An Electrochemical Route for Special Oxidative Ring-Opening of Indoles

Article abstract of DOI:10.1002/chem.202101527

A novel electrochemical protocol for the oxidative cleavage of indoles has been developed, which o?ers a simple way to access synthetically useful anthranilic acid derivatives. In undivided cells, a wide variety of indoles and alcohol compounds are examined to a?ord amide ester aromatics without using extra oxidants and stoichiometric metal catalysts, which avoids the formation of undesired by-products and exhibits high atom economy. The products we described in this perspective represent a synthetic intermediate in numerous drug molecules and industrial chemical reagents and remarkably show potential application in the future.

Full text of DOI:10.1002/chem.202101527

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Chemistry—A European Journal
An Electrochemical Route for Special Oxidative Ring-
Opening of Indoles
Hong Qin,[a] Zhao Yang,[b] Zhen Zhang,[a] Chengkou Liu,[a] Wei He,*[a] Zheng Fang,*[a, c] and
Kai Guo[a, c]
Abstract: A novel electrochemical protocol for the oxidative
cleavage of indoles has been developed, which offers a
simple way to access synthetically useful anthranilic acid
derivatives. In undivided cells, a wide variety of indoles and
alcohol compounds are examined to afford amide ester
aromatics without using extra oxidants and stoichiometric
metal catalysts, which avoids the formation of undesired by-
products and exhibits high atom economy. The products we
described in this perspective represent a synthetic intermedi-
ate in numerous drug molecules and industrial chemical
reagents and remarkably show potential application in the
future.
Introduction
lated indoles was reported by Wang.[9] However, all these
methodologies worked towards N-protected indole or indole
substituted with electron-donating groups, and did not show
any activity towards free indole (Scheme 1). In addition, their
environmental influences and atom economy were not ad-
dressed, which is contrary to the rising concept and awareness
of green chemistry. Recently, Tong[10] developed green oxida-
tion reactions of indoles using halide catalysis and Shoubhik
Das[11] achieved visible-light mediated dearomatization of C2-
As a privileged motif, indoles are prevalent molecular architec-
tures that are widely found in natural products.[1] Considering
that there have been numerous simple, efficient, and econom-
ical methods for the preparation[2] and functionalization[3] of
indoles, the discovery of indole ring-fragmentation methods to
realize the ortho-functionalization of the phenyl group shows
conspicuous significance. Oxidative cleavage of aromatic rings
occurs frequently in nature,[4] while oxidation of indoles is a
fundamental organic transformation to deliver a variety of
synthetically and pharmaceutically valuable nitrogen-containing
compounds. The corresponding oxidative cleavage of the
C2=C3 bond of indoles was first reported in 1951 by Witkop
using Pt/O2 oxidation.[5] Various oxidants including periodic acid
(NaIO4), chromic acid, peracids (m-CPBA), ozone and singlet
oxygen, were identified for Witkop oxidation.[6] Subsequently,
Kiyoshi Tanaka[7] developed a novel method for the oxidative
cleavage of indole carbon double bonds using plant cell
cultures as peroxidase in the presence of H2O2. In 2016, a
transition-metal-free CÀ C and CÀ N bond cleavage of 2-
[8]
°
arylindoles at 120 C was developed. Then, the development
of methylene blue-catalyzed oxidative cleavage of N-carbony-
[a] H. Qin, Z. Zhang, C. Liu, W. He, Prof. Z. Fang, Prof. K. Guo
College of Biotechnology and Pharmaceutical Engineering
Nanjing Tech University
30 Puzhu Rd S., Nanjing 211816 (P. R. China)
E-mail: hwkk208@163.com
fzcpu@njtech.edu.cn
[b] Z. Yang
School of Engineering
China Pharmaceutical University
No. 639 Longmian Avenue, Nanjing 211198 (P. R. China)
[c] Prof. Z. Fang, Prof. K. Guo
State Key Laboratory of Materials-Oriented Chemical Engineering
Nanjing Tech University
30 Puzhu Rd S., Nanjing 211816 (P. R. China)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202101527
Scheme 1. Oxidative cleavage of indoles: Prior arts and this work.
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and C3-substituted indoles and then synthesized ortho-formyl/ Results and Discussion
acyl anilide derivatives. Moreover, the realization of ring-open-
ing functionalization of the indoles requires not only strong
oxidants but also suitable substitutions at C2 and/or C3
positions, as well as the protecting group on the nitrogen.
In fact, those ortho-formyl/acyl anilide derivatives from the
oxidation ring opening of indoles are an important structural
motif for the synthesis of natural products and bioactive
compounds. Anthranilic acid derivatives are one of the down-
stream products that have exhibited a broad spectrum of
biological activities in the field of medicine and chemical
industry. For example, flufenamic acid (classical NSAIDs), an
anthranilic acid derivative, demonstrates its anti-inflammatory
and analgesic potential.[12] Benzodiazepines and benzotriaze-
pines with anti-anxiety, sedative and hypnotic effects also
contain the nucleus of o-amidobenzoate.[13] Over the years,
numerous synthetic strategies[14] have been developed for the
construction of ortho-formyl/acyl anilide derivatives. Unfortu-
nately, traditional methods mostly rely on the use of precious
transition metals, or require harsh conditions (high temperature,
strong oxidants, and prolonged times), or have possibility for
the formation of side products. In addition, it is relatively
difficult to selectively introduce amino groups to the ortho
position of substituted benzene compounds. The acylation
process of amino groups often involves reagents such as acid
anhydrides and acid chlorides, which may contaminate the
environmental or cause low atom economy problems. Con-
sequently, innovative efforts should be made in the synthesis of
ortho-formyl/acyl anilide scaffolds using indole as raw material
through environmentally friendly and easy routes. Vodopivecd
and co-workers[15] confirmed that electrochemical oxidation of
isatin gave a stable and strongly fluorescent main product
methyl N-(methoxycarbonyl) anthranilate. Electrochemistry has
become an appealing choice towards green oxygenation, which
could obviate the participation of transition-metals and strong
oxidants. A short time ago, our group have developed an
electrocatalytic fluoroalkylation and cyclization indole oxidative
cleavage reaction under catalyst- and oxidant-free conditions[16]
(Scheme 1). Inspired by the information mentioned above and
according to our previous work on indoles,[17] we envisaged the
feasibility of realizing the oxidation of indole to isatin and then
the cleavage of the latter under external-oxidant-free and
catalyst-free conditions using electrochemistry. Herein, we
reported a transformation of indoles to advanced products,
which were identified as the corresponding anthranilic acid
derivatives, through an environmentally responsible electro-
chemical oxidative ring-opening reaction. The oxidative cleav-
age of indoles in presence of alcohol leading to the formation
of two ester groups was unreported. In this process, our
protocol not only eliminates the use of hazardous oxidants
(e.g., PhI(OAc)2, CrO3, KMnO4, and m-CPBA, etc) but also the
production of organic by products or toxic heavy metals
derived from oxidants to minimize the environmental and
health impact of the indole oxidation. In addition, N-unsubsti-
tuted indoles, including indole itself, or indoles substituted with
electron-withdrawing groups on the benzene part are tolerated
in comparison with previous methods.
Initially, 1H-indole (1a) was used as a model substrate to start
our investigation under constant current (Table 1). Surprisingly,
n
the use of certain electrolytes, such as KBr, KI, Me4NI, Bu4NI,
NaNO2 and NaCl, could afford an unexpected product, different
from that the Witkop oxidation generated. After our careful
investigation and analysis, the product obtained was identified
as methyl 2-(methoxycarbonylamino) benzoate (3a). Then, the
effects of different reaction conditions, including the solvent,
electrolyte, equivalent, and electrode were investigated. Firstly,
different electrolytes showed that NaNO2 performed better than
the others, affording the desired product in 65% yield (Table 1,
entries 1–15). Then, the effect of solvent was explored, and the
results indicated that the cosolvent of CH3OH/CH3CN (v/v=1/1,
8 mL) showed the best performance (Table 1, entries 16–22).
While choosing Me4NI as the electrolyte, the yield of the
product was close to the optimal yield. Use of one rather than
two equiv. of sodium nitrite failed to lead to the product 3a
(Table 1, entry 23), for the possible reason that sodium nitrite,
selected as electrolyte, has poor solubility in this system. The
Table 1. Optimization of reaction conditions.[a,b,c]
Entry
Electrolyte
(equiv.)
Solvent
[8.0 mL]
I
Temp
Yield[b,c]
[%, 3a]
°
[mA]
[ C]
1
2
3
4
5
6
7
8
nBu4NPF6 (2)
KCl (2)
KBr (2)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/DCE (1/1)
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
2
4
10
20
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
trace
37
48
0
0
6
34
56
3
39
0
trace
7
65
32
0
KI (2)
Et4NClO4 (2)
nBu4NOAc (2)
Et4NCl (2)
TBAB (2)
9
Me4NI (2)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Et4NI (2)
nBu4NI (2)
I2 (2)
NaHCO3 (2)
NaCl (2)
NaNO2 (2)
NaNO2 (2)
NaNO2 (2)
NaNO2 (2)
NaNO2 (2)
NaNO2 (2)
NaNO2 (2)
NaNO2 (2)
NaNO2 (1)
NaNO2 (3)
NaNO2 (2)
NaNO2 (2)
NaNO2 (2)
NaNO2 (2)
MeOH/H2O (1/1)
MeOH/HFIP (1/1)
MeOH (1)
0
18
21
31
trace
8
60
trace
15
60
55
MeOH/CH3CN (1/3)
MeOH/CH3CN (3/1)
MeOH/CH3CN (1/7)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
MeOH/CH3CN (1/1)
[a] Reaction conditions: Pt plate cathode (10 mm×10 mm×0.1 mm)
cathode, graphite rod anode (Φ 6 mm), constant current, 1a (0.3 mmol,
1.0 equiv.), electrolyte (2.0 equiv., 0.6 mmol), solvent (8 mL), room temper-
ature, 4 h, undivided cell in air. [b] 1H NMR yield using CH2Br2 as the
internal standard. [c] Isolated yield.
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effect of the electrode material was probed. Results showed
that replacing the graphite rod anode and Pt plate cathode
with other electrode material both produce lower yields
(Table S1). Further investigation focused on the electrochemical
parameters, either increasing or decreasing the constant current
would lead to decreased reaction efficiency. Therefore, the
conditions used in entry 15 were selected as the best reaction
conditions.
Cl, Br and I) worked smoothly. Indoles bearing electron-
withdrawing groups, especially 5-Cl (3e, 70%) and 6-Cl (3j,
83%), demonstrated favorable reactivity and efficiency. Steric
and electronic factors can be invoked to account for the fact
that good product yields were obtained using indoles with
substituents in the C5-, and C6-positions. The indoles bearing
C4- and C7-substituent groups yielded almost no corresponding
products. In addition, indole derivatives with substitution at C1-
With these optimized reaction conditions in hand, we
applied our electrochemical system for the oxidation cleavage
of different indole derivatives (Table 2, 3a–3w). Indeed, screen-
ing of the substitution showed that indoles with electron-
donating groups (Me and OMe) resulted in the significant
decrease of reactivity while electron-withdrawing groups (CN, F,
, C2-, or C3-position were used as reactants (3x–3ab).
Unfortunately, only C2-substituted indole (3x) could give the
expected product, which provides valuable clues on the
reaction mechanism. We also examined the substrate scope of
alcohols such as ethanol, isopropyl alcohol, n-butanol, amyl
alcohol, tertbutyl alcohol, benzyl alcohol and HFIP, etc. How-
ever, long-chain alcohol, fluoroalcohol and benzyl alcohol were
not well tolerated under the optimized reaction conditions.
Only methanol and ethanol generated the corresponding
derivatives in medium to good yields.
Table 2. Substrates scope for the indoles and alcohol.[a,b]
Next, the mechanism of oxidation cleavage of indoles was
investigated. A series of control experiments were performed
(Scheme 2). Firstly, the reaction of 1a and methanol was
conducted under the standard conditions without current, and
there was no desired product detected. When 2.0 equivalents of
radical scavenger Tempo (2,2,6,6-tetramethylpiperidine-1-oxyl)
or BHT (2,6-ditert-butyl-4-methylphenol) were added, there was
no product observed. In addition, we added 10.0 equivalents of
triethyl phosphate to the system to trap any radical
intermediates.[18] The indole-phosphorylation product was ob-
tained, which indicated that an indole radical was produced
during the reaction.
Then, we explored the sources of the carbonyl oxygen and
methoxy in the product (Scheme 3). Deuterium incorporation
suggests that the methoxy group came from methanol. When
20.0 equivalents of H218O were added, no corresponding oxygen
18 labeled compound was found. When the reaction was
conducted under an atmosphere of 18O2, compound 3a was
isolated with 100% incorporation of two 18-oxygen atoms
which indicates that the two carbonyl oxygens originated from
the oxygen. This hypothesis has been confirmed by the fact
[a] Reaction conditions: undivided cell, platinum electrode as the cathode
(10 mm×10 mm×0.1 cm), graphite rod (Φ 6 mm) as the anode, constant
current of 8 mA, 1a (0.3 mmol), electrolyte (2.0 equiv., 0.6 mmol), solvent
°
(8 mL, v/v=1/1), stirred under air at room temperature (25 C) for 4 h
(4.0 F·molÀ 1). [b] Isolated yields. [c] CCDC: 2007967 (for 3I).
Scheme 2. Control experiments.
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During the experiment, we found that the solubility of NaNO2 in
this system is not good and the weak wave at 0.62 was
oxidative peak of NaNO2 (see Supporting Information Fig-
ure S1). The redox potential of sodium nitrite is lower than that
of indole, which is in line with the conditions of indirect
electrolysis.[19] Moreover, the oxygen atom source experiment
indirectly ruled out the possibility of the formation of CÀ O
bonds between sodium nitrite and indole. In addition to sodium
nitrite, the oxidative ring opening of indole can also be carried
out using other electrolytes. Sodium nitrite likely acts as an
electrolyte like others. Consequently, according to the
reference[19] and above experiments, sodium nitrite maybe not
only be used as an electrolyte but also a redox mediator which
plays the role of transporting electrons during the reaction.
Based on the above experimental results and some related
literature,[3,19–20] we propose a reasonable reaction mechanism in
Scheme 4. Indole 1a was oxidized to produce the indole
radical-cation intermediate A, which then reacted with the
methanol to produce the methoxy indole intermediate B. Then,
the resulting iminium ion B was poised to be trapped by a
second molecule of methoxide to afford the intermediate C.[3a]
Due to the instability of N-unprotected indole, the intermediate
C was quickly oxidized to the intermediate D which was then
intercepted by molecular oxygen.[21] In addition, a molecular ion
peak (m/z=178.0863) of the intermediate D was detected using
Electrospray Ionization-Time-of-Flight-Mass Spectrometry (ESI-
TOF-MS) and attributed to [D+H]+(exact mass: 178.0831).
(Supporting Information) Subsequently, along with the OÀ O
bond cleavage of four-membered ring E,[22] the CÀ C bond
cleavage led to the final product. Cathodic reduction of
methanol affords hydrogen and methoxide, the latter being a
critical component at several stages of the proposed mecha-
nism. In the whole process of the reaction, the sodium nitrite is
vital to the redox of the indole.
Scheme 3. Element source experiment.
that no oxidative cleavage is observed under an argon
atmosphere.
Complementary, cyclic voltammetry (CV) experiments (Fig-
ure 1) were performed to investigate the redox potential of the
substrates, including indole, methanol, NaNO2 and their combi-
nation in solution. As shown in Figure 1 (line 1b), no significant
oxidation peak of MeOH was observed in the potential window
of interest. In contrast, an obvious peak was observed in the CV
of indole (line 1a). It is illustrated that indole can be oxidized
more easily than MeOH under the optimized conditions, which
further excluded the possibility to generate methoxy radicals.
As shown in line 1c, we were confused by the appearance of
two weak waves at 0.62 V and 2.01 V. Whether NaNO2 has redox
potential or participates in the reaction? Therefore, we inves-
tigate the combination of NaNO2, MeOH, CH3CN and indole.
Figure 1. Cyclic voltammograms of substrates: a) 0.3 M Indole, 0.6 M
nBu4NPF6 in CH3CN; b) 0.6 M nBu4NPF6 in 8 mL MeOH/CH3CN (1:1); c) 0.6 M
NaNO2, 0.6 M nBu4NPF6 in CH3CN; d) 0.6 M NaNO2, 0.6 M nBu4NPF6 in 8 mL
MeOH/CH3CN (1:1); e) 0.3 M Indole, 0.6 M NaNO2, 0.6 M nBu4NPF6 in 8 mL
MeOH/CH3CN (1:1).
Scheme 4. Plausible reaction mechanism.
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In summary, we have developed a novel electrochemical
oxidative cleavage of indole derivatives. Combination of ring-
opened indoles and alcohols constructs a variety of useful o-
amidobenzoate building blocks. The reaction involves a mild
and facile protocol that occurs without any metals and extra
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Experimental Section
Crystal-structure analysis: Deposition Number 2007967 (for 3I)
contains the supplementary crystallographic data for this paper.
These data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum Karls-
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We thank the National Natural Science Foundation of China
(Grant No. 21776130); The National Natural Science Foundation
of China (Grant No. 21908094); The National Natural Science
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The authors declare no conflict of interest.
Keywords: electrochemistry
·
oxidative ring opening
·
transition-metal-free
indoles
·
strong oxidant-free unsubstituted
·
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Manuscript received: May 10, 2021
Accepted manuscript online: June 29, 2021
Version of record online: ■■■, ■■■■
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H. Qin, Z. Yang, Z. Zhang, C. Liu, W.
He*, Prof. Z. Fang*, Prof. K. Guo
1 – 6
An Electrochemical Route for Special
Oxidative Ring-Opening of Indoles
A novel method of electrochemical
oxidation cleavage of indole deriva-
tives and reorganization with alcohols
to construct a variety of useful o-ami-
dobenzoate building blocks was
occurs without any stoichiometric
metals and extra oxidants. N-unpro-
tected indoles or indoles substituted
with electron-withdrawing groups,
even free indole could give the
desired product, which expanded the
substrate range.
developed. The reaction involves a
mild and easy handling protocol that