O.I. El-Sabbagh et al. / European Journal of Medicinal Chemistry 44 (2009) 3746–3753
3751
4.1.3.1. 5-(4-(Benzyloxy)phenyl)-3-phenyl-1-thiocarbamoyl-4,5-
(C5 of pyrazole), 43.30 (C4 of pyrazole), 39.04 (C5 of thiazolone)
ppm. Analysis for C25H21N3O2S, Calcd: C, 70.24; H, 4.95; N, 9.83;
Found: C, 70.55; H, 5.26; N, 9.64.
dihydro-1H-pyrazole (9). Yield: 40%; m.p.: 205–206 ꢂC; crystal-
lized from toluene; IR:
2931 (CH, aliphatic), 1579 (C]N), 1513 (C]C), 1334 (C]S) cmꢀ1; 1H
NMR (500 MHz, DMSO-d6):
n
¼ 3440, 3280 (NH2), 3064 (CH, aromatic),
d
¼ 3.20–3.30 (dd, 1H, C4–H of pyr-
4.1.4.2. 2-(5-(4-(Benzyloxy)phenyl)-3-(4-bromophenyl)-4,5-dihy-
dro-1H-pyrazol-1-yl)thiazol-4(5H)-one (14). Yield: 57%; m.p.: 225–
azole), 3.80–3.95 (dd, 1H, C4–H of pyrazole), 5.05 (s, 2H, benzylic H),
5.95–6.05 (dd, 1H, C5–H of pyrazole), 6.95–7.80 (m, 16H, ArH) ppm;
226 ꢂC; crystallized from toluene; IR:
n
¼ 3051 (CH, aromatic), 2912
(CH, aliphatic), 1696 (C]O), 1590 (C]N), 1524 (C]C) cmꢀ1 1H
NMR (500 MHz, CDCl3):
13C NMR (CDCl3)
d
¼ 176.76 (C]S), 158.30 (C–O), 156.04 (C]N),
;
136.99–115.14 (phenyl-C), 70.06 (OCH2), 63.02 (C5 of pyrazole),
43.11 (C4 of pyrazole) ppm. Analysis for C23H21N3OS, Calcd: C, 71.29;
H, 5.46; N, 10.84; Found: C, 71.56; H, 5.30; N, 10.68.
d
¼ 3.34–3.38 (dd, 1H, C4–H of pyrazole),
3.86–3.88 (dd, 1H, C4–H of pyrazole), 3.90–3.99 (two d, 2H, C5–H of
thiazolone), 5.04 (s, 2H, benzylic H), 5.75–5.78 (dd, 1H, C5–H of
pyrazole), 6.93–7.69 (m, 13H, ArH) ppm; 13C NMR (CDCl3)
4.1.3.2. 5-(4-(Benzyloxy)phenyl)-3-(4-bromophenyl)-1-thiocarbamoyl-
d
¼ 187.62 (C]O), 178.41 (C]N, thiazolone), 158.89 (C–O), 158.56
4,5-dihydro-1H-pyrazole (10). Yield: 50%; m.p.: 226–227 ꢂC; crystal-
(C]N, pyrazole), 136.74–115.36 (phenyl-C), 70.11 (OCH2), 63.72 (C5
of pyrazole), 43.17 (C4 of pyrazole), 39.07 (C5 of thiazolone) ppm.
Analysis for C25H20BrN3O2S, Calcd: C, 59.29; H, 3.98; N, 8.30;
Found: C, 59.28; H, 4.00; N, 7.85.
lized from toluene; IR:
2900 (CH, aliphatic), 1577 (C]N), 1511 (C]C), 1336 (C]S) cmꢀ1; 1H
NMR (500 MHz, CDCl3):
n
¼ 3463, 3301 (NH2), 3031 (CH, aromatic),
d
¼ 3.16–3.21 (dd, 1H, C4–H of pyrazole),
3.78–3.84 (dd, 1H, C4–H of pyrazole), 5.05 (s, 2H, benzylic H), 6.01–
6.04 (dd, 1H, C5–H of pyrazole), 6.94–7.62 (m, 15H, ArH þ NH2) ppm;
4.1.4.3. 2-(5-(4-(Benzyloxy)phenyl)-3-(4-chlorophenyl)-4,5-dihydro-
1H-pyrazol-1-yl)thiazol-4(5H)-one (15). Yield: 51%; m.p.: 235–
13C NMR (CDCl3)
d
¼ 176.90 (C]S), 158 (C–O), 154.90 (C]N), 136.93–
115.18 (phenyl-C), 70.07 (OCH2), 63.16 (C5 of pyrazole), 42.94 (C4 of
pyrazole) ppm. MS: m/z (rel. int.) ¼ 466 (Mþ, 0.00), 465 (Mþ ꢀ 1, 15.6),
432 (10.5), 283 (21.1), 193 (26.1), 91 (100.0). Analysis for
C23H20BrN3OS, Calcd: C, 59.23; H, 4.32; N, 9.01; Found: C, 59.50; H,
4.49; N, 8.88.
236 ꢂC; crystallized from ethanol; IR:
n
¼ 3052 (CH, aromatic), 2913
(CH, aliphatic), 1695 (C]O), 1590 (C]N), 1525 (C]C) cmꢀ1 1H
NMR (500 MHz, CDCl3):
;
d
¼ 3.34–3.38 (dd, 1H, C4–H of pyrazole),
3.85–3.86 (dd, 1H, C4–H of pyrazole), 3.89–3.94 (two d, 2H, C5–H of
thiazolone), 5.04 (s, 2H, benzylic H), 5.75–5.78 (dd, 1H, C5–H of
pyrazole), 6.93–7.76 (m,13H, ArH) ppm; 13C NMR (CDCl3)
d
¼ 187.62
4.1.3.3. 5-(4-(Benzyloxy)phenyl)-3-(4-chlorophenyl)-1-thiocarbamoyl-
4,5-dihydro-1H-pyrazole (11). Yield: 45%; m.p.: >300 ꢂC; crystallized
(C]O), 178.38 (C]N, thiazolone), 158.88 (C–O), 158.48 (C]N,
pyrazole), 137.74–115.16 (phenyl-C), 70.10 (OCH2), 63.72 (C5 of
pyrazole), 43.23 (C4 of pyrazole), 39.07 (C5 of thiazolone) ppm.
Analysis for C25H20ClN3O2S, Calcd: C, 65.00; H, 4.36; N, 9.10; Found:
C, 65.32; H, 4.49; N, 9.36.
from toluene; IR:
(CH, aliphatic), 1577 (C]N), 1511 (C]C), 1336 (C]S) cmꢀ1; 1H NMR
(500 MHz, CDCl3):
n
¼ 3463, 3301 (NH2), 3050 (CH, aromatic), 2900
d
¼ 3.35–3.39 (dd, 1H, C4–H of pyrazole), 3.91–
4.00 (dd, 1H, C4–H of pyrazole), 5.07 (s, 2H, benzylic H), 5.75–5.78
(dd, 1H, C5–H of pyrazole), 6.93–7.71 (m, 15H, ArH þ NH2) ppm.
Analysis for C23H20ClN3OS, Calcd: C, 65.47; H, 4.78; N, 9.96; Found: C,
65.82; H, 4.79; N, 10.38.
4.1.4.4. 2-(5-(4-(Benzyloxy)phenyl)-3-(4-methylphenyl)-4,5-dihy-
dro-1H-pyrazol-1-yl)thiazol-4(5H)-one (16). Yield: 52%; m.p.: 151–
152 ꢂC; crystallized from ethanol; IR:
n
¼ 3050 (CH, aromatic), 2917
(CH, aliphatic), 1693 (C]O), 1590 (C]N), 1526 (C]C) cmꢀ1 1H
NMR (200 MHz, DMSO-d6):
¼ 2.43 (s, 3H, CH3), 3.48, 3.97 (two s,
;
4.1.3.4. 5-(4-(Benzyloxy)phenyl)-3-(4-methylphenyl)-1-thiocarbamoyl-
4,5-dihydro-1H-pyrazole (12). Yield: 56%; m.p.: 171–172 ꢂC; crystal-
d
2H, C4–H of pyrazole), 4.04–4.18 (two d, 2H, C5–H of thiazolone),
5.12 (s, 2H, benzylic H), 5.75–5.80 (d, 1H, C5–H of pyrazole), 7.03–
7.82 (m, 13H, ArH) ppm; MS: m/z (rel. int.) ¼ 442 (Mþ þ 1, 38.1), 441
(Mþ, 66.7), 296 (19.1), 91 (100.0). Analysis for C26H23N3O2S, Calcd:
C, 70.72; H, 5.25; N, 9.52; Found: C, 70.79; H, 5.23; N, 9.43.
lized from toluene; IR:
2969 (CH, aliphatic), 1577 (C]N), 1511 (C]C), 1335 (C]S) cmꢀ1; 1H
NMR (500 MHz, CDCl3):
n
¼ 3464, 3303 (NH2), 3049 (CH, aromatic),
d
¼ 2.42 (s, 3H, CH3), 3.18–3.22 (dd, 1H, C4–H
of pyrazole), 3.78–3.84 (dd, 1H, C4–H of pyrazole), 5.04 (s, 2H, benzylic
H), 5.99–6.02 (dd, 1H, C5–H of pyrazole), 6.94–7.40 (m, 15H,
ArH þ NH2) ppm. 13C NMR (CDCl3)
d
¼ 176.55 (C]S), 158.27 (C–O),
4.1.5. General procedures for the synthesis of compounds 17–24
To a suspension of compounds 9–12 (0.01 mol) in ethanol
(20 ml), phenacyl bromide derivatives (0.01 mol) were added and
heated at reflux for 1 h. After cooling, the obtained product was
collected by filtration and crystallized from an appropriate solvent.
156.19 (C]N), 141.57–115.11 (phenyl-C), 70.06 (OCH2), 62.93 (C5 of
pyrazole), 43.14 (C4 of pyrazole), 21.56 (CH3) ppm. Analysis for
C24H23N3OS, Calcd: C, 71.79; H, 5.77; N,10.47; Found: C, 72.02; H, 5.74;
N, 10.21.
4.1.4. General procedure for the synthesis of compounds 13–17
To a suspension of compounds 9–12 (0.01 mol) in ethanol
(20 ml), ethyl bromoacetate (0.01 mol) was added and heated at
reflux for 1 h. After cooling, the separated product was filtered and
washed. The product was crystallized from appropriate solvent.
4.1.5.1. 2-(5-(4-(Benzyloxy)phenyl)-3-phenyl-4,5-dihydro-1H-pyr-
azol-1-yl)-4-(4-chlorophenyl)thiazole (17). Yield: 60%; m.p.: 141–
142 ꢂC; crystallized from dioxane/H2O; IR:
n
¼ 3032 (CH, aromatic),
2926 (CH, aliphatic), 1585 (C]N), 1510 (C]C) cmꢀ1 1H NMR
(500 MHz, CDCl3):
;
d
¼ 3.33–3.38(dd,1H, C4–Hofpyrazole), 3.87–3.93
(dd, 1H, C4–H of pyrazole), 5.06 (s, 2H, benzylic H), 5.61–5.65 (dd,1H,
C5–H of pyrazole), 6.80 (s, 1H, C5–H of thiazole), 6.97–7.80 (m, 18H,
4.1.4.1. 2-(5-(4-(Benzyloxy)phenyl)-3-phenyl-4,5-dihydro-1H-pyr-
azol-1-yl)thiazol-4(5H)-one (13). Yield: 50%; m.p.: 193–194 ꢂC;
ArH) ppm; 13C NMR (CDCl3)
d
¼ 165.08 (C2 of thiazole), 158.39 (C–O),
crystallized from ethanol/H2O; IR:
(CH, aliphatic), 1704 (C]O), 1569 (C]N), 1538 (C]C) cmꢀ1
NMR (500 MHz, CDCl3):
3.86–3.97 (dd, 1H, C4–H of pyrazole), 3.91–3.96 (two d, 2H, C5–H of
thiazolone), 5.05 (s, 2H, benzylic H), 5.75–5.78 (dd, 1H, C5–H of
pyrazole), 6.92–7.84 (m, 14H, ArH) ppm; 13C NMR (CDCl3)
n
¼ 3060 (CH, aromatic), 2915
151.73 (C]N, pyrazole), 150.42 (C4 of thiazole), 136.93–114.97
(phenyl-C), 103.67 (C5 of thiazole), 70.06 (OCH2), 64.23 (C5 of pyr-
azole), 43.41 (C4 of pyrazole) ppm. Analysis for C31H24ClN3OS, Calcd:
C, 71.32; H, 4.63; N, 8.05; Found: C, 71.39; H, 4.67; N, 7.77.
;
1H
d
¼ 3.39–3.43 (dd, 1H, C4–H of pyrazole),
4.1.5.2. 2-(5-(4-(Benzyloxy)phenyl)-3-(4-bromophenyl)-4,5-dihy-
dro-1H-pyrazol-1-yl)-4-(4-chlorophenyl)thiazole (18). Yield: 72%;
m.p.: 191–192 ꢂC; crystallized from dioxane/H2O; 1H NMR (500 MHz,
d
¼ 187.67 (C]O), 178.29 (C]N, thiazolone), 159.63 (C–O), 158.84
(C]N, pyrazole), 136.78–115.32 (phenyl-C), 70.10 (OCH2), 63.57