Melting points were determined with a melting-temperature apparatus (SMP10) in open capillaries and are uncorrected. The progress of all reactions was monitored by TLC pre-coated plates with silica gel 60 F254 of a thickness of 0.25 mm (Merck). Detection was achieved by UV light absorption and/or treatment with a solution of 10 % H2SO4 in aqueous methanol with subsequent heating. For flash chromatography commercial silica gel 60 was used with particle sizes 0.040–0.063 mm (230–400 mesh ASTM). Solvents were purified by simple distillation. Nuclear magnetic resonance (1H NMR, 13C NMR and 2D NMR) spectra were determined in CDCl3 and DMSO-d
6 and were recorded on Bruker AC 300–600 spectrometers, with tetramethylsilane as internal standard. Chemical shifts are reported in δ (ppm) and coupling constants are given in Hz. The assignment of exchangeable OH and NH was confirmed by addition of D2O. EI mass spectra were recorded with a Finnigan MAT312 and a Jeol JMS.600H mass spectrometer. HREI mass spectral data were recorded with a Finnigan MAT 95XP instrument. FABMS was recorded with the Jeol JMS HX110 mass spectrometer. ESI were recorded with an Applied Biosystems QStar XL instrument. The crystallographic measurements were performed on an Agilent (formerly Oxford diffraction) SuperNova Atlas CCD diffractometer. The structures were solved by direct methods (SIR97) and refined by full-matrix anisotropic least squares (SHELXL-2014/7).
Synthesis of S-alkylated derivatives (2, 3)
To a mixture of traizole 1 (1.0 mmol) in acetone (10 ml) and appropriate base (4.0 mmol), 2,3-bis(bromomethyl)quinoxaline (0.5 mmol) or benzyl bromide (1.1 mmol) were added and stirring was continued overnight. The reaction mixture was filtered. The solvent was evaporated in vacuo and cold water was added. The solids formed were collected by filtration, dried, and separated by column chromatography (ethyl acetate/hexane 1:1) 2 or crystallization from ethanol 3.
2,3-Bis((5-(1H-indol-2-yl)-2H-1,2,4-triazol-3-ylsulfanyl)methyl)quinoxaline (2)
White solid, Yield 71 %; m.p. 203decomp. °C; R
f
0.35 (ethyl acetate/n-hexane 6:4); 1H NMR (DMSO-d
6, 300 MHz) δ 5.04 (s, 4 H, 2 CH2), 6.95 (s, 2 H, 2 H-3Indol), 7.00 (dd, 2 H, J
4,5 ≈ J
5,6 7.5, Hz, 2 H-5Indol), 7.13 (dd, 2 H, J
5,6 7.5, J
6,7 8.1 Hz, 2 H-6Indol), 7.41 (d, 2 H, J
6,7 8.1 Hz, 2 H-7Indol), 7.56 (d, 2 H, J
4,5 7.5 Hz, 2 H-4Indol), 7.78–7.82 (m, 2 H, 2 CHquinoxalin), 7.97–8.01 (m, 2 H, 2 CHquinoxalin), 11.70 (br. s, 2 H, NHIndol), 14.43 (br. s, 2 H, NHTriazol); 13C NMR (DMSO-d
6, 100 MHz) δ 36.16 (2 CH2), 101.70 (2 C-3Indol), 111.99 (2 C-7Indol), 119.72 (2 C-5Indol), 120.74 (2 C-4Indol), 122.70 (2 C-2Indol, 2 C-6Indol), 127.2 (2 C-3aIndol), 128.30 (2 CHquinoxalin), 130.27 (2 CHquinoxalin), 136.91 (2 C-7aIndol, 2 C-5Triazol, 2 C-3Triazol), 140.25 (2 Cquinoxalin), 151.39 (2 Cquinoxalin); HRMS (FAB +ve) calcd for C30H23N10S2 M + H)+: 587.15486. Found: 587.1508.
3-Benzylsulfanyl-5-(1H-indol-2-yl)-2H-1,2,4-triazole (3)
Yield 97 %; m.p. 219–220 °C; R
f
0.49 (ethyl acetate/n-hexane 4:6); 1H NMR (DMSO-d
6, 300 MHz) δ 4.45 (s, 2 H, CH
2Ph), 6.99–7.05 (m, 2H, H-3Indol, H-5Indol), 7.15 (dd, 1H, J
5,6 7.3, J
6,7 7.7 Hz, H-6Indol), 7.21–7.45 (m, 6 H, H-7Indol, 5HPh), 7.59 (d, 1 H, J
4,5 7.9 Hz, H-4Indol), 11.77 (br. s, 1H, NHIndol), 14.37 (br. s, H, NHTriazol); 13C NMR (DMSO-d
6, 75 MHz) δ 35.66 (CH2Ph), 100.99 (C-3Indol), 111.94 (C-7Indol), 119.67 (C-5Indol), 120.66, 122.60, 127.27, 127.67 (C-2Indol, C-4Indol, C-6Indol, CHPh, C-3aIndol), 128.42 (2 CHPh), 128.83 (2 CHPh), 136.84, 137.64 (C-7aIndol, C-3Triazol, C-5Triazol, CPh); HRMS (EI) calcd for C17H14N4S (M+.): 306.0939. Found: 306.0886.
Alkylation of S-benzylated triazole 3
To a mixture of traizole 3 (1.0 mmol) in acetone (10 ml) and K2CO3 (2.1 mmol), appropriate dihaloalkane compound (0.5 mmol) was added and stirring was continued overnight. The reaction mixture was filtered and dried. Then, the products were separated by column chromatography (ethyl acetate/hexane 0.5:9.5).
Bis(3-benzylsulfanyl-5-(1H-indol-2-yl)-1H-1,2,4-triazol-1-yl)methane (4)
Colorless needle crystals; Yield 15 %; m.p. 218–219 °C; R
f
0.73 (ethyl acetate/n-hexane 4:6); 1H NMR (DMSO-d
6, 300 MHz) δ 4.30 (s, 4H, 2 SCH2Ph), 6.92 (s, 2H, CH2), 7.08 (dd, 2H, J
4,5 = 7.9, J
5,6 = 7.3 Hz, H-5Indol), 7.16–7.30 (m, 12H, H-6Indol, 10 HPh), 7.48–7.51 (m, 4H, H-3Indol, H-7Indol), 7.62–7.65 (d, 1H, J
4,5 = 7.9 Hz, H-4Indol), 12.01 (br. s, 2H, NHIndol); 13C NMR (DMSO-d
6, 75 MHz) δ 34.8 (2 SCH2Ph), 60.0 (CH2), 104.8 (C-3Indol), 112.2 (C-7Indol), 120.1 (C-5Indol), 121.3 (C-4Indol), 123.1 (C-2Indol), 123.7 (C-6Indol), 127.2 (CHPh), 127.6 (C-3aIndol, CPh), 128.3 (2 CHPh), 128.9 (2 CHPh), 137.1, 137.7 (C-7aIndol, CPh), 150.6 (C-5Triazol), 160.04 (C-3Triazol); HRMS (ESI) calcd for C35H29N8S2 (M + H)+: 625.1951. Found: 625.1900.
1,2-Bis(3-benzylsulfanyl-5-(1H-indol-2-yl)-1H-1,2,4-triazol-1-yl)methane (5)
Colorless crystals; Yield 50 %; m.p. 214-215 °C; R
f
0.71 (ethyl acetate/n-hexane 4:6); 1H NMR (DMSO-d
6, 300 MHz) δ 4.31 (s, 2H, CH2), 4.60 (s, 2H, CH2), 6.64 (s, 2H, CH2), 6.98–7.03 (m, 2H, H-3Indol, H-5Indol), 7.09–7.19 (m, 5H, H-6Indol, H-5́Indol, 3HPh), 7.23–7.33 (m, 6H, H-6́Indol, 5HPh), 7.40–7.51 (m, 5H, H-3́Indol, H-7Indol, H-7́Indol, 2HPh), 7.57 (d, 1H, J
4,5 = 7.8 Hz, H-4Indol), 7.73 (d, 1H, J
4́,5́ = 7.9 Hz, H-4́Indol), 11.65 (br. s, 1H, NHIndol), 11.95 (br. s, 1H, NH́Indol); 13C NMR (DMSO-d
6, 75 MHz) δ 34.8 (SCH2Ph), 37.4 (SCH2Ph), 59.2 (CH2), 101.5 (C-3Indol), 104.9 (C-3́Indol), 111.9, 112.1 (C-7Indol, C-7́Indol), 119.6 (C-5Indol), 120.1, 120.6, 121.4, 122.5, 123.1 (C-4Indol, C-4́Indol, C-5́Indol, C-6Indol, C-6́Indol), (C-2Indol,), 127.1, 127.6 (CPh, ĆPh), 127.7, 128.2, 128.3, 128.5, 128.9, 130 (C-3aIndol, 2 CHPh, C-3áIndol, 2 CHPh, 2 CHPh́, 2 CHPh́), 136.9, 137.0, 137.1, 137.7 (C-7aIndol, C-7áIndol, CPh, CPh́), 150.3, 154.3, 156.7, 159.96 (C-3Triazol, C-3ʹTriazol, C-5Triazol, C-5́Triazol); HRMS (EI) calcd for C35H28N8S2 (M+.): 624.1878. Found: 624.1867.
Bis(3-benzylsulfanyl-5-(1H-indol-2-yl)-1H-1,2,4-triazol-2-yl)methane (6)
Colorless sunny crystals; Yield 10 %; m.p. 249–250 °C; R
f
0.65 (ethyl acetate/n-hexane 4:6); 1H NMR (DMSO-d
6, 300 MHz) δ 4.57 (s, 4H, 2 SCH2Ph), 6.32 (s, 2H, CH2), 6.94 (s, 2H, 2H-3Indol), 7.18 (dd, 2H, J
4,5 = 7.8, J
5,6 = 7.5 Hz, 2H-5Indol), 7.12 (dd, 2H, J
5,6 = 7.5, J
6,7 > 8.0 Hz, 2H-6Indol), 7.23–7.32 (m, 6H, 6Hph), 7.41–7.46 (m, 6H, 2H-7Indol, 4HPh), 7.56 (d, 1H, J
4,5 = 7.8 Hz, 2H-4Indol), 11.61 (br. s, 2H, NHIndol); 13C NMR (DMSO-d
6, 100 MHz) δ 37.5 (2 SCH2Ph), 58.7 (CH2), 101.4 (2C-3Indol), 112.0 (2C-7Indol), 119.6 (2C-5Indol), 120.6 (2C-2Indol, 2C-4Indol), 122.5 (C-6Indol), 127.65 (2CHPh), 127.7, 128.3 (2C-3aIndol, 2CPh), 128.5 (4 CHPh), 129.08 (4 CHPh), 136.75, 137.0 (2C-7aIndol, 2CPh), 153.6 (2C-3Triazol), 156.7 (2C-5Triazol); HRMS (ESI) calcd for C35H29N8S2 (M + H)+: 625.1951. Found: 625.1900.
3-Benzylsulfanyl-2-chloroethyl-5-(1H-indol-2-yl)-1H-1,2,4-triazole (7)
Colorless crystals, Yield 55 %; m.p. 126–127 °C; R
f
0.80 (ethyl acetate/n-hexane 6:4); 1H NMR (CDCL3, 400 MHz) δ 3.74 (t, 2 H, J 6.4 Hz, CH2Cl), 4.25 (t, 2 H, J 6.4 Hz, NCH2), 4.44 (s, 2 H, SCH2Ph), 7.10–7.14 (m, 2 H, H-3Indol, H-5Indol), 7.23 (dd, 1 H, J
5,6 6.8, J
6,7 8.4 Hz, H-6Indol), 7.27–7.29 (m, 5 H, Ph), 7.39 (d, 1 H, J
6,7 8.0 Hz, H-7Indol), 7.67 (d, 1 H, J
4,5 8.0 Hz, H-4Indol), 9.06 (br. s, 1H, NHIndol); 13C NMR (CDCl3, 100 MHz) δ 38.95 (SCH2Ph), 41.38 (CH2Cl), 49.81 (NCH2), 101.90 (C-3Indol), 111.18 (C-7Indol), 120.31 (C-5Indol), 121.34 (C-4Indol), 123.21 (C-2Indol, C-6Indol), 127.94 (CHPh), 128.68 (C-3aIndol), 128.80, 128.93 (4 CHPh), 136.36, 136.56 (C-7aIndol, CPh), 152.76 (C-5Triazol), 157.07 (C-2Triazol); LRMS-EI m/z (%): 65 (11.7), 91 (100), 115 (12.6), 142 (80.1), 143 (12.9), 241 (11.8), 242 (30.3), 332 (16.1), 333 (41.4), 368 (80.2), 370 (31.9); HRMS (EI) calcd for C19H17N4SCl (M): 368.0862 (80.2 %). Found: 368.0857, M + 2: 370.0 (31.9).
3-Benzylsulfanyl-2-(3-bromopropyl)-5-(1H-indol-2-yl) -1,2,4-triazole (8)
Colorless crystals, Yield 60 %; m.p. 96–97 °C; R
f
0.66 (ethyl acetate/n-hexane 4:6); 1H NMR (DMSO-d
6, 600 MHz) δ 2.48–2.50 (m, 2H, CH2), 3.74 (t, 2H, J = 5.4 Hz, CH2), 4.42 (t, 2H, J = 6.6 Hz, CH2), 4.81 (s, 2H, CH
2Ph), 7.22 (s, 1H, H-3Indol), 7.30 (dd, 1H, J
4,5 = 7.8, J
5,6 = 7.2 Hz, H-5Indol), 7.42 (dd, 1H, J
5,6 = 7.2, J
6,7 = 8.4 Hz, H-5Indol), 7.54–7.87 (m, 7H, H-4Indol, H-7Indol, 5HPh), 11.91 (s, 1H, NHIndol); 13C NMR (DMSO-d
6, 150 MHz) δ 31.0 (CH2), 31.9 (CH2), 37.4 (CH2Ph), 46.6 (NCH2), 100.6 (C-3Indol), 111.8 (C-7Indol), 119.5 (C-5Indol), 120.5 (C-4Indol), 122.2 (C-6Indol), 127.6, 127.8, 128.5, 128.6, 128.7, 128.9, 129.1, 128.2, 136.8, 137.2 (C-2Indol, C-3aIndol, 5CHPh, C-7aIndol, CPh), 151.4 (C-5Triazol), 156.2 (C-3Triazol); HRMS (ESI) calcd for C20H20BrN4S (M + H)+: 427.0592 Found: 427.0585 (M + H)+, 429 (100 %) for (M + H+2)+.
1H-Indolo[1,2-a]-3-phenylsulfanyl-1,2,4-triazolo[1,5-c]1,4-diazepine (10)
Colorless crystals, Yield 28 %; m.p. 148–149 °C; R
f
0.35 (ethyl acetate/n-hexane 4:6); 1H NMR (DMSO-d
6, 600 MHz) δ 2.43–2.48 (m, 2H, CH2), 4.39 (s, 2H, CH2Ph), 4.45–4.54 (m, 4H, 2 CH2), 7.12 (dd, 1H, J
4,5 = 7.8, J
5,6 = 7.2 Hz, H-5Indol), 7.24–7.32 (m, 5H, H-3Indol, H-6Indol, 3HPh), 7.44 (d, 2H, J = 7.2 Hz, 2HPh), 7.56 (d, 1H, J
6,7 = 8.4 Hz, H-7Indol), 7.64 (d, 1H, J
4,5 = 7.8 Hz, H-4Indol); 13C NMR (DMSO-d
6, 150 MHz) δ 25.2 CH2), 35.0 (CH2Ph), 44.7 (CH2), 51.7 (CH2), 105.7 (C-3Indol), 110.4 (C-7Indol), 120.3 (C-5Indol), 121.2 (C-4Indol), 123.3 (C-6Indol), 126.5, 126.7, 127.2 (C-2Indol, C-3aIndol, CHPh), 128.4 (2 CHPh), 128.9 (2 CHPh), 137.9, 137.6 (C-7aIndol, CPh), 148.6 (C-5Triazol), 158.5 (C-3Triazol); HRMS (EI) calcd for C20H18N4S (M+.): 346.1252. Found: 346.1243.
2,3-Bis((3-benzylsulfanyl-5-(1H-indol-2-yl)-1,2,4-triazol-1-yl)methyl)quinoxaline (11)
White solid, Yield 20 %; m.p. 175–176 °C; R
f
0.41 (ethyl acetate/n-hexane 3:7); 1H NMR (CDCl3, 300 MHz) δ 4.34 (s, 4 H, 2 SCH2Ph), 6.14 (s, 4 H, 2 NCH2 quinoxalin), 7.11–7.39 (m, 16 H, 2 H-3Indol, 2 H-5Indol, 2 H-6Indol, 10 H, 2Ph), 7.57 (d, 2 H, J
6,7 9.0 Hz, 2 H-4Indol), 7.76 (d, 2 H, J
4,5 9.0 Hz, 2 H-7Indol), 7.87–7.91 (m, 2 H, 2 CHquinoxalin), 8.15–8.18 (m, 2 H, 2 CHquinoxalin), 10.56 (s, 2 H, NHIndol); 13C NMR (CDCl3, 100 MHz) δ 36.44 (2 CH2ph), 51.97 (2 CH2 quinoxalin), 105.98 (2 C-3Indol), 111.80 (2 C-7Indol), 120.96 (2 C-5Indol), 122.04 (2 C-4Indol), 122.04(2 C-2Indol), 124.60 (2 C-6Indol), 127.41, 128.38, 128.52, 128.97, 129.01, 131.77, 137.13, 137.24 (2 C-3aIndol, 10 CHph, 2CPh, 4 CHquinoxalin, 2 C-7aIndol), 141.41, 149.05, 150.16, 160.33 (2 Cquinoxalin, 2 C-3Triazol, 2 C-5Triazol); ESI+-MS m/z (rel. abundance %): 119.7 (8), 148.9 (17), 301.0 (14), 360.2 (9), 413.1 (8), 663.4 (6), 767.3 (28) (M + H)+ for C44H35N10S2, 789.2 (45) (M + Na)+, 805.2 (100) (M + K)+.
2,3-Bis((3-benzylsulfanyl-5-(1H-indol-2-yl)-1,2,4-triazol-2-yl)methyl)quinoxaline (12)
White solid, Yield 50 %; m.p. 117–118 °C; R
f
0.65 (ethyl acetate/n-hexane 3:7); 1H NMR (DMSO-d
6, 600 MHz) δ 5.22 (s, 4 H, 2 SCH2-Ph), 5.42 (s, 4 H, 2 NCH2
quinoxalin), 6.90 (s, 2 H, 2 H-3Indol), 6.97 (dd, 2 H, J
4,5 7.8, J
5,6 7.2, Hz, 2 H-5Indol), 7.10 (dd, 2 H, J
5,6 7.2, J
6,7 7.8 Hz, 2 H-6Indol), 7.21–7.26 (m, 10 H, 2Ph), 7.39 (d, 2 H, J
6,7 8.1 Hz, 2 H-4Indol), 7.46 (d, 2 H, J
4,5 7.5 Hz, 2 H-7Indol), 7.82–7.34 (m, 2 H, 2 CHquinoxalin), 7.99–8.01 (m, 2 H, 2 CHquinoxalin), 11.60 (s, 2 H, NHIndol); 13C NMR (DMSO-d
6, 150 MHz) δ 37.9 (2 CH2ph), 52.3 (2 CH2 quinoxalin), 101.5 (2C-3Indol), 112.3 (2C-7Indol), 119.9 (2C-5Indol), 121.0 (2C-4Indol), 122.72 (2C-6Indol), 127.66, 127.72, 127.74, 128.2, 128.4, 128.75, 129.1, 129.4, 129.5, 130.9, 131.9, 136.1, 137.4 (2 C-2Indol, 2 C-3aIndol, 10 CHph, 2CPh, 4 CHquinoxalin, 2 C-7aIndol), 140.7, 151.4, 152.4, 156.8 (2 Cquinoxalin, 2 C-3Triazol, 2 C-5Triazol); ESI+-MS m/z (rel. abundance %): 148.9 (18), 239.1 (7), 276.0 (27), 301.0 (20), 344.0 (12), 413.0 (11), 540.1 (6), 633.5 (8), 767.2 (35) (M + H)+ for C44H35N10S2, 789.2 (87) (M + Na)+, 805.2 (100) (M + K)+.