Synthesis of Novel Pyrazole Derivatives as Antineoplastic Agent

Article abstract of DOI:10.1002/jhet.2956

Anticancer evaluation of pyrazole 2 and Schiff base 5 is reported. Synthesis of some important heterocyclic compounds via 2,3-diaryloxirane-2,3-dicarbonitrile 1, pyrazole 2, and Schiff base 5 with different nitrogen nucleophiles afforded new routes for synthesized fused heterocyclic derivatives. These compounds can be used as a key starting materials to synthesize some important imidazolo-[4,5-c]pyrazole, pyrazolo[3,4-e]1,2,4-triaging, imidazolo[3,2-b]pyrazole, and pyrazolo-pyrazine, as anticancer reagents showed good results at optimum conditions (400–500?ppm), particularly the bridge head nitrogen compounds, and could be used to improve them. Electromeric effect of the halogen atom in the aryl moieties can be controlled upon the rate of reaction and the yield of the product. The structure of the synthesized new compounds would be characterized by elemental and spectral data.

Full text of DOI:10.1002/jhet.2956

Month 2017
Synthesis of Novel Pyrazole Derivatives as Antineoplastic Agent
a
Sameh A. Rizk,a
Amira A. El-Sayed,
and Marwa M. Mounierb
*
aDepartment of Chemistry, Faculty of Science, University of Ain Shams, 11566 Cairo, Egypt
bDepartment of Pharmacognosy, National Research Centre, Dokki, Cairo 12622, Egypt
*
E-mail: amira_aa47@hotmail.com
Received April 16, 2017
DOI 10.1002/jhet.2956
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
Anticancer evaluation of pyrazole 2 and Schiff base 5 is reported. Synthesis of some important hetero-
cyclic compounds via 2,3-diaryloxirane-2,3-dicarbonitrile 1, pyrazole 2, and Schiff base 5 with different
nitrogen nucleophiles afforded new routes for synthesized fused heterocyclic derivatives. These com-
pounds can be used as a key starting materials to synthesize some important imidazolo-[4,5-c]pyrazole,
pyrazolo[3,4-e]1,2,4-triaging, imidazolo[3,2-b]pyrazole, and pyrazolo-pyrazine, as anticancer reagents
showed good results at optimum conditions (400–500 ppm), particularly the bridge head nitrogen com-
pounds, and could be used to improve them. Electromeric effect of the halogen atom in the aryl moieties
can be controlled upon the rate of reaction and the yield of the product. The structure of the synthesized
new compounds would be characterized by elemental and spectral data.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
RESULTS AND DISCUSSION
Pyrazole is considered as significant tender of
heterocyclic nitrogen compound [1–3], in which
derivatives show a widespread of biological activities
such as anticancer [4,5], anti-inflammatory [6], antifungal
[7,8], antiproliferative [9], insecticidal [10], plant growth
regulation [11], anti-biofilm [12], and herbicidal activities
[13–15]. Numerous pyrazole derivatives, for example,
tebufenpyrad as pesticides and penthiopyrad as
fungicides, have been successfully established. They
characterize an important class of natural and synthetic
products and are extremely useful for the creation of
bioactive materials in medicinal chemistry and
therapeutic drug industry.
Chemistry. The different kinds of electrophilic center in
2,3-diaryloxirane-2,3-dicarbonitrile 1 are allowed to react
with simply bi-nucleophiles [16,17] to afford the new
heterocyclic compounds; they are dependent upon the type
of nucleophile. 2,3-Diaryloxirane-2,3-dicarbonitrile 1 is
allowed to react with hydrazine precursors, such as hydrazine
hydrate, methylhydrazine, and phenylhydrazine to afford
the corresponding pyrazole derivative 2 that proposed the
mechanism of pyrazole product 2 as shown in Scheme 1.
The spectral analysis confirmed the existence of
carbonyl groups and absence of the cyano groups. 1H
NMR spectrum revealed three signals for acidic protons
exchangeable by D2O; these explained the presence of
© 2017 Wiley Periodicals, Inc.

S. A. Rizk, A. A. El-Sayed, and M. M. Mounier
Vol 000
Scheme 1. Outline the mechanism for the formation of compound 2.
amino pyrazole 2 in imine form (cisoid structure) (Fig. 1).
The product’s yields reflected the stability of compounds
2a–f and how the aryl substituents have saved theirs. In
case of derivatives 2e and 2f, intramolecular 1,2[H] shift
occurs to afford the more stable products. The substituted
aryl groups are expected to enhance the reaction rate that
can be affected by the migratory aptitude phenomena.
Synthesized pyrazole derivatives 2a–f can be supported
chemically and has confirmed the two stable resonating
structures (Fig. 1), when they allowed the reaction with
ethyl cyanoacetate. Reaction of pyrazoles 2a–f with ethyl
cyanoacetate at different conditions afforded isomers 3
and 4. Grinding followed by fusion of compounds 2a–f
with ethyl cyanoacetate afforded pyrazolopyrimidone
derivative 3, but when allowed to reflux at normal
condition, these afforded pyrazolopyrazolone derivative 4
(Scheme 2).
Compound 4a ΔE = ELUMO À EHOMO = À3.477 À
(À4.128) = 0.592 is more stable than compound 3a
ΔE = ELUMO-EHOMO = À2.421 À (À7.961) = 5.490. So
the thermochemical reaction afforded the more stable
product 4. But the grinding and fusion reaction
Figure 1. Outline the isomerization of the compound 2 to the cisoid
structure.
Scheme 2. Synthetic routes for compounds 3, 4 and 5 via reaction of compounds 2 with ethylcyanoacetate and aromatic aldehydes respectively.
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Novel Pyrazoles as Antineoplastic
Scheme 3. Synthetic routes for compounds 6 and 7 via reaction of compounds 2 with acetic anhydride and ethylglycinate respectively.
Scheme 4. Synthetic routes for compounds 8, 9 and 10 via reaction of compounds 5.
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S. A. Rizk, A. A. El-Sayed, and M. M. Mounier
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1
approached photochemical reaction that has ΔE = ELUMO(1)
À ELUMO = À1.502 À (À2.421) = 0.919 in compound 3a.
The spectral analysis of the chemical structures of
compounds 3 and 4 was outlined and approved by 1H
NMR. When pyrazole derivatives 2a–f were allowed to
react with aromatic aldehydes, the presence of boiling
ethanol afforded Schiff base 5. The stability of Schiff
base 5 can be controlled upon the migration of the aryl
groups in position 5 in pyrazole moiety, whenever the
attacking nucleophiles approached (see later in the
reaction of Schiff base 5). The presence of halogen atom
in the aryl group of Schiff bases can be affected by their
reactivity. It can be forced upon the rate of reaction and
increased the yield of products (see more in the
Experimental part).
the pyrazole ring. The H and 13C NMR confirmed the
existence of two aryl groups that were in different
positions and not in the same site, which can help us to
form the suggested mechanism that affords imidazolo-
pyrazolone derivatives 6a–d as outlined in Scheme 3. On
the other hand, pyrazole 2a is allowed to react with
ethylglycinate in boiling ethanol to afford pyrazolo[3,4-b]
pyrazine derivative 7.
Reaction of arylidenes 5a–f with ammonium acetate
afforded tetrahydroimidazo[4,5-c]pyrazoles 8a–f, and
products 8a, e treated with ethyl chloroacetate in the
presence of potassium carbonate afforded ester products
9a, b. Treatment of 5a–f with hydrazine hydrate in
ethanol gave pyrazolo[3,4-e]1,2,4-triazines 10a–f in good
yield (Scheme 4) via spontaneous [1,3]-hydrogen shift to
afford more thermodynamic stability. The [1,3]H
migration shift is energetically more favored than the aryl
group is, which transfers to nitrogen, although the authors
think that the electron-rich aryl groups are a good
migrating group, and so they can enhance the rate of
Reaction of pyrazoles 2a–d with acetic anhydride
afforded oxazolopyrazole 6a–d via acetylation and
migration and followed by the ring closure (Scheme 3).
The driving force of the migration of the aryl group is
due to the more thermodynamic stability (aromaticity) of
Scheme 5. Synthetic routes for compounds 11 via reaction of compounds 1 with hydrazine hydrate in boiling butanol.
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Novel Pyrazoles as Antineoplastic
reaction. However, we found experimentally that the time
allowed for the complete reaction of all derivatives 8a–f
was isolated at the same time.
When diaryloxirane dicarbonitrile 1, allowed to react
with hydrazine hydrate in boiling butanol afforded
products 11a–d, we suggested the following mechanism
that afforded imidazolo-pyrazolone derivatives 11a–d as
outlined in Scheme 5.
In the runaway of Schiff bases, the authors
reported that the behavior of 3-(arylidenimino)-5,5-
diphenyl-4-oxo-4,5-dihydropyrazole 5a with aliphatic
amine (e.g., ethylamine, 3-aminopropanol, or benzylamine,
in the presence of formaldehyde) via [4 + 2] cycloaddition
afforded pyrazolo[2,3-a]1,3,5-triazine derivatives 12a–c.
In the same manner, reaction of 3-(benzylideneamino)-
5,5-diphenyl-4-oxo-4,5-dihydropyrazole 5a with aromatic
amine, formaldehyde, in boiling dioxane afforded
N-substituted pyrazolone derivatives 13a–c via the
Mannich reaction (Scheme 6).
The homoannular diene tautomer can be equilibrated
and shifted to more stable pyrazolo[3,4-b]pyrazinone 7,
which can be evident by cyclization via the treatment of
7 with chloroacetic acid in the presence of phosphorous
oxychloride that afforded fused tricyclic heterocycle 14.
New chalcone 16 could be synthesized via reaction of
tricyclic derivative 15 with benzaldehyde (Scheme 7),
which garnered great attention because of its pharmaceutical
and biocidal activities [18].
Anticancer moiety. Eleven compounds were assayed
over three different human tumor cell lines using 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide
(MTT) assay as illustrated in Table 1 and Figure 2.
From Table 1, 10a possessed the highest cytotoxicity on
breast human tumor cell line (MCF-7). Therefore, it is
subjected to further assay at lower concentrations (50, 25,
and 12.5 ppm) to calculate their LC50, which is
8.4 0.02 on MCF-7. On the one hand, 2d, 8a, 12a, and
13a showed moderate activity over MCF-7. Meanwhile,
Scheme 6. Synthetic routes for compounds 12 and 13 via reaction of compound 5a with different mannish reagents.
Scheme 7. Synthetic routes for compounds 14, 15 and 16 via reaction of compounds 7 with different carbon electrophiles.
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S. A. Rizk, A. A. El-Sayed, and M. M. Mounier
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Table 1
Compound 10, which possessed high activity over each
carcinoma cell line, was further assayed at lower
concentrations to calculate their LC50 (Table 2).
Screening the cytotoxicity of sample, in vitro, against three human tumor
cell lines: breast carcinoma (MCF-7), colon carcinoma (HCT-116), and
hepatocellular carcinoma (HepG2).
Cytotoxicity (%)
CONCLUSION
Sample
MCF-7
HCT-116
HepG-2
2a
2d
5a
5d
6b
7
8a
10a
11a
12a
13a
Doxorubicin
18.9
63.7
2.1
10.4
6.8
10.5
11.1
7.5
12.6
27.4
40
8.5
0
I- In the present work, the authors successfully synthe-
sized a series of some important Schiff bases and novel
fused heterocycle derivatives, which are expected to
enhance the biological profile manyfold than do their
parent nuclei. Migration of the aryl groups in deriva-
9.8
5.7
14.5
6.8
18.2
48.1
6
21
7.8
99.5
5.5
13.1
10.1
38.2
96.6
13.4
46.4
39.9
99
1
tives of 2, 5, 11, and 7 is confirmed by H and 13C
1.1
NMR. The authors also successfully synthesized a se-
ries of some important derivatives, for example, amino
triazinone 10, pyrrolotriazine 12, pyrazolopyrazinone
13, tricyclic 15, and chalcone 16. Matching mono- or
bi-heterocyclic structure to the pyrazole moiety will be
enhanced the biological activity and become as bio-
isosterstructures.
22.6
17.2
98
Each result is a mean of three replicate samples.
II- Eleven compounds were preliminarily screened at
100 ppm for their cytotoxicity using three human tumor
cell lines [human breast carcinoma (MCF-7), human
colon carcinoma (HCT-116), and hepatocellular carci-
noma (HepG2).
EXPERIMENTAL
General.
All the chemicals and solvents, purchased
from Sigma-Aldrich (Egyptian branch, Egyptian
International Center for Import, Cairo, Egypt), were used
without further purification. Thin-layer chromatography
analyses of compounds were performed on silica gel
G-coated aluminum foils. The solutions of compounds
were applied as a spot on the aluminum foils about 2 cm
above the lower edge. The mobile phases were selected
according to the polarity of compounds (ethyl acetate:
hexane). All melting points were determined by using
open capillary melting point apparatus. Fourier transform
infrared FT-IR spectra (KBr) were recorded on a Thermo-
Scientific (Nicole 6700) spectrophotometer (Thermo
Electron Corporation, Waltham, MA). The 1H NMR
spectra were recorded on Bruker 800 (13C) (Bruker,
Middle East Branch Dubai) and Joel 400 (1H) MHz (Jeol
Service Bureau, Egypt), respectively, with high-resolution
NMR spectrometer using trimethylsily as an internal
standard. Chemical shifts were reported in ppm (δ), and
signals were described as singlet (s), doublet (d), triplet
(t), and multiple (m). The mass spectra were recorded via
direct infusion on a Waters Micro-Mass ZQ 2000 mass
spectrophotometer (Edwards / Waters Alliance, Milford,
MA), and data were acquired from electrospray ionization
Figure 2. The results of screening the cytotoxicity of 11 compounds,
in vitro, against three human tumor cell lines: breast carcinoma
(MCF-7), colon carcinoma (HCT-116), and hepatocellular carcinoma
(HepG2). [Color figure can be viewed at wileyonlinelibrary.com]
Table 2
LC50 (the concentration required to kill 50% of the cell population) of
active compound exhibiting more than 60% cytotoxicity on cell lines of
breast carcinoma (MCF-7).
LC50
Compound
MCF-7
10a
Doxorubicin
8.4 0.02
26.1 ( 1.3)
Values of LC50 ( standard errors) are calculated using SPSS statistical
program.
2a, 5a, 5d, 6b, 7, and 11a have weak cytotoxic effect on
MCF-7. On the other hand, 10a showed moderate
activity on both HCT-116 and HepG-2, while 2a, 2d, 5a,
5d, 6b, 7, 11a, and 12a have weak cytotoxicity on HCT-
116 and HepG-2.
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Novel Pyrazoles as Antineoplastic
source. Later, the microanalysis was performed by atomic
absorption spectrophotometer. All compounds were
analyzed for C, H, N, and Cl using Elementar (Vario
Micro Cube) (Elementar India Pvt Ltd, India), where
combustion tube was ignited at 1150°C, reduction tube
temperature was 850°C, and pressure was maintained at
1200 mbar using helium and oxygen gas. The mass
spectra were recorded on Shimadzu GCMS-QP-1000 EX
mass spectrometer (Kyoto, Japan) at 70 eV using the
electron ionization technique.
(CH), 131.3 (CH), 132.6 (2CH), 135.6 (CH), 139.6
(CH), 141.5 (C), 167.4 (C), 190.2 (C) and Anal. Calcd.
for C15H11Cl2N3O (320): C, 56.25; H, 3.44; N, 13.16;
Cl, 22.15. Found: C, 56.47; H, 3.39; N, 13.12; Cl, 21.88.
MS: m/z 320 [M+.], 284.5 [M+ À Cl], 234, 193, 137.5.
3-Amino-5,5-bis(furan-2-yl)-4-oxo-4,5-dihydropyrazole
(2d).
Yield 65%, mp 182–184°C, EtOH. IR (KBr): ν
1
[3457, 3338] (NH, NH2), 3065 (CHAr), 1718 (CO). H
NMR (DMSO): δ 6.82–7.12 (m, 6H, ArH), 6.2, 8.5, and
12.9 (s, 3NH, acidic protons exchanged in D2O); 13C
NMR: δ 119.4 (2C), 131.6 (CH), 132.2 (CH), 137.2
(CH), 137.9 (CH), 141.6 (CH), 141.9 (CH), 143.5 (C),
168.4 (C), 190.1 (C) and Anal. Calcd. for C11H9N3O3
(231): C, 57.14; H, 3.89; N, 18.18. Found: C, 57.10; H,
3.75; N, 18.15. MS: m/z 231 [M+.], 203 [M+. À CO],
176, 160, 93, 70.
General procedure for the preparation of compound 1 is
described in the literature [1]. A mixture of K4[Fe(CN)6]
(0.2 mmol) and aroyl chloride (1 mmol) was refluxed at
170°C for 1 h. After cooling the reaction mixture,
triphenyl-phosphine (0.5 mmol), and triethylamine
(0.02 mmol) in CH2Cl2 (20 mL) were added slowly, and
the reaction mixture was refluxed for 3 h. The reaction
was monitored by thin-layer chromatography. After
completion of the reaction, it was neutralized with
concentrated hydrochloric acid solution, and the precipitate
was filtered and recrystallized with proper solvent.
3-Amino-5,5-diphenyl-1-methyl-4-oxo-4,5-dihydropyrazole
(2e).
Yield 64%, mp 204–206°C, EtOH. IR (KBr): ν
[3324] (NH), 3056 (CHAr), 1722 (CO). 1H NMR
(DMSO): δ 3.36 (s, 3H, CH3), 7.21–7.66 (m, 10H, ArH),
6.3, 8.6 (s, 2NH, acidic protons exchanged in D2O); 13C
NMR: δ 35.2 (CH3), 113.2 (2C), 122.4 (2CH), 128.6
(2CH), 130.8 (CH), 131.7 (CH), 133.1 (2CH), 135.2
(CH), 137.7 (CH), 145.2 (C), 168.4 (C), 190.0 (C) and
Anal. Calcd. for C16H15N3O (265): C, 72.45; H, 5.66; N,
15.84. Found: C, 72.38; H, 5.58; N, 15.80. MS: m/z 265
[M+.], 253, 209, 158, 103, 85.
General procedure for the preparation of compound 2.
Reflux an equimolar mixture of compound 1 (0.01 mol)
and hydrazine derivatives (0.01 mol) in ethanol (30 mL)
for 5–6 h. The solid that separated after cooling was
filtered off, washed by petroleum ether (bp 40–60°C),
dried, and crystallized from the proper solvents.
3-Amino-5,5-diphenyl-4-oxo-4,5-dihydropyrazole (2a). Yield
73%, mp 230–232°C, EtOH. IR (KBr): ν [3310, 3270] (NH,
NH2), 3052 (CHAr), 1720 (CO). 1H NMR (DMSO): δ 7.38–
7.56 (m, 10H, ArH), 11.8 and 13.2 (s, 3NH, acidic protons
exchanged in D2O); 13C NMR: δ 112 (2C), 120.4 (2CH),
129.6 (2CH), 130.5 (CH), 131.5 (CH), 132.3 (2CH), 134.8
(CH), 137.4 (CH), 143.4 (C), 168.0 (C), 190.2 (C) and
Anal. Calcd. for C15H13N3O (251): C, 71.70; H, 5.21; N,
16.70. Found: C, 71.60; H, 5.15; N, 16.50. MS: m/z: 251
[M+.], 194, 180, 158, 121, 103.
3-Amino-1,5,5-triphenyl-4-oxo-4,5-dihydropyrazole (2f). Yield
60%, mp 218–220°C, EtOH. IR (KBr): ν 3321 (NH), 3060
1
(CHAr), 1720 (CO). H NMR (DMSO): δ 7.28–7.80 (m,
15H, ArH), 5.9, 8.5 (s, 2NH, acidic protons exchanged in
D2O); 13C NMR: δ 109.2 (2C), 121.8 (2CH), 122.6
(2CH), 126.8 (CH), 128.6 (2CH), 130.8 (CH), 131.7
(CH), 132.1 (2CH), 133.1 (2CH), 134.2 (CH), 135.2
(CH), 137.7 (CH), 145.2 (C), 168.4 (C), 190.0 (C) and
Anal. Calcd. for C21H17N3O (327): C, 72.45; H, 5.66; N,
15.84. Found: C, 72.38; H, 5.58; N, 15.80. MS: m/z 327
[M+.], 236, 193, 179, 147, 132, 103.
3-Amino-5,5-bis(2-chlorophenyl)-4-oxo-4,5-dihydropyrazole
General procedure for the preparation of compound 3.
A mixture of 2 (0.01 mol) and ethyl cyanoacetate
(0.05 mol) was grinded together using a mortar and
pestle for 25–30 min. And fusion of the reaction mixture
was for 1 h. The color of the reaction mixture turned
light yellow from colorless starting reactants. The
progress of the reaction was monitored by thin-layer
chromatography using CHCl3:EtOAC 50:50 as solvent
system. Then the reaction mixture was left overnight
whereby a yellow solid crude product was obtained,
which was recrystallized.
(2b). Yield 74%, mp 246–248°C, EtOH. IR (KBr): ν [3436,
3276] (NH, NH2), 3063 (CHAr), 1712 (CO). 1H NMR
(DMSO): δ 7.43–7.82 (m, 8H, ArH), 6.5, 8.4, and 13.2 (s,
3NH, acidic protons exchanged in D2O), 13C NMR: δ 114
(2C), 121.6 (2CH), 128.4 (2CH), 130.8 (CH), 131.9 (CH),
133.6 (2CH), 134.6 (CH), 136.9 (CH), 143.5 (C), 168.4
(C), 190.1 (C) and Anal. Calcd. for C15H11Cl2N3O (320):
C, 56.27; H, 3.46; N, 13.12; Cl, 22.15. Found: C, 56.55; H,
3.35; N, 13.07; Cl, 21.82. MS: m/z 292 [M+. À CO], 284.5
[M+. À Cl], 262, 234, 193.5, 137.5, 70, 56.
3-Amino-5,5-bis(3-chlorophenyl)-4-oxo-4,5-dihydropyrazole
(2c).
Yield 77%, mp 238–240°C, EtOH. IR (KBr): ν
7-Amino-2,2-diphenyl-1,2-dihydropyrazolo[1,5-a]pyrimidine-
3,5-dione (3a). Yield 82%, mp 140–142°C, crystallized
1
[3390, 3255] (NH, NH2), 3055 (CHAr), 1706 (CO). H
NMR (DMSO): δ 7.45–7.7 (m, 8H, ArH), 6.7, 8.3, and
13.2 (s, 3NH, acidic protons exchanged in D2O); 13C
NMR: δ 113.6 (2C), 122.1 (2CH), 128.0 (2CH), 129.9
from EtOH. IR (KBr): ν 3357, 3245 (NH, NH2), 3056
1
(CHAr), 1695, 1666 (CO). H NMR (DMSO): δ 6.11 (s,
1H, ═CH), 7.15–7.70 (m, 10H, ArH), 5.21, 6.50 (s, 3NH,
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S. A. Rizk, A. A. El-Sayed, and M. M. Mounier
Vol 000
acidic protons exchanged in D2O); 13C NMR: δ 73.2 (CH),
92.8 (C), 126.7 (2CH), 127.9 (2CH), 129.4 (4CH), 130.9
(2CH), 137.4 (2C), 150.9 (C═N), 161.4 (C═O), 171.2
(═C–NH2), 203.1 (C) and Anal. Calcd. for C18H14N4O2
(318): C, 67.92; H, 4.43; N, 17.60. Found: C, 67.63; H,
3NH, acidic protons exchanged in D2O); 13C NMR: δ
75.4 (CH), 94.3 (C), 127.4 (2CH), 129.2 (2CH), 130.2
(4CH), 130.9 (2CH), 137.4 (2C), 151.7 (C═N), 169.2
(═C–NH2), 170.4 (C═O), 200.4 (C) and Anal. Calcd. for
C18H14N4O2 (318): C, 67.92; H, 4.43; N, 17.60. Found:
C, 67.40; H, 4.25; N, 17.10. MS: m/z 318 [M+.], 241,
4.29; N, 17.29. MS: m/z 318 [M+.], 241, 159, 105.
7-Amino-5,5-bis(2-chlorophenyl)-1,2-dihydropyrazolo[1,5-a]
159, 105.
pyrimidine-3,5-dione (3b).
Yield 85%, mp 162–164°C,
3-Amino-5,5-bis(2-chlorophenyl)-7-imino-7-hydro-1H,5H-
pyrazolo[1,2-a]pyrazole-1,6-dione (4b).
Yield 77%, mp
crystallized from EtOH. IR (KBr): ν 3299, 3233 (NH,
NH2), 3054 (CHAr), 1702, 1668 (CO). 1H NMR
(DMSO): δ 6.02 (s, 1H, ═CH), 7.23–7.80 (m, 8H, ArH),
5.7, 6.4 (s, 3NH, acidic protons exchanged in D2O); 13C
NMR: δ 73.6 (CH), 92.3 (C), 127.6 (2CH), 129.1 (2CH),
130.6 (2CH), 131.3 (2CH), 137.2 (2C), 149.3 (2C), 153.2
(C═N), 170.2 (═C–NH2), 171.1 (C═O), 203.1 (C) and
Anal. Calcd. for C18H12Cl2N4O2 (386): C, 55.83; H,
3.12; Cl, 18.31; N, 14.47. Found: C, 55.41; H, 3.00; Cl,
18.00; N, 14.05. MS: m/z 386 [M+.], 350.5 [M+. À Cl],
216–218°C, crystallized from dioxane. IR (KBr): ν 3336,
3226 (NH), 3062 (CHAr), 1705, 1670 (CO). 1H NMR
(DMSO): δ 4.32 (s, 1H, ═CH), 7.5–7.8 (m, 8H, ArH),
6.3, 9.1 (s, 3NH, acidic protons exchanged in D2O); 13C
NMR: δ 76.8 (CH), 94.5 (C), 128.4 (2CH), 129.6
(2CH), 130.6 (2CH), 131.3 (2CH), 139.2 (2C), 151.6
(2C), 153.2 (C═N), 170.2 (═C–NH2), 171.1 (C═O),
203.1 (C) and Anal. Calcd. for C18H12Cl2N4O2 (386): C,
55.83; H, 3.12; Cl, 18.31; N, 14.47. Found: C, 55.45;
H, 3.08; Cl, 18.11; N, 14.00. MS: m/z 386 [M+.], 315
194, 140, 70.
[M+. À 2Cl], 194, 140, 70.
7-Amino-5,5-bis(3-chlorophenyl)-1,2-dihydropyrazolo[1,5-a]
pyrimidine-3,5-dione (3c).
Yield 80%, mp 184–186°C,
3-Amino-5,5-bis(3-chlorophenyl)-7-imino-7-hydro-1H,5H-
pyrazolo[1,2-a]pyrazole-1,6-dione (4c).
Yield 72%, mp
crystallized from EtOH. IR (KBr): ν 3336, 3267 (NH,
NH2), 3062 (CHAr), 1701, 1676 (CO). 1H NMR
(DMSO): δ 6.02 (s, 1H, ═CH), 7.5–7.8 (m, 8H, ArH),
5.3, 6.1 (s, 3NH, acidic protons exchanged in D2O); 13C
NMR: δ 73.6 (CH), 94.1 (C), 128.0 (2CH), 129.9 (2CH),
130.3 (2CH), 132.6 (2CH), 138.6 (2CH), 149.6 (2CH),
151.5 (C═N), 153.2 (C═O), 169.4 (═C–NH2), 204.2
(C═O) and Anal. Calcd. for C18H12Cl2N4O2 (386): C,
55.83; H, 3.12; Cl, 18.31; N, 14.47. Found: C, 55.40; H,
2.97; Cl, 17.95; N, 13.93. MS: m/z 386 [M+.], 350.5
238–240°C, crystallized from DMF. IR (KBr): ν 3336,
3226 (NH), 3062 (CHAr), 1705, 1670 (CO). 1H NMR
(DMSO): δ 4.32 (s, 1H, ═CH), 7.5–7.8 (m, 10H, Ar-H),
6.3, 9.1 (s, 3NH, acidic protons exchanged in D2O); 13C
NMR: δ 79.6 (CH), 95.1 (C), 128.0 (2CH), 129.9
(2CH), 131.3 (2CH), 132.6 (2CH), 139.6 (2C), 147.6
(2C), 152.1 (C═N), 168.5 (═C–NH2), 169.4 (C═O),
201.2 (C) and Anal. Calcd. for C18H12Cl2N4O2 (386): C,
55.83; H, 3.12; Cl, 18.31; N, 14.47. Found: C, 55.25;
H, 3.03; Cl, 18.02; N, 13.87. MS: m/z 386 [M+.], 350.5
[M+. À Cl], 194, 140, 70.
[M+. À Cl], 194, 140, 70.
7-Amino-5,5-bis(furan-2-yl)-1,2-dihydropyrazolo[1,5-a]
pyrimidine-3,5-dione (3d).
Yield 75%, mp 128–130°C,
3-Amino-5,5-di(furan-2-yl)-7-imino-7-hydro-1H,5H-pyrazolo
[1,2-a]pyrazole-1,6-dione (4d). Yield 68%, mp 204–206°C,
crystallized from EtOH. IR (KBr): ν 3448, 3327 (NH,
1
crystallized from dioxane. IR (KBr): ν 3402, 3321 (NH),
3058 (CHAr), 1703, 1672 (CO). 1H NMR (DMSO): δ
4.11 (s, 1H, ═CH), 6.62–7.54 (m, 6H, furH), 5.6, 9.3 (s,
3NH, acidic protons exchanged in D2O); 13C NMR: δ
75.8 (CH), 92.9 (C), 109.5 (2CH), 111.2 (2CH), 141.2
(2CH), 151.5 (C═N), 151.9 (2C), 167.4 (═C–NH2),
169.9 (C═O), 200.1 (C═O) and Anal. Calcd. for
C14H10N4O4 (298): C, 56.38; H, 3.38; N, 18.79. Found:
C, 56.09; H, 3.06; N, 18.05. MS: m/z 298 [M+.], 270
[M+. À CO], 194, 175.
NH2), 3058 (CHAr), 1700, 1667 (CO). H NMR (DMSO):
δ 6.02 (s, 1H, ═CH), 6.96–7.74 (m, 6H, ArH), 5.6, 6.5
(s, 3NH, acidic protons exchanged in D2O); 13C NMR: δ
72.8 (CH), 92.9 (C), 111.2 (2CH), 115.2 (2CH), 136.9
(2CH), 151.2 (2C), 151.6 (C═N), 153.5 (C═O), 169.4
(═C–NH2), 202.1 (C═O) and Anal. Calcd. for C14H10N4O4
(298): C, 56.38; H, 3.38; N, 18.79. Found: C, 56.00; H,
3.00; N, 18.00. MS: m/z 298 [M+.], 270 [M+. À CO], 194,
175.
General procedure for the preparation of compound 4.
A mixture of 2 (0.01 mol) and ethyl cyanoacetate
(0.015 mol) in pyridine (10 mL) was heated under reflux
for 6 h. The reaction mixture was allowed to cool and
poured into ice/conc. HCl, and the product was filtered,
General procedure for the preparation of compound 5.
Reflux an equimolar mixture of compound 2 (0.01 mol)
and aromatic aldehydes, namely, benzaldehyde, 4-
chlorobenzaldehyde,
and
2-chlorobenzaldehyde
(0.01 mol), in ethanol (30 mL) for 2–6 h. The solid that
separated after cooling was filtered off, dried, and
crystallized from the proper solvents.
dried, and crystallized from suitable solvent.
3-Amino-5,5-diphenyl-7-imino-7-hydro-1H,5H-pyrazolo[1,2-
a]pyrazole-1,6-dione (4a).
Yield 73%, mp 222–224°C,
crystallized from EtOH. IR (KBr): ν 3276, 3214 (NH),
3062 (CHAr), 1702, 1672 (CO). 1H NMR (DMSO): δ
4.21 (s, 1H, ═CH), 7.2–7.7 (m, 8H, ArH), 6.1, 9.2 (s,
3-(Benzylideneamino)-5,5-diphenyl-1H-pyrazol-4(5H)-one
(5a).
Yield 70%, mp 212–214°C, EtOH. IR (KBr): ν
1
3421 (NH), 3056 (CHAr), 1706 (CO). H NMR (DMSO):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Novel Pyrazoles as Antineoplastic
δ 6.2 (s, 1H, CH═), 7.16–7.72 (m, 15 ArH), 13.2 (s, 1H,
acidic NH protons exchanged in D2O); 13C NMR: δ 112
(2C), 114.8 (CH), 117.4 (CH), 120.4 (2CH), 128.2
(2CH), 129.1 (2CH), 130.5 (CH), 131.5 (CH), 132.2
(2CH), 133.8 (2CH), 134.8 (CH), 137.4 (C), 138.2 (CH),
143.4 (C), 167.0 (C), 189.7 (C) and Anal. Calcd. for
C22H17N3O (339): C, 77.87; H, 5.01; N, 12.38. Found:
C, 77.81; H, 5.05; N, 12.32. MS: m/z 339 [M+.], 246,
Calcd. for C22H16ClN3O (373.5): C, 70.68; H, 4.28; N,
11.24; Cl, 9.48. Found: C, 70.65; H, 4.26; N, 11.21; Cl,
9.38. MS: m/z 373.5 [M+.], 219.5 [M+. À biphenyl], 194,
179, 166.
3-(2-Chlorobenzylideneamino)-5,5-bis(3-chlorophenyl)-1H-
pyrazol-4(5H)-one (5f).
Yield 80%, mp 244–246°C,
EtOH. IR (KBr): ν 3289 (NH), 3050 (CHAr), 1721 (CO).
1H NMR (DMSO): δ 6.42 (s, 1H, CH═), 7.28–7.94 (m,
12ArH), 12.6 (s, 1H acidic NH proton exchanged in
D2O); 13C NMR: δ 109.2 (2C), 115.4 (CH), 118.9 (2C),
119.4 (2CH), 122.6 (2CH), 125.8 (CH), 126.7 (2CH),
130.8 (C), 131.7 (CH), 133.1 (2CH), 135.2 (CH), 137.7
(CH), 138.1 (C), 145.2 (C), 168.4 (C), 190.0 (C) and
Anal. Calcd. for C22H14Cl3N3O (442.5): C, 59.66; H,
3.17; N, 9.51; Cl, 24.02. Found: C, 59.55; H, 3.05; N,
9.22; Cl, 24.14. MS: m/z 444.5 [M+. + 2], 442.5 [M+.],
305, 260, 179.
General procedure for the preparation of compound 6.
Reflux a mixture of 2a–d (0.01 mol) and acetic anhydride
(0.1 mol) on water bath for 2 h. The excess acetic
anhydride was removed by distillation, and the separated
product was washed by (pet 40–60), dried, and
194, 178, 166, 145.
3-(Benzylideneamino)-5,5-bis(2-chlorophenyl)-1H-pyrazol-
4(5H)-one (5b). Yield 74%, mp 226–228°C, EtOH. IR
1
(KBr): ν 3322 (NH), 3058 (CHAr), 1670 (CO). H NMR
(DMSO): δ 6.2 (s, 1H, CH═), 7.16–7.72 (m, 13ArH),
13.0 (s, 1H, acidic NH protons exchanged in D2O); 13C
NMR: δ 109.5 (2C), 113.7 (CH), 115.4 (CH), 119.8
(2CH), 124.2 (2CH), 129.1 (2CH), 131.3 (CH), 131.7
(CH), 132.6 (2CH), 133.4 (2CH), 135.3 (C), 137.6 (CH),
139.2 (CH), 143.4 (C), 168.3 (C), 191.2 (C) and Anal.
Calcd. for C22H15Cl2N3O (408): C, 64.72, H, 3.68; N,
10.31; Cl, 17.37. Found: C, 64.83, H, 3.65, N, 10.35, Cl,
17.00. MS: m/z 391 [M+. À OH], 295, 280, 264, 236,
193, 145.
3-(Benzylideneamino)-5,5-bis(3-chlorophenyl)-1H-pyrazol-
4(5H)-one (5c). Yield 76%, mp 252–254°C, EtOH. IR
(KBr): ν 3264 (NH), 3058 (CHAr), 1729 (CO). H NMR
crystallized from toluene–ethanol mixture.
5-Methyl-2,3-diphenyl-2H-pyrazolo[3,4-d]oxazole (6a). Yield
1
75%, mp 140–142°C. IR (KBr): 3062 (CHAr), 2950 (CHAli),
1636 (C═N). 1H NMR (DMSO): δ 3.43 (s, 3H, CH3),
7.19–7.76 (m, 10ArH); 13C NMR: δ 22.1 (CH3), 112.1
(CH), 121.2 (CH), 128.8 (2CH), 133.2 (CH), 133.7 (CH),
134.2 (CH), 134.8 (CH), 137.6 (CH), 138.7 (CH), 140.2
(C), 142.1 (C), 143.4 (C), 144.5 (C), 155.2 (C), 190.4 (C)
and Anal. Calcd. for C17H13N3O (275): C, 74.18; H, 4.72;
N, 15.27. Found: C, 74.20; H, 4.75; N, 15.24. MS: m/z 275
(DMSO): δ 6.2 (s, 1H, CH═), 7.12–7.89 (m, 13ArH),
12.9 (s, 1H acidic NH proton exchanged in D2O); 13C
NMR: δ 110.7 (2C), 112.9 (CH), 114.4 (CH), 120.8
(2CH), 123.2 (2CH), 128.1 (2CH), 130.8 (CH), 131.2
(CH), 132.1 (2CH), 132.8 (2CH), 134.3 (C), 136.8 (CH),
138.1 (CH), 141.1 (C), 168.4 (C), 190.0 (C) and Anal.
Calcd. for C22H15Cl2N3O (408): C, 64.72; H, 3.67; N,
10.31; Cl, 17.37. Found: C, 64.80; H, 3.63; N, 10.33; Cl,
[M+], 260, 246, 232 [M+ À CH3CO], 198.
17.12. MS: m/z 408 [M+.], 354, 236, 260, 235, 145.
3-(Benzylideneamino)-5,5-di(furan-2-yl)-1H-pyrazol-4(5H)-
one (5d). Yield 64%, mp 210–212°C, EtOH. IR (KBr):
2,3-Bis(2-chlorophenyl)-5-methyl-2H-pyrazolo[3,4-d]oxazole
(6b).
Yield 77%, mp 152–154°C. IR (KBr): 3049
1
(CHAr), 2980 (CHAli), 1630 (C═N). H NMR (DMSO): δ
3.68 (s, 3H, CH3), 7.10–7.38 (m, 8H, ArH). 13C NMR: δ
22.6 (CH3), 110.1 (CH), 121.3 (CH), 128.9 (CH), 129.3
(CH), 132.5 (CH), 133.2 (CH), 133.6 (CH), 135.6 (2C),
137.6 (CH), 140.2 (C), 141.5 (C), 143.4 (C), 144.1 (C),
158.2 (C), 189.7 (C) and Anal. Calcd. for C17H11Cl2N3O
(344): C, 59.30; H, 3.20; N, 12.24; Cl, 20.60. Found: C,
59.44; H, 3.18; N, 12.23; Cl, 20.37. MS: m/z 344 [M+],
ν 3278 (NH), 3080 (CHAr), 1719 (CO). 1H NMR
(DMSO): δ 7.12–7.91 (m, 12ArH and olefinic proton),
12.7 (s, 1H, acidic NH proton exchanged in D2O); 13C
NMR: δ 120.4 (2C), 125.6 (2CH), 129.2 (CH), 131.6
(2CH), 132.2 (CH), 133.2 (CH), 134.9 (C), 136.2 (CH),
137.5 (CH), 138.2 (CH), 140.8 (CH), 141.9 (CH), 143.5
(C), 168.4 (C), 190.1 (C) and Anal. Calcd. for
C18H13N3O3 (319): C, 67.71; H, 4.07; N, 13.16. Found:
C, 67.70; H, 4.02; N, 13.15. MS: m/z 319 [M+.], 224,
328, 251, 232.
2,3-Bis(3-chlorophenyl)-5-methyl-2H-pyrazolo[3,4-d]oxazole
(6c). Yield 74%, mp 146–148°C. IR (KBr): 3050 (CHAr),
172, 148, 145.
3-(4-Chlorobenzylideneamino)-5,5-diphenyl-1H-pyrazol-
4(5H)-one (5e). Yield 72%, mp 226–228°C, EtOH. IR
1
2952 (CHAli), 1613 (C═N). H NMR (DMSO): δ 3.59
(s, 3H, CH3), 7.22–7.75 (m, 8H, ArH). 13C NMR: δ
22.4 (CH3), 109.6 (CH), 121.7 (CH), 129.7 (2CH),
132.5 (CH), 133.2 (CH), 133.6 (CH), 134.6 (CH),
138.6 (2C), 140.2 (C), 141.5 (C), 143.4 (C), 144.1 (C),
152.6 (C), 190.2 (C) and Anal. Calcd. for
C17H11Cl2N3O: C, 59.30; H, 3.20; N, 12.24; Cl, 20.60.
Found: C, 59.46; H, 3.19; N, 12.22; Cl, 20.39. MS:
m/z 344 [M+], 328, 285, 121.
(KBr): ν 3290 (NH), 3052 (CHAr), 1722 (CO). 1H NMR
(DMSO): δ 6.57 (s, 1H, CH═), 7.31–7.95 (m, 14ArH),
12.5 (s, 1H, acidic NH proton exchanged in D2O); 13C
NMR: δ 113.2 (CH), 113.8 (2C), 119.4 (2CH), 122.6
(2CH), 125.8 (CH), 126.7 (2CH), 128.6 (2CH), 130.8
(C), 131.7 (CH), 133.1 (2CH), 135.2 (CH), 137.7 (CH),
138.1 (C), 145.2 (C), 168.4 (C), 190.0 (C) and Anal.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. A. Rizk, A. A. El-Sayed, and M. M. Mounier
Vol 000
2,3-Bis(furan-2-yl)-5-methyl-2H-pyrazolo[3,4-d]oxazole
1H NMR: (DMSO): δ 5.3 (s, 1H, CHAr), 7.22–7.89 (m,
13ArH), 10.1 and 12.9 (s, 2NH, acidic protons
exchanged in D2O); 13C NMR: δ 110.7 (2C), 112.9
(CH), 114.4 (CH), 120.8 (2CH), 123.2 (2CH), 128.1
(2CH), 130.8 (CH), 131.2 (CH), 132.1 (2CH), 132.8
(2CH), 134.3 (C), 136.8 (CH), 138.1 (CH), 141.1 (C),
167.4 (C), 168.0 (C) and Anal. Calcd. for C22H16Cl2N4
(407): C, 64.88; H, 3.96; N, 17.41; Cl, 13.76. Found: C,
65.01; H, 3.94; N, 17.27; Cl, 13.78. MS: m/z 371.5
[M+. À Cl], 295, 281.
(6d).
Yield 70%, mp 136–138°C. IR (KBr): 3061
1
(CHAr), 2922 (CHAli), 1630 (C═N), H NMR (DMSO): δ
4.14 (s, 3H, CH3), 6.96–7.55 (m, 6H, ArH). 13C NMR: δ
23.2 (CH3), 129.7 (CH), 132.5 (CH), 133.6 (CH), 134.6
(CH), 138.6 (CH), 138.9 (CH), 141.5 (C), 143.4 (C),
144.1 (C), 189.6 (2C), 192.2 (C) and Anal. Calcd. for
C13H9N3O3 (255): C, 61.17; H, 3.52; N, 16.47. Found:
C, 61.15; H, 3.50; N, 16.43. MS: m/z 255 [M+], 240,
197, 188.
3,3-Diphenyl-6-oxo-1,2,7-trihydro-pyrazolo[3,4-b]pyrazine
(7). Reflux a mixture of 2a (0.01 mol) and ethylglycinate
3,3-Di(furan-2-yl)-5-phenyl-1,2,3,5-tetrahydroimidazo[4,5-c]
pyrazole (8d). Yield 76%, mp 224–228°C. IR (KBr): ν
1
(0.01 mol) in ethanol (30 mL) for 4 h. The solid that
separated after cooling was filtered off, dried, and
crystallized from dioxane. Yield 70%, mp 164–166°C. IR
(KBr): ν 3317, 3256 (NH), 3050 (CHAr), 1668 (C═O). 1H
NMR: (DMSO): δ 6.8 (s, 1H, CHpy), 7.21–7.70
(m, 10ArH), 6.4, 9.7, and 12.4 (s, 3NH, acidic protons
exchanged in D2O), and Anal. Calcd. for C17H14N4O
(290): % C, 70.34; H, 4.82; N, 19.31. Found: % C, 70.30;
H, 4.78; N, 19.28. MS: m/z 290 [M+.], 167, 123, 136.
General procedure for the preparation of compound 8.
Heat a mixture of 5 (0.01 mol) and ammonium acetate
(0.03 mol) in an oil bath at 190°C for 1–4 h. After
cooling, the mixture was poured onto water; the solid
3278, 3232 (NH), 3080 (CHAr), 1617 (C═N). H NMR:
(DMSO): δ 4.8 (s, 1H, CHAr), 6.64–7.23 (m, 11ArH),
10.2 and 12.7 (s, 2NH, acidic protons exchanged in
D2O); 13C NMR: δ 121.1 (2C), 124.6 (CH), 128.2
(2CH), 130.6 (CH), 131.2 (2CH), 133.2 (CH), 135.2 (C),
136.2 (CH), 137.5 (CH), 138.2 (CH), 140.8 (CH), 143.2
(CH), 144.5 (C), 167.4 (C), 168.1 (C) and Anal. Calcd.
for C18H14N4O2 (318): C, 67.91; H, 4.43; N, 17.60.
Found: C, 67.89; H, 4.37; N, 17.58. MS: m/z 318 [M+.],
147, 170, 148, 82.
5-(4-Chlorophenyl)-3,3-diphenyl-1,2,3,5-tetrahydroimidazo
[4,5-c]pyrazole (8e). Yield 72%, mp 226–228°C. IR (KBr):
1
ν 3323, 3190 (NH), 3052 (CHAr), 1620 (C═N). H NMR
that separated was filtered off, dried, and crystallized
from DMF.
3,3,5-Triphenyl-1,2,3,5-tetrahydroimidazo[4,5-c]pyrazole
(DMSO): δ 5.0 (s, 1H, CH-Ar), 7.11–7.75 (m, 14ArH),
10.3 and 12.5 (s, 2NH, acidic protons exchanged in D2O);
13C NMR: δ 113.2 (CH), 111.4 (2C), 117.4 (2CH), 123.6
(2CH), 126.8 (2CH), 127.2 (CH), 129.3 (2CH), 130.5 (C),
131.8 (CH), 132.7 (2CH), 136.2 (CH), 137.7 (CH), 138.1
(C), 144.2 (C), 167.4 (C), 168.3 (C) and Anal. Calcd. for
C22H17ClN4 (372.5): C, 70.87; H, 4.60; N, 15.03; Cl,
9.50. Found: C, 70.82; H, 4.54; N, 15.01; Cl, 9.63. MS:
m/z 372.5 [M+.], 218, 214, 159, 91.
(8a).
Yield 69%, mp 164–166°C. IR (KBr): ν 3333,
3196 (NH), 3066 (CHAr), 1604 (C═N). 1H NMR:
(DMSO): δ 5.1 (s, 1H, CH-Ar), 7.21–7.70 (m, 15ArH),
9.7 and 12.4 (s, 2NH, acidic protons exchanged in D2O);
13C NMR: δ 111.4 (2C), 113.9 (CH), 115.4 (2CH), 121.7
(CH), 126.2 (2CH), 128.3 (CH), 131.1 (2CH), 131.4
(CH), 132.0 (2CH), 133.0 (CH), 134.8 (2CH), 137.4 (C),
138.2 (CH), 142.6 (C), 167.6 (C), 169.2 (C) and Anal.
Calcd. for C22H18N4 (338): C, 78.08; H, 5.36; N, 16.56.
Found: C, 78.06; H, 5.27; N, 16.67. MS: m/z 338 [M+.],
5-(2-Cholorophenyl)-3,3-bis(3-chlorophenyl)-1,2,3,5-
tetrahydroimidazo[4,5-c]pyrazole (8f). Yield 80%, mp 244–
246°C. IR (KBr): ν 3328, 3200 (NH), 3050 (CHAr), 1619
1
(C═N). H NMR (DMSO): δ 5.2 (s, 1H, CHAr), 7.28–
292, 247, 194, 159, 91.
3,3-Bis(2-chlorophenyl)-5-phenyl-1,2,3,5-tetrahydroimidazo
7.94 (m, 12ArH), 9.5 and 12.6 (s, 2NH, acidic protons
exchanged in D2O).13C NMR: δ 111.2 (2C), 113.4 (CH),
117.9 (2C), 118.8 (2CH), 122.6 (CH), 124.8 (2CH),
126.7 (2CH), 129.8 (C), 131.7 (CH), 132.4 (CH), 134.2
(2CH), 136.7 (CH), 137.7 (C), 145.2 (C), 167.2 (C),
168.0 (C) and Anal. Calcd. for C22H15Cl3N4 (441.5): C,
59.82; H, 3.42; N, 12.68; Cl, 24.08. Found: C, 59.96; H,
3.38; N, 12.70; Cl, 23.96. MS: m/z 443.5 [M+. + 2],
441.5 [M+.], 305, 314.5, 251, 249, 191, 126.
[4,5-c]pyrazole (8b).
Yield 68%, mp 180–182°C. IR
(KBr): ν 3380, 3276 (NH), 3050 (CHAr), 1614 (C═N).
1H NMR: (DMSO): δ 5.8 (s, 1H, CH-Ar), 7.02–7.92 (m,
13ArH), 9.9 and 12.5 (s, 2NH, acidic protons exchanged
in D2O); 13C NMR: δ 112.5 (2C), 114.4 (CH), 115.8
(2CH), 118.4 (CH), 122.2 (CH), 128.1 (2CH), 130.6
(2CH), 131.3 (CH), 133.6 (2CH), 134.4 (2CH), 135.1
(C), 137.6 (CH), 139.7 (CH), 142.4 (C), 168.3 (C),
169.2 (C) and Anal. Calcd. for C22H16Cl2N4 (407): C,
64.88; H, 3.96; N, 17.41; Cl, 13.76. Found: C, 64.98; H,
3.95; N, 17.31; Cl, 13.76. MS: m/z 409 [M+. + 2], 407
[M+], 354, 280.5, 213, 193, 125.5.
General procedure for the preparation of compound 9.
Reflux an equimolar mixture of compound 5a (0.01 mol)
with ethyl chloroacetate (0.015 mol) in the presence of
fresh potassium carbonate (0.03 mol) and dioxane
(30 mL) for 24 h. The solid that separated after cooling
was filtered off, washed by petroleum ether (bp 40–60°C),
dried, and crystallized from DMF.
3,3-Bis(3-chlorophenyl)-5-phenyl-1,2,3,5-tetrahydroimidazo
[4,5-c]pyrazole (8c).
Yield 80%, mp 122–124°C. IR
(KBr): ν 3364, 3280 (NH), 3050 (CHAr), 1619 (C═N).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Novel Pyrazoles as Antineoplastic
Ethyl 2-(3,4,5-triphenyl-4,5-dihydroimidazo[4,5-c]pyrazol-
6(2H)-yl) acetate (9a).
for C22H17Cl2N5 (422): C, 62.57; H, 4.06; N, 16.58; Cl,
16.79. Found: C, 62.71; H, 4.01; N, 16.60; Cl, 16.68.
MS: m/z 424 [M+. + 2], 422 [M+], 295, 282, 236, 139.5,
Yield 76%, mp 154–158°C. IR
(KBr): ν 3260 (NH), 3080 (CHAr), 1765 (C═O), 1629
1
(C═N). H NMR (DMSO): δ 1.32 (t, 3H, CH3), 4.2 (q,
111.5, 91.
2H, CH2), 4.8 (s, 2H, CH2), 5.2 (s, 1H, CHN2), 6.64–
7.23 (m, 15ArH), 12.7 (s, NH, acidic proton exchanged
in D2O); 13C NMR: δ 34.2 (CH3), 61.3 (CH2), 70.2
(CH2), 121.1 (2C), 124.6 (CH), 128.2 (2CH), 130.6
(CH), 131.2 (2CH), 133.2 (CH), 135.2 (C), 136.2 (CH),
137.5 (2CH), 138.2 (2CH), 140.8 (CH), 143.2 (CH),
144.5 (2C), 167.4 (2C), 168.1 (C), 178.2 (C) and Anal.
Calcd. for C26H24N4O2 (424): C, 73.56; H, 5.70; N,
7,7-Bis(3-chlorophenyl)-3-phenyl-3,5,6,7-tetrahydro-2H-
pyrazolo[3,4-e][1,2,4]triazine (10c).
Yield 77%, mp
122–124°C. IR (KBr): ν 3430, 3260 (NH), 3058
1
(CHAr), 1645 (C═N). H NMR (DMSO): δ 5.3 (s, 1H,
CHAr), 7.09–7.98 (m, 13ArH), 6.7, 9.55, and 12.9
(s, 3NH, acidic protons exchanged in D2O); 13C NMR:
δ 110.9 (2C), 113.9 (CH), 115.4 (CH), 117.8 (2CH),
120.2 (2CH), 126.7 (2CH), 128.8 (CH), 130.2 (CH),
132.1 (2CH), 132.9 (2CH), 134.3 (C), 136.8 (CH),
138.1 (CH), 141.1 (C), 167.4 (C), 168.0 (C) and Anal.
Calcd. for C22H17Cl2N5 (422): C, 62.57; H, 4.06; N,
16.58; Cl, 16.79. Found: C, 62.69; H, 3.99; N, 16.58;
Cl, 16.74. MS: m/z 422 [M+.], 386.5 [M+. À Cl], 281,
13.20. Found: C, 73.49; H, 5.57; N, 13.08.
Ethyl-2-(5-(4-chlorophenyl)-3,4-diphenyl-4,5-dihydroimidazo
[4,5-c]pyrazol-6(2H)-yl)acetate (9b). Yield 76%, mp 138–
140°C. IR (KBr): ν 3278 (NH), 3084 (CHAr), 1762
1
(C═O), 1630 (C═N). H NMR (DMSO): δ 1.31 (t, 3H,
CH3), 4.0 (q, 2H, CH2), 4.9 (s, 2H, CH2), 5.3 (s, 1H,
CHN2), 7.04–7.63 (m, 14ArH), 12.3 (s, NH, acidic proton
exchanged in D2O); 13C NMR: δ 33.2 (CH3), 61.1 (CH2),
71.2 (CH2), 122.1 (2C), 124.4 (CH), 128.2 (2CH), 130.6
(CH), 131.5 (2CH), 133.4 (CH), 135.2 (C), 136.5 (CH),
137.1 (2CH), 138.3 (2CH), 140.9 (CH), 143.5 (CH),
144.9 (2C), 167.5 (2C), 168.8 (C), 179.2 (C) and Anal.
Calcd. for C26H23ClN4O2 (458.5): C, 68.04; H, 5.05; Cl,
7.72; N, 12.21. Found: C, 68.00; H, 5.00; Cl, 7.67; N,
12.10.
General procedure for the preparation of compound 10.
Reflux an equimolar mixture of compound 4 (0.01 mol)
and hydrazine derivatives (0.01 mol) in ethanol (30 mL)
for 3–6 h. The solid that separated after cooling was
filtered off, washed by petroleum ether (bp 40–60°C),
139.5, 111.5.
7,7-Di(furan-2-yl)-3-phenyl-3,5,6,7-tetrahydro-2H-pyrazolo
[3,4-e][1,2,4]triazine (10d). Yield 68%, mp 220–222°C. IR
(KBr): ν 3420, 3268 (NH), 3080 (CHAr), 1632 (C═N). 1H
NMR (DMSO): δ 4.9 (s, 1H, CHAr), 6.64–7.23 (m,
11ArH), 6.4, 10.2, and 12.7 (s, 3NH, acidic protons
exchanged in D2O); 13C NMR: δ 119.1 (2C), 122.6 (CH),
126.2 (2CH), 129.6 (CH), 131.1 (2CH), 132.2 (CH),
134.2 (C), 135.2 (CH), 136.5 (CH), 138.2 (CH), 140.8
(CH), 143.2 (CH), 145.5 (C), 167.7 (C), 168.6 (C) and
Anal. Calcd. for C18H15N5O2 (333): C, 64.86; H, 4.54;
N, 21.01. Found: C, 64.85; H, 4.47; N, 21.00. MS: m/z
333 [M+.], 237, 96.
3-(4-Chlorophenyl)-7,7-diphenyl-3,5,6,7-tetrahydro-2H-
pyrazolo[3,4-e][1,2,4]triazine (10e). Yield 70%, mp 232–
234°C. IR (KBr): ν 3429, 3259 (NH), 3050 (CHAr), 1633
dried, and crystallized from DMF.
1
(C═N). H NMR (DMSO): δ 5.0 (s, 1H, CHAr), 7.11–
3,7-Triphenyl-3,5,6,7-tetrahydro-2H-pyrazolo[3,4-e][1,2,4]
triazine (10a). Yield 70%, mp 190–192°C. IR (KBr): ν
7.75 (m, 14H, ArH), 6.6, 10.3, and 12.5 (bs, 3H, acidic
3NH protons exchanged in D2O); 13C NMR: δ 112.2
(CH), 112.6 (2C), 115.4 (2CH), 120.6 (2CH), 122.8
(2CH), 125.2 (CH), 128.3 (2CH), 130.5 (C), 131.8 (CH),
132.7 (2CH), 134.2 (CH), 136.7 (CH), 138.1 (C), 142.2
(C), 166.8 (C), 168.3 (C) and Anal. Calcd. for
C22H18ClN5 (387.5): C, 68.13; H, 4.68; N, 18.06; Cl,
1
3421, 3260 (NH), 3063 (CHAr), 1630 (C═N). H NMR
(DMSO): δ 5.3 (s, 1H, CHAr), 7.13–7.68 (m, 15ArH),
6.3, 10.2, and 12.8 (s, 3NH, acidic protons exchanged in
D2O); 13C NMR: δ 110.6 (2C), 112.4 (CH), 113.8 (2CH),
120.1 (CH), 124.4 (2CH), 127.4 (CH), 128.5 (2CH),
130.3 (CH), 131.3 (2CH), 133.6 (CH), 135.6 (2CH),
137.2 (C), 139.7 (CH), 144.6 (C), 167.6 (C), 168.7 (C)
and Anal. Calcd. for C22H19N5 (353): C, 74.77; H, 5.42;
N, 19.81. Found: C, 74.75; H, 5.36; N, 19.89. MS: m/z
9.14. Found: C, 68.10; H, 4.64; N, 18.03; Cl, 9.23. MS:
m/z 387.5 [M+.], 280.
3-(2-Chlorophenyl)-7,7-bis(3-chlorophenyl)-3,5,6,7-tetrahydro-
353 [M+.], 248 [M+ À PhNHNH2], 105, 91.
2H-pyrazolo[3,4-e][1,2,4]triazine (10f).
Yield 75%, mp
260–262°C. IR (KBr): ν 3430, 3279 (NH), 3050 (CHAr),
7,7-Bis(2-chlorophenyl)-3-phenyl-3,5,6,7-tetrahydro-2H-
1
pyrazolo[3,4-e][1,2,4]triazine (10b).
Yield 72%, mp
1631 (C═N). H NMR (DMSO): δ 5.2 (s, 1H, CHAr),
180–182°C. IR (KBr): ν 3424, 3252 (NH), 3056 (CHAr),
1642 (C═N). H NMR (DMSO): δ 5.2 (s, 1H, CHAr),
7.08–7.70 (m, 12ArH), 6.4, 10.7, and 12.6 (s, 3NH,
acidic protons exchanged in D2O); 13C NMR: δ 112.7
(2C), 115.4 (CH), 119.5 (2C), 120.8 (2CH), 122.6 (CH),
124.8 (2CH), 126.7 (2CH), 128.8 (C), 130.7 (CH), 133.4
(CH), 135.2 (2CH), 137.5 (CH), 139.7 (C), 145.2 (C),
166.2 (C), 168.2 (C) and Anal. Calcd. for C22H16Cl3N5
(456.5): C, 57.85; H, 3.53; N, 15.33; Cl 23.29. Found: C,
57.96; H, 3.49; N, 15.32; Cl, 23.20. MS: m/z 459.5
1
7.30–7.78 (m, 13ArH), 6.5, 9.8, and 12.4 (s, 3NH,
acidic protons exchanged in D2O); 13C NMR: δ 111.2
(2C), 114.7 (CH), 115.9 (2CH), 117.4 (CH), 120.2
(CH), 126.1 (2CH), 128.6 (2CH), 130.3 (CH), 132.6
(2CH), 133.4 (2CH), 134.1 (C), 136.6 (CH), 138.7
(CH), 142.4 (C), 167.3 (C), 168.2 (C) and Anal. Calcd.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. A. Rizk, A. A. El-Sayed, and M. M. Mounier
Vol 000
[M+. + 3], 458.5 [M+. + 2], 456.5 [M+.], 316, 278, 263,
234, 177, 139.5, 105.
General procedure for the preparation of compound 11.
Reflux an equimolar mixture of compound 1 (0.01 mol)
and hydrazine hydrate (0.01 mol) in butanol (15 mL) for
8 h. The solid that separated after cooling was filtered
off, washed by petroleum ether (bp 40–60°C), dried, and
General procedure for the preparation of compound 12.
In a one-pot reaction of arylidine 5a (0.01 mol), alkyl
amine (0.01 mol), for example, ethylamine, 3-
aminopropanol, and benzylamine, in the presence of
formaldehyde (0.01 mol) was heated in an oil bath at
190°C for 2–3 h. The mixture was poured onto water
after cooling. The solid that separated was filtered off,
dried, and crystallized from EtOH.
crystallized from the proper solvents.
3,6-Dioxo-2,2,5,5-tetraphenyl-[1H]imidazolo[3,2-b]pyrazole
(11a). Yield 30%, mp 296–298°C, DMF. IR (KBr): ν
3-Ethyl-2,7,7-triphenyl-3,4,6,7-tetrahydropyrazolo[1,5-a][1,3,5]
triazin-8(2H)-one (12a).
Yield 78%, mp 260–262°C. IR
3119 (NH), 3074 (CHAr), 1663 (C═O). 1H NMR
(DMSO): δ 7.04–7.582 (m, 20ArH), 13.00 (s, 1H, acidic
NH proton exchanged in D2O); 13C NMR: δ 112 (2C),
120.4 (2CH), 124.6 (2CH), 126.5 (2CH), 129.5 (2CH),
130.3 (2CH), 132.4 (2CH), 133.6 (2CH), 134.5 (2CH),
136.5 (2CH), 137.3 (2CH), 139.8 (C), 140.4 (C), 166.8
(2C), 168.0 (C), 190.1 (2C) and Anal. Calcd. for
C29H21N3O2 (443): C, 78.55; H, 4.74; N, 9.48. Found: C,
78.52; H, 4.73; N, 9.45. MS: m/z 443 [M+.], 415, 384,
(KBr): ν 3279 (NH), 3050 (CHAr), 1687 (CO), 1631
(C═N). H NMR: (DMSO): δ 1.23 (t, 3H, CH3), 3.2 (q,
1
2H, CH2), 4.31 (s, 2H, CH2N2), 5.2 (s, 1H, CH),
7.08–7.70 (m, 15ArH), 11.6 (s, 1NH, acidic proton
exchanged in D2O); 13C NMR: δ 38.3 (CH3), 57.2 (CH2),
74.5 (CH2), 112.7 (CH), 115.4 (CH), 119.5 (2C), 120.8
(2CH), 122.6 (CH), 124.8 (2CH), 126.7 (2CH), 128.8
(2C), 130.7 (CH), 133.4 (CH), 135.2 (2CH), 137.5 (CH),
139.7 (C), 145.2 (C), 166.2 (C), 178.2 (C) and Anal.
Calcd. for C25H24N4O (396): C, 75.73; H, 6.10; N, 14.13.
Found: C, 75.66; H, 5.99; N, 14.02.
347, 314, 262, 158.
3,6-Dioxo-2,2,5,5-tetra(2-chlorophenyl)-[1H]imidazolo[3,2-b]
pyrazole (11b).
Yield 27%, mp 282–284°C, DMF. IR
3-(3-Hydroxypropyl)-2,7,7-triphenyl-3,4,6,7-tetrahydropyrazolo
[1,5-a][1,3,5]triazin-8(2H)-one (12b). Yield 85%, mp 284–
(KBr): ν 3331 (NH), 3050 (CHAr), 1690 (C═O). 1H NMR
(DMSO): δ 7.54–8.20 (m, 16ArH), 12.51 (s, NH, acidic
proton exchanged in D2O); 13C NMR: δ 13C NMR:
δ 111.3 (2C), 121.4 (2CH), 123.7 (2CH), 125.8 (2CH),
128.6 (2CH), 131.8 (2C), 132.0 (2C), 133.2 (2CH),
134.0 (2CH), 137.1 (2C), 137.3 (2C), 139.8 (2CH),
142.4 (2CH), 168.6 (C), 190.2 (2C) and Anal. Calcd. for
C29H17Cl4N3O2 (581): C, 59.89; H, 2.92; N, 7.22; Cl,
24.44. Found: C, 59.88; H, 2.93; N, 7.10; Cl, 24.03.
MS: m/z 583 [M+. + 2], 581 [M+.], 550, 338, 262, 235,
286°C. IR (KBr): ν 3430 (OH), 3229 (NH), 3050 (CHAr),
1
1683 (CO), 1629 (C═N). H NMR (DMSO): δ 2.23 (m,
6H, (CH2)3), 4.2 (s, 2H, CH2N2), 5.2 (s, 1H, CH),
7.08–7.70 (m, 15ArH), 10.7 and 12.6 (s, 1NH and 1OH,
acidic protons exchanged in D2O); 13C NMR: δ 39.4
(CH2), 61.4 (2CH2), 76.4 (CH2), 112.7 (CH), 115.4 (2C),
119.5 (2C), 120.8 (2CH), 122.6 (CH), 124.8 (2CH),
126.7 (2CH), 128.8 (C), 130.7 (CH), 132.4 (CH), 136.2
(2CH), 137.5 (CH), 140.7 (C), 147.2 (C), 165.2 (C),
168.2 (C) and Anal. Calcd. for C26H26N4O2 (426): C,
73.22; H, 6.14; N, 13.14. Found: C, 73.16; H, 6.09; N,
13.12.
193.5.
3,6-Dioxo-2,2,5,5-tetra(3-chlorophenyl)-[1H]imidazolo[3,2-b]
pyrazole (11c).
Yield 26%, mp 302–304°C, DMF. IR
1
(KBr): ν 3336 (NH), 3100 (CHAr), 1678 (CO). H NMR
(DMSO): δ 7.50–8.11 (m, 16ArH), 13.2 (s, NH, acidic
proton exchanged in D2O); 13C NMR: δ 111.4 (2C),
121.3 (2CH), 123.9 (2CH), 126.0 (2CH), 129.0 (2CH),
131.7 (2C), 132.0 (2C), 133.3 (2CH), 133.8 (2CH), 137.0
(2C), 137.5 (2C), 139.4 (2CH), 142.1 (2CH), 167.4 (2C),
192.1 (2C) and Anal. Calcd. for C29H17Cl4N3O2 (581): C,
59.89; H, 2.92; N, 7.22; Cl, 24.44. Found: C, 59.87; H,
2.72; N, 7.24; Cl, 24.45. MS: m/z 583 [M+. + 2], 581
3-Benzyl-2,7,7-triphenyl-3,4,6,7-tetrahydropyrazolo[1,5-a]
[1,3,5]triazin-8(2H)-one (12c). Yield 74%, mp 222–224°C.
IR (KBr): ν 3250 (NH), 3040 (CHAr), 1682 (CO), 1629
1
(C═N). H NMR (DMSO): δ 5.2 (s, 2H, CH2Ph), 4.5 (s,
2H, CH2), 5.1 (s, 1H, CH), 7.08–7.70 (m, 20ArH), 11.4
(s, 1NH, acidic proton exchanged in D2O); 13C NMR: δ
53.4 (CH2), 77.2 (CH2), 112.7 (CH), 115.4 (2CH), 119.5
(2C), 120.8 (2CH), 122.6 (2CH), 124.8 (2CH), 126.7
(2CH), 128.8 (C), 130.7 (2C), 133.4 (2CH), 135.2 (2CH),
137.5 (2CH), 139.7 (2C), 145.2 (2C), 166.2 (C), 168.2
(C) and Anal. Calcd. for C30H26N4O (458): C, 78.58; H,
5.72; N, 12.22. Found: C, 78.36; H, 5.59; N, 12.12.
[M+.], 263.5, 235, 193.
2,6-Dihydro-3,3,7,7-tetrafuran-2-yl-bispyrazolo[3,4-b,e]pyrazine
(11d).
Yield 25%, mp 260–262°C, DMF. IR (KBr):
ν 3376 (NH), 3073 (CHAr), 1685 (C═O). 1H NMR
(DMSO): δ 6.98–7.34 (m, 12ArH), 12.9 (s, NH, acidic
proton exchanged in D2O); 13C NMR: δ 129.6 (2CH),
130.2 (2CH), 134.2 (2CH), 135.4 (2CH), 141.6 (2CH),
141.9 (2CH), 166.5 (C), 160.8 (2C), 188.5 (2C), 191.8
(2C), 191.1 (2C) and Anal. Calcd. for C21H13N3O6 (403):
C, 62.53; H, 3.22; N, 10.42. Found: C, 62.54; H, 3.23;
N, 10.39. MS: m/z 403 [M+.], 269, 175, 158, 145.
General procedure for the preparation of compound 13.
Reflux an equimolar mixture of compound 5a (0.01 mol)
with aromatic amine, for example, aniline, p-toluidine
and p-anisidine, formaldehyde (0.01 mol), and dioxane
(30 mL) for 6 h. The solid that separated after cooling
was filtered off, washed by petroleum ether (bp 40–60°C),
dried, and crystallized from DMF.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Novel Pyrazoles as Antineoplastic
3-(Benzylideneamino)-5,5-diphenyl-1-((phenylamino)methyl)-
1H-pyrazol-4(5H)-one (13a). Yield 77%, mp 194–196°C.
petroleum ether (bp 40–60°C), dried, and recrystallized
from ethanol. Yield 57%, mp 124–126°C. IR (KBr): ν
3245 (NH), 1650, 1672, 1691 (CO), 1630 (C═N), 1H
NMR (DMSO): δ 4.41 (s, 2H, CH2(CO)2), 6.7 (s, 1H,
PyH), 7.44–7.83 (s, 10H, ArH), 12.7 (s, acidic NH
proton exchanged in D2O), and Anal. Calcd. for
C20H14N4O3 (358): % C, 67.03; H, 3.94; N, 15.63.
Found: % C, 67.05; H, 3.88; N, 15.61. MS: m/z 358
[M+], 290, 281, 239.
IR (KBr): ν 3321 (NH), 3063 (CHAr), 1685 (CO), 1635
(C═N). 1H NMR (DMSO): δ 5.1 (s, 2H, CH2), 8.1
(s, 1H, CH), 7.13–7.68 (m, 20ArH), 11.8 (s, NH, acidic
proton exchanged in D2O); 13C NMR: δ 67.3 (CH2),
110.6 (2C), 112.4 (CH), 113.8 (2CH), 120.1 (CH), 124.4
(2CH), 127.4 (2CH), 128.5 (2CH), 130.3 (2CH), 131.3
(2CH), 133.6 (CH), 135.6 (2CH), 137.2 (2C), 139.7
(2CH), 144.6 (2C), 167.6 (2C), 188.7 (C) and Anal.
Calcd. for C29H24N4O (444): C, 78.36; H, 5.44; N,
1,2-(Benzylidinemethdicarbonyl)-3,3-diphenyl-6-oxo-1,2,7-
trihydro-pyrazolo[3,4-b]pyrazine (16). Method A.
Reflux
an equimolar mixture of compound 15 (0.01 mol) and
benzaldehyde (0.015 mol) in ethanol (30 mL) for 3 h; the
solid that separated after cooling was filtered off, washed
by petroleum ether (bp 40–60°C), dried, and crystallized
from butanol with yield of 25%.
12.60. Found: C, 78.25; H, 5.36; N, 12.42.
1-((p-Toluidino)methyl)-3-(benzylideneamino)-5,5-diphenyl-
1H-pyrazol-4(5H)-one (13b). Yield 77%, mp 184–186°C.
IR (KBr): ν 3319 (NH), 3060 (CHAr), 1680 (CO), 1628
1
(C═N). H NMR (DMSO): δ 2.21 (s, 3H, CH3), 5.1 (s,
2H, CH2), 7.9 (s, 1H, CH), 7.13–7.68 (m, 19ArH), 11.6
(s, NH, acidic proton exchanged in D2O); 13C NMR: δ
45.2 (CH3), 67.3 (CH2), 110.6 (2C), 112.4 (CH), 113.8
(2CH), 120.1 (CH), 124.4 (2CH), 127.4 (2CH), 128.5
(2CH), 130.3 (2CH), 131.3 (2CH), 133.6 (CH), 135.6
(2CH), 137.2 (2C), 139.7 (2CH), 144.6 (2C), 167.6 (2C),
188.7 (C) and Anal. Calcd. for C30H26N4O (458): C, 78.58;
Method B.
Reflux an equimolar mixture of compound
7 (0.01 mol) and diethyl benzylidene malonate (0.01 mol)
in ethanol (30 mL) for 6 h; the solid that separated after
cooling was filtered off, washed by petroleum ether (bp
40–60°C), dried, and crystallized from butanol with yield
of 24%. mp 180–182°C. IR (KBr): ν 3240 (NH), 1655,
1
1676, 1685 (CO), 1625 (C═N). H NMR (DMSO): δ 6.8
H, 5.72; N, 12.22. Found: C, 78.45; H, 5.56; N, 12.10.
3-(Benzylideneamino)-1-((4-methoxyphenylamino)methyl)-
5,5-diphenyl-1H-pyrazol-4(5H)-one (13c). Yield 77%, mp
(bs, 2H, PyH and H arylidine), 7.12–7.53 (m, 15ArH),
12.9 (s, acidic NH proton exchanged in D2O) and Anal.
Calcd. for C27H18N4O3 (446): % C, 72.64; H, 4.06; N,
12.55. Found: % C, 72.85; H, 4.15; N, 12.83. MS: m/z
446 [M+], 316, 267, 239.
194–196°C. IR (KBr): ν 3325 (NH), 3055 (CHAr), 1681
(CO), 1630 (C═N). 1H NMR (DMSO): δ 4.2 (s, 3H,
OCH3), 5.1 (s, 2H, CH2), 8.0 (s, 1H, CH), 7.13–7.78 (m,
19ArH), 11.4 (s, NH, acidic proton exchanged in D2O); 13
C
NMR: δ 58.2 (CH3), 67.3 (CH2), 110.6 (2C), 112.4 (CH),
113.8 (2CH), 120.1 (CH), 124.4 (2CH), 127.4 (2CH), 128.5
(2CH), 130.3 (2CH), 131.3 (2CH), 133.6 (CH), 135.6
(2CH), 137.2 (2C), 139.7 (2CH), 144.6 (2C), 167.6 (2C),
188.7 (C) and Anal. Calcd. for C30H26N4O2 (474): C,
75.93; H, 5.52; N, 11.81. Found: C, 75.75; H, 5.46; N, 11.52.
1,7-Acetyl-3,3-diphenyl-6-oxo-1,2,7-trihydro-pyrazolo[3,4-b]
pyrazine (14). Reflux an equimolar mixture of compound
ANTICANCER MOIETY
Materials and methods. Cell lines.
carcinoma (MCF-7 cell line), colon carcinoma (HCT-116
cell line), and liver carcinoma (HepG 2 cell line) were
Human breast
obtained from Vacsera (Giza, Egypt).
Cell culture. The procedure was performed in a sterile
area using a laminar air flow cabinet biosafety class II
level.
7 (0.01 mol) and chloroacetic acid (0.01 mol) in (20 mL)
phosphorous oxychloride for 2 h. The reaction mixture
was poured onto ice/H2O, and the solid that separated was
filtered off, washed by petroleum ether (bp 40–60°C),
dried, and crystallized from toluene. Yield 55%, mp 110–
112°C. IR (KBr): ν 3222 (NH), 1670, 1685 (CO), 1613
Culture was maintained in RPMI 1640 medium with 1%
antibiotic–antimycotic mixture (10,000 U/mL potassium
penicillin, 10,000 μg/mL streptomycin sulfate, and
25 μg/mL amphotericin B) and 1% L-glutamine and
supplemented with 10% heat-inactivated fetal bovine
serum. Culturing and subculturing were carried out
according to Thabrew et al. [19]. Doxorubicin was used
as a positive control. A negative control composed of
DMSO was also used.
Cell viability assay. This was performed according to
Moustafa et al. [20] as described by Mosmann [21].
Following culturing for 10 days, the cells were seeded at
concentration of 10 × 103 cells/well in case of MCF-7
and HepG 2, and 20 × 103 cells/well in a fresh
complete growth medium in case of HCT-116 cell lines
1
(C═N). H NMR (DMSO): δ 4.50 (s, 2H, CH2), 6.2 (s,
1H, PyH), 7.44–7.73 (m, 10ArH), 6.2 (s, 1H, acidic NH
proton exchanged in D2O) and Anal. Calcd. for
C19H14N4O2 (330): % C, 69.08; H, 4.27; N, 16.96.
Found: % C, 69.00; H, 4.19; N, 16.95. MS: m/z 330
[M+], 288, 134.
3,3-Diphenyl-1,2-(methylenedicarbonyl)-6-oxo-1,2,7-trihydro-
pyrazolo[3,4-b]pyrazine (15). Reflux an equimolar mixture
of compound
7
(0.01 mol) and diethylmalonate
(0.015 mol) in ethanol (30 mL) for 4 h. The solid that
separated after cooling was filtered off, washed by
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. A. Rizk, A. A. El-Sayed, and M. M. Mounier
Vol 000
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incubator. Fresh medium (without serum) was added, and
cells were incubated either alone (negative control) or
with samples to give a final concentration of 100 μg/mL.
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then 40 μL MTT salt (2.5 mg/mL) was added to each well
and incubated for further 4 h at 37°C under 5% CO2. To
stop the reaction and dissolve the formed crystals, 200 μL
10% sodium dodecyl sulfate in deionized water was
added to each well and incubated overnight at 37°C. The
absorbance was measured using a microplate multi-well
reader at 595 nm and a reference wavelength of 690 nm.
Cell viability was assessed according to the mitochondrial-
dependent reduction of yellow MTT to purple formazan.
Determination of LC50 values. The LC50 values were
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet