Synthesis of 3,5-diarylisoxazoles under solvent-free conditions using iodobenzene diacetate

Article abstract of DOI:10.1016/j.cclet.2013.07.022

A simple and efficient method has been developed for conversion of chalcone oximes to 3,5-diaryl isoxazoles in excellent yields under solvent-free conditions. The synthesized compounds were characterized by infrared spectroscopy, ¹H NMR, ¹³C NMR and HRMS.

Full text of DOI:10.1016/j.cclet.2013.07.022

Chinese Chemical Letters 24 (2013) 1045–1048
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Original article
Synthesis of 3,5-diarylisoxazoles under solvent-free conditions using
iodobenzene diacetate
Kondapalli Venkata Gowri Chandra Sekhar a,
,
*
Thripuraribhatla Venkata Naga Varuna Tara Sasank b, Hunsur Nagendra Nagesh a,
Narva Suresh a, Kalaga Mahalakshmi Naidu a, Amaroju Suresh a
a Department of Chemistry, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad 500 078, India
b Department of Pharmacy, Birla Institute of Technology and Science, Pilani 333 031, India
A R T I C L E I N F O
A B S T R A C T
Article history:
A simple and efficient method has been developed for conversion of chalcone oximes to 3,5-diaryl
isoxazoles in excellent yields under solvent-free conditions. The synthesized compounds were
characterized by infrared spectroscopy, 1H NMR, 13C NMR and HRMS.
Received 28 March 2013
Received in revised form 17 June 2013
Accepted 26 June 2013
ß 2013 Kondapalli Venkata Gowri Chandra Sekhar. Published by Elsevier B.V. on behalf of Chinese
Chemical Society. All rights reserved.
Available online 26 September 2013
Keywords:
Isoxazoles
Chalcones
Solid-state synthesis
Iodobenzene diacetate
1. Introduction
versatile use in solid-state organic reactions [12]. These reagents
are used in the synthesis of several heterocyclic compounds in
Isoxazoles represent an important class of aromatic hetero-
cycles, and are associated with a wide spectrum of biological
activities, such as antiviral [1], antimicrobial [2], anti-inflammato-
ry [3], anticonvulsant [4], antihyperglycemic [5], anticancer [6]
activity, etc.
In general, isoxazoles are obtained by two major routes: [3+2]
cycloaddition of alkenes/alkynes with nitrile oxides, or the reaction
of hydroxylamine with a three-carbon atom component [7,8].
Recently, synthesis of 3,5- and 3,4-disubstituted isoxazoles
through transition-metal-catalyzed [3+2] cycloaddition reactions
was also reported [9]. To date, a variety of other methods have also
been reported for synthesis of isoxazoles [10].
liquid and solid state [13].
In view of the above interest in these compounds and in
continuation of our studies on the cyclization of heterocyclic
compounds [14] we undertook to develop an efficient and
environmentally benign synthesis of 3,5-diarylisoxazoles that
proceed under solvent-free conditions. Herein, we report results
on the transformation of various substituted chalcone oximes to
3,5-diarylisoxazoles (Scheme 1) with iodobenzene diacetate that
leads to the expeditious formation of the title compounds in very
good yields. Chalcone oximes are prepared as per the literature
protocol [10f,g]. To the best of our knowledge, there is no report on
the synthesis of 3,5-diarylisoxazoles under solvent free conditions.
3,5-Diarylisoxazoles are also synthesized regioselectively by
the reaction of chalcones with hydroxylamine hydrochloride using
K2CO3 as solid support under microwave conditions [11]. However,
these methods usually are of limited scope and use harsh
conditions. Recently, organic reactions under solvent-free condi-
tions have received much attention due to advantages over the
conventional methods in terms of time, yields and relatively
benign conditions [12]. Presently, there is also a considerable
interest in organohypervalent iodine reagents because of their
2. Experimental
All starting materials were purified by standard methods before
use. All yields refer to isolated products after purification. Melting
points were determined in open capillaries using Bu¨chi 530
melting point apparatus without correction. The reactions were
monitored and the purity of the compounds checked by ascending
thin layer chromatography (TLC) on silica gel coated aluminium
plates (Merck 60 F254, 0.25 mm) using mixture of chloroform and
methanol. The developed plates were visualized under ultra violet
light at 254 and 366 nm. Infrared (IR) spectra were recorded as KBr
discs on a Schimadzu IR Prestige-21 FT-IR spectrophotometer
*
Corresponding author.
E-mail address: kvgcs@yahoo.com (K.V.G. Chandra Sekhar).
1001-8417/$ – see front matter ß 2013 Kondapalli Venkata Gowri Chandra Sekhar. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.07.022

1046
K.V.G. Chandra Sekhar et al. / Chinese Chemical Letters 24 (2013) 1045–1048
7.63–7.61 (d, 2H), 7.48–7.46 (d, 2H), 6.92 (s, 1H), 2.6 (s, 3H); 13C
NMR (100 MHz, CDCl3): 170.9, 168.1, 151.4, 146.3, 140.3, 132.7,
130.2, 129.1, 128.8, 126.9, 124.5, 115.6, 94.5, 22.9. HRMS calcd. for
16H11Cl2NO 304.1706, found 304.1729. IR (KBr, cmꢀ1):
823 (OOP
para substituent), 1623 (C55N).
5-(2,3-Dichlorophenyl)-3-(4-methylphenyl) isoxazole (2n): 1H
NMR (400 MHz, CDCl3): 8.61–8.67 (m, 1H), 7.82–7.78 (m, 1H),
7.76 (m, 1H), 7.58–7.56 (d, 2H), 7.39–7.37 (d, 2H), 6.83 (s, 1H), 2.3
(s, 3H); 13C NMR (100 MHz, CDCl3):
169.8, 164.2, 149.4, 138.3,
R
1
HO
d
H
N
C
n
PhI(OAc) , Neat
2
N
63 - 95%
1
R
2
O
H
R
2
d
R
2 (a-q)
1 (a-q)
d
Scheme 1. Synthesis of 3,5-diarylisoxazoles (2a–q).
132.1, 129.6, 125.2, 121.3, 119.8, 116.3, 115.5, 113.2, 98.7, 24.3.
HRMS calcd. for C16H11Cl2NO: 304.1706, found: 304.1711. IR (KBr,
cmꢀ1):
n
799 (OOP para substituent), 1629 (C55N).
5-(2,4-Dichlorophenyl)-3-(4-methylphenyl) isoxazole (2o): 1H
NMR (400 MHz, CDCl3): 8.72–8.69 (s, 1H), 8.02–8.05 (d, 1H),
7.87–7.89 (d, 1H), 7.57–7.59 (d, 2H), 7.48–7.51 (d, 2H), 6.97 (s, 1H),
2.37 (s, 3H); 13C NMR (100 MHz, CDCl3):
167.4, 165.2, 148.7,
(cmꢀ1). 1H NMR spectra were recorded on a Bruker DRX400
spectrometer using tetramethylsilane as internal standard, chemi-
cal shifts in ppm. Mass spectra were recorded on a VG-70-S mass
spectrometer.
d
d
General procedure for synthesis of 3,5-diarylisoxazoles (2 a–q): A
mixture of chalcone oxime (1 mmol) and iodobenzene diacetate
(1.2 mmol) was ground thoroughly in a pestle and mortar. After 2–
3 min, an exothermic reaction ensued while in some cases slightly
warming to ꢁ40 8C for 2 min was required to initiate the reaction.
The residue was washed with hexane and then recrystallized, or
filtered through a small pad of silica gel, to afford analytically pure
products. All the known compounds were identified by compari-
son of their melting points, 1H NMR, 13C NMR data with the
literature data.
135.3, 131.8, 129.1, 127.6, 126.5, 125.7, 122.5, 121.2, 115.3, 96.5,
25.3. HRMS calcd. for C16H11Cl2NO: 304.1706, found: 304.1734. IR
(KBr, cmꢀ1):
n
806 (OOP para substituent), 1627 (C55N).
5-(2,4-Dichlorophenyl)-3-(2-methoxyphenyl) isoxazole (2p): 1H
NMR (400 MHz, CDCl3): 8.57–8.52 (s, 1H), 7.93–7.98 (d, 1H),
7.61–7.68 (d, 1H), 7.26–7.29 (m, 2H), 7.15–7.18 (m, 1H), 7.05–7.08
(m, 1H), 6.81 (s, 1H), 3.42 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
d
169.1, 165.8, 150.7, 142.6, 138.3, 133.3, 130.1, 129.3, 127.9, 126.8,
125.7, 123.5, 121.2, 118.3, 94.1, 57.3. HRMS calcd. for
C
16H11Cl2NO2: 300.0302, found: 300.0299. IR (KBr, cmꢀ1):
n 763
5-(4-Chlorophenyl)-3-(4-nitrophenyl) isoxazole (2e): 1H NMR
(OOP ortho substituent), 1123 & 1186 (C-O), 1621 (C55N).
5-(2,3-Dichlorophenyl)-3-(2-methoxyphenyl) isoxazole (2q): 1H
NMR (400 MHz, CDCl3): 8.62–8.65 (m, 1H), 8.12–8.17 (m, 1H),
7.83–7.87 (m, 1H), 7.32–7.35 (m, 2H), 7.19–7.23 (m, 1H), 7.02–7.07
(m, 1H), 6.76 (s, 1H), 3.36 (s, 3H); 13C NMR (100 MHz, CDCl3):
(400 MHz, CDCl3):
1H); 13C NMR (100 MHz, CDCl3):
129.3, 128.9, 128.6, 127.8, 124.3, 99.7. HRMS calcd. for
15H9ClN2O3: 300.0302, found: 300.0301. IR (KBr, cmꢀ1):
813
and 828 (OOP para substituent), 1618 (C55N).
3-(4-Chlorophenyl)-5-(3-nitrophenyl) isoxazole (2i): 1H NMR
(400 MHz, CDCl3): 8.68–7.89 (m, 4H), 7.78–7.46 (m, 4H), 6.67
(s, 1H); 13C NMR (100 MHz, CDCl3):
168.4, 162.6, 145.2, 133.5,
d
7.98–8.07 (m, 4H), 7.48–7.53 (m, 4H), 6.81 (s,
d
169.8, 162.3, 151.2, 139.1, 134.3,
d
C
n
d
168.8, 164.1, 149.7, 139.3, 136.2, 132.6, 129.4, 128.9, 127.7, 126.3,
125.7, 123.3, 122.7, 119.3, 95.2, 53.7. HRMS calcd. for
16H11Cl2NO2: 300.0302, found: 300.0299. IR (KBr, cmꢀ1):
C n 779
d
d
(OOP ortho substituent), 1082 & 1167 (C-O), 1619 (C55N).
131.6, 130.6, 129.8, 128.9, 127.8, 124.3, 123.5, 122.7, 96.5. HRMS
calcd. for C15H9ClN2O3 300.0302, found 300.0299. IR (KBr, cmꢀ1):
n
3. Results and discussion
816, 782 and 703 (OOP para substituent), 1611 (C55N).
5-(2,6-Dichlorophenyl)-3-(4-methylphenyl) isoxazole (2m): 1H
This conversion simply involves
a thorough mixing of
NMR (400 MHz, CDCl3):
d
8.52–8.54 (d, 2H), 7.88–7.84 (s, 1H),
substrates with iodobenzene diacetate at room temperature
OAc
I
OAc
I
OAc
OAc
OAc
I
OH
O
AcOH
N
N
N
O
R1
R2
R1
R2
R1
R2
1 a-q
R2
I
N
R1
I
O
O
AcOH
+
+
N
R2
H
2 a-q
R1
OAc
Scheme 2. The plausible mechanism for the formation of the product.

K.V.G. Chandra Sekhar et al. / Chinese Chemical Letters 24 (2013) 1045–1048
1047
Table 1
Physical properties of 3,5-diarylisoxazoles (2a–q).
Compd.
R1
R2
Yield (%)
Mp (8C)
Lit. mp (8C) or mol. formula
2a
2b
2c
2d
2e
2f
H
4-Cl
95
85
92
78
92
91
82
82
76
84
88
90
63
72
81
76
73
177–178
220–222
175–177
126–127
230–232
185–186
214–216
147–149
140–142
286–287
221–222
200–201
214–215
205–207
184–186
163–165
181–183
178–179 [16a,d]
222 [16b]
H
4-NO2
H
4-Br
177–179 [16c]
126–128 [16c]
C15H9ClN2O3
188 [16d]
H
4-OCH3
4-NO2
4-Cl
4-OCH3
4-OCH3
4-NO2
3-NO2
4-NO2
4-Br
4-Cl
2g
2h
2i
4-NO2
217 [16d]
4-Cl
148–150 [16c]
C15H9ClN2O3
286–288 [16a]
222–223 [16a]
198–200 [16a]
C16H11Cl2NO
C16H11Cl2NO
C16H11Cl2NO
C16H11Cl2NO2
C16H11Cl2NO2
4-Cl
2j
4-NO2
2k
2l
4-NO2
4-Br
4-Cl
2m
2n
2o
2p
2q
4-Me
4-Me
4-Me
2-OMe
2-OMe
2,6-dichloro
2,3-dichloro
2,4-dichloro
2,4-dichloro
2,3-dichloro
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n
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resonated as a sharp singlet at
were seen as a multiplet at
7.48–8.07. In the 13C NMR, signals
appeared at 169.8, 162.3, 151.2, 139.1, 134.3, 129.3, 128.9, 128.6,
d 6.81 and the aromatic protons
d
d
127.8, 124.3, 99.7. The high resolution mass spectra of this
compound exhibited the molecular ion peak at m/z 300.0301
which is in agreement with the calculated value 300.0302.
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formation of the product is outlined in Scheme 2.
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In conclusion, we have developed a simple, benign and
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Acknowledgments
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The financial assistance provided by DST (under Fast Track
scheme: SR/FT/CS-076/2009), New Delhi, India is gratefully
acknowledged. Authors are thankful to SAIF, CDRI, Lucknow, India
and the SAIF, Punjab University, Chandigarh, India for analytical
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