ORGANIC
LETTERS
2009
Vol. 11, No. 17
3982-3985
Efficient and Regioselective One-Pot
Synthesis of 3-Substituted and
3,5-Disubstituted Isoxazoles
Shibing Tang,† Jinmei He,† Yongquan Sun,† Liuer He,† and Xuegong She*,†,‡
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry,
Lanzhou UniVersity, Lanzhou 730000, P. R. China, and State Key Laboratory for Oxo
Synthesis and SelectiVe Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000, P. R. China
Received July 16, 2009
ABSTRACT
A series of 3-substituted and 3,5-disubstituted isoxazoles have been efficiently synthesized in moderate to excellent yields by the reaction of
N-hydroxyl-4-toluenesulfonamide with r,ꢀ-unsaturated aldehydes/ketones. This novel strategy is associated with readily available starting
materials, mild conditions, high regioselectivity, and wide scope.
The isoxazole nucleus is a prominent structural motif found
in numerous natural products and synthetic compounds with
vital medicinal value.1 The development of new methods
for their synthesis is therefore an area of considerable
ongoing interest.2-9
oxides and the reaction of hydroxylamine with a three-carbon
atom component. Recently, Fokin’s group described a series
of novel routes to 3,5- and 3,4-disubstituted isoxazoles
through transition-metal-catalyzed [3 + 2] cycloaddition.4
The reaction of R-acetylenic ketones, a three-carbon atom
component, with methoxylamine to give highly substituted
In general, isoxazoles were obtained by two major
routes:2,3 [3 + 2] cycloaddition of alkenes/alkynes with nitrile
(6) (a) Wei, X.; Fang, J.; Hu, Y.; Hu, H. Synthesis 1992, 1205. (b) Desai,
V. G.; Tilve, S. G. Synth. Commun. 1999, 29, 3017. (c) Kurangi, R. F.;
Kawthankar, R.; Sawal, S.; Desai, V. G.; Tilve, S. G. Synth. Commun. 2007,
37, 585.
† Lanzhou University.
‡ Lanzhou Institute of Chemical Physics.
(1) For reviews, see: (a) Carlsen, L.; Do¨pp, D.; Do¨pp, H.; Duus, F.;
Hartmann, H.; Lang-Fugmann, S.; Schulze, B.; Smalley, R. K.; Wakefield,
B. J. In Houben-Weyl Methods in Organic Chemistry; Schaumann, E., Ed.;
Georg Thieme Verlag: Stuttgart, Germany, 1992; Vol. E8a, pp 45-204.
(b) Sperry, J.; Wright, D. Curr. Opin. Drug DiscoV. DeVel. 2005, 8, 723.
(2) For recent reviews, see: (a) Wakefield, B. J. In Science of Synthesis:
Houben-Weyl Methods of Molecular Transformations; Shaumann, E., Ed.;
Georg Thieme Verlag: Stuttgart, 2001; Vol. 11, pp 229-288. (b) Pinho e
(7) (a) Borkhade, K. T.; Marathey, M. G. Indian J. Chem. 1970, 8, 796.
(b) Kashima, C.; Yoshihara, N.; Shirai, S. I. Heterocycles 1981, 16, 145.
(c) Katritzky, A. R.; Wang, M.; Zhang, S.; Voronkov, M. V. J. Org. Chem.
2001, 66, 6787. (d) Dominguez, E.; Ibeas, E.; Marigorta, E. M.; Palacios,
J. K.; SanMartin, R. J. Org. Chem. 1996, 61, 5435. (e) Wittenberger, S. J.
J. Org. Chem. 1996, 61, 356. (f) Manferdini, M.; Morelli, C. F.; Veronese,
A. C. Heterocycles 2000, 53, 2775. (g) Ghosh, T.; Bandyopadhyay, C.
Tetrahedron Lett. 2004, 45, 6169. (h) Rosap, F. A.; Machado, P.; Bonacorso,
H. G.; Zanatta, N.; Martins, M. A. P. J. Heterocycl. Chem. 2008, 45, 879.
(8) Kidwai, M.; Kukreja, S.; Thakur, R. Lett. Org. Chem. 2006, 3, 135.
(9) For more examples: (a) Xu, J. P.; Hamme, A. T., II. Synlett 2008,
0919. (b) Ahmed, M. S. M.; Kobayashi, K.; Mori, A. Org. Lett. 2005, 7,
4487. (c) Denmark, S. E.; Kallemeyn, J. M. J. Org. Chem. 2005, 70, 2839.
(d) Bourbeau, M. P.; Rider, J. T. Org. Lett. 2006, 8, 3679. (e) Wang, K.;
Xiang, D.; Liu, J.; Pan, W.; Dong, D. Org. Lett. 2008, 10, 1691. (f) Girardin,
M.; Alsabeh, P. G.; Lauzon, S.; Dolman, S. J.; Ouellet, S. G.; Hughes, G.
Org. Lett. 2009, 11, 1159.
Melo, T. M. V. D. Curr. Org. Chem. 2005, 9, 925
.
(3) Ja¨ger, V.; Colinas, P. A. In Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products;
Padwa, A., Ed.; Wiley: Hoboken, 2002; Vol. 59, pp 361-472.
(4) (a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210. (b)
Hansen, T. V.; Wu, P.; Fokin, V. V. J. Org. Chem. 2005, 70, 7761. (c)
Grecian, S.; Fokin, V. V. Angew. Chem., Int. Ed. 2008, 47, 8285
(5) (a) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 23, 5203. (b) Waldo,
J. P.; Larock, R. C. J. Org. Chem. 2007, 72, 9643
.
.
10.1021/ol901626n CCC: $40.75
Published on Web 08/06/2009
2009 American Chemical Society