Synthesis and antioxidant activity of some new N-alkylated pyrazole-containing benzimidazoles

Article abstract of DOI:10.1007/s10593-017-2036-6

[Figure not available: see fulltext.] A series of new N-substituted pyrazole-containing benzimidazoles was synthesized starting from 1,2-diaminobenzene and pyrazole-4-carbaldehyde in good yield. Antioxidant activity of all title compounds was assessed usi

Full text of DOI:10.1007/s10593-017-2036-6

DOI 10.1007/s10593-017-2036-6
Chemistry of Heterocyclic Compounds 2017, 53(2), 173–178
Synthesis and antioxidant activity of some new
N-alkylated pyrazole-containing benzimidazoles
Mahesh Bellam1, Mohan Gundluru1, Santhisudha Sarva1, Sridevi Chadive2,
Vasudeva Reddy Netala1, Vijaya Tartte1, Suresh Reddy Cirandur1*
1 Sri Venkateswara University,
University Ave., Tirupati 517 502, India; e-mail: csrsvu@gmail.com
2 Sri Padmavathi Women's Degree & P.G. College,
University Ave., Tirupati 517 502, India; e-mail: sridevic64@gmail.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2017, 53(2), 173–178
Submitted June 8, 2016
Accepted after revision October 20, 2016
A series of new N-substituted pyrazole-containing benzimidazoles was synthesized starting from 1,2-diaminobenzene and pyrazole-
4-carbaldehyde in good yield. Antioxidant activity of all title compounds was assessed using 2,2-diphenyl-1-picrylhydrazyl and
hydrogen peroxide assays. Some of the synthesized compounds having benzyl substituent at the imidazole nitrogen exhibited good
activity in both assays.
Keywords: benzimidazole, 2,2-diphenyl-1-picrylhydrazyl, hydrogen peroxide, pyrazole, zinc chloride, antioxidant activity.
The basic heterocyclic moieties play a pivotal role in
regulation of macromolecular targets in the living systems.
Molecular structure is the most influential factor in
understanding of several biological pathways and in the
design and synthesis of therapeutical and pharmacological
agents for the cure of various diseases. Among the hetero-
cyclic structures, imidazole1–3 and pyrazole4–6 moieties are
of interest because of their wide range of clinical appli-
cations.
harsh dehydration conditions by using strong acids, such as
polyphosphoric, hydrochloric, boric, or p-toluenesulfonic
acids.17 It was found that the use of milder acidic reagents,
particularly Lewis acids18 or inorganic clays19 improves
both yield and purity of the synthesized benzimidazoles. A
variety of methods have been developed for the synthesis
of specifically substituted imidazoles,20 including the use of
a solid-phase combinatorial approach.21,22
Synthesis of 2-(pyrazol-4-yl)benzimidazoles via conden-
sation of 1,2-diaminobenzene with pyrazole-4-carbaldehydes
requires an oxidative reagent such as H2O2 to generate
benzimidazole nucleus.23 These aspects have motivated us
to design and synthesize various N-substituted benzimidazoles
bearing pyrazole ring at position 2 of the benzimidazole
ring and screen them for the exhibition of antioxidant
activity. Hence, a rapid, simple, and inexpensive method
for the synthesis of N-substituted pyrazole-containing
benzimidazole dertivatives via Vilsmeier–Haack reaction
has been developed. This protocol involves two steps as
shown in Scheme 1. In the first step, 1,2-diaminobenzene (1)
was reacted with 1,3-disubstituted pyrazole-5-carbaldehy-
des 2a–h to generate 2-(pyrazol-4-yl)benzimidazoles 3a–h.
To optimize the experimental conditions for the synthe-
sis of 2-substituted benzimidazoles 3a–h, the reaction of
The biological importance of the benzimidazole moiety
is illustrated by its presence in the structure of amino acid
histidine, vitamin B12 and DNA base structure. This
heterocycle is also found in a variety of drugs such as
thiabendazole and flubendazole, omeprazole, lansoprazole,
candesartan, telmisartan, pantoprazole, and mebendazole.7
Benzimidazole derivatives are also known to be anti-
microbial,8 anti-inflammatory,9 antiulcer,10 antitubercular,11
antiretroviral,12 antioxidant,13 antihypertensive,14 and anti-
parasitic agents.15 It is reported that benzimidazol-
1-ylmethyl derivatives of thiadiazole, thiosemicarbazide,
and triazole are good inhibitors of NADPH-dependent lipid
peroxidation.16
Traditionally, benzimidazoles can be prepared from the
reaction of 1,2-diaminobenzene and carboxylic acids under
0009-3122/17/53(02)-0173©2017 Springer Science+Business Media New York
173

Chemistry of Heterocyclic Compounds 2017, 53(2), 173–178
Scheme 1
1,2-diaminobenzene (1) and 1,4-diphenylpyrazole-4-carb-
aldehyde (2a) was studied as a model reaction under
various reaction conditions (Table 1). Initially, the catalyst-
free reaction resulted in poor yield of product 3a (Table 1,
entry 1). The model reaction carried out with catalysts like
iodine, neutral alumina, Silicagel 60, and Amberlyst 15® in
ethanol produced low to moderate yields of product (42–
51%, Table 1, entries 2–5). The use of Lewis acid catalysts
FeCl3, AlCl3, InCl3 in ethanol resulted in higher yields (69–
72%, Table 1, entries 6–8). Another catalyst ZnCl2 showed
still higher catalytic activity, allowing to increase the yield
to 88% with 10 mol % catalyst load (Table 1, entry 9).
Optimizing the minimum effective concentration of the
ZnCl2, the same reaction was carried out with 3 and 5 mol %
of catalyst. In the case of the reaction with 3 mol % of the
catalyst, the yield was significantly lower (Table 1,
entry 11), while the use of 5 mol % concentration of the
ZnCl2 catalyst was found as the effective and sufficient
concentration for the completion of the reaction and
yielded 82% of the product (Table 1, entry 10). Finally,
different solvents were screened in the model reaction
(Table 1, entries 12–15), and acetonitrile was identified as
the most effective (Table 1, entry 14).
Table 1. Synthetic condition optimization
for the synthesis of compound 3a*
Entry
Catalyst (mol %)
Solvent
Yield, %
1
2
–
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CHCl3
PhMe
MeCN
DMF
21
42
51
47
51
72
69
71
88
82
76
77
69
91
75
I2 (10)
3
Neutral alumina (10)
Silicagel 60 (10)
4
®
5
Amberlyst 15 (10)
6
FeCl3 (10)
AlCl3 (10)
InCl3 (10)
ZnCl2 (10)
ZnCl2 (5)
ZnCl2 (3)
ZnCl2 (5)
ZnCl2 (5)
ZnCl2 (5)
ZnCl2 (5)
7
8
9
10
11
12
13
14
15
* Experimental conditions: 1,2-diaminobenzene (1) and 1,3-diphenyl-
1H-pyrazole-4-carbaldehyde (2a) at equimolar ratio (1.00 mmol) in 15 ml
of solvent under reflux, reaction time 5 h.
The use of 5 mol % of ZnCl2 in refluxing acetonitrile
was identified as the optimal experimental conditions, and
such amount was applied for the synthesis of 2-pyrazolyl-
substituted benzimidazoles 3a–h in excellent yields
(Scheme 1). Since both electron-withdrawing and electron-
donating substituents on 4-phenyl group at the pyrazole
cycle are far away from the reacting center, the effect of
substituent does not significantly affect the product
formation. In the next step, pyrazole-substituted
benzimidazoles were alkylated by various alkyl bromides
in the presence of K2CO3 in acetone to produce a series of
N-substituted pyrazolylbenzimidazoles 4a–l (Scheme 1).
We have studied the antioxidant properties of the
synthesized compounds 4a–l by evaluating their radical
scavenging activity against 2,2-diphenyl-1-picrylhydrazyl
(DPPH) and H2O2. The obtained results reveal that all of
the tested compounds have an activity comparable to the
ascorbic acid standard (Table 2). Particularly, compounds
4c,f,l containing benzyl group as substituent on imidazole
nitrogen exhibit a good activity (especially compound 4f)
which may be attributed to the extended resonance by the
Table 2. Antioxidant activity of compounds 4a–l
determined by DPPH and H2O2 radical scavenging assays
IC50, mg · ml–1
Compounds
DPPH
H2O2
144.00 0.27
118.60 0.59
82.79 0.77
132.46 0.56
100.46 0.68
49.48 0.87
169.98 1.22
119.07 0.39
111.00 0.16
134.83 0.96
112.61 0.83
80.00 0.78
31.42 0.41
163.98 0.92
134.93 0.48
99.02 0.81
143.96 0.86
105.98 0.74
79.95 0.59
179.65 1.70
133.70 0.35
115.22 0.61
147.15 0.96
118.50 0.98
98.44 0.77
55.59 0.56
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
Ascorbic acid
174

Chemistry of Heterocyclic Compounds 2017, 53(2), 173–178
radical that is formed from the benzyl group upon reaction.
(C Ar); 146.1 (C Ar); 143.8 (C Ar); 140.3 (2C Ar); 139.2
(C Ar); 132.5 (CH Ar); 129.6 (4CH Ar); 127.0 (CH Ar);
124.7 (2CH Ar); 123.3 (2CH Ar); 120.2 (2CH Ar); 115.1
(2CH Ar); 109.5 (C-4 pyrazole). Mass spectrum, m/z: 382
[M+H]+. Found, %: C 69.17; H 3.90; N 18.21. C22H15N5O2.
Calculated, %: C 69.28; H 3.96; N 18.36.
Propargyl derivatives 4b,e,h,k have lower activity than com-
pounds 4c,f,l, but higher than pentyl derivatives 4a,d,g,j.
In conclusion, new N-substituted pyrazolylbenz-
imidazoles were successfully synthesized in a two-step
process. Since some of the synthesized compounds possess
potent antioxidant activity comparable to that of ascorbic
acid, we hope these compounds will find application in the
field of medicinal chemistry.
2-[3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl]-
1H-benzimidazole (3c). Yield 89%, mp 151–153°C (mp
150°C23). IR spectrum, ν, cm–1: 3349 (N–H), 2918 (C–H),
1
1105 (C–O–C). H NMR spectrum, δ, ppm (J, Hz): 3.86
Experimental
(3H, s, OCH3); 5.19 (1H, br. s, NH); 7.33–7.36 (2H, m,
H Ar); 7.41–7.45 (2H, m, H Ar); 7.54–7.72 (5H, m, H Ar);
8.62 (2H, d, J = 5.5, H Ar); 8.83 (2H, d, J = 5.4, H Ar);
9.24 (1H, s, H-5 pyrazole). 13C NMR spectrum, δ, ppm:
199.6 (C Ar); 153.0 (C Ar); 146.1 (C Ar); 143.2 (C Ar);
141.3 (2C Ar); 132.7 (CH Ar); 129.7 (2CH Ar); 128.7
(2CH Ar); 126.8 (CH Ar); 124.3 (C Ar); 122.9 (2CH Ar);
119.6 (2CH Ar); 116.3 (2CH Ar); 115.1 (2CH Ar); 109.1
(C-4 pyrazole) 55.8 (OCH3). Mass spectrum, m/z: 367
[M+H]+. Found, %: C 75.32; H 4.48; N 15.21. C23H18N4O.
Calculated, %: C 75.39; H 4.95; N 15.29.
IR spectra were recorded as neat samples on a Bruker
Alpha FTIR spectrometer with an Eco ATR single-
reflection sampling module equipped with ZnSe crystal.
1H and 13C NMR spectra were recorded on a Bruker AMX
spectrometer (400 and 100 MHz, respectively) in DMSO-d6
with TMS as internal standard. Partial assignment of
13C NMR signals was made using APT experiment. ESI
mass spectra were recorded on a Q-TOF Micromass
spectrometer. Melting points were determined using a
Guna Digital Melting Point apparatus and elemental
analysis was performed on a Thermo Finnigan Instrument.
All the chemicals were procured from Sigma-Aldrich and
used as such without further purification. All solvents used
for the spectroscopic and other physical studies were
reagent grade and were further purified by standard
methods.
2-[3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]-1H-
benzimidazole (3d). Yield 85%, mp 189–191°C. IR spectrum,
ν, cm–1: 3343 (N–H), 2912 (C–H). 1H NMR spectrum,
δ, ppm: 5.00 (1H, br. s, NH); 7.42–7.61 (11H, m, H Ar);
8.79–8.82 (2H, m, H Ar); 9.25 (1H, s, H-5 pyrazole).
13C NMR spectrum, δ, ppm: 149.0 (C Ar); 146.1 (C Ar);
143.6 (C Ar); 140.3 (2C Ar); 133.0 (C Ar); 131.6 (CH Ar);
131.1 (C Ar); 129.4 (2CH Ar); 129.3 (2CH Ar); 128.5
(2CH Ar); 127.0 (CH Ar); 122.9 (2CH Ar); 120.3 (2CH Ar);
115.6 (2CH Ar); 109.2 (C-4 pyrazole). Mass spectrum, m/z:
371 [M+H]+. Found, %: C 71.24; H 4.34; N 15.54.
C22H15ClN4. Calculated, %: C 71.25; H 4.08; N 15.11;
4-[4-(1H-Benzimidazol-2-yl)-1-phenyl-1H-pyrazol-3-yl]-
phenol (3e). Yield 90%, mp 200–202°C. IR spectrum,
Synthesis of 2-(1,3-diaryl-1H-pyrazol-4-yl)-1H-benz-
imidazoles 3a–h (General method). 1,2-Diaminobenzene
(1) (0.108 g, 1.00 mmol), an appropriate pyrazole aldehyde
2a–h (1.00 mmol), and ZnCl2 (6.82 mg, 5 mol %) were
placed into a 50-ml round-bottomed flask, and acetonitrile
(15 ml) was added. The contents were refluxed for about
5 h. The reaction progress was monitored by TLC on silica
gel (hexane–AcOEt, 2:1). After completion of the reaction,
as indicated by TLC, the reaction mixture was poured into
ice water, the precipitate was filtered off and dried under
vacuum.
1
ν, cm–1: 3496 (O–H), 3343 (N–H), 2912 (C–H). H NMR
spectrum, δ, ppm: 5.00 (1H, br. s, NH); 5.86 (1H, br. s,
OH); 6.45–6.48 (2H, m, H Ar); 7.42–7.60 (11H, m, H Ar);
9.03 (1H, s, H-5 pyrazole). 13C NMR spectrum, δ, ppm:
148.3 (C Ar); 153.4 (C Ar); 146.0 (C Ar); 143.0 (C Ar);
140.9 (2C Ar); 131.4 (CH Ar); 129.7 (2CH Ar); 128.6
(2CH Ar); 126.2 (CH Ar); 126.1 (C Ar); 123.0 (2CH Ar);
119.9 (2CH Ar); 118.4 (2CH Ar); 115.7 (2CH Ar); 110.0 (C-4
pyrazole). Mass spectrum, m/z: 353 [M+H]+. Found, %:
C 74.74; H 4.44; N 15.86. C22H16N4O. Calculated, %:
C 74.98; H 4.58; N 15.90.
2-(1,3-Diphenyl-1H-pyrazol-4-yl)-1H-benzimidazole (3a).
Yield 91%, mp 200–202°C (mp 200°C). 23 IR spectrum,
1
ν, cm–1: 3356 (N–H), 2910 (C–H). H NMR spectrum,
δ, ppm: 5.23 (1H, br. s, NH); 7.15–7.18 (2H, m, H Ar);
7.32–7.50 (10H, m, H Ar); 7.64–7.67 (2H, m, H Ar); 9.08
(1H, s, H-5 pyrazole). 13C NMR spectrum, δ, ppm: 148.8
(C Ar); 146.0 (C Ar); 143.2 (C Ar); 135.3 (C Ar); 134.2
(C Ar); 132.5 (CH Ar); 129.9 (2CH Ar); 129.8 (2CH Ar);
128.1 (CH Ar); 127.6 (2CH Ar); 127.0 (CH Ar); 122.9
(2CH Ar); 119.7 (2CH Ar); 115.0 (2CH Ar); 109.1 (C-4
pyrazole). Mass spectrum, m/z: 337 [M+H]+. Found, %:
C 78.35; H 4.61; N 16.45. C22H16N4. Calculated, %: C 78.55;
H 4.79; N 16.66.
4-[4-(1H-Benzimidazol-2-yl)-1-phenyl-1H-pyrazol-3-yl]-
aniline (3f). Yield 92%, mp 211–213°C. IR spectrum,
1
ν, cm–1: 3388 (N–H), 3343 (N–H), 2912 (C–H). H NMR
spectrum, δ, ppm: 5.00 (1H, br. s, NH); 5.99 (2H, br. s,
NH2); 6.66–6.69 (2H, m, H Ar); 7.41–7.59 (11H, m, H Ar);
8.79 (1H, s, H-5 pyrazole). 13C NMR spectrum, δ, ppm:
149.6 (C Ar); 146.3 (C Ar); 145.9 (C Ar); 143.8 (C Ar);
142.0 (2C Ar); 131.5 (CH Ar); 129.7 (2CH Ar); 128.4
(2CH Ar); 126.5 (CH Ar); 123.0 (2CH Ar); 124.3 (C Ar);
119.9 (2CH Ar); 116.7 (2CH Ar); 115.2 (2CH Ar); 109.1
(C-4 pyrazole).Mass spectrum, m/z: 352 [M+H]+. Found, %:
C 75.14; H 4.65; N 19.68. C22H17N5. Calculated, %:
C 75.19; H 4.88; N 19.93;
2-[3-(4-Nitrophenyl)-1-phenyl-1H-pyrazol-4-yl]-1H-
benzimidazole (3b). Yield 92%, mp 230–232°C (mp
230°C23). IR spectrum, ν, cm–1: 3343 (N–H), 2912 (C–H),
1
1346 (NO2). H NMR spectrum, δ, ppm (J, Hz): 5.24 (1H,
br. s, NH); 7.37–7.40 (2H, m, H Ar); 7.46–7.50 (2H, m,
H Ar); 7.56–7.74 (5H, m, H Ar); 8.80 (2H, d, J = 7.7,
H Ar); 8.92 (2H, d, J = 5.7, H Ar); 9.25 (1H, s, H-5
pyrazole). 13C NMR spectrum, δ, ppm: 148.0 (C Ar); 147.7
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Chemistry of Heterocyclic Compounds 2017, 53(2), 173–178
(2H, m, H Ar); 8.88 (1H, s, H-5 pyrazole). 13C NMR
2-[3-(4-Methylphenyl)-1-phenyl-1H-pyrazol-4-yl]-1H-
benzimidazole (3g). Yield 87%, mp 205–207°C. IR spectrum,
ν, cm–1: 3349 (N–H), 2918 (C–H). 1H NMR spectrum,
δ, ppm: 2.36 (3H, s, CH3); 5.01 (1H, br. s, NH); 7.18–7.22
(6H, m, H Ar); 7.91–8.01 (7H, m, H Ar); 8.95 (1H, s, H-5
pyrazole). 13C NMR spectrum, δ, ppm: 148.9 (C Ar); 145.9
(C Ar); 143.2 (C Ar); 141.4 (2C Ar); 131.4 (CH Ar); 130.9
(C Ar); 130.1 (C Ar); 129.6 (2CH Ar); 128.7 (2CH Ar);
126.3 (CH Ar); 125.2 (2CH Ar); 123.3 (2CH Ar); 119.5
(2CH Ar); 115.4 (2CH Ar); 109.7 (C-4 pyrazole); 21.7 (CH3).
Mass spectrum, m/z: 351 [M+H]+. Found, %: C 78.81; H 5.11;
N 15.88. C23H18N4. Calculated, %: C 78.83; H 5.18; N 15.99.
2-[3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl]-1H-
benzimidazole (3h). Yield 85%, mp 215–217°C. IR spectrum,
ν, cm–1: 3343 (N–H), 2912 (C–H). 1H NMR spectrum,
δ, ppm: 5.03 (1H, br. s, NH); 7.48–7.63 (11H, m, H Ar);
8.83–8.87 (2H, m, H Ar); 9.23 (1H, s, H-5 pyrazole).
13C NMR spectrum, δ, ppm: 149.1 (C Ar); 146.1 (C Ar);
143.4 (C Ar); 140.4 (2C Ar); 131.9 (CH Ar); 131.2 (C Ar);
129.4 (4CH Ar); 128.5 (2CH Ar); 126.7 (CH Ar); 126.0
(C Ar); 123.0 (2CH Ar); 120.3 (2CH Ar); 115.7 (2CH Ar);
109.2 (C-4 pyrazole). Mass spectrum, m/z: 416 [M+H]+.
Found, %: C 63.49; H 3.38; N 13.28. C22H15BrN4. Calcu-
lated, %: C 63.63; H 3.64; N 13.49.
spectrum, δ, ppm: 148.0 (C Ar); 145.7 (2C Ar); 145.0
(C Ar); 136.3 (8-C); 133.0 (C Ar); 131.4 (CH Ar); 131.0
(2CH Ar); 130.4 (2CH Ar); 129.6 (CH Ar); 127.7 (2CH Ar);
126.2 (CH Ar); 122.4 (2CH Ar); 120.1 (2CH Ar); 119.3
(CH Ar); 109.9 (CH Ar); 109.6 (C-4 pyrazole); 78.0
(C≡C); 75.3 (C≡C); 32.8 (CH2). Mass spectrum, m/z: 375
[M+H]+. Found, %: C 80.11; H 4.80; N 14.35. C25H18N4.
Calculated, %: C 80.19; H 4.85; N 14.96.
1-Benzyl-2-(1,3-diphenyl-1H-pyrazol-4-yl)-1H-benz-
imidazole (4c). Yield 98%, mp 164–166°C. IR spectrum,
1
ν, cm–1: 2918 (C–H), 1679 (–C=N–). H NMR spectrum,
δ, ppm: 5.25 (2H, s, CH2); 7.22–7.27 (2H, m, H Ar); 7.30–
7.38 (4H, m, H Ar); 7.47–7.55 (6H, m, H Ar); 7.60–7.67
(5H, m, H Ar); 7.92–7.97 (2H, m, H Ar); 8.41 (1H, s, H-5
pyrazole). 13C NMR spectrum, δ, ppm: 149.4 (C Ar); 145.5
(C Ar); 143.0 (C Ar); 142.9 (C Ar); 136.3 (C Ar); 136.0
(C Ar) 133.7 (C Ar); 131.7 (CH Ar); 130.5 (2CH Ar);
129.7 (2CH Ar); 128.6 (2CH Ar); 128.0 (CH Ar); 127.6
(2CH Ar); 127.4 (2CH Ar); 125.7 (CH Ar); 124.9 (CH Ar);
122.8 (2CH Ar); 120.3 (2CH Ar); 120.0 (CH Ar); 119.6
(CH Ar); 110.1 (C-4 pyrazole); 51.2 (CH2). Mass spectrum,
m/z: 427 [M+H]+. Found, %: C 81.35; H 5.34; N 13.00.
C29H22N4. Calculated, %: C 81.66; H 5.20; N 13.14.
Synthesis of 2-(1,3-diaryl-1H-pyrazol-4-yl)-1-pentyl-
1H-benzimidazoles 4a–l (General method). 2-(1,3-Diaryl-
1H-pyrazol-4-yl)-1H-benzimidazole 3a–d (1.00 mmol),
alkyl bromide (3.00 mmol), and K2CO3 (5.0 mol %,
6.90 mg) were placed into a 50-ml round-bottomed flask,
and acetone (15 ml) was added. The reaction mixture was
refluxed for 5–6.5 h. The reaction progress was monitored
by TLC (hexane–AcOEt, 2:1). After completion of the
reaction, as indicated by TLC, K2CO3 was separated
by filtration, the filtrate was evaporated, and the crude
product was purified by column chromatography by using
100–200 mesh silica gel as adsorbent and hexane–
AcOEt, 2:3.
2-[3-(4-Nitrophenyl)-1-phenyl-1H-pyrazol-4-yl]-1-pentyl-
1H-benzimidazole (4d). Yield 83%, mp 223–225°C.
IR spectrum, ν, cm–1: 2951 (C–H), 1682 (–C=N–), 1345
(NO2). 1H NMR spectrum, δ, ppm (J, Hz): 0.61 (3H, t, J = 5.2,
CH3); 0.93–0.98 (4H, m, CH2); 1.53–1.56 (2H, m, CH2);
4.13 (2H, t, J = 5.4, CH2); 7.30–7.34 (2H, m, H Ar); 7.44
(1H, t, J = 7.0 H Ar); 7.52–7.80 (4H, m, H Ar); 7.88 (2H,
d, J = 8.3, H Ar); 8.05 (2H, d, J = 7.7, H Ar); 8.12–8.36
(2H, m, H Ar); 9.15 (1H, s, H-5 pyrazole). 13C NMR
spectrum, δ, ppm: 148.2 (C Ar); 146.2 (C Ar); 145.9
(C Ar); 143.6 (C Ar); 139.1 (C Ar); 138.0 (C Ar); 135.6
(C Ar); 133.5 (CH Ar); 129.8 (2CH Ar); 128.9 (2CH Ar);
126.0 (CH Ar); 125.0 (2CH Ar); 121.9 (2CH Ar); 119.2
(2CH Ar); 118.7 (CH Ar); 111.0 (CH Ar); 109.9 (C-4
pyrazole); 43.6 (NCH2); 28.8 (CH2); 28.0 (CH2); 21.4 (CH2);
13.9 (CH3). Mass spectrum, m/z: 452 [M+H]+. Found, %:
C 71.57; H 5.21; N 15.32. C27H25N5O2. Calculated, %:
C 71.82; H 5.58; N 15.51.
2-(1,3-Diphenyl-1H-pyrazol-4-yl)-1-pentyl-1H-benz-
imidazole (4a). Yield 89%, mp 205–207°C. IR spectrum,
1
ν, cm–1: 2910 (C–H), 1680 (–C=N–). H NMR spectrum,
δ, ppm (J, Hz): 0.62 (3H, t, J = 5.5, CH3); 0.90–0.93 (2H,
m, CH2); 0.94–0.97 (2H, m, CH2); 1.52–1.55 (2H, m, CH2);
4.10 (2H, t, J = 5.9, CH2); 6.86 –7.00 (2H, m, H Ar); 7.01–
7.36 (10H, m, H Ar); 7.82 (2H, d, J = 8.2, H Ar); 8.49 (1H,
s, H-5 pyrazole). 13C NMR spectrum, δ, ppm: 147.2 (C Ar);
146.27 (C Ar); 145.9 (C Ar); 143.6 (C Ar); 135.6 (8-C);
134.0 (C Ar); 133.5 (CH Ar); 129.8 (4CH Ar); 128.0 (CH
Ar); 127.9 (2CH Ar); 126.0 (CH Ar); 121.9 (2CH Ar);
119.2 (2CH Ar); 118.7 (CH Ar); 111.0 (CH Ar); 109.9
(C-4 pyrazole); 43.6 (NCH2); 28.6 (CH2); 27.9 (CH2); 21.4
(CH2); 13.4 (CH3). Mass spectrum, m/z: 407 [M+H]+.
Found, %: C 79.64; H 6.35; N 13.66. C27H26N4. Calculated, %:
C 79.77; H 6.45; N 13.78.
2-[3-(4-Nitrophenyl)-1-phenyl-1H-pyrazol-4-yl]-1-(prop-
2-yn-1-yl)-1H-benzimidazole (4e). Yield 96%, mp 170–
171°C. IR spectrum, ν, cm–1: 3240 (≡C–H), 2191 (C≡C),
1
1671 (–C=N–); 1330 (NO2). H NMR spectrum, δ ppm
(J, Hz): 3.32 (1H, s, ≡CH); 5.14 (2H, s, CH2); 7.20–7.51
(3H, m, H Ar); 7.62 (2H, t, J = 7.1, H Ar); 7.74 (2H, t, J = 6.9,
H Ar); 7.88 (2H, d, J = 7.3, H Ar); 8.05 (2H, d, J = 7.7,
H Ar); 8.26 (2H, d, J = 7.9, H Ar); 9.19 (1H, s, H-5
pyrazole). 13C NMR spectrum, δ, ppm: 148.9 (C Ar); 147.1
(C Ar); 145.5 (C Ar); 142.6 (C Ar); 138.9 (C Ar); 138.4
(C Ar); 134.6 (C Ar); 131.5 (CH Ar); 129.7 (2CH Ar);
128.3 (2CH Ar); 127.5 (CH Ar); 123.8 (2CH Ar); 123.0
(2CH Ar); 122.4 (2CH Ar); 119.3 (CH Ar); 119.1 (CH Ar);
111.0 (C-4 pyrazole); 78.0 (C≡C); 75.8 (C≡C); 47.0 (CH2).
Mass spectrum, m/z: 420 [M+H]+. Found, %: C 71.33;
H 4.01; N 16.51. C25H17N5O2. Calculated, %: C 71.59;
H 4.09; N 16.70.
2-(1,3-Diphenyl-1H-pyrazol-4-yl)-1-(prop-2-yn-1-yl)-1H-
benzimidazole (4b). Yield 94%, mp 161–163°C. IR spectrum,
ν, cm–1: 2916 (C–H), 2099 (C≡C), 1688 (–C=N–). 1H NMR
spectrum, δ, ppm: 3.66 (1H, s, ≡CH); 5.14 (2H, s, CH2);
6.89–7.01 (4H, m, H Ar); 7.65–7.70 (2H, m, H Ar); 7.79–
7.97 (4H, m, H Ar); 8.05–8.11 (2H, m, H Ar); 8.54–8.58
176

Chemistry of Heterocyclic Compounds 2017, 53(2), 173–178
1-Benzyl-2-[3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-
OCH3); 5.36 (2H, s, CH2); 6.82 (2H, t, J = 7.8); 7.04 (3H,
d, J = 7.1); 7.18–7.24 (2H, m, H Ar); 7.36 (1H, t, J = 7.3,
H Ar); 7.50 (3H, t, J = 7.7, H Ar); 7.69-7.74 (3H, m, H Ar);
7.89 (2H, d, J = 8.1, H Ar); 8.19 (2H, d, J = 8.5, H Ar);
8.68 (1H, s, H-5 pyrazole). 13C NMR spectrum, δ, ppm:
150.6 (C Ar); 149.1 (C Ar); 144.8 (C Ar); 143.3 (C Ar);
142.6 (C Ar); 137.0 (C Ar); 136.2 (C Ar); 131.8 (CH Ar);
130.0 (2CH Ar); 128.1 (2CH Ar); 127.9 (2CH Ar); 127.0
(2CH Ar); 126.3 (CH Ar); 125.1 (CH Ar); 123.7 (C Ar);
123.0 (2CH Ar); 119.8 (2CH Ar); 119.0 (CH Ar); 118.7
(CH Ar); 115.7 (2CH Ar); 109.2 (C-4 pyrazole); 54.3
(OCH3); 51.8 (CH2). Mass spectrum, m/z: 457 [M+H]+.
Found, %: C 78.84; H 5.12; N 12.21. C30H24N4. Calculated,
%: C 78.92; H 5.30; N 12.27.
2-[3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]-1-
pentyl-1H-benzimidazole (4j). Yield 81%, mp 195–197°C.
IR spectrum, ν, cm–1: 2900 (C–H), 1681 (–C=N–).
1H NMR spectrum, δ, ppm (J, Hz): 0.60–0.63 (3H, m,
CH3); 0.91–0.95 (2H, m, CH2); 1.12–1.16 (2H, m, CH2);
1.53 (2H, m, CH2); 4.12 (2H, t, J = 5.4, CH2); 7.29–7.34
(2H, m, H Ar); 7.43 (1H, t, J = 7.0, H Ar); 7.08 (2H, d,
J = 7.7, H Ar); 7.26 (2H, d, J= 7.8, H Ar); 7.52–7.80 (4H,
m, H Ar); 8.12–8.34 (2H, m, H Ar); 9.11 (1H, s, H-5
pyrazole). 13C NMR spectrum, δ, ppm: 149.3 (C Ar); 147.4
(C Ar); 144.0 (C Ar); 143.0 (C Ar); 135.3 (C Ar); 135.2
(C Ar); 132.2 (C Ar); 131.3 (CH Ar); 129.5 (2CH Ar);
129.4 (2CH Ar); 128.0 (2CH Ar); 125.9 (CH Ar); 122.3
(2CH Ar); 119.4 (2CH Ar); 118.8 (CH Ar); 110.0 (CH Ar);
109.3 (C-4 pyrazole); 46.8 (NCH2); 29.0 (CH2); 28.5
(CH2); 21.9 (CH2); 14.0 (CH3). Mass spectrum, m/z: 441
[M+H]+. Found, %: C 73.35; H 5.62; N 12.57. C27H25ClN5.
Calculated, %: C 73.54; H 5.71; N 12.71.
yl]-1H-benzimidazole (4f). Yield 99%, mp 205–207°C.
IR spectrum, ν, cm–1: 2951 (C–H), 1691 (–C=N–), 1351
1
(NO2). H NMR spectrum, δ, ppm (J, Hz): 5.37 (2H, s,
CH2); 6.78–6.84 (2H, m, H Ar); 7.00–7.08 (3H, m, H Ar);
7.18–7.24 (2H, m, H Ar); 7.35 (1H, t, J= 7.3, H Ar); 7.51
(3H, t, J = 7.7, H Ar); 7.60–7.72 (3H, m, H Ar); 7.91 (2H,
d, J = 8.1, H Ar); 8.09 (2H, d, J = 8.5, H Ar); 8.98 (1H, s,
H-5 pyrazole). 13C NMR spectrum, δ, ppm: 148.7 (C Ar);
146.9 (C Ar); 146.0 (C Ar); 142.7 (C Ar); 138.9 (C Ar);
138.4 (C Ar); 136.6 (C Ar); 136.2 (C Ar); 135.3 (CH Ar);
131.5 (2CH Ar); 129.7 (2CH Ar); 128.5 (2CH Ar); 128.0
(2CH Ar); 127.4 (CH Ar); 126.6 (CH Ar); 123.7 (2CH Ar);
122.9 (CH Ar); 122.2 (CH Ar); 119.3 (2CH Ar); 119.0
(CH Ar); 111.6 (CH Ar); 111.1 (C-4 pyrazole); 47.07
(CH2). Mass spectrum, m/z: 472 [M+H]+. Found, %:
C 73.71; H 4.44; N 14.80. C29H21N5O2. Calculated, %:
C 73.87; H 4.49; N 14.85.
2-[3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl]-
1-pentyl-1H-benzimidazole (4g). Yield 81%, mp 159–
161°C. IR spectrum, ν, cm–1: 2918 (C–H), 1650 (–C=N–),
1105 (C–O–C). 1H NMR spectrum, δ, ppm (J, Hz): 0.62
(3H, t, J = 5.5, CH3); 0.94–0.97 (2H, m, CH2); 1.12–1.16
(2H, m, CH2); 1.52–1.55 (2H, m, CH2); 3.81 (3H, s,
OCH3); 4.13 (2H, t, J = 5.2, CH2); 7.31–7.33 (2H, m,
H Ar); 7.45 (1H, t, J = 7.1, H Ar); 7.50–7.81 (4H, m,
H Ar); 7.88 (2H, d, J = 8.2, H Ar); 8.06 (2H, d, J = 7.6,
H Ar); 8.12–8.36 (2H, m, H Ar); 9.16 (1H, s, H-5
pyrazole). 13C NMR spectrum, δ, ppm: 160.0 (C Ar); 148.1
(C Ar); 146.1 (C Ar); 144.0 (C Ar); 143.0 (C Ar); 134.0
(C Ar); 132.1 (CH Ar); 129.7 (2CH Ar); 128.1 (2CH Ar);
126.0 (CH Ar); 124.0 (C Ar); 123.8 (2CH Ar); 119.9
(2CH Ar); 119.2 (CH Ar); 116.3 (2CH Ar); 110.0 (CH Ar);
109.0 (C-4 pyrazole); 59.3 (OCH3); 48.5 (NCH2); 30.0
(CH2); 28.8 (CH2); 21.9 (CH2); 13.9 (CH3). Mass spectrum,
m/z: 437 [M+H]+. Found, %: C 77.01; H 6.33; N 12.69.
C28H28N4O. Calculated, %: C 77.04; H 6.46; N 12.83.
2-[3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl]-
1-(prop-2-yn-1-yl)-1H-benzimidazole (4h). Yield 85%,
mp 131–133°C. IR spectrum, ν, cm–1: 3265 (≡C–H), 2918
(N–H), 2121 (C≡C), 1690 (–C=N–), 1105 (C–O–C).
1H NMR spectrum, δ, ppm (J, Hz): 3.62 (1H, s, ≡CH); 3.64
(3H, s, OCH3); 5.14 (2H, s, CH2); 7.43–7.50 (3H, m,
H Ar); 7.61 (2H, t, J = 7.1, H Ar); 7.80 (2H, t, J = 7.1,
H Ar); 7.89 (2H, d, J = 7.1, H Ar); 8.11 (2H, d, J = 7.9,
H Ar); 8.19 (2H, d, J = 8.1, H Ar); 9.22 (1H, s, H-5
pyrazole). 13C NMR spectrum, δ, ppm: 153.9 (C Ar); 149.8
(C Ar); 145.1 (C Ar); 143.7 (C Ar); 142.2 (C Ar); 134.3
(C Ar); 131.6 (CH Ar); 130.1 (2CH Ar); 128.0 (2CH Ar);
126.2 (CH Ar); 126.0 (C Ar); 122.6 (2CH Ar); 119.6
(CH Ar); 119.1 (2CH Ar); 114.3 (2CH Ar); 110.4 (CH Ar);
109.3 (C-4 pyrazole); 78.3 (C≡C); 76.3 (C≡C); 59.3
(OCH3); 34.0 (CH2). Mass spectrum, m/z: 405 [M+H]+.
Found, %: C 77.54; H 4.84; N 13.55. C26H20N4O. Calcu-
lated, %: C 77.21; H 4.98; N 13.85.
2-[3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]-1-(prop-
2-yn-1-yl)-1H-benzimidazole (4k). Yield 87%, mp 173–
175°C. IR spectrum, ν, cm–1: 3240 (≡C–H), 2903 (N–H), 2151
1
(C≡C), 1690 (–C=N–). H NMR spectrum, δ, ppm (J, Hz):
3.61 (1H, s, ≡CH); 5.13 (2H, s, CH2); 7.43–7.49 (3H, m,
H Ar); 7.62 (2H, t, J = 7.0, H Ar); 7.80 (2H, t, J = 7.1,
H Ar); 7.90 (2H, d, J = 7.4, H Ar); 8.11 (2H, d, J = 7.5,
H Ar); 8.18 (2H, d, J = 7.8, H Ar); 8.56 (1H, s, H-5
pyrazole). 13C NMR spectrum, δ, ppm: 147.4 (C Ar); 145.9
(C Ar); 144.4 (C Ar); 143.3 (C Ar); 135.2 (C Ar); 134.7
(C Ar); 131.6 (C Ar); 131.5 (CH Ar); 130.9 (2CH Ar);
130.2 (2CH Ar); 128.1 (2CH Ar); 126.2 (CH Ar); 122.7 (2CH
Ar); 120.0 (2CH Ar); 119.4 (CH Ar); 110.1 (CH Ar); 109.6
(C-4 pyrazole); 79.1 (C≡C); 73.9 (C≡C); 33.7 (CH2). Mass
spectrum, m/z: 409 [M+H]+. Found, %: C 73.39; H 4.24;
N 13.35. C25H17ClN4. Calculated, %: C 73.44; H 4.19;
N 13.70.
1-Benzyl-2-[3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-
4-yl]-1H-benzimidazole (4l). Yield 92%, mp 154–156°C.
1
IR spectrum, ν, cm–1: 2918 (C–H), 1691 (–C=N–). H NMR
spectrum, δ, ppm (J, Hz): 5.36 (2H, s, CH2); 6.83 (2H, t,
J = 7.8); 7.04 (3H, d, J = 5.2, H Ar); 7.17–7.22 (2H, m,
H Ar); 7.34 (1H, t, J = 7.3, H Ar); 7.49 (3H, t, J = 7.7,
H Ar); 7.63–7.68 (3H, m, H Ar); 7.81 (2H, d, J = 8.1,
H Ar); 7.89 (2H, d, J = 8.6, H Ar); 8.97 (1H, s, H-5
pyrazole). 13C NMR spectrum, δ, ppm: 148.9 (C Ar); 146.0
(C Ar); 143.7 (C Ar); 142.9 (C Ar); 137.4 (C Ar); 136.8
1-Benzyl-2-[3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-
4-yl]-1H-benzimidazole (4i). Yield 90%, mp 136–138°C.
IR spectrum, ν, cm–1: 2918 (C–H), 1690 (–C=N–), 1105
(C–O–C). 1H NMR spectrum, δ, ppm (J, Hz): 3.76 (3H, s,
177

Chemistry of Heterocyclic Compounds 2017, 53(2), 173–178
(C Ar); 134.0 (C Ar); 132.6 (C Ar); 131.7 (CH Ar); 129.7
References
(2CH Ar); 129.5 (2CH Ar); 128.4 (2CH Ar); 128.0
(2CH Ar); 126.7 (2CH Ar); 125.8 (CH Ar); 125.1 (CH Ar);
122.8 (2CH Ar); 120.0 (2CH Ar); 119.6 (CH Ar); 118.9
(CH Ar); 109.9 (C-4 pyrazole); 51.24 (CH2). Mass spectrum,
m/z: 461 [M+H]+. Found, %: C 75.41; H 4.69; N 12.13.
C29H21ClN4. Calculated, %: C 75.56; H 4.59; N 12.15.
The antioxidant activity by DPPH and H2O2 radical
scavenging tests has been evaluated following the literature
protocols.24–26 Mean and standard deviation of radical
scavenging activity (RSA) values in % were obtained for
all the compounds along with ascorbic acid standard.
Absorbance for all the samples was recorded on a Varian,
CARY-300 Bio UV-visible spectrophotometer. The linear
regression analysis has been carried out for mean and
standard deviation values separately to obtain IC50 values in
mean SD mode, IC50 being the concentration at RSA 50%.
Experiment was conducted in triplicate, and radical
scavenging activity values are calculated from the
absorbance values using the following formula:
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solutions (1.0 ml) was taken in different 10-ml volumetric
flasks to which the DPPH stock solution (1.0 ml) was
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The Supplementary information file, containing detailed
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NMR and mass spectra of selected compounds, is available
from the journal website at http://link.springer.com/
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The authors thank Council of Scientific and Industrial
Research (CSIR), New Delhi, INDIA for providing financial
assistance (S. No. 02(0137)/13/EMR-II, dated 12-04-2013).
178