Electrochemically Enabled C3-Formylation and -Acylation of Indoles with Aldehydes

Article abstract of DOI:10.1021/acs.orglett.9b02433

Reported herein is an effective strategy for oxidative cross-coupling of indoles with various aldehydes. The strategy is based on a two-step transformation via a well-known Mannich-type reaction and a C-N bond cleavage for carbonyl introduction. The key step - the C-N bond cleavage of the Mannich product - was enabled by electrochemistry. This strategy (with over 40 examples) ensures excellent functional-group tolerance as well as late-stage functionalization of pharmaceutical molecules.

Full text of DOI:10.1021/acs.orglett.9b02433

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Electrochemically Enabled C3-Formylation and -Acylation of Indoles
with Aldehydes
Liquan Yang, Zhaoran Liu, Yujun Li, Ning Lei, Yanling Shen, and Ke Zheng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, P. R. China
S
* Supporting Information
ABSTRACT: Reported herein is an effective strategy for
oxidative cross-coupling of indoles with various aldehydes. The
strategy is based on a two-step transformation via a well-known
Mannich-type reaction and a C−N bond cleavage for carbonyl
introduction. The key stepthe C−N bond cleavage of the
Mannich productwas enabled by electrochemistry. This
strategy (with over 40 examples) ensures excellent functional-
group tolerance as well as late-stage functionalization of
pharmaceutical molecules.
Scheme 1. C3-Acylation of Indoles
he indole ring is a significant scaffold which plays an
Textensive role in pharmaceutical and biologically active
molecules.1 The introduction of carbonyl at the C3−H
position of the indole is one of the most important paths for
derivatization of this valuable structural skeleton. However,
traditional methods for this transformation (e.g., Vilsmeier−
Haack reaction2 for formylation and Friedel−Crafts reaction3
for acylation) require harsh conditions with low selectivity and
poor functional-group tolerance.4 To overcome these
adversities, a variety of reagents were developed as carbonyl
sources for acylation of the indoles, including aryl formates,5
nitriles,6 α-oxocarboxylic acids,7 amines,8 CO,9 etc. (Scheme
1a). Despite significant advances, these methods use special
carbonyl sources and always require transition metals under
harsh reaction conditions, which limit the scope of these
methods. Aldehydes are the desired atom-economic carbonyl
source for direct C3-acylation of the indoles due to their
widespread availability and cheap price (most of them are
commercially available). However, only a few precedents have
so far been reported utilizing aldehydes for acylation of
indoles.10,11 Therefore, a milder and more versatile way to
activate these aldehydes for the C3-acylation of the indoles
would be highly desirable.
reaction is a well-known method for the preparation of
aminomethylated compounds and has been widely investigated
in synthetic (especially asymmetric) fields.18 Meanwhile, the
electrochemical oxidation of N-containing molecules to
iminium ions, known as Shono-type oxidation, is widely
applied in the synthesis of α-functionalized amines.19 We
considered that if the C−N bond of the in situ Mannich
Utilizing electrochemistry to reshape the traditional organic
reaction has been deemed an attractive way to perfect the field
of organic synthesis.12 Several well-known reactions, such as
Buchwald−Hartwig−Ullmann,13 Sandmeyer,14 Scholl,15 New-
man−Kwart,16 and Birch17 reactions, have each been modified
into a corresponding electrochemical version. Inspired by these
works, we conceived that a cascade process that combines
traditional reactions with electrochemistry could be a way to
exploit a new transformation (Scheme 1b). The Mannich-type
Received: July 13, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02433
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
product intermediate can be oxidized to the iminium ion under
electrochemical conditions, then it should be possible to
achieve direct C3-acylation of the indoles with aldehydes
under mild conditions.
Table 1. Optimization of Reaction Conditions
Our strategy was based on a two-step transformation in a
one-pot reaction, which consisted of (1) a aminomethyl
introduction with a C−N bond formation through three-
component Mannich-type reactions, where the aldehyde,
amine, and indole produce the Mannich product, and (2)
the C−N bond cleavage through electrochemical oxidation of
Mannich products to corresponding iminium ions followed by
a quick hydrolysis to give the final C3-carbonyl indole
products. In this method, the Mannich reaction could be
deemed as an activation process of aldehyde, in which the
amine was an activating group that would be removed by the
C−N bond cleavage. Different from the diversity of outcomes
of the C−N bond formation reaction,12j,20 the cleavage of the
C−N bond was always limited to a transition-metal-catalyzed
process for inert reactivity of unactivated N-containing
compounds. This was due to the high C−N bond dissociation
energy.21 In this report, we reveal that the electrochemical
oxidation is a more robust but milder method for C−N bond
cleavage as well as CO bond introduction in the acylation of
the indoles by using aldehydes as carbonyl sources (Scheme
1c). To the best of our knowledge, our work represents the
first example of electrochemical oxidation to induce C−N
bond cleavage and CO bond introduction in a synthetically
useful fashion.12
b
entry
variations of condition
yield (%)
1
2
3
4
5
6
7
8
9
none
60 °C
Ecell = 1.8 V
Ecell = 2.2 V
72
53
33
62
76
95 (91)
95
62
0.6 equiv of 4-Cl-aniline
0.8 equiv of 4-Cl-aniline
1.0 equiv of 4-Cl-aniline
entry 6 but no PhCO2Na
entry 6 but no 4-chloroaniline, HCHO, H2O or
electricity
c
d
N.D.
10
entry 6 but under N2
88
a
Reaction conditions: 1a (0.3 mmol), 2a (30 wt % in water, 0.36
mmol), PhCO2Na (0.6 mmol), LiClO4 (0.6 mmol), and 4-Cl-aniline
(0.5 equiv), in solvent (6 mL), undivided cell, RVC anode (1.0 cm ×
1.0 cm × 0.6 cm) and Pt cathode (1.0 cm × 1.0 cm), under air, room
temperature, 20 h. GC yield, Standard condition, 2.6 F, isolated
yield in parentheses. Paraformaldehyde instead of formaldehyde (30
wt % in water) and anhydrous acetonitrile as solvent. N.D. = not
detected. RVC = reticulated vitreous carbon.
b
c
d
a b
,
Scheme 2. Scope of Indoles
The first step in our work was selecting an appropriate
amine. Here, we mainly considered two factors. First,
compared with aniline, the aliphatic amine containing α-H
would result in two different directions of C−N bond cleavage.
Second, the primary amine, which has a small steric hindrance,
would benefit imine formation. Therefore, the primary aniline
was chosen to be the aldehyde-activating reagent for the direct
C3-formylation of indoles with formaldehyde as a carbonyl
source. To our delight, after an initial screening of aniline,
additives, and solvents (for more details, see Supporting
Information (SI)), the expected product 3a was obtained in
72% yield with the following conditions: N-methylindole (1a,
1 equiv), 37% aqueous HCHO (2a, 1.2 equiv), 4-Cl-aniline
(0.5 equiv), sodium benzoate (2 equiv), LiClO4 (electrolyte,
0.1 M), and solvent (6.0 mL, MeCN/H2O, 1:1), under air in
an undivided cell, at a constant cell voltage (Ecell) of 2.0 V.
Further optimizations were listed in Table 1. Elevated
temperature and higher or lower cell voltages showed negative
effects for the reaction (entries 2−4). When the amount of 4-
Cl-aniline was increased to 0.8 equiv, product 3a could be
obtained in 91% isolated yield while 1.0 equiv of 4-Cl-aniline
could give similar results, though uneconomical (entries 5−7).
The use of sodium benzoate proved critical for achieving high
yields, as only 62% of 3a was obtained in its absence (entry 8).
Control experiments suggested that aniline, H2O, HCHO, and
electricity were also essential for this reaction (entry 9). The
reaction still proceeded well under nitrogen, indicating the
oxidant O2 was not necessary for this protocol (entry 10). To
the best of our knowledge, the present work provides the first
example of C3 formylation of indole under entirely oxidant-
free conditions.
a
Reaction conditions: 1 (0.3 mmol), 2a (30 wt % in water, 0.36
mmol), PhCO2Na (0.6 mmol), LiClO4 (0.6 mmol) and 4-Cl-aniline
(0.8 equiv), in solvent (6 mL), undivided cell, RVC anode (1.0 cm ×
1.0 cm× 0.6 cm) and Ni cathode (1.0 cm × 1.0 cm), under air, room
b
temperature. Isolated yield.
With the optimized conditions in hand, the scope of the
reaction was extended (Scheme 2). First, the effect of methyl
substitution at different positions of N-methylindole was
investigated. The results showed that substitution at C-4, -5,
-6, and -7 positions (3b−e) afford slightly lower yields than
standard substrate N-methylindole 1a. When it came to 2-
methyl-N-methylindole 3f, only traces of product were
observed, which could be ascribed to its electron-richness
B
DOI: 10.1021/acs.orglett.9b02433
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Organic Letters
Letter
making it unstable under electrochemical conditions.8g,h,11a
Regardless, C3-formylated 2-pheny-N-methlylindole 3g was
still obtained with yields of 70%.
without PhCO2Na, suggesting that PhCO2Na was crucial for
the formation of the Mannich product 4a (Scheme 3b). We
found that a high yield of 3a was obtained with 52% recovery
of 4-Cl-aniline when the Mannich product 4a was directly
subjected to electrolysis in the presence of H2O (Scheme 3c).
Moreover, the CV of 4a contains two oxidation peaks
representing two-electron oxidation of 4a to corresponding
iminium ions, respectively (for more details, see SI, Figure S2).
All of these results suggested that the Mannich product 4a was
the key intermediate in the reaction.
Next, to estimate the functional group tolerance of this
protocol, N-methylindoles, with various functional groups at
the phenyl skeleton, were subjected to standard reaction
conditions. To our delight, N-methylindole with halide (F, Cl,
Br), methoxy, and phenoxy groups at the C-5 position were all
well tolerated, affording formylation products in high yields
(3h−l). The electron-withdrawing group ester (42%, 3m) at
the C-6 position obviously gave a lower yield due to its lower
nucleophilicity at the C-3 position. The substituted groups on
the nitrogen of the indole were also studied. Good yields were
obtained for the substrates with different substituted groups on
the indole nitrogen, such as 2-hydroxyethyl (3n), allyl (3o),
cyclopropylmethyl (3p), and benzyl (3q) groups. Notably, the
1H-indole reacted smoothly under standard conditions,
affording the formylation product 3r in 61% yield. Never-
theless, when the NH of the indole was protected by a strong
electron-withdrawing group, such as N-Boc or N-Ts, only
traces of the desired product were obtained. Particularly, the
heteroaryl indoles, such as 7-aza-N-methylindole, provided the
desired product 3s in moderate yield. We then examined
whether C-2 formylation occurred when the C-3 position of N-
methylindole was blocked by a methyl group; however,
complicated products were formed under the standard reaction
conditions.
On the basis of the above experimental results, a plausible
mechanism is proposed in Scheme 4. The dehydration reaction
Scheme 4. Possible Mechanism
To gain insights into the nature of this strategy, additional
control experiments were carried out. First, radical processes
were excluded according to similar results that were obtained
when adding 4.0 equiv of (2,2,6,6-tetramethylpiperidin-1-yl)
oxyl (TEMPO) under standard conditions (Scheme 3a).
between 4-Cl-aniline and formaldehyde leads to the formation
of corresponding imine.23 The in situ generated imine quickly
reacts with the indole via a well-known Mannich-type reaction
to give the intermediate 4a. Then, electrochemical, two-
electron oxidation accompanied with deprotonation of 4a
produces iminium 4a′, which undergoes hydrolysis to give the
desired product 3a. Meanwhile, the 4-Cl-aniline is recovered.
To further evaluate the potential of this strategy, we try to
apply it to the acylation of the indoles with a variety of
aromatic aldehydes. In this method, 4-chloroaniline was
ineffective due to its low activity in the Mannich-type reaction
with aromatic aldehyde. Herein, a catalyst-free Mannich-type
reaction using 2-aminopyrimidine as the amine under an
elevated temperature reported by Olyaei et al. was carried out
for the first step.24 However, direct electrolysis of the Mannich
products that were generated in step 1 failed to produce
acylated products. To our delight, the introduction of the
catalytic amount DDQ, which is usually used for dehydrogen-
ation,25 dramatically affected the reaction and gave satisfactory
outcomes (for more details, see SI, Table S6). As shown in
Scheme 5, this method exhibited high functional-group
tolerance. Various aromatic aldehydes with different functional
groups smoothly converted to the corresponding acylated
products in moderate to high yields (39−89%, 6b−w). To our
surprise, substrates bearing easily oxidizable OH and SMe
groups were successfully subjected to the reaction, giving
acylated products 6n and 6p in good yields. The reaction of
Bpin substituted benzaldehyde (6q) gave a slightly decreased
yield. Except from benzene rings, a naphthalene nucleus (6r
and 6s), electron-deficient pyridine (6t), and dihydrobenzo-
furan (6u) were also compatible in the reaction (43−89%
yields). The utility of this mild catalytic strategy was also
demonstrated by its successful application in late-stage
functionalization of complex molecules for indole introduction
Scheme 3. Mechanistic Studies
Under standard conditions, 29% of 4-Cl-aniline was recovered,
while 55% was recovered with the addition of TEMPO,
indicating that aniline could be recycled in this strategy.
However, we failed to obtain satisfying results when using a
catalytic amount of aniline under standard conditions, which
might be due to the fact that aniline can be easily transformed
to the corresponding aniline radical and further oxidized to
undesired side products during the electrochemical process.22
The Mannich-type reaction proceeded smoothly to produce
4a with a 54% yield in 10 min in the presence of 2 equiv of
PhCO2Na, while only byproduct 5 was obtained in 86% yield
C
DOI: 10.1021/acs.orglett.9b02433
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Organic Letters
Letter
a b
,
Scheme 5. Scope of Aromatic Aldehydes
Scheme 6. Gram-Scale Experiment
successfully applied in an indole C−H/aldehyde C(O)H cross-
coupling reaction via an imine activation phase. High
functional-group tolerance of the strategy ensures its practical
viability in late-stage functionalization of pharmaceutical
molecules. Furthermore, the reaction was insensitive to air/
H2O and could be scaled up to gram scale. Further studies on
synthetic application of this method are ongoing in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02433.
Experimental procedures, supplementary mechanistic
studies, and compound characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kzheng@scu.edu.cn.
ORCID
Ke Zheng: 0000-0002-3345-7715
Notes
a
Reaction conditions: (1) 1a (0.3 mmol), 2b (0.36 mmol), 2-
Aminopyrimidine (0.36 mmol), DMSO: 50 μL, 80 °C; (2) LiClO4
(0.6 mmol) and DDQ (20 mol %), in solvent (6 mL), undivided cell,
RVC anode (1.0 cm × 1.0 cm× 0.6 cm) and Ni cathode (1.0 cm × 1.0
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
b
c
cm), under air, room temperature. Isolated yield. Workup with 1 M
HCl for hydrolysis. DDQ = 2,3-dichloro-5,6-dicyanop-benzoquinone.
We thank the National Natural Science Foundation of China
(No. 21602142) and the Fundamental Research Funds for the
Central Universities. We thank the Xiaoming Feng laboratory
(SCU) for access to equipment. We also thank the
comprehensive training platform of the Specialized Laboratory
in the College of Chemistry at Sichuan University for
compound testing.
d
(+)RVC/(−)Ni, Ecell = 2.5 V, 4-CF3-aniline (1.0 equiv), TEMPO
(20 mol %) MeCN/H2O (100:1), LiClO4 (0.1M), rt, 12 h.
(6v from cholesterol derivative, 31% yield; and 6w from
probenecid derivative, 41% yield). Besides, ethyl glyoxalate was
also suitable for this strategy when the reaction conditions
were slightly adjusted, demonstrating the viability of C3-
acylation of the indoles with activated aldehydes in electro-
chemical conditions. Moreover, the product 6x was a raw
material for the synthesis of GSK-3β inhibitors against bipolar
disorders.26
To further demonstrate the synthetic utility of this strategy,
the reaction was conducted on a gram scale under optimal
conditions, which successfully furnished the desired product 3a
in 71% yield and 6f in 64% yield under a higher voltage,
respectively (2.5 V, Scheme 6a and 6b).
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