Synthesis of Isoxazole, 1, 2, 4-Oxadiazole and (1H-Pyrazol-4-yl)-methanone Oxime Derivatives from N-Hydroxy-1H-pyrazole-4-carbimidoyl Chloride and their Biological Activity

Article abstract of DOI:10.1002/jhet.2309

Some novel isoxazole-, 1,2,4 oxadiazole-, and (1H-pyrazol-4-yl)-methanone oxime derivatives were synthesized from N-hydroxy-1H-pyrazole-4-carbimidoyl chloride and the structures of all products were identified by spectral data (¹H-NMR, ^13<

Full text of DOI:10.1002/jhet.2309

754
Synthesis of Isoxazole, 1, 2, 4-Oxadiazole and (1H-Pyrazol-4-yl)-
methanone Oxime Derivatives from N-Hydroxy-1H-pyrazole-4-
carbimidoyl Chloride and their Biological Activity
Vol 53
a
b
b
a
*
Bhavanarushi Sangepu, Bharath Gandu, Gangagnirao Anupoju, and Vatsalarani Jetti
aFluoroorganic Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500607, India
bBioengineering and Environmental Sciences, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad,
500607, India
*
E-mail: vatsala@iict.res.in
Received April 7, 2014
DOI 10.1002/jhet.2309
Published online 27 May 2015 in Wiley Online Library (wileyonlinelibrary.com).
Some novel isoxazole-, 1,2,4 oxadiazole-, and (1H-pyrazol-4-yl)-methanone oxime derivatives were syn-
thesized from N-hydroxy-1H-pyrazole-4-carbimidoyl chloride and the structures of all products were identi-
fied by spectral data (1H-NMR, 13C-NMR, IR, MS, and HRMS) and evaluated their antibacterial activity.
J. Heterocyclic Chem., 53, 754 (2016).
INTRODUCTION
ulcerative colitis, inflammatory bowel syndrome [17],
atherosclerosis [18], and Alzheimer’s disease [19].
Heterocyclic rings and, in particular, the pyrazole ring,
represent an expedient choice for the synthesis of phar-
maceutical compounds with different activities and noble
safety profiles [20]. In continuation of our research work
on synthesis of trifluoromethyl substituted pyrazole de-
rived heterocycles [21,22] and due to the wide applica-
tions of pyrazole derivatives in medicinal chemistry, we
wish to synthesize various heterocyclic compounds con-
taining pyrazole as a core moiety and screening of their
antibacterial activity.
Heterocyclic compounds with pyrazole moiety were
found to be valuable intermediates for medicinal drugs
[1]. They have wide-ranging collection of conventional
biological and pharmaceutical activities, such as antitu-
mor [2,3], anti-inflammatory, analgesic, antipyretic [4],
antiviral [5], antimicrobial [6,7], anti-ischemic effects
[8], sodium channel blocker [9], hypoglycaemic
[10,11], anti-hypertensive [12], antiangiogenic [13], anti-
oxidant [14], antidepressant, anxiolytic, neuroprotective
[15], and antidiabetic [16] activity. Pyrazole nucleus
containing drugs are widely used in the treatment of
© 2015 HeteroCorporation

May 2016
Synthesis of Isoxazole, 1, 2, 4-Oxadiazole and (1H-Pyrazol-4-yl)-methanone Oxime Derivatives
from N-Hydroxy-1H-pyrazole-4-carbimidoyl Chloride and their Biological Activity
755
RESULTS AND DISCUSSION
compounds such as isoxazoles [25], oxadiazoles [26],
benzimidazoles, benzothiazoles, and benzoxazoles [27].
By using this chloro oxime derivatives 6a–d, we synthe-
sized novel isoxazoles (7a–m and 9a–b) and oxadiazoles
(8a–d) as shown in Scheme 2. The compounds (1H-
pyrazol-4-yl)-isoxazole 7a–m were obtained by cyclization
of N-hydroxy-1H-pyrazole-4-carbimidoyl chloride 6a–d
with alkynes in the presence of Et3N by using benzene as
a solvent. The compounds 7a–m along with their yields
is given in Table 1. The structures of compounds 7a–m
were confirmed by their spectroscopic data (1H-NMR,
13C-NMR, and MS) and data provided in the experimental
We synthesized the compounds 6a–d by known
procedure [23,24], which involves the reaction of ethyl-
trifluoroacetoacetate 1 with hydrazine hydrochlorides 2a–d,
in ethanol yielded the corresponding 3-(trifluoromethyl)-
1H-pyrazol-5-ol 3a–d. Treatment of 1H-pyrazol-5-ol 3a–d,
with POCl3 in dimethylformamide (DMF) led to the
formation of corresponding 5-chloro-1-aryl-3-(trifluoro-
methyl)-1H-pyrazol-4-carbaldehyde 4a–d. The reaction of
4-formylpyrazole 4a–d with hydroxylamine hydrochloride
in EtOH gave the corresponding pyrazole oximes 5a–d in
good yield, which on reaction with NCS in DMF affords
N-hydroxy-1H-pyrazole-4-carbimidoyl chloride 6a–d as
shown in Scheme 1.
1
section. The H-NMR of compound 7b showed a singlet
signal at δ = 3.87 corresponding to methoxy protons, singlet
at δ = 6.70 corresponding to –CH proton, the two doublets
at δ = 7.01 and 7.80 corresponding to p-methoxy phenyl
ring protons attached to isoxazole ring and multiplet at
In medicinal chemistry, chloro oxime derivatives consti-
tute a class of compounds that have served as useful inter-
mediates towards construction of various heterocyclic
Scheme 1. Preparations of compounds 6a–d.
Scheme 2. Preparation of compounds 7a–m, 8a–d, and 9a–b.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

756
B. Sangepu, B. Gandu, G. Anupoju, and V. Jetti
Vol 53
Table 1
Compounds 7a–m along their yields.
Entry
R
R1
R2
Product
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
C6H5
H
H
H
H
H
C6H5
CO2Et
H
H
H
H
H
7a
7b
7c
7d
7e
5
5
5
5
5
5
5
5
5
5
5
5
5
80
78
77
76
73
48
67
70
67
61
69
65
62
4-OCH3C6H4
4-NO2C6H4
4-BrC6H4
4-FC6H4
C6H5
CO2Et
C6H5
4-OCH3C6H4
4-NO2C6H4
4-FC6H4
C6H5
7f
7 g
7 h
7i
7j
7 k
7 l
9
10
11
12
13
4-OCH3C6H4
4-OCH3C6H4
4-NO2C6H4
H
7 m
aIsolated yield
Scheme 3. Synthesis of (1H-pyrazol-4yl)methanone oximes 10a–g.
δ = 7.52–7.63 corresponding to phenyl group protons at-
tached to pyrazole moiety. It was also confirmed by high-
resolution mass spectrometry (HRMS) data which shows
peak for C20H14O2N3ClF3 (M + H+) at 420.0702. The com-
pounds (1H-pyrazol-4-yl)-oxadiazole 8a–d were obtained
by cyclization of N-hydroxy-1H-pyrazole-4-carbimidoyl
chloride 6a and 6c with aromatic nitriles in the presence
of Et3N using benzene as a solvent. The structures of com-
pounds 8a–d were confirmed by their spectroscopic data
(1H-NMR, 13C-NMR, and MS) and data provided in the ex-
1
perimental section. The H-NMR of compound 8a shows
Table 2
two multiplets at δ = 7.54–7.64 and 8.20–8.23 correspond-
ing to two phenyl group protons attached to pyrazole and
oxadiazol rings, and it was also confirmed by HRMS data
which shows peak for C18H11ON4ClF3 (M + H+) at
391.0571. On the other hand, when N-hydroxy-1H-
pyrazole-4-carbimidoyl chloride 6a was reacted with
malononitrile and cyanoacetamide afford isoxazole deriva-
tives 9a and b in moderate yield (63–68%). The structures
of compounds 9a and b were confirmed by their spectro-
scopic data (1H-NMR, 13C-NMR, and MS) and data pro-
vided in the experimental section. The 1H-NMR of
compound 9a shows multiplet at δ = 7.44–7.63 correspond-
ing to phenyl group protons attached to pyrazole ring, and
broad singlet at δ = 8.00 corresponding to NH2 protons.
The infrared spectrum of compound 9a shows characteristic
Compounds 10a–g along their yields.
Time
(min)
Yielda
(%)
Entry
R
Y
Product
1
2
3
4
5
6
7
C6H5
C6H5
CH2
O
10a
10b
15
15
15
15
15
15
15
59
70
65
67
62
64
69
C6H5
CH-CH2-C6H5 10c
C6H5
N-C6H5
CH2
CH-CH2-C6H5 10f
N-C6H5 10 g
10d
10e
4-ClC6H4
4-ClC6H4
4-ClC6H4
aIsolated yield
The structures of compounds 10a–g were confirmed by their
spectroscopic data (1H-NMR, 13C-NMR, and MS) and data
provided in the experimental section. The 1H-NMR
spectrum of compound 10e shows two multiplets at
δ = 1.42–1.68 and 2.97–3.21, corresponding to piperidine
ring, protons one broad singlet at δ = 7.20 corresponding
to oxime proton, and protons one multiplet at δ = 7.38–7.62
corresponding to 4-chlrophenyl group protons attached to
pyrazole ring. The IR spectrum of compound 10e shows
characteristic absorption bands at 3285 cmꢀ1 (N–OH),
1624 cmꢀ1 (C¼N), and it was also confirmed by HRMS data
which shows peak for C16H16ON4Cl2F3 (M + H+) at
407.0631.
absorptions corresponding to NH2 (3367 and 3211 cmꢀ1
)
and CN (2234 cmꢀ1) groups, and it was also confirmed by
HRMS data which shows peak for C14H8ON5ClF3
(M + H+) at 354.0363.
We also synthesized (1H-pyrazol-4-yl)methanone ox-
imes from chloro oxime (6a and c), which were reacted
with cyclic secondary amines such as morpholine, piperi-
dine, 4-phenylpiperazin, 4-benzylpiperdine, to obtain the
corresponding (1H-pyrazol-4-yl)methanone oximes 10a–g
as shown in Scheme 3 and the results are shown in Table 2.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2016
Synthesis of Isoxazole, 1, 2, 4-Oxadiazole and (1H-Pyrazol-4-yl)-methanone Oxime Derivatives
from N-Hydroxy-1H-pyrazole-4-carbimidoyl Chloride and their Biological Activity
757
Table 3
Antibacterial activity of newly synthesized compounds.
Zone of inhibition (mm)
Gram-negative (ꢀve) bacteria
Gram positive (+ve) bacteria
Escherichia
coli
Klebsiella
pneumonia
Pseudomonas
aeruginosa
Bacillus
licheniformis
Bacillus
subtilis
Staphylococcus
aureus
Organic compound
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
7m
8a
8b
8c
8d
9a
9b
10a
10b
10c
10d
10e
10f
10g
—
—
—
20
—
—
—
—
—
—
—
—
—
26
—
—
—
—
19
—
—
—
—
—
—
—
—
—
24
—
—
—
—
21
—
—
—
—
—
—
—
—
—
25
—
—
—
—
19
—
—
—
—
—
—
—
—
—
24
—
—
—
—
19
—
—
—
—
—
—
—
—
—
23
—
—
—
—
19
—
—
—
—
—
—
—
—
21
25
—
Cloxacillin
Ciprofloxacin
Control (1% DMSO)
—, no activity.
Antibacterial evaluation.
The 26 newly synthesized
oxime derivatives from N-hydroxy-1H-pyrazole-4-carbimidoyl
target compounds were evaluated for their antibacterial
activity against three Gram-negative bacteria such as
Escherichia coli, Klebsiella pneumonia, Pseudomonas
aeruginosa, and three gram positive bacteria like Bacillus
licheniformis, Bacillus subtilis, and Staphylococcus aureus.
Agar diffusion method was used for the determination of
the preliminary antibacterial activity. Ciprofloxacin and
cloxicilin were used as reference drugs. The results were
recorded for each tested compound diameter of inhibition
zones of microbial growth around the disks in mm. The
inhibition zone diameters values are revealed in Table 3.
The compound 9a shows good activities against (inhibitory
zone ≥ 20mm) bacterial strains.
chlorides and evaluated for their antibacterial activity.
EXPERIMENTAL
General. Melting points were determined on a Casiae-Siamia
(VMP-AM) melting point apparatus and are uncorrected. IR spectra
were recorded on a Perkin-Elmer FTIR 240-C spectrophotometer
1
using KBr optics. H-NMR and 13C-NMR spectra were recorded
on Bruker AV 300 MHz in CDCl3 (or DMSO-d6) using
tetramethylsilane (TMS) as an internal standard. Chemical shifts
are given in δ ppm and coupling constants (J) are given in Hz.
Electron Spray ionization (ESI) and high-resolution mass spectra
were recorded on a QSTARXL hybrid MS/MS system (Applied
Bio systems, USA) under electrospray ionization. Thin-layer
chromatography was performed on pre-coated silica gel 60 F254
(mesh); spots were visualized with ultraviolet light.
CONCLUSION
Preparation of 5-pyrazolones 3a–d. The compounds 3a–d
was prepared using reported procedure [28] with minor
modifications. To a stirred solution of hydrazine hydrochloride
(0.1 mol) and absolute ethanol (10 mL), the solution of
ethyltrifluoroacetoacetate (0.1 mol) with absolute ethanol
In conclusion, we have described synthesis of novel
trifluoromethyl substituted pyrazole derived heterocycles such
as isoxazoles, oxadiazoles, and (1H-pyrazol-4-yl)-methanone
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

758
B. Sangepu, B. Gandu, G. Anupoju, and V. Jetti
Vol 53
2
(10 mL) was added at 25–30°C, and the mixture was refluxed for
8 h. Then cooled to room temperature, adjusted the pH value of
mixture to 7 using 10% NaOH solution, added 20 mL water,
and stirred for 1 h at room temperature. The precipitated solid
was filtered and washed with cold water to get a solid.
136.81, 140.74 (q, J = 38.14 Hz, CF3), 148.56, 153.54, 167.91;
MS (ESI), m/z: 435 (M + H+); HRMS m/z calcd for
C19H11O3N4ClF3 (M + H+), 435.0466; found, 435.0461.
5-(4-Bromophenyl)-3-(5-chloro-1-phenyl-3-(trifluoromethyl)-
1H-pyrazol-4-yl)isoxazole (7d).
White solid; yield: 0.35 g
Preparation of 5-chloro-4-formylpyrazoles 4a–d.
The
(76%); mp 139–141°C; 1H-NMR (CDCl3, 300 MHz): 6.83
(s, 1H, CH), 7.54–7.62 (m, 5H), 7.65 (d, J = 8.55 Hz, 2H), 7.73
(d, J = 8.55 Hz, 2H); 13C-NMR (CDCl3, 75 MHz): δ 100.02,
known 5-chloro-4-formylpyrazoles were prepared from the 5-
pyrazolones employing Vilsmeier-Haack chloro formylation
[29]. Thus, 5-pyrazolones were heated with an excess
phosphorus oxychloride in DMF to afford the corresponding 5-
chloro-4-formyl pyrazoles 4a–d.
Preparation of pyrazole oximes 5a–d. The treatment of 4-
formyl pyrazole 4a–d (1.0 mmol) with hydroxyl amine
hydrochloride (1.5 mmol) in EtOH (5 mL) reflux for 5 hours
gave the corresponding pyrazole oximes 5a–d in good yield.
All pyrazole oximes purified by a column with silica gel using
petroleum ether/ethyl acetate (8.5:1.5 v/v) mixture to obtain pure
products of 5a–d.
1
108.04, 120.46 (q, J = 269.74 Hz, CF3), 124.95, 125.52, 125.81,
127.34, 129.38, 129.46, 129.83, 132.35, 136.99, 140.85
(q, 2J = 39.05 Hz, CF3), 153.32, 169.49; MS (ESI), m/z: 470
(M + H+); HRMS m/z calcd for C19H11BrClF3N3O (M + H+),
467.9721; found, 467.9716.
3-(5-Chloro-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5-
(4-fluorophenyl)isoxazole (7e).
Light brown solid; yield:
0.30 g (73%); mp 119–121°C; 1H-NMR (CDCl3, 300 MHz):
6.78 (s, 1H, CH), 7.20 (t, J = 8.69 Hz, 2H), 7.52–7.63 (m, 5H),
7.82–7.89 (m, 2H); 13C-NMR (CDCl3, 75 MHz): δ 99.45,
2
1
Preparation of N-hydroxy-1H-pyrazole-4-carbimidoyl chloride
108.13, 116.30 (d, J= 22.70 Hz, Ar-F), 120.47 (q, J= 270.65 Hz,
CF3), 123.31 (d, 4J= 2.72 Hz, Ar-F), 125.51, 128.02
(d, 3J= 8.17 Hz, Ar-F), 129.36, 129.43, 129.80, 137.00, 140.84
(q, J = 38.14 Hz, CF3), 153.26, 163.92 (d, J= 251.58 Hz, Ar-F),
169.59; MS (ESI), m/z: 408 (M+ H+); HRMS m/z calcd for
C19H11ON3ClF4 408.0521; found, 408.0509.
6a–d.
The reaction of pyrazole oxime 5a–d (1.0 mmol) with
NCS (1.5mmol) in DMF (2 mL) at 40°C for 2 h gave the
corresponding N-hydroxy-1H-pyrazole-4-carbimidoyl chlorides
6a–d.
2
1
General procedure for the synthesis of compounds 7a–m or
8a–d.
The alkyne or nitrile (1.0 mmol) and N-hydroxy-
3-(5-Chloro-1-Phenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-
4,5-diphenyl isoxazole (7f). Cream solid; yield: 0.22 g (48%);
mp 109–111°C; 1H-NMR (CDCl3, 300 MHz): δ 7.19–7.25
(m, 2H), 7.30–7.41 (m, 5H), 7.43–7.58 (m, 6H), 7.60–7.65
(m, 2H); 13C-NMR (CDCl3, 75 MHz): δ 99.40, 108.97, 120.10
(q, 1 J = 270.65 Hz, CF3), 125.20, 126.92, 128.32, 128.73,
128.87, 129.25, 129.60, 129.69, 130.14, 136.47, 136.95,
pyrazole-carboximidoyl chloride (1.0 mmol) were dissolved in
benzene (5 mL). A solution of triethylamine (1.0 mmol) in
benzene (2 mL) was added dropwise to the aforementioned
mixture and refluxed for 5 h. Then the triethylamine
hydrochloride was filtered off, the solvent removed in vacuo,
and the residue purified by a column with silica gel using
petroleum ether/ethyl acetate (9.5:0.5 v/v) mixture to obtain pure
products of 7a–m or 8a–d.
2
139.40 (q, J = 39.05 Hz, CF3), 153.57, 169.66; MS (ESI), m/z:
466 (M + H+); HRMS m/z calcd for C25H16ON3ClF3 (M + H+),
466.0928; found, 466.0923.
3-(5-Chloro-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5-
phenyl isoxazole (7a). Cream solid; yield: 0.31 g (80%); mp
142–144°C; H-NMR (CDCl3, 300 MHz): δ 6.34 (d, J = 7.93Hz,
Diethyl-3-(5-chloro-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-
1
4-yl)isoxazole-4,5-dicarboxylate (7g).
Brown liquid; yield:
1H), 6.84 (s, 1H, CH), 6.98 (t, J = 7.18 Hz, 1H), 7.07
(d, J = 8.31 Hz, 2H), 7.39 (t, J = 6.99Hz, 2H), 7.52–7.65 (m, 3H),
8.05 (d, J = 7.74 Hz, 1H); 13C-NMR (CDCl3, 75MHz): δ 99.65,
0.30g (67%); 1H-NMR (CDCl3, 300 MHz): δ 1.25 (t, J = 7.17Hz,
3H), 1.46 (t, J = 7.17Hz, 3H), 4.30 (q, J = 7.17 Hz, 2H), 4.52
(q, J = 7.17 Hz, 2H), 7.53–7.58 (m, 3H), 7.60 (d, J = 7.47Hz, 2H);
13C-NMR (CDCl3, 75 MHz): δ 13.71 (CH3), 13.93 (CH3), 61.99
(CH2), 63.25 (CH2), 106.07, 115.68, 120.08 (q, 1J = 270.65Hz,
CF3), 125.26, 129.36, 129.81, 130.06, 136.86, 141.76
(q, 2J = 39.05 Hz, CF3), 152.72, 156.00, 159.19 (C¼O), 161.69
(C¼O); IR (KBr, cmꢀ1): 2984, 2933 (CH), 1737 (CO), 1595
(C¼N), 1182, 1143 (C-F); MS (ESI), m/z: 458 (M+ H+); HRMS
m/z calcd for C19H16O5N3ClF3 (M+ H+), 458.0725; found,
458.0700.
1
108.25, 120.47 (q, J = 270.65 Hz, CF3), 125.52, 125.89, 126.90,
129.04, 129.36, 129.41, 129.78, 130.52, 137.00, 140.85
(q, 2J = 38.14 Hz, CF3), 153.16, 170.56; MS (ESI), m/z: 390
(M+ H+); HRMS m/z calcd for C19H12ON3ClF3 (M+ H+),
390.0615; found, 390.0610.
3-(5-Chloro-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5-
(4-methoxyphenyl)isoxazole (7b).
Light brown solid; yield:
0.32 g (78%); mp 143–145°C; 1H-NMR (CDCl3, 300 MHz):
3.87 (s, 3H, OCH3), 6.70 (s, 1H, CH), 7.01 (d, J = 8.69 Hz, 2H),
7.52–7.63 (m, 5H), 7.80 (d, J = 8.69 Hz, 2H); 13C-NMR
(CDCl3, 75 MHz): δ 55.38 (OCH3), 98.31, 114.44, 120.50
(q, 1J = 270.65 Hz, CF3), 119.75, 125.53, 127.12, 127.52,
3-(5-Chloro-1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-
4-yl)-5-phenylisoxazole (7h).
Light brown solid; yield: 0.28 g
(70%); mp 111–113°C; 1H-NMR (CDCl3, 300 MHz): δ 6.82
(s, 1H, CH), 7.20–7.30 (m, 2H), 7.46–7.54 (m, 3H), 7.56–7.63
(m, 2H), 7.83–7.89 (m, 2H); 13C-NMR (CDCl3, 75MHz): δ 99.60,
2
128.63, 129.34, 129.75, 137.05, 140.86 (q, J = 38.14 Hz, CF3),
153.10, 161.33, 170.54; MS (ESI), m/z: 420 (M + H+); HRMS
m/z calcd for C20H14O2N3ClF3 (M + H+), 420.0721; found,
420.0702.
108.33, 116.45 (d, J= 23.61 Hz, Ar-F), 120.42 (q, J= 270.65 Hz,
CF3), 125.89, 126.86, 127.60 (d, 3J= 9.08 Hz, Ar-F), 129.05,
129.57, 130.56, 133.02, 140.95 (q, 2J= 38.14 Hz, CF3), 153.04,
162.93 (d, 1J = 250.67 Hz, Ar-F), 170.63; MS (ESI), m/z: 408
(M + H+); HRMS m/z calcd for C19H11ON3ClF4 (M + H+),
408.0521; found, 408.0509.
2
1
3-(5-Chloro-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5-
(4-nitro phenyl)isoxazole (7c).
Cream solid; yield: 0.33 g
(77%); mp 172–174°C; 1H-NMR (CDCl3, 300 MHz): 7.01
(s, 1H, CH), 7.27 (t, J = 8.31 Hz, 3H), 7.57–7.63 (m, 2H), 8.04
(d, J = 8.88 Hz, 2H), 8.38 (d, J = 8.69 Hz, 2H); 13C-NMR
3-(5-Chloro-1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-
4-yl)-5-(4-methoxyphenyl) isoxazole (7i).
Light brown solid;
1
(CDCl3, 75 MHz): δ 102.15, 107.54, 120.35 (q, J = 269.74 Hz,
yield: 0.24 g (57%); mp 127–129°C; 1H-NMR (CDCl3, 300MHz):
δ 3.88 (s, 3H, OCH3), 6.69 (s, 1H, CH), 7.01 (d, J=8.55Hz, 2H),
CF3), 124.37, 125.42, 126.68, 129.35, 129.55, 129.85, 132.20,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2016
Synthesis of Isoxazole, 1, 2, 4-Oxadiazole and (1H-Pyrazol-4-yl)-methanone Oxime Derivatives
from N-Hydroxy-1H-pyrazole-4-carbimidoyl Chloride and their Biological Activity
759
7.22–7.28 (m, 2H), 7.56–7.61 (m, 2H), 7.79 (d, J= 8.55 Hz, 2H);
13C-NMR (CDCl3, 75MHz): δ 55.37, 98.26, 108.48, 114.45,
300 MHz): δ 7.53–7.62 (m, 5H), 7.72 (d, J = 8.55Hz, 2H), 8.08
(d, J = 8.55 Hz, 2H); 13C-NMR (CDCl3, 75 MHz): δ 108.60,
2
1
1
116.41 (d, J= 23.10 Hz, Ar-F), 120.34 (q, J= 271.23 Hz, CF3),
120.54 (q, J = 270.04 Hz, CF3), 122.65, 125.56, 128.12, 129.40,
119.67, 127.58 (d, 3J= 9.90 Hz, Ar-F), 129.50, 133.04, 140.95
129.60, 129.92, 132.57, 136.81, 139.46 (q, J = 39.34 Hz, CF3),
2
2
1
(q, J= 38.51 Hz, CF3), 152.95, 162.94 (d, J=250.88Hz, Ar-F),
161.36, 170.61; MS (ESI), m/z: 438 (M+ H+); HRMS m/z calcd
for C20H13 O2N3ClF4 (M + H+), 438.0626; found, 438.0615.
3-(5-Chloro-1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-
4-yl)-5-(4-nitrophenyl) isoxazole (7j). White solid; yield: 0.26 g
(51%); mp 134–136°C; 1H-NMR (CDCl3, 300 MHz): δ 7.01
(s, 1H), 7.23–7.30 (m, 2H), 7.57–7.64 (m, 2H), 8.04 (d, J=8.88Hz,
2H), 8.38 (d, J=8.69Hz, 2H); 13C-NMR (CDCl3, 75MHz): δ
102.13, 107.72, 116.54 (d, 2J= 23.61 Hz, Ar-F), 120.34
(q, 1J= 270.65 Hz, CF3), 124.48, 126.74, 127.60 (d, 3J=8.17Hz,
Ar-F), 129.76, 132.23, 132.93, 140.45 (q, 2J= 39.05 Hz, CF3),
148.69, 153.51, 163.05 (d, 1J= 250.67 Hz, Ar-F), 168.07; MS (ESI),
m/z: 453 (M+H+); HRMS m/z calcd for C19H10ClF4N4O3
(M + H+), 453.0372; found, 453.0368.
143.97, 161.13, 175.10; MS (ESI), m/z: 471 (M+ H+); HRMS m/z
calcd for C18H10BrClF3N4O(M + H+), 468.9673; found, 468.9668.
3-(5-Chloro-1-Phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-
5-(4-fluorophenyl)-1,2,4-oxadiazole (8c). White solid; yield:
1
0.22 g (56%); mp 125–127°C; H-NMR (CDCl3, 300 MHz): δ
7.17 (t, J = 8.69 Hz, 2H), 7.25 (t, J = 8.69 Hz, 1H), 7.53–7.63
(m, 3H), 7.65–7.72 (m, 2H), 8.20–8.27 (m, 1H); 13C-NMR
(CDCl3, 75 MHz): δ 108.37, 116.71 (d, 2J = 22.50 Hz, Ar-F),
117.90, 120.09 (q, 1J = 270.04 Hz, CF3), 125.45, 129.03,
3
129.30, 129.83, 130.62 (d, J = 8.78 Hz, Ar-F), 136.73, 139.41
(q, 2J = 39.42 Hz, CF3), 160.94, 165.01 (d, 1J = 254.67 Hz,
Ar-F), 174.86; MS (ESI), m/z: 431 (M + Na+); HRMS m/z calcd
for C18H10ON4ClF4 (M + H+), 409.0473; found, 409.0467.
3-(5-Chloro-1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-
3-(5-Chloro-1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-
4-yl)-5-(4-fluorophenyl) isoxazole (7k). Light brown solid; yield:
0.21 g (52%); mp 119–121°C; 1H-NMR (CDCl3, 300 MHz): δ 6.76
(s, 1H), 7.20 (t, J = 8.54 Hz, 2H), 7.25 (t, J= 8.54 Hz, 2H), 7.57–
7.61 (m, 2H), 7.83–7.87 (m, 2H); 13C-NMR (CDCl3, 75MHz): δ
99.44, 108.28, 116.23 (d, 2J= 9.90 Hz, Ar-F), 116.53
(d, J= 11.00 Hz, Ar-F), 120.50 (q, J= 270.13 Hz, CF3), 123.35,
127.59 (d, 3J= 8.80 Hz, Ar-F), 128.04 (d, 3J=8.25Hz, Ar-F),
129.57, 133.10, 138.82 (q, 2J= 39.42 Hz, CF3), 153.15, 163.01
(d, 1J= 250.32 Hz, Ar-F), 163.98 (d, 1J= 251.98 Hz, Ar-F),
169.68; MS (ESI), m/z: 426 (M + H+); HRMS m/z calcd for
C19H10ON3ClF5 (M + H+), 426.0427; found, 426.0414.
pyrazol-4-yl)-5-(p-tolyl)-1,2,4-oxadiazole (8d).
White solid;
yield: 0.23g (54%); mp 189–191°C; 1H-NMR (CDCl3,
300 MHz): δ 2.46 (s, 3H, CH3), 7.36 (d, J = 8.09Hz, 2H), 7.53–
7.59 (m, 4H), 8.10 (d, J = 8.09Hz, 2H); 13C-NMR (CDCl3,
75MHz): δ 21.77, 107.01,121.02, 120.06 (q, 1J = 270.65Hz,
CF3), 126.78, 128.22, 129.63, 130.69, 135.34, 135.97, 141.87
2
2
2
(q, J = 39.05 Hz, CF3), 143.95, 160.75, 176.13; MS (ESI), m/z:
439 (M+ H+); HRMS m/z calcd for C19H12ON4Cl2F3 (M + H+),
439.0334; found, 439.0329.
General procedure for the synthesis of compounds 9a
and b.
The N-hydroxy-pyrazole-carboximidoyl chloride
(1.0 mmol), malononitrile/cyanoacetamide (1.0 mmol), and sodium
methoxide(1.0 mmol) were dissolved in ethanol (15 mL), refluxed
for 5 h. After completion of the reaction, the residue was filtered
off, solvent removed in vacuo, and the residue purified by a
column with silica gel using petroleum ether/ethyl acetate (8:2v/v)
mixture to obtain pure products of 9a and b.
3-(5-Chloro-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-
pyrazol-4-yl)-5-phenylisoxazole (7l).
Light brown solid;
yield: 0.27 g (65%); mp 113–115°C; 1H-NMR (CDCl3, 300MHz):
δ 3.89 (s, OCH3, 3H), 6.82 (s, 1H), 7.04 (d, J=8.69Hz, 2H),
7.47–7.53 (m, 5H), 7.86 (d, J= 6.86 Hz, 2H); 13C-NMR (CDCl3,
300 MHz): δ 55.56, 99.65, 114.44, 114.67, 119.78, 120.55
1
5-Amino-3-(5-chloro-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-
(q, J = 270.65 Hz, CF3), 125.90, 126.19, 126.60, 127.03, 129.05,
129.89, 130.51, 137.05, 141.32 (q, 2J=38.14Hz, CF3), 160.46,
170.51; MS (ESI), m/z: 420 (M + H+); HRMS m/z calcd for
C20H14O2N3ClF3 (M + H+), 420.0721; found, 420.0702.
4-yl)isoxazole-4-carbonitrile (9a).
Light brown solid; yield:
0.24 g (68%); mp 193–195°C; 1H-NMR (CDCl3, 300 MHz): δ
7.44–7.63 (m, 5H), 8.00 (br, 2H, NH2); 13C-NMR
(CDCl3 + DMSO-d6, 75MHz): δ 100.04, 105.67, 111.98, 119.59
3-(5-Chloro-1-(4-methoxyhenyl)-3-(trifluoromethyl)-1H-
1
(q, J= 270.13 Hz, CF3), 124.84, 128.88, 129.39, 129.59, 136.27,
pyrazol-4-yl)-5-(4-nitrophenyl) isoxazole (7m).
Cream
2
141.09 (q, J =37.41 Hz, CF3), 152.67, 173.04; IR (KBr, cmꢀ1):
solid; yield: 0.28 g (62%); mp 141–143°C; 1H-NMR (CDCl3,
300 MHz): δ 3.87 (s, OCH3, 3H), 7.00 (s, 1H), 7.02 (d, J=8.85Hz,
2H), 7.05 (d, J= 9.00 Hz, 2H), 7.44 (d, J= 9.00 Hz, 2H), 7.50 (d,
J=8.85Hz, 2H); 13C-NMR (CDCl3, 75MHz): δ 55.13, 101.12,
109.91, 113.97, 119.96 (q, 1J= 270.66 Hz, CF3), 125.48, 126.39,
126.84, 129.30, 129.61, 133.89, 139.88 (q, 2J= 37.23 Hz, CF3),
148.43, 154.52, 159.92, 166.07; MS (ESI), m/z: 465 (M + H+); HRMS
m/z calcd for C20H12ClF3N4O4 (M + H+) 465.0572; found, 465.0568.
3-(5-Chloro-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5-
phenyl-1,2,4-oxadizole (8a). White solid; yield: 0.22 g (58%);
mp 117–119°C; 1H-NMR (CDCl3, 300 MHz): δ 7.54–7.64
(m, 8H), 8.20–8.23 (m, 2H); 13C-NMR (CDCl3, 75 MHz): δ
106.60, 119.99 (q, 1J = 270.59 Hz, CF3), 123.75, 125.55,
128.21, 129.13, 129.37, 129.88, 130.20, 133.04, 136.84, 141.52
(q, 2J = 38.97 Hz, CF3), 161.00, 175.90; MS (ESI), m/z: 391
(M + H+); HRMS m/z calcd for C18H11ON4ClF3 (M + H+)
391.0568; found, 391.0571.
3367, 3211 (NH2), 2234 (CN), 1190, 1138 (C-F); MS (ESI), m/z:
354 (M + H+); HRMS m/z calcd for C14H8ON5ClF3 (M + H+),
354.0364; found, 354.0363.
5-Amino-3-(5-chloro-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-
4-yl)isoxazole-4-carboxamide (9b).
Light brown solid; yield:
0.23 g (63%); mp 197–199°C; 1H-NMR (CDCl3, 300 MHz): δ
5.78 (s, NH2, 2H), 7.43 (br, CO-NH2, 2H), 7.57 (d, J=7.36Hz,
2H), 7.61–7.66 (m, 3H); 13C-NMR (CDCl3 +DMSO-d6,
75 MHz): δ 87.85, 106.70, 119.71 (q, 1J= 270.68 Hz, CF3),
124.89, 125.19, 129.01, 129.39, 129.54, 136.43, 139.57
2
(q, J = 32.46 Hz, CF3), 149.25, 164.02, 172.31; IR (KBr, cmꢀ1):
3492, 3410, 3283 (NH2), 1656 (C¼O), 1582 (C¼N), 1194, 1137
(C-F); MS (ESI), m/z: 372 (M + H+); HRMS m/z calcd for
C14H10ClF3N5O2 (M + H+), 372.0470; found, 372.0466.
General procedure for the synthesis of compounds 10a–g. The
N-hydroxy-pyrazole-carboximidoyl chloride (1.0mmol) and cyclic
secondary amine (1.0mmol) were dissolved in tetrahydrofuran and
stirred for 15min at room temperature. After completion of the
reaction, adjusted the pH value of mixture to 7 using 10% NaOH
5-(4-Bromophenyl)-3-(5-chloro-1-Phenyl)-3-(trifluoromethyl)-
1H-pyrazol-4-yl)-1,2,4-oxadiazole (8b).
Light brown solid;
yield: 0.24g (53%); mp 143–145°C; 1H-NMR (CDCl3,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

760
B. Sangepu, B. Gandu, G. Anupoju, and V. Jetti
Vol 53
solution, added 20 mL water and stirred for 15min. Then separated
organic layer and dried over anhydrous Na2SO4, the solvent
removed in vacuo and the residue purified by a column with
silica gel using petroleum ether/ethyl acetate (8.5:1.5v/v) mixture
to obtain pure products of 10a–g.
(4-Benzylpiperdine-1-yl)(5-chloro-1-(4-chlorophenyl)-3-
(trifluoromethyl)-1H-pyrazol-4-yl) methanone oxime (10f). Cream
solid; yield: 0.31 g (64%); mp 189–191°C; 1H-NMR (CDCl3,
300 MHz): δ 1.23–1.30 (m, 1H), 1.59–1.67 (m, 4H), 2.55 (d,
J= 7.17 Hz, 2H), 2.65 (t, J= 12.51 Hz, 2H), 3.53 (d, J= 12.35 Hz,
2H), 6.69 (s, N–OH, 1H), 7.13 (d, J= 6.86 Hz, 2H), 7.19
(t, J= 7.32 Hz, 1H), 7.27 (t, J= 7.17 Hz, 2H), 7.50 (d, J=9.00Hz,
2H), 7.57 (d, J=9.00Hz, 2H); 13C-NMR (CDCl3, 75MHz): δ
(5-Chloro-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)
(piperidin-1-yl) methanone oxime (10a).
White solid;
yield: 0.24 g (59%); mp 162–164°C; 1H-NMR (CDCl3,
300 MHz): δ 1.52–1.64 (m, 6H), 3.08–3.15 (m, 4H), 6.88
(s, N–OH, 1H), 7.47–7.55 (m, 3H), 7.62 (d, J = 8.08 Hz,
2H); 13C-NMR (CDCl3, 75 MHz): δ 24.41, 25.19, 47.51,
109.77, 120.29 (q, 1J = 270.59 Hz, CF3), 125.21, 128.46,
129.19, 129.38, 137.16, 141.15 (q, 2J = 38.42 Hz, CF3),
150.47; IR (KBr, cmꢀ1): 3290 (N–OH), 1625 (C¼N), 1135
(C-F); MS (ESI), m/z: 373 (M + H+); HRMS m/z calcd for
C16H17ClF3N4O(M + H+), 373.1038; found, 373.1031.
(5-Chloro-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)
(morpholine)methanone oxime(10b). Cream solid; yield:
1
31.62, 38.08, 43.05, 48.38, 110.07, 119.95 (q, J= 270.08 Hz, CF3),
125.93, 126.39, 128.22, 128.43, 129.05, 129.44, 135.46, 135.65,
140.16, 141.54 (q, 2J= 38.63 Hz, CF3),150.36; IR (KBr, cmꢀ1):
3269 (N–OH), 1639 (C¼N), 1147 (C-F); MS (ESI), m/z: 497
(M + H+); HRMS m/z calcd for C23H22Cl2F3N4O(M + H+),
497.1118; found, 497.1113.
(5-chloro-1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-
4-yl)(4-phenylpiperazin-1-yl) methanoneoxime (10g). Cream
solid; yield: 0.33 g (69%); mp 179–181°C; 1H-NMR (CDCl3,
300 MHz): δ 3.16–3.24 (m, 4H), 3.30 (t, J = 5.03 Hz, 4H), 6.73
(s, N–OH, 1H), 6.89 (t, J = 7.32 Hz, 1H), 6.94 (d, J = 7.93 Hz,
2H), 7.28 (t, J = 7.32 Hz, 2H), 7.52 (d, J = 8.85 Hz, 2H), 7.59
(d, J = 8.85 Hz, 2H); 13C-NMR (CDCl3 + DMSO-d6, 75 MHz): δ
46.07, 48.14, 109.42, 119.55 (q, 1J = 270.68 Hz, CF3), 115.62,
119.26, 125.73, 127.85, 128.35, 128.70, 134.49, 134.88, 140.57
1
0.24 g (70%); mp 135–137°C; H-NMR (CDCl3, 300 MHz):
δ 3.40 (t, J = 5.29, 4H), 3.75 (t, J = 5.29, 4H), 7.50 (s, N–
OH, 1H), 7.52–7.62 (m, 5H); 13C-NMR (CDCl3, 75 MHz):
δ 48.58, 66.90, 112.34, 120.20 (q, 1J = 270.04 Hz, CF3),
2
125.19, 129.30, 129.88, 129.63, 136.94, 139.82 (q, J = 39.51 Hz,
CF3), 143.29; IR (KBr, cmꢀ1): 3379 (N–OH), 1627 (C¼N),
1131 (C-F); MS (ESI), m/z: 375 (M + H); HRMS m/z calcd for
C15H15ClF3N4O2 (M+ H+), 375.0830; found, 375.0824.
(q, J = 39.61 Hz, CF3), 147.79, 150.44; IR (KBr, cmꢀ1): 3289
2
(N–OH), 1649 (C¼N), 1128 (C-F); MS (ESI), m/z: 484
(M + H+); HRMS m/z calcd for C21H19ON5Cl2F3 (M + H+),
484.0913; found, 484.0904.
(4-Benzylpiperdine-1-yl)(5-chloro-1-phenyl-3-(trifluoromethyl)-
1H-pyrazol-4-yl)methanone oxime (10c).
Cream solid; yield:
In vitro antibacterial assay. Standard sterilized filter paper
disks (5 mm diameter) impregnated with a solution of the test
compound in DMSO (1 mg/mL) was placed on agar plate
seeded with the appropriate test organism in triplicate.
Ciprofloxacin and cloxacillin were used as standard antibacterial
drugs. DMSO alone was used as control as the same
aforementioned concentration. The plates were incubated at 35°C
for 1–2 days. Antibacterial activity was determined by measuring
the diameter of the zone of inhibition surrounding microbial
growth [30,31].
0.24 g (65%); mp 164–166°C; 1H-NMR (CDCl3, 300 MHz): δ
1.18–1.32 (m, 2H), 1.57–1.75 (m, 3H), 2.55 (d, J=6.79Hz, 2H),
2.67 (t, J= 12.27 Hz, 2H), 3.55 (d, J=12.27Hz, 2H), 7.13
(d, J= 6.98 Hz, 2H), 7.19 (d, J= 7.17 Hz, 1H), 7.27 (t, J=6.79Hz,
2H), 7.29 (s, N–OH, 1H), 7.48–7.56 (m, 3H), 7.58–7.63 (m, 2H);
13C-NMR (CDCl3, 300 MHz): δ 31.24, 38.04, 43.00, 46.86,
1
109.70, 119.58 (q, J = 270.68 Hz, CF3), 125.21, 125.89, 128.19,
128.48, 129.03, 129.18, 129.39, 137.20, 140.14, 141.02
2
(q, J=38.18Hz, CF3), 150.26; IR (KBr, cmꢀ1): 3276 (N–OH),
1630 (C¼N), 1131 (C-F); MS (ESI), m/z: 463 (M + H+); HRMS
m/z calcd for C23H23ClF3N4O(M + H+), 463.1507; found, 463.1502.
(5-Chloro-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)(4-
phenylpiperazin-1-yl) methanone oxime (10d). Cream solid;
yield: 0.24 g (67%); mp 164–166°C; 1H-NMR (CDCl3,
300 MHz): δ 3.23–3.31 (m, 4H), 3.38–3.52 (m, 4H), 7.02
(s, N–OH, 1H), 7.10–7.16 (m, 2H), 7.33 (t, J = 7.78 Hz, 2H),
7.50–7.56 (m, 4H), 7.62 (d, J = 7.78 Hz, 2H); 13C-NMR
(CDCl3, 75 MHz): δ 45.75, 48.29, 108.83, 115.74, 119.50
(q, 1J = 269.74 Hz, CF3), 119.66, 124.23, 127.71, 128.28,
128.44, 128.72, 136.13, 140.02 (q, 2J = 38.14 Hz, CF3),
147.74, 149.78; IR (KBr, cmꢀ1): 3258 (N–OH), 1597 (C¼N),
1126 (C-F); MS (ESI), m/z: 450 (M + H+); HRMS m/z calcd
for C21H20ON5ClF3 (M + H+), 450.1303; found, 450.1288.
(5-Chloro-1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-
Acknowledgments. Authors thank the Director and Head, Fluo-
roorganic Division, IICT for their support. Bhavanarushi. S
thanks UGC, New Delhi for research fellowship.
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4-yl)(piperidin-1-yl) methanone oxime (10e).
White solid;
yield 0.25 g (62%); mp 163–165°C; 1H-NMR (CDCl3,
300 MHz): δ 1.42–1.68 (m, 6H), 2.97–3.21 (m, 4H), 7.20
(s, N–OH, 1H), 7.38–7.62 (m, 4H); 13C-NMR (CDCl3,
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δ 24.27, 25.16, 47.65, 109.73, 120.11 (q,
1J = 269.74 Hz, CF3), 126.36, 128.61, 129.43,135.45, 135.55,
141.47 (q, J = 39.05 Hz, CF3), 149.97; IR (KBr, cmꢀ1): 3285
2
(N–OH), 1624 (C¼N), 1139 (C-F); MS (ESI), m/z: 407
(M + H+); HRMS m/z calcd for C16H16ON4Cl2F3 (M + H+),
407.0647; found, 407.0631.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2016
Synthesis of Isoxazole, 1, 2, 4-Oxadiazole and (1H-Pyrazol-4-yl)-methanone Oxime Derivatives
from N-Hydroxy-1H-pyrazole-4-carbimidoyl Chloride and their Biological Activity
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet