An efficient solvent-free synthesis of 3,4-disubstituted isoxazole-5(4H)-ones using microwave irradiation

Article abstract of DOI:10.1016/j.jics.2021.100013

I have reported one-pot and three-component synthesis of 3-mehyl-4-arylmethyleneisoxazol-5(4H)-ones using microwave radiation under the solvent-free conditions, in the presence of potassium bromide as the catalyst. The method has given the products in hig

Full text of DOI:10.1016/j.jics.2021.100013

Journal of the Indian Chemical Society 98 (2021) 100013
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An efficient solvent-free synthesis of 3,4-disubstituted isoxazole-5(4H)-ones
using microwave irradiation
Pramod Kulkarni
Postgraduate Centre in Organic Chemistry and Department of Chemistry Hutatma Rajguru Mahavidyalaya, Rajgurunagar, Pune, 410505, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
I have reported one-pot and three-component synthesis of 3-mehyl-4-arylmethyleneisoxazol-5(4H)-ones using
microwave radiation under the solvent-free conditions, in the presence of potassium bromide as the catalyst. The
method has given the products in high yields and short reaction times with an easy work-up process. The present
method provides an easy and efficient approach for the synthesis of this class of compounds, because of its clean
reaction profile and operational simplicity.
Isoxazole-5(4H)-one
One-pot three component synthesis
Microwave
Eco-friendly
Condensation
Beta-keto ester
1. Introduction
isoxazole derivatives and their analogs. A Literature study displays that
many catalyzed methods reported for the synthesis of various isoxazole
Isoxazoles, a privileged class of five-member nitrogen and oxygen-
containing heterocycles, conquer reputation in organic chemistry for
their wide applications in pharmaceuticals, biologically active molecules,
advanced organic materials, and as intermediates in organic synthesis
[1]. Isoxazole-5(4H)-one showed important biological activity; such as
anti-obesity [2], antimycobacterial [3], anti-osteoporotic [4], anticancer
[5], antimicrobial and larvicidal [6], cytotoxic [7], nematicidal agents
[8], carbonic anhydrase inhibitor [9], and antiprotozoal activities [10].
Isoxazolone compounds have applications in the material sciences. They
are used for the design of materials such as liquid crystals [11], and
photochromic components [12]. An isoxazolone nucleus is a virtuous
proaromatic acceptor, when linked to aromatic donors, for conjugated
donor-acceptor (D-Π-A) merocyanine dyes. Isoxazolone nucleus is a good
proaromatic acceptor because of its good molar extinction coefficients
derivatives. To state a few, such protocols potassium phthalimide [21],
antimony chloride [22], ZnO@Fe3O4 core-shell nanocatalyst in water
[23], pyridinium p-toluenesulfonate [24], Boric acid [25], phthalimi-
de-N-oxyl salts [26], starch solution [27], sodium benzoate [28],
2-hydroxy-5-sulfobenzoic acid [29], N-bromosuccinimide [30],
nano-MgO [31], modified mesolite [32], sulfonated graphene-oxide
[33], nanocrystalline hydroxyapatite [34], 6-methylguanamine-sup-
ported CoFe2O4 [35], nano-SiO2- H2SO4 [36], salicylic acid [37], KI
[38], sulfated polyborate [39], and sulfanilic acid [40]. Furthermore,
different conditions and techniques such as using sonochemical condi-
tion using amine-modified [41], visible light in the presence of sodium
acetate in aqueous ethanol [42], Fruit juice [43], Microwave irradiation
in the presence of potassium fluoride on alumina [44], and ionic liquid
[45]. However, most of the above stated procedures for the synthesis of
these compounds suffer from disadvantages, including the use of toxic or
odorous, expensive catalysts, catalyst preparation required, strong acid
or base catalysts, use of organic solvent, tedious work-up procedures,
troublesome waste discarding, two step procedure, long reaction times,
and low yields. Thus, preclusion of these limitations is crucial to improve
more efficient and green synthesis of 3-methyl-4-(arylmethylene) iso-
xazole-5(4H)-one derivatives. Hence, we here report the preparation of
3-methyl-4-(arylmethylene)-isoxazole-5(4H)-one by one-pot three--
component condensation of aryl aldehydes (1), hydroxylamine hydro-
chloride (2), and ethyl acetoacetate (3), using microwave irradiation
under solvent free condition.
tunable
absorption
spectra
and
large
first
molecular
hyper-polarizabilities. Merocyanine dyes with an isoxazolone nucleus
have used for optical recording and nonlinear optical research [13].
4-(Arylmethylene) isoxazol-5-ones intermediates in synthetic organic
chemistry for the synthesis of β-branched carbonyl compounds [14], 3,
4-disubstituted 2H-isoxazol-5-ones [15], methyl 5-aminopyrrole-3-car-
boxylates via cyanide Michael addition, methylation and reductive
isoxazole-pyrrole [16], in the synthesis of heterocycle and terminal al-
kynes [17]. The isoxazole core is a backbone and a structural component
of a variety of natural products such as muscimol [18], pantherine [19],
ibotenic acid and isoxazol-4-carboxylic acid [20]. Multiple synthetic
protocols have been described in the literature for the synthesis of
Microwave irradiation (MWI) provides an alternative source of
E-mail address: pramodskulkarni3@gmail.com.
https://doi.org/10.1016/j.jics.2021.100013
Received 14 December 2020; Received in revised form 20 January 2021; Accepted 29 January 2021
0019-4522/© 2021 Indian Chemical Society. Published by Elsevier B.V. All rights reserved.

P. Kulkarni
Journal of the Indian Chemical Society 98 (2021) 100013
energy to the conventional energy for heating into the organic synthesis.
This method has been utilizes the capacity of mobile electric charges
existing in liquid or conducting ions in solid to transform electromagnetic
energy into heat. The reactions have performed by the microwave-
assisted irradiation is fast, clean, economical and environmentally
benign. This method has been suggested as the ‘technology of future’ as
various merits has been found [46].
4. (4Z)-4-(4-chlorobenzylidene)-3-methylisoxazol-5(4H)-one
(4d):
Yield 94%, m. p. 117–119 ꢀC (Lit. 118–119 ꢀC). IR max cmꢁ1: 3010
ν
–
–
–
(C–H stretches), 1653 (C O is stretching), 1552 (C C stretch-
–
ing), 1482 (N–O is stretching). 1HNMR (300 MHz, CDCl3, δ ppm):
1.89 (s, 3H), 7.14 (s, 1H), 7.26–7.23 (d, J ¼ 7.2 Hz, 2H), 7.45–7.41
(d, J ¼ 7.2 Hz, 1H); 13C NMR (75 MHz, CDCl3, δ ppm): 31.9,
126.8, 127.4, 128.2, 130.1, 130.9, 133.3, 142.4, 161.1, 171.9.
HRMS ESI (m/z): 221.43 (Mþ), 222.12 (Mþ1)þ. Anal. Calcd. for
C
11H8ClNO2: C 59.61, H 3.64, and N 6.32%; found C 59.57, H
2. Experimental
3.59, and N 6.30%.
5. (4Z)-4-(4-bromobenzylidene)-3-methylisoxazol-5(4H)-one
(4e):
Melting points were measured using an open capillary method and
are uncorrected. IR spectra were recorded on alpha T BRUKER model. 1H
NMR and 13C NMR spectra were recorded at ambient temperature on a
BRUKER AVANCE DRX-300 MHz spectrophotometer using CDCl3 or
DMSO-D6 as the solvent and TMS as an internal standard. The elemental
analysis were recorded on Thermo Scientific (FLASH 2000) Elemental
Analyser. The purity of newly synthesized compounds and the develop-
ment of the reaction was monitored by thin layer chromatography (TLC)
on Merck pre-coated silica gel 60 F254 aluminium sheets, visualized by
UV light.
Yield 92%, m. p. 123–124 ꢀC (Lit. 124–126 ꢀC). IR max cmꢁ1: 3005
ν
–
–
–
(C–H stretching), 1656 (C O stretching), 1545 (C C stretching),
–
1475 (N–O stretching). 1HNMR (300 MHz, CDCl3, δ ppm): 1.84 (s,
3H), 7.10 (s, 1H), 7.20–7.16 (d, J ¼ 7.6Hz, 2H), 7.38–7.34 (d, J ¼
7.6Hz, 1H); 13C NMR (75 MHz, CDCl3, δ ppm): 31.3, 125.4, 128.2,
128.9, 131.3, 133.1, 143.2, 160.4, 171.2. HRMS ESI (m/z): 264.85
(Mþ), 265.93 (Mþ1)þ. Anal. Calcd. for C11H8BrNO2: C 49.65, H
3.03, and N 5.26%; found C 49.62, H 3.02, and N 5.21%.
6. (4Z)-3-methyl-4-(3-phenylallylidene)isoxazole-5(4H)-one (4f): Yield
89%, m. p. 174–175 ꢀC (Lit. 175–176 ꢀC). IR max cmꢁ1: 3015 (C–H
ν
General procedure for preparation of 3,4-disubstituted isoxazole-
5(4H)-ones.
–
–
–
stretches), 1649 (C O is stretching), 1560 (C C stretching),
–
1468 (N–O is stretching). 1HNMR (300 MHz, CDCl3, δ ppm): 1.82
(s, 3H), 7.05–6.97 (m, 4H), 7.51–7.47 (d, J ¼ 6.9 Hz, 2H), 7.95 (s,
1H), 8.50–8.35 (d, J ¼ 6.9Hz, 1H); 13C NMR (75 MHz, CDCl3, δ
ppm): 30.6, 117.2, 117.9, 120.1, 120.7, 125.6, 132.8, 137.4,
146.8, 160.1, 162.8, 169.6. HRMS ESI (m/z): 213.18 (Mþ), 214.24
(Mþ1)þ. Anal. Calced. for C13H11NO2: C 73.23, H 5.20, and N
6.57%; found C 73.22, H 5.17, and N 6.54%.
A mixture of ethyl acetoacetate (1 mmol, 1.30 g), hydroxylamine
hydrochloride (1.5 mmol, 1.042 g), and substituted aromatic aldehyde
(1 mmol) and potassium bromide (0.2 mmol, 0.0238 g) was taken in a 50
mL beaker. The beaker was irradiated at 200 W in the microwave oven
for the respective time given in Table 3. The progress of the reaction
mixture was monitored by TLC. After completion of the reaction, the
reaction mass was cooled at room temperature. The reaction mass was
diluted with 20 mL chloroform and the catalyst was precipitated as solid.
The catalyst was separated by a filtration method and the product was
found in the filtrate. After evaporating, the organic layer gets crude
product in solid form. The product was purified by recrystallization in the
ethanol.
7. (4Z)-4-(4-mthylbenzylidene)-3-methylisoxazol-5(4H)-one
(4g):
Yield 96%, m. p. 136–137 ꢀC (Lit. 135–136 ꢀC). IR max cmꢁ1: 2998
ν
–
–
–
(C–H stretching), 1652(C O stretching), 1538 (C C stretching),
–
1376 (N–O stretching). 1HNMR (300 MHz, CDCl3, δ ppm): 1.78 (s,
3H), 2.38 (s, 3H), 7.19–7.14 (d, J ¼ 8.3Hz, 2H), 7.34 (s, 1H),
7.72–7.68 (d, J ¼ 8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3, δ ppm):
28.3 34.5, 115.8, 120.6, 129.3, 130.1, 136.8, 151.8, 162.4, 169.1.
HRMS ESI (m/z): 201.08 (Mþ), 202.10 (Mþ1)þ. Anal. Calcd. for
2.1. Spectral data of synthesized compounds
C
12H11NO2: C 71.63, H 5.51, and N 6.96%; found C 71.59, H 5.50,
and N 6.90%.
1. (4Z)-4-Benzylidene-3-methylisoxazol-5(4H)-one (4a): Yield 95%,
m. p. 140-141 ꢀC (Lit. 141-143 ꢀC). IRνmax cmꢁ1: 3072 (C–H
8. (4Z)-4-(3,4-dimethoxybenzylidene)-3-methylisoxazol-5(4H)-one
(4h): Yield 91%, m. p. 128–130 ꢀC (Lit. 129–131 ꢀC). IR
ν
max cmꢁ1
:
–
–
–
stretching), 1660 (C O stretching), 1543 (C C stretching), 1470
–
(N–O stretching). 1HNMR (300 MHz, CDCl3, δ ppm): 1.75 (s, 3H),
6.97 (s, 1H), 7.23–7.17 (m, 3H), 7.30–7.26 (m, 2H); 13C NMR (75
MHz, CDCl3, δ ppm): 29.3, 126.2, 128.4, 129.3, 140.2, 162.1,
171.8. HRMS ESI (m/z): 187.04 (Mþ), 188.10 (Mþ1)þ. Anal.
Calcd. for C11H9NO2: C 70.58, H 4.85 and N 7.48%; found C
70.40, H 4.82, and N 7.36%.
–
–
–
3016 (C–H stretching), 1640(C
O
stretching), 1556 (C
C
–
stretching), 1371 (N–O stretching), 1282 (O–CH3 stretching).
1HNMR (300 MHz, CDCl3, δ ppm): δ 2.26 (s, 3H), 3.97 (s, 3H),
3.98 (s, 3H), 6.92–6.94 (m, 1H), 7.31 (s, 1H), 7.57–7.59 (m, 1H),
8.72 (s, 1H); 13C NMR (75 MHz, CDCl3, δ ppm): 11.6, 56.1, 110.7,
115.0, 116.2, 126.3, 131.2, 149.0, 149.8, 154.5, 161.3, 169.0.
HRMS ESI (m/z): 247.15 (Mþ), 248.15 (Mþ1)þ. Anal. Calcd. for
2. (4Z)-4-(2-chloroBenzylidene)-3-methylisoxazol-5(4H)-one
(4b):
Yield 70%, m. p. 163–165 ꢀC. IR max cmꢁ1: 3055 (C–H stretching),
ν
C
13H13NO4: C 63.15, H 5.30, and N 5.67%; found C 63.14, H 5.27,
–
–
–
–
and N 5.63%.
1663 (C O stretching), 1547 (C C stretching), 1475 (N–O
stretching). 1HNMR (300 MHz, CDCl3, δ ppm): 1.76 (s, 3H), 7.03
(s, 1H), 7.10 (m, 1H), 7.14 (m, 1H), 7.23 (m, 1H), 7.29 (m, 1H);
13C NMR (75 MHz, CDCl3, δ ppm): 29.5, 124.6, 127.2, 128.6,
129.7, 130.8, 132.1, 134.5, 161.2, 172. HRMS ESI (m/z): 221.56
(Mþ), 222.43 (Mþ1)þ. Anal. Calcd. for C11H8ClNO2: C 59.61, H
3.64, and N 6.32%; found C 59.35, H 3.54, and N 6.20%.
9. (4Z)-4-(2,4,6-trimethoxybenzylidene)-3-methylisoxazol-5(4H)-one
(4i): Yield 83%, m. p. 230-231 ꢀC (Lit. 231–233 ꢀC). IR
ν
max cmꢁ1
:
–
–
3020 (C–H stretching), 1638(C
O
stretching), 1549 (C
C
–
–
stretching), 1376 (N–O stretching), 1276 (O–CH3 stretching).
1HNMR (300 MHz, CDCl3, δ ppm): δ 2.22 (s, 3H), 3.97 (s, 3H),
3.98 (s, 6H), 6.45–6.47 (s, 2H), 7.13 (s, 1H); 13CNMR (75 MHz,
CDCl3, δ ppm): 11.7, 56.2, 56.8, 100.8, 105.3, 124.7, 151.2,
159.8, 162.3, 164.6, 169.9. HRMS ESI (m/z): 277.25 (Mþ), 278.21
(Mþ1)þ. Anal. Calcd. for C14H15NO5: C 60.64, H 5.45, and N
5.05%; found C 60.59, H 5.44, and N 5.02%.
3. (4Z)-4-(3-nitrobenzylidene)-3-methylisoxazol-5(4H)-one (4c): Yield
91%, m. p. 143–144 ꢀC (Lit. 144-145 ꢀC). IR max cmꢁ1: 3040 (C–H
ν
–
stretching), 1667 (C O stretching), 1330 (N–O stretching) and
–
1088 (C–N stretching). 1HNMR (300 MHz, CDCl3, δ ppm)): 1.79
(s, 3H), 7.26 (s, 1H), 7.60–7.57 (m, 1H), 8.00–7.90 (m, 1H),
8.25–8.22 (m, 1H), 8.44–8.43 (m, 1H); 13C NMR (75 MHz, CDCl3,
δ ppm): 29.7, 121.8, 124.4, 129.8, 132.5, 133.8, 148.2, 148.5,
170.5. HRMS ESI (m/z): 232.10 (Mþ), 233.03 (Mþ1)þ. Anal.
Calcd. for C11H8N2O4: C 56.90, H 3.47, and N 12.06%; found C
56.74, H 3.31, and N 12.02%.
10. (4Z)-4-(2,4-dimethoxybenzylidene)-3-methylisoxazol-5(4H)-one
(4j): Yield 86%, m. p. 177-178 ꢀC (Lit. 176–179 ꢀC). IR
ν
max cmꢁ1
:
–
–
3012 (C–H stretching), 1649(C
O
stretching), 1557 (C
C
–
–
stretching), 1374 (N–O stretching), 1280 (O–CH3 stretching).
1HNMR (300 MHz, CDCl3, δ ppm): δ 2.16 (s, 3H), 3.95 (s, 3H),
3.99 (s, 3H), 6.32–6.29 (d, J ¼ 1.8 Hz, 1H), 6.39–6.36 (dd, J ¼ 1.8
2

P. Kulkarni
Journal of the Indian Chemical Society 98 (2021) 100013
Scheme 1. Model Reaction for optimization of reaction conditions.
IRνmax cmꢁ1: 3450 (OH stretching) 3002 (C–H stretching), 1645
Table 1
Screening of catalysts.a.
–
–
–
(C O stretching), 1547 (C C stretching), 1365 (N–O stretching).
–
1HNMR (300 MHz, CDCl3, δ ppm): δ 1.14 (t, J ¼ 6.7z, 6H), 1.97 (s,
3H), 3.32 (q, J ¼ 6.7 Hz, 4H) 6.10–6.05 (d, J ¼ 2 Hz, 1H),
6.25–6.22 (dd, J ¼ 2 Hz, 8 Hz, 1H), 6.83–6.78 (d, J ¼ 8 Hz, 1H),
7.02 (s, 1H), 10.67 (s, 1H);13C NMR (75 MHz, CDCl3, δ ppm):
14.6, 27.4, 45.3, 101.1, 106.7, 107.4, 125.8, 129.3, 149.9, 150.8,
160.8, 165.2, 170.1. HRMS ESI (m/z): 274.24 (Mþ), 275.17
(Mþ1)þ. Anal. Calcd. for C15H18N2O3: C 65.68, H 6.61, and N
10.21%; found C 65.67, H 6.57, and N 10.14%.
Sr.
No
Catalyst
Amount of
catalyst loaded
in gm
Product
4a
Time in
Sec
% yieldb
1
2
3
4
KCl
KBr
0.0149
0.0238
0.0164
0.0268
4a
4a
4a
4a
110
80
140
180
88
95
81
84
NaOAC
Sodium
oxalate
CaCl2
KOAc
MgBr2
MgCl2
KNO3
5
6
7
8
9
0.0221
0.0196
0.0368
0.0190
0.0202
4a
4a
4a
4a
4a
210
160
90
120
900
88
85
89
87
13. (4Z)-4-(2-nitrobenzylidene)-3-methylisoxazol-5(4H)-one (4m): The
product was not formed.
14. (4Z)-4-(4-(dimethylamino)benzylidene)-3-methylisoxazol-5(4H)-one
Unidentified
product
78
(4n): Yield 87%, m. p. 226–227 ꢀC (Lit. 225–227 ꢀC). IR
ν
max cmꢁ1
:
–
–
–
3010 (C–H stretching), 1663(C
O
stretching), 1533 (C
C
–
10
Potassium
oxalate
0.0332
4a
120
stretching), 1368 (N–O stretching). 1HNMR (300 MHz, CDCl3, δ
ppm): 1.83 (s, 3H), 3.23 (s, 3H), 3.36 (s, 3H), 6.79–6.75 (d, J ¼
8.6 Hz, 2H), 7.27 (s, 1H), 7.85–7.8 (d, J ¼ 8.6Hz, 2H); 13C NMR
(75 MHz, CDCl3, δ ppm): 25.8, 53.4, 54.1, 108.9, 112.2, 121.4,
135.1, 150.4, 154.2, 162.5, 169.8. HRMS ESI (m/z): 230.22 (Mþ),
231.26 (Mþ1)þ. Anal. Calcd. for C13H14N2O2: C 67.81, H 6.13,
and N 12.17%; found C 67.79, H 6.12, and N 12.16%.
a
Reaction conditions are: 1 mmol of ethyl acetoacetate, 1.5 mmol of hy-
droxylamine hydrochloride, 1 mmol benzaldehdye and 0.2 mmol of catalyst in a
50 mL beaker in microwave oven.
b
Isolated yield after purification.
Hz, 8.2 Hz, 1H), 6.98–6.95 (d, J ¼ 8.2 Hz, 1H), 7.07 (s, 1H);13
C
15. (4Z)-4-(2,3-dichlorobenzylidene)-3-methylisoxazol-5(4H)-one (4o):
NMR (75 MHz, CDCl3, δ ppm): 11.9, 55.9, 56.3, 101.8, 107.3,
109.1, 126.3, 129.2, 150.5, 159.3, 161.4, 165.2, 170.2. HRMS ESI
(m/z): 247.17 (Mþ), 248.25 (Mþ1)þ. Anal. Calcd. for C13H13NO4:
C 63.15, H 5.30, and N 5.67%; found C 63.14, H 5.28, and N
5.64%.
Yield 73%, m. p. 174–177 ꢀC. IR max cmꢁ1: 3013 (C–H stretching),
ν
–
–
–
1671 (C O stretching), 1545 (C C stretching), 1376 (N–O
–
stretching). 1HNMR (300 MHz, CDCl3, δ ppm): 1.92 (s, 3H),
7.05–7.09 (m, 2H), 7.15–7.11 (m, 1H), 7.20 (s, 1H); 13C NMR (75
MHz, CDCl3, δ ppm): 28.4, 125.2, 126.3, 127.9, 128.4, 129.7,
133.9, 134.4, 151.3, 164.7, 170.2. HRMS ESI (m/z): 256.06 (Mþ),
257.12 (Mþ1)þ. Anal. Calcd. for C11H7Cl2NO2: C 51.59, H 2.76,
and N 5.47%; found C 51.56, H 2.75, and N 5.47%.
11. (4Z)-4-(2-hydroxybenzylidene)-3-methylisoxazol-5(4H)-one (4k):
Yield 78%, m. p. 201-202 ꢀC (Lit. 202–204 ꢀC). IR max cmꢁ1: 3420
ν
–
–
(OH stretching) 3034 (C–H stretching), 1694 (C O stretching),
1534 (C C stretching), 1381 (N–O stretching). 1HNMR (300
–
–
16. (4Z)-4-(4-nitrobenzylidene)-3-methylisoxazol-5(4H)-one (4p): Yield
MHz, CDCl3, δ ppm): δ 2.0 (s, 3H), 6.99–6.96 (m, 2H), 7.50–7.44
(m, 1H), 7.83 (s, 1H), 8.04–7.99 (m, 1H), 10.75 (s, 1H);13C NMR
(75 MHz, CDCl3, δ ppm): 24.7, 117.1, 117.9, 119.8, 120.5, 132.1,
137.8, 145.7, 160.1, 163.4, 169.3. HRMS ESI (m/z): 203.18 (Mþ),
204.31 (Mþ1)þ. Anal. Calcd. for C11H9NO3: C 65.02, H 4.46, and
N 6.89%; found C 65.01, H 4.44, and N 6.87%.
92%, m. p. 145 ꢀC (Lit. 148–150 ꢀC). IRνmax cmꢁ1: 3030 (C–H
–
–
–
stretching), 1676 (C O stretching), 1520 (C C stretching), 1328
–
(N–O stretching) and 1083 (C–N stretching). 1HNMR (300 MHz,
CDCl3, δ ppm): 2.23 (s, 3H), 7.13–7.08 (d, J ¼ 8.2Hz, 2H), 7.52 (s,
1H), 8.43–8.38 (d, J ¼ 8.2Hz, 2H); 13C NMR (75 MHz, CDCl3, δ
ppm): 34.4, 123.4, 125.7, 133.2, 139.1, 142.8, 151.1, 163.6,
171.4. HRMS ESI (m/z): 232.08 (Mþ), 233.10 (Mþ1)þ. Anal.
Calcd. for C11H8N2O4: C 56.90, H 3.47, and N 12.06%; found C
56.89, H 3.48, and N 12.04%.
12. (4Z)-4-(4-(diethylamino)-2-hydroxybenzylidene)-3-methylisoxazol-
5(4H)-one (4l): Yield 78%, m. p. 256-260 ꢀC (Lit. 258-261 ꢀC).
Table 2
17. (4Z)-4-(4-methoxybenzylidene)-3-methylisoxazol-5(4H)-one (4q):
Yield 90%, m. p. 177–179 ꢀC (Lit. 178–180 ꢀC). IR max cmꢁ1: 3040
ν
Effect of Power on synthesis of synthesis of 3,4-disubstituted isoxazole-5(4H)-
ones.a.
–
–
–
(C–H stretching), 1670 (C O stretching), 1543 (C C stretching),
–
Entry
Power Watt
Product (4a)
Time in Seconds
% Yieldb
1367 (N–O stretching) and 1267 (O–CH3 stretching). 1HNMR
(300 MHz, CDCl3, δ ppm): 1.97 (s, 3H), 3.89 (s, 3H), 6.88–6.84 (d,
1
2
3
4
5
6
7
100
200
300
400
600
800
1200
4a
4a
4a
4a
4a
4a
4a
120
80
80
75
20
20
20
87
95
95
90
J ¼ 8.6 Hz, 2H), 7.32 (s, 1H), 7.94–7.91 (d, J ¼ 8.6 Hz, 2H); 13
C
NMR (75 MHz, CDCl3, δ ppm): 18.4, 56.3, 114.1, 116.2, 117.3,
125.5, 132.1, 148.2, 152.3, 154.4, 163.2, 169.4. HRMS ESI (m/z):
217.19 (Mþ), 218.21 (Mþ1)þ. Anal. Calcd. for C12H11NO3: C
66.35, H 5.10, and N 6.45%; found C 66.37, H 5.09, and N 6.43%.
Decomposed
Decomposed
Decomposed
18. (4Z)-4-((furan-2-yl)methylene-3-methylisoxazol-5(4H)-one
(4r):
a
Reaction conditions are: 1 mmol of ethyl acetoacetate, 1.5 mmol of hy-
droxylamine hydrochloride, 1 mmol benzaldehdye and 0.2 mmol of catalyst in a
50 mL beaker in microwave oven.
Yield 84%, m. p. 242–243 ꢀC (Lit. 240–243 ꢀC). IR max cmꢁ1: 3050
ν
–
–
–
–
(C–H stretching), 1685 (C O stretching), 1565 (C C stretching),
1371 (N–O stretching). 1HNMR (300 MHz, CDCl3, δ ppm): 1.93 (s,
b
Isolated yield after purification.
3

P. Kulkarni
Journal of the Indian Chemical Society 98 (2021) 100013
Table 3
Table 3 (continued)
Entry Ar-Aldehyde
Synthesis of arylmethylene-isoxazole-5(4H)-ones (4) catalyzed by potassium
Product
(4)
Time
Sec
%
M. P. ꢀ
[Ref]
C
bromide hexahydrate using Microwave irradiation.a.
Yielda
Entry
1
Ar-Aldehyde
Product
(4)
Time
Sec
%
M. P. ꢀC
[Ref]
Yielda
4a
80
95
140-141
[33]
14
4n
75
87
226-227
[33]
2
3
4b
4c
65
70
70
91
163
15
16
4o
4p
130
55
73
92
174–177
143-144
[33]
145 [48]
4
5
4d
4e
55
50
94
92
117-119
[33]
17
4q
70
90
177-179
[33]
123-124
[33]
18
19
4r
4s
65
80
84
82
242-243
[33]
9
6
7
4f
90
60
89
96
174-175
[33]
244-245
[33]
4g
136-137
[33]
0
a
Reaction conditions: Ethyl acetoacetate (1 mmol), aromatic aldehyde (1
mmol), hydroxylamine hydrochloride (1.5 mmol) in microwave oven. bAll yields
are of pure products after filtrated and recrystallization from ethanol.
8
4h
4i
85
91
83
86
128-130
[22]
3H), 6.93–6.90 (d, J ¼ 8.3 Hz, 2H), 7.06 (s, 1H), 7.99–7.96 (d, J ¼
8.3 Hz, 1H); 13C NMR (75 MHz, CDCl3, δ ppm): 23.4, 114.3, 116.5,
125.1, 137.8, 151.7, 162.6, 164.1, 169.8. HRMS ESI (m/z): 177.14
(Mþ), 178.20 (Mþ1)þ. Anal. Calcd. for C9H7NO3: C 61.02, H 3.98,
and N 7.91%; found C 61.01, H 3.99, and N 7.90%.
9
120
115
230-231
[47]
19. (4Z)-4-((1H-indol-3-ylmethylene)-3-methylisoxazol-5(4H)-one
0
(4s)): Yield 82%, m. p. 244–245 ꢀC (Lit. 243–246 ꢀC). IRνmax
cmꢁ1: 3350 (-NH stretching), 3045 (C–H stretching), 1665 (C
O
–
–
–
stretching), 1528 (C C stretching), 1366 (N–O stretching).
–
10
4j
177-178
[35]
1HNMR (300 MHz, CDCl3, δ ppm): 1.85 (s, 3H), 7.35–7.32 (m,
2H), 7.57–7.54 (s, 1H), 7.67–7.63 (s, 1H), 7.94–7.90 (m, 2H),
11.76 (s, 1H); 13C NMR (75 MHz, CDCl3, δ ppm): 27.4, 109.4,
113.2, 113.6, 119.4, 123.0, 124.5, 128.7, 136.7, 138.6, 141.2,
162.3, 170.6. HRMS ESI (m/z): 226.21 (Mþ), 227.08 (Mþ1)þ.
Anal. Calcd. for C13H10N2O2: C 69.02, H 4.46, and N 12.38%;
found C 69.01, H 4.44, and N 12.37%.
11
12
4k
4l
150
90
78
78
201-202
[33]
256-260
[37]
3. Results and discussion
The condensation of ethyl acetoacetate, hydroxylamine hydrochlo-
ride and benzaldehyde was selected as a model reaction (Scheme 1).
Initially we have various metal salts such as potassium chloride, potas-
sium bromide, sodium acetate, sodium oxalate, calcium chloride, po-
tassium acetate, magnesium bromide hexahydrate, magnesium chloride,
magnesium nitrate, potassium nitrate, and potassium oxalate as catalyst
for the condensation reaction under microwave irradiation and results
are summarized in table (Table 1). The model reaction is performed in 50
13
4m
900
NR
–
mL beaker using
1 mmol of ethyl acetoacetate, 1.5 mmol of
4

P. Kulkarni
Journal of the Indian Chemical Society 98 (2021) 100013
Scheme 2. Synthesis of various 3,4-disubstituted isoxazole-5(4H)-ones under microwave condition.
Scheme 3. A plausible mechanism for the synthesis of 3,4–disubstituted isoxazol–5(4H)–ones catalyzed by potassium bromide.
hydroxylamine hydrochloride, 1 mmol of benzaldehyde and 0.2 mmol of
catalyst irradiated in a household microwave oven. From Table 1 it was
observed that potassium bromide was found an efficient catalyst for
synthesis of 4-aryl-3-methyl isoxazole with 95% yield. However, potas-
sium nitrate did not afford the desired product.
To study the effect of power watt on the reaction was used the model
reaction of 1 mmol of ethyl acetoacetate, 1.5 mmol of hydroxylamine
hydrochloride, 1 mmol of benzaldehyde and 0.2 mmol of potassium
bromide. The reaction was irradiated at 100W, 200W, 300W, 400W,
600W, 800W and 1200W. The results of the study are tabulated in
Table 2 and the reaction well proceeded at 200W. The reaction was
decomposed at high power 600W, 800W and 1200W. Hence, all the re-
actions were performed at 200W in microwave oven.
With the above-optimized reaction conditions in hand, the conve-
nience of this method was well evaluated using a variety of aromatic
aldehydes and a series of compounds 4 were synthesized with this simple
approach (Scheme 2). The results are summarized in Table 3. The nature
and position of the functional groups on the phenyl ring affected the
reaction time and yields of the product. The results indicated that aro-
matic aldehydes bearing electron-donating groups such as –OCH3, –CH3,
–OH, as well as electron-withdrawing group such as NO2 reacts with
ethyl acetoacetate and hydroxylamine hydrochloride to afford high
yields of products. 2-Hydroxybenzaldehyde derivative yielded the cor-
responding isoxazol-5(4H)-one derivative in moderate yield of the
desired product presumably due to its higher crowded steric effect. 2-
Nitrobenzaldehyde on reaction with ethyl acetoacetate and hydroxyl-
amine does not afford the corresponding isoxazol-5(4H)-one derivative
due to bulky size, -E as well as –M effect of the nitro group, destabilize the
transition state. In the compound 4c, nitro group present at meta posi-
tion. The meta position does not participate in mesomeric effect, but only
electronic effect is operate. Hence the compound 4c, has obtained in
good yield. The product 4d and 4e has chloro and bromo group at para
position. The mesomeric effect in these compounds have not effective
due to overlapping between two different energy level orbitals viz, 2p
orbitals of carbon and 3p and 4p orbitals of chlorine and bromine
respectively. Hence, this effect have not strongly operative. Therefore, 4d
and 4e, have got in higher yields.
A
plausible mechanism for the synthesis of 3,4-disubstituted
isoxazole-54H-one was shown here 9Scheme 3 using potassium bro-
mide. The mechanism is based on the Knoevenagel condensation
5

P. Kulkarni
Journal of the Indian Chemical Society 98 (2021) 100013
Table 4
Comparison of the results of the reaction of benzyaldehyde (1a), with hydroxylamine hydrochloride (2) and ethyl acetoacetate (3), using microwave irradiation with
some reported methods.
Entry
Catalysts/conditions
Catalyst amount
Time
% Yield
Comment
Ref
1
2
3
4
5
6
7
8
PPI/H2O/r.t.
Nano-SiO2-H2SO4
Graphene Oxide
ZnO@Fe3O4
SbCl3
6-Methylguanamine-supported CoFe2O4
Pyridinium p-toluenesulfonate
Salicylic acid
Boric acid
2-hydroxy-5-sulfobenzoic acid
KBr/Microwave Oven
10 mol%
0.05 gm
0.025 gm
0.005 gm
0.05 gm
0.03 gm
5mol%
15mol%
10mol%
15mol%
0.0238
70min
30min
1hr
70min
120min
3min
90
89
90
93
90
94
63
85
90
96
95
Amount of catalyst high
Highly acidic and corrosive catalyst
[21]
[36]
[33]
[23]
[22]
[35]
[24]
[37]
Catalyst preparation has a drastic reaction condition
Catalyst preparation required
Toxic metals, liberated HCl on decomposition, highly acidic condition
Two steps catalyst preparation, expensive reagent required
Reaction was carried out at reflux condition, long reaction time
The work up is a tedious process
Inexpensive and easily available catalyst
High yield,
Simple reaction condition, easily available and inexpensive catalyst
3h
120min
100min
70min
80s
9
10
11
[25]
[29]
This work
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reaction. in this reaction, initially the potassium bromide coordinated
with oxygen of the carbonyl group of ethyl acetoacetate A then the lone
pair of nitrogen attacks to the carbonyl carbon and water is eliminated to
form B. Then, keto-enol tautomerism results to form the intermediate C,
after which nucleophilic addition of aldehyde is coordinated with po-
tassium bromide to form intermediate D. Further removal of water
molecules leads to the formation of an intermediate E, which eventually
undergoes cyclization to form the intermediate F that removes the
ethanol molecule to obtain the target molecule.
The efficiency of the method has compared with some other reported
method and comparison is given in Table 4.
4. Conclusions
Here, I developed an efficient synthesis of arylmethylene-isoxazol-
5(4H)-ones using desktop solid potassium bromide as catalyst in micro-
wave oven under solvent-free condition. The efficiency of the method has
been demonstrated by synthesizing various substituted isoxazole de-
rivatives. Some advantages of this method are high yield, short reaction
time, avoiding the use of hazardous chemicals and solvents, inexpensive
and easily available catalysts, use of non-conventional energy source and
eco-friendly method.
Declaration of competing interest
The author declares have no Conflict of Interest.
Acknowledgement
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Appendix A. Supplementary data
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Supplementary data to this article can be found online at https://do
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α
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