Electrosynthesis of 2-(1,3,4-Oxadiazol-2-yl)aniline Derivatives with Isatins as Amino-Attached C1 Sources

Article abstract of DOI:10.1021/acs.joc.0c01700

An intramolecular decarboxylative coupling reaction for the construction of 2-(1,3,4-oxadiazol-2-yl)aniline derivatives was developed from readily available isatins and hydrazides by virtue of electrochemistry. In this reaction, isatins were employed as amino-attached C1 sources, providing a variety of 2-(1,3,4-oxadiazol-2-yl)aniline derivatives with moderate to good yields.

Full text of DOI:10.1021/acs.joc.0c01700

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Article
Electrosynthesis of 2-(1,3,4-Oxadiazol-2-yl)aniline
Derivatives with Isatins as Amino-attached C1 Sources
Peng Qian, Zhenghong Zhou, Li Wang, Zhicheng Wang,
Zhongwei Wang, zhenlei zhang, and Liangquan Sheng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01700 • Publication Date (Web): 21 Sep 2020
Downloaded from pubs.acs.org on September 21, 2020
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Electrosynthesis of 2-(1,3,4-Oxadiazol-2-yl)aniline
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Derivatives with Isatins as Amino-attached C1 Sources
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Peng Qian,† Zhenghong Zhou,‡ Li Wang,† Zhicheng Wang,† Zhongwei Wang,† Zhenlei
†
†
Zhang* and Liangquan Sheng*
† 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, P. R .China
‡School of Chemistry and Materials Science, University of Science and Technology of China, Hefei,
Anhui 230026, P. R . China.
E-mail: zhenlei@fynu.edu.cn
shenglq2015@163.com
ABSTRACT: An intramolecular decarboxylative coupling reaction for the construction of 2-
(1,3,4-oxadiazol-2-yl)aniline derivatives was developed from readily available isatins and
hydrazides by virtue of electrochemistry. In this reaction, isatins were employed as amino-attached
C1 sources, providing a variety of 2-(1,3,4-oxadiazol-2-yl)aniline derivatives with moderate to good
yields.
INTRODUCTION
Decarboxylative coupling has attracted tremendous attention since it emerged as a
fascinating approach for the construction of C–C bond and C–heteroatom bond.1 However,
transition metal catalysts were generally required for achieving efficient transformation.2
The residues of metal catalysts restricted their wide applications, especially for the synthesis
of heterocyclic ring compounds. Furthermore, previous works mainly focused on the
formation of C–C bond and C–N bond, few reports were available for the construction of C–
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O bond in the heterocyclic ring compounds. Therefore, it is still highly desirable to construct
C–O bond in the heterocyclic ring compounds under metal free conditions via a
decarboxylative coupling process.
9
Organic electrochemistry represents a facile and green approach for various
transformation since it uses traceless electron as reagents.3 Recently, organic
electrosynthesis gained considerable progress, especially in the past decades. Some elegant
decarboxylative coupling reactions were developed by the group of Huang,4 Lam,5 Loren,6
Baran,7 Lei8 and Zeng.9 For instance, in 2016, Huang reported an electrochemical method
for the synthesis of 2-substituted benzimidazole via decarboxylative coupling of a-keto acids
with ortho-phenylenediamines (Scheme 1a).4a In 2018, the group of Huang achieved the
decarboxylative N-formylation of amines with glyoxylic acid via electrochemistry (Scheme
1b). 4c Lam developed an electrochemical oxidation of α-alkoxyl carboxylic acids to give
substituted acetals in 2018 (Scheme 1c).5 Recently, an electrochemical nickel-catalyzed
decarboxylative sp2-sp3 cross-coupling reaction of in situ generated N-hydroxyphthalimide
esters and aryl iodides was disclosed by Loren (Scheme 1d).6 Moreover, Baran reported a
practical method for the formation of C–O bond and applied to the synthesis of sterially
hindered ether via electrocatalytic decarboxylative coupling (Scheme 1e).7 Inspired by these
works and our interests on the electrosynthesis of heterocyclic ring compounds,10 we herein
reported a facile intramolecular decarboxylative coupling reaction for the electrosynthesis
of 2-(1,3,4-oxadiazol-2-yl)aniline derivatives with isatins as amino-attached C1 sources
(Scheme 1c). The 2-(1,3,4-oxadiazol-2-yl)aniline are important class of oxygen-containing
heterocycles.11 Furthermore, the free NH2 generated from this electrocatalytic reaction
provides the possbility for further manipulation. The preparation of 2-(1,3,4-oxadiazol-2-
yl)aniline were reported by Wu12 and Guo,13 employing CuI as catalyst for 48 h and Eosin
Y as photocatalyst for 24 h, respectively. With our developed approach, the 2-(1,3,4-
oxadiazol-2-yl)aniline were constructed smoothly in moderate to good yields within 2 h
without the requirement of metal or photocatalyst.
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Scheme 1. Electrochemical Decarboxylative Cross-Coupling Reactions
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RESULTS AND DISCUSSION
Our initial investigation began by electrolyzing isatin (1a) and benzoylhydrazine (2a
)
in the presence of K2CO3 at a constant current of 10 mA with KI as electrolyte. To our
delight, the desired product can be obtained in a yield of 79% (entry 1, Table 1). Firstly, the
o
reaction temperature was investigated and 120 C turned out to be the optimal reaction
temperature (entries 1−5). Then, we screened the reaction solvent. Experimental results
indicated that the DMSO gave superior results than DMA, DMF and NMP (entries 6−8).
Subsequently, various halide salts were explored, and KI show better performence than other
halide salts, including n-Bu4NI, Me4NI and KBr (entries 9−11). Moreover, when the
reaction was performed in the absence of KI, the reaction yield decreased sharply (entry 12).
On the other hand, the reaction proceeded smoothly to afford the desired product with 75%
and 61% yield when the amount of KI decreased to 50 mol% and 20 mol%, respectively
(entries 13 and 14). These results suggested KI also serves as the mediator for the reaction.
Furthermore, various bases were also examined (entries 15-17), and K2CO3 was still the
optimal base for this transformation. Changing the values of current also decreased the
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reaction yields (entries 18 and 19). Finally, no desired product was detected when the
reaction was carried out without the pass of electricity (entry 20). This result suggested the
pass of electricity was necessary for the reaction.
9
By using the optimal electrolytic reaction conditions, the generality of this developed
electrocatalytic decarboxylative coupling reaction was explored. As shown in Table 2,
various hydrazides were conducted smoothly to give the corresponding 2-(1,3,4-oxadiazol-
2-yl)aniline in moderate to good yields (entries 1-16). The benzoylhydrazines with electron-
donating substituents on the aromatic ring gave superior results than electron-withdrawing
substituents (entries 2-4 vs 9). Moreover, the halide substituted benzoylhydrazines were
compatible with the standard conditions to
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Table 1. Optimization of the Reaction Conditionsa
entry electrolyte solvent
base
I (mA)
10
T (oC)
120
110
130
50
yieldb (%)
1
2
KI
KI
DMSO K2CO3
DMSO K2CO3
DMSO K2CO3
DMSO K2CO3
DMSO K2CO3
79
70
10
3
KI
10
67
4
KI
10
28
5
KI
10
rt
15
6
KI
DMA
DMF
NMP
K2CO3
K2CO3
K2CO3
10
120
120
120
120
120
59
7
KI
10
trace
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KI
10
9
n-Bu4NI
Me4NI
DMSO K2CO3
DMSO K2CO3
10
48
10
10
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KBr
LiClO4
KI
DMSO K2CO3
DMSO K2CO3
DMSO K2CO3
DMSO K2CO3
DMSO Na2CO3
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10
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120
120
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120
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120
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120
30
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75
61
69
66
45
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59
n.d.
13c
14 d
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KI
KI
16
KI
DMSO
KOH
17
KI
DMSO K3PO4
DMSO K2CO3
DMSO K2CO3
DMSO K2CO3
18
KI
19
KI
20
KI
0
aReaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), electrolyte (0.3 mmol), Base (0.3 mmol), Solvent (3
mL) , Pt/Pt (1.0 x 1.0 cm2); the electrolysis was conducted in an undivided cell at oil bath (120 °C) for 2 h
(2.5 F). bYields of the isolated products. c The loading of KI was 50 mol %. d The loading of KI was 20 mol %
afford the desired products with 47-90% yields (entries 5-8). Notably, furan-2-
carbohydrazide (2j) and thiophene-2-carbohydrazide (2k) proceeded smoothly, providing
the corresponding products with 62% and 69% yields, respectively (entries 10 and 11).
Gratifyingly, the more challenging substrates containing amino groups were proved to be
compatible with the standard conditions, giving the desired products in moderate yields
(entries 12 and 13). However, when the benzoylhydrazine bearing a hydroxyl group was
employed, only a trace amount of the desired product was detected (entry 14). Furthermore,
when alkylhydrazides were employed as substrates, such as acetohydrazide,
butyrohydrazide, the reactions proceeded smoothly to give the desired products in 57% and
51% yields, respectively (entries 15 and 16).
Table 2. The Scope of Hydrazidesa
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entry
1
R1
product
3aa
3ab
3ac
yieldb (%)
77
Ph (2a)
2
4-Me-Ph (2b)
3-Me-Ph (2c)
4-OMe-Ph (2d)
4-Cl-Ph (2e)
2-Cl-Ph (2f)
4-F-Ph (2g)
2-F-Ph (2h)
4-CF3-Ph (2i)
2-furnal (2j)
2-thienyl (2k)
2-NH2-Ph (2l)
4-NH2-Ph (2m)
4-OH-Ph (2n)
Me (2o)
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3
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4
3ad
3ae
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90
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3af
73
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3ag
3ah
3ai
76
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72
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16
3aj
62
3ak
3a1
3am
3an
3ao
3ap
69
46
70
trace
57
n-Pr (2p)
51
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aReaction conditions: 1a (0.3 mmol), 2a
-2p (0.3 mmol), KI (0.3 mmol), K2CO3 (0.3 mmol), DMSO (3 mL),
Pt/Pt (1.0 x 1.0 cm2); the electrolysis was conducted in an undivided cell at oil bath (120 °C) for 2 h (2.5 F).
bThe isolated yields.
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Subsequently, various isatins were also investigated under standard conditions (Scheme
2). Both electron-donating and electron-withdrawing substituents on the aromatic cyclic
performed smoothly to give the corresponding products in moderate yields (3ba-3ia).
Moreover, the halide substituted group, including fluoro, chloro, bromo, were also conducted
smoothly to produce the desired products with 63-75% yields (3ca-3fa and 3ha).
Furthermore, a little steric effect was found since the 5-chloro isatin gave a better result than
6-chloro isatin (3fa vs 3ha).
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Scheme 2. The Scope of Isatins
a Reaction conditions: 1b-1i (0.3 mmol), 2a (0.3 mmol), KI (0.3 mmol), K2CO3 (0.3 mmol), DMSO (3 mL) ,
Pt/Pt (1.0 x 1.0 cm2); the electrolysis was conducted in an undivided cell at oil bath (120 °C) for 2 h (2.5 F).
b The isolated yields.
Then, we performed a gram scale experiment, employing 6 mmol of isatin (1a) and 6
mmol of benzoylhydrazine (2a) with 50 mol% of KI. Gratifyingly, the reaction proceeded
smoothly to produce the desired product 3aa with a satisfactory yield of 69% (Scheme 3a),
demonstrating the practicality of this approach. Moreover, the desired product 3aa could be
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further converted to N-(2-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)benzamide 4, which served
5
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as ATP-binding cassette transporter G2 inhibitor (Scheme 3b).14 Furthermore, the desired
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product 3aa could react with 3-bromoprop-1-yne to generate 2-(5-phenyl-1,3,4-oxadiazol-
9
2-yl)-N-(prop-2-yn-1-yl)aniline
5, which was an important intermediate for the construction
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of 2-(5-Phenyl-1,3,4-oxadiazol-2-yl)-N-[(1-aryl-1H-1,2,3-triazol-4-yl)methyl]anilines
6
(Scheme 3c). The 2-(5-Phenyl-1,3,4-oxadiazol-2-yl)-N-[(1-aryl-1H-1,2,3-triazol-4-
showed moderate antibacterial activity.15
yl)methyl]anilines
6
Scheme 3. The Scale-up Reaction and Its Synthetic Applications
To gain more insight into the reaction mechanism, some control experiments were
performed (Scheme 4). Initially, the compound of sodium 2-(2-aminophenyl)-2-oxoacetate
(
1') was synthesized and electrolyzed under standard conditions, only a trace amount of
desired product was detected (Scheme 4a). The result suggestted that the salt 2-(2-
aminophenyl)-2-oxoacetate was not involved in the reaction. Then isatin and
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benzoylhydrazine were heated at 120 oC in DMSO until the disappearance of reactants (about
1.5 h), giving the corresponding condensation product A in almost quantitative yield.
Subequently, KI and K2CO3 were added and the resulting mixture was electrolyzed under
standard conditions, the desired product 3aa could be obtained in 65% yield (Scheme 4b).
This result indicated that the condensation product A was likey to be an intermediate for this
reaction. Moreover, no desired product 3aa was detected when the reaction was electrolyzed
in the absence of K2CO3 (Scheme 4c). Furthermore, only a trace amount of corresponding
product 3ja was detected when N-methyl isatin was employed under standard conditions
(Scheme 4d). These results indicated that both K2CO3 and free N-H were necessary for the
ring opening of corresponding condensation product A generated in situ. Finally, the desired
product 3aa can be obtained in 40% yield when molecular iodine was employed as an
oxidant in place of electricity (Scheme 4e). This result showed that molecular iodine should
be the active species for the reaction.
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Scheme 4. Control Experiments
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Moreover, Cyclic voltammetric (CV) experiments were also conducted to investigate
this reaction. CV results indicated that iodide ion show two oxidation waves at 0.44 V and
0.71 V vs Ag/AgCl, repectively (Figure. 1). The desired product 3aa exhibited an oxidation
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wave ∼0. 62 V vs Ag/AgCl (Figure. 2). These results indicated that the iodide ion is proned
to be oxidized than the desired product 3aa, making it possibe for the tolerence of NH2 group
under electrolysis conditions.
Figure. 1 Cyclic voltammogram of KI (5 mM) in 0.1 M LiClO4/DMSO, using a Pt disk 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.
Figure. 2 Cyclic voltammogram of 3aa (5 mM) in 0.1 M LiClO4/DMSO, using a Pt disk 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.
According to the aboved results and previous reports,9,12,13 a possible reaction
mechanism was proposed based on the reaction of isatin (1a) and benzoylhydrazine (2a). As
shown in Scheme 5, the condenstion reaction occurs between 1a and 2a to form
acylhydrazone A.12 The formed acylhydrazone can be easily hydrolyzed in the presence of
K2CO3 to give potassium carboxylate
B
. Meanwhile, the iodide ion is oxidized to be
to generate intermediate . The
molecular iodine at anode, which could react with
B
C
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intermediate
C
is unstable and easily losses an iodine radical, followed by the liberation of
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carbon dioxide to give the corresponding carbon center radical D 9,13
radical can be further oxidized, followed by reaction with intramolecular masked O
reagent to give the desired product 3aa
.
The carbon center
D
9
.
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Scheme 5. The Proposed Reaction Mechanism
In summary, we have developed a facile approach for the construction of C-O bond and
demonstrated its application for the synthesis of 2-(1,3,4-oxadiazol-2-yl)aniline derivatives
under metal free conditions. This electrocatalytic protocol features a wide scope of substrate,
readily available starting materials, short reaction time and scalability. Moreover, the
generated NH2 group can be well-tolerated and further manipulated. More reactions for the
synthesis of other heterocycles by virtue of this electrocatalytic protocol are ongoing in our
laboratory.
EXPERIMENTAL SECTION
General Information: All products were characterized by 1H NMR and 13C{1H}NMR, using TMS
as an internal reference (1H NMR: 400MHz, 13C{1H}NMR: 100MHz). HRMS (ESI) data were
recorded on a Q-TOF Premier. Commercial reagent and compound were used without purification.
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Preparation of Substrates: Substrates 1a-1j and 2a-2p are commercially available. Substrate 1'
was synthesized according to the previous literature procedure.16
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9
Representative Procedures for the Synthesis of 2-(1,3,4-Oxadiazol-2-yl)aniline Derivatives: An
undivided cell was equipped with a magnet stirrer, two platinum plates (1.0 x 1.0 cm2, commercially
available from GaossUnion, China) electrodes as the working electrode and counter electrode. In
the electrolytic cell, a mixture of isatins 1 (0.3 mmol), hydrazides 2 (0.3 mmol), KI (0.3 mmol, 49.8
mg) and DMSO (3 mL) was allowed to stir and electrolyze at a constant current conditions (10 mA)
under 120 oC (2 h, 2.5 F). 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. The product was
dried under high vacuum for at least 0.5 h before it was weighed and characterized by NMR
spectroscopy.
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Gram-Scale Synthesis of 3aa
An undivided cell was equipped with a magnet stirrer, two platinum plates (1.5 x 1.5 cm2) electrodes
as the working electrode and counter electrode. In the electrolytic cell, a mixture of isatin 1a (6
mmol), benzoylhydrazine 2a (6 mmol), KI (3 mmol, 498 mg) and DMSO (60 mL) was allowed to
o
stir and electrolyze at a constant current conditions (23 mA) under 120 C until the reaction
intermediate finished (about 22 h, 3.1 F). Then the solvent was removed with a rotary evaporator
and the residue was recrystallized by EtOAc to afford the desired product (0.98 g, 69% yield).
Synthesis of Compound 4
The compound 4 was prepared according to the literature procedure14 and purified by column
chromatography (petroleum ether / ethyl acetate = 15:1) to give the product as a colorless solid: 79%
yield, (135 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 11.9 (br, 1H), 9.08 – 9.05 (m, 1H), 8.23 –
8.07 (m, 5H), 7.64 − 7.57 (m, 7H), 7.29 – 7.25 (m, 1H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ
= 166.2, 164.1, 163.6, 138.8, 134.6, 133.1, 132.2, 132.0, 129.2, 128.9, 127.7, 127.6, 127.1, 123.3,
123.2, 120.9, 110.6.14
Synthesis of Compound 5
The compound 5 was prepared according to the literature procedure15 and purified by column
chromatography (petroleum ether / ethyl acetate = 15:1) to give the product as a colorless solid: 43%
yield, (56 mg) ; 1H NMR (DMSO-d6, 400 MHz, ppm): δ = 8.16 – 8.12 (m, 2H), 7.98 (dd, J = 8.0
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Hz, J = 1.6 Hz, 1H), 7.68 − 7.60 (m, 4H), 7.49 – 7.45 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.85 (t, J =
8.0 Hz, 1H), 4.24 (dd, J = 6.0 Hz, J = 2.4 Hz, 2H), 3.21 (t, J = 2.4 Hz, 1H); 13C{1H}NMR (DMSO-
d6, 100 MHz, ppm): δ = 164.5, 162.7, 146.6, 133.4, 132.5, 129.9, 128.8, 127.2, 123.7, 116.8, 112.3,
105.9, 81.7, 74.2, 32.4.15
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2-(5-Phenyl-1,3,4-oxadiazol-2-yl)aniline (3aa)12
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 10:1) to give the product as a light yellow
solid: 77% yield, (55 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.16 – 8.12 (m, 2H), 7.86 − 7.84
(m, 1H), 7.55 − 7.51 (m, 3H), 7.30 − 7.26 (m, 1H), 6.82 – 6.77 (m, 2H), 5.90 (br, 2H); 13C{1H}NMR
(CDCl3, 100 MHz, ppm): δ = 164.6, 162.7, 147.1, 132.5, 131.6, 129.0, 127.8, 126.9, 123.8, 116.8,
116.2, 105.7.
2-(5-(p-Tolyl)-1,3,4-oxadiazol-2-yl)aniline (3ab) 12
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 10:1) to give the product as a light yellow
solid: 83% yield, (63 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.02 – 8.00 (m, 2H), 7.85 − 7.83
(m, 1H), 7.33 − 7.31 (m, 2H), 7.29 − 7.25 (m, 1H), 6.82 – 6.76 (m, 2H), 5.41 (br, 2H), 2.43 (s, 3H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 164.3, 162.8, 146.9, 142.1, 132.3, 129.7, 127.7, 126.8,
121.0, 116.8, 116.2, 105.8, 21.6.
2-(5-(m-Tolyl)-1,3,4-oxadiazol-2-yl)aniline (3ac) 13
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 10:1) to give the product as a light yellow
solid: 76% yield, (57 mg); 1H NMR (DMSO-d6, 400 MHz, ppm): δ = 7.93 − 7.83 (m, 3H), 7.49 −
7.40 (m, 2H), 7.28 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.79 (br, 2H), 6.70 (t, J = 7.4 Hz,
1H), 2.40 (s, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 164.5, 162.9, 147.0, 138.9, 132.4,
128.9, 127.8, 127.4, 124.1, 123.7, 116.8, 116.2, 105.8, 21.3.
2-(5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)aniline (3ad) 12
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The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 8:1) to give the product as a light yellow
solid: 84% yield, (67 mg); 1H NMR (DMSO-d6, 400 MHz, ppm): δ = 8.03 (d, J = 8.4 Hz, 2H), 7.82
(d, J = 7.9 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 7.12 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.3 Hz, 1H), 6.78
(br, 2H), 6.69 (t, J = 7.4 Hz, 1H), 3.83 (s, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 164.1,
162.7, 162.3, 147.0, 132.3, 128.7, 127.7, 116.8, 116.4, 116.1, 114.5, 105.9, 55.5.
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2-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)aniline (3ae)12
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 8:1) to give the product as a light yellow
solid: 90% yield, (73 mg); 1H NMR (DMSO-d6, 400 MHz, ppm): δ = 8.14 (d, J = 7.9 Hz, 2H), 7.85
(d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.78
(br, 2H), 6.70 (t, J = 7.5 Hz, 1H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 164.7, 161.9, 147.1,
137.9, 132.6, 129.4, 128.1, 127.8, 122.3, 116.9, 116.3, 105.5.
2-(5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl)aniline (3af) 12
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 10:1) to give the product as a light yellow
solid: 73% yield, (59 mg); 1H NMR (DMSO-d6, 400 MHz, ppm): δ = 8.13 (d, J = 7.6 Hz, 1H), 7.76
(d, J = 7.9 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.29
(t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.81 (br, 2H), 6.69 (t, J = 7.6 Hz, 1H); 13C{1H}NMR
(CDCl3, 100 MHz, ppm): δ = 165.1, 161.2, 147.1, 133.1, 132.7, 132.3, 131.3, 131.1, 128.1, 127.1,
123.1, 116.9, 116.2, 105.6.
2-(5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl)aniline (3ag)
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 10:1) to give the product as a light yellow
solid: 76% yield, (58 mg); 1H NMR (DMSO-d6, 400 MHz, ppm): δ = 8.19 – 8.16 (m, 2H), 7.85 (d,
J = 8.0 Hz, 1H), 7.45 (t, J = 8.6 Hz, 2H), 7.28 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.78 (br,
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2H) , 6.70 (t, J = 7.6 Hz, 1H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 164.7 (d, J = 251.6 Hz),
164.6, 161.9, 147.1, 132.5, 129.1 (d, J = 8.8 Hz), 127.7, 120.2 (d, J = 3.1 Hz), 116.8, 116.5, 116.2
(d, J = 4.4 Hz), 105.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H11N3OF 256.0886; Found:
256.0888.
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2-(5-(2-Fluorophenyl)-1,3,4-oxadiazol-2-yl)aniline (3ah)
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 10:1) to give the product as a light yellow
solid: 47% yield, (36 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.16 – 8.12 (m, 1H), 7.87 − 7.85
(m, 1H), 7.57 − 7.51 (m, 1H), 7.34 − 7.25 (m, 3H), 6.83 – 6.77 (m, 2H), 5.88 (br, 2H); 13C{1H}NMR
(CDCl3, 100 MHz, ppm): δ = 164.9, 160.1 (d, J = 256.9 Hz), 159.6 (d, J = 5.1 Hz), 147.1, 133.3 (d,
J = 8.4 Hz), 132.6, 129.6 (d, J = 1.2 Hz), 128.0, 124.6 (d, J = 3.7 Hz), 117.0 (d, J = 20.7 Hz), 116.8,
116.2, 112.4 (d, J = 11.6 Hz), 105.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H11N3OF
256.0886; Found: 256.0888.
2-(5-(4-(Trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)aniline (3ai)
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 10:1) to give the product as a light yellow
solid: 72% yield, (66 mg); 1H NMR (DMSO-d6, 400 MHz, ppm): δ = 8.34 (d, J = 8.04 Hz, 2H), 7.98
(d, J = 8.24 Hz, 2H), 7.89 − 7.87 (m, 1H), 7.32 − 7.28 (m, 1H), 6.94 – 6.92 (m, 1H), 6.79 (br, 2H),
6.44 – 6.70 (m, 1H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 165.2, 161.6, 147.3, 133.2 (q, J =
32.7 Hz), 132.9, 127.8, 127.2, 127.1, 126.1 (q, J = 3.7 Hz), 123.6 (q, J = 270.8 Hz), 116.9, 116.3,
105.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H11N3OF3 306.0854; Found: 306.0858.
2-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (3aj) 12
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 8:1) to give the product as a light yellow
solid: 62% yield, (42 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 7.84 − 7.81 (m, 1H), 7.68 − 7.67
(m, 1H), 7.30 − 7.26 (m, 1H), 7.23 − 7.22 (m, 1H), 6.82 – 6.76 (m, 2H), 6.63 – 6.62 (m, 1H), 5.89
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(br, 2H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.9, 155.7, 147.1, 145.6, 139.5, 132.6, 127.8,
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2-(5-(Thiophen-2-yl)-1,3,4-oxadiazol-2-yl)aniline (3ak) 12
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The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 8:1) to give the product as a light yellow
solid: 69% yield, (50 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 7.82 − 7.79 (m, 2H), 7.56 − 7.54
(m, 1H), 7.28 − 7.17 (m, 2H), 6.80 – 6.75 (m, 2H), 5.87 (br, 2H); 13C{1H}NMR (CDCl3, 100 MHz,
ppm): δ = 164.0, 159.0, 147.0, 132.5, 130.0, 129.6, 128.1, 127.7, 125.2, 116.7, 116.1, 105.4.
2,2'-(1,3,4-Oxadiazole-2,5-diyl)dianiline (3al) 12
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 6:1) to give the product as a light yellow
solid: 46% yield, (35 mg); 1H NMR (DMSO-d6, 400 MHz, ppm): δ = 7.89 − 7.86 (m, 2H), 7.31 −
7.26 (m, 2H), 6.93 – 6.91 (m, 2H), 6.77 (br, 4H), 6.73 – 6.69 (m, 2H); 13C{1H}NMR (DMSO-d6,
100 MHz, ppm): δ = 162.8, 148.3, 132.9, 128.3, 116.3, 116.1, 104.5.
2-(5-(4-Aminophenyl)-1,3,4-oxadiazol-2-yl)aniline (3am)
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 2:1) to give the product as a light yellow
solid: 70% yield, (53 mg); 1H NMR (DMSO-d6, 400 MHz, ppm): δ = 7.81 − 7.77 (m, 3H), 7.27 −
7.23 (m, 1H), 6.91 – 6.89 (m, 1H), 6.73 – 6.67 (m, 5H), 5.95 (br, 2H); 13C{1H}NMR (DMSO-d6,
100 MHz, ppm): δ = 163.5, 163.3, 152.8, 148.0, 132.5, 128.7, 127.9, 116.3, 116.0, 114.1, 110.1,
105.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H13N4O 253.1084; Found: 253.1091.
2-(5-Methyl-1,3,4-oxadiazol-2-yl)aniline (3ao) 12
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 6:1) to give the product as a light yellow
solid: 57% yield, (30 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 7.72 (dd, J = 6.4 Hz, 1H), 7.28 −
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ppm): δ = 164.9, 161.8, 146.8, 132.3, 127.7, 116.7, 116.1, 105.9, 10.9.
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The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 8:1) to give the product as a light yellow
solid: 51% yield, (31 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 7.74 (d, J = 8.0 Hz, 1H), 7.29 −
7.25 (m, 1H), 6.82 – 6.74 (m, 2H), 5.85 (br, 2H), 2.92 (t, J = 7.6 Hz, 2H), 1.95 – 1.86 (m, 2H), 1.08
(t, J = 7.6 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 165.0, 164.7, 146.8, 132.2, 127.7,
116.7, 116.1, 106.0, 27.1, 20.1, 13.6.
4-Methyl-2-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline (3ba) 12
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 10:1) to give the product as a light yellow
solid: 74% yield, (56 mg); 1H NMR (DMSO-d6, 400 MHz, ppm): δ = 8.15 – 8.13 (m, 2H), 7.68 (s,
1H), 7.64 − 7.62 (m, 3H), 7.13 − 7.10 (m, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.61 (br, 2H), 2.25 (s, 3H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 164.6, 162.7, 144.9, 133.6, 131.6, 129.0, 127.5, 126.9,
126.0, 123.9, 116.4, 105.6, 20.3.
4-Fluoro-2-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline (3ca) 12
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 10:1) to give the product as a light yellow
solid: 63% yield, (55 mg); 1H NMR (DMSO-d6, 400 MHz, ppm): δ = 8.18 (d, J = 8.4 Hz, 2H), 7.71
− 7.61 (m, 4H), 7.23 − 7.18 (m, 1H), 6.96 – 6.92 (m, 1H), 6.69 (br, 2H); 13C{1H}NMR (DMSO-d6,
100 MHz, ppm): δ = 164.0, 162.8, 153.6 (d, J = 229.9 Hz), 145.2, 132.5, 129.8, 127.3, 123.7, 120.8
(d, J = 23.1 Hz), 117.9 (d, J = 7.3 Hz), 113.2 (d, J = 24.2 Hz), 104.1 (d, J = 8.0 Hz).
4-Chloro-2-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline (3da) 12
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The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 10:1) to give the product as a light yellow
solid: 69% yield, (56 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.20 – 8.17 (m, 2H), 7.90 − 7.89
(m, 1H), 7.65 − 7.61 (m, 3H), 7.33 − 7.30 (m, 1H), 6.96 (d, J = 8.9 Hz, 1H), 6.92 (br, 2H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.6, 163.0, 145.6, 132.4, 131.9, 129.1, 127.0, 126.9,
123.5, 121.3, 117.6, 106.6.
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4-Bromo-2-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline (3ea) 12
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 10:1) to give the product as a light yellow
solid: 70% yield, (66 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.16 – 8.12 (m, 2H), 7.95 − 7.94
(m, 1H), 7.57 − 7.52 (m, 3H), 7.34 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 5.94
(br, 2H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.4, 163.0, 146.0, 135.1, 131.9, 129.8, 129.1,
127.0, 123.5, 117.9, 107.9, 107.1.
5-Chloro-2-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline (3fa)
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 10:1) to give the product as a light yellow
solid: 75% yield, (61 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.14 – 8.10 (m, 2H), 7.76 (d, J =
8.5 Hz, 1H), 7.56 − 7.50 (m, 3H), 6.82 – 6.81 (m, 1H), 6.76 – 6.74 (m, 1H), 6.00 (br, 2H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.9, 162.8, 147.8, 138.4, 131.8, 129.1, 128.9, 126.9,
123.6, 117.2, 115.6, 104.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H11N3OCl 272.0591;
Found: 272.0591.
5-Methoxy-2-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline (3ga)
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 6:1) to give the product as a light yellow
solid: 71% yield, (57 mg); 1H NMR (DMSO-d6, 400 MHz, ppm): δ = 8.13 – 8.10 (m, 2H), 7.78 (d,
J = 8.8 Hz, 1H), 7.64 − 7.60 (m, 3H), 6.80 (br, 2H), 6.46 – 6.45 (m, 1H), 6.35 – 6.33 (m, 1H), 3.77
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(s, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 164.6, 163.1, 162.2, 148.8, 131.4, 129.4, 129.0,
126.8, 124.0, 105.0, 99.6, 99.5, 55.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H14N3O2
268.1086; Found: 268.1088.
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2-Chloro-6-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline (3ha) 12
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 20:1) to give the product as a light yellow
solid: 66% yield, (54 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.15 – 8.10 (m, 2H), 7.81 − 7.79
(m, 1H), 7.59 − 7.51 (m, 3H), 7.42 − 7.40 (m, 1H), 6.74 (t, J = 7.9 Hz, 1H), 6.44 (br, 2H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 164.0, 163.0, 143.4, 132.2, 131.8, 129.1, 126.9, 126.4,
123.6, 120.0, 116.5, 106.8.
2,4-Dimethyl-6-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline (3ia)
The title compound was prepared according to the general working procedure and purified by
column chromatography (petroleum ether / ethyl acetate = 10:1) to give the product as a light yellow
solid: 61% yield, (48 mg); 1H NMR (DMSO-d6, 400 MHz, ppm): δ = 8.16 – 8.12 (m, 2H), 7.65 −
7.61 (m, 3H), 7.57 (s, 1H), 7.04 (s, 1H), 6.42 (br, 2H), 2.23 (s, 3H), 2.16 (s, 3H); 13C{1H}NMR
(CDCl3, 100 MHz, ppm): δ = 165.0, 162.6, 143.3, 134.6, 131.5, 129.0, 126.9, 125.6, 125.4, 123.9,
123.1, 105.3,20.3,17.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H16N3O 266.1298; Found:
266.1298.
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
E-mail: zhenlei@fynu.edu.cn
shenglq2015@163.com
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS：
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We are grateful to the Talent Project of Fuyang Normal University (No. 2019kyqd0017).
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Supporting Information
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1H NMR and 13C NMR spectra for all the products; This material is available free of charge via the
Internet at http://pubs.acs.org.
REFERENCES
1
(a) Shang, R.; Liu, L. Transition Metal-catalyzed Decarboxylative Cross-coupling
Reaction. Sci. China: Chem. 2011, 54, 1670. (b) Rodríguez, N.; Goossen, L. J.
Decarboxylative Coupling Reactions: a Modern Strategy for C-C Formation. Chem.
Soc. Rev. 2011, 40, 5030. (c) Shen, C.; Zhang, P.; Sun, Q.; Bai, S. Hor, T. S. A.; Liu,
X. Recent Advances in C-S Bond Formation via C-H Bond Functionalization and
Decarboxylation. Chem. Soc. Rev, 2015, 44, 291.
2
3
Wei, Y.; Hu, P.; Zhang, M. Z.; Su, W. P. Metal-catalyzed Decarboxylative C-H
Functionalization, Chem. Rev, 2017, 117, 8864.
(a) Yan, M.; Kawamata, Y. and Baran, P. S. Synthetic Organic Electrochemical
Methods Since 2000: On the Verge of a Renaissance. Chem. Rev., 2017, 117, 13230.
(b) Jiang, Y.; Xu, K. and Zeng, C. Use of Electrochemistry in the Synthesis of
Heterocyclic Structures. Chem. Rev., 2018, 118, 4485. (c) Wiebe, A.; Gieshoff, T.;
Mçhle, S.; Rodrigo, E.; Zirbes, M. and Waldvogel, S. R. Electrifying Organic Synthesis.
Angew. Chem. Int. Ed. 2018, 57, 5594. (d) Tang, S.; Liu. Y. C. and Lei, A. W.
Electrochemical Oxidative Cross-coupling with Hydrogen Evolution: a Green and
Sustainable Way for Bond Formation. Chem. 2018, 4, 27. (e) Qian, P.; Zha, Z. G. and
Wang, Z. Y. Recent Advances in C-H Functionalization with Electrochemistry and
Various Iodine-containing Reagents. ChemElectroChem. 2020, 7, 2527. (f) Singh, M.;
Sharma, L. K.; Dubey, R.; Patel, M. K.; Prakash, V.; Singh, R. K. P. An
Electrochemical Approach for the Direct Synthesis of 3, 5-Disubstituted 1, 2, 4-
Triazoles from Nitriles and Hydrazides. ChemistrySelect. 2020, 5, 3847. (g) Yang, Z.;
ACS Paragon Plus Environment

Page 21 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Zhang, J. Q.; Hu, L. P.; Li, L. J.; Liu, K.; Yang, T.; Zhou, C. S. Electrochemical
Oxidative Intramolecular N−S Bond Formation: Synthesis of 3-Substituted 5-Amino-
1,2,4-Thiadiazoles. J. Org Chem. 2020, 85, 3358. (h) Yang, Z.; Zhang, J. Q.; Hu, L. P.;
Li, A.; Li, L. J.; Liu, K.; Yang, T.; Zhou, C. S. Electrochemical HI-mediated
Intermolecular C−N Bond Formation to Synthesize Imidazoles from Aryl Ketones and
Benzylamines. J. Org Chem. 2020, 85, 5952.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
(a) Wang, H.-B.; Huang, J-M. Decarboxylative Coupling of a-Keto Acids with ortho-
Phenylenediamines Promoted by an Electrochemical Method in Aqueous Media. Adv.
Synth. Catal. 2016, 358, 1975. (b) Zhao, Y.; Lai, Y.-L.; Du, K-S.; Lin, D-Z. and Huang,
J-M. Electrochemical Decarboxylative Sulfonylation of Cinnamic Acids with
Aromatic Sulfonylhydrazides to Vinyl Sulfones. J. Org Chem. 2017, 82, 9655. (c) Lin,
D-Z. and Huang, J-M. Electrochemical N-Formylation of Amines via Decarboxylation
of Glyoxylic Acid. Org. Lett. 2018, 20, 2112. (d) Yang, S-M.; He, T-J.; Lin, D-Z. and
Huang, J-M. Electrosynthesis of (E)-Vinyl Thiocyanates from Cinnamic Acids via
Decarboxylative Coupling Reaction. Org. Lett. 2019, 21, 1958. (e) Li, F-Y.; Lin, D-Z.;
He, T-J.; Zhong, W-Q. and Huang, J-M. Electrochemical Decarboxylative
Trifluoromethylation of α, β
ChemCatChem. 2019, 11, 2350
‐Unsaturated Carboxylic Acids with CF3SO2Na.
5
(a) Luo, X-Y.; Ma, X. F.; Lebreux, F.; Marko, I. E.; Lam, K. Electrochemical
Methoxymethylation of Alcohols - a New, Green and Safe Approach for the
Preparation of MOM Ethers and Other Acetals. Chem. Commun, 2018, 54, 9969. (b)
Lecch, M. C.; Lam, K. Electrosynthesis Using Carboxylic Acid Derivatives: New
Tricks for Old Reactions, Acc. Chem. Res., DOI: 10.1021/acs.accounts.9b00586.
Koyanagi, T.; Herath. A.; Chong. A.; Ratnikov. M.; Valiere.; A.; Chang. J.; Molteni.
V.; Loren. J. One-Pot Electrochemical Nickel-Catalyzed Decarboxylative Sp2-Sp3
Cross-Coupling. Org. Lett. 2019, 21, 816.
6
7
Xiang, J. B.; Shang, M.; Kawamata, Y.; Lundberg, H.; Reisberg, S. H.; Chen, M.;
Mykhailiuk, P.; Beutner, G.; Collins, M. R.; Davies, A.; Bel, M. D.; Gallego, G. M.;
Spangler, J. E.; Starr, J. S.; Yang, L.; Blackmond, D. G.; Baran, P. S. Hindered Dialkyl
Ether Synthesis with Electrogenerated Carbocations, Nature. 2019. 573, 398.
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8
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Duirng the preparation of this manuscript, an electrochemical method for the
construction of 2,5-disubstituted 1,3,4-oxadiazoles from α-keto acids and
acylhydrazines was reported by Lei. See: Lu, F. L.; Gong, F. P.; Li, L. S.; Zhang, K.;
Li, Z.; Zhang, X. W.; Yin, Y.; Wang, Y.; Gao, Z. W.; Zhang, H.; Lei, A. W.
Electrochemical Synthesis of 2,5-Disubstituted 1,3,4-Oxadiazoles from α-Keto Acids
and Acylhydrazines under Mild Conditions. Eur. J. Org. Chem., 2020, 22, 3257.
Wang, Q-Q.; Xu, K.; Jiang, Y-Y.; Liu, Y-G.; Sun, B-G. and Zeng, C-C. Electrocatalytic
Minisci Acylation Reaction of N-Heteroarenes Mediated by NH4I. Org. Lett. 2017, 19,
5517.
10
11
12
13
14
15
16
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18
19
20
21
22
23
24
25
26
27
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50
51
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53
54
55
56
57
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60
9
10 (a) Qian, P.; Bi, M. X.; Su, J. H.; Zha, Z. G. and 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. (b) Qian, P.;
Su, J. H.; Wang, Y. K.; Bi, M. X.; Zha, Z. G. and Wang, Z. Y. Electrocatalytic
C−H/N−H Coupling of 2′-Aminoacetophenones for the Synthesis of Isatins. J. Org
Chem. 2017, 82, 6434. (c) Qian, P.; Yan, Z. C.; Zhou, Z. H.; Hu, K. F.; Wang, J. W.;
Li, Z. B.; Zha, Z. G. and 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. (d) Qian, P.; Yan, Z. C.;
Zhou, Z. H.; Hu, K. F.; Wang, J. W.; Li, Z. B.; Zha, Z. G. and Wang, Z. Y.
Electrocatalytic Tandem Synthesis of 1,3-Disubstituted Imidazo[1,5-a]quinolines via
Sequential Dual Oxidative C(sp3)-H Amination in Aqueous Medium, J. Org Chem.
2019, 84, 3148. (e) Qian, P.; Zhou, Z. H.; Hu, K. F.; Wang, J. W.; Li, Z. B.; Zha, Z. G.
and Wang, Z. Y. Wang, Electrocatalytic Three-Component Reaction: Synthesis of
Cyanide-Functionalization Imidazo-fused N-Heterocycles, Org. Lett. 2019, 21, 6403.
11 Li, Z.; Zhan, P. and Liu, X. 1,3,4-Oxadiazole: A Privileged Structure in Antiviral
Agents. Mini-Rev. Med. Chem., 2011, 11, 1130.
12 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.
,
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Page 23 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13 Diao, P. H.; Ge, Y. Q.; Zhang, W. P.; Xu, C.; Zhang, N. N.; Guo, C. Synthesis of 2,5-
Disubstituted 1,3,4-Oxadiazoles by Visible-light-mediated Decarboxylation–
cyclization of Hydrazides and Diketones. Tetrahedron Lett. 2018, 59, 767.
14 Köhler. S. C.; Vahdati. S.; Scholz. M. S.; Wiese. M.; Structure Activity Relationships,
Multidrug Resistance Reversal and Selectivity of Heteroarylphenyl ABCG2 Inhibitors.
Eur. J. Med. Chem. 2018, 146, 483.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15 Venkatagiri. N.; Krishna. T.; Thirupathi. P.; Bhavani. K.; Reddy. C. K. Synthesis,
Characterization, and Antimicrobial Activityof a Series of 2-(5-Phenyl-1,3,4-
oxadiazol-2-yl)-N-[(1-aryl-1H-1,2,3-triazol-4-yl)methyl]anilines
Using
Click
Chemistry. Russian Journal of General Chemistry, 2018, 88, 1488.
16 Ramkumar. N.; Nagarajan. R. A New Route to the Synthesis of Ellipticine Quinone
from Isatin. Tetrahedron Lett. 2014, 55, 1104.
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