Bromination of arenes using I2O5-KBr in water

Article abstract of DOI:10.1080/00397911.2013.796523

An efficient and environmentally benign bromination of various aromatic compounds using aN aqueous I2O5-KBr system at room temperature has been developed in this work. A series of aromatic compounds such as acetophenones, benzaldehydes, benzoic acids, anilines, amides, and aminopyridine have been successfully brominated in excellent regioselectivities and good yields under the typical reaction conditions. The features of KBr as brominating reagent, water as solvent, and mild conditions make this system an attractive synthetic procedure. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.796523

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A Bromination of Arenes Using I2O5-KBr in Water
Jieping Hou a , Zejiang Li b , Xiao-Dong Jia a & Zhong-Quan Liu b
a College of Chemistry and Chemical Engineering, Northwest Normal University , Lanzhou ,
Gansu
b State Key Laboratory of Applied Organic Chemistry , Lanzhou University , Lanzhou ,
Gansu , P. R. China
Accepted author version posted online: 27 Aug 2013.
To cite this article: Synthetic Communications (2013): A Bromination of Arenes Using I2O5-KBr in Water, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2013.796523
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A Bromination of Arenes Using I2O5-KBr in Water
Jieping Hou1, Zejiang Li2, Xiao-Dong Jia1, Zhong-Quan Liu2
1College of Chemistry and Chemical Engineering, Northwest Normal University,
Lanzhou, Gansu, 2State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou, Gansu, P. R. China
Abstract
An efficient and environmentally-benign bromination of various aromatic compounds
using aqueous I2O5-KBr system at room temperature has been developed in this work. A
series of aromatic compounds such as acetophenones, benzaldehydes, benzoic acids,
anilines, amides, and aminopyridine have been successfully brominated in excellent
regioselectivities and high yields under the typical reaction conditions. The features of
KBr as brominating reagent, water as solvent, and mild conditions make this system an
attractive synthetic procedure.
[Supplementary materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® for the following free supplemental resource(s): Full
experimental and spectral details.]
KEYWORDS: Arene, Bromination, KBr
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INTRODUCTION
Aromatic bromides represent a large class of useful compounds in the synthesis of
pharmaceuticals, natural products, and agrochemicals, etc.1 The most general and
convenient access to these compounds are direct bromination of aromatic compounds.2
Although numerous strategies for bromination of aromatic compounds using elemental
bromine have been developed in the past decades,3 more efficient, avoid to use bromine,
and organic solvent free systems are highly desirable due to clean production. Recently, a
few attractive procedures using KBr and NH4Br as the bromine source and the Oxone,
tert-butyl hydroperoxide (TBHP), and hydrogen peroxide as oxidant have been
established. 4 However, most of these systems suffer from acid assistance and using
organic solvent. Herein we wish to report an efficient and metal-free bromination of
various aromatic compounds using I2O5-KBr in water (Scheme 1).
EXPERIMENTAL
Initially, we chose 4-methoxyacetophenone as the model substrate to optimize suitable
conditions for this reaction (Table 1). It was found that the desired product 1a was
isolated in moderate to nearly quantitative yields by using I2O5-KBr in a mixture of
acetonitrile and water (Table 1, entries 1-8). We found that the yields increase with the
increasing volume of water in the mixed solvent (Table 1, entries 6-8). Interestingly, the
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corresponding aromatic bromide was isolated in a yield of 96% in water (Table 1, entry
9). The yield decreased very slightly when 1.5 equivalent of KBr was used as the
bromination reagent in water (Table 1, entry 10).
To examine the scope of this system, the bromination of various aromatic compounds
using I2O5-KBr were studied (Table 2). A variety of aromatic compounds such as
acetophenones, benzaldehydes, benzoic acids, amides, anilines, and aminopyridine have
been smoothly brominated in moderate to high yields with excellent regioselectivities
under the typical reaction conditions. Arenes bearing one electron-donating group and
one electron-withdrawing group in ortho or para relationship, such as
4-methoxyacetophenones, 4-methoxybenzaldehyde, 4-methoxybenzoic acid,
2-methoxybenzaldehyde, and methyl 2-methoxybenzoate gave good to excellent yields of
the corresponding aromatic bromides 1a-6a (Table 2, entries 1-6).
3-Methoxybenzaldehyde gave the monobrominated product 7a in 83% yield and the
dibrominated product 7b in 10% yield (Table 2, entry 7), 3-methoxyacetophenone gave
dibrominated product 8a as the only product, but in 24% yield, and no mono-brominated
products were obtained (Table 2, entry 8). In addition, amides were also effective
substrates in this system (Table 2, entries 9 and 10). A dibrominated product 11a was
obtained in 90% yield using 4-nitroaniline (Table 2, entry 11). Anisole gave 72% yield of
2,4-dibromoanisole (Table 2, entry 12). Bromination of 2,3-dihydrobenzofuran and
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2,3-dihydro-1,4-benzodioxane produced the corresponding dibrominated products 13a
and 14a in 89% and 78% yields, respectively (Table 2, entries 13 and 14). When phenols
were used as substrates, a complex mixture was produced, which involved oxidized
compounds due to the high reactivity of phenol. For example, p-dihydroxybenzene gave a
very low yield of the corresponding bromide 15a (Table 2, entry 15). Mesitylene also acts
as effective substrate and gives the dibrominated product 16a in 76% yield (Table 2, entry
16). A 33% yield of the bromide 17a was obtained using 2,4,6-trimethylbenzoic acid
(Table 2, entry 17). Piperonyl aldehyde gave 85% yield of the mono-brominated product
18a. Acetophenone and 4-methylacetophenone gave the methyl group brominated
products in 36% and 62% yields, respectively (Table 2, entries 19 and 20). It is
noteworthy that 2-aminopyridine also gave good yield of a dibrominated product (Table 2,
entry 21). Although highly electron-deficient arenes such as nitrobenzene and
polyfluorinated benzenes did not provide satisfactory yield in this system, the features of
commercial available oxidant, KBr as brominating reagent, water as solvent, and mild
conditions make this strategy an attractive synthetic procedure.
Furthermore, under the typical conditions, this bromination reaction could be scaled up
(Scheme 2). A mixture of 4-methoxyacetophenone (1.0 g, 6.67 mmol), I2O5 (4.45 g,
13.33 mmol), and KBr (1.97 g, 16.67 mmol) was dissolved in 50 mL of H2O. The
reaction was complete after stirring for 22.5 hours at room temperature. The mixture was
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extracted by ethyl acetate (3 × 100 mL), concentrated under reduced pressure, and the
mixture was purified by flash column chromatography (petroleum ether/ethyl
acetate=40:1) to afford the desired product 1a as a pale yellow solid (1.44 g, 95% isolated
yield).
The possible mechanism 5 of this process may involve oxidation of the KBr by
hypervalent iodine to generate an electrophilic bromine molecule, 6 which then
brominates the arenes, the aromatic bromide is formed followed by elimination of a
proton.
In summary, we have developed an efficient, mild and environmentally-benign protocol
for preparation of aromatic bromides using I2O5-KBr in water. Various aromatic
compounds such as benzaldehydes, benzoic acids, acetophenones, anilines, amides, and
aminopyridine etc. can be successfully brominated to generate the corresponding
aromatic bromides. Finally, this procedure can be conveniently scaled up to gram-scale
level which might be useful to its application in industry.
General Method
1H NMR spectra were recorded at 400 MHz in CDCl3 with TMS as internal standard. 13C
NMR spectra were recorded at 100 MHz and referenced to the internal solvent signals
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(center peak is 77.0 ppm in CDCl3 or 39.9 ppm in DMSO-d6). Mass spectroscopy data
were collected on HRMS-ESI and MS-EI instruments. All products were identified by 1H
and 13C NMR, MS, and/or HRMS. The starting materials were purchased from common
commercial sources and used without further purification.
Typical Procedure For The Bromination Of Aromatic Compounds By Using
I2O5-Kbr In Water
A mixture of arene (0.5 mmol), I2O5 (334 mg, 1.0 mmol), and KBr (148 mg, 1.25 mmol)
was dissolved in 2 mL of H2O. The reaction was complete after stirring for the indicated
time at room temperature. The mixture was extracted by ethyl acetate, concentrated under
reduced pressure, and the mixture was purified by flash column chromatography (silica
gel) to afford the desired product.
1-(3-bromo-4-methoxyphenyl)ethanone (1a): A light yellow solid after purification by
flash column chromatography (petroleum ether/ethyl acetate = 40/1). 1H NMR (400 MHz,
CDCl3): δ 8.16 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 8.8, 2.4 Hz, 1H), 6.93 (d, J = 8.8 Hz,
1H), 3.96 (s, 3H), 2.55 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 195.5, 159.5, 133.7,
131.1, 129.4, 111.8, 111.0, 56.4, 26.2. MS(EI): m/z(%): 230(34.1, M++2), 228(35.5, M+),
215(96.3), 213(100.0), 187(14.0), 185(14.5), 172(8.6), 170(10.1), 157(10.0), 155(9.0),
78(15.8), 63(11.8).
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ACKNOWLEDGMENT
This project is supported by the National Science Foundation of China (No. 21002045,
21272096) and the Fundamental Research Funds for the Central Universities
(lzujbky-2012-55). We also thank the State Key Laboratory of Applied Organic
Chemistry and Lanzhou University for financial support.
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6. Khazaei, A.; Zolfigol, M. A.; Kolvari, E.; Koukabi, N.; Soltani, H.; Komaki, F.
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Table 1. Optimization of the typical reaction conditionsa
Entry I2O5
(eq)
KBr
(eq)
2.5
Solvent
Yield
(%) b
57
1
2
3
4
5
6
7
8
1
CH3CN:H2O
(1:1)
2
2.5
2.5
2
CH3CN:H2O
(1:1)
79
98
88
78
96
97
99
2.5
2
CH3CN:H2O
(1:1)
CH3CN:H2O
(1:1)
2
3
CH3CN:H2O
(1:1)
2
2.5
2.5
2.5
CH3CN:H2O
(1:1.5)
2
CH3CN:H2O
(1:2)
2
CH3CN:H2O
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(1:4)
9
2
2.5
H2O
96
10
2
1.5
H2O
95
a Reaction conditions: 4-methoxyacetophenone (0.5 mmol, 1 eq.), solvent (2 mL), stirred
at room temperature for 10 h. b Isolated yield.
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Table 2. Bromination of aromatic compounds by using I2O5-KBr in watera
Entry
1
Arene
Product
Time Yield Entry
Arene
Product
Time Yield
(h)
10
(%)b
(h)
20
(%)b
96
12
72
Br
Br
Br
12a
1a
2
6
90
13
23
89
3
4
5
6
7
8
20
23
23
20
23
66
82
68
14
15
16
17
18
19
23
23
20
23
23
20
78
27
76
33
85
36
Br
Br
4a
15a
94
92
83/10
24
Br
18a
Br
19a
Br
Br
8a
9
20
23
78/18
82
20
21
23
23
62
75
Br
20a
21a
10
Br
Br
Br
10a
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23
90
a Reaction conditions: aromatic compound (0.5 mmol, 1 eq.), I2O5 (1.0 mmol, 2 eq.), KBr
(1.25 mmol, 2.5 eq.), H2O (2 mL), stirred at room temperature for the indicated time. b
Isolated yield.
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Scheme 1. Bromination of aromatic compounds by using I2O5-KBr in water.
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Scheme 2. Scaled-up experiment.
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