2. Experimental
General Comments. All reagents were purchased from Acros, Fluka, and Aldrich and used without further purification. All reactions were performed in standard glassware. All reactions were monitored by TLC plates precoated with silica gel Si 60 F254 from Merck and were visualized under UV lamp at λ = 254 nm. Melting points were determined with electrothermal apparatus, Gallenkamp and are uncorrected. IR spectra were recorded on PerkinElmer spectrophotometer by ATR technique. 1H-NMR and 13C-NMR spectra were recorded on Burker 300 MHz/400 MHz instruments and 75 MHz/100 MHz instruments, respectively; the solvent used is specified along with data. Mass spectra were recorded on Jeol mass spectrometer in electron ionization mode. Leco 3200CHNS analyzer was used for elemental analysis. The thiocarbohydrazide (2) and the 4-amino-3-(N-phthalimidomethyl)-1,2,4-triazole-5-thione (3) were synthesized by the previously reported method [26, 27]. All manipulations of microbial activity were performed in laminar flow chamber (LFC) with disposable surgical gloves, all standard biosafety measures were taken, and contaminated materials after experimentation were collected in autoclave bags and autoclaved at 120°C before disposal.
2.1. 4-Amino-3-(N-phthalimidomethyl)-1,2,4-triazole-5-thione (3)
To a clean test tube were added 0.01 mol (2.05 g) of N-phthaloylglycine and 0.01 mol (1.06 g) of thiocarbohydrazide, and the test tube was kept in a preheated oil bath. The molten mixture was kept at 145°C for 25 minutes. On cooling the mixture a solid mass was formed which was triturated with ethanol and filtered. The crude solid was recrystallized in acetonitrile and ethanol (1 : 1). Yield: 69%, white crystals, m.p. 189–192°C, IR (ATR) (v cm−1), 3305.08, 3152.47 (NH), 2982.12 (Ar-H), 2952.46 (CH2), 1767.06 (cyclic amide), 1605 (C=N), 1145 (C=S). 1H NMR (400 MHz, DMSO-d6, δ ppm): 13.98 (b, 1H, NH), 7.86–7.94 (m, 4H, C6H4), 5.63 (s, 2H, NH2), 4.84 (s, 2H, CH2). 13C NMR (100 MHz, DMSO-d6, δ ppm): 167.53 (C=S), 167.24 (C=O), 147.81 (N=C), 135.24 (N=C), (131.91, 123.86 (Ar-C)), 32.99 (CH2). MS-E1 (M/z), Relative intensity: 275.1 (M+1, 100%), 259.1 (65%), 160.1 (80%), 130.1 (30%), 104.0 (45%), 77.1 (30%); C11H9N5O2S: Calculated: C, 47.99; H, 3.30; N, 25.44; S, 11.65. Found: C, 48.10; H, 3.35; N, 25.49; S, 11.85.
2.2. General Procedure for Synthesis of Schiff Bases of 1,2,4-Triazole (3) (4a–4i)
Aromatic aldehyde (15 mmol) was dissolved in 8.0 mL of glacial acetic acid, and 10 mmol of 1,2,4-triazole (3) was added. The reaction mixture was refluxed for 25 minute to one hour in a preheated oil bath. The mixture was cooled, and the solid formed was filtered and washed with cold ethanol. The solid was recrystallized from ethanol and Schiff bases (4a–4i) were obtained in good to excellent yields.
2.3. 4-(Benzylidene)amino-3-(N-phthalimidomethyl)-1,2,4-triazole-5-thione (4a)
Yield 42.8%, Yellow crystals m.p. 198–200°C. IR (ATR, v cm−1): 3283.40, 3156.39 (N–H), 3012.31 (Ar-H), 2996.00 (CH2), 1770.75 (cyclic amide), 1599.79 (C=N), 1243.82 (C–N), 1120.06 (C=S). 1H NMR (300 MHz, DMSO-d6, δ ppm): 14.02 (s, 1H, NH), 9.92 (s, 1H, N=CH), 7.88 (m, 4H, Ph), 7.80 (d, 2H, J = 7.2 Hz, Ph), 7.59 (m, 1H, Ph), 7.50 (m, 2H, Ph), 4.99 (s, 2H, CH2). 13C NMR (75 MHz, DMSO-d6, δ ppm): 167.47 (C=S), 164.39 (C=O), 162.48 (N=CH), 146.52 (C=N), (135.33, 133.23, 132.29, 131.81, 129.52, 129.10, 123.90 (Ar-C)), 33.17 (CH2). MS-E1: (m/z, Relative intensity, %): 363.3 (20%), 260.2 (100%), 242.2 (24%), 228.2 (19%), 203.2 (5%), 183.2 (15.9%), 160.2 (28.8%), 148.2 (18.2%), 130.1 (24%), 104.1 (87%), 89.1 (7.1%), 76.1 (45%). C18H13N5O2S: Calculated: C, 59.49; H, 3.61; N, 19.27; S, 8.82. Found: C, 59.48; H, 3.66; N19.30; S, 8.84.
2.4. 4-(2-Hydroxybenzylidene)amino-3-(N-phthalimidomethyl)-1,2,4-triazole-5-thione (4b)
Yield 73%, white crystals, m.p. 239–241°C. IR (ATR, v cm−1): 3216.31 (O–H), 3055.35 (Ar-H), 2997.4 (CH2), 1774.02 (cyclic amide), 1601.09 (C=N), 1253.65 (C–N), 1119.56 (C=S). 1H NMR (300 MHz, DMSO-d6, δ ppm): 13.95 (s, 1H, NH), 10.40 (s, 1H, OH), 10.13 (s, 1H, N=CH), 7.89 (m, 4H, Ph), 7.70 (dd, 1H, J = 7.9, 1.5 Hz, Ph), 7.40 (dt, 1H, J = 7.8 Hz, 1.5 Hz, Ph), 6.94 (d, 1H, J = 8.1 Hz, Ph), 6.85 (t, 1H, J = 7.8 Hz, Ph), 4.97 (s, 2H, CH2). 13C NMR (75 MHz, DMSO-d6, δ ppm): 167.49 (C=S), 162.37 (C=O), 160.72 (N=CH), 158.90 (C–OH), 146.56 (C=N), (135.31, 134.80, 131.82, 127.28, 123.88, 119.88, 118.62, 117.03 (Ar-C)), 33.19 (CH2). MS-E1 (m/z, Relative intensity, %): 379.3 (M+, 2.7%), 347.4 (2.8%), 330.3 (5.2%), 260.2 (100%), 242.2 (8.6%), 228.2 (27.1%), 160.2 (53.4%), 148.2 (32.5%), 130.1 (57.3%), 119.1 (84.2%), 104.1 (85.3%), 91 (88%). C18H13N5O3S: Calculated: C, 56.98; H, 3.45; N, 18.46; S, 8.45. Found: C, 57.07; H, 3.54; N, 18.57; S, 8.57.
2.5. 3-(N-Phthalimidomethyl)-4-(3-pyridine)amino-1,2,4-triazole-5-thione (4c)
Yield 76.05%, off-white crystals, m.p. 219–221°C. IR (ATR, v cm−1): 3041.73 (Ar-H), 2905.69 (CH2), 1771.38 (cyclic amide), 1591.89 (C=N), 1302.07 (C–N), 1112.59 (C=S). 1H NMR (400 MHz, DMSO-d6, δ ppm): 14.07 (s, 1H, NH), 10.13 (s, 1H, N=CH), 8.95 (d, 1H, J = 1.8 Hz, Ph), 8.75 (dd, 1H, J = 4.8, 1.5 Hz, Ph), 8.22 (d, 1H, J = 8.1 Hz, Ph), 7.88 (m, 4H, Ph), 7.55 (dd, 1H, J = 7.8 Hz, 4.8 Hz, Ph), 5.01 (s, 2H, CH2). 13C NMR (100 MHz, DMSO-d6, δ ppm): 167.0 (C=S), 162.05 (C=O), 160.88 (HC=N), 152.0 (Py-C), 151.0 (Py-C), 149.0 (C=N), (133.7, 132.2, 130.4, 123.9, 123.6, 123.0 (Ar-C)), 33.5 (CH2). MS-E1 (m/z, Relative intensity, %): 364.0 (12.8%), 260.0 (100%), 242.0 (8.1%), 228.0 (4.6%), 183.0 (6.4%), 160.0 (16.9%), 148.0 (11.1%), 130.0 (16.1%), 104.0 (46.7%). C17H12N6O2S: Calculated: C, 56.04; H, 3.32; N, 23.06; S, 8.80. Found: C, 56.16; H, 3.45; N 23.10; S, 8.82.
2.6. 4-(3-Nitrobenzylidine)amino-3-(N-phthalimidomethyl)-1,2,4-triazole-5-thione (4d)
Yield 48%, yellow powder, m.p. 258–260°C. IR (ATR, v cm−1): 3200 (N–H), 3041.73 (Ar-H), 2919 (CH2), 1770.38 (cyclic amide), 1591.89 (C=N), 1302.07 (C–N), 1112.59 (C=S). 1H NMR (400 MHz, DMSO-d6, δ ppm): 14.06 (s, 1H, NH), 10.22 (s, 1H, N=CH), 8.61 (s, 1H, Ph), 8.40 (d, J = 6.8 Hz, 1H, Ph), 8.24 (d, J = 6.5 Hz, 1H, Ph), 7.85 (m, 5H, Ph), 5.01 (s, 2H, CH2). 13C NMR (100 MHz, DMSO-d6, δ ppm): 166.87 (C=S), 162.08 (C=O), 160.84 (N=CH), 148.21 (C=N), (146.09, 134.71, 134.61, 133.58, 131.23, 130.66, 126.65, 123.29, 122.47 (Ar-C)), 32.58 (CH2). MS-E1: m/z, (Relative intensity, %): 407.9 (7.3%), 260.0 (100%), 242 (5.1%), 228.0 (3.5%), 160.0 (13.3%), 148.0 (17.3%), 130.0 (11.0%), 104.0 (26.2%). C18H12N6O4S: Calculated: C, 52.94; H, 2.96; N, 20.58; S, 7.85. Found: C, 53.0; H, 3.10; N, 20.78; S, 8.02.
2.7. 4-(4-Chlorobenzylidine)amino-3-(N-phthalimidomethyl)-1,2,4-triazole-5-thione (4e)
Yield 64.52%, white crystals, m.p. 241–244°C. IR (ATR, v cm−1): 3035.73 (Ar-H), 2956 (CH2), 1772.18 (cyclic amide), 1611.24 (C=N), 1306.75 (C–N), 1118.19 (C=S). 1H NMR (400 MHz, DMSO-d6, δ ppm): 13.99 (s, 1H, NH), 9.99 (s, 1H, N=CH), 7.84 (m, 4H, Ph), 7.81 (d, 2H, J = 8.4 Hz, Ph), 7.57 (d, 2H, J = 8.4 Hz, Ph), 4.97 (s, 2H, CH2). 13C NMR: (100 MHz, DMSO-d6, δ ppm): 166.87 (C=S), 162.05 (C=O), 162.02 (N=CH), 145.99 (C=N), (137.29, 134.74, 131.25, 130.73, 130.14, 129.12, 123.32 (Ar-C)), 32.56 (CH2). MS-E1: (m/z, Relative intensity, %): 397.3 (14.1%), 260.2 (100%), 242.2 (23.1%), 228.2 (14.7%), 183.2 (15.7%), 160.2 (26.6%), 148.1 (15%), 137.1 (77.6%), 104.1 (61.7%), 76.1 (24.8%). C18H12ClN5O2S: Calculated: C, 54.34; H, 3.04; N, 17.60; S, 8.06. Found: C, 54.45; H, 3.16; N, 17.62; S, 8.08.
2.8. 4-(4-Bromobenzylidine)amino-3-(N-phthalimidomethyl)-1,2,4-triazole-5-thione (4f)
Yield 66.13%, white crystals, m.p. 215–217°C. IR (ATR, v cm−1): 3201 (N–H), 3041.73 (Ar-H), 2950.09 (CH2), 1772.54 (cyclic amide), 1620.89 (C=N), 1302.07 (C–N), 1112.07 (C=S), 710 (C–Br). 1H NMR (400 MHz, DMSO-d6, δ ppm) 14.04 (s, 1H, NH), 9.73 (s, 1H, N=CH), 7.79 (m, 4H, Ph), 7.57 (d, 2H, J = 8.4 Hz, Ph), 7.40 (d, 2H, J = 8.4 Hz, Ph), 5.0 (s, 2H, CH2). 13C NMR (100 MHz, DMSO-d6, δ ppm): 167.12 (C=S), 163.68 (C=O), 159.10 (N=CH), 144.94 (C=N), (134.39, 132.24, 131.85, 131.32, 130.08, 127.15, 123.75 (Ar-C)), 32.88 (CH2). MS-E1: (m/z, Relative intensity, %): 442.9 (3.7%), 274.0 (100%), 260.0 (84.1%), 241 (16.2%), 182.9 (28.7%), 148.0 (26.3%), 127.0 (51.1%), 104 (47.4%). C18H12BrN5O2S: Calculated: C, 48.88; H, 2.73; N, 15.8; S, 7.25. Found: C, 49.00; H, 2.88; N, 15.86; S, 7.29.
2.9. 3-(N-Phthalimidomethyl)-4-(4-pyridine)amino-1,2,4-triazole-5-thione (4g)
Yield 48.02%, amorphous solid, m.p. 217–218°C. IR (ATR, v cm−1): 3012.18 (Ar-H), 2896.83 (CH2), 1771.78 (cyclic amide), 1603.02 (C=N), 1268.54 (C–N), 1119.49 (C=S). 1H NMR (300 MHz, DMSO-d6, δ ppm): 13.90 (s, 1H, NH), 9.70 (s, 1H, N=CH), 8.66 (d, 2H, J = 7.9, Ph), 7.98 (d, 2H, J = 7.9 Hz, Ph), 7.80 (m, 4H, Ph), 4.98 (s, 2H, CH2). 13C NMR (75 MHz, DMSO-d6, δ ppm): 168.20 (C=S), 162.70 (C=O), 159.00 (N=CH), 152.20 (Py-C), 149.00 (Py-C), 144.30 (C=N), (132.2, 123.70, 123.10, 120.41 (Ar-C)), 37.23 (CH2). MS-E1 (m/z, Relative intensity, %): 364.0 (10.8%), 260.0 (100%), 242.0 (6.0%), 228.0 (3.1%), 183.0 (5.1%), 160.0 (12.9%), 148.0 (6.8%), 130.0 (8.6%), 104.0 (34.3%). C17H12N6O2S: Calculated: C, 56.04; H, 3.32; N, 23.06; S, 8.80. Found: C, 56.13; H, 3.51; N, 23.10; S, 8.81.
2.10. 4-(4-Methoxybenzylidine)amino-3-(N-phthalimidomethyl)-1,2,4-triazole-5-thione (4h)
Yield 36% white crystals, m.p. 239°C. IR (ATR, v cm−1): 3200 (Ar-H), 2919 (sp3 C–H), 1767 (C=O of anhydride), 1602 (C=N), 1279 (C=S) and 1255 (C–O). 1H NMR (400 MHz, DMSO-d6, δ ppm): 13.91 (s, 1H, NH), 9.69 (s, 1H, N=CH), 7.87 (m, 4H, Ph), 7.7 (d, 2H, J = 8.8 Hz, Ph), 7.33 (2H, J = 8.8 Hz, Ph), 4.94 (s, 2H, CH2), 3.83 (s, 3H, O–CH3). 13C NMR (100 MHz, DMSO-d6,δ ppm): 166.87 (C=S), 163.95 (C=O), 162.84 (N=CH), 161.99 (C–OCH3), 145.78 (C=N), (134.72, 131.26, 130.54, 124.16, 123.30, 114.46 (Ar-C)), 55.47 (O–CH3), 32.61 (CH2), MS-E1: (m/z, Relative intensity, %): 393.4 (26.0%), 361.4 (4.7%), 260.2 (100%), 242.2 (8.7%), 228.3 (17.8%), 186.2 (9.8%), 160.2 (32.2%), 148.2 (10.8%), 133.1 (100%), 104 (66.4%). C19H15N5O3S: Calculated: C, 58.01; H, 3.84; N, 17.80; S, 8.15. Found: C, 58.10; H, 4.01; N, 17.85; S, 8.20.
2.11. 4-(4-Fluorobenzylidine)amino-3-(N-phthalimidomethyl)-1,2,4-triazole-5-thione (4i)
Yield 35%, light yellow crystals, m.p. 231–233°C. IR (ATR, v cm−1): 3200 (Ar-H), 2912 (sp3 C–H), 1770 (C=O of anhydride), 1597 (C=N), 1279 (C=S). 1H NMR (300 MHz, DMSO-d6, δ ppm): 14.00 (s, 1H, NH), 9.93 (s, 1H, N=CH), 7.85 (m, 6H, Ph), 7.33 (t, 2H, J = 8.4 Hz, Ph), 4.98 (s, 2H, CH2). 13C NMR: (75 MHz, DMSO-d6, δ ppm): 166.91 (C=S), 164.62 (d, J1C–F=249 Hz, C–F), 162.43 (C=O), 162.02 (N=CH), 145.99 (C=N), 134.76, 131.27, 131.17 (J 3C–F=15 Hz), 128.46, 123.35, 116.21 (J 2C–F=21.7 Hz), (Ar-C), 32.62 (CH2). MS-E1 (m/z, Relative intensity, %): 381.0 (22.4%), 260.0 (100%), 242.0 (10.1%), 228.0 (4.5%), 183.0 (7.7%), 160.0 (18.4%), 148.0 (9.1%), 132.0 (9.3%), 104.0 (36.6%). C18H12FN5O2S: Calculated: C, 56.69; H, 3.17; N, 18.36; S, 8.41. Found: C, 56.74; H, 3.37; N, 18.39; S, 8.44.
2.12. General Procedure for the Synthesis of Mannich Bases (5a–5h)
The corresponding Schiff bases (4a–4h) (10 mmol) were dissolved in acetonitrile: dioxane (2 : 1) at RT. Then, a solution of formaldehyde (37%, 0.5 mL) and morpholine (10 mmol) in ethanol was added dropwise with vigorous stirring. The reaction mixture was stirred at RT for 2 hours and left over night. The solid product was filtered and washed with ethanol and recrystallized from acetonitrile: dioxane (2 : 1) to yield title compound.
2.13. 4-(Benzylideneamino)-1-(morpholinomethyl)-3-(N-phthalimidomethyl)-1,4-dihydro-5H-1,2,4-triazole-5-thione (5a)
Yield 72%, m.p. 208–210°C IR (ATR, v cm−1) 2958 (CH2, asym), 2855 (CH2, sym), 1771 (cyclic amide), 1591 (C=N), 1112 (C=S). 1H NMR (300 MHz, CDCl3, δ ppm): 10.50 (s, 1H, N=CH), 7.91 (dd, 2H, J = 5.7 Hz, J = 3.0 Hz, Ph), 7.80 (m, 2H, Ph), 7.77 (dd, 2H, J = 5.7 Hz, J = 3.0 Hz, Ph), 7.44–7.57 (m, 3H, Ph), 5.10 (s, 4H, 2 × CH2, N–CH2–N, N–CH2–C), 3.69 (b, 4H, morpholine), 2.79 (b, 4H, CH2, morpholine). 13C NMR (75 MHz, DMSO-d6, δ ppm): 167.20 (C=S), 163.70 (C=O), 161.06 (N=CH), 145.05 (C=N), (134.40, 132.52, 132.28, 131.87, 128.93, 128.88, 123.73 (Ar-C)), 69.08 (N–CH2–N), (66.85, 50.68 (CH2, morpholine)), 32.96 (CH2). MS-E1: (m/z, Relative intensity, %): 462.1 (M+1, 20.6%), 363.0 (10.5%), 260.0 (76.6%), 242.0 (4.6%), 228.0 (5.7%), 185 (4.9%), 160.0 (27.5%), 100.1 (100%). C23H22N6O3S: Calculated: C, 59.73; H, 4.79; N, 18.17; S, 6.93. Found: C, 59.82; H, 4.85; N, 18.20; S, 6.99.
2.14. 4-((2-Hydroxybenzylidene)amino)-1-(morpholinomethyl)-3-(N-phthalimidomethyl)-1,4-dihydro-5H-1,2,4-triazole-5-thione (5b)
Yield 74%, m.p. 214–216°C. IR (ATR, ν cm−1): 2942 (CH2, asym), 2849 (CH2, sym), 1774 (cyclic amide), 1618 (C=N), 1111 (C=S). 1H NMR (300 MHz, DMSO-d6, δ ppm) 10.43 (s, 1H, N=CH), 10.00 (s, 1H, OH), 7.88 (m, 4H, Ph), 7.66 (dd, 1H, J = 8.1 Hz, 1.5 Hz, Ph), 7.40 (t, 1H, J = 7.6 Hz, Ph), 6.94 (d, 1H, J = 8.1 Hz, Ph), 6.83 (t, 1H, J = 7.5 Hz, Ph), 5.03 (s, 2H, N–CH2–N), 5.02 (s, 2H, N–CH2–C), 3.53 (b, 4H, CH2, morpholine), 2.64 (b, 4H, CH2, morpholine). 13C NMR (75 MHz, DMSO-d6, δ ppm): 167.48 (C=S), 163.17 (C=O), 161.99 (N=CH), 159.00 (C–OH), 145.35 (C=N), (135.30, 134.98, 131.82, 127.24, 123.90, 119.86, 118.41, 117.05 (Ar-C)), 69.00 (N–CH2–N), (66.51, 50.63 (CH2, morpholine)), 32.27 (CH2). MS-E1 (m/z, Relative intensity, %): 478 (M+, 3%), 359 (5%), 260 (31.8%), 185 (3.8%), 160 (12%), 119 (18.1%), 110.1 (100%). C23H22N6O4S: Calculated: C, 57.73; H, 4.63; N, 17.56; S, 6.70. Found: C, 57.8; H, 4.73; N, 17.57; S, 6.79.
2.15. 1-(Morpholinomethyl)-4-((pyridin-3-ylmethylene)amino)-3-(N-phthalimidomethyl)-1,4-dihydro-5H-1,2,4-triazole-5-thione (5c)
Yield 69% m.p. 188–190°C IR (ATR, ν cm−1): 2953 (CH2, asym), 2848 (CH2, sym), 1772 cyclic amide, 1591 (C=N), 1115 (C=S). 1H NMR (300 MHz, CDCl3, δ ppm): 10.13 (s, 1H, N=CH), 8.94 (s, 1H, Ph), 8.73 (dd, 1H, J = 6.2 Hz, 1.5 Hz, Ph), 7.93–7.83 (m, 5H, Ph) 5.07 (s, 2H, N–CH2–N), 5.03 (s, 2H, N–CH2–C), 3.64 (b, 4H, CH2, morpholine), 2.71 (b, 4H, CH2, morpholine), 13C NMR (300 MHz, CDCl3, δ ppm): 167.13 (C=S), 163.75 (C=O), 157.17 (N=CH), 152.98 (Py-C), 150.62 (Py-C), 145.00 (C=N), (134.82, 134.45, 131.86, 128.57, 123.86, 123.73 (Ar-C)), 69.17 (N–CH2–N), (66.87, 50.73 (CH2, morpholine)), 32.85 (CH2). MS-E1 (m/z, Relative intensity, %): 463 (M+1, 7.5%), 363.9 (5.0%), 260.0 (40.0%), 228.0 (5.3%), 160.0 (14.0%), 100.1 (100%). C22H21N7O3S: Calculated: C, 57.01; H, 4.57; N, 21.15; S, 6.92. Found: C, 57.10; H, 4.68; N, 21.20; S, 7.02.
2.16. 1-(Morpholinomethyl)-4-((3-nitrobenzylidene)amino)-3-(N-phthalimidomethyl)-1,4-dihydro-5H-1,2,4-triazole-5-thione (5d)
Yield 80% m.p. 193–195°C (decomposed), IR (ATR, ν cm−1): 2940 (CH2, asym), 2840 (CH2, sym), 1774 (amide), 1610 (C=N), 1115 (C=S). 1H NMR (300 MHz, DMSO-d6, δ ppm): 10.01 (s, 1H, N=CH), 8.62 (t, 1H, J = 1.5 Hz, 1.8 = Hz, Ph), 8.42 (ddd, 1H, J = 8.1, 2.1 and 0.6 Hz, Ph), 8.23 (d, 1H, J = 7.8 Hz, Ph), 7.78–7.92 (m, 4H, Ph) 7.79 (d, 1H, J = 8.2 Hz, Ph), 5.07 (2H, N–CH2–N), 5.06 (s, 2H, N–CH2–C), 3.54 (b, 4H, CH2, morpholine), 2.66 (b, 4H, CH2, morpholine). 13C NMR (75 MHz, DMSO-d6, δ ppm): 167.46 (C=S), 163.20 (C=O), 162.93 (N=CH), 148.71 (C=N), (145.42, 135.31, 133.91, 131.76, 131.25, 127.43, 123.91, 123.13 (Ar-C)), 69.12 (N–CH2–N), (66.51, 50.62 (CH2, morpholine)), 33.20 (CH2). MS-E1: (m/z, Relative intensity, %): 507. (M+, 1.9%), 408.0 (2.5%), 260.0 (21.6%), 185.0 (2.7%), 160.0 (12.2%), 130.0 (6.1%), 100.1 (100%). C23H21N7O5S: Calculated: C, 54.43; H, 4.17; N, 19.32; S, 6.32. Found: C, 54.53; H, 4.28; N, 19.35; S, 6.33.
2.17. 4-((4-Chlorobenzylidene)amino)-1-(morpholinomethyl)-3-(N-phthalimidomethyl)-1,4-dihydro-5H-1,2,4-triazole-5-thione (5e)
Yield 79% m.p. 178–180°C IR (ATR, ν cm−1): 2958 (CH2, asym), 2855 (CH2, sym), 1771 (cyclic amide), 1593 (C=N), 1112 (C=S). 1H NMR (300 MHz, DMSO-d6, δ ppm): 9.85 (s, 1H, N=CH) 7.88 (m, 4H, Ph), 7.80 (d, 2H, J = 8.7 Hz, Ph), 7.57 (d, 2H, J = 8.4 Hz, Ph), 5.02 (s, 4H, 2 × CH2, N–CH2–N, N–CH2–C), 3.52 (b, 4H, CH2, morpholine), 2.63 (b, 4H, CH2, morpholine). 13C NMR (300 MHz, DMSO-d6, δ ppm): 166.95 (C=S), 163.62 (C=O), 162.73 (N=CH), 144.84 (C=N), (137.53, 134.84, 131.30, 130.60, 130.21, 129.21, 123.43 (Ar-C)), 68.60 (N–CH2–N), (66.01, 50.14 (CH2, morpholine)), 32.69 (CH2). MS-E1: (m/z Relative intensity, %): (496.0, M+, 5.7%), 396.9 (5.1%), 260.0 (56.5%), 242.0 (2.7%), 228.0 (3.5%), 185.0 (4.1%), 160.0 (20.8%), 137.0 (29.0%), 100.1 (100%). C23H21ClN6O3S: Calculated: C, 55.59; H, 4.26; N, 16.91; S, 6.45. Found: C, 55.74; H, 4.37; N, 16.99; S, 6.47.
2.18. 1-(Morpholinomethyl)-4-((4-bromobenzylidene)amino)-3-(N-phthalimidomethyl)-1,4-dihydro-5H-1,2,4-triazole-5-thione (5f)
Yield 39% m.p. 189−191°C IR (ATR, ν cm−1): 2958 (CH2, asym), 2854 (CH2, sym), 1772, 1719 (cyclic amide), 1607 (C=N), 1112 (C=S). 1H NMR (300 MHz, CDCl3, δ ppm): 10.56 (s, 1H, N=CH), 7.86 (dd, 2H, J = 5.4 Hz, 3.0 Hz, Ph), 7.74 (dd, 2H, J = 5.4 Hz, 3.0 Hz, Ph), 7.66 (d, 2H, J = 8.4 Hz, Ph), 7.56 (d, 2H, J = 8.4 Hz, Ph), 5.05 (s, 2H, N–CH2–N), 5.04 (s, 2H, N–CH2–C), 3.63 (b, 4H, CH2, morpholine), 2.73 (b, 4H, CH2, morpholine), 13C NMR (75 MHz, CDCl3, δ ppm): 167.12 (C=S), 163.68 (C=O), 159.10 (N=CH), 144.94 (C=N), (134.39, 132.24, 131.85, 131.85, 131.32, 130.08, 127.15, 123.75, 123.68 (Ar-C)), 69.12 (N−CH2−N), (66.84, 50.70 (CH2, morpholine)), 32.88 (CH2). MS-E1 (m/z, Relative intensity, %): 540 (M+, 3.1%), 441 (3.1%), 260.0 (84.4%), 242.0 (3.7%), 182.9 (22.6%), 160.0 (26.7%), 100.1 (100%). C23H21BrN6O3S: Calculated: C, 51.02; H, 3.91; N, 15.52; S, 5.92. Found: C, 51.00; H, 3.99; N, 15.59; S, 6.02.
2.19. 1-(Morpholinomethyl)-4-((pyridin-4-ylmethylene)amino)-3-(N-phthalimidomethyl)-1,4-dihydro-5H-1,2,4-triazole-5-thione (5g)
Yield 69% m.p. 201–203°C IR (ATR, ν cm−1): 2953 (CH2, asym), 2848 (CH2, sym), 1770 (cyclic amide), 1602 (C=N), 1112 (C=S). 1H NMR (300 MHz, CDCl3, δ ppm): 10.10 (s, 1H, N=CH), 8.65 (d, 2H, J = 7.8 Hz, Ph), 7.97 (d, 2H, J = 7.8 Hz, Ph), 7.80 (m, 4H, Ph), 5.07 (s, 2H, N–CH2–N), 5.03 (s, 2H, N–CH2–C), 3.64 (b, 4H, CH2, morpholine), 2.71 (b, 4H, CH2, morpholine). 13C NMR (300 MHz, CDCl3, δ ppm): 167.23 (C=S), 163.72 (C=O), 157.17 (N=CH), 152.97 (Py-C), 149.02 (Py-C), 145.40 (C=N), (133.82, 134.54, 131.80, 128.77, 122.96, 123.73 (Ar-C)), 70.02 (N–CH2–N), (66.89, 50.77 (CH2, morpholine)), 32.65 (CH2). MS-E1 (m/z, Relative intensity, %): 463 (M+1), 363.9 (5.8%), 260.0 (72.4%), 228.0 (2.8%), 160.0 (32.2%), 104 (26.8%), 100.1 (100%). C22H21N7O3S: Calculated: C, 57.01; H, 4.57; N, 21.15; S, 6.92. Found: C, 57.09; H, 4.63; N, 21.26; S, 7.03.
2.20. 4-((4-Methoxybenzylidene)amino)-1-(morpholinomethyl)-3-(N-phthalimidomethyl)-1,4-dihydro-5H-1,2,4-triazole-5-thione (5h)
Yield 82% m.p. 218–220°C IR (ATR, ν cm−1): 2939 (CH2, asym), 2840 (CH2, sym), 1770 (amide), 1598 (C=N), 1171 (C=S). 1H NMR (300 MHz, CDCl3, δ ppm): 10.21 (s, 1H, N=CH), 7.86 (dd, 2H, 5.4 Hz and 3.3 Hz, Ph), 7.72–7.74 (m, 4H, Ph), 6.93 (d, 2H, J = 8.4 Hz, Ph), 5.04 (s, 4H, 2 × CH2, N–CH2–N, N–CH2–C), 3.85 (s, 3H, OCH3), 3.65 (b, 4H, CH2, morpholine), 2.73 (b, 4H, CH2, morpholine), 13C NMR (75 MHz, CDCl3, δ ppm): 167.15 (C=S), 163.68 (C=O), 162.64 (N=CH), 161.99 (C–OCH3), 144.85 (C=N), (134.38, 134.31, 131.93, 130.79, 124.83, 123.74, 123.65, 114.38 (Ph-C)), (69.14, 66.87 (CH2, morpholine)), 55.48 (O–CH3), 50.71 (CH2), 32.9. MS-E1: (m/z, Relative intensity, %): 492 (M+, 5.9%), 393.0 (9.6%), 358.0 (3.8%), 260.0 (57.2%), 228.0 (2.9%), 185.0 (3.1%), 160.0 (23%), 133.0 (71.1%), 100.1 (100%). C24H24N6O4S: Calculated: C, 58.52; H, 4.91; N, 17.06; S, 6.51. Found: C, 58.59; H, 4.92; N, 17.08; S, 6.53.