Soluble polymer-supported synthesis of isoxazoles

Article abstract of DOI:10.1016/S0040-4039(02)00185-5

The first soluble polymer-supported synthesis of isoxazoles through a 1,3-dipolar cycloaddition is described. A soluble polymer-supported alkyne reacts with nitrile oxides generated in situ to give isoxazoles in good yield.

Full text of DOI:10.1016/S0040-4039(02)00185-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2247–2249
Soluble polymer-supported synthesis of isoxazoles
Yong-Jia Shang and Yan-Guang Wang*
Department of Chemistry, Zhejiang University, 310027 Hangzhou, China
Received 28 November 2001; revised 8 January 2002; accepted 24 January 2002
Abstract—The first soluble polymer-supported synthesis of isoxazoles through a 1,3-dipolar cycloaddition is described. A soluble
polymer-supported alkyne reacts with nitrile oxides generated in situ to give isoxazoles in good yield. © 2002 Published by
Elsevier Science Ltd.
1,3-Dipolar cycloaddition of alkynes and alkenes with
nitrile oxides is useful for the synthesis of isoxazoles
and isoxazolines, which are versatile intermediates for
the synthesis of a wide variety of complex natural
products1 and important pharmacophores in medicinal
chemistry. Solution methods for their preparation are
well documented, and several examples of dipolar
cycloaddition to insoluble polymer-supported dipolar-
ophiles have been reported recently.2 These polymer-
supported syntheses offer potential in the combinatorial
synthesis of small heterocycle libraries, since the estab-
lished advantages of solid-phase organic chemistry can
be readily applied. General difficulties in solid phase
work, however, include the possibility of lower reactiv-
ity at the polymer-solvent interface and characteriza-
tion of intermediate products while still attached to the
polymer. Some problems can be alleviated with the use
of a soluble polymer support.3 In this letter we would
like to describe a facile liquid-phase synthesis of
isoxazoles.4
For development of dipolar cycloaddition chemistry we
chose to employ polyethylene glycol (PEG) with an
average molecular weight of 4000. This inexpensive
polymer is attractive as a support since it is soluble in
many organic solvents, with the notable exception of
ethers and hexane, and is a solid at room temperature.
Not only does solubility allow for solution reactivity
but also intermediate products can be adequately char-
acterized by proton NMR.
The synthesis of isoxazoles is described in Scheme 1.
PEG4000 succinate 15 was condensed with propargyl
alcohol (3.0 mol equiv.) in the presence of dicyclohexyl-
carbodiimide (DCC, 4.0 mol equiv.) and 4-dimethyl-
aminopyridine (DMAP, 0.2 mol equiv.) to afford the
polymer supported alkyne 2.6 This material was reacted
with aryl hydroxyminoyl chlorides 3 by slow addition
of triethylamine over a period of 2 h in methylene
chloride.7 The resulting mixture was shaken at room
temperature overnight. To this was added five equiva-
Scheme 1.
* Corresponding author. Tel./fax: 86-571-87951512; e-mail: orgwyg@css.zju.edu.edu.cn
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00185-5

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Y.-J. Shang, Y.-G. Wang / Tetrahedron Letters 43 (2002) 2247–2249
Table 1. Liquid-phase synthesis of isoxazoles
lents of benzene to remove triethylamine hydrochloride.
The solution was concentrated and diethyl ether was
added to afford the polymer supported isoxazoles 4.8
Substrate cleavage was accomplished by treating 4 with
aqueous 2N NaOH at room temperature and moni-
tored for the disappearance of the polymeric isoxazoles
(3 h) (Table 1).9
(No. 29972037) and Foundation for University Key
Teachers by the Ministry of Education.
References
1. Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410.
2. (a) Kang, K. H.; Pae, A. N.; Choi, K. I.; Cho, Y. S.;
Chung, B. Y.; Lee, J. E.; Jung, S. H.; Koh, H. Y.; Lee, H.
Y. Tetrahedron Lett. 2001, 42, 1057–1060; (b) Larsen, K.
E.; Torssell, B. G. Tetrahedron Lett. 1984, 15, 2985–2988.
3. Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489–
509.
4. The synthesis of isoxazolines and isoxazoles through an
insoluble polymer-supported nitrile oxide, see: Shankar, B.
B.; Yang, D. Y.; Girton, S.; Ganguly, A. K. Tetrahedron
Lett. 1998, 39, 2447–2448.
Using this procedure, a variety of isoxazoles can be
synthesized by trapping in situ generated nitrile oxides
with the polymer-supported alkyne in a practical and
efficient one-pot operation. The products are of excel-
lent purity (>95%) and isolated in 48–91% yields, as
shown in Table 1.
Acknowledgements
5. Compound 1 was prepared in 96% yield by treatment of
PEG4000 with succinic anhydride and catalytic DMAP in
refluxing CH2Cl2.
We are greatly indebted for the financial support from
the National Natural Science Foundation of China

Y.-J. Shang, Y.-G. Wang / Tetrahedron Letters 43 (2002) 2247–2249
2249
6. The polymer supported alkyne was characterised by 500
MHz 1H NMR analysis in CDCl3 (l 2.50 [t, J=2.3 Hz,
alkyne proton], 2.69 [m, 4H, -OCCH2CH2CO], 4.25 [t,
J=4.2 Hz, 2H, -PEGOCH2CH2OCO], 4.70 [d, J=2.4 Hz,
propargylic CH2]).
7. Paton, R. M.; Young, A. A. J. Chem. Soc., Chem. Com-
mun. 1994, 993.
8. Typical procedure for isoxazole synthesis: N-Chlorosuc-
cinimide (NCS, 2 mmol) was stirred in a flask containing
dry methylene chloride. The oxime (2 mmol) was added at
25°C in one portion. The polymer-supported alkyne (0.5
mmol) was added in one portion after the chlorination was
over. Usually after ca. 30 min, triethylamine (0.14 mL in 2
mL of CH2Cl2) was added dropwise over ca. 2 h. The
reaction mixture was stirred overnight at room tempera-
ture. To this was added a five-fold excess of dry benzene to
remove triethylamine hydrochloride. The solution was
concentrated and diethyl ether was added to afford the
polymer-supported isoxazoles 4, which were characterised
1
1
by H NMR spectroscopy. Compound 4b: H NMR (500
MHz CDCl3): l 7.74 [d, J=8.7 Hz, 2H], 6.97 [d, J=8.7
Hz, 2H], 6.58 [s, 1H], 5.24 [s, 2H], 4.25 [t, J=4.7 Hz, 2H],
3.85 [s, 3H], 2.71 [br., 4H]. The resin was then cleaved with
aqueous 2N NaOH at room temperature to give the
desired isoxazoles. Compound 5b: 1H NMR (CDCl3): l
7.72 [d, J=8.7 Hz, 2H], 6.97 [d, J=8.8 Hz, 2H], 6.50 [s,
1H], 4.79 [s, 2H], 3.84 [s, 3H]); GC/MS: m/z 205 (M+,
59%), 174 (100%).
9. Purity was determined by GC/MS analysis of the crude
products. All products showed satisfactory NMR and
MS data, which were consistent with the proposed struc-
tures.