Synthesis of some 3,5-diaryl-2-isoxazoline derivatives in ionic liquids media

Article abstract of DOI:10.2298/JSC110831001S

Biologically active isoxazoline derivatives were efficiently synthesized in excellent yields and in smaller reaction times using mild, effective and environmentally friendly butylmethylimidazolium bromide as the solvent and catalyst. By use of this cataly

Full text of DOI:10.2298/JSC110831001S

J. Serb. Chem. Soc. 77 (6) 733–739 (2012)
JSCS–4304
UDC 547.78+66.095.252+544.354.3+
547.233:57–188
Short communication
SHORT COMMUNICATION
Synthesis of some 3,5-diaryl-2-isoxazoline derivatives
in ionic liquids media
*
JAVAD SAFAEI-GHOMI and MOHAMMAD ALI GHASEMZADEH
Department of Chemistry, Qom Branch, Islamic Azad University, Qom, I. R. Iran
(Received 31 August, revised 19 December 2011)
Abstract: Biologically active isoxazoline derivatives were efficiently synthe-
sized in excellent yields and in smaller reaction times using mild, effective and
environmentally friendly butylmethylimidazolium bromide as the solvent and
catalyst. By use of this catalyst, isoxazoline derivatives were produced via cyc-
lization reaction of a chalcone and hydroxylamine hydrochloride in the ionic li-
quid media. The separation of the product was facile and the catalyst could be
separated and recycled. The method is very rapid, safe and avoids the use of
hazardous and expensive reagents and solvents.
Keywords: isoxazoline; cyclization reaction; ionic liquids; butylmethylimidazo-
lium bromide; multi-component reactions; biological activities.
INTRODUCTION
Compounds incorporating heterocyclic ring systems continue to attract con-
siderable interest due to the wide range of their biological activities. Amongst
them, five-membered heterocyclic compounds occupy a unique place in the realm
of natural and synthetic organic chemistry. Isoxazolines as heterocyclic com-
pounds have found wide application as pharmaceutical and agrochemical agents.
1–8
For instance, isoxazolines possess biological activities,
such as insecticidal,
antibacterial, antibiotic, antitumour, antifungal, antimicrobial activity, and anti-
inflammatory and analgesic. In addition, isoxazoline derivatives have played a
crucial role in the theoretical development of heterocyclic chemistry and are also
9,10
used extensively in organic synthesis.
Consequently, much attention has been
paid to the development of new methodologies for their preparation. Several me-
thods have been reported for the synthesis of isoxazoline derivatives. The syn-
thetic routes for the preparation of isoxazoline derivatives mainly are cyclization
11–14
15,16
reaction of chalcones,
1,3-dipolar cycloaddition of oximes to alkenes,
*Corresponding author. E-mail: safaei@kashanu.ac.ir
doi: 10.2298/JSC110831001S
733
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SAFAEI-GHOMI and GHASEMZADEH
17
direct transformation of 3-arylpropargyl hydroxylamines hydrochlorides, reac-
18
tion of alkenes or alkynes with ketones, 1,3-dipolar cycloaddition of nitrile oxi-
19
20
des to vinylic compounds and cyclization of O-propargylic hydroxylamines.
In accordance with the significance of the application these compounds, a
mild and efficient route to the synthesis of isoxazoline derivatives in ionic liquid
media is reported herein.
In the past decade, ionic liquids have received substantial attention in orga-
nic synthesis because of their environmentally benign nature, high polarity, and
good thermal stability. Often shorter reaction times, high yields, cleaner reaction
21,22
products and high selectivity are obtained from ionic-liquid reaction media.
Ionic liquids (ILs) have attracted increasing interest recently in the context of
green organic synthesis. Although ionic liquids were initially introduced as alter-
native green reaction media because of their unique chemical and physical proper-
ties of non-volatility, non-inflammability, negligible vapor pressure, reusability
and high thermal stability, today they have marched far beyond this boundary,
23,24
showing their significant role in controlling reactions as solvents or catalysts.
There are many reports concerning the applications of ionic liquids as sol-
25
vents and catalysts in organic reactions, such as Friedel–Crafts reaction, Diels–
26,27
28
29
–Alder reaction,
Biginelli reaction, Beckmann rearrangement, Michael
30
31
32,33
reaction, reduction of aldehydes, electophilic substitution of aromatic rings,
1,3-dipolar cycloaddition
34,35
36–38
and other reactions.
In the continuation of ongoing studies on the application of IL media, it was
found that dialkylimidazolium halide derivatives have many advantages over
39–42
conventional solvents.
These reagents are safe, easy to handle, environment-
tally benign and present fewer disposal problems. Therefore, butylmethylimida-
zolium bromide ([bmim]Br) (Scheme 1) could be an excellent candidate for em-
ployment in organic reactions. The advantage of these methods over conven-
tional methods is that they provide greater selectivity, enhanced reaction rates,
cleaner products and manipulative simplicity. According to the development of
methods that consist of using environmentally friendly reagents and in continua-
tion of our ongoing program to develop environmentally benign methods, the use
of an ionic liquid in the synthesis of isoxazoline derivatives in a mild, facile and
clean manner is reported herein.
Scheme 1. 1-Butyl-3-methylimidazolium bromide ([bmim]Br).
EXPERIMENTAL
Butylmethylimidazolium bromide ([bmim]Br) was purchased from Fluka. All melting
points are uncorrected and were determined in a capillary tube using a Boetius melting point
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SYNTHESIS OF 3,5-DIARYL-2-ISOXAZOLINE DERIVATIVES
735
microscope. The Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Magna
550 spectrometer (KBr). The 1H- and 13C-NMR spectra were obtained on a Bruker 400 MHz
spectrometer in CDCl3 as solvent using tetramethylsilane (TMS) as an internal standard. All
reactions were monitored and checked by thin layer chromatography (TLC) using hexane/
/ethyl acetate (8:2) and the spots were examined using a UV lamp. The elemental analyses (C,
H, N) were obtained from a Carlo ERBA Model EA 1108 analyzer. The mass spectra were re-
corded on a Joel D-30 instrument at an ionization potential of 70 eV.
General procedures for the synthesis of chalcones 1a–j
Chalcone derivatives have been prepared by condensation of various aromatic aldehydes
and acetophenones in alkaline ethanol according to the procedure reported by Nielsen et al.43
To a mixture of NaOH (2.5 g) in 20 ml water and 15 ml EtOH, was added 0.050 mol of
the required acetophenone derivative and the solution was stirred at 0–5 °C for 10 min, then
0.050 mol of the required aromatic aldehyde was added and the reaction mixture was refluxed
for an appropriate time. After completion of reaction, as indicated by TLC using hexane/ethyl
acetate (7:3) the residue was filtered, washed with water and recrystallyzed from ethanol.
Typical procedures for the synthesis of isoxazolines 3a–j
Conventional heating. Hydroxylamine hydrochloride (0.010 mol) was dissolved in water
(5 ml) and added to a solution of chalcone (0.01 mol) in pyridine (10 ml). The reaction mix-
ture was refluxed (magnetic stirring) on oil bath for 3 h. After completion of the reaction, ob-
served by TLC using hexane/ethyl acetate (8:2), the mixture was cooled to room temperature,
poured into ice-cold water and then acidified with dilute acetic acid. The obtained solid was
filtered, washed with water and recrystallyzed from ethanol.
[Bmim]Br method. A mixture of chalcone (0.010 mol), hydroxylamine hydrochloride
(0.010 mol) and [bmim]Br (0.76 g, 0.0035 mol) was stirred at room temperature for the appro-
priate period After completion of the reaction, as indicated by TLC using hexane/ethyl acetate
(8:2), the reaction mixture was extracted with diethyl ether (3×10 ml). The organic layer was
evaporated under reduced pressure and the solid residue was recrystallyzed from ethanol. The
immiscible ionic liquid phase was recovered and heated for 3 h under vacuum for further use.
The best results were obtained with a molar ratio of 1:1:0.35 of chalcone, hydroxylamine hyd-
rochloride and [bmim]Br.
Data of synthesized compounds are are given in Supplementary material.
RESULTS AND DISCUSSION
In this research, the ring closure reaction of chalcone 1 and hydroxylamine
hydrochloride 2 occurred under I) conventional and II) in the presence of [bmim]Br
to afford the isoxazoline derivatives 3 (Scheme 2). The reactions were performed
using α,β-unsaturated carbonyl compounds with diverse substituents. The results
of the experiments are summarized in Table I.
A possible mechanism for this reaction, proposed based on our experimental
results together with some literature data for the cyclization reaction of chalcone,
is that it is realized in two steps; first nucleophilic attack of the carbonyl group by
the NH moiety occurs, which is followed by oxime formation and then intra-
2
12,13
molecular cyclization leads to the five-membered ring products.
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SAFAEI-GHOMI and GHASEMZADEH
Scheme 2. Preparation of isoxazolines 3 in [bmim]Br.
TABLE I. One-pot synthesis of substituted isoxazolines catalyzed by ([bmim]Br)
M.p., °C
Entry
R
R'
Product
Found
Reported
1
2
3
4
5
6
7
8
9
H
CH3
Cl
OCH3
NO2
OH
OH
NO2
Br
H
H
H
H
Br
3a
3b
3c
3d
3e
3f
3g
3h
3i
150–152
167–168
174–175
149–150
150–151
149–150
140–142
121–123
142–143
168–170
151–15211
16811
17511
148–15112
150–15115
a
H
–
a
CH3
CH3
CH3
Br
–
122–12315
142–14315
a
10
OCH3
3j
–
a
Compounds 3f, 3g and 3j are new products
The one-pot condensation of α,β-unsaturated carbonyl compounds and hyd-
roxylamine hydrochloride proceeded in the presence of the ionic liquid smoothly
to give the corresponding products in high yields and shorter reaction times in
comparison to thermal heating method; the results are summarized in Table II. It
was found that [bmim]Br is a fairly good catalytic medium for this reaction.
Compared with traditional catalysts, such as AcOH, KOH and NaOH, [bmim]Br
not only gives higher yields but also takes much less time and can be easily
recycled. Compared with traditional solvents, ionic liquids can be easily reused.
TABLE II. Comparison of the two methods for the synthesis of 3,5-diaryl-2-isoxazolines
Conventional conditions
Stirred in [bmim]Br
Product
Time, h
Yield, %
Time, min
Yield, %
63
3a
3b
3c
3d
3e
3f
3g
3h
3i
3.5
3.5
3
3
3
3
3
3
3
35
45
50
52
60
60
55
60
52
50
52
50
48
46
45
44
52
42
44
45
70
78
80
87
82
75
84
82
3j
3
80
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SYNTHESIS OF 3,5-DIARYL-2-ISOXAZOLINE DERIVATIVES
737
As mentioned earlier, one of the goals in the use of ionic liquids is to iden-
tify and exploit the advantages these compounds can offer over conventional or-
ganic solvents besides their greener nature. It has been documented that, com-
pared with classical organic solvents, reactions carried out in ionic liquids often
offer enhanced reactivity, better yields and simpler operational process. These
advantages were confirmed in the present paper for the synthesis of 3,5-diaryl-2-
-isoxazoline. The obtained results can be explained by the better catalytic and
44,45
coordinative properties
methods.
of this kind of ionic liquids in comparison to other
CONCLUSIONS
In conclusion, the ionic liquid promoted one-pot annulation reactions of
chalcones and hydroxylamine hydrochloride and was proved an efficient medium
for the synthesis of isoxazoline derivatives. Compared with conventional organic
solvents, the use of [bmim]Br had several advantages, i.e., high yields, mild con-
ditions and simpler procedure in shorter reaction times. In addition, the ionic
liquid used can be easily recovered and effectively reused at least 5 times more
without any significant loss in efficiency.
SUPPLEMENTARY MATERIAL
Spectral data of the compounds are available electronically from http://
//www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgement. The authors gratefully acknowledge the financial support of this work
by the Research Affairs Office of the Islamic Azad University, Qom Branch, Qom, I. R. Iran.
И З В О Д
СИНТЕЗА НОВИХ ДЕРИВАТА 3,5-ДИАРИЛ-2-ИЗОКСАЗОЛИНА
У ЈОНСКИМ ТЕЧНОСТИМА
JAVAD SAFAEI-GHOMI и MOHAMMAD ALI GHASEMZADEH
Department of Chemistry, Qom Branch, Islamic Azad University, Qom, I. R. Iran
Биолошки активни деривати изоксазолина синтетисани су у одличном приносу, у при-
суству бутилметилимидазолијум-бромида као растварача и катализатора. Производи су
добијени реакцијом циклизације халкона и хидроксиламин-хидрохлорида. Производи су
лако раздвојени, а катализатор је могуће одвојити и поновно користити. Описани поступак је
кратак и омогућава да се избегне употреба опасних и скупих реагенаса и растварача.
(Примљено 31. августа, ревидирано 19. децембра 2011)
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SAFAEI-GHOMI and GHASEMZADEH
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