Benign methodology and improved synthesis of 5-(2-chloroquinolin-3-yl)-3- phenyl-4,5-dihydroisoxazoline using acetic acid aqueous solution under ultrasound irradiation

Article abstract of DOI:10.1016/j.ultsonch.2010.12.003

In the present paper, we have executed the synthesis of substituted 5-(2-chloroquinolin-3-yl)-3-phenyl-4,5-dihydroisoxazolines via the reactions of substituted 3-(2-chloroquinolin-3-yl)-1-phenylprop-2-en-1-ones with hydroxylamine hydrochloride and sodium

Full text of DOI:10.1016/j.ultsonch.2010.12.003

Ultrasonics Sonochemistry 18 (2011) 911–916
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Short Communication
Benign methodology and improved synthesis of 5-(2-chloroquinolin-3-yl)-3-
phenyl-4,5-dihydroisoxazoline using acetic acid aqueous solution under
ultrasound irradiation
⇑
Vandana Tiwari, Ali Parvez, Jyotsna Meshram
Department of Chemistry, Rashtasant Tukadoji Maharaj, Nagpur University, Nagpur 440033, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present paper, we have executed the synthesis of substituted 5-(2-chloroquinolin-3-yl)-3-phenyl-
4,5-dihydroisoxazolines via the reactions of substituted 3-(2-chloroquinolin-3-yl)-1-phenylprop-2-en-1-
ones with hydroxylamine hydrochloride and sodium acetate in aqueous acetic acid solution in 72–90%
yields at room temperature under ultrasound irradiation. This method provides several advantages such
as operational simplicity, higher yield, safety and environment friendly protocol. The resulting substi-
tuted isoxazolines were characterized on the basis of 1H NMR, 13C NMR, IR, elemental analysis, and mass
spectral data.
Received 10 November 2010
Received in revised form 10 December 2010
Accepted 12 December 2010
Available online 28 December 2010
Keywords:
Ultrasound irradiation
Isoxazolines
Ó 2010 Elsevier B.V. All rights reserved.
Synthesis
Characterization
1. Introduction
be considered when an ultrasonic induced reaction is performed:
the acoustic field, the bubbles field and the chemical system
In the recent years, organic reactions driven in aqueous media
have attracted increasing interest currently because of environ-
mental issues and the understanding of biochemical processes.
As a reaction solvent, water offers many practical and economic
advantages including low cost, safe handling and environmental
compatibility. Many organic reactions in aqueous media have been
described in the literature [1]. In the recent years, organic reactions
carried out in aqueous media have received much attention from
chemists [2] because of concerns and compatibility about the envi-
ronment [3]. Also, most organic reactants including catalysts are
insoluble in water, and the surfactants, due to their hydrophobic
and hydrophilic nature, form micelles of the reactants and promote
the reaction to occur in water [4].
Ultrasound has increasingly been used in organic synthesis in
the last three decades. Ultrasonic irradiation leads to the accelera-
tion of numerous catalytic reactions in homogeneous and hetero-
geneous systems [5]. Furthermore, significant improvements can
be realized with respect to the yields [6,7]. The ultrasonic sono-
chemical phenomenon originates from the interaction between a
suitable field of acoustic waves and a potentially reacting chemical
system. The interaction takes place through the intermediate phe-
nomenon of acoustic cavitations. Three important factors have to
[8,9]. The chemical effects of ultrasounds have been attributed to
implosive collapse of the cavitations period of the sound waves.
The bubbles are generated at localized sites in the liquid mixture
that contain small amounts of dissolved gases. Trapped within a
micro bubble, the reactants are exposed to a high pressure and
temperature upon implosion and the molecules are fractured
forming highly reactive species with a great tendency to react with
the surrounding molecules. When one of the phases is a solid, the
ultrasonic irradiation has several additional enhancement effects,
and this is especially useful when the solid acts as a catalyst
[10]. The cavitation effect form microjects of solvent which bom-
bard the solid surface. This fact causes the exposition of unreacted
surfaces of solid and increases the chances of interphase surface
able to react. In general, the sonications have beneficial effects
on the chemical reactivity, such as to accelerate the reaction, to re-
duce the induction period and to enhance the efficiency of the
catalyst.
The isoxazoline nucleus is well known for its medicinal impor-
tance [11] and a number of related compounds are known to exhi-
bit antitumor [12] properties. Diaryl isoxazole derivatives have a
wide range of biological properties and commercial application
in various realm of therapy, including cytotoxic [13] agents. Isoxaz-
oline also serves as anti-influenza viral activity [14], inhibition of
human leukocyte elastase and cathepsin G [15]. The marketed
drugs of isoxazole, such as, acetylsulfisoxazole, cycloserine,
drazoxol, Sulfisoxazole and zonisamide have a great medicinal
⇑
Corresponding author.
E-mail addresses: vandanachemie@gmail.com (V. Tiwari), drjsmeshram@
rediffmail.com (J. Meshram).
1350-4177/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2010.12.003

912
V. Tiwari et al. / Ultrasonics Sonochemistry 18 (2011) 911–916
R3
H
R2
R1
Cl
H
R1
H
R2
H
O
C
COCH3
R1
CHO
H
H
N
HC
C
H
R3
(b)
O
(a)
+
)
)) ) )
N
N
N
Cl
R2
R3
2
Cl
4(a-h)
3
1
R1
-H
-Cl
-H
-H
R2
-H
R3
4a
4b
4c
-H
-H
-Cl
-Cl
-Cl
-H
-CH3
-H
4d
4e
4f
-CH3 -H
-H
-H
-H
-H
-H
-OCH3
-Br
4g
4h
-NO2 -H
Where: a) MeOH, 20% NaOH, stir, 24 h. b) NH2OH.HCl , CH3COOH , CH3COONa , H2O ,under ultrasonicator.
Scheme 1. Synthesis of target molecule 4(a–h).
value. These drugs show antimicrobial [16,18], tuberculostatic
[19], anticonvulsant [20], neurotoxic [21] and antiepileptic activi-
ties [22] and these activities are also observed in their derivatives
which led to the search for newer bioactive compounds of this
class.
NMR spectra and 13C NMR spectra of the synthesized compounds
were recorded on a Bruker-Avance II 400 (400 MHz), Varian-
Gemini (200 MHz) spectrophotometer using DMSO-d6 solvent
and TMS as the internal standard. Mass spectra were recorded on
a Micromass Q-ToF high resolution mass spectrometer equipped
with electrospray ionization (ESI) on Masslynx 4.0 data acquisition
system. The elemental analysis (C, H, N, and S) of compounds was
performed on Carlo Erba-1108 elemental analyzer. The results
were found to be in good agreement with the calculated values.
The ultrasonic assisted reactions are carried out in a ‘‘Spectralab
model UCB 40D Ultrsonic cleaner’’ with a frequency of 40 kHz
and a nominal power 250 W. The reaction flask was located in
the cleaner, where the surface of reactants is slightly lower than
the level of the water. The reaction temperature was controlled
by addition or removal of water from ultrasonic bath.
A variety of methods have been reported for the preparation of
this class of compounds. Gurubasavaraja Swamy et al. have synthe-
sized isoxazoline bearing hydroxy benzofuran from chalcones and
hydroxyl amine hydrochloride in presence of fused anhydrous so-
dium acetate by refluxing for 7 h [23]. Vikas Desai reported the
reaction of substituted chalcones and hydroxylamine hydrochlo-
ride in presence of potassium hydroxide in absolute ethanol [24].
Marei et al. reported the synthesis of 5-hydroxy-2-isoxazolines
from acetylenic ketone and hydroxyl amine hydrochloride in so-
dium acetate by refluxing for 5–8 h [25]. These reaction conditions
suffer from economic and environmental concerns. Recently, NaOH
and K2CO3-mediated microwave irradiation has been shown to be
an efficient method for the synthesis of isoxazolines [26]. Keeping
in view, the advantages of ultrasonic irradiation, we wish to report
an efficient and practical procedure for the synthesis of substituted
5-(2-chloroquinolin-3-yl)-3-phenyl-4,5-dihydroisoxazolines with
chalcones and hydroxylamine hydrochloride in sodium acetate–
acetic acid aqueous solution under ultrasound irradiation
(Scheme 1).
2.2. Synthesis of 3-(2-chloroquinolin-3-yl)-1-substituted phenyl prop-
2-en-1-ones
To the solution of (0.01 mol) 2-chloroquinoline-3-carbaldehyde
in 5 ml of methanol, freshly prepared 2 N methanolic NaOH solu-
tions (30 ml) was added in ice cold condition and stirred for
10 min. To this (0.01 mol) of appropriate ketones was added and
the reaction mixture was stirred at room temperature for 24 h.
The reaction mixture was cooled on an ice bath and neutralized
with dilute hydrochloric acid. The precipitate appeared was sepa-
rated by filtration and washed three times with 20 ml distilled
water to give the crude product. The product so obtained was
recrystallized from methanol. The purity of the products was
checked on TLC (Merck Silica gel 60F254) by using mixture of ethyl
acetate and hexane as mobile phase.
2. Experimental
2.1. Chemicals and apparatus
All the reagents, solvents and catalyst are of analytical grade
purchased from a commercial source and used directly. All the
melting points were determined by open tube capillaries method
and are uncorrected. The purity of compounds was checked rou-
tinely by TLC (0.5 mm thickness) using silica gel-G coated Al-plates
(Merck) and spots were visualized by exposing the dry plates in io-
dine vapours. IR spectra (mmax in cmꢀ1) were recorded on a Schi-
madzu-IR Prestige 21 spectrophotometer using KBr technique; 1H
2.2.1. 3-(2-Chloroquinolin-3-yl)-1-phenylprop-2-en-1-one (3a)
Yield: 74%; Rf = 0.44 in EtOAc/hexane, 3:7; yellow solid. m.p.:
132–140 °C; MS (M+): 293.75 (100%), 295.07 (33%). FTIR (cmꢀ1):
1662 (C@O), 1619 (CH@CH), 853 (CACl); 1H NMR (400 MHz, DMSO
d6): d/ppm 7.53 (1H, d, J = 15.4 Hz, H ), 8.52 (1H, d, J = 15.5 Hz, Hb),
a

V. Tiwari et al. / Ultrasonics Sonochemistry 18 (2011) 911–916
913
7.40–8.31 (m, 1H, 2H, 3H, 4H, 5H, 10H, 20H, 30H, 40H, 50H); 13C NMR
(C1-quinoline), 130.6 (C2-quinoline), 135.1 (C3-quinoline), 129.5
(C4-quinoline), 127.6 (C5-quinoline), 130.1 (C6-quinoline), 127.0
(C7-quinoline), 126.1 (C8-quinoline), 148.5 (C9-quinoline), 133.8
(C1-Phenyl), 139.6 (C2-Phenyl), 132.4 (C3-Phenyl), 134.5 (C4-Phe-
nyl), 126.4 (C5-Phenyl), 128.5 (C6-Phenyl). Anal. Calcd:
(200 MHz, DMSO-d6): d 128.4 (C ), 146.5 (Cb), 187.4 (>C@O), 149.6
a
(C1-quinoline), 130.6 (C2-quinoline), 135.8 (C3-quinoline), 129.2
(C4-quinoline), 127.6 (C5-quinoline), 130.4 (C6-quinoline), 127.7
(C7-quinoline), 126.9 (C8-quinoline), 148.3 (C9-quinoline), 138.8
(C1-Phenyl), 128.4 (C2-Phenyl), 130.8 (C3-Phenyl), 134.8 (C4-Phe-
nyl), 129.6 (C5-Phenyl), 128.8 (C6-Phenyl). Anal. Calcd:
C19H14ClNO: C, 74.11; H, 4.56; N, 4.49. Found: C, 74.15; H, 4.58;
N, 4.18.
C18H12ClNO: C, 73.54; H, 4.17; N, 4.75. Found: C, 73.60; H, 4.24;
N, 4.78.
2.2.6. 3-(2-Chloroquinolin-3-yl)-1-(4-methoxyphenyl) prop-2-en-1-
one (3f)
2.2.2. 3-(2-Chloroquinolin-3-yl)-1-(2,4-dichorophenyl)-) prop-2-en-
1-one (3b)
Yield: 77%, Rf = 0.65 in EtOAc/hexane, 3:7. Pale yellow solid.
m.p.: 135–138 °C; MS (M+): 360.68 (100%), 362.73 (95%). FTIR
(cmꢀ1): 1664 (C@O), 1614 (CH@CH), 852 (CACl); 1H NMR
Yield: 74%; Rf = 0.59 in EtOAc/hexane, 3:7. Pale yellow crystal-
line solid. m.p.: 146–150 °C; ESI-MS (M+): 323.13 (100%), 325.57
(37%). FTIR (cmꢀ1): 1667 (C@O), 1618 (CH@CH), 2827 (–OCH3),
853 (C–Cl). 1H NMR (400 MHz, DMSO d6): d/ppm 7.54 (1H, d,
J = 15.3 Hz, H ), 8.53 (1H, d, J = 15.6 Hz, Hb), 7.43–8.31 (m, 1H,
a
(400 MHz, DMSO d6) d/ppm: 7.65 (1H, d, J = 15.2 Hz, H ), 8.51
2H, 3H, 4H, 5H, 10H, 20H, 40H, 50H). 13C NMR (200 MHz, DMSO-
a
(1H, d, J = 15.6 Hz, Hb), 7.34–8.32 (m, 1H, 2H, 3H, 4H, 5H, 20H,
d6): d 129.1 (C ), 146.2 (Cb), 187.9 (>C@O), 55.7 (–OCH3), 149.3
a
40H, 50H). 13C NMR (200 MHz, DMSO-d6): d 128.5 (C ), 145.6 (Cb),
(C1-quinoline), 130.1 (C2-quinoline), 135.5 (C3-quinoline), 129.0
(C4-quinoline), 127.7 (C5-quinoline), 130.9 (C6-quinoline), 127.3
(C7-quinoline), 126.8 (C8-quinoline), 148.1 (C9-quinoline), 130.2
(C1-Phenyl), 131.9 (C2-Phenyl), 114.8 (C3-Phenyl), 166.5 (C4-Phe-
nyl), 115.3 (C5-Phenyl), 130.9 (C6-Phenyl). Anal. Calcd:
a
189.4 (>C@O), 149.4 (C1-quinoline), 130.3 (C2-quinoline), 135.7
(C3-quinoline), 129.1 (C4-quinoline), 127.8 (C5-quinoline), 130.4
(C6-quinoline), 127.9 (C7-quinoline), 126.6 (C8-quinoline), 148.4
(C0-quinoline), 136.2 (C1-Phenyl), 136.4 (C2-Phenyl), 130.9 (C3-
Phenyl), 141.5 (C4-Phenyl), 127.6 (C5-Phenyl), 132.8 (C6-Phenyl);
Anal. Calcd: C18H10Cl3NO: C, 59.60; H, 2.76; N, 3.81. Found: C,
59.65; H, 2.79; N, 3.86.
C19H14ClNO2: C, 70.46; H, 4.39; N, 4.38. Found: C, 70.49; H, 4.42;
N, 4.38.
2.2.7. 3-(2-Chloroquinolin-3-yl)-1-(4-bromophenyl) prop-2-en-1-one
(3g)
2.2.3. 3-(2-Chloroquinolin-3-yl)-1-(3,4-dichlorophenyl)prop-2-en-1-
one (3c)
Yield: 73%, Rf = 0.61 in EtOAc/hexane, 3:7. Pale yellow solid.
m.p.: 145–148 °C; MS (M+): 360.47 (100%), 362.73 (96%). FTIR
(cmꢀ1): 1660 (C@O), 1613 (CH@CH), 855 (CACl); 1H NMR
Yield: 76%, Rf = 0.58 in EtOAc/hexane, 3:7. Yellow crystalline so-
lid. m.p.: 166–170 °C; ESI-MS (M+): 372.12 (100%), 370.67 (77%).
FTIR (cmꢀ1): 1664 (C@O), 1613 (CH@CH), 853 (C–Cl), 588 (C–Br);
1H NMR (400 MHz, DMSO d6): d/ppm 7.54 (1H, d, J = 15.5 Hz, H ),
a
(400 MHz, DMSO d6): d/ppm 7.34 (1H, d, J = 15.5 Hz, H ), 8.55
7.90 (1H, d, J = 15.7 Hz, Hb), 7.43–8.32 (m, 1H, 2H, 3H, 4H, 5H,
a
(1H, d, J = 15.7 Hz, Hb), 7.54–8.25 (m, 1H, 2H, 3H, 4H, 5H, 10H,
10H, 20H, 40H, 50H). 13C NMR (200 MHz, DMSO-d6): d 129.5 (C ),
a
40H, 50H). 13C NMR (200 MHz, DMSO-d6): d 128.1 (C ), 145.3 (Cb),
146.2 (Cb), 187.3 (>C@O), 149.5 (C1-quinoline), 130.1 (C2-quino-
line), 135.9 (C3-quinoline), 129.2 (C4-quinoline), 127.9 (C5-quino-
line), 130.6 (C6-quinoline), 127.1 (C7-quinoline), 126.2
(C8-quinoline), 148.9 (C9-quinoline), 136.9 (C1-Phenyl), 132.1
(C2-Phenyl), 134.5 (C3-Phenyl), 128.5 (C4-Phenyl), 132.1 (C5-Phe-
nyl), 132.8 (C6-Phenyl). Anal. Calcd: C18H11ClBrNO: C, 58.01; H,
2.96; N, 3.74. Found: C, 58.04; H, 4.98; N, 3.78.
a
189.3 (>C@O) 149.1 (C1-quinoline), 130.3 (C2-quinoline), 135.5
(C3-quinoline), 129.7 (C4-quinoline), 127.2 (C5-quinoline), 130.4
(C6-quinoline), 127.6 (C7-quinoline), 126.8 (C8-quinoline), 148.4
(C9-quinoline), 138.2 (C1-Phenyl), 131.4 (C2-Phenyl), 134.9 (C3-
Phenyl), 140.3 (C4-Phenyl), 130.1 (C5-Phenyl), 128.2 (C6-Phenyl);
Anal. Calcd: C18H10Cl3NO: C, 59.40; H, 2.76; N, 3.80. Found: C,
59.45; H, 2.78; N, 3.88.
2.2.8. 3-(2-Chlroquinolin-3-yl)-1-(3-nitrophenyl) prop-2-en-1-one
(3h)
Yield: 70%, Rf = 0.54 in EtOAc/hexane, 4:6. Pale yellow solid.
m.p.: 145–150 °C; ESI-MS (M+): 338.09 (100%), 340.06 (32%). FTIR
(cmꢀ1): 1662 (C@O), 1615 (CH@CH), 855 (C–Cl), 1589 (–NO2); 1H
2.2.4. 3-(2-Chloroquinolin-3-yl)-1-p-tolyl prop-2-en-1-one (3d)
Yield: 75%, Rf = 0.56 in EtOAc/hexane, 3:7. Yellow crystalline so-
lid. m.p.: 140–148 °C; ESI-MS (M+): 307.10 (100%), 309.07 (32%).
FTIR (cmꢀ1): 1668 (C@O), 1616 (CH@CH), 851 (CACl); 1H NMR
(400 MHz, DMSO d6): d/ppm 2.38 (3H, s, CH3), 7.54 (1H, d,
NMR (400 MHz, DMSO d6): d/ppm 7.53 (1H, d, J = 15.6 Hz, H ),
a
J = 15.4 Hz, H ), 8.59 (1H, d, J = 15.6 Hz, Hb), 7.29–8.33 (m, 1H,
8.51 (1H, d, J = 15.7 Hz, Hb), 7.43–8.10 (m, 1H, 2H, 3H, 4H, 5H,
a
2H, 3H, 4H, 5H, 10H, 20H, 40H, 50H). 13C NMR (200 MHz, DMSO-
10H, 30H, 40H, 50H). 13C NMR (200 MHz, DMSO-d6): d 129.5 (C ),
a
d6): d 129.1 (C ), 146.2 (Cb), 188.3 (>C@O), 22.7 (–CH3), 149.5
146.1 (Cb), 187.7 (>C@O), 149.7 (C1-quinoline), 130.5 (C2-quino-
line), 135.4 (C3-quinoline), 129.6 (C4-quinoline), 127.2 (C5-quino-
line), 130.1 (C6-quinoline), 127.3 (C7-quinoline), 126.9
(C8-quinoline), 148.3 (C9-quinoline), 138.9 (C1-Phenyl), 124.1
(C2-Phenyl), 148.2 (C3-Phenyl), 126.6 (C4-Phenyl), 130.1 (C5-Phe-
nyl), 136.0 (C6-Phenyl). Anal. Calcd: C18H11ClN2O3: C, 68.71; H,
3.26; N, 8.24. Found: C, 63.84; H, 3.28; N, 8.28.
a
(C1-quinoline), 130.3 (C2-quinoline), 135.1 (C3-quinoline), 129.7
(C4-quinoline), 127.2 (C5-quinoline), 130.8 (C6-quinoline), 127.4
(C7-quinoline), 126.6 (C8-quinoline), 148.3 (C9-quinoline), 134.9
(C1-Phenyl), 130.8 (C2-Phenyl), 129.9 (C3-Phenyl), 144.5 (C4-Phe-
nyl), 129.8 (C5-Phenyl), 130.3 (C6-Phenyl). Anal. Calcd:
C19H14ClNO: C, 74.12; H, 4.56; N, 4.49. Found: C, 74.15; H, 4.58;
N, 4.18.
2.3. Ultrasonic mediated aqueous acetic acid catalyzed general
synthesis of 5-(2-chloroquinolin-3-yl)-3-substituted phenyl-4,5-
dihydroisoxazoline
2.2.5. 3-(2-Chloroquinolin-3-yl)-1-o-tolyl prop-2-en-1-one (3e)
Yield: 78%, Rf = 0.51 in EtOAc /hexane, 3:7. Yellow crystalline
solid. m.p.: 132–140 °C; ESI-MS (M+): 307.12 (100%), 309.10
(35%). FTIR(cmꢀ1):1663 (C@O), 1615 (CH@CH), 854 (C–Cl); 1H
NMR (400 MHz, DMSO d6): d/ppm 2.38 (3H, s, CH3), 7.54 (1H, d,
The reaction was carried out in Spectralab model UCB 40D
Ultrasonic cleaner. Chalcones (3, 2 mmol), hydroxylamine hydro-
chloride (6 mmol) and sodium acetate (0.3 mmol) were dissolved
in acetic acid aqueous solution (8 mL, HAc/H2O = 2/1, V/V) in a
50 ml conical flask. The mixture was irradiated in the water bath
J = 15.6 Hz, H ), 8.51 (1H, d, J = 15.7 Hz, Hb), 7.29–8.27 (m, 1H,
a
2H, 3H, 4H, 5H, 20H, 30H, 40H, 50H). 13C NMR (200 MHz, DMSO-
d6): d 129.3 (C ), 146.5 (Cb), 188.6 (>C@O), 18.6 (–CH3), 149.2
a

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V. Tiwari et al. / Ultrasonics Sonochemistry 18 (2011) 911–916
Table 1
Time taken and % yield for compounds 4(a–h).
Compound
Conventional method
Ultrasonic method
1:1 mol ratio
1:2 mol ratio
Time (h)
1:3 mol ratio
Time (h)
Time (h)
% Yield
Time (h)
% Yield
% Yield
% Yield
4a
4b
4c
4d
4e
4f
6
7
6
6.5
6
7
7
6
76
74
77
78
72
73
75
74
1.5
2
2
2
2
2
2
2
80
82
81
80
82
80
81
80
1.5
2
2
2
2
2
2
2
85
84
83
86
85
83
84
86
1.5
2
2
2
2
2
2
2
89
87
89
90
87
87
88
89
4g
4h
of an ultrasonic cleaner for the period as indicated in Table 1. The
progress of the reaction was monitored by TLC. The reaction mix-
ture was poured into crushed ice. The precipitate was separated
by filtration, washed with water, and recrystallized from ethanol
to obtain the 5-(2-chloroquinolin-3-yl)-3-phenyl-4,5-dihydroisox-
azolines in 80–90% yields. The purity of the products was checked
on TLC (Merck Silica gel 60F254) by using mixture of ethyl acetate
and hexane as mobile phase.
(C3-Isoxazoline), 150.2 (C1-quinoline), 131.4 (C2-quinoline),
136.6 (C3-quinoline), 127.8 (C4-quinoline), 128.1 (C5-quinoline),
130.3 (C6-quinoline), 126.5 (C7-quinoline), 128.7 (C8-quinoline),
145.9 (C9-quinoline), 133.5 (C1-Phenyl), 130.7 (C2-Phenyl), 133.5
(C3-Phenyl), 135.7 (C4-Phenyl), 130.4 (C5-Phenyl), 128.7 (C6-Phe-
nyl). Anal. Calcd: C18H11Cl3N2O: C, 57.25; H, 2.85; N, 7.37. Found: C,
57.22; H, 2.86; N, 7.39.
2.3.4. 5-(2-Chloroquinolin-3-yl)-3-p-tolyl-4,5-dihydroisoxazoline
(4d)
2.3.1. 5-(2-Chloroquinolin-3-yl)-3-phenyl-4,5-dihydroisoxazoline
(4a)
Rf = 0.63 in EtOAc/hexane, 3:7. Dark brown crystalline solid.
m.p.: 162–165 °C; ESI-MS (M+): 322.07 (100%), 324.16 (37%). FTIR
(cmꢀ1): 1634 (C@N, quinoline), 1633 (C@N, isoxazoline), 1235
(–C–O–N), 823 (C–Cl); 1H NMR (400 MHz, DMSO d6): d/ppm 2.43
(3H, s, CH3), 5.93 (1H, t, J = 9.8 Hz, –C–CH–O–), 3.99 (2H, d,
J = 9.5 Hz, –C–CH2–C–), 7.37–8.16 (m, 1H, 2H, 3H, 4H, 5H, 10H,
20H, 40H, 50H). 13C NMR (200 MHz, DMSO-d6): d 156.4 (C1-Isoxazo-
line), 43.6 (C2-Isoxazoline), 72.8 (C3-Isoxazoline), 25.7 (–CH3),
150.2 (C1-quinoline), 131.5 (C2-quinoline), 136.8 (C3-quinoline),
127.3 (C4-quinoline), 128.6 (C5-quinoline), 130.5 (C6-quinoline),
126.8 (C7-quinoline), 128.9 (C8-quinoline), 145.1 (C9-quinoline),
132.0 (C1-Phenyl), 129.1 (C2-Phenyl), 129.8 (C3-Phenyl), 142.7
(C4-Phenyl), 129.2 (C5-Phenyl), 129.1 (C6-Phenyl). Anal. Calcd:
Rf = 0.64 in EtOAc/hexane, 4:6. Brown crystalline solid. m.p.:
141–145 °C; ESI-MS (M+): 308.09 (100%), 310.06 (36%). FTIR
(cmꢀ1): 1635 (C@N, quinoline), 1637(C@N, isoxazoline), 1231
(–C–O–N), 823 (C–Cl). 1H NMR (400 MHz, DMSO d6): d/ppm 5.93
(1H, t, J = 9.8 Hz, –C–CH–O–), 3.97 (2H, d, J = 9.4 Hz, –C–CH2–C–),
7.43–8.27 (m, 1H, 2H, 3H, 4H, 5H, 10H, 20H, 30H, 40H, 50H). 13C
NMR (200 MHz, DMSO-d6): d 156.3 (C1-Isoxazoline), 43.9 (C2-Isox-
azoline), 72.9 (C3-Isoxazoline), 150.3 (C1-quinoline), 131.4
(C2-quinoline), 136.2 (C3-quinoline), 127.2 (C4-quinoline), 128.0
(C5-quinoline), 130.9 (C6-quinoline), 126.3 (C7-quinoline), 128.2
(C8-quinoline), 145.1 (C9-quinoline), 134.2 (C1-Phenyl), 130.9
(C2-Phenyl), 128.8 (C3-Phenyl), 131.5 (C4-Phenyl), 129.3 (C5-Phe-
nyl), 130.2 (C6-Phenyl). Anal. Calcd: C18H13ClN2O: C, 70.71; H,
4.26; N, 9.24. Found: C, 70.84; H, 4.28; N, 9.28.
C19H15ClN2O: C, 70.73; H, 4.68; N, 8.69. Found: C, 70.76; H, 4.71;
N, 8.70.
2.3.2. 5-(2-Chloroquinolin-3-yl)-3-(2,4-dichlorophenyl)-4,5-
dihydroisoxazoline (4b)
2.3.5. 5-(2-Chloroquinolin-3-yl)-3-o-tolyl-4,5-dihydroisoxazoline (4e)
Rf = 0.63 in EtOAc/hexane, 3:7. Yellowish brown crystalline so-
lid. m.p.: 154–156 °C; ESI-MS (M+): 322.04 (100%), 324.12 (37%).
FTIR (cmꢀ1): 1638 (C@N, quinoline), 1631 (C@N, isoxazoline),
1236 (–C–O–N), 823 (C–Cl); 1H NMR (400 MHz, DMSO d6): d/
ppm 2.40 (3H, s, CH3), 5.94 (1H, t, J = 9.8 Hz, –C–CH–O–), 3.95
(2H, d, J = 9.4 Hz, –C–CH2–C–), 7.37–8.18 (m, 1H, 2H, 3H, 4H, 5H,
10H, 30H, 40H, 50H). 13C NMR (200 MHz, DMSO-d6): d 156.2 (C1-Isox-
azoline), 43.3 (C2-Isoxazoline), 72.7 (C3-Isoxazoline), 18.9 (–CH3),
150.0 (C1-quinoline), 131.3 (C2-quinoline), 136.5 (C3-quinoline),
127.7 (C4-quinoline), 128.9 (C5-quinoline), 130.2 (C6-quinoline),
126.4 (C7-quinoline), 128.6 (C8-quinoline), 145.8 (C9-quinoline),
129.7 (C1-Phenyl), 138.1 (C2-Phenyl), 129.2 (C3-Phenyl), 131.0
(C4-Phenyl), 126.2 (C5-Phenyl), 129.1 (C6-Phenyl). Anal. Calcd:
Rf = 0.53 in EtOAc/hexane, 3:7. Yellowish brown solid. m.p.:
149–151 °C; ESI-MS (M+): 375.75 (100%), 377.16 (76%). FTIR
(cmꢀ1): 1633 (C@N, quinoline), 1636 (C@N, isoxazoline), 1231
(–C–O–N), 825 (C–Cl); 1H NMR (400 MHz, DMSO d6): d/ppm 5.91
(1H, t, J = 9.7 Hz –C–CH–O–), 3.98 (2H, d, J = 9.2 Hz –C–CH2–C–),
7.47–8.16 (m, 1H, 2H, 3H, 4H, 5H, 30H, 50H). 13C NMR (200 MHz,
DMSO-d6): d 156.2 (C1-Isoxazoline), 43.5 (C2-Isoxazoline), 72.7
(C3-Isoxazoline), 150.2 (C1-quinoline), 131.0 (C2-quinoline),
136.3 (C3-quinoline), 127.1 (C4-quinoline), 128.8 (C5-quinoline),
130.3 (C6-quinoline), 126.5 (C7-quinoline), 128.6 (C8-quinoline),
145.3 (C9-quinoline), 135.3 (C1-Phenyl), 134.9 (C2-Phenyl), 130.5
(C3-Phenyl), 138.0 (C4-Phenyl), 127.1 (C5-Phenyl), 132.2 (C6-Phe-
nyl). Anal. Calcd: C18H11Cl3N2O: C, 57.21; H, 2.86; N, 7.34. Found: C,
57.24; H, 2.88; N, 7.38.
C19H15ClN2O: C, 70.68; H, 4.71; N, 8.67. Found: C, 70.73; H, 4.74;
N, 8.72.
2.3.3. 5-(2-Chloroquinolin-3-yl)-3-(3,4-dichlorophenyl)-4,5-
dihydroisoxazoline (4c)
2.3.6. 5-(2-Chloroquinolin-3-yl)-3-(p-methoxyphenyl)-4,5-
dihydroisoxazoline (4f)
Rf = 0.58 in EtOAc/hexane, 3:7. Light brown solid. m.p.: 158–
160 °C; ESI-MS (M+): 375.45 (100%), 377.12 (71%). FTIR (cmꢀ1):
1638 (C@N, quinoline), 1632 (C@N, isoxazoline), 1236 (–C–O–N),
827 (C–Cl); 1H NMR (400 MHz, DMSO d6): d/ppm 5.95 (1H, t,
J = 9.8 Hz, –C–CH–O–), 3.96 (2H, d, J = 9.4 Hz, –C–CH2–C–), 7.47–
8.16 (m, 1H, 2H, 3H, 4H, 5H, 40H, 50H). 13C NMR (200 MHz,
DMSO-d6): d 156.1 (C1-Isoxazoline), 43.8 (C2-Isoxazoline), 72.5
Rf = 0.65 in EtOAc/hexane, 3:7. Dark orange solid. m.p.: 157–
160 °C; ESI-MS (M+): 338.10 (100%), 340.08 (32%). FTIR (cmꢀ1):
1634 (C@N, quinoline), 1633 (C@N, isoxazoline), 1235 (–C–O–N),
2827 (–OCH3), 823 (C–Cl); 1H NMR (400 MHz, DMSO d6): d/ppm
3.64 (s, 3H, –OCH3), 5.92 (1H, t, J = 9.7 Hz, –C–CH–O–), 3.94 (2H,
d, J = 9.3 Hz, –C–CH2–C–), 7.32–8.16 (m, 1H, 2H, 3H, 4H, 5H, 10H,
20H, 40H, 50H). 13C NMR (200 MHz, DMSO-d6): d 156.0 (C1-Isoxazo-

V. Tiwari et al. / Ultrasonics Sonochemistry 18 (2011) 911–916
915
line), 43.4 (C2-Isoxazoline), 72.2 (C3-Isoxazoline), 54.8 (–OCH3),
150.1 (C1-quinoline), 131.8 (C2-quinoline), 136.3 (C3-quinoline),
127.6 (C4-quinoline), 128.5 (C5-quinoline), 130.4 (C6-quinoline),
126.7 (C7-quinoline), 128.2 (C8-quinoline), 145.9 (C9-quinoline),
126.3 (C1-Phenyl), 120.2 (C2-Phenyl), 114.4 (C3-Phenyl), 164.0
(C4-Phenyl), 114.2 (C5-Phenyl), 130.1 (C6-Phenyl). Anal. Calcd:
hydroxylamine hydrochloride in sodium acetate–acetic acid aque-
ous solution under ultrasound irradiation. In the first step, 3-(2-
chloroquinolin-3-yl)-1-substituted phenyl prop-2-en-1-ones were
prepared in excellent yield starting with 2-chloroquinoline-3-carb-
aldehyde and different substituted ketones in the presence of
NaOH in methanol. In the next step, the substituted chalcones
were cyclized to dihydroisoxazolines using hydroxylamine hydro-
chloride under ultrasound irradiation. During the course of cycliza-
tion, we have tried to optimise the reaction conditions. The effect
of the reaction conditions on the reaction of chalcones and
hydroxylamine hydrochloride under ultrasound irradiation was
summarized in (Table 1). When the molar ratio of chalcones (1):
hydroxylamine hydrochloride (2) was 1:1, the yield of 5-(2-chloro-
quinolin-3-yl)-3-phenyl-4,5-dihydroisoxazoline obtained was
around 80% (Table 1). By increasing the molar ratio to 1:2, and
1:3 the yields of products were increased to 85% and 89%, respec-
tively (Table 1). The results showed that changing the molar ratio
of 1:2 had a significant effect on the yield, and the optimum molar
ratio of chalcones: hydroxylamine was found to be 1:3. The impor-
tant finding was that in the presence of sodium acetate in aqueous
acetic acid, the yield of isoxazolines can be increased. It may be due
to sodium acetate which is in favour of release of hydroxylamine
from hydroxylamine hydrochloride. In order to verify the effect
of ultrasound irradiation, we have performed the reaction of chal-
cone with hydroxylamine hydrochloride by refluxing for 6 h in the
absence of ultrasonic waves. The yield of isoxazolines was 76%
(Table 1) which was lesser as compared to ultrasonic induced
synthesis. While under ultrasound irradiation, the reaction can
be completed within 2 h in 88% yield at room temperature (Table
1). Thus, it was clear from the data that, ultrasound could acceler-
ate the reaction of chalcones and hydroxylamine hydrochloride
affording more yield than thermal conditions as clears from (Table
1). From the results above, the optimum reaction conditions was
chosen: i.e., chalcone (1, 2 mmol), hydroxylamine hydrochloride
(2, 6 mmol), sodium acetate (0.3 mmol). Under this reaction sys-
tem, a series of experiments for synthesis of 5-(2-chloroquinolin-
3-yl)-3-phenyl-4,5-dihydroisoxazoline under 25 kHz ultrasound
irradiation were performed. The results are summarized in (Table
1). The reaction may tentatively be visualized to occur via a tan-
dem sequence of reactions depicted in reaction mechanism [24]
(Scheme 2) involving (i) attack of oxygen on carbon–carbon double
bond forming aminooxy derivative, (ii) attack of nitrogen on car-
bonyl carbon leading to a five membered ring in either a sequential
or a concerted manner, and (iii) proton transfer and removal of
water molecule resulting to isoxazoline. Structural features of the
synthesized chalcones and isoxazolines were obtained from FTIR,
Elemental Analyses, 1H NMR, 13C NMR and mass spectral studies.
In the IR spectra of the chalcones, the characteristic absorption
C19H15ClN2O2: C, 67.34; H, 4.66; N, 8.29. Found: C, 67.38; H,
4.68; N, 8.31.
2.3.7. 5-(2-Chloroquinolin-3-yl)-3-(p-bromophenyl)-4,5-
dihydroisoxazoline (4g)
Rf = 0.58 in EtOAc/hexane, 4:6. Orange crystalline solid. m.p.:
171–175 °C; ESI-MS (M+): 387.12 (100%), 385.08 (36%). FTIR
(cmꢀ1): 1636 (C@N, quinoline), 1637 (C@N, isoxazoline), 1242
(–C–O–N), 588 (C–Br), 823 (C–Cl); 1H NMR (400 MHz, DMSO d6):
d/ppm 5.96 (1H, t, J = 9.8 Hz, –C–CH–O–), 3.98 (2H, d, J = 9.5 Hz, –
C–CH2–C–), 7.37–8.18 (m, 1H, 2H, 3H, 4H, 5H, 10H, 20H, 40H, 50H).
13C NMR (200 MHz, DMSO-d6): d 156.9 (C1-Isoxazoline), 43.7
(C2-Isoxazoline), 72.3 (C3-Isoxazoline), 150.5 (C1-quinoline),
131.7 (C2-quinoline), 136.3 (C3-quinoline), 127.1 (C4-quinoline),
128.2 (C5-quinoline), 130.6 (C6-quinoline), 126.4 (C7-quinoline),
128.0 (C8-quinoline), 145.8 (C9-quinoline), 134.0 (C1-Phenyl),
131.4 (C2-Phenyl), 130.8 (C3-Phenyl), 125.7 (C4-Phenyl), 131.6
(C5-Phenyl), 131.2 (C6-Phenyl). Anal. Calcd: C18H12BrClN2O: C,
55.75; H, 3.18; N, 7.24. Found: C, 55.78; H, 3.22; N, 7.28.
2.3.8. 5-(2-Chloroquinolin-3-yl)-3-(3-nitrophenyl)-4,5-
dihydroisoxazoline (4h)
Rf = 0.57 in EtOAc/hexane, 3:7. Brown crystalline solid. m.p.:
160–164 °C; ESI-MS (M+): 353.05 (100%), 355.08 (34%). FTIR
(cmꢀ1): 1632 (C@N, quinoline), 1638 (C@N, isoxazoline), 1239
(–C–O–N), 1589 (–NO2), 823 (C–Cl); 1H NMR (400 MHz, DMSO d6):
d/ppm 5.97 (1H, t, J = 9.8 Hz, –C–CH–O–), 3.93 (2H, d, J = 9.4 Hz, –
C–CH2–C–), 7.37–8.12 (m, 1H, 2H, 3H, 4H, 5H, 10H, 30H, 40H, 50H).
13C NMR (200 MHz, DMSO-d6): d 156.9 (C1-Isoxazoline), 43.6
(C2-Isoxazoline), 72.4 (C3-Isoxazoline), 150.7 (C1-quinoline),
131.9 (C2-quinoline), 136.5 (C3-quinoline), 127.3 (C4-quinoline),
128.2 (C5-quinoline), 130.4 (C6-quinoline), 126.6 (C7-quinoline),
128.7 (C8-quinoline), 145.8 (C9-quinoline), 140.3 (C1-Phenyl),
130.8 (C2-Phenyl), 122.2 (C3-Phenyl), 150.7 (C4-Phenyl), 122.5
(C5-Phenyl), 130.1 (C6-Phenyl). Anal. Calcd: C18H12ClN3O3: C,
61.16; H, 3.48; N, 11.87. Found: C, 61.18; H, 3.51; N, 11.88.
3. Results and discussion
We have reported the synthesis of substituted 5-(2-chloroquin-
olin-3-yl)-3-phenyl-4,5-dihydroisoxazolines from chalcones and
Cl
N
Cl
N
Cl
N
Proton
O
O
O
+
O
transfer
O
N
..
H2N
H
H2N
..
..
H2N OH
..
Cl
Cl
N
N
Cl
Proton
H+
OH
transfer
O
H
- H2O
N
O
N
O
N
H
O
H
Scheme 2. Probable mechanism for synthesis of 5-(2-chloroquinolin-3-yl)-3-phenyl-4,5-dihydroisoxazoline.

916
V. Tiwari et al. / Ultrasonics Sonochemistry 18 (2011) 911–916
around 1660–1668 cmꢀ1 (C@O), 1613–1619 cmꢀ1 (CH@CH) which
are absent in the spectra of the isoxazoline confirmed the
heterocyclization. The 1H NMR spectrum of the 5-(2-chloroquino-
lin-3-yl)-3-phenyl-4,5-dihydroisoxazoline in DMSO-d6 at room
temperature using TMS as an internal standard showed the follow-
ing signals: 5.92–5.97 (1H, t, –C–CH–O–), 3.93–3.99 (2H, d, –C–
CH2–C–) for isoxazoline ring and aromatic protons as multiplet
around 7.43–8.27 ppm (m, 10H). The structures were further con-
firmed by mass spectral studies. They gave molecular ion peaks
(M+) corresponding to the correct molecular formulas.
[6] J.M. Lopez-Pestana, M.J. Avila-Rey, R.M. Martin-Aranda, Ultrasound-promoted
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addition between imidazole and ethyl acrylate, Catal. Lett. 84 (2002) 201.
´
[10] V. Calvino-Casilda, A.J. Lo´pez-Peinado, R.M. Martın-Aranda, S. Ferrera-
´
Escudero, C.J. Duran-Valle, Ultrasound-promoted N-propargylation of
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4. Conclusion
In conclusion, we have developed a practical and cost effective,
and environmentally convenient procedure for the synthesis of 5-
(2-chloroquinolin-3-yl)-3-phenyl-4,5-dihydroisoxazoline in sodium
acetate–acetic acid aqueous solution at room temperature under
ultrasound irradiation.
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Acknowledgement
We are thankful to Head, Department of Chemistry, Rashtrasant
Tukadoji Maharaj Nagpur University, Nagpur (India) for providing
necessary laboratory facilities and Director, SAIF Chandigarh (India)
for providing necessary spectral data of compounds.
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7
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