The convenient synthesis of 4-arylmethylidene-4,5-dihydro-3-phenylisoxazol- 5-ones

Article abstract of DOI:10.1016/j.cclet.2010.09.023

4-Arylmethylidene-4,5-dihydro-3-phenylisoxazol-5-ones were synthesized by the convenient three-component reaction of ethyl benzoylacetate, hydroxylamine and aromatic aldehydes in the presence of pyridine. The target compounds were also obtained by the rea

Full text of DOI:10.1016/j.cclet.2010.09.023

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Chinese Chemical Letters 22 (2011) 151–154
www.elsevier.com/locate/cclet
The convenient synthesis of 4-arylmethylidene-4,5- dihydro-3-
phenylisoxazol-5-ones
*
Keyume Ablajan , Hainimu Xiamuxi
College of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, China
Received 7 May 2010
Abstract
4-Arylmethylidene-4,5-dihydro-3-phenylisoxazol-5-ones were synthesized by the convenient three-component reaction of ethyl
benzoylacetate, hydroxylamine and aromatic aldehydes in the presence of pyridine. The target compounds were also obtained by
the reaction between 3-phenylisoxazol-5-one and aromatic aldehydes at 105 8C under solvent free condition. Yields of products
depended considerably on the aldehyde used.
# 2010 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
Keywords: Isoxazole; One-pot synthesis; Three-component reaction
Isoxazole compound have attracted increasing interest due to their significant pharmaceutical and therapeutic
properties, such as hypoglycemic [1], immunosuppressive [2], anti-inflammatory [3], and anti-bacterial activity
[4]. Isoxazole derivatives have served as a versatile building block in organic synthesis [5]. In addition, the
synthesis of isoxazole derivatives has drawn more attention because of their wide range of application in
medicinal chemistry [6].
Being a high efficient and economic method, one-pot synthesis is an important way and become the most popular in
heterocyclic chemistry [7]. One-pot synthesis mainly decreases the reaction time as well as cut out purification in
reaction process [8]. The traditional synthesis of 4-arylmethylidene-4,5-dihydro-3-phenylisoxazol-5-one was carried
out in two steps [9,10]. At first step, ethyl benzoylacetate reacts with hydroxylamine hydrochloride to afford oxime,
and further ring closing bring product 3-phenylisoxazol-5-one. And then, the Knoevenagel reactions between 3-
phenylisoxazol-5-one and aromatic aldehydes produce 4-arylmethylidene-4,5-dihydro-3-phenylisoxazol-5-ones [10].
As part of our current studies on the development of efficient and simple method for the synthesis of biologically active
heterocyclic compounds [11], the current paper reports one-pot synthesis of 4-arylmethylidene-4,5-dihydro-3-
phenylisoxazol-5-one through three-component reaction (Scheme 1). In addition, the target products were also
prepared by the reaction between 3-phenylisoxazole-5-one and aldehydes via heating at 105 8C without solvent and
catalyst (Scheme 2). In this study, both methods show various advantages such as shorter reaction time and being
environmentally benign.
* Corresponding author.
E-mail address: ablajan209@hotmail.com (K. Ablajan).
1001-8417/$ – see front matter # 2010 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
doi:10.1016/j.cclet.2010.09.023

[()TD$FIG]
152
K. Ablajan, H. Xiamuxi / Chinese Chemical Letters 22 (2011) 151–154
H
C
Ar
H5C6
pyridine
C6H5COCH2CO2C2H5 + NH2OH.HCl + ArCHO
N
C2H5OH
O
3a~3g
2
O
1
4a~4g
Scheme 1. One-pot synthesis of 4-arylmethylidene-3-phenylisoxazol-5-ones.
[()TD$FIG]
H
C
Ar
H5C6
H5C6
3a~3g
C6H5COCH2CO2C2H5 + NH2OH.HCl
N
N
105 ºC
O
2
O
1
O
4a~4g
O
Scheme 2. Synthesis of 4-arylmethylidene-3-phenylisoxazol-5-ones under solvent free condition.
1. Experimental
The melting points were recorded on a Sweden BUCHIB 2540 melting point apparatus and uncorrected. Mass
spectra were measured with API 2000 spectrometer. The H1 NMR spectra were determined in CDCl3 solution on a
Varian Inova 400 NMR spectrometer using TMS as internal standard. Merck silica gel GF-254 was used for analytical
and preparative TLC. All the reagents are of analytical purity.
A mixture of 4 mmol ethyl benzoylacetate (1), 4 mmol hydroxylamine hydrochloride (2) and 4 mmol pyridine in
10 mL ethanol was refluxed for 5 min, after then 4 mmol aromatic aldehyde (3) was added, and the mixture was further
refluxed for 40–80 min till the completion of the reaction (monitored by TLC). The reaction mixture was cooled to
room temperature and allowed to stand overnight. The precipitate was filtered off and washed with water, and
recrystallized from EtOH (95%) to afford the pure product 4.
The aromatic aldehyde (4 mmol) (3) and 3-phenylisoxazol-5-one (4 mmol) were grinded in a mortar, and then the
mixture was heated in an oil bath at 105 8C for 20 min. The reaction mixture was cooled and washed with water and
diethyl ether in order. The crude product was recrystallized from EtOH (95%).
The data of products is as follows:
4-Phenylmethylidene-3-phenylisoxazol-5-one (4a). 1H NMR (400 MHz, CDC13): d 7.26 (s, 1H, ArCH ), 7.51 (d,
2H, J = 8.4 Hz, ArH), 7.57–7.64 (m, 5H, Ph–H), 8.33 (d, 2H, J = 8.4 Hz, ArH). IR (KBr, cmÀ1): 3077 (C–H), 1747
(C O), 1618, 1593, 1569, 1546 (C = N, C = C). ESI-MS m/z (%): 272 (M + Na, 100), 250 (M + 1, 68).
4-(4-Methoxyphenyl)methylidene-3-phenylisoxazol-5-one (4b). 1H NMR (400 MHz, CDC13): d 3.92 (s, 3H,
CH3O), 7.01 (d, 2H, J = 8.8 Hz, ArH), 7.53 (s, 1H, ArCH = ), 7.53–7.61 (m, 5H, Ph-H), 8.44 (d, 2H, J = 9.2 Hz, ArH).
IR (KBr, cmÀ1): 3075 (C–H), 1730 (C O), 1600, 1592, 1558 (C N, C C). ESI-MS m/z (%): 302 (M + Na, 100), 280
(M + H, 16).
4-(4-Dimethyaminophenyl)methylidene-3-phenylisoxazol-5-one (4c). 1H NMR (400 MHz, CDC13): d 3.18 (s, 6H,
N(CH3)2), 6.72 (d, 2H, J = 8.4 Hz, ArH), 7.38 (s, 1H, ArCH ), 7.22–7.60 (m, 5H, Ph-H), 8.40 (d, 2H, J = 8.8 Hz,
ArH). IR (KBr, cmÀ1): 3051 (C–H), 1711 (C O), 1600, 1590, 1562 (C N, C C). ESI-MS m/z (%): 315 (M + Na, 32),
293 (M + H, 100).
4-(4-Chlorophenyl)methylidene-3-phenylisoxazol-5-one (4d). 1H NMR (400 MHz, CDC13): d 7.49 (d, 2H,
J = 8.8 Hz, ArH), 7.56 (s, 1H, ArCH ), 7.58–7.63 (m, 5H, Ph-H), 8.30 (d, 2H, J = 8.8 Hz, ArH). IR (KBr, cmÀ1): 3059
(C–H), 1744 (C O), 1611, 1544 (C N, C C). ESI-MS m/z (%): 306 (M + Na, 29), 284 (M + H, 100).
4-(4-Methylphenyl)methylidene-3-phenylisoxazol-5-one (4e). 1H NMR (400 MHz, CDC13): d 7.38 (d, J = 8.8 Hz,
2H, ArH), 7.59 (s, 1H, ArCH ), 7.61–7.73 (q, 5H, Ph-H), 8.34 (d, J = 8.8 Hz, 2H, ArH), 2.45 (s, 3H, CH3). IR (KBr,
cmÀ1): 3069 (C–H), 1746 (C O), 1613, 1546, 1517 (C N, C C). ESI-MS m/z (%): 286 (M + Na, 36), 264 (M + 1,
100).

K. Ablajan, H. Xiamuxi / Chinese Chemical Letters 22 (2011) 151–154
153
Table 1
Reaction conditions and results.
Entry
Ar
m.p. (8C)
Product
Time (min)/yielda (%)
Time (min)/yieldb (%)
1
2
3
4
5
6
7
8
C6H5
215–216
4a
4b
4c
4d
4e
4f
70/72
60/77
40/87
60/65
50/74
80/58
80/61
80/59
20/60
20/69
20/74
20/65
20/68
20/45
20/48
20/51
4-H3COC6H4
4-(CH3)2NC6H4
4-ClC6H4
4-H3CC6H4
4-O2NC6H4
Thienyl
168–169[10]
194–196
175–176[10]
189–191
179–181
226–228
4g
4h
Furyl
183–184
a
Three-component reaction.
b
Heating at 105 8C.
4-(4-Nitrophenyl)methylidene-3-phenylisoxazol-5-one (4f). 1H NMR (400 MHz, CDC13): d 7.40 (d, 2H,
J = 9.2 Hz, ArH), 7.73 (d, 2H, J = 9.2 Hz, ArH), 7.62 (s, 1H, ArCH ), 7.63–7.75 (q, 5H, Ph-H), 8.34 (d, 2H,
J = 9.2 Hz, ArH). IR (KBr, cmÀ1): 3068 (C–H), 1745 (C O), 1610, 1539, 1523 (C N, C C). ESI-MS m/z (%): 317
(M + Na, 36), 295 (M + 1, 100).
4-(2-Thienyl)methylidene-3-phenylisoxazol-5-one (4 g). 1H NMR (400 MHz, CDC13): d 7.27 (dd, 1H, J = 4.0 Hz,
J = 5.2 Hz, thiophene-H), 7.57–7.64 (m, 5H, Ph-H), 7.79 (s, 1H, thiophene-CH ), 7.99 (d, 1H, J = 5.2 Hz, thiophene-
H), 8.07 (d, 1H, J = 4.0 Hz, thiophene-H). IR (KBr, cmÀ1): 3060 (C–H), 1743 (C O), 1611, 1544, 1515 (C N, C C).
ESI-MS m/z (%): 278 (M + Na, 22), 256 (M + H, 100).
1
4-(2-Furyl)methylidene-3-phenylisoxazol-5-one (4 h). H NMR (400 MHz, CDC13): d 6.72 (d, 1H, J = 2.8 Hz,
furan-H), 7.21 (dd, 1H, J = 6.8 Hz, J = 7.6 Hz, furan-H), 7.43–8.07 (m, 5H, Ph-H), 8.82 (d, 1H, J = 3.6 Hz, furan-H).
IR (KBr, cmÀ1): 3055 (C–H), 1740 (C O), 1613, 1546, 1518 (C N, C C). ESI-MS m/z (%): 293 (M + Na, 45), 271
(M + H, 100).
2. Results and discussion
As part of our interest on developing efficient route for the synthesis of b-unsaturated isoxazolone, we reported a
convenient and rapid method for the synthesis of 4-arylmethylidene-4,5-dihydro-3-phenylisoxazol-5-ones from
available starting materials. Pyridine being an organic base plays a significant role in the formation of products. This
synthetic method is an easy and simple procedure for the synthesis of target compound. In addition, we have tried
heating the mixture of 3-phenylisoxazol-5-one and aromatic aldehyde at 105 8C under solvent free condition without
catalyst, and obtained products in moderate yields. Both methods indicated that the reactivity and yields are better
when an electron donating group is attached to an aromatic ring of arylaldehyde (Table 1).
In order to investigate completion time of the reaction, the reaction was carried out for 30–120 min by continues
TLC checking, previously. As indicated in Table 1, the substituent at aromatic ring has played a major role in
completion of the reaction. For example, compound 4c was formed in 40 min due to the electron-donating property of
dimethylamino group at phenyl ring. While the reaction between 3-phenylisoxazol-5-one and arylaldehyde carried out
under solvent free condition via heating at 105 8C was completed in 20 min, and products were obtained in moderate
yield (Table 1).
In conclusion, the present work describes an efficient and simple method for the syntheses of 4-arylmethyl- idene-
4,5-dihydro-3-phenylisoxazol-5-ones in moderate yield via one-pot synthetic route. The target products were also
prepared under solvent free condition. This method has the advantage for its simple manipulation or green procedure
which is useful for the syntheses of b-unsaturated isoxazolone derivatives.
Acknowledgment
We are grateful to the Natural Science Foundation of Xinjiang Science Technology Agency (No. 2009211A02) for
the support.

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