Synthesis of Some New Fused Pyrazole Derivatives Bearing Indole Moiety as Antioxidant Agents

Article abstract of DOI:10.1002/jhet.2218

3-(1H-Indol-3-yl)-1H-pyrazol-5-amine 3 was prepared in a quantitative yield by heating 3-(1H-indol-3-yl)-3-oxopropanenitrile 2 in dry ethanol with hydrazine hydrate, and utilized as key intermediate for the synthesis of some new pyrazolo[1,5-a]pyrimidines and pyrazolo[5,1-c]triazines. Structures of the newly synthesized compounds were established by elemental analysis and spectral data and evaluated as antioxidant agents. Most of the tested compounds belonging to the pyrazolo[1,5-a]pyrimidine series exhibited better activities than members of the pyrazolotriazine one.

Full text of DOI:10.1002/jhet.2218

8
94
Synthesis of Some New Fused Pyrazole Derivatives Bearing Indole Moiety
as Antioxidant Agents
Vol 53
Ahmed El-Mekabaty,* Hassan A. Etman, and Ahmed Mosbah
Chemistry Department, Faculty of Science, Mansoura University, El-Gomhoria Street, ET-35516 Mansoura, Egypt
*
E-mail: a_el_m11@yahoo.com; elmekabaty@mans.edu.eg
Received December 1, 2013
DOI 10.1002/jhet.2218
Published online 15 July 2015 in Wiley Online Library (wileyonlinelibrary.com).
2
o
2
2
2
3
-(1H-Indol-3-yl)-1H-pyrazol-5-amine 3 was prepared in a quantitative yield by heating 3-(1H-indol-3-yl)-3-
oxopropanenitrile 2 in dry ethanol with hydrazine hydrate, and utilized as key intermediate for the synthesis of
some new pyrazolo[1,5-a]pyrimidines and pyrazolo[5,1-c]triazines. Structures of the newly synthesized com-
pounds were established by elemental analysis and spectral data and evaluated as antioxidant agents. Most
of the tested compounds belonging to the pyrazolo[1,5-a]pyrimidine series exhibited better activities than
members of the pyrazolotriazine one.
J. Heterocyclic Chem., 53, 894 (2016).
INTRODUCTION
the starting material, 3-(1H-indol-3-yl)-1H-pyrazol-5-amine
(
3) used in this study, was prepared in a quantitative yield
Indole, the potent basic pharmacodynamic nucleus, has been
reported to possess a wide variety of biological properties viz.,
anti-inflammatory [1–3], anticonvulsant [4], cardiovascular [5]
and antibacterial [6]. In addition, the indole nucleus is incorpo-
rated in various natural products such as alkaloids [7–12]. Fur-
thermore, substitution of heterocyclic moiety at 3-position of
the indole ring obviously influenced the anti-inflammatory activ-
ity [13]. Fused pyrazoles are biologically interesting compounds
by heating 3-(1H-indol-3-yl)-3-oxopropanenitrile (2) [19a]
in dry ethanol with hydrazine hydrate following a procedure
described earlier by Siena [19b].
Next, the 3-amino-pyrazole derivative 3 was served as
key intermediate in Scheme 2. 3(5)-Aminopyrazoles are
versatile reagents and have been extensively used as syn-
thetic starting materials for the synthesis of several
polysubstituted fused pyrazoles of potential biological ac-
tivity [20–23]. It was thus of interest to study the reactivity
of aminopyrazole 3 toward a variety of chemical reagents.
The general literature procedure [24–26] for the synthesis
of pyrazolo [1,5-a]pyrimidines involves cyclocondensation
of aminopyrazoles with reagents having 1,3-electrophilic
centers such as β-diketones. So, cyclocondensation of
compound 3 with either acetyl acetone or acetoacetanilide
in boiling ethanol containing a catalytic amount of piperi-
dine produced in each case a single product, as evidenced
by TLC. The reaction products can be formulated as
pyrazolo[1,5-a]pyrimidine derivatives 4 and 5, evidence
for assigned structures being provided by analytical and
[14–16]. Diverse biological activities have been reported in
the last 50 years for these derivatives. These are ranges from
CNS regulants [17] to antischistosomical activities [18].
Encouraged by the aforementioned observations, it was
thought of interest to combine the aforementioned boilable
rings together in a molecular framework to investigate the
additive effect of these rings toward antioxidant activity.
Several experimental protocols have been developed for
this purpose, and excellent results have been obtained.
RESULTS AND DISCUSSION
Chemistry. The synthetic strategies adopted to obtain the
target compounds are depicted in Schemes 1–3. In Scheme 1,
©
2015 HeteroCorporation

May 2016
Synthesis of Some New Fused Pyrazole Derivatives Bearing Indole Moiety
as Antioxidant Agents
895
Scheme 1. Synthesis of 3-(1H-indol-3-yl)-1H-pyrazol-5-amine (3).
lost water molecule to yield the acyclic intermediate, which
then undergoes intramolecular cyclization by missing
PhNH molecule to afford the target compound.
2
In the same manner, compound 3 reacts with diethyl
malonate and ethyl acetoacetate to afford pyrazolo[1,5-a]
pyrimidines 6 and 7, on the basis of both elemental analy-
sis and spectral data. The formation of compound 7 is
assumed to proceed via initial attack of the exocyclic
amino group of 3 with carbonyl group of ester and lost
ethanol molecule to yield the acyclic intermediate which
then undergoes intramolecular cyclization by missing
H O molecule to afford the target compound.
2
In a search for some new pyrazolo[1,5-a]pyrimidines,
the present investigation reports on the condensation of
aminopyrazole 3 with ethyl cyanoacetate and malononitrile
as 1,3-dielectrophilic centers. The reaction of aminopyrazole
3 with ethyl cyanoacetate in glacial acetic acid at reflux gave
a sole product that was identified as 7-amino-2-(1H-indol-3-
yl)pyrazolo[1,5-a]pyrimidin-5-ol (8). In addition, pyrazolo
[1,5-a]pyrimidine 9 could be achieved by refluxing 3 with
malononitrile in a basic dioxane solution containing a cata-
lytic amount of triethylamine (Scheme 2).
spectroscopic data. For example, The IR spectrum of com-
pound 4 showed the appearance of absorption band at
ꢀ
1
1
1
571 cm corresponding to C═C group. The H-NMR
spectrum of 4 exhibited two additional singlet signals at δ
.48 and 2.75 ppm assignable to the protons of two methyl
2
groups in pyrimidine ring and a singlet signal at δ 6.75 ppm
for proton in the pyrimidine ring. The mass spectrum
+
showed a molecular ion peak at m/z 262.10 (M , 100.00)
corresponding to a molecular formula C H N . The for-
The reactivity of aminopyrazole 3 towards arylidene
malononitrile was also investigated as an alternative route to
obtain pyrazolo[1,5-a]pyrimidine derivatives. Thus, reaction
of 3 with 2-(4-methoxybenzylidene)malononitrile in
1
6 14 4
mation of compound 5 is assumed to proceed via initial
attack of the exocyclic amino group of 3 with carbonyl
group (attached to methyl group) of acetoacetanilide and
Scheme 2. Synthesis of pyrazolo[1,5-a]pyrimidines 4–13.
2
2
EtOH/Piperidine
6
4
2
2
6
4
2
2
2
3
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A. El-Mekabaty, H. A. Etman, and A. Mosbah
Vol 53
pyridine solution yielded product for which structure 11a or
1b seemed possible. Spectroscopic data could not distin-
Shifting to Scheme 3, 3(5)-aminopyrazoles have been
reported to diazotize readily to yield the corresponding di-
azonium salts. The latter could be utilized for the synthesis
of a variety of pyrazolotriazine derivatives. The consider-
able biological and medicinal activities of pyrazolotriazines
[28] as adenine analogs, antagonists, and antitumor agents
[29] have stimulated recent interest in the synthesis of
derivatives of these ring systems. In the present work, we
molecularly designed, through a variety of synthetic routes,
some novel pyrazolotriazines. So, compound 3 reacts with
sodium nitrite in the presence of hydrochloric acid to yield
the corresponding diazonium salt 14. The latter could not be
isolated in a free state; however, it could be trapped via
reaction with different coupling components. Thus, diazo-
tized 14 coupled with malononitrile to yield the 4-amino-7-
(1H-indol-3-yl)pyrazolo[5,1-c][1,2,4]triazine-3-carbonitrile
(15). Elemental analysis and spectral data were in favor
of this proposed pyrazolo[5,1-c][1,2,4]triazine structure.
The IR spectrum of 15 showed absorption bands at (3387,
1
guish between these two possible regioisomers, but the
structure 11a appears more likely than 11b on the basis that
ring nitrogen is the most steric hindrance center in the
molecule [27]. The formation of 11a is assumed to proceed
via initial attack of the exocyclic amino group of 3 on the
activated double bond of arylidene malononitrile to yield
the acyclic intermediate which then undergoes intramolecu-
lar cyclization to afford the pyrazolo[1,5-a]pyrimidine
derivative 11a. The same compound, 11a, was also
prepared in two consequence steps by reacting 3 with
4
-methoxybenzaldehyde in basic pyridine to give the corre-
sponding Schiff base 10 that reacted with malononitrile in
boiling pyridine to give the target compound 11a. The
isolated reaction product 11a was found to be identical in
all respects (mp, mixed mp, TLC, and IR spectrum) with
those separated from the reaction of compound 3 with 2-
(4-methoxybenzylidene)malononitrile (Scheme 2). Simi-
ꢀ
1
larly, compound 3 reacted with cinnamaldehyde under the
same condition to furnish 2-(1H-indol-3-yl)-7-phenyl-6,7-
dihydropyrazolo[1,5-a]pyrimidine (12), which was con-
firmed from analytical and spectral data. On the other hand,
the reaction of 3 with acrylonitrile was also investigated as a
possible route for the synthesis of pyrazolo[1,5-a]pyrimidines.
In this manner, compound 3 was treated with acrylonitrile in
boiling pyridine to afford directly the 2-(1H-indol-3-yl)-6,7-
dihydropyrazolo[1,5-a]pyrimidin-5(4H)-imine (13) as the
sole product. Elemental analysis and spectral data were in
favor of this proposed structure (Scheme 2).
3315), 2226, and 1620 cm due to NH , CN, and N═N
2
1
groups, respectively. The H-NMR spectrum showed a mul-
tiplet signals in the region at δ 7.09–8.01 ppm correspond-
ing to the aromatic protons together with amino group and
a singlet signal at δ 6.77 ppm for proton in the pyrazole ring.
The mass spectrum revealed molecular ion peak at m/z
+
275.15 (M , 15.48) with relative abundance corresponding
to the molecular formula C H N . In a similar manner,
14 9 7
when the diazonium salt 14 coupled with an active hydro-
gen reagent, ethyl acetoacetate or diethylmalonate yielded
directly the pyrazolotriazines 16 and 17, respectively.
Scheme 3. Synthetic pathway to compounds 14–22.
H
N
N
COOEt
N
N
O
COOEt
CH2(COOEt)2
EtOH/NaOAc
N
COOEt
COCH3
EtOH/NaOAc
N
N
N
HN
CH3
HN
16
1
7
CN
N
N
N2 Cl
NH
CN
NaNO2/HCl
CN
EtOH/NaOAc
N
3
N
N
HN
NH2
1
5
HN
1
4
CN
O
HN
N
OH
O
N
2
N
NH
N
N
H
CN
EtOH/NaOAc
EtOH/NaOAc
EtOH/NaOAc
NH HO
N
N
HN
18
HN
20
COCH3
COCH3
DMF
AcOH
N
O
O
N
O
N
CH3
CH3
N
N
HN
NH
N
N
N
NH2
HN
N
HN
19
N
N
H
21
HN
2
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2016
Synthesis of Some New Fused Pyrazole Derivatives Bearing Indole Moiety
as Antioxidant Agents
897
Besides, the diazonium salt of compound 3 was coupled
with 3-(1H-indol-3-yl)-3-oxopropanenitrile (2) affording
compound 18, which readily cyclized into the pyrazolo-
triazine derivative 19 when treated with dimethyl-
formamide. On the other hand, coupling the diazonium salt
of compound 3 with β-naphthol in ethanolic sodium acetate
solution at 0–5°C gave the arylazo derivative 20. Compound
On the other hand, compounds 15–21 (Scheme 3) exhibited
weak to moderate growth inhibitory activity. Moreover, the
substitution pattern was also crucial. It is worth mentioning that
cyclization of compound 18 and incorporation of two
molecules of indole to pyrazolotriazine nucleus 19 produced
a high activity. Cyclization of compound 20 to the
pyrazolotriazine 21 enhanced also the antioxidant activity.
In conclusion, the objective of the present study was to
synthesize and investigate the antioxidant activity of some
new fused pyrazoles incorporating indole moiety with the
hope of discovering new structure leads serving as antiox-
idant agents. Our aim has been verified by the synthesis of
two different groups of structure hybrids comprising basi-
cally the indole moiety attached to either polysubstituted
pyrazolopyrimidine or pyrazolotriazine counter parts through
various linkages of synergistic purpose. The obtained results
clearly revealed that most of the tested compounds belonging
to the pyrazolo[1,5-a]pyrimidine series exhibited better
activities than members of the pyrazolotriazine one.
2
0 could be readily cyclized into compound 21 when treated
with acetic acid. Finally, the diazonium salt of compound 3
also reacted with acetylacetone to give the corresponding
hydrazone derivative 22. Attempts to cyclize this acyclic
product was unsuccessful (Scheme 3).
PHARMACOLOGY
Antioxidant activity.
The antioxidant activity for the
newly synthesized target compounds were evaluated
according to a literature procedure [30]. The results depicted
in Table 1 revealed that most of the tested compounds
displayed variable inhibitory effects. In general, most of
the tested compounds belonging to the pyrazolo[1,5-a]
pyrimidine series (Scheme 2) exhibited better activities than
members of the pyrazolotriazine one (Scheme 3). Regarding
the structure–activity relationship of the pyrazolo[1,5-a]
pyrimidines, the results revealed that compounds with
electron-donating groups such as OH or NH2 recorded
higher activity. In this view, compounds 8 and 9 were
equipotent to ascorbic acid, and compounds 5, 6, 7, 11a,
and 13 exhibited moderate activities whereas compounds 4
and 12 exhibited weak activities.
EXPERIMENTAL
General.
All melting points were determined on an
electrothermal Gallenkamp apparatus. The IR spectra were
measured on a Mattson 5000 FTIR spectrometer (USA) in
1
13
potassium bromide disks. The H NMR and C NMR spectra
were recorded in DMSO-d6 on a Bruker WP spectrometer
1
13
(300 MHz for H NMR and 75MHz for C NMR; USA) and the
chemical shifts δ downfield from TMS as an internal standard. The
mass spectra were recorded on Finnegan MAT 212 instrument
(
USA), and the ionizing voltage was 70ev at the Faculty of
Science, Cairo University. Elemental analyses were carried out by
the Microanalytical unit of Faculty of Science, Mansoura
University, Masoura, Egypt. All reactions were followed by TLC
Table 1
(
silica gel, aluminum sheets 60 F254, Merck). 3-(1H-Indol-3-yl)-
-oxopropanenitrile (2) and 3-(1H-indol-3-yl)-1H-pyrazol-5-amine
Antioxidant activity assay for the investigated compounds.
3
(
3) were prepared according to literature procedures [19].
General procedure for the reaction of 3(5)-aminopyrazole (3)
Compound no.
Absorbance of samples
% Inhibition
with 1,3-dicarbonyl compounds. To a mixture of compound 3
1.98 g, 0.01 mol) in ethanol (25 mL) containing a few drops of
Control of ABTS
Ascorbic acid
0.507
0.039
0.110
0.115
0.090
0.087
0.089
0.037
0.030
0.385
0.180
0.110
0.046
0.259
0.288
0.357
0.417
0.190
0.37
0.0
(
92.70
76.10
77.14
80.93
78.10
78.26
92.30
91.95
23.21
64.42
76.10
79.11
47.91
42.17
20.61
7.58
piperidine (three drops), an appropriate 1,3-dicarbonyl compound
(acetylacetone, acetoacetanilide, diethylmalonate, or ethylacetoacetate)
(0.01) was added. The reaction mixture was refluxed for 12–15 h
and then poured into crushed ice. The solid product was collected
by filtration, dried, and recrystallized from a suitable solvent to
give compounds 4–7, respectively.
3
4
5
6
7
8
9
2
-(1H-Indol-3-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine (4).
1
1
1
1
1
1
1
1
1
2
2
2
0
1
2
3
5
6
7
8
9
0
1
2
Yellow crystals (DMF); yield 41%; mp 240–242 °C; IR (KBr)
ꢀ
1
1
νmax/cm : 3309, (NH), 1623 (C═N), 1571 (C═C); H-NMR
DMSO-d ) δppm: 11.45 (s, 1H, indole NH), 8.10–7.2 (m, 5H,
(
6
Ar H), 6.75 (s, 1H, pyrimidine CH), 6.47 (s, 1H, pyrazole-CH),
2.75 (s, 3H, CH ), 2.48 (s, 3H, CH ); MS: m/z (%) 262.10
(M , 100.00), 234.10(9.99), 131.10(16.71), 89.05(10.54), 57.05
14.23). Anal. calcd for C H N (262.31): C, 73.26; H, 5.38;
3
3
+
(
16 14 4
62.41
8.22
33.29
6.33
N, 21.36%. Found: C, 73.21; H, 5.34; N, 21.30%.
-(1H-Indol-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-7-ol (5).
Pale yellow powder (DMF); yield 65%; mp 280–282 °C; IR (KBr)
2
0.384
0.393
ꢀ
1
1
ν
max/cm : 3430 (OH), 3222 (NH), 1630 (C═N); H-NMR
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98
A. El-Mekabaty, H. A. Etman, and A. Mosbah
Vol 53
(
DMSO-d ) δppm: 13.35 (s, 1H, OH), 11.44 (s, 1H, indole NH),
washed with ethanol and recrystallized from ethanol to afford
6
8
.11–7.21 (m, 5H, Ar H), 6.70 (s, 1H, pyrimidine-CH), 6.55
s, 1H, pyrazole-CH), 2.46 (s, 3H, CH ); MS: m/z (%) 264.1
M , 100.00), 230.0(18.13), 176.2(44.18), 128.3(21.18), 55.12
10.36). Anal. calcd for C15 O (264.28): C, 68.17; H, 4.58;
compound 10. Yellow crystal; yield 81%; mp 270–272 °C; IR
(KBr) νmax/cm : 3408, 3284 (2NH), 1640 (C═N); H-NMR
ꢀ
1
1
(
(
(
3
+
(DMSO-d ) δppm: 11.41 (s, 1H, indole NH), 9.41 (s, 1H, NH),
6
H
12
N
4
8.21 (s, 1H, =CH), 7.68–7.10 (m, 9H, Ar H), 6.73 (s, 1H,
+
N, 21.20%. Found: C, 68.11; H, 4.55; N, 21.17%.
-Hydroxy-2-(1H-indol-3-yl)pyrazolo[1,5-a]pyrimidin-7(6H)-
one (6). Green powder (EtOH); yield 60%; mp 235–237 °C; IR
pyrazole-CH), 3.85 (s, 3H, OCH ); MS: m/z (%) 316.2 (M ,
3
5
15.31), 284.15(34.35), 198.15(33.99), 108.10(19.42), 79.95
(64.55), 63.95(100.00). Anal. calcd for C H N O (316.36): C,
19 16 4
ꢀ
1
(
KBr) νmax/cm : 3530 (2OH), 3426 (NH), 1624 (C═N);
H-NMR (DMSO-d ) δppm: 12.53, 12.34 (br, 2H, 2OH), 11.37
72.13; H, 5.10; N, 17.71%. Found: C, 72.10; H, 5.09; N, 17.70%.
Synthesis of 7-amino-2-(1H-indol-3-yl)-5-(4-methoxyphenyl)
pyrazolo[1,5-a] pyrimidine-6-carbonitrile (11a).
1
6
(
s, 1H, indole NH), 7.79–7.11 (m, 5H, Ar H), 6.78 (s, 1H,
pyrazole-CH), 6.71 (s, 1H, pyrimidine-CH); MS: m/z (%) 266.10
Method A.
2-(4-Methoxybenzylidene)malononitrile (1.84 g,
.01 mol) was added to a mixture of aminopyrazole 3 (1.98 g,
.01 mol) in pyridine (30 mL). The reaction mixture was heated
+
(
M , 3.17), 229.10(18.18), 196.10(29.18), 149.10(10.15), 91.05
27.06), 63.90(100.00). Anal. calcd for C14 (266.25): C,
3.15; H, 3.79; N, 21.04%. Found: C, 63.10; H, 3.76; N, 21.00%.
-(1H-Indol-3-yl)-7-methylpyrazolo[1,5-a]pyrimidin-5-ol (7).
Yellow powder (MeOH); yield 66%; mp 255–257 °C; IR (KBr)
0
0
(
6
10 4 2
H N O
under reflux for 18 h, left to cool, and poured onto ice-cold water
containing few drops of 1 N HCl. The precipitate that formed was
collected by filtration, washed with ethanol, and recrystallized
from ethanol to afford compound 11a (yield 43%).
2
ꢀ
1
1
ν
(
8
max/cm : 3578 (OH), 3370 (NH), 1609 (C═N); H-NMR
DMSO-d ) δppm: 12.15 (s, 1H, OH), 11.42 (s, 1H, indole NH),
.11–7.10 (m, 5H, Ar H), 6.42 (s, 1H, pyrazole-CH), 5.55
6
Method B.
A solution of compound 10 (3.16 g, 0.01 mol)
and malononitrile (0.66 g, 0.01 mol) in pyridine (20 mL) was
refluxed for 22 h. The reaction mixture was left to cool and
poured onto ice-cold water containing few drops of 1 N HCl.
The precipitate that formed was collected by filtration, washed
with ethanol, and recrystallized from ethanol to afford compound
(s, 1H, pyrimidine-CH), 2.50 (s, 3H, CH ); MS: m/z (%)
3
+
2
(
(
64.10 (M , 100.00), 240.10(11.96), 198.10(24.68), 123.15
10.92), 85.10(40.75), 57.05(85.88). Anal. calcd for C15
264.28): C, 68.17; H, 4.58; N, 21.20%. Found: C, 68.11; H,
12 4
H N O
4
.54; N, 21.17%.
1
1a (yield 37%).
Green crystals; mp 280–282 °C; IR (KBr) νmax/cm : 3446
Synthesis of 7-amino-2-(1H-indol-3-yl)pyrazolo[1,5-a]pyrimidin-
ꢀ1
5
-ol (8).
To a mixture of compound 3 (1.98 g, 0.01 mol) in
1
2 6
(
NH); 3420, 3383 (NH ), 2206 (CN); H-NMR (DMSO-d ) δppm:
glacial acetic acid (25 mL), ethyl cyanoacetate (1.13 g, 0.01 mol)
was added. The reaction mixture was refluxed for 18 h and then
poured into crushed ice. The solid product was collected by
filtration, dried, and recrystallized from ethanol to give compound 8.
1
1.41 (s, 1H, indole NH), 8.81 (s, br, 2H, NH ), 8.14–7.11
2
(
m, 9H, Ar H), 6.88 (s, 1H, pyrazole-CH), 3.74 (s, 3H, OCH
3
);
): δppm = 158.8, 100.8 (C═C), 168.8, 154.4,
90.8 (pyrimidine-C), 130.3 (C═N), 136.8, 128.3, 121.5, 118.4,
111.4 (Ar-C), 117.8 (CN), 60.6 (OCH ); MS: m/z (%) 380.50
M , 0.44), 368.50(0.16), 342.20(0.52), 188.10(0.10), 118.10
2.27), 79.05(100.00). Anal. calcd for C22 O (380.40): C,
13
C-NMR (DMSO-d
6
ꢀ
1
Gray crystals; yield 71%; mp 295–297 °C; IR (KBr) νmax/cm
:
1
3
3452 (OH), 3410, 3355 (NH
2
), 3299 (NH); H-NMR (DMSO-d
6
)
+
(
(
δppm: 11.55 (s, br, 1H, OH), 11.43 (s, 1H, indole NH), 9.20 (s, 2H,
NH ), 8.13–7.11 (m, 5H, Ar H), 6.76 (s, 1H, pyrazole-CH), 6.32
16 6
H N
2
+
69.46; H, 4.24; N, 22.09%. Found: C, 69.42; H, 4.21; N, 22.04%.
(
(
s, 1H, pyrimidine-CH); MS: m/z (%) 265.30 (M , 0.97), 243.30
2.49), 149.10(31.17), 84.10(81.42), 57.05(100.00). Anal. calcd
Synthesis of 2-(1H-indol-3-yl)-7-phenyl-6,7-dihydropyrazolo
[
0
(
1,5-a]pyrimidine (12).
.01 mol) and cinnamaldehyde (1.32 g, 0.01 mol) in dry pyridine
20 mL)was heated under reflux for 8 h, allowed to cool, and
A mixture of compound 3 (1.98 g,
11 5
for C14H N O (265.27): C, 63.39; H, 4.18; N, 26.40%. Found:
C, 63.33; H, 4.14; N, 26.38%.
Synthesis of 2-(1H-indol-3-yl)pyrazolo[1,5-a]pyrimidine-5,7-
To a boiling solution of compound 3 (1.98 g,
.01 mol) in dioxane (20 mL) containing triethylamine (1 mL),
poured into cold water (50 mL). The solid product obtained was
collected by filtration, dried, and recrystallized from ethanol to
diamine (9).
0
give compound 12.
malononitrile (0.66 g, 0.01 mol) was added. The reaction mixture
was refluxed for 16 h and then cooled. The solid product so
formed was collected by filtration, washed with ethanol, and
recrystallized from dioxane to give compound 9. Yellow crystals;
ꢀ1
Brown crystals; yield 52%; mp 285–287 °C; IR (KBr) νmax/cm
:
1
3409 (NH), 1600 (C═N); H-NMR (DMSO-d ) δppm: 11.41 (s, 1H,
6
indole NH), 8.22 (t, J=2.1Hz, 1H, N═CH), 7.88–7.05 (m, 10H, Ar
ꢀ
1
H), 6.73 (s, 1H, pyrazole-CH), 4.43 (t, J= 2.6 Hz, 1H,ꢀCHPh), 1.81
yield 44%; mp 302–304 °C; IR (KBr) νmax/cm : 3376 (NH),
13
1
2 6
(t, J = 2.4 Hz, 2H, CH ); C-NMR (DMSO-d ): δppm = 168.9
2 6
3
360, 3299 (2NH ), 1630 (C═N); H-NMR (DMSO-d ) δppm:
(
pyrimidine-C═N), 161.3, 108.8 (pyrazole-C═C), 136.9, 128.8,
1
1.41 (s, 1H, indole NH), 8.68, 8.65 (br, 4H, 2NH ), 8.10–7.10
2
1
21.5, 111.7 (Ar-C), 70.7 (pyrimidine-CH), 29.6 (pyrimidine-
(
m, 5H, Ar H), 6.99 (s, 1H, pyrazole-CH), 6.35 (s, 1H,
+
1
3
CH
3.37), 198.15(5.31), 155.15(17.99), 127.15(11.92), 80.00(100.00),
57.05(60.64). Anal. calcd for C20 (312.37): C, 76.90; H,
.16; N, 17.94%. Found: C, 76.88; H, 5.14; N, 17.90%.
Synthesis of 2-(1H-indol-3-yl)-6,7-dihydropyrazolo[1,5-a]
2
); MS: m/z (%) 312.25 (M , 3.30), 310.25(94.21), 255.20
pyrimidine-CH);
6
C-NMR (DMSO-d ): δppm = 158.8, 100.8
(
(
C═C), 168.8, 154.4, 90.8 (pyrimidine-C), 134.4 (C═N), 136.8,
+
H N
16 4
1
1
5
4
28.3, 121.5, 118.4, 110.5 (Ar-C); MS: m/z (%) 264.30 (M ,
.47), 223.10(6.90), 168.20(2.16), 109.15(12.91), 71.10(53.70),
7.10(100.00). Anal. calcd for C14H N (264.29): C, 63.62; H,
12 6
.58; N, 31.80%. Found: C, 63.60; H, 4.55; N, 31.77%.
5
pyrimidin-5(4H)-imine (13). A solution of 3 (1.98 g, 0.01 mol)
in pyridine (40 mL) was treated with acrylonitrile (0.53 g,
Synthesis of (E)-3-(1H-indol-3-yl)-N-(4-methoxybenzylidene)-
0.01 mol); the mixture was refluxed for 4 h. The reaction mixture
1
H-pyrazol-5-amine (10).
A mixture of compound 3 (1.98 g,
was then poured into water, and the solid product was collected
0
.01 mol) and 4-methoxybenzaldehyde (1.36 g, 0.01mol) in dry
by filtration and recrystallized from ethanol.
pyridine (30 mL) was refluxed for 5 h. The reaction mixture was
cooled and poured onto ice-cold water containing few drops of
1
ꢀ
1
Yellow crystals; yield 81%; mp 275–277 °C; IR (KBr) νmax/cm :
1
N HCl. The precipitate that formed was collected by filtration,
6
3409, 3378, 3313 (3NH), 1623 (C═N); H-NMR (DMSO-d ) δppm:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2016
Synthesis of Some New Fused Pyrazole Derivatives Bearing Indole Moiety
as Antioxidant Agents
899
1
7
CH
1.41 (s, 1H, indole NH), 8.62 (s, 1H, C═NH), 8.44 (s, 1H, NH),
.70–7.13 (m, 5H, Ar H), 6.73 (s, 1H, pyrazole–CH), 2.71 (t, 2H,
(DMSO-d ) δppm: 11.49 (s, 1H, indole NH), 8.66 (s, 1H, NH),
6
8.30–7.17 (m, 11H, Ar H), 6.61 (s, 1H, pyrazole–CH), 3.35
13
13
2
), 2.11 (t, 2H, CH
2
); C-NMR (DMSO-d
6
): δppm =158.3
6
(s, br, 1H, OH); C-NMR (DMSO-d ): δppm = 158.8, 100.8
(
1
pyrimidine–C═NH), 148.4, 108.8 (pyrazole–C═C), 133.8, 128.8,
(C═C), 164.8, 143.5, 136.8, 128.3, 121.5, 118.4 (Ar-C); MS: m/z
(%) 353.45 (M , 3.34), 297.40(1.28), 255.30(4.65), 166.25
(2.88), 129.15(17.75), 69.10(71.77), 57.10(100.00). Anal. calcd
+
21.3, 111.5 (Ar-C), 55.6 (pyrimidine–CH), 38.3 (pyrimidine-
+
CH ); MS: m/z (%) 251.4 (M , 0.12), 249.30(0.18), 167.10(41.02),
2
149.10(100.00), 113.20(19.61), 83.10(15.85), 57.10(69.30). Anal.
for C H N O (353.38): C, 71.38; H, 4.28; N, 19.82%. Found:
2
1 15 5
calcd for C14 (251.29): C, 66.92; H, 5.21; N, 27.87%. Found:
H
13
N
5
C, 71.33; H, 4.25; N, 19.80%.
C, 66.90; H, 5.20; N, 27.80%.
3-(2-(3-(1H-Indol-3-yl)-1H-pyrazol-5-yl)hydrazono)pentane-
Coupling of diazonium salt of compound 3 with active
methylene reagents: malononitrile, ethyl acetoacetate,
diethylmalonate, 3-(1H-indol-3-yl)-3-oxopropanenitrile, β-naphthol
and acetylacetone. A solution of diazotized 14 (prepared from
2,4-dione (22).
Red crystals; yield 73%; mp 294–296 °C; IR
ꢀ
1
(KBr) νmax/cm : 3431–3237 (3NH), 1728 (C═O), 1600 (N═N);
1
H-NMR (DMSO-d
6
) δppm: 11.49 (s, 1H, indole NH), 8.81 (s, 1H,
NH), 8.10–7.10 (m, 6H, Ar H, NH), 6.81 (s, 1H, pyrazole–CH),
1.79 (s, 6H, 2CH ); C-NMR (DMSO-d ): δppm = 191.1 (2C═O),
3 6
13
0
.1 mol of 3 and the appropriate quantities of conc. HCl and
sodium nitrite) was added to a solution of the active methylene
reagents (0.1 mol) in ethanol (100 ml) and sodium acetate (8mg).
The reaction mixture was stirred at room temperature for 6–9 h,
and the solid product formed was collected by filteration.
135.5 (C═N), 148.4, 100.1 (pyrazole–C═C), 133.8, 128.8, 121.3,
+
111.5 (Ar-C), 28.3 (2CH ); MS: m/z (%) 309.30 (M , 0.45), 285.30
3
(1.57), 213.15(5.94), 185.15(4.41), 147.15(4.41), 115.10(12.36),
79.95(100.00), 57.10(48.99). Anal. calcd for C16H N O (309.32):
15 5 2
4
-Amino-7-(1H-indol-3-yl)pyrazolo[5,1-c][1,2,4]triazine-3-
C, 62.13; H, 4.89; N, 22.64%. Found: C, 62.10; H, 4.83; N, 22.60%.
Cyclization of 2-((3-(1H-Indol-3-yl)-1H-pyrazol-5-yl)diazenyl)-
3-(1H-indol-3-yl)-3-oxopropane nitrile (18). A solution of 18
(3.93 g, 0.01 mol) in DMF (30 mL) was refluxed for 4 h. The solid
product obtained on cooling was recrystallized from ethanol to
give a solid product of the bisindole derivative 19.
carbonitrile (15). Red crystals; yield 81%; mp 300–302 °C; IR
ꢀ
1
(
1
KBr) νmax/cm : 3450 (NH), 3387, 3315 (NH ), 2226 (CN),
2
1
620 (N═N); H-NMR (DMSO-d
6
) δppm: 11.49 (s, 1H, indole
), 6.77 (s, 1H, pyrazole–CH);
): δppm = 164.5, 159.5 (triazine–C═C),
58.8, 100.8 (C═C), 136.8, 128.3, 121.5, 118.4 (Ar-C), 117.8
NH), 8.01–7.09 (m, 7H, Ar H, NH
2
1
3
C-NMR (DMSO-d
6
1
Orange crystals; yield 45%; mp 288–290 °C; IR (KBr) νmax
/
+
ꢀ1
(
(
(
CN); MS: m/z (%) 275.15 (M , 15.48), 227.15(15.76), 181.10
15.44), 115.10(22.96), 79.95(92.23), 63.95(100.00), 57.05
24.30). Anal. calcd for C14
5.62%. Found: C, 61.00; H, 3.29; N, 35.60%.
Ethyl 7-(1H-indol-3-yl)-4-methylpyrazolo[5,1-c][1,2,4]triazine-
-carboxylate (16). Red crystals; yield 66%; mp 308–310 °C; IR
KBr) νmax/cm : 3446 (NH), 1718 (CO), 1610 (N═N); H-NMR
cm : 3431, 3380 (2NH), 3365, 3315 (NH ), 1709 (C═O),
2
1
1600 (N═N); H-NMR (DMSO-d ) δppm: 11.49, 11.44 (s, 2H,
6
H
9
N
7
(275.27): C, 61.09; H, 3.30; N,
indole NH), 8.28–7.01 (m, 12H, Ar H, NH ), 6.77 (s, 1H,
2
13
3
pyrazole–CH);
C-NMR (DMSO-d ): δ = 190.3 (C═O),
6 ppm
151.5, 145.4 (triazine–C═C), 148.4, 100.1 (pyrazole–C═C),
+
3
(
136.8, 128.8, 121.3, 111.5, (Ar-C); MS: m/z (%) 394.5 (M +1,
ꢀ
1
1
0.38), 358.30(2.7), 266.30(0.50), 213.15(19.99), 171.20(2.36),
(
DMSO-d ) δppm: 11.57 (s, 1H, indole NH), 8.10–7.10 (m, 5H, Ar
6
107.15(4.01), 57.10(100.00). Anal. calcd for C H N O
2
2 15 7
H), 6.79 (s, 1H, pyrazole–CH), 3.84 (q, J = 7.2 Hz, 2H, CH2),
(393.40): C, 67.17; H, 3.84; N, 24.92%. Found: C, 67.12; H,
3.80; N, 24.90%.
2
.40 (s, 3H, CH ), 1.31 (t, J = 7.2 Hz, 3H, CH ); MS: m/z (%)
3
3
+
3
21.1 (M , 1.3), 279.30(2.9), 250.30(1.11), 198.15(11.04), 142.15
Cyclization of 1-((3-(1H-Indol-3-yl)-1H-pyrazol-5-yl)diazenyl)
(100.00), 115.10(52.28), 71.05(25.68), 57.10(37.18). Anal. calcd
naphthalen-2-ol (20).
A solution of 20 (3.53 g, 0.01mol) in
for C17 (321.33): C, 63.54; H, 4.71; N, 21.79%. Found:
H
15
N
5
O
2
acetic acid (30 mL) was refluxed for 8 h. The solid product
C, 63.50; H, 4.70; N, 21.73%.
obtained on cooling was recrystallized from ethanol.
Ethyl 7-(1H-indol-3-yl)-4-oxo-1,4-dihydropyrazolo[5,1-c][1,2,4]
Yellow crystals; yield 38%; mp 266–268 °C; IR (KBr) νmax/
ꢀ
1
1
triazine-3-carboxylate (17).
06–308 °C; IR (KBr) νmax/cm : 3430, 3356 (2NH), 1723
CO-ester), 1681 (CO-amidic); H-NMR (DMSO-d
1.51 (s, 1H, indole NH), 8.81 (s, 1H, NH), 8.01–7.10 (m, 5H,
Ar H), 6.71 (s, 1H, pyrazole–CH), 4.2 (q, 2H, CH ), 1.2 (t, 3H,
Red crystals; yield 52%; mp
cm : 3431 (NH), 1588 (N═N); H-NMR (DMSO-d ) δppm:
6
ꢀ
1
3
(
1
11.44 (s, 1H, indole NH), 8.22–7.01 (m, 11H, Ar H), 6.77
1
+
6
) δppm
:
(s, 1H, pyrazole–CH); MS: m/z (%) 335.12 (M , 2.91), 280.30
(1.28), 197.20(3.46), 144.15(65.15), 106.10(21.28), 57.10(100.00).
2
Anal. calcd for C H N (335.36): C, 75.21; H, 3.91; N, 20.88%.
21 13 5
+
CH
3
); MS: m/z (%) 323.2 (M , 31.27), 317.20(20.85), 258.20
29.34), 181.20(11.58), 105.05(20.08), 80.95(100.00), 64.95
46.33). Anal. calcd for C H N O (323.31): C, 59.44; H,
Found: C, 75.19; H, 3.90; N, 20.85%.
(
(
4
Antioxidant activity assay. Antioxidant activity determinations
were evaluated from the bleaching of ABTS-derived radical cations.
The radical cation was derived from ABTS [2,2′-azino-bis (3-ethyl
benzothiazoline-6-sulfonic acid)] was prepared by reaction of ABTS
1
6 13 5 3
.05; N, 21.66%. Found: C, 59.40; H, 4.00; N, 21.64%.
-((3-(1H-Indol-3-yl)-1H-pyrazol-5-yl)diazenyl)-3-(1H-indol-
-yl)-3-oxopropane nitrile (18). Red crystals; yield 44%; mp
2
3
3
2
(
8
(60 μL) with MnO (3 mL, 25 mg/mL) in phosphate buffer solution
2
ꢀ
1
14–316 °C; IR (KBr) νmax/cm : 3430, 3390, 3320 (3NH),
(10 μM, pH 7, 5 mL) After shaking the solution for a few minutes, it
was centrifuged and filtered. The absorbance (A control) of the
resulting green-blue solution (ABTS radical solution) was recorded
at λmax 734 nm. The absorbance (A test) was measured upon the
addition of (20 μL of 1 mg/mL) solution of the tested sample in
spectroscopic grade MeOH/buffer (1:1, v/v) to the ABTS solution.
The decrease in the absorbance is expressed as % inhibition, which
is calculated from this equation:
1
215 (CN), 1586 (N═N); H-NMR (DMSO-d ) δppm: 12.22
6
s, 1H, NH), 11.66 (s, 1H, indole NH), 11.61 (s, 1H, indole NH),
.21–7.10 (m, 10H, Ar H), 6.73 (s, 1H, pyrazole–CH), 4.49
+
(
s, 1H, CH); MS: m/z (%) 393.4 (M , 0.48), 331.40(4.41),
2
6
3
27.15(12.03), 144.15(100.00), 127.15(6.62), 79.05(41.46),
3.05(16.93). Anal. calcd for C H N O (393.40): C, 67.17; H,
2
2 15 7
.84; N, 24.92%. Found: C, 67.10; H, 3.81; N, 24.88%.
-((3-(1H-Indol-3-yl)-1H-pyrazol-5-yl)diazenyl)naphthalen-2-
ol (20). Red crystals; yield 45%; mp 305–307 °C; IR (KBr) νmax
1
/
ꢀ
1
1
%
Inhibition ¼ ½AðcontrolÞ–AðtestÞ=AðcontrolÞꢁ ꢂ 100:
cm : 3431, 3402 (2NH), 3306 (OH), 1586 (N═N); H-NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

9
00
A. El-Mekabaty, H. A. Etman, and A. Mosbah
Vol 53
[
15] Xia, Y.; Chackalamannil, S.; Czarniecki, M.; Tsai, H.;
Ascorbic acid (20 μL, 2 mM) solution was used as standard
antioxidant (positive control). Blank sample was run using solvent
without ABTS.
Vaccaro, H.; Cleven, R.; Cook, J.; Fawzi, A.; Watkins, R.; Zhang, H.
J Med Chem 1997, 40, 4372.
[16] Ahn, H. S.; Bercovici, A.; Boykow, G.; Bronnenkant, A.;
Chackalamannil, S.; Chow, J.; Cleven, R.; Cook, J.; Czarniecki, M.;
Domalski, C.; Fawzi, A.; Green, M.; Gündes, A.; Ho, G.; Laudicina, M.;
Lindo, N.; Ma, K.; Manna, M.; McKittrick, B.; Mirzai, B.; Nechuta, T.;
Neustadt, B.; Puchalski, C.; Pula, K.; Silverman, L.; Smith, E.; Stamford, A.;
Tedesco, R. P.; Tsai, H.; Tulshian, D.; Vaccaro, H.; Watkins, R. W.;
Weng, X.; Witkowski, J. T.; Xia, Y.; Zhang, H. J Med Chem 1997,
40, 2196.
Acknowledgment. The authors are grateful to Mr. A. Abass,
Department of Pharmaceutical Organic Chemistry, Faculty of
Pharmacy, Mansoura University, Egypt, for performing the
antioxidant activity.
[
17] Traxler, P.; Bold, G.; Frei, J.; Lang, M.; Lydon, N.; Mett, H.;
Buchdunger, E.; Meyer, T.; Mueller, M.; Furet, P. , J Med Chem 1997,
0, 3601.
[18] Zacharie, B.; Connolly, T. P.; Rej, R.; Attardo, G.; Penney,
4
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