A Versatile C–H Halogenation Strategy for Indole Derivatives under Electrochemical Catalyst- and Oxidant-Free Conditions

Article abstract of DOI:10.1002/ejoc.201800267

Halogenated indoles are essential structural motifs in bioactive natural products. Reported herein is an economical and scalable electrochemical protocol for regioselective 3C–H halogenation of indole derivatives. This strategy provides access to a host of 3-iodo-, 3-bromo-, 3-chloro-, and 3-thiocyanoindole derivatives under mild conditions using inexpensive (pseudo)halide salts as the sole reagent. The optimized conditions do not require any supplementary electrolyte salts.

Full text of DOI:10.1002/ejoc.201800267

A Journal of
Accepted Article
Title: A versatile C-H halogenation strategy for indole derivatives under
electrochemical catalyst- and oxidant-free condition
Authors: Linhao Sun, Xing Zhang, Zilong Li, Jimei Ma, Zhen Zeng, and
Hong Jiang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800267
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800267
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10.1002/ejoc.201800267
European Journal of Organic Chemistry
COMMUNICATION
A versatile C-H halogenation strategy for indole derivatives under
electrochemical catalyst- and oxidant-free condition
Sun Linhao+, Zhang Xing+, Li Zilong, Ma Jimei, Zeng Zhen, Jiang Hong*
azidation[14] and thiocyanation[15], especially on the designated
Abstract: Halogenated indoles are essential structural motif in
organic molecules.[16] However there is no precedent for
bioactive natural products. Reported herein is an economical and
electrochemical mono-halogenation of indoles probably due to
the ready over-oxidation of indole under electrochemical
conditions. We present herein an efficient, versatile
electrocatalytic catalyst- and oxidant-free approach for direct C-
H mono-halogenation of indole and its derivatives using readily
available halide salts as the sole reagent under constant-current
conditions in an undivided cell (Scheme 1c).
scalable electrochemical protocol for regioselective 3C-H
halogenation of indole derivatives. This strategy provides access to
a host of 3-iodo-, 3-bromo-, 3-chloro- and 3-thiocyano indole
derivatives under mild condition using inexpensive (pseudo)halide
salts as the sole reagent. No supplementary electrolyte salt is
necessary in the optimized condition.
For over a century, halogenated organic compounds have
prided themselves on being the main building blocks in organic
synthesis.[1] Particularly the halogenated heterocycles, offering
numerous possibilities to the coupling reaction, are important
scaffolds in fine chemical and pharmaceutical industry.[2]
Currently, many medicinal chemists have been fascinated by
indole and its derivatives which possess a wide spectrum of
biological and pharmacological activities.[3] Indole skeleton-
based modification has naturally turned to a focus of organic
synthesis.[4] Thus in term of methodology, C-H halogenated
indoles have attracted many attentions because they can be
readily transformed into more functionalized structures.[5]
Since the mid-20th century, the halogenation strategies of
indole have been developed[6] particularly for the 3C-H
halogenation which appears the most reactive site of indole ring
towards electrophilic substitution.[4a] In these approaches, the
use of hazardous halogenation reagents such as molecular
halogen or N-halo-succinimides and the alkaline condition are
commonly required (Scheme 1a). More recently, direct C-H
halogenation methods of indole have been introduced employing
readily available halide salts as the halogen source (Scheme
1b).[7] Despite the halogen atom economy of these protocols,
costly metal-based catalyst and polluting oxidant will badly
complicate further large-scale application. Therefore, the
development of an environmentally friendly and economical C-H
halogenation strategy is still highly desired from the standpoint
of sustainability and green chemistry.
Electroorganic synthesis, employing electric current as
“reagents” in place of stoichiometric oxidants or reductants, is
recognized as a green and versatile method to prepare organic
compounds via a redox process.[8] Electrochemical anodic
oxidation presents an ideal alternative to chemical oxidants
which challenge orthodox C-H functionalization methods.[9] In
addition, electrochemistry has already exhibited a distinctive
ability in halogenation such as fluorination,[10] chlorination,[11]
bromination,[12] iodination,[13] even pseudo-halogenation such as
Scheme 1.Halogenation methods of indole derivatives
To initially verify the feasibility of the electro-oxidation of
indole and its derivatives, we characterized the redox property of
indole derivatives with cyclic voltammetry (see the part 2 of
Supporting Information). Cyclic voltammograms showed
irreversible oxidation waves for all indole derivatives due to the
electron-rich nature of indole ring. These results are in perfect
accordance with precedent work on electrochemical
characterization of indole derivatives.[10b, 15b]
We then optimized the electrosynthetic conditions involving
the iodination of 1H-indole as a model reaction. Extensive tests
varying electrode material, solvent, supporting electrolyte, iodine
source, current intensity were carried out (see the part 3 of
Supporting Information). The optimal conditions were defined
using readily available iodide potassium as iodine source with
1H-indole 1a at the ratio of 1:1. The highest yield (97% GC yield)
for 3-iodoindole 3a was obtained performing the electrolysis in a
four-necked flask containing an electrolyte solution of iodide
potassium in acetonitrile, combined with two identical platinum
plates as cathode and anode respectively with a constant
current of 12 mA. It is quite worth mentioning that, in the
optimized condition, no supplementary electrolyte salt is
required to ensure the conductivity, since iodide potassium
could play a double role as both iodine source and supporting
electrolyte. We have also monitored the quantity of electro-
generated 3a by gas chromatography during an electrolysis
under the optimal condition (for details, see the part 5 of
Supporting Information). Figure 1 shows a linear increase of
3a during the first half period of electrolysis, which appears
[a]
[+]
L. Sun,[+] X. Zhang,[+] Z. Li, J. Ma, Z. Zeng, Prof. H. Jiang
Department of Chemistry
College of Science, Huazhong Agricultural University
Wuhan 430070, Hubei, China
E-mail: jianghong@mail.hzau.edu.cn
These authors contributed equally
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800267
European Journal of Organic Chemistry
COMMUNICATION
slightly lower than the ideal value calculated by considering that
the electrochemical iodination of 1a is a process at two Faraday
per mole. Accordingly this reaction is consistent with an effective
electrochemical iodination of 1H-indole at two electrons with a
faradic yield of 84% approximately. Moreover the iodination
efficiency decreased dynamically during the latter half of the
reaction since the amount of reactants reduced.
Scheme 2. Substrate Scope. Standard conditions: Pt anode, Pt cathode,
constant current (12 mA), indole derivatives 1.0 mmol, KI 1.0 mmol, MeCN
10.0 mL. RT, argon, 6h (2.7F). Isolated yields are given.
The scalability of this approach was evaluated by
performing the electrochemical iodination of 1H-indole on a
gram-scale. The electrolysis of 10 mmol substrate led to 82%
yield of 3a, showing little loss in product formation efficiency
compared to the same reaction conducted on a 1 mmol scale
(Scheme 3), that confirms a great synthetic value of this method.
Moreover the double role of ready available KI (as both iodine
source and supporting electrolyte) has remarkably reduced the
budget of electrochemical iodination, showing the great potential
of this method on industrial applications.
Figure 1. Yield evolution of 3-iodoindole during the electrolysis process. The
method for quantification of yield is described in the supporting information.
With the optimized conditions identified, we subsequently
investigated the tolerance of the reaction towards functional
groups on the indole moiety (Scheme 2). Indoles with various
substituents at different positions underwent the electrochemical
C-H iodination selectively at C3 position and delivered the 3-iodo
indoles with moderate to good yields. Both unprotected indoles
and N-methyl indoles were suitable for this electrochemical
process. Overall, the unsubstituted N-H indoles containing an
electron donating group showed better reaction efficiency
(products 3b-3f 75%-88%) than those containing an electron
withdrawing group (products 3g-3l 58%-85%). Indole ring
bearing methyl, phenyl and ester substituents at the C2 position
led to lower yields of 3-iodo indoles probably due to the C2 steric
hindrance effect (products 3d, 3f, 3l). 5-halogenated indoles
were also suitable for this transformation (products 3g, 3i, 3j),
the isolated product yields followed the order Br>Cl>F, which
could be explained by the order of the electron withdrawing
ability of halogen. N-methyl indoles afforded the iodination
product in moderate yields (products 3m), however reaction
could not occur with t-Butyl 1H-indole-1-carboxylate due to the
strong electron withdrawing effect of the “Boc” group.
Futhermore 7-azaindole could also lead to 3-iodo product with
60% yield (product 3n).
Scheme 3. Gram-scale synthesis
In order to gain insights into the mechanism of the
electrochemical C-H iodination reaction, in the first step, we
carried out electrochemical analyses to investigate the redox
potential of the substrates (Figure 2). Iodide potassium exhibits
a dual oxidation peak at 0.07V and 0.46V versus Ag/Ag+ which
-
-
can be assigned to the oxidation of I- to I3 and I3 to I2
respectively.[17] At the same time, the oxidation peak of 1H-
indole was observed above the oxidation potential of KI.
Accordingly the oxidation of KI should be prior due to its lower
oxidation potential compared with 1H-indole. Afterwards a
control reaction was conducted using I2 as the iodine source
instead of KI, the electrochemical iodination was suppressed.
which led us to rule out the possibility of iodination by I2
(Scheme 4a). Literature research involving the electrochemical
halogenation of organic compounds have commonly proven the
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10.1002/ejoc.201800267
European Journal of Organic Chemistry
COMMUNICATION
anodic formation of iodonium (I+) as the active iodination reagent
corresponding (pseudo)halogen source instead of KI resulted in
3-bromo, 3-chloro and 3-thiocyano indole respectively with
success (see the part 7 of Supporting Information). The
chlorination was particularly more difficult to be accessed than
the iodination and bromination due to the difficulty to oxidize Cl-
through the anodic oxidation, only 30% desired product was
obtained and isolated in the best case. Unsurprisingly, the
mono-fluorination failed in the analogous process due to the
extremely high oxidation potential of fluoride. The thiocyanation
was also achieved with good efficiency.
In summary, an efficient and regioselective electro-
chemical (pseudo)halogenation method has been developed,
which enables C-X (X=I, Br, Cl, SCN) bond formation under mild
conditions exclusively at the C-3 position of indole ring. Various
electron-rich indole derivatives exhibited great efficiencies for
this transformation. Being catalyst- and external oxidant-free,
highly regioselective, using inexpensive (pseudo-)halide salt as
the sole reagent, and the optional use of supplementary
electrolyte: all these notable merits enable the adoption of this
strategy in modern synthetic chemistry and pharmaceutical
industry without significant environmental impact. Future studies
on similar electrochemical C-H activation approaches are
underway in our laboratory.
[13b, 16, 18]
,
which inspire
a
putative mechanism via the
electrophilic attack by iodonium.
0.30
0.25
0.20
0.15
0.10
0.05
0.00
1H-indole
KI
-0.5
0.0
0.5
1.0
1.5
2.0
Potential / V (vs Ag/Ag+)
Figure 2. Cyclic voltammetry of 1H-indole and KI in CH3CN with n-Bu4NPF6
(0.05M) at a glassy carbon-disk electrode at a scan rate of 0.1V/s
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (No.21502058) and the
Fundamantal Research Funds for the Central Universities
(No.2662015QC031).
Scheme 4. Mechanistic investigations
As illustrated in Scheme 4b, in the first step, anodic
oxidation of iodine anion led to the formation of iodonium by
losing two electrons. The two electron process has been
previously confirmed by monitoring reaction (see discussion of
Figure 1). Then the electrophile I+ will attack the electron-rich
site of indole ring (C3) to form a cation intermediate which can
furtherly release a proton to give the desired iodination product.
Concomitant cationic half-reaction involves the one-electron
reduction of H+ to H2, which can be confirmed by the observation
of gas release at the cathode surface during electrolysis.
Another one-electron reduction may concern potassium cation
provided by electrolyte KI, leading to the formation of base
during electrolysis. Accordingly both the anion and cation of KI
was totally consumed after electrolysis.
Keywords: C-H functionalization • electrochemistry • electro-
catalysis • halogenation • indole
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COMMUNICATION
Entry for the Table of Contents
Layout 1:
COMMUNICATION
Key topic: Halogenation
Sun Linhao+, Zhang Xing+, Li
Zilong, Ma Jimei, Zeng Zhen, Jiang
Hong*
Reported
economical
herein
and
is
scalable
protocol for
an
Page No. – Page No.
electrochemical
regioselective 3C-H halogenation
of indole derivatives. This strategy
provides access to a host of 3-
iodo-, 3-bromo-, 3-chloro- and 3-
thiocyano indole derivatives under
mild condition using inexpensive
(pseudo)halide salts as the sole
A versatile C-H halogenation
strategy for indole derivatives
under electrochemical catalyst-
and oxidant-free condition
reagent.
No
supplementary
electrolyte salt is necessary in the
optimized condition.
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