Electrochemical Regioselective Bromination of Electron-Rich Aromatic Rings Using n Bu 4 NBr

Article abstract of DOI:10.1055/s-0037-1611545

Electrochemical regioselective bromination of electron-rich aromatic rings using stoichiometric tetrabutylammonium bromide (ⁿ Bu ₄ NBr) has been accomplished under mild conditions. This protocol provides an environmentally friendly and simple way for the construction of C-Br bond in moderate to high yields with wide functional group tolerance.

Full text of DOI:10.1055/s-0037-1611545

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
W. Xie et al.
Letter
Synlett
Electrochemical Regioselective Bromination of Electron-Rich
Aromatic Rings Using nBu4NBr
Wenxia Xie
Br
C
C
Shulin Ning
Nian Liu
R
R
Ar
Ar
nBu4NBr
CH2Cl2, rt
24 examples
up to 96% yield
Ya Bai
Ar = benzene, indole, and pyridine
R = amino, halogen, alkyl, aryl
Shutao Wang
Siyu Wang
Lingling Shi
Xin Che
• Simple reaction conditions • High Br atom economy
• High regioselectivity • Inexpensive carbon electrodes
Jinbao Xiang*
The Center for Combinatorial Chemistry and Drug Discovery
of Jilin University, The School of Pharmaceutical Sciences,
Jilin University, 1266 Fujin Road, Changchun, Jilin 130021,
P. R. of China
jbxiang@jlu.edu.cn
Received: 05.04.2019
Accepted after revision: 29.04.2019
Published online: 14.05.2019
vironment-friendly and enabling synthetic tool.5 In the past
two decades, several important milestones in electrochemi-
cal C–H bond activation have been accomplished, such as
halogenation,6 azidation,7 thiocyanation,8 cross-coupling,9
and annulation.10 Electrochemical bromination of arenes
has been studied in recent years.11 For example, Thasan’s
group reported the two-phase (chloroform/water) electro-
chemical bromination of simple aromatic compounds using
a large amount of NaBr;12 Fuchigami’s group disclosed a
novel electrolytic system for anodic bromination using
NaBr-PEG/MeCN system;13 Liu and co-workers described
the applications of electrochemical arene bromination on
complex late-stage intermediates and drug molecules using
a large excess NaBr in water and methanol/acetonitrile mix-
ture.14 In 2019, Lei’s group reported the electrochemical ox-
idative halogenation of heteroarenes, arenes, alkenes,
alkynes, and aliphatic hydrocarbons using NaX (X = Cl or Br)
in DMF/H2O under 80 °C and N2 protection.15 Mei’s group
disclosed the palladium-catalyzed electrochemical C–H
bromination of benzamide derivatives using NH4Br as the
brominating reagent under divided cells.16 It is noteworthy
that these electrochemical bromination reactions were ac-
complished by using expensive platinum (Pt) electrode and
a large excess NaBr or NH4Br. In 2014, Baran’s group discov-
ered the byproduct bromoxiamycin (17% yields) during the
synthesis of dixiamycin B by electrochemical oxidation of
xiamycin A using Et4NBr as electrolyte and carbon as elec-
trode.17 Inspired by the seminal work, we envisioned that
aryl bromide 2 could be readily prepared from compound 1
via a one-pot direct electrochemical oxidative C–Br bond
formation in an undivided cell with inexpensive carbon
DOI: 10.1055/s-0037-1611545; Art ID: st-2019-k0193-l
Abstract Electrochemical regioselective bromination of electron-rich
aromatic rings using stoichiometric tetrabutylammonium bromide
(nBu4NBr) has been accomplished under mild conditions. This protocol
provides an environmentally friendly and simple way for the construc-
tion of C–Br bond in moderate to high yields with wide functional group
tolerance.
Key words electrochemistry, regioselective, bromination, aromatic
ring, stoichiometric, tetrabutylammonium bromide
Aryl bromides are among the most common and im-
portant chemicals and are extensively present in various
natural products and biologically active compounds.1 More-
over, they are versatile starting materials and synthetic in-
termediates in organic synthesis, especially in transition-
metal-catalyzed cross-coupling reactions.2 Thus, efficient
and mild methods to synthesize aryl bromides are of signif-
icant interest. Nowadays, considerable efforts have been de-
voted to the development of various effective brominating
reagent systems,1d,3 for example, Br2, NBS, and bromide
salts/oxidants. However, traditional methods generally suf-
fer from certain drawbacks such as application of hazard-
ous reagents, unavoidable overbromination, poor regiose-
lectivity, production of metal salts as stoichiometric by-
products, and the use of oxidants.3 More recently, visible-
light-mediated bromination of aromatic compounds using
NBS with the help of erythrosine B has been reported.4
While remarkable progress has been achieved, there is still
an urgent need to develop a mild, operationally simple,
cost-effective, site-selective, and environmentally benign
approach for aryl bromides synthesis.
n
electrodes using equivalent Bu4NBr as electrolyte and Br
source (Scheme 1). Herein, the details of these studies are
presented.
Organic electrosynthesis, which achieves redox reac-
tions with traceless electric current, is accepted to be an en-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
W. Xie et al.
Letter
Synlett
variety of tertiary (1a–f), secondary (1g), and primary ani-
lines (1h) were tolerated to afford para-brominated prod-
ucts in moderate to high yields (2a–h). Furthermore, a
range of functional groups, including alkyl (2i–o), aryl (2s–
v), alkoxy (2t, 2v), halogen (2n,o,u), ester (2q), hydroxyl
(2r), and even oxidation- and bromination-prone olefin
(2p) substituents at the N-1 position of indoles, were well
tolerated in the reaction system. Other heteroarene (pyri-
dine) could also be regioselectively brominated in moderate
yields (2w). Interestingly, the bromination proceeded
smoothly at the ortho position instead to furnish the de-
sired product 2x in 42% yield when the para position was
occupied (Scheme 2).
Br
C
C
R
R
Ar
Ar
nBu4NBr
2
1
Scheme 1 Electrochemical bromination using nBu4NBr
We first identified the optimal reaction conditions for
the electrochemical bromination of N,N-dimethylaniline
(1a), which involved constant-current electrolysis using
graphite rod as anode and cathode, in an undivided cell
n
containing an electrolyte solution of Bu4NBr in CH2Cl2 at
room temperature (Table 1). Under these mild conditions,
the desired 4-bromo-N,N-dimethylaniline (2a) was isolated
in 80% yield (Table 1, entry 1).18 In comparison, reduced
yields were obtained when the reaction conditions were
modified in one of the following manners: changing the an-
ode to RVC (Table 1, entry 2) or changing the cathode to Ni
foam (Table 1, entry 3), using other solvents such as EtOH
(Table 1, entry 4) or MeCN (Table 1, entry 5), or reducing the
amount of nBu4NBr (Table 1, entry 6). It is worth to mention
Table 2 Synthesis of Aryl Bromides 2a,b
Br
Br
or
C
C
or
nBu4NBr (1.5 equiv)
CH2Cl2, rt, 3–8 h
N
N
R
X
R
X
R
R
2i–v
2a–h, 2w
X = CH, 1a–h
X = N, 1w
1i–v
constant current = 5 mA
n
that increasing the amount of Bu4NBr does not improve
Entry
R
Time (h)
Product
Yield (%)
the yield (Table 1, entry 7), indicating that stoichiometric
nBu4NBr is sufficient for the reaction. A control experiment
revealed that no 2a was obtained in the absence of electric
current (Table 1, entry 8). This result suggested that the re-
action driving force should be the employment of electric
energy.
Having optimized the reaction conditions, we next ex-
amined the scope of the bromination reaction by testing a
series of aromatic substrates (Table 2). To our satisfaction, a
1
2
(Me)2N
3.5
3
2a
2b
2c
2d
2e
2f
80
81
55
91
62
72
35
33
92
85
80
96
83
82
93
71
54
79
80
73
89
81
37
nBuMeN
BnMeN
3
5
4
pyrrolidin-1-yl
piperidin-1-yl
morpholino
MeNH
4
5
3
6
5
7
6
2g
2h
2i
8
NH2
3
Table 1 Optimization of the Reaction Conditionsa
9
Me
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
nBu
3
2j
Br
Bn
3.5
3
2k
2l
C
C
Me
Me
N
N
nBu4NBr (1.5 equiv)
CH2Cl2, rt, 3.5 h
o-MeC6H4CH2
m-MeC6H4CH2
o-ClC6H4CH2
p-BrC6H4CH2
allyl
Me
Me
3
2m
2n
2o
2p
2q
2r
1a
2a
constant current = 5 mA
3
Entry
Variation from standard conditions above Yield (%)b
3
1
2
3
4
5
6
7
8
none
80
72
58
60
24
60
80
0
3
RVC as anode
EtO2CCH2
HOCH2CH2
Ph
4
Ni foam as cathode
EtOH instead of CH2Cl2
MeCN instead of CH2Cl2
nBu4NBr (1.0 equiv)
nBu4NBr (2.0 equiv)
no electric current
5
3
2s
2t
o-MeOC6H4
o-FC6H4
3
4
2u
2v
2w
m-MeOC6H4
NH2
3
5.5
a Standard conditions: graphite rod anode (d = 5 mm), graphite rod cath-
ode (d = 5 mm), constant current = 5 mA, 1a (0.25 mmol), nBu4NBr (0.375
mmol), CH2Cl2 (5 mL), undivided cell, room temperature, 3.5 h.
b Isolated yield.
a Standard conditions: graphite rod anode (d = 5 mm), graphite rod cath-
ode (d = 5 mm), constant current = 5 mA, 1 (0.25 mmol), nBu4NBr (0.375
mmol), CH2Cl2 (5 mL), undivided cell, room temperature, 3–8 h.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

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W. Xie et al.
Letter
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In summary, we have successfully developed an electro-
chemical bromination of electron-rich aromatic rings using
stoichiometric Bu4NBr under undivided cell. This reaction
could be carried out at room temperature without the use
of any catalysts, oxidants or additives. This process offers an
alternative to conventional methods that require chemical
oxidants and represents an environmentally benign tool for
regioselective oxidative C–Br bonds formation.
Br
Br
Br
C
C
Me
Me
n
nBu4NBr (1.5 equiv)
CH2Cl2, rt, 5 h
N
N
Me
Me
1x
2x, 42%
constant current = 5 mA
Scheme 2 Electrochemical bromination of compound 1x
Control experiments showed that red-brown Br2 was
generated on the surface of the anode and the solution be-
came yellow in color when nBu4NBr was directly electrolysis
under the standard conditions (Scheme 3, a). Moreover, the
solution remains colorless when radical scavenger P(OEt)3
was added, suggesting that a radical process should be in-
volved for formation of Br2 (Scheme 3, b). Indeed, only 8%
yield of product 2a was isolated when P(OEt)3 was added in
our system (Scheme 3, c).
Funding Information
This work was supported by the Sci-Tech Development Project of Jilin
Province in China (No. 20160520039JH), the Foundation of Jilin Edu-
cational Committee (No. JJKH20180244KJ), and the Norman Bethune
Program of Jilin University (No. 2015330). Additional support was
provided by Changchun Discovery Sciences, Ltd.()
Acknowledgment
We thank Mr. Xuyang Luo for NMR measurements.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611545.
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References and Notes
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ports,11,19 a possible mechanism for the electrochemical
bromination reaction was proposed (Scheme 4). As a start,
the Br– anions were oxidized on the anode to Br2. The reac-
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n
stoichiometric Bu4NBr is sufficient for full conversion of
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anode
cathode
e
e
(1)
R
Ar
Br
R
Ar
H2
Br2
– H+, – Br–
– 2e–
(2)
2Br–
2H+
Scheme 4 Proposed mechanism
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

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Letter
Synlett
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D