Tetrahedron Letters 48 (2007) 1295–1298
Isoxazoles from 1,1-disubstituted bromoalkenes
Sureshbabu Dadiboyena, Jianping Xu and Ashton T. Hamme, II*
Department of Chemistry, Jackson State University, Jackson, MS 39217, USA
Received 8 August 2006; revised 29 November 2006; accepted 4 December 2006
Available online 4 January 2007
Abstract—The regioselective synthesis of 3,5-disubstituted isoxazoles was achieved through the 1,3-dipolar cycloaddition of nitrile
oxides with 1,1-disubstituted bromoalkenes. The substituted bromoalkenes function as alkyne synthons which were used to con-
struct 5,5-disubstituted bromoisoxazoline intermediates that aromatize to the analogous isoxazoles through the loss of HBr.
Ó 2006 Elsevier Ltd. All rights reserved.
Since a number of isoxazoles display anti-inflamma-
tory,1 antiviral,2 as well as antitubulin3 activity, the syn-
thesis of this family of heterocycles continues to be of
interest. One of the most frequently used methods to
synthesize isoxazoles is a 1,3-dipolar cycloaddition
involving a nitrile oxide, and the usual dipolarophile
for this process is an alkyne.4 Although some alkynes
are commercially available, the synthesis of many func-
tionalized alkynes can take two or more steps. Addition-
ally, the 1,3-dipolar cycloaddition of alkynes, with a few
exceptions,5 often lead to a mixture of regioisomeric
products.4,6b The use of alkyne synthons6 can serve to
alleviate many of the alkyne preparatory and cyclo-
addition regioselectivity issues.7 These alkyne surrogates
are usually alkenes that have a functional group that
can be eliminated in situ during cycloaddition.6 Herein
we report the application of 1,1-disubstituted bromo-
alkenes as alkyne equivalents for the regioselective
synthesis of 3,5-disubstituted isoxazoles via 1,3-dipolar
cycloaddition.
During our study of the synthesis of functionalized 5,5-
disubstituted isoxazolines, we discovered that when
2-bromo-acrylic acid methyl ester (1) was used as the
alkene, isoxazole (4) was isolated as the sole product
instead of bromoisoxazoline (3, Scheme 1).8 The most
probable driving force for the formation of 4 is the
creation of a stable aromatic system through the loss
of HBr. Alternatively, since the reaction conditions are
basic, it is quite possible for bromoalkene, 1, to decom-
pose to the corresponding alkyne before reacting with
the nitrile oxide. In order to rule out this reaction
pathway, we exposed 1 to triethylamine for 24 h, and
no decomposition or formation of alkyne was observed.
The experimental data point to the formation of 3
followed by its aromatization to 4,6 and the regioselec-
tivity is in accordance with both steric and frontier
molecular orbital interactions of the 1,3-dipole and the
alkene.9 The study of the 1,3-dipolar cycloaddition
reaction of compound 1 and other bromoalkenes was
undertaken in order to determine the general efficacy
HO
N
O
O
O
Cl
O
O
2
CH3O
N
CH3O
N
-HBr
56%
Br
Br
CH3O
(C2H5)3N, CH2Cl2
3
4a
1
Scheme 1. Isoxazole synthesis from 2-bromo-acrylic acid methyl ester through a 5-bromoisoxazoline intermediate.
Keywords: Cycloaddition; Regioselectivity; Heterocycles; Alkyne surrogate; Dehydrohalogenation.
*
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.005