Copper(II) bromide: A simple and selective monobromination reagent for electron-rich aromatic compounds

Article abstract of DOI:10.1080/00908320701230026

Copper(II) bromide was found to be a simple and efficient reagent for monobromination of electron-rich aromatic compounds at room temperature. The reaction proceeded smoothly with phenols, aryl alkyl ethers, and aromatic amines to afford the corresponding monobrominated product selectively in moderate to good yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00908320701230026

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Copper(II) Bromide: A Simple and Selective
Monobromination Reagent for Electron‐Rich
Aromatic Compounds
a
a
Suchitra Bhatt & Sandip K. Nayak
a
Bio‐Organic Division, Bhabha Atomic Research Centre, Mumbai, India
Published online: 12 Apr 2007.
To cite this article: Suchitra Bhatt & Sandip K. Nayak (2007) Copper(II) Bromide: A Simple and Selective
Monobromination Reagent for Electron‐Rich Aromatic Compounds, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:8, 1381-1388, DOI:
10.1080/00908320701230026
To link to this article: http://dx.doi.org/10.1080/00908320701230026
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Synthetic Communications , 37: 1381–1388, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00908320701230026
Copper(II) Bromide: A Simple and Selective
Monobromination Reagent for Electron-
Rich Aromatic Compounds
Suchitra Bhatt and Sandip K. Nayak
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, India
Abstract: Copper(II) bromide was found to be a simple and efficient reagent for mono-
bromination of electron-rich aromatic compounds at room temperature. The reaction
proceeded smoothly with phenols, aryl alkyl ethers, and aromatic amines to afford
the corresponding monobrominated product selectively in moderate to good yields.
Keywords: anilines, aryl alkyl ethers, bromination, copper(II) bromide, phenols
Although CuBr had been extensively used for the a-bromination of carbonyl
2
[
compounds and bromination of alkenes and alkynes, very little work has
1]
[2]
[3]
been carried out on its use as a brominating agent in aromatic systems.
During the development of a new protocol for tetrahydroquinoline synthesis
with CuBr as a catalyst, we observed the formation of a trace amount of bro-
2
[
minated anilines. This prompted us to investigate the use of CuBr as a bro-
4]
2
minating agent for electron-rich aromatics.
The bromination of phenol with 2.1 equivalents of CuBr (corresponds to
2
1
nol in 63% yield, which was improved to 82% when 4 eq of CuBr were
.05 eq of bromine) in acetonitrile at ambient temperature gave 4-bromophe-
2
employed. Interestingly, neither 2-bromophenol nor polybrominated phenols
were detected (Table 1, entry 1) in the reaction. Our literature survey
[
3a,b]
revealed only two reports
on the use of alumina-supported CuBr for
2
Received in India September 15, 2006
Address correspondence to Sandip K. Nayak, Bio-Organic Division, Bhabha
Atomic Research Centre, Mumbai 400085, India. E-mail: sknayak@barc.gov.in
1
381

a
Table 1. Bromination of electron-rich aromatics with copper(II) bromide in acetonitrile
b
Entry
1
Substrate
Reagent and conditions
i) CuBr (4.2 eq)/CH CN/rt
Product
Time (h)
Yield (%)
2
3
i) 0.5
i) 82
ii) alumina supported CuBr
eq)/CCl /reflux
2
(3.3
ii) 1.0
ii) 23
4
2
3
CuBr
2
(2.1 eq)/CH
3
CN/rt
12.0
80
CuBr
CuBr
2
(4.2 eq)/CH
(4.2 eq)/CH
3
CN/rt
0.03
0.5
91
50
4
5
2
3
CN/rt
i) CuBr
2
(4.2 eq) /CH
3
CN/rt
i) 2.0
i) 50
ii)alumina supported CuBr (3.3
2
ii) 1.0
ii) 43
4
eq)/CCl /reflux

6
CuBr
2
(2.1 eq)/CH
3
CN/rt
0.5
83
7
8
CuBr
CuBr
2
2
(2.1 eq)/CH
(2.1 eq)/CH
3
CN/rt
CN/rt
0.5
0.5
54
48
3
9
0
CuBr
CuBr
2
(2.1 eq)/CH
(2.1 eq)/CH
3
CN/rt
3.0
3.0
74
64
1
2
3
CN/rt
(
continued)

Table 1. Continued
Entry Substrate
b
Reagent and conditions
Product
Time (h)
1.0
Yield (%)
86
11
CuBr (2.1 eq)/CH CN/rt
2
3
1
2
CuBr
2
(2.1 eq)/CH
3
CN/rt
4.0
55
76
1
3
4
CuBr (2.1 eq)/CH CN/rt
12.0
2
3
1
CuBr
2
(2.1 eq)/CH
3
CN/rt
12.0
70

15
16
17
18
CuBr
2
(2.1 eq)/CH
3
CN/rt
12.0
68
61
60
78
CuBr (2.1 eq)/CH CN/rt
0.03
2
2
2
3
3
3
CuBr
CuBr
(2.1 eq)/CH
CN/rt
CN/rt
0.03
0.03
(2.1 eq)/CH
a
b
All the reactions were carried out in acetonitrile (5 mL per mmol) at ambient temperature.
Isolated and unoptimized yields.

1
386
S. Bhatt and S. K. Nayak
the nuclear bromination of alkylbenzenes in CCl under reflux. Therefore, a
4
comparative study on the efficiency of an alumina-supported CuBr /CCl4
2
system with the present protocol (CuBr /CH CN) was undertaken.
2
3
For example, phenol and alumina-supported CuBr (3.3 eq)/CCl under
2
4
reflux yielded a mixture of mono- and polybrominated products from which
-bromophenol was isolated in 23% yield after preparative thin-layer chrom-
atography (TLC). This established CuBr (2.1 eq)/CH CN as a superior and
4
2
3
efficient brominating agent for the nuclear monobromination of phenols.
To see the generality of this reaction, bromination of several phenols and
aryl alkyl ether were investigated (Scheme 1, Table 1, entries 2–15).
To extend the scope of the reaction, bromination of aniline and CuBr2
(
2.1 eq) in acetonitrile for 5 min afforded 4-bromoaniline as the sole
product in 61% yield (Table 1, entry 16). Similarly, N,N-dimethylaniline
and N,N-diethylaniline underwent smooth bromination to yield 4-bromo-
N,N-dimethylaniline and 4-bromo-N,N-diethylaniline in 60% and 78%
yields respectively (Table 1, entries 17 and 18).
In conclusion, we have developed a simple reagent system: CuBr as an
2
efficient nuclear brominating agent for electron-rich aromatic compounds
such as phenols, aryl alkyl ethers, and anilines at ambient temperature.
EXPERIMENTAL
Melting points were determined using Fisher-Johns melting-point apparatus
and are uncorrected. IR spectra were scanned with a Jasco FT/IR 4100 spec-
1
trophotometer. The H NMR spectra were recorded with a Bruker AC 200
(200-MHz) spectrometer. Mass spectra were recorded with a Shimadzu
mass spectrometer. Microanalysis was performed with Carlo Erba elemental
analyzer (model 1110). CuBr was purchased from Aldrich Chemical Co.
2
and used without further purification. Acetonitrile was dried and distilled
over P O . All reactions were carried out under an argon atmosphere.
2
5
General Procedure for Bromination
solution of phenol/arylalkylether/aniline (2.0 mmol) and CuBr2
A
(
4.2 mmol, 1.0 g, 2.1 eq) in dry acetonitrile (10 mL) was stirred at room
Scheme 1.

Copper(II) Bromide
1387
temperature for an appropriate time (see Table 1). After completion of the
reaction, as indicated by tlc, the reaction mixture was concentrated,
quenched with water and ethyl acetate (10 mL), and passed through a bed
w
of Celite . The Celite bed was thoroughly washed with ethyl acetate
(10 mL). The organic layer was washed with brine and dried (Na SO ).
2 4
Removal of solvent followed by preparative TLC (silica gel; hexane/ethyl
acetate ¼ 9/1) afforded the monobrominated product. The spectroscopic
and analytical data for the unknown compounds are given next.
Data
2
-Bromo-4-tert-butylphenol (entry 3): solid; mp 37–388C; IR (neat):
21 1
n ¼ 3521, 3155, 2975, 1604, 1508, 1177, 820 cm ; H NMR (200 MHz,
CDCl ): d ¼ 7.46 (d, 1H, J ¼ 2.2 Hz), 7.24 (dd, 1H, J ¼ 2.2, 8.5 Hz), 6.96
3
1
3
(
d, 1H, J ¼ 8.5 Hz), 5.47 (bs, 1H, OH), 1.30 (s, 9H). C NMR (50 MHz,
CDCl ): d ¼ 149.8, 145.0, 128.8, 126.1, 115.5, 109.8, 34.1, 31.3; anal.
3
calcd. for C H BrO: C, 52.42; H, 5.72; found C, 52.59; H, 5.52.
10 13
1
1
-Bromo-3,4-dioctyloxybenzene (entry 10): oil; H NMR (200 MHz, CDCl ):
3
d ¼ 6.7 (d, 1H, J ¼ 9.0 Hz), 7.0 (m, 2H), 3.96 (t, 4H, J ¼ 6.6 Hz), 1.8
1
m, 4H), 1.3 (m, 20H), 0.9 (bt, 6H); C NMR (50 MHz, CDCl ):
3
(
3
d ¼ 149.9, 148.3, 123.3, 116.8, 115.0, 112.7, 69.4, 69.2, 31.8, 29.2, 25.9,
2.6, 14.0; EIMS: m/z ¼ 414, 412, 302, 300, 190, 188, 71, 69, 57, 55; anal.
calcd. for C H BrO : C, 63.91; H, 9.02; found C, 64.11; H, 9.17.
2
2
2
37
2
0
4
1
6
3
1
-Bromobenzo-15-crown-5 (entry 12): oil; IR (neat): n ¼ 2929, 2869, 1508,
21 1
257, 1137, 931, 725 cm ; H NMR (200 MHz, CDCl ): d ¼ 6.99 (m, 2H),
3
.72 (d, 1H, J ¼ 8.3 Hz), 4.08 (t, 4H, J ¼ 4.1 Hz), 3.88 (t, 4 H, J ¼ 4.1 Hz),
1
3
.73 (s, 8H); C NMR (50 MHz, CDCl ): d ¼ 149.7, 148.1, 123.6, 116.8,
3
15.0, 112.8, 71.0, 70.7, 70.1, 69.9, 69.3, 69.2, 68.9, 68.7; EIMS: m/
z ¼ 348, 346, 216, 214, 201, 199, 160, 158, 79; anal. calcd. for
C H BrO : C, 48.43; H, 5.52; found C, 48.31; H, 5.41.
1
4
19
5
4
1
-Bromo-3-methoxyphenol (entry 14): oil; IR (neat): n ¼ 3502, 2944, 2838,
2
1
1
603, 1483, 1207, 1021 cm
;
H NMR (200 MHz, CDCl ): d ¼ 7.3
3
(d, 1H, J ¼ 8.8 Hz), 6.59 (d, 1H, J ¼ 2.8 Hz), 6.4 (dd, 1H, J ¼ 2.8, 8.8 Hz),
1
3
5
1
1
3
.55 (bs, 1H, OH), 3.76 (s, 3H). C NMR (50 MHz, CDCl ): d ¼ 156.4,
3
52.5, 134.4, 102.4, 100.5, 100.2, 56.4; EIMS: m/z ¼ 204, 202, 189, 173,
61, 159, 150, 108, 93, 79, 65; anal. calcd. for C H BrO : C, 41.41; H,
7
7
2
.48; found C, 41.59; H, 3.66.
2
-Bromo-4-methoxyphenol (entry 15): solid, mp 59–608C IR (neat):
2
1 1
n ¼ 3421, 2924, 1654, 1498, 1207, 1031, 735 cm ; H NMR (200 MHz,
CDCl ): d ¼ 7.0 (d, 1H, J ¼ 2.8 Hz), 6.93 (d, 1H, J ¼ 8.9 Hz), 6.8 (dd, 1H,
3

1
388
S. Bhatt and S. K. Nayak
1
3
J ¼ 2.8, 8.9 Hz), 5.20 (bs, 1H, OH), 3.70 (s, 3H). C NMR (50 MHz, CDCl3):
d ¼ 153.7, 146.5, 116.8, 116.3, 115.3, 110.0, 55.9; EIMS: m/z ¼ 204, 202,
189, 187, 161, 141, 131, 108, 91, 79, 53; anal. calcd. for C H BrO : C,
7 7 2
41.41; H, 3.48; found C, 41.62; H, 3.66.
4
-Bromo-N,N-diethylaniline (entry 18): oil; IR (neat): n ¼ 2975, 2929, 1589,
2
1 1
1
498, 1262, 1197, 805 cm ; H NMR (200 MHz, CDCl ): d ¼ 7.65 (d, 2H,
3
J ¼ 8.9 Hz), 6.54 (d, 2H, J ¼ 8.8 Hz), 3.31 (q, 4H, J ¼ 7.1 Hz), 1.14 (t, 6H,
1
3
J ¼ 7.1 Hz). C NMR (50 MHz, CDCl ): d ¼ 146.7, 131.8, 113.4, 106.9,
3
4
1
6
4.4, 12.4; EIMS: m/z ¼ 230, 228, 216, 213, 200, 199, 187, 185, 168, 149,
35, 130, 115, 86, 84, 58; anal. calcd. for C H BrN: C, 52.65; H, 6.19; N,
1
0 14
.14; found C, 52.48; H, 6.11; N, 6.02.
ACKNOWLEDGMENTS
S. B. is thankful to the Department of Atomic Energy, Government of India,
for a fellowship. We thank S. Chattopadhyay, head of the Bio-Organic
Division, Bhabha Atomic Research Centre (BARC), for his valuable sugges-
tions in preparing the manuscript.
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1
2
3
. Fort, A. W. Reactions of some organic compounds with cupric bromide. J. Org.
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. (a) Kovacic, P.; Davis, K. E. Cupric bromide and alkylbenzenes: Influence of water
on nuclear bromination vs side chain attack. J. Am. Chem. Soc. 1964, 86, 427–432;
(
b) Kodomari, M.; Satoh, H.; Yoshotomi, S. Selective nuclear halogenation of poly-
methylbenzenes with alumina-supported copper(II) halides. Bull. Chem. Soc. Jpn.
988, 61, 4149–4150; (c) Ware, J. C.; Borchert, E. E. Chlorination of aromatic
1
hydrocarbons by cupric halide. J. Org. Chem. 1961, 26, 2263–2267.
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4