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M. M. Ramla et al. / Bioorg. Med. Chem. 14 (2006) 7324–7332
or ethyl chloroformate. The mixture was heated on a
water bath for 6 h. The mixture was diluted with water
and extracted with ethyl acetate, the organic layers were
dried over anhydrous sodium sulfate and the ethyl ace-
tate was removed under reduced pressure and recrystal-
lized from appropriate solvent.
added. The reaction mixture was heated under reflux for
15–30 min. during which a yellowish green crystalline
product separated. After cooling, the product was fil-
tered, washed with ether, dried, and recrystallized from
appropriate solvent.
4.18. 4-Amino-3-methyl-5-(2-methyl-5-nitro-1H-ben-
zimidazol-1-yl)thiazol-2(3H)-thione (14a)
4.13. 1,2-Dihydro-3-[(2-methyl-5-nitro-1H-benzimidazol-
1-yl)methyl]-1,2,4-triazin-5(6H)-one (10)
Crystallized from ethanol as a green solid. Rf 0.16 (petro-
leum ether/ethyl acetate, 1:1). Yield: 2.2 g (73%); mp
215 °C; H NMR (DMSO-d6) d 2.56 (s, 3H, CH3), 3.35
(s, 3H, CH3), 4.61 (s, 2H, NH2), 7.69 (d, J = 9 Hz, 1H,
H7), 8.06 (d, J = 9 Hz, 1H, H6), 8.30 (s, 1H, H4); IR
(cmꢀ1): 3366, 3269 (NH2), 1629, 1573 (C@N groups),
1502, 1434 (NO2), 1353 (C@S); Anal. Calcd for
C12H11N5O2S2 (321): C, 44.85; H, 3.45; N, 21.79; S,
19.95. Found: C, 44.90; H, 3.49; N, 21.82; S, 19.91.
Crystallized from acetone as a yellow solid. Rf 0.35 (petro-
leum ether/ethyl acetate/methanol, 1:1:1/2). Yield: 1.7 g
(73%); mp 171–173 °C; H NMR (DMSO-d6) d 2.49 (s,
3H, CH3), 3.36 (s, 2H, CH2), 4.49 (s, 2H, CH2), 7.62 (d,
J = 9 Hz, 1H, H7), 8.04 (d, J = 9 Hz, 1H, H6), 8.35 (s,
1H, H4); IR (cmꢀ1): 3332, 3219 (NH groups), 1662
(C@O), 1627–1594 (C@N groups), 1517, 1390 (NO2);
Anal. Calcd for C12H12N6O3 (288): C, 50.00; H, 4.20; N,
29.15. Found: C, 49.97; H, 4.11; N, 29.26.
1
1
4.19. 4-Amino-3-ethyl-5-(2-methyl-5-nitro-1H-ben-
zimidazol-1-yl)thiazol-2(3H)-thione (14b)
4.14. 2-Methyl-5-nitro-1-(2H-1,2,4-triazol-3-ylmethyl)-
1H-benzimidazole (11)
Crystallized from aqueous methanol as a brown solid.
Rf 0.25 (petroleum ether/ethyl acetate, 1:1). Yield:
2.3 g (74%); mp 231 °C; H NMR (DMSO-d6) d 1.30
(t, J = 6.9 Hz, 3H, CH3), 2.45 (s, 3H, CH3), 4.49 (q,
J = 6.9 Hz, 2H, CH2), 5.71 (s, 2H, NH2), 7.62 (d,
J = 9.1 Hz, 1H, H7), 8.06 (d, J = 9.1 Hz, 1H, H6), 8.38
(s, 1H, H4); Anal. Calcd for C13H13N5O2S2 (335): C,
46.55; H, 3.91; N, 20.88; S, 19.12. Found: C, 45.65; H,
3.86; N, 20.80; S, 19.06.
Crystallized from dichloromethane as a brown solid. Rf
0.38 (petroleum ether/ethyl acetate/methanol, 1:1:1/2).
Yield: 1.8 g (86%); mp 123–126 °C; H NMR (DMSO-
d6) d 2.49 (s, 3H, CH3), 4.52 (s, 2H, CH2), 7.14 (s, 1H,
CH@N), 7.62 (d, J = 9 Hz, 1H, H7), 8.04 (d, J = 9 Hz,
1H, H6), 8.35 (s, 1H, H4); IR (cmꢀ1): 3422 (NH),
1617, 1597 (C@N groups), 1523, 1339 (NO2); Anal.
Calcd for C12H13N6O2 (273): C, 52.74; H, 4.79; N,
30.75. Found: C, 52.89; H, 4.60; N, 30.61.
1
1
4.20. 4-Amino-5-(2-methyl-5-nitro-1H-benzimidazol-1-
yl)-3-phenylthiazol-2(3H)-thione (14c)
4.15. 2-Methyl-5-nitro-1-(1-oxo-2,3-dihydro-1,2,3,5-thia-
triazol-4-ylmethyl)-1H- benz-imidazole (12)
Crystallized from ethanol/ether (5:1) as a yellow powder.
Rf = 0.17 (petroleum ether/ethyl acetate, 1:1). Yield:
2.8 g (80%); mp 100 °C; H NMR (DMSO-d6) d 2.56
(s, 3H, CH3), 4.51 (br s, 2H, NH2), 7.13–7.36 (m, 5H,
aromatic protons), 7.90 (d, J = 9 Hz, 1H, H7), 8.15 (d,
J = 9 Hz, 1H, H6), 8.54 (s, 1H, H4); Anal. Calcd for
C17H13N5O2S2 (383): C, 53.25; H, 3.42; N, 18.26; S,
16.72. Found: C, 53.31; H, 3.57; N, 18.33; S, 16.82.
Crystallized from dichloromethane/methanol (2:1) as a
yellow solid. Rf 0.31 (petroleum ether/ethyl acetate/
methanol, 1:1:1/2). Yield: 1.8 g (76%); mp 209–211 °C;
IR (cmꢀ1): 3382, 3295 (NH groups), 1619, 1597 (C@N
groups), 1518, 1401 (NO2), 1335 (SO); Anal. Calcd for
C10H10N6O3S (294): C, 40.81; H, 3.42; N, 28.56; S,
10.90. Found: C, 40.74; H, 3.32; N, 28.23; S, 10.95.
1
4.16. 1,2-Dihydro-5-[(2-methyl-5-nitro-1H-benzimidazol-
1-yl)methyl]-1,2,4-triazol-3-one (13)
4.21. (4-Amino-5-(2-methyl-5-nitro-1H-benzimidazol-1-
yl)-2-thioxothiazol-3(2H)-yl)phenylmethanone (14d)
Crystallized from acetone as a brown solid. Rf 0.33 (petro-
leum ether/ethyl acetate/methanol, 1:1:1/2). Yield: 1.6 g
(72%); mp 144–146 °C; IR (cmꢀ1): 3306–3104 (NH
groups + enolic OH), 1718 (C@O), 1621, 1597 (C@N
groups), 1523, 1339 (NO2); Anal. Calcd for C11H10N6O3
(274): C, 48.18; H, 3.68; N, 30.65. Found: C, 48.23; H,
3.58; N, 30.56.
Crystallized from acetone as a gray powder. Rf = 0.13
(petroleum ether/ethyl acetate, 1:1). Yield: 2.8 g (73%);
mp 148–150 °C; H NMR (DMSO-d6) d 2.56 (s, 3H,
CH3), 4.52 (br s, 2H, NH2), 7.16–7.54 (m, 5H, aromatic
protons), 7.92 (d, J = 9 Hz, 1H, H7), 8.15 (d, J = 9 Hz,
1H, H6), 8.44 (s, 1H, H4); IR (cmꢀ1): 3403, 3232
(NH2), 1703 (C@O), 1621, 1611 (C@N groups), 1518,
1423 (NO2), 1338 (C@S); Anal. Calcd for
C18H13N5O2S2 (411): C, 52.54; H, 3.18; N, 17.02; S,
15.59. Found: C, 52.49; H, 3.20; N, 17.11; S, 15.48.
1
4.17. General procedure for the preparation of the
compounds 14a–e
To
a
well-stirred solution of compound
3
(2 g,
4.22. 4-Amino-3-(4-methoxyphenyl)-5-(2-methyl-5-nitro-
1H-benzimidazol-1-yl)thiazol-2(3H)-thione (14e)
9.26 mmol), finely divided sulfur (0.3 g, 9.26 mmol), and
triethylamine (0.9 ml, 9.26 mmol) in absolute ethanol
(30 ml), the proper isothiocyanate (methyl, ethyl, phenyl,
benzoyl or p-methoxyphenyl) (9.26 mmol) was gradually
Crystallized from ethanol as a yellow solid. Rf 0.15 (petro-
leum ether/ethyl acetate, 1:1). Yield: 3 g (79%); mp 95 °C;