Green Approach for the Synthesis of a New Class of Diamidomethane-linked Benzazolyl Pyrazoles and Evaluation as Antifungals

Article abstract of DOI:10.1002/jhet.3569

A new class of diamidomethane-linked benzoxazolyl pyrazoles, benzothiazolyl pyrazoles, and benzimidazolyl pyrazoles were synthesized from the synthetic intermediates N-benzazolylcarbamoylmethylcinnamides adopting environmentally benign methods. In fact, n

Full text of DOI:10.1002/jhet.3569

Month 2019
Green Approach for the Synthesis of a New Class of Diamidomethane-
linked Benzazolyl Pyrazoles and Evaluation as Antifungals
*
Jyothi Sowdari, Yamini Gudi, Sowmya V. Donthamsetty, Padmavathi Venkatapuram, and Padmaja Adivireddy
Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh, India
*E-mail: adivireddyp@yahoo.co.in
Received January 8, 2019
DOI 10.1002/jhet.3569
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A new class of diamidomethane-linked benzoxazolyl pyrazoles, benzothiazolyl pyrazoles, and
benzimidazolyl pyrazoles were synthesized from the synthetic intermediates N-benzazolyl
carbamoylmethylcinnamides adopting environmentally benign methods. In fact, nitrile imine was generated
from araldehyde phenylhydrazone in the presence of iodosobenzene and cetyltrimethylammonium bromide
followed by oxidation with iodine in dimethylsulfoxide. The structures of compounds were characterized by
IR, 1H NMR, 13C NMR, and mass spectra. The title compounds were also evaluated for their antifungal ac-
tivity. Amongst all the tested compounds benzimidazolyl pyrazolyl carboxamides (13a and 13b) were found
to be potential antifungal agents.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
addition, the carboxamide motif is also a suitable linkage
for combining different scaffolds and thus to design new
chemical entities with enhanced biological activities [15].
Further, the biologically important heterocycles—pyrazole
and benzazoles—were clubbed together into one molecule
that showed enhanced antifungal activity (Fig. 1). In view
of the earlier dicussion and in continuation of our study to
Amongst the nitrogen containing five-membered
heterocycles, pyrazoles represent a privileged class due to
their applications extensively in the pharmaceutical and
agrochemical industries. Pyrazole is
a
prominent
heterocyclic scaffold in more complex natural products.
Compounds based on this core template possess a wide
range of biological activities, including antimicrobial [1],
antiviral [2], anticancer [3], anti-inflammatory [4],
antihistaminic [5], pesticidal [6], antifungal [7],
anticonvulsant [8], antidepressant [9], antipyretic [10], and
antibacterial [11]. Besides, pyrazoles are valuable building
blocks not only for many heterocyclic systems but also in
the field of materials chemistry. Some well-known drugs
such as Viagra, Celebrex, Rimonabant, Lonazolac,
Fomepizole, Ceftolozane, Pyrazomycin, Antipyrine,
Pyrazofurin, Phenyl butazone, and Novalgine are
composed of pyrazole pharmacophore. Amongst the
various synthetic approaches for the construction of the
pyrazole, the versatile methods are cyclocondensation of
1,3-dicarbonyl compounds with hydrazines [12] and 1,3-
dipolar cycloaddition of diazoalkanes or nitrilimines with
alkenes or alkynes [13]. Pyrazole moieties occupy a
prominent place in the area of pharmaceuticals and
therapeutics; hence, significant effort has been put forth in
adopting newer approaches for their syntheses [14].
Moreover, the development of environmentally friendly
methods with improved yields is highly desirable. In
synthesize
a
variety of pharmacologically potent
heterocycles herein, we report a green approach for the
synthesis of a new class of diamidomethane-linked
benzazolyl tetrasubstituted pyrazoles and evaluation of
their antifungal activity.
RESULTS AND DISCUSSION
A new class of diamidomethane-linked benzazolyl
pyrazoles were synthesized by exploiting the synthetic
intermediates
E-N-((benzoxazol-2-ylcarbamoyl)methyl)
cinnamamide (5), E-N-((benzothiazol-2-ylcarbamoyl)-
methyl)cinnamamide (6), and E-N-((1H-benzimidazol-2-
ylcarbamoyl)methyl)cinnamamide (7), respectively. In fact,
the compounds 5, 6, and 7 were prepared by the reaction
of benzoxazol-2-amine (1), benzothiazol-2-amine (2), and
benzimidazol-2-amine (3) with 2-(cinnamamido)acetic acid
(4) in the presence of N,N’-dicyclohexylcarbodiimide
(DCC) and N,N-dimethylpyridin-4-amine (DMAP) in
dioxane under ultrasonication. The compound 4 in turn
obtained by the reaction of cinnamoyl chloride with
glycine in the presence of sodium hydroxide (Scheme 1).
© 2019 Wiley Periodicals, Inc.

J. Sowdari, Y. Gudi, S. V. Donthamsetty, P. Venkatapuram, and P. Adivireddy
Vol 000
Figure 1. Design strategy of the target compounds. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 1. Synthesis of bis amidomethane-linked styryl benzazoles.
1
The H NMR spectra of 5a, 6a, and 7a exhibited a singlet
The cycloaddition of dipolar reagent to an alkene
involving 3 + 2 principle is a facile route to prepare five-
membered heterocycles. The olefin functionality present
in compounds 5, 6, and 7 was utilized to develop
pyrazole ring. In fact, we have reported 1,3-dipolar
cycloaddition of nitrile imines generated from araldehyde
phenylhydrazones in the presence of chloramine-T to
activated olefins to synthesize pyrazolines [16]. From the
literature, it was observed that iodosobenzene not only
serves as a source of oxygen in various metal-catalyzed
oxidation reactions [17] but also oxidizes aldoximes to
nitrile oxides and in the presence of cationic surfactant
at δ 3.94, 3.97, and 3.89 (CH2) and two doublets at 6.71,
6.81, and 6.64 (HA) and 7.82, 7.89, and 7.77 (HB) ppm,
respectively. The downfield signal was assigned to HA
adjacent to the aromatic ring. The coupling constant,
J ≈ 16.2 Hz revealed that they possess trans geometry.
Besides, two broad singlets were also present at δ 8.07 and
8.60 in 5a; at 8.08 and 8.61 in 6a; and at 7.98 and
8.56 ppm in 7 due to a NHCO and CH2─NH,
respectively. Apart from these, 7a displayed another broad
singlet at 12.87 ppm due to NH of benzimidazole. The
signals due to NH protons disappeared on deuteration.
Scheme 2. Synthesis of diamidomethane-linked benzoxazolyl/benzothiazolyl/benzimidazolyl tetrasubstituted pyrazoles.
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Table 1
cetyltrimethylammonium bromide (CTAB) the reaction
proceeded well [18]. However, there are sparce reports to
generate nitrile imines from araldehyde phenylhydrazones
in the presence of iodosobenzene and CTAB. We
adopted this green protocol for the synthesis of
tetrasubstituted pyrazolines [19]. The cycloaddition of
nitrile imine generated from araldehyde phenylhydrazone
in the presence of iodosobenzene and CTAB at room
temperature to compounds 5, 6, and 7 resulted in N-(2-
(benzo[d]oxazol-2-ylamino)-2-oxoethyl)-1,3,5-triphenyl-
The in vitro antifungal activity of compounds 8–13.
Zone of inhibition (mm)
Penicillium
chrysogenum
Aspergillus niger
50 μg
100 μg
50 μg
per well
100 μg
per well
Compound
per well
per well
8a
8b
8c
9a
9b
9c
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
Ketoconazole
Control
(DMSO)
15 2.1
13 2.4
17 1.3
19 2.0
14 1.7
22 3.0
23 2.1
16 1.5
25 1.2
24 3.0
19 1.2
26 2.0
24 2.1
22 1.1
28 2.3
30 1.5
27 2.2
32 1.3
33 2.3
17 1.4 20 1.2 22 1.2
15 2.3 17 1.6 19 2.4
19 2.1 21 3.0 24 1.5
21 1.0 24 1.4 27 2.2
17 3.0 22 2.1 25 3.0
24 1.2 26 2.6 29 1.6
25 3.1 28 1.3 30 3.0
19 1.5 25 2.1 28 1.1
27 1.2 29 3.0 32 1.4
24 2.1 28 1.2 30 1.2
21 2.4 26 3.0 28 2.4
28 2.5 31 1.5 34 2.0
27 1.6 33 2.1 35 1.3
25 2.2 30 1.3 32 1.7
30 2.5 35 1.6 38 2.0
32 3.0 37 2.1 40 2.2
29 1.5 31 1.6 37 1.4
34 1.7 39 2.2 42 2.1
36 3.0 35 1.1 38 3.2
4,5-dihydro-1H-pyrazole-4-carboxamide
(8),
N-(2-
(benzo[d]thiazol-2-ylamino)-2-oxoethyl)-1,3,5-triphenyl-
4,5-dihydro-1H-pyrazole-4-carboxamide (9), and N-(2-
((1H-benzo[d]-imidazol-2-yl)amino)-2-oxoethyl)-1,3,5-
triphenyl-4,5-dihydro-1H-pyrazole-4-carboxamide
regio-selectively (Scheme 2). The mechanism of
oxidation cum dehydration of benzaldehyde
(10)
phenylhydrazone to nitrile imines is shown in Scheme 3.
The oxygen atom of PhIO transferred to C═N of
hydrazone by nucleophilic attack of PhIO followed by
the loss of PhI that produced 3-phenyl-1,2-oxaziridin-2-
amine. The N─O bond rupture of unstable intermediate
provided hydroxyl hydrazone by proton shift. The
elimination of proton and hydroxyl ion and deprotonation
—
—
—
—
1
gave nitrile imine. The H NMR spectra of 8a, 9a, and
10a presented a singlet at δ 3.80, 3.87, and 3.75 (CH2)
and two doublets at 5.22, 5.33, and 5.36 (C4-H) and 5.54,
“—” denotes no activity and “ ” denotes standard deviation.
Scheme 3. Mechanism for formation of nitrile imines.
Scheme 4. Mechanism for oxidation of benzazolyl pyrazolinyl carboxamides.
Journal of Heterocyclic Chemistry
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J. Sowdari, Y. Gudi, S. V. Donthamsetty, P. Venkatapuram, and P. Adivireddy
Vol 000
5.57, and 5.48 (C5-H), respectively, in addition to signals
due to aromatic protons. The coupling constant, J = 7.2,
7.6, and 7.0 Hz indicated their cis geometry. Besides, two
broad singlets were also observed at δ 8.06, 8.08, and
8.02 (NHCO) and 7.73, 7.79, and 7.83 (CH2NH),
respectively. The signals due to highly acidic protons
disappeared when D2O was added.
aromatization took place. Moreover, two broad singlets
also appeared at δ 8.01, 8.12, and 8.04 (NHCO) and
7.89, 7.87, and 7.88 ppm (CH2NH), respectively, which
disappeared on deuteration. The compounds 5–13 were
obtained in higher yield and in shorter reaction times by
green approach when compared with the conventional
method. The structures of all the synthesized compounds
were further ascertained by IR, 13C NMR, mass, and
microanalyses.
There are various methods for the oxidation of
pyrazolines to pyrazoles [20,21]. However, we have
reported the oxidation of differently substituted
pyrazolines adopting chloranil in xylene [22] and MnO2
in benzene [23]. However, we focused our interest
towards the synthesis of pyrazoles using green
methodology. In fact, the oxidation of compounds 8, 9,
and 10 with I2 in DMSO led to the formation of N-(2-
(benzo[d]oxazol-2-ylamino)-2-oxoethyl)-1,3-diphenyl-5-
(aryl)-1H-pyrazole-4-carboxamide (11), N-(2-(benzo[d]
thiazol-2-yl-amino)-2-oxo-ethyl)-1,3-diphenyl-5-(aryl)-
1H-pyrazole-4-carboxamide (12), and N-(2-((1H-benzo[d]
imidazol-2-yl)amino)-2-oxoethyl)-1,3-diphenyl-5-(aryl)-
1H-pyrazole-4-carboxamide (13), respectively. The iodine
picks the hydride ion at 4th carbon of the pyrazoline
followed by removal of proton. The HI generated during
the course of the reaction liberates I2 in the presence of
DMSO (Scheme 4). The absence of doublets due to C4-H
and C5-H of pyrazoline ring and the presence of a singlet
due to methylene protons at δ 3.94, 3.97, and 3.85 ppm
Antifungal activity.
The compounds 8–13 were
screened for antifungal activity at two different
concentrations 50 and 100 μg per well against the fungi
Aspergillus niger and Penicillium chrysogenum. All the
tested compounds inhibited the spore germination against
the tested fungi. It was observed that all the tested
compounds displayed higher inhibitory activity towards
P. chrysogenum than on A. niger. The aromatized bis
heterocycles 11, 12, and 13 showed greater antifungal
activity than the non-aromatized heterocycles 8, 9, and 10.
On the other hand, the dihydro derivatives 8, 9, and 10
exhibited low to moderate activity. Amongst all the tested
compounds, 13a and 13c displayed greater antifungal
activity than the standard drug Ketoconazole at all tested
concentrations particularly against P. chrysogenum
(Table 1 and Fig. 2). It was also observed that
benzimidazolyl pyrazoles and benzothiazolyl pyrazoles
exhibited greater antifungal activity than the benzoxazolyl
pyrazoles. The presence of chloro substituent on the
1
in the H NMR spectra of 11a, 12a, and 13a confirm that
Figure 2. The in vitro antifungal activity of compounds 8–13. [Color figure can be viewed at wileyonlinelibrary.com]
Table 2
Minimum inhibitory concentration and minimum fungicidal concentration of compounds 13a and 13c.
Minimum inhibitory concentration (minimum fungicidal concentration) (μg per well)
Compound
Aspergillus niger
Penicillium chrysogenum
13a
13c
Ketoconazole
50 (100)
25 (50)
6.25
12.5 (25)
12.5 (25)
12.5
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Green Synthesis of Benzazolyl Pyrazoles
aromatic ring increased the antifungal activity when
compared with the compounds having unsubstitution and
methyl substituent. The compounds that exhibited higher
antifungal activity were further tested for minimum
inhibitory concentration (MIC) and minimum fungicidal
concentration (MFC), and the values are given in Table 2.
The compounds 13a and 13c displayed low MIC values
against P. chrysogenum, and the MFC is 2xMIC.
added while stirring. To this, dicyclohexylcarbodiimide
(1.4 mmol) in dioxane (10 mL) was added dropwise and
kept under ultrasonication at room temperature for 30–
45 min. The separated precipitate, dicyclohexylurea, was
removed by filtration. The solution was evaporated to
dryness, and the residual solid was purified by column
chromatography (silica gel, 60–120 mesh) using ethyl
acetate–hexane (1:3) as eluent.
(E)-N-((Benzoxazol-2-ylcarbamoyl)methyl)cinnamamide
(5a). Yield: 72%; white solid, mp 160–162°C; IR (KBr):
3312 (NH), 1657 (C═O), 1619 (C═C), 1580 (C═N) cmꢀ1
;
CONCLUSIONS
1H NMR (400 MHz, DMSO-d6): δ 3.94 (s, 2H, CH2), 6.71
(d, 1H, HB, J = 16.2 Hz), 7.13–7.32 (m, 9H, Ar─H), 7.82
(d, 1H, HA, J = 16.2 Hz), 8.07 (bs, 1H, NHCO), 8.60 (bs,
1H, CH2─NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ
43.4, 110.5, 117.9, 118.7, 123.6, 124.4, 126.1, 128.2,
128.9, 134.8, 142.0, 143.2, 150.3, 163.9, 167.5,
170.4 ppm (aromatic carbons); HRMS (m/z): 344.3267
[M+ Na], Calcd. 344.3258. Anal. Calcd. for C18H15N3O3:
C, 67.28; H, 4.71; N, 13.08%. Found: C, 67.37; H, 4.74;
A new class of diamidomethane-linked benzoxazolyl
pyrazoles, benzothiazolyl pyrazoles, and benzimidazolyl
pyrazoles were prepared adopting eco-friendly
methodologies. In fact, nitrile imine was generated from
benzaldehyde phenylhydrazone in the presence of
iodosobenzene. Besides, dehydrogenation of pyrazoline
ring was performed with I2 in DMSO. All the
synthesized compounds were characterized by IR, NMR,
and mass spectral parameters. All the lead compounds
were also tested for antifungal activity. Amongst all the
tested compounds, 13a and 13c are found to be potential
antifungal agents.
N, 13.25%.
(E)-N-((Benzoxazol-2-ylcarbamoyl)methyl)-3-(4-
methylphenyl)acrylamide (5b).
Yield: 70%; white solid,
mp 156–158°C; IR (KBr): 3309 (NH), 1654 (C═O),
1
1614 (C═C), 1574 (C═N) cmꢀ1; H NMR (400 MHz,
DMSO-d6): δ 2.37 (s, 3H, CH3), 3.91 (s, 2H, CH2), 6.68
(d, 1H, HB, J = 16.0 Hz), 7.09–7.30 (m, 8H, Ar─H),
7.77 (d, 1H, HA, J = 16.0 Hz), 8.04 (bs, 1H, NHCO),
8.57 (bs, 1H, CH2─NH) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 24.7, 42.6, 110.9, 117.5, 119.8, 123.5,
125.3, 126.7, 129.4, 132.8, 137.2, 141.3, 142.8, 150.5,
163.4, 166.6, 169.2 ppm (aromatic carbons); HRMS (m/
z): 358.3541 [M+ Na], Calcd. 358.3528. Anal. Calcd. for
C19H17N3O3: C, 68.05; H, 5.11; N, 12.53%. Found: C,
EXPERIMENTAL
Melting points were determined in open capillaries on a
Mel-Temp apparatus and are uncorrected. Ultrasonication
was performed in a Bandelin Sonorex RK 102H ultrasonic
bath operating at frequency of 35 kHz. The IR spectra
were recorded on a Thermo Nicolet IR 200 FT-IR
spectrometer as KBr pellets, and the wave numbers were
68.18; H, 5.15; N, 12.75%.
(E)-N-((Benzoxazol-2-ylcarbamoyl)methyl)-3-(4-
chlorophenyl)acrylamide (5c). Yield: 75%; white solid, mp
1
given in cmꢀ1. The H NMR spectra were recorded in
DMSO-d6 on a Jeol JNM λ-400 MHz. The 13C NMR
spectra were recorded in DMSO-d6 on a Jeol JNM
spectrometer operating at 100 MHz. All chemical shifts
are reported in δ (ppm) using TMS as an internal standard.
High-resolution mass spectra were recorded on Micromass
Q-TOF mass spectrometer using electrospray ionization.
The microanalyses were performed on a Perkin-Elmer
240C elemental analyzer. The starting compounds
benzoxazol-2-amine (1), benzothiazol-2-amine (2), 1H-
benzimidazol-2-amine (3), and 2-(cinnamamido)acetic
acid (4) were prepared as per the literature precedent
[24,25].
173–175°C; IR (KBr): 3317 (NH), 1658 (C═O), 1621
;
(C═C), 1584 (C═N) cmꢀ1 1H NMR (400 MHz,
DMSO-d6): δ 3.96 (s, 2H, CH2), 6.73 (d, 1H, HB,
J = 16.3 Hz), 7.17–7.45 (m, 8H, Ar─H), 7.84 (d, 1H,
HA, J = 16.3 Hz), 8.10 (bs, 1H, NHCO), 8.62 (bs, 1H,
CH2─NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ
43.9, 110.1, 118.3, 119.3, 124.1, 125.6, 128.3, 129.5,
133.2, 134.6, 141.7, 143.9, 150.7, 164.2, 167.8,
170.7 ppm (aromatic carbons); HRMS (m/z): 378.7660
[M+ Na], Calcd. 378.7678. Anal. Calcd. for
C18H14ClN3O3: C, 60.77; H, 3.97; N, 11.81%. Found: C,
60.88; H, 3.95; N, 12.00%.
General procedure for the synthesis of (E)-N-((benzoxazol-
(E)-N-((Benzothiazol-2-ylcarbamoyl)methyl)cinnamamide
(6a). Yield: 80%; white solid, mp 168–170°C; IR (KBr):
2-ylcarbamoyl)methyl)-cinnamamide
((benzothiazol-2-ylcarbamoyl)methyl)cinnamamide (6)/(E)-
N-((1H-benzimidazol-2-yl-carbamoyl)methyl)cinnamamide
(5)/(E)-N-
3320 (NH), 1661 (C═O), 1624 (C═C), 1581 (C═N) cmꢀ1
;
1H NMR (400 MHz, DMSO-d6): δ 3.97 (s, 2H, CH2), 6.81
(d, 1H, HB, J = 16.6 Hz), 7.20–7.78 (m, 9H, Ar─H), 7.89
(d, 1H, HA, J = 16.6 Hz), 8.08 (bs, 1H, NHCO), 8.61 (bs,
(7).
To a solution of 2-(cinnamamido)acetic acid (4)
(1 mmol) in dioxane (20 mL), compounds 1/2/3
(2 mmol) and 4-dimethylaminopyridine (0.1 mmol) were
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J. Sowdari, Y. Gudi, S. V. Donthamsetty, P. Venkatapuram, and P. Adivireddy
Vol 000
1H, CH2─NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ
44.3, 118.6, 121.4, 121.8, 124.1, 125.3, 125.8, 126.2,
127.8, 128.6, 135.4, 144.7, 149.1, 166.7, 167.9,
170.8 ppm (aromatic carbons); HRMS (m/z): 360.3882
[M+ Na], Calcd. 360.3868. Anal. Calcd. for
C18H15N3O2S: C, 64.08; H, 4.48; N, 12.45%. Found: C,
8.54 (bs, 1H, CH2─NH), 12.85 (bs, 1H, Imidazole─NH)
ppm; 13C NMR (100 MHz, DMSO-d6): δ 24.5, 43.0,
114.6, 117.1, 123.8, 126.5, 129.1, 132.8, 137.5, 139.2,
142.5, 151.4, 166.7, 169.5 ppm (aromatic carbons);
HRMS (m/z): 357.3674 [M+ Na], Calcd. 357.3688. Anal.
Calcd. for C19H18N4O2: C, 68.25; H, 5.43; N, 16.76%.
64.15; H, 4.49; N, 12.60%.
Found: C, 68.39; H, 5.49; N, 16.97%.
(E)-N-((1H-Benzimidazol-2-ylcarbamoyl)methyl)-3-(4-
chlorophenyl)acrylamide (7c). Yield: 88%; white solid, mp
(E)-N-((Benzothiazol-2-ylcarbamoyl)methyl)-3-(4-
methylphenyl)acrylamide (6b).
Yield: 77%; white solid,
mp 163–164°C; IR (KBr): 3319 (NH), 1657 (C═O),
164–166°C; IR (KBr): 3302 (NH), 1655 (C═O), 1618
1
1622 (C═C), 1575 (C═N) cmꢀ1; H NMR (400 MHz,
(C═C), 1582 (C═N) cmꢀ1 1H NMR (400 MHz,
;
DMSO-d6): δ 2.39 (s, 3H, CH3), 3.95 (s, 2H, CH2), 6.77
(d, 1H, HB, J = 16.4 Hz), 7.16–7.74 (m, 8H, Ar─H),
7.85 (d, 1H, HA, J = 16.4 Hz), 8.06 (bs, 1H, NHCO),
8.59 (bs, 1H, CH2─NH) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 24.8, 44.0, 118.5, 121.3, 122.4, 124.6,
125.1, 125.9, 126.5, 129.7, 132.4, 137.9, 144.5, 149.5,
166.4, 167.6, 170.4 ppm (aromatic carbons); HRMS (m/
z): 374.4123 [M+ Na], Calcd. 374.4138. Anal. Calcd. for
C19H17N3O2S: C, 64.94; H, 4.88; N, 11.96%. Found: C,
DMSO-d6): δ 3.91 (s, 2H, CH2), 6.67 (d, 1H, HB,
J = 16.0 Hz), 7.14–7.72 (m, 8H, Ar─H), 7.79 (d, 1H,
HA, J = 16.0 Hz), 8.02 (bs, 1H, NHCO), 8.58 (bs, 1H,
CH2─NH), 12.91 (bs, 1H, Imidazole─NH) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 43.5, 115.9, 117.7,
123.0, 127.5, 128.2, 133.7, 133.4, 138.8, 142.9, 152.2,
167.4, 170.3 ppm (aromatic carbons); HRMS (m/z):
377.7851 [M+ Na], Calcd. 377.7838. Anal. Calcd. for
C18H15ClN4O2: C, 60.94; H, 4.26; N, 15.79%. Found: C,
61.04; H, 4.30; N, 15.97%.
65.89; H, 4.89; N, 12.08%.
(E)-N-((Benzothiazol-2-ylcarbamoyl)methyl)-3-(4-
chlorophenyl)acrylamide (6c). Yield: 82%; white solid, mp
General procedure for the synthesis of N-(2-(benzo[d]
oxazol-2-ylamino)-2-oxoethyl)-1,3,5-triphenyl-4,5-dihydro-
177–179°C; IR (KBr): 3324 (NH),1666 (C═O), 1625
1H-pyrazole-4-carboxamide
(8)/N-(2-(benzo[d]thiazol-2-
;
(C═C), 1586 (C═N) cmꢀ1 1H NMR (400 MHz,
ylamino)-2-oxoethyl)-1,3,5-triphenyl-4,5-dihydro-1H-
pyrazole-4-carboxamide (9)/N-(2-((1H-benzo[d]imidazol-2-yl)
amino)-2-oxoethyl)-1,3,5-triphenyl-4,5-dihydro-1H-pyrazole-
DMSO-d6): δ 3.99 (s, 2H, CH2), 6.84 (d, 1H, HB,
J = 16.8 Hz), 7.25–7.83 (m, 8H, Ar─H), 7.91 (d, 1H,
HA, J = 16.8 Hz), 8.11 (bs, 1H, NHCO), 8.65 (bs, 1H,
CH2─NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ
44.5, 118.9, 120.4, 121.9, 124.0, 125.6, 126.8, 128.3,
129.4, 133.1, 133.9, 145.0, 149.2, 166.9, 168.3,
170.9 ppm (aromatic carbons); HRMS (m/z): 394.8267
[M+ Na], Calcd. 394.8288. Anal. Calcd. for
C18H14ClN3O2S: C, 58.14; H, 3.79; N, 11.30%. Found:
4-carboxamide (10).
A
mixture of benzadehyde
phenylhydrazone (0.75 mmol), E-N-((benzoxazol-2-yl-
carbamoyl)methyl)cinnamamide (5)/E-N-((benzothiazol-
2-ylcarbamoyl)-methyl)cinnamamide
benzimidazol-2-ylcarbamoyl)methyl)cinnamamide
(6)/E-N-((1H-
(7)
(1.50 mmol), water (8 ml), and CTAB (0.25 mmol) were
stirred at room temperature for 15 min. Then
iodosobenzene (244 mg, 2.10 mmol) was added to the
reaction mixture, and stirring was continued at room
temperature for 3–6 h. After completion of the reaction
(monitored by TLC), it was extracted with ethyl acetate.
The organic layer was washed with brine solution and
dried over anhydrous sodium sulfate, and the solvent was
concentrated in vacuo. The resultant solid was purified by
column chromatography using hexane–ethyl acetate (3:1)
C, 58.26; H, 3.83; N, 11.54%.
(E)-N-((1H-Benzimidazol-2-ylcarbamoyl)methyl)
cinnamamide (7a).
Yield: 86%; white solid, mp 155–
157°C; IR (KBr): 3299 (NH), 1652 (C═O), 1615 (C═C),
1
1576 (C═N) cmꢀ1; H NMR (400 MHz, DMSO-d6): δ
3.89 (s, 2H, CH2), 6.64 (d, 1H, HB, J = 15.9 Hz), 7.10–
7.70 (m, 9H, Ar─H), 7.77 (d, 1H, HA, J = 15.9 Hz), 7.98
(bs, 1H, NHCO), 8.56 (bs, 1H, CH2─NH), 12.87 (bs,
1H, Imidazole─NH); 13C NMR (100 MHz, DMSO-d6): δ
43.1, 117.3, 115.4, 123.5, 126.9, 128.4, 128.8, 135.2,
139.3, 142.8, 151.7, 167.1, 169.9 ppm (aromatic
carbons); HRMS (m/z): 343.3429 [M+ Na], Calcd.
343.3418. Anal. Calcd. for C18H16N4O2: C, 67.49; H,
as eluent.
N-(2-(Benzo[d]oxazol-2-ylamino)-2-oxoethyl)-1,3,5-
triphenyl-4,5-dihydro-1H-pyrazole-4-carboxamide (8a).
Yield: 85%; white solid, mp 178–180°C; IR (KBr): 3283
;
(NH), 1665 (C═O), 1565 (C═N) cmꢀ1 1H NMR
(400 MHz, DMSO-d6): δ 3.80 (s, 2H, CH2), 5.22 (d, 1H,
5.03; N, 17.49%. Found: C, 67.57; H, 5.05; N, 17.66%.
(E)-N-((1H-Benzimidazol-2-ylcarbamoyl)methyl)-3-(4-
0
0
C4 , J = 7.2 Hz), 5.54 (d, 1H, C5 -H, J = 7.2 Hz), 7.13–
7.62 (m, 19H, Ar─H), 7.73 (bs, 1H, CH2─NH), 8.06 (bs,
1H, NH─CO) ppm; 13C NMR (100 MHz, DMSO-d6): δ
45.8 (CH2), 62.5 (C-40), 84.6 (C-50), 154.5 (C-30), 163.2
(C-2), 165.5 (CH2NHCO), 168.4 (NHCO), 110.3, 119.8,
123.4, 124.6, 124.9, 125.7, 126.2, 126.8, 127.3, 128.5,
128.7, 129.7, 130.4, 131.2, 132.9, 133.7, 134.2,
methylphenyl)acrylamide (7b).
Yield: 84%; white solid,
mp 152–154°C; IR (KBr): 3297 (NH), 1651 (C═O),
1
1610 (C═C), 1572 (C═N) cmꢀ1; H NMR (400 MHz,
DMSO-d6): δ 2.35 (s, 3H, CH3), 3.85 (s, 2H, CH2), 6.60
(d, 1H, HB, J = 15.7 Hz), 7.05–7.67 (m, 8H, Ar─H),
7.73 (d, 1H, HA, J = 15.7 Hz), 7.95 (bs, 1H, NHCO),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Green Synthesis of Benzazolyl Pyrazoles
1
135.3 ppm (aromatic carbons); HRMS (m/z) 538.5640 [M+
Na], Calcd. 538.5628. Anal. Calcd. for C31H25N5O3: C,
72.22; H, 4.89; N, 13.58%. Found: C, 72.34; H, 4.91; N,
3284 (NH), 1670 (C═O), 1571 (C═N) cmꢀ1; H NMR
(400 MHz, DMSO-d6): δ 2.36 (s, 3H, CH3), 3.83 (s,
2H, CH2), 5.28 (1H, C4 , J = 7.8 Hz), 5.53 (d, 1H,
0
0
13.83%.
C5 -H, J = 7.8 Hz), 7.18–7.65 (m, 18H, Ar─H), 7.75
(bs, 1H, CH2─NH), 8.10 (bs, 1H, NH─CO) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 24.6 (CH3), 45.6
(CH2), 61.2 (C-40), 86.1 (C-50), 155.3 (C-30), 165.2
(CH2NHCO), 166.1 (C-2), 168.1 (NHCO), 118.6,
121.1, 122.1, 124.2, 125.8, 126.5, 126.8, 127.1, 127.8,
128.3, 129.3, 130.4, 131.2, 132.8, 133.8, 134.7, 135.2,
135.8 ppm (aromatic carbons). HRMS (m/z) 568.6567
[M+ Na], Calcd. 568.6508. Anal. Calcd. for
C32H27N5O2S: C, 70.69; H, 5.39; N, 12.49%. Found:
N-(2-(Benzo[d]oxazol-2-ylamino)-2-oxoethyl)-1,3-diphenyl-
5-(p-tolyl)-4,5-dihydro-1H-pyrazole-4-carboxamide (8b).
Yield: 87%; white solid, mp 173–175°C. IR (KBr): 3282
(NH), 1662 (C═O), 1560 (C═N) cmꢀ1
;
1H NMR
(400 MHz, DMSO-d6): δ 2.34 (s, 3H, CH3), 3.76 (s, 2H,
0
0
CH2), 5.19 (1H, C4 , J = 7.5 Hz), 5.51 (d, 1H, C5 -H,
J = 7.5 Hz), 7.05–7.68 (m, 18H, Ar─H), 7.72 (bs, 1H,
CH2─NH), 8.02 (bs, 1H, NH─CO) ppm; 13C NMR
(100 MHz, DMSO-d6): δ 24.1 (CH3), 45.5 (CH2), 62.2
(C-40), 84.8 (C-50), 154.2 (C-30), 163.0 (C-2), 165.1
(CH2NHCO), 167.8 (NHCO), 110.1, 118.5, 122.8, 123.6,
124.6, 125.2, 126.5, 127.5, 128.9, 129.3, 130.5, 130.9,
131.5, 132.5, 133.0, 133.4, 134.7, 135.1 ppm (aromatic
carbons). HRMS (m/z) 552.5874 [M+ Na], Calcd.
552.5898. Anal. Calcd. for C32H27N5O3: C, 72.57; H,
C, 70.82; H, 5.42; N, 12.77%.
N-(2-(Benzo[d]thiazol-2-ylamino)-2-oxoethyl)-5-(4-
chlorophenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazole-4-
carboxamide (9c).
Yield: 89%; white solid, mp 196–
198°C. IR (KBr): 3295 (NH), 1674 (C═O), 1578
1
(C═N) cmꢀ1; H NMR (400 MHz, DMSO-d6): δ 3.89
0
(s, 2H, CH2), 5.36 (d, 1H, C4 -H, J = 7.4 Hz), 5.61 (d,
5.14; N, 13.22%. Found: C, 72.67; H, 5.17; N, 13.49%.
N-(2-(Benzo[d]oxazol-2-ylamino)-2-oxoethyl)-5-(4-
chlorophenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazole-4-
0
1H, C5 -H, J = 7.4 Hz), 7.28–7.72 (m, 18H, Ar─H),
7.80 (bs, 1H, CH2─NH), 8.14 (bs, 1H, NH─CO) ppm;
13C NMR (100 MHz, DMSO-d6): δ 46.4 (CH2), 61.5
(C-40), 87.3 (C-50), 156.1 (C-30), 166.0 (CH2NHCO),
166.8 (C-2), 169.2 (NHCO), 119.6, 120.9, 123.1, 124.9,
125.4, 126.1, 126.8, 127.3, 127.9, 128.3, 129.0, 129.5,
130.0, 130.8, 131.5, 132.7, 135.2, 135.8 ppm (aromatic
carbons). HRMS (m/z) 589.0639 [M+ Na], Calcd.
589.0658. Anal. Calcd. for C31H24ClN5O2S: C, 65.78;
H, 4.27; N, 12.37%. Found: C, 65.88; H, 4.29; N,
carboxamide (8c).
Yield: 88%; white solid, mp 190–
192°C. IR (KBr): 3287 (NH), 1672 (C═O), 1568 (C═N)
1
cmꢀ1; H NMR (400 MHz, DMSO-d6): δ 3.85 (s, 2H,
0
0
CH2), 5.26 (d, 1H, C4 , J = 7.1 Hz), 5.59 (d, 1H, C5 -H,
J = 7.1 Hz), 7.23–7.61 (m, 18H, Ar─H), 7.75 (bs, 1H,
CH2─NH), 8.12 (bs, 1H, NH─CO) ppm; 13C NMR
(100 MHz, DMSO-d6): δ 46.1 (CH2), 62.7 (C-40), 85.2
(C-50), 154.8 (C-30), 163.6 (C-2), 165.8 (CH2NHCO),
168.5 (NHCO), 110.9, 119.6, 122.9, 124.1, 124.8, 125.0,
125.8, 126.7, 127.2, 128.1, 128.8, 129.0, 131.7, 132.5,
133.6, 134.0, 134.9, 135.6 ppm (aromatic carbons).
HRMS (m/z) 573.0019 [M + Na], Calcd. 573.0048. Anal.
Calcd. for C31H24ClN5O3: C, 67.70; H, 4.40; N, 12.73%.
12.61%.
N-(2-((1H-Benzo[d]imidazol-2-yl)amino)-2-oxoethyl)-1,3,5-
triphenyl-4,5-dihydro-1H-pyrazole-4-carboxamide (10a).
Yield: 84%; white solid, mp 172–174°C. IR (KBr): 3286
;
(NH), 1670 (C═O), 1575 (C═N) cmꢀ1 1H NMR
Found: C, 67.80; H, 4.39; N, 12.93%.
N-(2-(Benzo[d]thiazol-2-ylamino)-2-oxoethyl)-1,3,5-
triphenyl-4,5-dihydro-1H-pyrazole-4-carboxamide (9a).
(400 MHz, DMSO-d6): δ 3.75 (s, 2H, CH2), 5.28 (1H,
0
0
C4 , J = 7.0 Hz), 5.48 (d, 1H, C5 -H, J = 7.0 Hz), 7.22–
7.78 (m, 18H, Ar─H), 7.83 (bs, 1H, CH2─NH), 8.02 (bs,
1H, CH2─CO), 12.67 (bs, 1H, Imidazole─NH) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 45.3 (CH2), 62.4 (C-40),
86.3 (C-50), 153.3 (C-2), (C-30), 165.5 (CH2NHCO),
168.4 (NHCO), 115.2, 123.3, 123.5, 124.1, 125.0, 126.3,
126.7, 127.1, 127.6, 128.5, 128.9, 130.5, 131.6, 132.6,
133.0, 134.4, 134.2, 135.9 ppm (aromatic carbons).
HRMS (m/z) 537.5771 [M+ Na], Calcd. 537.5788. Anal.
Calcd. for C31H26N6O2: C, 72.36; H, 5.09; N, 16.33%.
Yield: 83%; white solid, mp 182–184°C. IR (KBr): 3290
(NH), 1660 (C═O), 1563 (C═N) cmꢀ1
;
1H NMR
(400 MHz, DMSO-d6): δ 3.87 (s, 2H, CH2), 5.33 (d, 1H,
0
0
C4 , J = 7.6 Hz), 5.57 (d, 1H, C5 -H, J = 7.6 Hz), 7.20–
7.72 (m, 19H, Ar─H), 7.79 (bs, 1H, CH2─NH), 8.08 (bs,
1H, NH─CO) ppm; 13C NMR (100 MHz, DMSO-d6): δ
45.9 (CH2), 60.8 (C-40), 86.4 (C-50), 155.6 (C-30), 165.4
(CH2NHCO), 166.5 (C-2), 168.9 (NHCO), 118.9, 121.3,
122.3, 123.0, 124.4, 125.5, 125.9, 126.2, 127.7, 128.1,
128.9, 129.2, 130.2, 130.6, 131.4, 132.3, 133.5,
134.8 ppm (aromatic carbons). HRMS (m/z) 554.6252
[M+ Na], Calcd. 554.6238. Anal. Calcd. for
C31H25N5O2S: C, 70.04; H, 4.74; N, 13.17%. Found: C,
Found: C, 72.47; H, 5.11; N, 16.57%.
N-(2-((1H-Benzo[d]imidazol-2-yl)amino)-2-oxoethyl)-1,3-
diphenyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazole-4-carboxamide
(10b).
Yield: 82%; white solid, mp 187–188°C. IR
1
(KBr): 3278 (NH), 1657 (C═O), 1570 (C═N) cmꢀ1; H
NMR (400 MHz, DMSO-d6): δ 2.31 (s, 3H, CH3), 3.70
70.17; H, 4.76; N, 13.45%.
N-(2-(Benzo[d]thiazol-2-ylamino)-2-oxoethyl)-1,3-diphenyl-
5-(p-tolyl)-4,5-dihydro-1H-pyrazole-4-carboxamide (9b).
0
(s, 2H, CH2), 5.18 (1H, C4 , J = 7.2 Hz), 5.42 (d, 1H,
0
C5 -H, J = 7.2 Hz), 7.26–7.73 (m, 18H, Ar─H), 7.86 (bs,
Yield: 86%; white solid, mp 175–177°C. IR (KBr):
1H, CH2─NH), 8.05 (bs, 1H, CH2CO), 12.65 (bs, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Sowdari, Y. Gudi, S. V. Donthamsetty, P. Venkatapuram, and P. Adivireddy
Vol 000
Imidazole─NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ
23.9 (CH3), 45.0 (CH2), 62.7 (C-40), 86.8 (C-50), 150.5 (C-
2), 153.8 (C-30), 164.9 (CH2NHCO), 167.7 (NHCO),
115.2, 121.8, 123.4, 124.5, 125.9, 126.7, 126.8, 127.5,
128.1, 128.8, 129.5, 130.4, 131.8, 133.1, 133.7, 134.6,
135.4, 135.8 ppm (aromatic carbons). HRMS (m/z)
551.6013 [M+ Na], Calcd. 551.6058. Anal. Calcd. for
C32H28N6O2: C, 72.91; H, 5.75; N, 15.46%. Found: C,
N-(2-(Benzo[d]oxazol-2-ylamino)-2-oxoethyl)-1,3-diphenyl-
5-(p-tolyl)-1H-pyrazole-4-carboxamide (11b).
Yield: 90%;
white solid, mp 166–168°C. IR (KBr): 3297 (NH),
1672 (C═O), 1610 (C═C), 1573 (C═N) cmꢀ1 1H
;
NMR (400 MHz, DMSO-d6): δ 2.31 (s, 3H, CH3), 3.92
(s, 2H, CH2), 7.42–7.84 (m, 18H, Ar─H), 7.90 (bs,
1H, CH2─NH), 8.08 (bs, 1H, NH─CO) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 24.7 (CH3), 46.0
(CH2), 134.9 (C-40), 138.7 (C-50), 157.4 (C-30), 163.6
(C-2), 166.1 (CH2NHCO), 168.8 (NHCO), 110.4,
121.8, 123.5, 124.7, 125.2, 126.3, 127.6, 128.1, 128.9,
129.3, 130.6, 131.4, 132.8, 133.7, 134.2, 135.7, 136.1,
136.8 ppm (aromatic carbons). HRMS (m/z) 550.5717
[M+ Na], Calcd. 550.5738. Anal. Calcd. for
C32H25N5O3: C, 72.85; H, 4.78; N, 13.27%. Found: C,
73.03; H, 5.78; N, 15.75%.
N-(2-((1H-Benzo[d]imidazol-2-yl)amino)-2-oxoethyl)-5-(4-
chlorophenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazole-4-
carboxamide (10c).
Yield: 85%; white solid, mp 193–
195°C. IR (KBr): 3285 (NH), 1676 (C═O), 1580 (C═N)
1
cmꢀ1; H NMR (400 MHz, DMSO-d6): δ 3.77 (s, 2H,
0
0
CH2), 5.30 (1H, C4 , J = 6.8 Hz), 5.45 (d, 1H, C5 -H,
J = 6.8 Hz), 7.35–7.81 (m, 18H, Ar─H), 7.89 (bs, 1H,
CH2─NH), 8.09 (bs, 1H, CH2─CO), 12.69 (bs, 1H,
Imidazole─NH) ppm; 13C NMR (100 MHz, DMSO-d6):
δ 45.4 (CH2), 63.1 (C-40), 85.9 (C-50), 154.2 (C-30),
163.8 (C-2), 166.4 (CH2NHCO), 169.7 (NHCO), 115.9,
122.9, 123.7, 124.3, 125.7, 126.9, 127.2, 127.9, 128.3,
128.3, 129.0, 129.8, 130.9, 131.4, 133.6, 134.0, 134.8,
136.2 ppm (aromatic carbons). HRMS (m/z) 572.0225
[M+ Na], Calcd. 572.0208. Anal. Calcd. for
C31H25ClN6O2: C, 67.82; H, 4.59; N, 15.31%. Found: C,
67.89; H, 4.60; N, 15.51%.
72.96; H, 4.81; N, 13.53%.
N-(2-(Benzo[d]oxazol-2-ylamino)-2-oxoethyl)-1,3-diphenyl-
5-(p-chlorophenyl)-1H-pyrazole-4-carboxamide
(11c).
Yield: 91%; white solid, mp 197–199°C. IR (KBr): 3295
1
(NH), 1680 (C═O), 1625 (C═C), 1582 (C═N) cmꢀ1; H
NMR (400 MHz, DMSO-d6): δ 3.96 (s, 2H, CH2), 7.55–
7.79 (m, 18H, Ar─H), 7.85 (bs, 1H, CH2─NH), 8.13 (bs,
1H, NH─CO) ppm; 13C NMR (100 MHz, DMSO-d6): δ
46.9 (CH2), 135.3 (C-40), 139.2 (C-50), 158.8 (C-30),
164.1 (C-2), 166.6 (CH2NHCO), 169.5 (NHCO), 110.9,
122.6, 123.1, 125.2, 126.1, 126.8, 127.3, 127.5, 128.7,
129.3, 129.8, 130.5, 131.5, 132.9, 133.4, 134.9, 135.6,
137.1 ppm (aromatic carbons). HRMS (m/z) 570.9853
[M+ Na], Calcd. 570.9888. Anal. Calcd. for
C31H25ClN5O3: C, 66.01; H, 3.93; N, 12.42%. Found: C,
General procedure for the synthesis of N-(2-(benzo[d]
oxazol-2-ylamino)-2-oxoethyl)-1,3-diphenyl-5-(aryl)-1H-
pyrazole-4-carboxamide
(11)/N-(2-(benzo[d]thiazol-2-yl-
amino)-2-oxo-ethyl)-1,3-diphenyl-5-(aryl)-1H-pyrazole-4-
carboxamide (12)/N-(2-((1H-benzo[d]-imidazol-2-yl)amino)-2-
oxoethyl)-1,3-diphenyl-5-(aryl)-1H-pyrazole-4-carboxamide
(13). The compounds 8/9/10 (0.2 mmol) were dissolved
in dimethyl sulfoxide (5 mL). To this, iodine (1 mg,
2.2 mol%) was added while stirring and refluxed for 2–
4 h. The progress of the reaction was monitored by thin
layer chromatography. After completion of the reaction,
the contents of the flask were poured onto crushed ice.
The resultant compound was filtered, dried, and
recrystallized from 2-propanol.
66.10; H, 3.95; N, 12.64%.
N-(2-(Benzo[d]thiazol-2-ylamino)-2-oxoethyl)-1,3,5-
triphenyl-1H-pyrazole-4-carboxamide (12a).
Yield: 84%;
white solid, mp 169–171°C. IR (KBr): 3312 (NH), 1685
(C═O), 1622 (C═C), 1563 (C═N) cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6): δ 3.97 (s, 2H, CH2), 7.24–7.80
(m, 19H, Ar─H), 7.87 (bs, 1H, CH2─NH), 8.12 (bs, 1H,
NH─CO) ppm; 13C NMR (100 MHz, DMSO-d6): δ 46.5
(CH2), 146.2 (C-40), 151.2 (C-50), 158.9 (C-30), 166.7 (C-
2), 167.1 (CH2NHCO), 169.3 (NHCO), 121.3, 121.9,
123.4, 124.6, 125.2, 125.9, 126.2, 127.7, 128.4, 129.0,
129.7, 130.2, 131.4, 132.6, 133.1, 134.5, 135.4,
136.8 ppm (aromatic carbons); HRMS (m/z) 552.6083
[M+ Na], Calcd. 552.6078. Anal. Calcd. for
C31H23N5O2S: C, 70.30; H, 4.38; N, 13.22%. Found: C,
N-(2-(Benzo[d]oxazol-2-ylamino)-2-oxoethyl)-1,3,5-
triphenyl-1H-pyrazole-4-carboxamide (11a).
Yield: 87%;
white solid, mp 170–172°C. IR (KBr): 3294 (NH), 1680
(C═O), 1615 (C═C), 1575 (C═N) cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6): δ 3.94 (s, 2H, CH2), 7.34–7.82
(m, 18H, Ar─H), 7.89 (bs, 1H, CH2─NH), 8.01 (bs, 1H,
NH─CO) ppm; 13C NMR (100 MHz, DMSO-d6): δ 46.3
(CH2), 135.1 (C-40), 138.9 (C-50), 158.5 (C-30), 163.8 (C-
2), 166.4 (CH2NHCO), 169.7 (NHCO), 110.3, 119.7,
123.5, 124.7, 124.9, 125.7, 126.0, 126.8, 127.2, 127.9,
128.3, 129.5, 130.2, 131.2, 131.8, 132.6, 134.4,
135.9 ppm (aromatic carbons). HRMS (m/z) 536.5482
[M+ Na], Calcd. 536.5468. Anal. Calcd. for C31H23N5O3:
C, 72.50; H, 4.51; N, 13.64%. Found: C, 72.63; H, 4.55;
N, 13.94%.
70.43; H, 4.67; N, 12.91%.
N-(2-(Benzo[d]thiazol-2-ylamino)-2-oxoethyl)-1,3-diphenyl-
5-(p-tolyl)-1H-pyrazole-4-carboxamide (12b).
Yield: 88%;
white solid, mp 192–194°C. IR (KBr): 3305 (NH), 1684
(C═O), 1620 (C═C), 1560 (C═N) cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6): δ 2.31 (s, 3H, CH3), 3.95 (s, 2H,
CH2), 7.21–7.79 (m, 18H, Ar─H), 7.85 (bs, 1H,
CH2─NH), 8.12 (bs, 1H, NH─CO) ppm; 13C NMR
(100 MHz, DMSO-d6): δ 24.9 (CH3), 46.7 (CH2), 136.8
(C-40), 139.6 (C-50), 158.4 (C-30), 166.0 (CH2NHCO),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Green Synthesis of Benzazolyl Pyrazoles
166.4 (C-2), 169.0 (NHCO), 121.8, 122.9, 123.9, 124.3,
124.9, 125.2, 126.3, 127.8, 128.5, 129.4, 129.9, 130.6,
131.8, 132.3, 133.4, 134.2, 135.8, 136.7 ppm (aromatic
carbons); HRMS (m/z) 566.6362 [M+ Na], Calcd.
566.6348. Anal. Calcd. for C32H25N5O2S: C, 70.70; H,
4.64; N, 12.88%. Found: C, 70.82; H, 4.67; N, 13.19%.
N-(2-(Benzo[d]thiazol-2-ylamino)-2-oxoethyl)-1,3-diphenyl-
N-(2-((1H-Benzo[d]imidazol-2-yl)amino)-2-oxoethyl)-1,3-
diphenyl-5-(p-chlorophenyl)-1H-pyrazole-4-carboxamide
(13c).
Yield: 89%; white solid, mp 196–198°C. IR
(KBr): 3290 (NH), 1668 (C═O), 1620 (C═C), 1580
1
(C═N) cmꢀ1; H NMR (400 MHz, DMSO-d6): δ 3.91 (s,
2H, CH2), 7.49–7.81 (m, 18H, Ar─H), 7.87 (bs, 1H,
CH2NH), 8.10 (bs, 1H, CH2CO), 12.89 (bs, 1H,
Imidazole─NH) ppm; 13C NMR (100 MHz, DMSO-d6):
δ 46.4 (CH2), 136.2 (C-40), 149.3 (C-50), 151.9 (C-2),
157.4 (C-30), 165.8 (CH2NHCO), 168.6 (NHCO), 115.9,
122.9, 124.3, 125.5, 125.8, 126.7, 127.5, 128.9, 129.2,
129.6, 130.3, 131.4, 132.5, 133.8, 134.7, 135.9 ppm
(aromatic carbons). HRMS (m/z) 585.0378 [M+ Na],
Calcd. 585.0398. Anal. Calcd. for C31H23ClN6O2: C,
68.38; H, 4.66; N, 14.95%. Found: C, 68.49; H, 4.68; N,
15.23%.
5-(p-chlorophenyl)-1H-pyrazole-4-carboxamide
(12c).
Yield: 92%; white solid, mp 200–202°C. IR (KBr):
3312 (NH), 1680 (C═O), 1625 (C═C), 1565 (C═N)
1
cmꢀ1; H NMR (400 MHz, DMSO-d6): δ 3.99 (s, 2H,
CH2), 7.45–7.89 (m, 18H, Ar─H), 7.94 (bs, 1H,
CH2NH), 8.16 (bs, 1H, NHCO) ppm; 13C NMR
(100 MHz, DMSO-d6): δ 47.1 (CH2), 136.6 (C-40),
139.6 (C-50), 159.0 (C-30), 166.9 (CH2NHCO), 167.0
(C-2), 169.8 (NHCO), 121.8, 122.3, 123.9, 124.3,
124.9, 125.2, 125.8, 126.2, 127.9, 128.5, 129.8, 130.7,
131.2, 132.8, 133.4, 134.2, 135.8, 136.7 ppm (aromatic
carbons). HRMS (m/z) 587.0479 [M+ Na], Calcd.
587.0498. Anal. Calcd. for C31H22ClN5O2S: C, 66.37;
H, 4.30; N, 12.09%. Found: C, 66.46; H, 4.29; N,
12.37%.
Experimental procedure for antifungal activity.
The
compounds 8–13 were tested for antifungal activity by
agar well diffusion method against test organisms [26].
Using the sterile cork borer, wells (6 mm) were made
into each petriplate. Two concentrations of DMSO-
dissolved compounds (50 and 100 μg per well) were
added into the wells by using sterile pipettes.
Simultaneously, the standard Ketoconazole for antifungal
activity (as positive control) was tested against the
pathogens. The samples were dissolved in DMSO, which
showed no zone of inhibition acts as negative control.
The plates were incubated at 28°C for 48 h for fungi.
After appropriate incubation, the diameter of zone of
inhibition of each well was measured. Duplicates were
maintained, and the average values were calculated for
eventual antifungal activity. Broth dilution test was used
to determine MIC of the aforementioned samples. Freshly
prepared nutrient broth was used as diluents. The fungi
A. niger and P. chrysogenum were diluted 100 folds in
nutrient broth (100-μL fungal cultures in 10-mL Nutrient
Broth medium (NB)). Increasing concentrations of the
test samples (1.25, 2.5, 5, 10, 20, and 40 μL of stock
solution contains 6.25, 12.5, 25, 50, 100, and 200 μg per
well of the compounds) were added to the test tubes
containing the fungal cultures. All the tubes were
incubated at 28°C for 48 h for fungi. The tubes were
examined for visible turbidity and using NB as control.
Control without test samples and with solvent was
assayed simultaneously. The lowest concentration that
inhibited visible growth of the tested organisms was
recorded as MIC. To determine the MFC for each set of
test tubes in the MIC determination, a loopful of broth
was collected from those tubes that did not show any
growth and inoculated on Potato Dextrose Agar medium
(PDA) for fungi by streaking. Plates inoculated with
fungi were incubated at 28°C for 48 h, respectively. After
incubation, the lowest concentration was noted as MFC
for fungi at which no visible growth was observed.
N-(2-((1H-Benzo[d]imidazol-2-yl)amino)-2-oxoethyl)-1,3,5-
triphenyl-1H-pyrazole-4-carboxamide (13a).
Yield: 86%;
white solid, mp 167–169°C. IR (KBr): 3287 (NH),
1660 (C═O), 1618 (C═C), 1570 (C═N) cmꢀ1 1H
;
NMR (400 MHz, DMSO-d6): δ 3.85 (s, 2H, CH2),
7.33–7.74 (m, 19H, Ar─H), 7.88 (bs, 1H, CH2NH),
8.04 (bs, 1H, CH2CO), 12.84 (bs, 1H, Imidazole─NH)
ppm; 13C NMR (100 MHz, DMSO-d6): δ 46.2 (CH2),
137.2 (C-40), 139.9 (C-50), 151.6 (C-2), 156.5 (C-30),
165.3 (CH2NHCO), 168.3 (NHCO), 115.5, 123.7,
124.3, 124.7, 125.1, 125.7, 126.8, 127.8, 128.5, 128.8,
129.6, 130.3, 130.7, 131.4, 132.3, 132.6, 133.8,
135.7 ppm (aromatic carbons). HRMS (m/z) 535.5640
[M+ Na], Calcd. 535.5628. Anal. Calcd. for
C31H24N6O2: C, 72.64; H, 4.72; N, 16.40%. Found: C,
72.77; H, 4.75; N, 16.72%.
N-(2-((1H-Benzo[d]imidazol-2-yl)amino)-2-oxoethyl)-1,3-
diphenyl-5-(p-tolyl)-1H-pyrazole-4-carboxamide (13b).
Yield: 84%; white solid, mp 171–173°C. IR (KBr): 3280
1
(NH), 1664 (C═O), 1610 (C═C), 1575 (C═N) cmꢀ1; H
NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H, CH3), 3.88
(s, 2H, CH2), 7.35–7.77 (m, 18H, Ar─H), 7.85 (bs, 1H,
CH2NH), 8.06 (bs, 1H, CH2CO), 12.86 (bs, 1H,
Imidazole─NH) ppm; 13C NMR (100 MHz, DMSO-d6):
δ 24.5 (CH3), 45.8 (CH2), 136.7 (C-40), 149.6 (C-50),
151.0 (C-2), 156.3 (C-30), 165.1 (CH2NHCO), 168.0
(NHCO), 115.2, 123.0, 123.6, 124.0, 124.8, 125.6, 126.3,
127.4, 128.7, 129.5, 129.7, 130.1, 130.8, 131.5, 132.7,
133.2, 133.9, 134.6 ppm (aromatic carbons). HRMS (m/
z) 549.5874 [M+ Na], Calcd. 549.5898. Anal. Calcd. for
C32H26N6O2: C, 72.99; H, 4.98; N, 15.96%. Found: C,
73.10; H, 5.00; N, 16.24%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Sowdari, Y. Gudi, S. V. Donthamsetty, P. Venkatapuram, and P. Adivireddy
Vol 000
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Acknowledgments. One of the authors, G. Yamini, is thankful to
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet