Synthetic Communicationsw, 38: 135140, 2008

Copyright # Taylor & Francis Group, LLC

ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701651326

Heteropolyacids as Green and Reusable

Catalysts for the Synthesis of Isoxazole
Derivatives
Majid M. Heravi,1 Fatemeh Derikvand,1 Anahita Haeri,1
Hossein A. Oskooie,1 and Fatemeh F. Bamoharram2
1

Department of Chemistry, School of Science, Azzahra University,

Vanak, Tehran, Iran
2
Department of Chemistry, Azad University of Mashhad, Mashad, Iran

Abstract: Heteropolyanions with different structures, including Keggin, Dawson,

Preyssler, mixed addenda, and sandwich types, catalyzed the formation of 1,3diphenyl-isoxazole from the condensation of 1,3-diphenyl-propane-1,3-dione and
hydroxylamine hydrochloride in different solvents and under heating conditions. Our
data vividly indicate that H3PW11CuO40 is the catalyst of choice and could catalyze
the synthesis of other isoxazole derivatives in high yields and good selectivities.
Keywords: b-dicarbonyl compounds, heteropolyacids, HPAs, hydroxyl amine,
isoxazole derivatives

INTRODUCTION
Heteroaromatic compounds have attracted considerable attention in the design
of biologically active molecules and advanced organic materials.[1] Hence, a
practical method for the preparation of such compounds is of great interest
in synthetic organic chemistry.
Nitrogen-containing ring systems have been widely used as ligands in
organometallic chemistry, and their role as tunable ligands, as well as
their application as cryptands, cannot be overstated.[2,3] An important class
of nitrogen-containing heterocycles includes the oxazole ring systems.
Received in Poland March 28, 2007
Address correspondence to Majid M. Heravi, Department of Chemistry, School of
Science, Azzahra University, Vanak, Tehran, Iran. E-mail: [email protected]
135

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Isoxazole moieties represent a class of unique pharmacophores, which are

constituent units of diverse therapeutic agents.[4] Therefore, they are interesting targets in the development of new drug leads in solid-phase combinatorial
chemistry. A considerable number of methods to synthesize substituted isoxazoles have been published including approaches based on condensation of 1,3dicarbonyl compounds with hydroxylamine,[5] addition of nitrile oxides to
supported alkynes[6] or anchoring a nitrile oxide precursor onto the solid
phase,[7] intermolecular cycloadditions,[8] condensations,[9] and intramolecular cyclizations of amino acids.[10]
The drive toward clean technologies, which was brought about by public,
legislative, and corporate force, will provide new and exciting opportunities
for catalysis and catalytic processes.[11] Chemical clean technology or green
chemistry has at its heart the utilization of methods that reduce or eliminate
the use or generation of hazardous substances.[12,13] This embraces the
principle of clean synthesis, which involves improvements in process
selectivity, high atom efficiency, and easy separation with reuse of nonproduct components. The efficient use of solid catalysts can go a long way to
achieving these goals.[14] Heteropoly compounds have many advantages as
catalysts that make them economically and environmentally attractive both
in academic and industrial chemistry. They are effective catalysts for
various reactions and have high capability in practical uses,[15,16] because
their redox and acidic activity can be controlled at the atomic/molecular
levels by changing the constituent elements wherever it is needed in the
chemical processes.[17] These solid acids are applied in bulk or supported
forms and also in homogeneous and heterogeneous catalysis.[18]
In continuation of our interest on the catalytic activities of heteropolyacids,[19 27] herein we report that H3PW11CuO40 as a Keggin-type heteropolyacid is an excellent and effective catalyst for the synthesis of isoxazole
derivatives in ethanol (Scheme 1).
To choose the most appropriate medium in this heterocyclization reaction,
synthesis of 3,5-diphenyl-isoxazole from the condensation of 1,3-diphenylpropane-1,3-dione and hydroxylamine hydrochloride in the presence of a
catalytic amount of H4SiW12O40 was selected as a model reaction. We
carried out the model reaction in different solvents. Among the tested
solvents, the best results were obtained in refluxing ethanol (Table 1).
The effect of a variety of heteropolyacids including Keggin, Dawson,
Preyssler, mixed addenda, and sandwich types in the synthesis of 3,5diphenyl-isoxazole in refluxing ethanol was also explored. As shown in

Scheme 1.

Heteropolyacids as Green Catalysts

137

Table 1. Effect of the solvent on the synthesis of 3,5-diphenyl-isoxazole using

catalytic amount of H14[Na P5W30O110]
Entry
1
2
3
4
5

Solvent
C6H5CH3
H2O
CH3COOH
MeOH
EtOH

Temperature
(8C)

Time (min)

Yield (%)a

110
100
118
64
78

240
240
90
90
45

50
50
65
97
99

Yields were obtained using GC analysis.

Table 2, H3PW11CuO40 gave the best results in terms of yields and times. It is
difficult to clarify clearly the different activity between these catalysts.
Obviously there is a complex relationship between the activity and structure
of polyanions and by changing the constituent elements of polyanion (both
hetero and addenda atoms), the acid strength of HPAs is able to vary in a
wide range. It is suggested that the interactions of the polarized polyanion
with substrate is an important factor in catalytic activity in this reaction.
To establish the scope of this novel methodology, we tested a variety of
b-dicarbonyl- compounds under optimized reaction conditions (Table 3).
The reusability of the catalyst was also studied. After completing the
model reaction in refluxing ethanol (entry 1, Table 3), the catalyst was
removed by simple filtration, washed with diethyl ether, and subjected to a
second run of the reaction process with the same substrate. The results of
the first experiment and subsequent ones were almost consistent in yields
after three runs (99%, 97%, 95%).
In summary, we have developed an alternative simple procedure for the
synthesis of isoxazole derivatives using H3PW11CuO40 as an ecofriendly, inexpensive, and efficient catalyst. High yields, relatively short reaction times,
Table 2. Effect of the catalysts on the synthesis of 3,5-diphenyl-isoxazole
Entry
1
2
3
4
5
6
7
8
9
10
a

Catalyst

Time (min)

Yield (%)a

H6PMo9VO40
H4SiW12O40
H4SiMo12O40
H3PW12O40
K7Na3P2W18O62
H14NaP5W29MoO110
H6P2W18O62
H14NaP5W30O110
K10P2W18Co4(H2O)2O62 . 20H2O
H3PW11CuO40

240
120
90
100
150
120
120
180
150
45

97
98
80
80
70
98
96
96
95
99

Yields were obtained using GC analysis.

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M. M. Heravi et al.

Table 3. Synthesis of isoxazole derivatives in the presence of a catalytic amount of

H14[NaP5W30O110] under solvent-free conditions at 1308C
Entry

Substrate

Product

Time (min)

Yield (%)a

1,3-Diphenyl-pro
pan1,3-dione

45

99

Acetylacetone

60

98

1,3-Di(tert-butyl)1,3-propandione

45

97

Benzoylacetone

65

97

Ethyl benzoyl acetate

45

97

Ethylacetoacetate

140

92

Methylacetoacetate

140

90

2-Acetylcyclohexanone

30

98

Yields were obtained using GC analysis.

simplicity of operation, and easy workup procedure are some advantages of this
protocol. We believe this methodology can find use in organic synthesis.

EXPERIMENTAL
All compounds were known, and their physical and spectroscopic data were
compared with those of authentic samples and found to be identical. Yields
were obtained using GC analysis.
Synthesis of Isoxazole Derivatives: General Procedure
A mixture of a b-dicarbonyl compound (1 mmol), hydroxylamine hydrochloride (1 mmol), and a catalytic amount of heteropolyacid (1 mol%) was

Heteropolyacids as Green Catalysts

139

refluxed in ethanol (5 cc) for the indicated time as required to complete the
reaction (Table 3). Upon completion of the reaction, monitored by thinlayer chromatography (TLC), the mixture was filtered to separate the
insoluble catalyst and then cooled to room temperature. The precipitated
products were separated by filtration.
In the case of liquid products, after separation of catalyst, the solvent was
evaporated. More purification was obtained by column chromatography.
The separated catalyst could be washed with diethyl ether and reused.
Selected Spectroscopic Data
3,5-Diphenyl-isoxazole (entry 1, Table 3): 1H NMR (80 MHz, CDCl3) d
(ppm): 6.83 (s, 1H), 7.25 7.51 (m, 4H), 7.79 7.94 (m, 6H). IR, y (KBr):
3114, 1649, 1619, 1594 cm21.
3,5-Di(t-butyl)-isoxazole (entry 3, Table 3): 1H NMR (300 MHz, CDCl3) d
(ppm): 1.28 (s, 3H), 1.32 (s, 3H), 6.12 (s, 1H). IR, y (KBr): 2971, 1590 cm21.

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