ORGANIC
LETTERS
2009
Vol. 11, No. 5
1159-1162
Synthesis of 3-Aminoisoxazoles via the
Addition-Elimination of Amines on
3-Bromoisoxazolines
Me´lina Girardin,* Pamela G. Alsabeh, Sophie Lauzon, Sarah J. Dolman, Ste´phane
G. Ouellet, and Greg Hughes
Department of Process Research, Merck Frosst Centre for Therapeutic Research,
16711 Trans Canada Highway, Kirkland, Que´bec, Canada H9H 3L1
Received January 7, 2009
ABSTRACT
A novel two-step procedure for the synthesis of 3-amino-5-substituted-isoxazoles is described. In the presence of a base, readily available
3-bromoisoxazolines react with amines to afford 3-aminoisoxazolines. An oxidation protocol was developed for these heterocycles to provide
3-aminoisoxazoles in consistently high yield.
To rapidly access structurally diverse targets, medicinal
chemists require convenient and reliable methodologies,
especially in the area of heterocyclic chemistry. Syntheses
of 3-alkyl- and 3-aryl-substituted isoxazoles are well-
established1 and include 1,3-dipolar cycloadditions,2 hy-
droxylamine condensations,3 Claisen condensations of ke-
toxime dianions,4 and cyclizations of propargylic oximes.5
However, there are few reported methodologies for the
synthesis of N-substituted 3-aminoisoxazoles.6 A key discon-
nection for their synthesis would be at the C3-N bond, which
would allow for a variety of analogues to be prepared from
a single precursor. Despite recent advances in copper- and
palladium-catalyzed amination of aryl halides,7 3-bromoisox-
azoles 3 remain poor substrates for these methodologies and
do not provide access to the corresponding 3-aminoisoxazoles
4 (Scheme 1).8 Thermally mediated aromatic nucleophilic
substitution (SNAr) of 3-chloro-1,2-benzisoxazoles with
amines has been reported on a small number of substrates.9
(6) (a) Moore, J. E.; Spinks, D.; Harrity, J. P. A. Tetrahedron Lett. 2004,
3189–3191. (b) Alberola, A.; Antolin, L. F.; Cuadrado, P.; Gonza´lez, A. M.;
Laguna, M. A.; Pulido, F. J. Synthesis 1988, 203–207. (c) Sugai, S.; Sato,
K.; Kataoka, K.; Iwasaki, Y.; Tomita, K. Chem. Pharm. Bull. 1984, 32,
530–537. (d) For a recent review on aminoisoxazoles, see: Kislyi, V. P.;
Danilova, E. B.; Semenov, V. V. AdV. Heterocycl. Chem. 2007, 94, 173–
214.
(1) (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 Melo, T. M. V. D. Curr.
Org. Chem. 2005, 9, 925–958.
(2) (a) Hansen, T. V.; Wu, P.; Fokin, V. V. J. Org. Chem. 2005, 70,
7761–7764. (b) Denmark, S. E.; Kallemeyn, J. M. J. Org. Chem. 2005, 70,
2839–2842. (c) Moore, J. E.; Davies, M. W.; Goodenough, K. M.; Wybrow,
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(7) (a) Kienle, M.; Dubbaka, S. R.; Brade, K.; Knochel, P. Eur. J. Org.
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(8) This issue was also noted by others; see ref 6a. For a review of
azoles cross-couplings, see: Schnu¨rch, M.; Flasik, R.; Khan, A. F.; Spina,
M.; Mihovilovic, M. D.; Stanetty, P. Eur. J. Org. Chem. 2006, 2006, 3283–
3307.
(3) (a) Bandiera, T.; Gru¨nanger, P.; Albini, F. M. J. Heterocycl. Chem.
1992, 29, 1423–1428. (b) Lautens, M.; Roy, A. Org. Lett. 2000, 2, 555–
557.
(9) (a) Yevich, J. P.; New, J. S.; Smith, D. W.; Lobeck, W. G.; Catt,
J. D.; Minielli, J. L.; Eison, M. S.; Taylor, D. P.; Riblet, L. A.; Temple,
D. L., Jr. J. Med. Chem. 1986, 29, 359–369. (b) Urban, F. J.; Breitenbach,
R.; Murtiashaw, C. W.; Vanderplas, B. C. Tetrahedron: Assymetry 1995,
6, 321–324. (c) Bo¨shagen, H. Chem. Ber. 1967, 100, 3326–3330. (d) For
an example with an isoxazolo[4,5-d]pyrimidine, see: Wagner, E.; Becan,
L. Pol. J. Chem. 1995, 69, 70–73.
(4) (a) He, Y.; Lin, N.-H. Synthesis 1994, 989–992. (b) Nitz, T. J.;
Volkots, D. L.; Aldous, D. J.; Oglesby, R. C. J. Org. Chem. 1994, 59,
5828–5832.
(5) (a) Short, K. M.; Ziegler, C. B., Jr. Tetrahedron Lett. 1993, 34, 75–
78. (b) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203–5205.
10.1021/ol9000284 CCC: $40.75
Published on Web 02/11/2009
2009 American Chemical Society