Site-Selective Electrochemical C-H Cyanation of Indoles

Article abstract of DOI:10.1021/acs.orglett.1c02063

An electrochemical approach for the site-selective C-H cyanation of indoles employing readily available TMSCN as cyano source has been developed. The electrosynthesis relies on the tris(4-bromophenyl)amine as a redox catalyst, which achieves better yield and regioselectivity. A variety of C2- and C3-cyanated indoles were obtained in satisfactory yields. The reactions are conducted in a simple undivided cell at room temperature and obviate the need for transition-metal reagent and chemical oxidant.

Full text of DOI:10.1021/acs.orglett.1c02063

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Site-Selective Electrochemical C−H Cyanation of Indoles
Laiqiang Li, Zhong-Wei Hou,* Pinhua Li, and Lei Wang*
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ABSTRACT: An electrochemical approach for the site-selective C−H cyanation of indoles employing readily available TMSCN as
cyano source has been developed. The electrosynthesis relies on the tris(4-bromophenyl)amine as a redox catalyst, which achieves
better yield and regioselectivity. A variety of C2- and C3-cyanated indoles were obtained in satisfactory yields. The reactions are
conducted in a simple undivided cell at room temperature and obviate the need for transition-metal reagent and chemical oxidant.
Scheme 1. Direct C−H Cyanation of Indoles
ndoles are extremely important heterocyclic compounds
1
Iand prevalent in natural products and drug molecules. The
direct C−H functionalization of indoles as a rapid and
straightforward method for the synthesis of indole derivatives
have gained increased attention.2 The cyano group serves as
one of the most useful functional groups in organic synthesis
and can be easily utilized in a variety of chemical trans-
formations, including reduction, hydration, hydrolysis, nucle-
ophilic addition, [3 + 2] cycloaddition and the preparation of
nitrogen-containing heterocycles by cyclization reaction.3 Over
the past few decades, the Lewis acid promoted4 and transition-
metal catalyzed5 (e.g., Pd, Cu, Rh, Co, etc.) C−H cyanation of
indoles provided powerful paths to synthesize C2- or C3-
indole nitriles, in which these reactions suffer from the need for
high catalyst loading, stoichiometric amounts of expensive
additives, harsh reaction conditions, or prefunctionalized
substrates (Scheme 1a). Therefore, the development of
green, efficient and metal-free routes for the C−H cyanation
of indoles is still highly desirable.
Organic electrosynthesis,6 utilizing traceless electrons as
surrogate chemicals, has emerged as a powerful synthetic
strategy to achieve atom- and step-economical C−H
functionalization reactions in organic synthesis and has
attracted great attention in recent years.7 The electrochemical
oxidation of electron-rich indoles presents the prospect of
efficient formation of indole derivatives via radical addition8 or
nucleophilic addition after anodic oxidation.9 However, there
are only limited methods for the electrochemical C−H
functionalization10 of indoles so far. One of the successful
examples was that Lei and co-workers reported electrochemical
oxidative dehydrogenative C−H/S−H cross-coupling of
indoles with aryl/heteroaryl thiols, achieving the formation of
the C−S bonds.10a
The electrochemical cyanation of C(sp2)−H bonds provides
an effective method for generating aryl nitriles. Gooßen and
Received: June 20, 2021
Published: July 23, 2021
https://doi.org/10.1021/acs.orglett.1c02063
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5983−5987
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Letter
co-workers11a developed an efficient method for the electro-
chemical C−H cyanation of arenes by using NaCN as the
cyano source. Sun and co-workers11b,c described an electro-
chemical oxidative C−H cyanation of imidazo[1,2-a]pyridines
and quinoxalin-2(1H)-ones. Based on the importance of
indoles and our interest in the electrochemical C−H
functionalization,12 we herein report a site-selective electro-
chemical C(sp2)−H cyanation of indoles for the synthesis of
indole nitriles with TMSCN as a cyanation reagent and tris(4-
bromophenyl)amine13 serves as a redox catalyst, achieving
better regioselectivity (Scheme 1b).
First, 1-phenyl-1H-indole 1 and TMSCN were selected as
model substrates for the optimization of the electrosynthesis
conditions. The electrochemical C−H cyanation was per-
formed in an undivided cell equipped with a reticulated
vitreous carbon (RVC) anode and a platinum cathode at a
constant current of 10 mA (Table 1). When the reaction was
carried out at room temperature for 2.5 h with tris(4-
bromophenyl)amine 4 (5 mol %) and NaOH (1.0 equiv) as a
basic additive in an electrolyte solution of nBu4NBF4 in
MeCN/H2O (11:1) under argon atmosphere, the C2-
cyanation product 2 was obtained in 80% yield with C3-
cyanation product 3 in 5% yield (entry 1). The reaction
regioselectivity and yield were reduced in the absence of 4
(entry 2). Other catalysts such as 5−7 were not more effective
(entries 3−5). Electricity (entry 6) and the amount of NaOH
(entries 7−9) were pivotal for success. The basic additive has a
great influence on the electrosynthesis; Na2CO3 (entry 10),
NaHCO3 (entry 11), NaOAc (entry 12), and NaOtBu (entry
13) failed to give better results. When MeCN or MeCN/H2O
(5:1) was used as solvent, lower yields were obtained (entries
14 and 15). Product 2 could be obtained in 73% or 33% yield
when the reactions were performed with 1.5 or 1.0 equiv of
TMSCN (entries 16 and 17). The yields of 2 were slightly
decreased when the electrosynthesis was conducted in the
absence of nBu4NBF4 (entry 18) or under air (entry 19).
After the optimized reaction conditions were defined, we
then explored the substrate scope of the electrochemical C−H
cyanation. 3-Alkyl-substituted indoles reacted with TMSCN
successfully to afford C2-cyanation products in which methyl
(8), TBS-protected alcohol (9), free alcohol (10), amino acid
methyl ester (11), amide (12), acrylate (13), and electron-
deficient methyl formate (14) all could be tolerated under mild
electrosynthesis conditions (Scheme 2).
a
Table 1. Optimization of Reaction Conditions
Using 2-substituted indoles as the substrates, C3-cyanation
products (15−18) were conveniently prepared in moderate to
good yields (Scheme 2). Furthermore, the electrosynthesis
could tolerate a wide range of N-alkyl moieties in 2,3-
unsubstituted indoles, including methyl (19), benzyl (20),
isopropyl (21), cyclopropyl (22), allyl (23), and propargyl
(24), generating C2-cyanation products preferentially (Scheme
2). The C2 position of indole with a higher positive charge
could react more easily with TMSCN.11d The indole substrate
with ibuprofen reacted with TMSCN to produce the C2-
cyanation product 25 in 58% yield (Scheme 2). Simulta-
neously, the electrosynthesis reaction showed broad compat-
ibility with 4-substituted indoles (26−28), 5-substituted
indoles (29−31), 6-substituted indole (32), and 7-substituted
indole (33) (Scheme 2). The C−H cyanation product 34
could not be obtained due to the higher oxidation potential of
indole (Scheme 2). However, the reactions of benzofuran and
benzothiophene with TMSCN could not occur under the
standard conditions or in the absence of catalyst 4 (see the
Supporting Information for details).
Subsequently, we investigated the electrocatalytic C−H
cyanation of arenes to synthesize aromatic nitriles14 (Scheme
3). These reactions of substrates containing 1,3,5-trimethox-
ybenzene (35), methyl(naphthalen-2-yl)sulfane (36), 2-
methoxynaphthalene (37), 1-methylquinoxalin-2(1H)-one
(38), and 1-phenyl-1H-pyrrole (39) proceeded well to afford
C−H cyanation products. α-Aminonitriles (40 and 41) could
be obtained through electrochemical C(sp3)−H cyanation15 of
N,N-dimethylaniline and 1-phenylpyrrolidine. Moreover, the
electrochemical cyanation reactions of electron-rich arenes
could be conducted in the absence of tris(4-bromophenyl)-
amine 4. The C−H cyanation products also could be obtained
in moderate to good yields under the direct electrolysis
conditions.
b
entry
deviation from standard conditions
yield of 2/3 (%)
c
c
1
2
3
4
5
6
7
8
none
no 4
5 as catalyst
6 as catalyst
7 as catalyst
no electricity
no NaOH
NaOH (1.5 equiv) as base
NaOH (0.5 equiv) as base
Na2CO3 (1.0 equiv) as base
NaHCO3 (1.0 equiv) as base
NaOAc (1.0 equiv) as base
tBuONa (1.0 equiv) as base
MeCN as solvent
MeCN/H2O (5:1) as solvent
TMSCN (1.5 equiv)
TMSCN (1.0 equiv)
no nBu4NBF4
80 /5
56/19
20/5 (62)
49/13
70/12
0/0 (99)
0/0 (80)
73/10 (6)
26/trace (45)
16/trace (47)
7/0 (48)
29/trace (37)
52/11 (12)
16/0 (27)
16/trace (50)
73/6
9
10
11
12
13
14
15
16
17
18
19
33/5 (34)
60/8 (5)
62/7 (5)
under air
a
Reaction conditions: RVC anode, Pt cathode, 1 (0.30 mmol),
To demonstrate the practicality of the electrochemical C−H
cyanation reaction, the gram-scale synthesis of 16 was achieved
with a constant current of 62 mA at room temperature for 7 h
in 90% yield (Scheme 4). In addition, the C−H cyanation
products 16 and 24 could easily be transformed into
TMSCN (0.60 mmol, 2.0 equiv), 4 (5 mol %), NaOH (0.30 mmol),
nBu4NBF4 (0.15 mmol), MeCN (5.5 mL), H2O (0.5 mL), argon, 2.5
b
h (3.1 F·mol−1). Yield determined by 1H NMR analysis of the crude
reaction mixture using 1,3,5-trimethoxybenzene as an internal
c
standard, unreacted 1 in parentheses. Isolated yield.
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a
Scheme 2. Scope C(sp2)−H Cyanation of Indoles
Scheme 3. Scope of (Hetero)arenes C(sp2)−H and C(sp3)−
a
H Cyanation
a
Reaction conditions: Table 1, entry 1, unless otherwise mentioned.
The yields are isolated under standard conditions without 4 in
parentheses.
Scheme 4. Gram-Scale Synthesis of 16 and Cyclization
Transformations
a
Reaction conditions: Table 1, entry 1, unless otherwise mentioned.
All yields are isolated yields.
indolo[3,2-c]quinoline 433b and pyrido[1,2-a]indoles 44 and
45,3c which are biologically important heterocyclic motifs,
following the method reported in the literature. Rutaecarpine16
is the major active component of Wu-Chu-Yu, a well-known
Chinese herbal drug. Rutaecarpine derivate 46 could be rapidly
prepared in 53% yield from cyanation indole 12 in the
presence of DBU (Scheme 4).
To better understand the reaction mechanism, the cyclic
voltammograms (CVs) of catalyst 4 or substrate 1 were
recorded in an electrolyte of nBu4NBF4 (0.1 M) in MeCN/
H2O (11:1, 5 mL) (Figure 1). The obviously increase of
oxidation current and entire disappearance of reduction
current was found when substrate 1 was added to the solution
of 4. These results suggested that 4•+ produced through anodic
oxidation of 4 (Ep/2 = 1.10 V vs Ag/AgCl) could effectively
oxidize substrate 1 (Ep/2 = 1.27 V vs Ag/AgCl) to generate
radical cation intermediate. When a radical scavenger 2,6-di-
tert-butyl-4-methylphenol (BHT) or (2,2,6,6-tetramethylpiper-
idin-1-yl)oxyl (TEMPO) (2.0 equiv) was added to the model
reaction the cyanation of 1-phenyl-1H-indole 1 was inhibited
completely, demonstrating a possible radical pathway in this
system (see the Supporting Information for details).
Based on cyclic voltammograms and previous reports, a
possible mechanism for the electrochemical C−H cyanation
reaction is proposed using 1-phenyl-1H-indole 1 and TMSCN
as model substrate (Scheme 5). The anodic oxidation of 4
forms 4•+, and the latter oxidizes 1-phenyl-1H-indole 1 via
single electron transfer (SET) to furnish radical cation 47,
followed by TMSCN reaction to give a carbon radical 48,
which was trapped by 2,6-di-tert-butyl-4-methylphenol (BHT)
and detected by GC−MS analysis (Figure S9). Then the
formed radical 48 was oxidized by 4•+ to generate carbocation
49, which undergoes proton elimination to produce the final
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Letter
University, Huaibei, Anhui 235000, P.R. China; State Key
Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P.R. China; orcid.org/0000-0001-
6580-7671; Email: leiwang@chnu.edu.cn
Zhong-Wei Hou − Advanced Research Institute and
Department of Chemistry, Taizhou University, Taizhou
318000, P.R. China; Email: zhongwei.hou@tzc.edu.cn
Authors
Laiqiang Li − Advanced Research Institute and Department of
Chemistry, Taizhou University, Taizhou 318000, P.R.
China; Department of Chemistry, Huaibei Normal
University, Huaibei, Anhui 235000, P.R. China;
orcid.org/0000-0002-6199-0349
Pinhua Li − Department of Chemistry, Huaibei Normal
University, Huaibei, Anhui 235000, P.R. China; State Key
Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P.R. China; orcid.org/0000-0002-
8528-8087
Figure 1. Cyclic votammograms in MeCN/H2O (11:1): (a) 4 (3
mM); (b) 1 (10 mM); (c) 4 (3 mM) and 1 (10 mM).
Scheme 5. Proposed Mechanism
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02063
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the National Natural Science
Foundation of China (22071171).
■
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02063.
■
sı
Experimental procedure and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Lei Wang − Advanced Research Institute and Department of
Chemistry, Taizhou University, Taizhou 318000, P.R.
China; Department of Chemistry, Huaibei Normal
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