Facile and selective solvent-free synthesis of 2-isoxazolines under microwave irradiation

Article abstract of DOI:10.1002/jhet.102

(Chemical Equation Presented) Triarylpyrylium perchlorates are readily and selectively converted into corresponding 2-isoxazolines in good yield and short reaction time using solventless conditions.

Full text of DOI:10.1002/jhet.102

778
Facile and Selective Solvent-Free Synthesis of 2-Isoxazolines
under Microwave Irradiation
Vol 46
Arash Mouradzadegun* and Shima Dianat
Department of Chemistry, Faculty of Science, University of Shahid Chamran, Ahvaz-Iran
*E-mail: arash_m@scu.ac.ir
Received May 21, 2008
DOI 10.1002/jhet.102
Published online 30 June 2009 in Wiley InterScience (www.interscience.wiley.com).
Triarylpyrylium perchlorates are readily and selectively converted into corresponding 2-isoxazolines
in good yield and short reaction time using solventless conditions.
J. Heterocyclic Chem., 46, 778 (2009).
INTRODUCTION
ration [9], application [10], and other transformation of
pyrylium and thiopyrylium salts [11,12], herein, we
report our results for a solvent-free microwave reaction
protocol that leads to a facile preparation of 2-isoxazo-
lines from the corresponding pyrylium salts.
Isoxazoline heterocycles have been employed for a
wide variety of uses in chemistry. These ring systems
represent a class of unique pharmacophores, which are
observed in many therapeutic agents and are versatile
intermediates for the synthesis of complex natural prod-
ucts and are found in GPII/IIIa inhibitors and human
leukocyte elastase inhibitors [1]. Besides being potential
pharmaceutical agents, the isoxazolines have found
numerous applications in synthesis through reductive
cleavage of the NAO bond to give 1,3-amino alcohols
[2]. Typically, 1,3-dipolar cycloaddition between nitrile
oxide and alkene are used for synthesis of isoxazoline
derivatives [3]. An alternative synthetic route could be
offered for preparation of some 2-isoxazolines on treat-
ment of a suspension of some 2,4,6-triarylpyrylium salts
in aqueous ethanol with hydroxylamine in the presence
of sodium hydroxide [4–6].
RESULTS AND DISCUSSION
In efforts to improve the conversion of triarylpyry-
liums to corresponding 2-isoxazolines, these transforma-
tions were studied on solid materials such as silica gel,
basic alumina, and nontraditional solid support material,
such as K2CO3, which couple poorly with microwaves.
Before introducing general protocol, preliminary tests
were carried out to survey the requisite reaction condi-
tions and establish the modifications required for this
methodology. Triphenylpyrylium perchlorate was chosen
as the model compound to identify and optimize the
ideal solid support. In the cases of basic alumina and
K2CO3 as solid support 2-isoxazolines obtained as sole
product in comparable yields under microwave irradia-
tion. More importantly, isolation of the product was
more simplified and environmentally acceptable espe-
cially in the case of K2CO3, in which only washing the
reaction mixture with water gave pure product. The
same reaction in the presence of silica gel showed less
selectivity toward 2-isoxazoline. Other attempts in the
absence of solid phases were not successful and notice-
able amount of starting materials remained intact. With
these experiments, we have demonstrated that the tradi-
tional solid supports with soft acidic surface is less
selective and effective, whereas solid supports with soft
basic surface and nontraditional ones are moderately
Mechanistic studies [5b,6] demonstrated that in the
presence of bases the reaction proceeded, after initial
attacked of the nucleophile and the ring opening to the
d-oxo-a,b-unsaturated ketoximes, not via path (a) but
through Michael addition (path b) of two competing
intramolecular cyclizations (Scheme 1). Even though
this reaction is well studied in solution phase, however,
solid supports procedures remain unexplored. The sol-
vent-free use of supported reagents in combination with
microwave irradiation provide ideal reaction conditions
with special attributes such as reduced reaction time,
easier work-up procedure, and enhanced selectivity and
reactivity [7,8]. In connection with this trend and in
continuation with our studies to develop selective, prep-
arative, and synthetically useful methodology for prepa-
C
V
2009 HeteroCorporation

July 2009
Facile and Selective Solvent-Free Synthesis of 2-Isoxazolines
under Microwave Irradiation
779
Scheme 1
completion of these reactions in the presence of extra
amount of hydroxylamine need more power of micro-
wave irradiation and also more reaction times in com-
parison with the others. Interestingly, unlike to those
obtained from trialkyl pyrylium [6a] these oximes were
obtained as single E-isomer. This is also in accordance
with the general trend in oximes, namely prevalence of
the configuration in which the bulkier R group is oppo-
site to hydroxyl group [13]. Pyryliums carrying N,N-di-
methyl substituents in para position of 4-phenyl rings
(Ih) do not react completely and selectively with hy-
droxylamine under these conditions and typical reaction
times.
effective and perform the high selectivity toward desired
product. Following these tests, the relative molar ratio
of reactants and the amounts of solid support were also
optimized under suitable microwave power. For eluci-
dating the relative importance of this method and other
effects in determining the selectivity course of these
conversions, we proceeded to develop the solid support
route to other triarylpyrylium perchlorates which con-
tains electron donor and withdrawing group in para
position of substituted phenyl rings and the results com-
pared with those obtain from traditional method (in
EtOH solvent). The data in Table 1 clearly showed that
in the all cases (Ia–g) the reactions exhibit high regiose-
lectivity toward corresponding 2-isoxazolines derivatives
as favored products in very short reaction times. The
long reaction time (e.g., 18 h for model compound)
which is one of the main drawbacks of traditional
method overcomes in this method. The products undergo
elimination of phenacyl in presence of sodium hydrox-
ide as base in solvent so here; any attempt to increase
the rate of the reaction at elevated temperature will
decrease the yields [5a]. The formation of the oximes
IIId–f may be described by considering the fact that the
In conclusion, a new and general procedure for the
construction of 2-isoxazoline derivatives (IIIa–g) from
readily available starting material has been developed.
We believe present solvent-free procedure under micro-
wave irradiation; provide efficient, selective, and envi-
ronmentally friendly methodology for conversion of tri-
arylpyrylium perchlorates in which desired products can
be obtained by simple filtration and washings without
the need for a chromatographic workup.
EXPERIMENTAL
Chemicals were purchased from Fluka, Merck, and Aldrich
chemical companies. All yields refer to isolated products.
Monitoring of the reactions was accomplished by TLC. A
domestic Butan microwave oven (1000 W) was used. Melting
points were determined on a Gallenkamp melting point appara-
tus and are uncorrected. IR spectra were obtained on a
Bomen.MB:102 FTIR spectrophotometer in KBr disks. 1H
NMR spectra were recorded on 400 MHz Brucker using
CDCl3 as the solvent and TMS as the internal standard.
Syntheses. All triarylpyrylium perchlorates were synthe-
sized from the corresponding aldehydes and ketones by the
Table 1
The results for solvent-free microwave-assisted preparation of 2-isoxazoline derivatives (III).
Yield (%)b
K2CO3
Entry
R
R0
X
Time (MW power)a
Basic alumina
EtOHc
a
b
c
d
e
f
Ph
Ph
Ph
4-CH3C6H4
Ph
O
O
3 (300) þ 0.5 (400)
3(300)
84
79
80
76
79
67
79
–
86
85
89
81
81
80
87
–
74
49
67
63
41
43
69
–
4-CH3OC6H4
Ph
Ph
O
3 (300) þ 0.5 (400)
4.5 (300) þ 1 (400)
4 (300) þ 1 (400)
4 (300) þ 1 (400)
3 (300) þ 0.5 (400)
4.5 (300) þ 1 (400)d
4-CH3OC6H4
4-NO2C6H4
4-BrC6H4
4-CH3C6H4
4-(CH3)2NC6H4
NOH
NOH
NOH
O
Ph
4-CH3OC6H4
Ph
g
h
–
a The time and microwave power units are minute and watt, respectively.
b Based on the isolated products.
c After at least 18 h products were isolated as x ¼ O.
d A mixture of unidentified products obtained.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

780
A. Mouradzadegun and S. Dianat
Vol 46
method previously described [14,15]. The isoxazolines IIIa and
IIIf were identical with samples (IR, m.p.) prepared from the
pervious method [5].
(1H, d, 2J
¼
13.9, COCHAHB). Anal. Calcd. for
(C23H19N3O4): C, 68.82; H, 4.77; N, 10.47. Found: C, 68.58;
H, 4.84; N, 10.71.
General procedure. In ethanol. 2,4,6-Triarylpyrylium per-
chlorate (0.5 mmol) was suspended in ethanol (10 ml). To the
stirred suspension was added an aqueous of hydroxylamine
hydrochloride (2.5 mmol) and excess sodium hydroxide. The
suspension was stirred for 18 h at room temperature. The prod-
ucts was extracted and purified by chromatography (PLC) and
then recrystalized from suitable solvents.
Solvent free. Triarylpyrylium perchlorate (1 mmol) was
added to 1 g of basic alumina and/or K2CO3 in a mortar (this
ratio was optimized under our experimental condition), after
homogenizing 5 mmol of hydroxylamine gradually added in
portion and the mixtures were grinded for further homogeniza-
tion, then irradiated in different energy and required reaction
times (Table 1). The reactions were monitored by TLC using a
30:70 mixture of ether:n-hexane as an eluent. After completion
of the reaction, the mixtures were washed with water in the
case of K2CO3 then the products were isolated by filtration. In
the case of basic alumina, the reaction mixture diluted with
CH2Cl2 then washed with water and dried (using MgSO4).
Evaporation of the solvent under vacuum provided a residue
which was purified by PLC to afford the desired 2-isoxazolines
or their oxime derivatives.
2-[5-(4-bromo-phenyl)-3-phenyl-4,5-dihydro-isoxazol-5-yl]-
1-phenyl-ethanone oxime (IIIf). White crystals, m.p.: 164–
165ꢀC. IR (m max/cmꢁ1): 1340, 1380, 1430, 1450, 3327
(broad). 1H NMR: 9 (1H, oxime proton), 7.40–7.60 (14H, m,
2
2
Ar), 3.78 (1H, d, J ¼ 16.6, CHAHB), 3.71 (1H, d, J ¼ 13.4,
2
COCHAHB), 3.42 (1H, d, J ¼ 13.4, COCHAHB) 3.38 (1H, d,
2J ¼ 16.6, CHAHB). Anal. Calcd. for (C23H19N2O2Br): C,
63.43; H, 4.40; N, 6.44; Br, 18.36. Found: C, 64.12; H, 4.54;
N, 6.12; Br, 17.82.
1-(4-Methoxy-phenyl)-2-[3-(4-methoxy-phenyl)-5-p-tolyl-4,5-
dihydro-isoxazol-5-yl] ethanone (IIIg). White crystals, m.p.:
124–128ꢀC. IR (m max/cmꢁ1): 1340, 1370, 1430, 1450, 1680.
1H NMR: 6.70–8.00 (12H, m, Ar), 4.05 (1H, d, 2J ¼ 16.5,
CHAHB), 3.77 (6H, s, OCH3), 3.70 (1H, d, 2J ¼ 16.5,
CHAHB), 3.70 (2H, s, COCH2), 2.37 (3H, s, CH3). Anal.
Calcd. for (C25H23NO4): C, 78.17; H, 6.31; N, 3.51. Found: C,
78.20; H, 6.44; N, 3.50.
Acknowledgment. This work was supported by the Research
Council at the University of Shahid Chamran.
REFERENCES AND NOTES
2-(3,5-Diphenyl-4,5-dihydro-isoxazol-5-yl)-1-phenyl-ethanone
(IIIa). White crystals, m.p.: 123–124ꢀC. IR (m max/cmꢁ1):
1340, 1370, 1450, 1680. 1H NMR: 7.3–7.88 (15H, m, Ar),
4.12 (1H, d, J ¼ 17, CHAHB), 3.75 (1H, d, J ¼ 17, CHAHB),
3.74 (2H, s, COCH2). Anal. Calcd. for (C23H19NO2): C, 80.91;
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COCH2), 3.71 (1H, d, 2J ¼ 17, CHAHB), 2.31 (3H, s, CH3).
Anal. Calcd. for (C24H21NO2): C, 81.10; H, 5.95, N, 3.94.
Found: C, 80.84; H, 6.02; N, 4.03.
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CHAHB), 3.9 (3H, s, OCH3), 3.8 (3H, s, OCH3), 3.70 (1H, d,
2J ¼ 17, CHAHB), 3.67 (2H, s, COCH2). Anal. Calcd. for
(C25H23NO4): C, 74.80; H, 5.77; N, 3.49. Found: C, 74.68; H,
5.93; N, 3.69.
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7.91(14H, m, Ar), 4.10 (1H, d, J ¼ 17, CHAHB), 3.73 (1H, d,
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(1H, d, 2J ¼ 13.9, COCHAHB), 3.80 (3H, s, OCH3). Anal.
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(broad), 3585. 1H NMR: 8.89 (1H, oxime proton), 7.20–8.20
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2
2J ¼ 16.9, CHAHB), 3.88 (1H, d, J ¼ 13.9, COCHAHB), 3.81
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Facile and Selective Solvent-Free Synthesis of 2-Isoxazolines
under Microwave Irradiation
781
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