Synthesis and Antimicrobial Activities of Novel 2-[substituted-1H-pyrazol-4-yl] Benzothiazoles, Benzoxazoles, and Benzimidazoles

Article abstract of DOI:10.1002/jhet.1506

In an endeavor to find a new class of antimicrobial agents, a series of novel substituted benzimidazole, benzoxazole, and benzothiazole derivatives 6 containing pyrazole moiety have been synthesized by reaction of 3-aryl-4-formyl pyrazole 4 with substitut

Full text of DOI:10.1002/jhet.1506

Month 2016
Synthesis and Antimicrobial Activities of Novel 2-[substituted-
1H-pyrazol-4-yl] Benzothiazoles, Benzoxazoles, and Benzimidazoles
*
Vikas S. Padalkar, Bhushan N. Borse, Vinod D. Gupta, Kiran R. Phatangare, Vikas S. Patil, and Nagaian Sekar
Department of Intermediate and Dyestuff Technology, Institute of Chemical Technology (Formerly UDCT),
N. P. Marg, Matunga, Mumbai 400 019, Maharashtra, India
*
E-mail: n.sekar@ictmumbai.edu.in
Received July 26, 2011
DOI 10.1002/jhet.1506
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
N
N
X
R
a
X
NH
b
N
c
NH2
X1
X = CH, N
a = substituted acetophenones
b = DMF: POCl3
R1
c = substituted phenylene diamine
X = O, S, NH
1
substituted o-amino phenols
o-amino thiophenol
R = OH, H
R1= NO2, H
In an endeavor to find a new class of antimicrobial agents, a series of novel substituted benzimidazole,
benzoxazole, and benzothiazole derivatives 6 containing pyrazole moiety have been synthesized by reaction
of 3-aryl-4-formyl pyrazole 4 with substituted phenylenediamine or o-aminophenol or o-aminothiophenol 5.
Reaction of phenyl hydrazine or 2-hydrazinopyridine 1 with substituted acetophenones 2 gave
the corresponding hydrazones 3, which on Vilsmeier–Haack reaction with POCl3–DMF gave substituted
3-aryl-4-formyl pyrazoles 4. All final compounds 6a–6k were evaluated for in vitro antibacterial activities
against Escherichia coli and Staphylococcus aureus strains and in vitro antifungal activity against Candida
albicans and Aspergillus niger strains by using serial dilution method. The antimicrobial activities were
expressed as the minimum inhibitory concentration in mg/mL. The compound containing benzimidazole
and benzoxazole moiety gave better antibacterial and antifungal activities than benzothiazole compounds.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
Moreover, pyrazoles are one of the precursors of
benzimidazole, benzoxazole, and benzothiazole derivatives
and are also important intermediates for the synthesis of bio-
logically active benzofuran and coumarin systems. Although
various pyrazole derivatives are reported in literature [15],
antimicrobial activities of these classes of compounds have
received little attention [16]. Pyrazoles and substituted
pyrazoles are also reported to be potent inhibitors of many
bacteria [17]. Synthesis of compounds containing benzoxa-
zole and benzimidazole anchored with nitrogen heterocyclic
ring system is known in the literature [18]. However there are
no reports available describing synthesis and antibacterial
activities of benzimidazole, benzoxazole, and benzothiazole
with pyrazole heterocycles in a single moiety. Therefore, a
series of benzimidazole, benzoxazole, and benzothiazole
containing pyrazoles ring system was synthesized; their
antimicrobial properties have been evaluated and compared
with standard drug fluconazole and streptomycin.
Molecules with benzimidazole, benzoxazole, and
benzothiazoles moieties often exhibit diverse and important
biological properties. These heterocycles have shown differ-
ent pharmacological activities such as antibiotic [1], antiviral
[2], anticancer [3], and antimicrobial [4]. They have also
been used as ligands for asymmetric transformations [5].
Benzimidazole derivatives are unique and broad-spectrum
class of antirhino/enteroviral agents such as antihistaminic
[6], anti-ulcerative [7], anti-allergic [8], and effective against
the human cytomegalovirus [9], and are also efficient
selective neuropeptide YY1 receptor antagonists [10].
Over the last decade, a variety of benzimidazole, benzox-
azole, and benzothiazole derivatives has been synthesized
and studied for their antibacterial activity [11–13]. Substi-
tuted benzoxazole UK-1 (I) and benzoxazole AJI9561 (II)
(Fig. 1) are reported to possess growth inhibitory activity
against murine cancer cell line P388 with IC50 value in the
range of 0.3–1.6 mM [3]. Literature survey has also revealed
that many hydrazone derivatives of benzimidazole,
benzoxazole, and benzothiazole possesses as anticancer
and antibacterial properties [14].
RESULTS AND DISCUSSIONS
The syntheses of various hydrazones 3 were carried out by
condensation of phenyl hydrazine or 2-hydrazino pyridine
© 2016 Wiley Periodicals, Inc.

V. S. Padalkar, B. N. Borse, V. D. Gupta, K. R. Phatangare, V. S. Patil, and N. Sekar
Vol 000
O
O
O
its proposed mechanism is shown in Scheme 2. The purity
of the compounds was confirmed by TLC using precoated
silica gel as stationary phase, using appropriate solvent
system as mobile phase, and visualized under UV light. Struc-
OH
CH3
O
N
O
N
1
HO
HO
tures of the titled compounds were confirmed by FTIR, H
NMR, 13C NMR, and mass spectral and elemental analysis.
The strategies adopted for the synthesis of the intermedi-
ates and target compounds are depicted in Scheme 1, in
which intermediate hydrazones 3 were prepared according
to literature procedure [19]. Intermediate hydrazones deriva-
tives 3 were converted into formyl pyrazole derivatives 4
using Vilsmeier–Haack reaction with POCl3–DMF.
Aldehyde formation was confirmed by alcoholic solution
of 2,4-DNP. Aldehyde gives pink spot on TLC after dipping
into 2,4-dinitrophenylhydrazine (DNP) solution. It was also
N
O
N
O
H3C
AJI 9561 (II)
Figure 1. Structure of UK-1 and AJI9561.
UK - 1 (I)
1 with substituted acetophenones 2 in ethanol in the
presence of catalytic amounts of acetic acid. Substituted
hydrazones 3 were further converted into 1-phenyl-3-
substituted-1H-pyrazole-4-carbaldehyde or 3-substituted-
1-(pyridin-2-yl)-1H-pyrazole-4-carbaldehyde 4 derivatives
by Vilsmeier–Haack reaction with POCl3–DMF. Compounds
4 were condensed with o-substituted aromatic amines 5
in the presence of PCl3 in ethanol to obtain corresponding
2-[substituted-1H-pyrazol-4-yl]-1H-benzimidazole, 2-[sub-
stituted-1H-pyrazol-4-yl]-1,3-benzoxazole, and 2-[substi-
tuted-1H-pyrazol-4-yl]-1,3-benzothiazole 6. The synthetic
route of the compounds is outlined in Scheme 1, and synthe-
sized compounds are shown in Table 1. The synthesis of
intermediate 4 is through Vilsmeier–Haack formylation, and
1
confirmed by FTIR as well as H NMR analysis. FTIR
shows sharp band at 1678 cmÀ1, and 1H NMR shows signal
at 9.90 d. Title compounds 6a–6k were confirmed by FTIR,
1H NMR, and mass and elemental analysis. Compounds 6a–
6k has shown absence of absorption band at 1678cmÀ1 con-
firming conversion of aldehydic functional group into
corresponding benzimidazole, benzoxazole, and benzothia-
zole. Absence of peak at 9.90 d ppm in 1H NMR confirmed
the conversion of formyl functional group into target com-
1
pound. The H NMR spectrum of 6a–6k showed singlets
at 8.9–9.6 d ppm, which are characteristics of pyrazole ring.
Mass spectra showed an accurate molecular ion for each title
compounds.
Scheme 1. Synthesis of 2-[substituted-1H-pyrazol-4-yl]-1H-benzimidazole, 2-[substituted-1H-pyrazol-4-yl]-1,3-benzoxazole, and 2-[substituted-
1H-pyrazol-4-yl]-1,3-benzothiazole.
O
Ethanol, Acetic acid
R
1h, 78 oC
N
+
X
NH
R
X
N
H
NH2
X = CH, N
1
R = OH
2
3
DMF:POCl3
8h, R.T.
R
N
N
R
X
N
X
N
H
4
H
3
O
N
NH2
X1
N
N
N
PCl3 / Ethanol
60 oC, 4h
X
+
X
R
R
R1
N
O
H
X2
R1 : NO2
X2 = NH, O, S
R1
X1 = NH2, OH, SH
6a-6k
5a-5d
4a-4d
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis and Antimicrobial Activities of Benzothiazoles, Benzoxazoles, and Benzimidazoles
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

V. S. Padalkar, B. N. Borse, V. D. Gupta, K. R. Phatangare, V. S. Patil, and N. Sekar
Vol 000
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis and Antimicrobial Activities of Benzothiazoles, Benzoxazoles, and Benzimidazoles
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

V. S. Padalkar, B. N. Borse, V. D. Gupta, K. R. Phatangare, V. S. Patil, and N. Sekar
Vol 000
Scheme 2. Proposed mechanism for intermediate 4. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
DMF:POCl3
R
N
O
N
R
X
N
X
N
H
3
4
H
O
P
O
P
O
Cl
H
O
Cl
..
N
N
+
PO2Cl2
Cl
Cl
N
Cl
H
H
Cl
Cl
H
R
R
R
N
N
H
N
N
X
N
X
N
X
N
Cl
H
H
PO2Cl2
H
N
N
H
H
PO2Cl2
PO2Cl2
PO2Cl2
R
R
N
R
X
N
H2O
Hydrolysis
N
N
X
N+
X
N
H
H
N
O
N
Cl
H
PO2Cl2
H
PO2Cl2
Biological activity. The novel compounds 6a–6k were
evaluated for their in vitro antibacterial activity against
Escherichia coli and Staphylococcus aureus strains
and in vitro antifungal activity against Candida albicans
and Aspergillus niger strains by using serial dilution
method. The minimum inhibitory concentration (MIC)
measurement determined for the compounds showed
significant growth inhibition zones with the use of serial
dilution method. The MIC (mg/mL) values recorded in
Table 2 indicate that most of the tested compounds
Table 2
Antibacterial and antifungal activities of newly synthesized compounds indicated by MIC (mg/mL) using the modified resazurin assay.
Compound
Escherichia coli
Staphylococcus aureus
Candida albicans
Aspergillus niger
6a
6b
6c
6d
6e
6f
6g
6h
125
187.5
62.5
62.5
312
250
187.5
312
312
250
125
125
–
62.5
312
62.5
187.5
312
312
62.5
312
187.5
62.5
62.5
125
125
312
312
62.5
312
187.5
312
312
62.5
250
62.5
–
312
312
312
312
312
312
250
312
312
187.5
125
–
6i
6j
6k
Streptomycin
Fluconazole
–
125
125
MIC, minimal inhibitory concentration values; bacterial strain, E. coli and S. aureus; fungal strain, C. albicans and A. niger; solvent used, DMSO;
standard: bacterial strain, streptomycin 125 mg/mL; fungal strains, fluconazole 125 mg/mL.
Journal of Heterocyclic Chemistry
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Month 2016
Synthesis and Antimicrobial Activities of Benzothiazoles, Benzoxazoles, and Benzimidazoles
displayed variable inhibitory effects on the growth of
tested against bacterial and fungal strains.
activity against C. albicans and A.niger with the use of
serial dilution technique. Benzimidazole and benzoxazole
incorporating pyrazole moiety gives excellent results than
benzothiazole contains pyrazole moiety. All synthesized
The compounds 6a, 6c, 6d, 6g, 6j, and 6k showed good
antibacterial activity against E. coli and S. aureus,
respectively. On the other hand, compounds 6b, 6f, and 6i
exhibited weak to moderate growth inhibitory activity
against both E. coli and S. aureus as revealed from their
MIC values. Among these compounds, 6e and 6h showed
relatively poor growth inhibitory activity against both E. coli
and S. aureus bacterial strains. Regarding the structure–
activity relationship of the novel 2-[substituted-1H-pyrazol-
4-yl]-1H-benzimidazole, 2-[substituted-1H-pyrazol-4-yl]-1,
3-benzoxazole, and 2-[substituted-1H-pyrazol-4-yl]-1,3-
benzothiazole derivative 6a–6k against the tested bacteria,
the results revealed that new compounds containing
benzimidazole (6b, 6c, 6g, 6h, 6i, 6j, and 6k) and benzoxazole
(6a and 6d) exhibited broad-spectrum antibacterial profile
against tested organisms as compared with benzothiazole
moiety (6e and 6f) in target molecules. The electron-donating
and electron-withdrawing groups in target molecules 6a–6k
do not affect the growth inhibitory activity against tested
bacterial strain.
Regarding the activity of benzimidazole, benzoxazole,
and benzothiazole incorporating pyrazole moiety 6a–6k
against fungal strains (C. albicans and A. niger), the results
mentioned in Table 2 showed that compounds 6d, 6i, and
6k shows good inhibitory growth in case of C. albicans
fungal strain, whereas the activity of compounds 6a and
6k was 50% lower inhibitory growth for A. niger fungal
strain than C. albicans. Compounds 6f, 6g, and 6j showed
moderate antifungal activity against tested fungal strains,
whereas compounds 6b, 6c, 6e, and 6h showed poor
inhibitory profile against C. albicans as well as A. niger
fungal strains. Electron-donating and electron-withdrawing
groups on benzimidazole, benzoxazole, and benzothiazole
containing pyrazole moiety does not affect the growth
inhibitory activity against tested fungal strains.
1
compounds are confirmed by FTIR, H NMR, 13C NMR,
and mass and elemental analysis. We believe that the
insights gained in this study would be useful for the
development of potential drug candidates derived from
benzimidazole, benzoxazole, and benzothiazole incorpo-
rating pyrazole moiety in the development of novel anti-
infective agent.
EXPERIMENTAL
All commercial reagents and solvents were procured from S.D.
Fine Chemicals (India) and were used without purification. The
reaction was monitored by TLC using on 0.25-mm E-Merck silica
gel 60 F254 (Merck Millipore, Darmstadt, Germany) precoated
plates, which were visualized with UV light. The FTIR spectra were
recorded on PerkinElmer 257 spectrometer (UK) using KBr discs.
1H NMR and 13C NMR spectra were recorded on Varian MR
400 MHz (Palo Alto, CA, USA) instrument using TMS as an
internal standard. Mass spectra were recorded on Finnigan mass
spectrometer (San Jose, CA).
General. Incubator at 35 and 37ꢀC; pipettes of various sizes
(Gilson, Middleton, WI); sterile tips, 100, 200, 500, and 1000mL;
sterile normal saline; sterile isosensitest agar (Southern Group
Laboratory, Corby, UK); antibiotic solutions (Sigma-Aldrich, St.
Louis, MO); sterile solution of 10% (v/v) DMSO in water
(Sigma-Aldrich).
Medium.
Isosensitest medium was used throughout the
assay, as it is pH buffered. Although the National Committee for
Clinical Laboratory Standards recommends the use of Mueller
Hinton medium for susceptibility testing, the isosensitest medium
had comparable results for most of the tested bacterial strains.
Preparation of the plates.
Plates were prepared under
aseptic conditions. A sterile 96-well plate was labeled. A volume
of 100 mL of test material in 10% (v/v) DMSO (usually a stock
concentration of 4 mg/mL) was pipetted into the first row of the
plate. To all other wells, 50mL of nutrient broth was added. Serial
dilutions were performed using a multichannel pipette. Tips were
discarded after use such that each well had 50mL of the test
material in serially descending concentrations. To each well,
10mL of resazurin indicator solution was added. With the use of a
pipette, 30 mL of 3.3Â strength isosensitised broth was added to
each well to ensure that the final volume was single strength of
the nutrient broth. Finally, 10 mL of bacterial suspension
(5 Â 106 cfu/mL) was added to each well to achieve a concentration
of 5 Â 105 cfu/mL. Each plate was wrapped loosely with cling
film to ensure that bacteria did not become dehydrated. Each plate
had a set of controls: a column with a broad-spectrum antibiotic
as positive control, a column with all solutions with the exception
of the test compound, and a column with all solutions with the
exception of the bacterial solution, adding 10mL of nutrient broth
instead. The plates were prepared in triplicate and placed in an
incubator set at 37ꢀC for 18–24h. The color change was then
assessed visually. Any color changes from purple to pink or
colorless were recorded as positive. The lowest concentration at
which color change occurred was taken as the MIC value. The
In general, most of the tested compounds revealed better
activity against the bacterial strain (E. coli and S. aureus)
and fungal strain (C. albicans and A. niger). It would also
be noticed that compounds benzimidazole and benzoxazole
containing pyrazole moiety give better antibacterial and
antifungal potentials than benzothiazole compounds contain-
ing pyrazole moiety. Novel compounds are very active
against bacterial strain as compared with fungal strain over
tested microorganisms.
CONCLUSION
In conclusion, we have designed and synthesized a se-
ries of novel benzimidazole, benzoxazole, and benzothia-
zole derivatives containing pyrazole moiety. These novel
compounds were evaluated for in vitro antibacterial activ-
ity against E. coli and S. aureus as well as for antifungal
Journal of Heterocyclic Chemistry
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V. S. Padalkar, B. N. Borse, V. D. Gupta, K. R. Phatangare, V. S. Patil, and N. Sekar
Vol 000
average of three values was calculated, and that was the MIC for the
test material and bacterial or fungal strain [20].
(KBr): 3382, 3210, 2872 (OH), 1574, 1538, 1499, 1472 (C═N,
C═C), 762, 740cmÀ1 1H NMR (DMSO-d6, d, ppm): 9.50 (s,
.
General procedure for the synthesis of substituted-2-(1-
phenylethylidene) hydrazine or substituted-2-(1-phenylethylidene)
1H, OH), 9.21 (s, 1H, NH), 8.92 (s, 1H, pyrazole H), 8.45–8.49
(d, 1H, J = 8.0, 2.4 Hz, Ar–H), 7.86–8.07 (d, 4H, J = 8.2, 6.8,
2.0 Hz, Ar–H), 6.89–7.45 (d, 5H, J = 8.0, 6.8, 1.8 Hz, Ar–H), 6.84
(d, 2H, J = 7.0 Hz, Ar–H). 13C NMR (DMSO-d6, d, ppm): 160.9,
152.2, 148.0, 147.6, 142.0, 139.7, 138.3, 135.9, 133.0, 128.9,
123.8, 123.0, 122.2, 120.4, 118.7, 118.5, 117.9, 116.9, 113.8,
112.0, 100.0. HRMS (m/z): 353.371 (M + 1: 17%), 350.234
(78%), 260.020 (15%), 258.234 (100%), 118.451 (49%). Anal.
Calcd. for C21H15N5O: C, 71.38; H, 4.28; N, 19.82. Found: C,
71.37; H, 4.26; N, 19.85.
hydrazinyl]pyridine 3.
A mixture of phenyl hydrazine or 2-
hydrazinopyridine 1 (0.01 mol) and appropriate acetophenones
2 (0.01 mol) in ethanol (20 mL) containing 0.05 mL of glacial
acetic acid was refluxed for 1 h. The solid that separated out on
cooling was filtered and recrystallized from ethanol to afford 3.
General procedure for synthesis of 1-phenyl-3-substituted-1H-
pyrazole-4-carbaldehyde or 3-substituted-1-(pyridin-2-yl)-1H-
pyrazole-4-carbaldehyde 4.
To the Vilsmeier–Haack reaction,
2-[4-(1,3-Benzoxazol-2-yl)-1-(pyridin-2-yl)-1H-pyrazol-3-yl]
phenol (6d). Yield: 73%; recrystallized from ethyl alcohol. FTIR
(KBr): 3199, 2870 (OH), 1576, 1546, 1500, 1471 (C═N, C═C),
the reagent prepared from DMF (10 mL) and POCl3 (1.1 mL,
0.012 mol), intermediates 3 (0.01 mol) was added and the reaction
mixture stirred at room temperature for 8 h. and poured into ice-cold
water. The solid that separated on neutralization with NaHCO3 was
filtered, washed with water, and recrystallized from ethanol to give 4.
General procedure for synthesis of 2-[substituted-1H-
pyrazol-4-yl]-1H-benzimidazole or 2-[substituted-1H-pyrazol-4-
1
1168, 770, 739 cmÀ1. H NMR (DMSO-d6, d, ppm): 9.45 (s, 1H,
OH), 8.90 (s, 1H, pyrazole H), 8.36 (d, 1H, J=8.2, 2.0 Hz, Ar–H),
7.70–7.98 (d, 4H, J=7.8, 2.4 Hz, Ar–H), 6.78–7.32 (d,5H, J=8.0,
6.8, 1.8 Hz, Ar–H), 6.71 (d, 2H, J=6.8Hz, Ar–H). 13C NMR
(DMSO-d6, d, ppm): 161.3, 159.9, 156.8, 148.3, 148.0 (s), 142.3,
139.8, 133.0, 129.5, 126.6, 124.8, 122.3, 120.9, 120.7 (s), 119.3,
118.0, 114.8, 113.4, 112.9. HRMS (m/z): 354.373 (M + 1: 45%),
262.452 (23%), 165.879 (100%), 120.017 (69%). Anal. Calcd. for
C21H14N4O2: C, 71.18; H, 3.98; N, 15.81. Found: C, 71.16; H, 3.98;
N, 15.78.
yl]-1,3-benzoxazole
or
2-[substituted-1H-pyrazol-4-yl]-1,3-
benzothiazole 6.
Phosphorus trichloride (0.33 mol) was added
dropwise to a solution of the 1-phenyl-3-substituted-1H-pyrazole-
4-carbaldehyde or 3-substituted-1-(pyridin-2-yl)-1H-pyrazole-4-
carbaldehyde (0.33 mol) and substituted phenylenediamine or
aminophenol or thiophenol (0.33 mol) in ethanol (50mL),
maintaining the temperature at 40–45ꢀC. The mixture was heated
at 60ꢀC for 4 h, after completion of reaction (checked by TLC)
cooled the reaction mass at room temperature and made alkaline
to pH8 with 20% aqueous sodium bicarbonate solution. Separated
solid was collected by filtration and crystallized from isopropyl
alcohol.
2-[4-(1,3-Benzothiazol-2-yl)-1-(pyridin-2-yl)-1H-pyrazol-3-yl]
phenol (6e). Yield: 80%; recrystallized from ethyl alcohol. FTIR
(KBr): 3204, 2879 (OH), 1580, 1543, 1509, 1479 (C═N, C═C),
1
766, 745 cmÀ1. H NMR (DMSO-d6, d, ppm): 9.66 (s, 1H, OH),
9.21 (s, 1H, pyrazole H), 8.58–8.59 (d, 1H, Ar–H), 7.95–8.07 (d,
4H, J = 8.8, 8.0, 2.0 Hz, Ar–H), 7.00–7.51 (d, 5H, J = 8.0, 6.4,
2.0 Hz, Ar–H), 6.96–7.00 (d, 2H, J = 7.8, 6.4Hz, Ar–H).
13C NMR (DMSO-d6, d, ppm): 181.4, 160.7, 153.8, 150.3, 148.1,
147.7, 139.7, 133.6, 132.7, 128.1, 126.0, 125.5, 125.1, 125.0,
124.8, 120.3, 118.9, 118.0, 116.9, 113.3, 113.1. HRMS: m/z
371.000 (M+ 1: 37%), 370.035 (35%), 373.012 (10%), 161.218
(30%), 154.476 (100%), 129.203 (15%). Anal. Calcd. for
C21H14N4OS: C, 68.09; H, 3.81; N, 15.12; S, 8.66. Found: C,
68.07; H, 3.79; N, 15.13, S, 8.65.
Spectral Data of compounds 6a–6k. 2-[4-(1,3-Benzoxazol-
2-yl)-1-phenyl-1H-pyrazol-3-yl]phenol (6a).
recrystallized from ethyl alcohol. FTIR (KBr): 3197, 2874 (OH),
1574, 1546, 1500, 1473 (C═C), 1168, 770 cmÀ1 1H NMR
Yield: 78%;
.
(DMSO-d6, d, ppm): 9.21 (s, 1H, OH), 8.92 (s, 1H, pyrazole H),
7.93–7.96 (d, 2H, J=8.2, 2.0 Hz, Ar–H), 7.54–7.57 (d, 2H, J = 8.0,
2.4 Hz, Ar–H), 7.33–7.38–7.39 (d, 2H, J = 7.8,1.8 Hz, Ar–H),
7.21 (t, 1H, Ar–H), 6.98 (d, 4H, J = 6.8, 2.0 Hz, Ar–H), 6.87 (d,
2H, Ar–H). 13C NMR (DMSO-d6, d, ppm): 160.1, 159.8, 155.9,
148.3, 141.0, 140.5, 132.6, 130.7 (s), 128.3, 127.8, 124.7, 122.4,
122.0, 121.1 (s), 120.5, 119.3, 118.1, 115.2, 113.0, 112.6. HRMS
(m/z): 353.371 (M + 1: 48%), 261.232 (10%), 250.291 (35%),
235.198 (100%), 122.024 (53%). Anal. Calcd. for C22H15N3O2:
C, 74.78; H, 4.28; N, 11.89. Found: C, 74.76; H, 4.26; N, 11.90.
2-[4-(1H-Benzimidazol-2-yl)-1-phenyl-1H-pyrazol-3-yl]phenol
2-(1,3-Diphenyl-1H-pyrazol-4-yl)-1,3-benzothiazole (6f).
Yield: 87%; recrystallized from ethyl alcohol. FTIR (KBr): 1587,
1533, 1500, 1479, 1347 (C═N, C–N, C═C), 761, 738 cmÀ1
.
1H NMR (DMSO-d6, d, ppm): 9.35 (s, 1H, NH), 8.54 (s, 1H,
pyrazole H), 8.19 (d, 1H, Ar–H), 7.95–7.98 (d, 3H, J = 8.2,
2.0 Hz, Ar–H), 7.81–7.849 (d, 2H, J = 8.0, 1.8 Hz, Ar–H),
7.60–7.63 (d, 3H, J = 7.8, 2.4 Hz, Ar–H), 7.39–7.45 (d, 5H,
Ar–H). 13C NMR (DMSO-d6, d, ppm): 177.9, 153.9, 150.8,
140.0, 133.6, 133.5, 130.7 (s), 129.9, 127.9, 127.7, 127.4, 126.4,
126.0, 125.5, 125.4, 125.0, 124.6, 121.0 (s), 117.7. HRMS (m/z):
353.430 (M+ 1: 24%), 235.023 (10%), 221.193 (36%), 135.000
(100%). Anal. Calcd. for C22H15N3S: C, 74.76; H, 4.28; N, 11.89;
S, 9.07. Found: C, 74.75; H, 4.26; N, 11.90; S, 9.05.
(6b).
Yield: 66%; recrystallized from ethyl alcohol. FTIR
(KBr): 3391, 3206, 2872 (OH), 1578, 1536, 1500, 1480 (C═N,
1
C═C), 756, 743 cmÀ1. H NMR (DMSO-d6, d, ppm): 9.45 (s,
1H, OH), 9.25 (s, 1H, NH) 8.93 (s, 1H, pyrazole H), 8.54–8.57
(d, 2H, J = 8.0,1.8Hz, Ar–H), 7.81–7.85 (d, 2H, J = 8.0, 2.4 Hz,
Ar–H), 7.46–7.52 (d, 2H, J = 7.4,1.8 Hz, Ar–H), 7.24 (t, 1H,
Ar–H), 7.17–7.21 (d, 4H, J = 7.0, 6.4 Hz, Ar–H), 6.86–6.90 (d,
2H, J = 6.8 Hz, Ar–H). 13C NMR (DMSO-d6, d, ppm): 161.0,
151.5, 142.0, 140.0, 138.0, 135.7, 132.6, 130.3 (s), 127.7, 127.4,
125.6, 123.0, 122.1, 119.6 (s), 118.3 (s), 117.5, 116.8, 113.6,
104.3. HRMS (m/z): 352.376 (M + 1: 27%), 352.378 (22%),
236.259 (100%), 119.001 (49%). Anal. Calcd. for C22H16N4O: C,
74.98; H, 4.58; N, 15.90. Found: C, 74.75; H, 4.25; N, 15.88.
2-[4-(1H-Benzimidazol-2-yl)-1-(pyridin-2-yl)-1H-pyrazol-3-yl]
phenol (6c). Yield: 84%; recrystallized from ethyl alcohol. FTIR
2-[3-Phenyl-1-(pyridin-2-yl)-1H-pyrazol-4-yl]-1H-benzimidazole
(6g). Yield: 80%; recrystallized from ethyl alcohol. FTIR (KBr):
3388, 1582, 1548, 1514, 1484, 1361 (C═N, C–N, C═C), 810, 770,
748 cmÀ1. 1H NMR (DMSO-d6, d, ppm): 9.28 (s, 1H, NH), 8.64 (s,
1H, pyrazole H), 8.21 (d, 1H, Ar–H), 7.89–7.91 (d, 3H, J = 8.2,
2.0 Hz, Ar–H), 7.67–7.70 (d, 2H, J = 8.0,1.8 Hz, Ar–H),
7.54–7.57 (d, 3H, J = 7.8, 6.8, 2.0 Hz, Ar–H), 7.39–7.41
(d, 4H, J = 6.8, 7.8, 1.8 Hz, Ar–H). 13C NMR (DMSO-d6, d,
ppm): 149.0, 148.2, 147.5, 141.9, 139.7, 136.5, 135.0, 131.1,
128.7 (s), 128.0 (s), 127.9, 123.8, 123.0, 122.1, 120.4, 118.7 (s),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis and Antimicrobial Activities of Benzothiazoles, Benzoxazoles, and Benzimidazoles
112.0, 99.0. HRMS (m/z): 337.371 (M + 1: 38%), 262.344 (27%),
221.651 (43%), 118.901 (100%). Anal. Calcd. for C21H15N5:
C, 74.76; H, 4.48; N, 20.76. Found: C, 74.73; H, 4.45; N, 20.77.
2-(1,3-Diphenyl-1H-pyrazol-4-yl)-5-nitro-1H-benzimidazole
(DMSO-d6, d, ppm): 161.0, 153.0, 149.0, 148.0, 144.0,
142.0, 140.1, 139.7(s), 132.9, 129.0, 124.0, 120.4, 118.2,
118.0, 117.6, 116.9, 116.2, 114.5, 112.0, 100.0. HRMS (m/
z): 398.377 (M + 1: 65%), 237.449 (56%), 163.088 (45%),
118.032 (100%). Anal. Calcd. for C21H14N6O3: C, 63.31; H,
3.54 N, 21.10. Found: C, 63.29; H, 3.53; N, 21.13.
(6h).
(KBr): 3378, 1584, 1539, 1508, 1482, 1361 (C═N, C–N,
C═C), 1528, 1330 (–NO2), 812, 780, 732 cmÀ1 1H NMR
Yield: 88%; recrystallized from ethyl alcohol. FTIR
.
(DMSO-d6, d, ppm): 9.45 (s, 1H, NH), 7.95 (d, 2H, Ar–H),
7.79–7.81 (d, 2H, J = 8.0, 2.0 Hz, Ar–H), 7.72 (d, 2H, J = 7.8,
1.8 Hz, Ar–H), 7.66–7.68 (t, 2H, J = 7.8, 2.4 Hz, Ar–H),
7.56–7.58 (d, 2H, J = 6.8 Hz, Ar–H), 7.50 (d, 4H, J = 7.8, 6.8,
1.8 Hz, Ar–H). 13C NMR (DMSO-d6, d, ppm): 146.3, 144.0,
142.0, 140.0, 137.6, 134.0, 130.8 (s), 128.0, 127.7, 127.5 (s),
126.6 (s), 125.3, 120.0 (s), 118.1, 117.6, 116.2, 100.0. HRMS
(m/z): 381.383 (M + 1: 34%), 304.120 (10%), 220.185 (100%),
163.090 (38%). Anal. Calcd. for C22H15N5O2: C, 69.28; H,
3.96; N, 18.36. Found: C, 69.26; H, 3.96; N, 18.33.
Acknowledgements. The author is greatly thankful to IIT Mumbai
for recording the 1H NMR, 13C NMR, and Mass spectra.
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5-Nitro-2-[3-phenyl-1-(pyridin-2-yl)-1H-pyrazol-4-yl]-1H-
benzimidazole (6i).
Yield: 68%; recrystallized from ethyl
alcohol. FTIR (KBr): 3381, 1585, 1539, 1511, 1483, 1365 (C═N,
1
C–N, C═C), 1532, 1335 (–NO2), 814, 782, 735 cmÀ1. H NMR
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7.59–7.62 (d, 2H, J = 8.0, 2.0 Hz Ar–H), 7.54–7.57 (d, 3H,
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127.9, 127.6, 123.8, 120.4, 118.2, 117.6, 116.0, 112.0, 99.0.
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21.98. Found: C, 65.94; H, 3.68; N, 21.97.
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2-[4-(5-Nitro-1H-benzimidazol-2-yl)-1-phenyl-1H-pyrazol-3-
yl]phenol (6j).
FTIR (KBr): 3376, 3212, 2880, 1583, 1537, 1507, 1481, 1361
(C═N, C–N, C═C), 1528, 1328 (–NO2), 807, 782, 728 cmÀ1
Yield: 74%; recrystallized from ethyl alcohol.
.
1H NMR (DMSO-d6, d, ppm): 9.50 (s, 1H, OH), 9.25 (s, 1H, NH),
8.45 (d, 1H, Ar–H), 7.97 (d, 1H, Ar–H), 7.94 (d, 1H, Ar–H), 7.78
(d, 1H, Ar–H), 7.60 (d, 3H, J=8.0, 2.0 Hz, Ar–H), 7.44 (d, 1H,
Ar–H), 7.29 (d, 1H, Ar–H), 6.98 (d, 1H), 6.86 (d, 1H, Ar–H).
13C NMR (DMSO-d6, d, ppm): 159.1, 151.4, 144.0, 142.0, 140.0,
139.9, 137.9, 132.9, 130.9 (s), 127.9, 127.3, 125.6, 119.9 (s), 118.2,
118.0, 117.7, 116.4, 113.5, 104.2. HRMS (m/z): 397.388 (M + 1:
56%), 305.228 (12%), 236.089 (34%), 163.669 (100%), 94.228
(20%). Anal. Calcd. for C22H15N5O3: C, 66.49; H, 3.80; N, 17.62.
Found: C, 66.48; H, 3.81; N, 17.63.
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pyrazol-3-yl]phenol (6k).
Yield: 79%; Recrystallized from
ethyl alcohol. FTIR (KBr): 3383, 3218, 2889, 1591, 1542,
1511, 1487, 1368 (C═N, C–N, C═C), 1532, 1343 (–NO2),
814, 785, 735 cmÀ1 1H NMR (DMSO-d6, d, ppm): 9.61
.
(s, 1H, OH), 9.42 (s, 1H, NH), 8.97 (s, 1H, pyrazole H),
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet