Copper-Catalyzed Oxidative Cross-Dehydrogenative Coupling/Oxidative Cycloaddition: Synthesis of 4-Acyl-1,2,3-Triazoles

Article abstract of DOI:10.1021/acs.joc.7b01429

A copper-catalyzed three-component reaction of methyl ketones, organic azides, and various one-carbon (C1) donors was developed that provides 4-acyl-1,2,3-triazoles in moderate to good yields. While DMF, DMA, TMEDA, or DMSO can serve as the C1 donor, best yields were obtained using DMF. The transformation is proposed to proceed via an oxidative C-H/C-H cross-dehydrogenative coupling followed by an oxidative 1,3-dipolar cycloaddition.

Full text of DOI:10.1021/acs.joc.7b01429

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Note
Copper-Catalyzed Oxidative Cross-Dehydrogenative Coupling/
Oxidative Cycloaddition: A Synthesis of 4-Acyl-1,2,3-Triazoles
Yi Liu, Gang Nie, Zhongzhen Zhou, Lihui Jia, and Yunfeng Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01429 • Publication Date (Web): 27 Jul 2017
Downloaded from http://pubs.acs.org on July 28, 2017
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Copper-Catalyzed Oxidative Cross-Dehydrogenative
Coupling/Oxidative Cycloaddition: A Synthesis of
4-Acyl-1,2,3-Triazoles
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Yi Liu,† Gang Nie,† Zhongzhen Zhou,*,‡ Lihui Jia,† and Yunfeng Chen*,†
†School of Chemistry and Environmental Engineering, Wuhan Institute of Technology,
Wuhan 430073, China.
‡Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical
Sciences, Southern Medical University, Guangzhou 510515, China.
O
O
N
Cu(II), oxidant
N
N
"C-H"
C1 donor
C
+
RN3
+
Ar
CH3
C
H
Ar
R
29 examples
up to 85% yield
ABSTRACT: A copper-catalyzed three-component reaction of methyl ketones, organic
azides and various one-carbon (C1) donors has been developed that provides 4-acyl-
1,2,3-triazoles in moderate to good yields. While DMF, DMA, TMEDA or DMSO, can
serve as the C1 donor, best yields were obtained using DMF. The transformation is
proposed to proceed via an oxidative C-H/C-H cross-dehydrogenative coupling followed by
an oxidative 1,3-dipolar cycloaddition.
1,2,3-Triazoles are important N-heterocycles, which have shown many applications in
various fields.1 Presently, synthesis of diverse 1,2,3-triazoles is a hot research topic.2 Among
them, 4-acyl-1,2,3-triazoles have drawn particular attention due to their unique biological
activities.3 Some approaches have been disclosed for providing them now, such as CuAAC
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reaction of ynones or acetylenic carbinols with organic azides (Scheme 1A)4,
cyclization/oxidation reaction of enones (Scheme 1B)5. Unfortunately, there was the potential
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polymerization
for
ynones
or
enones.
Moreover,
an
enaminone-based
cycloaddition/elimination strategy was also developed for the synthesis of
4-acyl-1,2,3-triazoles recently.6 For example, a metal-free one-pot multi-component reaction
between methyl ketones, N,N-dimethylformamide dimethyl acetal (DMF dimethyl acetal)
and organic azide; this system shows wide substrate scope, but requires a high
temperature/microwave step for the formation of the enaminone intermediate (Scheme
1C-i)6a. Another approach is a base-promoted cycloaddition of NH-based secondary
enaminones and tosyl azide involving a Regitz diazo transfer process (Scheme 1C-ii).7
Nonetheless, it is desirable for a direct, convenient and efficient method to access
4-acyl-1,2,3-triazoles.
Recently, advances have been made towards direct C-H bond functionalization reactions,
especially the C-H/C-H cross-dehydrogenative coupling (CDC) reaction.8 This approach
allows the efficient assembly of N-heterocycles, using, for example, the “Me” in aryl methyl
ketones as a carbon source for direct C(sp3)-H bond functionalization.9,10
Based on the synthetic analysis of acyl substituted 1,2,3-triazoles，our previous research on
1,2,3-triazoles and related heterocyclic chemistry,11 we propose that the “Me” group in aryl
methyl ketones might serve as a carbon source to construct 1,2,3-triazole ring. Herein, we
report a three-component Cu(II)-catalyzed oxidative C-H/C-H CDC/oxidative cycloaddition
for the convenient construction of 4-acyl-1,2,3-triazoles, in which aryl methyl ketones,
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organic azides and other C1 donor compounds (such as DMF) are used as starting material
(Scheme 1D). This three-component one-pot protocol avoids the requirement for
purification of reaction intermediates and prevents certain side reactions leading to higher
yields.12
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Scheme 1. Strategies for Synthesis of 4-Acyl-1,2,3-Triazoles
A: alkyne-based CuAAC strategies
O
HO
R'
N
O
N
N
CuAAC
1. CuAAC
+ RN3
+ RN3
2. oxidation
R'
R'
R
B: enone-based cycloaddition/oxidation strategies
O
O
N
method A:CuO
N
N
+ RN3
Ar
R'
method B: R3N
Ar
R
R'
C: enaminone-based cycloaddition/elimination strategies
O
N
N
O
NHR
RN3
i
O
TsN3
N
R
R'
N
R'
t-BuONa
ii
R'
D: This work (oxidative CDC/oxidative cycloaddition strategy)
N
O
O
H3C
O
H
Cu(II), oxidant
N
N
C
RN3
+
+
N
Ar
CH3
C
Ar
R
H
Initially, the reaction of acetophenone (1a) and benzyl azide (2a) were examined in DMF at
o
100 C in the presence of CuSO4 and K2S2O8. To our delight, after 5 hours, the desired
4-acyl substituted 1,2,3-triazole 4a was isolated in 64% yield (Table 1, entry 1), and the
structure of 4a was also identified by X-ray single crystal analysis (see supporting
information). Encouraged by this result, we decided to further optimize the reaction
conditions by varying the catalysts and oxidants. Firstly, different Cu(I) and Cu(II) salts
were investigated (entries 1-6). It was found that Cu(II) salts showed a better catalytic
efficiency than Cu(I), and Cu(NO3)2 produced the best result with 73% yield. The
inexpensive iron salt FeCl3, which can promote the cross-dehydrogenative coupling,13 was
examined, but did not give satisfactory result (entry 7). Therefore, Cu(NO3)2 was selected as
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the catalyst for all further reactions. Subsequently, different common oxidants such as
benzoyl peroxide (BPO), tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide (DTBP)
were examined, still K2S2O8 was the best choice (entries 4, 10-12). The desired product can
not be produced without oxidants, even when stoichiometric metal salt was used (entry 13).
In order to enhance the catalytic efficiency, some ligands were evaluated (entries 14-17).
L-Proline did not promote the efficiency, and 1,10-phenanthroline (phen) inhibited the
reaction. Surprisingly, the yield of 4a was promoted to 82% when
N,N,N',N'-tetramethylethylenediamine (TMEDA) was used. We also tested the hindered
monoamine N,N-diisopropyl-ethylamine (DIPEA), but it provided only a small
improvement, suggesting that TMEDA serves not only as a base but may also act as a
ligand for the metal. Furthermore, the temperature was also evaluated, and the results
revealed that the optimal temperature for this reaction was 100 oC (entry 18).
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Table 1. Optimization of the Reaction Conditionsa
O
H
O
C
H3C
O
H
C
N
N3
CH3
N
+
+
N N
1a
2a
4a
Entry Catalyst
Oxidant Additive Yield(%)b
1
CuSO4
CuX
K2S2O8
K2S2O8
K2S2O8
64
28/20/22
42
2c
3
CuO
4
5
6
Cu(NO3)2 K2S2O8
Cu(OAc)2 K2S2O8
Cu(OTf)2 K2S2O8
73
60
55
7
8
FeCl3
-
Cu(NO3)2 K2S2O8
Cu(NO3)2 BPO
Cu(NO3)2 TBHP
Cu(NO3)2 DTBP
K2S2O8
K2S2O8
32
trace
63
65
46
9d
10
11
12
13e
47
0
Cu(NO3)2
-
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18f
Cu(NO3)2 K2S2O8 L-proline 72
Cu(NO3)2 K2S2O8 TMEDA 82
Cu(NO3)2 K2S2O8 phen
Cu(NO3)2 K2S2O8 DIPEA
45
70
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Cu(NO3)2 K2S2O8 TMEDA trace/74
aReaction conditions: 1a (1 mmol), 2a (1.5 mmol), catalyst (0.2 mmol), oxidant (3 mmol),
additive (0.2 mmol), DMF (5 mL), reaction time: 3 h, in air. bIsolated yields based on 1a. cX
d
e
= Cl, I, Br. K2S2O8 (2 mmol) was used; 0.2 mmol or 3 mmol Cu(NO3)2 were used and
both of them without product. f80 oC/110 oC were used.
Following the previous investigations, alternative one-carbon sources were employed to test
this transformation, especially different N-substituted amides (Table 2). The reaction
occurred smoothly when DMA was used as solvent, although the yield of 4a was slightly
lower than DMF. When DMSO was employed, the reaction could also occur, albeit in lower
yield. When TMEDA served as solvent solely, 4a could still be generated. However, the
conversion was low and prolonging the reaction time did not give the satisfactory result,
which suggested that TMEDA served as ligand for the reaction in DMF. In contrast, using
N,N-dimethylformamide dimethyl acetal (DMF-DMA) as the carbon source resulted in very
slow reaction with lower isolated yield (only 24%) after 24 h. 4a could not be obtained
using
N-methyl
amides
such
as
N-methylacetamide
(MeNHAc),
N-methyl-N-phenylacetamide
(PhMeNAc),
methylpyrrolidin-2-one
(NMP), and
N,N-dimethylaniline (Me2NPh) as solvents. In addition, N,N-diethylformamide (DEF) also
failed to promote this reaction, which suggested that the extended carbon atom originated
from the N,N-dimethyl moiety rather than the carbonyl carbon in the amides. Therefore,
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DMF was chosen as carbon source for this three-component reaction. Indeed, DMF has
been reported to serve as a convenient reactant to provide various functional units,14
especially as one-carbon synthons (CH3 or CH) in Rh-, Ru- and Cu-catalyzed reactions.15
Table 2. Screening of the C1-H Sourcea
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O
H
O
C
C
Cu(NO3)2, K2S2O8
100 oC, 3 h
N
N3
C1-H
sources
CH3
+
+
N
N
4a
1a
2a
Entry
C1-H source
DMF
Yield(%)b
1
2
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4
5
6
7
8
73
62
25
30c
48d
24e
trace
0
DMA
DMSO
TMEDA
TMEDA
DMF-DMA
MeNHAc
othersf
aReaction conditions: 1a (1 mmol), 2a (1.5 mmol), Cu(NO3)2 (0.2 mmol), K2S2O8 (3
mmol)，C1-H source (5 mL), in air. bIsolated yields based on 1a. c65% of 1a was recovered.
dReaction time: 10 h. eReaction time: 24 h. fOthers: PhMeNAc, NMP, Me2NPh and DEF.
With the optimal condition established, we then explored the scope of this three-component
reaction by employing various methyl ketones and organic azides, and the results are
summarized in Table 3. Various acetophenones with both electron-withdrawing groups
(such as Br, F, NO2) and electron-donating groups (such as CH3, OMe) were viable
substrates for this reaction. The substrates with electron-withdrawing groups in the
acetophenones delivered slightly higher yields. Furthermore, methyl 2-thienyl ketone can
also react with different organic azides to generate the 1,2,3-triazoles containing thiophene
moiety (4h, 4aa-4ac), however, alkyl methyl ketones, such as acetone, 2-butanone cannot
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give the corresponding 1,2,3-triazoles in this reaction system. Pinacolone and benzalacetone
with even higher selective reactivity were used, but we still could not obtain the
corresponding product. Different organic azides, including aryl aizdes, substituted benzyl
azides, and ethyl 2-azidoacetate was all suitable material for this three-component reaction,
although ethyl 2-azidoacetate generally produced lower yields than other azides.
Table 3. Synthesis of 4-Acyl-1,2,3-triazolesa
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N
O
R
O
N
N
Cu(NO3)2, TMEDA, K2S2O8
DMF, 100 oC, 3-8 h
C
R'N3
+
CH3
R
C
H
4
R'
2
1
O
H
O
O
H
C
C
N
C
C
S
CH
C
N
N
N
N
N
N
N
N
R
4h: 67%
4i: 63%
4a: R = H, 82%b
4b: R= 4-OMe, 76%
4c
4d: R= 4-F, 62%
4e: R = 4-NO2, 80%
O
H
O
: R = 4-CH3, 75%
H
C
C
C
C
N
N
N
N
N
N
Br
Cl
4f
: R = 3-Br, 78%
4g
4j: 78%
: R = 4-Br, 85%
4k
: 72%
O
H
O
O
H
C
C
H
C
C
N
C
N
C
N
N
N
N
N
O
Br
N
N
R
R
O
R'
4l: R' = 2-Br, 83%
4m
4n
4s
4p: R = H, 70%
: R = F, 58%
: R = Br, 65%
: R' = 4-Cl, 77%
4t
4q: R = CH3, 68%
: R' = 4-OMe, 71%
4r
: R = Br, 73%
4o: R' = 4-F, 70%
H
O
C
N
4u: R = 4-OMe, R' = 2-Br, 75%
4v: R= 4-CH3, R' = 4-Cl, 74%
: R = 4-F, R' = 4-OMe, 70%
: R = 4-CH3, R' = 4-F, 75%
4y: R = 4-OMe, R' = 4-F, 76%
4z: R = 4-NO2, R' = 4-F, 78%
C
O
H
C
S
N
N
R'
C
N
4w
4x
R
N
N
4aa
4ab
4ac
: R' = 4-F, 63%
: R' = 4-Cl, 64%
: R' = 2-Br, 79%
R'
aReaction conditions: 1 (2 mmol), 2 (3 mmol), Cu(NO3)2 (0.4 mmol), K2S2O8 (6 mmol),
TMEDA (0.4 mmol), DMF (10 mL), in air. bIsolated yields based on 1.
In order to obtain deeper insight into this reaction, some control experiments were
conducted (Scheme 2). Equation 1 shows that this three-component reaction was inhibited
by 2,2,6,6- tetramethylpiperidinooxy (TEMPO, 3 equiv), which indicated that the reaction
involves a radical process. Equation 2 shows that the enaminone 5 did not react with benzyl
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azide to give 4a under standard reaction conditions, which implies that this reaction may not
go via an enaminone intermediate; this key result suggests that this work differs from
previous enaminone-azide cyclization processes.6a Equation 3 shows that without benzyl
azide, acetophenone gave the intermediates 6 and 7 in 8% and 7% yields, respectively, and
the conversion of 1a was only 55%. Reactions between benzyl azide and 6 or 7 were
complete in 1.5 h (eqs 4 and 5); however, the yields were only 36% and 38%, respectively,
which were lower than the one-pot protocol; it appears that most of reaction materials
instead polymerized. These results show that the cycloaddition reactions of intermediates 6
and 7 with benzyl azide are fast, but that the polymerizations of 6 and 7 were fast too.
Equation 6 shows that a stepwise reaction in which 1a was treated with Cu(NO3)2 and
K2S2O8 in DMF at 100℃ for 5 h, then benzyl azide 2a was added to the reaction mixture,
followed by an additional 3 h heating afforded triazole 4a in 34% yield; this low yield is
accounted for unreacted acetophenone 1a.
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Scheme 2. Control Experimentsa
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O
N
O
N
N
Cu(NO3)2, K2S2O8, TMEDA
+
BnN3
(1)
(2)
TEMPO (3 equiv)
DMF, 100 oC, 3 h
Ph
Ph
Bn
1a
2a
4a
, trace
N
O
O
N
Cu(NO3)2, K2S2O8, TMEDA
DMF, 100 oC, 3 h
10
11
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+ BnN3
N
Ph
N
Ph
Bn
2a
5
4a
, trace
O
O
O
O
DMF
+
H
(3)
(4)
Ph
Ph
N
Ph
Cu(NO3)2, K2S2O8,
1a
100 oC, 5 h
6, 8%
7, 7%
55% conversion
O
O
O
N
N
N
Cu(NO3)2, K2S2O8, TMEDA
+
BnN3
DMF, 100 oC, 1.5 h
100% conversion of 6
Ph
N
H
Ph
O
Bn
2a
6
4a, 36%
O
N
N
Cu(NO3)2, K2S2O8, TMEDA
DMF, 100 oC, 1.5 h
(5)
(6)
+
BnN3
N
Ph
Ph
Ph
Bn
2a
7
7
4a, 38%
100% conversion of
O
N
O
N
DMF
then BnN3, TMEDA
N
Ph
100 oC, 3 h
100% conversion of 1a
Bn
Cu(NO3)2, K2S2O8,
100 oC, 5 h
4a
, 34%
1a
aGeneral reaction conditions: Cu(NO3)2 (0.2 mmol), K2S2O8 (3 mmol), TMEDA (0.2 mmol),
2a (1.5 mmol), DMF (5 mL), other reactants (1 mmol), in air.
Based on the results above and previous literature reports,5 a plausible reaction path is
outlined (Scheme 3). Oxidative coupling of acetophenone with DMF in the presence of
Cu(II)/K2S2O8, forms the intermediate 6, which can eliminate N-methylformamide to give
intermediate 7. Intermediate 6 and 7 can react with benzyl azide to form 1,2,3-triazole (4a)
in the presence of copper catalyst and oxidant.5 The control experiments suggest that the
oxidative coupling step is slow, while the second oxidative cycloaddition step is fast.
However, polymerization of intermediates can be fast if they accumulate to high
concentration. Thus the presence of organic azides in the three-component reaction protocol
should consume the intermediate 6 and 7, preventing their polymerization. This suggests
that the rate of polymerization is probably second order or higher, whereas under the
conditions of the reaction, the azide cycloaddition is pseudo-first order.
Scheme 3. Plausible Reaction Path
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O
OH
CH2
O
H
Cu(II)/K2S2O8
O
H
N
N
Ph
CH3
Ph
1a'
1a
10
11
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oxidative CDC
SLOW
O
O
O
polymerization
FAST
N
H
_
HCONHCH3
BnN3
6
7
in high concentration
Cu(II)
oxidative cycloaddition
FAST
O
N
N
N
4a
In conclusion, we have developed an efficient copper-catalyzed three-component protocol
to synthesize 4-acyl-1,2,3-triazoles in moderate to good yields under operationally
convenient conditions. In addition to the readily available materials, mild reaction
conditions and shorter reaction time than previous works, this method avoids the isolation
of reaction intermediates and inhibits some side reactions as well, which thus improves the
overall efficiency. Further investigations on the mechanistic pathway and the synthesis of
other heterocycles by using the similar strategy are underway in our laboratory.
EXPERIMENTAL SECTION
General Methods and materials: All of the reactions were carried out in 25mL
round-bottom flasks with air condensers. Unless otherwise noted, all commercial reagents
and solvents were obtained from the commercial provider and used without further
1
13
purification. H NMR and C NMR spectra were recorded on Varian 600 MHz and 400
MHz spectrometers. Chemical shifts were reported relative to internal tetramethylsilane
1
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(TMS) (0.00 ppm) or CDCl3 (7.26 ppm) for H, CDCl3 (77.0 ppm) for C. Flash column
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chromatography was performed on 200-300 mesh silica gel. Analytical thin layer
chromatography was performed with precoated glass baked plates (250μ) and visualized by
fluorescence. High-resolution mass spectra were recorded on a Solarix XR quadrupole
Fourier transform tandem mass spectrometer. Melting points were measured on a melting
point tester RY-1G apparatus and uncorrected.
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General experimental procedure for synthesis of 4-acyl-1,2,3-triazoles. To a solution of
ketone 1 (1mmol) and azide 2 (1.5 mmol, 1.5 equiv) in DMF (5 mL), was added Cu(NO3)2
(0.2 mmol), K2S2O8 (3 mmol, 3.0 equiv) and TMEDA (0.2mmol, 0.2 equiv), the mixture
o
was stirring at 100 C in oil bath under the air atmosphere (1 atm) for 3-8 h. The reaction
was checked by TLC (thin layer chromatography). After the completion of the reaction, the
mixture was poured into water, and extracted by ethyl acetate, washed with Na2CO3(aq),
dried with anhydrous Na2SO4, then the solvent was removed under reduced pressure to
obtain crude product, further purification by column chromatography on silica gel gave the
4-acyl-1,2,3-triazoles.
(1-Benzyl-1H-1,2,3-triazol-4-yl)(phenyl)methanone (4a) Yield: 82% (220 mg). White
solid. mp: 116-117 oC. Eluent: EtOAc/Pet ether (V/V = 1:30, Rf = 0.1). 1H NMR (600 MHz,
CDCl3) δ 8.41 (d, J = 8.2 Hz, 2H), 8.17 (s, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz,
2H), 7.40 (d, J = 6.6 Hz, 3H), 7.33 (d, J = 7.8 Hz, 2H), 5.60 (s, 2H). 13C NMR (150 MHz,
CDCl3) δ 185.6, 148.3, 136.4, 133.6, 133.2, 130.5, 129.2, 129.1, 128.3, 128.2, 54.4. Spectral
data match those previously reported in the literature.6a
(1-Benzyl-1H-1,2,3-triazol-4-yl)(4-methoxyphenyl)methanone (4b) Yield: 76% (223 mg).
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White solid. mp:129-131 oC. Eluent: EtOAc/Pet ether (V/V = 1:20, Rf = 0.1). 1H NMR (400
MHz, CDCl3) δ 8.54 – 8.47 (m, 2H), 8.14 (s, 1H), 7.43 – 7.29 (m, 5H), 6.99 (d, J = 9.0 Hz,
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2H), 5.60 (s, 2H), 3.90 (s, 3H). C NMR (100 MHz, CDCl3) δ 183.9, 163.8, 148.8, 133.7,
133.1, 129.4, 129.3, 129.1, 128.3, 128.1, 113.6, 55.5, 54.4. Spectral data match those
previously reported in the literature.6b
(1-Benzyl-1H-1,2,3-triazol-4-yl)(p-tolyl)methanone (4c) Yield: 75% (208 mg). White
solid. mp: 130-132 oC. Eluent: EtOAc/Pet ether (V/V = 1:20, Rf = 0.1). 1H NMR (600 MHz,
CDCl3) δ 8.34 (d, J = 8.2 Hz, 2H), 8.16 (s, 1H), 7.41 – 7.28 (m, 7H), 5.59 (s, 2H), 2.42 (s,
3H). 13C NMR (150 MHz, CDCl3) δ 185.1, 148.4, 144.0, 133.9, 133.7, 130.6, 129.2, 129.0,
128.2, 128.1, 54.3, 21.6. Spectral date match those previously reported in the literature.17
(1-Benzyl-1H-1,2,3-triazol-4-yl)(4-fluorophenyl)methanone (4d) Yield: 62% (174 mg).
White solid. mp: 145-146 oC. Eluent: EtOAc/Pet ether (V/V = 1:20, Rf = 0.2). 1H NMR (600
MHz, CDCl3) δ 8.58 – 8.50 (m, 2H), 8.18 (s, 1H), 7.45 – 7.31 (m, 5H), 7.21 – 7.14 (m, 2H),
5.61 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 183.7, 166.7, 165.0, 148.3, 133.6, 133.4 (d, J =
9.0 Hz), 132.7 (d, J = 3.0 Hz), 129.3, 129.1, 128.3, 115.4 (d, J = 21.6 Hz), 54.4. Spectral
data match those previously reported in the literature.6b
(1-Benzyl-1H-1,2,3-triazol-4-yl)(4-nitrophenyl)methanone (4e) Yield: 80% (246 mg).
Light yellow solid. mp:137-139 oC. Eluent: EtOAc/Pet ether (V/V = 1:20, Rf = 0.2). 1H
NMR (600 MHz, CDCl3) δ 8.70 – 8.58 (m, 2H), 8.42 – 8.31 (m, 2H), 8.24 (s, 1H), 7.45 –
7.29 (m, 5H), 5.64 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 183.7, 150.3, 147.7, 141.0, 133.3,
131.6, 129.4, 129.3, 128.6, 128.4, 123.4, 54.6. Spectral data match those previously
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(1-Benzyl-1H-1,2,3-triazol-4-yl)(3-bromophenyl)methanone (4f) Yield: 78% (266 mg).
1
White solid. mp: 95-98 oC. Eluent: EtOAc/Pet ether (V/V = 1:30, Rf = 0.2) H NMR (600
MHz, CDCl3) δ 8.54 (s, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.19 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H),
7.44 – 7.29 (m, 6H), 5.61 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 183.9, 147.8, 138.0, 136.0,
133.5, 133.2, 129.8, 129.3, 129.2, 129.1, 128.4, 128.3, 122.5, 122.4, 54.4. HRMS
(EI-FTMS) m/z [M] calcd. for C16H12BrN3O: 341.0158, found: 341.0152.
(1-Benzyl-1H-1,2,3-triazol-4-yl)(4-bromophenyl)methanone (4g) Yield: 85% (291 mg).
1
White solid. mp: 149-151 oC. Eluent: EtOAc/Pet ether (V/V = 1:20, Rf = 0.2). H NMR
(600 MHz, CDCl3) δ 8.35 (d, J = 8.4 Hz, 2H), 8.17 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.43 –
7.31 (m, 5H), 5.61 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 184.3, 148.1, 135.0, 133.5, 132.1,
131.6, 129.3, 129.2, 128.6, 128.3, 54.5. Spectral data match those previously reported in the
literature.6b
(1-Benzyl-1H-1,2,3-triazol-4-yl)(thiophen-2-yl)methanone (4h) Yield: 67% (180 mg).
1
White solid. mp: 141-143 oC. Eluent: EtOAc/Pet ether (V/V = 1:20, Rf = 0.2). H NMR
(600 MHz, CDCl3) δ 8.75 (d, J = 3.6 Hz, 1H), 8.15 (s, 1H), 7.75 (d, J = 4.8 Hz, 1H), 7.43 –
7.38 (m, 3H), 7.35 – 7.30 (m, 2H), 7.23 (t, J = 4.8 Hz, 1H), 5.61 (s, 2H). 13C NMR (150
MHz, CDCl3) δ 177.2, 147.9, 142.2, 136.3, 135.0, 133.6, 129.3, 129.2, 128.4, 128.3, 127.6,
54.5. Spectral data match those previously reported in the literature.4c
(1-Benzyl-1H-1,2,3-triazol-4-yl)(9H-fluoren-2-yl)methanone (4i) Yield: 63% (221 mg).
1
White solid. mp: 209-210 oC. Eluent: EtOAc/Pet ether (V/V = 1:10, Rf = 0.2). H NMR
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(400 MHz, CDCl3) δ 8.68 (s, 1H), 8.51 (d, J = 8.2 Hz, 1H), 8.19 (s, 1H), 7.93 – 7.84 (m,
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2H), 7.60 (d, J = 7.2 Hz, 1H), 7.47 – 7.32 (m, 7H), 5.63 (s, 2H), 4.00 (s, 2H). C NMR
(100 MHz, CDCl3) δ 185.2, 148.8, 146.7, 144.7, 143.0, 140.6, 134.8, 133.7, 130.0, 129.3,
129.2, 128.4, 128.2, 128.0, 127.4, 127.0, 125.2, 121.0, 119.6, 54.5, 37.0. HRMS
(ESI-FTMS) m/z [M + 2H]+ calcd. for C23H19N3O: 353.2665, found: 353.2660.
(1-Benzyl-1H-1,2,3-triazol-4-yl)(naphthalen-2-yl)methanone (4j) Yield: 78% (244 mg).
1
White solid. mp: 155-157 oC. Eluent: EtOAc/Pet ether (V/V = 1:40, Rf = 0.2). H NMR
(400 MHz, CDCl3) δ 9.23 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 8.03 (d, J = 7.8 Hz,
1H), 7.98 – 7.82 (m, 2H), 7.71 – 7.29 (m, 7H), 5.62 (s, 2H). 13C NMR (100 MHz, CDCl3) δ
185.3, 148.7, 135.7, 133.7, 133.5, 132.5, 132.0, 130.1, 129.4, 129.2, 128.7, 128.4, 128.2,
127.7, 126.6, 125.5, 54.5. Spectral data match those previously reported in the literature.4c
(4-Bromophenyl)(1-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl)methanone (4k) Yield: 72%
(261 mg). White solid. mp: 112-123 oC. Eluent: EtOAc/Pet ether (V/V = 1:40, Rf = 0.3). 1H
NMR (600 MHz, CDCl3) δ 8.74 (s, 1H), 8.44 (d, J = 8.4 Hz, 2H), 7.74 – 7.68 (m, 3H), 7.64
(t, J = 8.4 Hz, 1H), 7.57 – 7.49 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 184.2, 147.6, 135.1,
134.1, 132.2, 131.8, 131.4, 130.9, 130.5, 128.8, 128.7, 128.1, 127.6. HRMS (ESI-FTMS)
m/z [M + Na]+ calcd. for C15H9BrClN3ONa: 383.9509, found: 383.9504.
(1-(2-Bromobenzyl)-1H-1,2,3-triazol-4-yl)(4-bromophenyl)methanone (4l) Yield: 83%
(349 mg). White solid. mp: 106-108 oC. Eluent: EtOAc/Pet ether (V/V = 1:40, Rf = 0.2). 1H
NMR (600 MHz, CDCl3) δ 8.41 – 8.32 (m, 2H), 8.27 (s, 1H), 7.66 (d, J = 8.4 Hz, 3H), 7.37
(t, J = 7.2 Hz, 1H), 7.34 – 7.27 (m, 2H), 5.75 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 184.3,
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148.0, 135.0, 133.5, 133.1, 132.2, 131.7, 131.0, 130.9, 128.7, 128.7, 128.4, 124.0, 54.2.
HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C16H12Br2N3O: 419.9341, found: 419.9326.
(4-Bromophenyl)(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methanone (4m) Yield: 77%
(290 mg). White solid. mp: 175-176 oC. Eluent: EtOAc/Pet ether (V/V = 1:30, Rf = 0.2). 1H
NMR (600 MHz, CDCl3) δ 8.38 – 8.33 (m, 2H), 8.19 (s, 1H), 7.68 – 7.65 (m, 2H), 7.41 –
7.38 (m, 2H), 7.30 – 7.26 (m, 2H), 5.59 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 184.2, 148.3,
135.4, 135.0, 132.2, 132.0, 131.7, 129.7, 129.6, 128.8, 128.3, 53.7. HRMS (ESI-FTMS) m/z
[M + Na]+ calcd. for C16H11BrClN3ONa: 397.9666, found: 397.9658.
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(4-Bromophenyl)(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methanone (4n) Yield:
71% (264 mg). White solid. mp: 145-147 oC. Eluent: EtOAc/Pet ether (V/V = 1:30, Rf =
0.2). 1H NMR (600 MHz, CDCl3) δ 8.44 – 8.24 (m, 2H), 8.13 (s, 1H), 7.70 – 7.61 (m, 2H),
7.32 – 7.27 (m, 2H), 6.97 – 6.85 (m, 2H), 5.54 (s, 2H), 3.82 (s, 3H). 13C NMR (150 MHz,
CDCl3) δ 184.3, 160.2, 148.0, 135.1, 132.1, 131.6, 130.0, 128.6, 128.1, 125.4, 114.7, 55.3,
54.0. HRMS (EI-FTMS) m/z [M] calcd. for C17H14BrN3O2: 371.0263, found: 371.0263.
(4-Bromophenyl)(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methanone (4o) Yield: 70%
(252 mg). White solid. mp: 134-135 oC. Eluent: EtOAc/Pet ether (V/V = 1:30, Rf = 0.1). 1H
NMR (600 MHz, CDCl3) δ 8.38 – 8.31 (m, 2H), 8.18 (s, 1H), 7.69 – 7.61 (m, 2H), 7.37 –
7.32 (m, 2H), 7.10 (t, J = 8.4 Hz, 2H), 5.58 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 184.2,
163.1(d, J = 249.2 Hz), 148.3, 135.0, 132.1, 131.7, 130.3(d, J = 8.4 Hz), 129.4(d, J = 3.0
Hz), 128.7, 128.2, 116.4(d, J = 22.0 Hz), 53.7. HRMS (EI-FTMS) m/z [M] calcd. for
C16H11BrFN3O: 359.0064, found: 359.0061.
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Phenyl(1-phenyl-1H-1,2,3-triazol-4-yl)methanone (4p) Yield: 70% (174 mg). White solid.
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mp: 126-127 oC. Eluent: EtOAc/Pet ether (V/V = 1:40, Rf = 0.2). H NMR (600 MHz,
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CDCl3) δ 8.20 (s, 1H), 7.92 (d, J = 7.2 Hz, 2H), 7.80 (d, J = 7.8 Hz, 2H), 7.56 (t, J = 7.8 Hz,
2H), 7.47 (m, 3H), 7.38 (t, J = 7.2 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 130.2, 129.7,
128.9, 128.7, 128.6, 128.4, 125.8, 120.5, 117.5. Spectral data match those previously
reported in the literature.6a
(1-Phenyl-1H-1,2,3-triazol-4-yl)(p-tolyl)methanone (4q) Yield: 68% (179 mg). White
solid. mp: 152-153 oC. Eluent: EtOAc/Pet ether (V/V = 1:40, Rf = 0.2). 1H NMR (600 MHz,
CDCl3) δ 8.70 (s, 1H), 8.42 (d, J = 8.4 Hz, 2H), 7.83 – 7.78 (m, 2H), 7.62 – 7.54 (m, 2H),
7.53 – 7.46 (m, 1H), 7.39 – 7.30 (m, 2H), 2.46 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 185.0,
148.7, 144.3, 136.4, 133.9, 130.7, 129.9, 129.4, 129.1, 126.2, 120.7, 21.7. Spectral data
match those previously reported in the literature.17
(4-Bromophenyl)(1-phenyl-1H-1,2,3-triazol-4-yl)methanone (4r) Yield: 73% (239 mg).
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White solid. mp: 177-178 oC. Eluent: EtOAc/Pet ether (V/V = 1:40, Rf = 0.2). H NMR
(600 MHz, CDCl3) δ 8.71 (s, 1H), 8.42 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 7.2 Hz, 2H), 7.71 –
13
7.67 (m, 2H), 7.60 – 7.56 (m, 2H), 7.54 – 7.49 (m, 1H). C NMR (150 MHz, CDCl3) δ
184.2, 148.4, 136.3, 135.0, 132.2, 131.7, 130.0, 129.6, 128.8, 126.4, 120.8. Spectral data
match those previously reported in the literature.3d
Ethyl 2-(4-(4-fluorobenzoyl)-1H-1,2,3-triazol-1-yl)acetate (4s) Yield: 58% (161 mg).
1
White solid. mp: 160-161 oC. Eluent: EtOAc/Pet ether (V/V = 1:50, Rf = 0.2). H NMR
(600 MHz, CDCl3) δ 8.65 – 8.48 (m, 2H), 8.42 (s, 1H), 7.20 (t, J = 8.4 Hz, 2H), 5.25 (s, 2H),
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4.31 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 183.6,
166.8, 165.5, 165.1, 148.3, 133.4 (d, J = 9.6 Hz), 129.9, 115.5 (d, J = 21.9 Hz), 62.8, 50.9,
14.0. HRMS (EI-FTMS): m/z [M] calcd. for C13H12FN3O3: 277.0857, found: 277.0856.
Ethyl 2-(4-(4-bromobenzoyl)-1H-1,2,3-triazol-1-yl)acetate (4t) Yield: 65% (219 mg).
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White solid. mp: 162-164 oC. Eluent: EtOAc/Pet ether (V/V = 1:10, Rf = 0.2). H NMR
(600 MHz, CDCl3) δ 8.42 (s, 1H), 8.39 – 8.31 (m, 2H), 7.72 – 7.63 (m, 2H), 7.26 (s, 1H),
5.26 (s, 2H), 4.32 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3)
δ 184.2, 165.5, 148.2, 135.0, 132.1, 131.7, 129.9, 128.7, 62.8, 51.0, 14.0. HRMS
(ESI-FTMS) m/z [M + H]+ calcd. for C13H13BrN3O3: 338.0134, found: 338.0129.
(1-(2-Bromobenzyl)-1H-1,2,3-triazol-4-yl)(4-methoxyphenyl)methanone (4u) Yield:
75% (279 mg). White solid. mp: 125-127 oC. Eluent: EtOAc/Pet ether (V/V = 1:10, Rf =
0.2). 1H NMR (600 MHz, CDCl3) δ 8.65 – 8.42 (m, 2H), 8.24 (s, 1H), 7.64 (d, J = 7.8 Hz,
13
1H), 7.42 – 7.10 (m, 3H), 7.09 – 6.84 (m, 2H), 5.74 (s, 2H), 3.89 (s, 3H). C NMR (150
MHz, CDCl3) δ 183.7, 163.8, 148.6, 133.4, 133.3, 133.1, 130.8, 130.7, 129.3, 128.4, 128.3,
128.3, 123.8, 113.6, 55.4, 54.0. HRMS (EI-FTMS) m/z [M] calcd. for C17H14BrN3O2:
371.0263, found: 371.0260.
(1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)(p-tolyl)methanone (4v) Yield: 74% (231 mg).
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White solid. mp: 178-180 oC. Eluent: EtOAc/Pet ether (V/V = 1:15, Rf = 0.3). H NMR
(600 MHz, CDCl3) δ 8.34 (d, J = 8.4 Hz, 2H), 8.16 (s, 1H), 7.40 – 7.35 (m, 2H), 7.31 (d, J =
8.4 Hz, 2H), 7.29 – 7.25 (m, 2H), 5.58 (s, 2H), 2.44 (s, 3H). 13C NMR (150 MHz, CDCl3) δ
185.0, 148.7, 144.3, 135.3, 133.9, 132.3, 130.7, 129.6, 129.5, 129.1, 128.1, 53.7, 21.7.
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HRMS (EI-FTMS) m/z [M] calcd. for C17H14ClN3O: 311.0819, found: 311.0819.
(4-Fluorophenyl)(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methanone (4w) Yield:
70% (218 mg). White solid. mp: 144-145 oC. Eluent: EtOAc/Pet ether (V/V = 1:40, Rf =
0.1). 1H NMR (600 MHz, CDCl3) δ 8.58 – 8.50 (m, 2H), 8.13 (s, 1H), 7.31 – 7.27 (m, 2H),
7.21 – 7.14 (m, 2H), 6.95 – 6.89 (m, 2H), 5.54 (s, 2H), 3.82 (s, 3H). 13C NMR (150 MHz,
CDCl3) δ 183.8, 165.9 (d, J = 255.0 Hz), 160.2, 148.2, 133.4 (d, J = 9.3 Hz), 132.7 (d, J =
3.0 Hz), 130.0, 128.1, 125.4, 115.5 (d, J = 21.9 Hz), 114.7, 55.3, 54.0. HRMS (ESI-FTMS)
m/z [M + H]+ calcd. for C17H15FN3O2: 312.1142, found: 312.1132.
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(1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)(p-tolyl)methanone (4x) Yield: 75% (221 mg).
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White solid. mp: 145-147 oC. Eluent: EtOAc/Pet ether (V/V = 1:20, Rf = 0.1). H NMR
(600 MHz, CDCl3) δ 8.42 – 8.24 (m, 2H), 8.22 – 8.04 (m, 1H), 7.37 – 7.05 (m, 6H), 5.57 (d,
J = 5.4 Hz, 2H), 2.43 (d, J = 5.4 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 185.1, 163.0 (d, J
= 249.0 Hz), 148.6, 144.2, 133.8, 130.7, 130.2 (d, J = 8.4 Hz), 129.6 (d, J = 3.3 Hz), 129.0,
128.0, 116.3 (d, J = 21.9 Hz), 53.6, 21.7. HRMS (EI-FTMS) m/z [M] calcd. for C17H14FN3O:
295.1115, found: 295.1112.
(1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)(4-methoxyphenyl)methanone (4y) Yield:
76% (237 mg). White solid. mp: 131-132 oC. Eluent: EtOAc/Pet ether (V/V = 1:15, Rf =
0.3). 1H NMR (600 MHz, CDCl3) δ 8.63 – 8.38 (m, 2H), 8.15 (s, 1H), 7.38 – 7.30 (m, 2H),
7.10 (t, J = 8.4 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H), 5.58 (s, 2H), 3.90 (s, 3H). 13C NMR (150
MHz, CDCl3) δ 183.7, 163.8 (d, J = 2.4 Hz), 162.2, 148.8, 133.0, 130.2 (d, J = 8.4 Hz),
129.6, 129.2, 127.9, 116.3 (d, J = 21.9 Hz), 113.6, 55.4, 53.6. HRMS (ESI-FTMS) m/z [M +
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H]+ calcd. for C17H15FN3O2: 312.1142, found: 312.1134.
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(1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)(4-nitrophenyl)methanone (4z) Yield: 78%
(184 mg). White solid. mp: 127-128 oC. Eluent: EtOAc/Pet ether (V/V = 1:20, Rf = 0.2). 1H
NMR (600 MHz, CDCl3) δ 8.65 – 8.55 (m, 2H), 8.38 – 8.29 (m, 2H), 8.25 (s, 1H), 7.39 –
7.32 (m, 2H), 7.12 (t, J = 8.4 Hz, 2H), 5.62 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 183.6,
163.9, 162.2, 149.0 (d, J = 377.2 Hz), 140.9, 131.6, 130.3 (d, J = 8.4 Hz), 129.2 (d, J = 3.3
Hz), 128.5, 123.4, 116.4 (d, J = 21.9 Hz), 53.8. HRMS (EI-FTMS) m/z [M] calcd. for
C16H11FN4O3: 326.0809, found: 326.0808.
(1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)(thiophen-2-yl)methanone (4aa) Yield: 63%
(181 mg). White solid. mp: 152-154 oC. Eluent: EtOAc/Pet ether (V/V = 1:10, Rf = 0.3). 1H
NMR (600 MHz, CDCl3) δ 8.85 – 8.69 (m, 1H), 8.16 (s, 1H), 7.81 – 7.65 (m, 1H), 7.37 –
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7.30 (m, 2H), 7.24 – 7.21 (m, 1H), 7.10 (t, J = 8.4 Hz, 2H), 5.58 (s, 2H). C NMR (150
MHz, CDCl3) δ 177.1, 147.9, 142.1, 136.3, 135.1, 130.2 (d, J = 8.7 Hz), 128.44, 127.49,
116.39 (d, J = 21.9 Hz), 53.74. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C14H11FN3OS:
288.0601, found: 288.0600.
(1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)(thiophen-2-yl)methanone (4ab) Yield: 64%
(194 mg). White solid. mp:193-195 oC. Eluent: EtOAc/Pet ether (V/V = 1:10, Rf = 0.3). 1H
NMR (600 MHz, CDCl3) δ 8.75 (d, J = 3.6 Hz, 1H), 8.17 (s, 1H), 7.76 (d, J = 4.8 Hz, 1H),
7.39 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 10.2 Hz, 2H), 7.23 (t, J = 4.8 Hz, 1H), 5.58 (s, 2H). 13C
NMR (150 MHz, CDCl3) δ 177.1, 147.7, 142.2, 136.3, 135.1, 133.5, 133.1, 130.9, 130.8,
128.4, 128.4, 127.9, 123.9, 54.2. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for
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C14H11ClN3OS: 304.0305, found: 304.0300.
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(1-(2-Bromobenzyl)-1H-1,2,3-triazol-4-yl)(thiophen-2-yl)methanone (4ac) Yield: 79%
(275 mg). White solid. mp: 121-123 oC. Eluent: EtOAc/Pet ether (V/V = 1:10, Rf = 0.3). 1H
NMR (600 MHz, CDCl3) δ 8.76 (d, J = 3.6 Hz, 1H), 8.25 (s, 1H), 7.75 (d, J = 4.8 Hz, 1H),
7.65 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.32 – 7.25 (m, 2H), 7.23 (t, J = 4.2 Hz,
1H), 5.75 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 177.1, 147.7, 142.2, 136.3, 135.1, 133.5,
133.1, 130.9, 130.8, 128.5, 128.4, 127.9, 123.9, 54.2. HRMS (ESI-FTMS) m/z [M + H]+
calcd. for C14H11BrN3OS: 347.9800, found: 347.9797.
(E)-3-(Dimethylamino)-1-phenylprop-2-en-1-one (5) According to the reported
procedure16, yield: 81% (70 mg). Eluent: EtOAc/Pet ether (V/V = 3:2, Rf = 0.3). Light
yellow solid, 1H NMR (400 MHz, CDCl3) δ 7.95 – 7.85 (m, 2H), 7.79 (d, J = 12.4 Hz, 1H),
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7.49 – 7.30 (m, 3H), 5.71 (d, J = 12.4 Hz, 1H), 3.01 (d, J = 71.2 Hz, 6H). C NMR (100
MHz, CDCl3) δ 188.6, 154.2, 140.6, 130.8, 128.1, 127.5, 92.2, 44.9, 37.2..
N-Methyl-N-(3-oxo-3-phenylpropyl)formamide (6) Yield: 8% (15 mg). Yellow liquid.
Eluent: EtOAc/Pet ether (V/V = 1:3, Rf = 0.2). 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 0.5H),
8.02 (s, 0.5H), 7.98 – 7.89 (m, 2H), 7.65 – 7.54 (m, 1H), 7.48 (q, J = 7.2 Hz, 2H), 3.74 (t, J
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= 6.8 Hz, 2H), 3.34 – 3.21 (m, 2H), 3.03 (s, 1.5H), 2.89 (s, 1.5H). C NMR (100 MHz,
CDCl3) δ 198.4, 197.2, 163.1, 162.8, 136.5, 136.3, 133.6, 133.4, 128.8, 128.7, 128.1, 127.9,
44.5, 40.5, 36.7, 36.2, 35.7, 29.6. Spectral data match those previously reported in the
literature.17
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ASSOCIATED CONTENT
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI: 10.1021/ x0xx00000x. Scanned copies of H, 13C NMR and HRMS spectra of the
1
synthesized compounds (PDF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: yfchen@wit.edu.cn
*E-mail: zhouzz@smu.edu.cn
ORCID
Yunfeng Chen: 0000-0002-6220-5015
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (21002076, 21441007),
the Key Projects of Hubei Provincial Department of Education (D20151502), and Graduate
Innovative Fund of Wuhan Institute of Technology (No. CX2016168).
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