A new pathway via intermediate 4-amino-3-fluorophenol for the synthesis of regorafenib

Article abstract of DOI:10.1080/00397911.2018.1564832

A practical synthetic route to regorafenib, in which the target compound was obtained via a 10-step synthesis starting from 2-picolinic acid, 4-chloro-3-(trifluoromethyl)aniline, and 3-fluorophenol, is reported. Crucial to the strategy is the preparation of 4-amino-3-fluorophenol via Fries and Beckman rearrangements using an economical and practical protocol. The main advantages of the route include inexpensive starting materials and an acceptable overall yield. A scale-up experiment was carried out to provide regorafenib with 99.96% purity in 46.5% total yield.

Full text of DOI:10.1080/00397911.2018.1564832

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
A new pathway via intermediate 4-amino-3-
fluorophenol for the synthesis of regorafenib
Fangyu Du, Qifan Zhou, Yajie Shi, Miao Yu, Wenjiao Sun & Guoliang Chen
To cite this article: Fangyu Du, Qifan Zhou, Yajie Shi, Miao Yu, Wenjiao Sun & Guoliang Chen
(2019): A new pathway via intermediate 4-amino-3-fluorophenol for the synthesis of regorafenib,
Synthetic Communications
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2018.1564832
A new pathway via intermediate 4-amino-3-fluorophenol
for the synthesis of regorafenib
Fangyu Du, Qifan Zhou, Yajie Shi, Miao Yu, Wenjiao Sun, and Guoliang Chen
Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang
Pharmaceutical University, Shenyang, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 3 October 2018
A practical synthetic route to regorafenib, in which the target com-
pound was obtained via a 10-step synthesis starting from 2-picolinic
acid, 4-chloro-3-(trifluoromethyl)aniline, and 3-fluorophenol, is
reported. Crucial to the strategy is the preparation of 4-amino-3-fluo-
rophenol via Fries and Beckman rearrangements using an econom-
ical and practical protocol. The main advantages of the route include
inexpensive starting materials and an acceptable overall yield. A
scale-up experiment was carried out to provide regorafenib with
99.96% purity in 46.5% total yield.
KEYWORDS
Regorafenib; Fries
rearrangement; Beckman
rearrangement;
Optimization
GRAPHICAL ABSTRACT
Introduction
Regorafenib (1, Figure 1), a broad-spectrum kinase inhibitor developed by Bayer, was
approved by U.S. FDA for the treatment of metastatic colorectal cancer in 2012.[1] It
inhibits tumor angiogenesis and proliferation by inhibiting various enzymes (VEGFR-1,
VEGFR-2, VEGFR-3, PDGFR, FGFR, c-KIT, etc.) that promote tumor tissue growth.[2]
From a structural perspective, regorafenib features three substituted aromatic rings
functionalized with a urea group and an ether group. Retrosynthetically, this structure
is most straightforwardly dissociated to the commercially accessible building blocks 2, 3,
CONTACT Guoliang Chen
chenguoliang@syphu.edu.cn
Key Laboratory of Structure-Based Drugs Design and
Discovery of Ministry of Education, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenhe District,
Shenyang 110016, P. R. China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
F. DU ET AL.
Figure 1. Chemical structure of regorafenib (1).
Scheme 1. Retrosynthetic Analysis of Regorafenib.
and 4 (Scheme 1), which had previously been established according to the synthesis of
sorafenib.[3] In the initial work, picolinamide 13 was obtained via Williamson ether syn-
thesis with aminophenol 2 and picolinamide 3 as the raw materials and then was
coupled with isocyanate 4 to afford regorafenib 1.[4] An improved synthetic method for
the Williamson reaction, where aminophenol 2 was converted to a more nucleophilic
imine by reaction with 4-methyl-2-pentanone, followed by a Williamson esterification,
was reported.[5]
As intermediate 2 is a key fragment in the synthesis of regorafenib, several synthetic
methods have been reported for its preparation. Schlegel and Johnson disclosed a
method where 3-fluorophenol as a starting material provided 2 with a total yield of
19% via nitration and reduction reactions.[6,7] The main drawbacks of this approach
were that the isomer 3-fluoro-6-nitrophenol, dinitro compounds, quinones, oxides, and
other byproducts were readily produced, which greatly reduced the yield. Furthermore,
the reduction process required expensive palladium on carbon as a catalyst, thereby
increasing the cost. Hodgson et al. developed another method to obtain 2 from 3-fluo-
roaniline in five steps with a total yield of 20%.[8] The process involving amino protec-
tion, nitration, deprotection, diazotization, hydrolysis, palladium-on-carbon reduction,
and steam distillation was complex and cumbersome, leading to a low yield. In 2016,
Ye et al. reported two synthetic routes that avoided the safety and regioselectivity issues
associated with nitration reactions.[9,10] In the first route, the 2,4-difluoronitrobenzene
substrate was subjected to etherification, AlCl3-mediated demethylation, and reduction
based on a composite catalyst (nickel nitrate/palladium chloride/tetrabutyl titanate),
affording 2. The second route was a long synthetic procedure in which the starting
material 4-nitrophenol underwent reduction, sulfonation, fluorine substitution, and

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3
Scheme 2. Alternative Synthetic Route to Regorafenib.
desulfonation to provide the product with a total yield of 60%. Klausener et al. prepared
2 using o-fluoronitrobenzene as the starting material.[11] Because of the use of porous
extractors, this method was not applicable to industrial production. Sun et al.[12] opti-
mized the reaction conditions based on Klausener’s work and prepared 2 in 56% yield.
However, this process needed expensive platinum catalysts and produced a considerable
amount of o-fluoroaniline. Muddasani et al. disclosed a patent for the optimization of
the synthetic process for regrofeinib; this patent described a method for obtaining 2 by
refluxing o-fluoronitrobenzene in the presence of aluminum and oxalic acid dihydrate,
but the subsequent treatment process was very complicated.[4]
Herein, we discuss our attempts to develop a safe, scalable process for the synthesis
of 2 and seek to define a more efficient and cost-effective route to regorafenib that is
appropriate for more sustainable long-term supply of the drug.
Results and discussion
Initially, our study focused on the synthesis of intermediate 2. The synthetic route to 2
from commercially available 3-fluorophenol 5 involved esterification with acetic anhyd-
ride to afford acetate 6. Then, 6 was transformed via Fries rearrangement using alumi-
num chloride to yield ketone 7.[13] The reaction between 7 and hydroxylamine
hydrochloride in the presence of potassium carbonate furnished the intermediate oxime
8. Compound 8 was transformed into acetamide 9 via Beckmann rearrangement cata-
lyzed by potassium iodide and thionyl chloride.[14] Then, 9 was hydrolyzed to afford 2
(Scheme 2).
Having established a route to the synthesis of intermediate 2, we turned our efforts
toward the synthesis of regorafenib. The fragment of picolinamide 3 was prepared using
picolinic acid 10 as a raw material in a procedure involving chlorination and amidation.
Another fragment, compound 4, was synthesized by treating aniline 12 with triphos-
gene. The Williamson etherification reaction of intermediate 2 with 3 in the presence of

4
F. DU ET AL.
Table 1. Friedel–Crafts acylation reaction.a
Entry
AlCl3 (equiv)
Solvent
Temp (oC)
Yield (%)b
1
2
3
4
1.1
1.1
2.5
1.1
DCE
DCE
DCE
DCM
0
5
8
0!reflux
0!rt
Dc
D
0!rt
aStandard conditions: aluminum chloride (31.2 mmol), 3-fluorophenol (27.6 mmol), solvent (100 mL).
bIsolated yield after chromatography.
cDetected by the TLC analysis but not isolated.
potassium tert-butoxide afforded 13, which was subsequently condensed with 4 to give
regorafenib 1.
Having established the above mentioned synthetic route, we also investigated possible
ways to simplify the synthesis. One approach to shorten the synthesis was to make com-
pound 7 via a direct Friedel–Crafts acylation of 5. However, much lower yields were
obtained under numerous conditions (Table 1, entries 1–4). An attempt to improve
yield by increasing either the temperature or the amount of aluminum chloride used
was unsuccessful (entries 2 and 3). The use of Friedel–Crafts acylation failed mainly
due to the electron-withdrawing fluorine group and acetylation of the phenolic hydroxyl
group as a side reaction.[15a] The failure of direct Friedel–Crafts acylation led us to use
the Fries rearrangement to achieve acylation.
Acetate 6 was synthesized on the kilogram scale via acetylation of 5 in 99.8% yield,
thus setting the stage for the key Fries rearrangement. While the Fries rearrangement
is normally promoted using a large excess of aluminum chloride, we managed to
optimize the amount of aluminum chloride used to only 1.5 equiv (Table 2, entries
2–4).[15b] Efforts to improve the conversion rate and promote the consumption of 6
by elevating the temperature were unsuccessful (entries 5 and 8). An attempt to opti-
mize the reaction by using more polar solvents proved successful, but further studies
revealed an issue with residual nitrobenzene; however, nitromethane proved to be
optimal in terms of yield and ease of use (entries 8–10). When 6 was mixed with
aluminum chloride in nitromethane by one-time addition, intense heat was released,
resulting in a sticky substance that immediately solidified. Moreover, the reaction did
not proceed smoothly. These issues made workup inconvenient and decreased the
yield. This problem was solved by adding acetate 6 in a dose-controlled manner
(entries 11–12). Under these optimized conditions, the desired product was isolated
in 82% yield (entry 11). It is speculated that nitromethane can dissolve AlCl3. The
AlCl3–CH3NO2 complex, an addition product formed after dissolution, is more react-
ive than AlCl3. However, considering the safety issues caused by the AlCl3–CH3NO2
system in scale-up preparation, we tried to carry out the Fries rearrangement cata-
lyzed by the AlCl3–CH3NO2 system in chloroform (entry 13). Fortunately, this pro-
cedure was successful in reducing the amount of nitromethane used to 1.5 equiv
while maintaining a satisfactory yield of 80%. Finally, compound 6 (1.0 equiv) was
added in portions to a solution of aluminum chloride (1.5 equiv), nitromethane (1.5

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5
Table 2. Effects of AlCl3, temperature, and solvent on the Fries rearrangement.a
Yield (%)d
7
Entry
AlCl3 (equiv)
Solvent
Temp (ꢀC)
6
14
1
2
3
4
5
6
7
8
1.0
1.0
1.5
1.7
1.7
1.7
1.5
1.5
1.5
1.5
1.5
1.5
1.5
DCM
DCM
DCM
DCM
CHCl3
CHCl3
CHCl3
25
40
40
40
60
40
40
90
40
40
40
40
40
80
76
73
70
50
70
69
10
46
48
10
12
12
7
8
NDe
ND
ND
ND
15
25
24
26
25
23
30
43
45
82
85
80
ND
ND
50
ND
ND
ND
ND
ND
PhNO2
PhNO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2/CHCl3
9
10
11b
12bc
13bc
f
aStandard conditions: 6 (13 mmol), solvent (15 mL).
b6 was added to a solution of AlCl3, nitromethane, and solvent.
cThe loading of 6 was 800 g.
dIsolated yield after chromatography except entry 12.
f
eNot detected by TLC analysis. CH3NO2 (1.5 equiv, 420 mL) was added.
equiv), and CHCl3 at room temperature, and the resulting solution was then stirred
at 40 ꢀC to obtain compound 7. The crude product 7 was dissolved in alkaline solu-
tion, purified by washing with ethyl acetate and adjusted to pH 5. The product was
isolated by filtration and recrystallized from water. This process was successfully
reproduced on an 800 g scale (entry 13).
Subsequently, a method for the synthesis of compound 9 was developed and opti-
mized. The Beckmann rearrangement reaction was then investigated using a literature
procedure, where ammonium hydroxide was added dropwise to a mixture of 70% aque-
ous sulfuric acid and oxime 8 at 20 ꢀC until pH 8.[16] However, only 50% yield of the
desired product 9 was obtained. The low yield could be explained by the hydrolysis of
oxime 8 back to ketone 7, as indicated by TLC analysis. Therefore, it became logical for
us to attempt the rearrangement reaction under nonaqueous conditions.
Encouraged by the report by Chen et al. that thionyl chloride and potassium iodide
could be conducive to the Beckmann rearrangement, we added thionyl chloride (0.1
equiv) and potassium iodide (0.01 equiv) to the reaction mixture.[17] The reaction
worked well in ethyl acetate, which, compared with other solvents, is a preferred class 3
solvent. Crude 9 was obtained from ethyl acetate and was directly used in the next step.
Hydrolysis carried out in 2 N aqueous hydrochloric acid at 80 ꢀC afforded 2 in satisfac-
tory yield. High-purity 2 (98.7% (relative area) using HPLC analysis) was obtained via
decolorization using a small amount of sodium dithionite and activated carbon that had
been preprocessed by dilute nitric acid and crystallized from water.
The synthesis of compound 3 in 76% overall yield through a sequence of chlorin-
ation, esterification, and amidation reactions using 2-picolinic acid as the starting
material was reported in the literature (Scheme 3).[18] However, byproduct 16 may be

6
F. DU ET AL.
Scheme 3. Reported Synthetic Routes to Intermediate 3.
Table 3. Preparation of intermediate 3 in “One Pot”.a
Yield (%)
Entry
SOCl2 (equiv)
Temp (oC)
Methylamine (equiv)
11
3
1b
2b
3
2.5
3
6
10
3
6
6
6
6
6
80!110
–
–
–
–
52
55
73
96
–
–
–
–
–
–
–
–
110
80
80
80
80!0
80!-10
80!0
80!-10
80!0
4
–
5bc
6c
40% methylamine (10)
40% methylamine (10)
40% methylamine (10)
methylamine (gas, 10)
methylamine (gas, 10)
methylamine (gas, 10)
60
70
79
95
96
93
7c
8c
9c
10cd
–
aStandard conditions: 10 (60 mmol), 3 drops of DMF.
bToluene as solvent (50 mL).
cSodium bromide (0.4 equiv) was added to the reaction system.
dThe loading of 10 was 210 g.
formed due to incomplete chlorination (Table 3, entries 1–3). Interestingly, formation
of this byproduct can be minimized by using a large excess of thionyl chloride
(10 equiv). The reaction was optimized by reducing the thionyl chloride amount to 6
equiv along with the addition of sodium bromide (0.4 equiv), as reported in the litera-
ture (entries 5–10).[19] In fact, with 6 equiv of thionyl chloride, it can function as the
reaction solvent, providing a faster reaction rate and a cleaner reaction profile. After the
reaction was complete, the excess thionyl chloride was distilled off under reduced pres-
sure, and the residue was directly used in the next step.
To avoid the ester intermediate, we investigated direct amidation with methylamine.
We found that a certain amount of acyl chloride was hydrolyzed when 40% aqueous
methylamine was used. As anticipated, this problem was avoided by using methylamine
gas generated by adding 40% aqueous methylamine (10 equiv) to solid sodium hydrox-
ide (equipment setup is shown in Figure S13). Compound 3 was isolated in 93–96%
yield. This process was successfully reproduced on a 210 g scale (entry 10).

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7
Table 4. Effects of the amounts of 2, potassium tert-butoxide and potassium carbonate on the
formation of 13.a
Entry
2 (equiv)
t-BuOK (equiv)
K2CO3 (equiv)
Time (hour)
Yield (%)b
1
2
3
4
5
6
7
8
1.0
1.2
1.0
1.0
1.0
1.0
1.0
1.1
1.2
2.0
1.2
1.2
1.2
2.0
1.5
1.2
–
–
20
18
3
4
18
4
80
55
87
85
84
72
80
92
0.5
1.0
0.1
0.5
0.5
0.5
4
3
aStandard conditions: 3 (39 mmol), DMA (50 mL), 85 ꢀC, argon.
bIsolated yield after column chromatography.
With an acceptable route to key intermediates 2 and 3 in hand, the two remaining
procedures were the Williamson ether synthesis and coupling reaction. Several issues
with the etherification-condensation step needed to be addressed to develop a route
suitable for further scale-up.
Picolinamide 13 was obtained in the presence of potassium tert-butoxide in 80%
yield, but according to the literature procedure, the Williamson reaction took 20 h to go
to completion a (Table 4, entry 1).[4b] To shorten the reaction time, our study focused
on increasing the molar ratio of potassium tert-butoxide (entry 2); however, the yield
was dramatically reduced, presumably due to the formation of varying amounts of the
bis-addition product when significantly more than 1 equiv of potassium tert-butoxide
was present.
Inspired by the synthesis of sorafenib, we added anhydrous potassium carbonate (0.5
equiv) was to the Williamson etherification reaction mixture, which clearly shortened
the reaction time and maintained the yield (entry 3).[3d] Interestingly, the conversion of
13 remained essentially unchanged when the molar ratio of potassium carbonate was
raised to 1 equiv (entry 4). It is not clearly understood how potassium carbonate
affected the rate, but our studies indicated that a dramatically shorter reaction time was
not witnessed when less than 0.5 equiv of this base was employed (entry 5). However, a
slight excess of 2 (1.1 equiv) could effectively promote the reaction in 92% yield (entry
8). Finally, this process was successfully reproduced on a 165 g scale, as shown in the
experimental section.
Compound 12 could be condensed with 13 in the presence of N,N’-carbonyldiimida-
zole (CDI) to afford the desired product.[3d] The drawback of this method was that the
self-condensation byproduct readily formed.
Consequently, isocyanato 4 was prepared via the reaction of 12 and bis(trichlorome-
thyl)carbonate by utilizing toluene as the solvent in 72% yield in accordance with the
literature.[3c] Strangely, some product was lost during vacuum distillation due to pos-
sible formation of the product-toluene binary azeotrope. The optimized conditions con-
sisted of ethyl acetate serving as the solvent and refluxing for 1 h. The target product
was obtained by distillation at 120 ꢀC (0.1 MPa) under reduced pressure in 95% yield.
After the high-quality key intermediates 13 and 4 were obtained, the title compound
regorafenib (1) was readily prepared through a nucleophilic addition reaction between
the two fragments using dichloromethane as the solvent, and product 1 was isolated as
a white solid by filtration.

8
F. DU ET AL.
In summary, a concise and efficient synthesis of key intermediate 2 was developed.
Intermediate 2 was synthesized in 68% overall yield through a 5-step sequence involving
esterification, Fries rearrangement, condensation, Beckmann rearrangement, and
hydrolysis. Compared with traditional synthetic methods, this method avoided isomer
formation, steam distillation, and catalytic hydrogenation, making it suitable for indus-
trial applications. Moreover, the synthetic methods for intermediate 3 and 4 reported in
the literature were also optimized.
Meanwhile, we provide an alternative method for the production of regorafenib, and
this method is acceptable in both product quality and yield. The method proceeds in
ten convergent steps to afford the product with a total yield of 46.5% and HPLC purity
of 99.96%. All of the intermediates and the final target were isolated cleanly in
high yield.
Experimental section
General
All of the starting materials, reagents, and solvents are commercially available and used
without further purification. Melting points were determined with an X-4 apparatus and
were uncorrected. Nuclear magnetic resonance (NMR) spectra were recorded on a
Bruker Ascend 400 and 600 (Billerica, MA, USA) using tetramethylsilane (TMS) as an
internal standard. Electrospray ionization mass spectrometry (ESI-MS) analyses were
recorded on an Agilent 1100 Series MSD Trap SL (Santa Clara, CA, USA). The reac-
tions were monitored using thin-layer chromatography (TLC; HG/T2354-92, GF254),
and compounds separated using TLC were visualized with UV light. The purity of
regorafenib was determined by HPLC using a Shimadzu LC-20A series instrument. The
HPLC analysis data were reported in relative area % and were not adjusted to
weight %.
Synthesis of 1-(2-fluoro-4-hydroxyphenyl)ethanone (7)
To a solution of aluminum chloride (1.04 kg, 7.8 mol) and nitromethane (420 mL) in
CHCl3 (3 L), acetate 6 (800 g, 5.2 mol) was added in portions at room temperature, and
then the mixture was heated to 40 ꢀC. After 15 h, the reaction was complete, as moni-
tored using TLC. The reaction was cooled to room temperature and slowly poured into
1 N hydrochloric acid (8 L) containing crushed ice (1 kg). After stirring adequately, the
organic layer was separated. The aqueous layer was extracted two additional times
(2 L ꢁ 2). The combined organic layers were washed with water until the pH was 4–5
and were concentrated in vacuo to provide black oil. The black oil was dissolved in
ethyl acetate (3.6 L) and extracted with 15% NaOH (2 L ꢁ 4). The aqueous layer was col-
lected and adjusted to pH 5 using 6 N hydrochloric acid. The pink precipitate was fil-
tered to provide 682 g of crude product. The crude product was dissolved in hot water
(6.5 L), decolorized with active carbon (20 g), then filtered and recrystallized to give
ketone 7 as a pale yellow tabular crystal (640 g, 80%). Mp 120–122 ꢀC, (Lit.[19] Mp
1
120–121 ꢀC). H NMR (400 MHz, CDCl3): d (ppm) 7.85 (t, J ¼ 8.4 Hz, 1H), 6.85 (s, 1H),
6.73 (dd, J ¼ 2.0 Hz, 2.4 Hz, 1H), 6.64 (dd, J ¼ 2.0 Hz, 2.4 Hz, 1H), 2.63 (d,
J ¼ 5.2 Hz, 3H).

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9
Synthesis of N-(2-fluoro-4-hydroxyphenyl)acetamide (9)
To a solution of fluorophenol 5 (610 g, 3.6 mol) in dried ethyl acetate (3 L), potassium
iodide (6 g, 0.04 mol) and thionyl chloride (9 mL, 1 mmol) was added dropwise at room
temperature. The mixture was heated to 65 ꢀC. After 3 h, the reaction was complete, as
monitored using TLC. The mixture was cooled to room temperature and concentrated
in vacuo to give 9 as a pale brown solid, Mp 121–122 ꢀC, (Lit.[20] Mp 124 ꢀC). Spectral
1
properties for intermediate 9, ESI MS(m/z): 170.1 [M þ H]þ, 339.1 [2M þ Na]þ. H
NMR (400 MHz, DMSO-d6): d (ppm) 9.71 (s, 1H), 9.39 (s, 1H), 7.39 (t, J ¼ 8.8 Hz, 1H),
6.59 (dd, J ¼ 2.4 Hz, 2.8 Hz, 1H), 6.54 (dd, J ¼ 2.4 Hz; 2.8 Hz, 1H), 2.00 (s, 3H).
Synthesis of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-
methylpicolinamide (regorafenib, 1)
To a solution of intermediate 13 (288 g, 1.1 mol) and dichloromethane (960 mL), iso-
cyanate 4 (292 g, 1.3 mol) in dichloromethane (500 mL) was added dropwise at 0 ꢀC
under argon. The mixture was stirred at room temperature, and a brown solid precipi-
tated after 20 min. The mixture was stirred for 16 h and then filtered. The precipitate
was suspended in diethyl ether (2 L) and stirred for 2 h. Then, the mixture was filtered
and dried under vacuum for 4 h at 35 ꢀC to provide 1 (478 g, 90%) as a white sþolid with
99.96% HPLC purity. Mp: 206–207 ꢀC, ESI MS (m/z): 483.3 [M þ H] , 505.3
[M þ Na]þ. HRMS (ESI): m/z calcd for C21H15ClF4N4O3 [M þ Na]þ 505.0661, found
1
505.0667. H NMR (400 MHz, DMSO-d6): d (ppm) 10.40 (s, 1H), 9.78 (s, 1H), 9.11 (s,
1H), 8.58 (d, J ¼ 5.96 Hz, 1H), 8.12–8.21 (m, 2 H), 7.64-7.69 (m, 2H), 7.60 (d, J ¼ 8.8 Hz,
1H), 7.34 (dd, J ¼ 2.8 Hz, 2.4 Hz, 1H), 7.30 (dd, J ¼ 2.4 Hz, 2.4 Hz, 1H), 7.08 (d,
J ¼ 1.52 Hz, 1H), 2.81 (d, J ¼ 4.68 Hz, 3H).
Acknowledgments
We thank the ACS ChemWorx Authoring Services (support@es.acschemworx.acs.org) for its lin-
guistic assistance during the preparation of this manuscript.
Funding
This work was financially supported by the Liaoning Provincial Natural Science Foundation of
China [No. 201602707].
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