A rapid and efficient solvent-free microwave-assisted synthesis of pyrazolone derivatives containing substituted isoxazole ring

Article abstract of DOI:10.1016/j.tet.2016.04.014

An efficient synthesis of 4-substituted pyrazolone derivatives was developed. 4-Substituted pyrazolone derivatives were synthesized in 78-97% yields starting from various 3-substituted isoxazole-5-carbaldehydes, ethyl acetoacetate and hydrazine under micr

Full text of DOI:10.1016/j.tet.2016.04.014

Accepted Manuscript
A rapid and efficient solvent-free microwave-assisted synthesis of pyrazolone
derivatives containing substituted isoxazole ring
Dawei Zhang, Yumin Zhang, Tianqi Zhao, Jing Li, Yaya Hou, Professor Qiang Gu
PII:
S0040-4020(16)30267-8
10.1016/j.tet.2016.04.014
TET 27657
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 January 2016
Revised Date: 1 April 2016
Accepted Date: 6 April 2016
Please cite this article as: Zhang D, Zhang Y, Zhao T, Li J, Hou Y, Gu Q, A rapid and efficient solvent-
free microwave-assisted synthesis of pyrazolone derivatives containing substituted isoxazole ring,
Tetrahedron (2016), doi: 10.1016/j.tet.2016.04.014.
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ACCEPTED MANUSCRIPT
Graphical Abstract:
A rapid and efficient solvent-free microwave-assisted synthesis of pyrazolone
derivatives containing substituted isoxazole ring
Dawei Zhang, Yumin Zhang, Tianqi Zhao, Jing Li, Yaya Hou, Qiang Gu *
College of Chemistry, Jilin University, Changchun 130012, P. R. China.
* Corresponding Author: Professor Qiang Gu.
Qianjin Street 2699, Changchun 130012, P. R. China.
Tel: (+86)-431-85168470 (3).
Fax: (+86)-431-85168441.
E-mail: guq@jlu.edu.cn.
An efficient synthesis of 4-substituted pyrazolone derivatives was developed via condensation
starting from ethylacetoacetate, hydrazine and isoxazole-aldehyde over solid support SiO2 under
microwave-assisted solvent-free conditions in satisfactory yields.

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A rapid and efficient solvent-free microwave-assisted synthesis of pyrazolone
derivatives containing substituted isoxazole ring
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Dawei Zhang, Yumin Zhang, Tianqi Zhao, Jing Li, Yaya Hou, Qiang Gu *
College of Chemistry, Jilin University, Changchun 130012, P. R. China.
* Corresponding Author: Professor Qiang Gu.
Qianjin Street 2699, Changchun 130012, P. R. China.
Tel: (+86)-431-85168470 (3).
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Fax: (+86)-431-85168441.
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E-mail: guq@jlu.edu.cn.
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Abstract
An efficient synthesis of 4-substituted pyrazolone derivatives was developed. 4-Substituted
pyrazolone derivatives were synthesized in 78–97% yields starting from various 3-substituted
isoxazole-5-carbaldehydes, ethyl acetoacetate and hydrazine under microwave irradiation and
solvent-free conditions, and were characterized by HRMS, FT-IR, H NMR and 13C NMR
1
spectroscopy. SiO2 was found to possess favorable catalytic activity and dispersancy for the
condensation reaction. The merits of this method include the environmentally friendly reaction
conditions, simple operation, broad substrate, satisfied yields and the reuse of the silica.
Moreover, the crystal structure of the compound 2-(4-chlorophenyl)-4-((1-(4-chlorophenyl)-5-
hydroxy-3-methyl-1H-pyrazol-4-yl)(3-phenylisoxazol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H)-
one (5a) in the monoclinic space group C2/c was presented.
Keywords 3-methyl-1H-pyrazol-5-ol, 5-methyl-1H-pyrazol-3(2H)-one, isoxazole, microwave
irradiation, solid support SiO2, solvent-free.
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1. Introduction
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In recent years, focusing on green chemistry by using eco-friendly benign media and reaction
conditions is one of the most fascinating developments in synthesis of organic compounds.
Microwave irradiation as an unconventional energy source has been increasingly used in organic
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synthesis. Microwave-assisted organic synthesis could obtain rapid, reproducible, and scalable
processes to prepare new compounds in high yields compared with the traditional heating
methods.1 It is reported that the organic compound was easily polarized to generate electronic
polarization, atom polarization, orientation polarization and interfacial polarization in the
microwave irradiation. Also, electronic and atom polarization rates are much faster than the
frequency of the microwave, and the other polarization rates are close to the frequency of the
microwave. Thus, microwave irradiation resulting in the motion state of organic molecules was
transformed from original thermal motion to alternating arrangement corresponding to the
frequency of the microwave, oscillation intensifying, further generating thermal efficiency. As a
result, microwave irradiation as dielectric heating is a process in which the organic compounds
consume electromagnetic energy, which can accelerate the reaction rate for several times, 10
times or even tens of thousands of times compared with the conventional heating.2
Pyrazoles and isoxazoles are important classes of heterocyclic compounds and attractive targets
both in medicinal chemistry and organic synthesis in recent years.3–8 Pyrazoles, especially
1H-pyrazol-5(4H)-one derivatives including 4,4’-(arylmethylene)bis(1H-pyrazol-5-ols)s are not
only a very useful synthetic intermediate, but also an important pharmacophore found in a large
number of biologically active and potential therapeutic compounds.9–11 These compounds have
been widely used in significant antipyretic,12 antidepressant,13 antibacterial,14 antiviral,15
antitumor,16 antiinflammatory.17 Moreover, a number of these compounds have been considered
as the chelating and extracting reagents for different metal ions.18,19 Some of the pyrazolone
derivatives are now included in many commercialized drugs for brain ischemia and myocardial
ischemia.20,21
One-pot tandem Knoevenagel–Michael reaction is one of the most broadly used methods for
preparing 4,4’-(arylmethylene)bis(1H-pyrazol-5-ol)s via three-component condensation of
aldehydes with 2 equiv of 3-methyl-1-phenyl-5-pyrazolone. In the last few years, some catalysts
have been applied to access these compounds, such as acetic acid or piperidine,22 cesium fluoride
(CsF),23 3-aminopropylated silica gel,24 heteropolyacids,25,26 sodium dodecyl sulfate (SDS),27
ceric ammonium nitrate (CAN),15 Na+-MMT-[pmim]HSO4,28 1,3,5-tris(hydrogensulfato) benzene
(THSB),29 benzyltriethylammonium chloride,30 ZnAl2O4 nanoparticles,31 silica-bonded S-sulfonic
acid (SBSSA),32 LiOH·H2O,33 [Cu(3,4-tmtppa)](MeSO4)4,34 and so on. However, the synthesis of
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4-substituted-((5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-aryl-isoxazol-5-yl)methyl)-5-methyl-1H-
pyrazol-3(2H)-ones (4-substituted pyrazolone derivatives) was rarely reported using one-pot
tandem Knoevenagel–Michael reaction, although few literature has reported about 4-substituted
pyrazolone derivatives synthesized via the condensation reaction of aromatic aldehydes with
3-methyl-1-phenyl-5-pyrazolone.35,36 It is known that many of the methods reported above suffer
from one or more limitations such as long reaction time, strongly acidic or basic conditions, high
solvent consumption, difficulty in handling and separation of catalyst, use of expensive catalysts
and also occurrence of side reactions that restrict their usage in practical applications.
Consequently, it is very significant to study and develop new, environmentally friendly scalable
synthetic routes able to construct fused 4-substituted pyrazolone derivatives in high yields.
Recently, the applications of the solid support Al2O3 and silica gel (SiO2) have drawn much
attention as they are the inexpensive, non-toxic dispersant and catalyst for many organic
transformations providing high yields. It is reported that Al2O3 and SiO2 in a solvent-free process
has greatly simplified the workup procedures.37,38 Also, it is found that
4,4’-(arylmethylene)bis(1H-pyrazol-5-ol)s with benzene ring and/or furan ring, could be
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synthesized using different catalyst 2-HEAP,39 or [Dsim]AlCl4 under solvent-free and
conventional heating condition. Nevertheless, solvent-free microwave-assisted method was not
yet introduced into the synthesis of 4-substituted pyrazolone derivatives. Considering the above
points, and in continuation of our interest in multi-component organic reactions, a convenient and
eco-friendly strategy for the synthesis of 4-substituted pyrazolone derivatives was designed
starting from 3-substituted isoxazole-5-carbaldehydes, ethylacetoacetate and hydrazine in
microwave irradiation using SiO2 as solid support under solvent-free condition. The structures of
1
the synthesized compounds were characterized by HRMS, FT-IR, H NMR and 13C NMR
spectroscopy. Moreover, the crystal structure of 2-(4-chlorophenyl)-4-((1-(4-chlorophenyl)-
5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-phenylisoxazol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H
)-one (5a) was described. It suggested that the used slovent and heating method in the process of
reaction played an important role in the single crystal formation.
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2. Results and discussion
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It is known that isoxazole is a versatile scaffold for the synthesis of varieties of complex natural
products, and functionalized isoxazole derivatives are active pharmacophores in many
pharmacologically important molecules,41–43 e.g. pyrazole derivatives with 3-substituted phenyl
isoxazole-ring which may extend the application of pyrazole derivatives. In the present work,
3-substituted isoxazole-5-carbaldehydes were synthesized in three steps starting form substituted
benzaldehyde according to the literature (Scheme 1).37 Aldoximes (2), a kind of important
intermediates for the whole synthetic process, were readily synthesized from aromatic aldehyde
(1) and hydroxylamine and prepared in over 95% yield in accordance with the literature.35
(3-Substituted phenylisoxazol-5-yl)methanols (3) were synthesized by one-pot method according
to the reported procedures via 1,3-dipolar cycloaddition reaction where the aldoximes were
subjected to successive reactions in just one reactor using ZnCl2 as a catalyst in the literature
(Scheme 1).44 A series of 3-substituted isoxazole-5-carbaldehydes were prepared by employing
intermediates 3 under I2, TEMPO and NaHCO3 (aq.) in 58%–93% yields (Table 1).
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Scheme 1. Synthetic pathway of 3-substituted isoxazole-5-carbaldehydes: i) 6 M NaOH (aq.), EtOH, reflux; ii)
a) NCS, DMF. b) propargyl alcohol, ZnCl2, Et3N.
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Table 1. Synthesis and yields of 3-substituted isoxazole-5-carbaldehydes
Entry Alcohol
3a
R
Product Time/h Yield/% a M.p./oC
4a 81 62–63
1
phenyl
9
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2
3
4
5
6
7
8
3b
3c
3d
3e
3f
2-methoxyphenyl
4-methoxyphenyl
4-methylphenyl
2-fluorophenyl
4-chlorophenyl
styryl
4b
4c
4d
4e
4f
14
14
10
9
58
66
81
88
82
92
93
74–76
72–74
70–72
71–73
9
126–128
102–103
222–224
3g
3h
4g
4h
8
3-nitrophenyl
8
103
104
105
106
107
108
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110
111
112
113
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a Isolated yields.
At the beginning of our investigation, referring to the previous literature,39,40 the synthesis of
4,4’-(arylmethylene)bis(1H-pyrazol-5-ol) with 3-substituted phenyl isoxazole-ring was explored
by employing 3-phenylisoxazole-5-carbaldehyde, ethyl acetoacetate and hydrazine using solid
support SiO2 under solvent-free condition. Michael addition and self-cycloaddition reaction
among 3-phenylisoxazole-5-carbaldehyde (1 mmol), 4-chlorophenylhydrazine (2 mmol), ethyl
acetoacetate (2 mmol) were readily carried out. The brown red product was obtained and
1
13
characterized by HRMS, FT-IR, H NMR and C NMR spectroscopy. The characterized result
showed: The band around 1732 cm–1 and 1701 cm–1 attributed to stretching vibration of C=O
presented in IR spectrum. Also, the chemical shift δ=173.33 ascribed to the resonances of C=O
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was found using DMSO as solvent in C NMR. It suggested that C=O group was found on the
synthesized product molecule. Accordingly, the structure of the product was confirmed to
2-(4-chlorophenyl)-4-((1-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-phenylisoxaz
ol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H)-one. The possible reason about the reaction not
obtaining 4,4’-(arylmethylene)bis(1H-pyrazol-5-ol) was related to the heating method and the
solvent used in the course of reaction.
To find an appropriate reaction medium for the solid synthesis of 5a, under otherwise similar
experimental conditions, the effects of different heating conditions, solid support, and different
reaction temperatures on the yield of the desired product in the presence/absence of solvent are
summarized in Table 2.
Table 2. Synthesis of 5a under different reaction conditions a
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Entry
1
Media
Time
Temp./ oC
Reflux
Reflux
Reflux
Reflux
70
Yield b/ %
Trace
N. D.
N. D.
Trace
42
C2H5OH
4 h
2
CH3CN
5 h
3
C7H8
6 h
4
THF
4 h
5
Solvent-free (M.W.)
SiO2 (M.W.)
SiO2 (M.W.)
SiO2 (M.W.)
SiO2 (M.W.)
SiO2 (M.W.)
SiO2 (M.W.)
SiO2 (M.W.)
Al2O3 (M.W.)
Al2O3 (M.W.)
Al2O3 (M.W.)
SiO2 (M.W.) (100–200 mesh)
SiO2 (M.W.) (300–400 mesh)
10 min
10 min
10 min
10 min
10 min
5 min
8 min
12 min
10 min
10 min
12 min
10 min
10 min
6
40
46
7
60
77
8
70
84
9
80
83
10
11
12
13
14
15
16
70
67
70
81
70
84
70
74
80
74
70
75
70
76
17
70
85
a
124
125
126
127
128
The reaction was conducted with aromatic aldehyde (1 mmol), ethyl acetoacetate (2 mmol) and
4-chlorophenyl hydrazine hydrochloride (2 mmol). N.D. (not detected), b Isolated product yields.
As shown in Table 2, the desired 5a was successfully synthesized with 42–84% yields in the
different reaction condition. To our delighted, microwave irradiation as a green and convenient
process, could accelerate the reaction and obtain the desired product in better yields (Table 2,
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entries 5–15) compared with traditional method (Table 2, entries 1–4). The yield used Al2O3 or
SiO2 as solid support under microwave irradiation (entries 6–12) is higher than that of the product
obtained both under conventional heating (Table 2, entries 1–4) and under microwave heating in
the absence of solid support (Table 2, entry 5), respectively. Also, the yield of loading equal SiO2
was higher than that of loading Al2O3. The reason might be SiO2 possessing bigger specific
surface area compared with the same loading Al2O3. To investigate the effect of specific surface
area on the yield, the different particle sizes of SiO2 were introduced into the reaction (Table 2,
entry 16 and 17). The yield was gradually increased from 76% (100–200 mesh) to 84% (200–300
mesh, Table 2, entry 8), then basically remained unchanged (85%, 300–400 mesh) with the
increase of the particle size of SiO2, which proved that the particle sizes of SiO2 assuredly
affected the catalysis and dispersancy of SiO2. Additionally, under conventional heating, the
yields of the obtained product were trace or no reaction (Table 2, entries 1–3). Hence, solid
support SiO2 and microwave irradiation were chosen to synthesize the other 4-substituted
pyrazolone derivatives.
Furthermore, the effect of microwave irradiation time and reaction temperature on the yields of
product 5a was investigated on solid support SiO2 under solvent-free microwave radiation
condition. It was observed that the yields of 5a were gradually increased to 84% (70oC), followed
decrease (46%) with increasing reaction temperatures from 40oC to 80oC (Table 2, entries 6–9).
As for the effect of microwave irradiation time on yields obtained similar law in which the
highest yield obtained was microwave irradiation for 10 min (Table 2, entries 8, 10–12).
Therefore, optimization for microwave reaction temperature and time revealed that the best yield
could be obtained with solvent-free solid support SiO2 at 70 oC for 10 min. (Table 2, entry 8, yield
is 84%).
Table 3. Synthesis of 4-substituted pyrazolone derivatives 5a–h and 6a–g on SiO2 solid support under
microwave irradiation a
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Entry Aldehyde R1
R2
Product Time b/ min T c/ oC Yield d/ %
1
2
4a
4b
4c
4d
4e
4f
phenyl
4-chlorophenyl
5a
5b
5c
5d
5e
5f
10
10
10
10
10
10
12
12
8
70
70
70
70
70
70
80
80
60
60
60
60
60
60
60
84
90
87
87
86
83
79
78
90
97
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94
94
90
87
2-methoxyphenyl 4-chlorophenyl
4-methoxyphenyl 4-chlorophenyl
3
4
4-methylphenyl
2-fluorophenyl
4-chlorophenyl
styryl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
H
5
6
7
4g
4h
4a
4b
4c
4d
4e
4f
5g
5h
6a
6b
6c
6d
6e
6f
8
3-nitrophenyl
phenyl
9
10
11
12
13
14
15
2-methoxyphenyl H
4-methoxyphenyl H
8
8
4-methylphenyl
2-fluorophenyl
4-chlorophenyl
styryl
H
H
H
H
8
8
8
4g
6g
9
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a The reaction was conducted with aromatic aldehyde (1 mmol), ethyl acetoacetate (2 mmol) and hydrazine (2
mmol). b Reaction time. c Reaction temperature. d Isolated product yields.
Having been optimized the reaction conditions for the model system (Table 2, entry 8) was
chosen to explore the scope and limitations of this protocol (Table 3). As shown in Table 3, all
scanned reactants afforded the corresponding 4-substituted pyrazolone derivatives in excellent
yields (78–97%). It was relatively sensitive to isoxazole terminal aldehyde bearing varieties of
functional groups. When benzene ring on isoxazole terminal aldehydes was substituted by ortho-
and para-position directing group (Table 3, entries 1–6 and 9–14), the yields of the synthesized
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compounds were higher than that of benzene ring substituted by meta-position directing group
(Table 3, entries 7–8, 15). The reason might be that eletrophilicity of the aldehyde was
diminished when benzene ring on isoxazole terminal aldehyde was substituted by meta-position
directing group.
Finally, recyclability of solid support SiO2 was examined through the reaction of
3-phenylisoxazole-5-carbaldehyde, ethyl acetoacetate and 4-chlorophenylhydrazine under
microwave irradiation (Fig. 1). As showed in Fig. 1, solid support SiO2 could be easily recovered
and reused at least five times without any significant loss of yield. Besides, the satisfied result
was also obtained when the reaction was circulated five times.
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Fig. 1. Recycle of silica under microwave irradiation a, b
.
a
173
174
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177
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183
The reaction was conducted with aromatic aldehyde (1 mmol), ethyl acetoacetate (2 mmol) and
4-chlorophenylhydrazine (2 mmol). b Isolated product yields.
1
The structures of 4-substituted pyrazolone derivatives were confirmed by FT-IR, H and 13C
NMR and HRMS spectra analysis. With compounds 5b–5h as examples, the –CH3 protons on
pyrazole ring and –CH– protons exhibited resonances at δ 2.34–2.36 ppm and δ 5.21–5.30 ppm
using DMSO as solvent, while the resonances for the corresponding –CH3 and –CH– carbon
atom were observed peaks at δ 11.89–11.98 ppm and δ 27.85–28.04 ppm, respectively.
Besides, summarizing the previous work35,45,46 found the structure of the synthesized
compound 5a have six conceivable structures (Scheme 2) due to bearing active hydroxyl group,
carbonyl group, benzene ring and several heterocycle rings from the tandem
Knoevenagel–Michael reaction.
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Scheme 2. Probable structures of compound 5a
As shown in scheme 2, six possible structures (I–VI) of compound 5a were proposed. To
confirm the structure of 5a, crystals of compound suitable for X-ray crystal structure
determination were slowly grown from methanol at about 40oC for three days. The structure of 5a
was determined by single crystal X-ray diffraction analysis. All non-hydrogen atoms were refined
anisotropically. N−H hydrogen was located from difference electron density maps. Other
hydrogen atoms were included in idealized position and were allowed to ride. The details of
crystallographic collection and refinement data are given in Table 4. Hydrogen-Bond Geometries
for 5a are given in Table 5. The ORTEP drawing of molecule structure is shown in Fig 2.
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Fig. 2. Molecular structure of 5a. The thermal ellipsoids are drawn at 30% probability levels.
Table 4. Crystal Data and Structure Refinement for Compound 5a
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5a
Data
C32 H31Cl2N5O5
636.52
Formula
Fw
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293(2)
Temperature / K
Monoclinic
C2/c
Crystal system
Space group
28.207(6)
13.384(3)
16.643(3)
90
a/ Å
b/ Å
c/ Å
α/˚
92.46(3)
90
β/˚
γ/˚
6277(2)
8
Volume(Å3)
Z
1.347
Dcalcd (Mg m–3)
F(000)
2656
3.00o to 27.48o
range for data collection
Limiting indices
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I>2(I)]
R indices (all data)
Largest diff. peak and hole/ e.A–3
–36 ≤ h ≤ 35, –17 ≤ k ≤17, –21≤ l ≤ 21
7150 / 0 / 408
1.067
a
b
R1 = 0.0568, wR2 = 0.1733
a
b
R1 = 0.0856, wR2 = 0.1939
0.362 and –0.445
2
2 2
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198
a R1 = ∑||Fo|–|Fc||/ ∑|Fo|. b wR2 = [∑[ w (Fo –Fc2)2] / ∑[ w (Fo ) ]]1/2
Table 5. Hydrogen-Bond Geometries for 5a
structure
D–H···A
d(D–H)
(Å)
d(H···A)
(Å)
d(D···A)
(Å)
<(DHA)
(deg)
O(2)–H(2)···O(3)
O(4)–H(4)···O(5)
O(5)–H(5A)···N(3)#1
C(24)–H(24)···O(2)
0.82
0.82
0.82
0.93
1.71
2.531(3)
2.695(4)
2.863(3)
2.977(4)
173.0
175.5
172.1
109.3
5a
1.88
2.05
2.54
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C(26)–H(26)···O(3)
C(21)–H(21)···O(3)#2
C(30)–H(30)···O(4)
N(5)–H(100)···O(4)
C(30)–H(30)···Cl(1)#3
C(29)–H(29)···Cl(1)#3
0.93
2.38
2.915(3)
3.579(3)
3.520(4)
2.713(3)
3.531(3)
3.507(3)
116.3
156.1
145.5
166(3)
124.4
126.1
0.93
2.71
0.93
2.71
0.76(3)
0.93
1.97(3)
2.92
0.93
2.88
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211
212
213
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219
220
221
Symmetry transformations used to generate equivalent atoms:
#1 x,-y+1,z+1/2; #2 x,-y,z-1/2; #3 -x+2,y+1,-z+1/2.
Compound 5a crystallizes in the monoclinic space group C2/c. Due to the enol tautomerism,
the two dihydral angles between the two five-membered rings and the two phenyl plane are
different, being 142.5o (the angle between the 1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-ol
C11/C12/C13/N2/N3 and the phenyl ring C19/C20/C21/C22/C23/C24) and 25.5o (the angle
between the 2-(4-chlorophenyl)-5-methyl-1H-pyrazol-3(2H)-one C15/C16/C17/N4/N5 and the
phenyl ring C25/C26/C27/C28/C29/C30), respectively. Meanwhile, the C10 atom becomes a
chiral atom and has a distorted tetrahedral structure. The bond angles around the C10 atom being
112.75(19)o (C(1)–C(10)–C(16)), 111.4(2)o (C(1)–C(10)–C(12)), 113.3(2)o (C(16)–C(10)–C(12)),
106.2o (C(1)–C(10)–H(10)), 106.2o (C(16)–C(10)–H(10)), 106.2o (C(12)–C(10)–H(10)),
respectively. The dihedral angles between the three five-membered rings are 117.0o
(C15/C16/C17/N4/N5 and C1/C2/C3/N1/O1), 85.6o (C1/C2/C3/N1/O1 and C11/C12/C13/N2/N3),
and 114.8o (C15/C16/C17/N4/N5 and C11/C12/C13/N2/N3), respectively. The dihedral angle
between the isoxazole ring (C1/C2/C3/N1/O1) and the phenyl ring (C4/C5/C6/C7/C8/C9) bonded
to isoxazole ring is 14.7o. The packing of 5a was stabilized by intramolecular and intermolecular
hydrogen bonds, shown in Figs 3–4. The hydrogen-bond geometries for 5a are summarized in
Table 5. In the pack of 5a, the molecules form one-dimensioned chains through C30−H30···Cl1
and C29−H29···Cl1 hydrogen bonds with the graph-set motifs R2 (5),47 as shown in Fig. 3. There
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also exist intramolecular C26−H26···O3 hydrogen bond with the graph-set motif S(6) and
intramolecular O2−H2···O3 hydrogen bond with the graph-set motif S(8). The two methanol
solvent molecules are linked together through intermolecular O4−H4···O5 hydrogen bond. There
also exist intermolecular hydrogen bonds between the one-dimensioned chain and the solvent
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molecules to form graph-set motifs R2 (7) through N5−H100···O4 and C30−H30···O4 hydrogen
bonds. The chains are further linked together through O5−H5A···N3 and C21−H21···O3 to form
three-dimensioned network, shown in Fig. 4.
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Fig. 3. 1-D chains formed by C–H···Cl hydrogen bonds. Green dashed lines: C–H···Cl hydrogen bonds ; Blue
dashed lines: N–H···O hydrogen bonds; Red dashed lines: O–H···O hydrogen bonds; Yellow dashed lines:
C–H···O hydrogen bonds.
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Fig. 4. Packing of 5a. (Only two methanol molecules are shown for clarity.) Green dashed lines: C–H···Cl
hydrogen bonds; Blue dashed lines: N–H···O hydrogen bonds; Red dashed lines: O–H···O hydrogen bonds;
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Yellow dashed lines: C–H···O hydrogen bonds.
Therefore, it can be seen from single crystal structure analysis of 5a (Table 4, Table 5, Fig. 3
and Fig. 4) that 5a (Scheme 2d) from recrystallizing in methanol is stable, which was in
accordance with the characterized structure by HRMS, FT-IR, H NMR and 13C NMR
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spectroscopy. As for the other structure compounds were not obtained mainly resulting from
microwave heating. Thus, based on the structure of the obtained 5a could infer the tentative
reaction mechanism for the formation of 4-substituted pyrazolone derivatives is shown in Scheme
3. Firstly, compound 7 nucleophilicly attacked β-keto esters 6, the intermediate hydrazone was
obtained. Amino group on hydrazone subsequently nucleophilicly attacked itself carbonyl group
to remove a molecular ethanol and cyclize to intermediate 8. Then, intermediate 8 interconverted
the stable intermediate 9. Further, the formation of intermediate 10 by the nucleophilic addition
of intermediate 9 to 3-substituted isoxazole-5-carbaldehydes 1 followed by dehydration.48 The
next step is a Michael addition of the second molecule intermediate 9 to intermediate 11. Finally,
the target product 5 is formed by tautomeric proton shift.
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Scheme 3. Proposed mechanism for the one-pot pseudo-three-component synthesis of 4-substituted pyrazolone
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derivatives under microwave irradiation
3. Conclusions
In conclusion, a green method for the synthesis of 4-substituted pyrazolone derivatives under
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solvent-free conditions using microwave irradiation has been presented. SiO2 has been proved to
be an efficient dispersant and a favorable catalyst for the reaction as it is inexpensive,
easy-to-handle, commercially available and reusable. Fifteen desired 4-substituted pyrazolone
derivatives bearing substituted isoxazole ring were obtained in 78–97% yields. Therefore, the
method is an important contribution to the 4,4’-(arylmethylene)-(1H-pyrazol-5-ol and
1H-pyrazol-5-one) compounds synthesis pathways, and can be extended to the synthesis of the
other heterocyclic compounds. Besides, the synthesis of more 4-substituted pyrazolone
derivatives compounds and biological tests of the synthesized compounds are being studied in
our laboratory. We believe that the synthesized 4-substituted pyrazolone derivatives bearing
isoxazole ring compounds can be used for many practical application in sterilization, antiviral and
anticancer fields.
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4. Experimental
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4.1. General Remarks
Various substituted benzaldehydes were of analytical-reagent grade from Aladdin reagent Co
(China). and used without further purification. The other solvents and reagents used were
supplied by Tianjin Tiantai Chemical Co. Ltd (China) and and Beijing Chemical Plant (China).
All melting points were determined on an XT−4 melting point apparatus (China) and were
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uncorrected. H and 13C NMR spectra were measured using a Bruker AVANCE-500 NMR
(Germany) spectrometer and with TMS as an internal standard. The chemical shift is given in δ
relative to TMS. HRMS was collected using an Agilent 1290-micrOTOF Q II spectrometer
(USA). FT-IR spectra were obtained as KBr pellets using an IRAffinity-1 instrument (Shimadzu,
Japan) in the range of 500 – 4000 cm–1. An MCL-3-type microwave reactor (200 W, single-mode)
Sichuan University (China) with a thermometer for microwave application was used in all
experiments.
4.2. General synthesis process for 3-substituted isoxazole-5-carbaldehydes
3-Substituted isoxazole-5-carbaldehydes were synthesized according to reported procedures.37
(3-Phhenylisoxazol-5-yl)methanols (5.0 mmol) were dissolved into benzene (10 mL). An aqueous
solution of sodium bicarbonate (13 mL, 1.2 mol/L) was added into the benzene slurry at room
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temperature. Then, the mixed solid TEMPO (0.5 mmol) was added and solid iodine (10 mmol)
dissolved in alcohol was added into the reaction mixture. The reaction mixture was then aged for
10–12 h at room temperature; the reaction was monitored by TLC. The crude product was diluted
with ethyl acetate (15 mL). The batch was washed with Na2S2O3 and transferred to a separatory
funnel, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The organic layers
were mixed and dried over anhydrous sodium sulfate for 30 min, filtrated and evaporated under
vacuum to give the crude product which was purified by column chromatography (silica gel,
200–300 mesh) using petroleum ether/ethyl acetate (ϕr = 5 : 1) to furnish the product. The yields
of obtained 3-substituted isoxazole-5-carbaldehydes products were 58–92 %.
4.3. General synthesis process for 4-substituted-((5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-
aryl-isoxazol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H)-ones
SiO2 or Al2O3 (200–300 mesh, pH 6–7, 1.0 g) was added to a mixture of ethylacetoacetate (2.0
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mmol) and hydrazine (2.0 mmol). The reaction mixture was irradiated in a microwave at 60 C
for 5–10 min. 3-substituted isoxazole-5-carbaldehydes (1.0 mmol) was added to a mixture. The
o
reaction mixture was irradiated in a microwave at 70 C for 5–10 min. The reaction was
monitored by TLC. The crude products were directly purified by column chromatography using
ethyl acetate/methanol (ϕr = 10 : 1) to afford 5a–h and 6a–g.
4.4 Crystal structure determination for compounds 5a
The single crystal X-ray diffraction data for compound 5a was collected on a Rigaku R-AXIS
RAPID IP diffractometer equipped with graphite-monochromated Mo-Kα radiation (λ = 0.71073
Å), operating at 293±2 K. The structure was solved by direct method49 and refined by full-matrix
least squares based on F2 using the SHELXTL 5.1 software package.50 CCDC–1440588 (5a)
contains the supplementary crystallographic data for this paper. These data can be obtained free
of charge at www.ccdc.cam.ac.uk/deposit or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44-1223-336-033; E-mail:
deposit@ccdc.cam.ac.uk.
4.5 Spectroscopic data for the products
4.5.1.
2-(4-chlorophenyl)-4-((1-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-
o
phenylisoxazol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H)-one (5a). Yield: 84%, mp 160–162 C.
IR (KBr) (ν/cm–1) 3647, 3320, 3118, 3069, 3044, 2977, 2920, 2789, 2752, 1732, 1701, 1605,
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1567, 1493, 1446, 1404, 1275, 1092, 1013, 920, 829, 692, 592; H NMR (500 MHz, DMSO) δ:
13.89 (s, 1H), 7.87 – 7.83 (m, 2H), 7.77 (d, J = 8.9 Hz, 4H), 7.52 (d, J = 8.8 Hz, 4H), 7.49 – 7.45
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(m, 3H), 6.80 (d, J = 0.9 Hz, 1H), 5.25 (s, 1H), 2.35 (s, 6H); C NMR (126 MHz, DMSO) δ:
173.33, 165.13, 162.23, 148.72, 147.03, 134.14, 131.78, 130.48, 129.42, 129.33, 129.15, 127.03,
122.43, 100.80, 27.96, 14.52; HRMS (EI): calcd for C30H24Cl2N5O3 [M+H]+ 572.1256,
[M+H+2]+ 574.1256, found 572.1286, 574.1256.
4.5.2.
2-(4-chlorophenyl)-4-((1-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-(2-
methoxyphenyl)isoxazol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H)-one (5b). Yield: 90%, mp
209–211 C. IR (KBr) (ν/cm–1) 3626, 3343, 3137, 3096, 3013, 2974, 2940, 2835, 2790, 2758,
o
1742, 1701, 1605, 1573, 1497, 1468, 1402, 1275, 1174, 1088, 1022, 829, 773, 602; 1H NMR (500
MHz, DMSO) δ: 13.96 (s, 1H), 7.78 – 7.74 (m, 4H), 7.70 (dd, J = 7.7, 1.7 Hz, 1H), 7.52 (d, J =
8.8 Hz, 4H), 7.48 – 7.43 (m, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.61 (d, J =
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0.9 Hz, 1H), 5.26 (d, J = 6.1 Hz, 1H), 3.80 (s, 3H), 3.18 (s, 2H), 2.36 (s, 6H); C NMR (126
MHz, DMSO) δ: 171.98, 159.89, 157.30, 154.49, 147.07, 137.76, 135.52, 131.86, 129.36, 129.32,
122.37, 121.14, 117.84, 112.70, 103.53, 56.18, 49.03, 27.85, 11.93; HRMS (EI): calcd for
C31H26Cl2N5O4 [M+H]+ 602.1362, [M+H+2]+ 604.1362, found 602.1394, 604.1369.
4.5.3.
2-(4-chlorophenyl)-4-((1-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-(4-
methoxyphenyl)isoxazol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H)-one (5c). Yield: 87%, mp
151–153 C. IR (KBr) (ν/cm–1) 3647, 3346, 3076, 3001, 2930, 2831, 1723, 1701, 1609, 1573,
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1493, 1429, 1254, 1173, 1092, 1013, 829, 611; H NMR (500 MHz, DMSO) δ: 13.88 (s, 1H),
7.78 (dd, J = 8.6, 6.5 Hz, 6H), 7.52 (d, J = 8.8 Hz, 4H), 7.01 (d, J = 8.8 Hz, 2H), 6.71 (s, 1H),
5.22 (s, 1H), 3.80 (s, 3H), 2.34 (s, 6H); 13C NMR (126 MHz, DMSO) δ: 172.95, 161.83, 161.04,
160.95, 156.20, 147.02, 130.13, 129.32, 128.51, 122.42, 121.56, 114.81, 100.49, 55.69, 27.92,
11.92; HRMS (EI): calcd for C31H26Cl2N5O4 [M+H]+ 602.1362, [M+H+2]+ 604.1362, found
602.1391, 604.1365.
4.5.4.
2-(4-chlorophenyl)-4-((1-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-(p-
tolyl)isoxazol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H)-one (5d). Yield: 87%, mp 219–221 oC. IR
(KBr) (ν/cm–1) 3669, 3360, 3069, 3039, 2954, 2920, 2810, 1738, 1701, 1593, 1579, 1493, 1431,
1
1180, 1094, 1012, 826, 654; H NMR (500 MHz, DMSO) δ: 13.89 (s, 1H), 7.77 (d, J = 8.9 Hz,
4H), 7.73 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.8 Hz, 4H), 7.27 (d, J = 8.1 Hz, 2H), 6.74 (s, 1H),
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5.23 (s, 1H), 2.34 (d, J = 2.6 Hz, 9H); C NMR (126 MHz, DMSO) δ: 173.14, 167.66, 162.13,
147.04, 140.15, 129.99, 129.98, 129.33, 126.93, 126.36, 122.43, 119.97, 100.63, 27.95, 21.36;
HRMS (EI): calcd for C31H26Cl2N5O3 [M+H]+ 586.1413, [M+H+2]+ 588.1413, found 586.1431,
588.1416.
4.5.5.
2-(4-chlorophenyl)-4-((1-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-(2-
fluorophenyl)isoxazol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H)-one (5e). Yield: 86%, mp
163–165 C. IR (KBr) (ν/cm–1) 3636, 3308, 3073, 3027, 2920, 2849, 2790, 2740,1730, 1711,
o
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1618, 1572, 1495, 1458, 1404, 1267, 1180, 1092, 1013, 953, 831, 590; H NMR (500 MHz,
DMSO) δ: 13.96 (s, 1H), 7.87 (td, J = 7.7, 1.7 Hz, 1H), 7.76 (d, J = 8.9 Hz, 4H), 7.58 – 7.54 (m,
1H), 7.52 (d, J = 8.9 Hz, 4H), 7.35 (ddd, J = 15.2, 9.8, 4.8 Hz, 2H), 6.65 (d, J = 2.1 Hz, 1H), 5.30
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(s, 1H), 2.36 (s, 6H); C NMR (126 MHz, DMSO) δ: 173.40, 164.38, 160.88, 158.89, 157.86,
147.11, 132.73, 130.25, 129.73, 129.40, 125.54, 122.47, 117.10, 117.04, 102.66, 27.91, 11.96;
HRMS (EI): calcd for C30H23Cl2FN5O3 [M+H]+ 590.1162, [M+H+2]+ 592.1162, found 590.1191,
592.1168.
4.5.6.
2-(4-chlorophenyl)-4-((1-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-(4-
chlorophenyl)isoxazol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H)-one (5f). Yield: 83%, mp
205–207 C. IR (KBr) (ν/cm–1) 3647, 3321, 3069, 3045, 2970, 2922, 2797, 2751, 1740, 1700,
o
1603, 1572, 1493, 1427, 1271, 1174, 1092, 1013, 949, 826, 590; 1H NMR (500 MHz, DMSO) δ:
13.86 (s, 1H), 7.89 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.9 Hz, 4H), 7.53 (t, J = 8.2 Hz, 6H), 6.84 (s,
1H), 5.25 (s, 1H), 2.35 (s, 6H); 13C NMR (126 MHz, DMSO) δ: 173.65, 165.21, 161.31, 147.02,
135.17, 130.17, 129.52, 129.33, 128.83, 128.02, 122.43, 119.95, 100.87, 27.96, 11.91; HRMS
(EI): calcd for C30H23Cl3N5O3 [M+H]+ 606.0866, [M+H+2]+, 608.0866, found 606.0902,
608.0878.
4.5.7.
(E)-2-(4-chlorophenyl)-4-((1-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-
styrylisoxazol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H)-one (5g). Yield: 79%, mp 161–163 oC. IR
(KBr) (ν/cm–1) 3647, 3360, 3061, 3034, 2947, 2922, 2790, 2751, 1732, 1701, 1605, 1573, 1493,
1431, 1275, 1174, 1092, 1013, 829, 694, 592; 1H NMR (500 MHz, DMSO) δ: 13.88 (s, 1H), 7.78
(d, J = 8.9 Hz, 4H), 7.64 (d, J = 7.4 Hz, 2H), 7.53 (d, J = 8.8 Hz, 4H), 7.38 (t, J = 7.4 Hz, 2H),
7.32 (dd, J = 13.5, 6.3 Hz, 1H), 7.18 (d, J = 16.6 Hz, 1H), 6.68 (s, 1H), 5.21 (s, 1H), 2.34 (s, 6H);
13C NMR (126 MHz, DMSO) δ: 172.36, 167.08, 162.09, 159.16, 147.07, 136.69, 136.23, 130.17,
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129.35, 129.20, 127.48, 122.41, 119.95, 116.19, 99.91, 27.85, 11.90; HRMS (EI): calcd for
C32H26Cl2N5O3 [M+H]+ 598.1413, [M+H+2]+ 600.1413, found 598.1403, 600.1378.
4.5.8.
2-(4-chlorophenyl)-4-((1-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-(3-
nitrophenyl)isoxazol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H)-one (5h). Yield: 78%, mp
o
207–209 C. IR (KBr) (ν/cm–1) 3649, 3308, 3080, 3052, 2974, 2922, 2790, 2758, 1732, 1701,
1605, 1566, 1493, 1403, 1274, 1174, 1092, 1013, 829, 731, 592; 1H NMR (500 MHz, DMSO) δ:
13.86 (s, 1H), 8.65 – 8.62 (m, 1H), 8.32 (dd, J = 10.9, 5.0 Hz, 2H), 7.80 – 7.76 (m, 5H), 7.52 (d, J
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= 8.9 Hz, 4H), 7.07 (d, J = 1.1 Hz, 1H), 5.30 (d, J = 0.8 Hz, 1H), 2.36 (s, 6H); C NMR (126
MHz, DMSO) δ: 174.29, 160.80, 153.67, 148.79, 147.05, 136.77, 133.40, 131.94, 131.19, 130.75,
130.16, 129.34, 125.10, 122.42, 121.45, 119.96, 101.27, 28.04, 11.98; HRMS (EI): calcd for
C30H23Cl2N6O5 [M+H]+ 617.1107, [M+H+1]+ 618.1107, found 617.1067, 618.1091.
4.5.9.
4-((5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-phenylisoxazol-5-yl)methyl)-5-methyl-1H-
pyrazol-3(2H)-one (6a). Yield: 90%, mp 200–202 oC. IR (KBr) (ν/cm–1) 3648, 3183, 3117, 3052,
2960, 2928, 1730, 1703, 1597, 1489, 1468, 1281, 1213, 1146, 1032, 928, 768, 600, 513; 1H NMR
(500 MHz, DMSO) δ: 11.34 (s, 2H), 7.81 (dd, J = 6.6, 3.0 Hz, 2H), 7.47 (dd, J = 5.0, 1.7 Hz, 3H),
6.52 (s, 1H), 5.07 (s, 1H), 2.11 (s, 6H); 13C NMR (126 MHz, DMSO) δ: 175.04, 162.19, 161.90,
151.50, 130.37, 129.45, 129.35, 126.92, 101.74, 100.45, 27.66, 10.62; HRMS (EI): calcd for
C18H18N5O3 [M+H]+ 352.1410, found 352.1408.
4.5.10.
4-((5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-(2-methoxyphenyl)isoxazol-5-yl)methyl)-5-
o
methyl-1H-pyrazol-3(2H)-one (6b). Yield: 97%, mp 177–179 C. IR (KBr) (ν/cm–1) 3648, 3177,
3116, 3002, 2956, 2934, 2836, 1732, 1705, 1603, 1509, 1472, 1432, 1281, 1252, 1117, 1024, 949,
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758, 665; H NMR (600 MHz, DMSO) δ: 11.43 (s, 2H), 7.70 (dd, J = 7.7, 1.8 Hz, 1H), 7.47 –
7.44 (m, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.05 – 7.02 (m, 1H), 6.47 (s, 1H), 5.06 (s, 1H), 3.81 (s,
3H), 2.12 (s, 6H); 13C NMR (151 MHz, DMSO) δ: 173.59, 159.85, 159.62, 157.31, 145.73,
131.84, 129.29, 121.20, 118.05, 112.72, 103.59, 101.94, 56.22, 27.58, 10.68; HRMS (EI): calcd
for C19H20N5O4 [M+H]+ 382.1515, found 382.1509.
4.5.11.
4-((5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-(4-methoxyphenyl)isoxazol-5-yl)methyl)-5-
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methyl-1H-pyrazol-3(2H)-one (6c). Yield: 95%, mp 197–199 C. IR (KBr) (ν/cm–1) 3647, 3184,
3117, 3001, 2955, 2934, 2836, 1735, 1703, 1611, 1528, 1455, 1431, 1297, 1254, 1028, 835, 608;
1H NMR (500 MHz, DMSO) δ: 11.33 (s, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H),
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6.45 (s, 1H), 5.03 (s, 1H), 3.80 (s, 3H), 2.11 (s, 6H); C NMR (126 MHz, DMSO) δ: 174.67,
167.01, 161.51, 160.95, 156.13, 128.39, 121.77, 114.84, 101.79, 100.17, 55.70, 27.64, 10.62;
HRMS (EI): calcd for C19H20N5O4 [M+H]+ 382.1515, found 382.1510.
4.5.12. 4-((5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-(p-tolyl)isoxazol-5-yl)methyl)-5-methyl-1H-
pyrazol-3(2H)-one (6d). Yield: 94%, mp 206–208 oC. IR (KBr) (ν/cm–1) 3647, 3183, 3117, 3026,
2955, 2924, 1732, 1704, 1601, 1526, 1460, 1429, 1279, 1141, 1042, 951, 822, 600; 1H NMR (500
MHz, DMSO) δ: 11.36 (s, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.48 (s, 1H),
5.04 (s, 1H), 2.34 (s, 3H), 2.11 (s, 6H); 13C NMR (126 MHz, DMSO) δ: 174.84, 166.59, 161.80,
140.00, 130.00, 126.81, 126.55, 119.95, 101.78, 100.30, 27.64, 21.35, 10.61; HRMS (EI): calcd
for C19H20N5O3 [M+H]+ 366.1566, found 366.1562.
4.5.13.
4-((3-(2-fluorophenyl)isoxazol-5-yl)(5-hydroxy-3-methyl-1H-pyrazol-4-yl)methyl)-5-
methyl-1H-pyrazol-3(2H)-one (6e). Yield: 94%, mp 190–192 C. IR (KBr) (ν/cm–1) 3647, 3185,
3112, 3039, 2980, 2934, 1732, 1704, 1597, 1507, 1472, 1405, 1268, 1221, 1146, 1042, 953, 762,
662; 1H NMR (600 MHz, DMSO) δ: 11.40 (s, 2H), 7.87 (td, J = 7.7, 1.7 Hz, 1H), 7.57 – 7.52 (m,
o
13
1H), 7.39 – 7.31 (m, 2H), 6.45 (d, J = 3.1 Hz, 1H), 5.10 (s, 1H), 2.13 (s, 6H). C NMR (151
MHz, DMSO) δ: 175.10, 166.95, 160.77, 159.11, 157.47, 132.70, 129.55, 125.63, 117.16, 117.13,
102.64, 101.76, 27.64, 10.67. HRMS (EI): calcd for C18H17FN5O3 [M+H]+ 370.1315, found
370.1318.
4.5.14.
4-((3-(4-chlorophenyl)isoxazol-5-yl)(5-hydroxy-3-methyl-1H-pyrazol-4-yl)methyl)-5-
methyl-1H-pyrazol-3(2H)-one (6f). Yield: 90%, mp 204–206 C. IR (KBr) (ν/cm–1) 3648, 3190,
3112, 3052, 2980, 2923, 1735, 1704, 1603, 1507, 1455, 1427, 1273, 1219, 1145, 1092, 1015, 951,
835, 608; 1H NMR (600 MHz, DMSO) δ: 11.33 (s, 2H), 7.86 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6
Hz, 2H), 6.57 (s, 1H), 5.07 (s, 1H), 2.11 (s, 6H); 13C NMR (151 MHz, DMSO) δ: 175.09, 160.77,
159.11, 157.46, 152.24, 132.70, 129.53, 125.62, 117.21, 117.02, 102.64, 101.74, 27.64, 10.67;
HRMS (EI): calcd for C18H17ClN5O3 [M+H]+ 386.1020, found 386.1034.
o
4.5.15.
(E)-4-((5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-styrylisoxazol-5-yl)methyl)-5-methyl-
o
1H-pyrazol-3(2H)-one (6g). Yield: 87%, mp 198–200 C. IR (KBr) (ν/cm–1) 3648, 3183, 3112,
3033, 2921, 1732, 1704, 1593, 1526, 1487, 1475, 1435, 1260, 1208, 1147, 1075, 1034, 964, 822,
1
754, 608; H NMR (500 MHz, DMSO) δ: 11.34 (s, 2H), 7.67 – 7.64 (m, 2H), 7.39 (dd, J = 8.1,
13
6.7 Hz, 3H), 7.36 – 7.31 (m, 2H), 6.43 (s, 1H), 5.01 (s, 1H), 2.10 (s, 6H); C NMR (126 MHz,
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DMSO) δ: 174.09, 162.01, 161.72, 152.09, 136.28, 136.26, 129.18, 129.16, 127.47, 116.40,
101.73, 99.64, 27.56, 10.59; HRMS (EI): calcd for C20H20N5O3 [M+H]+ 378.1566, found
378.1570.
Acknowledgements. We are grateful to Mr C. Y. Wang for NMR spectra, Mr Z. L. Wei for Ms
spectra and Ms Q. Su for X-ray.
References and notes
1. Baghbanzadeh, M.; Carbone, L.; Cozzoli P. D.; Kappe ,C. O. Angew. Chem. Int. Ed. 2011, 5, 11312–11359.
2. Jin, Q.; Dai, S.; Huang, K.; Microwave chemistry, Beijing: Science Press, 1999, 1st ed, p 13, 120–146.
3. Kalaria, P. N.; Satasia, S.P.; Raval, D.K. RSC. Adv. 2014, 4, 32353–32362.
4. Tantawy, A. S.; Nasr, M. N. A.; El-Sayed, M. A. A.; Tawfik, S. S. Med. Chem. Res. 2012, 21, 4139–4149.
5. Jadhav, S. Y.; Shirame, S.P.; Kulkarni, S. D.; Patil, S. B.; Pasale, S. K.; Bhosale, R. B. Bioorg. Med. Chem.
Lett. 2013, 23, 2575–2578.
6. Harigae, R.; Moriyama, K.; Togo, H. J. Org. Chem. 2014, 79, 2049−2058.
7. Barbachyn, M. R.; Cleek, G. J.; Dolak, L. A.; Garmon, S. A.; Morris, J. J. Med. Chem. 2003, 46, 284–302.
8. Pirrung, M. C.; Tumey, L. N.; Raetz, C. R. H.; Jackman, J. E.; Snehalatha, K. J. Med. Chem. 2002, 45,
4359–4370.
9. Kalaria, P. N.; Satasia, S. P.; Raval, D. K. New J. Chem. 2014, 38, 2902–2910.
10. Wei, F.; Zhao, B. X.; Huang, B.; Zhang, L.; Sun, C. H.; Dong, W. L.; Shin, D. S.; Miao, J. Y. Bioorg. Med.
Chem. Lett. 2006, 16, 6342–6347.
11. Abbasi-Tarighat, M.; Shahbazi, E.; Niknam, K. Food Chem. 2013, 138, 991–997.
12. Uramaru, N.; Shigematsu, H.; Toda, A.; Eyanagi, R.; Kitamura, S.; Ohta, S. J. Med. Chem. 2010, 53,
8727–8733.
13. Bailey, D. M.; Hansen, P. E.; Hlavac, A. G.; Baizman, E. R.; Pearl, J.; Defelice, A. F.; Feigenson, M. E. J.
Med. Chem. 1985, 28, 256–260.
14. Bhavanarushi, S.; Kanakaiah, V.; Bharath, G.; Gangagnirao, A.; Rani, J.V. Med. Chem. Res. 2014, 23,
158–167.
15. Sujatha, K.; Shanthi, G.; Selvam, N. P.; Manoharan, S.; Perumal, P. T.; Rajendran, M. Bioorg. Med. Chem.
Lett. 2009, 19, 4501–4503.
21

ACCEPTED MANUSCRIPT
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
16. Liu, J. J.; Zhao, M. Y.; Zhang, X.; Zhao, X.; Zhu, H. L. Mini. Rev. Med. Chem. 2013, 13, 1957–1966.
17. Sugiura, S.; Ohno, S.; Ohtani, O.; Izumi, K.; Kitamikado, T.; Asai, H.; Kato, K.; Hori, M.; Fujimura, H. J.
Med. Chem. 1977, 20, 80–85.
18. Modi, C. K.; Jani, D. H. Appl. Organometal. Chem. 2011, 25, 429–436.
19. Wisniewski, M. Z.; Surga, W. J.; Opozda, E. M. Transit. Met. Chem. 1994, 19, 353–354.
20. Nakagawa, H.; Ohyama, R.; Kimata, A.; Suzuki, T.; Miyata, N. Bioorg. Med. Chem. Lett. 2006, 16,
5939−5942.
21. Kessler, P.; Aybek, T.; Neidhart, G.; Dogan, S.; Bremerich, D. H.; Lischke, V.; Byhahan, C. J. Cardiothorac.
Vasc. Anesth. 2005, 19, 32−39.
22. Soleimani, E.; Ghorbani, S.; Taran, M.; Sarvary A. C. R. Chim. 2012, 15, 955–961.
23. Khan, K. M.; Muhammad, M. T.; Khan, I.; Perveen, S.; Voelter, W. Monatsh. Chem. 2015, 146, 1587–1590.
24. Sobhani, S.; Hasaninejad, A.; Maleki, M. F.; Parizi, Z. P. Synth. Commun. 2012, 42, 2245–2255.
25. Phatangare, K. R.; Padalkar, V. S.; Gupta, V. D.; Patil, V. S.; Umape, P. G.; Sekar, N. Synth. Commun. 2012,
42, 1349–1358.
26. Asieh, V.; Abolghasem, D.; Mehdi, P. Res. Chem. Intermed. 2015, 41, 8343−8354.
27. Wang, W.; Wang, S. X.; Qin, X. Y.; Li, J. T. Synth. Commun. 2005, 35, 1263–1269.
28. Shirini, F.; Seddighi, M.; Mazloumi, M.; Makhsous, M.; Abedini, M. J. Mol. Liq. 2015, 208, 291–297.
29. Karimi-Jaberi, Z.; Pooladian, B.; Moradi, M.; Ghasemi, E. Chin. J. Catal. 2012, 33, 1945–1949.
30. Shi, D.; Chen, J.; Wu, N.; Zhuang, Q.; Wang, X. Chin. J. Org. Chem. 2005, 25, 405–408.
31. Safaei-Ghom, J.; Khojastehbakht-Koopaei, B.; Shahbazi-Alavi, H. RSC Adv. 2014, 4, 46106–46113.
32. Niknam, K.; Saberi, D.; Sadegheyan, M.; Deris, A. Tetrahedron Lett. 2010, 51, 692−694.
33. Gouda, M. A.; Abu-Hashem, A. A. Green Chem. Lett. Rev. 2012, 5, 203–209.
34. Sobhani, S.; Safaei, E.; Hasaninejad, A. R.; Rezazadeh, S. J. Organomet. Chem. 2009, 694, 3027–3031.
35. Zang, H. J.; Su, Q. H.; Mo, Y. M.; Cheng, B. W. Ultrason. Sonochem. 2011, 18, 68–72.
36. Zang, H. J.; Su, Q. H.; Song, G.; Mo, Y. M.; Cheng, B. W. Chin. J. Chem. 2011, 29, 2202–2204.
37. Zhang, D. W.; Zhang, Y. M.; Zhang, Y. L.; Zhao, T. Q.; Liu, H. W.; Gan, Y. M.; Gu, Q. Chem. Pap. 2015, 69,
470–478.
38. Li, B. Z.; Gu, Q.; He, Y. H.; Zhao, T. Q.; Wang, S. J.; Kang, J.; Zhang, Y. M. C. R. Chim. 2012, 15,
784–792.
39. Zhou, Z. Q.; Zhang, Y. L. Green Chem. Lett. Rev. 2014, 7, 18–23.
22

ACCEPTED MANUSCRIPT
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
40. Khazaei, A.; Zolfigol, M. A.; Moosavi-Zare, A. R.; Asgari, Z.; Shekouhy, M.; Zare, A.; Hasaninejad, A.
RSC Adv. 2012, 2, 8010–8013.
41. Liu, J. H.; Yu, L. F.; Eaton, J. B.; Caldarone, B.; Cavino, K.; Ruiz, C.; Terry, M.; Fedolak, A.; Wang, D.;
Ghavami, A.; Lowe, D. A.; Brunner, D.; Lukas, R. J.; Kozikowski, A. P. J. Med. Chem. 2011, 54, 7280–7288.
42. Natale, N. R.; Rogers, M. E.; Staples, R.; Triggle, D. J.; Rutledge, A. J. Med. Chem. 1999, 42, 3087–3093.
43. Mirzaei, Y. R.; Bavili-Tabrizi, S.; Hashemi-Gohare, M.; Zare-Neirizi, H.; Edjlali, L. Org. Prep. Proced. Int.
2003, 35, 207–214.
44. Tanaka, K.; Inoue, S.; Murai, N.; Shirotori, S.; Nakamoto, K.; Abe, S.; Horii, T.; Miyazaki, M.; Hata, K.;
Watanabe, N.; Asada, M.; Matsukura, M. Chem. Lett. 2010, 39, 1033–1035.
45. Sobhani, S.; Nasseri, R.; Honarmand, M. Can. J. Chem. 2012, 90, 798–804.
46. Hasaninejed, A.; Kazerooni, M. R.; Zare, A. ACS Sustain. Chem. Eng. 2013, 1, 679−684.
47. Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N. L. Angew. Chem. Int. Ed. Engl. 1995, 34, 1555–1573.
48. Ma, R. Q.; Zhu, J.; Liu, J.; Chen, L. L.; Shen, X.; Jiang, H. L.; Li, J. Molecules 2010, 15, 3593–3601.
49. Sheldrick, G. M. SHELXS-97, Program for Crystal Structure Solution. University of Göttingen, Göttingen
1997.
50. Sheldrick, G. M. SHELXL-97, Program for Crystal Structure Refinement. University of Göttingen,
Göttingen 1997.
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