Synthesis of 3-substituted pyrazole derivatives by mixed anhydride method and study of their antibacterial activities

Article abstract of DOI:10.1080/00397911.2013.765483

A convenient synthesis of 3-substituted pyrazole derivatives by a mixed anhydride method using i-butylchloroformate and N-methylmorpholine at-20 °C in tetrahydrofuran and study of in vitro antibacterial activities of the prepared compounds against Staphyl

Full text of DOI:10.1080/00397911.2013.765483

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Synthesis of 3-Substituted Pyrazole
Derivatives by Mixed Anhydride Method
and Study of Their Antibacterial
Activities
a
a
Sushanta Kumar Mishra , Poulomi Majumdar , Rajani Kanta Behera
a
a
&
Ajaya Kumar Behera
a
Organic Synthesis Laboratory, School of Chemistry , Sambalpur
University, Jyoti Vihar , Burla , Odisha , India
Accepted author version posted online: 15 Aug 2013.Published
online: 11 Oct 2013.
To cite this article: Sushanta Kumar Mishra , Poulomi Majumdar , Rajani Kanta Behera & Ajaya Kumar
Behera (2014) Synthesis of 3-Substituted Pyrazole Derivatives by Mixed Anhydride Method and Study
of Their Antibacterial Activities, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 44:1, 32-41, DOI: 10.1080/00397911.2013.765483
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1
Synthetic Communications , 44: 32–41, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.765483
SYNTHESIS OF 3-SUBSTITUTED PYRAZOLE
DERIVATIVES BY MIXED ANHYDRIDE METHOD AND
STUDY OF THEIR ANTIBACTERIAL ACTIVITIES
Sushanta Kumar Mishra, Poulomi Majumdar,
Rajani Kanta Behera, and Ajaya Kumar Behera
Organic Synthesis Laboratory, School of Chemistry, Sambalpur University,
Jyoti Vihar, Burla, Odisha, India
GRAPHICAL ABSTRACT
Abstract A convenient synthesis of 3-substituted pyrazole derivatives by a mixed anhydride
ꢁ
method using i-butylchloroformate and N-methylmorpholine at ꢀ20 C in tetrahydrofuran
and study of in vitro antibacterial activities of the prepared compounds against Staphylo-
coccus epidermidis, Bacillus subtilis, Pseudomonas aeruginosa, and Proteus valguris by
agar-diffusion method were carried out. The results suggested that the products 4a, 4b,
and 4c exhibited moderate to feeble inhibition against all test bacteria at greater concen-
tration but 4d was best against Staphylococcus epidermidis (22 mm) and worst against
Pseudomonas aeruginosa (16 mm) at the greatest concentration (2.5 mg=ml), and the
activities decreased with decrease in concentration.
[Supplementary materials are available for this article. Go to the publisher’s online
1
edition of Synthetic Communications for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Acid anhydride; antibacterial activity; pyrazole
INTRODUCTION
Pyrazole scaffold and its derivatives, a class of well-known nitrogen-containing
heterocyclic compounds, play vital roles in biologically active compounds and
therefore represent an interesting template for combinatorial as well as medicinal
[
1–5]
chemistry. Pyrazoles are one of the oldest classes of bioactive compounds, which
are principally used in medicine and have enormous potential as pharmaceutical
Received September 27, 2012.
Address correspondence to Ajaya K. Behera, Organic Synthesis Laboratory, School of Chemistry,
Sambalpur University, Jyoti Vihar, Burla 768019, Odisha, India. E-mail: ajaykumar.behera@yahoo.com
3
2

SYNTHESIS OF 3-SUBSTITUTED PYRAZOLES
33
[
6–8]
agents because of their biological activities such as anti-inflammatory,
[
9,10]
[11]
[12,13]
anticonvulsant,
[14–17]
antipyretic,
antiarrhythmic,
crinological, and antihyperglycaemic
antibacterial,
endo-
activities and are also found to exhibit
HIV-1 reverse transcriptase and IL-1 synthesis inhibition. Certain alkyl pyrazoles
have shown significant analgesic, antipyretic, bacteriostatic, bactericidal, and fungi-
cidal activities. Benzopyrano[4,3]-pyrazoles are found to be potential pharma-
ceutical agents because of their biological activities such as antimicrobial,
[18]
[
19]
[20–23]
[
24–27]
anti-inflammatory, and immunomodulator activity.
Substituted pyrazoles have
[
28]
pronounced sedative action on the central nervous system. The recent success of
pyrazole COX-2 inhibitor has further highlighted the importance of these hetro-
cycles in medicinal chemistry. The synthesis of pyrazole and its analogs has been a
subject of consistent interest because of the wide range of applications for such het-
erocycles in the pharmaceutical and agrochemical industries. Pyrazole-containing
compounds have inhibitors and deactivators of liver alcohols dehydrogenase and
oxidoreductase. Though many syntheses have been developed for pyrazole deriva-
tives because of their great importance, designing facile synthetic routes remains
as an active research area.
In view of these facts, the aim of the present study was to obtain pyrazole
derivatives as antibacterial agents by the mixed anhydride method.
RESULTS AND DISCUSSION
The route used for the synthesis of the pyrazole derivatives 4 assessed in this
study is shown in Scheme 1. The reaction of equimolar amount of 4-(4-chloro-
phenyl)-3-methyl-2,4-dioxo-butyric acid ethyl ester 1 with 2,4-dichlorophenylhydra-
zine in ethanol (10 times) in the presence of a catalytic amount of acetic acid under
reflux condition furnished 4-(4-chloro-phenyl)-2-[(2,4-dichloro-phenyl)-hydrazono]-
3
-methyl-4-oxo-butyric acid ethyl ester 2 with more than 90% yield. Compound 2
was formed regioselectively becauseof high electron deficiency of carbonyl carbon
at C-2 as compared to other two carbonyl carbon at C-1 and C-4. The reactivity
at C-1 is decreased by its conjugation with ethoxy group whereas the electropositive
character at C-4 relatively lessens because of the þM effect of p-chlorophenyl group.
The ester derivative 2 on subsequent cyclization followed by hydrolysis with
potassium hydroxidein refluxing ethanol (5 times) gave the precursor 5-(4-chloro-
phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid 3 in 90%
yield (4g). The novel pyrazole derivatives 4 were prepared by the reaction of
5
-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid
3
formate
with different amines by novel mixed anhydride method using isobutylchloro-
[
29–31]
in tetrahydrofuran (THF) and in the presence of N-methylmorpholine
ꢁ
(NMM) at ꢀ20 C with more than 95% yield, which has the advantage of giving
better yield than the earlier acid chloride method using thionyl chloride and N,N-
dimethylformamide in toluene at reflux temperature. To our delight, under these
conditions, the reactions proceeded smoothly and a variety of the desired pyrazole
products 4a–i were obtained in good yields (Table 1). The probable mechanism
for acid anhydride method is outlined in Scheme 2.
The structures of the synthesized compounds were confirmed by analytical and
spectral data (IR, NMR, mass). The IR spectrum of compound 2 illustrates a band at

34
S. K. MISHRA ET AL.
Scheme 1. Synthesis of pyrazole derivatives 4.
ꢀ
1
227 cm for NH stretching frequency along with the bands at 1694 and 1681 cm
ꢀ1
3
1
assignable to carbonyl groups. H NMR of compound 2 shows a sharp singlet at d
2.41 for NH proton. C=O peaks of 2 in C NMR spectrum appears at d 162.36
C-1) and 199.17 (C-4). Appearance of a carbonyl peak at d 1687 cm in the IR
1
3
1
(
ꢀ
1
spectrum of 3 and a broad singlet at d 8.49 for OH proton along with the disappear-
1
13
ance of NH peak in the H NMR spectrum indicates the formation of 3. C NMR
spectrum of 3 shows a carbonyl peak at d 164. The IR and NMR spectrum of 4a, 4b,
and 4f–i exhibited the disappearance of OH signal. Also, the PMR spectrum of 4a,
4
b, and 4f–i showed the appearance of a singlet or quartetfor methyl protons and
Table 1. Synthesis of compound 4 from 3
ꢁ
Compound
Time (min)
Yield (%)
M ( C)
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
20
20
20
20
20
20
20
20
20
95
96
95
95
96
97
96
96
95
185–195
187–192
190–195
188–195
181–185
172–177
174–181
189–194
165–170
g
h
i

SYNTHESIS OF 3-SUBSTITUTED PYRAZOLES
35
Scheme 2. Plausible mechanism for the formation of pyrazole derivatives 4.
multiplet or triplet for methylene protons at d 3.54–3.95 and 1.25–3.80, respectively.
ꢀ
1
In the IR spectrum of pyrazole derivatives 4c–4e absorbs strongly at 3221–3385 cm
,
assignable to -NH- group. Moreover, the PMR spectrum of 4c–4e showed the
appearance of broad singletsor quartet at d 8.55–8.69 or 4.41, respectively. All the
detailed spectral data were given in the experimental section.
ANTIMICROBIAL ACTIVITY
All the synthesized compounds were screened for their antibacterial activity
in vitro against two Gram-positive bacteria (Staphylococcus epidermidis and Bacillus
subtilis) and two Gram-negative bacteria (Pseudomonas aeruginosa and Proteus
valguris), which were obtained from the microbial type culture collection and Gene
Bank (MTCC). The MTCC is a modern facility housed at the Institute of Microbial
Technology (IMTECH), Chandigarh, India, and maintained in usual laboratory
conditions.
For preliminary screening the antimicrobial tests were carried out by the
agar-diffusion method. The turbidity of bacterial cultures in broth media was
adjusted with sterile saline (0.92 w=v) according to 0.5 McFarland turbidity
standards for the preparation of the inoculums. Mueller–Hinton agar medium
ꢁ
(
2
Hi-media), previously prepared and sterilized, was cooled down to 45–50 C, and
0 ml of this media were poured into 9-cm sterile glass Petri dishes previously
marked suitably at the bottom surface, to a depth of approximately 4 mm. The
inoculums were added to the molten agar media in the Petri dishes and the plates
were swirled gently to disperse the microorganisms homogeneously. The plates were
then allowed to solidify. Then wells were made with the help of a cylinder and
impregnated with 50 ml of each test compounds at four different concentrations
(2.5, 1.2, 0.6, and 0.3 mg=ml) and placed on the solidified surface of the media seeded
with the respective microorganism. Similarly, vehicle dimethylsulfoxide (DMSO)
impregnated in the well was used as the negative control. Kanamycine sulfate
(10 mg=disc) was used as a positive reference standard to determine the sensitivity
of each microbial species tested (Table 2). The inoculated plates were incubated at
ꢁ
3
7 C for 24 h for bacteria strains. Antimicrobial activity was evaluated by measuring

36
S. K. MISHRA ET AL.
Table 2. Minimum inhibitory concentration values of Kanamycin
sulfate by Agar diffused method
Bacteria
Zone of inhibition (mm)
Staphylococcus epidermidis
Pseudomonas aeruginosa
Proteus valguris
30
15
25
33
Bacillus subtilis
the diameter of zone of inhibition against test organisms. The antibacterial activity
of compounds against four bacterial strains was initially assessed by the agar-
diffusion method. The compounds showed antibacterial activity against most of
the tested bacteria, mainly at higher concentrations. The compounds 4a, 4b, and 4c
exibited moderate to feeble inhibition against all test bacteria, but 4d was best against
Staphylococcus epidermidis (22 mm) and worst against Pseudomonas aeruginosa
(16 mm) at the greatest concentration (2.5 mg=ml). The activities decreased with
decrease in concentration. All the synthesized compounds were found to possess
activity at maximum concentration. The results indicated that 4d was more effective
than the rest of the compounds. This may be due to the fact that the 4d had more
antibacterial constituents, which were less or absent in the rest of the compounds.
The compounds were effective against most Gram-positive and Gram-negative
bacteria tested, thereby indicating a broad spectrum of activity. However, the results
revealed that the Gram-positive bacteria were in general more sensitive to this
compound. In this investigation the agar disk diffusion method was employed to
serve as initial antibacterial screening procedure. The diameter of zone of inhibition
is a function of initial concentration (in the well), solubility, and diffusion rate of
the antibacterial compounds present through the agar media and thus not a true
measure of effectiveness. Many physical and chemical factors unrelated to anti-
bacterial activity affect the rate of diffusion of compounds through bacteria-seeded
solid media. Therefore, it is not possible to measure the antibacterial activity of
a new compound in terms of another antibiotic as standard by comparing the
diameter zone of inhibition produced by agar diffusion; hence in the present
study no antibiotic standard was employed while the agar diffusion method was used
to assess the antibacterial activity, where the compounds were diluted serially in
a sequence of decreasing concentration and inoculated with test bacteria. The smallest
concentration of the extract that prevented visible growth (turbidity) was called the
minimum inhibitory concentration (MIC). Here, a reference broad-spectrum
antibiotic, kanamycin sulfate, was employed as standard. Furthermore, some MIC
values obtained for kanamycin sulfate were roughly in agreement with literature
[
32–37]
values.
Therefore, the standard antibiotic was employed not only for the
comparison but also to ensure the bacteria used in the study and the experimental
conditions were appropriate and acceptable. The present investigation is the first
experimental demonstration of any biological activity as well as broad-spectrum
antibacterial efficacy compounds. The results of the antimicrobial screening are
given in Table 3. From the results obtained, it is obvious that most of the
compounds showed promising activity against bacteria.

SYNTHESIS OF 3-SUBSTITUTED PYRAZOLES
37
Table 3. In vitro antibacterial activity of 4a–i (mg=ml) by agar diffusion method
Zone of inhibition (mm)
a
a
Gram-positive bacteria
Gram-negative bacteria
Compound
Conc. (mg=ml)
Se
Bs
Pa
Pv
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
2.5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
20
17
15
13
21
20
18
17
21
19
18
17
22
18
16
14
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
19
14
—
—
15
13
—
—
16
15
—
—
25
15
14
12
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
17
—
—
—
16
15
13
—
17
14
13
—
16
12
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
21
—
—
—
18
15
14
—
15
13
11
10
20
18
16
15
—
—
—
—
1
0
0
.2
.6
.3
2.5
1
0
0
.2
.6
.3
2.5
1
0
0
.2
.6
.3
2.5
1
0
0
.2
.6
.3
2.5
1
0
0
.2
.6
.3
2.5
1
0
0
.2
.6
.3
g
h
i
2.5
1
0
0
.2
.6
.3
2.5
1
0
0
.2
.6
.3
2.5
1
0
0
.2
.6
.3
a
The screening organisms. Gram-positive bacteria: Staphylococcus epidermidis (Se), Bacillus subtilis
Bs). Gram-negative bacteria: Pseudomonas aeruginosa (Pa), Proteus valguris (Pv).
(
EXPERIMENTAL
Melting points were recorded on an Electrothermal type 9100 melting-point
apparatus. The IR spectra were obtained on a 4300 Shimadzu spectrometer as pallets
1
on KBr discs. The H NMR (400 MHz) spectra were recorded on a Bruker Advace II
400 spectrometer. Chemical shifts are reported in parts per million (ppm) downfield
from tetramethylsilane (TMS) as internal standard (chemical shifts in delta, ppm).

38
S. K. MISHRA ET AL.
Data are given in the following order: d value, multiplicity (s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; bs, broad), number of protons, and coupling
constants J (given in hertz). The mass spectra were scanned on a Varian Mat
CH-7 at 70 eV. All of the chemicals were purchased from Sigma, Fluka, Hi-media,
and Merck. The reaction were monitored by thin-layer chromatography (TLC) using
glass plates coated with silica gel-G containing 13% calcium sulfate as binder.
General Procedure for Synthesis of Pyrazole Derivatives of 4
To a mixture of 3 (3 g, 0.008 mol) in tetrahydrofuran (30 mL) and N-methyl-
morpholine (1.59 g, 0.016 mol) was slowly added i-butychloroformate (1.6 g,
ꢁ
0
stirred at the same temperature for 20 min. Then a solution of respective amines
.012 mmol) in tetrahydrofuran (10 mL) at ꢀ10 to ꢀ20 C, and the mixture was
(
1.2 mol eq.) in tetrahydrofuran (30 mL) was added over a period of 30–45 min,
ꢁ
and the solution was stirred for 1 hr at ꢀ10 to ꢀ20 C. After completion of the
reaction from TLC (mobile phase 2:8 methanol and dichloromethane) solvent was
distilled up to get a residue, which was taken in water (100 ml), and the product
was extracted with dichloromethane. The organic layer was dried over sodium
sulfate, and the solvent was distilled out under vacuum to get a residue, which was
crystallized with di-isopropyl ether to get solid 4a–i.
[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-
3-yl]-(octahydro-isoindol-2-yl)-methanone (4a)
Anal. calcd. for C H Cl N O: C, 61.42; H, 4.95; N, 8.60. Found: C, 61.19; H,
2
5
24
3
3
ꢀ
1
1
4
.80; N, 8.45. IR (KBr, nmax, cm ): 1624 (C=O); H NMR (400 MHz, d, ppm,
CDCl ): 1.25–1.53 (m, 8H, 4 ꢂ CH of cyclohexane ring of indolene), 2.13–2.20
3
2
(
6
7
m, 5H, -CH & C -H, C -H of indolene), 3.48–3.80 (m, 4H, 2 ꢂ CH of indolene),
3
8
13
2
.99 (d, 2H, J ¼ 8.32 Hz, ArC 00-H & ArC600-H), 7.10 (d, 1H, J ¼ 8.44 Hz, ArC 00-H),
5
3
.15–7.21(m, 3H, ArC
0
-H, ArC
0
-H & ArC
0
5
-H), 7.34–7.35 (d, 1H, J ¼ 1.88 Hz,
6
3
1
3
ArC2 -H); C NMR (100 MHz, d, ppm, CDCl ): 9.50 (C-7), 22.56, 22.87, 25.73,
3
2
(
(
(
0
00
5.78, 35.56, 37.83, 50.03, 53.08, 118.60 (carbon of indolene), 117.47 (C-6 ), 127.55
00 00 0 0 00 00
C-2 ), 127.79 (C-5 ), 128.85 (C-2 & C-6 ), 130.27 (C-3 ), 130.56 (C-4 ), 130.76
C-3 & C-5 ), 133.03 (C-4 ), 134.66 (C-1 ), 135.56 (C-1 ), 136.15 (C-5), 141.62
0
0
0
0
00
þ
C-3), 147.17 (C-4), 163.38 (C-6); MS (m=z): M þ 1] 488.17.
SUPPORTING INFORMATION
Experimental details, spectral and analytical data of synthesized compounds,
1
13
and copies of IR, H NMR, C NMR, and mass spectra of compounds 2, 3, and
a–j are given in the supplementary content. This material can be found via the
Supplementary Content section of this article’s Web page.
4
ACKNOWLEDGMENTS
The authors thank the University Grants Commission, Funding for Infra-
structure in Science and Technology, Department of Science and Technology, for

SYNTHESIS OF 3-SUBSTITUTED PYRAZOLES
39
providing infrastructural facility, Central Drug Research Institute (CDRI) Lucknow
for antibacterial study, and Sophisticated Analytical Instrument Facility (SAIF),
Punjab University, for providing NMR spectral data.
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