Electrocatalytic Dehydrogenative Cyclization of 2-Vinylanilides for the Synthesis of Indoles

Article abstract of DOI:10.1021/acs.joc.1c00988

Indole is prevalent in bioactive compounds and natural products. The development of efficient and sustainable methods to access this privileged structural scaffold has been a long-standing interest of synthetic chemists. Herein, we report an electrocataly

Full text of DOI:10.1021/acs.joc.1c00988

pubs.acs.org/joc
Article
Electrocatalytic Dehydrogenative Cyclization of 2‑Vinylanilides for
the Synthesis of Indoles
Yun-Tao Zheng, Jinshuai Song, and Hai-Chao Xu*
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ABSTRACT: Indole is prevalent in bioactive compounds and
natural products. The development of efficient and sustainable
methods to access this privileged structural scaffold has been a
long-standing interest of synthetic chemists. Herein, we report an
electrocatalytic method for the synthesis of indoles through
dehydrogenative cyclization of 2-vinylanilides. The reactions
employ an organic redox catalyst and do not require any external
chemical oxidant, providing speedy and efficient access to 3-
substituted and 2,3-disubstituted indoles.
but also produce stoichiometric waste products that may
complicate product isolation and interfere with the desired
transformation.12 It is thus highly desirable to develop
alternative technologies to reduce the use and manufacture
of chemical oxidants.
INTRODUCTION
■
The development of efficient and sustainable synthetic
methods to access indoles has been constantly pursued by
organic chemists because of the prevalence of the indole
moiety in bioactive compounds and natural products.1,2
Among various methods for the synthesis of indoles, the
oxidative cyclization of 2-vinylanilines provides regio-specific
access to functionalized indoles from easily available materials.
These reactions are commonly achieved using chemical
oxidants with3−7 or without8−11 transition metal catalysts
(Scheme 1A). The use of chemical oxidants in organic solvents
not only pose significant safety and environmental concerns,
Organic electrochemistry can achieve oxidation and
reduction reactions without using common chemical oxidants
or reductants and is enjoying a renaissance.13−29 Under
electrochemical conditions, dehydrogenative transformations
can proceed through H2 evolution, obviating the need for any
chemical oxidants. This feature makes electrochemistry a
highly attractive tool to address the “oxidant problem”.30 In
this context, many electrochemical methods have been
developed for the synthesis of heterocycles through dehydro-
genative processes.31−33 Related to this work, Wang and co-
workers have reported iodide mediated electrochemical
cyclization of 2-vinylanilides for the synthesis of indoles that
bear no substituents at positions 2 and 3 (Scheme 1B).34 With
our continued interests in electrochemically driven radical
reactions,35−39 we report herein an electrocatalytic method for
the synthesis of 3-substituted and 2,3-disubstituted indoles
(Scheme 1C). The reactions employ an organic redox catalyst
and provides metal- and oxidant-free access to functionalized
indoles.
Scheme 1. Synthesis of Indoles via Oxidative Cyclization of
2-Vinylanilines
Special Issue: Electrochemistry in Synthetic Organic
Chemistry
Received: April 27, 2021
https://doi.org/10.1021/acs.joc.1c00988
J. Org. Chem. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

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Article
RESULTS AND DISCUSSION
Our studies began by optimizing the electrolysis conditions for
the cyclization of sulfonamide 1 (Table 1). The electrolysis
Scheme 2. Scope of the Electrocatalytic Synthesis of
Indoles
■
a
a
Table 1. Optimization of Reaction Conditions
b
entry
deviation from standard conditions
yield, %
c
1
2
3
4
5
6
7
8
none
no electricity
no catalyst 3
45 °C
83
0 (90)
12 (41)
58
25 (8)
34 (32)
42 (23)
42 (14)
25 (47)
58
rt
ferrocene as catalyst
MeCN as solvent
MeCN/H2O (1:1) as solvent
10 mA
Cs2CO3 (0.1 equiv) as base
2.4 g (8.0 mmol) of 1
d
9
10
11
e
71
a
Reaction conditions: RVC anode (100 PPI), Pt cathode, 1 (0.2
b
mmol), solvent (6 mL), argon, 7.5 mA, 1.7 h (2.3 F mol−1). Yield
determined by H NMR analysis using 1,3,5-trimethoxybenzene as
1
the internal standard. Recovery of unreacted 1 shown within
c
d
e
parentheses. Yield of isolated product. Reaction for 1.3 h. Reaction
with a constant current of 300 mA for 1.8 h.
was carried out with a Schlenk tube equipped with a reticulated
vitreous carbon anode (RVC) and a Pt plate cathode. These
experiments revealed that the desired 2,3-disubstituted indole
2 could be isolated in 83% yield when the reaction was
conducted in MeCN/H2O (2:1) at 55 °C employing
phenothiazine 3 as the molecular catalyst (entry 1).
Phenothiazine-based redox catalysts had been previously
studied by us and others for the electrocatalytic generation
of carbon- and nitrogen-centered radicals.40,41 Electricity
(entry 2) and catalyst 3 (entry 3) were critical in obtaining a
synthetically useful yield of 2. Conducting the reaction at 45
°C (entry 4) or rt (entry 5) resulted in reduced yields of 58%
and 25%, respectively. Ferrocene was much less effective than
3 in promoting the formation of 2 despite its extensive
application in electrocatalytic generation of nitrogen- and
carbon-centered radicals (entry 6).42−46 The yield of 2 was
also diminished by changing the solvent to either pure MeCN
(entry 7) or MeCN/H2O (1:1) (entry 8), using a higher
current of 10 mA to increase productivity (entry 9), or
addition of Cs2CO3 as a base (entry 10). Scaling up the
electrochemical reaction by 40-fold to 8.0 mmol produced
indole 2 in 71% yield (entry 11).
The scope of the electrosynthesis of indoles was probed by
changing the substituents on the alkene and the benzene ring
(Scheme 2). Terminal alkenes bearing an alkyl or phenyl group
at the R2 position cyclized smoothly to generate 3-substituted
indoles (4−6). Trisubstituted alkenes, both acyclic (7, 8) and
cyclic ones (9−13), all reacted successfully to afford 2,3-
disubstituted indoles. The benzene ring tolerated substituents
of various electronic properties such as alkyl groups (14, 15),
halides (16−18), CF3O (19), and CF3 (20). Limitations of the
method included the failure in the cyclization of monosub-
a
Reactions were conducted at 0.2 mmol scale. Boc = tert-
butyloxycarbonyl. Ac = acetyl.
stituted alkenes (21) and anilides bearing a Boc (22) or Ac
(23) group on the aniline nitrogen atom. For the latter two
cases, most of the starting anilides remained unreacted.
The catalytic role of phenothiazine 3 in oxidizing the anilide
substrates was confirmed by observing a catalytic current when
its voltammogram was taken in the presence of anilide 1 and a
base, Cs2CO3 (Scheme 3A). The voltammogram of 3 did not
change in the presence of 1 without a base. These results
suggested that the deprotonation of the anilide was critical in
its oxidation by the catalyst.40,42 This observation was
consistent with the dramatic decrease in oxidation potential
of 1 from its neutral form (Ep/2 = 1.41 V) to its conjugate base
(Ep/2 = 0.49 V vs SCE). The oxidation of the latter occurred at
a potential close to that of the catalyst 3 (Ep/2 = 0.37 V vs
SCE).
Based on the results of this study and our previous work,40,42
a possible mechanism was proposed for electrocatalytic
synthesis of indoles (Scheme 3B). The electrochemical
processes commenced with the anodic oxidation of the catalyst
3 to its radical cation 3·+ and cathodic reduction of solvent
H2O to generate H2 and HO−. The cathodically generated
HO− deprotonates the anilide 1 [pKa (TsNHPh) = 8.46 in
H2O] to its conjugate base 24, which is oxidized by radical
B
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recorded on Bruker AV-400, Bruker AV-500, or Bruker AV-600
instruments. Data were reported as chemical shifts in ppm relative to
TMS (0.00 ppm) for 1H and CDCl3 (77.2 ppm) for 13C. High-
resolution mass spectra (ESI) were recorded on an Agilent 6500
series Q-TOF. Sulfonamide substrates 1,47 4s,47 6s,11 8s,48 9s,49
15s,50 16s,51 17s,52 18s,51 21s,11 22s,53 23s54 are known compounds
and prepared according the reported procedures.
Scheme 3. Mechanistic Studies and Proposal
General Procedures for the Electrolysis. A 10 mL Schlenk
tube equipped with a magnetic stir bar was charged with the
sulfonamide substrate (0.2 mmol, 1 equiv), 3 (0.03 mmol, 15 mol %),
and nBu4NPF6 (0.2 mmol, 1 equiv). The Schlenk tube was equipped
with a reticulated vitreous carbon (100 PPI) anode (0.6 cm × 1.0 cm
× 1.2 cm) and a platinum plate (1 cm × 1 cm) cathode (Figure S1).
The resulting mixture was sealed and degassed via vacuum evacuation
and backfilled with argon three times. MeCN (4 mL) and H2O (2
mL) were added. The constant current (7.5 mA) electrolysis was
carried out at 55 °C (oil bath temperature) until complete
consumption of the substrate (monitored by TLC or 1H NMR).
The reaction mixture was cooled to rt and concentrated under
reduced pressure. The residue was chromatographed through silica gel
eluting with ethyl acetate/petroleum ether to give the product.
Procedure for Gram Scale Synthesis of 2. A beaker-type cell
was charged with 1 (2.4 g, 8.0 mmol), 3 (0.48 g, 1.2 mmol), and
nBu4NPF6 (3.2 g, 8.2 mmol). The flask was equipped with a rubber
stopper, two pieces of reticulated vitreous carbon (100 PPI, 1.2 cm ×
4.0 cm × 6.0 cm) as anode, and a platinum plate (5.0 cm × 5.0 cm)
cathode (Figure S2). The flask was flushed with argon. MeCN (160
mL) and H2O (80 mL) were added. The constant current (300 mA)
electrolysis was carried out at 55 °C (oil bath temperature) under
argon for 1.8 h (2.5 F mol−1). The reaction mixture was concentrated
under reduced pressure and then extracted by CH2Cl2. The combined
organic solution was concentrated under reduced pressure. The
residue was chromatographed through silica gel eluting with ethyl
acetate/petroleum ether to give 2 in 71% yield (1.7 g) of 2,3-
dimethyl-1-tosyl-1H-indole (2).8 Pale blue solid (51 mg, 83%)
(petroleum ether/EtOAc = 15:1), electricity = 2.3 F mol−1. 1H NMR
(400 MHz, CDCl3): δ 8.18 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 8.5 Hz,
2H), 7.35 (d, J = 7.6 Hz, 1H), 7.30−7.17 (m, 2H), 7.14 (d, J = 8.0
Hz, 2H), 2.51 (s, 3H), 2.29 (s, 3H), 2.10 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3): δ 144.5, 136.6, 136.4, 132.4, 131.4, 129.9, 126.4,
124.0, 123.3, 118.4, 116.1, 114.7, 21.6, 12.8, 9.0.
3-Methyl-1-tosyl-1H-indole (4).8 White solid (50 mg, 84%)
(petroleum ether/EtOAc = 25:1), electricity = 2.3 F mol−1. 1H NMR
(400 MHz, CDCl3): δ 7.92 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 8.3 Hz,
2H), 7.36 (d, J = 7.6 Hz, 1H), 7.26−7.20 (m, 2H), 7.19−7.13 (m,
1H), 7.09 (d, J = 8.1 Hz, 2H), 2.22 (s, 3H), 2.16 (d, J = 1.3 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 144.8, 135.6, 135.4, 131.9,
129.9, 126.9, 124.7, 123.2, 123.1, 119.5, 118.7, 113.8, 21.7, 9.8.
3-Ethyl-1-tosyl-1H-indole (5). White solid (37 mg, 60%)
(petroleum ether/EtOAc = 15:1), electricity = 2.3 F mol−1. 1H
NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.4
Hz, 2H), 7.46 (d, J = 7.8 Hz, 1H), 7.32−7.26 (m, 2H), 7.24−7.15 (m,
3H), 2.67 (qd, J = 7.5, 1.3 Hz, 2H), 2.30 (s, 3H), 1.30 (t, J = 7.5 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 144.7, 135.5, 131.2, 129.9,
126.8, 125.4, 124.7, 123.0, 122.1, 119.5, 113.8, 21.6, 18.3, 13.4. IR
(neat, cm−1): 2965, 1596, 1447, 1364, 1170, 664, 576. HRMS (ESI),
m/z: (M + Na)+ Calcd for C17H17NO2SNa: 322.0872. Found:
322.0872.
cation 3·+ to form radical 25. Cyclization of 25 followed by
further oxidation by 3·+ and deprotonation affords the final
indole product 2. The failure to form 21 was probably caused
by the more difficult radical cyclization to form a secondary C-
radical. Although no base is added for the preparative
electrolysis, the cathodic reduction can generate continuously
the requisite base to promote the oxidation of the substrate,
showcasing the unique features of electrochemistry.
In summary, we have developed an electrocatalytic method
to accomplish the cyclization of 2-vinylanilides for the
synthesis of functionalized indoles. The reactions employ an
organic redox catalyst and proceed through H2 evolution
without using any external chemical oxidants. The reactions
provide speedy and scalable access to 3-substituted and 2,3-
disubstituted indoles.
3-Phenyl-1-tosyl-1H-indole (6).8 White solid (71 mg, 96%)
(petroleum ether/EtOAc = 20:1), electricity = 2.4 F mol−1. 1H NMR
(400 MHz, CDCl3): δ 8.06 (d, J = 8.3 Hz, 1H), 7.82−7.72 (m, 3H),
7.70 (d, J = 1.8 Hz, 1H), 7.61−7.56 (m, 2H), 7.44 (t, J = 7.6 Hz, 2H),
7.37−7.31 (m, 2H), 7.29−7.23 (m, 1H), 7.17 (d, J = 8.1 Hz, 2H),
2.28 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 145.1, 135.7,
135.4, 133.2, 130.0, 129.4, 129.0, 128.0, 127.7, 127.0, 125.0, 124.1,
123.7, 123.1, 120.6, 114.0, 21.7.
2-Ethyl-3-methyl-1-tosyl-1H-indole (7).55 Pale blue oil (62 mg,
96%) (petroleum ether/EtOAc = 20:1), electricity = 2.3 F mol−1. 1H
NMR (400 MHz, CDCl3): δ 8.21−8.13 (m, 1H), 7.60−7.52 (m, 2H),
7.37−7.33 (m, 1H), 7.27−7.19 (m, 2H), 7.11 (d, J = 8.0 Hz, 2H),
EXPERIMENTAL SECTION
■
General Information. All reagents and solvents were commer-
cially available and used as received. Flash column chromatography
was performed with silica gel (200−300 mesh). NMR spectra were
C
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Article
3.00 (q, J = 7.4 Hz, 2H), 2.28 (s, 3H), 2.13 (s, 3H), 1.26 (t, J = 7.4
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 144.4, 139.0, 136.7,
136.4, 131.7, 129.8, 126.3, 124.1, 123.4, 118.4, 116.2, 115.2, 21.6,
19.9, 15.1, 8.9.
1171, 671. HRMS (ESI), m/z: (M + Na)+ Calcd for C20H23NO2SNa:
364.1342. Found: 364.1341.
3,5-Dimethyl-1-tosyl-1H-indole (15).57 Colorless oil (51 mg,
83%) (petroleum ether/EtOAc = 30:1), electricity = 2.3 F mol−1. 1H
NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.3 Hz, 1H), 7.70 (d, J = 7.7
Hz, 2H), 7.24 (s, 1H), 7.20 (s, 1H), 7.17−7.07 (m, 3H), 2.39 (s, 3H),
2.26 (s, 3H), 2.18 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
144.6, 135.6, 133.7, 132.7, 132.2, 129.8, 126.8, 126.0, 123.3, 119.4,
118.6, 113.5, 21.6, 21.4, 9.8.
2-Methyl-3-phenyl-1-tosyl-1H-indole (8).8 White solid (73
mg, 95%) (petroleum ether/EtOAc = 20:1), electricity = 2.3 F mol−1.
1H NMR (400 MHz, CDCl3): δ 8.26 (d, J = 8.4 Hz, 1H), 7.71 (d, J =
7.6 Hz, 2H), 7.48−7.36 (m, 3H), 7.37−7.25 (m, 4H), 7.25−7.16 (m,
3H), 2.59 (s, 3H), 2.32 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3):
δ 144.8, 136.5, 136.4, 133.2 (2C), 130.2, 130.1, 130.0, 128.7, 127.4,
126.5, 124.3, 123.6, 122.7, 119.3, 114.6, 21.7, 13.6.
5-Chloro-3-methyl-1-tosyl-1H-indole (16).8 Colorless oil (62
mg, 94%) (petroleum ether/EtOAc = 25:1), electricity = 2.3 F mol−1.
1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.8 Hz, 1H), 7.71 (d, J =
8.4 Hz, 2H), 7.38 (d, J = 2.1 Hz, 1H), 7.32−7.30 (m, 1H), 7.24 (dd, J
= 8.8, 2.1 Hz, 1H), 7.18 (d, J = 8.1 Hz, 2H), 2.30 (s, 3H), 2.18 (d, J =
1.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 145.1, 135.3,
133.7, 133.2, 130.0, 129.1, 126.8, 124.9, 124.6, 119.3, 118.2, 114.9,
21.7, 9.7.
9-Tosyl-2,3,4,9-tetrahydro-1H-carbazole (9).8 Colorless oil
(45 mg, 69%) (petroleum ether/EtOAc = 30:1), electricity = 2.4 F
mol−1. 1H NMR (500 MHz, CDCl3): δ 8.14 (d, J = 8.1 Hz, 1H), 7.64
(d, J = 8.3 Hz, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.27−7.22 (m, 1H),
7.22−7.18 (m, 1H), 7.15 (d, J = 8.1 Hz, 2H), 3.00 (tt, J = 6.5, 2.0 Hz,
2H), 2.57 (tt, J = 6.0, 2.0 Hz, 2H), 2.30 (s, 3H), 1.90−1.83 (m, 2H),
1.80−1.73 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 144.5,
136.5, 136.4, 135.5, 130.5, 129.9, 126.5, 124.0, 123.3, 118.7, 118.1,
114.5, 24.8, 23.4, 22.2, 21.6, 21.2.
9-Tosyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (10). White
solid (20 mg, 30%) (petroleum ether/EtOAc = 10:1), electricity =
2.6 F mol−1. 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.2 Hz, 1H),
7.67 (d, J = 8.4 Hz, 2H), 7.40−7.36 (m, 1H), 7.33−7.27 (m, 1H),
7.26−7.21 (m, 1H), 7.19 (d, J = 8.1 Hz, 2H), 5.05 (t, J = 2.0 Hz, 2H),
3.96 (t, J = 5.5 Hz, 2H), 2.73 (tt, J = 5.5, 2.1 Hz, 2H), 2.33 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 145.1, 135.9, 135.6, 132.7,
5-Bromo-3-methyl-1-tosyl-1H-indole (17).57 Pale blue solid
(76 mg, 95%) (petroleum ether/EtOAc = 25:1), electricity = 2.3 F
mol−1. 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 8.7 Hz, 1H), 7.70
(d, J = 8.4 Hz, 2H), 7.55 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 8.8, 1.9 Hz,
1H), 7.31−7.28 (m, 1H), 7.18 (d, J = 8.2 Hz, 2H), 2.30 (s, 3H), 2.17
(d, J = 1.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 145.1,
135.2, 134.1, 133.7, 130.0, 127.5, 126.8, 124.4, 122.4, 118.1, 116.7,
115.2, 21.7, 9.7.
5-Fluoro-3-methyl-1-tosyl-1H-indole (18).8 White solid (59
mg, 90%) (petroleum ether/EtOAc = 25:1), electricity = 2.3 F mol−1.
1H NMR (400 MHz, CDCl3): δ 7.91 (dd, J = 9.0, 4.4 Hz, 1H), 7.71
(d, J = 8.4 Hz, 2H), 7.33 (s, 1H), 7.18 (d, J = 8.1 Hz, 2H), 7.06 (dd, J
= 8.8, 2.5 Hz, 1H), 7.01 (td, J = 9.0, 2.6 Hz, 1H), 2.30 (s, 3H), 2.18
(d, J = 1.3 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 159.7 (d,
130.1, 129.9, 126.6, 124.6, 123.6, 118.5, 116.2, 114.2, 65.0, 64.6, 22.3,
21.7. IR (neat, cm−1): 2922, 1655, 1451, 1364, 1173, 587. HRMS
(ESI), m/z: (M + Na)+ Calcd for C18H17NO3SNa: 350.0821. Found:
350.0821.
tert-Butyl 5-Tosyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]-
J
C−F = 240.3 Hz), 145.0, 135.3, 133.0 (d, JC−F = 9.3 Hz), 131.7, 123.0,
indole-2-carboxylate (11). Colorless oil (59 mg, 68%) (petroleum
126.9, 124.9, 118.6 (d, JC−F = 4.1 Hz), 114.8 (d, JC−F = 9.3 Hz), 112.6
(d, JC−F = 25.5 Hz), 105.2 (d, JC−F = 23.8 Hz), 21.7, 9.8.
1
ether/EtOAc = 5:1), electricity = 2.3 F mol−1. H NMR (400 MHz,
CDCl3): δ 8.15 (d, J = 8.3 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.34−
7.27 (m, 2H), 7.25−7.20 (m, 1H), 7.18 (d, J = 8.1 Hz, 2H), 4.51 (s,
2H), 3.75 (t, J = 5.8 Hz, 2H), 3.13 (t, J = 5.9 Hz, 2H), 2.32 (s, 3H),
1.49 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3): δ 155.0, 145.0,
136.4, 136.0, 130.0, 126.5, 124.6, 123.6, 118.0, 114.6, 80.3, 28.6, 21.7.
IR (neat, cm−1): 2975, 1698, 1597, 1367, 1172, 661, 571. HRMS
(ESI), m/z: (M + Na)+ Calcd for C23H26N2O4SNa: 449.1505. Found:
449.1505.
3-Methyl-1-tosyl-5-(trifluoromethoxy)-1H-indole (19). White
solid (51 mg, 66%) (petroleum ether/EtOAc = 40:1), electricity = 2.3
1
F mol−1. H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.9 Hz, 1H),
7.74 (d, J = 8.4 Hz, 2H), 7.39−7.35 (m, 1H), 7.29−7.26 (m, 1H),
7.21 (d, J = 8.1 Hz, 2H), 7.18−7.14 (m, 1H), 2.33 (s, 3H), 2.21 (d, J
= 1.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 145.4 (q, JC−F
=
1.9 Hz), 145.2, 135.3, 133.5, 132.7, 130.1, 126.9, 125.0, 120.8 (q, JC−F
= 256.5 Hz). 118.5, 118.2, 114.7, 112.1, 21.7, 9.7. 19F NMR (471
MHz, CDCl3): δ −58.01. IR (neat, cm−1): 2924, 1597, 1452, 1372,
1256, 1171, 587. HRMS (ESI), m/z: (M + Na)+ Calcd for
C17H14F3NO3SNa: 392.0539. Found: 392.0538.
7-Tosyl-6,7-dihydro-5H-benzo[c]carbazole (12).56 White
solid (74 mg, 95%) (petroleum ether/EtOAc = 15:1), electricity =
1
2.3 F mol−1. H NMR (400 MHz, CDCl3): δ 8.33−8.25 (m, 1H),
7.99−7.91 (m, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.6 Hz,
2H), 7.36−7.20 (m, 4H), 7.18−7.09 (m, 3H), 3.33 (t, J = 7.8 Hz,
2H), 2.98 (t, J = 7.8 Hz, 2H), 2.25 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 145.0, 137.7, 137.3, 135.9, 134.7, 131.7, 130.0,
128.0, 127.4, 126.9, 126.5, 126.4, 124.2, 124.1, 123.4, 120.0, 118.1,
115.1, 29.5, 22.7, 21.6.
3-Methyl-1-tosyl-5-(trifluoromethyl)-1H-indole (20).57 White
solid (58 mg, 82%) (petroleum ether/EtOAc = 30:1), electricity = 2.3
1
F mol−1. H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 8.6 Hz, 1H),
7.79−7.70 (m, 3H), 7.54 (d, J = 8.8 Hz, 1H), 7.42 (s, 1H), 7.21 (d, J
= 7.7 Hz, 2H), 2.32 (s, 3H), 2.26 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3): δ 145.4, 136.8, 135.2, 131.6, 130.1, 126.9, 125.5 (q, JC−F
=
8-Tosyl-5,6,7,8-tetrahydrobenzo[3,4]cyclohepta[1,2-b]-
indole (13). Pale blue oil (75 mg, 95%) (petroleum ether/EtOAc =
20:1), electricity = 2.3 F mol−1. 1H NMR (400 MHz, CDCl3): δ 8.32
(d, J = 8.3 Hz, 1H), 7.72−7.64 (m, 3H), 7.58 (d, J = 7.5 Hz, 1H),
7.37−7.20 (m, 5H), 7.17 (d, J = 8.1 Hz, 2H), 3.06 (t, J = 7.1 Hz, 2H),
2.48 (t, J = 6.9 Hz, 2H), 2.30 (s, 3H), 2.25 (p, J = 7.1 Hz, 2H).
13C{1H} NMR (101 MHz, CDCl3): δ 144.9, 141.2, 138.1, 137.0,
136.3, 133.8, 129.9, 129.7, 128.6, 128.1, 127.1, 126.4 (2C), 124.2,
123.8, 121.5, 119.0, 115.2, 34.4, 32.4, 23.6, 21.6. IR (neat, cm−1):
2928, 1597, 1447, 1367, 1188, 1141, 577. HRMS (ESI), m/z: (M +
Na)+ Calcd for C24H21NO2SNa: 410.1185. Found: 410.1184.
5-(tert-Butyl)-3-methyl-1-tosyl-1H-indole (14). Yellow oil (71
mg, 95%) (petroleum ether/EtOAc = 20:1), electricity = 2.3 F mol−1.
1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.7 Hz, 1H), 7.73 (d, J =
8.4 Hz, 2H), 7.41 (d, J = 1.9 Hz, 1H), 7.37 (dd, J = 8.8, 1.9 Hz, 1H),
7.26 (s, 1H), 7.15 (d, J = 8.1 Hz, 2H), 2.28 (s, 3H), 2.23 (d, J = 1.3
Hz, 3H), 1.34 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3): δ 146.2,
144.6, 135.7, 133.4, 131.6, 129.8, 126.9, 123.1, 122.7, 118.8, 115.5,
113.2, 34.8, 31.8, 21.6, 9.8. IR (neat, cm−1): 2921, 1596, 1452, 1368,
32.3 Hz), 124.8, 124.8 (q, JC−F = 277.2 Hz), 121.5 (q, JC−F = 3.6 Hz),
118.7, 117.2 (q, JC−F = 4.2 Hz), 114.0, 21.7, 9.7.
N-(2-(But-1-en-2-yl)phenyl)-4-methylbenzenesulfonamide
(5s). To a solution of 2-(but-1-en-2-yl)aniline (0.68 g, 4.6 mmol) and
pyridine (1.2 mL, 15 mmol) in CH2Cl2 (30 mL) was added TsCl (1.0
g, 5.2 mmol) at 0 °C. The reaction mixture was warmed up to rt and
stirred for 12 h. The reaction was quenched with H2O and extracted
by CH2Cl2. The combined organic phase was washed with brine and
concentrated under reduced pressure. The residue was chromato-
graphed through silica gel to afford 5s as a white solid (0.60 g, 44%)
1
(petroleum ether/EtOAc = 10:1). H NMR (400 MHz, CDCl3): δ
7.68−7.60 (m, 3H), 7.24−7.18 (m, 3H), 7.03 (t, J = 7.6 Hz, 1H),
7.00−6.94 (m, 2H), 5.23 (s, 1H), 4.68 (s, 1H), 2.36 (s, 3H), 1.96 (q,
J = 7.5 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 147.8, 144.0, 136.4, 134.1, 133.4, 129.7, 128.4, 128.1,
127.3, 124.2, 120.0, 115.1, 30.7, 21.6, 12.0. IR (neat, cm−1): 3260,
2921, 1743, 1488, 1339, 1167, 670, 569. HRMS (ESI), m/z: (M +
Na)+ Calcd for C17H19NO2SNa: 324.1029. Found: 324.1028.
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4-Methyl-N-(2-(pent-2-en-2-yl)phenyl)benzenesulfonamide
(7s). To a solution of 2-(pent-2-en-2-yl)aniline (0.72 g, 4.1 mmol)
and pyridine (1.0 mL, 12 mmol) in CH2Cl2 (30 mL) was added TsCl
(0.91 g, 4.8 mmol) at 0 °C. The reaction mixture was warmed up to rt
slowly and stirred for 12 h. The reaction was quenched with H2O and
extracted with CH2Cl2. The combined organic phase was washed with
brine and concentrated under reduced pressure. The residue was
chromatographed through silica gel to afford 7s as yellow oil (0.63 g,
49%) (petroleum ether/EtOAc = 20:1). Z/E = 2.5/1. 1H NMR (400
MHz, CDCl3): δ 7.75−7.60 (m, 4.2H), 7.26−7.17 (m, 4.2H), 7.08−
7.01 (m, 1.4H), 7.00−6.92 (m, 1.8H), 6.78 (s, 1H), 5.62 (tq, J = 7.5,
1.6 Hz, 1H), 5.05 (tq, J = 7.1, 1.5 Hz, 0.4H), 2.41−2.32 (m, 4.2H),
2.13 (p, J = 7.2 Hz, 0.8H), 1.73−1.53 (m, 6.2H), 1.02 (t, J = 7.5 Hz,
1.2H), 0.86 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
143.9, 136.5, 133.4, 133.3, 132.1, 131.3, 129.6, 128.6, 127.8, 127.2,
124.2, 118.5, 24.8, 22.3, 21.5, 13.9. IR (neat, cm−1): 3276, 2963, 1599,
1490, 1338, 1169, 664, 560. HRMS (ESI), m/z: (M + Na)+ Calcd for
C18H21NO2SNa: 338.1185. Found: 338.1185.
N-(2-(3,6-Dihydro-2H-pyran-4-yl)phenyl)-4-methylbenzene-
sulfonamide (10s). To a mixture of 4-methyl-N-(2-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (1.1
g, 2.9 mmol) and PdCl2(dppf)·CH2Cl2 (50 mg, 0.061 mmol) in 15
mL of 1,4-dioxane was added 5 mL of a 3 N solution of NaOH
followed by 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (1.0
g, 4.3 mmol). The resulting mixture was heated to 80 °C. After 12 h,
the mixture was cooled to rt and filtered through a pad of Celite. The
filtrate was diluted with saturated NH4Cl aqueous solution and
extracted with CH2Cl2. The combined organic phase was washed with
brine and concentrated under reduced pressure. The residue was
chromatographed through silica gel to afford 10s as a white solid
(0.52 g, 52%) (petroleum ether/EtOAc = 5:1). 1H NMR (400 MHz,
CDCl3): δ 7.65−7.59 (m, 3H), 7.26−7.19 (m, 3H), 7.08 (td, J = 7.5,
1.2 Hz, 1H), 7.02−6.96 (m, 2H), 5.42−5.37 (m, 1H), 4.19 (q, J = 2.8
Hz, 2H), 3.78 (t, J = 5.4 Hz, 2H), 2.36 (s, 3H), 1.92−1.86 (m, 2H).
13C{1H} NMR (101 MHz, CDCl3): δ 144.0, 136.5, 134.2, 133.2,
residue was chromatographed through silica gel to afford 12s as
yellow solid (0.46 g, 38%) (petroleum ether/EtOAc = 25:1). 1H
NMR (400 MHz, CDCl3): δ 7.73 (dd, J = 8.2, 1.2 Hz, 1H), 7.43 (d, J
= 8.3 Hz, 2H), 7.33 (td, J = 7.8, 1.7 Hz, 1H), 7.19−7.05 (m, 5H),
7.03 (dd, J = 7.5, 1.7 Hz, 1H), 6.90 (td, J = 7.7, 2.1 Hz, 1H), 6.45 (s,
1H), 6.27 (d, J = 7.6 Hz, 1H), 5.45 (t, J = 4.5 Hz, 1H), 2.81 (t, J = 8.1
Hz, 2H), 2.35 (s, 3H), 2.33−2.25 (m, 2H). 13C{1H} NMR (101
MHz, CDCl3): δ 143.7, 136.1, 135.6, 134.9, 134.5, 133.4, 132.3,
130.7, 130.3, 129.5, 128.6, 128.0, 127.9, 127.3, 126.9, 125.2, 124.4,
121.8, 27.7, 23.3, 21.6. IR (neat, cm−1): 3330, 2933, 1598, 1488,
1166, 671, 564. HRMS (ESI), m/z: (M + Na)+ Calcd for
C23H21NO2SNa: 398.1185. Found: 398.1183.
N-(2-(6,7-Dihydro-5H-benzo[7]annulen-9-yl)phenyl)-4-
methylbenzenesulfonamide (13s). To a mixture of 4-methyl-N-
(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
benzenesulfonamide (0.93 g, 2.5 mmol), 6,7-dihydro-5H-benzo[7]-
annulen-9-yl trifluoromethanesulfonate (1.2 g, 4.1 mmol), Pd(PPh3)4
(0.15 g, 0.13 mmol), and K2CO3 (1.1 g, 8.0 mmol) was added a 1:1:2
(v/v/v) mixture of EtOH/H2O/toluene (12 mL). The resulting
mixture was heated to 80 °C. After 12 h, water was added and the
mixture was extracted with ethyl acetate. The combined organic
solution was evaporated under reduced pressure. The residue was
chromatographed through silica gel to afford 13s as a white solid
(0.55 g, 57%) (petroleum ether/EtOAc = 25:1). 1H NMR (400 MHz,
CDCl3): δ 7.64 (d, J = 8.1 Hz, 1H), 7.43−7.39 (m, 2H), 7.29−7.22
(m, 2H), 7.18 (td, J = 7.5, 1.4 Hz, 1H), 7.13 (d, J = 8.1 Hz, 2H),
7.09−7.01 (m, 2H), 6.97 (td, J = 7.5, 1.4 Hz, 1H), 6.51 (s, 1H), 6.37
(dd, J = 7.7, 1.2 Hz, 1H), 5.87 (t, J = 6.8 Hz, 1H), 2.69 (t, J = 6.8 Hz,
2H), 2.36 (s, 3H), 2.16 (p, J = 7.0 Hz, 2H), 1.99 (q, J = 7.3 Hz, 2H).
13C{1H} NMR (101 MHz, CDCl3): δ 143.7, 141.5, 138.8 (2C),
136.2, 134.8, 134.4, 133.1, 131.1, 129.6, 129.4, 128.5, 128.4, 127.8,
127.3, 126.5, 124.6, 120.6, 34.5, 33.1, 26.2, 21.6. IR (neat, cm−1):
3334, 2927, 1598, 1429, 1337, 1165, 764, 564. HRMS (ESI), m/z: (M
+ Na)+ Calcd for C24H23NO2SNa: 412.1342. Found: 412.1341.
N-(4-(tert-Butyl)-2-(prop-1-en-2-yl)phenyl)-4-methylbenze-
nesulfonamide (14s). To a mixture of potassium trifluoro(prop-1-
en-2-yl)borate (0.92 g, 6.2 mmol), Cs2CO3 (5.4 g, 17 mmol),
PdCl2(dppf)·CH2Cl2 (0.23 g, 0.27 mmol) and N-(2-bromo-4-(tert-
butyl)phenyl)-4-methylbenzenesulfonamide (1.9 g, 5.0 mmol) was
added a 10:1 (v/v) mixture of THF/H2O (66 mL). The reaction
mixture was stirred at reflux for 16 h. The mixture was cooled to room
temperature and diluted with H2O, followed by extraction with ether.
The organic layer was washed with 1 N HCl and brine successively,
and concentrated under reduced pressure. The residue was chromato-
graphed through silica gel to afford 14s as a white solid (1.2 g, 71%)
132.7, 129.7, 128.5, 128.2, 127.3, 127.2, 124.9, 121.6, 65.2, 64.2, 29.8,
21.6. IR (neat, cm−1): 3269, 2924, 1596, 1488, 1336, 1163, 542.
HRMS (ESI), m/z: (M + Na)+ Calcd for C18H19NO3SNa: 352.0978.
Found: 352.0978.
tert-Butyl 5-(2-((4-methylphenyl)sulfonamido)phenyl)-3,6-
dihydropyridine-1(2H)-carboxylate (11s). To a mixture of N-
(2-iodophenyl)-4-methylbenzenesulfonamide (1.0 g, 2.7 mmol), tert-
butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyri-
dine-1(2H)-carboxylate (1.2 g, 3.9 mmol), Pd(PPh3)4 (0.17 g, 0.14
mmol) and K2CO3 (1.1 g, 8.0 mmol) was added a 1:1:2 (v/v/v)
mixture of EtOH/H2O/toluene (20 mL). The resulting mixture was
heated to 80 °C. After 12 h, water was added and the mixture was
extracted with ethyl acetate. The combined organic solution was
evaporated under reduced pressure. The residue was chromato-
graphed through silica gel to afford 11s as a white solid (0.36 g, 31%)
1
(petroleum ether/EtOAc = 10:1). H NMR (400 MHz, CDCl3): δ
7.66−7.59 (m, 2H), 7.51 (d, J = 8.6 Hz, 1H), 7.24−7.19 (m, 3H),
7.00 (d, J = 2.3 Hz, 1H), 6.95 (s, 1H), 5.23 (p, J = 1.6 Hz, 1H), 4.68−
4.66 (m, 1H), 2.37 (s, 3H), 1.71 (t, J = 1.3 Hz, 3H), 1.26 (s, 9H).
13C{1H} NMR (101 MHz, CDCl3): δ 147.4, 143.8, 142.7, 136.7,
134.5, 130.2, 129.6, 127.3, 125.2, 124.8, 120.4, 116.9, 34.4, 31.4, 24.6,
21.6. IR (neat, cm−1): 3287, 2952, 1597, 1496, 1167, 654, 553.
HRMS (ESI), m/z: (M + Na)+ Calcd for C20H25NO2SNa: 366.1498.
Found: 366.1498.
4-Methyl-N-(2-(prop-1-en-2-yl)-4-(trifluoromethoxy)-
phenyl)benzenesulfonamide (19s). To a mixture of potassium
trifluoro(prop-1-en-2-yl)borate (0.87 g, 5.9 mmol), Cs2CO3 (4.4 g, 14
mmol), PdCl2(dppf)·CH2Cl2 (0.22 g, 0.27 mmol), and N-(2-bromo-
4-(trifluoromethoxy)phenyl)-4-methylbenzenesulfonamide (1.8 g, 4.5
mmol) was added a 10:1 (v/v) mixture of THF/H2O (66 mL). The
reaction mixture was stirred at reflux for 16 h. The mixture was cooled
to room temperature and diluted with H2O, followed by extraction
with ether. The organic layer was washed with 1 N HCl and brine
successively, and concentrated under reduced pressure. The residue
was chromatographed through silica gel to afford 19s as yellow solid
(1.1 g, 70%) (petroleum ether/EtOAc = 10:1). 1H NMR (400 MHz,
CDCl3): δ 7.66 (d, J = 9.0 Hz, 1H), 7.66−7.59 (m, 2H), 7.24 (d, J =
8.1 Hz, 2H), 7.10−7.05 (m, 1H), 7.02 (s, 1H), 6.89−6.86 (m, 1H),
5.30 (p, J = 1.6 Hz, 1H), 4.71 (t, J = 1.3 Hz, 1H), 2.38 (s, 3H), 1.69
(t, J = 1.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 145.7 (q,
1
(petroleum ether/EtOAc = 2:1). H NMR (400 MHz, CDCl3): δ
7.67−7.56 (m, 3H), 7.27−7.19 (m, 3H), 7.07 (t, J = 7.4 Hz, 1H),
7.01 (dd, J = 7.6, 1.7 Hz, 1H), 5.40 (tt, J = 4.0, 2.0 Hz, 1H), 3.68−
3.44 (m, 4H), 2.37 (s, 3H), 2.21 (tq, J = 5.8, 2.9 Hz, 2H), 1.50 (s,
9H). 13C{1H} NMR (151 MHz, CDCl3): δ 155.1, 144.2, 136.4, 133.9,
132.2, 129.8, 129.2, 128.7, 127.3, 124.9, 80.3, 28.6, 25.2, 21.7. IR
(neat, cm−1): 3275, 2927, 1694, 1598, 1416, 1166, 664, 572. HRMS
(ESI), m/z: (M + Na)+ Calcd for C23H28N2O4SNa: 451.1662. Found:
451.1660.
N-(2-(3,4-Dihydronaphthalen-1-yl)phenyl)-4-methylbenze-
nesulfonamide (12s). To a mixture of 4-methyl-N-(2-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (1.2
g, 3.2 mmol) and PdCl2(dppf)·CH2Cl2 (49 mg, 0.060 mmol) in 15
mL of 1,4-dioxane was added 5 mL of a 3 N solution of NaOH
followed by 3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate
(1.1 g, 4.0 mmol). The resulting mixture was heated to 80 °C.
After 12 h, the mixture was cooled to rt and filtered through a pad of
Celite. The filtrate was diluted with saturated NH4Cl aqueous
solution and extracted with CH2Cl2. The combined organic phase was
washed with brine and concentrated under reduced pressure. The
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J
C−F = 1.9 Hz), 144.4, 140.9, 136.6, 136.2, 131.7, 129.9, 127.3, 122.1,
ACKNOWLEDGMENTS
■
120.8, 120.7, 120.5 (q, JC−F = 257.2 Hz), 118.3, 24.2, 21.7. 19F NMR
(471 MHz, CDCl3): δ −58.07. IR (neat, cm−1): 3279, 2922, 1597,
1496, 1256, 1163, 664, 551. HRMS (ESI), m/z: (M + Na)+ Calcd for
C17H16F3NO3SNa: 394.0695. Found: 394.0698.
The authors acknowledge financial support from NSFC (No.
21971213) and Fundamental Research Funds for the Central
Universities.
4-Methyl-N-(2-(prop-1-en-2-yl)-4-(trifluoromethyl)phenyl)-
benzenesulfonamide (20s). To a mixture of potassium trifluoro-
(prop-1-en-2-yl)borate (0.64 g, 4.3 mmol), Cs2CO3 (3.5 g, 11 mmol),
PdCl2(dppf)·CH2Cl2 (0.23 g, 0.27 mmol), and N-(2-bromo-4-
(trifluoromethyl)phenyl)-4-methylbenzenesulfonamide (1.4 g, 3.6
mmol) was added a 10:1 (v/v) mixture of THF/H2O (66 mL).
The reaction mixture was stirred at reflux for 16 h. The mixture was
cooled to room temperature and diluted with H2O, followed by
extraction with ether. The organic layer was washed with 1 N HCl
and brine successively and concentrated under reduced pressure. The
residue was chromatographed through silica gel to afford 20s as a
white solid (0.25 g, 20%) (petroleum ether/EtOAc = 10:1). 1H NMR
(400 MHz, CDCl3): δ 7.73 (d, J = 8.6 Hz, 1H), 7.71−7.64 (m, 2H),
7.45 (dd, J = 8.7, 2.2 Hz, 1H), 7.30−7.22 (m, 3H), 7.15 (s, 1H), 5.37
(p, J = 1.6 Hz, 1H), 4.81−4.77 (m, 1H), 2.39 (s, 3H), 1.80 (t, J = 1.2
Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 144.7, 141.0, 136.3,
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136.1, 134.3, 130.0, 127.4, 126.2 (q, JC−F = 32.7 Hz), 125.3 (q, JC−F
=
3.9 Hz), 124.0 (q, JC−F = 271.8 Hz). 119.4, 118.7, 24.4, 21.7. 19F
NMR (471 MHz, CDCl3): δ −62.24. IR (neat, cm−1): 3266, 2925,
1497, 1335, 1166, 1083, 747. HRMS (ESI), m/z: (M + Na)+ Calcd
for C17H16F3NO2SNa: 378.0746. Found: 378.0745.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00988.
Description of reaction setups, cyclic voltammograms,
and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Hai-Chao Xu − Key Laboratory of Chemical Biology of Fujian
Province, State Key Laboratory of Physical Chemistry of Solid
Surfaces, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen 361005, P. R. China;
orcid.org/0000-0002-3008-5143; Email: haichao.xu@
xmu.edu.cn
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H. Large-scale oxidations in the pharmaceutical industry. Chem. Rev.
2006, 106, 2943−2989.
(13) Yuan, Y.; Lei, A. Electrochemical Oxidative Cross-Coupling
with Hydrogen Evolution Reactions. Acc. Chem. Res. 2019, 52, 3309−
3324.
(14) Ackermann, L. Metalla-electrocatalyzed C−H Activation by
Earth-Abundant 3d Metals and Beyond. Acc. Chem. Res. 2020, 53,
84−104.
Authors
Yun-Tao Zheng − Key Laboratory of Chemical Biology of
Fujian Province, State Key Laboratory of Physical Chemistry
of Solid Surfaces, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, P. R.
China
Jinshuai Song − Green Catalysis Center, and College of
Chemistry, Zhengzhou University, Zhengzhou, Henan
450001, P. R. China
(15) Elsherbini, M.; Wirth, T. Electroorganic Synthesis under Flow
Conditions. Acc. Chem. Res. 2019, 52, 3287−3296.
(16) Feng, R.; Smith, J. A.; Moeller, K. D. Anodic Cyclization
Reactions and the Mechanistic Strategies That Enable Optimization.
Acc. Chem. Res. 2017, 50, 2346−2352.
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Complete contact information is available at:
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Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
F
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