An efficient solvent-free synthesis of 3-methyl-4-nitro-5-styrylisoxazoles using solid nano-titania

Article abstract of DOI:10.1007/s12039-018-1534-0

Abstract: An efficient and solvent-free procedure for the synthesis of 3-methyl-4-nitro-5-styrylisoxazoles using nano-titania as solid support and recyclable catalyst is presented. This method provides clean, simple, solvent-free and useful alternative to

Full text of DOI:10.1007/s12039-018-1534-0

J. Chem. Sci. (2018) 130:129
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-018-1534-0
RAPID COMMUNICATION
An efficient solvent-free synthesis
of 3-methyl-4-nitro-5-styrylisoxazoles using solid nano-titania
KARTIKEY DHAR DWIVEDIa, SAMEER REDDY MARRIb, SATISH KUMAR NANDIGAMAc
and RAJU L CHOWHANa,∗
aCentre for Applied Chemistry, Central University of Gujarat, Gandhinagar, Gujarat 382 030, India
bSchool of Chemical Sciences, Central University of Gujarat, Gandhinagar, Gujarat 382 030, India
cNanoscience and Nanotechnology Laboratory, Department of Chemistry, Gitam Institute of Science, GITAM,
Visakhapatnam, Andhra Pradesh 530 045, India
E-mail: rchowhan@cug.ac.in
MS received 10 July 2018; revised 6 August 2018; accepted 7 August 2018
Abstract. An efficient and solvent-free procedure for the synthesis of 3-methyl-4-nitro-5-styrylisoxazoles
using nano-titania as solid support and recyclable catalyst is presented. This method provides clean, simple,
solvent-free and useful alternative to synthesize styrylisoxazoles. The use of nano-titania provides excellent
yield, leading to an easy separation and reuse of the catalyst up to four times without loss of yield. Also,
the green matrices calculation shows low environment impact. The green chemistry matrices atom economy,
reaction mass efficiency (RME), process mass intensity and E-factor are also calculated which show that this
methodology is green and eco-friendly. The catalytic efficiency of heterogeneous TiO2 NPs was successfully
demonstrated by recyclability experiment (up to 4 cycles). The sustainability of the catalyst was tested by
performing recyclability experiment up to 4 cycles. Calculated turn over frequency (TOF) for each cycle indicates
the protocol as sustainable.
Keywords. Styrylisoxazoles; nano-titania (TiO2 NPs); solvent-free synthesis, green methodology; nano-
catalyst.
1. Introduction
such as synthesis of dibenzo [a,j] xanthenes,7 cross
linking of cotton cellulose with succinic acid under UV.8
Reports also inferred that the catalytic properties of TiO2
nano particles were improved by functionalising with
sulfonic acid by reacting it with chlorosulfonic acid
which was used as a catalyst for the synthesis of pyrim-
idines, benzothioles and chalcones under solvent-free
conditions.9
Compounds containing isoxazole (Figure 1)
framework are known to inhibit targets COX-1 inhibitor,
NSAID, COX-2 inhibitor (Valdecoxib), 5-lipoxygenase
and cyclooxygenase inhibitors,10 and additionally they
possess diverse biological activities such as antimicro-
bial, anti-inflammatory, analgesic,11 antifungal,12 and
antiviral. Due to high potential of the isoxazole deriva-
tives in drug discovery, there is a growing interest to
design a clean and rapid method for their synthesis.
Green chemistry has become an important area of
research in the field of chemistry. Designing of a cata-
lyst which is easy to separate, reusable, inexpensive and
heterogeneous in nature is an important area of research
in green chemistry.1 Along with it, organic reactions in
solvent-free condition are current topics of interest in
green chemistry.
For the formation of catalysts, nanoparticles have
proved to be useful due to their high level of catalytic
activities and their structural features.2 After decades
of research, nano TiO2 was found to have multiple
potential application in catalytic reactions such as ester-
ification,3 for proton membrane cell,4 degradation of
methyl parathion,5 photodecomposition of methylene-
blue by highly dispersed Ag6 and synthetic reactions
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-018-1534-0) contains
supplementary material, which is available to authorized users.
0123456789().: V,-vol

129 Page 2 of 6
J. Chem. Sci. (2018) 130:129
3a as yellow solid. R f = 0.30 (Hexane); M.p. 120 − 122 ◦C;
1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 16.5 Hz, 1H),
7.68 (d, J = 16.4 Hz, 3H), 7.46 (s, 2H), 7.26 (s, 1H), 2.61
(s, 3H).
N
NH2
O
O
N
O
H
C
3
N
S
O
O
O
N
HN
O
O
l
C
O
a
ecox
-
V ld
ib
n
nt v ra
i i
A
l
-
n
or
X 1 i hibi
CO
tor
NSAID COX 2 i hibi
,
3. Results and Discussion
Figure 1. Some examples of biologically active isoxazole
derivatives.
TiO2 NPs catalyst was synthesized and characterized as
described in literature.22 Formation of the TiO2 NPs was
confirmed by the analytical data (Figure 2). The sharp
peak powder XRD (Figure 2a) pattern shows the crys-
talline nature of the synthesized catalyst. Peaks at (101),
(004), (200), (105), (211), (204), (116), (220) and (215)
correspond to anatase phase of TiO2 NPs and compared
with standard (JCPDS card no. 21-1272). DLS analysis
of the sample has shown the size of TiO2 NPs was within
narrow range of 30–60 nm (Figure 2d).
SEM images indicate the uniform size and
spherical shape of the particles (Figure 2b). TEM image
(Figure 2c) at 200 nm scale spherical shape of the
particles uniform size. The EDS (energy dispersive
X-ray spectroscopy) spectrum of synthesized TiO2 NPs
confirms the presence of Ti and O (Figure 2f). The
FTIR (Figure 2e) analysis shows peaks at 3390 cm−1
in the spectra is due to the stretching vibration of the
–OH group. In the spectrum of pure TiO2, the peaks at
512 cm−1 show stretching vibration of Ti-O and peaks
at 812 cm−1 as stretching vibrations of Ti-O-Ti.
To optimize the conditions, the one-pot reaction
of aldehyde 1a (1 mmol) and 3,5-dimethyl-4-
nitroisoxazole 2 (1 mmol) in the presence of nanocrys-
taline TiO2NPs as solid support was carried out under
different conditions (Table 1). Examining different sol-
vents confirms that solvent-free condition is the best
choice (Entries 1–9). Investigation of the temperature
effect, corroborated that 90 ◦C is the best (Entries 9–
15). The catalyst amount has been also examined to
obtain the satisfactory results and optimum 20 mol%
of TiO2 gave best results (Table 1, Entries 12–14). It
was also observed that further increasing the tempera-
ture did not increase the yield of the reaction. (Entries 12
and 15).
O
N
N
O
N
O2
F
F
s
mo
l
%
Ti NP 20
O2
(
)
O
+
N
90 o
C
ea
t
,
N
O2
2
3b
1b
Scheme 1. Recyclability experiment of TiO2 nano particle.
Various catalytic methods have been developed for
the synthesis of styrylisoxazoles in different conditions
like in piperidine,13 ionic liquids,14 sodium hydrox-
ide,15 and pyrrolidine. Dehydration reaction performed
in different catalytic media in different conditions like in
sulphuric acid,16 sulphuric acid in glacial acetic acid,17
Cobalt(III)(salpr)(OH) under neutral condition,16 P2O5
under grinding condition,18 copper(II) chloride in
ethanol and microwaves,19 and Preyssler and Wells-
Dawson hetero-polyacids in bulk and supported on
silica.20,21
Herein we report our findings using nano-titania
as a cheap, stable, reusable and easily recoverable
catalyst for a simple, clean, environmentally friendly
and solvent-free method for synthesis of 3-methyl-
4-nitro-5-styrylisoxazoles (Scheme 1). Products were
isolated quantitatively in analytically pure form without
performing column chromatography. The recyclabil-
ity experiment has shown good results with negligible
reduction in yield after four cycles. Green chemistry
matrices (Atom Economy, Reaction Mass Efficiency
(RME), E-factor, and Process Mass Intensity) were cal-
culated under optimized conditions which indicated that
the developed protocol is in good agreement with green
and sustainable parameters.
On the basis of optimized condition (Table 1) the
reaction of various aldehydes 1 with nitroisoxazole 2
have been conducted by TiO2 (20 mol%) under solvent
free condition at 90 ◦C to obtain 3-methyl-4-nitro-5-
styrylisoxazoles (Table 2). In case of the solid aldehyde
the solvent was added 1–2 drop and reaction performed
in same manner. It could be seen different aldehy-
des with electron-withdrawing and electron-donating
substituents at the C2, C3 and C4 position of the aldehy-
2. Experimental
To the mixture of aldehyde 1a (1 mmol) and 3,5-dimethyl-4-
nitroisoxazole 2 (1 mmol) the TiO2 NPs (20 mol%) added and
stirred for the 90 min at 90 ◦C. Reaction progresses was deter-
mined by thin layer chromatography (TLC). After completion
of the reaction was cooled to room temperature, the residue
was dissolved in dichloromethane and filtered. The organic
layerwasconcentratedunderreducedpressuretogiveresidue,
recrystallized in methanol to give analytically pure product des underwent the condensation reaction successfully

J. Chem. Sci. (2018) 130:129
Page 3 of 6 129
Figure 2. Characterization of TiO2 NP catalyst. (2a) Powder XRD with the simulated graph (JCPDS Card no. 21-1272).
(2b) FESEM image at 200 nm scale. (2c) TEM image at 200nm scale. (2d) DLS analysis plot showing the distribution of
particle size narrow range with avg. size of 38 5 nm. (2e) FTIR spectra from 500 to 4000 cm−1. (2f) EDX elemental
analysis.
(Table 2, Entries 3a–3p) The methoxy substituents at cycles using 1b and 2 (Scheme 1) (for experimental
C4 position (Table 2, Entry 3h) lower the yield to see supplementary information). It was observed that
80% but in presence of strong electron withdrawing the efficiency of the catalyst was found to be retained
group at C3 and C4 position (Table 2, Entries 3b, 3c) even after four consecutive cycles with negligible loss in
afforded the desired product in 86% and 85% yield catalytic property.
respectively.
Turn over frequency was calculated for each cycle
The recyclability and sustainability of the catalyst (Figure 3) of the reaction (3b). For freshly prepared
TiO2 was examined (Figure 3) and performed up to four catalyst 9.10 × 10−4 s−1 and for 4th run it was found

129 Page 4 of 6
J. Chem. Sci. (2018) 130:129
Table 1. Optimization of the one-pot condensation Table 2. Substrate scope for synthesis of 3-methyl-4-nitro-
reaction.a
5-styrylisoxazolesa,b
.
N
O
O
O2N
TiO2 NPs(20mol%)
Condition
O
NO2
+
N
3a
1a
2
N
N
O
O
O
N
O
O
Entry Solvent
T ◦C
Rt
Reflux
Rt
Reflux
Rt
Reflux
Rt
Catalyst
(wt. %)
Time
(min)
Yield
CH
F
CH
3
3
CH
3
3
(%)b
NO
F
NO
2
2
NO
2
3a,84%
3c. 85%
3b, 86%
3e, 84%
1.
2
3.
4.
5.
6.
7.
8.
EtOH
EtOH
DCM
DCM
MeOH
MeOH
Water
Water
–
20
20
20
20
20
20
20
20
20
20
20
20
25
10
20
120
90
130
100
135
95
150
110
135
120
100
78
55
68
40
52
50
67
50
65
50
75
81
86
86
75
86
N
Br
N
Cl
N
O
CH
N
CH
N
3
CH
3
Cl
NO
2
NO
2
NO
2
3f, 84
3d, 85%
O
O
O
O
3
N
2
N
O
CH
3
CH
CH
CH
3
MeO
NO
NO
2
2
Br
Reflux
Rt
NO
2
3i, 75%
3h, 80%
3g, 83
9.
N
O
10.
11.
12.
13.
14.
15.
–
–
–
–
–
–
50 ◦C
80 ◦C
90 ◦C
90 ◦C
90 ◦C
110 ◦C
N
N
O
O
CH
3
CH
3
3
NO
2
H C
3
O
N
2
NO
2
NO
2
3l, 84%
3j, 72%
3k, 83%
85
90
100
N
O
O
N
N
O
CH
3
S
CH
3
CH
3
NO
2
NO
2
NO
2
3m, 80%
aReaction conditions; aldehyde (1 mmol), 3,5-dimethyl-4-
nitroisoxazole (1 mmol) and solvent (2 mL). bIsolated yield.
3n, 84%
O
N
3o, 83%
CH
3
NO
2
3p, 82%
8.65 × 10−4 s−1 observations clearly show there is
very slight change in the frequency. These observa-
tions clearly indicate that there is very small loss in
the catalytic efficiency of the catalyst at the end of 4th
cycle.
aReaction conditions: unless otherwise specified, the reaction
was carried out with aldehydes (1a–p) (1.0 mmol), 3,5-
dimethyl-4-nitroisoxazole (2) (1.0 mmol) and TiO2 NPs (20
b
mol%) under neat condition. Isolated yields of the product
(3a–p).
Green chemistry matrices calculations23 like atom
economy reaction catalysts for mass efficiency should
be high, and environmental factor, as well as process
mass intensity, should be low for a standard green
chemistry reaction.24 Green chemistry matrixes were
calculated for reaction involving substrates 1b and 2 to
give 3b as model optimized reaction, and found high
atom economy (A.E. = 93.23%), reaction mass effi-
ciency (R.M.E. = 91.36%), small E-factor (E-factor =
0.0945) and process mass intensity (P.M.I. factor =
1.094). (Detailed calculations for all the reactions are
included in supplementary information). These values
clearly indicate the efficacy of the present protocol.
The mechanism of product formation was reasoned as
follows. The TiO2 nano particles provide solid support
facilitateactivationofthe3,5-dimethyl-4-nitroisoxazole
known to undergo keto–enol tautomerism type (I).24
The TiO2 catalyst activated the aldehyde which gives
the intermediate aldol adduct (II) and due to heating
condition dehydration occurs giving the 3-methyl-4-
nitro-5-styrylisoxazoles (III), (Figure 4).
Figure 3. Recyclability experiment of TiO2 nano particle.
bIsolated yield.

J. Chem. Sci. (2018) 130:129
Page 5 of 6 129
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Figure 4. Plausible mechanism for the synthesis of
3-methyl-4-nitro-5-styrylisoxazoles using nano titania.
4. Conclusions
In conclusion, we have successfully synthesized
3-methyl-4-nitro-5-styrylisoxazoles in solvent-free
TiO2 NPs-catalyzed at 90 ◦C for the first time. This
newly developed method offers several advantages
including mild reaction condition, high yield, and
reusable catalyst. In addition, turn over frequency cal-
culations for recyclability experiment have shown good
results indicating negligible loss in catalytic activity
of the TiO2 NPs. Greenness and sustainability of the
protocol were established by green chemistry matri-
ces calculations for the reaction which gave high atom
economy and reaction mass efficiency values, and low
E-factor.
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Supplementary Information (SI)
Characterization data and spectra for all the compounds are
provided in the Supplementary Information which is available
at www.ias.ac.in/chemsci.
Acknowledgements
M. S. R and K.D.D thank UGC for Non-NET fellowship and
the Central University of Gujarat for infrastructure to carry
out the work. K.D.D would like to thank Dr. P.C. Jha, Chair-
person, CAC, CUG for encouragement and support. Authors
also thank MRC, MNIT, Jaipur for analytical support.
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