Green synthesis of 3,4-disubstituted isoxazol-5(4H)-ones using ZnO@Fe3O4 core–shell nanocatalyst in water

Article abstract of DOI:10.1002/aoc.5544

An effective and environmentally benign methodology for the synthesis of isoxazol-5(4H)-one derivatives has been developed using a ZnO@Fe₃O₄ core–shell nanocatalytic system. The one-pot, multicomponent reaction of an aromatic/heteroc

Full text of DOI:10.1002/aoc.5544

Received: 21 October 2019
DOI: 10.1002/aoc.5544
Revised: 18 December 2019
Accepted: 29 December 2019
F U L L P A P E R
Green synthesis of 3,4-disubstituted isoxazol-5(4H)-ones
using ZnO@Fe3O4 core–shell nanocatalyst in water
M. Shanshak1 | Srinivasa Budagumpi1 | Jan Grzegorz Małecki2
|
Rangappa S. Keri1
1Centre for Nano and Material Sciences,
Abstract
Jain University, Jain Global Campus,
Kanakapura, Ramanagaram, Bangalore,
562112, India
2Department of Crystallography, Institute
of Chemistry, University of Silesia, 9th
Szkolna St., 40-006, Katowice, Poland
An effective and environmentally benign methodology for the synthesis of
isoxazol-5(4H)-one derivatives has been developed using a ZnO@Fe3O4
core–shell nanocatalytic system. The one-pot, multicomponent reaction of an
aromatic/heterocyclic aldehyde, hydroxylamine hydrochloride and ethyl
acetoacetate under aqueous conditions at slightly elevated temperature
resulted in the formation of title compounds in extremely good yields. The pre-
sent new protocol is environmentally friendly as it offers heterocyclization
with some interesting promising features such as safety, atom efficiency, low
cost, mild conditions, minimal waste, catalyst recyclability, water as a solvent,
easy workup and possession of excellent functional group tolerance for the
synthesisis of structurally diverse isoxazole derivatives. All products were char-
acterized by spectral and analytical methods. A representative title derivative
was studied for its structure by single crystal X-ray diffraction method.
Correspondence
Rangappa S. Keri, Organic and Medicinal
Chemistry Laboratory, Centre for Nano
and Material Sciences, Jain University,
Jain Global Campus, Jakkasandra post,
Kanakapura Road, Ramanagara District,
Karnataka 562112, India.
E–mail.
Email: keriphd@gmail.com; sk.
rangappa@jainuniversity.ac.in
Funding information
Nanomission, Grant/Award Number:
SR/NM/ NS-20/2014
K E Y W O R D S
Fe3O4, green synthesis, isoxazoles, multicomponent reaction, nanocatalyst
1 | INTRODUCTION
Multicomponent reactions, where three or more
accessible reactants react together in one step to form
Functionalized heterocyclic small molecules are impor-
tant in the discovery of new drug molecules owing to
their selective binding ability to the biological targets.[1]
Development of organic transformations for the con-
struction of bioactive heterocyclic molecules that can
serve as effective drug molecules in a reduced number
of synthetic steps with high molecular complexity is a
key aspect of green chemistry. In the past decade, the
synthesis of heterocyclic molecules through one-pot
multicomponent reactions has gained considerable
attention as they avoid multistep synthesis and conse-
quently reduce costs. Therefore, these reactions can
efficiently assist as synthetic tools for the formation of
structurally combined molecular frameworks that
are suitable for diverse biological applications.[2]
a single product without isolating the intermediates,
have been found to be effective from an industry
perspective as they reduce the required labor and
energy, simplify workup and improve cost-effectiveness,
among other advantages.[3] Multicomponent reactions
offer many benefits such as shorter reaction times,
high yields, reduced waste generation, minimized
reagent comsumption and purification stages, and
many other significant advantages over conventional
multistep synthesis. Meanwhile, the pharmaceutical
industry supports the use of water rather than toxic
organic solvents for the synthesis of drug entities. As
a
result, much effort has been directed towards
using water as a solvent for organic reactions in
recent years.[4]
Appl Organometal Chem. 2020;e5544.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5544

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SHANSHAK ET AL.
Nitrogen-containing heterocycles are core structures
of numerous bioactive natural and synthetic compounds.
A recent analysis showed that nearly 60% of small-mole-
cule-based drugs approved by the US Food and Drug
Administration contain at least one N-heterocyclic moi-
ety.[5] Among these, isoxazole and its derivatives are an
important class of nitrogen- and oxygen-containing het-
erocyclic compounds with a variety of applications in the
pharmaceutical industry, medicinal chemistry and
organic synthesis, as well as optoelectronic and light-
conversion molecular devices.[6] Among isoxazoles,
3,4-disubstituted isoxazol-5(4H)-ones are attractive tar-
gets in both medicinal chemistry and organic synthe-
sis.[7,8] These heterocyclic systems play an important role
in the field of chemotherapy and agrochemicals owing to
their properties, such as antitumor,[9] anti-HIV,[10]
fungicidal,[11] antiobesity,[12] selective inhibition of pro-
tein kinase C[13] and enzyme inhibition.[14] Owing to the
broad biological and material importance of this hetero-
cycle, researchers have reported various methods to con-
struct different motifs depending on the target
applications.
Essentially, these heterocyclic compounds have been
synthesized via a multicomponent condensation reaction
of various aldehydes, β-keto esters and hydroxylamine
hydrochloride in the presence of a catalyst. A number of
catalysts have been used in one-pot multicomponent
reactions for the synthesis of isoxazol-5(4H)-one scaffolds
including boric acid,[15] citric acid,[16] molecular iodine,
KI, Ag/SiO2, 4-(N,N-dimethylamino) pyridinium acetate,
tetrabutylammonium perchlorate/glycine/sodium oxa-
late, amine-modified montmorillonite nanoclay, anti-
mony trichloride, mesolite, DABCO functionalized
dicationic ionic liquid, nano-MgO, sodium silicate
pentahydrate, citrus fruit juice, pyridinium p-tol-
uenesulfonate, cerium chloride heptahydrate, pyridine,
nickel (II) acetate and many more.[17] Also, advanced
techniques such as microwave heating,[18] grinding,[19]
ultrasonic irradiation[20] and visible light in the presence
of sodium acetate in aqueous EtOH[21] have also been
reported for the preparation of isoxazol-5(4H)-ones,
Although many of these protocols suffer from drawbacks
and limitations such as low yields/long reaction times,
strongly acidic or basic conditions and the use of toxic
reagents, stringent reaction conditions, the use of
expensive catalyst, multistep synthetic sequence and
difficult work up procedures that restrict their scope in
practical applications. Considering the above points, we
report an efficient and green method for the synthesis
of a wide variety of isoxazol-5(4H)-one derivatives via
the one-pot, three-component process catalyzed by
ZnO@Fe3O4 core–shell nanoparticles under aqueous
conditions (Scheme 1).
SCHEME 1 Synthesis of 3,4-disubstituted isoxazole-5(4H)-
ones catalyzed by ZnO@Fe3O4
2 | RESULTS AND DISCUSSION
The heterogeneous catalyst was prepared in two steps
following literature procedures with slight modifica-
tion.[22] First, Fe3O4 (magnetite nanoparticles) was pre-
pared by the reaction of ferric and ferrous chlorides in
water at 80ꢀC for 30 min after which ammonium hydrox-
ide was added and stirred for a further 30 min under the
same conditions. Next the obtained precipitate was repeat-
edly washed with plenty of water and methanol, and dried
under vacuum to obtain a black powder of Fe3O4. Sec-
ondly, the ZnO@Fe3O4 core–shell nanoparticles were
achieved by subsequent deposition of a layer of ZnO on
the surface of magnetite nanoparticles through thermal
decomposition of zinc precursor in the presence of magne-
tite seeds (Scheme SI1). The fourier-transform infrared
spectroscopy (FTIR) spectrum of the nanocatalyst showed
a strong band at 445 cm−1 as indicated by the vibration of
the Zn–O bonding. Other two characteristic peaks near to
each other at 536 and 620 cm−1 were attributed to the
vibrations of the Fe–O bonding (Figure SI1). In the UV–
vis spectrum of the catalyst two absorption maxima at
315 and 371 nm were observed, which were unlike the
maxima observed for individual metal oxides (Figure 1a).
In the X-ray powder diffraction(p-XRD) pattern of the cat-
alyst, characteristic peaks for Fe3O4 nanoparticles
(2θ = 30.16, 35.48, 43.13, 53.49, 56.91 and 62.71ꢀ) marked
by their indices (220, 311, 400, 422, 511 and 440, respec-
tively), were recognized. These peaks are well matched
with the magnetite characteristic peaks (ICDD card
no. 19-0629). The characteristic peaks for ZnO complex
(2θ = 31.84, 34.52, 36.33, 47.63, 56.71, 62.96, 68.13 and
69.18ꢀ) confirm that Fe3O4 nanoparticles are coated with
ZnO (Figure 1b). Further, from field emission scanning
electron microscope (FESEM) analysis using a 20.0 kV
acceleration
voltage,
uniform-sized
magnetic
nanoparticles with fairly flake-like morphology were
observed for Fe3O4 nanoparticles (Figure 1c) with a mar-
ked tendency to form large clusters. Furthermore, the
image (Figure 1d) of core–shell nanocatalyst indicates the
coating of ZnO over Fe3O4 magnetic nanoparticles, which
was further complemented by energy-dispersive X-ray
spectroscopy (EDX) studies (Figure SI2).
Initially, a model reaction was conducted comprising
three components, benzaldehyde (1a), hydroxylamine
hydrochloride (2) and ethyl acetoacetate (3), with varying

ISOXAZOLE SYNTHESIS USING FE3O4@ZNO AS A CATALYST
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FIGURE 1 (a) Stacked UV–vis
spectra of bare metal oxides and the
core–shell nanocatalyst; (b) p-XRD of
core–shell nanocatalyst; (c) FESEM
image of Fe3O4 nanoparticles;
(d) FESEM image of Fe3O4
nanoparticles decorated with ZnO;
(e) molecular structure of isoxazole
derivative 4b; hydrogen atoms are
excluded due to clarity; (f) Recyclability
profile of the nanocatalyst in obtaining
4a under optimized reaction conditions
nanocatalyst loading, temperature and solvent, as these
are the important parameters which affect the yield of
desired product 4a to a great extent. The effects of the
reaction temperature and amounts of catalyst were inves-
tigated and the experimental results are summarized in
Table 1. First, the reaction was carried out without any
catalytic heterocyclization reaction. Conversely, the reac-
tion was carried out without catalyst at 70ꢀC, which did
not yield any product even after 40 h (entry 1), indicating
the significance of the core–shell nanocatalyst.
With the parameters optimized as water as a solvent
and 5 mg of nanocatalyst at 70ꢀC, the universality of the
catalytic system was explored. A series of structurally and
electronically diverse aldehydes were treated with ethyl
acetoacetate and hydroxylamine hydrochloride to access
diverse isoxazole derivatives (Scheme 2). All of the sub-
strate variants reacted with 2 and 3 under the optimized
ꢀ
catalyst with varying temperature (70, 100 and 120 C;
entries 1, 2 and 3), and a trace amount of product formed.
Further, the multicomponent catalytic reaction was car-
ried out with 5 mg of nanocatalyst at room temperature
for 40 h in water, which resulted in the formation of trace
amount of product (entries 4 and 5). Therefore, the reac-
tion temperature was increased and time decreased to
obtain an optimized temperature of 70ꢀC that resulted in
the yield of 93% in 30 min. However, further increase in
the temperature affected the yield owing to rapid deacti-
vation of the active species. Furthermore, catalyst loading
was decreased to 1, 2 and 3 mg (entries 12, 13 and 14),
with the corresponding yield of oxazole 47, 63 and 79%,
respectively, while loading of 10 mg (entry 16) resulted in
the formation of 92% yield. Therefore, a nanocatalyst
loading of 5 mg at 70ꢀC for 30 min was considered as
optimum reaction conditions for this multicomponent
reaction
conditions
to
afford
corresponding
3,4-disubstituted isoxazol-5(4H)-one products in high
yields (57–93%). Aromatic aldehydes bearing electron-
donating or electron-withdrawing groups at different
positions on the aromatic ring system reacted efficiently
and smoothly under the optimized conditions. It was
found that substituted benzaldehydes containing
electron-donating groups on the phenyl ring at the para
and meta positions afforded corresponding heterocyclic
products, 4b–4i, in high isolated yields in the range
67–91%. The para nitro and fluoro substituted benzalde-
hydes resulted in the formation of products with the

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SHANSHAK ET AL.
TABLE 1 Optimization of the reaction conditions for a multicomponent heterocyclization using ZnO@Fe3O4 core–shell catalyst
Entry
1
Catalyst (mg)
Temperature (ꢀC)
Time (min)
Yield (%) (isolated)
––
––
––
5
70
100
120
r.t
2400
2400
2400
2400
600
120
60
––
2
Trace
Trace
Trace
Trace
45
3
4
5
5
40
50
60
70
80
90
100
70
70
70
70
70
6
5
7
5
81
8
5
30
93
9
5
30
92
10
11
12
13
14
15
16
5
30
83
5
30
74
1
200
90
47
2
63
3
90
79
5
30
93
10
30
92
lowest and highest percentage yields, respectively. The
interesting fact of this protocol is that the ortho-hydroxy
benzaldehyde can also undergo cyclocondensation, pro-
viding a corresponding product in 57% yield, which is not
reported in some of the reported methods. Further, this
methodology has also been extended to α,β-unsaturated
and heteroaromatic aldehydes, which also reacted very
well and afforded good to high yields – 84, 75 and 82% of
the corresponding isoxazole-5(4H)-ones (4k, 4l and 4m),
respectively. This protocol was also applicable to aliphatic
and alicyclic aldehydes, which is still under investigation.
The model reaction (Scheme 2, Figure SI3) was scalable
up to 10 g with mechanical overhead stirring resulting in
the formation of the desired product.
To obtain the solid-state bonding and special connec-
tivity information for these isoxazol-5(4H)-ones, a repre-
sentative derivative, 4d (Figure 1e), was analyzed by
single-crystal X-ray diffraction technique (Table SI1).
Suitable X-ray quality crystals were obtained through the
diffusion of diethyl ether into ethanol solution of iso-
xazole over a period of 7 days at room temperature. Com-
pound 4d crystalized in a monoclinic system with a C2/c
space group having one molecule in an asymmetric unit.
Both isoxazole and phenyl ring systems are coplanar,
separated by an angle 133.23(12)o (for C2–C5–C6). Inter-
nal bond angles at heteroatoms 109.75(10) (for C1–O1–
N1) and 107.33(10)o (for O1–N1–C3) (Table SI2), are in
line with the reported isoxazole analogs. Compound 4d
possessed weak π–π stacking interactions between iso-
xazole and phenyl rings of adjacent molecules with a
centroid-to-centroid distance of 3.444 Å, along with
hydrogen bonding interactions. The O3–H3
…
N1[−½ + x, −½ + y, z] hydrogen bond between creates
the infinite chain of C11ð10Þ type along the a axis
(Table SI3).
Recyclability of the catalyst is an important attribute
for industrial suitability. Therefore, the reusability of the
nanocatalyst in the model reaction under optimized reac-
tion conditions was evaluated. After completion of the
reaction, the catalyst was recovered with an external
magnet and was washed with ethanol and dried at
ꢀ
120–150 C under reduced pressure for 2 h. The recycled
nanocatalyst was found to be reusable without significant
loss of catalytic activity for six consecutive runs. Figure 1f
depicts the yields of 4a in the second and third runs,
which are almost identical to that in the first run. In the
fourth and sixth runs 90 and 88% yields of 4a were
obtained, respectively.

ISOXAZOLE SYNTHESIS USING FE3O4@ZNO AS A CATALYST
5 of 6
TABLE 2 Scope of aldehydes for ZnO@Fe3O4-catalyzed heterocyclization to obtain 3,4–disubstituted isoxazol-5(4H)-one derivatives
(isolated yields). Reaction conditions: aldehyde (1 equiv.), ethyl acetoacetate (2 equiv.) and hydroxylamine hydrochloride (1 equiv.) in the
presence of ZnO@Fe3O4 (5 mg) catalyst at 70ꢀC for 30 min in 10 ml water
A plausible mechanism (Figure 2) for the synthesis of
3,4-disubstituted isoxazol-5(4H)-one is suggested over
ZnO@Fe3O4 core–shell nanocatalyst on the basis of the
Knoevenagel condensation reaction. In this catalysis,
initially the core–shell nanocatalyst is coordinated with
oxygen of the carbonyl group of ethylacetoacetate
(A) then the lone pair of nitrogen attacks to the carbonyl
carbon and water is eliminated to form (B). Then, keto-
FIGURE 2 A plausible mechanism for the
synthesis of 3,4–disubstituted isoxazol–5(4H)–
ones catalyzed by ZnO@Fe3O4

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SHANSHAK ET AL.
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3 | CONCLUSIONS
In summary, we prepared ZnO-decorated Fe3O4 magnetic
core–shell nanoparticles and characterized them by
FTIR, UV–vis, FESEM, EDX and p-XRD techniques.
Further, this nanocatalyst was used for the highly
efficient, green and one-pot, three-component reaction
for the synthesis of structurally electronically varied
3,4-disubstituted isoxazol-5(4H)-ones, which are consid-
ered as biologically and pharmacologically active com-
pounds. The present procedure was accomplished by the
use of nanocatalyst in water, which in turn helps to
reduce cost-effectiveness and energy. The significant
merits of the nanocatalyst were ascribed to its high selec-
tivity, promising catalytic activity, easy separation and
recyclability. The process does not require the use of any
volatile organic solvent, harmful metal catalysts and high
temperatures. Moreover, this method also has the ability
to tolerate a wide variety of substituents with varied steric
and electronic parameters. The versatility of this method-
ology is suitable for library synthesis in drug discovery
efforts. We believe that the present improved modifica-
tion is a convenient and efficient alternative to the exis-
ting methods for the multicomponent synthesis of
isoxazol-5(4H)-one derivatives.
ACKNOWLEDGEMENTS
We are grateful to the Jain University, Bangalore for
financial support. Also, thanks are due to Dr Karam
Chand, Umea University, Sweden for valuable sugges-
tions. We also thank Nanomission (SR/NM/NS-20/2014)
for providing FESEM, EDX and p-XRD facilities.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Shanshak M,
Budagumpi S, Małecki JG, Keri RS. Green
synthesis of 3,4-disubstituted isoxazol-5(4H)-ones
using ZnO@Fe3O4 core–shell nanocatalyst in
water. Appl Organometal Chem. 2020;e5544.
https://doi.org/10.1002/aoc.5544
ORCID
Rangappa S. Keri https://orcid.org/0000-0001-6262-
8379
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