Synthesis of isoxazolines and isoxazoles using poly(ethylene glycol) as support

Article abstract of DOI:10.1055/s-2002-33655

A general method for the liquid-phase syntheses of isoxazoles and isoxazolines through a 1,3-dipolar cycloaddition is described. The poly(ethylene glycol) (PEG)-supported alkyne 2 or alkene 6 reacted with nitrile oxides generated in situ from aldoximes 3, followed by cleavage from the PEG, to give isoxazoles or isoxazolines in good yield and purity.

Full text of DOI:10.1055/s-2002-33655

PAPER
1663
Synthesis of Isoxazolines and Isoxazoles Using Poly(ethylene glycol)
as Support
S
ynthesis of Isoxa
o
z
olines and
I
n
soxazoles g-Jia Shang, Yan-Guang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
Fax +86(571)87951512; E-mail: orgwyg@css.zju.edu.cn
Received 1 April 2002; revised 24 May 2002
try.9 Solution methods for their preparation via 1,3-dipo-
lar cycloaddition10 of alkyne with nitrile oxide are well
documented. The solid-phase synthesis of isoxazoles has
been described earlier using either polymer-supported ni-
Abstract: A general method for the liquid-phase syntheses of isox-
azoles and isoxazolines through a 1,3-dipolar cycloaddition is de-
scribed. The poly(ethylene glycol) (PEG)-supported alkyne 2 or
alkene 6 reacted with nitrile oxides generated in situ from al-
doximes 3, followed by cleavage from the PEG, to give isoxazoles trile oxide precursors11 or polymer-supported alkynes.12
or isoxazolines in good yield and purity.
For the preparation of isoxazole and isoxazoline libraries,
we envisioned that the use of liquid-phase 1,3-dipolar cy-
cloaddition would be a good alternative to both classical
and solid-phase synthesis. We, therefore, decided to test
the possibility of preparing isoxazoles and isoxazolines by
anchoring the acetylenic compounds13 on soluble
poly(etheylene glycol) and generating the nitrile oxide in
situ from suitable carbonyl compounds. Our efforts at ob-
taining a representative library of isoxazoles and isoxazo-
lines are presented below.
Key words: poly(ethylene glycol), isoxazolines, isoxazoles, cy-
cloaddition, liquid-phase
Cross-linked polymer supports are now ubiquitous
throughout the fields of combinatorial chemistry, organic
synthesis, catalysts and reagents.1 However, emerging
problems associated with the heterogeneous nature of the
ensuing chemistry and with ‘on-bead’ spectroscopic char-
acterization have meant that soluble polymers are being
developed as alternative matrices for combinatorial li-
brary production2 and organic synthesis.3 We chose to
perform our reactions on the soluble polymer support4
poly(ethylene glycol) 4000 (PEG). This polymer is solu-
ble in many solvents, e.g., THF, CH2Cl2, or H2O at room
temperature,5 but can be precipitated from a solution and
thus purified by addition of diethyl ether, hexane, or pro-
pan-2-ol.6 Soluble polymers have several advantages over
polystyrene-derived resins. Reactions of soluble polymer
bound and the corresponding nonpolymer-bound sub-
strates generally show the same kinetics, however, insol-
uble byproducts or reagents can easily be separated from
the polymer solution by filtration and the soluble polymer
is significantly less expensive than polystyrene-resins.
Furthermore, each reaction can be easily monitored by so-
lution phase 1H NMR of a polymer sample in CDCl3. He-
gedus described the use of MeOPEG in a two-phase
reaction as advantageous compared to the use of Merri-
field resin.7 Kahn and Blaskovich have successfully dem-
onstrated the optimization of a multistep sequence using
MeOPEG bound substrates.8 Our work presented here
shows that the use of PEG bound substrates can help to
rapidly evaluate the substrate spectrum of a multistep se-
quence.
As shown in Scheme 1, PEG4000 succinate 1 was prepared
by treatment of PEG4000 with succinic anhydride with 4-
dimethylaminopyridine (DMAP) as catalyst in refluxing
dichloromethane. Condensation of 1 with propargyl alco-
hol in the presence of 1,3-dicyclohexycarbodiimide with
a catalytic amount of DMAP in dichloromethane afforded
the polymer-supported alkyne 2. The loading was deter-
1
mined by H NMR spectrometry and was complete after
16 hours at room temperature. After precipitation with di-
ethyl ether, the resin 2 was treated with 4 equivalents of
the aldoxime and of N-chlorosuccinimide (NCS) in
dichloromethane in a one-pot procedure. Successively,
triethylamine was added slowly over a period of 2 hours
to generate the nitrile oxide and the resulting mixture was
stirred at room temperature overnight. The triethylamine
hydrochloride was removed by precipitation with ben-
zene. The solution was concentrated and the polymer sup-
ported isoxazoles 4 were precipitated out by addition of
diethyl ether. The cleavage of PEG was accomplished by
treating 4 with 2 N NaOH aqueous solution at room tem-
perature and monitoring the disappearance of the poly-
meric isoxazoles (Scheme 1).
Eight isoxazoles 5a–h were thus prepared by trapping in
situ the PEG-supported alkyne with the nitrile oxide gen-
erated by the appropriate aldoxime in a practical one-pot
operation. As shown in Table 1, the yields were satisfac-
tory (48–91%), and the purity of recovered compounds af-
ter cleavage was greater than 95%. In every case, only one
isomer was obtained. When there are electron-withdraw-
ing groups such as NO2 on the aromatic ring, the 1,3-dipo-
lar cycloaddition turned stunt with low yields or
conversion, while the electron-donating groups, i.e. MeO
Isoxazoles and isoxazolines are versatile scaffolds for the
synthesis of a wide variety of complex natural products
and are important pharmacophores in medicinal chemis-
Synthesis 2002, No. 12, Print: 06 09 2002.
Art Id.1437-210X,E;2002,0,12,1663,1668,ftx,en;F02402SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1664
Y.-J. Shang, Y.-G. Wang
PAPER
Scheme 1
Table 1 Liquid-Phase Synthesis of Isoxazoles 5a–h
Entry
Aldoxime
Isoxazole
Yield (%)a
91
Purity (%)b
a
99
b
c
86
80
89
100
98
d
100
e
f
48
54
96
99
g
87
62
96
96
h
a Yields by gravimetric analysis based on isolated material following cleavage from support.
b Purity based on GC-MS analysis of cleaved samples. GC-MS purity was consistent with the purity determined by 1H NMR spectroscopy.
Synthesis 2002, No. 12, 1663–1668 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Isoxazolines and Isoxazoles
1665
Ar
O
O
NOH
allyl alcohol
3
OH
Cl
O
O
DCC,DMAP
DCM, r.t
O
triethylamine
DCM, r.t
O
1
O
6
O
O
N
O
N
2N NaOH
3h, r.t
O
HO
O
R
R
O
8
7
= PEG
Scheme 2
present on the aromatic ring accelarated the reaction lead- In summary, facile 1,3-dipolar cycloaddition methodolo-
ing to good yield and high conversion.
gies for the preparation of structurally different isoxazoles
and isoxazolines were developed under mild liquid-phase
conditions. Poly(etheylene glycol)-supported alkyne and
alkene react with in situ generated nitrile oxides, followed
by cleavage from the resin, to give isoxazoles and isox-
azolines, respectively, in good yields.
In a similar procedure, six isoxazolines 8a–f were pre-
pared from the resin-bound alkene 6 and corresponding
aldoximes as shown in Scheme 2. The yields were also
satisfactory (57–96%), and the purity of recovered com-
pounds after cleavage was more than 95% as given in
Table 2.
Table 2 Liquid-Phase Synthesis of Isoxazolines 8a–f
Entry
Aldoxime
Isoxazoline
Yield (%)a
88
Purity (%)b
99
a
b
c
96
86
100
98
d
93
100
e
f
57
91
95
99
a Yields by gravimetric analysis based on isolated material following cleavage from support.
b Purity based on GC-MS analysis of cleaved samples. GC-MS purity was consistent with the purity determined by 1H NMR spectroscopy.
Synthesis 2002, No. 12, 1663–1668 ISSN 0039-7881 © Thieme Stuttgart · New York

1666
Y.-J. Shang, Y.-G. Wang
PAPER
All chemicals and resin were obtained from commercial suppliers
and used without further purification. IR spectra were recorded on
a Perkin-Elmer 983 FT-IR spectrometer. 1H NMR spectra were re-
corded on a Bruker Avance DMX 500 instrument. GC-MS analyses
were performed on a HP-5973 spectrometer. Elemental analyses
were carried out on a EA-1110 elemental analyzer.
4d
1H NMR (500 MHz, CDCl3): = 7.70 (d, 2 H), 7.27 (d, 2 H), 6.62
(s, 1 H), 5.25 (s, 2 H), 4.25 (t, 2 H, PEGOCH2CH2OCO), 3.50–3.78
(m, PEG), 2.71 (br, 4 H, OCCH2CH2CO), 2.40 (s, 3 H).
4e
1H NMR (500 MHz, CDCl3): = 8.64 (s, 1 H), 8.31 (d, 1 H), 8.19
(d, 1 H), 7.65 (m, 2 H), 6.75 (s, 1 H), 5.30 (s, 2 H), 4.25 (t, 2 H,
PEGOCH2CH2OCO), 3.50–3.7 8 (m, PEG), 2.71 (br, 4 H,
OCCH2CH2CO).
Yields and Purity Determination of PEG-Supported Compounds:
The yields of the PEG-supported compounds were determined by
weight with the assumption that Mw is 4000 Da for the PEG frag-
ment. The Mw actually ranged from 3500 to 4500. The indicated
yields were for pure compounds. The purity of these compounds
4f
1
was determined by H NMR analysis in CDCl3 at 500 MHz (with
1H NMR (500 MHz, CDCl3): = 7.72 (d, 1 H), 7.49 (d, 1 H), 7.35–
7.41 (m, 2 H), 6.72 (s, 1 H), 5.53 (s, 2 H), 4.25 (t, 2 H,
pre-saturation of the CH2 signals of the polymer), exploiting the PE-
GOCO–CH2CH2–CO2R signal at = 4.25 as internal standard. The
estimated integration error is 7%.
PEGOCH2CH2OCO), 3.50–3.78 (m, PEG), 2.73 (br,
OCCH2CH2CO).
4 H,
Polymer-Supported Alkyne 2 and Alkene 6; General Procedure
Propargyl alcohol or allyl alcohol (2 mmol), DCC (206 mg, 1
mmol) and a catalytic amount of DMAP were added to PEG-sup-
ported succinate 1 (1 g, 0.5 mmol) in CH2Cl2 (5 mL). The mixture
was stirred at r.t. for 16 h. The precipitate was removed by filtration
and the filtrate was diluted with Et2O. The precipitate was collected,
washed with Et2O and dried affording the polymer-supported
alkyne 2 or alkene 6. TLC (EtOAc–hexane, 1:2) showed that the
solid did not contain free propargyl alcohol or allyl alcohol.
4g
1H NMR (500 MHz, CDCl3): = 7.31 (s, 1 H), 7.26 (d, 1 H), 6.87(d,
1 H), 6.55 (s, 1 H), 6.02 (s, 2 H), 5.24 (s, 2 H), 4.25 (t, 2 H,
PEGOCH2CH2OCO), 3.50–3.78 (m, PEG), 2.71 (br,
OCCH2CH2CO).
4 H,
4h
1H NMR (500 MHz, CDCl3): = 9.87 (s, 1 H), 7.65 (d, 2 H), 6.95
(d, 2 H), 6.57 (s, 1 H), 5.24 (s, 2 H), 4.25 (t, 2 H,
PEGOCH2CH2OCO), 3.50–3.78 (m, PEG), 2.71 (br,
OCCH2CH2CO).
4 H,
2
1H NMR (500 MHz, CDCl3): = 2.50 (t, 1 H, C H), 2.69 (m, 4 H,
OCCH2CH2CO), 3.56–3.78 (m, PEG), 4.25 (t,
PEGOCH2CH2OCO), 4.70 (d, 2 H, CH2CH).
2
H,
7a
1H NMR (500 MHz, CDCl3): = 7.68 (m, 2 H), 7.42 (m, 3 H), 4.98
(m, 1 H), 4.28 (dd, 2 H), 4.25 (t, 2 H, PEGOCH2CH2OCO), 3.50–
3.78 (m, PEG), 3.30 (dd, 2 H), 2.65 (br, 4 H, OCCH2CH2CO).
6
1H NMR (500 MHz, CDCl3): = 2.66 (m, 4 H, OCCH2CH2CO),
3.61–3.78 (m, PEG), 4.25 (t, 2 H, PEGOCH2CH2OCO), 4.60 (d, 2
H, CH2CH=CH2), 5.28 (dd, 2 H, CH2CH=CH2), 5.85 (m, 1 H,
CH2CH=CH2).
7b
1H NMR (500 MHz, CDCl3): = 7.61 (d, 2 H), 6.92 (d, 2 H), 4.97
(m, 1 H), 4.26 (dd, 2 H), 4.21 (t, 2 H, PEGOCH2CH2OCO), 3.84 (s,
3 H), 3.50–3.78 (m, PEG), 3.26 (dd, 2 H), 2.66 (br, 4 H,
OCCH2CH2CO).
Polymer-Supported Isoxazoles 4 and Isoxazolines 7; General
Procedure
To a solution of N-chlorosuccinimide (267 mg, 2 mmol) in anhyd
CH2Cl2 (5 mL) was added the aldoxime (2 mmol). After the chlori-
nation was over, the polymer-supported alkyne 2 or alkene 6 (0.5
mmol) was added in one portion. The reaction mixture was stirred
at r.t. for ca. 30 min, and then Et3N (0.14 mL) in CH2Cl2 (2 mL) was
added dropwise over ca. 2 h and the mixture was stirred overnight
at r.t. Then, a five-fold excess of anhyd benzene was added to re-
move the triethylamine hydrochloride formed. The mixture was fil-
tered and the filtrate was concentrated. Addition of Et2O to the
residue precipitated the resin, which was then filtered and washed
with Et2O to affording the polymer-supported isoxazoles 4a–h or
isoxazolines 7a–f.
7c
1H NMR (500 MHz, CDCl3): = 7.67 (m, 2 H), 7.10 (m, 2 H), 4.98
(m, 1 H), 4.28 (dd, 2 H), 4.23 (t, 2 H, PEGOCH2CH2OCO), 3.50–
3.78 (m, PEG), 3.30 (dd, 2 H), 2.67 (br, 4 H, OCCH2CH2CO).
7d
1H NMR (500 MHz, CDCl3): = 7.56 (d, 2 H), 7.21 (d, 2 H), 4.96
(m, 1 H), 4.28 (dd, 2 H), 4.25 (t, 2 H, PEGOCH2CH2OCO), 3.50–
3.78 (m, PEG), 3.30 (dd, 2 H), 2.65 (br, 4 H, OCCH2CH2CO), 2.38
(s, 3 H).
7e
1H NMR (500 MHz, CDCl3): = 8.44 (s, 1 H), 8.28 (d, 1 H), 8.10
(d, 1 H), 7.63 (m, 1 H), 5.08 (m, 1 H), 4.28 (dd, 2 H), 4.25 (t, 2 H, J
= ? Hz, PEGOCH2CH2OCO), 3.50–3.78 (m, PEG), 3.30 (dd, 2 H),
2.69 (br, 4 H, OCCH2CH2CO).
4a
1H NMR (500 MHz, CDCl3): = 7.80 (m, 2 H), 7.46 (m, 3 H), 6.64
(s, 1 H), 5.26 (s, 2 H), 4.25 (t, 2 H, PEGOCH2CH2OCO), 3.50–3.78
(m, PEG), 2.71 (br, 4 H, OCCH2CH2CO).
7f
4b
1H NMR (500 MHz, CDCl3): = 7.62 (d, 1 H), 7.42 (d, 1 H), 7.35
(m, 1 H), 7.30 (m, 1 H), 5.01 (m, 1 H), 4.28 (dd, 2 H), 4.25 (t, 2 H,
PEGOCH2CH2OCO), 3.50–3.78 (m, PEG), 3.32 (dd, 2 H), 2.68 (br,
4 H, OCCH2CH2CO).
1H NMR (500 MHz, CDCl3): = 7.74 (d, 2 H), 6.97 (d, 2 H), 6.58
(s, 1 H), 5.24 (s, 2 H), 4.25 (t, 2 H, PEGOCH2CH2OCO), 3.85 (s, 3
H), 3.50–3.78 (m, PEG), 2.71 (br, 4 H, OCCH2CH2CO).
4c
Isoxazoles 5 and Isoxazolines 8; General Procedure
1H NMR (500 MHz, CDCl3): = 7.79 (m, 2 H), 7.14 (m, 2 H), 6.59
(s, 1 H), 5.24 (s, 2 H), 4.24 (t, 2 H, PEGOCH2CH2OCO), 3.50–3.78
(m, PEG), 2.71 (br, 4 H, OCCH2CH2CO).
The cleavage of the PEG support was accomplished by treating 4 or
7 with 2 N aq NaOH at r.t. for 3 h. Et2O was added to the reaction
mixture and the organic phase was separated. Removal of Et2O gave
Synthesis 2002, No. 12, 1663–1668 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Isoxazolines and Isoxazoles
1667
the desired isoxazoles 5a–h or isoxazolines 8a–f. Analytical sam-
ples were prepared by column chromatography on silica gel
(EtOAc–hexane, 1:1).
Anal. Calcd for C11H9NO4: C, 60.27; H, 4.11; N, 6.39. Found: C,
60.14; H, 4.15; N, 6.42.
5h
5a
IR (KBr): 3348 (OH), 1612 (C=N) cm–1.
1H NMR (500 MHz, CDCl3): = 9.88 (s, 1 H), 7.67 (d, 2 H), 6.86
(d, 2 H), 5.66 (s, 1 H), 4.58 (s, 2 H), 2.85–3.10(1 H, br).
IR (KBr): 3357 (OH), 1612 (C =N) cm–1.
1H NMR (500 MHz, CDCl3): = 7.78 (m, 2 H), 7.44 (m, 3 H), 6.55
(s, 1 H), 4.79 (s, 2 H), 2.95–3.20 (1 H, br).
EIMS: m/z = 175 (M+), 144 (100%), 116.
EIMS: m/z 191 (M+), 160 (100%), 132.
Anal. Calcd for C10H9NO3: C, 62.83; H, 4.71; N, 7.33. Found: C,
62.86; H, 4.67; N, 7.22.
Anal. Calcd for C10H9NO2: C, 68.57; H, 5.14; N, 8.00. Found: C,
68.86; H, 5.24; N, 7.92.
8a
5b
IR (KBr): 3384 (OH), 1613 (C=N) cm–1.
1H NMR (500 MHz, CDCl3): = 7.66 (m, 2 H), 7.41 (m, 3 H), 4.88
(m, 1 H), 3.83 (dd, 2 H), 3.35 (dd, 2 H), 2.35 (1 H, br).
IR (KBr): 3353 (OH), 1616 (C=N) cm–1.
1H NMR (500 MHz, CDCl3): = 7.72 (d, 2 H), 6.97 (d, 2 H), 6.64
(s, 1 H), 4.78 (s, 2 H), 3.85 (s, 3 H), 2.92–3.18(1 H, br).
EIMS: m/z = 205 (M+), 174 (100%), 146.
EIMS: m/z = 177 (M+), 146 (100%), 118.
Anal. Calcd for C10H11NO2: C, 67.80; H, 6.21; N, 7.91. Found: C,
67.86; H, 6.35; N, 7.92.
Anal. Calcd for C11H11NO3: C, 64.39; H, 5.36; N, 6.83. Found: C,
64.79; H, 5.41; N, 6.77.
8b
5c
IR (KBr): 3364 (OH), 1611 (C=N) cm–1.
1H NMR (500 MHz, CDCl3): = 7.60 (d, 2 H), 6.92 (d, 2 H), 4.84
(m, 1 H), 3.84 (s, 3 H), 3.82 (dd, 2 H), 3.32 (dd, 2 H), 2.38 (1 H, br).
IR (KBr): 3353 (OH), 1611 (C=N) cm–1.
1H NMR (500 MHz, CDCl3): = 7.76 (m, 2 H), 7.13 (m, 2 H), 6.52
(s, 1 H), 4.80 (s, 2 H), 2.96–3.20 (1 H, br).
EIMS: m/z = 193 (M+), 162 (100%), 134.
EIMS: m/z = 207 (M+), 176 (100%), 148.
Anal. Calcd for C11H13NO3: C, 63.77; H, 6.28; N, 6.76. Found: C,
64.02; H, 6.38; N, 6.69.
Anal. Calcd for C10H8FNO2: C, 62.18; H, 4.15; N, 7.25. Found: C,
62.09; H, 4.24; N, 7.18.
8c
5d
IR (KBr): 3368 (OH), 1614 (C=N) cm–1.
1H NMR (500 MHz, CDCl3): = 7.66 (m, 2 H), 7.09 (m, 2 H), 4.88
(m, 1 H), 3.78 (dd, 2 H), 3.33 (dd, 2 H), 2.33(1 H, br).
IR (KBr): 3351 (OH), 1619 (C=N) cm–1.
1H NMR (500 MHz, CDCl3): = 7.69 (d, 2 H), 7.26 (d, 2 H), 6.53
(s, 1 H), 4.81 (s, 2 H), 2.30–3.21 (1 H, br), 2.69 (s, 3 H).
EIMS: m/z = 189 (M+), 158 (100%), 130.
EIMS: m/z = 195 (M+), 164 (100%), 136.
Anal. Calcd for C10H10FNO2: C, 61.54; H, 5.13; N, 7.18. Found: C,
61.16; H, 5.32; N, 7.05.
Anal. Calcd for C11H11NO2: C, 69.84; H, 5.82; N, 7.41. Found: C,
69.75; H, 5.66; N, 7.50.
8d
5e
IR (KBr): 3376 (OH), 1613 (C=N) cm–1.
1H NMR (500 MHz, CDCl3): = 7.55 (d, 2 H), 7.21 (d, 2 H), 4.85
(m, 1 H), 3.71 (dd, 2 H), 3.34 (dd, 2 H), 2.38 (s, 3 H), 2.31 (1 H, br).
IR (KBr): 3349 (OH), 1614 (C=N) cm–1.
1H NMR (500 MHz, CDCl3): = 8.64 (s, 1 H), 8.30 (d, 1 H), 8.19
(d, 1 H), 7.68 (m, 1 H), 6.71 (s, 1 H), 4.83 (s, 2 H), 2.89–3.18 (1 H,
br).
EIMS: m/z = 220 (M+), 189 (100%), 161.
EIMS: m/z = 191 (M+), 160 (100%), 132.
Anal. Calcd for C11H13NO2: C, 69.11; H, 6.81; N, 7.33. Found: C,
69.65; H, 6.56; N, 7.46.
Anal. Calcd for C10H8N2O4: C, 54.55; H, 3.64; N, 12.73. Found: C,
54.67; H, 3.38; N, 12.84.
8e
IR (KBr): 3370 (OH), 1602 (C=N) cm-1.
5f
1H NMR (500 MHz, CDCl3): = 8.43 (s, 1 H), 8.26 (d, 1 H), 8.05
(d, 1 H), 7.60 (m, 1 H), 4.97 (m, 1 H), 3.83 (dd, 2 H), 3.40 (dd, 2 H),
2.34 (1 H, br).
IR (KBr): 3357 (OH), 1612 (C=N) cm–1.
1H NMR (500 MHz, CDCl3): = 7.72 (m, 1 H), 7.49 (m, 1 H), 7.37
(m, 2 H), 6.72 (s, 1 H), 4.83 (s, 2 H), 2.93–3.17 (1 H, br).
EIMS: m/z = 209 (M+), 178 (100%), 150.
EIMS: m/z = 222 (M+), 191 (100%), 163.
Anal. Calcd for C10H10N2O4: C, 54.05; H, 4.50; N, 12.63. Found: C,
53.86; H, 4.38; N, 12.85.
Anal. Calcd for C10H8ClNO2: C, 57.42; H, 3.83; N, 6.70. Found: C,
57.67; H, 3.58; N, 6.61.
8f
5g
IR (KBr): 3363 (OH), 1609 (C=N) cm–1.
IR (KBr): 3364 (OH), 1615 (C=N) cm–1.
1H NMR (500 MHz, CDCl3): = 7.60 (m, 1 H), 7.42 (m, 1 H), 7.34
(m, 1 H), 7.29 (m, 1 H), 4.89 (m, 1 H), 3.78 (dd, 2 H), 3.47 (dd, 2
H), 2.35 (1 H, br).
1H NMR (500 MHz, CDCl3): = 7.27 (s, 1 H), 7.23 (d, 1 H), 6.85
(d, 1 H), 6.46 (s, 1 H), 6.01 (s, 2 H), 4.77 (s, 2 H), 2.92–3.21(1 H,
br).
EIMS: m/z = 211 (M+), 180 (100%), 152.
EIMS: m/z = 219 (M+), 188 (100%), 160.
Synthesis 2002, No. 12, 1663–1668 ISSN 0039-7881 © Thieme Stuttgart · New York

1668
Y.-J. Shang, Y.-G. Wang
PAPER
(5) MeOPEG is not soluble in THF or CH2Cl2 at –78 °C. To
Anal. Calcd for C10H10ClNO2: C, 56.87; H, 4.74; N, 6.64. Found: C,
57.10; H, 4.86; N, 6.48.
circumvent this problem Janda et al. have successfully used
noncross-linked chloromethylated polystyrene (NCPS) as a
soluble polymer support: Chen, S.; Janda, K. D. J. Am.
Chem. Soc. 1997, 119, 8724.
Acknowledgement
(6) Zhao, X. Y.; Metz, W. A.; Sieber, F.; Janda, K. D.
Tetrahedron Lett. 1998, 39, 8433.
The work was financially supported by the National Natural Sci-
ence Foundation of China (No. 29972037) and Foundation for Uni-
versity Key Teacher by the Ministry of Education.
(7) Zhu, J.; Hegedus, L. S. J. Org. Chem. 1995, 60, 5831.
(8) Blaskovich, M. A.; Kahn, M. J. Org. Chem. 1998, 63, 1119.
(9) A search in MDDR (MDL data base) revealed the presence
of more than 250 structures based on the isoxazole scaffold
and endowed with several pharmacological activities used
for analgesia, inflammation, immunology and CNS diseases
(such as anxiety, memory impairment, depression,
Parkinson’s and stroke).
References
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