Electrochemical Tri- and Difluoromethylation-Triggered Cyclization Accompanied by the Oxidative Cleavage of Indole Derivatives

Article abstract of DOI:10.1002/chem.202005368

Considering their unique roles in organic synthesis, and pharmaceutical and agrochemical applications, the development of fluoroalkylation, cyclization, and indole oxidative cleavage are important topics. Herein, an unprecedented electrochemical tri- and difluoromethylation/cyclization/indole oxidative cleavage process occurring in an undivided cell is presented. The protocol employs a readily prepared Langlois reagent as the fluoroalkyl source, affording a series of tri- or difluoromethylated 2-(2-acetylphenyl)isoquinoline-1,3-diones in good yields with excellent stereoselectivity. It is worth noting that this new methodology merges the fluoroalkylation/cyclization of N-substituted acrylamide alkenes with the oxidative cleavage of an indole C(2)=C(3) bond under external oxidant-free conditions.

Full text of DOI:10.1002/chem.202005368

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Chemistry—A European Journal
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&
Fluoroalkylation
Electrochemical Tri- and Difluoromethylation-Triggered
Cyclization Accompanied by the Oxidative Cleavage of Indole
Derivatives
+
[a]
+ [a]
[a]
[a]
[a]
[a]
Xin Yuan , Yu-Sheng Cui , Xin-Peng Zhang, Long-Zhou Qin, Qi Sun, Xiu Duan,
[
a]
[b, c]
[a]
[a]
Lin Chen, Guigen Li,
Jiang-Kai Qiu,* and Kai Guo*
Abstract: Considering their unique roles in organic synthe-
sis, and pharmaceutical and agrochemical applications, the
development of fluoroalkylation, cyclization, and indole oxi-
dative cleavage are important topics. Herein, an unprece-
dented electrochemical tri- and difluoromethylation/cycliza-
tion/indole oxidative cleavage process occurring in an undi-
vided cell is presented. The protocol employs a readily pre-
pared Langlois reagent as the fluoroalkyl source, affording a
series of tri- or difluoromethylated 2-(2-acetylphenyl)isoqui-
noline-1,3-diones in good yields with excellent stereoselec-
tivity. It is worth noting that this new methodology merges
the fluoroalkylation/cyclization of N-substituted acrylamide
alkenes with the oxidative cleavage of an indole C(2)=C(3)
bond under external oxidant-free conditions.
Introduction
metric amounts of oxidants and transition-metal catalysts to
generate fluoromethyl radicals (Scheme 1a). To a certain
extent, photoredox catalysis is advantageous over convention-
Owing to their synthetic utility and unique biological proper-
ties, organofluorine compounds are of great importance in or-
ganic synthesis, and pharmaceutical and agrochemical applica-
[
4]
al radical fluoroalkylation. However, its development has also
been restricted by the high cost of Ir- or Ru-based photoredox
catalysts. Recently, organic electrosynthesis has been presented
[
1]
tions. Therefore, methods for the installation of a fluoroalkyl
group into drugs or bioactive molecules continue to be in
strong demand as the incorporation of such a group can sig-
nificantly modify their metabolic stability, lipophilicity, and bio-
[
2]
potency. Among the existing methods, radical-triggered fluo-
roalkylation/cyclization of unactivated alkenes is one of the
most promising strategies for the synthesis of complex fluori-
nated compounds, which requires the selection of suitable flu-
oroalkyl sources and the specific design of fluoroalkyl radical-
[3]
triggered transformations. Indeed, such transformations of al-
kenes are very well documented and usually require stoichio-
+
+
[
a] X. Yuan, Y.-S. Cui, X.-P. Zhang, L.-Z. Qin, Q. Sun, X. Duan, L. Chen,
J.-K. Qiu, Prof. K. Guo
College of Biotechnology and Pharmaceutical Engineering
Nanjing Tech University
30 Puzhu Rd S, Nanjing, 211816 (P. R. China)
E-mail: qiujiangkai@njtech.edu.cn
guok@njtech.edu.cn
[
b] G. Li
Institute of Chemistry & Biomedical Science
Nanjing University
No.163, Xianlin Avenue, Qixia District, Nanjing 210093 (P. R. China)
[
c] G. Li
Department of Chemistry and Biochemistry
Texas Tech University
Lubbock, TX 79409-1061 (USA)
+
[
] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under:
Scheme 1. Overview of the electrochemical fluoroalkylation/cyclization/
https://doi.org/10.1002/chem.202005368.
indole oxidative cleavage strategy employed in this study.
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as an efficient and mild alternative to traditional chemical ap-
tions (Scheme 1b). Herein, a mild and environmentally friendly
approach is reported for the preparation of fluoroalkylated ar-
ylpiperidine-2,6-dione derivatives, bearing both CF and CF H
[5]
proaches for carrying out redox transformations, wherein the
redox processes proceed smoothly under extremely mild con-
ditions (room temperature, with no hazardous reagents re-
3
2
units, produced through the reaction between N-substituted
2-aryl indoles and Langlois reagent. Remarkably, this powerful
and green strategy exhibits a wide substrate scope, broad
functionality tolerance, with the formation of a tetrasubstituted
stereogenic center and an NÀC axis of chirality with high ste-
reoselectivity. To the best of our knowledge, the merging of
the three radical reactions—fluoroalkylation, tandem cycliza-
tion, and indole oxidative cleavage—in one step under mild
electro-oxidation conditions has never been reported.
[
6]
quired). In particular, electrochemical protocols for the tri-
fluoromethylation/cyclization of N-arylacrylamides by using
Langlois reagent (CF SO Na) have been extensively em-
3
2
[
7]
ployed. For example, the challenging task of constructing
functionalized oxindoles has been accomplished by the groups
[
7d]
[7e]
[7g]
of Lei, Zeng, Mo, and other groups (Scheme 1a). Also,
[8]
addition of various carbon or phosphorous radicals, including
[
8c]
fluorinated ones, to the same 2-Ph indoles N-substituted by
an acryloyl group is known to be promoted by electrochemis-
[8a]
[8b,c]
[8d,e]
try, visible light,
or stoichiometric oxidants.
The differ-
Results and Discussion
ence with the present work is that the oxidative cleavage of
the indole does not occurs in these previous reports. In spite
of these significant achievements, the development of general
methods for the fluoromethylation/cyclization of unactivated
alkenes under mild conditions with readily available reagents
is still highly desirable.
The study was initiated by screening the optimal electrolysis
conditions by using 2-methyl-1-(3-methyl-2-phenyl-1H-indol-1-
yl) prop-2-en-1-one (1a) and CF SO Na (2a) as model sub-
3
2
strates to examine the reaction conditions in an undivided cell
with a graphite anode and a platinum cathode. This electro-
chemical process proceeded smoothly, giving the trifluorome-
thylated 2-(2-acetylphenyl)isoquinoline-1,3-diones (3a’ and
3a’’) in 79% yield as a 13:1 mixture of diastereoisomers (con-
sidering the steric hindrance and X-ray diffraction (XRD) results,
it was speculated that 3a“ was the main product), in a mixed
solvent system (CH CN/H O=5:1, 6 mL) in the presence of
The selective oxidative cleavage of heterocyclic C=C bonds
[9]
is a promising strategy for organic transformations. In partic-
ular, the oxidative cleavage of the indole C(2)=C(3) double
bond has attracted considerable attention for the construction
[10,11]
of N-formylated products.
In 1951, Witkop and co-workers
reported the first chemical oxidative cleavage of the indole
3
2
C(2)=C(3) double bond through catalytic oxidation (Pt/O ) and
0.1 mmol of Et NClO as the electrolyte when using a
4 4
2
[12]
À2
also by autoxidation, and since then this reaction has been
greatly developed into the Witkop–Winterfeldt oxidation. For
the preparation of 2-aminoarylcarbonyl substrates, various
methods using different reagents, such as peracids, periodic
acid, chromic acid, and ozone, have gained attention
4 mAcm constant current at 508C for 14 h (Table 1, entry 1).
Changing the electrolyte to nBu NBF , nBu ClO , or Et NBF led
4
4
4
4
4
4
to lower yields (Table 1, entries 2–4). The results of electrode
screening indicated that a carbon rod cathode and platinum
both from the industrial and academic communi-
[13]
ties. More recently, the processes of visible-light-
induced aerobic radical C=C bond cleavage and oxy-
genation of indoles have been developed by several
[a]
Table 1. Optimization of the reaction conditions.
[
14]
groups (Scheme 1a). In contrast to most tradition-
al methods, which are limited by their chemical oxi-
dant and reductant requirements, electrochemical
organic synthesis, considered as a powerful and sus-
tainable synthetic tool, has been scarcely explored
for the oxidative cleavage of indoles with the forma-
tion of carbonyl and amide fragments.
[b]
Entry
Deviation from standard conditions
none
3a (3a’ and 3a’’), yield [%]
1
2
3
4
5
6
7
8
9
79
14
27
trace
46
33
60
20
21
nBu
nBu
4
4
NBF
ClO
4
as the electrolyte
as the electrolyte
Encouraged by the advances made in fluoroalkyla-
tion/cyclization/indole oxidative cleavage, this study
was devised to investigate whether the fluoromethyl
radicals electro-oxidatively generated by using Lan-
glois reagent (CF SO Na or CF HSO Na), which can
4
Et
4
NBF
4
as the electrolyte
C (+)jC (À) instead of C (+)jPt (À)
Pt (+)jPt (À) instead of C (+)jPt (À)
À2
À2
8 mAcm instead of 4 mAcm , 10 h
À2
À2
12 mAcm instead of 4 mAcm , 10 h
THF/H O instead of CH CN/H
3
2
2
2
2
3
2
O
be easily handled, are bench-stable and inexpensive
fluoroalkyl sources, and could react with electron-
poor alkenes tethered to substituted indoles and
then trigger cyclization to form a benzo[4,5]imida-
zo[2,1-a]isoquinolin-6(5H)-one intermediate, fol-
lowed by the selective oxidative cleavage of the
C(2)=C(3) double bond in the indole skeleton to
afford the desired tri- or difluoromethylated 2-(2-ace-
tylphenyl)isoquinoline-1,3-diones under mild condi-
10
without current
without water
N.D.
N.D.
76
1
1
12
reaction in N
2 h instead of 14 h
2
13
trace
[a] Standard conditions: 1a (0.2 mmol), 2a (0.4 mmol), Et
4 4 3
NClO (0.4 mmol) in CH CN/
H O solvent (6.0 mL, v/v=5/1) in an undivided cell with carbon cloth (10”10”
.3 mm ) as the anode, Pt plate (10”10”0.1 mm ) as the cathode, under a constant
current of 4.0 mAcm at 508C for 14 h. [b] The isolated yield is based on 1a. N.D.=
2
3
3
0
À2
not detected.
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plate anode had a negative effect on product formation
Table 1, entries 5 and 6), and increasing or decreasing the
position of the indole ring was found to be tolerated, resulting
in the formation of their corresponding products with efficien-
cy (49%, 3p). Various different substituents at the C5-position
of the indole ring were also readily tolerated in this system, de-
livering the corresponding products in good to moderate
yields (3j–3o). Besides these examples, substrates containing
an electron-donating methyl group at the C6-position of the
indole ring were found to be similarly suitable (80%, 3q).
Owing to their special chemical and biological properties, di-
fluoromethyl compounds are important and widely used in the
(
electric current was found to lead to lower yields (Table 1, en-
tries 7 and 8). When the CH CN/H O mixed solvent was re-
3
2
placed with THF/H O, the yield of product 3a decreased signif-
2
icantly (Table 1, entry 9). Furthermore, the electric current and
water proved to be crucial parameters for this transformation,
as evidenced by the dramatic diminishing of efficiency when
the reactions were carried out in the absence of electric cur-
rent or water (Table 1, entries 10 and 11). Performing the reac-
tion under inert atmosphere did not improve the yield
[
15]
pharmaceutical and agrochemical industries. Therefore, the
method was extended to an electrochemical difluoromethyla-
tion/indole oxidative cleavage reaction using N-substituted 2-
(
Table 1, entry 12). Notably, the reaction efficiency had a pro-
found dependence on the reaction time. Upon reducing the
reaction time to 2 h, only a trace amount of product 3a was
detected (Table 1, entry 13).
aryl indoles 1 as the starting materials and the CF H-analog of
2
the Langlois reagent CF HSO Na (2b) as the difluoromethyl
2
2
With the optimized standard reaction conditions established,
the substrate scope of this electrocatalytic trifluoromethyla-
tion/cyclization/indole oxidative cleavage reaction was then in-
vestigated. As shown in Scheme 2, a wide variety of N-substi-
tuted 2-aryl indoles 1, bearing an unactivated terminal alkene
moiety were examined. Notably, the variation in the electronic
source (Scheme 3). Gratifyingly, it was found that using 20%
MnCl ·4H O as a mediator, with 2.0 equivalents of Et NClO as
2
2
4
4
an electrolyte, a carbon anode and a platinum cathode, under
a constant electric current of 4 mA for 14 h, this difluoromethy-
lation/indole oxidative cleavage transformation tolerated vari-
ous different electrophilic functional substituents, and the de-
sired difluoromethyl-substituted arylpiperidine-2,6-dione prod-
ucts 5 were obtained in moderate to good yields (25–57%,
5a–5l). Moreover, the stereostructure of 5g was identified by
single-crystal XRD (for details see the Supporting Information,
1
properties of the substituents (R ) at the para position of the
2
-phenyl moiety of the N-substituted 2-aryl indole was found
to have little influence on its catalytic efficiency. Electron-neu-
tral substituents (-Me, -Et), electron-withdrawing groups (-F, -Cl,
-
Br, -CF ), and an electron-donating group (-MeO) were suc-
CCDC 2023507) and the ratio of the obtained CF H-containing
3
2
cessfully introduced into the structure, giving the correspond-
ing products in 56–79% yields (3a–3g). Both ortho or meta
substitution on the 2-phenyl moiety were also well tolerated,
and the meta-substituted analogs afforded the corresponding
products with 1.6:1 regioselectivity (3h and 3i). Subsequently,
the electronic nature of the substituents located in the indole
ring was also investigated. The presence of a phenyl at the C3-
2-(2-acetylphenyl)isoquinoline-1,3-dione diastereomer mixture
was found to be 2:1–4:1.
Once the method was established, a series of control reac-
tions were carried out to determine and understand the reac-
Scheme 2. Overview of the electrochemical trifluoromethylation/cyclization/
indole oxidative cleavage reaction. Reaction conditions: 1 (0.2 mmol), 2a
Scheme 3. Overview of the electrochemical difluoromethylation/cyclization/
indole oxidative cleavage reaction. Reaction conditions: 1 (0.2 mmol), 2b
(
1
0.4 mmol), Et
4
NClO
4
(0.4 mmol), CH
3
CN/H
2
O as the solvent (6.0 mL, v/v=5/
4 4 3 2
(0.4 mmol), Et NClO (0.4 mmol), and CH CN/H O as the solvent (6.0 mL, v/
3
) in an undivided cell with carbon (10 mm”10 mm”0.3 mm) as the anode,
v=5/1) in an undivided cell with carbon (10”10”0.3 mm ) as the anode, Pt
3
Pt plate (10 mm”10 mm”0.1 mm) as the cathode, under a constant current
of 4.0 mAcm at 508C for 14 h. The isolated yields (diastereomeric ratio of
plate (10”10”0.1 mm ) as the cathode, under a constant current of
À2
À2
4.0 mAcm at room temperature for 14 h. The isolated yields (diastereo-
the major isomer as drawn) are based on 1.
meric ratio of the major isomer as drawn) are based on 1.
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tion mechanism of the electrocatalytic difluoromethylation/
cyclization/indole oxidative cleavage reaction (Scheme 4). First,
the radical trapping reagent 2,2,6,6-tetramethylpiperidine-1-
oxyl (TEMPO) were added as radical scavengers under standard
reaction conditions (Scheme 4a). As expected, the reactions
were completely quenched, and the corresponding trapping
adducts were detected (see the Supporting Information for full
details), which indicated that a tri- or difluoromethyl radical
was involved in this reaction. Second, studies were carried out
to understand the sequence of the three reactions, fluoroalky-
lation, cyclization, and indole oxidative cleavage. As shown in
Scheme 4b, electrolysis of 1a and 2a over 2 h led to the fluo-
roalkylation/cyclization product trifluoromethylated indolo[2,1-
a]isoquinoline 6 being obtained in 65% yield. Subsequently, 6
was reacted with 2a under the optimized conditions deter-
mined in this study. Furthermore, 6 was reacted in the pres-
ence of Langlois reagent under the optimized conditions for
sence of Langlois reagent under the optimal conditions, and
the corresponding indole oxidative cleavage product 7 was
isolated in 71% yield (Scheme 4d). Taken together, it was
speculated that 6 might be the key intermediate of this elec-
trochemical transformation. In other words, the fluoroalkylation
and cyclization steps may procced prior to the oxidative cleav-
age of the indole C=C double bond. Next, the source of the
oxygen atoms on the two newly formed carbonyl groups of
the target product was investigated. When the reaction was
performed in the absence of water, only a trace amount of the
desired product was obtained (Table 1, entry 11). As this trans-
formation also proceeded smoothly under a nitrogen atmos-
phere, it was conjectured that the oxygen atoms present in
the structure might not originate from oxygen in the air
(Table 1, entry 12). To investigate this further, an isotope label-
ing study was carried out (Scheme 4 f). When substrates 1 f
18
and 2a were reacted under optimal conditions with O -la-
18
18
6
h to obtain the target product 3a in a yield of 93%
beled H O , doubly labeled [O ] 3 f was detected (see the
2
(
Scheme 4c). Moreover, substrate 1r was reacted in the ab-
Supporting Information for full details). These results indicate
that the source of the two newly formed carbonyl groups
might be the H O that is present in the reaction solvent.
2
Cyclic voltammetry (CV) experiments were performed to
study the redox potentials of the substrates. As shown in
Scheme 5, the oxidation potentials of CF SO Na and
3
2
CF HSO Na were observed 1.1 and 0.8 V (vs. Ag/AgCl), respec-
2
2
tively, well below the oxidation potential of the substrate 1a
1.58 V), indicating that CF SO Na and CF HSO Na are much
(
3
2
2
2
Scheme 4. (a–e) A series of control reactions carried out to determine and
understand the reaction mechanism and sequence of the electrocatalytic di-
fluoromethylation/cyclization/indole oxidative cleavage reaction. (a–f) Reac-
tions were carried out by using the respective starting reagent (0.2 mmol)
Scheme 5. CV voltammetry studies. Glassy carbon working electrode, plati-
num wire counter electrode, Ag/AgCl as the reference electrode. Scan
À1
either in the presence or absence of CF
3
SO
2
Na (0.4 mmol) to furnish the
rate:0.1 Vs . Conditions: a) 1a (0.2 mmol), 2a (CF
3
SO
O (5:1, 6.0 mL); b) 1a (0.2 mmol), 2b
(0.4 mmol), 4a (MnCl ·4H O, 20 mol%) in
2
Na, 0.4 mmol),
1
8
products, the isolated yields are based on the starting reagent. (f) O -la-
Et
(CF
CH
4
NClO
SO Na, 0.4 mmol), Et
CN/H O (5:1, 6.0 mL).
4
(0.4 mmol) in CH
3 2
CN/H
18
beled H
2
O
reaction to determine the origin of the newly formed double
2
2
4
NClO
4
2
2
carbonyl groups present in the structures.
3
2
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easier to electrochemically oxidize to generate their corre-
at the cathode, releasing molecular hydrogen. It should be
sponding radicals than the N-substituted 2-aryl indoles 1a.
mentioned that the generation of the CF H radical is different
2
III
However, the much lower oxidation potentials of the CF and
from the CF radical. At the anode, the Mn -CF H species is
3
3
2
II
CF H radical precursors than those of the substrates 1a also
generated by anodic oxidation of Mn in the presence of Lan-
2
[
6j,f,7g,17]
shows that the radical fluoroalkylation/cyclization steps may
take place before the oxidative cleavage of the indole double
bond.
glois reagent.
Subsequently, Mn-assisted delivery of
CF H· to the olefin moiety and went through the same path as
2
the CF radical to obtain the target product 3 (for details, see
3
On the basis of the trapping of intermediates and related lit-
erature reports, a possible mechanism for the electrochemical
radical fluoroalkylation/indole oxidative cleavage reaction was
Figure S6 in the Supporting Information).
Conclusion
devised and is shown in Scheme 6. Initially, a CF radical is gen-
3
erated from 2a by anodic oxidation, and addition of the N-
substituted 2-aryl indole 1 affords a new carbon radical inter-
mediate A, which rapidly undergoes radical cyclization to pro-
duce intermediate B. Subsequently, the anodic oxidation of in-
termediate B and the following deprotonation afford the cycli-
zation product 6. Next, the cyclized product 6 is oxidized di-
rectly at the anode into a radical cation intermediate D. Then,
the C3-position of the intermediate D is immediately attacked
by a hydroxide ion formed by the reduction of water mole-
cules at the cathode to give the intermediate E. The resulting
iminium ion E is then poised to be attacked by a second hy-
droxide ion at the C2-position to eventually deliver intermedia-
te F as the more stable isomer (as most of the substrates are
We have developed an electrocatalytic fluoroalkylation/cycliza-
tion/indole oxidative cleavage reaction under catalyst- and oxi-
dant-free conditions. A vast array of tri- or difluoromethylated
2
-(2-acetylphenyl)isoquinoline-1,3-diones were obtained in
moderate to good yields with excellent stereoselectivity by
using a readily accessible Langlois reagent as the CF or CF H
3
2
source. Detailed mechanistic studies provided strong support
for the radical fluoroalkylation, cyclization, and indole oxidative
cleavage sequence. Moreover, this radical sequence provides a
highly valuable methodology for fluorinated diketone synthesis
and could be further elaborated to access more valuable heter-
ocyclic compounds. By the way, another significant work of
our group is in progress on the oxidative cleavage of indoles
by an electrochemical method.
3
-substituted indoles, the two hydroxyl groups are trans to
each other to avoid electronic repulsion). Intermediate F then
undergoes deprotonation to give the intermediate G and the
following carbon–carbon bond cleavage to form intermedia-
Experimental Section
[
16]
te H.
Finally, intermediate H is deprotonated to give the
General procedure A for trifluoromethylated products
target product 3. Hydrogen cations are concurrently reduced
The electrocatalysis was carried out in an undivided cell under air,
with a carbon anode (10 mm”10 mm”0.3 mm) and a platinum
cathode (10 mm”15 mm). Substrate
1 (0.2 mmol, 1.0 equiv),
CF SO Na (0.4 mmol, 2.0 equiv), Et NClO (0.4 mmol, 2.0 equiv)
3
2
4
4
were dissolved in the solvent mixture CH CN/H O (5:1, 6 mL). Elec-
3
2
trocatalysis was performed at 508C with a constant current of
.0 mA maintained for 14 h. After the reaction was completed, the
4
anode and cathode were washed with ethyl acetate (3”5 mL), and
all the solvent was extracted with ethyl acetate. The combined or-
ganic extracts were dried over Na SO , concentrated in vacuum,
2
4
and the resulting reside was purified by silica gel column chroma-
tography (eluent: petroleum ether/EtOAc=5:1) to afford the de-
sired product 3.
General procedure B for difluoromethylated products
The electrocatalysis was carried out in an undivided cell under air,
with a carbon anode (10 mm”10 mm”0.3 mm) and a platinum
cathode (10 mm”10 mm”0.1 mm). Substrate
1
(0.2 mmol,
1
2
.0 equiv), CF HSO Na (0.4 mmol, 2.0 equiv), Et NClO (0.4 mmol,
2
2
4
4
.0 equiv), and MnCl ·4H O (0.04 mmol, 20%) were dissolved in the
2
2
solvent mixture CH CN/H O (5:1, 6 mL). Electrocatalysis was per-
3
2
formed at room temperature with a constant current of 4.0 mA
maintained for 14 h. After the reaction was completed, the anode
and cathode were washed with ethyl acetate (3”5 mL), and all the
solvent was extracted with ethyl acetate. The combined organic
extracts were dried over Na SO , concentrated in vacuum, and
2
4
the resulting reside was purified by silica gel column chromatogra-
phy (eluent: petroleum ether/EtOAc=5:1) to afford the desired
product 5.
Scheme 6. A possible mechanism for the electrochemical radical trifluoroal-
kylation/cyclization/indole oxidative cleavage procedure studied in this
work.
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Deposition number 2023507 contains the supplementary crystallo-
graphic data for this paper. These data are provided free of charge
by the joint Cambridge Crystallographic Data Centre and Fachin-
formationszentrum Karlsruhe Access Structures service.
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Acknowledgments
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21702103, 21522604,
U1463201, and 21402240) and the Youth in Jiangsu Province
Natural Science Fund (Grant No. BK20150031, BK20130913, and
BY2014005-03).
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Manuscript received: December 16, 2020
Revised manuscript received: January 25, 2021
Version of record online: March 10, 2021
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