Synthesis of ethyl isoxazole-3-carboxylates using an ionic liquid as a soluble support

Article abstract of DOI:10.1002/jhet.1673

A regioselective 1,3-dipolar cycloadditions of ionic liquid-supported vinyl ethers, derived from ionic liquid-supported α-phenylselenomethyl ether, with ethyl cyanoformate N-oxide gave supported isoxazoline derivatives, which were then cleaved from the io

Full text of DOI:10.1002/jhet.1673

March 2014
Synthesis of Ethyl Isoxazole-3-Carboxylates Using an Ionic Liquid as a
Soluble Support
315
a
a
b
b
a
*
Shouri Sheng, Wusheng Sheng, Qiaosheng Hu, Hongen Qu, and Mingzhong Cai
aInstitutes of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi, 330022, People’s
Republic of China
bCollege of Chemistry and Life Science, Gannan Normal University, Ganzhou, Jiangxi, 341000, People’s Republic of China
*
E-mail: shengsr@jxnu.edu.cn
Received August 31, 2011
DOI 10.1002/jhet.1673
Published online 4 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
O
R
O N C CO2Et
O
R
H2O2
N
N
N
N
BF4
BF4
SePh
O
O
CO2Et
N
N
TFA
R
N
BF4
N
R
O
CO2Et
A regioselective 1,3-dipolar cycloadditions of ionic liquid-supported vinyl ethers, derived from ionic
liquid-supported a-phenylselenomethyl ether, with ethyl cyanoformate N-oxide gave supported isoxazoline
derivatives, which were then cleaved from the ionic liquid support under mild acidic conditions to afford
ethyl isoxazole-3-carboxylates. This new synthetic method is simple and efficient and the products are
obtained in good yields.
J. Heterocyclic Chem., 51, 315 (2014).
INTRODUCTION
(PEG) in combinatorial synthetic methodologies facilitate
the library synthesis and supersede the difficulties usually
encountered during the solid-phase reactions [11]. How-
ever, the main limitation of soluble polymer supports is
low loading capacity. So, the idea of searching for alterna-
tive soluble supports for high-throughput organic synthesis
has been advocated. Recently, ionic liquids have been
introduced as soluble supports in LPOS [12]. They have
the advantages of retaining the nature of a homogeneous
reaction, high loading capacity, a wide range of solvents,
simple monitoring technology, and low cost. Encouraged
by the aforementioned facts, and as part of our continuing
effort to develop effective methods for the synthesis of
substituted isoxazoles using selenium reagents [9d,13],
we report here a new synthetic approach to ethyl isoxazole-
3-carboxylates using an ionic liquid as a soluble support, as
shown in Scheme 1. To our knowledge, this methodology
has never been reported and may complement those existing
in the literature.
Functionalized isoxazoles are present in a variety of
natural products and represent useful synthetic building
blocks [1]. They have shown considerable antimicrobial,
antifungal, and herbicide activity [2]. The isoxazole moiety
is present in sulfonamide antibiotics (sulfisoxazoles,
oxacillin, cloxacillin, and dicloxacillin) [3], anti-rheumatic
and anti-arthritic agents (leflunomide) [3], anti-inflammatory
agents (isoxicam) [4], and anti-leprous agents and it is also
present in
a
monoaminoxidase inhibitor used in
psychotherapy [3]. Such a spectrum of biological activity
has attracted considerable attention to these compounds,
and recently, researchers have reported several solid-phase
organic synthesis (SPOS) approaches using insoluble solid
supports such as cross-linked polystyrene resins toward
isoxazoles, including the condensation of 1,3-dicarbonyl
compounds with hydroxylamine [5], the addition of nitrile
oxides to the supported alkynes [6] or alkenes [7], the
anchoring of nitrile oxide precursor onto the solid phase
[8], or using polymer-supported selenium reagents [9]. In
the field of combinatorial chemistry, although SPOS has
been accepted as an efficient method to build small mole-
cule libraries to accelerate lead generation and lead optimi-
zation [10], SPOS still exhibits several shortcomings due
to the nature of the heterogeneous reaction and difficulties
in reaction monitoring. Liquid-phase organic synthesis
(LPOS) approaches using soluble polymer supports such as
non-cross-linked polystyrene and poly(ethylene glycol)
RESULTS AND DISCUSSION
During this investigation, the b-hydroxyalkyl phenyl
selenides were selected as starting materials to be anchored
to ionic liquid 1-(2-hydroxyethyl)-3-methylimidazolium
tetrafluoroborate ([2-hydemim][BF4], 1) via an ether bond,
followed by oxidation–elimination to yield ionic liquid-
supported vinyl ethers, which is based on the fact that the
oxidation of phenyl selenides under extremely mild
© 2013 HeteroCorporation

316
S. Sheng, W. Sheng, Q. Hu, H. Qu, and M. Cai
Vol 51
Scheme 1. Liquid-phase organic synthesis of ethyl isoxazole-3-carboxylates.
OH
SePh
SePh
R
Cl3CCN
H2O2
NH
R
OH
O
R
O
CCl3 BF3 OEt2, CH2Cl2
DBU, CH2Cl2
CH2Cl2
O
2
3
4
1
CO2Et
N
CO2Et
HON=C(Cl)CO2Et
CH2Cl2, Et3N
5% TFA
CH2Cl2
OH
N
N
OH
=
N
O
BF4
R
O
O
R
5
6
conditions is widely employed in the formation of carbon–
carbon double bonds [14]. Obviously, ionic liquid-
supported a-phenylselenomethyl ether 3 derived from
b-hydroxyalkyl phenyl selenides and 1 represents the key
intermediate in the present procedure.
cleavage of 5 to give products 6 was achieved by treatment
of 5 with trifluoroacetic acid in dichloromethane. On
completion of the reaction, the crude product was purified
by flash chromatography on silica gel to afford ethyl
5-substituted isoxazole-3-carboxylate 6, which was char-
acterized by conventional techniques (1H and 13C NMR and
IR). As shown in Table 1, this method was found to be gen-
erally applicable, and all the products as a single regioisomer
were obtained in good overall yields (78–90%).
Finally, the typical Suzuki reaction of the ionic liquid-
supported intermediate 5f with phenylboronic acid under
similar reaction conditions [17] was further investigated
(Scheme 2). Treatment of 5f with phenylboronic acid in
the presence of a catalytic amount of Pd(OAc)2 in an
aqueous solution of cesium fluoride under nitrogen at
80ꢀC for 20 h gave the crude product, which was purified
by evaporation of the reaction mixture under reduced
pressure, followed by extraction of the crude product with
ether to afford the Suzuki coupling intermediate 7. Cleav-
age of 7 with the same protocol as aforementioned
produced the target compound 8 in 82%.
Initially, we attempted to anchor the b-hydroxyalkyl
phenyl selenides to 1 via an ether linkage directly under
Mitsunobu reaction conditions [triphenylphosphine/diethyl
azodicarboxylate (TPP/DEAD)] [15], but the conversion of
the ionic liquid-supported hydroxyethyl group to ether
bond was not complete. Interestingly however, after a con-
siderable number of experiments, b-hydroxyalkyl phenyl
selenides were almost quantitatively anchored to 1 via
two-step reaction. In the first step, reaction of 1 with
trichloroacetonitrile in the presence of 1,8-diazabicyclo[5,
4, 0]undec-7-ene (DBU) [16] afforded the trichloroacetimide
intermediate 2. The complete conversion of the hydroxy
group of 1 to ionic-liquid-supported trichloroacetimide 2
was confirmed by treating 2 with acetyl chloride/triethyla-
mine: no acetoxy absorption band was observed in the IR
spectrum of the product. b-Hydroxyalkyl phenyl selenides
were then loaded onto the trichloroacetimide derivative of
ionic liquid 2 through the action of BF3ÁOEt2 to give ionic
liquid-supported a-phenylselenomethyl ether 3, which was
confirmed by the complete disappearance of the strong
C═N stretching band near 1662 cmÀ1. After this, the result-
ing ether 3 was subjected to the deselenation reaction directly
with 30% hydrogen peroxide at 0ꢀC and then at room temper-
ature to afford the corresponding ionic liquid-supported vinyl
ether 4, which was found to have lost all its selenium by
elemental analysis of 4, indicating the oxidation–elimination
was complete.
It is worthy of note that, in each step of the sequence, the
ionic liquid-supported intermediates were purified by
washing with diethyl ether. The excess reaction reagents
Table 1
The yields of ethyl isoxazole-3-carboxylates (6a–6k).
Entry
R
Product
Yield (%)a
1
2
3
4
5
6
7
8
C6H5
6a
6b
6c
6d
6e
6f
6g
6h
6i
82
90
90
88
86
85
84
81
80
78
78
4-CH3C6H4
4-CH3OC6H4
3-CH3OC6H4
4-ClC6H4
3-IC6H4
4-FC6H4
C6H5OCH2
C6H5CH2OCH2
CH3(CH2)3OCH2
CH3
Then, 1,3-dipolar cycloaddition of 4 with nitrile oxides
was investigated. Herein, the ionic liquid-supported vinyl
ether 4 was reacted with nitrile oxides generated in situ
from commercially available ethyl chlorooximidoacetate
in the presence of triethylamine to form ionic liquid-
supported ethyl isoxazoline-3-carboxylate 5. The formation
of the ionic liquid-supported isoxazoline 5 was also easily
monitored by IR spectroscopy for the appearance of a new
carbonyl stretching near 1720 cmÀ1. The subsequent
9
10
11
6j
6k
aOverall yields based on [2-hydemim][BF4] (1).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Synthesis of Ethyl Isoxazole-3-Carboxylates
317
Scheme 2. Suzuki reaction of 5f with phenylboronic acid.
CO2Et
CO2Et
N
CO2Et
N
C6H5B(OH)2
O
5% TFA
CH2Cl2
O
O
N
O
O
Pd(OAc)2, CsF
H2O, 80 o
C
I
5f
7
8
Preparation of ionic-liquid-supported trichloroacetimide
(2). To a solution of [2-hydemim][BF4] (1) (2.8 g, 13 mmol)
in dry CH2Cl2 (50 mL) was added trichloroaceonitrile (2.16 g,
15 mmol). After the mixture was cooled to 0ꢀC, DBU (1.0 mL,
6.5 mmol) was added slowly, and the reaction was allowed to
proceed at 0ꢀC for 40 min, the solvent was eliminated in
a rotary evaporator under reduced pressure. The resulting
crude mixture was washed three times with anhydrous ether
(15 Â 3 mL) with vigorous magnetic stirring. After decantation,
the residual solvent was removed in vacuo. The ionic liquid-
supported trichloroacetimide (2) was further dried under high
vacuum and led to a pale yellow viscous oil in 98% yield. IR
and the by-products were removed by simple decantation.
Moreover, the ionic liquid [2-hydemim][BF4] (1) could
be typically recovered (the yield of recovered 1 was
≥90%) and reused with no appreciable decrease in yields
and reaction activity.
CONCLUSIONS
In summary, we report an efficient and new method for the
synthesis of ethyl isoxazoline-3-carboxylates by 1,3-dipolar
cycloaddition of ionic liquid-supported vinyl ethers, derived
from ionic liquid-supported a-phenylselenomethyl ether, with
ethyl cyanoformate N-oxide, and subsequent cleavage from
ionic liquid support under acidic conditions. Compared with
previously reported methods, this new method using the ionic
liquid as soluble support offers many advantages such as
environmental friendliness, much higher loading capacity,
easy isolation and purification of the products, recyclability
of the soluble support, and so on. Additionally, a typical
example of Suzuki coupling reaction was applied to
prepare 5-biphenyl-substituted-isoxazoline-3-carboxylate
for extending this methodology. Further investigations
based on the ionic liquid-supported vinyl ether reagents
are now in progress.
(film): n 1662 cmÀ1
.
General procedure for the preparation of ionic liquid-
supported a-phenylselenomethyl ether (3). To a solution of
2 (5 mmol) and b-hydroxyalkyl phenyl selenide (7 mmol) in dry
CH2Cl2 (25 mL) was added a catalytic amount of BF3ÁOEt2.
The mixture was stirred at room temperature for 30 min and
then was concentrated under reduced pressure, and the resulting
crude mixture was washed with anhydrous ether (15 Â 3 mL)
and dried under vacuum to give 3.
3a. Yellow viscous oil; 1H NMR (400 MHz, acetone-d6): d 8.89
(s, 1H), 7.69 (t, J = 1.6 Hz, 1H), 7.60 (t, J = 1.6 Hz, 1H), 7.45–
7.42 (m, 2H), 7.34–7.20 (m, 8H), 4.52 (dd, J = 8.4, 5.2 Hz, 1H),
4.05 (s, 3H), 3.88 (t, J = 4.8 Hz, 2H), 3.70 (t, J = 4.8 Hz, 2H),
3.36 (dd, J = 12.4, 8.4 Hz, 1H), 3.11 (dd, J = 12.4, 5.2 Hz, 1H);
13C NMR (100 MHz, acetone-d6): d 141.1, 137.1, 132.4, 130.8,
128.9, 128.5, 128.0, 126.8, 123.6, 122.8, 119.5, 80.5, 65.0,
52.1, 37.5, 35.5; IR (film): n 3029, 2925, 1502, 1460, 1070 cmÀ1
.
EXPERIMENTAL
3b. Yellow viscous oil; 1H NMR (400 MHz, acetone-d6): d 8.89
(s, 1H), 7.69 (t, J = 1.6 Hz, 1H), 7.60 (t, J = 1.6 Hz, 1H), 7.55–7.53
(m, 2H), 7.24–7.20 (m, 3H), 7.16 (d, J= 8.4 Hz, 2H), 6.96 (d,
J= 8.4 Hz, 2H), 4.49 (dd, J=8.3, 5.3Hz, 1H), 4.05 (s, 3H), 3.87 (t,
J= 4.8 Hz, 2H), 3.69 (t, J= 4.8 Hz, 2H), 3.34 (dd, J= 12.2, 8.3 Hz,
1H), 3.09 (dd, J= 12.2, 5.3 Hz, 1H), 2.27 (s, 3H); 13C NMR
(100 MHz, acetone-d6): d 140.2, 138.2, 137.0, 129.1, 128.7, 128.6,
127.5, 127.2, 126.9, 123.3, 122.7, 80.2, 65.4, 52.4, 37.3, 35.4,
FTIR spectra were taken on a Perkin-Elmer SP One FT-IR
spectrophotometer (Waltham, MA). 1H NMR (400 MHz) and
13C NMR (75 MHz) spectra were recorded on a Bruker Avance
(400 MHz) spectrometer (Billerica, MA), using CDCl3 or
acetone-d6 as both solvent and reference. Mass spectra (EI,
70 eV) were recorded on an HP5989B mass spectrometer (Palo
Alto, CA). Microanalyses were performed with a Carlo Erba
1106 elemental analyzer (Milan, Italy). Melting points were mea-
sured on a Kofler melting point apparatus and are uncorrected.
TLCs were performed on pre-coated plates of silica gel HF254
(0.5 mm, Qindao, China). Flash column chromatography was
performed on silica gel H (Qindao, China). 1-(2-Hydroxyethyl)-
3-methylimidazolium tetrafluoroborate ([2-hydemim][BF4], 1) was
prepared according to the literature method [18]. b-Hydroxyalkyl
phenyl selenides were prepared by the reaction of benzenesele-
nolate ions with the corresponding epoxides according to the
procedure reported previously [19]. The other chemicals were
commercially available. All organic solvents were dried by
standard methods.
20.5; IR (film): n 3030, 2927, 1500, 1461, 1375, 1068 cmÀ1
.
3c. Yellow viscous oil; 1H NMR (400 MHz, acetone-d6): d 8.91
(s, 1H), 7.70 (t, J = 1.6 Hz, 1H), 7.61 (t, J = 1.6 Hz, 1H), 7.34–
7.22 (m, 5H), 7.14 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H),
4.50 (dd, J = 8.4, 5.6 Hz, 1H), 4.02 (s, 3H), 3.86 (t, J = 5.0 Hz,
2H), 3.80 (s, 3H), 3.68 (t, J = 5.0 Hz, 2H), 3.36 (dd, J = 12.4,
8.4 Hz, 1H), 3.15 (dd, J = 12.4, 5.6 Hz, 1H); 13C NMR
(100 MHz, acetone-d6): d 159.2, 137.5, 137.0, 135.4, 129.6,
129.2, 128.8, 127.3, 123.5, 122.8, 117.1, 79.8, 65.6, 54.8, 52.7,
36.8, 35.6; IR (film): n 3028, 2925, 1505, 1464, 1378, 1065 cmÀ1
.
3d. Yellow viscous oil; 1H NMR (400 MHz, acetone-d6): d
8.90 (s, 1H), 7.69 (t, J = 1.6 Hz, 1H), 7.60 (t, J = 1.6 Hz, 1H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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S. Sheng, W. Sheng, Q. Hu, H. Qu, and M. Cai
Vol 51
7.42–7.37 (m, 3H), 7.32–7.18 (m, 5H), 7.06 (s, 1H), 4.50 (dd,
J = 8.3, 5.8 Hz, 1H), 4.03 (s, 3H), 3.90 (t, J = 4.8 Hz, 2H), 3.82
(s, 3H), 3.70 (t, J = 4.8 Hz, 2H), 3.36 (dd, J = 12.2, 8.3 Hz, 1H),
3.15 (dd, J = 12.2, 5.8 Hz, 1H); 13C NMR (100 MHz, acetone-
d6): d 155.6, 137.1, 135.5, 130.8, 129.4, 128.7, 127.8, 127.1,
123.5, 122.8, 120.8, 117.5, 112.2, 80.1, 65.5, 55.2, 52.5, 36.7,
(m, 2H), 7.30–7.25 (m, 3H), 4.02 (s, 3H), 3.95 (t, J=5.0Hz, 2H),
3.73–3.65 (m, 3H), 3.22 (dd, J= 12.3, 6.0 Hz, 1H), 3.09 (dd,
J= 12.3, 5.8 Hz, 1H), 1.06 (d, J=7.0Hz, 3H); 13C NMR
(100 MHz, acetone-d6): d 137.3, 135.7, 129.3, 128.8, 127.3, 123.4,
122.4, 77.4, 65.3, 52.3, 36.4, 34.5, 21.5; IR (film): n 3035, 2930,
1498, 1380, 1058 cmÀ1
.
35.4; IR (film): n 3027, 2926, 1503, 1465, 1375, 1062 cmÀ1
.
General procedure for the preparation of ionic liquid-
supported vinyl ethers (4a–4k). To a solution of 3 (5 mmol)
in CH2Cl2 (20 mL) was added 30% (aq) H2O2 (1.5 mL,
14.5 mmol), and the mixture was stirred for 30 min at 0ꢀC,
followed by 1 h at room temperature. After completion of the
reaction, the solvent was evaporated and the crude mixture was
washed with anhydrous ether (15 Â 3 mL) and dried under
vacuum to give 4.
1
3e. Pale yellow solid, mp 68–70ꢀC; H NMR (400 MHz, ace-
tone-d6): d 8.93 (s, 1H), 7.71–7.65 (m, 3H), 7.65 (t, J = 1.6 Hz,
1H), 7.39 (d, J = 8.8 Hz, 2H), 7.35–7.21 (m, 5H), 4.50 (dd,
J = 8.2, 5.9Hz, 1H), 4.06 (s, 3H), 3.90 (t, J= 5.0 Hz, 2H), 3.72
(t, J= 5.0 Hz, 2H), 3.28 (dd, J= 12.5, 8.2 Hz, 1H), 3.17 (dd,
J= 12.5, 5.9 Hz, 1H); 13C NMR (100 MHz, acetone-d6): d
139.5, 136.5, 134.8, 129.8, 129.1, 128.8, 128.4, 128.0, 127.2,
123.6, 122.7, 79.8, 65.3, 52.4, 36.6, 35.7; IR (KBr): n 3033, 2928,
4a. Colorless viscous oil; 1H NMR (400 MHz, acetone-
d6): d 9.00 (s, 1H), 7.78 (t, J = 1.7 Hz, 1H), 7.65 (t,
J = 1.7 Hz, 1H), 7.16–7.12 (m, 3H), 6.98–6.95 (m, 2H), 4.68 (d,
J = 3.0Hz, 1H), 4.25 (d, J = 3.0 Hz, 1H), 4.04 (s, 3H), 3.95 (t,
J = 4.6Hz, 2H), 3.77 (t, J = 4.6 Hz, 2H); 13C NMR (100
1509, 1468, 1071 cmÀ1
.
1
3f. Pale yellow solid, mp 85–87ꢀC; H NMR (400 MHz, ace-
tone-d6): d 8.92 (s, 1H), 7.67 (t, J = 1.6 Hz, 1H), 7.59 (t,
J = 1.6 Hz, 1H), 7.48–6.40 (m, 2H), 7.37–7.23 (m, 5H), 7.05–
6.95 (m, 2H), 4.50 (dd, J = 8.3, 5.8 Hz, 1H), 4.05 (s, 3H), 3.89
(t, J = 4.8 Hz, 2H), 3.70 (t, J = 4.8 Hz, 2H), 3.32 (dd, J = 12.7,
8.3 Hz, 1H), 3.15 (dd, J = 12.7, 5.8 Hz, 1H); 13C NMR
(100 MHz, acetone-d6): d 139.5, 137.0, 136.5, 132.2, 131.0,
129.3, 128.9, 127.4, 127.3, 126.2, 123.8, 122.9, 97.1, 80.1,
65.6, 52.5, 36.8, 35.5; IR (KBr): n 3031, 2926, 1505, 1466,
MHz, acetone-d6):
127.3, 123.6, 122.8, 86.5, 62.9, 49.2, 35.5; IR (film): n
3031, 2876, 1610, 1240, 994, 912 cmÀ1
d 153.4, 137.2, 131.5, 129.8, 128.1,
.
4b. Colorless viscous oil; 1H NMR (400 MHz, acetone-d6): d
9.01 (s, 1H), 7.79 (t, J = 1.7 Hz, 1H), 7.67 (t, J = 1.7 Hz, 1H), 7.52
(d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 4.70 (d, J = 3.6 Hz,
1H), 4.36 (d, J = 3.6 Hz, 1H), 4.03 (s, 3H), 3.94 (t, J = 4.6 Hz,
2H), 3.72 (t, J = 4.6 Hz, 2H), 2.40 (s, 3H); 13C NMR
(100 MHz, acetone-d6): d 153.7, 140.5, 137.0, 129.0, 128.8,
127.1, 123.5, 122.4, 86.8, 62.6, 49.1, 35.4, 21.5; IR (film): n
1068 cmÀ1
.
1
3g. Pale yellow solid, mp 57–59ꢀC; H NMR (400 MHz, ace-
tone-d6): d 8.90 (s, 1H), 7.67 (t, J = 1.6 Hz, 1H), 7.60 (t,
J = 1.6 Hz, 1H), 7.50–7.45 (m, 2H), 7.35–7.15 (m, 7H), 4.47
(dd, J = 8.4, 5.8Hz, 1H), 4.03 (s, 3H), 3.92 (t, J= 4.8 Hz, 2H),
3.70 (t, J= 4.8 Hz, 2H), 3.32 (dd, J= 12.6, 8.4 Hz, 1H), 3.15 (dd,
J= 12.6, 5.8 Hz, 1H); 13C NMR (100 MHz, acetone-d6): d 163.6
3032, 2878, 1612, 1378, 1240, 990, 824 cmÀ1
.
4c. Colorless viscous oil; 1H NMR (400 MHz, acetone-d6): d
9.89 (s, 1H), 7.77 (t, J = 1.7 Hz, 1H), 7.67 (t, J = 1.7 Hz, 1H), 7.65
(d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 4.73 (d, J = 3.8 Hz,
1H), 4.35 (d, J = 3.8 Hz, 1H), 4.02 (s, 3H), 3.95 (t, J = 4.6 Hz,
2H), 3.83 (s, 3H), 3.72 (t, J = 4.6 Hz, 2H); 13C NMR
(100 MHz, acetone-d6): d 154.2, 153.3, 136.8, 127.8, 123.6,
122.6, 118.8, 116.5, 86.8, 62.3, 54.5, 49.0, 35.7; IR (film): n
1
(d, Jc-F = 250.0 Hz), 139.8, 136.7, 129.5, 129.3, 128.9, 127.1,
124.2, 123.5, 122.5, 116.8 (d, 3Jc-F = 4.2 Hz), 80.3, 65.6, 52.4, 36.7,
35.3; IR (KBr): n 3032, 2923, 1505, 1465, 1175, 1135, 1062 cmÀ1
.
3h. Yellow viscous oil; 1H NMR (400 MHz, acetone-d6): d 8.86
(s, 1H), 7.67 (t, J= 1.6 Hz, 1H), 7.61 (t, J= 1.6Hz, 1H), 7.52–7.50
(m, 2H), 7.30–7.20 (m, 5H), 7.01–7.92 (m, 3H), 4.15–4.09 (m,
3H), 4.05 (s, 3H), 3.92 (t, J= 5.0Hz, 2H), 3.70 (t, J= 5.0 Hz, 2H),
3.24 (dd, J = 12.8, 6.4 Hz, 1H), 3.18 (dd, J= 12.8, 5.8 Hz, 1H); 13C
NMR (100 MHz, acetone-d6): d 150.5, 137.1, 132.6, 129.4, 129.1,
128.8, 127.0, 123.6, 122.8, 121.0, 117.5, 76.8, 69.1, 65.0, 52.1,
3036, 2978, 1610, 1375, 1242, 994, 834 cmÀ1
.
4d. Colorless viscous oil; 1H NMR (400 MHz, acetone-d6): d
9.88 (s, 1H), 7.76 (t, J = 1.7 Hz, 1H), 7.67 (t, J = 1.7 Hz, 1H),
7.45–7.38 (m, 3H), 7.10 (s, 1H), 4.72 (d, J = 3.8 Hz, 1H), 4.36
(d, J = 3.8 Hz, 1H), 4.02 (s, 3H), 3.94 (t, J = 4.6 Hz, 2H), 3.84
(s, 3H), 3.73 (t, J = 4.6 Hz, 2H); 13C NMR (100 MHz, acetone-
d6): d 155.6, 153.5, 136.8, 130.2, 127.7, 123.6, 122.6, 120.1,
116.7, 112.8, 86.7, 62.3, 55.0, 49.1, 35.6; IR (film): n 3032,
36.5, 30.2; IR (film): n 3027, 2922, 1500, 1460, 1065 cmÀ1
.
3i. Yellow viscous oil; 1H NMR (400 MHz, acetone-d6): d 8.88
(s, 1H), 7.68 (t, J= 1.6 Hz, 1H), 7.60 (t, J= 1.6Hz, 1H), 7.50–7.47
(m, 2H), 7.37–7.20 (m, 8H), 4.50 (s, 2H), 4.06 (dt, J= 5.8, 1.6 Hz,
2H), 4.05 (s, 3H), 3.92 (t, J= 5.0 Hz, 2H), 3.74–3.70 (m, 3H), 3.15
(dd, J= 12.5, 6.0 Hz, 1H), 3.10 (dd, J= 12.6, 5.8 Hz, 1H); 13C
NMR (100 MHz, acetone-d6): d 138.5, 137.1, 132.6, 130.4, 129.0,
128.3, 127.6, 127.5, 126.8, 123.5, 122.7, 77.5, 73.3, 71.1, 65.2,
2982, 1612, 1377, 1240, 965 cmÀ1
.
4e. White solid, mp 137–139ꢀC; 1H NMR (400 MHz, acetone-
d6): d 9.91 (s, 1H), 7.78 (t, J = 1.7 Hz, 1H), 7.68 (t, J = 1.7 Hz,
1H), 7.68 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 4.75
(d, J = 3.6 Hz, 1H), 4.41 (d, J = 3.6 Hz, 1H), 4.04 (s, 3H), 3.92
(t, J = 4.6 Hz, 2H), 3.75 (t, J = 4.6 Hz, 2H); 13C NMR
(100 MHz, acetone-d6): d 153.5, 137.0, 136.2, 129.5, 128.3,
126.8, 123.5, 122.6, 86.9, 62.5, 49.2, 35.6; IR (KBr): n 3036,
52.3, 36.5, 29.5; IR (film): n 3028, 2923, 1501, 1458, 1066 cmÀ1
.
3j. Yellow viscous oil; 1H NMR (400 MHz, acetone-d6): d 8.89
(s, 1H), 7.67 (t, J= 1.6 Hz, 1H), 7.62 (t, J= 1.6Hz, 1H), 7.52–7.50
(m, 2H), 7.30–7.25 (m, 3H), 4.10 (dt, J= 6.0, 1.8 Hz, 2H), 4.02 (s,
3H), 3.93 (t, J= 5.0 Hz, 2H), 3.73–3.69 (m, 3H), 3.27 (t, J=7.0Hz,
2H), 3.27 (dd, J= 12.3, 6.0 Hz, 1H), 3.09 (dd, J= 12.3, 5.8 Hz, 1H),
1.55–1.50 (m, 2H), 1.38–1.32 (m, 2H), 0.92 (t, J= 6.8 Hz, 3H); 13C
NMR (100 MHz, acetone-d6): d 137.0, 135.2, 129.2, 128.7, 127.2,
123.3, 122.5, 80.4, 73.4, 70.1, 65.2, 52.3, 36.3, 34.1, 32.9, 20.5,
2980, 1608, 1445, 1240, 996, 845 cmÀ1
.
4f. White solid, mp 152–154ꢀC; 1H NMR (400 MHz, acetone-
d6): d 9.90 (s, 1H), 8.10 (s, 1H), 7.78–776 (m, 2H), 7.70 (t,
J = 1.7 Hz, 1H), 7.37–7.28 (m, 2H), 4.80 (d, J = 3.4 Hz, 1H),
4.42 (d, J = 3.4 Hz, 1H), 4.04 (s, 3H), 3.93 (t, J = 4.6 Hz, 2H),
3.75 (t, J = 4.6 Hz, 2H); 13C NMR (100 MHz, acetone-d6): d
154.2, 139.0, 137.0, 134.3, 130.2, 129.0, 127.2, 125.6, 123.7,
122.7, 87.2, 62.6, 50.3, 35.7; IR (KBr): n 3045, 2980, 1611,
15.1; IR (film): n 3035, 2928, 1378, 1060 cmÀ1
.
3k. Yellow viscous oil; 1H NMR (400 MHz, acetone-d6): d 8.88
(s, 1H), 7.66 (t, J= 1.6 Hz, 1H), 7.62 (t, J= 1.6Hz, 1H), 7.52–7.50
1446, 1243, 990 cmÀ1
.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Synthesis of Ethyl Isoxazole-3-Carboxylates
319
4g. White solid, mp 126–128ꢀC; 1H NMR (400 MHz, acetone-
d6): d 9.90 (s, 1H), 7.77 (t, J = 1.7 Hz, 1H), 7.67 (t, J = 1.7Hz, 1H),
7.70 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 4.78
(d, J = 3.6Hz, 1H), 4.45 (d, J = 3.6 Hz, 1H), 4.03 (s, 3H), 3.91
(t, J = 4.6 Hz, 2H), 3.74 (t, J =4.6Hz, 2H); 13C NMR (100 MHz,
156.3, 141.0, 136.9, 130.1, 127.5, 126.2, 123.3, 122.7, 102.8,
65.2, 63.4, 52.3, 44.4, 35.5, 20.2, 13.8; IR (KBr): n 3178, 2986,
1742, 1365, 1209, 910, 862 cmÀ1
.
1
5c. Pale yellow solid, mp 122–124ꢀC; H NMR (400 MHz,
acetone-d6): d 8.91 (s, 1H), 7.86 (t, J = 1.7 Hz, 1H), 7.70
(t, J = 1.7 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz,
2H), 4.48 (t, J = 5.0 Hz, 2H), 4.03 (s, 3H), 3.94 (t, J = 5.0 Hz,
2H), 3.81 (s, 3H), 4.36 (q, J = 7.2 Hz, 2H), 3.50 (s, 2H), 1.34
1
acetone-d6): d 164.0 (d, Jc-F = 250.4 Hz), 153.8, 137.1, 129.5,
125.8, 123.5, 122.6, 117.8 (d, 3Jc-F = 4.2 Hz), 86.9, 62.7, 49.9, 35.6;
IR (KBr): n 3036, 2980, 1608, 1445, 1240, 1135, 996, 845 cmÀ1
.
4h. White solid, mp 67–69ꢀC; 1H NMR (400 MHz, acetone-
d6): d 9.87 (s, 1H), 7.72 (t, J = 1.7 Hz, 1H), 7.64 (t, J = 1.7 Hz,
1H), 7.50–7.47(m, 2H), 7.26–7.18 (m, 3H), 4.95 (d, J = 3.8 Hz,
1H), 4.56 (d, J = 3.8 Hz, 1H), 4.42 (s, 2H), 4.03 (s, 3H), 3.95
(t, J = 4.6 Hz, 2H), 3.72 (t, J = 4.6 Hz, 2H); 13C NMR
(100 MHz, acetone-d6): d 154.0, 137.0, 130.8, 123.6, 123.3,
122.6, 121.6, 115.0, 86.3, 65.6, 62.4, 49.1, 35.4; IR (film): n
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, acetone-d6):
d
168.1, 159.4, 156.0, 136.8, 128.7, 123.5, 122.5, 121.5, 115.4,
103.0, 65.3, 63.5, 55.4, 52.2, 44.1, 35.6, 13.9; IR (KBr): n
3201, 2981, 1746, 1605, 1362, 1209, 911, 846 cmÀ1
.
1
5d. Pale yellow solid, mp 101–103ꢀC; H NMR (400 MHz,
acetone-d6): d 8.90 (s, 1H), 7.87 (t, J = 1.7 Hz, 1H), 7.69
(t, J = 1.7 Hz, 1H), 7.42–7.26 (m, 3H), 6.98 (s, 1H), 4.48 (t,
J = 5.0 Hz, 2H), 4.03 (s, 3H), 3.95 (t, J = 5.0 Hz, 2H), 3.83
(s, 3H), 4.40 (q, J = 7.2 Hz, 2H), 3.54 (s, 2H), 1.32
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, acetone-d6): d 168.2,
159.0, 156.2, 137.0, 130.0, 129.7, 123.5, 122.5, 120.2, 117.4,
111.2, 103.2, 65.4, 63.5, 55.3, 52.4, 43.9, 35.5, 14.1; IR (KBr):
n 3430, 2980, 1740, 1608, 1364, 1296, 1219, 1078, 913,
3132, 2928, 1618, 1378, 1242, 965 cmÀ1
.
4i. White solid, mp 70–72ꢀC; 1H NMR (400 MHz, acetone-d6):
d 9.86 (s, 1H), 7.70 (t, J = 1.7 Hz, 1H), 7.62 (t, J = 1.7 Hz, 1H),
7.51–7.47 (m, 2H), 7.30–7.20 (m, 3H), 4.92 (d, J = 3.8 Hz,
1H), 4.53 (d, J = 3.8 Hz, 1H), 4.40 (s, 2H), 4.07 (s, 2H), 4.03
(s, 3H), 3.95 (t, J = 4.6 Hz, 2H), 3.72 (t, J = 4.6 Hz, 2H); 13C
NMR (100 MHz, acetone-d6): d 154.2, 137.1, 130.5, 129.0,
128.2, 125.8, 123.5, 122.6, 86.3, 73.4, 66.6, 62.4, 49.0, 35.5; IR
756 cmÀ1
.
5e. Pale yellow solid, mp 135–137ꢀC; 1H NMR (400 MHz,
acetone-d6): d 8.92 (s, 1H), 7.89 (t, J = 1.7 Hz, 1H), 7.71
(t, J = 1.7 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz,
2H), 4.51 (t, J = 5.0 Hz, 2H), 4.05 (s, 3H), 3.96 (t, J = 5.0 Hz,
2H), 4.40 (q, J= 7.0 Hz, 2H), 3.62 (s, 2H), 1.35 (t, J= 7.0 Hz, 3H);
13C NMR (100 MHz, acetone-d6): d 167.8, 155.7, 137.0, 135.5,
128.9, 128.6, 127.8, 123.6, 122.7, 103.8, 65.5, 62.1, 52.4, 44.5, 35.6,
(film): n 3135, 2930, 1620, 1375, 1240, 967 cmÀ1
.
4j. White solid, mp 46–48ꢀC; 1H NMR (400 MHz, acetone-d6):
d 8.87 (s, 1H), 7.69 (t, J = 1.6 Hz, 1H), 7.62 (t, J = 1.6 Hz, 1H),
4.92 (d, J = 3.8 Hz, 1H), 4.53 (d, J = 3.8 Hz, 1H), 4.12 (s, 2H),
4.02 (s, 3H), 3.95 (t, J = 4.6 Hz, 2H), 3.72 (t, J = 4.6 Hz, 2H),
3.32 (t, J = 7.0 Hz, 2H), 1.53–1.50 (m, 2H), 1.36–1.32 (m, 2H),
0.94 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, acetone-d6): d
154.8, 137.0, 123.4, 122.5, 86.4, 74.4, 73.1, 62.2, 49.3, 35.3,
14.1; IR (KBr): n 3190, 2985, 1748, 1365, 1230, 1139, 917, 865 cmÀ1
.
5f. Pale yellow solid, mp 156–158ꢀC; 1H NMR (400 MHz,
acetone-d6): d 8.91 (s, 1H), 7.88 (t, J = 1.7 Hz, 1H), 7.70
(t, J= 1.7Hz, 1H), 7.48–6.40 (m, 3H), 7.03 (s, 1H), 4.50 (t,
J= 5.0 Hz, 2H), 4.03 (s, 3H), 3.95 (t, J = 5.0Hz, 2H), 4.38 (q,
J= 7.2 Hz, 2H), 3.60 (s, 2H), 1.37 (t, J= 7.2 Hz, 3H); 13C NMR
(100 MHz, acetone-d6): d 166.5, 155.4, 137.1, 139.0, 134.3, 130.2,
129.0, 127.2, 125.6, 123.5, 122.6, 104.1, 65.4, 62.6, 52.2, 43.9, 35.6,
32.7, 19.8, 14.8; IR (film): n 3131, 2928, 1378, 1058 cmÀ1
.
1
4k. Colorless viscous oil; H NMR (400 MHz, acetone-d6): d
8.89 (s, 1H), 7.67 (t, J = 1.6 Hz, 1H), 7.64 (t, J = 1.6 Hz, 1H), 4.62
(d, J = 3.2 Hz, 1H), 4.43 (d, J = 3.2 Hz, 1H), 4.03 (s, 3H), 3.95 (t,
J = 4.8 Hz, 2H), 3.72 (t, J = 4.8 Hz, 2H), 2.16 (s, 3H); 13C NMR
(100 MHz, acetone-d6): d 152.8, 137.0, 123.5, 122.6, 85.4, 62.4,
49.1, 35.3, 22.5; IR (film): n 3045, 2830, 1365, 1050 cmÀ1
.
14.1; IR (KBr): n 3187, 2981, 1749, 1362, 1290, 1203, 923, 861 cmÀ1
.
Ionic liquid-supported isoxazolines 5—General procedure for the
preparation of ionic-liquid-supported vinyl ethers (5a–5k). To
a stirred solution of 4 (5 mmol) in dry CH2Cl2 (20 mL) was first
added Et3N (2.1 mL, 15 mmol). Then ethyl chlorooximidoacetate
(2.2 g, 14.5 mmol) was dissolved in dry CH2Cl2 (10 mL) and
added via syringe over 1 h, and the mixture was finally stirred
overnight under nitrogen atmosphere at room temperature. After
completion of the reaction, the solvent was evaporated, and the
crude mixture was washed with anhydrous ether (15 Â 3 mL) and
dried under vacuum to give 5.
5g. Pale yellow solid, mp 127–129ꢀC; 1H NMR (400 MHz,
acetone-d6): d 8.90 (s, 1H), 7.87 (t, J = 1.7 Hz, 1H), 7.69
(t, J = 1.7 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz,
2H), 4.52 (t, J = 4.8 Hz, 2H), 4.04 (s, 3H), 3.95 (t, J = 4.8 Hz,
2H), 4.35 (q, J = 7.2 Hz, 2H), 3.65 (s, 2H), 1.35
(t, J=7.2Hz, 3H); 13C NMR (100 MHz, acetone-d6): d 168.0, 163.9
(d, 1Jc-F = 249.5 Hz), 162.5, 155.5, 137.1, 129.4, 123.6, 122.7, 116.6
3
(d, Jc-F = 4.3 Hz), 103.6, 65.5, 63.8, 52.4, 44.3, 35.5, 14.4; IR
(KBr): n 3192, 1747, 1361, 1292, 1208, 1135, 918, 866 cmÀ1
.
5h. Pale yellow solid, mp 60–62ꢀC; 1H NMR (400 MHz, ace-
tone-d6): d 8.90 (s, 1H), 7.86 (t, J = 1.7Hz, 1H), 7.68 (t, J = 1.7 Hz,
1H), 7.51–7.46 (m, 2H), 7.27–7.20 (m, 3H), 4.50 (t, J = 5.0Hz,
2H), 4.04 (s, 3H), 3.95 (t, J= 5.0 Hz, 2H), 4.36 (q, J=7.2Hz, 2H),
3.52 (s, 2H), 3.40 (s, 2H), 1.35 (t, J= 7.2 Hz, 3H); 13C NMR
(100 MHz, acetone-d6): d 166.1, 155.2, 137.0, 131.2, 124.3, 123.5,
122.6, 121.2, 115.5, 102.7, 65.6, 63.5, 62.4, 52.4, 45.7, 35.6, 13.8;
1
5a. Pale yellow solid, mp 132–134ꢀC; H NMR (400 MHz,
acetone-d6): d 8.92 (s, 1H), 7.90 (t, J = 1.7 Hz, 1H), 7.01 (t,
J = 1.7Hz, 1H), 7.50–7.43 (m, 2H), 7.30–7.21 (m, 3H), 4.51
(t, J = 5.0 Hz, 2H), 4.02 (s, 3H), 3.97 (t, J = 5.0 Hz, 2H), 4.35 (q,
J = 7.2Hz, 2H), 3.50 (s, 2H), 1.35 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, acetone-d6): d 168.3, 156.6, 136.8, 130.7, 128.9,
128.5, 126.8, 123.2, 122.6, 102.5, 65.0, 63.5, 52.1, 44.8, 35.6,
IR (KBr): n 3038, 2982, 1750, 1363, 1280, 1205, 963 cmÀ1
.
14.0; IR (KBr): n 3230, 2987, 1742, 1448, 1215 cmÀ1
.
5i. Pale yellow solid, mp 65–67ꢀC; 1H NMR (400 MHz, acetone-
d6): d 8.89 (s, 1H), 7.87 (t, J= 1.7 Hz, 1H), 7.68 (t, J= 1.7 Hz, 1H),
7.50–7.45 (m, 2H), 7.28–7.20 (m, 3H), 4.50 (t, J= 5.0 Hz, 2H),
4.03 (s, 3H), 3.95 (t, J= 5.0 Hz, 2H), 4.35 (q, J = 7.2Hz, 2H), 3.56
(s, 2H), 3.44 (s, 2H), 3.37 (s, 2H), 1.36 (t, J=7.2Hz, 3H); 13C
NMR (100 MHz, acetone-d6): d 165.3, 155.4, 137.0, 130.6, 129.3,
128.0, 126.8, 123.5, 122.6, 102.8, 65.5, 64.5, 63.1, 62.4, 52.6,
5b. Pale yellow solid, mp 137–139ꢀC; 1H NMR (400 MHz,
acetone-d6): d 8.90 (s, 1H), 7.87 (t, J = 1.7 Hz, 1H), 7.68
(t, J = 1.7 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz,
2H), 4.50 (t, J = 5.0 Hz, 2H), 4.03 (s, 3H), 3.96 (t, J = 5.0 Hz,
2H), 4.35 (q, J = 7.2 Hz, 2H), 3.51 (s, 2H), 2.34 (s, 3H), 1.35
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, acetone-d6): d 168.2,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

320
S. Sheng, W. Sheng, Q. Hu, H. Qu, and M. Cai
Vol 51
45.4, 35.5, 13.9; IR (KBr): n 3036, 2984, 1747, 1365, 1278, 1206,
965 cmÀ1
(q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 170.4, 160.7, 157.3, 136.5, 129.3, 128.1,
126.2, 100.3, 62.4, 14.2; MS (EI): m/z 251 (M+); Anal. Calcd
for C12H10ClNO3: C, 57.27; H, 4.01; N, 5.57. Found: C, 57.16;
H, 4.10; N, 5.51; IR (KBr): n 3132, 2983, 1728, 1606, 1448,
.
5j. Pale yellow viscous oil; 1H NMR (400 MHz, acetone-d6): d
8.86 (s, 1H), 7.86 (t, J= 1.7 Hz, 1H), 7.66 (t, J= 1.7 Hz, 1H), 4.49 (t,
J= 5.0Hz, 2H), 4.02 (s, 3H), 3.96 (t, J = 5.0 Hz, 2H), 4.36
(q, J= 7.2 Hz, 2H), 3.56 (s, 2H), 4.36 (s, 2H), 3.35 (t, J=7.0Hz,
2H), 1.55–1.53 (m, 2H), 1.38–1.34 (m, 5H), 0.95 (t, J=6.8Hz,
3H); 13C NMR (100 MHz, acetone-d6): d 165.0, 155.1, 137.0,
123.6, 122.4, 103.2, 74.0, 67.8, 65.6, 62.4, 52.5, 44.6, 35.6, 32.5,
1250, 1024, 828, 762 cmÀ1
.
Ethyl 5-(3-iodophenyl)isoxazole-3-carboxylate (6f).Colorless
solid, mp 131–133ꢀC; 1H NMR (400 MHz, CDCl3): d 8.15 (s, 1H),
7.80 (t, J= 8.0 Hz, 1H), 7.28–7.24 (m, 2H), 6.95 (s, 1H), 4.48 (q,
J=7.0Hz, 2H), 1.45 (t, J= 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 169.8, 159.8, 156.8, 139.5, 134.3, 130.6, 129.3, 125.1,
127.2, 100.5, 62.3, 14.2; MS (EI): m/z 343 (M+); Anal. Calcd for
C12H10INO3: C, 42.01; H, 2.94; N, 4.08. Found: C, 41.94; H, 3.03;
20.2, 15.0, 13.8; IR (film): n 3045, 2980, 1744, 1375, 1106 cmÀ1
.
1
5k. Colorless viscous oil; H NMR (400 MHz, acetone-d6): d
8.88 (s, 1H), 7.88 (t, J = 1.7 Hz, 1H), 7.67 (t, J = 1.7 Hz, 1H), 4.50
(t, J = 5.0 Hz, 2H), 4.03 (s, 3H), 3.97 (t, J = 5.0 Hz, 2H), 4.35
(q, J = 7.2 Hz, 2H), 3.61 (s, 2H), 2.22 (s, 3H), 1.35
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, acetone-d6): d 164.8,
155.3, 137.0, 123.5, 122.6, 103.0, 65.6, 62.2, 52.5, 44.6, 35.6,
N, 4.02; IR (KBr): n 3120, 2980, 1725, 1445, 1278, 1250 cmÀ1
.
Ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate (6g).Brown-
1
ish solid, mp 108–110ꢀC; H NMR (400 MHz, CDCl3): d 7.85–
22.6, 13.8; IR (film): n 3035, 2828, 1380, 1052 cmÀ1
.
7.81 (m, 2H), 7.26–7.22 (m, 2H), 6.91 (s, 1H), 4.45 (q,
General procedure for the preparation of ethyl isoxazole-3-
carboxylates (6a–6k). To a solution of 5 (5 mmol) in CH2Cl2
(20 mL) was added trifluoroacetic acid (5%) and following
stirring for 30 min. After removing the solvent under reduced
pressure, the residue was extracted with ether (15 Â 3 mL). The
combined ether extracts were concentrated and the crude
solution was purified by flash chromatography (silica gel,
n-hexane-EtOAc, 10 : 1 to 3 : 1) to give the products 6a–6k.
Ethyl 5-phenylisoxazole-3-carboxylate (6a).Colorless oil; 1H
NMR (400 MHz, CDCl3): d 7.80–7.78 (m, 2H), 7.44–7.41 (m,
3H), 6.91 (s, 1H), 4.45 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): d 169.5, 160.2, 156.8,
130.9, 129.8, 128.2, 127.3, 100.7, 62.6, 14.5; MS (EI): m/z 217
(M+); Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45.
Found: C, 66.26; H, 5.17; N, 6.39; IR (film): n 3328, 2982,
J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
1
CDCl3): d 169.2, 163.8 (d, Jc-F = 250.6 Hz), 159.6, 156.5,
3
129.5, 124.3, 117.0 (d, Jc-F = 4.2 Hz), 100.7, 62.4, 14.3; MS
(EI): m/z 235 (M+); Anal. Calcd for C12H10FNO3: C, 61.28; H,
4.28; N, 5.96. Found: C, 61.20; H, 4.36; N, 5.91; IR (KBr): n
3133, 2986, 1728, 1445, 1245, 1022, 828 cmÀ1
.
Ethyl 5-phenoxymethylisoxazole-3-carboxylate (6h).Yellow
oil; 1H NMR (400 MHz, CDCl3): d 7.35–7.29 (m, 2H), 6.90–
6.79 (m, 3H), 6.87 (s, 1H), 4.52 (s, 2H), 4.45 (q, J = 7.0 Hz,
2H), 1.44 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
172.4, 160.2, 156.4, 130.6, 123.3, 121.8, 114.8, 101.2, 68.3,
62.1, 13.8; MS (EI): m/z 247 (M+); Anal. Calcd for C13H13NO4:
C, 63.15; H, 5.30; N, 5.67. Found: C, 63.05; H, 5.38; N, 5.60;
IR (film): n 3130, 2928, 1731, 1590, 1455, 1250, 1060 cmÀ1
.
Ethyl 5-benzyloxymethylisoxazole-3-carboxylate (6i).Yellow
oil; 1H NMR (400 MHz, CDCl3): d 7.50–7.42 (m, 2H), 7.37–
7.27 (m, 3H), 6.88 (s, 1H), 4.56 (s, 2H), 4.45 (q, J=7.0Hz, 2H),
3.75 (s, 2H), 1.45 (t, J= 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 171.8, 160.0, 156.2, 128.0, 127.5, 127.2, 122.1 101.8, 70.0, 62.4,
57.8, 14.3; MS (EI): m/z 261 (M+); Anal. Calcd for C14H15NO4: C,
64.36; H, 5.79; N, 5.36. Found: C, 64.28; H, 5.85; N, 5.30; IR (film):
1726, 1448, 1245, 1024 cmÀ1
.
Ethyl 5-(4-methylphenyl)isoxazole-3-carboxylate (6b).Pale
yellow solid; mp 107–109ꢀC; 1H NMR (400 MHz, CDCl3): d
7.72 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 6.90 (s, 1H),
4.45 (q, J = 7.2 Hz, 2H), 2.41 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d 169.3, 160.0, 156.9, 140.7,
129.3, 128.8, 127.2, 100.7, 62.7, 21.6, 14.5; MS (EI): m/z 231
(M+); Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67; N, 6.06.
Found: C, 67.44; H, 5.76; N, 6.01; IR (KBr): n 3430, 2985,
n 3132, 2925, 1730, 1589, 1456, 1248, 1061 cmÀ1
.
Ethyl 5-(n-buoxymethyl)isoxazole-3-carboxylate (6j).Color-
less oil; 1H NMR (400 MHz, CDCl3): d 6.85 (s, 1H), 4.50 (s,
2H), 4.42 (q, J = 7.2 Hz, 2H), 3.61 (t, J = 7.0 Hz, 2H), 1.76–1.70
(m, 2H), 1.45 (t, J = 7.2 Hz, 3H), 1.38–1.32 (m, 2H), 0.95
(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 170.7,
159.5, 156.0, 100.4, 70.1, 62.4, 56.3, 31.6, 19.2, 14.4, 13.8; MS
(EI): m/z 227 (M+); Anal. Calcd for C11H17NO4: C, 58.14; H,
7.54; N, 6.16. Found: C, 58.06; H, 7.62; N, 6.11; IR (film): n
1728, 1447, 1290, 1248, 1020, 820 cmÀ1
.
Ethyl 5-(4-methoxyphenyl)isoxazole-3-carboxylate (6c).Yellow
1
oil; H NMR (400 MHz, CDCl3): d 7.71 (d, J =8.4Hz, 2H), 7.25
(d, J= 8.4 Hz, 2H), 6.88 (s, 1H), 4.45 (q, J= 7.2Hz, 2H), 3.85 (s,
3H), 1.45 (t, J= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
169.4, 160.5, 157.1, 154.5, 127.3, 118.6, 113.8, 100.5, 62.5, 54.4,
14.0; MS (EI): m/z 247 (M+); Anal. Calcd for C13H13NO4: C,
63.15; H, 5.30; N, 5.67. Found: C, 63.07; H, 5.38; N, 5.60; IR (film):
2928, 1735, 1250, 1055 cmÀ1
.
1
Ethyl 5-Methylisoxazole-3-carboxylate (6k).Colorless oil; H
NMR (400 MHz, CDCl3): d 6.87 (s, 1H), 4.44 (q, J = 7.2 Hz,
2H), 2.70 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 170.1, 159.2, 155.8, 100.6, 62.2, 24.6, 14.5; MS
(EI): m/z 155 (M+); Anal. Calcd for C7H9NO3: C, 54.19; H,
5.85; N, 9.03. Found: C, 54.09; H, 5.92; N, 9.00; IR (film): n
n 3438, 2980, 1730, 1455, 1283, 1250, 1030, 830, 765 cmÀ1
.
Ethyl 5-(3-methoxyphenyl)isoxazole-3-carboxylate (6d).Yel-
low oil; 1H NMR (400 MHz, CDCl3): d 7.45–7.42 (m, 2H),
7.37–7.34 (m, 1H), 7.07–7.04 (m, 1H), 6.89 (s, 1H), 4.45 (q,
J = 7.2 Hz, 2H), 3.85 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 170.6, 161.7, 158.4, 156.6, 130.2, 127.6,
119.4, 116.6, 111.9, 100.2, 62.2, 55.3, 14.4; MS (EI): m/z 247
(M+); Anal. Calcd for C13H13NO4: C, 63.15; H, 5.30; N, 5.67.
Found: C, 63.06; H, 5.39; N, 5.61; IR (film): n 3445, 2978,
2927, 1733, 1246, 1048 cmÀ1
.
Procedure for the preparation of ethyl 5-(3-phenylphenyl)
isoxazole-3-carboxylate (8). To a solution of ionic liquid-
supported ethyl 5-(3-iodophenyl)isoxazoline-3-carboxylates 5f
(1.41 g, 3 mmol) in 10 mL of degassed water at 80ꢀC under
nitrogen was added phenylboronic acid (0.55 g, 4.5 mmol) and
CsF (0.90 g, 6 mmol) in one portion. The resulting mixture was
stirred at this temperature for 15 min before 10 mol.% of Pd
1735, 1452, 1251, 1032, 762 cmÀ1
.
Ethyl 5-(4-chlorophenyl)isoxazole-3-carboxylate (6e).Color-
1
less solid; mp 124–125ꢀC; H NMR (400 MHz, CDCl3): d 7.71
(d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 6.91 (s, 1H), 4.46
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Synthesis of Ethyl Isoxazole-3-Carboxylates
321
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(OAc)2 (0.03 mmol) was added. The reaction system was then
stirred vigorously for 20 h at 80ꢀC under nitrogen atmosphere.
On completion of the reaction, the solvent was removed in a
rotary evaporator under reduced pressure. The residue was
washed with ether (15 Â 3 mL) and small amount of water
(1 mL). After decanting the liquid phase, the crude product 7
was dried on vacuum pump, examined by NMR, and subjected
to the next step of cleavage reaction to afford the product 8 in
82% yield based on 1, according to the experimental procedure
used for 6. Colorless solid, mp 143–144ꢀC; 1H NMR (400
MHz, CDCl3): d 7.84 (d, J = 8.2 Hz, 2H), 7.80–7.78 (m, 4H),
7.58 (s, 1H), 7.46–7.40 (m, 2H), 6.90 (s, 1H), 4.44
(q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 169.8, 160.1, 156.5, 133.2, 130.6, 129.5, 129.1,
128.8, 128.4, 128.0, 127.1, 122.3, 117.4, 100.5, 62.3, 14.2; MS
(EI): m/z 293 (M+); Anal. Calcd for C18H15NO3: C, 73.71; H,
5.15; N, 4.78. Found: C, 73.60; H, 5.25; N, 4.71; IR (KBr): n
3330, 2985, 1730, 1450, 1248, 1022 cmÀ1
.
Acknowledgments. We gratefully acknowledge financial support
from the National Natural Science Foundation of China (No.
21062007), NSF of Jiangxi Province (No. 2009GZH0016), and
the Research Program of Jiangxi Province Department of
Education (No. GJJ10385, GJJ11380).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet