Synthesis and antimicrobial activity of linked heterocyclics containing pyrazole and oxadiazoles

Article abstract of DOI:10.1002/jhet.913

A new series of 3-(arylaminomethyl)-5-(5-methyl-1-phenyl-1H-4-pyrazolyl)-2, 3-dihydro-1,3,4-oxadiazole-2-thiones 6a-j has been synthesized by the reaction of 5-(5-methyl-1-phenyl-1H-4-pyrazolyl)-1,3,4-oxadiazol-2-ylhydrosulfide 5 with formaldehyde and corresponding anilines. The chemical structures of newly synthesized compounds were elucidated by IR, ¹H, ¹³C-NMR, MS, and elemental analyses. The compounds 6a-j were evaluated for their antibacterial activity against three representative Gram positive bacteria viz. Bacillus subtilis (MTCC 441), Bacillus sphaericus (MTCC 11) and Staphylococcus aureus (MTCC 96), and three Gram negative bacteria viz. Pseudomonas aeruginosa (MTCC 741), Klobsinella aerogenes (MTCC 39) and Chromobacterium violaceum. Among the screened 6b, 6d, 6i, and 6j in which oxadiazole moiety bearing 4-fluoroanilinomethyl, 4-chloroanilinomethyl, 2-trifluoromethylanilinomethyl, and 2,5-difluoroanilinomethyl groups, respectively, showed high activity against all the microorganisms used. In addition these compounds were also screened for their antifungal activity against four fungal organisms viz. Candida albicans (ATCC 10231), Aspergillus fumigatus (HIC 6094), Trichophyton rubrum (IFO 9185), and Trichophyton mentagrophytes (IFO 40996). Most of these new compounds showed appreciable activity against test fungi, and emerged as potential molecules for further development.

Full text of DOI:10.1002/jhet.913

1038
Synthesis and Antimicrobial Activity of Linked Heterocyclics
Containing Pyrazole and Oxadiazoles
Vol 49
*
Ch. Sanjeeva Reddy, L. Sanjeeva Rao, M. Vani Devi, and A. Nagaraj
Department of Chemistry, University College, Kakatiya University, Warangal 506 009, India
*
E-mail: chsrkuc@yahoo.co.in
Received January 10, 2011
DOI 10.1002/jhet.913
Published online 26 October 2012 in Wiley Online Library (wileyonlinelibrary.com).
A new series of 3‐(arylaminomethyl)‐5‐(5‐methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐2,3‐dihydro‐1,3,4‐oxadia-
zole‐2‐thiones 6a–j has been synthesized by the reaction of 5‐(5‐methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐1,3,4‐
oxadiazol‐2‐ylhydrosulfide 5 with formaldehyde and corresponding anilines. The chemical structures of
1
newly synthesized compounds were elucidated by IR, H, 13C‐NMR, MS, and elemental analyses. The
compounds 6a–j were evaluated for their antibacterial activity against three representative Gram positive
bacteria viz. Bacillus subtilis (MTCC 441), Bacillus sphaericus (MTCC 11) and Staphylococcus aureus
(MTCC 96), and three Gram negative bacteria viz. Pseudomonas aeruginosa (MTCC 741), Klobsinella
aerogenes (MTCC 39) and Chromobacterium violaceum. Among the screened 6b, 6d, 6i, and 6j in which
oxadiazole moiety bearing 4‐fluoroanilinomethyl, 4‐chloroanilinomethyl, 2‐trifluoromethylanilinomethyl,
and 2,5‐difluoroanilinomethyl groups, respectively, showed high activity against all the microorganisms
used. In addition these compounds were also screened for their antifungal activity against four fungal
organisms viz. Candida albicans (ATCC 10231), Aspergillus fumigatus (HIC 6094), Trichophyton
rubrum (IFO 9185), and Trichophyton mentagrophytes (IFO 40996). Most of these new compounds
showed appreciable activity against test fungi, and emerged as potential molecules for further
development.
J. Heterocyclic Chem., 49, 1038 (2012).
INTRODUCTION
3‐(arylaminomethyl)‐5‐(5‐methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐
2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thiones 6a–j in good yields
from 5‐(5‐methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐1,3,4‐oxadiazol‐
2‐ylhydrosulfide 5 (Scheme 1) and their evaluated
in vitro antibacterial and antifungal activity.
Pyrazole and their derivatives could be considered as
possible antimicrobial agents [2]. The other activities in-
clude antidepressant [3], inhibitors of protein kinases [4],
antiaggregating [5], antiarthritic [6], and cerebro‐protectors
[7]. Some aryl pyrazoles [8] were reported to have non-
nucleoside human immunodeficiency virus‐1 reverse
transcriptase inhibitory [9], COX‐2 inhibitory [10], acti-
vator of the nitric oxide receptor and soluble guanylate
cyclase activity [11]. In addition, 1,3,4‐oxadiazole deriv-
ative were reported to possess significant antibacterial
[12] and anti‐inflammatory [13], tyrosinase inhibitory
[14], antiviral [15], antihypertensive [16], cortical mus-
carinic receptor agonists [17], herbicidal [18], Ca2+ chan-
nel blocker [19], antitumour [20], anticonvulsant [21],
antielmintic [22], and antioxidant activities [23]. In view
of these reports and in continuation of our ongoing
research on the synthesis of new heterocyclic compounds
[24,25], it was thought of interest to accommodate
pyrazole, oxadiazole moieties in a single molecular
frame work and to obtain a new class of heterocyclic
compounds with potential biological activity. In this ar-
ticle, we wish to report the synthesis of a new class of
RESULTS AND DISCUSSION
The starting material, (E)‐2‐acetyl‐3‐(dimethylamino)‐2‐
propenoate 2, required for the synthesis of title compounds
was prepared by the condensation of ethylacetaoacetate
1 with N,N‐dimethyldimethoxymethanamine [26], which
on cyclo‐condensation with phenyl hydrazine gave the
ethyl‐5‐methyl‐1‐phenyl‐1H‐4‐pyrazole‐carboxylate 3. The
5‐methyl‐1‐phenyl‐1H‐4‐pyrazole‐carbohydrazide 4 was
obtained in 72% yield via hydrazinolysis of compound 3
with hydrazine hydrate. The hydrazide 4 on reaction with
carbon disulfide and potassium hydroxide, in ethanol,
followed by acidification resulted the 5‐(5‐methyl‐1‐phenyl‐
1H‐4‐pyrazolyl)‐1,3,4‐oxadiazol‐2‐ylhydrosulfide 5 in 70%
yield. The N‐Mannich derivatives, 3‐(arylaminomethyl)‐
5‐(5‐methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐2,3‐dihydro‐1,3,4‐
oxadiazole‐2‐thiones 6a–j, were prepared in excellent
© 2012 HeteroCorporation

September 2012
Synthesis and Antimicrobial Activity of Linked Heterocyclics
Containing Pyrazole and Oxadiazoles
1039
Scheme 1. Reagents and conditions: (i) Me2NCH(OMe)2/EtOH, reflux; (ii) Ph NH NH2, reflux, 80%; (iii) NH2 NH2·H2O/EtOH, reflux, 72%; (iv) CS2,
KOH/EtOH, reflux, 70%; and (v) Ar‐NH2, CH2O/EtOH, stirring, 66–74%.
Antibacterial assay. All the newly prepared compounds
6a–j were screened for their antibacterial activity against
three representative Gram positive bacteria viz. Bacillus
subtilis (MTCC 441), Bacillus sphaericus (MTCC 11)
and Staphylococcus aureus (MTCC 96), and three
Gram negative bacteria viz. Pseudomonas aeruginosa
(MTCC 741), Klobsinella aerogenes (MTCC 39), and
Chromobacterium violaceum (MTCC 2656) by disc
diffusion/tube dilution methods [27,28]. In addition, the
minimum inhibitory concentration (MIC, μg/mL) of all
the compounds were determined by the broth dilution
method [29]. For the antibacterial assay standard
inoculums (1–2 × 107 c.f.u/mL0.5 Mc Farland standards)
were introduced on to the surface of sterile agar plates,
and a sterile glass spreader was used for even distribution
of the inoculum. The discs measuring 6.26 mm in
diameter were prepared from Whatman No. 1 filter paper
and sterilized by dry heat at 140°C for 1 h. The sterile
discs previously soaked in a known concentration of the
test compounds were placed in nutrient agar medium.
The plates were inverted and incubated for 24 h at 37°C.
The inhibition zones were measured and compared with
the standards (Table 1). For the determination of
MIC bacteria were grown over night in Luria Bertani
broth at 37°C, harvested by centrifugation, and then
washed twice with sterile distilled water. Stock solutions
of the series of compounds were prepared in DMSO.
Each stock solution was diluted with standard method
broth (Difco) to prepare serial two‐fold dilutions in the
range of 50–0.8 μg/mL. Ten microliters of the broth
containing about 105 c.f.u/mL of test bacteria were added
to each well of 96‐well microtiter plate. Culture plates
were incubated for 24 h at 37°C, and the growth was
monitored visually and spectrometrically. The lowest
concentration required to arrest the growth of bacteria
yields via the reaction of 5 with formaldehyde solution
and the corresponding aromatic primary amine in ethanol
at room temperature (Scheme 1).
The structures of the newly synthesized compounds
were confirmed by their IR, 1H, 13C‐NMR MS and elemen-
tal analyses. In the IR spectra of compounds 6a–j, the ab-
sorption band corresponding to the NH stretching of
arylamino group was observed at 3326 cm−1 and the ab-
sorption band corresponding to the C N of the oxadiazole
ring was observed at about 1604 cm−1. All other aromatic
and aliphatic C H stretching frequencies were observed at
the expected regions.
In the 1H‐NMR spectra of compounds 6a–j, recorded in
DMSO‐d6, the signal due to methylene bridge protons of
arylaminomethyl group, appeared at 5.47 ppm as a doublet,
the NH proton of arylamino group at 5.10 ppm as a triplet,
the signal corresponding to the CH3 group of pyrazole
appeared at 2.57 ppm as a singlet. The protons of phenyl
group on pyrazole ring and aryl group of arylamino moi-
ety were appeared at 7.00–7.10 and 7.25–7.30 ppm as
multiplet, respectively. The aromatic proton of the pyra-
zole ring at 4‐position appeared at 8.10 ppm as a singlet.
These signals demonstrate the structure of compounds
6a–j.
In the 13C‐NMR spectrum of compounds 6a–j, recorded
in DMSO‐d6, the prominent signals corresponding to the
carbons of pyrazole ring in all compounds observed
nearly at 122.9, 138.7, and 143.2 ppm, similarly the sig-
nals of oxadiazole ring observed nearly at 155.0 and
171.4 ppm, are proof of further evidence of their struc-
tures. Mass spectra of all the synthesized compounds
showed M+/M+1 peaks, in agreement with their molecular
formulae. In summary, all the synthesized compounds
exhibited satisfactory spectral data consistent with their
structures.
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C. S. Reddy, L. S. Rao, M. V. Devi, and A. Nagaraj
Vol 49
Table 1
Antibacterial activity of compounds 6a–j.
Diameter of growth inhibition zone (mm at 100 μg/mL) and minimum inhibitory concentration
Compound
B. subtilis
B. sphaericus
S. aureus
P. aeruginosa
K. aerogenes
C. violaceum
6a
6b
6c
6d
6e
6f
6g
6h
14 (12.5)a
23 (6.25)
14 (25.0)
27 (6.25)
16 (12.5)
18 (12.5)
19 (12.5)
20 (12.5)
25 (3.12)
24 (3.12)
30 (6.25)
25 (1.56)
14 (25.0)a
30 (3.12)
14 (12.5)
25 (6.25)
13 (12.5)
15 (12.5)
10 (25.0)
11 (25.0)
30 (3.12)
30 (6.25)
30 (6.25)
28 (3.12)
18 (12.5)a
35 (3.12)
20 (12.5)
38 (6.25)
19 (6.25)
21 (12.5)
21 (6.25)
20 (6.25)
38 (3.12)
40 (3.12)
41 (6.25)
40 (1.56)
16 (12.5)a
25 (3.12)
10 (25.0)
25 (1.56)
11 (25.0)
12 (25.0)
14 (12.5)
16 (12.5)
26 (1.56)
20 (1.56)
15 (6.25)
25 (1.56)
14 (12.5)a
25 (6.25)
18 (12.5)
25 (3.12)
10 (25.0)
11 (25.0)
13 (12.5)
15 (12.5)
25 (1.56)
25 (3.12)
25 (1.56)
30 (6.25)
10 (25.0)a
20 (6.25)
10 (25.0)
25 (3.12)
11 (25.0)
12 (25.0)
10 (25.0)
14 (25.0)
22 (3.12)
25 (6.25)
20 (3.12)
25 (12.5)
6i
6j
Streptomycin
Penicillin
aValues in the parentheses indicate the minimum inhibitory concentration (MIC, μg/mL).
was regarded as MIC (μg/mL), and were determined. The
antibacterial activity of each compound was compared
with the standard drugs streptomycin and penicillin. The
inhibition zone data and the MIC values of the
compounds screened are presented in Table 1.
The antibacterial screening data showed that almost all the
compounds 6a–j are active and showing moderate to good
antibacterial activity, among the screened 6b, 6d, 6i, and 6j
in which oxadiazole moiety bearing 4‐fluoro‐anilinomethyl,
4‐chloroanilinomethyl, 2‐trifluoromethyl‐anilinomethyl, and
2,5‐difluoroanilinomethyl groups, respectively showed high
activity against all the microorganisms used. The activities
of these compounds are almost equal to the standards.
The remaining compounds showed moderate to good
antibacterial activity.
Antifungal assay. The newly prepared compounds 6a–j
were also screened for their antifungal activity against
four fungal organisms viz. Candida albicans (ATCC
10231), Aspergillus fumigatus (HIC 6094), Trichophyton
rubrum (IFO 9185) and Trichophyton mentagrophytes
(IFO 40996) in DMSO by agar diffusion method [30].
In addition, the MIC values are also determined by broth
dilution method [29]. For the antifungal assay
Sabourands agar media was prepared by dissolving
peptone (1 g), D‐glucose (4 g) and agar (2 g) in distilled
water (100 mL) and adjusting the pH to 5.7. Normal
saline was used to make a suspension of spore of fungal
strain for lawning. A loopful of particular fungal strain
was transferred to 3 mL saline to get a suspension of
corresponding species. Twenty millilitres of agar media
was poured into each petri‐dish, excess of suspension
was decanted and the plates were dried by placing in an
incubator at 37°C for 1 h. Using an agar punch wells
were made and each well was labeled. A control was also
prepared in triplicate and maintained at 37°C for 3–4
days. The C. albicans was grown for 48 h at 28°C in
YPD broth (1% yeast extract, 2% peptone, and 2%
dextrose), harvested by centrifugation and then washed
twice with sterile distilled water. A. fumigatus, T. rubrum,
and T. mentagrophytes were plated in potato dextrose
agar (Difco) and incubated at 28°C for two weeks.
Spores were washed three times with sterile distilled
water and resuspended in distilled water to obtain an
initial inoculums size of 105 spores/mL. Each test
compound was dissolved in DMSO and diluted with
potato dextrose broth (Difco) to prepare serial two‐fold
dilutions in the range 100–0.8 μg/mL. Ten microliters of
the broth containing about 103 (for yeast) and 104 (for
filamentous fungi) cells/mL of test fungi was added to
each well of a 96‐well microtiter plate. Culture plates
were incubated for about 48–72 h at 28°C. The
antifungal activity of each compound was compared with
the standard drug amphotericin B. The zone of fungal
inhibition and MIC values of the compounds screened are
presented in Table 2.
The antifungal screening data showed moderate activity
of the test compounds, among the screened, the com-
pounds 6b, 6d, and 6j in which oxadiazole ring bearing
4‐fluoroanilinomethyl, 4‐chloroanilinomethyl, and 2,5‐di‐
fluoroanilinomethyl moiety, respectively, showed highest
activity against all the microorganisms used. The activity
of these compounds is almost equal to the standard. Com-
pounds 6c and 6i in which the oxadiazole ring containing
2‐chloroanilinomethyl and 2‐trifluoro‐anilinomethyl moiety
showed good inhibition towards C. albicans at the concentra-
tion of 3.12 μg/mL, which is less than amphotericin B
standard. Further, comparison of the antifungal activity
(diameter of growth inhibition zone) of the selected
compounds 6 and standard drug against different fungi is
presented in Figure 1.
Journal of Heterocyclic Chemistry
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September 2012
Synthesis and Antimicrobial Activity of Linked Heterocyclics
Containing Pyrazole and Oxadiazoles
1041
Table 2
Antifungal activity of compounds 6a–j.
Diameter of growth inhibition zone (mm at 100 μg/mL) and minimum inhibitory concentration
Compound
C. albicans
A. fumigatus
T. rubrum
T. mentagrophytes
6a
6b
6c
6d
6e
6f
6g
6h
15 (12.5)a
26 (6.25)
22 (3.12)
25 (6.25)
12 (12.5)
10 (25.0)
12 (25.0)
16 (25.0)
25 (3.12)
26 (6.25)
25 (6.25)
9 (25.0)a
21 (3.12)
10 (25.0)
20 (3.12)
16 (12.5)
12 (12.5)
10 (25.0)
6 (50.0)
15 (12.5)a
20 (6.25)
12 (25.0)
20 (3.12)
10 (25.0)
9 (50.0)
18 (6.25)
12 (12.5)
11 (12.5)
22 (3.12)
20 (3.12)
9 (25.0)a
20 (3.12)
9 (50.0)
20 (3.12)
10 (50.0)
9 (50.0)
12 (12.5)
14 (12.5)
12 (25.0)
19 (6.25)
18 (3.12)
6i
6j
10 (12.5)
20 (6.25)
20 (3.12)
Amphotericin B
aValues in the parentheses indicated the minimum inhibitory concentration (MIC, μg/mL).
5‐Methyl‐1‐phenyl‐1H‐4‐pyrazolecarbohydrazide (4).
A
In conclusion, a new series of 3‐(arylaminomethyl)‐5‐(5‐
methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐2,3‐dihydro‐1,3,4‐oxa‐
diazole‐2‐thiones 6a–j has been synthesized and evaluated
for their antibacterial and antifungal activity. Among the
synthesized compounds 6b, 6d, 6i, and 6j showed good
activity against test microorganisms and emerged as po-
tential molecules for further development.
mixture of compound 3 (0.01 mol) and hydrazine hydrate (0.01
mol) in ethanol (25 mL) was refluxed for 4 h. The reaction
mixture was cooled to room temperature and the solid thus
separeated, was filtered, washed with water and recrystallized
from ethanol to afford pure intermediate 4 as white solid; Yield
72%, mp 162–64°C; IR (KBr): ν 3269, 3062, 2933, 1660,
1
1612, 1501 cm−1; H‐NMR (CDCl3): δ 2.61 (s, 3H, CH3), 5.49
(s, 2H, NH2), 7.15–7.25 (m, 5H, ArH), 8.26 (s, 1H, ArH), 8.96
(s, 1H, NH); 13C‐NMR (CDCl3): δ 15.6, 110.7, 124.9, 127.7,
128.3, 138.5, 139.6, 141.0, 165.1; MS: m/z 217 (M++1). Anal.
Calcd. for C11H12N4O: C, 61.10; H, 5.59; N, 25.91. Found: C,
61.06; H, 5.65; N, 25.95.
EXPERIMENTAL
Research chemicals were either purchased from Aldrich or
Fluka and used without further purification in the reactions
or were prepared according to procedures described in the lit-
erature. Column chromatography was performed on silica gel
60 (0.043–0.060 mm), Merck. Melting points were determined
with a Fisher–Johns apparatus and are uncorrected. IR spectra
were recorded on a Perkin–Elmer FTIR 5000 spectrometer,
using KBr pellet. 1H, 13C‐NMR spectra were recorded on a
Varian Gemini spectrometer, operating at 300, 75 MHz,
respectively. Chemical shifts (δ) are reported in parts per mil-
lion downfield from tetramethyl silane. Mass spectra were
obtained on a VG micro mass 7070H spectrometer. Elemental
analyses were performed on a Perkin–Elmer 240 CHN ele-
mental analyzer.
5‐(5‐Methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐1,3,4‐oxadiazol‐2‐yl
hydrosulfide (5). A mixture of compound 4 (0.01 mol), potassium
hydroxide (0.01 mol) and carbon disulfide (0.015 mol), in
ethanol (100 mL) was heated under reflux with stirring for
12 h and the solvent was distilled in vacuo. The residual mass
was poured over crushed ice, neutralized the alkaline solution
with 10% hydrochloric acid. The precipitated crude product
was filtered, washed with water, dried, and crystallized from
ethanol to give compound 5 as white solid; Yield 70%, mp
136–38°C; IR (KBr): ν 3162, 2914, 2845, 1612, 1604, 1504,
1
1343, 1266 cm−1; H‐NMR (DMSO‐d6): δ 2.52 (s, 3H, CH3),
7.15–7.28 (m, 5H, ArH), 8.21 (s, 1H, ArH). 11.61 (s, 1H, NH/SH);
13C‐NMR (DMSO‐d6): δ 13.7, 124.0, 125.1, 127.5, 128.7, 136.7,
Ethyl 5‐methyl‐1‐phenyl‐1H‐4‐pyrazolecarboxylate (3). A
mixture of compound 2 (0.01 mol) and phenyl hydrazine
hydrochloride (0.01 mol) in ethanol (20 mL) was heated under
reflux for 3 h on a water bath. After completion of the reaction,
ethanol was evaporated. The residue was poured in ice‐cold
water, neutralized with sodium bicarbonate and extracted with
ether. The solvent was evaporated under reduced pressure to get
the compound 3 as yellow‐brown liquid; Yield 80%; bp
260–262°C; IR (KBr): ν 3010, 1698, 1630, 1610, 1247 cm−1
;
1H‐NMR (CDCl3): δ 1.10 (t, 3H, CH3), 2.44 (s, 3H, CH3), 4.05
(q, 2H, CH2), 7.15–7.25 (m, 5H, ArH), 7.80 (s, 1H, ArH);
13C‐NMR (CDCl3): δ 14.5, 15.4, 62.0, 111.5, 124.9, 127.5,
128.3, 139.1, 139.9, 141.2, 162.8; MS: m/z 230 (M+). Anal.
Calcd. for C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found: C,
67.76; H, 6.08; N, 12.15.
Figure 1. Comparison of antifungal activity of selected compounds with
amphotericin B (AB).
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C. S. Reddy, L. S. Rao, M. V. Devi, and A. Nagaraj
Vol 49
138.5, 139.7, 157.8, 170.0; MS: m/z 258 (M+). Anal. Calcd. for
C12H10N4OS: C, 55.80; H, 3.90; N, 21.69. Found: C, 55.86; H,
3.82; N, 21.64.
(m, 7H, ArH), 8.11 (s, 1H, ArH); 13C‐NMR (DMSO‐d6):
δ 12.6, 55.4, 109.2119.0, 122.7, 126.4, 128.2, 130.0, 130.8,
136.2, 138.6, 139.7, 143.6, 155.1, 171.5; MS: m/z 442 (M+).
Anal. Calcd. for C19H16BrN5OS: C, 51.59; H, 3.65; N, 15.83.
Found: C, 51.55; H, 3.66; N, 15.78.
5‐(5‐Methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐3‐[(3‐nitroanilino)
methyl]‐2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thione (6f). This compound
was obtained as brown solid; Yield 74%; mp 166–68°C; IR
(KBr): ν 3345, 3031, 2930, 1607, 1520, 1370 cm−1; 1H‐NMR
(DMSO‐d6): δ 2.47 (s, 3H, CH3), 5.10 (t, 1H, NH), 5.46 (d, 2H,
CH2), 7.05 (s, 1H, ArH), 7.20–7.30 (m, 7H, ArH), 7.65 (d, J = 8.3
Hz, 1H, ArH), 8.21 (s, 1H, ArH); 13C‐NMR (DMSO‐d6): δ 12.6,
55.3, 112.2, 116.5, 117.1, 122.8, 126.1, 128.1, 128.9, 130.1, 135.1,
138.7, 139.8, 146.0, 146.5, 155.2, 170.4; MS: m/z 408 (M+). Anal.
Calcd. for C19H16N6O3S: C, 55.87; H, 3.95; N, 20.58. Found: C,
55.84; H, 3.90; N, 20.60.
5‐(5‐Methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐3‐[(4‐nitroanilino)
methyl]‐2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thione (6g). This compound
was obtained as brown solid; Yield 68%; mp 160–62°C; IR (KBr): ν
3334, 3032, 1609, 1540, 1367, 1252 cm−1; 1H‐NMR (DMSO‐d6):
δ 2.56 (s, 3H, CH3), 5.12 (t, 1H, NH), 5.45 (d, 2H, CH2), 7.05
(d, J = 8.7 Hz, 2H, ArH), 7.25–7.30 (m, 5H, ArH), 8.10 (s, 1H,
ArH), 8.20 (s, 1H, ArH); 13C‐NMR (DMSO‐d6): δ 12.4, 56.3,
120.5, 122.8, 124.8, 126.0, 128.2, 130.2, 135.2, 138.0, 138.6,
139.8, 145.1, 155.2, 170.1; MS: m/z 408 (M+). Anal. Calcd. for
C19H16N6O3S: C, 55.87; H, 3.95; N, 20.58. Found: C, 55.84;
H, 3.91; N, 20.54.
3‐(Arylaminomethyl)‐5‐(5‐methyl‐1‐phenyl‐1H‐4‐pyrazol‐
yl)‐2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thione (6a–j). To a solution
of compound 5 (0.01 mol) in ethanol (25 mL), appropriate
primary aromatic amine (0.01 mol) and 40% formaldehyde
solution (20 mL) were added and the mixture was stirred at
room temperature for 4 h and allowed to stand overnight.
The precipitate separated was filtered, washed with cold
ethanol, dried and crystallized from ethanol to afford pure
compounds.
3‐(Anilinomethyl)‐5‐(5‐methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐
2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thione (6a). This compound
was obtained as yellow solid; Yield 70%; mp 127–29°C; IR
(KBr): ν 3336, 3034, 2909, 2849, 1604, 1457, 1370, 1258
1
cm−1; H‐NMR (DMSO‐d6): δ 2.57 (s, 3H, CH3), 5.10 (t, 1H,
NH), 5.47 (d, 2H, CH2), 7.00–7.10 (m, 5H, ArH), 7.25–7.30
(m, 5H, ArH), 8.12 (s, 1H, ArH); 13C‐NMR (DMSO‐d6): δ
12.7, 56.4, 120.7, 121.0, 122.9, 126.3, 127.9, 128.0, 129.5,
136.1, 138.7, 139.8, 143.2, 155.0, 171.2; MS: m/z 363 (M+).
Anal. Calcd. for C19H17N5OS: C, 62.79; H, 4.71; N, 19.27.
Found: C, 62.73; H, 4.71; N, 19.23.
3‐[(4‐Fluoroanilino)methyl]‐5‐(5‐methyl‐1‐phenyl‐1H‐4‐
pyrazolyl)‐2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thione (6b). This
compound was obtained as yellow solid; Yield 67%; mp
122–24°C; IR (KBr): ν 3351, 3039, 1609, 1370, 1254 cm−1
;
1H‐NMR (DMSO‐d6): δ 2.56 (s, 3H, CH3), 5.10 (t, 1H, NH),
5.46 (d, 2H, CH2), 6.72 (d, J = 8.8 Hz, 2H, ArH), 7.25–7.30
(m, 7H, ArH), 8.12 (s, 1H, ArH); 13C‐NMR (DMSO‐d6): δ
12.4, 54.5, 119.2, 120.5, 122.9, 126.0, 128.2, 129.0, 135.2,
138.7, 139.8, 140.1, 141.6, 155.0, 171.0; MS: m/z 381 (M+).
Anal. Calcd. for C19H16FN5OS: C, 59.83; H, 4.23; N, 18.36.
Found: C, 59.80; H, 4.20; N, 18.29.
3‐[(4‐Methoxyanilino)methyl]‐5‐(5‐methyl‐1‐phenyl‐1H‐4‐
pyrazolyl)‐2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thione (6h). This
compound was obtained as yellow solid; Yield 66%; mp 140–42°C;
IR (KBr): ν 3320, 3026, 1609, 1370, 1072 cm−1 1H‐NMR
;
(DMSO‐d6): δ 2.55 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 5.10
(t, 1H, NH), 5.44 (d, 2H, CH2), 6.60–6.70 (m, 4H, ArH),
7.25–7.30 (m, 5H, ArH), 8.15 (s, 1H, ArH), 8.10 (s, 1H, ArH),
8.20 (s, 1H, ArH); 13C‐NMR (DMSO‐d6): δ 12.5, 54.7, 56.0,
115.4, 121.8, 122.8, 126.4, 128.1, 129.4, 136.2, 138.0, 138.7,
139.7, 153.1, 155.0, 170.7; MS: m/z 393 (M+). Anal. Calcd. for
C20H19N5O2S: C, 61.05; H, 4.87; N, 17.80. Found: C, 61.01;
H, 4.83; N, 17.76.
3‐[(2‐Chloroanilino)methyl]‐5‐(5‐methyl‐1‐phenyl‐1H‐4‐
pyrazolyl)‐2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thione (6c). This
compound was obtained as yellow solid; Yield 71%; mp
136–38°C; IR (KBr): ν 3342, 3042, 1610, 1370, 685 cm−1
;
1H‐NMR (DMSO‐d6): δ 2.56 (s, 3H, CH3), 5.15 (t, 1H, NH),
5.90 (d, 2H, CH2), 6.60–6.70 (m, 2H, ArH), 7.25–7.30 (m,
7H, ArH), 8.12 (s, 1H, ArH); 13C‐NMR (DMSO‐d6): δ 12.3,
54.5, 115.4, 119.6, 122.0, 122.8, 126.1, 127.6, 128.1, 128.7,
129.3, 135.1, 138.6, 138.9, 139.8, 155.0, 171.0; MS: m/z 398
(M+). Anal. Calcd. for C19H16ClN5OS: C, 57.36; H, 4.05; N,
17.60. Found: C, 57.31; H, 4.06; N, 17.55.
5‐(5‐Methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐3‐[2‐(trifluoromethyl)
anilino]methyl‐2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thione (6i).
This compound was obtained as brown solid; Yield 67%; mp
152–54°C; IR (KBr): ν 3325, 3025, 2910, 1604, 1367 cm−1
;
1H‐NMR (DMSO‐d6): δ 2.54 (s, 3H, CH3), 5.11 (t, 1H, NH),
5.42 (d, 2H, CH2), 6.60 (m, 1H, ArH), 7.20–7.30 (m, 8H,
ArH), 8.12 (s, 1H, ArH); 13C‐NMR (DMSO‐d6): δ 12.6,
55.7, 116.9, 120.1, 120.9, 122.8, 124.9, 126.3, 128.1, 129.4,
129.8, 132.4, 136.2, 138.7, 139.6, 143.3, 155.1, 170.1; MS:
m/z 432 (M+). Anal. Calcd. for C20H16F3N5OS: C, 55.68; H,
3.74; N, 16.23. Found: C, 55.66; H, 3.72; N, 16.21.
3‐[(4‐Chloroanilino)methyl]‐5‐(5‐methyl‐1‐phenyl‐1H‐4‐
pyrazolyl)‐2,3‐dihydro‐1,3, 4‐oxadiazole‐2‐thione (6d). This
compound was obtained as white solid; Yield 66%; mp 141–43°C;
IR (KBr): ν 3337, 3041, 2927, 1605, 686 cm−1; 1H‐NMR (DMSO‐d6):
δ 2.54 (s, 3H, CH3), 5.10 (t, 1H, NH), 5.46 (d, 2H, CH2), 6.70
(d, J = 8.6 Hz, 2H, ArH), 7.20–7.30 (m, 7H, ArH), 8.14 (s, 1H, ArH);
13C‐NMR (DMSO‐d6): δ 12.7, 54.5, 120.8, 122.8, 123.4, 126.2, 128.0,
128.7, 129.4, 135.2, 138.7, 139.7, 143.7, 155.0, 170.2; MS: m/z 398
(M+). Anal. Calcd. for C19H16ClN5OS: C, 57.36; H, 4.05; N, 17.60.
Found: C, 57.35; H, 4.01; N, 17.56.
3‐[(2,5‐Difluoroanilino)methyl]‐5‐(5‐methyl‐1‐phenyl‐1H‐
4‐pyrazolyl)‐2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thione (6j). This
compound was obtained as yellow solid; Yield 70%; mp
141–43°C; IR (KBr): ν 3328, 3021, 2930, 1611, 1362 cm−1
;
1H‐NMR (DMSO‐d6): δ 2.56 (s, 3H, CH3), 5.10 (t, 1H, NH),
5.44 (d, 2H, CH2), 6.27 (s, 1H, ArH), 6.90–7.00 (m, 2H, ArH),
7.25–7.30 (m, 5H, ArH), 8.14 (s, 1H, ArH); 13C‐NMR (DMSO‐d6):
δ 12.6, 55.8, 104.6, 111.6, 117.8, 122.8, 126.3, 127.6, 128.1, 129.5,
136.2, 138.7, 139.5, 155.0, 168.2, 169.2; MS: m/z 339 (M+). Anal.
Calcd. for C19H15F2N5OS: C, 57.14; H, 3.79; N, 17.53. Found: C,
57.10; H, 3.73; N, 17.50.
3‐[(4‐Bromoanilino)methyl]‐5‐(5‐methyl‐1‐phenyl‐1H‐4‐
pyrazolyl)‐2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thione (6e). This
compound was obtained as brown solid; Yield 70%; mp
154–56°C; IR (KBr): ν 3347, 3032, 2931, 1606, 582 cm−1
;
1H‐NMR (DMSO‐d6): δ 2.50 (s, 3H, CH3), 5.11 (t, 1H, NH),
5.48 (d, 2H, CH2), 6.71 (d, J = 8.4 Hz, 2H, ArH), 7.20–7.30
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Synthesis and Antimicrobial Activity of Linked Heterocyclics
Containing Pyrazole and Oxadiazoles
1043
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Acknowledgments. The authors are grateful to the Director,
Indian Institute of Chemical Technology, Hyderabad, India, for
providing NMR and Mass spectral data. Financial assistance
from the UGC SAP (Phase‐I)‐DRS Programme, New Delhi,
India, is greatly acknowledged.
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