634 JOURNAL OF CHEMICAL RESEARCH 2010
(DMSO-d6): δ 2.91 (s, 3H, CH3), 3.13 (s, 3H, CH3), 5.87 (d, J = 13.0
Hz, 1H, –CO–CH=), 7.25 (d, J = 13.0 Hz, 1H, =CH–N–), 7.45–7.78
(m, 10H, ArH); MS m/z (%): 456 (M++1, 2), 455 (M+, 4), 438 (11),
350 (16), 98 (55), 77 (100). Anal. Calcd for C27H23ClN3O2 (455.95):
C, 71.13; H, 4.86; N, 9.22. Found: C, 71.31; H, 4.81; N, 9.14%.
3-[(E)-4-benzoyl-3-(N,N-dimethylamino)acryloyl]-1-(4-nitrophe-
nyl)-5-phenyl-1H-pyrazole (6e): This compound was obtained as dark
yellow crystals in 85 % yield. m.p. 170°C (AcOH); IR (KBr) νmax/cm−1
1660, 1644 (2C=O); 1H NMR (DMSO-d6): δ 2.88 (s, 3H, CH3), 3.12
(s, 3H, CH3), 5.86 (d, J = 13.0 Hz, 1H, –CO–CH=), 7.22 (d, J = 13.0
Hz, 1H, =CH–N–), 7.46-7.77 (m, 14H, ArH); MS m/z (%): 467 (M++1,
3), 466 (M+, 8), 449 (14), 361 (16), 98 (100), 77 (83). Anal. Calcd for
C27H22N3O3 (466.52): C, 69.52; H, 4.75; N, 12.01. Found: C, 69.42;
H, 4.80; N, 12.22%.
6-(4-Benzoyl-1,5-diphenyl-1H-pyrazol-3-yl)-3–cyano-2-oxo-pyridin-
2(1H)-one (12a): Yield 70%, m.p. 115–117°C; IR (KBr) νmax/cm−1
3190 (NH), 2212 (C≡N), 1662, 1649 (2C=O); H NMR (DMSO-d6)
δ 7.14–7.73 (m, 15H, ArH), 8.04 (d, J = 9.0 Hz, 1H, pyridine-H-5),
8.60 (d, J = 9.0 Hz, 1H, pyridine-H-4), 12.3 (s, 1H, NH, D2O-
exchangeable); MS m/z (%) 443 (M+, 65), 442 (100), 77 (7). Anal.
Calcd for C28H18N4O2 (442.47): C, 76.01; H, 4.10; N, 12.66. Found: C,
75.86; H, 4.33; N, 12.47%.
1
6-(4-Benzoyl-1,5-diphenyl-1H-pyrazol-3-yl)-3-ethoxycarbonylpyr-
idin-2(1H)-one (12b): Yield 68%, m.p. 107–109°C; IR (KBr) νmax
/
cm−1 3168 (NH), 1722, 1658, 1618 (3C=O); H NMR (DMSO-d6)
δ 1.15 (t, J = 7.0 Hz, 3H, CH3), 4.14 (q, J = 7.0 Hz, 2H, CH2), 7.19–
7.72 (m, 15 H, ArH), 8.19 (d, J = 9.0 Hz, 1H, pyridine-H-5), 8.60 (d,
J = 9 Hz, 1H, pyridine-H-4), 9.32 (s, 1H, NH, D2O-exchangeable);
MS m/z (%) 490 (M++1, 3), 489 (M+, 10), 444 (9), 400 (37), 180 (24),
105 (100). Anal. Calcd for C30H23N3O4 (489.52): C, 73.61; H, 4.74;
N, 8.58. Found: C, 73.48; H, 4.92; N, 8.35%.
1
4-Benzoyl-1,5-diphenyl-3-(1H-pyrazol-3-yl)-1H-pyrazole (7):
A
mixture of enaminone (1) (0.42 g, 1 mmol) and hydrazine hydrate (1
mL, 99%) in absolute ethanol (30 mL) was refluxed for 2 h, then left
to cool. The precipitated product was collected by filtration, washed
with ethanol, dried and crystallised from ethanol to afford the pyr-
azole derivative 7 as white powder in 70 % yield. m.p. 120–122°C; IR
(KBr) νmax/cm−1 3148 (NH), 1664 (C=O); 1H NMR (DMSO-d6) δ 6.35
(s, 1H, pyrazole), 6.78 (s, 1H, pyrazole), 7.09–7.70 (m, 18H, ArH),
12.9 (s, 1H, NH, D2O-exchangeable); MS m/z (%) 390 (M+, 80), 389
(100), 77 (45). Anal. Calcd for C25H18N4O (390.44): C, 76.91; H, 4.65;
N, 14.35. Found: C, 77.12; H, 4.78; N, 14.22%.
Cytotoxic activity against human breast cancer (MCF-7) in vitro.
The method applied is similar to that reported by Skehan et al. using
Sulfo-Rhodamine-B stain (SRB).15 Cells were plated in 96-multiwell
plate (104 cells/well) for 24 h before treatment with the test com-
pound to allow attachment of cell to the wall of the plate. Five differ-
ent concentrations of the compound 6 under test (0, 5, 12.5, 25, and
50 µg mL−1) were added to the cell monolayer in triplicate wells indi-
vidual dose, monolayer cells were incubated with the compounds for
48 h at 37°C and in atmosphere of 5 % CO2. After 48 h, the cells were
fixed, washed and stained with SRB stain, the excess stain was washed
with acetic acid and the attached stain was recovered with tris-EDTA
buffer; the colour intensity was measured in an ELISA reader. The
relation between the surviving fraction and drug concentration is
plotted to obtain the survival curve of tumour cell line and the IC50 was
calculated. The results are summarised in Table 1.
2-Amino-4-(4-benzoyl-1,5-diphenyl-1H-pyrazol-3-yl)pyrimidine
(8): Enaminone 6c (0.42 g, 1 mmol) was added to an ethanolic sodium
ethoxide solution [prepared from sodium metal (0.023 g, 1 mmol)
and absolute ethanol (50 mL)] then guanidine hydrochloride (0.1 g,
1 mmol) was added. The reaction mixture was refluxed for 12 h, then
left to cool and poured into crushed ice. The precipitated product was
collected by filtration, washed with ethanol and dried. Recrystallisa-
tion from EtOH–DMF afforded the pyrimidine derivatives 8 as yellow
powder in 74 % yield. m.p. 125–127 °C; IR (KBr) νmax/cm−1 3258
1
(NH2), 1658 (C=O); H NMR (DMSO-d6) δ 6.62 (s, 2H, NH2, D2O-
Received 15 June 2010; accepted 24 September 2010
Paper 1000203 doi: 10.3184/030823410X12878479991509
Published online: 24 November 2010
exchangeable), 7.0 (s, 1H, C-5 pyrimidine), 7.1–7.72 (m, 18H, ArH),
8.35 (s, 1H, C-6 pyrimidine); MS m/z (%) 418 (M++1, 8.5), 417 (M+,
18), 399 (25), 77 (100). Anal. Calcd for C26H19N5O (417.46): C, 74.80;
H, 4.59; N, 16.78. Found: C, C, 74.68; H, 4.82; N, 16.75%.
Reaction of enaminone 6c with heterocyclic amines: A mixture
of the enaminone 6c (0.42 g, 1 mmol) and 3-amino-1,2,4-triazole
(1 mmol) in absolute ethanol (50 mL) containing piperidine (0.5 mL)
was refluxed for 12 h, then left to cool. The solid product was filtered
off, washed with ethanol, dried and finally recrystallised from EtOH-
DMF to afford the corresponding triazolo[1,5-a]pyrimidine 9. When
the above procedure was repeated using 2-aminobenzimidazole, in
place of 3-amino-1,2,4-triazole, the pyrimido[1,2-a]benzimidazole
derivative 10 was obtained.
5-(4-Benzoyl-1,5-diphenyl-1H-pyrazole-3-yl)-1,2,4-triazolo[1,5-a]
pyrimidine (9): Yield 75%, m.p. 110–112°C; IR (KBr) νmax/cm−1 1648
(C=O); 1H NMR (DMSO-d6) δ 7.14–7.72 (m, 15 H, ArH), 7.58 (d, J =
4.5 Hz, 1H, H-6), 8.46 (s, 1H, H-2), 8.84 (d, J = 4.5 Hz, 1H, H-7); MS
m/z (%) 443 (M++1, 15), 442 (M+, 16), 180 (9), 110 (31), 77 (41).
Anal. Calcd for C27H18N6O (442.47): C, 73.29; H, 4.10; N, 18.99.
Found: C, 73.44; H, 4.32; N, 19.21%.
References
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4-(4-Benzoyl-1,5-diphenyl-1H-pyrazole-3-yl)pyrimido[1,2-a]-
benzimidazole (10): Yield 72%, m.p. 115–117°C; IR (KBr) νmax/cm−1
1643 (C=O); 1H NMR (DMSO-d6) δ 7.14–7.72 (m, 19 H, ArH), 7.59
(d, J = 4.5 Hz, 1H, H-3), 8.26 (d, J = 4.5 Hz, 1H, H-2); MS m/z (%)
492 (M++1, 23), 491 (M+, 14), 405 (42), 316 (54), 180 (17), 77 (100).
Anal. Calcd for C32H21N5O (491.54): C, 78.19; H, 4.31; N, 14.2.
Found: C, 78.03; H, 4.51; N, 14.28%.
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Synthesis of 3-substituted-6-(4-benzoyl-1,5-diphenylpyrazol-3-yl)-
pyridin-2(1H)-ones (12a,b)
To a mixture of the enaminone 6c and malononitrile (1 mmol of each)
in absolute ethanol (25 mL), piperidine (0.5 mL) was added and the
reaction mixture was refluxed for 12 h, then left to cool. The solid
product was filtered off, washed with ethanol, dried and finally recrys-
tallised from EtOH-DMF to afford the corresponding pyridin-2(1H)-
one derivative 12a.
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When the above procedure was repeated using ethyl cyanoacetate
in place of malononiytrile, product 12b was obtained.