Synergy of Anodic Oxidation and Cathodic Reduction Leads to Electrochemical C—H Halogenation

Article abstract of DOI:10.1002/cjoc.201900091

We herein uncovered an electrochemical C—H halogenation protocol that synergistically combines anodic oxidation and cathodic reduction for C—X bond formation. The reaction was demonstrated under exogenous-oxidant-free conditions. Moreover, this is the first example of activating CBr₄, CHBr₃, and CCl₃Br under electrochemical conditions.

Full text of DOI:10.1002/cjoc.201900091

Accepted Article
Title: Synergy of Anodic Oxidation and Cathodic Reduction Leads to
Electrochemical C-H Halogenation
Authors: Zhilin Zhou, Yong Yuan, Yangmin Cao, Jin Qiao, Anjin Yao, Jing Zhao,
Wanqing Zuo, Wenjie Chen, and Aiwen Lei*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2019, 37, 10.1002/cjoc.201900091.
The final Version of Record (VoR) of it with formal page numbers will soon be
published online in Early View: http://dx.doi.org/10.1002/cjoc.201900091.
ISSN 1001-604X • CN 31-1547/O6
mc.manuscriptcentral.com/cjoc
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Synergy of Anodic Oxidation and Cathodic Reduction Leads to
Electrochemical C-H Halogenation
Zhilin Zhou,†a Yong Yuan,†b Yangmin Cao,a Jin Qiao,a Anjin Yao,a Jing Zhao,a Wanqing Zuo,a Wenjie Chen, a and Aiwen
Lei,*ab
a National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, P. R. China
b College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, Wuhan, Hubei 430072, China
*E-mail: aiwenlei@whu.edu.cn
†Zhilin Zhou and Yong Yuan contributed equally to this work
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion We herein uncovered an electrochemical C-H halogenation protocol that synergistically combines anodic
oxidation and cathodic reduction for C-X bond formation. The reaction was demonstrated under exogenous-oxidant-free conditions. Moreover, this is the
first example of activating CBr4, CHBr3, and CCl3Br under electrochemical conditions.
studies have revealed that carbon tetrabromide could take one
electron from the electron donors and is reduced to bromine ion
Background and Originality Content
Electrochemical synthesis is a cost-effective, scalable and
environmentally friendly method for C-H functionalization with
the prospect of avoiding the use of stoichiometric oxidants or
reductants.[1] In the past few years, extensive efforts have been
made and great achievements have been accomplished.[2] In most
cases, however, only one of the two electrochemical half-reaction
leads to the product of interest, the chemistry that occurs at the
counter electrode does not generate the target products. For
example, the electrochemical anodic oxidation drived C-H
functionalization, in which only anodic reaction yields expected
products. Undoubtedly, synergy of anodic oxidation and cathodic
reduction leads to C-H functionalization is a more ideal strategy.
However, up to now, the strategic use of this concept in organic
reaction design and discovery remains very rare and great
challenge.[3]
and tribromomethyl radical.[9] We recognized that above
reductive transformation might also be achieved under the
electrochemical conditions. Inspired by this idea and the fact that
synergy of anodic oxidation and cathodic reduction forms the
useful products is a more ideal strategy for C-H functionalization,
we herein uncovered an electrochemical C-H halogenation
protocol that tactfully makes anodic oxidation and cathodic
reduction synergy for C-X bond formation (Scheme 1, bottom). It
is worth noting that this is the first example of activating CBr4,
CHBr3, and CCl3Br under electrochemical conditions. Moreover,
this reaction features broad substrate scope and can be easily
scaled-up.
Table 1 Effect of reaction parametersa
Organic halides, either aryl or alkyl halides are significant
motifs frequently found in many biologically active compounds,[4]
and serve as versatile building blocks for constructing various
complex molecules.[5] Despite of remarkable progress in the field
of synthesizing organic halides,[6] the reported methods
frequently require stoichiometric oxidants/additives, metal
catalysts, leaving groups/directing group, and/or toxic
halogenating reagents (Scheme 1, top).
Scheme 1 Methods for C-H halogenation
a Reaction conditions: carbon rod anode, nickel plate cathode, constant
current = 12 mA, 1a (0.5 mmol), CBr4 (0.5 mmol), nBu4NBF4 (0.1 mmol),
MeCN (10 mL), MeOH (1 mL), 75 oC, N2, 2.5 h, isolated yields, SS = stainless
steel plate.
Carbon tetrabromide is a readily available commercial reagent
and has been widely used for organic synthesis.[7,8] Previous
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substituents such as methyl, fluorine, or trifluoromethyl groups at
different positions of the pyridine ring also furnished the C-H
bromination products in high yields (Table 2, 2n-2q). Notably, the
current electrochemical C-H bromination system was also
compatible with other electron-rich heteroarene/arenes, such as
1,3,5-trimethoxybenzene, benzothiophene, and 2-aminopyridine
(Table 2, 2r-2t).
Results and Discussion
Our initial studies of the electrochemical C-H halogenation
focused on the bromination of 2-phenylimidazo[1,2-a]pyridine (1a)
(Table 1). We were motivated to use this substrate because
imidazopyridines represent one of the most prevalent structural
units in many biologically active molecules, and the resultant
products can be subsequently transformed into the other
biologically active molecules. Gratifyingly, when CH3CN and MeOH
were employed as the co-solvent, the desired C-H bromination
product 2a was produced in 93% yield under a 12 mA constant
current in an undivided cell (Table 1, entry 1). Both replacing the
nickel plate cathode with stainless steel plate or platinum plate
and replacing the carbon rod anode with platinum plate led to
slightly decreased reaction yields (Table 1, entries 2-4). Either
decreasing the operating current to 6 mA or increasing the
operating current to 18 mA also led to slightly decreased reaction
yields (Table 1, entries 5-6). Latter, different electrolytes were
investigated. However, all had slightly lower effectiveness than
nBu4NBF4 (Table 1, entries 7-8). Next, some solvents were explored.
Either using MeCN as the sole solvent or using CH3CN and H2O as
the co-solvent showed similar reactivity with CH3CN and MeOH
(Table 1, entries 9-12). Control experiment confirmed that the
reaction does not proceed without electric current (Table 1, entry
13). Notably, the bromination of 2-phenylimidazo[1,2-a]pyridine
(1a) could be easily conducted on a 10 mmol scale to afford 2a in
81% yield (Table 1, entry 14, See ESI for details).
Table 3 Electrochemical C-H bromination of α-carbonyl compoundsa
a Reaction conditions: carbon rod anode, nickel plate cathode, constant
current = 12 mA, 3 (0.5 mmol), CBr4 (0.5 mmol), nBu4NBF4 (0.1 mmol),
MeCN (10 mL), MeOH (1 mL), 75 oC, N2, 2.5 h, isolated yields.
Significantly, the scope of the electrochemical C-H
bromination could be extended to α-carbonyl compounds (Table
3). It was observed that the desired C-H bromination products
were obtained in 82-86% yields when ethyl benzoylacetate
derivatives were used (Table 3, 4a-4c). Notably, besides ethyl
benzoylacetates, acetophenone derivatives were also suitable
substrates in this electrochemical C-H bromination. For example,
when the reaction was performed with 4-methylacetophenone,
4-chloroacetophenone, or 2-acetonaphthone, the reaction
reacted smoothly and delivered the desired C-H bromination
products in 82-87% yields (Table 3, 4d-4f).
Table 2 Electrochemical C-H bromination of heteroarene/arenes a
Table 4 Electrochemical C-H chlorinationa
a Reaction conditions: carbon rod anode, nickel plate cathode, constant
n
current = 12 mA, 1 or 3 (0.5 mmol), CCl4 (0.5 mmol), Bu4NBF4 (0.1 mmol),
MeCN (10 mL), MeOH (1 mL), 75 oC, N2, 2.5 h, isolated yields.
a Reaction conditions: carbon rod anode, nickel plate cathode, constant
current = 12 mA, 1 (0.5 mmol), CBr4 (0.5 mmol), nBu4NBF4 (0.1 mmol),
MeCN (10 mL), MeOH (1 mL), 75 oC, N2, 2.5 h, isolated yields.
It is worth noting that this versatile electrochemical C-H
halogenation protocol was not limited to the bromination with
carbon tetrabromide. Indeed, carbon tetrachloride was identified
as amenable halogenating agents as well, delivering the desired
C-H chlorination products in moderate to good yields (Table 4,
5a-5f).
To gain some insights into the mechanism of this
electrochemical C-H halogenation, some control experiments
were conducted. First, cyclic voltammetry experiments were
carried out (Figure S1-S3, See ESI for details). An oxidation peak of
With the optimized conditions in hand, the substrate scope of
the electrochemical C-H bromination was investigated by using
various heteroarene/arenes (Table 2). Gratefully, our method was
successfully amenable to a wide range of imidazo[1,2-a]pyridines.
Imidazo[1,2-a]pyridines with either aryl or alkyl groups at the C-2
position were tolerated under the standard conditions, delivering
the corresponding C-H bromination products in high to excellent
yields (Table 2, 2a-2m). Imidazo[1,2-a]pyridines bearing
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1a was observed at 1.55 V (vs Ag/AgCl), whereas the reduction
pecks of CBr4 and MeOH were observed at -0.67 V and -1.1 V (vs
Ag/AgCl), respectively. This result indicates that CBr4 is very easily
reduced under electrochemical conditions. On the basis of this
experimental result and literature reports,[9] we believe that this
reaction should begin with the cathodic reduction of halogenating
reagents. To further verify this conjecture, the other easily
reduced substrates,[10] such as CHBr3, CH2Br2, and CCl3Br were also
employed to this electrochemical C-H halogenation system
(Scheme 2). To our delight, in the reaction of 1a with CHBr3,
CH2Br2, or CCl3Br, good to high yields of products were achieved
under the standard reaction conditions, consistent with our
hypothesis. Given that bromine ion and chlorine ion have a similar
oxidation potential with 1a (Figure S3, See ESI for details), the
cathodic reduction generated bromine ion or chlorine ion may be
subsequently oxidized to molecular Br2 or Cl2. To clarify whether
this reaction involved a molecular Br2 or Cl2 intermediate, the
reaction of 1a with Br2 and Cl2 under the conditions of without
current was carried out respectively and the C-H bromination
product could be obtained in 89% yield, while no C-H chlorination
product was detected (Scheme 2). This result indicates that
molecular Br2 might be the key intermediate of C-H bromination,
while molecular Cl2 might not be involved as the intermediate in
C-H chlorination. In addition, when the reaction of 1a was carried
out in the absence of halogenating reagents, the capture product
6a was not detected (Scheme 2). This result indicates that 1a is
first oxidized to the corresponding radical cation, followed by
nucleophilic attack with bromine ion or chloride ion, can be ruled
out.
be detected by GC-MS in the reaction mixture, which verifies the
possibility of this mechanism. In addition, according to the above
experimental results, the generated tribromomethane would also
be reduced at the cathode and finally access to desired product
2a. Notably, the mechanism of C-H chlorination and C-H
bromination might be different. In C-H chlorination, the
generated chlorine ion might be oxidized at the anode to
generate chlorine radical instead of molecular Cl2.
Scheme 3 Proposed mechanism
Control experiments showed that CHBr3, CH2Br2, and CCl3Br
were all suitable brominating reagents for the reaction. We
subsequently investigated the substrate scope of the
electrochemical C-H bromination using CHBr3, CH2Br2, and CCl3Br.
It was found that imidazopyridines bearing aryl, alkyl, even -H
groups at the C-2 position all delivered the corresponding C-H
bromination products in good to excellent yields (Table 5).
Scheme 2 Control experiments
Moreover,
α-carbonyl
compounds,
such
as
ethyl
3-(4-methoxyphenyl)-3-oxopropanoate, were also amendable to
this procedure, although 3.0 equiv. of brominating reagents were
used.
Table 5 Electrochemical C-H bromination with CHBr3, CH2Br2, and CCl3Bra
a Reaction conditions: carbon rod anode, nickel plate cathode, constant
n
current = 12 mA, 1 or 3 (0.5 mmol), [Br] (0.5 mmol), Bu4NBF4 (0.1 mmol),
MeCN (10 mL), MeOH (1 mL), 75 oC, N2, 2.5 h, isolated yields. b [Br] (1.5
mmol).
On the basis of the above experimental results and previous
reports,[2q,9,10] a plausible mechanism for the electrochemical C-H
C-H Halogenation is shown in Scheme 3. CBr4 is first reduced at
the cathode to generate bromine ion and tribromomethyl radical.
Then, the generated tribromomethyl radical abstracts a hydrogen
atom from solvent to afford tribromomethane. In the meanwhile,
the generated bromine ion is oxidized at the anode to generate
molecular Br2. The reaction of 1a with molecular Br2 finally
affords the corresponding C-H bromination product 2a. It is worth
noting that the generated tribromomethane intermediate could
Conclusions
In conclusion, we have developed an efficient electrochemical
C-H halogenation protocol using CBr4, CHBr3, CH2Br2, CCl3Br and
CCl4 as the halogenating agents. A series of significant aryl and
alkyl halides were prepared under external-oxidant-free reaction
conditions. It is worth noting that this is the first example of
activating CBr4, CHBr3, and CCl3Br under electrochemical
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conditions. Importantly, in this reaction, not only anodic oxidation
but also cathodic reduction is reconciled to synergistically
construct C-X bond. In addition, this reaction can be easily
scaled-up.
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In an oven-dried undivided three-necked bottle (25 mL)
equipped with a stir bar, 2-phenylimidazo[1,2-a]pyridine (1a, 0.5
mmol), carbon tetrabromide (0.5 mmol), and nBu4NBF4 (0.1 mmol)
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graphite rod (ϕ 6 mm, about 18 mm immersion depth in solution)
as the anode and nickel plate (15 mm × 15 mm × 1 mm) as the
cathode and was then charged with nitrogen. Under the
protection of N2, MeCN (10.0 mL) and MeOH (1.0 mL) were
injected respectively into the tubes via syringes. The reaction
mixture was stirred and electrolyzed at a constant current of 12
o
mA at 75 C for 2.5 h. When the reaction was finished, the pure
product was obtained by flash column chromatography on silica
gel.
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Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
This work was supported by the National Natural Science
Foundation of China (21520102003). The Program of Introducing
Talents of Discipline to Universities of China (111 Program) is also
appreciated.
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
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Entry for the Table of Contents
Page No.
Synergy of Anodic Oxidation and Cathodic
Reduction Leads to Electrochemical C-H
Halogenation
We herein uncovered an electrochemical C-H halogenation protocol that synergistically combines
anodic oxidation and cathodic reduction for C-X bond formation.
Zhilin Zhou, Yong Yuan, Yangmin Cao, Jin Qiao,
Anjin Yao, Jing Zhao, Wanqing Zuo, Wenjie Chen,
and Aiwen Lei,*
This article is protected by copyright. All rights reserved.