Solid-phase organic synthesis of methyl isoxazole-5-carboxylates based on wang resin-bound 1-phenylselenoacrylate

Article abstract of DOI:10.1080/00397911.2011.580641

A novel Wang resin-bound 1-phenylselenoacrylate reagent has been developed and used as dipolarophile for the 1,3-dipolar cycloaddition with nitrile oxides to the regioselective synthesis of methyl 3-substituted isoxazole-5-carboxylates in good yields and

Full text of DOI:10.1080/00397911.2011.580641

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Solid-Phase Organic Synthesis of Methyl
Isoxazole-5-carboxylates Based on Wang
Resin–Bound 1-Phenylselenoacrylate
Ni Tang a , Shou-Ri Sheng a , Qiao-Sheng Hu b , Hong-En Qu b & Ming-
Zhong Cai a
a College of Chemistry and Chemical Engineering , Jiangxi Normal
University , Nanchang , China
b College of Chemistry and Life Science , Gannan Normal University ,
Ganzhou , China
Accepted author version posted online: 12 Jan 2012.Published
online: 18 Jul 2012.
To cite this article: Ni Tang , Shou-Ri Sheng , Qiao-Sheng Hu , Hong-En Qu & Ming-Zhong Cai (2012)
Solid-Phase Organic Synthesis of Methyl Isoxazole-5-carboxylates Based on Wang Resin–Bound 1-
Phenylselenoacrylate, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 42:22, 3279-3287, DOI: 10.1080/00397911.2011.580641
To link to this article: http://dx.doi.org/10.1080/00397911.2011.580641
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Synthetic Communications1, 42: 3279–3287, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.580641
SOLID-PHASE ORGANIC SYNTHESIS OF METHYL
ISOXAZOLE-5-CARBOXYLATES BASED ON WANG
RESIN–BOUND 1-PHENYLSELENOACRYLATE
Ni Tang,1 Shou-Ri Sheng,1 Qiao-Sheng Hu,2 Hong-En Qu,2
and Ming-Zhong Cai1
1College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang, China
2College of Chemistry and Life Science, Gannan Normal University,
Ganzhou, China
GRAPHICAL ABSTRACT
Abstract A novel Wang resin–bound 1-phenylselenoacrylate reagent has been developed and
used as dipolarophile for the 1,3-dipolar cycloaddition with nitrile oxides to the regioselec-
tive synthesis of methyl 3-substituted isoxazole-5-carboxylates in good yields and purities.
Keywords 1,3-Dipolar cycloaddition; methyl 3-substituted-isoxazole-5-carboxylate;
oxidation–elimination; solid–phase organic synthesis; Wang resin–bound 1-phenylsele-
noacrylate
INTRODUCTION
The application of solid-phase organic synthesis (SPOS) is important in the
preparation of small compound libraries for the discovery and development of
new drug compounds.[1] Synthesis on a polymer support has a number of advantages
as compared to solution chemistry. The most salient one is the possibility of applying
excesses of reagents and removing them without time-consuming separation techni-
ques. The isoxazole ring system is present in a variety of natural products and is a
useful synthetic building block.[2] In addition, it has shown considerable
Received October 23, 2010.
Address correspondence to Shou-Ri Sheng, College of Chemistry and Chemical Engineering,
Jiangxi Normal University (Yaohu Campus), Nanchang, 330022, China. E-mail: shengsr@jxnu.edu.cn
3279

3280
N. TANG ET AL.
anti-inflammatory,[3] antiviral,[4] and antitubulin[5] activities. Therefore, the synthesis
of this family of heterocycles continues to be of interest. Although several groups
have studied the synthesis of isoxazoles using SPOS technology[6] by the conden-
sation of 1,3-dicarbonyl compounds with hydroxylamine,[7] the addition of nitrile
oxides to the supported alkynes,[8] the anchoring of a nitrile oxide precursor onto
the solid phase,[9] or using polymer-supported vinyl ethers as chameleon catches,[10]
a real need still exists for efficient solid-phase procedures to be applied for the gen-
eration of functionalized isoxazole libraries. It is well known that organoselenium
reagents have been increasingly used to introduce functional groups into organic
substrates under extremely mild conditions.[11] Recently, Huang et al.[12] reported
SPOS of isoxazole compounds using polystyrene-supported selenium reagent that
had decreased volatility and simplified of product workup. Our research group
has also developed a methodology for the preparation of 3-substituted isoxazoles
and 3-substituted 5-iodoisoxazolines based on polystyrene-supported vinyl selenide
reagent.[13] As part of an ongoing research program focused on the use of Wang
resin–bound selenium reagent in solid-phase organic synthesis,[14] we report here
our preliminary study in solid-phase synthesis of methyl isoxazole-5-carboxylates
based on a novel Wang resin–bound 1-phenylselenoacrylate.
As shown in Scheme 1, acryloyl chloride was quantitatively anchored to
Wang resin 1 loaded with 0.96 mmol=g via an ester linkage in the presence of
N,N-diisopropylethylamine (DIPEA). The resin-bound acrylate 2 was characterized
by microscopy Fourier transform infrared (FTIR),[15] which showed complete disaꢀp1-
=
pearance of the hydroxyl stretch and the appearance of a C O stretch at 1724 cm
and a C C stretch at 1651 cmꢀ1. Pale yellow a-phenylseleno-b-bromopropionate
=
resin 3 was obtained efficiently by treatment of resin 2 with benzeneselenenyl bro-
mide in the presence of zinc chloride after stirring for 2 h according to the reported
method.[16] FTIR revealed the appearance of a new strong carbonyl absorption at
1735 cmꢀ1, a weak C–Br band at 570 cmꢀ1, and the complete disappearance of
absorptions at 1725 and 1651 cmꢀ1. Resin 3 was then reacted with tert-BuOK in
tetra hydrofuran (THF) at room temperature almost quantitatively to afford resin
4 containing a load of 0.80 Se mmol=g by selenium elementary analysis (no bromine
was found by microanalysis of resin 4), which was evidenced by its FTIR spectrum
ꢀ1
featuring a strong carbonyl absorption at 1724 cmꢀ1, a C C stretch at 1635 cm
and the complete disappearance of C–Br (570 cmꢀ1) absorption.
,
=
Scheme 1. SPOS route to methyl 3-substituted isoxazole-5-carboxylate.

SPOS OF METHYL ISOXAZOLE-5-CARBOXYLATES
3281
Table 1. Yields and purities of methyl isoxazole-5-carboxylates (7a–7l)
Entry
R
Product
Yield (%)a
Purity (%)b
1
2
C6H5
7a
7b
7c
7d
7e
7f
90
86
85
90
89
85
84
84
85
82
85
82
95
95
95
96
94
93
92
95
93
94
96
93
4-CH3C6H4
3-CH3C6H4
4-MeOC6H4
3-MeOC6H4
4-ClC6H4
3
4
5
6
7
2,6-Cl2C6H3
4-NO2C6H4
4-FC6H4
7g
7h
7i
8
9
10
11
12
1-Naphthyl
2-Furyl
(CH3)2CH
7j
7k
7l
aOverall yields based on Wang resin–bound 1-phenylselenoacrylate 4 (0.80 mmol Se=g).
bDetermined by HPLC of crude cleavage product.
With resin 4 in hand, [3 þ 2] cycloaddition reaction of resin 4 with nitrile oxides
was then investigated. It has been reported that 1,3-dipolar cycloadditions of nitrile
oxides in solution are suffer from many side reactions, including dimerization as a
result of the high reactivity.[17] Therefore, it is synthetically interesting to perform
these reactions using solid-phase synthesis, which makes isolation of the product
easier. Thus, the resin 4 was allowed to react with nitrile oxides generated in situ
by chlorination of the corresponding aldoximes with N-chlorosuccinimide in the
presence of triethylamine to form the supported isoxazoline 5. In this process, we
found that it was necessary for triethylamine to be slowly added dropwise to avoid
the dimerization of the nitrile oxides. Subsequently, the deselenation of the isoxazo-
line resin 5 was carried out with 30% hydrogen peroxide at 0 ꢁC and then at room tem-
perature to afford the corresponding resin-bound isoxazole-5-carboxylate 6, which
lost all its selenium by elemental analysis of 6, indicating the oxidation–elimination
was complete. After accomplishment of the oxidation–elimination reaction, cleavage
of the product from isoxazole-5-carboxylate resin 6 was achieved readily by transes-
terification [NaOMe, MeOH=THF (1:4), reflux for 18 h] to provide the methyl
3-substituted-isoxazole-5-carboxylates 7 in good yields and purities (Table 1). Besides
good yields and purities, this process also exhibits excellent stereoselectivity. Methyl
isoxazole-5-carboxylates 7 are formed exclusively, indicating the cycloaddition of
resin 4 with nitrile oxides occurred with complete regioselectivity.
In summary, we have developed a novel, efficient, and regioselective synthesis
of methyl isoxazole-5-carboxylates using Wang resin–bound 1-phenylselenoacrylate.
Simple workup procedure replaces the time-consuming isolation and purification
steps in the corresponding solution-phase synthesis. Further investigations based
on Wang resin–bound 1-phenylselenoacrylate are now in progress.
EXPERIMENTAL
Melting points were uncorrected.1H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a Bruker Avance (400 MHz) spectrometer,

3282
N. TANG ET AL.
using CDCl3 as the solvent and tetramethylsilane (TMS) as internal standard. Mass
spectra (EI, 70 eV) were recorded on a HP5989B mass spectrometer. FTIR spectra
were taken on a Perkin-Elmer SP One FTIR spectrophotometer. Microanalyses were
performed with a Carlo Erba 1106 elemental analyzer. High-performance liquid
chromatogrphy (HPLC) was performed on an Agilernt 1100 high-performance
liquid chromatograph. Wang resin (0.96 mmol=g) and other starting materials were
purchased from commercial suppliers and used without further purification.
1,2-Dichloroethane was refluxed with phosphorous pentoxide and distilled. THF
was distilled from sodium benzophenone immediately prior to use.
Preparation of Wang Resin–Bound 1-Phenylselenoacrylate (4)
Wang resin (1.0 g, 0.96 mmol=g) was swollen in CH2Cl2 (10 mL). Diisopropy-
lethylamine (DIPEA, 0.65 g, 5.0 mmol) and acryloyl chloride (0.45 g, 5.0 mmol) were
added, and the reaction mixture was shaken at room temperature for 4 h. The mix-
ture was filtered, and the resin was washed sequentially with DMF (2 ꢂ 10 mL), H2O
(2 ꢂ 10 mL), MeOH (2 ꢂ 20 mL), CH2Cl2(2 ꢂ 10 mL), and ether (2 ꢂ 10 mL) and
dried overnight in a vacuum oven at 40 ꢁC to afford resin 2. The resultant resin 2
swollen in CH2Cl2 (3 ꢂ 10 mL) for 30 min and ZnCl2 (0.1 mmol) was added After
10 min with shaking at room temperature, PhSeBr (5.0 mmol) was added, and the
mixture was shaken for 2.0 h. The resin was collected on a filter and washed succes-
sively with H2O (2 ꢂ 10 mL), THF (2 ꢂ 10 mL), THF=H2O (2:1) (2 ꢂ 10 mL), THF
(2 ꢂ 10 mL), and CH2Cl2 (2 ꢂ 10 mL) and then dried under vacuum overnight to
afford resin 3. Then t-BuOK (4.0 mmol) was added to a suspension of the swollen
resin 3 in anhydrous diethyl ether (20 mL), and the mixture was shaken for 12 h at
room temperature. The resin was collected by filtration, washed with H2O
(2 ꢂ 10 mL), THF=H2O (2:1) (2 ꢂ 10 mL), THF (2 ꢂ 10 mL), and CH2Cl2(2 ꢂ 10 mL)
and then dried under vacuum overnight to afford resin 4 with a loading value of 0.80
Se mmol=g by selenium elemental analysis. FTIR (KBr): n ¼ 3045, 2925, 1724, 1635,
1595, 1455, 1248, 1180, 1105, 994, 950, 825, 765 cmꢀ1
.
Preparation of Methyl Isoxazole-5-carboxylates (7a–7l): General
Procedure
Under a positive pressure of nitrogen, to a suspension of the swollen resin 4
(1.0 mmol, 1.25 g) in CH2Cl2 (15 mL) was added a solution of hydroximoyl halide
(4.0 mmol) in CH2Cl2 (10 mL) (prepared from 4.0 mmol of aldoxime and 4.0 mmol
of NCS in CH2Cl2 (15 mL) stirring at room temperature for 4 h before use). A sol-
ution of Et3N (5 mmol) in CH2Cl2 (15 mL) was slowly added dropwise in three por-
tions every 8 h [each time, 1.66 mmol in anhydrous CH2Cl2 (5 mL) was added]. After
shaking for 24 h at room temperature, resin 5 was collected by filtration and washed
with DMF (2 ꢂ 10 mL), THF (2 ꢂ 10 mL), THF=H2O (2:1) (2 ꢂ 10 mL), H2O
(2 ꢂ 10 mL), and CH2Cl2(2 ꢂ 10 mL). The washed resin 5 was suspended in THF
(15 mL), 30% (aq.) H2O2 (0.5 mL) was added, and the mixture was shaken for
30 min at 0 ꢁC, followed by 1 h at room temperature. After completion of the reac-
tion, the resin 6 was then filtered and washed successively with THF=H2O (2:1)
(3 ꢂ 10 mL), THF (3 ꢂ 5 mL), MeOH (3 ꢂ 5 mL), and Et2O (3 ꢂ 5 mL). Then the

SPOS OF METHYL ISOXAZOLE-5-CARBOXYLATES
3283
resin 6 was cleaved in a mixture of THF (8 mL) and MeOH (2 mL) in the presence of
45 mg of sodium methoxide at 70 ꢁC for 18 h. After cooling, the resin was filtered and
washed with THF=H2O (1=1) (3 ꢂ 10 mL), MeOH (3 ꢂ 5 mL), and Et2O (3 ꢂ 5 mL).
Evaporation of the solvent from the filtrate afforded crude products 7a–7l with
92–96% purity as determined by HPLC, which were further purified by passing
the crude products through silica-gel chromatographic column (ethyl acetate–hexane
as the eluent, 1:4), affording the pure products. All of the isolated products were
1
unambiguously characterized by H NMR, 13C NMR, and IR, and for regiochem-
ical assignment, all analytical data is consistent with literature precedent.
Methyl 3-Phenylisoxazole-5-carboxylate (7a)
Colorless solid, mp 105–106 ꢁC (lit.[18] 107–109 ꢁC); 1H NMR: d ¼ 3.98 (s, 3 H),
7.26 (s, 1 H), 7.44–7.49 (m, 3 H), 7.81–7.85 (m, 2 H); IR (KBr): n ¼ 3425, 2982, 1745,
1450, 1294, 1245, 1025, 770 cmꢀ1
.
Methyl 3-(4-Methylphenyl)isoxazole-5-carboxylate (7b)
Colorless solid, mp 112–113 ꢁC; 1H NMR: d ¼ 2.40 (s, 3 H), 3.95 (s, 3 H), 7.27
(s, 1 H), 7.36 (d, J ¼ 8.4 Hz, 2 H), 7.73 (d, J ¼ 8.4 Hz, 2 H); 13C NMR: d ¼ 21.5, 52.7,
107.7, 127.0, 127.5, 129.8, 141.0, 157.2, 161.1, 163.3; IR (KBr): n ¼ 3430, 2985, 1730,
1447, 1294, 1248, 1021, 820, 766 cmꢀ1; EIMS: m=z (%) ¼ 217 (Mþ). Anal. calcd. for
C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.28; H, 5.18; N, 6.38.
Methyl 3-(3-Methylphenyl)isoxazole-5-carboxylate (7c)
Brownish oil; 1H NMR: d ¼ 2.39 (s, 3 H), 3.97 (s, 3 H), 7.25 (s, 1 H), 7.42–7.47
(m, 2 H), 7.62 (d, J ¼ 8.4 Hz, 1 H), 7.68 (s, 1 H); 13C NMR: d ¼ 21.6, 52.7, 107.7,
124.3, 127.7, 128.5, 129.5, 131.9, 140.1, 157.7, 161.2, 163.2; IR (neat): n ¼ 3436,
2988, 1733, 1440, 1288, 1252, 1034, 767 cmꢀ1; EIMS: m=z (%) ¼ 217 (Mþ). Anal.
calcd. for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.26; H, 5.17; N, 6.40.
Methyl 3-(4-Methoxyphenyl)isoxazole-5-carboxylate (7d)
Colorless solid, mp 116–118 ꢁC (lit.[19] 118–119 ꢁC); 1H NMR: d ¼ 3.84 (s, 3 H),
3.99 (s, 3 H), 7.02 (d, J ¼ 8.8 Hz, 2 H), 7.21 (s, 1 H), 7.75 (d, J ¼ 8.8 Hz, 2 H); IR
(KBr): n ¼ 3062, 2981, 1735, 1445, 1295, 1245, 1026, 765 cmꢀ1
.
Methyl 3-(3-Methoxyphenyl)isoxazole-5-carboxylate (7e)
Brownish oil; 1H NMR: d ¼ 3.83 (s, 3 H), 4.01 (s, 3 H), 7.24 (s, 1 H), 7.05–7.10
(m, 1 H), 7.38 (s, 1 H), 7.43–7.46 (m, 2 H); 13C NMR: d ¼ 52.6, 55.3, 107.4, 111.7,
116.6, 119.4, 130.0, 127.6, 156.7, 160.0, 160.7, 162.7; IR (neat): n ¼ 3445, 2976,
1736, 1453, 1285, 1252, 1032, 762 cmꢀ1. EIMS: m=z (%) ¼ 233 (Mþ). Anal. calcd.
for C12H11NO4: C, 61.80; H, 4.75; N, 6.01. Found: C, 61.71; H, 4.85; N, 6.09.

3284
N. TANG ET AL.
Methyl 3-(4-Chlorophenyl)isoxazole-5-carboxylate (7f)
Colorless solid, mp 120–122 ꢁC; 1H NMR: d ¼ 4.00 (s, 3 H), 7.27 (s, 1 H), 7.38
(d, J ¼ 8.4 Hz, 2 H), 7.78 (d, J ¼ 8.4 Hz, 2 H); 13C NMR: d ¼ 52.9, 107.1, 128.1,
129.3, 126.3, 136.5, 157.0, 161.2, 163.3; IR (KBr): n ¼ 3440, 2982, 1730, 1448,
1285, 1246, 1025, 925, 825 cmꢀ1; EIMS: m=z (%) ¼ 237 (Mþ). Anal. calcd. for
C11H8ClNO3: C, 55.60; H, 3.39; N, 5.89. Found: C, 55.51; H, 3.47; N, 5.82.
Methyl 3-(2,6-Dichlorophenyl)isoxazole-5-carboxylate (7g)
Colorless solid, mp 114–116 ꢁC (lit.[18] 114–116 ꢁC); 1H NMR: d ¼ 4.02 (s, 3 H),
7.06 (s, 1 H), 7.35–7.48 (m, 3 H); IR (KBr): n ¼ 3062, 2981, 1750, 1445, 1295, 1245,
1026, 765 cmꢀ1
.
Methyl 3-(4-Nitrophenyl)isoxazole-5-carboxylate (7h)
Yellow solid, mp 168–169 ꢁC; 1H NMR: d ¼ 4.02 (s, 3 H), 7.30 (s, 1 H), 7.60 (d,
J ¼ 8.6 Hz, 2 H), 8.20 (d, J ¼ 8.6 Hz, 2 H); 13C NMR: d ¼ 53.2, 107.8, 123.8, 126.1,
127.6, 135.8, 156.8, 161.2, 163.3; IR (KBr): n ¼ 3440, 2961, 1735, 1550, 1520, 1385,
1246, 1080, 928, 858 cmꢀ1; EIMS: m=z (%) ¼ 248 (Mþ). Anal. calcd. for
C11H8N2O5: C, 53.23; H, 3.25; N, 11.29. Found: C, 53.35; H, 3.37; N, 11.22.
Methyl 3-(4-Fluorophenyl)isoxazole-5-carboxylate (7i)
1
Colorless oil; H NMR: d ¼ 3.92 (s, 3 H), 7.25 (s, 1 H), 7.23–7.27 (m, 2 H),
7.80–7.85 (m, 2 H); 13C NMR: d ¼ 52.8, 107.2, 116.8, 124.3, 129.4, 156.8, 161.2,
163.2, 164.0; IR (KBr): n ¼ 3443, 3133, 2982, 1731, 1448, 1284, 1246, 1023, 925,
830, 762 cmꢀ1. EIMS: m=z (%) ¼ 221 (Mþ). Anal. calcd. for C11H8FNO3: C,
59.73; H, 3.65; N, 6.33. Found: C, 59.61; H, 3.77; N, 6.39.
Methyl 3-(1-Naphthyl)isoxazole-5-carboxylate (7j)
Black oil; 1H NMR: d ¼ 3.97 (s, 3 H), 7.27 (s, 1 H), 7.50–7.53 (m, 3 H),
7.70–7.72 (m, 1 H), 7.90–7.93 (m, 2 H), 8.30–8.34 (m, 1 H); 13C NMR: d ¼ 52.9,
107.4, 125.2, 125.5, 125.6, 126.8, 127.7, 128.2, 128.5, 130.7, 131.3, 133.9, 156.8,
160.1, 163.0; IR (neat): n ¼ 3436, 2985, 1734, 1445, 1386, 1284, 1025, 920, 775 cmꢀ
1; EIMS: m=z (%) ¼ 253 (Mþ). Anal. calcd. for C15H11NO3: C, 71.14; H, 4.38; N,
5.53. Found: C, 71.07; H, 4.47; N, 5.60.
Methyl 3-(2-Furyl)isoxazole-5-carboxylate (7k)
Colorless oil; 1H NMR: d ¼ 3.95 (s, 3 H), 7.28 (s, 1 H), 6.71 (d, J ¼ 3.0 Hz, 1H),
7.37–7.42 (m, 1 H), 7.48 (d, J ¼ 7.5 Hz, 1 H); 13C NMR: d ¼ 52.8, 102.8, 110.5, 114.7,
126.5, 151.0, 156.5, 160.1, 163.0; EIMS: m=z (%) ¼ 193; IR (neat): n ¼ 3058, 2933,
1722, 1435, 1385, 1225, 1205, 1170, 1031, 770 cmꢀ1. Anal. calcd. for C9H7NO4: C,
55.96; H, 3.65; N, 7.25. Found: C, 55.90; H, 3.74; N, 7.18.

SPOS OF METHYL ISOXAZOLE-5-CARBOXYLATES
3285
Methyl 3-Isopropylisoxazole-5-carboxylate (7l)
1
Colorless oil; H NMR: d ¼ 0.87 (d, J ¼ 6.0 Hz, 6 H), 2.25–2.28 (m, 1 H), 3.88
(s, 3 H), 7.20 (s, 1 H); 13C NMR: d ¼ 14.6, 21.7, 52.1, 107.2, 154.8, 156.3, 163.5; IR
(neat): n ¼ 3060, 2985, 1725, 1445, 1295, 1375, 1242, 1165, 1023, 760 cmꢀ1; EIMS:
m=z (%) ¼ 169 (Mþ). Anal. calcd. for C8H11NO3: C, 56.80; H, 6.55; N, 8.28. Found:
C, 56.86; H, 6.63; N, 8.37.
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 (Nos. GJJ10385 and GJJ11380).
REFERENCES
1. Recent reviews on SPOS: (a) Guillier, F.; Orain, D.; Bradley, M. Linkers and cleavage
strategies in solid-phase organic synthesis, and combinatorial chemistry. Chem. Rev.
2000, 100, 2091–2158; (b) Sammelson, R. E.; Kurth, M. J. Carbon-carbon bond-forming
solid-phase reactions, part II. Chem. Rev. 2001, 101, 137–202 (c) Blaney, P.; Grigg, R.;
Sridharan, V. Traceless solid-phase organic synthesis. Chem. Rev. 2002, 102, 2607–2624.
2. Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simoni, D. Synthesis of natural pro-
ducts via isoxazoles. Synthesis 1987, 857–869.
3. Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M.; Masferrer, J. L.;
Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K.
4-[5-Methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide, valdecoxib: A potent and selec-
tive inhibitor of COX-2. J. Med. Chem. 2000, 43, 775–777
4. (a) Lee, Y. S.; Kim, B. H. Heterocyclic nucleoside analogues: Design and synthesis of anti-
viral, modified nucleosides containing isoxazole heterocycles. Bioorg. Med. Chem. Lett.
2002, 12, 1395–1397; (b) Srivastava, S.; Bajpai, L. K.; Batra, S.; Bhaduri, A. P.; Maikhuri,
J. P.; Gupta, G.; Dhar, J. D. In search of new chemical entities with spermicidal and
anti-HIV activities. Bioorg. Med. Chem. 1999, 7, 2607–2613.
5. (a) Simoni, D.; Grisolia, G.; Giannini, G.; Roberti, M.; Rondanin, R.; Piccagli, L.;
Baruchello, R.; Rossi, M.; Romagnoli, R.; Invidiata, F. P.; Grimaudo, S.; Jung, M. K.;
Hamel, E.; Gebbia, N.; Crosta, L.; Abbadessa, V.; Di Cristina, A.; Dusonchet, L.; Meli,
M.; Tolomeo, M. Heterocyclic and phenyl double-bond-locked combretastatin analogues
possessing potent apoptosis-inducing activity in HL60 and in MDR cell lines. J. Med.
Chem. 2005, 48, 723–736; (b) Kaffy, J.; Pontikis, R.; Carrez, D.; Croisy, A.; Monneret,
C.; Florent, J. C. Isoxazole-type derivatives related to combretastatin A-4, synthesis
and biological evaluation. Bioorg. Med. Chem. 2006, 14, 4067–4077.
6. (a) Franzen, R. G. Recent advances in the preparation of heterocycles on solid support: A
review of the literature. J. Comb. Chem. 2000, 2, 195–214; (b) Dowald, F. Z. Organic Syn-
thesis on Solid Phase, Wiley-VCH: Weinheim, 2002.
7. (a) Shen, D. M.; Shu, M.; Chapman, K. T. Versatile and efficient solid-phase syntheses of
pyrazoles and isoxazoles. Org. Lett. 2000 2, 2789–2792; (b) Marzinzik, A. L.; Felder, E. R.
Solid-support synthesis of highly functionalized pyrazoles and isoxazoles: Scaffolds for
molecular diversity. Tetrahedron Lett. 1996, 37, 1003–1006.
8. (a) Yedidia, V.; Leznoff, C. C. Regioselectivity in cycloaddition reactions on solid phases.
Can. J. Chem. 1980, 58, 1144–1150; (b) Pei, Y. Z.; Moos, W. H. Post-modification of pep-

3286
N. TANG ET AL.
toid side chains: [3 þ 2] Cycloaddition of nitrile oxides with alkenes and alkynes on the
solid phase. Tetrahedron Lett. 1994, 35, 5825–5828; (c) Haino, T.; Tanaka, M.; Ideta,
K.; Kubo, K.; Mori, A.; Fukazawa, Y. Solid-phase synthesis of liquid crystalline isoxazole
library. Tetrahedron Lett. 2004, 45, 2277–2279; (d) Kantorowski, E. J.; Kurth, M. J.
Solid-phase synthesis of isoxazoles and isoxazolines: En route to a new class of iono-
phores. J. Org. Chem. 1997, 62, 6797–6803; (e) Gao, D.; Zhai, H. M.; Parvez, M.; Back,
T. G. 1,3-Dipolar cycloadditions of acetylenic sulfones in solution and on solid supports.
J. Org. Chem. 2008, 73, 8057–8068.
9. (a) Shankar, B. B.; Yang, D. Y.; Girton, S.; Ganguly, A. K. One-pot solid-phase synthesis
of isoxazolines. Tetrahedron Lett. 1998, 39, 2447–2448; (b) Alonso, C.; Nantz, M. H.
Kurth, M. J. b-Dimethylphenylsilylethyl esters: A linker for solid-phase chemistry. Tetra-
hedron Lett. 2000, 41, 5617–5622
10. (a) Barrett, A. G. M.; Procopiou, P. A.; Voigtmann, U. Solid-phase synthesis of isoxazoles
using vinyl ethers as chameleon catches. Org. Lett. 2001, 3, 3165–3168; (b) Engler, T. A. In
Studies in Natural Product Chemistry; Attaur-Rahman (Ed)., Elsevier Science: New York,
1995; Vol. 16.
11. (a) Reich, H. J. Functional group manipulation using organoselenium reagents. Acc.
Chem. Res. 1979, 12(1), 22–30; (b) Paulmier, C. (Ed). Selenium Reagents and Intermediates
in Organic Synthesis; Pergamon Press: Oxford, 1986.
12. (a) Huang, X.; Xu, W. M. Use of selenium-bound resin for the solid-phase synthesis of
substituted isoxazolyl-substituted (E)-olefins. Org. Lett. 2003, 5, 4649–4652; (b) Xu, W.
M.; Wang, Y. G.; Miao, M. Z.; Huang, X. A novel cleavage for polystyrene-supported
selenium resins: An efficient route to 3,5-disubstituted isoxazolines and their derivatives.
Synthesis 2005, 2143–2146; (c) Xu, W. M.; Huang, X.; Tang, E. Solid-phase synthesis
of 1,2-diheterocyclic-substituted (E)-olefins from a supported selenium resin. J. Comb.
Chem. 2005, 7, 726–733 (d) Huang, X.; Wang, Y. G. Solid-phase synthesis of linked het-
erocycles from a selenopolystyrene resin. J. Comb. Chem. 2007, 9, 121–130; (e) Wang, Y.
G.; Xu, W. M.; Huang, X. An efficient solid-phase synthesis of substituted isoxazole, tria-
zole, and cycloalkadiene derivatives using supported selenium resin. Synthesis 2007,
28–32; (f) Cao, J.; Huang, X. Solid-phase synthesis of heterocyclic nucleoside analogues:
Substituted uracils tethered to isoxazoles, isoxazolines, and triazoles from a selenopolys-
tyrene resin. J. Comb. Chem. 2008, 10, 526–533.
13. Sheng, S. R.; Xin, Q.; Liu, X. L.; Sun, W. K.; Guo, R.; Huang, X. Traceless solid-phase
synthesis of 3-substituted isoxazoles and 3-substituted 5-iodoisoxazolines using
polystyrene-supported vinyl selenide. Synthesis 2006, 2293–2296.
14. Sheng, S. R.; Huang, F. F.; Lin, S. Y.; Liu, X. L.; Huang, X. Solid-phase synthesis
of 3-hydroxy-2-methylenealkanoates and their derivatives using polymer-supported
a-phenylselenopropionate. Synthesis 2007, 1373–1377.
15. Yan, B.; Kumaravel, G.; Anjaria, H.; Wu, A.; Petter, R. C.; Jewell, C. F.; Wareing, J. R.
Infrared spectrum of a single resin bead for real-time monitoring of solid-phase reactions.
J. Org. Chem. 1995, 60, 5736–5738.
16. Huang, X.; Xu, J. F. Solid-phase synthesis of 2,5-dihydro-1H-pyrroles, 1,3-dioxo-2,3,5,7a-
tetrahydro-1H-pyrrolo[1,2-c]imidazoles, and 1,4-dioxo-1,2,3,4,6,8a-hexa-hydropyrrolo
[1,2-a]pyrazines using a supported selenium resin. J. Comb. Chem. 2009, 11, 350–354.
17. (a) Torsell, K. G. B. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH:
New York, 1998; (b) Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry toward Heterocycles and Natural Products. In The Chemistry
of Heterocyclic Compounds; John Wiley & Sons: New York, 2002; Vol. 59. (c) Pinho e
Melo, T. M. V. D. Recent advances on the synthesis and reactivity of isoxazoles. Curr.
Org. Chem. 2005, 9, 925-958.

SPOS OF METHYL ISOXAZOLE-5-CARBOXYLATES
3287
18. Dadiboyena, S.; Xu, J. P.; Hamme II, A. T. Isoxazoles from 1,1-disubstituted bromoalk-
enes. Tetrahedron Lett. 2007, 48, 1295–1298.
19. Hamme, A. T. II; Xu, J.; Wang, J.; Cook, T.; Ellis, E. Synthesis of functionalized 5,5-
disubstituted isoxazolines via 1,3-dipolar cycloaddition reactions of geminal disubstituted
alkenes. Heterocycles 2005, 65, 2885–2895.