydrazide (581 mg, 3.6 mmol), and NaOMe (394 mg, 7.3 mmol). Yield: 683 mg of 3 (78%) as a transparent oil. Mp = 129–132°C oxalate (to a solution of the free base in Et2O, a solution of oxalic acid in EtOAc was added; the white solid was filtered off, washed with EtOAc, and dried). 1H-NMR (CDCl3) δ: 10.65 (bs, 1H, NH); 7.96 (m, 2H, Ho); 7.34 (m, 3H, Hm and Hp); 2.69 (t, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.65 (p, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.16 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.79 (bt, 3H, J=6.3 Hz, CH3). 13C-NMR (CDCl3) δ: 160.4 and 160.0 C3 and C5; 129.8 Cipso; 129.5 Cp; 128.6 Cm; 126.4 Co; 31.5 CH2CH2CH2CH2CH2CH2CH3; 29.1 CH2CH2CH2CH2CH2CH2CH3; 28.8 CH2CH2CH2CH2CH2CH2CH3; 28.1 CH2CH2CH2CH2CH2CH2CH3; 27.0 CH2CH2CH2CH2CH2CH2CH3; 22.5 CH2CH2CH2CH2CH2CH2CH3; 13.9 CH3. MS (ES+) m/z: 244 (100%) [M+H]+. Anal (C15H21N3·C2H2O4) % calculated (% found) C: 61.25 (61.41); H: 6.95 (7.12); N: 12.60 (12.62).
5-(4-Chlorophenyl)-3-heptyl-1H-1,2,4-triazole (
4
). Compound 4 was prepared from 1 (1.00 g, 5.2 mmol), octanoic hydrazide (549 mg, 3.5 mmol), and NaOMe (375 mg, 7.0 mmol). Yield 392 mg of 4 (40%) as a white solid. Mp = 108–111°C. 1H-NMR (CDCl3) δ: 7.91 (d, 2H, J=8.6 Hz, Ho); 7.34 (d, 2H, J=8.6 Hz, Hm); 2.72 (t, 2H, J=7.6 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.68 (p, 2H, J=7.6 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.20 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.82 (bt, 3H, J=6.5 Hz, CH3). 13C-NMR (CDCl3) δ: 160.4 and 159.5 C3 and C5; 135.5 Cipso; 128.9 Cm; 128.7 Cp; 127.7 Co; 31.6 CH2CH2CH2CH2CH2CH2CH3; 29.2 CH2CH2CH2CH2CH2CH2CH3; 28.8 CH2CH2CH2CH2CH2CH2CH3; 28.0 CH2CH2CH2CH2CH2CH2CH3; 26.9 CH2CH2CH2CH2CH2CH2CH3; 22.5 CH2CH2CH2CH2CH2CH2CH3; 14.0 CH3. MS (ES+) m/z: 278 (100%) [M+H]+. Anal (C15H20ClN3) % calculated (% found) C: 64.85 (65.09); H: 7.26 (7.42); N: 15.13 (15.35).
4-(3-Heptyl-1H-1,2,4-triazol-5-yl)pyridine (
5
) and N′-[imino(pyridin-4-yl)methyl]octa-nehydrazide (6). Compound 5 was prepared from 2 (2.00 g, 12.7 mmol), octanoic hydrazide (1.35 g, 8.5 mmol), and NaOMe (918 mg, 17.0 mmol). Yield: 459 mg of 5 (23%) as a white solid and 1.61 g of 6 (45%) as a white solid. 5: Mp = 109–112°C. 1H-NMR (CDCl3) δ: 8.69 (d, 2H, J=6.1 Hz, Hm); 8.06 (d, 2H, J=6.1 Hz, Ho); 2.85 (t, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.78 (p, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.21 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.81 (bt, 3H, J=6.7 Hz, CH3). 13C-NMR (CDCl3) δ: 159.4 and 159.2 C3 and C5; 149.4 Cm; 139.5 Cipso; 121.0 Co; 31.5 CH2CH2CH2CH2CH2CH2CH3; 29.1 CH2CH2CH2CH2CH2CH2CH3; 28.8 CH2CH2CH2CH2CH2CH2CH3; 28.1 CH2CH2CH2CH2CH2CH2CH3; 26.7 CH2CH2CH2CH2CH2CH2CH3; 22.5 CH2CH2CH2CH2CH2CH2CH3; 13.9 CH3. MS (ES+) m/z: 245 (100%) [M+H]+. Anal (C14H20N4) % calculated (% found) C: 68.82 (68.71); H: 8.25 (8.36); N: 22.93 (22.78). 6: Mp = 135–138°C. 1H-NMR (CD3OD) δ: 8.67 (d, 2H, J=6.1 Hz, Hm); 7.94 (d, 2H, J=6.1 Hz, Ho); 2.41 (t, 2H, J=7.4 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.76 (m, 2H, CH2CH2CH2CH2CH2CH2CH3); 1.41 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0,99 (bt, 3H, J=6.0 Hz, CH3). 13C-NMR (CD3OD) δ: 172.7 CONH; 151.7 C=NH; 150.4 Cm; 144.1 Cipso; 122.9 Co; 35.7 CH2CH2CH2CH2CH2CH2CH3; 32.9 CH2CH2CH2CH2CH2CH2CH3; 30.4 and 30.2 CH2CH2CH2CH2CH2CH2CH3; 27.1 CH2CH2CH2CH2CH2CH2CH3; 23.7 CH2CH2CH2CH2CH2CH2CH3; 14.4 CH3. MS (ES+) m/z: 263 (100%) [M+H]+. Anal (C14H22N4O·1/2HCl) % calculated (% found) C: 59.93 (59.10); H: 8.08 (8.11); N: 19.97 (20.45).
Intermediate 6 (1.00 g, 3.6 mmol) in dry EtOH (20 mL) reacted by refluxing with NaOMe (1.03 g, 19.0 mmol) for 4 days. Under this procedure, 5 was obtained in 78% yield (676 mg).
2.1.4. General Procedure for the Synthesis of 7a–15a and 7b–15b
To a solution of the 3,5-disubstituted triazole (1 equiv) in 40% NaOH aq solution (3–5 mL) and toluene (7–10 mL) (Bu)4NBr (0.05 equiv) were first added, and later the corresponding alkylating agent (1 equiv) was added. The reaction mixture was stirred at 80–90°C (bath temperature) for the reaction time indicated. Afterwards, organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was removed in vacuo. The residue was purified by MPLC [cyclohexane/EtOAc (9 : 1)], except for compound 13a, which was purified by flash chromatography [CH2Cl2 → CH2Cl2/MeOH (60 : 1)].
1-Benzyl-5-heptyl-3-phenyl-1H-1,2,4-triazole (
7a
) and 1-Benzyl-3-heptyl-5-phenyl-1H-1,2,4-triazole (
7b
). Compounds 7a and 7b were prepared from 3 (100 mg, 0.4 mmol), benzyl bromide (52 μL, 0.4 mmol), and (Bu)4NBr (6 mg, 0.02 mmol); reaction time: 1.5 h. Yield: 106 mg of 7a (78%) as a transparent oil, and 13 mg of 7b (9%) as a transparent oil. 7a: 1H-NMR (CDCl3) δ: 8.08 (m, 2H, Ph); 7.40 (m, 3H, Ph); 7.31 (m, 3H, Bn); 7.18 (m, 2H, Bn); 5.34 (s, 2H, CH2Ph); 2.69 (t, 2H, J=7.8 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.64 (p, 2H, J=7.5 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.22 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.85 (bt, 3H, J=6.1 Hz, CH3). 13C-NMR (CDCl3) δ: 160.8 C3; 157.0 C5; 135.7 Cipso Bn; 131.2 Cipso Ph; 128.9 Cm Bn and Cp Ph; 128.5 Cm Ph; 126.9 Co Bn; 126.3 Co Ph; 128.1 Cp Bn; 52.1 (CH2Ph); 31.6 CH2CH2CH2CH2CH2CH2CH3; 29.2 CH2CH2CH2CH2CH2CH2CH3; 28.8 CH2CH2CH2CH2CH2CH2CH3; 27.8 CH2CH2CH2CH2CH2CH2CH3; 26.2 CH2CH2CH2CH2CH2CH2CH3; 22.5 CH2CH2CH2CH2CH2CH2CH3; 14.0 CH3. MS (ES+) m/z: 334 (100%) [M+H]+. Anal (C22H27N3) % calculated (% found) C: 79.24 (79.35); H: 8.16 (8.40); N: 12.60 (12.64). 7b: 1H-NMR (CDCl3) δ: 7.53 (m, 2H, Ph); 7.41 (m, 3H, Ph); 7.30 (m, 3H, Bn); 7.14 (m, 2H, Bn); 5.35 (s, 2H, CH2Ph); 2.75 (t, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.78 (p, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.23 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.85 (bt, 3H, J=6.4 Hz, CH3). 13C-NMR (CDCl3) δ: 164.1 C3; 155.3 C5; 136.1 Cipso Bn; 130.2 Cipso Ph; 128.9 Cm Bn; 128.8 and 128.7 Co and Cm Ph; 126.7 Co Bn; 127.9 Cp Bn and Cp Ph; 52.4 CH2Ph; 31.8 CH2CH2CH2CH2CH2CH2CH3; 29.3 CH2CH2CH2CH2CH2CH2CH3; 29.0 CH2CH2CH2CH2CH2CH2CH3; 28.5 CH2CH2CH2CH2CH2CH2CH3; 28.3 CH2CH2CH2CH2CH2CH2CH3; 22.6 CH2CH2CH2CH2CH2CH2CH3; 14.1 CH3. MS (ES+) m/z: 334 (100%) [M+H]+. Anal (C22H27N3) % calculated (% found) C: 79.24 (79.10); H: 8.16 (7.95); N: 12.60 (12.42).
1-(4-Chlorobenzyl)-5-heptyl-3-phenyl-1H-1,2,4-triazole (
8a
) and 1-(4-Chlorobenzyl)-3-heptyl-5-phenyl-1H-1,2,4-triazole (
8b
). Compounds 8a and 8b were prepared from 3 (73 mg, 0.3 mmol), 4-chlorobenzyl chloride (48 mg, 0.3 mmol), and (Bu)4NBr (6 mg, 0.02 mmol); reaction time: 11 h. Yield: 96 mg of 8a (87%) as a yellow solid and 10 mg of 8b (9%) as a transparent oil. 8a: 1H-NMR (CDCl3) δ: 8.07 (m, 2H, Ho Ph); 7.37 (m, 3H, Hm and Hp Ph); 7.29 (d, 2H, J=8.4 Hz, Hm Bn); 7.11 (d, 2H, J=8.4 Hz, Ho Bn); 5.27 (s, 2H, CH2Ar); 2.67 (t, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.69 (p, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.24 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.85 (ta, 3H, J=6.9 Hz, CH3). 13C-NMR (CDCl3) δ: 161.0 C3; 156.9 C5; 134.2 Cipso Bn; 134.0 Cp Bn; 131.1 Cipso Ph; 129.0 and 128.3 Co Bn, Cm Bn and Cp Ph; 128.5 Cm Ph; 126.2 Co Ph; 51.3 CH2Ar; 31.5 CH2CH2CH2CH2CH2CH2CH3; 29.2 CH2CH2CH2CH2CH2CH2CH3; 28.8 CH2CH2CH2CH2CH2CH2CH3; 27.7 CH2CH2CH2CH2CH2CH2CH3; 26.1 CH2CH2CH2CH2CH2CH2CH3; 22.5 CH2CH2CH2CH2CH2CH2CH3; 14.0 CH3. MS (ES+) m/z: 368 (100%) [M+H]+. Anal (C22H26ClN3) % calculated (% found) C: 71.82 (71.75); H: 7.12 (6.98); N: 11.42 (11.63). 8b: 1H-NMR (CDCl3) δ: 7.50 (m, 2H, H Ph); 7.43 (m, 3H, Ph); 7.29 (d, 2H, J=8.4 Hz, Hm Bn); 7.06 (d, 2H, J=8.4 Hz, Ho Bn); 5.30 (s, 2H, CH2Ar); 2.75 (t, 2H, J=7.5 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.77 (p, 2H, J=7.5 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.23 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.85 (ta, 3H, J=6.2 Hz, CH3). 13C-NMR (CDCl3) δ: 164.6 C3; 155.5 C5; 134.7 Cipso Bn; 133.8 Cp Bn; 130.1 Cp Ph; 129.0 Cm Bn; 128.8 Co Bn; 128.6 Cm Ph; 128.1 Co Ph; 128.0 Cipso Ph; 51.7 CH2Ar; 31.8 CH2CH2CH2CH2CH2CH2CH3; 29.4 CH2CH2CH2CH2CH2CH2CH3; 29.0 CH2CH2CH2CH2CH2CH2CH3; 28.5 CH2CH2CH2CH2CH2CH2CH3; 22.6 CH2CH2CH2CH2CH2CH2CH3; 14.1 CH3. MS (ES+) m/z: 368 (100%) [M+H]+. HPLC: Acetonitrile/H2O 95 : 5, tR=28.5 min (99% purity).
1-(2,4-Dichlorobenzyl)-5-heptyl-3-phenyl-1H-1,2,4-triazole (
9a
) and 1-(2,4-Dichloro-benzyl)-3-heptyl-5-phenyl-1H-1,2,4-triazole (
9b
). Compounds 9a and 9b were prepared from 3 (100 mg, 0.4 mmol), 2,4-dichlorobenzyl chloride (57 μL, 0.4 mmol), and (Bu)4NBr (6 mg, 0.02 mmol); reaction time: 5 h. Yield: 123 mg of 9a (74%) as a white solid and 12 mg of 9b (7%) as a transparent oil. 9a: Mp = 70–73°C. 1H-NMR (CDCl3) δ: 8.11 (m, 2H, Ho Ph); 7.42 (m, 4H, Hm′ Bn, Hm and Hp Ph); 7.19 (dd, 1H, J = 8.3 Hz and 1.6 Hz, Hm Ph); 6.85 (d, 1H, J=8.3 Hz, Ho Bn); 5.41 (s, 2H, CH2Ar); 2.73 (t, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.73 (p, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.27 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.88 (bt, 3H, J=6.4 Hz, CH3). 13C-NMR (CDCl3) δ: 161.4 C3; 157.4 C5; 134.5 Cipso Bn; 132.8 Cp Bn; 132.2 Co′ Bn; 131.0 Cipso Ph; 129.3 Co Bn; 129.2 Cm′ Bn; 129.1 Cp Ph; 128.5 Cm Ph; 127.7 Cm Bn; 126.3 Co Ph; 48.6 CH2Ar; 31.5 CH2CH2CH2CH2CH2CH2CH3; 29.1 CH2CH2CH2CH2CH2CH2CH3; 28.8 CH2CH2CH2CH2CH2CH2CH3; 27.8 CH2CH2CH2CH2CH2CH2CH3; 26.0 CH2CH2CH2CH2CH2CH2CH3; 22.5 CH2CH2CH2CH2CH2CH2CH3; 14.0 CH3. MS (ES+) m/z: 402 (100%) [M+H]+. Anal (C22H25Cl2N3) % calculated (% found) C: 65.67 (65.42); H: 6.26 (6.50); N: 10.44 (10.35). 9b: 1H-NMR (CDCl3) δ: 7.50–7.43 (m, 5H, Ph); 7.40 (d, 1H, J=1.7 Hz, Hm′ Bn); 7.20 (dd, 1H, J=8.6 Hz and 1.7 Hz, Hm Bn); 6.84 (d, 1H, J=8.6 Hz, Ho Bn); 5.39 (s, 2H, CH2Ar); 2.76 (t, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.79 (p, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.23 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.85 (bt, 3H, J=6.1 Hz, CH3). 13C-NMR (CDCl3) δ: 165.2 C3; 156.2 C5; 134.6 Cipso Bn; 133.0 Cp Bn; 132.9 Co′ Bn; 130.5 Co Bn; 129.7 Cm′ Bn; 129.2 Cm Ph; 129.0 Cp Ph; 128.6 Co Ph; 127.9 Cm Bn; 127.8 Cipso Ph; 50.1 CH2Ar; 32.0 CH2CH2CH2CH2CH2CH2CH3; 29.6 CH2CH2CH2CH2CH2CH2CH3; 29.2 CH2CH2CH2CH2CH2CH2CH3; 28.7 CH2CH2CH2CH2CH2CH2CH3; 22.9 CH2CH2CH2CH2CH2CH2CH3; 14.3 CH3. MS (ES+) m/z: 402 (100%) [M+H]+. Anal (C22H25Cl2N3·C6H12) % calculated (% found) C: 69.12 (69.42); H: 7.67 (7.79); N: 8.64 (8.24).
1-Benzyl-3-(4-chlorophenyl)-5-heptyl-1H-1,2,4-triazole (
10a
) and 1-Benzyl-5-(4-chlo-rophenyl)-3-heptyl-1H-1,2,4-triazole (
10b
). Compounds 10a and 10b were prepared from 4 (80 mg, 0.3 mmol), benzyl bromide (34 μL, 0.3 mmol), and (Bu)4NBr (6 mg, 0.02 mmol); reaction time: 20 min. Yield: 94 mg of 10a (89%) as a white solid and 9 mg of 10b (8%) as a yellow oil. 10a: Mp = 47–50°C. 1H-NMR (CDCl3) δ: 8.02 (d, 2H, J=8.8 Hz, Ho Ar); 7.36 (d, 2H, J=8.8 Hz, Hm Ar); 7.29 (m, 3H, Bn); 7.19 (m, 2H, Bn); 5.31 (s, 2H, CH2Ph); 2.67 (t, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.66 (p, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.22 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.85 (bt, 3H, J=6.9 Hz, CH3). 13C-NMR (CDCl3) δ: 159.9 C3; 157.1 C5; 135.5 Cipso Ar; 134.7 Cipso Bn; 129.8 Cp Ar; 128.9 Cm Ar; 128.6 Cm Bn; 128.1 Cp Bn; 127.6 Co Ar; 126.9 Co Bn; 52.1 (CH2Ph); 31.5 CH2CH2CH2CH2CH2CH2CH3; 29.2 CH2CH2CH2CH2CH2CH2CH3, 28.8 CH2CH2CH2CH2CH2CH2CH3; 27.7 CH2CH2CH2CH2CH2CH2CH3; 26.1 CH2CH2CH2CH2CH2CH2CH3; 22.5 CH2CH2CH2CH2CH2CH2CH3; 14.0 CH3. MS (ES+) m/z: 368 (100%) [M+H]+. Anal (C22H26ClN3) % calculated (% found) C: 71.82 (72.02); H: 7.12 (6.89); N: 11.42 (11.24). 10b: 1H-NMR (CDCl3) δ: 7.47 (d, 2H, J=8.5 Hz, Hm Ar); 7.38 (d, 2H, J=8.5 Hz, Ho Ar); 7.30 (m, 3H, Bn); 7.00 (m, 2H, Bn); 5.33 (s, 2H, CH2Ph); 2.75 (t, 2H, J=7.6 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.78 (p, 2H, J=7.6 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.25 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.85 (bt, 3H, J=6.4 Hz, CH3). 13C-NMR (CDCl3) δ: 164.6 C3; 155.0 C5; 136.3 Cipso Ar; 136.2 Cipso Bn; 130.0 Cm Ar; 129.4 Cp Ar; 129.1 Co Ar; 129.0 Cm Bn; 128.0 Cp Bn; 52.6 (CH2Ph); 31.8 CH2CH2CH2CH2CH2CH2CH3; 29.4 CH2CH2CH2CH2CH2CH2CH3; 29.0 CH2CH2CH2CH2CH2CH2CH3; 28.5 CH2CH2CH2CH2CH2CH2CH3; 22.6 CH2CH2CH2CH2CH2CH2CH3; 14.0 CH3. MS (ES+) m/z: 368 (100%) [M+H]+.
1-(4-Chlorobenzyl)-3-(4-chlorophenyl)-5-heptyl-1H-1,2,4-triazole (
11a
) and 1-(4-Chlo-robenzyl)-5-(4-chlorophenyl)-3-heptyl-1H-1,2,4-triazole (
11b
). Compounds 11a and 11b were prepared from 4 (100 mg, 0.4 mmol), 4-chlorobenzyl chloride (64 mg, 0.4 mmol), and (Bu)4NBr (6 mg, 0.02 mmol); reaction time: 6 h. Yield: 132 mg of 11a (91%) as a white solid and 2 mg of 11b (1%) as a transparent oil. 11a: Mp = 58–60°C. 1H-NMR (CDCl3) δ: 8.00 (d, 2H, J=8.8 Hz, Ho Ar); 7.35 (d, 2H, J=8.8 Hz, Hm Ar); 7.28 (d, 2H, J=8.4 Hz, Hm CH2Ar); 7.10 (d, 2H, J=8.4 Hz, Ho CH2Ar); 5.26 (s, 2H, CH2Ar); 2.66 (t, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.66 (p, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.23 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.84 (bt, 3H, J=6.3 Hz, CH3). 13C-NMR (CDCl3) δ: 160.1 C3; 157.1 C5; 134.8 Cipso Ar; 134.1 Cipso CH2Ar; 134.0 Cp CH2Ar; 129.6 Cp Ar; 129.0 Cm Ar; 128.6 Cm CH2Ar; 128.3 Co CH2Ar; 127.5 Co Ar; 51.3 (CH2Ar); 31.5 CH2CH2CH2CH2CH2CH2CH3; 29.2 CH2CH2CH2CH2CH2CH2CH3; 28.8 CH2CH2CH2CH2CH2CH2CH3; 27.7 CH2CH2CH2CH2CH2CH2CH3; 26.1 CH2CH2CH2CH2CH2CH2CH3; 22.5 CH2CH2CH2CH2CH2CH2CH3; 14.0 CH3. MS (ES+) m/z: 402 (100%) [M+H]+. Anal (C22H25Cl2N3) % calculated (% found) C: 65.67 (65.72); H: 6.26 (6.12); N: 10.44 (10.40). 11b: 1H-NMR (CDCl3) δ: 7.45 (d, 2H, J=9.0 Hz, Ho Ar); 7.39 (d, 2H, J=9.0 Hz, Hm Ar); 7.30 (d, 2H, J=8.3 Hz, Hm CH2Ar); 7.05 (d, 2H, J=8.3 Hz, Ho CH2Ar); 5.29 (s, 2H, CH2Ar); 2.70 (t, 2H, J=7.8 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.75 (p, 2H, J=7.8 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.23 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.82 (bt, 3H, J=6.2 Hz, CH3). 13C-NMR (CDCl3) δ: 164.7 C3; 154.4 C5; 136.4 Cipso Ar; 134.4 Cipso CH2Ar; 134.0 Cp CH2Ar; 129.9 Cm and Cp Ar; 129.2 Co Ar and Cm CH2Ar; 128.0 Co CH2Ar; 51.8 CH2Ar; 31.8 CH2CH2CH2CH2CH2CH2CH3; 29.7 CH2CH2CH2CH2CH2CH2CH3; 29.3 CH2CH2CH2CH2CH2CH2CH3; 29.0 CH2CH2CH2CH2CH2CH2CH3; 28.4 CH2CH2CH2CH2CH2CH2CH3; 22.6 CH2CH2CH2CH2CH2CH2CH3; 14.1 CH3. MS (ES+) m/z: 402 (100%) [M+H]+. HPLC: Acetonitrile/H2O 95 : 5, tR=25.5 min (81% purity).
3-(4-Chlorophenyl)-1-(2,4-dichlorobenzyl)-5-heptyl-1H-1,2,4-triazole (
12a
) and 5-(4-Chlorophenyl)-1-(2,4-dichlorobenzyl)-3-heptyl-1H-1,2,4-triazole (
12b
). Compounds 12a and 12b were prepared from 4 (90 mg, 0.3 mmol), 2,4-dichlorobenzyl chloride (45 μL, 0.3 mmol), and (Bu)4NBr (6 mg, 0.02 mmol); reaction time: 6 h. Yield: 122 mg of 12a (86%) as a white solid and 8 mg of 12b (6%) as a transparent oil. 12a: Mp = 97–99°C. 1H-NMR (CDCl3) δ: 8.00 (d, 2H, J=8.6 Hz, Ho Ar); 7.41 (d, 1H, J=2.0 Hz, Hm′ CH2Ar); 7.37 (d, 2H, J=8.6 Hz, Hm Ar); 7.18 (dd, 1H, J=8.4 Hz and 2.0 Hz, Hm CH2Ar); 6.84 (d, 1H, J=8.4 Hz, Ho CH2Ar); 5.37 (s, 2H, CH2Ar); 2.70 (t, 2H, J=7.6 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.69 (p, 2H, J=7.6 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.22 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.85 (bt, 3H, J=7.1 Hz, CH3). 13C-NMR (CDCl3) δ: 160.5 C3; 157.6 C5; 135.0 Cipso Ar; 134.6 Cipso CH2Ar; 132.9 Cp CH2Ar; 132.0 Co′ CH2Ar; 129.5 Cp Ar; 129.4 Co CH2Ar; 129.3 Cm′ CH2Ar; 128.7 Cm Ar; 127.7 Cm CH2Ar; 127.6 Co Ar; 48.7 CH2Ar; 31.5 CH2CH2CH2CH2CH2CH2CH3; 29.1 CH2CH2CH2CH2CH2CH2CH3; 28.8 CH2CH2CH2CH2CH2CH2CH3; 27.7 CH2CH2CH2CH2CH2CH2CH3; 26.0 CH2CH2CH2CH2CH2CH2CH3; 22.5 CH2CH2CH2CH2CH2CH2CH3; 14.0 CH3. MS (ES+) m/z: 436 (100%) [M+H]+. Anal (C22H24Cl3N3) % calculated (% found) C: 60.49 (60.42); H: 5.54 (5.74); N: 9.62 (9.42). 12b: 1H-NMR (CDCl3) δ: 7.41 (bs, 5H, Ho Ar, Hm Ar and Hm′ CH2Ar); 7.21 (dd, 1H, J=8.3 Hz and 2.0 Hz, Hm CH2Ar); 6.84 (d, 1H, J=8.3 Hz, Ho CH2Ar); 5.37 (s, 2H, CH2Ar); 2.75 (t, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.77 (p, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1,23 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.85 (bt, 3H, J=6.1 Hz, CH3). 13C-NMR (CDCl3) δ: 165.1 C3; 154.9 C5; 136.6 Cipso Ar; 134.7 Cipso CH2Ar; 132.8 Cp CH2Ar; 132.5 Co′ CH2Ar; 129.7 Cm and Cp Ar; 129.6 Co CH2Ar; 129.3 Co Ar; 129.0 Cm′ CH2Ar; 127.8 Cm CH2Ar; 49.9 CH2Ar; 31.8 CH2CH2CH2CH2CH2CH2CH3; 29.7 CH2CH2CH2CH2CH2CH2CH3; 29.3 CH2CH2CH2CH2CH2CH2CH3; 29.0 CH2CH2CH2CH2CH2CH2CH3; 28.4 CH2CH2CH2CH2CH2CH2CH3; 22.6 CH2CH2CH2CH2CH2CH2CH3; 14.0 CH3. MS (ES+) m/z: 436 (99%) [M+H]+. HPLC: Acetonitrile/H2O 90 : 10, tR=66.2 min (99% purity).
4-(1-Benzyl-5-heptyl-1H-1,2,4-triazol-3-yl)pyridine (
13a
). Compound 13a was prepared from 5 (150 mg, 0.6 mmol), benzyl chloride (73 μL, 0.6 mmol), and (Bu)4NBr (6 mg, 0.02 mmol); reaction time: 2.5 h. Yield: 166 mg of 13a (81%) as an orange oil. 1H-NMR (CDCl3) δ: 8.63 (d, 2H, J=6.0 Hz, Hm pyr); 7.93 (d, 2H, J=6.0 Hz, Ho pyr); 7.31 (m, 3H, Ph); 7.16 (m, 2H, Ph); 5.33 (s, 2H, CH2Ar); 2.68 (t, 2H, J=7.8 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.65 (p, 2H, J=7.0 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.21 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.83 (bt, 3H, J=7.1 Hz, CH3). 13C-NMR (CDCl3) δ: 158.7 C3; 157.5 C5; 150.1 Cm pyr; 138.5 Cipso pyr; 135.2 Cipso Ph; 128.9 Cm Ph; 128.2 Cp Ph; 127.0 Co Ph; 120.4 Co pyr; 52.3 CH2Ph; 31.5 CH2CH2CH2CH2CH2CH2CH3; 29.1 CH2CH2CH2CH2CH2CH2CH3; 28.8 CH2CH2CH2CH2CH2CH2CH3; 27.6 CH2CH2CH2CH2CH2CH2CH3; 26.1 CH2CH2CH2CH2CH2CH2CH3; 22.5 CH2CH2CH2CH2CH2CH2CH3; 14.0 CH3. MS (ES+) m/z: 335 (100%) [M+H]+. Anal (C21H26N4) % calculated (% found) C: 75.41 (75.71); H: 7.84 (7.79); N: 16.75 (16.54).
4-[1-(4-Chlorobenzyl)-5-heptyl-1H-1,2,4-triazol-3-yl]pyridine (
14a
) and 4-[1-(4-Chlo-robenzyl)-3-heptyl-1H-1,2,4-triazol-5-yl]pyridine (
14b
). Compounds 14a and 14b were prepared from 5 (180 mg, 0.7 mmol), 4-chlorobenzyl chloride (119 mg, 0.7 mmol), and (Bu)4NBr (12 mg, 0.04 mmol); reaction time: 6 h. Yield: 150 mg of 14a (51%) as a brown solid and 10 mg of 14b (4%) as a brown oil. 14a: Mp = 77–80°C. 1H-NMR (CDCl3) δ: 8.61 (d, 2H, J=6.0 Hz, Hm pyr); 7.90 (d, 2H, J=6.0 Hz, Ho pyr); 7.27 (d, 2H, J=8.6 Hz, Hm Ar); 7.09 (d, 2H, J=8.6 Hz, Ho Ar); 5.27 (s, 2H, CH2Ar); 2.66 (t, 2H, J=7.8 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.65 (p, 2H, J=7.8 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.20 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.82 (bt, 3H, J=6.6 Hz, CH3). 13C-NMR (CDCl3) δ: 158.9 C3; 157.5 C5; 150.2 Cm pyr; 138.4 Cipso pyr; 134.2 Cipso Ar; 133.7 Cp Ar; 129.1 Cm Ar; 128.4 Co Ar; 120.4 Co pyr; 51.8 CH2Ar; 31.5 CH2CH2CH2CH2CH2CH2CH3; 29.1 CH2CH2CH2CH2CH2CH2CH3; 28.8 CH2CH2CH2CH2CH2CH2CH3; 26.0 CH2CH2CH2CH2CH2CH2CH3; 22.5 CH2CH2CH2CH2CH2CH2CH3; 14.0 CH3. MS (ES+) m/z: 369 (100%) [M+H]+. Anal (C21H25ClN4) % calculated (% found) C: 68.37 (68.55); H: 6.83 (6.90); N: 15.19 (15.21). 14b: 1H-NMR (CDCl3) δ: 8.65 (d, 2H, J=6.2 Hz, Hm pyr); 7.44 (d, 2H, J=6.2 Hz, Ho pyr); 7.31 (d, 2H, J=8.5 Hz, Hm Ar); 7.06 (d, 2H, J=8.5 Hz, Ho pyr); 5.35 (s, 2H, CH2Ar); 2.76 (t, 2H, J=7.6 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.74 (p, 2H, J=7.6 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.27 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.85 (m, 3H, CH3). 13C-NMR (CDCl3) δ: 165.1 C3; 152.8 C5; 150.5 Cm pyr; 135.4 Cipso pyr; 134.2 Cipso Ar; 134.0 Cp Ar; 129.3 Cm Ar; 128.0 Co Ar; 122.5 Co pyr; 52.1 CH2Ar; 31.7 CH2CH2CH2CH2CH2CH2CH3; 29.3 CH2CH2CH2CH2CH2CH2CH3; 29.2 CH2CH2CH2CH2CH2CH2CH3; 28.4 and 29.0 CH2CH2CH2CH2CH2CH2CH3; 22.6 CH2CH2CH2CH2CH2CH2CH3; 14.1 CH3. MS (ES+) m/z: 369 (100%) [M+H]+.
4-[1-(2,4-Dichlorobenzyl)-5-heptyl-1H-1,2,4-triazol-3-yl]pyridine (
15a
) and 4-[1-(2,4-Dichlorobenzyl)-3-heptyl-1H-1,2,4-triazol-5-yl]pyridine (
15b
). Compounds 15a and 15b were prepared from 5 (200 mg, 0.8 mmol), 2,4-dichlorobenzyl chloride (114 μL, 0.8 mmol), and (Bu)4NBr (12 mg, 0.04 mmol.); reaction time: 2 h. Yield: 118 mg of 15a (36%) as a white solid and 7 mg of 15b (2%) as a yellow oil. 15a: Mp = 104-105°C. 1H-NMR (CDCl3) δ: 8.65 (d, 2H, J=6.1 Hz, Hm pyr); 7.93 (d, 2H, J=6.1 Hz, Ho pyr); 7.42 (d, 1H, J=2.2 Hz, Hm′ Ar); 7.19 (dd, 1H, J=8.4 Hz and 2.2 Hz, Hm Ar); 6.58 (d, 1H, J=8.4 Hz, Ho Ar); 5.39 (s, 2H, CH2Ar); 2.72 (t, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.70 (p, 2H, J=7.7 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.23 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.84 (bt, 3H, J=6.5 Hz, CH3). 13C-NMR (CDCl3) δ: 159.3 C3; 158.1 C5; 150.3 Cm pyr; 138.3 Cipso pyr; 134.8 Cipso Ar; 133.0 Cp Ar; 131.7 Co′ Ar; 129.5 Co and Cm′ Ar; 127.8 Cm Ar; 120.4 Co pyr; 48.9 (CH2Ar); 31.6 CH2CH2CH2CH2CH2CH2CH3; 29.1 CH2CH2CH2CH2CH2CH2CH3; 28.8 CH2CH2CH2CH2CH2CH2CH3; 27.7 CH2CH2CH2CH2CH2CH2CH3; 26.0 CH2CH2CH2CH2CH2CH2CH3; 22.5 CH2CH2CH2CH2CH2CH2CH3; 14.0 CH3. MS (ES+) m/z: 403 (100%) [M+H]+. Anal (C21H24Cl2N4) % calculated (% found) C: 62.53 (62.28); H: 6.00 (6.30); N: 13.89 (14.04). 15b: 1H-NMR (CDCl3) δ: 8.70 (d, 2H, J=6.1 Hz, Hm pyr); 7.43 (d, 1H, J=2.2 Hz, Hm′ Ar); 7.41 (d, 2H, J=6.1 Hz, Ho pyr); 7.19 (dd, 1H, J=8.1 Hz and 2.2 Hz, Hm Ar); 6.85 (d, 1H, J=8.1 Hz, Ho Ar); 5.44 (s, 2H, CH2Ar); 2.77 (t, 2H, J=7.6 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.73 (p, 2H, J=7.6 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.25 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.85 (ta, 3H, J=6.7 Hz, CH3). 13C-NMR (CDCl3) δ: 165.5 C3; 152.8 C5; 150.6 Cm pyr; 138.3 Cipso pyr; 135.1 Cipso Ar; 132.8 Cp Ar; 131.9 (Co′ Ar); 129.7 Co Ar; 128.8 Cm′ Ar; 127.8 Cm Ar; 122.3 Co pyr; 50.1 CH2Ar; 31.6 CH2CH2CH2CH2CH2CH2CH3; 29.3 CH2CH2CH2CH2CH2CH2CH3; 29.0 CH2CH2CH2CH2CH2CH2CH3; 28.3 CH2CH2CH2CH2CH2CH2CH3; 22.6 CH2CH2CH2CH2CH2CH2CH3; 14.1 CH3. MS (ES+) m/z: 403 (100%) [M+H]+. HPLC: Acetonitrile/H2O 90 : 10, tR=30.3 min (90% purity).
2.1.5. General Procedure for the Synthesis of 16–18
To a solution of the corresponding triazole (1 equiv) in dry CH2Cl2 (4–10 mL), excess of MeI was added. The reaction mixture was stirred at room temperature for the time indicated. Afterwards, solvent was removed in vacuo and the residue was purified by chromatography or recrystallization from Et2O/CH2Cl2.
4-(1-Benzyl-5-heptyl-1H-1,2,4-triazol-3-yl)-1-methylpyridinium Iodide (
16
). Compound 16 was prepared from 13a (15 mg, 0.05 mmol) and MeI (4 μL, 0.07 mmol); reaction time: 16 h. Purification: flash chromatography [CH2Cl2/MeOH (99 : 1) → CH2Cl2/MeOH (9 : 1)]. Yield: 14 mg of 16 (66%) as a yellow gummy solid. 1H-NMR (CDCl3) δ: 9.18 (d, 2H, J=6.7 Hz, Hm pyr); 8.54 (d, 2H, J=6.7 Hz, Ho pyr); 7.35 (m, 3H, Ph); 7.19 (m, 2H, Ph); 5.36 (s, 2H, CH2Ar); 4.68 (s, 3H, NMe); 2.71 (t, 2H, J=7.6 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.67 (p, 2H, J=7.6 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.23 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.85 (bt, 3H, J=7.0 Hz, CH3). 13C-NMR (CDCl3) δ: 159.0 C3; 155.3 C5; 146.7 Cipso pyr; 145.6 Cm pyr; 134.3 Cipso Ph; 129.1 Cm Ph; 128.6 Cp Ph; 127.3 Co Ph; 123.7 Co pyr; 53.0 CH2Ar; 49.1 NMe; 31.5 CH2CH2CH2CH2CH2CH2CH3; 29.0 CH2CH2CH2CH2CH2CH2CH3; 28.8 CH2CH2CH2CH2CH2CH2CH3; 27.2 CH2CH2CH2CH2CH2CH2CH3; 26.1 CH2CH2CH2CH2CH2CH2CH3; 22.5 CH2CH2CH2CH2CH2CH2CH3; 14.0 CH3. MS (ES+) m/z: 349 (100%), [M]+. Anal (C22H29IN4) % calculated (% found) C: 55.47 (55.42); H: 6.14 (6.30); N: 11.76 (11.57).
4-[1-(4-Chlorobenzyl)-5-heptyl-1H-1,2,4-triazol-3-yl]-1-methylpyridinium Iodide (
17
). Compound 17 was prepared from 14a (70 mg, 0.2 mmol) and MeI (140 μL 2.3 mmol); reaction time: 8 days. Purification: flash chromatography [CH2Cl2/MeOH (95 : 5)]. Yield: 87 mg of 17 (90%) as a yellow gummy solid. 1H-NMR (CDCl3) δ: 9.21 (d, 2H, J=6.8 Hz, Hm pyr); 8.54 (d, 2H, J=6.8 Hz, Ho pyr); 7.33 (d, 2H, J=8.5 Hz, Hm Ar); 7.15 (d, 2H, J=8.5 Hz, Ho Ar); 5.33 (s, 2H, CH2Ar); 4.68 (s, 3H, NMe); 2.71 (t, 2H, J=7.5 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.69 (p, 2H, J=7.5 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.23 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.85 (bt, 3H, J=6.5 Hz, CH3). 13C-NMR (CDCl3) δ: 158.9 C3; 155.4 C5; 146.3 Cipso pyr; 145.7 Cm pyr; 134.4 Cipso Ar; 132.7 Cp Ar; 129.1 Cm Ar; 128.7 Co Ar; 123.5 Co pyr; 52.1 CH2Ar; 48.9 NMe; 31.4 CH2CH2CH2CH2CH2CH2CH3; 28.9 CH2CH2CH2CH2CH2CH2CH3; 28.6 CH2CH2CH2CH2CH2CH2CH3; 27.0 CH2CH2CH2CH2CH2CH2CH3; 25.9 CH2CH2CH2CH2CH2CH2CH3; 22.4 CH2CH2CH2CH2CH2CH2CH3; 13.9 CH3. MS (ES+) m/z: 383 (100%) [M]+. Anal (C22H28ClIN4) % calculated (% found) C: 51.73 (51.58); H: 5.52 (5.41); N: 10.97 (10.72).
4-[1-(2,4-Dichlorobenzyl)-5-heptyl-1H-1,2,4-triazol-3-yl]-1-methylpyridinium Iodide (
18
). Compound 18 was prepared from 15a (50 mg, 0.1 mmol) and MeI (277 μL 4.45 mmol); reaction time: 8 days. Purification: recrystallization from Et2O/CH2Cl2. Yield: 43 mg of 18 (64%) as a yellow solid. Mp = 136–138°C. 1H-NMR (CDCl3) δ: 9.22 (d, 2H, J=6.7 Hz, Hm pyr); 8.53 (d, 2H, J=6.7 Hz, Ho pyr); 7.44 (d, 1H, J=1.9 Hz, Hm′ Ar); 7.25 (dd, 1H, J=8.4 Hz and 1.9 Hz, Hm Ar); 7.00 (d, 1H, J=8.4 Hz, Ho Ar); 5.42 (s, 2H, CH2Ar); 4.69 (s, 3H, NMe); 2.76 (t, 2H, J=7.6 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.72 (p, 2H, J=7.6 Hz, CH2CH2CH2CH2CH2CH2CH3); 1.26 (m, 8H, CH2CH2CH2CH2CH2CH2CH3); 0.86 (bt, 3H, J=7.3 Hz, CH3). 13C-NMR (CDCl3) δ: 159.4 C3; 155.8 C5; 146.5 Cipso pyr; 145.7 Cm pyr; 135.4 Cipso Ar; 133.4 Cp Ar; 130.6 Co′ Ar; 130.3 Co Ar; 129.7 Cm′ Ar; 128,0 (Cm BnAr); 123,7 (Co CAr); 49,5 (CH2Ar); 49,2 (NMe); 31.5 CH2CH2CH2CH2CH2CH2CH3; 29.0 CH2CH2CH2CH2CH2CH2CH3; 28.8 CH2CH2CH2CH2CH2CH2CH3; 27.3 CH2CH2CH2CH2CH2CH2CH3; 25.9 CH2CH2CH2CH2CH2CH2CH3; 22.5 CH2CH2CH2CH2CH2CH2CH3; 14.0 CH3. MS (ES+) m/z: 417 (100%) [M]+. Anal (C22H27Cl2IN4) % calculated (% found) C: 48.46 (48.71); H: 4.99 (5.20); N: 10.27 (10.06).