Efficient and convenient method for the synthesis of isoxazoles in ionic liquid

Article abstract of DOI:10.1002/jhet.20

An efficient one-pot synthesis of 3,5-disubstitueted isoxazoles from β-diketones in room temperature ionic liquids (ILs) is described. Compared with the classical reaction conditions, this new synthetic method is environmentally friendly and has the advan

Full text of DOI:10.1002/jhet.20

108
Efficient and Convenient Method for the Synthesis of Isoxazoles
in Ionic Liquid
Vol 46
Hassan Valizadeh,* Mohammad Amiri, and Hamid Gholipur
Department of Chemistry, Faculty of Science, Azerbaijan University of Tarbiat-Moallem, Tabriz, Iran
*E-mail: h-valizadeh@azaruniv.edu
Received March 13, 2008
DOI 10.1002/jhet.20
Published online 6 February 2009 in Wiley InterScience (www.interscience.wiley.com).
An efficient one-pot synthesis of 3,5-disubstitueted isoxazoles from b-diketones in room temperature
ionic liquids (ILs) is described. Compared with the classical reaction conditions, this new synthetic
method is environmentally friendly and has the advantages of recyclability of IL and very good to
excellent yields.
J. Heterocyclic Chem., 46, 108 (2009).
INTRODUCTION
in reusable imidazolium-based ILs using NaOH as base
Scheme 1.
Synthesis of substituted isoxazole derivatives is par-
ticularly important because a lot of compounds contain-
ing the isoxazole ring system are known to have a vari-
ety of biological activities in pharmaceutical and agri-
cultural areas [1]. Their range of uses includes medici-
nal, herbicidal, fungicidal, pesticidal applications, dyes,
insulating oils, and lubricants. Since Claisen’s report in
1891 [2], many methods have been developed for the
preparation of substituted isoxazoles which can gener-
ally be divided into two synthetic routes. The first
involves the condensation reaction of a hydroxylamine
with a carbonyl compound and provides easy access to
3,5-disubstituted isoxazoles [1]. The second route
involves the 1,3-dipolar cycloaddition of a nitrile oxide
with an alkyne. In this transformation, nitrile oxides
react intermolecularly with monosubstituted alkynes to
again give a preponderance of 3,5-disubstituted isoxa-
zoles [3] and furoxan is a significant byproduct.
A
typical reaction of dibenzoylmethane with
hydroxyl-amine was carried out in the IL, [bmim]Br, at
ambient conditions to form 3,5-diphenyl isoxazole.
However, at room temperature, reaction does not pro-
ceed further to afford the product even in trace amounts.
Consequently, the reaction was carried out at higher
temperatures and optimum results were obtained at
65ꢀC (75%).
For further optimization, several ILs based on butyl-
methylimidazolium salts [bmim]X with varying anions
were screened for the typical reaction of dibenzoil-meth-
ane with hydroxylamine at 65ꢀC for complete conver-
sions as monitored by TLC to afford 3,5-diphenyl isoxa-
zole. The results are recorded in Table 1. Evidently,
[bmim]BF4 was found to be superior in terms of yield
(83%) and reaction time (5 h) when compared with
other ILs.
Consequently, all further reactions with other b-dike-
tones were conducted by using [bmim]BF4 as the reac-
tion medium Table 2. Acetylacetone and 2,4-hexane-
dione were mostly recovered unchanged. All the pro-
Room temperature ionic liquids (ILs) have been the
subject of considerable interest as new, nonvolatile, and
environmentally friendly alternatives to conventional or-
ganic solvents. They are salts of organic cations and a
variety of anions [4–7]. ILs are compatible with several
organic transformations [8–10], they readily immobilize
several catalysts in their native form [11,12] or the sup-
ported catalysts [13]. They have been found to alter the
outcome of chemical reactions in a dramatic fashion
[14], thus forming a new paradigm in organic synthesis.
In continuation of our recent interest to use ILs, water
or solventless systems as green reaction mediums [15],
we report herein the synthesis of isoxazole derivatives
ducts were fully characterized by M.P., 13C NMR, H
1
Scheme 1
C
V
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January 2009
Efficient and Convenient Method for the Synthesis of Isoxazoles in Ionic Liquid
109
Table 1
Synthesis of 3,5-diphenyl isoxazole in [bmim]X at 65ꢀC.
was observed in runs carried out using ‘‘old’’ IL, and
furthermore the products obtained were of the same
purity as in the first run.
Entry
Ionic liquid
Time (h)
Yielda (%)
In conclusion, a novel method for the one-pot synthe-
sis of the biologically active isoxazoles has been devel-
oped by the reaction of b-diketone and hydroxylamine
hydrochloride in the IL [bmim]Br in excellent isolated
yields. The solvent IL was recovered almost entirely
and recycled successfully. The moderate reaction condi-
tions, easy workup procedure and recyclability of the
nonvolatile IL make this an environment friendly
method amenable for scaleup.
1
2
3
4
5
[bmim]Br
[bmim]BF4
[bmim]Cl
[bmim]ClO4
[bmim]PF6
5
5
5
5
5
75
83
72
70
72
a
Isolated yield after column chromatography.
NMR, and the values [16] were in agreement with those
reported in literature.
Recycling of the IL was carried out for the reaction
of b-diketone and hydroxylamine hydrochloride follow-
ing an extremely straightforward protocol. After com-
plete reaction and workup the residue containing IL was
dissolved in EtOAc, filtered through a filter paper, dried
over Na2SO4, and the solvent was removed on a rotary
evaporator. The IL was further vacuum dried at 0.1
mmHg for 1 h and used for two more runs under identi-
cal conditions as for run 1. The results gained are shown
in Table 3. It can be seen that a slight reduction in yield
EXPERIMENTAL
All of the melting points are uncorrected and were deter-
mined with a Stuart scientific apparatus. Infrared spectra were
recorded in KBr and were determined on a PerkinElmer FT-IR
spectrometer. 1H NMR spectra were recorded on a Bruker
Avance 300 MHz spectrometer in CDCl3 as solvent and TMS
as internal standard. All solvents and chemicals were of
research grade and were used as obtained from Merck. The
imidazolium-based ILs investigated were prepared according
to the procedure reported in the previous literature [17].
Table 2
Preparation of 3,5-disubstituted isoxazoles in [bmim]BF4.
Melting point (ꢀC)
Product number
R1
R2
R3
Time (h)
Found
Reported
Yielda (%)
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Me
Ph
H
H
Me
H
5
138–142
65–68
140-141 [18]
67 [19]
83
78
78
78
81
75
73
6.2
5.5
6
121–123
223–227
170–177
169–174
207–211
–
4-NO2C6H4
4-ClC6H4
4-NO2C6H4
4-ClC6H4
226–228 [20]
172–178 [21]
172–175 [21]
210 [20]
Ph
4-MeOC6H4
4-MeOC6H4
H
H
6
5.5
5.5
H
a
Isolated yield after column chromatography.
Table 3
Ionic liquid recycling for the reaction of b-diketone and hydroxylamine hydrochloride.
Cycle 1
Cycle 2
Cycle 3
Ionic liquid
Time (h)
Yield (%)
Time (h)
Yield (%)
Time (h)
Yield (%)
[bmim]Br
[bmim]BF4
[bmim]Cl
5
5
5
5
5
80
83
72
70
72
6
6
6
6
6
78
80
70
68
71
7
7
7
7
7
76
79
69
65
67
[bmim]ClO4
[bmim]PF6
aIsolated yields of 3,5-diphenylisoxazole.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

110
H. Valizadeh, M. Amiri, and H. Gholipur
Vol 46
ate time (Table 1). The completion of reaction was monitored by TLC
using (EtOAc/petroleum 1:8) as eluent. After completion of the reac-
tion, the mixture was extracted with Et2O (15 mL ꢁ 3). The Et2O
layers were collected and concentrated in vacuum. Then the crude
mixture was purified by column chromatography using (HEX/EtOAc
9:1) on silica gel to afford corresponding isoxazoles. C15H11NO (1):
1H NMR (300 MHz, CDCl3): d ¼ 7.65 (d, 4H, Ph), 7.34 (m, 6H, Ph),
6.43 (s, 1H, CH); 13C NMR (75 MHz, CDCl3): d ¼ 156.9, 147.1,
136.9, 127.9, 127.0, 126.1, 98.3; Anal. Calcd. for C15H11NO: C, 81.43;
H, 5.01; N, 6.33; O, 7.23. Found: C, 81.40; H, 4.98; N, 6.30; O, 7.32.
Acknowledgment. The authors thank the office of the Research
Vice Chancellor of Azerbaijan, University of Tarbiat-Moallem.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet