A fast and efficient bromination of isoxazoles and pyrazoles by microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2007.04.118

A fast and efficient method has been developed for the bromination of isoxazoles and pyrazoles using microwave irradiation. In this method, N-bromosuccinimide was used in different acid solvents according to the reactivity of the substrates to give mono-b

Full text of DOI:10.1016/j.tetlet.2007.04.118

Tetrahedron Letters 48 (2007) 4595–4599
A fast and efficient bromination of isoxazoles and pyrazoles
by microwave irradiation
Guo Li,* Ramesh Kakarla and Samuel W. Gerritz
Early Discovery Chemistry, Bristol Myers Squibb R&D, 5 Research Parkway, Wallingford, CT 06492, USA
Received 29 March 2007; revised 18 April 2007; accepted 24 April 2007
Available online 29 April 2007
Abstract—A fast and efficient method has been developed for the bromination of isoxazoles and pyrazoles using microwave
irradiation. In this method, N-bromosuccinimide was used in different acid solvents according to the reactivity of the substrates
to give mono-brominated isoxazoles and pyrazoles in good yields. Trifluoroacetic acid was found to be the best solvent for highly
unreactive isoxazoles and pyrazoles.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
of 4-haloisoxazole has been synthesized by thermolysis
of 2-halo-2H-azirines or haloazidoalkenes,10 which re-
quired multi-step synthesis to get the 4-halo products.
Isoxazole and pyrazole derivatives are interesting het-
erocyclic compounds since they show a wide range of
pharmacological properties including anti-inflamma-
tory,1 anti-cancer,2 anti-bacterial,3 anti-viral,4 anti-
diabetic,5 antimicrobial, and antifungal activities.6 Some
isoxazoles and pyrazoles display agrochemical proper-
ties (i.e., herbicidal and soil fungicidal activity) and have
applications as pesticides and insecticides.7 Brominated
isoxazoles and pyrazoles are useful synthetic intermedi-
ates capable of undergoing transition-metal-catalyzed
cross-coupling reactions, such as Heck, Stille, Suzuki,
Sonogashira, and Negishi couplings.8 There is an obvi-
ous demand for brominated isoxazoles and pyrazoles
due to their importance both as synthetic intermediates
and as pharmacological targets. A number of methods
have been described previously for the halogenation of
isoxazoles and pyrazoles.9 Stephens and co-workers de-
scribed a methodology for the bromination of 3,5-diary-
lisoxazoles using N-bromosuccinimide (NBS) in acetic
acid.9a But for deactivated isoxazoles, such as 5-phen-
yl-isoxazole-3-carboxylate, especially with electron with-
drawing substituents on the 5-phenyl ring, the known
bromination methods proved to be unsatisfactory, giv-
ing only traces of the brominated products. Our search
of the literature showed no precedent for the direct bro-
mination of 5-phenyl-isoxazole-3-carboxylate. This type
Microwave heating has been widely used for many
organic reactions, including Diels–Alder, esterification,
etherification, oxidation, hydrolysis, cyclization, Cla-
isen, Reformatsky, Knoevenagel, and metal-catalyzed
couplings.11 Although microwave induced bromination
has been used for bromination of activated aromatics
or heteroaromatics,12a a-bromination of carbonyl com-
pounds12b and side chain bromination of methyl aro-
matic compounds,12c no report exists on microwave
induced bromination of non-activated heteroaromatics,
such as isoxazoles and pyrazoles.
In this Letter, we report a new, rapid, and efficient meth-
od for the bromination of isoxazoles and pyrazoles via
microwave irradiation. With this method, the C-4 posi-
tion of isoxazoles and pyrazoles can be selectively bro-
minated in good yield. In addition, we also describe
the iodination of isoxazoles and pyrazoles by N-iodo-
succinimide (NIS) under similar conditions.
2. Bromination of the isoxazoles
The reactivity of the C-4 position of the isoxazole ring is
sensitive to the electronic properties of its neighboring
substituents.9a Electron withdrawing groups on the C-
3 or C-5 position of isoxazoles deactivate electrophilic
bromination on the C-4 position. When we used existing
Keywords: Bromination; Isoxazole; Pyrazole; Microwave.
*
Corresponding author. Fax: +1 203 6776984; e-mail: Guo.Li@
bms.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.118

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G. Li et al. / Tetrahedron Letters 48 (2007) 4595–4599
bromination methods for these deactivated isoxazoles,
we observed little or no products even after prolonged
heating. As NBS has shown enhanced activity in acidic
solvents, we attempted to brominate these unreactive
isoxazoles using NBS in different acid solvents via
microwave irradiation.
nitric acid in acetic acid, or trifluoroacetic acid (Scheme
1). The bromination conditions which gave the best
yields for each isoxazole are shown in Table 1. The
reactions were performed using 50–100 mg of starting
isoxazoles and 1.2 equiv of NBS.13 The starting 5-
phenylisoxazole-3-carboxylates were prepared by cycli-
zation of 2,4-dioxo-4-phenylbutanoate with hydroxyl-
amine hydrochloride.14 The bromination reaction has
been scaled up to gram quantities using 30-ml size
microwave vessels.
To determine the optimal acidic solvent for the bromin-
ation of isoxazoles, a series of isoxazoles were studied
under microwave irradiation. For each isoxazole, we
used three different acid solvents: acetic acid, 5% fuming
N,N-Dimethyl-5-phenylisoxazole-3-carboxamide
was
brominated readily by a mixture of NBS in acetic acid
with the formation of the mono-brominated product
(Table 1, entry 1). Deactivated isoxazoles (Table 1,
entries 2–5) required more acidic conditions and the use
of 5% fuming nitric acid in acetic acid. Bromination of
methyl 5-(2-Cl–phenyl)isoxazole-3-carboxylate (Table
1, entry 5) was relatively slow and needed an extended
reaction time (45 min) to be completely brominated. Tri-
fluoroacetic acid was especially suitable for highly unre-
active compounds (Table 1, entries 6 and 7), which have
m- or p-NO2 groups on the 5-phenyl ring. Most of these
Br
4
NBS, Acid solvent
3
R1
R2
R1
R2
5
Microwave
150 °C, 10 mins
1O N2
O N
Acid solvent: A. HOAc
B. 5% HNO3 in HOAc
C. TFA
Scheme 1. Bromination of isoxazoles.
Table 1. Bromination of isozazoles using NBS under microwave irradiation
Entry
Substrate
Product
Methoda
A
Yieldb (%)
87
Br
O
O
1
N
N
O N
O N
O N
Br
2
3
B
B
84
84
O N
Br
Br
Br
O
O
O
O
O N
O N
Cl
Cl
Cl
Cl
Br
O
O
4
5
B
88
80
O
O
O N
O
O N
O
Br
Bc
O
O
O N
O N
Cl
Cl
Br
O
O
6
7
C
C
90
81
O
O
O2N
O
2N
O N
O N
Br
O
O
2N
O
O2N
O
O
O N
O N
a Reaction conditions: microwave heating at 150 °C for 10 min or as otherwise indicated. Method A. HOAc as solvent; Method B. 5% HNO3 in
HOAc as solvent; Method C. TFA as solvent.
b Yields of isolated products.
c Microwave heating at 150 °C for 45 min.

G. Li et al. / Tetrahedron Letters 48 (2007) 4595–4599
4597
reactions were completed within 10 min under micro-
wave irradiation. The yields for brominated isoxazoles
varied from 80% to 90% (Table 1). Traditional heating
in an oil bath using the same acid solvents also gave sat-
isfactory yields but required much longer reaction time.
For example, 5-(3-nitro-phenyl)isoxazole-3-carboxylate
(substrate in Table 1, entry 6) was heated at reflux with
NBS in TFA for 24 h to give the mono-brominated
product in 82% yield.15
acid provided 66% conversion of the starting material.
With the addition of 5% fuming nitric acid to acetic
acid, the reaction went to completion after heating for
10 min. However, when trifluoroacetic acid was used
as solvent, the product was accompanied by 15% of
bis-brominated byproduct. The second Br was added
to the phenyl ring based on the NMR data.17 For 5-
(4-nitrophenyl)-isoxazole-3-carboxylic acid methyl ester
(Table 2, entry 3), heating in acetic acid gave no bromi-
nated product while trifluoroacetic acid as solvent pro-
vided complete bromination after 10 min. No bis-
brominated product was observed in this reaction.
While trifluoroacetic acid as solvent greatly increased
the reactivity of isoxazoles, acetic acid or 5% fuming
nitric acid in acetic acid provided better selectivity for
mono-bromination.
The structure of methyl 4-bromo-5-phenylisoxazole-3-
carboxylate (Table 1, entry 3) was confirmed by single
crystal X-ray crystallography (Fig. 1).16 The phenyl
and isoxazole rings have an intersecting angle of
20.8°.
To compare the reactivity and selectivity of the bromin-
ation conditions, three isoxazoles were examined as
shown in Table 2. All the reactions were heated under
microwave irradiation at 150 °C for 10 min. The mole
ratio of starting material/brominated product/bis-bro-
minated product was determined after separation of
the reaction mixture. For bromination of 5-(2-bromo-
phenyl)isoxazole (Table 2, entry 1), heating in acetic
3. Bromination of pyrazoles
The microwave assisted bromination method was also
applied to pyrazoles (Scheme 2). As shown in Table 3,
pyrazoles were brominated using NBS in different acid
solvents, with yields ranging from 78% to 91% (Table
3). As observed in the isoxazole case, the use of a stron-
ger acid was required for unreactive pyrazoles.
Following the successful demonstration of the bromina-
tion of isoxazoles and pyrazoles, we proceeded to extend
the generality of the reaction conditions to iodination
using NIS. Two examples are shown in Scheme 3. The
reactions afforded the desired mono-iodinated products
in good yields.
In conclusion, we have developed a fast and efficient
method for the bromination of isoxazoles and pyrazoles
employing NBS in acid solvents under microwave irradi-
ation conditions. Trifluoroacetic acid as solvent was
shown to be an effective and useful solvent for the bro-
mination of very unreactive heteroaromatics. This pro-
cedure offers several advantages, providing enhanced
yields, shorter reaction times, and operational simplic-
ity. Iodination of isoxazoles and pyrazoles was also
achieved by this method in good yields. This method
has provided simple and convenient synthesis of bro-
mo-intermediates which can be further transformed to
aryl, vinyl, and alkynyl-substituted isoxazoles and pyr-
azoles via Suzuki, Stille, and Heck coupling reactions.
This bromination method is under investigation for fur-
ther application to other aromatic or heteroaromatic
compounds.
Figure 1. X-ray structure of methyl 4-bromo-5-phenylisoxazole-3-
carboxylate.
Table 2. Comparison of different acid solvents for bromination of
isoxazoles
Entry Substrate
Methoda SM/Br-product/
bis-Br-product
A
B
C
34/66/0
0/100/0
0/85/15
1
O N
O N
Br
O
A
B
C
100/0/0
52/48/0
0/87/13
2
Br
O
NBS, Acid solvent
R1
R2
Cl
R1
R2
Microwave
150 °C, 10 mins
N N
R3
N N
R3
O
O2N
A
B
C
100/0/0
44/56/0
0/100/0
3
O
Acid solvent: A. HOAc
O N
B. 5% HNO3 in HOAc
C. TFA
a Reaction conditions: microwave heating with 1.5 equiv NBS at
150 °C for 10 min. Method A. HOAc as solvent; Method B. 5%
HNO3 in HOAc as solvent; Method C. TFA as solvent.
Scheme 2. Bromination of pyrazoles.

4598
G. Li et al. / Tetrahedron Letters 48 (2007) 4595–4599
Table 3. Bromination of pyrazoles using NBS under microwave irradiation
Entry
1
Substrate
Product
Methoda
A
Yieldb (%)
84
Br
N
N
N
N
Br
O
O
2
A
89
O
O
HN N
HN N
Br
O
Br
Cl
O
Br
3
4
A
B
91
83
O
O
N N
N N
Br
Cl
Cl
Cl
O
O
O
O
HN N
HN N
Br
O
O
O
O
5
6
B
88
78
O
O
O
O
HN N
HN N
Br
O
O
Cc
O
O
O2N
O2N
HN N
HN N
a Reaction conditions: microwave heating at 150 °C for 10 min or otherwise indicated. Method A. HOAc as solvent; Method B. 5% HNO3 in HOAc
as solvent; Method C. TFA as solvent.
b Yields of isolated products.
c Microwave heating at 130 °C for 10 min.
Cl
Cl
NIS, CF3COOH
I
O
O
Cl
Cl
Microwave
150 °C, 10 mins
O
O
O N
O N
Yield: 85%
I
NIS, CH3COOH
N N
N N
Microwave
150 °C, 10 mins
Yield: 83%
Scheme 3. Iodination.
Acknowledgments
bromo-5-(2,5-dibromophenyl)isoxazole and X-ray crys-
tallography data for 4-bromo-5-phenylisoxazole-3-car-
boxylate. Supplementary data associated with this
article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.04.118.
The authors acknowledge Baoqing Ma for the crystal
structure analysis of 4-bromo-5-phenylisoxazole-3-car-
boxylate; Yingzi Wang, Xiaohua Huang, Xinxing Cai
and Gary Bao for the characterization of the new com-
pounds. We also thank Dr. Michael A. Poss for
suggestions.
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4599
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4-bromo-5-phenyl-isoxazole-3-carboxylate (Table 1, entry
17. When trifluoroacetic acid was used as solvent, the
bromination of 5-(2-bromophenyl)-isoxazole gave some
bis-brominated byproduct 4-bromo-5-(2,5-dibromophen-
yl)isoxazole. The structure of the bis-brominated byprod-
uct was determined based on 1D 1H NMR and 2D HMBC
NMR data.