A facile, regioselective and controllable bromination of aromatic amines using a CuBr2/Oxone system

Article abstract of DOI:10.1039/c3ra41664j

A combination of cupric bromide and Oxone serves as a facile, mild and effective reagent for the bromination of aromatic amines. Primary, secondary and tertiary aromatic amines are all suitable substrates. The reaction possesses high regioselectivity and functional group tolerance, and mono- and multi-brominated products can be obtained controllably in moderate to excellent yields. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra41664j

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A facile, regioselective and controllable bromination of
aromatic amines using a CuBr2/Oxone1 system3
Cite this: DOI: 10.1039/c3ra41664j
Xin-Le Li,ab Wei Wu,ab Xin-Heng Fanb and Lian-Ming Yang*b
Received 7th April 2013,
Accepted 29th May 2013
DOI: 10.1039/c3ra41664j
www.rsc.org/advances
A combination of cupric bromide and Oxone1 serves as a facile,
mild and effective reagent for the bromination of aromatic
amines. Primary, secondary and tertiary aromatic amines are all
suitable substrates. The reaction possesses high regioselectivity
and functional group tolerance, and mono- and multi-brominated
products can be obtained controllably in moderate to excellent
yields.
narrow range of aromatic amines. In the studies that specialized
in the halogenation of aromatic amines, in 2002 Smith et al.15
reported a bromination method for anilines using n-BuLi/R3SnCl/
Br2 at 278 uC, while in 2001 Tour et al.16 employed BnNEt3ICl2 as
a halogenating reagent for the iodination of anilines. Accordingly,
we desired to develop an improved protocol for the halogenation
of aromatic amines, which should be mild, regioselective,
substitution-controllable and, in particular, general (i.e., suitable
for primary, secondary, and tertiary arylamines). Herein, we report
our work on the oxidative bromination of aromatic amines. After a
comprehensive evaluation of the existing methods, we decided on
the use of a brominating system consisting of a bromide salt and
an oxidant for the bromination of aromatic amines. Cupric
bromide was selected as the preferred bromine source since it has
long been known to affect the bromination of alkenes and alkynes,
cause the a-bromination of carbonyl compounds,17 and was
recently used for the mono-bromination of some electron-rich
arenes.14
As a starting point, N-phenyl-1-naphthylamine was chosen as a
model substrate in order to optimize the reaction conditions
(Table 1). Upon the use of cupric bromide alone (0.5 molecules of
CuBr2 are equal to 1 equivalent of Br atoms), monobromination
took place, but the reaction did not go to completion (Table 1, run
1). However, the use of excess CuBr2 had a disappointing outcome
where a substantial amount of the dibrominated product was
produced, while the monobrominated product was isolated in
only a low yield (run 2). We then examined protocols using CuBr2
plus an additional oxidizing agent. Several commonly used
oxidants were tested. H2O2 (30% aqueous solution) and TPHP
(70% aqueous solution) totally suppressed the reaction (runs 3
and 4), while m-CPBA and DTBP did not work well (comparing
runs 5 and 6 with run 1). To our pleasure, a rapid, clean
conversion was observed using Oxone1 as the additional
oxidant,18 with a high 75% isolated yield of the monobrominated
product obtained (run 7). The effect of O2 on the reaction could be
excluded since a similar yield was obtained when the reaction was
carried out under a nitrogen atmosphere (run 8 vs. run 7). A
brominating system consisting of a catalytic amount of cupric
bromide and other bromine sources (such as KBr or NH4Br)
Halogenation of aromatic compounds continues to be an
important reaction in synthetic organic chemistry. Bromoarenes
are particularly versatile intermediates for a variety of transforma-
tions that range from the synthesis of functionalized aromatic
molecules1 to aryl organometallic reagents utilized in modern
transition metal-catalyzed couplings.2 The classical electrophilic
bromination of aromatic compounds involves the use of
molecular bromine and mineral acids. However, this leads to
obvious drawbacks such as harsh conditions (e.g., strongly acidic),
hazardous waste, and problems associated with bromine-econ-
omy. Furthermore, aromatic amines, due to their high reactivity,
tend to suffer from poor regioselectivity and polybromination is a
common problem.3 Over the past decade, a wide range of mild,
regio-specific protocols for the bromination of activated aromatic
compounds have been developed with varying degrees of
success.4–14 Representative methods include: the use of brominat-
ing
agents
other
than
molecular
bromine
like
N-bromosuccinimide,4 hexamethylenetetramine-bromine com-
plex,5 PVPP-Br2 complex6 and bromide/DMSO systems;7 the use
of a combination of a bromide salt and oxidant such as NH4Br/
H2O2,8 MPHT/H2O2,9 KBr/peroxodisulfate,10 KBr/Oxone1,11
NH4Br/Oxone1,12 and LiBr/O2;13 as well as the use of CuBr2
alone.14 However, these methods, aiming largely at the bromina-
tion of electron-rich substrates such as phenols, aryl alkyl ethers,
and polyalkyl-substituted arenes, involved only a few types and
aBeijing National Laboratory for Molecular Sciences (BNLMS), Laboratory of New
Materials, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R.
China
bGraduate School of Chinese Academy of Sciences, Beijing 100049, P. R. China.
E-mail: yanglm@iccas.ac.cn; Fax: +86-10-62559373; Tel: +86-10-62565609
Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra41664j
3
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Table 1 Screening of the reaction conditionsa
Table 2 Monobromination of aromatic amines using a CuBr2/Oxone1 reagenta
Run Amine 1
Product 2 (yield) Run Amine
Product 2 (yield)
1
12
2
13
Br source
Run (mmol)
Oxidant (mmol) Solvent Time (h) Yieldb (%)
3
4
14
15
1
2
3
4
5
6
7
CuBr2 (0.5) None
CuBr2 (1–2) None
MeCN
MeCN
12
12
12
12
12
12
3
3
6
3
3
3
8
3
8
12
12
3
45
y40
Trace
None
46
49
75
74
60
None
32
71
68
55
26
41
43
62
CuBr2 (0.5) 30% H2O2 (1.2) MeCN
CuBr2 (0.5) 70% TPHPc (1.2) MeCN
CuBr2 (0.5) m-CPBAd (1.2)
CuBr2 (0.5) DTBPe (1.5)
CuBr2 (0.5) Oxone1 (1.2)
CuBr2 (0.5) Oxone1 (1.2)
CuBr2 (0.05) Oxone1 (1.2)
CuBr2 (0.5) Oxone1 (1.2)
CuBr2 (0.5) Oxone1 (1.2)
CuBr2 (0.5) Oxone1 (1.2)
CuBr2 (0.5) Oxone1 (1.2)
MeCN
MeCN
MeCN
MeCN
MeCN
H2O
MeOH
Dioxane
DCEh
MeCN
MeCN
MeCN
MeCN
MeCN
8f
9g
10
11
12
13
14
15
16
17
18
5
6
16
17
CuBr (1.0)
KBr (1.0)
Oxone1 (1.2)
Oxone1 (1.2)
NH4Br (1.0) Oxone1 (1.2)
TBABi (1.0) Oxone1 (1.2)
CuBr2 (0.5) Oxone1 (0.5)
a
7
18
Conditions: 1a (1 mmol), solvent (8 mL), room temperature, in air,
b
c
d
monitored by TLC. Isolated yields. t-Butyl hydroperoxide. m-
Chloroperbenzoic acid. Di(t-butyl) peroxide. The reaction mixture
e
f
g
was degassed and run under an N2 atmosphere. 5 mol% of CuBr2
and 1.5 equiv. KBr or NH4Br. h 1,2-Dichloroethane. i Tetrabutyl ammo-
nium bromide.
8
9
19
20
seemed effective (run 9), but the Cu-catalyzed bromonation
suffered from a relatively slower conversion rate and a complex
product distribution. The nature of the solvent used has a notable
effect on the reaction; protonic solvents, such as H2O and
methanol, which are usually used with Oxone1, are poor (runs 10
and 11), whereas polar non-protonic solvents (runs 7, 12 and 13)
are a more suitable reaction medium. Cuprous bromide (run 14),
despite being slightly inferior to cupric bromide (run 7),
performed better than other bromide salts (runs 15, 16 and 17),
indicating that the presence of copper cations is favorable for this
reaction. Additionally, the use of a suitable amount of the oxidant
Oxone1 is necessary for an efficient transformation (see run 18 vs.
run 7). Based on a comprehensive assessment of the experiments
mentioned above, we chose run 7 (Table 1) as our standard
conditions.
10
11
a
21
Conditions: amine (1 mmol), cupric bromide (0.5 mmol), Oxone1 (1.2
mmol), acetonitrile (8 mL), room temperature, in air, 3 h; isolated yields.
b
50 mmol scale bromination carried out, 24 h. c 0.5 h, 0–5 uC.
Next, we examined the substrate scope of this monobromina-
tion reaction (Table 2). Most of the primary arylamines afforded
good to excellent yields of the desired product (Table 2, runs 1–6,
8, and 9). Bromination of aniline proceeded with clean conversion
and a high yield of 72% (run 1). In the case of 1-naphthylamine,
the reaction was slow at room temperature, but heating resulted in
a complicated mixture (run 7). The mono-bromination of anilines
took place preferentially at the para position unless the position
was blocked. For example, p-substituted anilines (run 4 and 8) and
2-naphthylamine (run 6) were brominated at their ortho positions.
Furthermore, this method can be extended to the bromination of
heteroaromatics like 2-aminopyridine (run 9) and carbazole (run
10) which gave high isolated yields. Note that deactivated N-acyl
aniline was not suitable for this bromination (run 11). Secondary
aromatic amines can be brominated smoothly (runs 12–15):
4-Bromo-N-methylaniline was obtained in 76% yield (run 12); both
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Table 3 Polybromination of aromatic amines under controlled conditionsa
N-phenyl-1-naphthylamine (run 13) and N-phenyl-2-naphthyla-
mine (run 15) gave the desired products selectively monobromi-
nated at the para position of phenyl group; and using
diphenylamine gave a 67% yield of the p-monobrominated
product (run 14), with a small amount of 4,49-dibromodipheny-
lamine. Tertiary aromatic amines are also suitable substrates for
monobromination (run 16–21). N,N-Dialkylanilines were para or
ortho (if the para position was blocked) brominated in good to
excellent yields (runs 16–19). Moreover, sensitive functional groups
like aldehydes survived under the reaction conditions (runs 18 and
19). The monobromination of triarylamines resulted in high yields
of the desired products (runs 20 and 21).
Polybrominated products
Mixed polybromination of the aromatic amines was anticipated
to be a potential concern to address. However, under the
monobromination conditions mentioned above no appreciable
amount of multibrominated product was observed for any of the
substrates studied. On the other hand, a controllable multi-
bromination reaction would be desirable for use in synthetic
chemistry. For this purpose, diphenylamine (1n) was chosen as a
test substrate. The starting material, 1n, was first treated using a
large excess of cupric bromide (2.5 equivalents) and Oxone1 (6
equivalents) (Scheme 1). It was found that when the reaction was
quenched after less than 0.5 h, 4,49-dibromodiphenylamine (3n)
was obtained in a 69% isolated yield and no mono-brominated
product (2n) remained. When the reaction time was increased up
to 2 h, a mixture of 3n, 4n and 5n was observed qualitatively using
TLC. Finally, if the reaction time was prolonged to over 5 h,
exhaustive bromination was achieved, giving an 84% yield of
2,29,4,49-tetrabromodiphenylamine (5n). Alternatively, and also
conveniently, specific multi-brominated products can be afforded
solely, or as the main product formed, by precise control of the
number of equivalents of CuBr2 used. For example, 3n is obtained
in 75% yield using 1 equiv. of CuBr2 plus Oxone1 (2.5 equiv.) at
room temperature for 3 h. 4n is obtained in 53% yield using 1.5
equiv. of CuBr2 plus Oxone1 (4 equiv.) at room temperature for 16
h. Finally, 5n is obtained in 87% yield using 4 equiv. of CuBr2 plus
Oxone1 (10 equiv.) at room temperature for 10 h. Interestingly, the
treatment of diphenylamine with only cupric bromide (3–5
equivalents) (i.e., in the absence of Oxone1) always afforded a
mixture of 3n and 4n, whether reaction times were short or long,
with none of 5n being detected. In none of the reactions described
above did we observe the formation of penta- or hexabromodi-
a
Conditions: amine (1 mmol), CuBr2 (2.5 mmol), Oxone1 (6 mmol),
b
acetonitrile (10 mL), room temperature, 5 h; isolated yields. 0.5 h.
c
d
2 h. 16 h.
phenylamine, even after prolonged reaction times. Accordingly, a
controllable multi-bromination of aromatic amines can be
achieved by simple control of the equivalents of the brominating
reagents used and/or the reaction times. Some representative
cases of multi-bromination are shown in Table 3.
It must be pointed out that dealkylation and bromination may
be observed when N,N-dialkylaniline reacts with the CuBr2/
Oxone1 system under heating conditions.19 For example, by
elevating the temperature and prolonging the reaction time, a
mono N-dealkylation-bromination would be the main reaction
(Scheme 2).
Lastly, a very preliminary attempt was made to perform the
chlorination of aromatic amines under similar conditions by
replacing cupric bromide with cupric chloride. The chlorination
reaction of aromatic amines is inferior to the corresponding
bromination (Table 4), and further studies to improve the reaction
conditions are under way in our laboratory.
We propose a possible mechanism for the monobromination
+
of the aromatic amines in Scheme 3. A radical cation PhNR2 is
formed via a single electron transfer from PhNR2 to Cu2+ and is
immediately trapped by the nucleophile (Br2) forming a radical,
which then transfers a further electron to Cu2+ to form a cationic
species. Finally, the cationic species releases H+ to give the
product. CuBr formed in the first step of the reaction is oxidized
by Oxone1 in the second step, to regenerate the CuBr2 reactant.
There is some supportive evidence for this proposed mechanistic
pathway in the literature,11,20 and is also in good agreement with
Scheme 1
Scheme 2
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Table 4 Chlorination of aromatic amines using CuCl2/Oxone1 systema
acetate (15 mL 6 3). The combined organic layers were washed
with brine, dried over anhydrous MgSO4, and evaporated under
reduced pressure. The residue was purified by column chromato-
graphy.
Products
General procedure for multi-bromination of aromatic amines
An oven-dried 50 mL three necked flask was charged with amine
(1 mmol), cupric bromide (2.5 mmol) and Oxone1 (6 mmol), then
acetonitrile (10 mL) was added via syringe. The reaction mixture
was stirred at room temperature. The reaction was monitored by
TLC and quenched according to the time mentioned in the above
text. The mixture was then filtered through a pad of silica gel and
the filtrate washed with ethyl acetate (20 mL 6 2). The combined
organic phases were evaporated under reduced pressure and the
residue purified by column chromatography.
a
Conditions: amine (1 mmol), CuCl2?2H2O (0.5 mmol), Oxone1 (1.2
mmol), acetonitrile (8 mL), in air, room temperature, 18 h; isolated
yield.
our experimental observations. For example, it was found that the
presence of a Cu2+ species is always favorable for this transforma-
tion (Table 1, runs 1, 7, 9, and 14 vs. runs 15–17). Furthermore, a
radical-trapping experiment using (2,2,6,6-tetramethylpiperidinyl)-
N-oxyl (TEMPO) in the model reaction showed that the starting
amine was consumed completely to afford a complicated
distribution of products, with only extremely small amounts of
mono- or multi-brominated aromatic amines detected. This also
implies that the mechanistic pathway involving a radical cation is
feasible.
Acknowledgements
The authors thank National Natural Science Foundation of
China (Project Nos. 20872142 and 21102150) for financial
support of this work.
Notes and references
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Century, John Wiley & Sons, New York, 2004.
In conclusion, we have developed a simple, mild and efficient
protocol for the bromination of aromatic amines, with high
regioselectivity and functional group tolerance. This reaction
covers a wide range of substrates and, in particular, provides a
controllable synthesis for various levels of brominated aromatic
amines by simple adjustment of the reaction conditions. Thus,
this method represents an attractive synthetic route to expensive
low-volume aromatic bromoamines. It is noteworthy that this
reaction could have the potential to become a catalytic reaction,
i.e., a copper-catalyzed bromination of aromatic amines (see run 9
of Table 1). This study is under way in our group and will be
published in due course.
3 M. B. Smith and J. March, Advanced Organic Chemistry:
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General procedure for mono-bromination of aromatic amines
An oven-dried 50 mL three necked flask was charged with amine
(1 mmol), cupric bromide (0.5 mmol), and Oxone1 (1.2 mmol).
After acetonitrile (8 mL) was added via syringe, the mixture was
stirred for 3 h at room temperature until the starting amine was
completely consumed (monitored by TLC). Saturated sodium
carbonate (5 mL) was added, with stirring for 5 min, and then 10
mL of water added. The aqueous layer was extracted with ethyl
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Scheme 3 Proposed possible mechanistic pathway.
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