Sonochemical synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones by amine-modified montmorillonite nanoclay

Article abstract of DOI:10.1016/j.catcom.2016.08.018

Ultrasound irradiation was applied for the rapid and clean synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones through condensation of hydroxylamine hydrochloride, ethyl acetoacetate and benzaldehyde derivatives. This methodology was effectively ca

Full text of DOI:10.1016/j.catcom.2016.08.018

Catalysis Communications 86 (2016) 91–95
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Catalysis Communications
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Short communication
Sonochemical synthesis of 3-methyl-4-arylmethylene
isoxazole-5(4H)-ones by amine-modified montmorillonite nanoclay
⁎
Javad Safari , Majid Ahmadzadeh, Zohre Zarnegar
Laboratory of Organic Compound Research, Department of Organic Chemistry, College of Chemistry and Biochemistry, University of Kashan, P.O. Box: 87317-51167, Kashan, Islamic Republic of Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Ultrasound irradiation was applied for the rapid and clean synthesis of 3-methyl-4-arylmethylene isoxazole-
5(4H)-ones through condensation of hydroxylamine hydrochloride, ethyl acetoacetate and benzaldehyde deriv-
atives. This methodology was effectively catalyzed by amine functionalized montmorillonite K10 nanoclay (NH2-
MMT). Compared with conventional methods, this protocol has promising features for the reaction response
such as shorter reaction times, easier work-up, ease of separation of pure product with high yields and simplicity
in the experimental procedure.
Received 11 February 2016
Received in revised form 11 August 2016
Accepted 12 August 2016
Available online 13 August 2016
Keywords:
Isoxazoles
© 2016 Published by Elsevier B.V.
Ultrasound irradiation
Montmorillonite
Nanoclay
Water
1. Introduction
solid basic catalytic systems utilizing inexpensive, clean, environmen-
tally benign, and commercially available catalysts has been a challenge
Isoxazoles are important heterocycles and possess various pharma-
cological activities. These heterocyclic compounds can act as immuno-
suppressive, antibacterial, antifungal [1], anticancer [2], anticancer [3],
analgesic [4], antitumor [5] and show hypoglycemic activity [6]. Recent-
ly, organic chemists are interested in the synthesis of isoxazole scaffolds
due to wide importance in medicinal, industrial and the field of synthet-
ic organic chemistry [7]. The conventional synthesis of the title com-
pound consists of two consecutive steps. In the first step, the
formation of oxime is occurred by the reaction of ethyl acetoacetate
and hydroxylamine hydrochloride followed by ring closure affords 3-
methyl-isoxazole-5(4H)-one. Then, in second step, the Knoevenagel
condensation reaction between 3-methyl-isoxazole-5(4H)-ones and ar-
omatic aldehydes, which finally gives 3-methyl-4-arylmethylene-
isoxazole-5(4H)-ones [8].
More recently, different catalyst such as sodium citrate [9], sodium
sulfide [10], DABCO [11], sodium saccharin [12], sodium silicate [13], so-
dium tetraborate [14], DABCO and pyridine [15] and some new methods
such as solid state grinding, solid state heating [16], stirring in water
[17] and visible light induced reaction [8] have appeared to be effective
techniques. In general, these methods have its own merits as well as de-
merits such as expansive catalyst and solvent, harsh reaction condition,
longer reaction time, poor yields and difficulties in work-up procedure
[18]. Therefore, the introduction of a simple and efficient procedure
based on green methodology is still in demand. The development of
in the synthesis of isoxazoles.
On the other hand, the use of clays particularly montmorillonite K10
(MMT-K10) as a catalyst and catalyst support has received considerable
attention in chemical synthesis [19]. The nanolayered structure of
MMT-K10 by encapsulating organic substrates can be act as a
nanoreactor for the chemical reactions and a drug nanocarrier for phar-
maceutical purposes. Organo-modified MMT has received a great deal
of attention in catalytic processes because of their nano-size, large sur-
face area, high surface reactivity, cheap and nonhazardous, high stability
and relatively simple processing [20]. MMT-K10 has been modified by
introducing 3-aminopropyltriethoxysilane and used in organic transfor-
mation. The amine-modified MMT is used as nanocatalyst in a variety of
chemical reactions and as a good support for heterogeneous catalytic
processes, such as Ullmann coupling reaction [21], the synthesis of het-
erocyclic compounds [22], Henry reaction [23], C\\S coupling reactions
[24], Knoevenagel reaction [25], and other process.
In this communication, we disclosed an eco-friendly methodology
for the synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones
using NH2-MMT nanoclay as a solid acid–base catalyst under sonication
conditions (Scheme 1).
2. Experimental
2.1. Chemicals and apparatus
All chemicals were purchased from the Merck, Aldrich and Sigma
⁎
Corresponding author.
E-mail addresses: safari_jav@yahoo.com, safari@kashanu.ac.ir (J. Safari).
Chemical Companies. NanoClay (Cloisite 30B) is a commercial
http://dx.doi.org/10.1016/j.catcom.2016.08.018
1566-7367/© 2016 Published by Elsevier B.V.

92
J. Safari et al. / Catalysis Communications 86 (2016) 91–95
O
O
O
O
NH2-MMT, 30 °C
+
+
NH2OH.HCl
O
Ar
O
Ar
H2O, U.S
H
N
Me
Scheme 1. Sonochemical synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones by NH2-MMT.
organically modified montmorillonite with specific surface area of
250 m2/g, pH = 3–4, with a grain diameter of 10–30 nm, prepared by
Southern Clay Products, Inc. and was used as received. Melting points
were determined on an Electrothermal MK3 apparatus using an open-
glass capillary and are uncorrected. 1H NMR and 13C NMR spectra
were recorded on a Bruker DRX-400 spectrometer at 400 and
100 MHz respectively. FT-IR spectra were obtained with KBr pellets in
the range 400–4000 cm−1 with a Perkin-Elmer 550 spectrometer.
Nanostructures were characterized using a Holland Philips Xpert X-
3. Results and discussion
The objectives of the present investigation are: (i) to prepare 3-
methyl-4-arylmethylene isoxazole-5(4H)-ones, (ii) heterogenization
of homogeneous organocatalyst based on MMT nanoclay as recyclable
catalytic system, (iii) to develop an efficient ultrasound-assisted syn-
thetic process for the facile one-pot reaction under optimal conditions.
For the surface modification, the MMT was functionalized with
APTES via silanization reaction to obtain NH2-MMT (scheme S1) [24].
The results of elemental analysis of the NH2-MMT (Anal. found. (%): C
7.46, H 1.98, N 2.38, C/N 3.13) suggest that N was grafted onto the
ray diffraction (XRD) diffractometer (CuK, radiation,
λ
=
0.154056 nm), at a scanning speed of 2°/min from 10° to 100° (2θ). A
Bandelin Sonorex Super 10P Ultrasonic Bath (water) (with a frequency
of 35 kHz and a nominal power 100 W) was used.
nanoclay at 1.57 mmol g−1
.
Fig. S1 shows the FT-IR spectra of MMT and NH2-MMT. In Fig. S1(a)
for pure MMT, the absorbance bands at 3590 and 1045 cm−1 are related
to Al\\O\\H and O\\Si stretching vibration, respectively. The other
bands related to H\\O\\H stretching and bending vibrations could be
found at 3432 and 1632 cm−1 respectively. In the case of NH2-MMT in
Fig. S1(b), the two weak peaks at 2927 and 2870 cm−1 correspond to
the\\CH stretching mode and a broad band peak at 3417 cm−1 is attrib-
uted to the NH2 groups on the nanoclay surface. In addition, the peak at
525 and 467 cm−1 is the stretching vibration due to the interactions of
Al\\O and Mg\\O bonds respectively. NH2-MMT showed an absorption
peak at 1560 cm−1 corresponding to the NH2 bending vibration. Since
both the NH2 and CH2 groups are attached to the APTMS skeleton, the
above observations suggest the presence of organosilane on the surface
of MMT [22,24,26].
2.2. Synthesis of NH2-MMT nanoclay
NH2-MMT was prepared according to reported procedure in the lit-
erature. MMT (0.50 g) was further was diluted with n-hexane (15 mL)
containing 3-aminopropyl-triethoxysilane (APTES) (1.2 mmol) and
stirred at room temperature under mechanical stirring for 2 h. Then,
the solvent was removed by filtration and the functionalized MMT
was washed with ethanol and n-hexane. The NH2-MMT was dried at
50 °C under vacuum [24].
2.3. General procedure for the synthesis of 3-methyl-4-arylmethylene
isoxazole-5(4H)-ones
The SEM micrographs of samples are shown in Fig. 1(a) and (b). It
shows that naked MMT nanoclay has a layered morphology consisting
of broken plates. The morphology of the NH2-MMT was quite similar
to that of the parent nanoclay, as can be seen from the inset of
Fig. 1(b). The micrographs of NH2-MMT clearly show highly porous
morphology [25].
The broad angle XRD spectra of MMT and NH2-MMT are shown in
Fig. 2(a). The hkl and two dimensional hk reflections for MMT can be
seen in two the samples. However, some peaks are also present due to
many impurities such as cristobalite, quartz and feldspar. The similari-
ties in the spectra of the two samples suggest no structural changes
A mixture of aldehyde (1 mmol), ethyl acetoacetate (1 mmol), hy-
droxylamine hydrochloride (1 mmol) and NH2-MMT (0.01 g) in dis-
tilled water (5 mL) as a solvent in a 50 mL round-bottomed flask and
irradiated under sonication at 30 °C. After completion of the reaction
(monitored on TLC), the nanocatalyst was separated by filtration, and
reused as such for the next experiment and the solvent was evaporated.
The filtrate was concentrated to dryness, and the crude solid product
was crystallized from EtOH to afford the pure product in high yield.
(a)
(b)
Fig. 1. SEM micrographs of (a) MMT and (b) NH2-MMT.

J. Safari et al. / Catalysis Communications 86 (2016) 91–95
93
(b)
(a)
MMT
NH2-MMT
(110,
020)
#
*
*
$
Cristobalite
Feldspar
(200,
130)
$
# Quartz
(002)
(060,
330)
*
#
#
#
Fig. 2. (a) XRD patterns of MMT and NH2-MMT; (b) Low angle XRD spectra of MMT and NH2-MMT.
have occurred in the clay matrix after functionalization with the organic
groups [21,24]. The low angle XRD spectra of neat and aminosilane
modified MMT are shown in Fig. 2(b). The shifting of the (001) peak to-
wards a lower 2θ value suggests the intercalation of NH2 groups into the
nanoclay interlayer.
The TGA curves of nanoclays are shown in Fig. S2, For the NH2-MMT,
there are two steps of mass losses at temperatures of 50–200 and 200–
750 °C. The weight loss below 200 °C could be attributed to the physical
adsorption of water or solvent in the clays. The weight loss of NH2-MMT
is about 12% at 200–750 °C, corresponding to the thermal decomposi-
tion of organic components in nanoclay.
NH2-MMT shows one desorption peak at 62 °C that corresponds to the
decomposition of the product of alkylamine groups with CO2. Amine
groups in NH2-MMT react with CO2 molecules to form carbamate
through zwitterionic intermediates. For this purpose, a pair of electrons
in the amine groups, attacks the CO2 carbon atom to produce the zwit-
terion species. Then, free base deprotonates the zwitterion to produce
carbamate [26].
The synthesized NH2-MMT was assessed for its activity for the syn-
thesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones. We carried
out a reaction of 4-methoxy benzaldehyde, ethyl acetoacetate, and hy-
droxylamine hydrochloride as the model reaction in the presence of
NH2-MMT catalyst using H2O as solvent under ultrasound irradiation.
Fig. 3 shows the temperature programmed desorption of carbon di-
oxide (CO2-TPD) patterns of MMT before and after the amine modifica-
tion in the temperature range 10–200 °C. It can be observed that the
Table 1
Optimization of reaction conditions of the model reaction under ultrasound irradiation at
30 °C.a
Entry Solvent
Catalyst (g)
Power intensity (W) Time (min) Yield (%)b
1
2
3
4
5
6
7
8
H2O
H2O
Ethanol
Methanol
DCM
0.008
0.008
0.008
0.008
0.008
100
100
100
100
100
100
100
100
100
100
30
90
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
40c
93
Trace
Trace
Trace
10
80
96
96
93
32
74
92
30
70
55
Solvent free 0.008
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
0.006
0.01
0.02
0.03
0.01
0.01
0.01
None
MMT
9
10
11
12
13
14
15
16
70
90
100
100
APTES (0.004 mL) 100
a
Ethyl acetoacetate (1 mmol), 4-methoxy benzaldehyde (1 mmol), hydroxylamine
hydrochloride (1 mmol), and NH2-MMT in solvent (5 mL) at 30 °C under ultrasound
irradiation.
b
Isolated yield of the pure compound.
Without sonication.
c
Fig. 3. CO2-TPD patterns of MMT before and after modification.

94
J. Safari et al. / Catalysis Communications 86 (2016) 91–95
Table 2
Preparation of different isoxazole-5(4H)-ones catalyzed by NH2-MMT in ultrasonic conditions.a
Entry
Ar
Product
Time (min)/yield(%)b
Mp (Lit.mp) [Ref]
1
2
3
4
5
6
7
8
4-OMe-C6H4
2-OMe-C6H4
3,4-(OMe)2-C6H3
4-OH-C6H4
3-OH-C6H4
2-OH-C6H4
4a
4b
4c
4d
4e
4f
4g
4h
4i
25/96
17/94
25/93
15/90
30/89
50/80
50/80
13/94
10/97
55/86
14/93
22/91
174–175 (173–174) [12]
137–139
134–135 (135) [8]
214–215 (213–215) [12]
202–203 (202−203) [12]
197–199 (198–199) [12]
130–133 (130−132) [12]
187–189
224–226 (226–228) [12]
141–143 (141–142) [12]
243–244 (240) [8]
4-Me-C6H5
3-OH-4-OMe-C6H3
4-N(CH3)2-C6H4
C6H5
3-Indole-carboxaldehyde
2-Tiophen
9
10
11
12
4j
4k
4l
144–145 (144–146) [12]
a
Ethyl acetoacetate (1 mmol), aldehyde (1 mmol), hydroxylamine hydrochloride (1 mmol), and 0.01 g NH2-MMT in H2O (5 mL) at 30 °C under ultrasound irradiation (100 W).
Isolated yield of the pure compound.
b
The effect of different solvents was examined on the model reaction
produced corresponding isoxazoles in excellent isolated yields with
high purity.
under ultrasound irradiation (Table 1). In the absence of ultrasound,
the reaction must be performed for 90 min to produce only 40% yield
(Table 1, entry 1), while under ultrasound irradiation, the yield was
93% after 25 min (Table 1, entry 2). Liquids irradiated with ultrasound
can produce cavitational collapse, which generates localized microscop-
ic “hot spots” with transient high temperatures and pressures to induce
favorable conditions for organic reactions [27].
Then, the reaction was evaluated by varying the concentrations of
nanocatalyst (0.006–0.03 g). It was observed that the reaction in the
presence of 0.01 g NH2-MMT and ultrasound irradiation gave the
best result as the obtained product with 96% isolated yield during
25 min (Table 1, entry 8). The model reaction was evaluated by pure
MMT, NH2-MMT and APTES as catalyst. All catalysts have demonstrated
their ability to act as promoters in this process (Table 1, entry 15 and 16).
MMT is known as an acid catalyst in chemical transformation [25]. APTES
as basic homogeneous catalyst has appeared to be mild catalyst. But, cata-
lyst separation is not easy. Therefore, we used from amine-modified
nanocatalyst as a solid acid–base catalyst towards the desired reaction.
After optimization of the reaction conditions, this methodology was
evaluated for the synthesis of different isoxazoles from various structur-
ally diverse aldehydes. The results are summarized in Table 2. These re-
sults were shown that a wide range of aromatic aldehyde derivatives
containing electron withdrawing as well as electron donating groups
A plausible reaction mechanism is proposed based on these results
and provided mechanism in literature (Scheme 2). As the initiation
step (1), the NH2-MMT helps to generate the hydroxylamine from hy-
droxylamine hydrochloride (2), and the nucleophilic attack of the
amino group of NH2OH on the carbonyl carbon of the ethyl acetoacetate
resulted in intermediate oxime (A). Then cyclization of intermediate
(A) was done for the synthesis of 3-methyl-isoxazole-5(4H)-one
under ultrasound irradiation. In the next step, the Knoevenagel conden-
sation was occurred between 3-methyl-isoxazole-5(4H)-one and aro-
matic aldehyde (3) in the presence of catalyst, which finally gives 3-
methyl-4-arylmethylene-isoxazole-5(4H)-one (4) [11,12].
In continuation of this research, the recovery, and reusability of NH2-
MMT were studied for 6 cycles for the model reaction (run 1 and 2: 96%;
run 3 and 4: 95%; run 5 and 6: 94%). The recovered nanocatalyst was
characterized with FT-IR spectroscopy (Fig. S1(c). There are the two
peaks at 3626 and 3431 cm−1 correspond to the NH2 groups, and a
weak band peak at 2933 cm−1 is attributed to the C\\H stretching
mode. In addition, the peak at 1563 cm−1 is the bending vibration due
to the interactions of NH2.
In conclusion, we have successfully developed an efficient, atom-
economical, environment friendly and simple protocol for the synthesis
of isoxazole-5(4H)-ones. The use of catalytic amount of NH2-MMT,
NH2OH.HCl
+
NH2-MMT
Cl
NH3-MMT
O
..
O
EtOOC
OH
..
U.S
NH2-MMT
OEt
+
NH2OH
(1)
O
-
H2O
..
-
EtOH
O
O
N
N
OH
+
N
Cl
NH3-MMT
Oxime
(A)
(1)
(2)
3-methyl-isoxazole-5(4H)-one
..
OH
O
Ar
H
OH
O
O
NH2-MMT
Ar
(2)
+
O
-
Ar
H
O
H2O
(4)
+
O
N
N
Cl
NH3-MMT
N
3-methyl-4-arylmethylene-isoxazole-5(4H)- ones
(3)
Scheme 2. The plausible mechanism for the formation of 4-arylmethylene isoxazole-5(4H)-ones.

J. Safari et al. / Catalysis Communications 86 (2016) 91–95
95
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Acknowledgments
We gratefully acknowledge the financial support from the Research
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MOL Files. MOL Files ZIP file containing the MOL files of the most im-
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Appendix A. Supplementary data
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