One-pot Synthesis of 3-phenyl-4-pyrazolylmethylene-isoxazol-(5H)-ones Catalyzed by Sodium Benzoate in Aqueous Media under the Influence of Ultrasound Waves: A Green Chemistry Approach

Article abstract of DOI:10.1002/jhet.2848

A series of 4-pyrazolylmethylene-3-phenylisoxazol-5(4H)-ones have been prepared from Knoevenagel condensation of pyrazole-4-carbaxaldehyde with isoxazolone precursors or via one-pot three-component cyclocondensation of pyrazole-4-carbaxaldehyde with β-ketoesters and hydroxylamine hydrochloride in the presence of sodium benzoate in water under the influence of ultrasonic waves. The merits of this method are efficient, clean, green, easy work-up, high yields, and shorter reaction time, and the catalyst could be recycled easily without affecting the catalytic activity.

Full text of DOI:10.1002/jhet.2848

Month 2017
One-pot Synthesis of 3-phenyl-4-pyrazolylmethylene-isoxazol-(5H)-ones
Catalyzed by Sodium Benzoate in Aqueous Media under the Influence of
Ultrasound Waves: A Green Chemistry Approach
*
and Pramod Kumar Dubey
Veera Swamy Konkala
Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, College of Engineering, Kukatpally,
Hyderabad, Telangana 500085, India
*
E-mail: veeruchem06@gmail.com
Additional Supporting Information may be found in the online version of this article.
Received August 26, 2016
DOI 10.1002/jhet.2848
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
A series of 4-pyrazolylmethylene-3-phenylisoxazol-5(4H)-ones have been prepared from Knoevenagel
condensation of pyrazole-4-carbaxaldehyde with isoxazolone precursors or via one-pot three-component
cyclocondensation of pyrazole-4-carbaxaldehyde with β-ketoesters and hydroxylamine hydrochloride in
the presence of sodium benzoate in water under the influence of ultrasonic waves. The merits of this method
are efficient, clean, green, easy work-up, high yields, and shorter reaction time, and the catalyst could be
recycled easily without affecting the catalytic activity.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
cavity during the activation process and accelerates the
reaction. Any factor that increases the hydrophobic effect
will increase the reaction rate [8–10]. The use of the
aqueous medium as solvent also reduces the harmful
effects of organic solvents on the environment.
Multicomponent reactions in water are one of the most
suitable methods for developing variety of organic
compounds under green conditions [1,2]. Water is one of
the best solvents because of its large applications such as
being environmentally friendly, safe, non-toxic, clean,
green, inexpensive, and readily available for many
organic transformations [3–5]. Also, use of water not
only diminishes the risk of organic solvents but also
enhances the rate of many chemical reactions. Thus, a
water-mediated reaction is very attractive from both the
economical and environmental point of view [6].
Moreover, because the pioneering studies by Breslow [7]
on Diels–Alder reactions, there has been an increasing
recognition that organic reactions could proceed well in
aqueous media offering key advantages over organic
solvents, such as rate enhancement and insolubility of the
final products, which facilitates their isolation. The
hydrophobic effect of water generates internal pressure
and promotes the association of reactants in the solvent
On the other hand, ultrasonic irradiation can be used as
an efficient technique for accelerating organic reactions
[11]. Compared with conventional method, ultrasonic
irradiation is widely applied to promote numerous organic
reactions in good yields and shorter reaction times [12].
Isoxazol-5(4H)-ones have attracted increasing interest
because of their significant pharmaceutical and therapeutic
properties, such as hypoglycaemic, immunosuppressive,
anti-inflammatory, and anti-bacterial activities [13–16]. In
addition, isoxazol core is a structural element in many
commercial pharmaceuticals [17–20] shown in Table 1.
Sodium benzoate inhibits yeasts and bacterial growth in
acidic medium; thus, it can use as safe, common food
preservative agent. In the United States, sodium benzoate
is classified as “generally recognized as safe.” It is permitted
to use in food materials up to a maximum level of 0.1%
© 2017 Wiley Periodicals, Inc.

V. S. Konkala and P. K. Dubey
Vol 000
Table 1
Examples of isoxazol active pharmaceuticals.
[21]. Although, it has been neglected as a catalyst for a long
time and less number of reactions carried by using it as cat-
alyst [22]. Therefore, the study of sodium benzoate as envi-
ronmentally benign catalyst appears to be very reasonable.
was taken as model reaction, and it was examined in the
presence of various bases in different solvents at room
temperature under ultrasonic irradiations (Scheme 2), the
obtained results are summarized in Table 2.
As shown in Table 2, the reaction was also checked
without the catalyst in which the reaction did not proceed
even after 1 h (Table 2, entry 1). Only sodium benzoate,
piperidine, and sodium acetate were effective in catalyzing
the reaction, and other catalysts did not work (Table 2,
entries 1–6). The basicity of different catalysts itself
sometimes plays an important role in the high catalytic
activity in base-catalyzed reactions. However, mention
must be made here that hydroxylamine hydrochloride was
active and would react with the base tempestuously.
Sodium benzoate was found to be the best because it
resulted in the highest yield of the desired product.
RESULTS AND DISCUSSION
The starting materials, 1-phenyl-3-aryl-1H-pyrazole-4-
carbaldehyde 4(a–e) were prepared by using Vilsmeier–
Haack reaction of acetophenone phenylhydrazone 3(a–e)
[23], which was obtained from acetophenone 1(a–e) and
phenyl hydrazine 2 in the presence of ethanol containing
a catalytic amount of acetic acid (Scheme 1).
In order to find the best reaction conditions for the
synthesis of isoxazolone derivatives, the one-pot three-
component condensation of 1,3-diphenyl-1H-pyrazole-4-
carbaldehyde 4a (1 mmol), ethyl benzoylacetate 5b
(1 mmol), and hydroxylamine hydrochl ride 6 (1 mmol)
The effect of the solvent was also tested for model
reaction. As it is clear from Table 2, the best results were
obtained in the presence of sodium benzoate in water as
Scheme 1. Synthesis of 1, 3-di-phenyl-1H-pyrazolin-5-(4H)-4-carbaldehyde 4(a–e).
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Scheme 2. Screening of different catalysts and solvents for synthesis of compound 7f.
precursor 8b (Scheme 3) was prepared from ethyl
Table 2
benzoylacetate 5b and hydroxylamine hydrochloride 6,
which further reacts with 1,3-diphenyl-1H-pyrazole-4-
carbaldehyde 4a to form the Knoevenagel product 7f
(Scheme 4) under the above optimized conditions. In this
method, the final product was obtained in 92% yield
within 5–15 min.
After screening of reaction conditions, sodium benzoate
in water was found to be the best condition for this multi-
component reaction. Although various catalysts and
solvent systems promoted the reaction to a good extent,
from the view-point of performance and eco-friendly
nature of sodium benzoate and water system under
ultrasonic irradiations was found to be best reaction
conditions. The scope and efficiency of the process was
explored under the optimized conditions. For this
purpose, a broad range of structurally diverse pyrazole-4-
carbaxaldehydes as well as β-ketoester hydroxylamine
hydrochloride (Scheme 5) were condensed and the results
are shown in Tables 3 and 4.
Recycling of catalyst. The possibility of recycling of the
catalyst was examined for model reaction under the
optimized conditions. Sodium benzoate is highly soluble
in water, and moreover, the resulting products are
insoluble in aqueous medium. After completion of
reaction, the insoluble products were separated by simple
filtration and recrystallized from suitable solvents. TLC
showed that there was no starting material or product in
the filtered solution. All of the substrates were transferred
to target products completely. The aqueous sodium
benzoate was recycled and reused with fresh starting
materials. The results of this study were shown in Figure 1
. The catalyst was successfully recycled six times without
any noticeable decrease in its catalytic activity. After sixth
recycling, the solvent was evaporated under reduced
pressure, and the solid was dried. The melting point of the
One-pot three-component reaction of 4a (1 mmol), 5b (1 mmol), and 6
(1 mmol) was carried out in the presence of various catalysts and solvents
under ultrasonic irradiation.
Time
(min)
Yields
(%)d
Entry
Solvent/catalyst
1
2
3
4
5
6
7
8
No catalyst/ethanol
NaOH/ethanol
KOH/ethanol
Na2CO3/ethanol
K2CO3/ethanol
NaHCO3/ethanol
(C2H5)3N/ethanol
Piperidine/ethanol
CH3COONa/ethanol
Sodium benzoate/ethanol
Sodium benzoate/CH3CN
Sodium benzoate/DMF
Sodium benzoate/H2O
Sodium benzoate/chloroform
Sodium benzoate/CH2Cl2
Sodium benzoate/H2O
65
60
60
60
60
60
60
40
55
35
60
60
30
60
60
85
Nila
Nila
Nila
Nila
Nila
Nila
80
76
60
72
9
10
11
12
13
14
15
16
52
Nila
88
Nilb
Nilb
82c
aIt refers to reaction that did not proceed and starting materials recovered.
bOxime formed between ethyl benzoyl acetate 6a and hydroxyl amine
hydrochloride.
cReaction carried out under conventional method.
dIt refers to isolated yields.
solvent (Table 2, entry 13). The use of various organic
solvents such as EtOH and CH3CN gave 80% and 72%
of 7f, respectively. In DMF, the reaction did not proceed
even after 60 min. (Table 2, entry 12). In other solvents,
such as chloroform and dichloromethane, formation of
oxime from 5b and 6 took place (Table 2, entries 14
and 15). Probably, the low yields obtained in organic
solvents are due to a low solubility of sodium benzoate
in these solvents.
Herein, we also report both ultrasound-promoted and
classical methodology for the synthesis of the titled
compound. In conventional method, the one-pot reaction
was stirred at room temperature for 85 min, which resulted
the final product in 82% of yield (Table 2, entry 16). It is
clear that, when the reaction is carried out under ultrasonic
irradiation, it gave good yields in a short time without
formation of any by products.
Scheme 3. Synthesis of isoxazolone 8(a,b).
Alternatively, the product 7f could also be prepared in a
step-wise manner. In this method, the isoxazolone
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Scheme 4. Knoevenagel condensation of 4a and 8a to form compound 7f.
Scheme 5. Synthesis of 4-pyrazolylmethylene isoxazol-5(4H)-ones derivatives 7(a–j).
Table 3
One-pot three-component synthesis of compound 7(a–j) (Method A).
Entry
1
Starting materials
Product 7(a–j)
Time (min)
32
Yield (%)
86
2
40
76
3
36
82
(Continued)
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Sodium Benzoate Catalysed One-pot, Three Component Synthesis of Pyrazolyl
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Table 3
(Continued)
Entry
4
Starting materials
Product 7(a–j)
Time (min)
36
Yield (%)
82
5
40
75
6
30
88
7
35
80
8
33
84
9
32
84
(Continued)
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V. S. Konkala and P. K. Dubey
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Table 3
(Continued)
Entry
10
Starting materials
Product 7(a–j)
Time (min)
36
Yield (%)
79
Table 4
Step-wise synthesis of compound 7(a–j) (Method A).
Entry
1
4(a–e)
8(a,b)
Product 7(a–j)
Time (min)
8
Yield (%)
90
2
15
83
3
15
85
4
12
85
5
15
74
(Continued)
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Sodium Benzoate Catalysed One-pot, Three Component Synthesis of Pyrazolyl
Isoxazolones under Green Conditions
Table 4
(Continued)
Entry
6
4(a–e)
8(a,b)
Product 7(a–j)
Time (min)
5
Yield (%)
92
7
10
86
8
9
86
9
9
88
10
12
76
recovered catalyst was measured to find the stability and
properties. The measured melting points of sodium
benzoate are matching to reported melting points. Hence,
we concluded that the properties of sodium benzoate are
stable under the applied conditions even after six recycles.
There are two possible steps for the formation of 7f in
the presence of sodium benzoate as catalyst, shown in
Scheme 6. In the first step, ethyl benzoylacetate 5b reacts
with hydroxylamine hydrochloride to afford the oxime
5b1, which loses one ethanol molecule and gives a cyclic
compound 8b. This 8b also can exist as enolic form 8b1
because of keto-enol tautomerism. In the second step, 8b1
losses it alcoholic proton and forms alkoxide ion, which
can generate carbanion. This carbanion develops a C═C
bond via Knoevenagel condensation with 1,3-diphenyl-
1H-pyrazole-4-carbaldehyde 4a very easily and brings the
product 3-methyl-4-pyrazolylmethylene-isoxazol-5(4H)-
one 7f.
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V. S. Konkala and P. K. Dubey
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Figure 1. Recyclability of the catalyst (reaction conditions: one-pot three-component reaction of 4a (1 mmol), 5b (1 mmol), and 6 (1 mmol) was carried
out in the presence of aqueous sodium benzoate under ultrasonic irradiation).
Scheme 6. Proposed mechanism for the one-pot synthesis of compound 7f in the presence of sodium benzoate. [Color figure can be viewed at
wileyonlinelibrary.com]
CONCLUSION
gel-G and visualization was performed using Iodine or
UV-light, IR spectra were recorded using PerkinElmer
spectrum version 10.03.02 instrument in KBr Pellets. H
NMR spectra were recorded in CDCl3/DMSO using 400-
MHz instrument. Mass spectra were recorded on an
Agilent LC–MS instrument giving only M+ values in
Q + 1 mode.
1
Further, this method offers many advantages, like eco-
friendly, economically cheaper, avoiding of hazardous
organic solvents, short reaction time, high yields,
reusable catalyst, and without isolation of intermediates
in one-pot synthesis, thus making it an attractive strategy
for the Knoevenagel condensation.
Synthesis of 4-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-
3-methylisoxazol-5(4H)-ones 7(a–j).
synthesis of compound 7f. A mixture of appropriate 1, 3-
di-phenyl-1H-pyrazolin-5-(4H)-4-carbaldehyde (4a,
Method A: one-pot
EXPERIMENTAL
2.48 g 10 mmol), Ethyl benzoylacetate (5b, 1.72 mL
10 mmol), hydroxyl amine hydrochloride (6, 0.69 g
10 mmol), and sodium benzoate (0.25 g) was taken in to
round-bottomed flask containing (25 mL) water. The
reaction mixture was placed in sonicator bath and
irradiated under ultrasonic vibrations for 30–42 min at
All the chemicals derivatives of acetophenones, phenyl
hydrazine, and β-ketoesters were obtained from
commercial sources and used without further purification.
Melting points were determined using open capillary
tube in sulphuric acid bath, TLC were run on Silica
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Isoxazolones under Green Conditions
room temperature until the TLC indicated the completion of
the starting materials. After the completion of the reaction,
the solid was separated out as yellow. The separated solid
was filtered, washed with water (2 × 15 mL), and dried to
obtain a crude product 7f. Then, the crude product was
recrystallized from hot ethanol to afford pure 7f.
Ar─H), δ = 7.58–7.62 (t, 2H, Ar─H), δ = 7.86–7.89 (d,
2H, Ar─H), δ = 9.65–9.68 (d, 1H pyrazole-H), LC–MS:
m/z 408; Anal. Calcd for: C20H14BrN3O2 C, 58.84; H,
3.46; N, 10.29; found: C, 58.66; H, 3.40; N, 10.11.
4-((3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)-
3-methylisoxazol-5(4H)-one (7e). This compound obtained as
1
pale yellow solid; mp 176–178°C; H NMR (400 MHz,
Method B: step-wise synthesis of compound 7f.
A
DMSO-d6/ TMS): δ = 2.36(s, 3H, ─CH3), δ = 4.32 (s, 3H,
─CH3), δ = 7.40–7.42 (m, 1H, C═C─H), δ = 7.44–7.52
(m, 5H, Ar─H), δ = 7.55–7.59 (t, 2H, Ar─H), δ = 7.82–
7.85 (d, 2H, Ar─H), δ = 9.59–9.64 (s, 1H, pyrazole-H),
LC–MS: m/z 358; Anal. Calcd for: C21H17N3O3: C, 70.18;
H, 4.77; N, 11.69; found: C, 71.20; H, 4.06; N, 11.52.
mixture of appropriate 1, 3-di-phenyl-1H-pyrazolin-5-
(4H)-4-carbaldehyde (4a, 2.48 10 mmol) 3-
g
phenylisoxazol-5(4H)-one (8b, 1.61 g 10 mmol) and
sodium benzoate (0.25 g) was taken in round bottomed
flask containing water (25 mL). The reaction mixture was
kept in sonicator bath and irradiated under ultrasonic
vibrations for 5–15 min at room temperature until the
TLC indicated the completion of the starting materials.
After the completion of the reaction, a yellow solid
separated out. The separated solid was filtered, washed
with water (2 × 15 mL), and dried to obtain a crude
product 7f. Then, the crude product was recrystallized
from hot ethanol to afford pure 7f.
4-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-3-phenylisoxa
zol-5(4H)-one (7f). This compound obtained as yellow
solid; mp 222–224°C;1H NMR (400 MHz, DMSO-d6/
TMS): δ = 7.38–7.39 (m, 1H, C═C─H), δ = 7.41–7.44
(m, 1H, Ar─H), δ = 7.45–7.49 (m, 7H, Ar─H),
δ = 7.67–7.69 (d, 2H, Ar─H), δ = 7.76–7.79 (m, 4H,
Ar─H), δ = 7.81–8.08 (d, 1H, Ar─H), δ = 9. 64 (s, 1H,
pyrazole-H), LC–MS: m/z 390; Anal. Calcd for:
C25H17N3O2: C, 76.71; H, 4.38; N, 10.74; found: C,
76.52; H, 4.30; N, 10.67.
Spectral data for compound 7(a–j). 4-((1,3-Diphenyl-1H-
pyrazol-4-yl)methylene)-3-methylisoxazol-5(4H)-one (7a).
This compound obtained as yellow solid; mp 216–218°C.
1H NMR (400 MHz, DMSO-d6/ TMS): δ = 2.24(s,3H,
─CH3), δ = 7.45–7.47 (m, 1H, C═C─H), δ = 7.54–7.57
(m, 6H, Ar─H), δ = 7.75–7.77 (t, 2H, Ar─H),
δ = 7.91–7.93 (d, 2H, Ar─H), δ = 9.84–9.86 (d, 1H
pyrazole-H), LC–MS: m/z 330; Anal. Calcd for:
C20H15N3O2: C, 72.94; H, 4.59; N, 12.76; found: C,
72.91; H, 4.57; N, 12.78.
4-((3-(3-Nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)-
3-phenylisoxazol-5(4H)-one
(7g).
This compound
obtained as yellow solid; mp 248–250°C; 1H NMR
(400 MHz, DMSO-d6/ TMS): δ = 7.40–7.42 (m, 1H,
C═C─H), δ = 7.45–7.48 (m, 2H, Ar─H), δ = 7.52–7.59
(m, 5H, Ar─H), δ = 7.63–7.64 (d, 2H, Ar─H),
δ = 7.72–8.16 (m, 5H, Ar─H), δ = 9.54 (s, 1H,
pyrazole-H), LC–MS: m/z 437; Anal. Calcd for:
C25H16N4O4: C, 68.80; H, 3.70; N, 12.84; found: C,
68.62; H, 3.78; N, 12.81.
3-Methyl-4-((3-(3-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)isoxazol-5(4H)-one (7b).
This compound
obtained as yellow solid; mp > 300°C. 1H NMR
(400 M Hz, DMSO-d6/ TMS): δ = 2.28(s, 3H, ─CH3),
δ = 7.42–7.47 (m, 1H, C═C─H), δ = 7.50–7.56 (m,
4-((3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)
-3-phenylisoxazol-5(4H)-one
(7h).
This compound
1
obtained as pale yellow solid; mp 220–224°C; H NMR
(400 MHz, DMSO-d6/ TMS): δ = 7.40–7.41 (m, 1H,
C═C─H), δ = 7.47–7.50 (m, 2H, Ar─H), δ = 7.54–7.59
(m, 5H, Ar─H), δ = 7.67–7.70 (d, 2H, Ar─H),
δ = 7.76–8.24 (m, 5H, Ar─H), δ = 9.65 (s, 1H, pyrazole-
H), LC–MS: m/z 426; Anal. Calcd for: C25H16ClN3O2: C,
5H, Ar─H),
δ
=
7.71–7.75 (m, 1H, Ar─H),
δ = 7.96–7.99 (m, 3H, Ar─H), δ = 9.84–9.86 (d, 1H
pyrazole-H), LC–MS: m/z 375; Anal. Calcd for:
C20H14N4O4; C, 64.17; H, 3.77; N, 14.97; found: C,
64.20; H, 3.62; N, 14.02.
4-((3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)
70.51; H, 3.79; N, 9.87; found: C, 71.25; H, 3.58; N, 9.77.
4-((3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)
-3-phenylisoxazol-5(4H)-one (7i). This compound obtained
-3-methylisoxazol-5(4H)-one
(7c).
This compound
obtained as yellow solid; mp 250–252°C; 1H NMR
(400 MHz, DMSO-d6/ TMS): δ = 2.33(s, 3H, ─CH3),
δ = 7.44–7.48 (m, 1H,C═C─H), δ = 7.51–7.57 (m, 5H,
Ar─H), δ = 7.62–7.68 (t, 2H, Ar─H), δ = 7.96–7.98 (d,
2H, Ar─H), δ = 9.82–9.83 (d,1H pyrazole-H), LC–MS:
m/z 364; Anal. Calcd for: C20H14ClN3O2: C, 66.03; H,
3.88; N, 11.55; found: C, 65.82; H, 3.55; N, 10.81.
as yellow solid; mp 274–278°C; 1H NMR (400 MHz,
DMSO-d6/ TMS): δ = 7.44–7.47 (m, 1H, C═C─H),
δ = 7.44–7.52 (m, 5H, Ar─H), δ = 7.55–7.59 (t, 2H,
Ar─H), δ = 7.82–7.85 (d, 2H, Ar─H), δ = 7.90–8.26 (m,
5H, Ar─H), δ = 9.65–9.68 (d, 1H, pyrazole-H), LC–MS:
m/z 468; Anal. Calcd for: C25H16BrN3O2: C, 63.84; H,
4-((3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)
3.43; N, 8.93; found: C, 64.42; H, 3.41; N, 8.86.
-3-methylisoxazol-5(4H)-one
(7d).
This compound
4-((3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)-
3-phenylisoxazol-5(4H)-one (7j). This compound obtained as
obtained as yellow solid; mp 224–228°C; 1H NMR
(400 MHz, DMSO-d6/ TMS): δ = 2.38(s, 3H, ─CH3),
δ = 7.40–7.42 (m, 1H, C═C─H), δ = 7.48–7.55 (m, 5H,
yellow solid; mp 230–232°C; 1H NMR (400 MHz,
DMSO-d6/ TMS): δ = 4.36 (s, 3H, ─CH3), δ = 7.39–7.42
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Acknowledgments. The authors are thankful to the authorities of
Jawaharlal Nehru Technological University Hyderabad, for
providing laboratory facilities. They also indebted to University
Grants Commission ,Govt. of India, New Delhi, for providing
financial support to one of them (K.V.S.) in the form of
UGC-SRF.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet