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M.M. Aly et al. / European Journal of Medicinal Chemistry 45 (2010) 3365e3373
C7-H quinazoline), 8.49 (s, 1H, ArH at C5-H quinazoline), 9.44 (s, 1H,
CHO). MS, m/z 394 (Mþ), 395 (18.9%), 396 (3.0%), 366 (15.01%), 365
(40.9%), 338 (1.8%), 270 (2.5%), 216 (17.9%), 121 (6.7%), 75 (20.0%).
Anal. Calcd for C15H8FIN2O2 (394.14): C, 45.71; H, 2.05; N, 7.11.
Found: C, 45.70; H, 2.10; N, 7.10.
A mixture of aldehyde 2a or b (0.01 mol) and the desired thio-
semicarbazide (0.012 mol) in benzene (25 ml) was heated under
reflux for 1 h, the reaction mixture was then left to cool and diluted
by methanol. The solid obtained was filtered and crystallized from
dioxane/ethanol (1:2) to give the desired thiosemicarbazones
4aeh.
4.2. Synthesis of 3-aryl-6-iodo-2-((4-alkyloxyphenylimino)
Method B:
methyl)-4(3H)-quinazolinones (3aed)
A mixture of the hydrazone 5a or b (0.01 mol) and the desired
isothiocyanate derivative (0.01 mol) in dioxane (25 ml) was heated
under reflux for 2 h. The reaction mixture was concentrated under
vacuum. The solid product obtained was filtered and crystallized
from dioxane/ethanol (1:2) to give the desired thiosemicarbazones
4aeh.
General procedure:
A
mixture of 4(3H)-quinazolinone-2-carboxaldehyde 2a,
b (0.01 mol) and aromatic amine (0.01 mol) in benzene (30 ml) was
heated under reflux for 1 h. The reaction mixture was concentrated
under vacuum, left to cool and then cold ethanol was added. The
solid product obtained was filtered off and crystallized from
ethanol/benzene to give 3aed.
4.3.1. 2-((6-Iodo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)
methylene)hydrazinecarbothioamide (4a)
M.P. 237e240 ꢁC. Yield 80%. IR:
n
/cmꢀ1: 3284, 3156 (NH, NH2)
d/ppm: 6.45e8.40 (m, 11H,
4.2.1. 6-Iodo-2-((4-methoxyphenylimino)methyl)-3-phenylquinazolin-
and 1681 (C]O). 1H NMR (DMSO-d6):
4(3H)-one (3a)
ArH þ CH]N þ NH2), 11.72 (s, 1H, NH, D2O-exchangeable). Anal.
Calcd for C16H12IN5OS (449.27): C, 42.77; H, 2.69; N,15.59. Found: C,
42.80; H, 2.70; N, 15.69.
M.P. 258e260 ꢁC. Yield 80%. IR:
n
/cmꢀ1: 2951 (CH-aliph), 1686
d/ppm: 3.74 (s, 3H, OCH3), 6.22e6.78
(C]O). 1H NMR (DMSO-d6):
(m, 4H, ArH), 7.18e7.54 (m, 5H, ArH), 7.68 (d, 1H, J ¼ 8.00 Hz, ArH at
C8-H quinazoline), 8.21 (d, 1H, J ¼ 8.00 Hz, ArH at C7-H quinazo-
line), 8.40 (s,1H, ArH at C5-H quinazoline), 8.43 (s,1H, CH]N). Anal.
Calcd for C22H16IN3O2 (481.29): C, 54.90; H, 3.35; N, 8.73. Found: C,
54.90; H3.40; N, 8.70.
4.3.2. 2-((3-(4-Fluorophenyl)-6-iodo-4-oxo-3,4-dihydroquinazolin-
2-yl)methylene)hydrazinecarbothioamide (4b)
M.P. 249e251 ꢁC. Yield 85%. IR:
n
/cmꢀ1: 3341, 3153 (NH, NH2)
/ppm: 6.95e8.91 (m, 10 H,
and 1674 (C]O). 1H NMR (DMSO-d6):
d
ArH þ CH]N þ NH2), 11.74 (s, 1H, NH, D2O-exchangeable). MS, m/z
(Ir/%) 467 (Mþ; 6.2), 391 (100%). Anal. Calcd for C16H11FIN5OS
(467.26): C, 41.13; H, 2.37; N, 14.99. Found: C, 41.10; H, 2.40; N,
15.00.
4.2.2. 2-((4-Ethoxyphenylimino)methyl)-6-iodo-3-phenylquinazolin-
4(3H)-one (3b)
M.P. 219e220 ꢁC. Yield 80%. IR:
n
/cmꢀ1: 2974 (CH-aliph), 1688
d/ppm: 1.30 (t, 3H, CH2CH3), 3.98 (q,
(C]O). 1H NMR (DMSO-d6):
2H, CH2CH3), 6.88e7.67 (m, 10H, ArH), 7.93 (s, 1H, ArH), 8.20 (d, 1H,
ArH), 8.45 (s, 1H, CH]N). MS, m/z 495 (4.4%), 65 (100%), 359 (2.9%),
220 (5.1%), 216 (30.0%), 192 (8.4%), 120 (66.9%), 93 (87.1%). Anal.
Calcd for C23H18IN3O2 (495.31): C, 55.77; H, 3.66; N, 8.48. Found:
C55.80; H, 3.70; N, 8.50.
4.3.3. 2-((6-Iodo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)
methylene)-N-methylhydrazinecarbothioamide (4c)
M.P. 255e258 ꢁC. Yield 80%. IR: /cmꢀ1: 3343, 3200 (NH) and
n
1688 (C]O). 1H NMR (DMSO-d6):
d/ppm: 2.90 (d, 3H, CH3), 7.00 (br,
1H, NH, D2O-exchangable), 7.4 (m, 2H, ArH at C8-H þ CH]N),
7.5e7.7 (m, 5H, Ar-H), 8.1 (d, 1H, C7-H), 8.4 (s, 1H, ArH at C5-H), 11.8
(s, 1H, NH, D2O-exchangeable). Anal. Calcd for C17H14IN5OS
(930.55): C, 44.07; H, 3.05; N, 15.12. Found: C, 44.10; H, 3.00; N,
15.10.
4.2.3. 3-(4-Fluorophenyl)-6-iodo-2-((4-methoxyphenylimino)
methyl)quinazolin-4(3H)-one (3c)
M.P. 226e228 ꢁC. Yield 85%. IR:
n
/cmꢀ1: 2932 (CH-aliph), 1680
d/ppm: 3.75 (s, 3H, OCH3), 6.34 e7.56
(C]O). 1H NMR (DMSO-d6):
(m, 8H, ArH), 7.68 (d, 1H, ArH at C8-H quinazoline), 8.18 (d, 1H, ArH
at C7-H quinazoline), 8.39 (s, 1H, ArH at C5-H quinazoline), 8.52 (s,
1H, CH]N). MS, m/z 394 (Mþ), 395 (18.9%), 396 (2.9%), 366 (15.0%),
365 (40.8%), 338 (1.7%), 270 (2.5%), 216 (17.8%), 121 (6.7%), 75
(19.9%). Anal. Calcd for C22H15FIN3O2 (499.28): C, 52.92; H, 3.03; N,
8.42. Found: C, 52.90; H, 3.00; N, 8.40.
4.3.4. 2-((3-(4-Fluorophenyl)-6-iodo-4-oxo-3,4-dihydroquinazolin-
2-yl)methylene)-N-methylhydrazinecarbothioamide (4d)
M.P. 254e256 ꢁC. Yield 85%. IR: /cmꢀ1: 3354, 3129 (NH) and
n
1687 (C]O). 1H NMR (DMSO-d6):
d/ppm: 2.92 (d, 3H, CH3),
7.12e8.45 (m, 7H, Ar-H þ NH þ CH]N), 8.12 (d, 1H, C7-H), 8.37 (s,
1H, ArH at C5-H), 11.78 (s, 1H, NH, D2O-exchangeable). MS, m/z (Ir/
%) 481 (0.3%), 74 (100%). Anal. Calcd for C17H13FIN5OS (481.29): C,
42.42; H, 2.72; N, 14.55. Found: C, 42.40; H, 2.70; N, 14.50.
4.2.4. 2-((4-Ethoxyphenylimino)methyl)-3-(4-fluorophenyl)-6-
iodoquinazolin-4(3H)-one (3d)
M.P. 197e198 ꢁC. Yield 90%. IR:
n
/cmꢀ1: 2974 (CH-aliph), 1688
4.3.5. N-Ethyl-2-((6-iodo-4-oxo-3-phenyl-3,4-dihydroquinazolin-
(C]O). 1H NMR (DMSO-d6):
d/ppm: 1.40 (t, 3H, J ¼ 6.8 Hz, CH2CH3),
2-yl)methylene)hydrazinecarbothioamide (4e)
4.00 (q, 2H, J ¼ 6.8 Hz, CH2CH3), 6.82 (d, 2H, J ¼ 8.80 Hz, ArH), 7.04
(d, 1H, J ¼ 8.80 Hz, ArH), 7.26 (m, 4H, ArH), 7.67 (d, 1H, J ¼ 8.80 Hz,
ArH), 7.99 (s, 1H, ArH), 8.10 (d, 2H, J ¼ 8.80 Hz, ArH), 8.66 (s, 1H,
CH]N). MS, m/z 394 (Mþ), 395 (18.9%), 396 (2.9%), 366 (15.0%), 365
(40.8%), 338 (1.7%), 270 (2.5%), 216 (17.8%), 121 (6.7%), 75 (19.9%).
Anal. Calcd for C23H17FIN3O2 (513.30): C, 53.82; H, 3.34; N, 8.19.
Found: C, 53.80; H, 3.30; N, 8.20.
M.P. 254e255 ꢁC. Yield 80%. IR: /cmꢀ1: 3320, 3137 (NH) and
n
1682 (C]O). 1H NMR (DMSO-d6):
d
/ppm: 1.09 (t, 3H, J ¼ 6.80 Hz,
CH3), 3.48 (q, 2H, J ¼ 6.80 Hz, CH2), 6.97 (t, 1H, J ¼ 6.20 Hz, NH, D2O-
exchangeable), 7.46e7.64 (m, 7H, Ar-H þ CH]N), 8.18 (d, 1H,
J ¼ 8.50 Hz, ArH at C7-H), 8.42 (s, 1H, ArH at C5-H), 11.78 (s, 1H, NH,
D2O-exchangeable). Anal. Calcd for C18H16IN5OS (477.32): C, 45.29;
H, 3.38; N, 14.67. Found: C, 45.00; H, 3.00; N, 16.50.
4.3. Synthesis of 2-((3-aryl-6-iodo-4(3H)-quinazolinon-2-yl)
4.3.6. N-Ethyl-2-((3-(4-fluorophenyl)-6-iodo-4-oxo-3,4-
methylene)-N-substituted hydrazine-carbothioamides (4aeh)
dihydroquinazolin-2-yl)methylene)hydrazinecarbothioamide (4f)
M.P. 228e230 ꢁC. Yield 80%. IR: /cmꢀ1: 3354, 3214 (NH) and
n
General procedure:
Method A:
1687 (C]O). 1H NMR (DMSO-d6):
2H, CH2), 7.44e7.64 (m, 7H, Ar-H þ CH]N), 8.18 (d, 1H, ArH at C7-
d/ppm: 1.09 (t, 3H, CH3), 4.08 (q,