Electrochemical umpolung of bromide: Transition-metal-free bromination of indole C–H bond

Article abstract of DOI:10.3390/molecules24040696

A facile and sustainable electrochemical umpolung of bromide ion protocol was developed under mild reaction conditions. Transition metal catalysts and exogenous chemical oxidants were obviated for the bromination of C–H bond. Notably, graphite rod, which is commercially available at supermarkets and is inexpensive, was employed as the electrode material. This operationally easy and environmentally friendly approach accomplished the synthesis of 3-bromoindole in excellent yield and regioselectivity.

Full text of DOI:10.3390/molecules24040696

molecules
Communication
Electrochemical Umpolung of Bromide:
Transition-Metal-Free Bromination of Indole
C–H Bond
1
1,
1
1
2
1
Pan Zhang , Jianbin Chen * , Wei Gao , Yiting Xiao , Changwei Liu , Shanghui Xu ,
1
1
Xiaoli Yan and Dawei Qin
1
Shandong Provincial Key Laboratory of Molecular Engineering, School of Chemistry and Pharmaceutical
Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China;
panzhang11@163.com (P.Z.); gaowei161212@163.com (W.G.); Olivia9802@163.com (Y.X.);
ShanghuiXu111@163.com (S.X.); xiaoliyan1a@163.com (X.Y.); qdw109@163.com (D.Q.)
Faculty of Science and Forestry, University of Eastern Finland, 80101 Joensuu, Finland; changwl@uef.fi
Correspondence: jchen@qlu.edu.cn
2
*
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 13 January 2019; Accepted: 12 February 2019; Published: 15 February 2019
Abstract: A facile and sustainable electrochemical umpolung of bromide ion protocol was developed
under mild reaction conditions. Transition metal catalysts and exogenous chemical oxidants were
obviated for the bromination of C–H bond. Notably, graphite rod, which is commercially available at
supermarkets and is inexpensive, was employed as the electrode material. This operationally easy
and environmentally friendly approach accomplished the synthesis of 3-bromoindole in excellent
yield and regioselectivity.
Keywords: umpolung; C–H functionalization; electrochemical organic synthesis; anodic oxidation;
sustainable chemistry
1
. Introduction
Umpolung or polarity inversion, one of the attractive techniques, is a fundamental concept that
was first introduced by Seebach and Corey in the 1970s [
synthesis as it can alter the reactivity of a specific functional group for a desirable reaction that would
otherwise not be possible [ 19]. Under the concept, two nucleophiles can couple with each other
Scheme 1). Many functional groups, for instance, cyanides, N-heterocyclic carbenes (NHC), thiamine
1–3]. It has been widely used in organic
4
–
(
pyrophosphates (TPP) as well as dithiane moieties, have been treated as the mediators and/or catalysts
for umpolung transformation [4–19].
umpolung
Nu1
Nu2
Nu -Nu
1 2
Scheme 1. Umpolung concept for coupling two nucleophiles.
Halogen ions, especially bromide ions, are typical nucleophiles, which are frequently used for
nucleophilic substitution and addition. In order to achieve the umpolung of bromide to bromo-based
electrophiles, strong chemical oxidants are regularly required [20–28]. However, based on the intrinsic
disadvantages of chemical oxidants, such as toxicity, environmental pollution, explosion risk, and
economic costs, there is a growing need for green and sustainable approaches for the umpolung of
bromides. Electrochemistry represents one of the most sustainable ways because only clean electrons
are involved in the process [29
–48]. In line with this strategy, in 2015, Bell and Wang reported that
bromide ion can be electro-oxidized with observation current and potential oscillations [49]. Xu et al.
Molecules 2019, 24, 696; doi:10.3390/molecules24040696
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Molecules 2019, 24, 696
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and Yu et al. described electrochemical oxidation of bromide on platinum electrodes in aqueous
acidic solution and ionic liquid, respectively [50 52]. Some new materials have also been exploited
as electrodes for the electro-oxidation of bromides [53 54]. Inspired by these elegant discoveries, we
–
,
envisioned that umpolung of bromide can be achieved by electrochemical strategy.
Aromatic bromides are an important class of compounds, which are commonly utilized as the
coupling partner in transition-metal-catalyzed cross-coupling reactions [55
of a synthetic method of arylbromides has attracted tremendous efforts [68
–
67]. Thus, the development
82]. Among them, much
–
progress has been made on palladium-catalyzed regioselective bromination of C–H bonds using
different agents. Sanford and co-workers elegantly delineated Pd-catalyzed C–H bromination of
benzoquinoline with N-bromosuccinimide (NBS) as the brominating reagent [83
and Jia et al. unraveled that copper halides can be treated as brominating agents in Pd-catalyzed
bromination of arenes [86 87]. Notably, stoichiometric chemical oxidants are indispensable in the
–85]. Wan et al.
,
abovementioned Pd-catalyzed C–H bromination reactions. Moreover, electrophilic bromination
of indoles has also been developed with sodium bromide (NaBr) or potassium bromide (KBr) as
bromiding agents, which were mediated by strong chemical oxidants [88,89]. Interestingly, NBS was
straightforwardly utilized for the electrophilic bromination under ultraviolet UV irradiation [90].
However, the high cost and the toxicity of chemical oxidants is associated with heavy pollution to
the environment, making them a major concern for the synthetic industry. In order to overcome the
disadvantages inherent in chemical oxidants, Kakiuchi and co-workers elegantly substantiated the
Pd-catalyzed bromination of arylpyridine with hydrogen bromide via electrochemical oxidation [91].
Compared with regular palladium-catalyzed C–H bromination, many advances were achieved for
this electrochemical protocol. However, the involvement of corrosive acid (HBr) and noble metal as
the catalyst was the main drawback. Herein, we report on an electrochemical transition-metal-free
C–H bromination with bromide salts as the source under mild conditions with inexpensive electrode
materials that are commercially available in supermarkets. [92]
2
. Results and Discussions
To prove the concept, we chose ubiquitous bromide salts, i.e., tetrabutylammonium bromide
(
nBu NBr) and/or ammonium bromide (NH Br), as the bromide source as well as the supporting
4
4
electrolyte. In order to gain rational understanding of the oxidative process, cyclic voltammetric (CV)
−
−
experiments were conducted. As shown in Figure 1 (dark red line), the oxidative peak potential of Br
+
appeared at 0.96 V and 1.22 V versus Ag/Ag , which were assigned to the corresponding Br
·
/Br
+
and Br /Br
·
redox couple, respectively [
5–
7
]. Indole, one of the electron-rich heterocyclics, displayed
a profound nucleophilicity, and its CV behavior was surveyed. Notably, the oxidative potential of
indole was observed at 1.39 V versus Ag/Ag (Figure 1, bright red line). Intriguingly, both the peak
potentials of Br and indole unambiguously shifted and diminished to the positive side when equal
+
−
molar of substrates were added. This scenario can be explained by the hydrogen bonding between
the free N–H moiety of indole and the bromide anion (Figure 1, blue line). Interestingly, the addition
of equal molar of NH Br to the mixture of nBu NBr and indole resulted in a recovery of the intrinsic
4
4
peak potential (Figure 1, pink line).

Molecules 2019, 24, 696
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LiClO4
LiClO +indole
4
2
0
4
LiClO +indole+Bu NBr
4
4
LiClO +indole+Bu NBr+NH Br
4
4
4
LiClO +Bu NBr
4
4
LiClO +NH Br
4
4
0
1
2
3
+
E / V vs Ag/Ag
Figure 1. Cyclic voltammetry investigation of indole and bromide salts. Conditions: LiClO (0.1 M in
4
MeCN) as background supporting electrolyte, glassy carbon as working electrode, Pt wire as counter
electrode, Ag in AgNO (0.01 M)–LiClO (0.1 M) in MeCN as reference electrode, indole (0.1 M),
3
4
nBu NBr (0.1 M), and NH Br (0.1 M). The scan rate is 100 mV/s.
4
4
With the aim of confirming the existence of hydrogen bonding, infrared (IR) spectroscopy of
indole and/or bromide sources was further performed. As shown in Figure 2, the characteristic
−
1
wavenumber (approximately 3370 cm ) of free indole (free N–H) shifted distinctly to a new broad
−
1
peak around 3200 cm when equal molar of nBu NBr was added to the sample of indole. This
4
phenomenon can again be attributed to the H-bonding interaction between the free N–H and the
bromide anion.
200
150
100
50
indole
indole+Bu NBr
4
0
4
indole+Bu NBr+NH Br
4
4
000
3500
3000
2500
2000
1500
1000
500
-1
Wave number / cm
Figure 2. Infrared spectroscopy studies of indole and bromide salts.
With the understanding of electrochemical oxidative course, we carried out the reaction with
indole
1 and nBu NBr as well as NH Br to testify the electrochemical umpolung of bromide. Initially,
4 4
the procedure employed the mixture of nBu NBr and NH Br in order to interrupt the H-bonding with
4
4
indole and was set up in 1,4-dioxane under a galvanostatic model. Unfortunately, trace of the desired
product was formed (Table 1, entry 1). However, when the reaction was run in tetrahydrofuran
THF), 39% of was generated (Table 1, entry 2). Chlorine-containing solvents, such as dichloroethane
DCE), provided moderate efficiency (43% yield, Table 1, entry 3). Then, we screened the aprotic polar
2
(
(
2

Molecules 2019, 24, 696
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media, for instance, dimethylforamide (DMF), dimethyl sulfoxide (DMSO), and ethyl acetate, in which
2
2
5% to 58% of the final product was isolated (Table 1, entries 4–6). The ethanol as medium resulted in
0% yield (Table 1, entry 7). Satisfyingly, when the reaction was set up in acetonitrile (MeCN), excellent
efficiency was observed (81% yield, Table 1, entry 8). Notably, this transformation was sensitive to
water as the yield decreased sharply in the presence of water (Table 1, entry 11). Interestingly, this
protocol worked smoothly when the amount of bromide salts was reduced, whereas no significant
enhanced performance was detected when the quantity of bromide anion was increased (Table 1, entry
1
2 vs. 15). It should be noted that this approach almost shut down when only NH Br was applied as
4
the bromide source because of the poor solubility (Table 1, entry 16). In addition, diminished yield was
observed with only nBu NBr as the nucleophile (Table 1, entry 17), presumably due to the slowdown
4
in the cathodic reduction of proton to hydrogen. This was the case in the absence of NH Br (Table 1,
4
entries 9–10). Increasing or decreasing the current value and displacement of the graphite rod with
platinum plate led to diminished yields.
Table 1. Reaction optimization. a.
Entry
Bromide Source
Solvent
Constant Current
Yield (%)
nBu4NBr/NH4Br
1
1,4-dioxane
2 mA
<5
(
2 equiv.-2 equiv.)
nBu4NBr/NH4Br
2 equiv.-2 equiv.)
nBu4NBr/NH4Br
2 equiv.-2 equiv.)
nBu4NBr/NH4Br
2 equiv.-2 equiv.)
nBu4NBr/NH4Br
2 equiv.-2 equiv.)
nBu4NBr/NH4Br
2 equiv.-2 equiv.)
nBu4NBr/NH4Br
2 equiv.-2 equiv.)
nBu4NBr/NH4Br
2
3
4
5
6
7
8
9
THF
DCE
2 mA
2 mA
2 mA
2 mA
2 mA
2 mA
2 mA
2 mA
2 mA
2 mA
2 mA
2 mA
2 mA
2 mA
39
43
25
54
58
20
81
60
28
12
80
62 b
64
82
(
(
DMF
(
DMSO
EtOAc
EtOH
MeCN
MeCN
MeCN
(
(
(
(
(
(
2 equiv.-2 equiv.)
nBu4NBr/NaBr
2 equiv.-2 equiv.)
nBu4NBr/KBr
2 equiv.-2 equiv.)
1
1
1
1
1
1
0
1
2
3
4
5
nBu4NBr/NH4Br
2 equiv.-2 equiv.)
MeCN/H2O
(10-2 mL)
(
nBu4NBr/NH4Br
1 equiv.-1 equiv.)
MeCN
MeCN
MeCN
MeCN
(
nBu4NBr/NH4Br
1 equiv.-1 equiv.)
(
nBu4NBr/NH4Br/NaBr
1 -0.5-0.5 equiv.)
(
nBu4NBr/NH4Br
4 equiv.-2 equiv.)
(
1
1
6
7
NH4Br (2 equiv.)
MeCN
MeCN
2 mA
2 mA
<5
15
nBu4NBr (2 equiv.)
a
Reaction conditions: graphite rod anode and graphite rod cathode, indole 1 (0.2 mmol), bromide salts as indicated,
solvents (10 mL), 2 mA, air, 11.5 h, room temperature. b under O2.

Molecules 2019, 24, 696
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Next, we focused our attention on the substrate scope. We tested a wide range of indole
derivatives, as illustrated in Table 2. Good to excellent conversion of the corresponding starting
materials was observed, as indicated by gas chromatography–mass spectrometry (GC–MS) and
thin-layer chromatography (TLC). Surprisingly, we observed that most of the 3-bromoindole derivative
◦
products were not stable and decomposed quickly at ambient temperature of 28 C. Furthermore, the
titled products could only be stored for a few hours at 4 C in the refrigerator.
◦
Table 2. Testing of indole derivatives.
Based on the cyclic voltammetric analysis, a putative mechanism was proposed (Scheme 2).
Consecutive anodic oxidation of bromide ion provided bromine cation to furnish the umpolung step.
After nucleophilic addition of another nucleophile, indole accomplished the eventual product by
releasing a proton. Cathodic evolution of hydrogen via reduction of proton served as the half-reaction.
Scheme 2. Proposed mechanism for the umpolung coupling of two nucleophiles.
3
. Experimental Section
General Information: Chemicals and solvents were purchased from commercial suppliers and
1
13
used as received. H NMR and C NMR spectra were recorded on a Bruker AVANCE II 400 (400 MHz)
spectrometer (Bruker, Switzerland). Chemical shifts were calibrated using residual undeuterated
1
13
solvent as an internal reference (CDCl : 7.26 ppm H NMR, 77.0 ppm C NMR). The abbreviations
3
used for explaining the multiplicity were as follows: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, dd = doublet of doublet, brs = broad singlet. GC–MS spectra were recorded on Agilent
7
890B-5977B (Agilent Technologies Inc., California, CA, USA). Both anode and cathode electrodes were
carbon rod electrodes (diameter 1.0 cm, length 10 cm). TLC employed 0.25-mm glass silica gel plates.
The developed chromatogram was analyzed by a UV lamp (254 nm). Flash chromatography columns
◦
were packed with 200–300 mesh silica gel in petroleum (bp: 60–90 C). Cyclic voltammograms were

Molecules 2019, 24, 696
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obtained on a CHI 760E potentiostat. IR spectra (CH Instruments Ins., Shanghai, China) were recorded
on a Nicolet10 spectrometer (CH Instruments Ins., Shanghai, China).
General Procedure for the Electrolysis: An oven-dried, 10 mL two-neck glass flask was equipped
with a magnetic stir bar. The substrate (0.20 mmol, 1 equiv.), nBu NBr (0.20–0.80 mmol), NH Br
4
4
(
0.20–0.40 mmol), and CH CN (10 mL) were combined and added. The flask was equipped with
3
carbon rod electrodes (diameter 1.0 cm, length 10 cm) as both the anode and the cathode. The reaction
was initiated at a constant current of 2 mA at room temperature. After complete consumption of the
starting material, the solvent was removed with a rotary evaporator. The residue was then subjected
to flash column chromatography on silica gel to afford the product.
Cyclic Voltammetry Studies: Cyclic voltammetric measurements were carried out in a 50 mL
glass vial at room temperature. A glassy carbon disk electrode (diameter is 3.0 mm) was used as the
2
working electrode, while a platinum plate electrode (1.0
×
1.0 cm ) was used as counter electrode.
+
The reference Ag/Ag electrode was made by immersing a sliver wire in a solution of AgNO
3
(
0.01 M)–LiClO (0.1 M) in MeCN and separated from the reaction by a salt bridge. The scan rate was
4
1
00 mV/s.
Characterization of 3-Bromo-1H-indole: Column chromatography was used for purification on
a silica gel column using petroleum ether:ethyl acetate = 10:1 as the eluent to give the product as a pale
1
white solid. The data were consistent with the authentic sample. H NMR (400 MHz, DMSO)
δ
11.41
(s, 1H), 7.48 (d, J = 2.7 Hz, 1H), 7.34–7.38 (m, 2H), 7.10–7.14 (m, 1H), 7.03–7.07 (m, 1H).
4
. Conclusions
In summary, we developed a concise electrochemical umpolung of bromide ion under
mild conditions. The electrolysis utilized cheap electrode material in undivided cell, providing
-bromoindole in excellent yield.
3
Author Contributions: For research articles with several authors, a short paragraph specifying their individual
contributions must be provided. The following statements should be used “conceptualization, J.C.; methodology,
P.Z.; software, W.G.; validation, P.Z., W.G., Y.X. and C.L.; formal analysis, P.Z.; investigation, P.Z., W.G., S.X., X.Y.;
resources, J.C.; data curation, D.Q.; writing—original draft preparation, P.Z., J.C., W.G.; writing—review and
editing, J.C.; visualization, W.G.; supervision, J.C.; project administration, J.C.; funding acquisition, J.C.
Funding: This research was funded by Qilu University of Technology (Shandong Academy of Sciences), grant
number No. 0412048811; Shandong Provincial Natural Science Foundation, grant number No. ZR2018BB017;
National Natural Science Fundation of China, grant number No. 21801144, 81872744, 51602164. The APC was
funded by No. 0412048811, No. ZR2018BB017, No. 21801144.
Acknowledgments: We greatly appreciate the financial support from the Qilu University of Technology
(
Shandong Academy of Sciences) (No. 0412048811), the Shandong Provincial Natural Science Foundation (No.
ZR2018BB017), the National Natural Science Fundation of China (No. 21801144, 81872744, 51602164), and the
Program for Scientific Research Innovation Team in Colleges and Universities of Shandong Province.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds “3-bromoindole” are available from the authors.
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