2
96
Chemistry Letters Vol.36, No.2 (2007)
Addition of Allylindium Bromide to Nitrile Oxides in Aqueous Media:
Convenient Synthesis of 5-Methylisoxazolines
ꢀ
Sanghapal D. Sawant, Parvinder P. Singh, Naveed A. Qazi, and H. M. Sampath Kumar
Regional Research Laboratory, Jammu-Tawi, 180 001, India
(Received November 27, 2006; CL-061395)
Ar
Ar
Ar
5
-Methylisoxazolines were obtained in good yields through
_
+
N
ZnBr
THF, RT
O
2
a highly selective nucleophilic addition of allylindium reagent to
benzonitrile oxides with concominant C–O heterocyclization.
Ar
N
N
+
OH
+
N
O
3
O
1
4
5
Major Product(>50%)
Scheme 2. Addition of allylzinc bromide to nitrile oxides.
The addition of organometallic reagents to C=N compounds
1
is a well-known C–C bond-forming reaction. However, the de-
important to note that, when zinc was employed instead of indi-
7
velopment of these addition reactions has been severely limited
due to poor electrophilicity of the azomethine carbon and also by
the tendency of imine and imino derivatives to undergo de-pro-
tonation in preference to additions. However, subsequent devel-
opment of a variety of organometallic reactions greatly im-
proved the scope of such addition reactions involving imines
or imine derivatives. Electrophilicity of imine carbon can be en-
hanced through N-acylation, N-alkylation, or N-oxide formation.
Use of resonance stabilized allyl organometallics that are com-
paratively more reactive can be alternative strategy for establish-
ing C–C bond through the addition to C=N compounds. Thus,
nucleophilic additions of organometallic reagents to various
C=N compounds such as imines, hydrazones, oxime-ethers
um, corresponding 5-butenylisoxazolines 5 were isolated as
major products (>50%) generated through domino addition, to-
8
gether with 10–15% of aryl oxime 4 derived from the nucleo-
philic allylation of nitrile oxides along with trace amounts
(<4%) of 5-methylisoxazolines (Scheme 2). However, in case
of indium-promoted reaction, crude product did not contain
any trace of either 5-butenylisoxazolines or hydroxamic acids
even when excess of allylindium bromide was used, which clear-
ly shows the superiority of indium and aqueous conditions for
achieving the high product selectivity. However, when the reac-
tion was carried out in anhydrous THF or DMF, corresponding
7
5-butenylisoxazoline was isolated in 32–55% yield together
with minor quantities of 5-methylisoxazolines (6–18%).
In all the nitrile oxides studied, 5-methylisoxazoline was the
sole product at the end of 24-h reaction. The preparation of
5-methylisoxazolines can be otherwise visualized only through
1,3-dipolar nitrile oxide cycloaddition to propylene gas which
might be relatively inconvenient as the reaction has to be carried
2
are well established. Nitrones have been successfully employed
as substrates for such additions, even though the same has not
been studied in depth with regard to nitrile oxides despite the fact
that nitrile oxides are known to add to a number of nucleophiles
3
to generate hydroximic acid derivatives. Among all the metals
3
h
used for such purpose, indium occupies unique position due to its
superior reactivity and stability under aqueous conditions, which
makes it an eco-friendly metal. In the recent past, we have
reported a number of addition reactions to C=N compounds like
out under adiabatic conditions or via a tandem rearrangement–
3i
cyclization reaction of O-propargylic hydroxylamines. Thus, it
may not be presumptuous to anticipate that the methodology dis-
played in this paper may find utility as attractive alternative to
existing preparative protocols for 5-methylisoxazolines required
for any possible biological and synthetic application. The forma-
tion of 5-methylisoxazolines can be visualized through nucleo-
philic addition of allylindium bromide with nitrile oxide fol-
lowed by concomitant C–O heterocyclization (Scheme 3) How-
ever, the high product selectivity may be attributed to relatively
low stability of the intermediate 3b as compared to the stabilized
allylindium bromide which readily undergo proton capture to
generate 5-methylisoxazolines. Even though the possibility of
allylindium species under going dipolar cycloaddition can not
be ruled out, the same could not be supported either through any
literature precedent or establish empirically. However, as dis-
cussed before, nucleophilic addition of various organometallic
species to nitrile oxides has been well established and hence
we propose the plausible mechanism to explain the product
4
azides, nitrones, and hydrazones. Because of our continued
interest in the application of indium in environmental friendly
organic transformations, we report in this communication, a
selective addition of allylindium bromide to various nitrile
oxides under aqueous conditions.
Several in situ generated as well as stable benzonitrile ox-
ides were reacted with allylindium bromide in THF–Water
5
(
1:1) medium. The addition reaction proceeds to completion
6
smoothly within 24 h at ambient temperature as indicated by in-
termittent TLC examination. 5-Methyl isoxazolines 3 were iso-
lated in high yields after workup and chromatographic purifica-
tion (Scheme 1). The structure of the product could be unequiv-
ocally assigned based on spectroscopic data and the presence of
5
-methyl group could be confirmed by DEPT experiments. It is
Ar
+
-
Ar
Ar
N
Ar
Br, In, THF/Water
+
N
N
Ar
N
O
Ar
O
H+
N
THF/H
2
O
O
OIn
N
ArCNO
1
+
In
O
O
3
In
In
1
2
3a
3b
3
Scheme 1. Selective addition of allylindium bromide to nitrile
oxides.
Scheme 3. Plausible mechanism for the formation of 5-methyl-
isoxazolines.
Copyright Ó 2007 The Chemical Society of Japan
Sawant, Sanghapal D.
