Efficient access to isoxazoles from alkenes

Article abstract of DOI:10.1055/s-2008-1042906

The direct regioselective synthesis of 3,5-disubstituted isoxazoles was achieved in one reaction vessel through a sequence of reactions involving the net bromination of an electron-deficient alkene, in situ generation of a nitrile oxide, 1,3-dipolar cycloaddition, and loss of HBr from an intermediate 5,5-disubstituted bromoisoxazoline. This one-pot process enables the synthesis of 3,5-disubstituted isoxazoles directly from electron-deficient alkenes thereby negating the isolation of the 1,1-disubstituted bromoalkene alkyne surrogate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042906

LETTER
919
Efficient Access to Isoxazoles from Alkenes
Efficient
a
i
ndDir
a
t
A
ccess
n
to
I
soxazoles
p
from
A
lken
i
es ng Xu, Ashton T. Hamme II*
Department of Chemistry, Jackson State University, Jackson, MS 39217-0510, USA
Fax +1(601)9793674; E-mail: ashton.t.hamme@jsums.edu
Received 18 December 2007
HO
N
Abstract: The direct regioselective synthesis of 3,5-disubstituted
isoxazoles was achieved in one reaction vessel through a sequence
of reactions involving the net bromination of an electron-deficient
alkene, in situ generation of a nitrile oxide, 1,3-dipolar cycloaddi-
tion, and loss of HBr from an intermediate 5,5-disubstituted bro-
moisoxazoline. This one-pot process enables the synthesis of 3,5-
disubstituted isoxazoles directly from electron-deficient alkenes
thereby negating the isolation of the 1,1-disubstituted bromoalkene
alkyne surrogate.
O
Cl
O
O
2
MeO
N
Br
Br
MeO
Et3N, CH2Cl2
3
1
O
Key words: cycloadditions, heterocycles, tandem reactions, alkyne
surrogate, dehydrohalogenation
O
N
MeO
– HBr
56%
4
A number of isoxazoles display anti-inflammatory1 anti-
viral,2 antitubulin,3 antithrombotic4 as well as T-type Ca2+
channel blocking5 activity. The major synthetic route to-
wards these heterocycles is 1,3-dipolar cycoaddi-
tion.2a,3,4d,5 For the synthesis of isoxazoles, alkynes are
often used as the dipolarophile in the 1,3-dipolar cycload-
dition reaction with nitrile oxides, however, regioselectiv-
ity issues often arise.6 Moreover, isoxazoles can be
synthesized from simple alkenes, but an additional oxida-
tion step is usually required.3a,6c On the other hand, gemi-
nally disubstituted alkenes with a bromine atom as one of
the substituents have been shown to be effective alkyne
surrogates that lead to the isolation of only one isoxazole
regioisomer without the isolation of an isoxazoline inter-
mediate.6c,7 However, these bromoalkenes are usually
synthesized and isolated before they are incorporated into
the cycloaddition process. Furthermore, some of these
bromoalkenes are unstable and quickly decompose after
their isolation.7 These instability issues motivated our re-
search group to investigate the possibility of generating
and reacting the bromoalkene and the nitile oxide in situ.
The highly regioselective isoxazole formation that utilizes
the in situ bromination of an alkene, followed by dehydro-
bromination and 1,3-dipolar cycloaddition is reported
herein.
Scheme 1 Isoxazole synthesis from 1,1-disubstituted bromoalkene
tivity that was achieved during the cycloaddition process
was appealing. The regioselectivity of 1,3-dipolar cy-
cloaddition reactions of nitrile oxides with geminally di-
substituted alkenes is often high due to both steric and
frontier molecular orbital interactions of the 1,3-dipole
and the alkene.9 We postulate that during the cycloaddi-
tion, the nitrile oxide approaches the 1,1-disubstituted alk-
ene in a manner such that the nitrile oxide skirts the steric
bulk of the bromine substituent which leads to the ob-
served regioselectivity. The 5,5-disubstituted bromoisox-
azoline intermediate then aromatizes to the analogous
isoxazole through the loss of HBr. On the basis of this re-
sult,7,8 we then decided to take advantage of the fact that
triethylamine promotes the synthesis of not only
bromoalkenes10 but also nitrile oxides11 by exposing the
brominated alkene intermediate and the a-chlorobenzald-
oxime to triethylamine. Upon generation of the bromoalk-
ene and nitrile oxide, 1,3-dipolar cycloaddition should
result in an intermediate, which follows the same reaction
pathway as the aforementioned cycloaddition process.
Scheme 2 shows our proposed reaction pathway for the
synthesis of 4 from alkene 5. The successful isolation of 4
as the exclusive product in high yield prompted an inves-
tigation into the scope and limitations of this methodology
using other activated alkenes and a-chlorobenzaldoximes.
Many of the activated alkenes were chosen in order to
compare their regioselectivities with the published 1,3-di-
polar cycloaddition regioselectivities for the correspond-
ing alkyne compounds.6 The results for the cycloaddition
of 5, methyl vinyl ketone, and acrolein with three different
nitrile oxides are shown in Table 1. All of these cycload-
ditions occurred with complete regiochemical integrity
and in reasonable to good isolated yields.
While we were investigating the synthesis of functional-
ized 5,5-disubstituted isoxazolines, we discovered that
when 2-bromoacrylic acid methyl ester 1 was used as the
alkene, isoxazole 4 was the only product that was isolated8
(Scheme 1). Even though this result can be anticipated
due to the aromatic stability created by the loss of HBr
from bromoisoxazoline 3, the high degree of regioselec-
SYNLETT 2008, No. 6, pp 0919–0923
x
x.
x
x.
2
0
0
8
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042906; Art ID: S10307ST
© Georg Thieme Verlag Stuttgart · New York

920
J. Xu, A. T. Hamme II
LETTER
HO
oxidation of the pendant alcohol to the aldehyde with
PCC.5 Our synthetic methodology negates the necessity of
additional isolation and heavy-metal-promoted oxidation
steps since the desired aldehydes are directly obtained.
N
Cl
O
O
2
Br2, CH2Cl2
MeO
Br
Br
MeO
According to literature precedent, the major regioisomer
that is isolated from the reaction of nitrile oxides with
phenyl sulfone containing alkynes is the 4-substituted
isoxazole,13 however, the reversal of cycloaddition regio-
selectivity was observed in similar cycloadditions with
halogenated alkenes.7 With this precedent in mind, we de-
cided to take advantage of the latter regioselectivity for
the eventual application of our methodology towards the
synthesis of 5-substituted isoxazoles. When phenyl vinyl
sulfone was subjected to the bromination–dehydrobromi-
nation and cycloaddition reaction conditions with a-chlo-
robenzaldoxime, only the 5-(benzenesulfonyl)isoxazole
product was isolated (Table 2, entry 1). Similar results
from the reaction of phenyl vinyl sulfone with two other
aromatic nitrile oxides are reported in Table 2. Since
phenyl sulfoxides can serve as leaving groups under cer-
tain reaction conditions,14 phenyl vinyl sulfoxide was bro-
minated, dehydrobrominated, and reacted with three
different nitrile oxides in order to determine if the phenyl
sulfoxide would compete with the bromide ion as a leav-
ing group. Table 2 (entries 4–6) shows that the cycloaddi-
tion occurred with complete regioselectivity, and only the
5-(benzenesulfinyl)isoxazole was isolated.
then Et3N
5
6
O
O
N
O
O
MeO
N
[4+2]
Br
Br
+
MeO
1
3
7
O
O
MeO
N
– HBr
85%
4
Scheme 2 Proposed intermediates for one-pot isoxazole synthesis
from acrylate
In summary, we report a facile and regioselective synthe-
sis of 5-isoxazoles through the cycloaddition of nitrile ox-
ides with in situ generated bromoalkenes.15 Because the
bromoisoxazoline intermediates lose HBr to generate the
isoxazole, the 1,1-disubstituted bromoalkenes serve as
alkyne synthetic equivalents.
Many isoxazoles which possess aldehyde substituents
serve as precursors to more complex molecules.4c,d,5,12
One of the most interesting series in this regard involves
prop-2-enal (entries 7–9, Table 1). Prior syntheses of
these isoxazoles involves the 1,3-dipolar cycloaddition of
a nitrile oxide with a propargyl alcohol followed by the
Table 1 Isoxazoles Constructed from the 1,3-Dipolar Cycloaddition Reactions Using Carbonyl-Containing Alkenes as the Dipolarophile
Entry
1
Alkene
a-Chloro oxime
Product
Yield (%)
91
O
HO
N
O
O
MeO
MeO
N
N
Br
Br
Cl
MeO
MeO
O
HO
O
N
Cl
O
2
75
Cl
Cl
Cl
Cl
Synlett 2008, No. 6, 919–923 © Thieme Stuttgart · New York

LETTER
Efficient and Direct Access to Isoxazoles from Alkenes
921
Table 1 Isoxazoles Constructed from the 1,3-Dipolar Cycloaddition Reactions Using Carbonyl-Containing Alkenes as the Dipolarophile
(continued)
Entry
Alkene
a-Chloro oxime
Product
Yield (%)
O
HO
N
O
MeO
N
O
3
84
Br
Cl
MeO
OMe
OMe
O
HO
N
O
O
Me
Me
Me
N
4
5
70
79
Br
Cl
Me
Me
O
O
HO
O
N
Cl
O
O
N
N
Br
Br
Cl
Cl
Cl
Cl
O
HO
N
6
86
Cl
Me
OMe
OMe
O
HO
Cl
O
N
O
H
H
H
N
7
8
81
67
Br
H
H
O
HO
Cl
O
N
Cl
O
N
N
Br
Br
Cl
Cl
Cl
O
O
HO
Cl
N
O
9
73
H
OMe
OMe
Synlett 2008, No. 6, 919–923 © Thieme Stuttgart · New York

922
J. Xu, A. T. Hamme II
LETTER
Table 2 Isoxazoles Synthesized from the 1,3-Dipolar Cycloaddition Reactions Using Sulfone- and Sulfoxide-Containing Alkenes as the
Dipolarophile
Entry
Alkene
a-Chloro oxime
Product
Yield (%)
97
O
PhO2S
HO
N
N
SO2Ph
1
Cl
O
O
PhO2S
HO
N
N
Cl
SO2Ph
Cl
2
3
92
88
Cl
Cl
Cl
PhO2S
HO
Cl
N
N
SO2Ph
OMe
OMe
O
HO
Cl
Ph(O)S
Ph(O)S
N
N
N
S(O)Ph
S(O)Ph
4
5
78
58
O
O
HO
Cl
N
N
Cl
Cl
Cl
Cl
Ph(O)S
HO
Cl
N
S(O)Ph
6
63
OMe
OMe
Cristina, A.; Dusonchet, L.; Meli, M.; Tolomeo, M. J. Med.
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2006, 14, 4067.
Acknowledgment
We thank the National Institutes of Health (3S06GM008047-34S1,
G12RR13459-07S18186, and G12RR13459) for their generous fi-
nancial support.
(4) (a) Pruitt, J. R.; Pinto, D. J.; Estrella, M. J.; Bostrom, L. L.;
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Synlett 2008, No. 6, 919–923 © Thieme Stuttgart · New York

LETTER
Efficient and Direct Access to Isoxazoles from Alkenes
923
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(15) General Experimental Procedure
After the alkene (0.5 mmol) was dissolved in CH2Cl2 (15
mL), bromine (0.55 mmol) was added dropwise. After all of
the alkene was completely consumed, as confirmed by TLC
on silica gel (hexanes–EtOAc, 4:1), the hydroximoyl
chloride (0.5 mmol) was added, and Et3N (1.2 mmol) was
added shortly thereafter. The reaction mixture was stirred at
r.t. until the disappearance of the bromoalkene, as verified
by TLC on silica gel (hexanes–EtOAc, 4:1). The reaction
mixture was washed with H2O (3 × 10 mL), and the organic
layer was dried over anhyd Na2SO4. The crude products
were purified by flash column chromatography over silica
gel using hexanes–EtOAc (4:1) as the eluent system. This
procedure provides pure isoxazole products for entries 1–15
in 58–97% yield.
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Spectroscopic data for Entry 9, Table 1
Colorless solid (74 mg, 73%), mp 84–87 °C. IR (CaF2,
CCl4): n = 1696 cm–1. 1H NMR: d = 3.89 (s, 3 H), 7.00 (d,
J = 8.9 Hz, 2 H), 7.25 (s, 1 H), 7.79 (d, J = 8.9 Hz, 2 H),
10.02 (s, 1 H). 13C NMR: d = 55.4, 106.4, 114.2 (2 C), 119.9,
128.3 (2 C), 161.5, 162.7, 165.9, 178.5. HRMS (EI): m/z
calcd for C11H9NO3 [M+ + 1]: 203.0582; found: 203.0628.
All spectroscopic and HRMS data were obtained for
previously unreported compounds.
Synlett 2008, No. 6, 919–923 © Thieme Stuttgart · New York