Regioselective, photochemical bromination of aromatic compounds using N-bromosuccinimide

Article abstract of DOI:10.1016/j.tetlet.2007.10.126

Regioselective nuclear bromination of aromatic compounds is investigated with N-bromosuccinimide as the brominating agent under UV irradiation to afford the corresponding brominated compounds. The reaction proceeds at ambient temperature (30 ± 2 °C) without any catalyst. In most of the reactions, regioselectively mono-brominated products are obtained in good to high yields. The conversion and selectivity for bromination depend on the nature of the substituent on the aromatic ring.

Full text of DOI:10.1016/j.tetlet.2007.10.126

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 189–194
Regioselective, photochemical bromination of aromatic
compounds using N-bromosuccinimide
Prakash K. Chhattise, A. V. Ramaswamy and Suresh B. Waghmode*
Department of Chemistry, Ganeshkhind, University of Pune, Pune 411 007, India
Received 23 July 2007; revised 12 October 2007; accepted 25 October 2007
Available online 30 October 2007
Abstract—Regioselective nuclear bromination of aromatic compounds is investigated with N-bromosuccinimide as the brominating
agent under UV irradiation to afford the corresponding brominated compounds. The reaction proceeds at ambient temperature
(
30 ± 2 °C) without any catalyst. In most of the reactions, regioselectively mono-brominated products are obtained in good to high
yields. The conversion and selectivity for bromination depend on the nature of the substituent on the aromatic ring.
Ó 2007 Elsevier Ltd. All rights reserved.
Halogenated aromatic compounds belong to an impor-
tant class of organic intermediates that are used as pre-
cursors of organometallic reagents in synthetic organic
an important goal. Among various brominating
2
1
reagents, NBS
is environmentally friendly, easy to
work with and is extensively used for allylic, benzylic,
and aromatic nuclear bromination under mild condi-
1
chemistry. They can be used as potent, antitumor, anti-
2
2
bacterial, antifungal, antineoplastic, antiviral, antioxi-
dizing agents and also as industrial intermediates in
the manufacture of pharmaceuticals and agrochemi-
tions.
Recently, we reported a-bromination of
aliphatic and aromatic ketones using NBS under UV–
vis light irradiation at ambient temperatures without
2
23
cals. Various methods have been developed and
the use of a catalyst. A major advantage of the use
reported for the bromination of aromatic compounds
using a variety of brominating agents under various con-
ditions. Conventional, direct bromination involves the
of NBS is that the by-product succinimide, can be easily
recovered and recycled to NBS. Carreno et al.
2
4
3
reported aromatic ring bromination and benzylic bro-
mination of substituted methyl anisoles using NBS in
CH CN and CCl under severe reaction conditions
use of molecular bromine and metal halides including
4
5
Br –Lewis acids, Br /SbF /HF, N-bromosuccinimide
2
2
3
7
3
4
6
8
(
NBS)/H SO , NBS/SiO2, NBS/H SO /CF COOH,
and with a long reaction time. However, photochemical
nuclear bromination of activated aromatic compounds
using NBS has not been studied so far. Here, we report
the photochemical bromination of a number of substi-
tuted phenols and anilines, giving mono- and di-substi-
tuted derivatives, using NBS as the brominating agent
at ambient temperature in acetonitrile, without a
catalyst, in a very short time (Schemes 1 and 2). Optimi-
zation of the reaction conditions for the photochemical
bromination of phenol with NBS was investigated as a
model transformation.
2
4
9
2
4
3
11
10
NBS/PTSA,
DMSO,
NBS/NaOH,
quaternary ammonium
Br /zeolites,
HBr/
2
1
2
13
tribromide,
1
4
15
KBrO3, KBr/H O /Oxone, and sodium monobro-
2
1
2
6
moisocyanourate. Recently, bromination of aromatic
compounds has been reported using hexamethylenetet-
1
7
raamine–Br2 and KBr–benzyltriphenylphosphonium
1
8
19
peroxo disulfate and monosulfate, under neutral
conditions. In the reported reactions, the brominating
agent used was either molecular bromine or Br in com-
2
bination with an acid or an oxidizing agent. These
reagents are potentially hazardous, and it is difficult to
2
0
handle and store elemental halogens. From the ‘green
chemistry’ point of view, the replacement of such harm-
ful reagents with non-toxic, inexpensive, commercially
available, non-polluting, and more selective reagents is
R
R
NBS
CH CN, hν
3
Br
*
Corresponding author. Tel.: +91 20 2560 1225x535/585; fax: +91 20
569 1728; e-mail: suresh@chem.unipune.ernet.in
2
Scheme 1. R = H, OH, OCH
3
, NH
2
, NMe
2
3 2
, NHAc, CH and NO .
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.126

190
P. K. Chhattise et al. / Tetrahedron Letters 49 (2008) 189–194
R1
Benzene and nitrobenzene did not undergo bromination
R1
NBS
CH CN, hν
even after a prolonged reaction time (entries 6 and 7).
Thus, less reactive aromatic substrates did not undergo
nuclear bromination under these reaction conditions.
Toluene was brominated at a benzylic position, rather
than on the ring, requiring a longer reaction time (Table
3
R2
Br
R2
1
2
Scheme 2. R and R may be electron-donating or withdrawing
1
2
groups. R = NH
2
, OH; R = NO
2
, OH, OCH
3
, Cl, CH
3
, CHO and
2
, entry 8). Aniline was brominated at the para position
COOH.
with 90% selectivity (2,4,6-tribromoaniline, 10% selec-
tivity was also obtained), with 73% conversion (entry
9
). N,N-Dimethylaniline was rapidly brominated at the
The effect of various solvents on the bromination of phe-
nol was studied and the results are shown in Table 1.
The reaction was complete within 3 min with no cata-
lyst, in acetonitrile, with 99% conversion, to give para-
bromophenol regioselectively in 88% yield. However,
in hexane, the reaction was slower and less selective
towards para-bromophenol (34%), also yielding ortho-
bromophenol and 2,6-dibromophenol (Table 1, entry
para position to give 4-bromo-N,N-dimethylaniline
within 1 min with 93% conversion and 100% selectivity
(
4
entry 10). Bromination of acetanilide afforded
-bromoacetanilide with low conversion. To obtain the
best yield of 4-bromoacetanilide, NBS was added in four
2
3
portions, which increased the conversion from 40% to
3% (entry 11).
8
9
). The extent of conversion of phenol was in the order,
Various disubstituted aromatic compounds were bromi-
nated within 3 min with good to excellent conversions.
Bromination of ortho-substituted electron-rich phenols
and anilines occurred at the para position. Hydroxy
derivatives of phenol (catechol, resorcinol, and hydro-
quinone, entries 12–14) gave the corresponding brom-
ophenols with good conversion but low selectivity. The
bromination of hydroquinone gave mono-brominated
hydroquinone as the major product but oxidation as a
side reaction gave benzoquinone as a minor product.
Bromination of 2- and 4-chlorophenols gave the corre-
sponding brominated products in good yields (entries
CH CN > DMSO > CHCl ꢀ Et O > MeOH > DMF >
3
3
2
DCM ꢀ THF > CCl > hexane, whereas the selectiv-
4
ity for para-bromophenol decreased in the order,
CHCl > Et O ꢀ MeCN > DMSO > DMF > THF >
3
2
MeOH > CCl > hexane. This observation suggests that
4
more polar or more ionizing solvents enhance the reac-
tivity of NBS and favor nuclear bromination. To estab-
lish the general applicability of NBS, various mono- and
di-substituted aromatic compounds having electron-
donating substituents were brominated in acetonitrile
under UV–vis light. The mono-substituted phenols and
their derivatives (a-naphthol, b-naphthol, 1- and
1
5 and 16). Methyl phenols underwent nuclear bromin-
2
-methoxynaphthalene and anisole) were readily bromi-
ation rather than benzylic bromination to give the
corresponding brominated products 4-bromo-3-methyl-
phenol and 2-bromo-4-methylphenol, respectively
nated to afford the desired mono-brominated products
with excellent selectivity (100%) and conversion
(
1
<97%) (Table 2, entries 1–5). The bromination of
- and 2-methoxynaphthalene was carried out by
(entries 17 and 18). It may be noted that Carreno
et al. had earlier reported on the bromination of the
respective ethers of the methyl phenols, which was com-
Carreno et al. at room temperature in acetonitrile as sol-
vent affording 94% and 92% yields of mono-brominated
products in 2 and 3 h, respectively. The same bromin-
ation carried out by us using UV–vis irradiation took
only 3 min and gave 99% conversion and 100%
selectivity.
2
4
2
4
pleted within 0.5–3 h. The bromination of 3-amino-
phenol gave 4-bromo-3-hydroxyaniline with low
conversion, along with 2,6-dibromo-3-hydroxyaniline
and 2,4,6-tribromo-3-hydroxyaniline as side products.
When the reagent-to-substrate mol ratio was increased
from 0.25:1 to 2:1, the conversion increased from 48%
to 100% with no change in the product distribution
(entry 19). 4-Nitrophenol and 2-hydroxybenzoic acid
were brominated to give 2-bromo-4-nitrophenol and 4-
bromo-2-hydroxybenzoic acid with 55% and 56% con-
versions and 78% and 100% selectivity, respectively
(entries 20 and 21). While using a substrate to reagent
ratio of 1:1.5 moles increased the conversion from 56%
to 96% for 2-hydroxybenzoic acid. Bromination of vani-
lin afforded a brominated product with 88% conversion
and 100% selectivity (entry 22). Both 2- and 4-chloroani-
lines were brominated with excellent conversion and
selectivity for 4-bromo-2-chloroaniline and 2-bromo-4-
chloroaniline, respectively (entries 23 and 24).
Table 1. Effect of solvents on the bromination of phenol
Entry
Solvent
Conversion (%)
Selectivity (%)
a
b
Product
Others
1
2
2
4
5
6
7
8
9
MeCN
99
89
83
87
89
85
92
83
43
46
88
91
32
69
89
80
83
75
34
47
12
9
CHCl
DCM
3
68
31
11
20
17
25
66
53
Methanol
Et
2
O
DMF
DMSO
THF
Hexane
1
0
CCl
4
4-Methoxyaniline
gave
2-bromo-4-methoxyaniline
along with 2,6-dibromo-4-methoxyaniline as a minor
product (entry 25). Bromination of 4-aminobenzoic acid
and 4-nitroaniline yielded 4-amino-3-bromobenzoic acid
and 2-bromo-4-nitroaniline, respectively, at 84% and
80% conversion levels and with 86% and 100% selectiv-
ity for the brominated products, respectively (entries 26
Reaction conditions: temp = 30 ± 2 °C; substrate: reagent (mol)
ratio = 1:1, the conversions are based on GC analysis. Products were
characterized by NMR and GC–MS.
a
para-Bromophenol.
ortho-Bromophenol and 2,4-dibromophenol. All reactions were
b
conducted for a duration of 3 min.

P. K. Chhattise et al. / Tetrahedron Letters 49 (2008) 189–194
191
Table 2. Bromination of mono-substituted aromatics using NBS
Entry Substrate Product
Time (min)
Conv. (wt %)
Selectivity (%)
Product Others
OH
OH
1
3
99
100
—
Br
Br
OH
OH
2
3
3
3
97
99
100
100
—
—
Br
OCH3
OCH3
OCH3
OCH3
3
a
3
99
100
—
12
Br
OH
OH
4
5
3
99
98
88
Br
OCH3
OCH3
20
100
Br
6
7
8
No reaction
180
180
15
—
—
—
—
—
—
NO2
CH3
No reaction
CH Br
2
b
76
95
100
95
—
5
3
0
NH2
NH2
9
0
1
3
73
93
40
90
10
—
Br
Br
Br
NMe2
NHAc
NMe2
1
1
1
3
100
NHAc
100
99
—
1
a
12
83
OH
OH
OH
OH
1
1
2
3
3
58
77
82
66
18
34
a
1
3
2
Br
OH
OH
90
62
38
OH
Br
OH
Br
OH
OH
14
3
1
62
79
45
47
55
53
HO
a
2
HO
(
continued on next page)

192
P. K. Chhattise et al. / Tetrahedron Letters 49 (2008) 189–194
Table 2 (continued)
Entry Substrate
Product
Time (min)
Conv. (wt %)
Selectivity (%)
Product Others
OH
Cl
OH
Cl
1
5
6
3
3
85
65
74
94
26
6
Br
OH
OH
Br
1
Cl
Cl
OH
OH
17
18
19
3
1
89
99
86
93
14
7
a
2
CH3
CH3
Br
OH
OH
3
12
80
98
93
92
7
8
a
H C
H C
3
Br
3
OH
OH
Br
3
3
60
100
49
43
51
57
c
NH2
NH2
OH
OH
Br
2
0
1
3
55
78
22
O N
2
O N
2
OH
OH
2
3
3
56
d
100
100
—
—
CO H
Br
CO H
96
2
2
Br
OH
OH
2
2
3
30
3
88
98
100
99
—
1
OHC
OCH3
OHC
OCH3
NH2
Cl
NH2
Cl
2
Br
Cl
NH2
NH2
Br
2
2
4
5
3
3
99
86
99
82
1
Cl
NH2
NH2
NH2
Br
18
H CO
3
H CO
3
NH2
Br
2
2
6
7
3
84
51
86
14
HO C
HO C
2
2
NH2
NH2
Br
3
12
78
100
22
—
a
O N
2
O N
2
80
H CO
3
NHAc
H CO
NHAc
3
28
30
100
100
—
H CO
3
H CO
3
Br

P. K. Chhattise et al. / Tetrahedron Letters 49 (2008) 189–194
193
Table 2 (continued)
Entry Substrate
Product
Time (min)
Conv. (wt %)
Selectivity (%)
Product Others
H CO
3
NH
2
H CO
3
NH
2
29
30
31
30
98
100
100
100
—
—
—
H CO
H CO
Br
3
3
Br
12
3
85
85
N
H
N
H
NH2
NH2
Br
N
N
H C
3
O
H C
3
O
NMe2
NMe2
Br
3
3
2
3
30
95
100
—
N
N
N
N
30
85
82
18
N
N
H
Br
H
Reaction conditions: temp = 30 ± 2 °C; solvent = acetonitrile, substrate: reagent (mol) ratio = 1:1; conversions are based on GC analysis. Products
1
were characterized by H NMR and GC–MS.
a
Portion-wise addition of NBS.
Benzylic bromination.
b
c
2:1 ratio of reagent to substrate.
d
1.5:1 ratio of reagent to substrate.
and 27). Synthetically useful and protected homoverat-
rylamine and veratrylamine were mono-brominated
with excellent conversions (entries 28 and 29), but the
reactions were sluggish compared to those of other aro-
matic compounds.
pounds having electron-donating substituents were bro-
minated readily with high conversion and invariably
with high selectivity for the mono-brominated products.
However, with electron-withdrawing substituents, the
bromination was slow and resulted in lower conversions.
The reported photochemical methodology provides a
convenient route to a number of brominated aromatics
in good yield and within short reaction times.
Some heterocyclic aromatic compounds were also bro-
minated under similar reaction conditions to yield the
desired products (entries 30–33). Indole was brominated
at C-3 with 85% conversion and 100% selectivity. Imid-
azole gave a tri-bromo product without exposure to
UV–vis light. A similar reaction at À10 °C afforded
General reaction procedure
5
-bromoimidazole as the major product accompanied
A mixture of substrate (1 mmol) and NBS (1.05 mmol)
by tribromoimidazole as a minor product (entry 33).
was stirred in 5 ml of acetonitrile under an N atmo-
2
sphere in the presence of a Philips HPL-N (250 W,
kmax = 200–600 nm) lamp fitted with a water circulation
arrangement at room temperature (30 ± 2 °C). To
obtain the best yields of the products, NBS was added,
in some cases, in four aliquots (each time 0.25 equiv at
3 min intervals). After completion (monitored by GC),
the reaction mixture was quenched with cold water
and extracted with ethyl acetate. The organic phase
was washed with water and brine, dried over anhydrous
Na SO and concentrated under reduced pressure to af-
The mechanism of these brominations is believed to
2
5
involve radicals.
This was confirmed by adding to
the reaction mixture a 2,2-diphenyl-1-picrylhydrazyl
(
DPPH) methanol solution and recording the UV–vis
2
3,26
spectrum.
A blue shift in the absorption wavelength,
from kmax at 516 nm for DPPH in methanol to 385 nm
for DPPH in the reaction mixture confirmed the forma-
tion of free radicals but this does not confirm that the
radicals are involved in the substitutions.
2
4
ford the crude product, which was purified by column
chromatography over silica gel (60–120 mesh) using
ethyl acetate and petroleum ether as eluents. The prod-
uct was analyzed by GC (HP 5890) using a capillary col-
umn (HP-5). The GC–MS spectra were taken on a
Shimadzu GC–MS QP5050A spectrometer equipped
The present study demonstrates an efficient and simple
procedure for nuclear monobromination of aromatic
compounds with NBS under UV–vis light irradiation.
The selectivity and reactivity depend upon the nature
of the substituents on the aromatic ring. Aromatic com-

194
P. K. Chhattise et al. / Tetrahedron Letters 49 (2008) 189–194
with a DB-5 column to identify the products. All com-
pounds gave satisfactory data and were identical with
authentic samples.
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Shimadzu Analytical Centre of the Department of
Chemistry, University of Pune for spectral analyses.
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