Fast and efficient bromination of aromatic compounds with ammonium bromide and Oxone

Article abstract of DOI:10.1055/s-0033-1338431

A highly efficient, rapid and regioselective protocol was developed for the ring bromination of aromatic compounds under mild conditions with ammonium bromide as a source of bromine source and Oxone (potassium peroxysulfate) as an oxidant. No metal catalyst or acidic additive is required. A variety of aromatic compounds, including methoxy, hydroxy, amino, and alkyl arenes, reacted smoothly to give the corresponding monobrominated products in good to excellent yields in very short reaction times. Moreover, dibromination of deactivated anilines to give the corresponding dibromides proceeded in high yields. Interestingly, 1-(2-naphthyl)ethanone provided a ring-brominated product. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0033-1338431

PAPER
▌1497
pFapaerst and Efficient Bromination of Aromatic Compounds with Ammonium
Bromide and Oxone
Fast and Efficient Bromination of Aromat
a
ic Compounds
a
a
a
b
Mameda Naresh, Macharla Arun Kumar, Marri Mahender Reddy, Peraka Swamy, Jagadeesh Babu Nanubolu,
Nama Narender*a
a
I&PC Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160387; E-mail: narendern33@yahoo.co.in
b
X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received: 05.02.2013; Accepted after revision: 28.03.2013
riety of brominating agents under a range of conditions.
Abstract: A highly efficient, rapid and regioselective protocol was
developed for the ring bromination of aromatic compounds under
Among the brominating agents that have been used are
7
;
calcium(II) bromide and bromine sodium bromide, sodi-
mild conditions with ammonium bromide as a source of bromine
8
®
source and Oxone (potassium peroxysulfate) as an oxidant. No um bromite, and sulfuric acid; silica gel immobilized
metal catalyst or acidic additive is required. A variety of aromatic copper(II) perfluorophthalocyanine and potassium bro-
9
compounds, including methoxy, hydroxy, amino, and alkyl arenes, mide; N-bromosuccinimide (NBS) in the an ionic liq-
reacted smoothly to give the corresponding monobrominated prod-
ucts in good to excellent yields in very short reaction times. More-
over, dibromination of deactivated anilines to give the
corresponding dibromides proceeded in high yields. Interestingly,
10
11
uid; ethylenebis(N-methylimadazolium ditribromide;
12
NBS and poly(ethylene glycol); 1-butyl-3-methylpyri-
dinium tribromide; sodium bromide, hydrogen perox-
ide, and cerium(III) chloride; isoamyl nitrite and
hydrobromic acid; photochemically activated NBS;
potassium bromide, hydrogen bromide, hydrogen perox-
ide, and ammonium metavanadate; sodium bromide and
hydrogen peroxide in a water/supercritical carbon dioxide
biphasic medium; bromine and β-cyclodextrin; potas-
1
3
1
4
1-(2-naphthyl)ethanone provided a ring-brominated product.
1
5
16
Key words: halogenation, bromination, arenes, regioselectivity,
aryl halides
1
7
1
8
19
The bromination of aromatic compounds is an important
sium bromide and benzyl(triphenyl)phosphonium per-
1
electrophilic substitution reaction in organic chemistry
2
0
oxymonosulfate; NBS and sulfonic acid functionalized
and the resultant bromoarenes are useful synthetic inter-
mediates for the manufacture of pharmaceuticals, fine
chemicals, agrochemicals, and other specialty chemicals,
2
1
silica; sodium bromide and hydrobromic acid (electro-
2
2
chemical method); hexamethylenetetramine and bro-
2
3
24
mine; ethylenebis(pyridinium ditribromide) (DPTBE);
2
such as flame retardants, pesticides, and herbicides. Bro-
25
1
-butyl-3-methylimidazolium tribromide; bromine and
a polymer-supported organotin reagent; and pentylpyri-
dinium tribromide.
moarenes are also useful and important intermediates for
2
6
3
cross-coupling reactions and as precursors to organome-
2
7
4
tallic reagents. In addition, several aryl bromides are
Although many methods are available for nuclear bromi-
nation of aromatic compounds, most suffer from one or
more disadvantages. Some require prolonged reaction
times, harsh reaction conditions, or complex experimental
procedures; some give unsatisfactory product yields; and
others involve the use of hazardous, toxic, expensive, or
moisture-sensitive reagents, or reagents that are not read-
ily available or need to be freshly prepared. These prob-
lems limit the use of many of these methods in situations
where an environmentally benign process is required.
biologically active and potentially useful as antitumor, an-
tibacterial, antifungal, antineoplastic, or antiviral agents.
5
Conventional nuclear bromination of aromatic substrates
involves the use of molecular bromine, a hazardous, cor-
rosive, and inconvenient reagent, and in some cases it re-
6
quires expensive transition-metal-based catalysts.
Moreover, with bromine as the reagent, the atom efficien-
cy is effectively reduced to 50%, as only half of the bro-
mine atoms are used, the other half being converted into
hydrobromic acid, which is corrosive, toxic, and a poten-
tial pollutant that must be neutralized before it can be dis-
charged in effluent. Despite these problems, however,
bromine is still being used in industry and in academia be-
cause of its ready availability and low cost, and because of
the lack of a better alternative.
There is still need, therefore, to develop an efficient,
rapid, ecofriendly, atom-economic (100% with respect to
bromine), cheap, and selective procedure for nuclear bro-
mination of aromatic compounds. In continuation of our
research program on the development of environmentally
2
8
benign halogenation processes, we previously reported a
bromination of aromatic rings by using ammonium bro-
To overcome some of these problems, various alternative
methods have recently been developed for the nuclear
bromination of aromatic compounds. These employ a va-
®
mide and Oxone (potassium peroxysulfate) in acetoni-
trile, methanol or water as a solvent to give moderate to
excellent yields of the bromo derivatives in moderately
SYNTHESIS 2013, 45, 1497–1504
Advanced online publication: 14.05.2013
29
short times. Here, we report, in detail, a very simple,
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
rapid, mild, and efficient modified procedure for ring bro-
mination of aromatic compounds by using ammonium
DOI: 10.1055/s-0033-1338431; Art ID: SS2013-Z0106-OP
Georg Thieme Verlag Stuttgart · New York
©

1498
M. Naresh et al.
PAPER
®
bromide and Oxone in 1:1 methanol–water as the reac- Table 2 Monobromination of Aromatic Compounds with Ammoni-
um Bromide and Oxone®
tion medium (Scheme 1).
Entrya Substrate
Time Product
min)
Yield
(%)
R
R
b
(
NH4Br, Oxone®
OMe
Br
MeOH–H2O (1:1), r.t.
OMe
2–90 min
Br
1
2
1a
97
R = OMe, OH, NH2, Me
Scheme 1 Bromination of aromatic compounds
OMe
Br
Br
OMe
Initially, we attempted to brominate anisole with ammoni-
um bromide and Oxone in various solvents (methanol,
2
3
4
4
1b
1c
96
98
®
OMe
O
OMe
O
acetonitrile, acetone, tetrahydrofuran, or ethanol) alone or
in combination with water (Table 1). The best results, par-
ticularly in terms of the reaction yields and time, were ob-
tained when we used a 1:1 mixture of methanol and water
as the solvent system (Table 1, entry 7).
OMe
OMe
OMe
O
O
Table 1 Bromination of Anisole with Ammonium Bromide and
Br
®
4
4
1d
98
Oxone : Solvent Effects
OMe
OMe
OMe
OMe
NH4Br, Oxone®
solvent, r.t.
OMe
5
6
7
3
2
2
1e
1f
77
89
Br
Entrya
b
Br
Br
Solvent
Time
Yield (%)
OMe
1
2
3
4
5
6
7
8
9
MeOH
MeCN
acetone
THF
1.3 h
5 h
90
9729a
25
15
42
39
97
89
89
90
90
OMe
5 h
OH
OH
OH
5 h
9 (9)c
7
1g
d
(
8)
EtOH
5 h
Br
H O
5 h
2
OH
MeOH–H O (1:1)
2 min
2 min
2 min
5 min
3 min
2
8
2
1h
89 (9)d
MeCN–H O (1:1)
2
OH
OH
acetone–H O (1:1)
2
Br
10
THF–H O (1:1)
OH
2
OH
OH
11
EtOH–H O (1:1)
2
9
0
2
2
6
1i
79
a
Reaction conditions: substrate (2 mmol), NH Br (2.2 mmol),
Oxone (2.2 mmol), solvent (10 mL), r.t.
The product was characterized by H NMR and MS, and quantified
4
®
Br
b
1
OH
by GC.
Br
1
1j
1k
95
Having optimized the reaction conditions, we subjected a
variety of aromatic compounds, including anisoles, phe-
nols, anilines, and alkylaromatic compounds to the bromi-
nation process to explore its scope and generality. The
OH
Br
OH
NO2
NO2
16 (41)d
results are summarized in Table 2. Various functional 11
groups played significant roles in governing the yield of
the product.
Synthesis 2013, 45, 1497–1504
© Georg Thieme Verlag Stuttgart · New York

PAPER
Fast and Efficient Bromination of Aromatic Compounds
1499
Table 2 Monobromination of Aromatic Compounds with Ammoni-
um Bromide and Oxone (continued)
Table 2 Monobromination of Aromatic Compounds with Ammoni-
®
um Bromide and Oxone® (continued)
Entrya Substrate
Time Product
min)
Yield
(%)
Entrya Substrate
Time Product
(min)
Yield
(%)
b
b
(
Br
O
OH
O
OH
1
2
3
2
3
1l
94
70
HN
HN
2
2
4
1v
85
NH2
NH2
Br
1
1m
Br
Br
2
2
3
4
30
10
1w
1x
97
79
NH2
NH2
Br
14
15
16
17
18
3
5
5
5
4
1n
1o
1p
1q
1r
60 (25)d
20 (40)d
72
Br
Br
NH2
NH2
Br
Br
Cl
Cl
2
2
5
6
30
30
1y
1z
96
82
Br
NH2
NH2
CN
CN
Br
Br
NH2
NH2
O
Br
O
70 (15)d
70 (15)d
2
7
90
6
58
CN
CN
Br
NH2
NH2
a
NO2
Reaction conditions: substrate (2 mmol), NH Br (2.2 mmol),
4
NO2
®
Oxone (2.2 mmol), MeOH–H O (1:1; 10 mL), r.t.
2
b
1
The products were characterized by H NMR and MS, and quantified
by GC.
Br
c
Yield of o-bromo product.
Yield of dibromo product.
d
NH2
NH2
Br
19
20
21
5
5
5
1s
1t
20 (45)d
All the substrates were treated with 1.1 equivalents of am-
monium bromide and 1.1 equivalents of Oxone in a 1:1
®
NO2
NH2
NO2
NH2
mixture of methanol and water at room temperature.
Within few minutes (2–90 min), each of the substrates
gave the corresponding ring-brominated product in good
to excellent yield and high regioselectivity. As can be seen
from Table 2, bromination of methoxy and hydroxy deriv-
atives by using this reagent system gave the correspond-
ing ring-brominated products in high yields within very
short reaction times (2–4 min), whereas much longer re-
action times (5–8 h) were required when acetonitrile was
Br
50 (25)d
O
OMe
O
OMe
O
O
1u
62 (31)d
29a
used as the solvent. Anisoles containing electron-donat-
H2N
ing or electron-withdrawing functional groups in various
positions on the aromatic ring worked well and did not
show any marked difference in their yields of products or
reaction times (entries 2–4). 2-Methoxynaphthalene and
H2N
Br
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1497–1504

1500
M. Naresh et al.
PAPER
2-naphthol were also rapidly (2 min) brominated under It is noteworthy that 1-(2-naphthyl)ethanone provided the
similar reaction conditions and afforded the correspond- ring-brominated product 1-(5-bromo-2-naphthyl)etha-
ing 1-bromo derivatives exclusively in yields of 89% and none (6) in 58% yield by this method (Table 2, entry 27),
9
4%, respectively (entries 6 and 12). Phenol gave the whereas the α-brominated product was obtained in meth-
28b
para-brominated derivative as the major product (79%), anol (Scheme 2). Product 6 was unambiguously charac-
3
0
along with smaller amounts of the corresponding ortho- terized by means of X-ray crystallography (Figure 1).
brominated product (9%) and dibrominated product (8%)
entry 7). Resorcinol was also smoothly brominated to
(
give the para-brominated and dibrominated products in
yields of 89% and 9%, respectively (entry 8). However, in
the case of strongly deactivated 2-nitrophenol, the dibro-
minated product (2,6-dibromo-4-nitrophenol) predomi-
nated; the dibrominated and monobrominated products
were obtained in yields of 41% and 16%, respectively (en-
try 11).
Next, we explored the scope of the method by treating an-
ilines under our optimized reaction conditions. 2,6-Dieth-
ylaniline exclusively gave the corresponding 4-
brominated product in 70% yield in three minutes (entry
1
3). On the other hand, when acetonitrile, methanol, or
water was used as the solvents, the yields were 48%, 45%
and 28%, respectively, even after three hours. Deactivated
anilines gave the corresponding monobrominated prod-
Figure 1 ORTEP diagram of compound 6 (30% probability)
uct, along with substantial amounts of the dibrominated The systems described above selectively gave the corre-
product (entries 14–16 and 18–20), except for 2-amino- sponding aromatic derivatives that were brominated in the
benzonitrile which gave the monobrominated product ex- para-position with respect to the activating substituent.
clusively (entry 17). 1,2,3,4-Tetrahydronaphthalen-2- However, when the para-position of the substrate was
amine also reacted smoothly to give mono- and dibromi- blocked by a substituent, the ortho-brominated product
nated products in 62% and 31% yield, respectively (entry was obtained.
2
1).
Encouraged by these results, we also successfully carried
Next, we investigated the efficiency of the method with out dibrominations of several deactivated anilines by us-
alkylaromatic compounds, which are moderately activat- ing 2.2 equivalents of each of the reagents (ammonium
ed, under similar reaction conditions. m-Xylene, mesity- bromide and Oxone ), and we obtained excellent yields of
®
lene, and 1,2,4-trimethylbenzene reacted exclusively at the corresponding products, which are industrially impor-
the aromatic ring to give ring-brominated monobromo tant compounds or pharmaceutical intermediates, within a
compounds in excellent yields, without forming any side- short reaction time (5 min) (Table 3).
chain brominated products (Table 2, entries 23–25); how-
ever, the reaction took a little longer (10–30 min) than that
Table 3 Dibromination of Substituted Anilines with Ammonium
of the highly activated aromatics. In methanol or water as Bromide and Oxone®
the solvent, bromination of alkylaromatic compounds to
Entrya Substrate
Product
Yield (%)
b
give ring-brominated products required 40 minutes to 24
hours.2 Bromination of 2-methylnaphthalene gave the
9b
NH2
NH2
corresponding 1-bromo derivative in 82% yield in 30 min-
utes (entry 26), whereas the corresponding reaction in
Br
Br
Br
Br
1
2a
95
methanol or water gave 80% and 75% yields, respective-
ly, in 24 hours.2
9b
Br
Br
NH2
NH2
O
Br
MeOH
2
2b
2c
95
95
O
Br
r.t., 24 h
NH4Br
CN
CN
Oxone®
O
NH2
NH2
CN
MeOH–H2O
r.t., 13 h
CN
3
Br
Br
Scheme 2 Bromination of 1-(2-naphthyl)ethanone
Synthesis 2013, 45, 1497–1504
© Georg Thieme Verlag Stuttgart · New York

PAPER
Fast and Efficient Bromination of Aromatic Compounds
1501
Table 3 Dibromination of Substituted Anilines with Ammonium
Bromide and Oxone (continued)
EtOAc–hexane) to give pure products that were identified by means
of H NMR spectroscopy and mass spectrometry.
®
1
Entrya Substrate
Product
Yield (%)
b
31
1-Bromo-4-methoxybenzene (1a)
1
H NMR (500 MHz, CDCl ): δ = 3.77 (s, 3 H), 6.76 (d, J = 8.61 Hz,
3
NH2
NH2
2 H), 7.36 (d, J = 8.61 Hz, 2 H).
Br
Br
Br
+
+
MS (EI): m/z (%) = 188 (98) [M + 2] , 186 (100) [M ], 171 (50),
4
2d
90
173 (50), 143 (45), 145 (45), 77 (20), 63 (35).
4
-Bromo-1,2-dimethoxybenzene (1b)32
H NMR (300 MHz, CDCl ): δ = 3.86 (s, 3 H), 3.87 (s, 3 H), 6.74
(d, J = 8.49 Hz, 1 H), 6.98 (d, J = 2.26 Hz, 1 H), 7.03 (dd, J = 8.68,
.26 Hz, 1 H).
MS (EI): m/z (%) = 218 (58) [M + 2] , 216 (60) [M ], 201 (30), 203
30), 173 (20), 138 (25), 94 (100), 79 (50), 51 (50).
NO2
NO2
1
3
NH2
NH2
2
NO2
NO2
+
+
5
2e
2f
95
95
(
Br
-(5-Bromo-2-methoxyphenyl)ethanone (1c)33
H NMR (300 MHz, CDCl ): δ = 2.60 (s, 3 H), 3.90 (s, 3 H), 6.86
d, J = 9.0 Hz, 1 H), 7.54 (dd, J = 9.0, 3.0 Hz, 1 H), 7.82 (d, J = 2.6
1
1
3
NH2
NH2
(
Br
Br
Hz, 1 H).
6
1
-(2-Bromo-5-methoxyphenyl)ethanone (1d)34
H NMR (300 MHz, CDCl ): δ = 2.63 (s, 3 H), 3.81 (s, 3 H), 6.85
1
3
O
OMe
O
OMe
(dd, J = 8.30, 3.02 Hz, 1 H), 6.98 (d, J = 3.02 Hz, 1 H), 7.49 (d, J =
9
.06 Hz, 1 H).
a
Reaction conditions: substrate (2 mmol), NH Br (4.4 mmol),
4
®
35
Oxone (4.4 mmol), MeOH–H O (1:1; 10 mL), 5 min, r.t.
1-Bromo-4-methoxynaphthalene (1e)
2
b
1
1
The products were characterized by H NMR and MS, and quanti-
H NMR (500 MHz, CDCl ): δ = 3.99 (s, 3 H), 6.67 (d, J = 8.08 Hz,
3
fied by GC.
1 H), 7.48–7.55 (m, 1 H), 7.58–7.68 (m, 2 H), 8.17 (d, J = 8.89 Hz,
1
H), 8.27 (d, J = 8.08 Hz, 1 H).
MS (EI): m/z (%) = 238 (98) [M + 2] , 236 (100) [M ], 221 (60),
23 (60), 193 (75), 195 (75), 158 (40), 114 (70), 88 (25), 63 (25).
+
+
In summary, we have developed an efficient, rapid, and
versatile method for the regioselective nuclear bromina-
2
3
6
tion of aromatics by using ammonium bromide and 1-Bromo-2-methoxynaphthalene (1f)
1
®
H NMR (500 MHz, CDCl ): δ = 4.04 (s, 3 H), 7.23 (d, J = 9.35 Hz,
3
Oxone in aqueous methanol. A wide range of aromatic
compounds were found to react under mild conditions
(
corresponding ring-brominated products. Salient features
of this method are shorter reaction times (rapid conver-
1
7
H), 7.35 (dd, J = 8.01, 1.2 Hz, 1 H), 7.53 (dt, J = 7.8, 1.2 Hz, 1 H),
.71–7.79 (m, 2 H), 8.19 (d, J = 8.57 Hz, 1 H).
room temperature) to give good to excellent yields of the
+
+
MS (EI): m/z (%) = 238 (98) [M + 2] , 236 (100) [M ], 221 (25),
23 (25), 193 (75), 195 (75), 114 (60), 88 (15), 63 (25).
2
3
7
sion), simple reaction conditions, commercial availability 4-Bromophenol (1g)
1
H NMR (500 MHz, CDCl ): δ = 5.20 (s, 1 H), 6.73 (d, J = 8.30 Hz,
3
of reagents, environmental compatibility, no evolution of
hydrogen bromide, easy setup and workup, high yields,
and low costs. An interesting feature of the method is that
2
H), 7.33 (d, J = 8.30 Hz, 2 H).
MS (EI): m/z (%) = 174 (8) [M + 2] , 172 (10) [M ], 143 (30), 93
12), 62 (100), 39 (50).
4-Bromobenzene-1,3-diol (1h)
+
+
(
1
-(2-naphthyl)ethanone gave the corresponding ring-
3
8
brominated product in good yield.
1
H NMR (500 MHz, DMSO-d ): δ = 6.18 (dd, J = 8.90, 1.98 Hz, 1
6
H), 6.45 (d, J = 1.98 Hz, 1 H), 7.12 (d, J = 7.91 Hz, 1 H), 8.99 (br s,
All chemicals used were of reagent grade and used as received with-
1
H), 9.33 (br s, 1 H).
1
out further purification. H NMR spectra were recorded at 300 and
13
39
5
00 MHz and C NMR spectra were recorded at 75 MHz in CDCl3
4-Bromo-3-methylphenol (1i)
1
or DMSO-d with Bruker VX NMR FT-300 and Varian Unity 500
H NMR (500 MHz, CDCl ): δ = 2.33 (s, 3 H), 5.34 (br s, 1 H), 6.55
3
6
spectrometers The chemical shifts (δ) are reported in ppm relative
(dd, J = 9.06, 3.02 Hz, 1 H), 6.73 (d, J = 3.02 Hz, 1 H), 7.35 (d, J =
9.06 Hz, 1 H).
.
1
13
to TMS as internal standard for H NMR and to CDCl for
C
3
NMR. Mass spectra were recorded with a Finnigan MAT 1020 mass
spectrometer operating at 70 eV. Column chromatography was per-
formed on 100–200 mesh silica gel.
2
-Bromo-4-methylphenol (1j)40
1
H NMR (500 MHz, CDCl ): δ = 2.9 (s, 3 H), 5.32 (br s, 1 H), 6.81
3
(
d, J = 8.0 Hz, 1 H), 7.0 (d, J = 8.0 Hz, 1 H), 7.26 (d, J = 2.02 Hz, 1
Monobromination of Aromatic Compounds; General Proce-
H).
MS (EI): m/z (%) = 186 (75) [M + 2] , 188 (73) [M ], 107 (100), 77
40), 51 (25).
dure
+
+
®
NH Br (2.2 mmol) and Oxone (2.2 mmol) were added to a stirred
4
(
soln of substrate (2 mmol) in MeOH–H O (1:1; 10 mL), and the
2
mixture was stirred at r.t. for the time shown in Table 2. When the
reaction was complete (TLC), the mixture was filtered and the sol-
vent was removed under reduced pressure. The residue was dis-
solved in EtOAc (25 mL) and the soln was filtered and washed
successively with 0.2 M aq Na S O (10 mL) and H O. The organic
-Bromo-2-nitrophenol (1k)41
4
1
H NMR (500 MHz, CDCl ): δ = 7.08 (d, J = 8.8 Hz, 1 H), 7.66 (dd,
3
J = 9.0, 2.4 Hz, 1 H), 8.24 (d, J = 2.4 Hz, 1 H), 10.49 (s, 1 H).
+
+
MS (EI): m/z (%) = 219 (73) [M + 2] , 217 (75) [M ], 202 (12), 200
12), 143 (25), 63 (100).
2
2
3
2
(
layer was dried (Na SO ) and concentrated in vacuo. The crude
2
4
product was purified by column chromatography (silica gel, 5–50%
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1497–1504

1502
M. Naresh et al.
PAPER
48
2
,4-Dibromo-6-nitrophenol (1k)41
6-Amino-5-bromo-3,4-dihydronaphthalen-1(2H)-one (1u)
1
1
H NMR (500 MHz, CDCl ): δ = 8.00 (d, J = 2.4 Hz, 1 H), 8.25 (d,
H NMR (300 MHz, CDCl ): δ = 2.07–2.15 (m, 2 H), 2.58 (t, J =
3
3
J = 2.4 Hz, 1 H), 11.05 (s, 1 H).
6.04 Hz, 2 H), 2.97 (t, J = 6.79 Hz, 2 H), 4.67 (br s, 2 H), 6.68 (d,
+
+
J = 9.06 Hz, 1 H), 7.89 (d, J = 8.9 Hz, 1 H).
MS (EI): m/z (%) = 299 (48) [M + 4] , 297 (100) [M + 2] , 295 (50)
[
+
+
+
M ], 250 (10), 143 (25), 141 (25), 62 (35).
MS (EI): m/z (%) = 241 (86) [M + 2] , 239 (88) [M ], 211 (100),
2
50 (98), 185 (12), 183 (13), 143 (10), 104 (50).
1
-Bromo-2-naphthol (1l)42
1
7
H NMR (500 MHz, CDCl ): δ = 5.92 (s, 1 H), 7.27 (d, J = 8.83 Hz,
N-(4-Bromophenyl)acetamide (1v)
3
1
1
H), 7.39 (t, J = 7.72 Hz, 1 H), 7.57 (t, J = 7.72 Hz, 1 H), 7.73–7.79
H NMR (300 MHz, DMSO-d ): δ = 2.12 (s, 3 H), 7.36 (d, J = 8.8
6
(m, 2 H), 8.03 (d, J = 7.72 Hz, 1 H).
Hz, 2 H), 7.54 (d, J = 8.87 Hz, 2 H), 9.73 (br s, 1 H).
+
+
+
+
MS (EI): m/z (%) = 222 (8) [M + 2] , 224 (10) [M ], 141 (10), 114
15), 60 (20), 43 (100).
MS (EI): m/z (%) = 214 (4) [M + 2] , 212 (5) [M ], 172 (30), 136
(25), 94 (100), 43 (50).
(
49
4
-Bromo-2,6-diethylaniline (1m)43
1-Bromo-2,4-dimethylbenzene (1w)
1
1
H NMR (300 MHz, CDCl ): δ = 1.24 (t, J = 7.55 Hz, 6 H), 2.49 (q,
H NMR (300 MHz, CDCl ): δ = 2.27 (s, 3 H), 2.36 (s, 3 H), 6.85
3
3
J = 7.55 Hz, 4 H), 3.62 (br s, 2 H), 7.07 (s, 2 H).
(d, J = 8.30 Hz, 1 H), 7.04 (s, 1 H), 7.39 (d, J = 8.30 Hz, 1 H).
+
+
+
+
MS (EI): m/z (%) = 229 (98) [M + 2] , 227 (100) [M ], 212 (95),
MS (EI): m/z (%) = 186 (58) [M + 2] , 184 (60) [M ], 105 (100), 77
214 (93), 148 (20), 133 (40), 91 (35).
(50), 43 (60).
46
2
,4-Dibromoaniline (1n)26
2-Bromo-1,3,5-trimethylbenzene (1x)
1
1
H NMR (300 MHz, CDCl ): δ = 4.09 (br s, 2 H), 6.64 (d, J = 8.49
H NMR (300 MHz, CDCl ): δ = 2.22 (s, 3 H), 2.36 (s, 6 H), 6.83
3
3
Hz, 1 H), 7.20 (dd, J = 8.49, 2.07 Hz, 1 H), 7.52 (d, J = 2.07 Hz, 1
(s, 2 H).
H).
+
+
MS (EI): m/z (%) = 200 (18) [M + 2] , 198 (20) [M ], 168 (100),
+
+
MS (EI): m/z (%) = 253 (58) [M + 4] , 251 (100) [M + 2] , 249 (60)
141 (80), 119 (75), 71 (70), 57 (100), 43 (90).
+
[
M ], 172 (18), 170 (20), 157 (20), 155 (20), 91 (20).
1
-Bromo-2,4,5-trimethylbenzene (1y)50
-Bromo-4-chloroaniline (1o)40
1
2
H NMR (500 MHz, CDCl
3
): δ = 2.17 (s, 3 H), 2.20 (s, 3 H), 2.32
1
H NMR (300 MHz, CDCl ): δ = 4.08 (br s, 2 H), 6.69 (d, J = 9.06
(s, 3 H), 6.98 (s, 1 H), 7.28 (s, 1 H).
3
Hz, 1 H), 7.07 (dd, J = 8.30, 2.26 Hz, 1 H), 7.40 (d, J = 2.26 Hz, 1
H).
+
+
MS (EI): m/z (%) = 200 (78) [M + 2] , 198 (80) [M ], 119 (100), 91
25), 39 (12).
(
+
+
MS (EI): m/z (%) = 209 (30) [M + 4] , 207 (100) [M + 2] , 205 (75)
46
+
1-Bromo-2-methylnaphthalene (1z)
H NMR (300 MHz, CDCl ): δ = 2.64 (s, 3 H), 7.32 (d, J = 8.30 Hz,
1 H), 7.41–7.60 (m, 2 H), 7.68 (d, J = 9.06 Hz, 1 H), 7.76 (d, J =
7.55 Hz, 1 H), 8.28 (d, J = 8.30 Hz, 1 H).
[M ], 126 (25), 90 (18).
1
3
2
-Amino-5-bromobenzonitrile (1p)44
1
H NMR (300 MHz, CDCl ): δ = 4.44 (br s, 2 H), 6.64 (d, J = 8.99
3
Hz, 1 H), 7.40 (dd, J = 8.99, 2.00 Hz, 1 H), 7.48 (d, J = 2.00 Hz, 1
H).
+
+
MS (EI): m/z (%) = 223 (48) [M + 2] , 221 (50) [M ], 142 (100),
1
16 (25), 92 (25), 43 (12).
+
+
MS (EI): m/z (%) = 198 (98) [M + 2] , 196 (100) [M ], 117 (70), 90
60), 63 (25).
1
-(5-Bromo-2-naphthyl)ethanone (6)
H NMR (300 MHz, CDCl ): δ = 2.75 (s, 3 H), 7.41 (t, J = 7.55 Hz,
1 H), 7.88–7.97 (m, 2 H), 8.12 (dd, J = 8.30, 1.51 Hz, 1 H), 8.30 (d,
J = 9.06 Hz, 1 H), 8.45 (d, J = 1.51 Hz, 1 H).
(
1
3
4
-Amino-3-bromobenzonitrile (1q)45
1
H NMR (300 MHz, CDCl ): δ = 4.63 (br s, 2 H), 6.77 (d, J = 8.30
3
Hz, 1 H), 7.38 (dd, J = 8.30, 2.26 Hz, 1 H), 7.70 (d, J = 2.26 Hz, 1
H).
13
C NMR (75 MHz, CDCl ): δ = 26.8, 122.7, 125.4, 127.2, 127.8,
3
1
29.5, 130.3, 132.4, 133.8, 134.0, 135.0, 197.6.
+
+
MS (EI): m/z (%) = 198 (98) [M + 2] , 196 (100) [M ], 117 (30), 90
30), 63 (20).
ESI-MS: m/z (%) = 249 (40) [M + H]+.
Crystal data:30 C H BrO; M = 249.10; monoclinic; a = 10.4152(7),
b = 11.8496(8), c = 9.0740(6) Å; V = 1026.79(12) Å ; T = 293(2) K;
space group P2 /c (No. 14); 9463 reflections measured of which
1808 were unique reflections (Rint = 0.0359) used in all calculations.
The final wR2 was 0.1916.
(
12
9
-Bromo-2-nitroaniline (1r)26
3
4
1
H NMR (300 MHz, CDCl ): δ = 6.09 (br s, 2 H), 6.73 (d, J = 8.30
3
1
Hz, 1 H), 7.43 (dd, J = 9.06, 2.26 Hz, 1 H), 8.27 (d, J = 2.26 Hz, 1
H).
+
+
MS (EI): m/z (%) = 218 (98) [M + 2] , 216 (100) [M ], 186 (25),
Dibromination of Aromatic Compounds; General Procedure
1
88 (25), 170 (50), 172 (50), 143 (30), 145 (30), 90 (70), 63 (75).
This was performed by a similar procedure to monobromination,
®
-Bromo-4-nitroaniline (1s)46
except that NH
4
Br (4.4 mmol) and Oxone (4.4 mmol) were used,
2
1
and the reaction mixture was stirred at r.t. for the time shown in Ta-
ble 3.
H NMR (300 MHz, CDCl ): δ = 4.83 (br s, 2 H), 6.75 (d, J = 9.06
3
Hz, 1 H), 8.04 (dd, J = 9.0, 2.26 Hz, 1 H), 8.38 (d, J = 2.26 Hz, 1 H).
+
+
26
MS (EI): m/z (%) = 218 (68) [M + 2] , 216 (70) [M ], 186 (75), 188
75), 170 (25), 90 (100), 63 (60).
2,4,6-Tribromoaniline (2a)
1
(
H NMR (300 MHz, CDCl ): δ = 4.55 (br s, 2 H), 7.51 (s, 2 H).
3
+
+
4
7
MS (EI): m/z (%) = 333 (48) [M + 6] , 331 (100) [M + 4] , 329 (100)
Methyl 4-Amino-3-bromobenzoate (1t)
+
+
1
[M + 2] , 327 (50) [M ], 252 (9), 250 (20), 248 (10), 170 (25), 168
25).
H NMR (300 MHz, CDCl ): δ = 3.86 (s, 3 H), 4.52 (br s, 2 H), 6.73
d, J = 8.30 Hz, 1 H), 7.79 (dd, J = 8.30, 2.26 Hz, 1 H), 8.12 (d, J =
3
(
(
2
.02 Hz, 1 H).
MS (EI): m/z (%) = 231 (68) [M + 2] , 229 (70) [M ], 200 (98), 198
100), 150 (14), 90 (30).
4
-Amino-3,5-dibromobenzonitrile (2b)51
1
+
+
H NMR (300 MHz, CDCl ): δ = 5.11 (br s, 2 H), 7.66 (s, 2 H).
3
(
+
+
MS (EI): m/z (%) = 278 (58) [M + 4] , 276 (100) [M + 2] , 274 (60)
+
[
M ], 195 (8), 197 (7), 116 (20), 88 (18).
Synthesis 2013, 45, 1497–1504
© Georg Thieme Verlag Stuttgart · New York

PAPER
Fast and Efficient Bromination of Aromatic Compounds
1503
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-Amino-3,5-dibromobenzonitrile (2c)52
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Reddy, T. S. Synth. Commun. 2009, 39, 215.
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Garzan, A. Adv. Synth. Catal. 2009, 351, 1925.
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1
H NMR (300 MHz, CDCl ): δ = 4.90 (br s, 2 H), 7.48 (d, J = 2.07
3
Hz, 1 H), 7.73 (d, J = 2.3 Hz, 1 H).
+
+
MS (EI): m/z (%) = 278 (35) [M + 4] , 276 (75) [M + 2] , 274 (35)
+
[M ], 196 (100), 198 (98), 117 (40), 90 (30).
2
,6-Dibromo-4-nitroaniline (2d)46
1
H NMR (300 MHz, CDCl ): δ = 5.30 (br s, 2 H), 8.34 (s, 2 H).
3
+
+
MS (EI): m/z (%) = 298 (50) [M + 4] , 296 (100) [M + 2] , 294 (50)
+
[M ], 268 (35), 266 (75), 264 (36), 170 (45), 168 (45), 90 (40).
(
4
,6-Dibromo-2-nitroaniline (2e)53
1
H NMR (300 MHz, CDCl ): δ = 6.60 (br s, 2 H), 7.82 (d, J = 2.26
3
Hz, 1 H), 8.28 (d, J = 2.26 Hz, 1 H).
+
+
(
MS (EI): m/z (%) = 298 (58) [M + 4] , 296 (100) [M + 2] , 294 (60)
+
[M ], 252 (24), 250 (48), 264 (24), 90 (30).
(
1
-(4-Amino-3,5-dibromophenyl)ethanone (2f)47
1
H NMR (300 MHz, CDCl ): δ = 3.87 (s, 3 H), 5.00 (br s, 2 H), 8.07
3
(s, 2 H).
(
(
(
20) Adibi, H.; Hajipour, A. R.; Hashemi, M. Tetrahedron Lett.
007, 48, 1255.
2
21) Das, B.; Venkateswarlu, K.; Krishnaiah, M.; Holla, H.
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U.; Malini, R.; Muthukumaran, A. Tetrahedron Lett. 2006,
Acknowledgment
We thanks the CSIR Network project CSC-0125 for financial sup-
port. M.N, M.A.K., and M.M.R acknowledge financial support
from CSIR, India, in the form of fellowships. P.S. acknowledges fi-
nancial support from UGC, India, in the form of a fellowship.
4
7, 4581.
(
23) Heravi, M. M.; Abdolhosseini, N.; Oskooie, H. A.
Tetrahedron Lett. 2005, 46, 8959.
(
24) Kavala, V.; Naik, S.; Patel, B. K. J. Org. Chem. 2005, 70,
4267.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. SnuIoipgfmr tooatrin guSIopi
n
nfo itrmart
(25) Le, Z. G.; Chen, Z. C.; Hu, Y.; Zheng, Q. G. Chin. Chem.
Lett. 2005, 16, 1007.
(
26) Chrétien, J.-M.; Zammattio, F.; LeGrognec, E.; Paris, M.;
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Synthesis 2013, 45, 1497–1504
© Georg Thieme Verlag Stuttgart · New York