One-pot and three-component synthesis of isoxazol-5(4H)-one derivatives in the presence of citric acid

Article abstract of DOI:10.13005/ojc/320317

In this context, the one-pot three-component synthesis of 3-methyl-4-arylmethylene-isoxazol-5(4H)-ones has been performed in the presence of citric acid as catalyst in water. The products have been obtained in high yields (70-90%) and convenient reaction

Full text of DOI:10.13005/ojc/320317

ISSN: 0970-020 X
CODEN: OJCHEG
016, Vol. 32, No. (3):
Pg. 1433-1437
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
2
www.orientjchem.org
One-pot and Three-Component Synthesis of Isoxazol-5
(
4H)-one Derivatives in the presence of Citric Acid
ASHkAN bASHASH RIkANI and DAꢀOOD SETAMDIDEH*
Department of Chemistry, Mahabad Branch, Islamic Azad University, Mahabad, Iran.
*
Corresponding author E-mail: davood.setamdideh@gmail.com
http://dx.doi.org/10.13005/ojc/320317
(Received: February 02, 2016; Accepted: March 06, 2016)
AbSTRACT
In this context, the one-pot three-component synthesis of 3-methyl-4-arylmethylene-isoxazol-
5(4H)-ones has been performed in the presence of citric acid as catalyst in water.The products have
been obtained in high yields (70-90%) and convenient reaction times (5-24 hours).
keywords: Citric Acid, isoxazol-5(4H)-one, one-pot reaction, water, green chemistry.
INTRODUCTION
synthesis of 4-arylmethylidene-3-methyl-isoxazol-
(4H)-ones was attempted by using equimolecular
5
Isoxazolones and its derivatives have
a variety of biological activities. The synthesis
quantities of ethyl acetoacetate, hydroxylamine
hydrochloride, and a variety of aromatic aldehydes
in the presence of citric acid as catalyst in water as
shown in scheme 1.
1
of aryl-3-methylisoxazol-5(4H)-one derivatives
involves a coupling of aromatic aldehydes with ethyl
acetoacetate and hydroxylamine.This procedure has
2
been carried out by different reagents and catalysts .
RESULTS AND DISCUSSION
Also, multi-component reactions (MCRs) have been
used for the synthesis of a variety of natural products
and biologically active compounds, because they
have many advantages such as excellent functional
group compatibility, minimization of waste, versatility,
atom economy, environmentally friendly, and easy
work-up . In this context we have done a convenient
and environmentally benign procedure by citric acid
as the catalyst for the synthesis of 4-arylmethylidene-
We conceived the preparation of diverse
arylmethylidene-isoxazole-5(4H)-ones from
the reaction between an aromatic aldehyde,
hydroxylamine hydrochloride, and ethyl acetoacetate
(EAA) catalyzed by citric acid. For determine
the optimal reaction conditions, we screened
different amounts of citric acid (0-2 mmol) (Table
1) using benzaldehyde as a model compound.
Consequently, the amount of 1 mmol for citric acid
3
3
-substituted-isoxazol-5(4H)-ones. Thus, the

1434
RIꢀANI & SETAMDIDEH, Orient. J. Chem., Vol. 32(3), 1433-1437 (2016)
was selected as the optimized amount of the catalyst after recrystallization from ethanol or acetone and
1
13
for this procedure.The efficiency of this protocol was were characterized by H-NMR, C-NMR, and FT-IR
examined by the reaction of a variety of aldehydes. spectroscopy.
all reactions were completed in appropriate
times within 5-24 hours in good yields (70-90%) Spectral data for prepared compounds
1
(
Table 2). The products were characterized by H- (Z)-4-ꢄenzylidene-3-methylisoxazol-5(4H)-one
NMR spectroscopy, FT-IR spectrum and melting (1)
points of the products (Table 2, column 6) were
Yellow crystal: mp 140-142°C (Lit [2k] mp
1
measured and compared with the literature for 142-144°C); H-NMR (300 MHz, CDCl ): d 2.31 (s,
3
2
the known compounds . Characterization and 3H, CH ), 7.44 (s, 1H, ArCH=), 7.49-7.59 (m, 3H,
3
13
comparison of the formed products with suitable Ar), 8.35 (dd, J = 1.3, 7.4 Hz, 2H, Ar); C-NMR (300
references [2ꢁ and 2l] supports the selectivity for the MHz, CDCl ): d 11.63 (CH ), 119.65 (C=, inside of
3
3
formation of the (Z)-isomer. Therefore, the products isoxazolone ring), 129.03 (Ar), 130.47 (Ar), 132.29
are assumed to have the double bond with the (Z) (Ar), 134.01 (Ar), 149.98 (ArCH=), 161.16 (C=N),
geometry.
167.88 (C=O); IR (ꢀBr) n: 1732 (C=O), 1620, 1100,
-1
1216, 879, 763 cm .
Two proposed mechanism for the formation
of the products and the influences of citric acid are (Z)-4-(4-methoxyꢄenzylidene)-3-methylisoxazol-
shown in Schemes 2. 5(4H)-one (2)
Yellow crystal: mp 177-179°C (Lit [2k]
1
EꢂꢃERIMENTAL
mp 177-178°C); H-NMR (300 MHz, CDCl ): d 2.28
3
(
s, 3H, CH ), 3.92 (s, 3H, OCH ), 7.34 (s, 1H, ArCH=),
3
3
General
7.00 (d, J = 8.7 Hz, 2H, Ar), 8.44 (d, J = 8.7 Hz,
13
All substrates and reagents were purchased 2H, Ar); C-NMR (300 MHz, CDCl ): d 11.63 (CH ),
3
3
from commercially sources (Merck and Sigma- 55.70 (OCH ), 114.64 (C=, inside of isoxazolone
3
1
13
Aldrich).FT-IR, H-NMR, and C-NMR spectra were ring), 116.31 (Ar), 125.82 (Ar), 136.96 (Ar), 149.35
recorded on PerkinElmer FT-IR RXI and 300 MHz (ArCH=), 161.29 (Ar-O), 164.60 (C=N), 168,77
Bruker spectrometers, respectively. The products (C=O); IR (ꢀBr) n: 1730 (C=O), 1590, 1267, 1018,
1
-1
were characterized by their FT-IR, H-NMR, and 875, 775 cm .
1
3
C-NMR spectra and comparison with authentic
samples. Organic layers were dried over anhydrous (Z)-4-(2-methoxyꢄenzylidene)-3-methylisoxazol-
sodium sulfate. All yields referred to isolated pure 5(4H)-one (3)
1
products.The purity of products was determinate by
1
Yellow crystal: mp 159-160°C; H-NMR
H NMR. Also, reactions were monitored over silica (300 MHz, CDCl ): d 2.31 (s, 3H, CH ), 3.95 (s, 3H,
3
3
gel 60 F254 aluminum sheet.
OCH ), 6.96 (d, J = 8.4 Hz, 1H, Ar), 7.09 (t, J = 7.8
3
Hz, 1H, Ar), 7.56 (t, J = 7.05 Hz, 1H, Ar), 8.06 (s, 1H,
13
A typical procedure for the synthesis of (Z)-4- ArCH=), 8.92 (d, J = 8.1 Hz, 1H, Ar); C-NMR (300
arylmethylene-3-methyl-isoxazol-5(4H)-ones MHz, CDCl ): d 11.67 (CH ), 55.47 (OCH ), 110.70
3
3
3
In a round-bottomed flask (25 mL) equipped (C=, inside of isoxazolone ring), 118.32 (Ar), 120.84
with a magnetic stirrer, a mixture of ethyl acetoacetate (Ar), 121.20 (Ar), 133.37 (Ar), 136.27 (Ar), 143.98
(
1.30 g, 10 mmol), hydroxylamine hydrochloride (0.7 (ArCH=), 159.82 (C=N), 161.52 (C=O); IR (ꢀBr)
-
1
g, 10 mmol), aromatic aldehyde (10 mmol), and n: 1732 (C=O), 1590, 1256, 1103, 887, 765 cm .
citric acid (1.9 g, 10 mmol) in 25 mL of distilled IR (ꢀBr) n: 1732 (C=O), 1590, 1256, 1103, 887,
water was prepared and stirred at room temperature 765 cm .
-1
for mentioned time in Table 2. After completion of
reaction (monitored by TLC), the precipitate was (Z)-3-methyl-4-(3-phenylallylidene)isoxazol-
filtered off and washed with cold distilled water.Then 5(4H)-one (4)
products were recrystallized from ethanol or acetone
as mentioned inTable 2.Pure (Z)-4-arylmethylene-3- 179-181°C); H-NMR (300 MHz, CDCl ): d 2.25
Yellow crystal: mp 180-182°C (Lit [2k] mp
1
3
methyl-isoxazol-5(4H)-ones were obtained as solids (s, 3H, CH ), 7.28-7.36 (m, 2H, CH=CH), 7.36-7.47
3

RIꢀANI & SETAMDIDEH, Orient. J. Chem., Vol. 32(3), 1433-1437 (2016)
1435
(
8
m, Ar (2H) & ArCH= (1H)), 7.64-7,66 (m, 2H, Ar),
121.12 (Ar-Br), 122.89 (C=, inside of isoxazolone
ring), 130.48 (Ar), 131.90 (Ar), 133.87 (Ar), 136.03
(Ar), 136.50 (Ar), 147.71 (ArCH=), 160.86 (C=N),
167.45 (C=O); IR (ꢀBr) n: 1729 (C=O), 1544, 1217,
13
.26-8.35 (m, 1H, Ar); C-NMR (300 MHz, CDCl ):
3
d 11.19 (CH ), 117.86 (C=, inside of isoxazolone
ring), 121.34 (Ar), 122.38 (Ar), 129.31 (Ar), 131.53
(
3
-1
C=C), 134.96 (C=C), 147.53 (Ar), 151.45 (ArCH=),
1123, 871, 775 cm .
1
59.89 (C=N), 168.99 (C=O);IR (ꢀBr) n:1733 (C=O),
-1
1542, 1103, 993, 848, 753 cm .
(Z)-4-(4-methylꢄenzylidene)-3-methylisoxazol-
5(4H)-one (6)
(
5
Z)-4-(3-ꢄromoꢄenzylidene)-3-methylisoxazol-
(4H)-one (5)
Yellow crystal: mp 141-143 °C; H-NMR
300 MHz, CDCl ): d 2.31 (s, 3H, CH ), 7.35 (s, 1H,
Lemon crystal: mp 129-131°C (Lit [2j] mp
1
126-127°C); H-NMR (300 MHz, CDCl ): d 2.29 (s,
3
1
3H, CH ), 2.45 (s, 3H, CH ), 7.32 (d, J = 7.8 Hz,
3
3
(
2H, Ar), 7.40 (s, 1H, ArCH=), 8.29 (d, J = 7.8 Hz,
3
3
1
3
ArCH=), 7.41 (t, J = 8.1 Hz, 1H, Ar), 7.71 (d, J = 7.80
2H, Ar); C-NMR (300 MHz, CDCl ): d 11.65 (CH ),
3
3
Hz, 1H, Ar), 8.34 (d, J = 7.8 Hz, 1H, Ar), 8.46 (s,
22.07 (CH ), 118.40 (C=, inside of isoxazolone
ring), 129.88 (Ar), 134.14 (Ar), 145.73 (Ar), 149.96
3
13
1
H, Ar); C-NMR (300 MHz, CDCl ): d 11.60 (CH ),
3
3
N O
O
CHO
+
OEt
Citric Acid (1 mmol)
+
H NOH
2
O
O
H O (10 ml)/RT
2
(
10 mmol)
(10 mmol)
(10 mmol)
8 h
(90%)
Scheme 1:The synthesis of (Z)-3-methyl-4-ꢄenzylmethylene-
isoxazol-5(4H)-ones in the presence of citric acid
O
OH O
HO
OH
H
CO H
2
Citric acid
H
O
H NOH
2
O
O
O
-H O
2
-
E
tO
N O
H
OEt
OEt
O
NOHO
Ar
NOH O
OEt
Citric acid
OEt
H
Ar
NOH O
H
H
NOH O
OEt
OEt
O
2
O
O
-H
Ar
OH
Ar
H
Ar
H
Scheme 2:The proposed mechanism for the synthesis of
Z)-3-methyl-4-arylmethylene-isoxazol-5(4H)-ones in the presence of citric acid
(

1436
RIꢀANI & SETAMDIDEH, Orient. J. Chem., Vol. 32(3), 1433-1437 (2016)
Taꢄle 1: Optimization reaction condition
for the synthesis of (Z)-4-ꢄenzylidene-
-methylisoxazol-5(4H)-one (5a) from
Taꢄle 2: Synthesis of (Z)-4-arylmethylidene
-3-methyl-isoxazol-5(4H)-ones with Citric
3
ꢄenzaldehyde (10 mmol), ethyl acetoacetate (10
Acid/H O
2
mmol) and NH OH.HCl (10 mmol) in
2
H O (10 ml) in the presence of Citric Acid as
Entry ꢃroduct
time
(h)
yield
(%) a
mp
(°C) b
2
shown in scheme 1
Entry Citric
Acid (g)
time
(min)
conversion yield
1
2
3
4
5
6
7
Ph
8
5
5
6
24
5
90
90
85
96
70
90
80
140-142
177-179
159-160
180-182
141-143
206-209
129-131
(%)a
(%)b
4-MeO-Ph
2-MeO-Ph
Ph-CH=CH
3-Br-Ph
1
2
3
4
5
0
0.25
0.5
1
10
10
10
8
100<
100<
100<
100
30
50
70
90
90
4-Me N-Ph
2
4-Me-Ph
6
2
7
100
a
Yields refer to isolated pure products after recrystallization
a
b
b
Conversion refers to TLC monitoring. Yield refers inappropriate solvent. The melting points have been
to isolated pure product.
compared with the literatures
(
ArCH=), 161.22 (C=N), 168.21(C=O); IR (ꢀBr)
CONCLUSION
-1
n: 1731 (C=O), 1594, 1114, 873, 777 cm .
In conclusion, we have shown that citric acid
(
Z)-4-(4-(dimethylamino)ꢄenzylidene)-3- in water is a convenient catalyst for the preparation
methylisoxazol-5(4H)-one (7)
of a variety of alkylidene isoxazol-5(4H)-ones,
Red crystal: mp 206-209°C (Lit [2k] mp using aromatic aldehydes, ethyl acetoacetate, and
1
2
06-207°C); H-NMR (300 MHz, CDC1 ): d 2.23 hydroxylamine hydrochloride precursors in one-pot,
3
(
s, 3H, CH ), 3.15 (s, 6H, N(CH ) ), 6.71 (d, J = 9 three-component condensation reaction at room
3
3
2
Hz, 2H, Ar), 7.27 (s, 1H, ArCH=), 8.39 (d, J = 9 Hz, temperature in excellent yields. High efficiency,
1
3
2
4
H, Ar); C-NMR (300 MHz, CDCl ): d 11.71 (CH ), convenient reaction times, easy work-up, mild
3
3
0.10 ((CH ) N), 111.07 (Ar), 111.50 (C=, inside of reaction conditions, and using of water as a green
3
2
isoxazolone ring), 121.51 (Ar), 137.62 (Ar), 149.26 solvent make to this new protocol attractive for the
Ar), 154.22 (ArCH=), 161.59 (C=N), 170.12 (C=O); synthesis of these heterocycles.
IR (ꢀBr) n: 1714 (C=O), 1557, 1380, 1196, 1095,
(
-1
8
67, 765 cm .
ACkNOꢅLEDGMENTS
The authors gratefully appreciated the
financial support of this work by the research council
of Islamic Azad University branch of Mahabad.
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