Tunable Electrosynthesis of Anthranilic Acid Derivatives via a C-C Bond Cleavage of Isatins

Article abstract of DOI:10.1021/acs.joc.1c01017

A facile and direct electrocatalytic C-C bond cleavage/functionalization reaction of isatins was developed. With isatins as the amino-attached C1 sources, a variety of aminobenzoates, and aminobenzamides were synthesized in moderate to good yields under mild conditions.

Full text of DOI:10.1021/acs.joc.1c01017

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Article
Tunable Electrosynthesis of Anthranilic Acid Derivatives via a C−C
Bond Cleavage of Isatins
Peng Qian, Jiaojiao Liu, Yan Zhang, and Zhiyong Wang*
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ABSTRACT: A facile and direct electrocatalytic C−C bond
cleavage/functionalization reaction of isatins was developed. With
isatins as the amino-attached C1 sources, a variety of amino-
benzoates, and aminobenzamides were synthesized in moderate to
good yields under mild conditions.
combination of electrochemistry and photocatalysis (Scheme
1e).12 Inspired by these results and our interest in electro-
chemical synthesis,15 we herein report an electrochemical
approach for the oxidative ring-opening of isatins to synthesize
anthranilic acid derivatives under metal-free and chemical
oxidant-free conditions (Scheme 1f). Furthermore, the
products can be modulated easily through varying electrolytic
conditions.
INTRODUCTION
■
The carbon−carbon bond constitutes the core part of the basic
skeleton of organic molecules, and its cleavage/functionaliza-
tion is an important way to modify the skeleton of organic
molecules. Consequently, continuous efforts have been made
to the development of novel strategies for selective C−C bond
cleavage under mild conditions.1,2 Isatin represents a class of
important and privileged structures, containing a ketone and
lactam group. Because of its unique structure and ready
availability, various transformations have been well established
on the basis of the ketone and lactam group in isatin.3 In
contrast, the reactions of isatins involving the cleavage/
functionalization of the C−C bond is less explored.4 Moreover,
the known methods for the C−C bond transformation of
isatins usually suffered from transition metal catalysts, chemical
oxidants, and high temperature. Hence, developing greener
and milder approaches for the selective C−C bond cleavage of
isatins remains desirable.
Electrochemical synthesis is recognized as a sustainable and
elegant technique with electrons as the reaction reagents.5,6 It
provides a green alternative approach for C−C bond cleavage/
functionalization.7−14 For instance, in 2017, Zeng reported the
acylation of electron-deficient N-heteroarenes via the scission
of α-keto acids under electrochemical conditions (Scheme
1a).7 In 2019, Huang achieved the N-formylation of indole via
an electrochemical decarboxylation of glyoxylic acid (Scheme
1b).9 Lam developed a green method for the synthesis of γ-
substituted butyrolactones from hemioxalate ammonium salts
and aliphatic acids via an anodic generation of oxycarbonyl
radicals (Scheme 1c).10 In 2020, Lei reported the synthesis of
1,2-diaryl ethers through an electrochemical oxidative decar-
boxylation and 1,2-aryl migration of 3,3-diarylpropionic acids
(Scheme 1d).11 Recently, Xu realized an efficient C−H
alkylation and a carbamoylation of N-heteroarenes with the
RESULTS AND DISCUSSION
■
Initially, we chose the electrolysis of isatin (1a) in methanol as
the model reaction. The model reaction proceeded smoothly at
a constant current of 15 mA to give the desired product 2a in
60% yield when n-Bu4NClO4 was employed as a supporting
electrolyte and K2CO3 as a base (entry 1, Table 1). When
other supporting electrolytes were employed, such as n-
Bu4NPF6 and n-Bu4NBF4, the reactions gave inferior results
(entries 2 and 3). After the reaction, we found that the surface
of the anode was coated with a black material for all supporting
electrolytes. To solve this issue, the mixed solvents were
screened (entries 4−6), and the combination of MeOH and
CH3CN (5/1 v/v) could increase the yield from 60% to 84%
without the formation of a black coating (entry 4). Further
decreasing or increasing the values of current gave 2a in lower
yields (entries 7−9). Next, various bases were examined.
Replacing K2CO3 with Cs2CO3, K3PO4, and NaOMe afforded
the desired product with lower yields (entries 10−12).
Special Issue: Electrochemistry in Synthetic Organic
Chemistry
Received: April 30, 2021
https://doi.org/10.1021/acs.joc.1c01017
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© XXXX American Chemical Society
A

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a
Scheme 1. Representive Electrochemical C−C Cleavage
Reactions
Table 1. Optimization of the Reaction Conditions
b
yield
entry
electrolyte
solvent
base
I (mA)
(%)
1
2
3
4
n-Bu4NClO4 MeOH
K2CO3
K2CO3
K2CO3
K2CO3
15
15
15
15
60
40
44
84
n-Bu4NPF6
n-Bu4NBF4
MeOH
MeOH
n-Bu4NClO4 MeOH/CH3CN
(5/1)
5
6
n-Bu4NClO4 MeOH/H2O
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
NaOMe
K2CO3
K2CO3
K2CO3
K2CO3
15
15
10
20
25
15
15
15
15
15
15
0
44
64
65
79
44
60
62
44
55
45
77
n.d.
(5/1)
n-Bu4NClO4 MeOH/THF
(5/1)
7
n-Bu4NClO4 MeOH/CH3CN
(5/1)
8
n-Bu4NClO4 MeOH/CH3CN
(5/1)
9
n-Bu4NClO4 MeOH/CH3CN
(5/1)
10
11
12
n-Bu4NClO4 MeOH/CH3CN
(5/1)
n-Bu4NClO4 MeOH/CH3CN
(5/1)
n-Bu4NClO4 MeOH/CH3CN
(5/1)
c
13
n-Bu4NClO4 MeOH/CH3CN
(5/1)
d
14
n-Bu4NClO4 MeOH/CH3CN
(5/1)
e
15
n-Bu4NClO4 MeOH/CH3CN
(5/1)
16
n-Bu4NClO4 MeOH/CH3CN
(5/1)
a
Reaction conditions: 1a (0.3 mmol), electrolyte (0.3 mmol), base
Afterward, the electrode was optimized. When the platinum
anode or cathode was replaced with a carbon rod electrode, the
reaction yield was decreased obviously (entries 13 and 14). On
the other hand, the inert gas shielding disfavored this reaction.
For instance, the desired product 2a can be obtained in 77%
yield when the reaction was performed under a nitrogen
atmosphere (entry 15). More importantly, no desired product
was observed when the reaction proceeded without electrolysis
under the standard conditions. This result indicated that the
reaction should be initiated by electricity, and the passage of
electricity was necessary for the reaction (entry 16).
After establishing the optimal electrolytic conditions, we
investigated the substrate scope for the synthesis of 2-
aminobenzoates (Scheme 2). To our delight, substrates 1
with various substituents on the aryl ring can proceed the
reaction smoothly to give the corresponding 2-aminobenzoates
in 44−84% yields. In general, the indoline-2,3-dione with
substituents on the position 5 gave superior results to the
positions 6 and 7 (2e vs 2f and 2j). It was found that the
electronic properties of the substituents on the aryl ring had a
great influence on the reaction. For instance, the weak
electron-donating (Me, 1b) and electron-withdrawing (F, Cl,
1d and 1e) substituents caused a slight erosion in the yields
(2b, 2d, and 2e). Even worse, the strong electron-donating
(OMe, 1c) and electron-withdrawing (NO2, 1g) substituents
led to a sharp decrease in the yields (2c and 2g). Similarly, the
steric effect of substituents on the aryl ring had a great
influence on the reaction. For example, the indoline-2,3-dione
with substituents on the position 5 gave superior results to the
(0.3 mmol), solvent (3 mL), Pt/Pt (1.0 × 1.0 cm2). The electrolysis
was conducted in an undivided cell at room temperature. Yields of
the isolated products. Graphite was employed as anode. Graphite
was employed as cathode. N2 atmosphere.
b
c
d
e
position 7 (2b vs 2h, 2d vs 2i, and 2e vs 2j). As for the solvent
effect, an obvious influence was observed. When MeOH was
replaced with EtOH, the reaction can also be carried out
smoothly to afford the corresponding product with 44% yield,
perhaps due to the lower electrical conductivity and
nucleophilicity of ethanol.
It was noteworthy that a trace amount of methyl 2-
methoxycarbonylbenzamide 3a was detected during the
synthesis of methyl 2-aminobenzoate 2a. This meant that the
distribution of the electrolyzed products was perhaps
modulated. To increase the yield of 3a, an indirect electrolysis
strategy was adopted by using n-Bu4NI as the mediator at a
constant current of 5 mA in the presence of 2 equiv of K2CO3.
Under this modified reaction condition, the desired product 3a
could be obtained in 64% yield. Then, the substrate scope of
isatins 1 was investigated, and the results are listed in Scheme
3. A variety of methyl 2-methoxycarbonylbenzamides 3 can be
obtained despite the relatively lower yields (3a−3h). For
instance, when 5-methylindoline-2,3-dione and 7-methylindo-
line-2,3-dione were used as the substrates, the reaction
proceeded smoothly to give the corresponding products in
57% and 42% yields, respectively (3b and 3g). The lower yield
B
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a b
,
Scheme 2. Synthesis of 2-Aminobenzoates
Scheme 3. Synthesis of Methyl 2-
a b
,
((Methoxycarbonyl)amino)benzoates
a
a
Reaction conditions: 1 (0.3 mmol), n-Bu4NI (0.3 mmol), K2CO3
(0.6 mmol), R1OH/CH3CN (2.5/0.5 mL), Pt/Pt (1.0 × 1.0 cm2).
The electrolysis was conducted in an undivided cell at room
Reaction conditions: 1 (0.3 mmol), n-Bu4NClO4 (0.3 mmol),
K2CO3 (0.3 mmol), R1OH/CH3CN (2.5/0.5 mL), Pt/Pt (1.0 × 1.0
cm2). The electrolysis was conducted in an undivided cell at room
b
b
temperature for 3 h (I = 5 mA). The isolated yields.
temperature for 1 h (I = 15 mA). The isolated yields.
a b
,
Scheme 4. Synthesis of 2-Aminobenzamides
of product 3 was perhaps attributed to the retention of 2-
aminobenzoates 2.
Considering the importance of 2-aminobenzamide deriva-
tives, we also turned our attention to the synthesis of 2-
aminobenzamides 4 via an electrocatalytic C−C cleavage of
isatins. After extensive experiments, the optimal electrolytic
reaction conditions were identified as follows: electrolyzing
isatins 1 at room temperature with the electrolyte solution of
n-Bu4NClO4 in a mixed solvent of MeOH (7 M NH3)/
CH3CN (1/5 v/v), two platinum plates being as anode and
cathode at a constant current of 5 mA. Under this condition,
the desired product 4a can be obtained with a yield of 66%.
Subsequently, the other typical isatins were examined in the
reaction to give 2-aminobenzamide derivatives with moderate
yields (Scheme 4). It should be mentioned that the side
products of methyl 2-aminobenzoates 2 were also observed,
which resulted in the lower yields of product 4.
Subsequently, a gram scale synthesis of methyl 2-amino-
benzoate 2a experiment was conducted to demonstrate the
synthetic practicality of this electrocatalytic C−C cleavage
approach. The direct electrolysis of isatin 1a proceeded
smoothly to give the desired product 2a in 66% yield without
significantly decreasing the efficiency (Scheme 5). The
generated amino group of 2a can be further converted into
methyl 2-benzamidobenzoates 5. In addition, the product 2a
can react with trimethyl orthoformate and aniline in the
presence of NH4Cl to produce 3-phenylquinazolin-4(3H)-one
6 with a moderate yield. These diverse transformations
highlighted the synthetic value of electrogenerated amino-
bearing methyl benzoates.
a
Reaction conditions: 1 (0.3 mmol), n-Bu4NClO4 (0.3 mmol), 7 M
NH3 in CH3OH (0.5 mL), CH3CN (2.5 mL), Pt/Pt (1.0 × 1.0 cm2).
The electrolysis was conducted in an undivided cell at room
b
temperature for 5 h (I = 5 mA). The isolated yields.
In order to understand the reaction mechanism clearly, some
control experiments were carried out (Scheme 6). Initially,
only a trace amount of the desired product 2a was observed
when the reaction was conducted in the absence of K2CO3
C
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Scheme 5. Gram-Scale Synthesis and Product
Transformations
a
Reaction conditions: 2a (1.0 mmol), PhCOCl (1.0 mmol), DMAC
b
(1 mL), air, 0 °C−RT. Reaction conditions: 2a (1.0 mmol),
HC(OMe)3 (1.0 mmol), PhNH2 (1.0 mmol), NH4Cl (0.4 mmol), air,
100 °C.
Figure 1. Cyclic voltammograms in 0.1 M n-Bu4NClO4 in different
solvents using a Pt plate as the working electrode, and Pt wire and
Ag/AgCl as the counter and reference electrodes, respectively, at a
scan rate of 100 mV/s: (a) 1a (5 mM) + MeOH/CH3CN (5/1 v/v),
(b) 1a (5 mM) + NaOMe (5 mM) + MeOH/CH3CN (5/1 v/v), (c)
2a (5 mM) + MeOH, (d) 2a (5 mM) + MeOH/CH3CN (5/1 v/v).
Scheme 6. Control Experiments
voltammogram of 1a in the presence of NaOMe was measured,
two oxidation waves were observed. One was at ∼0. 55 V vs
Ag/AgCl; the other was at ∼0. 85 V vs Ag/AgCl (curve b).
Moreover, the product 2a exhibited an oxidation wave at ∼0.
57 V vs Ag/AgCl in MeOH (curve c). When the mixed solvent
of MeOH and CH3CN was employed instead of the single
solvent MeOH, the oxidation peak of product 2a was shifted
from 0.57 to 0.62 V vs Ag/AgCl (curve d). These results
implied that the co-solvent disfavored the oxidation of product
2a, reducing the generation of the side products. Besides, the
slight difference of oxidation potential of la in the presence of a
base and 2a made it possible for the direct synthesis of
anthranilic acid derivatives.
On the basis of these experiments and previous reports,4a,15f
a possible reaction mechanism was proposed, as shown in
Scheme 7. Initially, MeOH is reduced to the methoxide anion
accompanied with the liberation of hydrogen gas on the
cathode surface. Then, the electrogenerated methoxide anion
can react with 1a to afford intermediate A, which is further
converted into intermediate B with the assistance of K2CO3.
Subsequently, the intermediate B can be further sequentially
oxidized to give the final product 2a on the anode surface (see
the top of Scheme 7). In the case of the formation of 3a,
substrate 1a reacts with the molecular iodine generated in situ
to give intermediate A′. The intermediate A′ can further react
with the electrogenerated methoxide anion to produce
intermediate B′. Subsequently, the reaction between inter-
mediate B′ and methoxide anion occurs to give the desired
product 3a (see the bottom of Scheme 7).
In conclusion, we developed a tunable electrochemical
synthesis of anthranilic acid derivatives from readily available
isatins. This electrocatalytic reaction proceeded smoothly at
room temperature, avoiding the usage of external chemical
oxidants and transition metal catalysts. Furthermore, the
distribution of the electrolyzed products can be modulated
easily.
(Scheme 6a). Then, when N-methyl isatin (1l) was employed
to replace isatin under standard conditions, the corresponding
product 2l was obtained in 20% yield (Scheme 6b). These
experimental results indicated that both K2CO3 and free N-H
of the isatin were important for this efficient transformation.
Subsequently, sodium 2-(2-aminophenyl)-2-oxoacetate (1′)
was electrolyzed under the standard conditions. It was found
that a trace amount of the desired product 2a was detected
(Scheme 6c). This result implied that 2-(2-aminophenyl)-2-
oxoacetate (1′) was not an intermediate for this trans-
formation. Moreover, the process of the formation of product
3 was also investigated. When molecular iodine was employed
as an oxidant in the absence of the electricity under the
standard conditions, the reaction gave product 3a in 55% yield
(Scheme 6d). This result indicated that molecular iodine was
likely to be an active species for the formation of 3.
Next, we performed some cyclic voltammetric (CV)
experiments to further investigate the reaction process. As
shown in curve a of Figure 1, no obvious oxidation wave was
found for isatin 1a from 0 to 1 V vs Ag/AgCl. When the
D
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counter electrode. In the electrolytic cell, a mixture of isatins 1 (0.3
mmol, 1.0 equiv), n-Bu4NClO4 (0.3 mmol, 1.0 equiv, 102.6 mg), 7 M
NH3 in CH3OH (0.5 mL), and CH3CN (2.5 mL) was allowed to stir
and electrolyze at constant current conditions (5 mA) at room
temperature (5 h). Then the solvent was removed with a rotary
evaporator and the residue was purified by column chromatography
on silica gel to afford the desired product 4. The product was dried
under high vacuum for at least 0.5 h before it was weighed and
characterized by NMR spectroscopy.
Scheme 7. Proposed Reaction Mechanism
Gram-Scale Synthesis of 2a. An undivided cell was equipped
with a magnetic stirrer and two platinum plates (1.0 × 1.0 cm2)
electrodes as the working electrode and counter electrode. In the
electrolytic cell, a mixture of isatin 1a (6 mmol, 1.0 equiv, 883 mg), n-
Bu4NClO4 (6 mmol, 1.0 equiv, 2052 mg), K2CO3 (6 mmol, 1.0 equiv,
829 mg), and MeOH/CH3CN (50/10 mL) was allowed to stir and
electrolyze at constant current conditions (15 mA) at room
temperature (about 20 h). Then the solvent was removed with a
rotary evaporator and the residue was purified by column
chromatography on silica gel to afford the desired product 2a (598
mg, 66% yield).
Synthesis of Methyl 2-Benzamidobenzoate (5). The com-
pound 5 was prepared according to the literature procedure17 and
purified by column chromatography (petroleum ether/ethyl acetate =
1
10:1) to give the product as a white solid: 88% yield, (225 mg); H
NMR (CDCl3, 400 MHz, ppm): δ = 12.1 (br, 1H), 8.95 (d, J = 8.4
Hz, 1H), 8.11−8.06 (m, 3H), 7.64−7.52 (m, 4H), 7.14 (t, J = 7.6 Hz,
1H), 3.98 (s, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ = 169.1,
165.7, 141.8, 134.8, 131.9, 130.9, 128.8, 127.3, 122.6, 120.4, 115.1,
52.5.17
Synthesis of 3-Phenylquinazolin-4(3H)-one (6). The com-
pound 6 was prepared according to the literature procedure18 and
purified by column chromatography (petroleum ether/ethyl acetate =
EXPERIMENTAL SECTION
■
1
General Information. All products were characterized by 1H
NMR and 13C NMR, using TMS as an internal reference (1H NMR:
400 MHz, 13C NMR: 100 MHz). HRMS (ESI) data were recorded
on a Q-TOF Premier. Flash column chromatography was performed
using silica gel (200−300 mesh). The CV experiments were
performed in a three-electrode cell equipped with a Pt plate (1.0 ×
1.0 cm2) as the working electrode, and Pt wire and Ag/AgCl (KCl
(sat)) as the counter and reference electrodes, respectively, at a scan
rate of 100 mV/s. All the compounds 1 were purchased from
commercial supplies and used without purification. Substrate 1′ was
synthesized according to the previous literature procedure.16
3:1) to give the product as a white solid: 62% yield, (138 mg); H
NMR (CDCl3, 400 MHz, ppm): δ = 8.38 (d, J = 8.0 Hz, 1H), 8.14 (s,
1H), 7.84−7.77 (m, 2H), 7.58−7.49 (m, 4H), 7.44 (d, J = 7.6 Hz,
2H); 13C NMR (CDCl3, 100 MHz, ppm): δ = 160.7, 147.8, 146.1,
137.4, 134.6, 129.6, 129.1, 127.6, 127.6, 127.2, 127.0, 122.3.18
Methyl 2-Aminobenzoate (2a).4e The title compound was
prepared according to the general working procedure A and purified
by column chromatography (petroleum ether/ethyl acetate = 10:1) to
1
give the product as a light yellow oil: 84% yield, (38 mg); H NMR
(CDCl3, 400 MHz, ppm): δ = 7.88 (d, J = 8.0 Hz, 1H), 7.29 (t, J =
8.4 Hz, 1H), 6.69−6.65 (m, 2H), 5.74 (br, 2H), 3.89 (s, 3H); 13C
NMR (CDCl3, 100 MHz, ppm): δ = 168.6, 150.4, 134.1, 131.2, 116.6,
116.2, 110.7, 51.5.
Representative Procedure for the Synthesis of 2 (A). An
undivided cell was equipped with a magnetic stirrer and two platinum
plates (1.0 × 1.0 cm2) electrodes as the working electrode and
counter electrode. In the electrolytic cell, a mixture of isatins 1 (0.3
mmol, 1.0 equiv), n-Bu4NClO4 (0.3 mmol, 1.0 equiv, 102.6 mg),
K2CO3 (0.3 mmol, 1.0 equiv, 41.5 mg), and R1OH/CH3CN (2.5/0.5
mL) was allowed to stir and electrolyze at constant current conditions
(15 mA) at room temperature (1 h). Then the solvent was removed
with a rotary evaporator and the residue was purified by column
chromatography on silica gel to afford the desired product 2. The
product was dried under high vacuum for at least 0.5 h before it was
weighed and characterized by NMR spectroscopy.
Representative Procedure for the Synthesis of 3 (B). An
undivided cell was equipped with a magnetic stirrer and two platinum
plates (1.0 × 1.0 cm2) electrodes as the working electrode and
counter electrode. In the electrolytic cell, a mixture of isatins 1 (0.3
mmol, 1.0 equiv), n-Bu4NI (0.3 mmol, 1.0 equiv, 110.8 mg), K2CO3
(0.6 mmol, 2.0 equiv 83.0 mg), and R1OH/CH3CN (2.5/0.5 mL)
was allowed to stir and electrolyze at constant current conditions (5
mA) at room temperature (3 h). Then the solvent was removed with
a rotary evaporator and the residue was purified by column
chromatography on silica gel to afford the desired product 3. The
product was dried under high vacuum for at least 0.5 h before it was
weighed and characterized by NMR spectroscopy.
Methyl 2-Amino-5-methylbenzoate (2b).4e The title compound
was prepared according to the general working procedure A and
purified by column chromatography (petroleum ether/ethyl acetate =
10:1) to give the product as a light yellow oil: 71% yield, (35 mg); 1H
NMR (CDCl3, 400 MHz, ppm): δ = 7.67 (s, 1H), 7.12−7.09 (m,
2H), 6.60 (d, J = 8.4 Hz, 1H), 5.56 (br, 2H), 3.87 (s, 3H), 2.24 (s,
3H); 13C NMR (CDCl3, 100 MHz, ppm): δ = 168.7, 148.4, 135.3,
130.9, 125.5, 116.9, 110.8, 51.6, 20.4.
Methyl 2-Amino-4-methoxybenzoate (2c).19 The title compound
was prepared according to the general working procedure A and
purified by column chromatography (petroleum ether/ethyl acetate =
1
10:1) to give the product as a white solid: 46% yield, (25 mg); H
NMR (CDCl3, 400 MHz, ppm): δ = 7.79 (d, J = 8.8 Hz, 1H), 6.24
(dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 6.12−6.11 (m, 1H), 5.78 (br, 2H),
3.84 (s, 3H), 3.79 (s, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ =
168.3, 164.2, 152.4, 133.0, 104.5, 104.4, 99.3, 55.1, 51.2.
Methyl 2-Amino-5-fluorobenzoate (2d).4e The title compound
was prepared according to the general working procedure A and
purified by column chromatography (petroleum ether/ethyl acetate =
10:1) to give the product as a light yellow oil: 69% yield, (35 mg); 1H
NMR (CDCl3, 400 MHz, ppm): δ = 7.54 (dd, J = 9.6 Hz, J = 2.8 Hz,
1H), 7.06−7.02 (m, 1H), 6.64−6.61 (m, 1H), 5.59 (br, 2H), 3.88 (s,
3H); 13C NMR (CDCl3, 100 MHz, ppm): δ = 167.7, 153.9 (d, J =
233.1 Hz), 146.9, 122.0 (d, J = 23.3 Hz), 117.8 (d, J = 7.1 Hz), 116.1
(d, J = 23.2 Hz), 110.6 (d, J = 6.7 Hz), 51.8.
Representative Procedure for the Synthesis of 4 (C). An
undivided cell was equipped with a magnetic stirrer and two platinum
plates (1.0 × 1.0 cm2) electrodes as the working electrode and
E
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Methyl 2-Amino-5-chlorobenzoate (2e).4e The title compound
was prepared according to the general working procedure A and
purified by column chromatography (petroleum ether/ethyl acetate =
yield, (38 mg); H NMR (CDCl3, 400 MHz, ppm): δ = 10.4 (br,
1H), 8.31 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.36−7.34 (m, 1H), 3.91
(s, 3H), 3.78 (s, 3H), 2.32 (s, 3H); 13C NMR (CDCl3, 100 MHz,
ppm): δ = 168.5, 154.1, 139.3, 135.3, 130.9, 130.9, 118.8, 114.4, 52.2,
52.2, 20.5.
1
1
10:1) to give the product as a white solid: 67% yield, (37 mg); H
NMR (CDCl3, 400 MHz, ppm): δ = 7.83−7.82 (m, 1H), 7.22−7.19
(m, 1H), 6.61 (d, J = 8.8 Hz, 1H), 5.74 (br, 2H), 3.88 (s, 3H); 13C
NMR (CDCl3, 100 MHz, ppm): δ = 167.6, 148.9, 134.0, 130.4, 120.6,
118.0, 111.4, 51.7.
Methyl 5-Methoxy-2-((methoxycarbonyl)amino)benzoate (3c).23
The title compound was prepared according to the general working
procedure B and purified by column chromatography (petroleum
ether/ethyl acetate = 10:1) to give the product as a white solid: 38%
Methyl 2-Amino-4-chlorobenzoate (2f).4e The title compound
was prepared according to the general working procedure A and
purified by column chromatography (petroleum ether/ethyl acetate =
10:1) to give the product as a light yellow oil: 61% yield, (34 mg); 1H
NMR (CDCl3, 400 MHz, ppm): δ = 7.78 (d, J = 8.8 Hz, 1H), 6.67 (s,
1H), 6.61 (d, J = 8.4 Hz, 1H), 5.82 (br, 2H), 3.87 (s, 3H); 13C NMR
(CDCl3, 100 MHz, ppm): δ = 168.0, 151.1, 140.0, 132.6, 116.7,
115.9, 109.2, 51.6.
1
yield, (27 mg); H NMR (CDCl3, 400 MHz, ppm): δ = 10.2 (br,
1H), 8.34 (d, J = 9.2 Hz, 1H), 7.50−7.49 (m, 1H), 7.14−7.11 (m,
1H), 3.92 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H); 13C NMR (CDCl3, 100
MHz, ppm): δ = 168.1, 154.2, 153.8, 135.3, 121.3, 120.4, 115.4,
114.3, 55.6, 52.3, 52.2.
Methyl 4-Methoxy-2-((methoxycarbonyl)amino)benzoate
(3d).23 The title compound was prepared according to the general
working procedure B and purified by column chromatography
(petroleum ether/ethyl acetate = 10:1) to give the product as a
white solid: 45% yield, (32 mg); 1H NMR (CDCl3, 400 MHz, ppm):
δ = 10.7 (br, 1H), 8.07 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 6.56 (d, J =
9.2 Hz, 1H), 3.88 (s, 6H), 3.79 (s, 3H); 13C NMR (CDCl3, 100 MHz,
ppm): δ = 168.4, 164.5, 154.2, 144.0, 132.5, 109.1, 107.1, 102.3, 55.4,
52.2, 51.9.
Methyl 2-Amino-3-methylbenzoate (2h).20 The title compound
was prepared according to the general working procedure A and
purified by column chromatography (petroleum ether/ethyl acetate =
10:1) to give the product as a light yellow oil: 63% yield, (31 mg); 1H
NMR (CDCl3, 400 MHz, ppm): δ = 7.79 (d, J = 8.0 Hz, 1H), 7.20 (d,
J = 7.2 Hz, 1H), 6.60 (t, J = 7.6 Hz, 1H), 5.84 (br, 2H), 3.88 (s, 3H),
2.18 (s, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ = 169.0, 148.9,
134.8, 129.1, 122.9, 115.6, 110.2, 51.5, 17.4.
Methyl 5-Fluoro-2-((methoxycarbonyl)amino)benzoate (3f).4f
The title compound was prepared according to the general working
procedure B and purified by column chromatography (petroleum
ether/ethyl acetate = 10:1) to give the product as a white solid: 31%
Methyl 2-Amino-3-fluorobenzoate (2i).4e The title compound was
prepared according to the general working procedure A and purified
by column chromatography (petroleum ether/ethyl acetate = 10:1) to
1
1
yield, (21 mg); H NMR (CDCl3, 400 MHz, ppm): δ = 10.3 (br,
give the product as a light yellow oil: 61% yield, (31 mg); H NMR
1H), 8.45−8.42 (m, 1H), 7.71−7.67 (m, 1H), 7.29−7.24 (m, 1H),
3.93 (s, 3H), 3.79 (s, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ =
167.5 (d, J = 2.5 Hz), 156.8 (d, J = 240.5 Hz), 154.1, 138.0 (d, J = 2.5
Hz), 121.7 (d, J = 22 Hz), 120.6 (d, J = 7.1 Hz), 116.8 (d, J = 24.2
Hz), 115.6 (d, J = 6.9 Hz), 52.5, 52.3.
Methyl 2-((Methoxycarbonyl)amino)-3-methylbenzoate (3g).
The title compound was prepared according to the general working
procedure B and purified by column chromatography (petroleum
ether/ethyl acetate = 10:1) to give the product as a light yellow oil:
42% yield, (28 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.50 (br,
1H), 7.79 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.19−7.15
(m, 1H), 3.91 (s, 3H), 3.77 (s, 3H), 2.34 (s, 3H); 13C NMR (CDCl3,
100 MHz, ppm): δ = 167.9, 154.6, 137.2, 135.8, 135.5, 128.3, 125.1,
52.6, 52.3, 18.9. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C11H13NO4Na 246.0737; Found: 246.0746.
(CDCl3, 400 MHz, ppm): δ = 7.65 (d, J = 8.0 Hz, 1H), 7.14−7.09
(m, 1H), 6.59−6.54 (m, 1H), 5.80 (br, 2H), 3.89 (s, 3H); 13C NMR
(CDCl3, 100 MHz, ppm): δ = 168.0 (d, J = 3.6 Hz), 151.4 (d, J =
237.6 Hz), 139.6 (d, J = 13.9 Hz), 126.2 (d, J = 3.4 Hz), 118.4 (d, J =
18.0 Hz), 114.7 (d, J = 7.2 Hz), 112.5 (d, J = 4.3 Hz), 51.7.
Methyl 2-Amino-3-chlorobenzoate (2j).21 The title compound
was prepared according to the general working procedure A and
purified by column chromatography (petroleum ether/ethyl acetate =
10:1) to give the product as a light yellow oil: 47% yield, (26 mg); 1H
NMR (CDCl3, 400 MHz, ppm): δ = 7.82 (d, J = 8.0 Hz, 1H), 7.41 (d,
J = 8.0 Hz, 1H), 6.59 (t, J = 7.6 Hz, 1H), 6.28 (br, 2H), 3.89 (s, 3H);
13C NMR (CDCl3, 100 MHz, ppm): δ = 168.1, 146.6, 133.8, 129.9,
120.2, 115.7, 111.8, 51.8.
Ethyl 2-Aminobenzoate (2k).4e The title compound was prepared
according to the general working procedure A and purified by column
chromatography (petroleum ether/ethyl acetate = 10:1) to give the
2-Aminobenzamide (4a).4e The title compound was prepared
according to the general working procedure C and purified by column
chromatography (petroleum ether/ethyl acetate = 1:1) to give the
product as a light yellow solid: 66% yield, (27 mg); 1H NMR
(DMSO-d6, 400 MHz, ppm): δ = 7.71 (br, 1H), 7.52 (d, J = 8.0 Hz,
1H), 7.12 (t, J = 7.6 Hz, 1H), 7.05 (br, 1H), 6.67 (d, J = 8.4 Hz, 1H),
6.55 (br, 2H), 6.47 (t, J = 7.6 Hz, 1H); 13C NMR (DMSO-d6, 100
MHz, ppm): δ = 171.8, 150.7, 132.3, 129.2, 116.9, 114.8, 114.1.
2-Amino-5-methylbenzamide (4b).4e The title compound was
prepared according to the general working procedure C and purified
by column chromatography (petroleum ether/ethyl acetate = 1:1) to
give the product as a light yellow solid: 44% yield, (20 mg); 1H NMR
(DMSO-d6, 400 MHz, ppm): δ = 7.66 (br, 1H), 7.34 (s, 1H), 7.00
(br, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 6.32 (br,
2H), 2.14 (s, 3H); 13C NMR (DMSO-d6, 100 MHz, ppm): δ = 171.8,
148.3, 133.2, 129.1, 123.1, 117.0, 114.2, 20.5.
1
product as a light yellow oil: 44% yield, (22 mg); H NMR (CDCl3,
400 MHz, ppm): δ = 7.89 (d, J = 7.6 Hz, 1H), 7.29−7.25 (m, 1H),
6.68−6.64 (m, 2H), 5.73 (br, 2H), 4.34 (q, J = 6.8 Hz, 2H), 1.39 (t, J
= 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ = 168.2, 150.4,
133.9, 131.2, 116.6, 116.2, 110.0, 60.3, 14.3.
Methyl 2-(Methylamino)benzoate (2l).22 The title compound was
prepared according to the general working procedure A and purified
by column chromatography (petroleum ether/ethyl acetate = 10:1) to
1
give the product as a light yellow oil: 20% yield, (10 mg); H NMR
(CDCl3, 400 MHz, ppm): δ = 7.92−7.90 (m, 1H), 7.75 (br, 1H),
7.42−7.38 (m, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.61 (t, J = 8.0 Hz, 1H),
3.86 (s, 3H), 2.92 (s, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ =
169.0, 151.8, 134.6, 131.5, 114.4, 110.8, 109.9, 51.5, 29.6.
Methyl 2-((Methoxycarbonyl)amino)benzoate (3a).4f The title
compound was prepared according to the general working procedure
B and purified by column chromatography (petroleum ether/ethyl
acetate = 15:1) to give the product as a white solid: 64% yield, (40
mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 10.5 (br, 1H), 8.43 (d, J
= 8.4 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.03
(t, J = 7.6 Hz, 1H), 3.92 (s, 3H), 3.79 (s, 3H); 13C NMR (CDCl3,
100 MHz, ppm): δ = 168.5, 154.1, 141.7, 134.6, 130.8, 121.5, 118.7,
114.5, 52.2, 52.2.
2-Amino-5-fluorobenzamide (4c).4e The title compound was
prepared according to the general working procedure C and purified
by column chromatography (petroleum ether/ethyl acetate = 1:1) to
1
give the product as a white solid: 56% yield, (26 mg); H NMR
(DMSO-d6, 400 MHz, ppm): δ = 7.78 (br, 1H), 7.40−7.37 (m, 1H),
7.20 (br, 1H), 7.06−7.01 (m, 1H), 6.71−6.67 (m, 1H), 6.46 (br,
2H); 13C NMR (DMSO-d6, 100 MHz, ppm): δ = 170.7 (d, J = 2.4
Hz), 153.0 (d, J = 228.8 Hz), 147.4, 119.8 (d, J = 22.5 Hz), 118.1 (d,
J = 7.1 Hz), 114.5 (d, J = 22.3 Hz), 113.8 (d, J = 5.5 Hz).
Methyl 2-((Methoxycarbonyl)amino)-5-methylbenzoate (3b).4f
The title compound was prepared according to the general working
procedure B and purified by column chromatography (petroleum
ether/ethyl acetate = 15:1) to give the product as a white solid: 57%
2-Amino-5-chlorobenzamide (4d).4e The title compound was
prepared according to the general working procedure C and purified
F
https://doi.org/10.1021/acs.joc.1c01017
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
by column chromatography (petroleum ether/ethyl acetate = 10:1) to
give the product as a light yellow solid: 61% yield, (31 mg); 1H NMR
(DMSO-d6, 400 MHz, ppm): δ = 7.85 (br, 1H), 7.59 (s, 1H), 7.21
(br, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.71−6.69 (m, 3H); 13C NMR
(DMSO-d6, 100 MHz, ppm): δ = 170.5, 149.5, 132.1, 128.4, 118.5,
118.0, 115.0.
Fuyang Normal University, Fuyang, Anhui 236037, People’s
Republic of China
Yan Zhang − Hefei National Laboratory for Physical Sciences
at Microscale, Technology & School of Chemistry and
Materials Science, University of Science and Technology of
China, Hefei, Anhui 230026, People’s Republic of China
2-Amino-4-chlorobenzamide (4e).4e The title compound was
prepared according to the general working procedure C and purified
by column chromatography (petroleum ether/ethyl acetate = 1:1) to
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01017
1
give the product as a white solid: 53% yield, (27 mg); H NMR
(DMSO-d6, 400 MHz, ppm): δ = 7.78 (br, 1H), 7.53 (d, J = 8.4 Hz,
1H), 7.16 (br, 1H), 6.83 (br, 2H), 6.74 (s, 1H), 6.48 (d, J = 8.4 Hz,
1H); 13C NMR (DMSO-d6, 100 MHz, ppm): δ = 170.9, 152.0, 136.8,
131.1, 115.5, 114.4, 112.8.
Notes
The authors declare no competing financial interest.
2-Amino-3-methylbenzamide (4g).4e The title compound was
prepared according to the general working procedure C and purified
by column chromatography (petroleum ether/ethyl acetate = 1:1) to
give the product as a light yellow solid: 38% yield, (17 mg); 1H NMR
(DMSO-d6, 400 MHz, ppm): δ = 7.73 (br, 1H), 7.42 (d, J = 8.0 Hz,
1H), 7.07−7.05 (m, 2H), 6.46−6.40 (m, 3H), 2.07 (s, 3H); 13C
NMR (DMSO-d6, 100 MHz, ppm): δ = 172.2, 148.7, 133.1, 127.1,
123.5, 114.6, 114.0, 18.1.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the National
Natural Science Foundation of China (21772185) and the
assistance of the product characterization from the National
Demonstration Center for Experimental Chemistry Education
of the University of Science and Technology of China. P.Q. is
also grateful for the financial support from the Talent Project
of Fuyang Normal University (No. 2019kyqd0017), and the
College Students Innovative Entrepreneurial Training Plan
Program (Grants S202010371040).
2-Amino-3-fluorobenzamide (4h).4e The title compound was
prepared according to the general working procedure C and purified
by column chromatography (petroleum ether/ethyl acetate = 1:1) to
give the product as a light yellow solid: 48% yield, (22 mg); 1H NMR
(DMSO-d6, 400 MHz, ppm): δ = 7.86 (br, 1H), 7.41 (d, J = 8.0 Hz,
1H), 7.27 (br, 1H), 7.16−7.11 (m, 1H), 6.52−6.47 (m, 3H); 13C
NMR (DMSO-d6, 100 MHz, ppm): δ = 170.9 (d, J = 3.1 Hz), 151.6
(d, J = 235.9 Hz), 139.2 (d, J = 14 Hz), 124.7 (d, J = 3.0 Hz), 117.3
(d, J = 18.0 Hz), 116.6 (d, J = 4.7 Hz), 114.0 (d, J = 7.2 Hz).
2-Amino-3-chlorobenzamide (4i).4e The title compound was
prepared according to the general working procedure C and purified
by column chromatography (petroleum ether/ethyl acetate = 1:1) to
give the product as a light yellow solid: 49% yield, (25 mg); 1H NMR
(DMSO-d6, 400 MHz, ppm): δ = 7.92 (br, 1H), 7.56 (d, J = 7.6 Hz,
1H), 7.38−7.33 (m, 2H), 6.71 (br, 2H), 6.55 (t, J = 8.0 Hz, 1H); 13C
NMR (DMSO-d6, 100 MHz, ppm): δ = 171.0, 146.2, 132.4, 128.2,
119.5, 116.2, 115.4.
REFERENCES
■
(1) (a) Chen, F.; Wang, T.; Jiao, N. Recent Advances in Transition
Metal Catalyzed Functionalization of Unstrained Carbon-Carbon
Bonds. Chem. Rev. 2014, 114, 8613−8661. (b) Song, F.; Gou, T.;
Wang, B.-Q.; Shi, Z.-J. Catalytic Activations of Unstrained C-C Bond
Involving Organometallic Intermediates. Chem. Soc. Rev. 2018, 47,
7078−7115.
(2) (a) Li, H. J.; Bunrit, A.; Li, N.; Wang, F. Heteroatom-
Participated Lignin Cleavage to Functionalized Aromatics. Chem. Soc.
Rev. 2020, 49, 3748−3763. (b) Yu, X.-Y.; Chen, J.-R.; Xiao, W.-J.
Visible Light-Driven Radical-Mediated C-C Bond Cleavage/Func-
tionalization in Organic Synthesis. Chem. Rev. 2021, 121, 506−561.
(3) Singh, G. S.; Desta, Z. Y. Isatins As Privileged Molecules in
Design and Synthesis of Spiro-Fused Cyclic Frameworks. Chem. Rev.
2012, 112, 6104−6155.
ASSOCIATED CONTENT
■
sı
* Supporting Information
(4) (a) Xu, C.; Jia, F.-C.; Cai, Q.; Li, D.-K.; Zhou, Z.-W.; Wu, A.-X.
Intramolecular Decarboxylative Coupling as the Key Step in Copper-
Catalyzed Domino Reaction: Facile Access to 2-(1,3,4-Oxadiazol-2-
yl)aniline Derivatives. Chem. Commun. 2015, 51, 6629−6632. (b) Jia,
F. C.; Zhou, Z. W.; Xu, C.; Wu, Y. D.; Wu, A. X. Divergent Synthesis
of Quinazolin-4(3H)-ones and Tryptanthrins Enabled by a tert-Buty
Hydroperoxide/K3PO4-Promoted Oxidative Cyclization of Isatins at
Room Temperature. Org. Lett. 2016, 18, 2942−2945. (c) Ma, Y.; Zhu,
Y.; Zhang, D.; Meng, Y.; Tang, T.; Wang, K.; Ma, J.; Wang, J.; Sun, P.
Eco-friendly Decarboxylative Cyclization in Water: Practical Access to
the Anti-malarial 4-Quinolones. Green Chem. 2019, 21, 478−482.
(d) Jia, F. C.; Chen, T. Z.; Hu, X. Q. TFA/TBHP-Promoted
Oxidative Cyclisation for the Construction of Tetracyclic Quinazo-
linones and Rutaecarpine. Org. Chem. Front. 2020, 7, 1635−1639.
(e) Wang, Y.-W.; Zheng, L.; Jia, F. C.; Chen, Y.-F.; Wu, A. X.
Oxidative Ring-Opening of Isatins for the Synthesis of 2-Amino-
benzamides and 2-Aminobenzoates. Tetrahedron 2019, 75, 1497−
1503. (f) Kalbandhe, A. H.; Kavale, A. C.; Thorat, P. B.; Karade, N. N.
Oxidative Cleavage of C2-C3 Bond in Isatin Using (Diacetoxyiodo)-
benzene: A Facile Synthesis of Carbamates of Alkyl Anthranilates.
Synlett 2016, 27, 763−768.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01017.
1H NMR and 13C NMR spectra for all the products
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
Zhiyong Wang − Hefei National Laboratory for Physical
Sciences at Microscale, Technology & School of Chemistry
and Materials Science, University of Science and Technology
of China, Hefei, Anhui 230026, People’s Republic of China;
orcid.org/0000-0002-3400-2851; Email: zwang3@
ustc.edu.cn
Authors
Peng Qian − School of Chemistry and Material Engineering,
Engineering Research Center of Biomass Conversion and
Pollution Prevention of Anhui Educational Institutions,
Fuyang Normal University, Fuyang, Anhui 236037, People’s
Republic of China
Jiaojiao Liu − School of Chemistry and Material Engineering,
Engineering Research Center of Biomass Conversion and
Pollution Prevention of Anhui Educational Institutions,
(5) (a) Yan, M.; Kawamata, Y.; Baran, P. S. Synthetic Organic
Electrochemical Methods Since 2000: On the Verge of a Renaissance.
Chem. Rev. 2017, 117, 13230−13319. (b) Jiang, Y.; Xu, K.; Zeng, C.
Use of Electrochemistry in the Synthesis of Heterocyclic Structures.
Chem. Rev. 2018, 118, 4485−4540. (c) Tang, S.; Liu, Y. C.; Lei, A. W.
Electrochemical Oxidative Cross-coupling with Hydrogen Evolution:
a Green and Sustainable Way for Bond Formation. Chem. 2018, 4,
G
https://doi.org/10.1021/acs.joc.1c01017
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
27−45. (d) Qian, P.; Zha, Z. G.; Wang, Z. Y. Recent Advances in C-H
Functionalization with Electrochemistry and Various Iodine-contain-
ing Reagents. ChemElectroChem 2020, 7, 2527−2544.
Disubstituted Imidazo[1,5-a]quinolines via Sequential Dual Oxidative
C(sp3)-H Amination in Aqueous Medium. J. Org. Chem. 2019, 84,
3148−3157. (e) Qian, P.; Zhou, Z. H.; Hu, K. F.; Wang, J. W.; Li, Z.
B.; Zha, Z. G.; Wang, Z. Y. Electrocatalytic Three-Component
Reaction: Synthesis of Cyanide-Functionalization Imidazo-fused N-
Heterocycles. Org. Lett. 2019, 21, 6403−6407. (f) Qian, P.; Zhou, Z.
H.; Wang, L.; Wang, Z. C.; Wang, Z. W.; Zhang, Z. L.; Sheng, L. Q.
Electrosynthesis of 2-(1,3,4-Oxadiazol-2-yl)aniline Derivatives with
Isatins as Amino-Attached C1 Sources. J. Org. Chem. 2020, 85,
13029−13036.
(6) (a) Yang, Q.-L.; Wang, X.-Y.; Lu, J.-Y.; Zhang, L.-P.; Fang, P.;
Mei, T.-S. Copper-Catalyzed Electrochemical C-H Amination of
Arenes with Secondary Amines. J. Am. Chem. Soc. 2018, 140, 11487−
11494. (b) Li, J.; Huang, W. H.; Chen, J. Z.; He, L. F.; Cheng, X.; Li,
G. G. Electrochemical Aziridination by Alkene Activation Using a
Sulfamate as the Nitrogen Source. Angew. Chem., Int. Ed. 2018, 57,
5695−5698. (c) Mo, Y.; Lu, Z.; Rughoobur, G.; Patil, P.; Gershenfeld,
N.; Akinwande, A. I.; Buchwald, S. L.; Jensen, K. F. Microfluidic
Electrochemistry for Single-Electron Transfer Redox-Neutral Reac-
tions. Science 2020, 368, 1352−1357. (d) Xu, Z.; Huang, Z.; Li, Y.;
Kuniyil, R.; Zhang, C.; Ackermann, L.; Ruan, Z. Catalyst-Free, Direct
Electrochemical Synthesis of Annulated Medium-Sized Lactams
through C-C Bond Cleavage. Green Chem. 2020, 22, 1099−1104.
(e) Zhang, S.; Li, L. J.; Li, J. J.; Shi, J. X.; Xu, K.; Gao, W. H.; Zong, L.
Y.; Li, G. G.; Findlater, M. Electrochemical Arylation of Aldehydes,
Ketones, and Alcohols: from Cathodic Reduction to Convergent
Paired Electrolysis. Angew. Chem., Int. Ed. 2021, 60, 7275−7282.
(7) Wang, Q.-Q.; Xu, K.; Jiang, Y.-Y.; Liu, Y.-G.; Sun, B.-G.; Zeng,
C.-C. Electrocatalytic Minisci Acylation Reaction of N-Heteroarenes
Mediated by NH4I. Org. Lett. 2017, 19, 5517−5520.
(16) Ramkumar, N.; Nagarajan, R. A New Route to the Synthesis of
Ellipticine Quinone from Isatin. Tetrahedron Lett. 2014, 55, 1104−
1106.
(17) Otsuka, R.; Maruhashi, K.; Ohwada, T. Latent Brønsted Base
Solvent-Assisted Amide Formation fromAmines and Acid Chlorides.
Synthesis 2018, 50, 2041−2057.
(18) Huang, G. L.; Liu, B.; Teng, M. Y.; Chen, Y. G. Ammonium
Chloride-Catalyzed One-Pot Synthesis of 4(3H)-Quinazolinones
under Solvent-Free Conditions. Synth. Commun. 2014, 44, 1786−
1794.
(19) McAulay, K.; Hoyt, E. A.; Thomas, M.; Schimpl, M.;
Bodnarchuk, M. S.; Lewis, H. J.; Barratt, D.; Bhavsar, D.; Robinson,
D. M.; Deery, M. J.; Ogg, D. J.; Bernardes, G. L. L.; Ward, R. A.;
Waring, M. J.; Kettle, J. G. Alkynyl Benzoxazines and Dihydroqui-
nazolines as CysteineTargeting Covalent Warheads and Their
Application inIdentification of Selective Irreversible Kinase Inhibitors.
J. Am. Chem. Soc. 2020, 142, 10358−10372.
(20) Paillet-Loilier, M.; Fabis, F.; Lepailleur, A.; Bureau, R.; Butt-
Gueulle, S.; Dauphin, F.; Delarue, C.; Vaudry, H.; Rault, S.
Phenylpyrroles, a New Chemolibrary Virtual Screening Class of 5-
HT7 Receptor Ligands. Bioorg. Med. Chem. Lett. 2005, 15, 3753−
3757.
(21) Zhao, C.-Y.; Li, K.; Pang, Y.; Li, J.-Q.; Liang, C.; Su, G.-F.; Mo,
D.-L. Iodine(III) Reagent-Mediated Intramolecular Amination of 2-
Alkenylanilines to Prepare Indoles. Adv. Synth. Catal. 2018, 360,
1919−1925.
(22) Roell, D.; Rosler, T. W.; Hessenkemper, W.; Kraft, F.;
Hauschild, M.; Bartsch, S.; Abraham, T. E.; Houtsmuller, A. B.;
Matusch, R.; van Royen, M. E.; Baniahmad, A. Halogen-Substituted
Anthranilic Acid Derivatives Provide a Novel Chemical Platform for
Androgen Receptor Antagonists. J. Steroid Biochem. Mol. Biol. 2019,
188, 59−70.
(23) Moriyama, K.; Ishida, K.; Togo, H. Hofmann-Type Rearrange-
ment of Imides by in Situ Generation of Imide-Hypervalent
Iodines(III) from Iodoarenes. Org. Lett. 2012, 14, 946−949.
(8) Xiang, J.; Shang, M.; Kawamata, Y.; Lundberg, H.; Reisberg, S.
H.; Chen, M.; Mykhailiuk, P.; Beutner, G.; Collins, M. R.; Davies, A.;
Del Bel, M.; Gallego, G. M.; Spangler, J. E.; Starr, J.; Yang, S.;
Blackmond, D. G.; Baran, P. S. Hindered Dialkyl Ether Synthesis with
Electrogenerated Carbocations. Nature 2019, 573, 398−402.
(9) Lin, D.-Z.; Huang, J.-M. Synthesis of 3-Formylindoles via
Electrochemical Decarboxylation of Glyoxylic Acid with an Amine as
a Dual Function Organocatalyst. Org. Lett. 2019, 21, 5862−5866.
(10) Petti, A.; Leech, M. C.; Garcia, A. D.; Goodall, I. C. A.; Dobbs,
A. P.; Lam, K. Economical, Green and Safe Route Towards
Substituted Lactones via the Anodic Generation of Oxycarbonyl
Radicals. Angew. Chem., Int. Ed. 2019, 58, 16115−16118.
(11) Bu, F. X.; Lu, L. J.; Hu, X.; Wang, S. C.; Zhang, H.; Lei, A. W.
Electrochemical Oxidative Decarboxylation and 1,2-Aryl Migration
towards the Synthesis of 1,2-Diaryl Ethers. Chem. Sci. 2020, 11,
10000−10004.
(12) Lai, X.-L.; Shu, X.-M.; Song, J. S.; Xu, H.-C. Electro-
photocatalytic Decarboxylative C-H Functionalization of Heteroar-
enes. Angew. Chem., Int. Ed. 2020, 59, 10626−10632.
(13) Adeli, Y.; Huang, K.; Liang, Y.; Jiang, Y.; Liu, J.; Song, S.; Zeng,
C.-C.; Jiao, N. Electrochemically Oxidative C-C Bond Cleavage of
Alkylarenes for Anilines Synthesis. ACS Catal. 2019, 9, 2063−2067.
(14) (a) Zhang, Z.; Zhang, L.; Zhang, X.; Yang, J.; Yin, Y.; Jiang, Y.;
Zeng, C.; Lu, G.; Yang, Y.; Mo, F. Anodic Oxidation Triggered
Divergent 1,2- and 1,4- Group Transfer Reactions of β-Hydrox-
ycarboxylic Acids Enabled by Electrochemical Regulation. Chem. Sci.
2020, 11, 12021−12028. (b) Lehnherr, D.; Lam, Y.-H.; Nicastri, M.
C.; Liu, J.; Newman, J. A.; Regalado, E. L.; DiRocco, D. A.; Rovis, T.
Electrochemical Synthesis of Hindered Primary and Secondary
Amines via Proton-Coupled Electron Transfer. J. Am. Chem. Soc.
2020, 142, 468−478. (c) Zhang, S.; Li, L.; Li, X.; Zhang, J.; Xu, K.; Li,
G.; Findlater, M. Electroreductive 4-Pyridylation of Electron-deficient
Alkenes with Assistance of Ni(acac)2. Org. Lett. 2020, 22, 3570−3575.
(15) (a) Qian, P.; Bi, M. X.; Su, J. H.; Zha, Z. G.; Wang, Z. Y.
Electrosynthesis of (E)- Vinyl Sulfones Directly from Cinnamic Acids
and Sodium Sulfinates via Decarboxylative Sulfono Functionalization.
J. Org. Chem. 2016, 81, 4876−4882. (b) Qian, P.; Su, J. H.; Wang, Y.
K.; Bi, M. X.; Zha, Z. G.; Wang, Z. Y. Electrocatalytic C-H/N-H
Coupling of 2′-Aminoacetophenones for the Synthesis of Isatins. J.
Org. Chem. 2017, 82, 6434−6440. (c) Qian, P.; Yan, Z. C.; Zhou, Z.
H.; Hu, K. F.; Wang, J. W.; Li, Z. B.; Zha, Z. G.; Wang, Z. Y.
Electrocatalytic Intermolecular C(sp3)-H/N-H Coupling of Methyl
N-Heteroaromatics with Amines and Amino Acids: Access to
Imidazo-fused N-Heterocycles. Org. Lett. 2018, 20, 6359−6363.
(d) Qian, P.; Yan, Z. C.; Zhou, Z. H.; Hu, K. F.; Wang, J. W.; Li, Z.
B.; Zha, Z. G.; Wang, Z. Y. Electrocatalytic Tandem Synthesis of 1,3-
H
https://doi.org/10.1021/acs.joc.1c01017
J. Org. Chem. XXXX, XXX, XXX−XXX