Aerobic photooxidative bromination of aromatic compounds using carbon tetrabromide mediated by anthraquinone-2-carboxylic acid

Article abstract of DOI:10.1016/j.tetlet.2015.09.008

We developed the aerobic photooxidative bromination of aromatic compounds using carbon tetrabromide in the presence of anthraquinone-2-carboxylic acid under visible light irradiation.

Full text of DOI:10.1016/j.tetlet.2015.09.008

Accepted Manuscript
Aerobic photooxidative bromination of aromatic compounds using carbon tet-
rabromide mediated by anthraquinone-2-carboxylic acid
Masanori Tanaka, Yuji Kamito, Cui Lei, Norihiro Tada, Akichika Itoh
PII:
S0040-4039(15)30050-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.008
TETL 46680
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 July 2015
1 September 2015
4 September 2015
Please cite this article as: Tanaka, M., Kamito, Y., Lei, C., Tada, N., Itoh, A., Aerobic photooxidative bromination
of aromatic compounds using carbon tetrabromide mediated by anthraquinone-2-carboxylic acid, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.09.008
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Aerobic photooxidative bromination of
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aromatic compounds using carbon
tetrabromide mediated by anthraquinone-2-carboxylic acid
Masanori Tanaka, Yuji Kamito, Cui Lei, Norihiro Tada, Akichika Itoh*

1
Tetrahedron Letters
Aerobic photooxidative bromination of aromatic compounds using carbon
tetrabromide mediated by anthraquinone-2-carboxylic acid
Masanori Tanaka, Yuji Kamito, Cui Lei, Norihiro Tada, Akichika Itoh*
Gifu Pharmaceutical University 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We developed the aerobic photooxidative bromination of aromatic compounds using
carbon tetrabromide in the presence of anthraquinone-2-carboxylic acid under visible light
irradiation.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Aerobic
Anthraquinone-2-carboxylic acid
Photooxidation
Carbon tetrabromide
Air.
Aryl bromides are important reagents in synthetic organic
chemistry, especially in cross-coupling reactions.1 Aryl bromide
motifs are present in various useful products such as
pharmaceuticals, agrochemicals, dyes, and fire-retardants.
Moreover, several natural products such as 6,6′-dibromoindigo2
and Tambjamine B3 are aryl bromides.
Various synthetic methods of aryl bromides have been
developed using aryldiazonium,4 aryl boronic acid derivatives,5
or aryl triflate6 as substrates. Of the various synthetic methods,
the bromination of aryl C(sp2)–H to C(sp2)–Br using a
representative brominating agent such as Br2 or NBS has been a
direct, economical, and reliable method.7 Furthermore, oxidative
bromination is enabled using easy to handle brominating agents,
such as NH4Br, LiBr, NaBr, and KBr, together with a suitable
oxidant such as H2O2, MCPBA, or oxone.8 Light is an important
factor in many reactions9 and can exhibit specific reactivity.
However, the photo bromination of aromatic rings using bromine
sources, such as HBr, NBS, and Br2, is relatively rare.10
MgBr2, HBr, Br2, NBS, and CBr4 are effective bromine radical
sources.12 Among them, CBr4 is an easy to handle air and
moisture stable crystalline solid, and has been used for the Appel
reaction and the Corey–Fuchs reaction. However, because of its
stability, the bromination of aromatic rings using CBr4 requires a
high temperature ranging from 150 to 180 °C,13 or lithiated
aromatic compounds.14 Thus, a more mild activation method of
Table1. Optimization of reaction conditionsa
OMe
OMe
O2, VIS
Catalyst (0.1 equiv)
Br source
Br
Solvent, 20 h
MeO
OMe
MeO
OMe
1a
2a
O
O
X
AQN-2-CO2H X=CO2H
2-Cl-AQN
2-tBu-AQN X=tBu
X=Cl
Entry
1
2
3
4
5
6
7
8
Br source (equiv)
CBr4 (1.0)
CBr4 (1.0)
CBr4 (1.0)
CBr4 (1.0)
CBr4 (1.0)
CBr4 (1.0)
CBr4 (0.25)
CBr4 (0.25)
CBr4 (0.25)
CBr4 (0.25)
CBr4 (0.25)
CBr4 (0.25)
CBr4 (0.25)
CH2Br2 (0.5)
CHBr3 (0.33)
NBS (1.0)
Catalyst
AQN-2-CO2H
Yield (%)b
20
Solvent
EtOAc
CHCl3
Toluene
THF
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
2-Cl-AQN
20
33
50
55
63
93 (92)
62
67
15
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
2-tBu-AQN
9
10
11
12
13
14
15
16
17
18
19c
Methylene Blue
Anthracene
Benzophenone
Eosin Y
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
26
46
35
Due to the increasing demand for more environmentally
friendly syntheses, molecular oxygen has received much
attention as an attractive oxidant, which is inexpensive and has a
greater atom efficiency than that of other oxidants.11 We have
been studying aerobic photooxidative reactions using various
photocatalysts, and discovered that compounds such as LiBr,
0
49
17
52
35
Br2 (0.5)
HBr (1.0)
CBr4 (0.25)
93 (90)
a A solution of 1,3,5-trimethoxybenzene (1a, 0.3 mmol), Br source,
and catalyst (0.1 equiv) in dry solvent (5 mL) purged with an O2
balloon was stirred and irradiated externally with 21W fluorescent
lamp for 20 h.
b 1H NMR yields. Numbers in parentheses are isolated yields.
c The reaction was carried out under the air.

2
Tetrahedron
Table 2 shows the results of scope and limitations of the aerobic
CBr4 is desirable. Here, we report a detailed study of the
photooxidative bromination of aromatic compounds under the
reaction conditions mentioned above.15 Generally the
corresponding brominated compounds are obtained by using
electron rich substrates in good to high yields (2b-f, 2i-2m). In
addition, dibrominated compounds were selectively obtained in
the presence of 0.5 equiv CBr4 (2g and 2h). On the other hand,
anisole and nitrobenzene was poor substrate (2n and 2o). In this
reaction, caffeine was also brominated albeit in low yield (2p).
We also conducted a control experiments to elucidate reaction
mechanism (Table 3). Oxygen environment and visible light
irradiation were found to be essential for this reaction (entries 1
and 2). The yield was decreased to 17% when the reaction
performed without AQN-2-COOH (entry3). Furthermore, the
reaction performed with 1 equivalent of TEMPO, which led to
the desired compound in 7% yield (entry 4). This result indicated
that the radical intermediate is involved in this reaction
mechanism. However, important feature of the mechanism is that
this reaction may allow the selective bromination of aromatic C–
H bond at most electron-rich and less hindered position without
damaging at benzylic position.
photocatalytic bromination of aromatic compounds using CBr4 as
a brominating agent under aerobic photoirradiation conditions
(Scheme 1).
To explore this approach, we selected 1,3,5-trimethoxybenzene
(1a) as a test substrate to optimize the reaction conditions (Table
1). First, we screened the solvents in the presence of CBr4 (1
equiv), AQN-2-CO2H (0.1 equiv), and molecular oxygen
(balloon) under photo-irradiation from 21 W fluorescent lamp
(entries 1-6). The desired monobrominated product, 2-Bromo-
1,3,5-trimethoxybenzene (2a), was produced most efficiently in
moderate yields when using ethanol as solvents (entry 6).
However, polybrominated products were also generated under
the conditions. Interestingly, when the amount of CBr4 was
reduced to 0.25 equivalents, the yield was increased to 92%
isolated yield (entry 7). Thus catalyst and bromine source were
investigated using 1 equivalent of Br atom (entries 7-18), and
revealed that combination of AQN-2-CO2H and CBr4 gave best
result (entry 7). It is noteworthy that the reaction proceeded even
under air atmosphere instead of oxygen atmosphere (entry 19).
Table 2. Scope and limitationsa, b
Air, VIS
Table 3. Study of reaction mechanisma
AQN-2-CO2H (0.1 equiv)
Br
OMe
OMe
CBr4 (x equiv)
Air, VIS
Ar
Ar
Br
AQN-2-CO2H (0.1 equiv)
CBr4 (0.25 equiv)
EtOH
1
2
MeO
OMe
EtOH, 20 h
MeO
OMe
Me
2a
OMe
OMe
1a
MeO
OMe
Br
OMe
Br
Entry
Changed conditon
Under Ar
Yield (%)b
1
2
3
4
7
0
Br
MeO
OMe
In the dark
OMe
2c 64%
No catalyst
17
7
OMe
TEMPO (1.0 equiv) was added
2b 73%
2d 77%
a A solution of 1a (0.3 mmol), CBr4 (0.25 equiv), and AQN-2-CO2H (0.1 equiv)
(0.5 equiv, 20 h)
(0.5 equiv, 30 h)
(0.5 equiv, 20 h)
in EtOH (5 mL) was stirred under air and irradiated externally with
fluorescent lamp for 20 h. b 1H NMR yields.
a
OMe
OEt
OMe
Br
OMe
OEt
Br
OMe
Br
Br
2e 92%
(0.25 equiv, 63 h)
2f 86%
(0.25 equiv, 72 h)
2g 77%
(0.5 equiv, 60 h)
OEt
Br
NEt2
NMe2
Br
OEt
Br
Br
2h 73%
(0.5 equiv, 72 h)
2i 54%
(1.0 equiv, 68 h)
2j 60%
(1.0 equiv, 64 h)
NEt2
H
N
NBu2
Br
OEt
Br
Br
2k 70%
(1.0 equiv, 48 h)
2l 68%
(0.5 equiv, 48 h)
2m 56%
(0.5 equiv, 70 h)
O
OMe
N
NO2
N
Br
N
O
N
Br
Br
2n 14%
(1.0 equiv, 50 h)
2o 0%
(1.0 equiv, 20 h)
2p 20%
(1.0 equiv, 50 h)
Scheme 2 shows a plausible path of this oxidative photo
a Isolated yields. b A solution of 1 (0.3 mmol), CBr4, and AQN-2-CO2H (0.1
equiv) in dry EtOH (5 mL) was stirred under air and irradiated externally with
a 21 W fluorescent lamp for the indicated time.
bromination of aromatic compounds, which is postulated by the
necessity of molecular oxygen, continuous irradiation, and AQN-
2-CO2H in this reaction. The major path is illustrated above in
scheme 2. The bromine radical is generated by homolysis of C-Br

3
Synlett 2013, 24, 607-610; (c) Nobuta, T. Fujiya, A.; Hirashima,
bond along with dibromomethyl carbene. The dibromomethyl
carbene produces hydrogen bromide in the presence of solvent
and oxygen. Then, the hydrogen bromide is reoxidized to
bromine. In this reaction, we suppose that bromine atom is
installed to the arene by aromatic electrophilic substitution
reaction. On the other hand, the minor path is illustrated below in
scheme 2. The excited AQN, which is formed by absorption of
visible light, causes SET and produces radical cation species.15
This radical species react with bromine radical and the product is
aromatized again via deprotonation and AQN hydroxyl radical is
formed. The generated AQN hydroxyl radical are reoxidized
under the photooxidative condition and the catalytic cycle is
established.
S.; Tada, N.; Miura, T.; Itoh, A. Tetrahedron Lett. 2012, 53, 5306-
5308; (d) Tada, N.; Ban, K.; Nobuta, T.; Hirashima, S.; Miura, T.;
Itoh, A. Synlett 10, 1381-1384; (e) Nobuta, T.; Tada, N.; Hattori,
K.; Hirashima, S.; Miura, T.; Itoh, A. Tetrahedron Lett. 2011, 52,
875-877; (f) Tada, N.; Ban, K.; Yoshida, M.; Hirashima, S.;
Miura, T.; Itoh, A. Tetrahedron Lett. 2010, 51, 6098-6100; (g)
Hirashima, S.; Nobuta, T.; Tada, N.; Miura, T.; Itoh, A. Org. Lett.
2010, 12, 3645-3647; (h) Tada, N.; Ban, K.; Hirashima, S.; Miura,
T.; Itoh, A. Org. Biomol. Chem. 2010, 8, 4701-4704; (i) Nobuta,
T.; Hirashima, S.; Tada, N.; Miura, T.; Itoh, A. Tetrahedron Lett.
2010, 51, 4576-4578; (j) Nobuta, T.; Hirashima, S.; Tada, N.;
Miura, T.; Itoh, A. Synlett 15, 2335-2339.
13. Hunter, W. H.; Edgar, D. E. J. Am. Chem. Soc. 1932, 54, 2025-
2028.
14. a) Posner, G. H.; Canella, K. A. J. Am. Chem. Soc. 1985, 107,
2571-2573; b) Friedmann, C.; Braise, S. Synlett 2010, 5, 774-776.
15. Cui, L.; Furuhashi, S.; Tachikawa. Y.; Tada, N.; Miura, T.; Itoh,
A.; Tetrahedron Lett. 2013, 54, 162-165.
In conclusion, we developed the aerobic photooxidative
bromination of aromatic compounds using CBr4 in the presence
of the catalytic amounts of AQN-2-CO2H under photo-irradiation
from fluorescent lamp.
16. Typical procedure: A pyrex test tube containing solid of 1,3,5-
Trimethoxybenzene (1a, 0.3 mmol), carbon tetrabromide
(0.075 mmol), AQN-2-CO2H (0.03 mmol) and dry EtOH (5
mL) was irradiated for 20 h at room temperature with stirring
by a 21 W fluorescent lamp under air. The reaction mixture
was concentrated in vacuo, quenched with aq. Na2S2O3 and
extracted with EtOAc. The organic layer was dried over
MgSO4 and concentrated in vacuo. Purification of the residue
by flash chromatography on silica gel (hexane : ethyl acetate =
6 : 1) provided 2-bromo-1,3,5-trimethoxybenzene (2a) (66.8
mg, 90%, ) as a white solid.
Acknowledgment
This work was supported by Grant-in-Aid for Young
Scientists (B)(No. 24790015) from the Japan Society for
the Promotion of Science (JSPS).
References and notes
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Table1. Optimization of reaction conditionsa
OMe
OMe
O2, VIS
Catalyst (0.1 equiv)
Br source
Br
Solvent, 20 h
MeO
OMe
MeO
OMe
1a
2a
O
O
X
AQN-2-CO2H X=CO2H
2-Cl-AQN X=Cl
2-tBu-AQN X=tBu
Yield (%)b
20
Entry
1
2
3
4
5
6
7
8
Br source (equiv)
CBr4 (1.0)
CBr4 (1.0)
CBr4 (1.0)
CBr4 (1.0)
CBr4 (1.0)
CBr4 (1.0)
CBr4 (0.25)
CBr4 (0.25)
CBr4 (0.25)
CBr4 (0.25)
CBr4 (0.25)
CBr4 (0.25)
CBr4 (0.25)
CH2Br2 (0.5)
CHBr3 (0.33)
NBS (1.0)
Catalyst
Solvent
EtOAc
CHCl3
Toluene
THF
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
2-Cl-AQN
20
33
50
55
63
93 (92)
62
67
15
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
2-tBu-AQN
Methylene Blue
Anthracene
Benzophenone
Eosin Y
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
9
10
11
12
13
14
15
16
17
18
19c
26
46
35
0
49
17
52
35
Br2 (0.5)
HBr (1.0)
CBr4 (0.25)
93 (90)
a A solution of 1,3,5-trimethoxybenzene (1a, 0.3 mmol), Br source,
and catalyst (0.1 equiv) in dry solvent (5 mL) purged with an O2
balloon was stirred and irradiated externally with 21W fluorescent
lamp for 20 h.
b 1H NMR yields. Numbers in parentheses are isolated yields.
c The reaction was carried out under the air.