Simple and highly efficient synthesis of 3,5-disubstituted isoxazoles using Cu/graphene/clay nanohybrid as a new heterogeneous nano catalyst

Article abstract of DOI:10.3184/174751915X14452715274657

A facile and convenient protocol for 'click' cycloaddition of structurally diverse alkynes with in situ generated nitrile oxides catalysed by Cu/aminoclay/reduced graphene oxide nanohybrid (Cu/AC/r-GO nanohybrid) as a highly efficient heterogeneous nano-c

Full text of DOI:10.3184/174751915X14452715274657

JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39 DECEMBER, 683–687
RESEARCH PAPER 683
Simple and highly efficient synthesis of 3,5-disubstituted isoxazoles using
Cu/graphene/clay nanohybrid as a new heterogeneous nano catalyst
Somayeh Behrouz* and Mohammad Navid Soltani Rad
Medicinal Chemistry Research laboratory, Department of Chemistry, Shiraz University of Technology, Shiraz 71555-313, Iran
A facile and convenient protocol for ‘click’ cycloaddition of structurally diverse alkynes with in situ generated nitrile oxides catalysed
by Cu/aminoclay/reduced graphene oxide nanohybrid (Cu/AC/r-GO nanohybrid) as a highly efficient heterogeneous nano-catalyst is
described. In this method, Cu/AC/r-GO nanohybrid catalyses the 1,3-dipolar cycloaddition of alkynes and nitrile oxides in the presence
of NaHCO in H O/THF (50:50, V/V) to afford the corresponding 3,5-disubstituted isoxazoles. The Cu/AC/r-GO nanohybrid is a low cost,
non-hygro3scopi2c, chemically and thermally stable catalyst that can be reused for many consecutive reaction runs without significant loss
in its reactivity.
Keywords: alkyne, Cu/AC/r-GO nanohybrid, heterogeneous nano-catalyst, isoxazole, nitrile oxide
Isoxazoles are an important class of heterocyclic compounds with
a broad range of applications in medicinal and organic chemistry.1,2
Isoxazole derivatives display a wide spectrum of biological
activities.3 Several isoxazole derivatives such as cloxacillin,
isocarboxazid, dicloxacillin, glisoxepide, leflunomide, oxacillin,
and valdecoxib are well-known drugs exhibiting different
chemotherapeutic activities.3 As a result of the easy cleavage of
the N–O bond in isoxazoles, they play a significant role in organic
synthesis as masked 1,3-dicarbonyl equivalents.4
the nucleophilic trapping of the nitrile oxide; however, it can
be easily minimised by the in situ generation of the nitrile
oxide. The nitrile oxides can be efficiently prepared in situ
via the oxidation of aldoximes,8-12 the dehydrohalogenation of
hydroximyl chlorides,13,14 and the dehydration of nitroalkanes.15
The non-catalysed thermal cycloaddition reactions between
alkynes and nitrile oxides can lead to mixtures of 3,5- and
3,4-regioisomers. Recently, it has become established that the
copper and the N-heterocyclic carbene-mediated cycloaddition
of alkynes with nitrile oxides promotes the formation of
3,5-disubstituted isoxazoles, while ruthenium catalysts afford
3,4-disubstituted isoxazoles.1,4,5 To prepare 3,5-disubstituted
isoxazoles, the presence of active copper(I) as the catalytic
There are many synthetic approaches to isoxazoles.1,4,5 The
most common strategies to access 3,5-disubstituted isoxazoles
involve oxidation of 2-isoxazolines, cyclisation of alkynyl
oxime ethers, condensation of hydroxylamine with α,β-
unsaturated carbonyl compounds or 1,3-dicarbonyl compounds,
and cyclisation of α,β-unsaturated oximes or β-keto oximes.1,4,5
The 1,3-dipolar cycloaddition reaction between alkyne and
nitrile oxide is a direct and extensively used approach to
afford numerous isoxazole derivatives.1,4-7 In this protocol,
the instability of the nitrile oxide leads to dimerisation or
16
species like CuI is essential. Moreover, this active species
can be prepared in situ by reduction of a copper(II) salt, or a
copper(II)/copper(0) combination.1,4
It is well established that the application of a heterogeneous
catalyst is superior to a homogeneous catalyst from both
economic and environmental perspectives. The immobilisation
OH
N
R2
O
Cu/AC/r-GO Nanohybrid, NaHCO3
N
R2
H
R1
Cl
H2O/THF (50:50), r.t.
R1
3
2
1
CO2H
CO2H
O
O Si
O
Si O
H2N
Cu
H2N
NH2
CO2H
CO2H
HO2C
HO2C
O
O
Si O
O Si
NH2
O
O
Cu/AC/r-GO Nanohybrid
CO2H
CO2H
3a: R1= 4-Me2N-C6H4; R2= phenyl
3b: R1= 4-EtO2C-C6H4; R2= phenyl
3c: R1= 3-Br-C6H4; R2= phenyl
3d: R1= phenyl; R2= phenyl
3i: R1= 2-furanyl; R2= 4-MeC(=O)-C6H4-CH2O
3j: R1= phenyl; R2= N7-theophyllinyl-CH2
3k: R1=4-MeO-C6H4; R2= N7-theophyllinyl-CH2
3l: R1= 4-Cl-C6H4; R2= N-saccharinyl-CH2
3m: R1= n-C5H11; R2= N-phthalimidyl-CH2
3n: R1= n-C4H9; R2= n-C5H11
3e: R1= phenyl; R2= 3-pyridinyl
3f: R1= 2,6-Cl2-C6H3; R2= phenyl
3g: R1= 4-Cl-C6H4; R2= C(Me)2OH
3o: R1= cyclohexyl; R2= phenyl
3h: R1= 4-NO2-C6H4; R2= 4-MeO-C6H4-CH2O
Scheme 1 Cu/AC/r-GO nanohybrid-catalysed synthesis of 3,5-disubstituted isoxazoles.
* Correspondent. E-mail: behrouz@sutech.ac.ir

684 JOURNAL OF CHEMICAL RESEARCH 2015
of active catalysts on the heterogeneous supports mostly leads
to mild reaction conditions, thermal stability of the catalyst,
selectivity, the minimisation of undesirable chemical wastes,
ease of handling, simple reaction workup, reusability and
recyclability of the catalyst by simple flash filtration.17 The
successful application of heterogeneous systems in various
organic transformations is well documented. There have also
been a few reports on the application of heterogeneous catalysts
for 1,3-dipolar cycloadditions of nitrile oxides with alkynes.18-20
There is a great need for the development of efficient
heterogeneous catalytic systems for catalysing 3,5-disubstituted
isoxazoles synthesis.
Organic–inorganic hybrid catalysts are well-known
heterogeneous catalysts in which an organic spacer is
covalently anchored to the surface of inorganic supports.21
Among solid supports, those which are covalently bonded with
amine residues have received particular attention due to their
capability to chelate with metals especially copper species. This
chelation not only promotes the catalytic activity of copper but
also largely prevents desorption of the copper species from the
surface of the support and leaching during the course of the
reaction. In this context, graphene oxide (GO) has proved to be
an ideal candidate due to the presence of different functional
groups which allows the possibility of GO grafting with many
organic materials. After functionalising or modifying GO with
the desired molecules, the modified GO is reduced to graphene
(r-GO) to retrieve the exclusive properties characteristic of
graphene.22
efficient heterogeneous nano-catalyst for the synthesis of
1,2,3-triazolyl carboacyclic nucleosides via the Cu(I)-catalysed
‘click’ cycloaddition of organic azides with terminal alkynes.23
We now report the application of a Cu/AC/r-GO nanohybrid for
synthesis of 3,5-disubstituted isoxazoles through 1,3-dipolar
cycloaddition of alkynes with in situ generated nitrile oxides
from hydroximyl chlorides using NaHCO3 in H2O/THF (50:50,
V/V) at room temperature (Scheme 1).
Results and discussion
After preparing the catalyst,23 we then evaluated the catalytic
potency of the Cu/AC/r-GO nanohybrid in 1,3-dipolar
cycloadditions of nitrile oxides from hydroximyl chlorides (1)
with alkynes (2) to afford the corresponding 3,5-disubstituted
isoxazoles (3). To optimise the reaction conditions, the
cycloaddition reaction of N-hydroxybenzimidoyl chloride
and phenyl acetylene was studied bearing neither electron-
donating nor electron-withdrawing functional groups. Thus,
the influence of different reaction parameters including solvent
type, base and catalyst amount were examined on the model
reaction at room temperature to afford 3,5-diphenylisoxazole
(3d). The results are depicted in Table 1.
The choice of an appropriate solvent is of great importance
for the efficient progress of the reaction. There is growing
interest in the use of water as the reaction medium in organic
transformations since it is cheap, clean, and a universal
solvent which has extraordinary physical properties and
enviroeconomic benefits. Thus, the cycloaddition reaction
of the model substrates was achieved in pure water at room
temperature. However, these conditions led to the synthesis
of the corresponding 3,5-diphenylisoxazole only in 18% yield
Recently, we have reported the synthesis, characterisation,
and application of a Cu/aminoclay/reduced graphene oxide
nanohybrid (Cu/AC/r-GO nanohybrid) as a novel and highly
Table 1 Effect of various reaction parameters on the model reaction at room temperature
Entry
1
2
3
4
5
6
7
8
Solvent a
H2O
H2O b
Base
Catalyst/mol%
Time/h
Yield/%e
18
45
88
85
76
68
63
94
37
NR f
87
85
57
68
71
24
53
67
83
96
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
None
Et3N
DBU
NaH
DMAP
DABCO
MgO
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.008)
Cu/AC/r-GO nanohybrid (0.002)
Cu/AC/r-GO nanohybrid (0.004)
Cu/AC/r-GO nanohybrid (0.006)
Cu/AC/r-GO nanohybrid (0.01)
CuI (0.008)
24
12
2
3
5
6
6
1
8
48
3
3
6
5
6
9
7
5
H2O/Dioxane
H2O/Acetone
H2O/MeCN
H2O/DMSO
H2O/DMF
H2O/THF
THF
H2O/THF
H2O/THF
H2O/THF
H2O/THF
H2O/THF
H2O/THF
H2O/THF
H2O/THF
H2O/THF
H2O/THF
H2O/THF
H2O/THF
H2O/THF
H2O/THF
H2O/THF
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1
1
6
7
4
3
81
80
87
90
CuSO4.5H2O (.008) c
Cu(OAC)2 (0.008) c
CDSCS (0.008) d
a Except for entries 1, 2 and 9 a mixture of 50:50 (v/v) solvents were used.
b The reaction was carried out under reflux conditions.
c The reaction was carried out in the presence of sodium ascorbate.
d Copper-doped silica cuprous sulfate.19
e Isolated yield.
f No reaction.

JOURNAL OF CHEMICAL RESEARCH 2015 685
after 24 h (Table 1, entry 1). To improve the reaction yield, the
model reaction was carried out in refluxing pure water which
affords the desired isoxazole 3d in 45% yield after 12 h. This
moderate yield can be attributed to the lack solubility of the
starting materials in pure water (Table 1, entry 2). Thus, the
effects of a water mixture with several organic solvents in 50:50
(V/V) ratios was examined. As the data in Table 1 demonstrate,
employing a solution of H2O/THF (50:50, V/V) afforded the
corresponding isoxazole 3d in high yield and short reaction time
in comparison with the other tested solvents (Table 1, entry 8).
Consequently, it was selected as the most appropriate solvent for
all subsequent reactions. The combination of water with dioxane
or acetone led to the corresponding isoxazole 3d in reasonable
yield; however, longer times were needed for completion of the
reaction (Table 1, entries 3 and 4). Additionally, the use of water
combined with other examined solvents, afforded moderate
yields of product (Table 1, entries 5–7). Moreover, only 37% of
3,5-diphenylisoxazole was obtained when pure THF was used
as the reaction media (Table 1, entry 9).
To have efficient in situ generation of nitrile oxides from
hydroximyl chlorides, the choice of an appropriate base is
critical. Thus, the effect of various organic and inorganic
bases was evaluated on the model reaction. As shown in Table
1, attempts to carry out the model reaction in the absence of
base failed even after prolonging the reaction time up to 48 h.
(entry 10). As is clear from Table 1, NaHCO3 proved to be the
most appropriate base for 1,3-dipolar cycloaddition reactions of
the model substrates (entry 8). While Et3N and DBU provided
satisfactory results, they were not as effective as NaHCO3
to achieve the model reaction (Table 1, entries 11 and 12).
Other examined bases afforded low to moderate yields of the
corresponding isoxazole 3d (Table 1, entries 13–16).
To evaluate the catalytic potency of Cu/AC/r-GO nanohybrid,
the cycloaddition reaction of N-hydroxybenzimidoyl chloride
and phenyl acetylene was investigated using several reported
copper catalysts under the optimised condition. As the results
in Table 1 indicate, using Cu/AC/r-GO nanohybrid (entry 8)
increased the reaction rate and yield in comparison with other
examined catalysts. The use of the other copper catalysts also
led to the preparation of 3,5-diphenylisoxazole in satisfactory
yields after prolonging the reaction time.
The generality and versatility of this protocol was screened
by application to structurally diverse alkynes and hydroximyl
chlorides (Table 2). Cu/AC/r-GO nanohybrid proved to be an
appropriate nano catalyst that efficiently catalyses the 1,3-dipolar
cycloaddition reaction of alkynes-nitrile oxides with excellent
regioselectivity. As shown in Table 2, both aromatic and/or
aliphatic alkynes and hydroximyl chlorides bearing different
electron-rich and/or electron-deficient functional groups
underwent the cycloaddition reaction to produce the corresponding
3,5-disubstituted isoxazoles in good to excellent yields. The
formation of the Cu(I)-acetylide species is an important step
in the Cu(I)-catalysed cycloaddition reaction of alkynes with
nitrile oxides; thus, disubstituted alkynes do not participate in
this reaction as shown in the attempted cycloaddition reaction
of diphenyl acetylene with N-hydroxybenzimidoyl chloride. The
structure of all synthesised compounds was confirmed by 1H and
13C NMR, elemental analysis, mass and IR spectroscopy methods.
To confirm the recoverability and the heterogeneous nature of
the Cu/AC/r-GO nanohybrid, the catalyst was reused for several
consecutive runs and through each run, no fresh catalyst was
added. In this connection, the model reaction was efficiently
performed after 1 h in the presence of 0.008 mol% of Cu/
AC/r-GO nanohybrid in the first run. For the reusability study,
the catalyst was recycled from the reaction mixture through
a sintered glass funnel by vacuum filtration. The catalyst was
then washed successively with distilled water (20 mL) and
then anhydrous acetone (20 mL) and dried in a vacuum oven
at 80 °C for 1 h which was tested for five consecutive runs
(Fig. 1). Figure 1 clearly shows that Cu/AC/r-GO nanohybrid
is a reusable and recyclable catalyst which undergoes negligible
desorption of the copper species from the AC/r-GO matrix.
According to the ICP analysis, the amount of leached copper
from Cu/AC/r-GO nanohybrid is 0.008% after five consecutive
runs and this is rationalised as due to the powerful binding
present between the copper species and the aminoclay (AC)
group on the surface of the r-GO.
The results obtained by inductively coupled plasma (ICP)
analysis have revealed the presence of 0.013 g of active copper
catalyst in each gram of Cu/AC/r-GO nanohybrid (0.02 mol%).
In a series of other experiments, different amounts of catalyst
were employed for cycloaddition of model substrates. As the
data in Table 1 indicate, using 0.008 mol% of catalyst afforded
the best results (entry 8). Lower yields of isoxazole were
obtained when the amount of the catalyst decreased to less than
0.008 mol % (Table 1, entries 17–19). Using an excess amount
of catalyst gave no improvement in the reaction yield (Table 1,
entry 20).
Table 2 Cu/AC/r-GO nanohybrid-catalysed synthesis of 3,5-disubstituted
isoxazoles
In conclusion, we have described the application of a Cu/
AC/r-GO nanohybrid as a highly efficient heterogeneous
nano-catalyst for regioselective synthesis of 3,5-disubstituted
isoxazoles. The 1,3-dipolar cycloaddition reaction of various
structurally diverse alkynes and in situ generated nitrile oxides
using a Cu/AC/r-GO nanohybrid in the presence of NaHCO3 in
Entry ref.
1
Product a
3a
Time/h
1
Yield/%b
84
2
318
47
3b
3c
3d
1
1.3
1
92
90
94
524
618
7
3e
3f
3g
3h
3i
3j
3k
3l
1.1
1.7
1
1.1
1.4
2
92
83
91
95
84
86
81
85
87
97
1019
1119
12
2
2
13
3m
3n
3o
2
1.5
1.6
83
81
87
147
157
aAll products were characterised by 1H- and 13C NMR, IR, CHN, and MS analysis.
bIsolated yield.
Fig. 1 The reusability of Cu/AC/r-GO nanohybrid.

686 JOURNAL OF CHEMICAL RESEARCH 2015
293 (12.3) (M+). Anal. calcd for C18H15NO3: C, 73.71; H, 5.15; N, 4.78;
found: C, 73.79; H, 5.04; N, 4.70%.
H2O/THF (50:50, V/V) at room temperature affords the desired
isoxazoles in reasonable yields. The Cu/AC/r-GO nanohybrid
proved to be a stable, non-hygroscopic, easy to prepare,
inexpensive, and environmentally benign heterogeneous nano-
catalyst that can be recycled for several reaction runs without
significant loss in its reactivity. The presence of amine groups on
the surface of the catalyst provides a ligand-free and leaching-
free catalyst which will be highly useful and economical for
industrial applications.
3-(3-Bromophenyl)-5-phenylisoxazole (3c): White solid; yield:
90%; m.p. 30–31°C (lit.18 30–32 °C); IR (νmax): 3100, 1596, 1471 cm–1;
1H NMR (CDCl3) δ 6.72 (s, 1H, C(4)-H of isoxazole), 6.85–6.89 (m,
1H, aryl), 7.41–7.48 (m, 2H, aryl), 7.48–7.53 (m, 4H, aryl), 7.92–7.99
(m, 2H, aryl); 13C NMR (CDCl3) δ 98.5, 123.1, 124.8, 125.1, 126.9,
128.7, 129.2, 130.7, 130.9, 131.5, 133.6, 160.6, 172.0; MS (EI) m/z (%):
299 (9.8) (M+). Anal. calcd for C15H10BrNO: 60.02; H, 3.36; Br, 26.62;
N, 4.67; found: 60.15; H, 3.47; Br, 26.69; N, 4.73%.
3,5-Diphenylisoxazole (3d): White solid; yield: 94%; m.p.
140–141 °C (lit.7 139–140 °C).; IR (νmax): 3050, 1594, 1456 cm–1;
1H NMR (CDCl3) δ 6.75 (s, 1H, C(4)-H of isoxazole), 7.45–7.52 (m,
6H, aryl), 7.89-7.95 (m, 4H, aryl); 13C NMR (CDCl3) δ 98.1, 120.3,
121.8, 125.9, 127.0, 129.3, 129.8, 130.1, 131.4, 162.8, 170.8; MS (EI)
m/z (%): 221 (6.9) (M+). Anal. calcd for C15H11NO: C, 81.43; H, 5.01; N,
6.33; found: C, 81.56; H, 5.14; N, 6.47%.
3-Phenyl-5-(pyridin-3-yl)isoxazole (3e): White solid, yield: 92%;
m.p. 143–144 °C (lit.24 143–144 °C); IR (νmax): 3112, 1598, 1463 cm–1;
1H NMR (CDCl3) δ 6.83 (s, 1H, C(4)-H of isoxazole), 7.34–7.40 (m,
4H, aryl), 7.61–7.69 (m, 2H, aryl), 8.03 (s, 1H, aryl), 8.27 (d, J = 8.0 Hz,
2H); 13C NMR (CDCl3) δ 97.1, 122.5, 124.7, 127.0, 128.9, 129.4, 131.2,
133.8, 145.9, 152.0, 164.1, 169.3; MS (EI) m/z (%): 222 (14.8) (M+).
Anal. calcd for C14H10N2O: C, 75.66; H, 4.54; N, 12.60; found: C, 75.74;
H, 4.62; N, 12.69%.
Experimental
All chemical reagents were purchased from either Fluka or Merck.
Solvents were purified by standard procedures, and stored over 3Å
molecular sieves. Reactions were followed by TLC using SILG/UV
254 silica-gel plates. Column chromatography was performed on silica
gel 60 (0.063–0.200 mm, 70–230 mesh; ASTM). Melting points were
measured using an Electrothermal IA 9000 melting point apparatus
in open capillary tubes and are uncorrected. IR spectra were obtained
using a Shimadzu FT-IR-8300 spectrophotometer. H and 13C NMR
1
spectrum was recorded on Bruker Avance-DPX-250 spectrometer
operating at 250/62.5 MHz, respectively. Chemical shifts are given
in δ relative to TMS as an internal standard, coupling constants J are
1
given in Hz. Abbreviations used for H NMR signals are: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. GC-MS
was performed on a Shimadzu GC/MS-QP 1000-EX apparatus (m/z;
rel.%). Elemental analyses were performed on a PerkinElmer 240-B
micro-analyser. Halogen atoms in compounds were analysed using
the oxygen-flask combustion method (Schoniger application) and
subsequent potentiometric titration by a 835 Titrando Metrohm Titro
processor instrument and ion chromatography analysis using a Dionex
IC system.
3-(2,6-Dichlorophenyl)-5-phenyl-isoxazole (3f): Colourless liquid;
1
yield: 83%; IR (νmax): 3085, 1563, 1462, 764 cm-1; H NMR (CDCl3)
δ 6.85 (s, 1H, C(4)-H of isoxazole), 7.38–7.43 (m, 1H, aryl), 7.47–7.52
(m, 5H, aryl), 7.91–7.98 (m, 2H, aryl); 13C NMR (CDCl3) δ 99.8, 126.0,
127.5, 128.9, 129.1, 129.9, 130.8, 132.1, 136.4, 162.7, 171.2; MS (EI) m/z
(%): 289 (11.9) (M+). Anal. calcd for C15H9Cl2NO: C, 62.09; H, 3.13;
Cl, 24.44; N, 4.83; found: C, 62.17; H, 3.21; Cl, 24.49; N, 4.96%.
2-(3-(4-Chlorophenyl)isoxazol-5-yl)propan-2-ol (3g): White solid;
yield 91%; m.p. 97–98 °C; IR (νmax): 3400, 3048, 2976, 1598, 1461,
Synthesis of 3,5-disubstituted isoxazoles using Cu/AC/r-GO nanohybrid;
general procedure
1
784 cm–1; H NMR (CDCl3) δ 1.73 (s, 6H, 2CH3), 2.81 (s, 1H, OH),
In a round-bottom flask (50 mL), a mixture of Cu/AC/r-GO
nanohybrid (0.4 g, 0.008 mol %), appropriate hydroximyl chloride
(0.01 mol), alkyne (0.012 mol), and NaHCO3 (0.012 mol) were stirred
in H2O/THF (50:50, V/V) for the appropriate times (Table 2). After
completion of the reaction, the reaction mixture was vacuum-filtered
using a sintered-glass funnel and the residue was washed with acetone
(2 × 10 mL). The filtrate was then evaporated under vacuum to remove
the solvent. The remaining foam was dissolved in CHCl3 (100 mL) and
subsequently washed with water (2 × 100 mL). Afterwards, the organic
layer was dried over anhydrous sodium sulfate and evaporated. The
crude product was purified by short column chromatography on silica
gel eluting with n-hexane:EtOAc.
6.68 (s, 1H, C(4)-H of isoxazole),7.25 (d, J = 7.9 Hz, 2H, aryl), 7.67 (d,
J = 7.9 Hz, 2H, aryl); 13C NMR (CDCl3) δ 31.5, 70.4, 98.1, 126.0, 128.4,
+
130.8, 137.2, 162.7, 175.1; MS (EI) m/z (%): 237 (13.7) (M ). Anal.
calcd for C12H12ClNO2: C, 60.64; H, 5.09; Cl, 14.92; N, 5.89; found: C,
60.51; H, 5.17; Cl, 15.03; N, 5.96%.
5-((4-Methoxyphenoxy)methyl)-3-(4-nitrophenyl)isoxazole (3h):
White solid; yield: 95%; m.p. 139–140 °C (lit.7 138–140 °C); IR (νmax):
3071, 2943, 1590, 1563, 1480, 1348, 1216 cm–1; 1H NMR (CDCl3)
δ 3.47 (s, 3H, OCH3), 5.29 (s, 2H, OCH2), 6.83 (s, 1H, C(4)-H of
isoxazole), 6.75 (d, J = 8.0 Hz, 2H, aryl), 6.89 (d, J = 8.0 Hz, 2H, aryl),
7.80 (d, J = 8.1 Hz, 2H, aryl), 8.01 (d, J = 8.1 Hz, 2H, aryl); 13C NMR
(CDCl3) δ 53.1, 64.5, 97.6, 117.9, 119.0, 126.2, 129.7, 136.1, 148.5,
152.0, 156.9, 163.4, 171.8; MS (EI) m/z (%): 326 (15.6) (M+). Anal.
calcd for C17H14N2O5: C, 62.57; H, 4.32; N, 8.59; found: C, 62.65; H,
4.39; N, 8.72%.
Recycling the catalyst
After completion of the reaction, the catalyst was vacuum-filtered
from the reaction mixture using a sintered glass funnel followed
by successive washing with distilled water (20 mL) and anhydrous
acetone (20 mL). The catalyst was then kept in a vacuum oven at 80 °C
for 1 h and stored in a sealed vessel in a refrigerator.
1-(4-((3-(Furan-2-yl)isoxazol-5-yl)methoxy)phenyl)ethanone (3i):
White solid; yield: 84%; m.p. 136–137 °C (lit.7 135–136 °C); IR (νmax):
1
3100, 2951, 1715, 1561, 1479, 1228 cm–1; H NMR (CDCl3) δ 2.78 (s,
N,N-Dimethyl-4-(5-phenylisoxazol-3-yl)benzenamine (3a): White solid;
yield 84%; m.p. 126–128 °C; IR (νmax): 3105, 2973, 1596, 1483 cm–1;
1H NMR (CDCl3) δ 2.97 (s, 6H, 2CH3), 6.02 (s, 1H, C(4)-H of isoxazole),
6.98 (d, J = 8.5 Hz, 2H, aryl), 7.39 (d, J = 8.5 Hz, 2H, aryl), 7.68–7.73 (m,
2H, aryl), 7.81–7.86 (m, 3H, aryl); 13C NMR (CDCl3) δ 44.6, 99.1, 120.3,
124.5, 125.9, 127.5, 128.1, 129.9, 131.2, 141.5, 169.8, 171.1; MS (EI) m/z
(%): 264 (10.5) (M +). Anal. calcd for C17H16N2O: C, 77.25; H, 6.10; N,
10.60; found: C, 77.38; H, 6.17; N, 10.52%.
Ethyl 4-(5-phenylisoxazol-3-yl)benzoate (3b): White solid; yield
92%; m.p. 139–141 °C; IR (νmax): 3072, 2973, 1742, 1590, 1483 cm–1;
1H NMR (CDCl3) δ 1.38 (t, J = 7.6 Hz, 3H, CH3), 4.26 (q, J = 7.6 Hz,
2H,CH2), 6.42 (s, 1H, C(4)-H of isoxazole), 7.21–7.26 (m, 3H, aryl),
7.50–7.54 (m, 2H, aryl), 7.69 (d, J = 8.1 Hz, 2H, aryl), 7.90 (d, J = 8.1
Hz, 2H, aryl); 13C NMR (CDCl3) δ 13.5, 64.2, 97.9, 126.2, 127.0, 127.8,
129.0, 130.4, 131.0, 132.1, 133.7, 163.5, 167.8, 179.9; MS (EI) m/z (%):
3H, CH3), 5.29 (s, 2H, OCH2), 6.58 (s, 1H, C(4)-H of isoxazole), 6.90
(d, J = 2.5 Hz, 1H, C(3)-H of furan), 7.15 (d, J = 8.3 Hz, 2H, aryl), 7.62
(t, J = 2.5 Hz, 1H, C(4)-H of furan), 7.83 (d, J = 2.5 Hz, 1H, C(5)-H of
furan), 7.98 (d, J = 8.3 Hz, 2H, aryl); 13C NMR (CDCl3) δ 23.0, 62.7,
99.2, 108.9, 115.8, 116.3, 131.7, 132.5, 142.9, 143.7, 154.8, 162.5, 168.0,
184.5; MS (EI) m/z (%): 283 (12.6) (M +). Anal. calcd for C16H13NO4:
C, 67.84; H, 4.63; N, 4.94; found: C, 67.92; H, 4.70; N, 5.08 %.
1,3-Dimethyl-7-((3-phenylisoxazol-5-yl)methyl)-1H-purine-
2,6(3H,7H)-dione (3j): White solid; yield: 86%; m.p. 123–124 °C
(lit.19 123 °C); IR (νmax): 3075, 2938, 1725, 1708, 1697, 1556, 1462 cm–1;
1H NMR (CDCl3) δ (s, 3H, N3-CH3), 3.59 (s, 3H, N1-CH3), 5.69 (s,
2H, NCH2), 6.75 (s, 1H, C(4)-H of isoxazole), 7.44–7.46 (m, 3H, aryl),
7.75–7.79 (m, 3H, aryl, C(8)-H of theophylline); 13C NMR (CDCl3) δ
28.0, 31.2, 41.1, 102.4, 106.2, 126.8, 128.2, 128.9, 130.3, 141.2, 148.8,
151.5, 155.2, 162.8, 165.7; MS (EI) m/z (%): 337 (7.4) (M +). Anal. calcd

JOURNAL OF CHEMICAL RESEARCH 2015 687
for C17H15N5O3: C, 60.53; H, 4.48; N, 20.76; found: C, 60.41; H, 4.45; N,
20.69%.
calcd for C15H17NO: C, 79.26; H, 7.54; N, 6.16; found: C, 79.34; H, 7.61;
N, 6.08%.
7-((3-(4-Methoxyphenyl)isoxazol-5-yl)methyl)-1,3-dimethyl-
1H-purine-2,6(3H,7H)-dione (3k): White solid; yield: 81%; m.p.
215–216 °C (lit.19 215 °C); IR (νmax): 3100, 2946, 1720, 1706, 1693,
1558, 1470 cm–1; 1H NMR (CDCl3) δ 3.28 (s, 3H, N3-CH3), 3.50 (s, 3H,
N1-CH3), 3.88 (s, 3H, OCH3), 5.82 (s, 2H, NCH2), 6.95 (s, 1H, C(4)-H
of isoxazole), 7.08 (d, J = 8.5 Hz, 2H, aryl), 7.83 (d, J = 8.5 Hz, 2H,
aryl), 8.36 (s, 1H, C(8)-H of theophylline); 13C NMR (62.5 MHz): δ
27.9, 29.9, 41.9, 55.7, 101.2, 106.3, 114.8, 120.8, 128.5, 143.3, 148.8,
151.4, 154.7, 161.2, 162.1, 168.2; MS (EI) m/z (%): 367 (5.2) (M+).
Anal. calcd for C18H17N5O4: C, 58.85; H, 4.66; N, 19.06; found: C,
58.94; H, 4.71; N, 19.02%.
2-{[3-(4-Chlorophenyl)-5-isoxazolyl]methyl}-1,2-benzisothiazol-3-
(2H)-one 1,1-dioxide (3l): White solid; yield 85%; m.p. 185–186 °C; IR
(νmax): 3100, 2983, 1710, 1600, 1481, 1215, 792 cm–1; 1H NMR (CDCl3) δ
5.16 (s, 2H, NCH2), 6.89 (s, 1H, C(4)-H of isoxazole), 7.26 (d, J = 8.2 Hz,
2H, aryl), 7.51 (d, J = 8.2 Hz, 2H, aryl), 7.74–7.81 (m, 4H, aryl); 13C NMR
(CDCl3) δ 33.6, 100.1, 121.3, 125.6, 127.2, 127.9, 128.1, 129.2, 132.2,
134.7, 136.2, 141.7, 160.6, 162.9, 166.1; MS (EI) m/z (%): 374 (15.9) (M
+). Anal. calcd for C17H11ClN2O4S: C, 54.48; H, 2.96; Cl, 9.46; N, 7.47; S,
8.56; found: C, 54.40; H, 3.07; Cl, 9.51; N, 7.60; S, 8.62%.
2-((3-Pentylisoxazol-5-yl)methyl)isoindoline-1,3-dione (3m): White
foam; yield 83%; IR (νmax): 3046, 2971, 1720, 1589, 1460 cm–1; 1H NMR
(CDCl3) δ 0.91 (t, J = 7.5 Hz, 3H, CH3), 1.19–1.23 (m, 2H, CH3CH2),
1.50–1.56 (m, 4H, 2CH2), 2.62–2.67 (t, J = 7.6 Hz, 2H, CH2C=N), 5.03
(s, 2H, NCH2), 6.79 (s, 1H, C(4)-H of isoxazole), 7.37–7.46 (m, 4H, aryl);
13C NMR (CDCl3) δ 15.3, 23.0, 29.7, 31.8, 32.9, 45.1, 99.8, 126.8, 133.5,
135.2, 152.9, 159.4, 171.6; MS (EI) m/z (%): 298 (8.6) (M +). Anal. calcd
for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39; found: C, 68.53; H, 6.20; N,
9.31%.
The authors thank Shiraz University of Technology Research
Council for partial support of this work.
Received 8 September 2015; accepted 14 October 2015
Paper 1503582 doi: 10.3184/174751915X14452715274657
Published online: 1 December 2015
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3-Butyl-5-pentylisoxazole (3n): Pale yellow oil; yield: 81%; IR (νmax):
1
3079, 2972, 1586, 1458 cm–1; H NMR (CDCl3) δ 0.82 (t, J = 7.4 Hz,
3H, CH3), 0.97 (t, J = 7.7 Hz, 3H, CH3), 1.34–1.41 (m, 8H, 4CH2), 1.74
(t, J = 7.4 Hz, 2H, CH2), 2.28–2.36 (m, 2H,CH2), 2.85 (t, J = 7.7 Hz, 2H,
CH2), 5.96 (s, 1H, C(4)-H of isoxazole), 13C NMR (CDCl3) δ 10.5, 12.7,
23.0, 26.1, 27.3, 27.9, 28.7, 30.6, 33.5, 97.4, 158.2, 174.0; MS (EI) m/z
(%): 195 (13.8) (M+). Anal. calcd for C12H21NO: C, 73.80; H, 10.84; N,
7.17; found: C, 73.89; H, 10.94; N, 7.08%.
3-Cyclohexyl-5-phenylisoxazole (3o): White solid; yield: 87%;
m.p. 33–34 °C (lit.7 33–34 °C); IR (νmax): 3049, 2970, 1598, 1457 cm–1;
1H NMR (CDCl3) δ 1.47–1.95 (m, 10H, 5CH2), 2.98 (m, 1H, CHC=N),
6.73 (s, 1H, C(4)-H of isoxazole), 7.12–7.19 (m, 3H, aryl), 7.56–7.62 (m,
2H, aryl); 13C NMR (CDCl3) δ 23.8, 38.0, 31.4, 34.9, 98.3, 126.1, 127.9,
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+
129.2, 131.5, 168.5, 178.2; MS (EI) m/z (%): 227 (11.4) (M ). Anal.