Synthesis, identification and in vitro biological evaluation of some novel 5-imidazopyrazole incorporated pyrazoline and isoxazoline derivatives

Article abstract of DOI:10.1039/c4nj00244j

In the present study, novel combinatorial libraries of substituted pyrazolines 6a-l and isoxazolines 7a-l have been synthesized via the reactions of chalcones with the hydrazine hydrate and hydroxylamine hydrochloride in ethanol. The title compounds were screened for their preliminary in vitro antibacterial activity against a panel of pathogenic strains, in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv, in vitro antimalarial activity against Plasmodium falciparum and in vitro antioxidant activity by the ferric-reducing antioxidant power method. Compounds 6k, 6l, 7h and 7k exhibited excellent antibacterial activity and a few of them exhibited moderate antituberculosis activity compared with the first line drugs. Half of the compounds exhibited terrific antimalarial activity and the majority of compounds showed highest antioxidant potency. the Partner Organisations 2014.

Full text of DOI:10.1039/c4nj00244j

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Synthesis, identification and in vitro biological
evaluation of some novel 5-imidazopyrazole
incorporated pyrazoline and isoxazoline
derivatives†
Cite this: New J. Chem., 2014,
38, 2902
Piyush N. Kalaria,* Shailesh P. Satasia and Dipak K. Raval
In the present study, novel combinatorial libraries of substituted pyrazolines 6a–l and isoxazolines 7a–l
have been synthesized via the reactions of chalcones with the hydrazine hydrate and hydroxylamine
hydrochloride in ethanol. The title compounds were screened for their preliminary in vitro antibacterial
activity against a panel of pathogenic strains, in vitro antituberculosis activity against Mycobacterium
tuberculosis H37Rv, in vitro antimalarial activity against Plasmodium falciparum and in vitro antioxidant
activity by the ferric-reducing antioxidant power method. Compounds 6k, 6l, 7h and 7k exhibited
excellent antibacterial activity and a few of them exhibited moderate antituberculosis activity compared
with the first line drugs. Half of the compounds exhibited terrific antimalarial activity and the majority of
compounds showed highest antioxidant potency.
Received (in Montpellier, France)
18th February 2014,
Accepted 31st March 2014
DOI: 10.1039/c4nj00244j
www.rsc.org/njc
inhibitors, dopamine transporter inhibitors, GPCR antagonists
and even agonists, cyclooxygenase inhibitors, and phosphatase
1. Introduction
Malaria remains one of the most imperative infectious diseases in inhibitors.11 Pyrazole containing drugs having two adjacent aryl
the world. During the past decade, concerted efforts of prevalent groups in a vicinal position have often been occupying a
countries, donors and global malaria partners led to strengthened position in the list of top selling pharmaceutical products since
malaria control around the world.1 Malaria has placed the the establishment of this decade.12 Pyrazole signifies a key
strongest known selective pressure on the human genome since motif in heterocyclic chemistry and occupies a major position
the commencement of agriculture within the past 10 000 years.2,3 in medicinal and pesticide chemistry due to its wide range of
Plasmodium falciparum, the most dangerous malarial parasite, is bioactivities such as antibacterial,13 anticancer,14 analgesic,15
accountable for about 1 million deaths every year.4–6 Infectious anti-convulsant,16 anti-depressant17 and anti-inflammatory.18
diseases are influencing the world through their morbidity and Whereas, the class of pyrazoles and isoxazolines possess a
mortality among which tuberculosis is also a major infectious broad spectrum of pharmacological activities such as anti-
disease caused by Mycobacterium tuberculosis.7 Solitary agent TB bacterial,19 antiviral20 and antidepressant.21 The synthesis of
treatment quickly leads to drug-resistant organisms,8 while multi- heterocyclic motifs containing multi-structure in one molecule
drug treatment needs to be extended as MTB divides gradually. It has received much interest in recent years.22
is metabolically capable of becoming drug insensitive and may
After the pioneering work of Fischer and Knoevenagel in the
become sequestered.9,10 Therefore, the growth of new drugs with late 19th century,23 the reaction of a,b-unsaturated ketones and
action besides MDR-TB, XDR-TB, and latent TB is a main concern. aldehydes with hydrazines became one of the most admired
For this reason as drug-resistant strains of the parasite emerge, methods for the preparation of 2-pyrazolines. Many pyrazoline
there is a vital need to recognize new pharmacological targets for
developing antimalarial and antituberculosis therapeutics.
Five-membered heterocycles having a vicinal 1,2-diaryl sub-
stitution pattern are important scaffolds that are found in
several pharmacologically active compounds, including kinase
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar-388 120,
Gujarat, India. E-mail: piyush_kalaria@yahoo.com; Fax: +91-02692-236475;
Tel: +91-02692-226856 ext. 211
Fig. 1 Structural comparison of the representative compound with the
† Electronic supplementary information (ESI) available: The spectral data of
standard drugs.
synthesized compounds. See DOI: 10.1039/c4nj00244j
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derivatives are reported to have a large spectrum of biological 2935–3017 cmꢀ1. A strong absorption band was observed in the
activities, such as antimalarial,24 antibacterial,25 antitubercu- range of 1368–1379 cmꢀ1 due to the presence of the CH3 group.
lar, analgesic,26 antiviral,27 antioxidant,28 antidiabetic,29 anti- In the 1H NMR spectra of these compounds the pro-chiral
fungal30,31 and antimycobacterial.32
methylene protons of pyrazoline appeared as two distinct
In view of these findings and in continuation of our research doublets of a doublet, thereby indicating that both the protons
work,33–41 we herein report the synthesis and pharmacological are magnetically non-equivalent and diastereotopic. The chiral
activity of substituted pyrazolines 6a–l and isoxazolines 7a–l. It C–H proton of pyrazoline appeared as a triplet. The aromatic
was considered valuable to incorporate two five membered protons resonate as multiplets at around d 6.93–7.70 ppm. The
heterocyclic rings mutually in a molecular framework to study mass spectrum of all the synthesized compounds showed a
the synergistic effect of these rings towards the antibacterial, molecular ion peak at M + 1 corresponding to their molecular
antituberculosis, antimalarial and antioxidant activities (Fig. 1). weights, which confirmed the respective chemical structures.
2.2. Biological evaluation
2. Results and discussion
2.2.1. In vitro antimicrobial activity. All the synthesized
compounds were evaluated for their antibacterial activity
2.1. Chemistry
The synthetic route used to synthesize the unreported title against three Gram positive bacteria (Streptococcus pneumoniae
compounds 6a–l and 7a–l is illustrated in Scheme 1. The starting MTCC 1936, Bacillus subtilis MTCC 441 and Clostridium tetani
material 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde 1 MTCC 449) and three Gram negative bacteria (Escherichia coli
was prepared according to Vilsmeier–Haack reaction of 3-methyl- MTCC 443, Salmonella typhi MTCC 98, and Vibrio cholerae
1-phenyl-1H-pyrazol-5(4H)-one.42 5-(1H-imidazol-1-yl)-3-methyl-1- MTCC 3906) by using ampicillin, norfloxacin and ciprofloxacin
phenyl-1H-pyrazole-4-carbaldehydes 3a–b were prepared by as the standard antibacterial drugs. Antifungal activity was
nucleophilic displacement of the chloro group at C5 in screened against two fungal species (Candida albicans MTCC
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde 1 with 3008 and Aspergillus fumigatus MTCC 227) where nystatin and
secondary amine of imidazole 2a–b in refluxing DMF using griseofulvin were used as the standard antifungal drugs. The
anhydrous potassium carbonate as the base. The pyrazolic minimal inhibitory concentration (MIC) of all the synthesized
chalcones 5a–l were prepared by the reaction of aldehydes compounds was determined by the broth microdilution
3a–b with appropriately substituted acetophenones 4a–f in method according to National Committee for Clinical Labora-
ethanolic sodium hydroxide as the catalyst at room temperature. tory Standards (NCCLS).43 The standard deviation value is
Finally pyrazolic chalcones 5a–l were treated with hydrazine expressed in terms of ꢁSD (r0.5). All the synthesized com-
hydrate/hydroxylamine hydrochloride in ethanol containing a pounds (6a–l, 7a–l) are screened for their antibacterial and
catalytic amount of glacial acetic acid giving pyrazoline 6a–l/ antifungal activities in three sets (n = 3) against bacteria and
isoxazoline 7a–l derivatives.
fungi used in the present protocol. The results are summarized
The structures of all the synthesized compounds were con- in Table 1.
firmed by 1H NMR, FT-IR, mass spectrometry and elemental
The antibacterial screening of compounds 3a and 3b and
analysis. The IR spectrum of all the synthesized compounds their pyrazoline 6a–l and isoxazoline 7a–l derivatives (Table 1)
showed absorption in the range of 1590–1654 cmꢀ1 due to pointed out that compounds 6k and 7h showed an outstanding
CQN stretching. The C–H stretching was observed at around inhibitory effect i.e. 62.5 mg mLꢀ1 against C. tetani as compared
Scheme 1 Synthesis of the substituted pyrazolines 6a–l and isoxazolines 7a–l. (i) DMF, K2CO3, reflux 2 h. (ii) 20% Ethanolic NaOH, room temperature.
(iii) Hydrazine hydrate, glacial acetic acid, ethanol, reflux 1 h. (iv) Hydroxylamine hydrochloride, glacial acetic acid, ethanol, reflux 1 h.
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Table 1 In vitro antimicrobial activity (MIC, mg mLꢀ1) of the synthesized
compounds (3a–b, 6a–l, 7a–l)
ampicillin. In the case of inhibiting S. pneumoniae, compound
6h was found to be equipotent as ampicillin. Whereas in the
case of inhibiting Gram negative bacteria, compounds 6l and
7k showed maximum activity against V. cholera and S. typhi as
compared to ampicillin. Compounds 3a, 6b, 6e, 6l, 7b, 7c, and
7e showed similar activity against E. coli upon comparison with
the standard drug ampicillin. Compound 6h was found to be
equally active against V. cholera as compared to ampicillin. The
antibacterial results revealed that most of the prepared com-
pounds showed improved activity against the Gram-positive
bacteria rather than Gram-negative bacteria.
From in vitro antifungal activity data, it is found that
compounds 3b, 6f and 7k displayed highest antifungal activity
against C. albicans as compared to griseofulvin. Compounds 6a,
6b, 6d, 6j, 6k, 7a, 7d and 7h showed the same potency as
griseofulvin. While none of the compounds were found to be
active against A. fumigatus.
2.2.2. In vitro antituberculosis activity. All the synthesized
compounds were tested for their in vitro antituberculosis
activity against the Mycobacterium tuberculosis H37Rv strain.
Primary screening of all the newly synthesized compounds was
conducted at 250 mg mLꢀ1 and 100 mg mLꢀ1 by using Low-
ensteine–Jensen medium (conventional method) as described
by Rattan.44 The standard deviation value is shown in terms of
ꢁSD (r0.75). All the newly synthesized compounds are
screened for their antituberculosis activity in three sets (n = 3)
against M. tuberculosis used in this study. The standard drugs
rifampicin and isoniazid were used for comparison.
The bioassay results obtained for the efficacy of all
the synthesized compounds 3a–3b, 6a–l and 7a–l against
M. tuberculosis H37Rv are summarized in Table 2. The anti-
tuberculosis screening data revealed that all the tested com-
pounds showed moderate to very good inhibitory activity. The
outcome of the results showed that compounds 6f, 6j, 7j and 7f
are found to possess excellent activity, respectively, 92%, 88%,
90% and 88% at 250 mg mLꢀ1 against M. tuberculosis H37Rv.
Gram positive bacteria Gram negative bacteria Fungi
S.P.
B.S.
C.T.
E.C.
S.T.
V.C.
C.A.
A.F.
MTCC MTCC MTCC MTCC MTCC MTCC MTCC MTCC
Comp. 1936 441
449
443
98
3906
227
3008
3a
3b
6a
6b
6c
6d
6e
6f
6g
6h
6i
500
500
250
500
250
250
200
500
200
100
200
200
500
250
500
500
500
200
500
250
250
500
250
200
200
250
100
10
250
250
100
500
250
200
100
200
125
200
200
250
100
100
500
250
200
200
125
100
200
500
200
200
250
200
250
100
50
250
150
250
200
200
200
125
200
100
250
200
250
100
250
200
100
250
125
100
200
125
125
250
125
125
200
200
200
250
500
250
200
250
250
250
200
250
200
250
200
500
250
125
200
250
200
250
200
250
250
250
500
250
500
250
500
125
100
250
250
500
41000 41000
250
500
500
500
500 1000
1000 250
500 1000
1000
250
250
250
1000 1000
41000 41000
1000
500
6j
6k
6l
500 1000
62.5 200
100
500
250
500
500
250
500
100
125
100
100
200
100
250
200
62.5 41000
500
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
A
B
200
250
200
250
200
100
250
500
1000
1000
500
250
250
500
250
200
250
500
250
500 1000
1000
1000
200
200
41000 41000
62.5 200
200
500 1000
250
250
200
250
100
10
25
n.t.
n.t.
1000
500
200
200
250
250
50
100
n.t.
n.t.
500 1000
250 1000
62.5 125
200
100
10
25
n.t.
n.t.
500
100
10
25
n.t.
n.t.
41000 1000
n.t.a
n.t.
n.t.
n.t.
n.t.
n.t.
C
D
E
25
n.t.
n.t.
n.t.
n.t.
100
500
100
100
S.P.: streptococcus pneumoniae, B.S.: bacillus subtilis, C.T.: clostridium
tetani, E.C.: escherichia coli S.T.: salmonella typhi, V.C.: vibrio cholerae,
C.A.: candida albicans, A.F.: aspergillus fumigatus, MTCC: microbial
type culture collection. A: ampicillin, B: norfloxacin, C: ciprofloxacin, D:
a
nystatin, E: griseofulvin. n.t.: not tested.
to ampicillin i.e. 250 mg mLꢀ1 and ciprofloxacin. The majority Among the above four compounds, two compounds 6f and 7j
of the compounds showed excellent activity against gram also showed brilliant activity (i.e. 90%) at 100 mg mLꢀ1 concen-
positive bacteria B. subtilis and C. tetani as that of the tration. While compounds 6b and 7b were found to be
Table 2 In vitro antituberculosis activity (% inhibition) of the synthesized compounds (3a–b, 6a–l, 7a–l) against M. tuberculosis H37Rv (at
concentrations 250 mg mLꢀ1 and 100 mg mLꢀ1
)
Inhibition (%)
Inhibition (%)
Comp.
100 mg mLꢀ1
250 mg mLꢀ1
Comp.
100 mg mLꢀ1
250 mg mLꢀ1
3a
3b
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
22
56
28
76
30
56
60
92
48
56
23
88
68
76
18
48
22
62
24
48
52
90
34
44
21
82
62
67
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
68
75
48
40
46
88
47
32
48
90
46
86
98
99
54
54
32
34
34
76
30
28
36
90
39
82
98
99
Rifampicin
Isoniazid
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Table 3 In vitro antimalarial activity of the synthesized compounds (3a–b,
6a–l, 7a–l)
All the synthesized compounds (3a–b, 7a–l and 8a–l) were
screened for their antimalarial activity against chloroquine and
quinine sensitive strains of P. falciparum. All experiments were
performed in duplicate and the mean value of IC50 is men-
tioned in Table 3. Compounds 6a, 6b, 6d, 6e, 6f, 6g, 7a, 7b, 7d,
7g, 7i and 7l were found to have IC50 in the range of 0.012 to
0.089 for the P. falciparum strain. These compounds displayed
excellent activity against the P. falciparum strain as compared to
quinine with IC50 0.268. Among all the above compounds, only
compound 6d demonstrates superior activity, i.e. IC50 0.012,
against chloroquine with IC50 0.020. Moreover compounds 6f
and 7d were found to possess moderate activity, i.e. IC50 0.036
in agreement with chloroquine i.e. IC50 0.020. All other remain-
ing compounds were found to be not as much active as
chloroquine and quinine against the P. falciparum strain.
2.2.4. In vitro antioxidant activity. The antioxidant activity
Comp.
IC50 (mg mLꢀ1
)
Comp.
IC50 (mg mLꢀ1
)
3a
3b
6a
6b
6c
6d
6e
6f
1.25
7a
7b
7c
7d
7e
7f
7g
7h
0.074
0.084
0.70
0.036
0.78
0.988
0.081
0.067
0.69
0.012
0.058
0.036
0.089
0.70
1.24
0.084
1.047
0.068
1.046
0.32
6g
6h
6i
7i
7j
7k
0.72
6j
6k
6l
0.88
1.032
0.78
7l
0.080
0.020
0.268
Chloroquine
Quinine
moderately active against M. tuberculosis H37Rv. All of the entire series was investigated by using ascorbic acid as
other remaining compounds showed poor inhibition of the standard antioxidant compound and results are listed in
M. tuberculosis growth. From the above results, it can be Table 4. Ferric reducing antioxidant power (FRAP) was mea-
concluded that compounds 6f and 7j may become a new class sured by a modified method.45 The antioxidant potentials of
of antitubercular agents in the future.
the compounds were estimated as their power to reduce the
2.2.3. In vitro antimalarial activity. All the new pyrazoline TPTZ–Fe(III) complex to the TPTZ–Fe(II) complex. The absor-
6a–l and isoxazoline 7a–l derivatives were tested for their bance of the intense blue coloured [Fe(II)–TPTZ] complex was
antimalarial activity against the P. falciparum strain. The measured at 593 nm. The standard deviation value is shown in
obtained results are presented in Table 3. The results of the terms of ꢁSD (r0.75). All the newly synthesized compounds
pharmacological screening data are expressed as the drug are screened for their antioxidant activity in three sets (n = 3) in
concentration resulting in 50% inhibition (IC50) of parasite this study. The results were expressed as ascorbic equivalents
growth.
(mmol per 100 g of the compound).
The standard deviation value is expressed in terms of ꢁSD
The measurement of ferric reducing power (FRAP) for the
(r0.5). Compounds 6a–l and 7a–l are screened for their malarial synthesized compounds (6c, 6d, 6e, 6f, 6h, 6k, 7c, 7e, 7h and 7k)
activity in three sets (n = 3) against P. falciparum used in the gave the FRAP value ranging from 421.71 to 497.49 mmol per
present procedure. Chloroquine and quinine were used as the 100 g of compounds. This indicates that these compounds are
standard drugs for comparison (Fig. 2).
good antioxidants. Compound 6g showed poor antioxidant
Fig. 2 Structure–activity relationship for antimicrobial, antituberculosis, antimalarial and antioxidant activities of the synthesized compounds.
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Table 4 In vitro antioxidant activity of compounds 6a–l and 7a–l
ring worsens the antimalarial activity of 7e and 7f. The same kind
of result was observed for the antioxidant activity. Compound 6d
has the pyrazoline ring, which increases its antioxidant
potency. While compound 7d has the isoxazoline ring, which
decreases its antioxidant activity. Compounds 6k and 6l having
the pyrazoline ring showed enhanced antibacterial activity
against C. tetani and V. cholerae respectively. Whereas com-
pounds 7k and 7l showed decreased antibacterial activity. In
contrast, compound 7k having the isoxazoline ring showed
increased antibacterial activity against S. typhi, while com-
pound 6k has decreased potency because of the isoxaline ring.
Comp. OD (593 nm) Frap valuea Comp. OD (593 nm) Frap valuea
3a
3b
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
1.013
1.169
1.289
1.959
2.120
2.206
2.488
2.212
0.378
2.501
1.689
1.995
2.485
1.824
201.50
232.53
256.40
389.68
421.71
438.81
494.91
440.01
75.19
497.49
335.97
396.84
494.31
362.83
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
A.A.
1.789
1.818
2.293
1.846
2.489
1.986
1.105
2.501
1.959
1.745
2.419
1.732
2.501
355.86
361.63
456.12
367.20
495.11
395.05
219.80
497.49
389.68
347.11
481.18
344.52
3. Conclusion
A.A. = ascorbic acid, concentration of compounds used = 200 mg mLꢀ1
,
a
concentration of standard (A.A.) = 176 mg mLꢀ1
of the sample.
.
A.A. mmol per 100 g A series of pyrazoline and isoxazoline derivatives carrying a
5-imidazo pyrazole moiety have been synthesized in good yield
and screened for their biological activity with the aim of
discovering innovative structure leads serving as potent anti-
power while the remaining other compounds showed moderate
antioxidant activity (Table 4).
microbial, antituberculosis, antimalarial and antioxidant
agents. Half of the compounds showed brilliant antimalarial
activity against P. falciparum strains as compared to quinine.
Two leading candidates (6f and 7j) displayed modest anti-
tuberculosis activity. Most of the compounds were found to
be active against C. tetani and B. subtilis and also illustrate good
antioxidant activity. As for antifungal activity, compounds 3b,
6f and 7k showed excellent activity against C. albicans as
compared to griseofulvin. The results indicated that com-
pounds bearing the electron withdrawing bromo group in the
aryl moiety showed the highest antituberculosis and antimalar-
ial activities.
2.3. Structure–activity relationship (SAR)
The substitution pattern of the aryl ring at the third position in
the pyrazoline/isoxazoline ring was observed to affect biological
activity. It emerged that the electron withdrawing and releasing
groups were found to be responsible for variation in activity.
The electronic nature of the substituents led to significant
variation in all kinds of pharmacological activities. Compounds
containing electron-donating substituents (–OH, –OCH3) in the
basic skeleton led to an increase in the antibacterial activity
against B. subtilis and C. tetani (6i, 6l, 7i). While only the –OH
group was found to increase antimalarial, antituberculosis and
antioxidant activities. The phenyl group (weak electron donat-
ing) was found to be accountable for increasing antimalarial
activity (6b, 7b). The phenyl ring without any electron donating
4. Experimental section
4.1. Chemistry
or withdrawing group also showed potent antimalarial activity All the chemicals were purchased from Sigma Aldrich and
(6a, 6g, 7a, and 7g). In contrast, compounds bearing electron Merck – India. Commercial grade solvents were used and were
withdrawing groups (–Br) possessed stronger antituberculosis distilled before use. Melting points were determined using a
(6j, 7j) and antimalarial activity (6d, 7d). Whereas fluorine was melting point apparatus mThermoCal10 (Analab Scientific Pvt.
observed to be responsible for intensified antibacterial and Ltd, India) and are uncorrected. The completion of the reac-
antioxidant activities. The substitution pattern (–H, –CH3) at tions was checked by thin-layer chromatography (TLC) on
the fourth position in the imidazole moiety was also found to aluminium plates coated with silica gel 60 F254, 0.25 mm
be responsible for discrepancy in activities. Compounds having thickness (Merck) and detection of the components was made
hydrogen showed increased antimalarial activity while methyl by exposure to iodine vapors or UV light. The IR spectra (in KBr
substituted compounds showed higher antibacterial activity. pellets) were recorded on a Perkin-Elmer Spectrum GX FT-IR
On the basis of SAR, it has been observed that compounds 157 spectrophotometer (Perkin-Elmer, USA) and only the char-
having electron withdrawing fluoro groups show increased acteristic peaks are reported in cmꢀ1 1H-NMR spectra were
.
antimalarial and antioxidant activities. While the bromine recorded in DMSO-d6 on a Bruker Avance 400F (MHz) spectro-
group is responsible for enhancing the antimalarial activity meter (Bruker Scientific Corporation Ltd., Switzerland) using
and substitution of the methyl group on the imidazole ring the residual solvent signal as an internal standard at 400 MHz.
enhances the antituberculosis activity.
Chemical shifts (d) are given in ppm and coupling constants ( J)
The substitution pattern of pyrazoline and isoxazoline rings are in Hz. Mass spectra were recorded on a Shimadzu LCMS
was also found to affect the biological activity. Compounds 6e 2010 spectrometer (Shimadzu, Tokyo, Japan) at Sardar Patel
and 6f have the pyrazoline ring, which enhanced the anti- University (PURSE programme of DST), Vallabh Vidyanagar.
malarial activity. But the replacement of the nitrogen atom of The elemental analysis was carried out by using a Perkin-Elmer
the pyrazoline ring by the oxygen atom to form the isoxazoline 2400 series-II elemental analyzer (Perkin-Elmer, USA) and all
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compounds were found to be within ꢁ0.4% of the theoretical DMSO-d6): d 2.28 (s, 3H, CH3), 2.85 (dd, 1H, CH2, J = 6.0 Hz,
compositions.
12.4 Hz), 3.72 (dd, 1H, CH2, J = 12.4 Hz, 17.2 Hz), 4.56 (t, 1H,
CH, J = 10.8 Hz), 6.84–7.82 (m, 13H, Ar–H + 1H, NH); ESI-MS
(m/z): = 369.40 (M + 1); anal. calcd (%) for C22H20N6: C, 71.72; H,
5.47; N, 22.81. Found: C, 71.63; H, 5.53; N, 21.91.
4.2. General procedure for the synthesis of substituted 5-(1H-
imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehydes
(3a–b)
4.4.2. 5-([1,10-Biphenyl]-4-yl)-50-(1H-imidazol-1-yl)-30-
5-Chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde 1 (1.1 g, methyl-10-phenyl-3,4-dihydro-10H,2H-3,40-bipyrazole (6b). Yield
5 mmol), substituted imidazoles 2a–b (7.5 mmol), anhydrous 82%; m.p. 232 1C; IR (KBr, nmax, cmꢀ1): 3284 (secondary amine
potassium carbonate (0.6 g, 10 mmol) and dimethylformamide –NH), 2944 (aromatic ring –CH), 1599 (–CQN), 1370 (Ar–CH3);
(5 mL) were charged in a 50 mL round bottom flask equipped 1H NMR (400 MHz, DMSO-d6): d 2.32 (s, 3H, CH3), 2.95 (dd, 1H,
with a mechanical stirrer and a condenser. The reaction mixture CH2, J = 11.2 Hz, 16.4 Hz), 3.36 (dd, 1H, CH2, J = 11.2 Hz,
was refluxed for 2 h and the progress of the reaction was 16.4 Hz), 4.55 (td, 1H, CH, J = 3.2 Hz, 10.8 Hz), 7.07–7.84
monitored by TLC. After the completion of the reaction (as (m, 17H, Ar–H + 1H, NH); ESI-MS (m/z): = 445.20 (M + 1); anal.
evidenced by TLC), the reaction mixture was cooled to room calcd (%) for C28H24N6: C, 75.65; H, 5.44; N, 18.91. Found: C,
temperature and then poured into ice cold water (50 mL) with 75.63; H, 5.53; N, 18.71.
continuous stirring followed by neutralization with 1 N HCl to
4.4.3. 50-(1H-Imidazol-1-yl)-5-(4-methoxyphenyl)-30-methyl-
pH 7. The separated precipitates of substituted 5-(1H-imidazol-1- 10-phenyl-3,4-dihydro-10H,2H-3,40-bipyrazole (6c). Yield 75%;
yl)-3-methyl-1-phenyl-1H-pyrazole-4 carbaldehydes 3a–b were fil- m.p. 262 1C; IR (KBr, nmax, cmꢀ1): 3229 (secondary amine
tered, thoroughly washed with water, dried, and recrystallized –NH), 3012 (aromatic ring –CH), 1651 (–CQN), 1375 (Ar–
1
from hot ethanol.
CH3); H NMR (400 MHz, DMSO-d6): d 2.33 (s, 3H, CH3), 2.94
4.2.1. 5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazole-4- (dd, 1H, CH2, J = 6.0 Hz, 16.4 Hz, C4-H pyrazoline), 3.13 (dd, 1H,
1
carbaldehyde (3a). Yield 79%; m.p. 204 1C; H NMR (400 MHz, CH2, J = 10.2 Hz, 16.4 Hz, C4-H pyrazoline), 3.92 (s, 3H,
DMSO-d6): d 2.59 (s, 3H, CH3), 7.07–7.46 (m, 7H, Ar–H), 7.94 CH3),4.51 (t, 1H, CH, J = 11.2 Hz, C5-H pyrazoline), 7.09–8.23
(s, 1H, imidazole), 9.74 (s, 1H, CHO); ESI-MS (m/z): = 252.00 (m, 12H, Ar–H + 1H, NH); ESI-MS (m/z): = 399.60 (M + 1); anal.
(M + 1).
4.2.2. 3-Methyl-5-(4-methyl-1H-imidazol-1-yl)-1-phenyl-1H-
calcd (%) for C23H22N6O: C, 69,33; H, 5.57; N, 21.09. Found: C,
69.23; H, 5.55; N, 21.18.
1
pyrazole-4-carbaldehyde (3b). Yield 82%; m.p. 215 1C; H NMR
4.4.4. 5-(4-Bromophenyl)-50-(1H-imidazol-1-yl)-30-methyl-10-
(400 MHz, DMSO-d6): d 2.05 (s, 3H, CH3), 2.52 (s, 3H, CH3), phenyl-3,4-dihydro-10H,2H-3,40-bipyrazole (6d). Yield 71%; m.p.
7.10–7.58 (m, 7H, Ar–H), 7.97 (s, 1H, imidazole), 9.59 (s, 1H, 234 1C; IR (KBr, nmax, cmꢀ1): 3306 (secondary amine –NH), 3017
CHO); ESI-MS (m/z): = 267.00 (M + 1).
(aromatic ring –CH), 1613 (–CQN), 1378 (Ar–CH3); 1H NMR
(400 MHz, DMSO-d6): d 2.45 (s, 3H, CH3), 2.90 (dd, 1H, CH2, J =
11.6 Hz, 16.4 Hz, C4-H pyrazoline), 3.28 (dd, 1H, CH2, J = 16 Hz,
16.4 Hz, C4-H pyrazoline), 4.48 (t, 1H, CH, J = 11.2 Hz, C5-H
pyrazoline), 7.12–8.12 (m, 12H, Ar–H + 1H, NH); ESI-MS (m/z): =
4.3. General procedure for the synthesis of (E)-3-(5-(1H-imidazol-
1-yl)-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-phenylprop-2-en-1-one
derivatives (pyrazolic chalcones 5a–l)
To a mixture of substituted 5-(1H-imidazol-1-yl)-3-methyl-1- 447.9 (M + 1), 449.80 (M + 2); anal. calcd (%) for C22H19BrN6: C,
phenyl-1H-pyrazole-4-carbaldehydes 3a–b (5.0 mmol) and aceto- 59.07; H, 4.28; N, 18.79. Found: C, 58.93; H, 4.23; N, 18.91.
phenones 4a–f (5.0 mmol), 20% ethanolic NaOH (5 mL) was
4.4.5. 5-(4-Fluorophenyl)-50-(1H-imidazol-1-yl)-30-methyl-10-
added. The reaction mixture was stirred at room temperature phenyl-3,4-dihydro-10H,2H-3,40-bipyrazole (6e). Yield 78%; m.p.
until formation of a precipitate. The solid obtained was isolated 263 1C; IR (KBr, nmax, cmꢀ1): 3296 (secondary amine –NH), 2981
by filtration, washed with cold ethanol and recrystallized in (aromatic ring –CH), 1651 (–CQN), 1370 (Ar–CH3); 1H NMR
CHCl3.
(400 MHz, DMSO-d6): d 2.29 (s, 3H, CH3), 2.90 (dd, 1H, CH2, J =
10.4 Hz, 15.6 Hz, C4-H pyrazoline), 3.31 (dd, 1H, CH2, J =
16.4 Hz, 27.6 Hz, C4-H pyrazoline), 4.52 (t, 1H, CH, J = 10.4 Hz,
C5-H pyrazoline), 7.04–7.81 (m, 12H, Ar–H + 1H, NH); ESI-MS
(m/z): = 387.30 (M + 1); anal. calcd (%) for C22H19FN6: C, 68.38;
4.4. General procedure for the synthesis of substituted 50-(1H-
imidazol-1-yl)-30-methyl-10,5-diphenyl-3,4-dihydro-10H,2H-3,40-
bipyrazoles (6a–l)
The pyrazolic chalcones 5a–l (1.0 mmol), hydrazine hydrate H, 4.96; N, 21.75. Found: C, 68.44; H, 4.93; N, 21.80.
(1.5 mmol) and ethanol (5 mL) were refluxed for 1 h by using
4.4.6. 4-(50-(1H-Imidazol-1-yl)-30-methyl-10-phenyl-3,4-dihydro-
glacial acetic acid (1–2 drops) as the catalyst. After completion 10H,2H-[3,40-bipyrazol]-5-yl)phenol (6f). Yield 84%; m.p. 212 1C;
of the reaction (as monitored by TLC), the reaction mixture was IR (KBr, nmax, cmꢀ1): 3289 (secondary amine –NH), 3012 (aromatic
cooled and poured into crushed ice. The resulting product was ring –CH), 1621 (–CQN), 1378 (Ar–CH3); 1H NMR (400 MHz, DMSO-
filtered, washed with cold water for several times and recrys- d6): d 2.06 (s, 3H, CH3), 2.30 (s, 3H, CH3), 2.83 (dd, 1H, CH2, J =
tallized from hot ethanol to give compounds 6a–l.
11.6 Hz, 16.4 Hz, C4-H pyrazoline), 3.33 (dd, 1H, CH2, J = 11.2 Hz,
16.4 Hz, C4-H pyrazoline), 4.55 (td, 1H, CH, J = 11.2 Hz, 16.4 Hz,
4.4.1. 50-(1H-Imidazol-1-yl)-30-methyl-10,5-diphenyl-3,4-
dihydro-10H,2H-3,40-bipyrazole (6a). Yield 78%; m.p. 241 1C; IR C5-H pyrazoline), 6.76–7.81 (m, 11H, Ar–H + 1H, NH), 9.63 (1H, OH);
(KBr, nmax, cmꢀ1): 3288 (secondary amine –NH), 2950 (aromatic ESI-MS (m/z): = 385.90 (M + 1); anal. calcd (%) for C22H20N6O: C,
ring –CH), 1590 (–CQN), 1375 (Ar–CH3); 1H NMR (400 MHz, 68.73; H, 5.24; N, 21.86. Found: C, 68.83; H, 5.25; N, 21.88.
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4.4.7. 30-Methyl-50-(4-methyl-1H-imidazol-1-yl)-10,5-diphenyl-
Paper
1
2949 (aromatic ring –CH), 1591 (–CQN), 1375 (Ar–CH3); H NMR
3,4-dihydro-10H,2H-3,40-bipyrazole (6g). Yield 76%; m.p. 249 1C; (400 MHz, DMSO-d6): d 2.31 (s, 3H, CH3), 2.84 (dd, 1H, CH2, J =
IR (KBr, nmax, cmꢀ1): 3339 (secondary amine –NH), 2996 (aromatic 11.6 Hz, 16.4 Hz, C4-H pyrazoline), 3.27 (dd, 1H, CH2, J = 11.2 Hz,
ring –CH), 1641 (–CQN), 1370 (Ar–CH3); 1H NMR (400 MHz, 16.4 Hz, C4-H pyrazoline), 4.50 (td, 1H, CH, J = 11.2 Hz, 16.4 Hz,
DMSO-d6): d 2.05 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.87 (dd, 1H, C5-H pyrazoline), 6.73–7.89 (m, 11H, Ar–H + 1H, NH), 9.68 (1H, OH);
CH2, J = 9.6 Hz, 16.4 Hz, C4-H pyrazoline), 3.60 (dd, 1H, CH2, J = ESI-MS (m/z): = 399.10 (M + 1); anal. calcd (%) for C23H22N6O: C,
6.8 Hz, 17.2 Hz, C4-H pyrazoline), 4.56 (t, 1H, CH, J = 6.0 Hz, C5-H 69.33; H, 5.57; N, 21.09. Found: C, 69.26; H, 5.58; N, 21.21.
pyrazoline), 6.85–7.89 (m, 12H, Ar–H + 1H, NH); ESI-MS (m/z): =
4.5. General procedure for the synthesis of substituted 5-(5-
(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazol-4-yl)-3-phenyl-4,5-
dihydroisoxazoles (7a–l)
383.50 (M + 1); anal. calcd (%) for C23H22N6: C, 72.23; H, 5.80; N,
21.97. Found: C, 72.05; H, 5.80; N, 22.18.
4.4.8. 5-([1,10-Biphenyl]-4-yl)-30-methyl-50-(4-methyl-1H-
imidazol-1-yl)-10-phenyl-3,4-dihydro-10H,2H-3,40-bipyrazole (6h). A mixture of pyrazolic chalcones 5a–l (1.0 mmol), hydroxyl-
Yield 82%; m.p. 239 1C; IR (KBr, nmax, cmꢀ1): 3286 (secondary amine hydrochloride (1.5 mmol) and ethanol (5 mL) was
amine –NH), 2999 (aromatic ring –CH), 1631 (–CQN), 1374 refluxed for 1 h by using glacial acetic acid (1–2 drops) as the
(Ar–CH3); 1H NMR (400 MHz, DMSO-d6): d 2.07 (s, 3H, CH3), catalyst. After completion of the reaction (as monitored by
2.33 (s, 3H, CH3), 2.94 (dd, 1H, CH2, J = 11.2 Hz, 16.4 Hz, C4-H TLC), the reaction mixture was cooled and poured into crushed
pyrazoline), 3.36 (dd, 1H, CH2, J = 11.2 Hz, 16.4 Hz, C4-H ice. The resulting product was filtered, washed with cold water
pyrazoline), 4.54 (td, 1H, CH, J = 3.2 Hz, 10.8 Hz, C5-H pyrazo- for several times and recrystallized from hot ethanol to give
line), 7.05–7.89 (m, 16H, Ar–H + 1H, NH); ESI-MS (m/z): = 459.7 compounds 7a–l.
(M + 1); anal. calcd (%) for C29H26N6: C, 75.96; H, 5.71; N, 18.33.
Found: C, 76.05; H, 5.80; N, 28.08.
4.5.1. 5-(5-(1H-Imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazol-
4-yl)-3-phenyl-4,5-dihydroisoxazole (7a). Yield 77%; m.p. 249 1C;
4.4.9. 5-(4-Methoxyphenyl)-30-methyl-50-(4-methyl-1H-imidazol- IR (KBr, nmax, cmꢀ1): 3010 (aromatic ring –CH), 1587 (–CQN),
1-yl)-10-phenyl-3,4-dihydro-10H,2H-3,40-bipyrazole (6i). Yield 76%; 1520 (N–O), 1374 (Ar–CH3); 1H NMR (400 MHz, DMSO-d6): d
m.p. 249 1C; IR (KBr, nmax, cmꢀ1): 3342 (secondary amine –NH), 2.34 (s, 3H, CH3), 2.90 (dd, 1H, CH2, J = 3.2 Hz, 16.4 Hz, C4-H
2937 (aromatic ring –CH), 1651 (–CQN), 1375 (Ar–CH3); 1H NMR isoxazoline), 3.30 (dd, 1H, CH2, J = 3.2 Hz, 16.4 Hz, C4-H
(400 MHz, DMSO-d6): d 2.12 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.88 (dd, isoxazoline), 4.55 (t, 1H, CH, J = 10.8 Hz, C5-H isoxazoline),
1H, CH2, J = 6.0 Hz, 16.4 Hz, C4-H pyrazoline), 3.13 (dd, 1H, CH2, J = 6.33–7.87 (m, 13H, Ar–H); ESI-MS (m/z): = 370.10 (M + 1); anal.
7.6 Hz, 16.4 Hz, C4-H pyrazoline), 3.93 (s, 3H, CH3),4.41 (t, 1H, CH, calcd (%) for C22H19N5O: C, 71.53; H, 5.18; N, 18.96. Found: C,
J = 11.2 Hz, C5-H pyrazoline), 6.10–7.78 (m, 11H, Ar–H + 1H, NH); 71.46; H, 5.12; N, 19.06.
ESI-MS (m/z): = 413.3 (M + 1); anal. calcd (%) for C24H24N6O: C,
4.5.2. 5-(5-(1H-Imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazol-
4-yl)-3-(biphenyl-4-yl)-4,5-dihydroisoxazole (7b). Yield 83%;
69.88; H, 5.86; N, 20.37. Found: C, 70.05; H, 5.80; N, 20.58.
4.4.10. 5-(4-Bromophenyl)-30-methyl-50-(4-methyl-1H-imidazol- m.p. 229 1C; IR (KBr, nmax, cmꢀ1): 3017 (aromatic ring –CH),
1
1-yl)-10-phenyl-3,4-dihydro-10H,2H-3,40-bipyrazole (6j). Yield 69%; 1630 (–CQN), 1549 (N–O), 1374 (Ar–CH3); H NMR (400 MHz,
m.p. 239 1C; IR (KBr, nmax, cmꢀ1): 3321 (secondary amine –NH), DMSO-d6): d 2.29 (s, 3H, CH3), 2.93 (dd, 1H, CH2, J = 6.0 Hz,
2981 (aromatic ring –CH), 1599 (–CQN), 1368 (Ar–CH3); 1H NMR 12.4 Hz, C4-H isoxazoline), 3.34 (dd, 1H, CH2, J = 12.4 Hz,
(400 MHz, DMSO-d6): d 2.11 (s, 3H, CH3), 2.45 (s, 3H, CH3), 2.89 17.6 Hz, C4-H isoxazoline), 4.52 (t, 1H, CH, J = 10.8 Hz, C5-H
(dd, 1H, CH2, J = 11.6 Hz, 16.4 Hz, C4-H pyrazoline), 3.28 (dd, 1H, isoxazoline), 6.80–7.63 (m, 17H, Ar–H); ESI-MS (m/z): = 446.30
CH2, J = 16 Hz, 16.4 Hz, C4-H pyrazoline), 4.45 (t, 1H, CH, J = (M + 1); anal. calcd (%) for C28H23N5O: C, 75.49; H, 5.20; N,
11.2 Hz, C5-H pyrazoline), 6.10–7.77 (m, 11H, Ar–H + 1H, NH); 15.72. Found: C, 75.46; H, 5.12; N, 15.86.
ESI-MS (m/z): = 462.30 (M + 1), 463.20 (M + 2); anal. calcd (%) for
4.5.3. 5-(5-(1H-Imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazol-
C23H21BrN6: C, 59.88; H, 4.59; N, 18.22. Found: C, 59.76; H, 4.60; 4-yl)-3-(4-methoxyphenyl)-4,5-dihydroisoxazole (7c). Yield 73%;
N, 18.28.
m.p. 235 1C; IR (KBr, nmax, cmꢀ1): 3010 (aromatic ring –CH),
1
4.4.11. 4-(3-(4-Fluorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)-3- 1587 (–CQN), 1537 (N–O), 1379 (Ar–CH3); H NMR (400 MHz,
methyl-5-(4-methyl-1H-imidazol-1-yl)-1-phenyl-1H-pyrazole (6k). DMSO-d6): d 2.32 (s, 3H, CH3), 2.94 (dd, 1H, CH2, J = 6.4 Hz,
Yield 86%; m.p. 219 1C; IR (KBr, nmax, cmꢀ1): 3344 (secondary 9.6 Hz, C4-H isoxazoline), 3.23 (dd, 1H, CH2, J = 6.0 Hz, 7.2 Hz,
amine –NH), 2969 (aromatic ring –CH), 1611 (–CQN), 1372 C4-H isoxazoline), 3.92 (s, 3H, CH3),4.60 (t, 1H, CH, J = 10.0 Hz,
(Ar–CH3); 1H NMR (400 MHz, DMSO-d6): d 2.11 (s, 3H, CH3), C5-H isoxazoline), 7.26–8.23 (m, 12H, Ar–H); ESI-MS (m/z): =
2.42 (s, 3H, CH3), 2.89 (dd, 1H, CH2, J = 11.6 Hz, 16.4 Hz, C4-H 400.50 (M + 1); anal. calcd (%) for C23H21N5O2: C, 69.16; H, 5.30;
pyrazoline), 3.27 (dd, 1H, CH2, J = 15.6 Hz, 16.4 Hz, C4-H N, 17.53. Found: C, 68.98; H, 5.22; N, 17.91.
pyrazoline), 4.43 (t, 1H, CH, J = 10.8 Hz, C5-H pyrazoline),
4.5.4. 5-(5-(1H-Imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazol-
6.02–7.72 (m, 11H, Ar–H + 1H, NH); ESI-MS (m/z): = 401.30 4-yl)-3-(4-bromophenyl)-4,5-dihydroisoxazole (7d). Yield 76%;
(M + 1); anal. calcd (%) for C23H21FN6: C, 68.98; H, 5.29; N, m.p. 233 1C; IR (KBr, nmax, cmꢀ1): 3019 (aromatic ring –CH),
20.99. Found: C, 68.86; H, 5.18; N, 21.12.
1601 (–CQN), 1515 (N–O), 1379 (Ar–CH3); 1H NMR
4.4.12. 4-(5-(3-Methyl-5-(4-methyl-1H-imidazol-1-yl)-1-phenyl- (400 MHz, DMSO-d6): d 2.44 (s, 3H, CH3), 2.90 (dd, 1H, CH2,
1H-pyrazol-4-yl)-4,5-dihydro-1H-pyrazol-3-yl)phenol (6l). Yield 86%; J = 12 Hz, 16.4 Hz, C4-H isoxazoline), 3.26 (dd, 1H, CH2, J =
m.p. 219 1C; IR (KBr, nmax, cmꢀ1): 2935 (secondary amine –NH), 16.4 Hz, 16.4 Hz, C4-H isoxazoline), 4.46 (t, 1H, CH, J = 10.8 Hz,
2908 | New J. Chem., 2014, 38, 2902--2910
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1
C5-H isoxazoline), 6.00–7.73 (m, 12H, Ar–H); ESI-MS (m/z): = 1596 (–CQN), 1521 (N–O), 1368 (Ar–CH3); H NMR (400 MHz,
449.00 (M + 1), 450.80 (M + 2); anal. calcd (%) for C22H18BrN5O: DMSO-d6): d 2.09 (s, 3H, CH3), 2.44 (s, 3H, CH3), 2.89 (dd, 1H,
C, 58.94; H, 4.05; N, 15.62. Found: C, 58.98; H, 3.96; N, 15.71. CH2, J = 12 Hz, 16.4 Hz, C4-H isoxazoline), 3.28 (dd, 1H, CH2, J =
4.5.5. 5-(5-(1H-Imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazol- 16.4 Hz, 16.8 Hz, C4-H isoxazoline), 4.46 (t, 1H, CH, J = 10.8 Hz,
4-yl)-3-(4-fluorophenyl)-4,5-dihydroisoxazole (7e). Yield 86%; C5-H isoxazoline), 5.98–7.78 (m, 11H, Ar–H); ESI-MS (m/z): =
m.p. 219 1C; IR (KBr, nmax, cmꢀ1): IR (KBr, nmax, cmꢀ1): 2979 463.20 (M + 1), 464.80 (M + 2); anal. calcd (%) for C23H20BrN5O:
(aromatic ring –CH), 1654 (–CQN), 1525 (N–O), 1369 (Ar–CH3); C, 59.57; H, 4.36; N, 15.15. Found: C, 59.67; H, 4.33; N, 15.09.
1H NMR (400 MHz, DMSO-d6): d 2.43 (s, 3H, CH3), 2.88 (dd, 1H,
4.5.11. 3-(4-Fluorophenyl)-5-(3-methyl-5-(4-methyl-1H-imidazol-
CH2, J = 11.6 Hz, 16.4 Hz, C4-H isoxazoline), 3.28 (dd, 1H, CH2, 1-yl)-1-phenyl-1H-pyrazol-4-yl)-4,5-dihydroiso xazole (7k). Yield
J = 16.4 Hz, 16.8 Hz, C4-H isoxazoline), 4.48 (t, 1H, CH, J = 11.2 86%; m.p. 219 1C; IR (KBr, nmax, cmꢀ1): 2965 (aromatic ring
Hz, C5-H isoxazoline), 5.97–7.77 (m, 12H, Ar–H); ESI-MS (m/z): = –CH), 1613 (–CQN), 1542 (N–O), 1372 (Ar–CH3); 1H NMR
388.40 (M + 1); anal. calcd (%) for C22H18FN5O: C, 68.21; H, 4.68; (400 MHz, DMSO-d6): d 2.08 (s, 3H, CH3), 2.42 (s, 3H, CH3),
N, 18.08. Found: C, 68.18; H, 4.66; N, 18.01.
2.88 (dd, 1H, CH2, J = 12 Hz, 16.4 Hz, C4-H isoxazoline), 3.26
4.5.6. 4-(5-(5-(1H-Imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazol- (dd, 1H, CH2, J = 15.6 Hz, 16.8 Hz, C4-H isoxazoline), 4.46 (t, 1H,
4-yl)-4,5-dihydroisoxazol-3-yl)phenol (7f). Yield 86%; m.p. 219 1C; CH, J = 11.2 Hz, C5-H isoxazoline), 6.29–7.71 (m, 11H, Ar–H); ESI-
IR (KBr, nmax, cmꢀ1): 3015 (aromatic ring –CH), 1619 (–CQN), 1529 MS (m/z): = 401.90 (M + 1); anal. calcd (%) for C23H20FN5O: C,
(N–O), 1378 (Ar–CH3); 1H NMR (400 MHz, DMSO-d6): d 2.32 (s, 3H, 68.81; H, 5.02; N, 17.45. Found: C, 69.04; H, 4.89; N, 17.69.
CH3), 2.87 (dd, 1H, CH2, J = 11.6 Hz, 16.4 Hz, C4-H isoxazoline),
4.5.12. 3-(4-Bromophenyl)-5-(3-methyl-5-(4-methyl-1H-
3.28 (dd, 1H, CH2, J = 10.8 Hz, 16.4 Hz, C4-H isoxazoline), 4.48 imidazol-1-yl)-1-phenyl-1H-pyrazol-4-yl)-4,5-dihydroisoxazole (7l).
(td, 1H, CH, J = 10.8 Hz, 16.4 Hz, C5-H isoxazoline), 6.70–7.76 Yield 86%; m.p. 219 1C; IR (KBr, nmax, cmꢀ1): 3012 (aromatic
1
(m, 12H, Ar–H), 9.59 (1H, OH); ESI-MS (m/z): = 386.20 (M + 1); anal. ring –CH), 1621 (–CQN), 1560 (N–O), 1373 (Ar–CH3); H NMR
calcd (%) for C22H19N5O2: C, 68.56; H, 4.97; N, 18.17. Found: C, (400 MHz, DMSO-d6): d 2.33 (s, 3H, CH3), 2.85 (dd, 1H, CH2, J =
68.45; H, 4.96; N, 18.29.
12.0 Hz, 16.4 Hz, C4-H isoxazoline), 3.27 (dd, 1H, CH2, J = 10.8 Hz,
4.5.7. 5-(3-Methyl-5-(4-methyl-1H-imidazol-1-yl)-1-phenyl- 16.4 Hz, C4-H isoxazoline), 4.48 (td, 1H, CH, J = 11.2 Hz, 16.4 Hz,
1H-pyrazol-4-yl)-3-phenyl-4,5-dihydroisoxazole (7g). Yield 80%; C5-H isoxazoline), 6.72–7.76 (m, 11H, Ar–H), 9.62 (1H, OH); ESI-
m.p. 250 1C; IR (KBr, nmax, cmꢀ1): 2995 (aromatic ring –CH), MS (m/z): = 400.30 (M + 1); anal. calcd (%) for C23H21N5O2: C,
1
1633 (–CQN), 1554 (N–O), 1370 (Ar–CH3); H NMR (400 MHz, 69.16; H, 5.30; N, 17.53. Found: C, 69.34; H, 4.99; N, 17.61.
DMSO-d6): d 2.07 (s, 3H, CH3), 2.30 (s, 3H, CH3), 2.87 (dd, 1H,
CH2, J = 11.2 Hz, 16.4 Hz, C4-H isoxazoline), 3.31 (dd, 1H, CH2,
J = 15.6 Hz, 16.4 Hz, C4-H isoxazoline), 4.53 (t, 1H, CH, J = 11.6
Hz, C5-H isoxazoline), 6.90–7.84 (m, 12H, Ar–H); ESI-MS (m/z): =
Acknowledgements
384.50 (M + 1); anal. calcd (%) for C23H21N5O: C, 72.04; H, 5.52; SPS and PNK acknowledge UGC, New Delhi, for providing
N, 18.26. Found: C, 71.90; H, 5.42; N, 18.38.
research fellowships. The authors thank the Head, Department
4.5.8. 3-(Biphenyl-4-yl)-5-(3-methyl-5-(4-methyl-1H-imidazol-1- of Chemistry, Sardar Patel University for providing research
yl)-1-phenyl-1H-pyrazol-4-yl)-4,5-dihydroisoxazole (7h). Yield 85%; facilities and SICART, Vallabh Vidyanagar for FT-IR and ele-
m.p. 241 1C; IR (KBr, nmax, cmꢀ1): 2992 (aromatic ring –CH), 1632 mental analysis at concessional rates. We are also thankful to
1
(–CQN), 1532 (N–O), 1374 (Ar–CH3); H NMR (400 MHz, DMSO- Dhanji P. Rajani, Microcare Laboratory, Surat, for timely anti-
d6): d 2.08 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.93 (dd, 1H, CH2, J = microbial, antituberculosis and antimalarial screening of the
11.2 Hz, 16.4 Hz, C4-H isoxazoline), 3.34 (dd, 1H, CH2, J = 10.8 Hz, compounds reported herein.
16.4 Hz, C4-H isoxazoline), 4.52 (td, 1H, CH, J = 3.2 Hz, 10.8 Hz,
C5-H isoxazoline), 6.99–7.74 (m, 16H, Ar–H); ESI-MS (m/z): = 460.5
(M + 1); anal. calcd (%) for C29H25N5O: C, 75.80; H, 5.48; N, 15.24.
Found: C, 76.10; H, 5.43; N, 14.98.
References
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