General Information
Melting points were measured on an Electrothermal IA 9000 series digital melting point apparatus (Bibby Sci. Lim. Stone, Staffordshire, UK). IR spectra were recorded in potassium bromide discs on PyeUnicam SP 3300 (PyeUnicam Ltd., Cambridge, UK) and FTIR 8101 PC infrared spectrophotometers (Shimadzu, Tokyo, Japan). NMR spectra were measured on a Mercury VX-300 NMR spectrometer (Varian, Inc., Karlsruhe, Germany).
1H-NMR spectra were recorded at 300 MHz and
13C-NMR spectra were recorded at 75.46 MHz in deuterated dimethyl sulfoxide (DMSO-
d6). Mass spectra were run on a Shimadzu GCMS-QP1000 EX mass spectrometer (Tokyo, Japan) at 70 eV. Elemental analyses were measured using Elementarvario LIII CHNS analyzer (GmbH & Co.KG, Hanau, Germany). Biological activities of the synthesized compounds were carried out at the Regional Center for Mycology and Biotechnology at Al-Azhar University, Cairo, Egypt. Irradiation was done in a domestic microwave oven (2500 MHz, 400 W). The reactions were carried out in a closed Teflon vessel which was placed at the center of the oven for irradiation. 5-Acetyl-4-methyl-2-phenyl-thiazole (
1) [
26], 2-cyanoacetohydrazide (
2) [
27], hydrazonoyl halides
4a [
28,
29],
4b–
d [
30],
4e–
g [
31],
4h [
32],
8a, b [
23] and arylidine malononitriles
9a–
c [
31] were prepared as described in the literature.
Synthesis of 2-cyano-N′-(1-(4-methyl-2-phenylthiazol-5-yl)ethylidene)acetohydrazide (3). A mixture of 5-acetyl-4-methyl-2-phenyl-thiazole 1 (2.17 g, 10 mmol) and 2-cyanoacetohydrazide 2 (0.99 g, 10 mmol) in 50 mL of EtOH containing catalytic amounts of HCl was refluxed for 6 h as monitored by TLC. The precipitated solid product was filtered, washed with ethanol and recrystallized from acetic acid to give pure product of thiazole derivative 3 as white solid (81%); mp 201–203 °C; IR (KBr) ν 3430 (NH), 3060, 2923 (C–H), 2338 (C≡N), 1643 (C=O), 1599 (C=N) cm−1; 1H-NMR (DMSO-d6): δ 2.49 (s, 3H, CH3), 2.72 (s, 3H, CH3), 3.30 (s, 2H, CH2), 7.51–8.03 (m, 5H, Ar-H), 10.60 (s, br, 1H, NH); MS m/z (%) 298 (M+, 83), 217 (96), 202 (100), 174 (53), 104 (69), 64 (72). Anal. Calcd: for C15H14N4OS (298.36): C, 60.38; H, 4.73; N, 18.78. Found: C, 60.45; H, 4.81; N, 18.66%.
General method for synthesis of 5-amino-1-aryl-3-substituted-N′-(1-(4-methyl-2-phenyl thiazol-5-yl) ethylidene)-1H-pyrazole-4-carbohydrazides 6a–h.
Method A. A mixture of hydrazone 3 (0.298 g, 1 mmol) and the appropriate hydrazonoyl halides 4 (1 mmol) in dioxane (20 mL) containing TEA (0.07 mL) was irradiated by MW at 400 Watt in a closed Teflon vessel until all the starting material was consumed (6–10 min as monitored by TLC). The hot reaction mixture was allowed to cool to room temperature and the precipitated solid was filtered off, washed with EtOH, dried and recrystallized from the suitable solvent to give the corresponding thiazole derivatives 6a–h.
Method B. A mixture of hydrazone 3 (0.298 g, 1 mmol) and the appropriate hydrazonoyl halides 4 (1 mmol) in dioxane (20 mL) containing grafted-chitosan (0.1 g) was irradiated by MW at 400 Watt in a closed Teflon vessel until all the starting material was consumed (6–10 min as monitored by TLC). The hot solution was filtered to remove grafted-chitosan and excess solvent was removed under reduced pressure. The reaction mixture was triturated with methanol and the product separated was filtered, washed with methanol, dried and recrystallized from the proper solvent to give the corresponding products, 6a–h which were identical in all aspects (m.p., mixed m.p. and IR spectra) with those obtained from method A. The physical constants of products 6a–h are provided below:
3-Acetyl-5-amino-N′-(1-(4-methyl-2-phenylthiazol-5-yl)ethylidene)-1-phenyl-1H-pyrazole-4-carbohydrazide (6a). Yellow solid; mp 163–165 °C (EtOH); IR (KBr) ν = 3432, 3264 (NH2 and NH), 3056, 2998, 2924 (C–H), 1694, 1643 (2C=O), 1601 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6) δ 2.49 (s, 3H, CH3), 2.58 (s, 3H, CH3), 2.71 (s, 3H, CH3), 7.50–8.01 (m, 12H, Ar-H and NH2), 10.63 (s, br, 1H, NH); 13C-NMR (DMSO-d6) δ 16.80, 18.38, 25.25 (CH3), 113.00, 119.78, 120.51, 125.51, 127.53, 127.56, 128.32, 128.38, 130.14, 130.67, 136.11, 136.63, 143.46, 145.17, 145.58 (Ar-C and C=N), 167.58, 184.58 (C=O) ppm; MS, m/z (%) 458 (M+, 37), 390 (66), 329 (78), 80 (100), 64 (70). Anal. calcd for C24H22N6O2S (458.54): C, 62.86; H, 4.84; N, 18.33. Found: C, 62.77; H, 4.81; N, 18.24%.
3-Acetyl-5-amino-N′-(1-(4-methyl-2-phenylthiazol-5-yl)ethylidene)-1-(p-tolyl)-1H-pyrazole-4-carbo-hydrazide (6b). Yellow solid; mp 181–183 °C (EtOH); IR (KBr) ν = 3422, 3255 (NH2 and NH), 3059, 2920 (C–H), 1698, 1646 (2C=O), 1601 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H, CH3), 2.49 (s, 3H, CH3), 2.63 (s, 3H, CH3), 2.75 (s, 3H, CH3), 7.44–8.00 (m, 11H, Ar-H and NH2), 10.59 (s, br, 1H, NH); 13C-NMR (DMSO-d6) δ 16.82, 18.30, 20.61, 25.25 (CH3), 114.80, 119.35, 121.83, 125.69, 127.00, 127.83, 128.37, 129.14, 132.36, 133.07, 136.49, 137.19, 143.49, 144.92, 146.41 (Ar-C and C=N), 167.25, 184.49 (C=O) ppm; MS, m/z (%) 472 (M+, 40), 430 (39), 214 (100), 121 (84), 71 (62). Anal. calcd for C25H24N6O2S (472.56): C, 63.54; H, 5.12; N, 17.78. Found: C, 63.37; H, 5.04; N, 17.55%.
3-Acetyl-5-amino-1-(4-methoxyphenyl)-N′-(1-(4-methyl-2-phenylthiazol-5-yl)ethylidene)-1H-pyrazole-4-carbohydrazide (6c). Yellow solid; mp 157–159 °C (EtOH); IR (KBr) ν = 3427, 3264 (NH2 and NH), 3064, 2928 (C–H), 1667, 1643 (2C=O), 1597 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6) δ 2.12 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.64 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 6.67–7.72 (m, 11H, Ar-H and NH2), 10.73 (s, br, 1H, NH); 13C-NMR (DMSO-d6) δ 17.03, 18.35, 25.58, 53.90 (CH3), 113.91, 119.04, 120.82, 123.94, 126.80, 127.06, 129.32, 129.74, 130.26, 132.37, 135.27, 137.04, 142.91, 143.48, 145.18 (Ar-C and C=N), 167.62, 184.97 (C=O) ppm; MS, m/z (%) 488 (M+, 51), 477 (72), 369 (84), 121 (70), 80 (71), 64 (100). Anal. calcd for C25H24N6O3S (488.56): C, 61.46; H, 4.95; N, 17.20. Found: C, 61.25; H, 4.74; N, 17.05%.
3-Acetyl-5-amino-1-(4-chlorophenyl)-N′-(1-(4-methyl-2-phenylthiazol-5-yl)ethylidene)-1H-pyrazole-4-carbo-hydrazide (6d). Yellow solid; mp 214–216 °C (DMF); IR (KBr) ν = 3424, 3252 (NH2 and NH), 3064, 2966 (C–H), 1668, 1623 (2C=O), 1596 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6) δ 2.46 (s, 3H, CH3), 2.64 (s, 3H, CH3), 2.74 (s, 3H, CH3), 7.31–8.12 (m, 11H, Ar-H and NH2), 10.77 (s, br, 1H, NH); MS, m/z (%) 494 (M+ + 2, 24), 492 (M+, 61), 440 (69), 369 (70), 212 (47), 142 (100), 127 (62), 64 (55). Anal. calcd for C24H21ClN6O2S (492.98): C, 58.47; H, 4.29; N, 17.05. Found: C, 58.26; H, 4.22; N, 16.93%.
Ethyl 5-amino-4-(2-(1-(4-methyl-2-phenylthiazol-5-yl)ethylidene)hydrazinecarbonyl)-1-phenyl-1H-pyrazole-3-carboxylate (6e). Yellow solid; mp 177–179 °C (EtOH); IR (KBr) ν = 3433,3270 (NH2 and NH), 3041, 2922 (C–H), 1737, 1640 (2C=O), 1599 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6) δ 0.97 (t, J = 7.0 Hz, 3H, CH3CH2), 2.37 (s, 3H, CH3), 2.68 (s, 3H, CH3), 4.02 (q, J = 7.0 Hz, 2H, CH2CH3), 7.21–7.62 (m, 12H, Ar-H and NH2), 10.69 (s, br, 1H, NH); 13C-NMR (DMSO-d6) δ 12.45, 15.93, 19.21 (CH3), 61.46 (CH2), 118.14, 118.99, 119.75, 120.74, 125.87, 127.36, 127.56, 128.13, 128.62, 128.97, 130.06, 130.11, 130.68, 146.20, 146.90 (Ar-C and C=N), 160.06, 166.11 (C=O) ppm; MS, m/z (%) 488 (M+, 75), 462 (69), 214 (100), 121 (47), 104 (47), 80 (73), 64 (99). Anal. calcd for C25H24N6O3S (488.56): C, 61.46; H, 4.95; N, 17.20. Found: C, 61.31; H, 4.73; N, 17.08%.
Ethyl 5-amino-4-(2-(1-(4-methyl-2-phenylthiazol-5-yl)ethylidene)hydrazinecarbonyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylate (6f). Pale yellow solid; mp 161–163 °C (EtOH); IR (KBr) ν = 3428, 3266 (NH2 and NH), 3061, 2919 (C–H), 1731, 1644 (2C=O), 1595 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6) δ 1.04 (t, J = 6.9 Hz, 3H, CH3CH2), 2.12 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.59 (s, 3H, CH3), 4.15 (q, J = 6.9 Hz, 2H, CH2CH3), 7.27–7.55 (m, 11H, Ar-H and NH2), 10.68 (s, br, 1H, NH); 13C-NMR (DMSO-d6) δ 12.18, 16.03, 19.15, 20.73 (CH3), 61.83 (CH2), 117.93, 118.37, 119.58, 120.00, 125.69, 127.18, 128.09, 128.47, 129.36, 130.05, 130.83, 132.46, 133.04, 144.94, 146.55 (Ar-C and C=N), 161.77, 166.82 (C=O) ppm; MS, m/z (%) 502 (M+, 33), 408 (97), 356 (73), 217 (100), 202 (44), 104 (70), 71 (86). Anal. calcd for: C26H26N6O3S (502.59): C, 62.13; H, 5.21; N, 16.72. Found: C, 62.26; H, 5.22; N, 16.60%.
Ethyl 5-amino-1-(2,4-dichlorophenyl)-4-(2-(1-(4-methyl-2-phenylthiazol-5-yl)ethylidene) hydrazine-carbonyl)-1H-pyrazole-3-carboxylate (6g). Brown solid; mp 209–211 °C (DMF); IR (KBr) ν = 3429, 3253 (NH2 and NH), 3057, 2928 (C–H), 1738, 1643 (2C=O), 1603 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6) δ 1.27 (t, J = 7.9 Hz, 3H, CH3CH2), 2.49 (s, 3H, CH3), 2.74 (s, 3H, CH3), 4.32 (q, J = 7.9 Hz, 2H, CH2CH3), 7.36–8.16 (m, 10H, Ar-H and NH2), 10.57 (s, br, 1H, NH); MS, m/z (%) 557 (M+, 27), 498 (60), 347 (61), 202 (100), 111 (69), 80 (78), 64 (100). Anal. calcd for C25H22Cl2N6O3S (557.45): C, 53.86; H, 3.98; N, 15.08. Found: C, 53.75; H, 3.91; N, 14.88%.
5-Amino-4-(2-(1-(4-methyl-2-phenylthiazol-5-yl)ethylidene)hydrazinecarbonyl)-N,1-diphenyl-1H-pyrazole-3-carboxamide (6h). White solid; mp 231–233 °C (DMF); IR (KBr) ν = 3426, 3239 (NH2 and 2NH), 3057, 2928 (C–H), 1671, 1627 (2C=O), 1598 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6) δ 2.12 (s, 3H, CH3), 2.65 (s, 3H, CH3), 7.13–7.83 (m, 17H, Ar-H and NH2), 10.81 (s, br, 1H, NH), 11.15 (s, br, 1H, NH); MS, m/z (%) 535 (M+, 73), 498 (60), 420 (51), 369 (79), 255 (100), 134 (66), 93 (100), 77 (98). Anal. calcd for C29H25N7O2S (535.62): C, 65.03; H, 4.70; N, 18.31. Found: C, 65.09; H, 4.64; N, 18.19%.
Synthesis of N′-(1-(4-cyano-1,4-diaryl-1H-pyrazol-3-yl)ethylidene)-4-methyl-2-phenylthiazole-5-carbohydrazides 11a–f.
Method A: Equimolecular mixture of 2-(2-(4-methyl-2-phenylthiazole-5-carbonyl)hydrazono)-N′-arylpropane hydrazonoyl chlorides 8a,b (l mmol) and the appropriate arylidine malononitriles 9a–c (1 mmol) in absolute EtOH (10 mL) containing catalytic amounts of piperidine (0.50 mL) was irradiated by MW at 400 Watt in a closed Teflon vessel until all the starting material was consumed (4–8 min as monitored by TLC), then cooled to room temperature. The solid product was filtered off, washed with ethanol and recrystallized from the proper solvent to give the thiazole derivatives 11a–f, respectively.
Method B: A mixture of 8a,b (1 mmol) and the appropriate arylidine malononitriles 9a–c (1 mmol) in absolute EtOH (10 mL) containing grafted-chitosan (0.1 g) was irradiated by MW at 400 Watt in a closed Teflon vessel until all the starting material was consumed (4–8 min as monitored by TLC). The hot solution was filtered to remove grafted-chitosan and excess solvent was removed under reduced pressure. The reaction mixture was triturated with MeOH and the product separated was filtered, washed with MeOH, dried and recrystallized from the proper solvent to give the corresponding products, 11a–f which were identical in all aspects (m.p., mixed m.p. and IR spectra) with those obtained from method A. The physical constants of the products 11a–f are listed below.
N′-(1-(4-cyano-1,5-diphenyl-1H-pyrazol-3-yl)ethylidene)-4-methyl-2-phenylthiazole-5-carbohydrazide (11a). Yellow solid; mp 201–203 °C (EtOH); IR (KBr) ν = 3439 (NH), 3056, 2926 (C–H), 2226 (C≡N), 1643 (C=O), 1599 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6) δ 2.31 (s, 3H, CH3), 2.73 (s, 3H, CH3), 7.22–8.01(m, 15H, Ar-H), 10.52 (s, br, 1H, NH); 13C-NMR (DMSO-d6) δ 11.05, 16.93 (CH3), 103.73, 118.14, 118.99, 119.75, 120.74, 125.87, 127.36, 127.56, 128.13, 128.62, 128.97, 130.06, 130.11, 130.68, 131.58, 145.17, 145.56, 151.93, 156.20, 156.90 (Ar-C and C=N), 170.83 (C=O) ppm; MS, m/z (%) 502 (M+, 15), 462 (30), 273 (41), 202 (29), 80 (100), 64 (89). Anal.Calcd for C29H22N6OS (502.59): C, 69.30; H, 4.41; N, 16.72. Found C, 69.17; H, 4.27; N, 16.55%.
N′-(1-(4-Cyano-5-(4-methoxyphenyl)-1-(p-tolyl)-1H-pyrazol-3-yl)ethylidene)-4-methyl-2-phenylthiazole-5-carbohydrazide (11b). Yellow solid; mp 227–229 °C (EtOH); IR (KBr) ν = 3313 (NH), 3041, 2917 (C–H), 2229 (C≡N), 1645 (C=O), 1588 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H, CH3), 2.49 (s, 3H, CH3), 2.70 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 7.16–7.73 (m, 13H, Ar-H), 10.27 (s, br, 1H, NH); 13C-NMR (DMSO-d6) δ 11.28, 17.16, 20.37, 54.06 (CH3), 102.93, 117.91, 119.38, 119.93, 121.49, 124.82, 126.66, 127.31, 128.00, 128.85, 129.48, 130.83, 131.46, 132.84, 135.08, 144.32, 145.59, 150.13, 153.91, 156.15 (Ar-C and C=N), 171.01 (C=O) ppm; MS, m/z (%) 546 (M+, 31), 479 (60), 399 (47), 338 (69), 149 (36), 80 (100). Anal.Calcd for C31H26N6O2S (546.64): C, 68.11; H, 4.79; N, 15.37. Found C, 68.04; H, 4.72; N, 15.25%.
N′-(1-(5-(4-Chlorophenyl)-4-cyano-1-phenyl-1H-pyrazol-3-yl)ethylidene)-4-methyl-2-phenylthiazole-5-carbohydrazide (11c).Yellow solid; mp 237–239 °C (DMF); IR (KBr) ν = 3426 (NH), 3057, 2930 (C–H), 2190 (C≡N), 1642 (C=O), 1606 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6) δ 2.50 (s, 3H, CH3), 2.73 (s, 3H, CH3), 7.37–7.92 (m, 14H, Ar-H), 10.31 (s, br, 1H, NH); MS, m/z (%) 539 (M+ + 2, 6), 537 (M+, 23), 429 (55), 315 (40), 399 (47), 338 (69), 202 (100), 174 (51), 64 (73). Anal. Calcd for C29H21ClN6OS (537.03): C, 64.86; H, 3.94; N, 15.65. Found C, 64.66; H, 3.79; N, 15.47%.
N′-(1-(4-Cyano-5-phenyl-1-(p-tolyl)-1H-pyrazol-3-yl)ethylidene)-4-methyl-2-phenylthiazole-5-carbohydrazide (11d).Yellow solid; mp 206–208 °C (EtOH); IR (KBr) ν = 3434 (NH), 3045, 2924 (C–H), 2229 (C≡N), 1644 (C=O), 1600 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H, CH3), 2.50 (s, 3H, CH3), 2.72 (s, 3H, CH3), 7.29–7.63 (m, 14H, Ar-H), 10.19 (s, br, 1H, NH); 13C-NMR (DMSO-d6) δ 11.06, 16.94, 20.16 (CH3), 102.38, 117.36, 118.43, 119.56, 120.94, 122.84, 125.39, 127.06, 127.83, 128.29, 128.45, 130.17, 131.26, 132.39, 134.90, 143.79, 145.17, 149.85, 152.31, 155.96 (Ar-C and C=N), 170.92 (C=O) ppm; MS, m/z (%) 516 (M+, 16), 472 (31), 327 (28), 299 (27), 202 (100), 174 (44), 71 (62). Anal. Calcd for C30H24N6OS (516.62): C, 69.75; H, 4.68; N, 16.27. Found C, 69.69; H, 4.60; N, 16.11%.
N′-(1-(4-Cyano-5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)ethylidene)-4-methyl-2-phenythiazole-5-carbohydrazide (11e). Yellow solid; mp 191–193 °C (EtOH); IR (KBr) ν = 3435 (NH), 3057, 2965 (C–H), 2196 (C≡N), 1643 (C=O), 1605 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6) δ 2.37 (s, 3H, CH3), 2.68 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 6.96-7.58 (m, 14H, Ar-H), 10.68 (s, br, 1H, NH); 13C-NMR (DMSO-d6) δ 12.13, 17.72 (CH3), 52.10 (OCH3), 105.91, 119.97, 120.76, 124.19, 124.69, 127.40, 128.80, 129.68, 130.10, 130.87, 135.22, 137.33, 142.13, 145.06, 146.48, 150.06, 150.48, 155.20, 157.33, 160.18 (Ar-C and C=N), 170.20 (C=O) ppm; MS, m/z (%) 532 (M+, 17), 425 (29), 311 (23), 202 (100), 174 (37), 64 (49). Anal. Calcd for C30H24N6O2S (532.62): C, 67.65; H, 4.54; N, 15.78. Found C, 67.49; H, 4.46; N, 15.69%.
N′-(1-(5-(4-Chlorophenyl)-4-cyano-1-(p-tolyl)-1H-pyrazol-3-yl)ethylidene)-4-methyl-2-phenylthiazole-5-carbohydrazide (11f). Yellow solid; mp 237–239 °C (DMF); IR (KBr) ν = 3431 (NH), 3040, 2926 (C–H), 2197 (C≡N), 1641 (C=O), 1602 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6) δ 2.32 (s, 3H, CH3), 2.50 (s, 3H, CH3), 2.76 (s, 3H, CH3), 7.31–7.83 (m, 13H, Ar-H), 10.38 (s, br, 1H, NH); MS, m/z (%) 553 (M+ + 2, 3), 551 (M+, 12), 380 (53), 202 (100), 109 (48), 64 (70). Anal.Calcd for C30H23ClN6OS (551.06): C, 65.39; H, 4.21; N, 15.25. Found C, 65.22; H, 4.15; N, 15.10%.