Silver-Mediated [3 + 2] Cycloaddition of Azomethine Ylides with Trifluoroacetimidoyl Chlorides for the Synthesis of 5-(Trifluoromethyl)imidazoles

Article abstract of DOI:10.1021/acs.joc.1c00131

A silver-mediated [3 + 2] cycloaddition of azomethine ylides with trifluoroacetimidoyl chlorides for the rapid assembly of 5-(trifluoromethyl)imidazoles has been developed. Notable features of the reaction include readily accessible reagents, a broad substrate scope, and high efficiency. The protocol can be successfully applied to construct the analogue of the specific allosteric modulator of GABAA receptors. The silver species could be recycled by a simple operation.

Full text of DOI:10.1021/acs.joc.1c00131

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Silver-Mediated [3 + 2] Cycloaddition of Azomethine Ylides with
Trifluoroacetimidoyl Chlorides for the Synthesis of
5‑(Trifluoromethyl)imidazoles
Hefei Yang, Shu-Ning Lu, Zhengkai Chen,* and Xiao-Feng Wu*
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ABSTRACT: A silver-mediated [3 + 2] cycloaddition of
azomethine ylides with trifluoroacetimidoyl chlorides for the
rapid assembly of 5-(trifluoromethyl)imidazoles has been
developed. Notable features of the reaction include readily
accessible reagents, a broad substrate scope, and high efficiency.
The protocol can be successfully applied to construct the analogue
of the specific allosteric modulator of GABAA receptors. The silver species could be recycled by a simple operation.
Scheme 1. Synthesis of Imidazolidines or Imidazoles from
[3 + 2] Cycloaddition of Azomethine Ylides
ultisubstituted imidazoles are kinds of highly privileged
Mstructural cores that have found extensive application in
the fields of biological and pharmaceutical chemistry, as ligands
as well as functional materials.1 Imidazole skeletons exist in
several commercial drugs and bioactive compounds, such as
losartan, eprosartan, econazole, clotrimazole, selective inhib-
itors of COX-2, and specific allosteric modulators of the
GABAA receptor.2 Due to their unique properties and wide
application prospects, considerable synthetic approaches for
the construction of imidazole scaffolds have been explored over
the past decades.3 Despite numerous elegant achievements
regarding imidazole synthesis having been made, the general
methods for the preparation of specifically functionalized
imidazoles, such as trifluoromethyl-substituted imidazoles,4
still remain underdeveloped. It is well-known that the
incorporation of fluorine-containing groups into heterocycles
could dramatically improve the chemical, physical, and
biological properties of the parent molecule.5 Therefore, the
development of an efficient and straightforward route for
producing valuable trifluoromethyl-substituted imidazoles is of
great significance and will be particularly appealing.
Azomethine ylides are regarded as kinds of versatile building
blocks and have been widely applied to 1,3-dipolar cyclo-
addition reactions with different dipolarophiles for the
assembly of various five-membered heterocyclic compounds.6
With respect to the synthesis of imidazole derivatives, a variety
of literature reports involving catalytic asymmetric [3 + 2]
cycloaddition of azomethine ylides with imines to construct
chiral imidazolidines have been published (Scheme 1a).7 It is
noteworthy that fluorinated imidazolidines could be success-
fully assembled through 1,3-dipolar cycloaddition of azome-
thine ylides with fluorinated imines, which were completed by
the groups of Wu7c and Wang.7d,e Bi and Xu independently
demonstrated a silver-promoted [3 + 2] cycloaddition of
azomethine ylides with isocyanides for the production of 1,2,4-
trisubstituted imidazoles with good functional group tolerance
(Scheme 1b).8 Inspired by the unique property of silver in the
construction of heterocycles9 and our ongoing efforts on the
synthesis of trifluoromethyl-containing N-heterocycles,10 we
herein describe a synthetic protocol for delivering 5-
(trifluoromethyl)imidazoles via silver-mediated [3 + 2]
cycloaddition of azomethine ylides with trifluoroacetimidoyl
chlorides (Scheme 1c). It is notable that trifluoroacetimidoyl
chloride can be easily obtained by simply mixing the parent
amine with TFA, CCl4, and PPh3,11 which is significantly
cheaper than the preparation of the aforementioned fluori-
Received: January 18, 2021
Published: February 22, 2021
https://dx.doi.org/10.1021/acs.joc.1c00131
© 2021 American Chemical Society
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nated imine from expensive trifluoroacetaldehyde ethyl
hemiacetal. Trifluoroacetimidoyl chlorides have been fre-
quently utilized as versatile trifluoromethyl synthons for the
construction of an array of important trifluoromethyl-
containing molecules.12
The reaction conditions were optimized by using (E)-methyl
2-(benzylideneamino)acetate (1a) and N-(4-(tert-butyl)-
phenyl)-2,2,2-trifluoroacetimidoyl chloride (2e) as benchmark
substrates. The reaction was performed in the presence of 2.0
equiv of Ag2CO3, 2.0 equiv of DBU, and 4 Å MS in toluene at
60 °C under an N2 atmosphere for 3 h. Gratifyingly, the [3 +
2] cycloaddition reaction occurred smoothly to deliver the
desired imidazole product 4e in 32% yield (Table 1, entry 1).
entry 16). Further increasing the ratio of 1a and 2e to 2/1 or
2.5/1 caused a slight decrease in the reaction yield (see the
Supporting Information for details). Reducing the amounts of
Ag2O to 1.5 or 1.0 equiv resulted in an obvious decrease in
reaction efficiency (Table 1, entry 17). When the reaction was
carried out in the presence of 0.3 equiv of Ag2O under an air or
O2 atmosphere, the reaction yield was decreased to 14% or
15% (Table 1, entry 18). In the meantime, the hydrolysis and
decomposition of trifluoroacetimidoyl chloride 2e were
observed. Elevating the reaction temperature to 80 °C enabled
a comparable reactivity, whereas lowering the temperature had
a harmful influence on the reaction (Table 1, entries 19 and
20).
Having established the optimal conditions, the scope of the
reaction was investigated with a wide range of azomethine
ylides, and the results are summarized in Scheme 2. Various
a
Table 1. Optimization of the Reaction Conditions
a b
,
Scheme 2. Scope of the Imino Esters
b
Entry
[Ag]
base
DBU
DBU
DBU
DBU
solvent
yield (%)
1
2
3
4
5
6
7
8
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2O
toluene
DMF
DMSO
DCE
32
15
9
6
DBU
Et3N
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
36
68
70
62
72
69
71
DIPEA
NaHCO3
Na2CO3
K2CO3
K3PO4
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
9
10
11
12
13
14
15
16
17
18
19
20
c
91 (88)
AgF
58
18
60
AgOAc
AgOTFA
Ag2O
Ag2O
Ag2O
cd
,
99 (97)
de
,
71−81
14−15
df
,
dg
,
Ag2O
Ag2O
96
71
dh
,
a
Reaction conditions unless specified otherwise: 1a (0.2 mmol), 2e
(0.4 mmol), [Ag] (2.0 equiv), base (2.0 equiv), and 4 Å MS (40 mg)
b
in solvent (2.0 mL) at 60 °C under N2 atmosphere for 3 h. Yields
determined by GC analysis using dodecane as an internal standard.
c
d
e
Isolated yield. 1a (0.3 mmol), 2e (0.2 mmol). The reaction was
a
Reaction conditions: 1 (0.3 mmol), 2a (0.2 mmol), Ag2O (2.0
performed in the presence of 1.5 equiv of Ag2O (81%) or 1.0 equiv of
equiv), Na2CO3 (2.0 equiv), and 4 Å MS (40 mg) in CH3CN (2.0
f
Ag2O (71%). The reaction was performed in the presence of 0.3
b
mL) under an N2 atmosphere at 60 °C for 3 h. Isolated yields.
g
equiv of Ag2O under an air (14%) or O2 (15%) atmosphere. 80 °C.
h
40 °C.
imino ester substrates with electron-donating or -withdrawing
groups at the benzene ring could successfully participate in the
reaction to furnish the highly substituted imidazoles 3a−h in
67−96% yields. A slight steric effect was observed with regard
to the products 3b−d. The electron-rich substrates 3a−e
generally showed higher reactivity in comparison to that of
electron-deficient substrates 3f−h. The transformation was
also tolerant of a naphthalene ring to deliver the imidazole
product 3i in 70% yield. Notably, azomethines containing a
heterocyclic motif, such as pyridine or furan, were also
compatible with the standard conditions, albeit with relatively
lower yields (3j,k). The obtained imidazole products could
possibly be utilized as bidentate ligands in metal-catalyzed
cross-coupling reactions. The imino ester from cinnamalde-
The solvent effect was next investigated by the employment of
different solvents, and the result indicated that CH3CN could
lead to superior reactivity (Table 1, entries 2−5). Then, we
screened a variety of other organic and inorganic bases,
including Et3N, DIPEA, NaHCO3, Na2CO3, K2CO3, and
K3PO4, which showed that Na2CO3 was the best choice to give
the 5-(trifluoromethyl)imidazole product 4e in 72% yield
(Table 1, entries 6−11). The examination of other silver salts
was also performed, and Ag2O was the optimal promoter to
improve the reaction yield to 91% (Table 1, entries 12−15). It
was noteworthy that switching the ratio of the starting
substrates 1a and 2e to 1.5/1 further facilitated the reaction
and the product 4e could be isolated in 97% yield (Table 1,
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hyde was unstable under the optimal conditions and did not
participate in the reaction (3l). The reaction was also
amendable to imino esters from aliphatic aldehydes, and the
corresponding alkyl-substituted imidazole products 3m,n were
afforded in acceptable yields. Other azomethines with diverse
alkyl-substituted ester groups were applicable to the current
reaction system, resulting in the formation of targeted products
3o−q in acceptable yields.
corresponding fluoroalkyl-substituted imidazoles (4q−t) with
moderate to good reactivity. The observation data indicated
the excellent generality and compatibility of the reaction.
A series of control experiments were performed to help
understand the reaction mechanism (Scheme 4). The coupling
Scheme 4. Mechanistic Investigations
The generality of the [3 + 2] cycloaddition reaction was
further surveyed by using a library of fluorinated imidoyl
chlorides (Scheme 3). To our surprise, the reaction proceeded
a b
,
Scheme 3. Scope of Fluorinated Imidoyl Chlorides
product 5 of azomethine ylide 1a and trifluoroacetimidoyl
chloride 2e was successfully detected by GC-MS in the model
reaction (Scheme 4a). We also synthesized intermediate 5 and
treated it with 2.0 equiv of Ag2O, and the imidazole product 4e
was afforded in 88% yield, suggesting the plausible
intermediacy of 5 (Scheme 4b). Radical trapping experiments
were conducted by the addition of 2.0 equiv of radical
scavengers. A comparable yield was obtained when TEMPO
(2,2,6,6-tetramethylpiperidine 1-oxyl) was added into the
reaction, whereas a trace of the product was observed with
BHT (2,4-di-tert-butyl-4-methylphenol). With regard to 1,1-
DPE (1,1-diphenylethylene), a 73% yield of the product 4e
was achieved (Scheme 4c). Therefore, a single-electron-
transfer (SET) process was likely not invoved in the reaction.
The serious problem of this reaction is the employment of
stoichiometric Ag2O. Although 2 equiv of Ag2O enables the
high efficiency of the reaction and Ag2O is one of the cheapest
silver sources, we still want to recycle the Ag2O and reduce the
cost.13 As depicted in Scheme 5, excess Ag2O and other silver
a
Reaction conditions: 1a (0.3 mmol), 2 (0.2 mmol), Ag2O (2.0
equiv), Na2CO3 (2.0 equiv), and 4 Å MS (40 mg) in CH3CN (2.0
mL) under an N2 atmosphere at 60 °C for 3 h. Isolated yields. Two
mmol scale.
b
c
with very high efficiency, as it was demonstrated that most of
the N-aryl-trifluoroacetimidoyl chlorides bearing electron-
donating or -withdrawing groups react smoothly with
azomethine ylide 1a to lead to the corresponding 5-
(trifluoromethyl)imidazoles 4b−n in almost quantitative
yields. The electronic effect (4b−n) and steric hindrance
(4b−d) of the aryl ring seemingly made little difference in the
reaction due to the comparable yields obtained of these
substrates. The good tolerance of the halogen atoms (F, Cl,
and Br) on the aryl ring provided a synthetic handle for further
derivatization (4g−j). Several strongly electron deficient
groups, such as −CF3, −NO2, and −CN, were compatible
with the optimized conditions (4k−m). More importantly, the
reaction could be easily reproducible on a 2 mmol scale
without any difficulty (4e). The naphthalene ring could also be
incorporated into the desired imidazole product 4o in 99%
yield under the standard conditions. Unfortunately, the
trifluoroacetimidoyl chlorides from heteroaryl amines could
not be prepared and the trifluoroacetimidoyl chloride derived
from an aliphatic amine was not a viable substrate for the
transformation. The protocol was amenable to a range of other
fluorinated imidoyl chlorides for the preparation of the
Scheme 5. Recovery Experiment of Ag Salts
salts could be readily collected by simple filtration. The residue
was treated with dilute nitric acid and filtrated to remove
insoluble AgCl. Subsequently, an NaOH solution was added to
the resulting AgNO3 solution to precipitate Ag2O in 64% yield.
When the removal of 1 equiv of insoluble AgCl is considered,
the actual recovery rate of Ag2O is 85%. The obtained Ag2O
was recycled in the reaction to afford the imidazole product 4e
in 65% yield.
On the basis of the mechanistic studies and previous
reports,8 a plausible reaction pathway was proposed as
depicted in Scheme 6. First, the interaction of azomethine
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silica gel (200−300 mesh) using petroleum ether (bp 60−90 °C) and
Scheme 6. Plausible Reaction Mechanism
ethyl acetate as eluents. NMR spectra were recorded on a Bruker
1
Avance instrument operating for H NMR at 400 MHz, 13C NMR at
100 MHz, and 19F NMR at 377 MHz, and spectral data are reported
in ppm relative to tetramethylsilane (TMS) as an internal standard
and CDCl3 (1H NMR δ 7.26, 13C NMR δ 77.16) as a solvent. All
coupling constants (J) are reported in Hz. The following
abbreviations were used to describe peak splitting patterns when
appropriate: s = singlet, d = doublet, dd = doublet of doublets, ddd =
doublet of doublets of doublets, t = triplet, dt = doublet of triplets, q =
quadruplet, m = multiplet, br = broad. Gas chromatography (GC)
analyses were performed on a Shimadzu GC-2014C chromatograph
equipped with a FID detector. Mass spectra (MS) were measured on
a spectrometer by direct inlet at 70 eV. Mass spectroscopy data of the
products were collected on an HRMS-TOF instrument or a Waters
TOFMS GCT Premier apparatus using EI or ESI ionization. Melting
points were measured with a WRR digital point apparatus and were
not corrected.
ylide 1 with silver and base formed dipole intermediate A.6c,14
The reaction of trifluoroacetimidoyl chloride with silver gave
the trifluoroacetimidoyl cation B, which could isomerize to
complex B′. Then, the nucleophilic attack of intermediate A to
complex B′ led to the intermediate C, which underwent an
isomerization and cyclization process to furnish the dihy-
droimidazole-silver complex D.8a Finally, the further oxidation
of D with the aid of Ag2O could deliver the desired imidazole
product 3 or 4.
Ethyl 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-4-imi-
dazolecarboxylate is regarded as a specific allosteric modulator
of the GABAA receptor, which shows high potency and
efficacy.2d The CF3 analogue of this bioactive molecule 6 could
be successfully assembled in 87% yield by using the developed
protocol (Scheme 7). The positive result further highlights the
huge synthetic utility of the present [3 + 2] cycloaddition
reaction.
In conclusion, we have explored an efficient approach for the
rapid construction of 5-(trifluoromethyl)imidazoles through
the silver-mediated [3 + 2] cycloaddition of azomethine ylides
with trifluoroacetimidoyl chlorides. The reaction features
simple operation, readily available reagents, a broad substrate
scope, high efficiency, and good application prospects and
presents a rapid and straightforward pathway for the synthesis
of biologically valuable imidazole molecules. The reaction
could be scaled up to a 2 mmol scale and be successfully
applied to construct the analogue of a specific allosteric
modulator of GABAA receptors. Furthermore, the recycling of
silver species could allow for more applications of this protocol
in organic synthesis.
Preparation of Imino Esters 1.15 To a stirred methanolic
suspension (1.0 M) of glycine cooled to 0 °C was added SOCl2 (1.2
equiv) dropwise (note: a vigorous exotherm with concomitant
evolution of HCl is observed). The resulting clear solution was
warmed to room temperature and stirred until complete conversion of
the amino acid as indicated by TLC (ninhydrin stain, 5% MeOH/
CH2Cl2). The mixture was concentrated under vacuum to afford the
glycine methyl ester hydrochlorides. Workup: the volatiles were
removed in vacuo, and the residue was further concentrated under
high vacuum to afford the amino acid methyl ester hydrochlorides in
all cases as off-white or white solids. The obtained amino acid methyl
ester hydrochlorides could be directly used in the next step without
further purification.
To a suspension of the glycine ester hydrochloride salt (1.5 equiv)
were added anhydrous MgSO4 (1.5 equiv) in CH2Cl2 (25 mL) and
Et3N (1.5 equiv) under an N2 atmosphere. The mixture was stirred at
room temperature for 1 h before the aldehyde (1.0 equiv) was added.
After the mixture was stirred at room temperature for 24 h, MgSO4
was removed by filtration and the filtrate was washed sequentially with
brine, saturated aqueous NaHCO3 solution, and water. The combined
organic phases were dried over anhydrous Na2SO4 and concentrated
under vacuum to afford the glycine imino ester.
Preparation of Fluorinated Imidoyl Chlorides 2.11 A 200 mL
two-necked flask equipped with a septum cap, a condenser, and a
Teflon-coated magnetic stir bar was charged with PPh3 (34.5 g, 132
mmol), Et3N (7.3 mL, 53 mmol), CCl4 (21.1 mL, 220 mmol), and
TFA (3.4 mL, 44 mmol). After the solution was stirred for about 10
min (ice bath), an amine (53 mmol) dissolved in CCl4 (21.1 mL, 220
mmol) was added. The mixture was then refluxed with stirring (3 h).
After the reaction was completed, residual solid Ph3PO, PPh3, and
Et3N-HCl were washed with hexane several times. Then the hexane
was filtered and concentrated under vacuum. The crude product was
purified by column chromatography on silica gel or neutral alumina to
afford the corresponding product.
General Procedure for the Synthesis of 5-(Trifluoromethyl)-
imidazoles (3 or 4). Ag2O (92.7 mg, 0.4 mmol), Na2CO3 (42.4 mg,
0.4 mmol), and 4 Å MS (40 mg) were added to a solution of
azomethine ylide 1 (0.3 mmol) and trifluoroacetimidoyl chloride 2
(0.2 mmol) in CH3CN (2 mL). The mixture was stirred at 60 °C
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all reactions were
carried out under an N2 atmosphere. All reagents were from
commercial sources and were used as received without further
purification. All solvents were dried by standard techniques and
distilled prior to use. Column chromatography was performed on
Scheme 7. Synthetic Utility
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under an N2 atmosphere for 3 h. After the reaction was completed,
the mixture was slowly cooled to room temperature and extracted
three times with EtOAc (3 × 10 mL). The extracts were combined
and concentrated under vacuum. The residue was purified by column
chromatography on silica gel (petroleum ether/EtOAc) to yield the
product 3 or 4.
raphy (petroleum ether/ethyl acetate 5/1, Rf = 0.4) to give the title
product 3e as a white solid (59.4 mg, 79%).
1H NMR (400 MHz, CDCl3): δ 7.53−7.43 (m, 3H), 7.29−7.23
(m, 4H), 6.73 (d, J = 8.9 Hz, 2H), 3.99 (s, 3H), 3.75 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 162.2, 160.6, 149.9, 135.8,
2
134.0, 130.7, 130.0, 129.5, 127.9, 125.1 (C−F, q, JC−F = 39.7 Hz),
120.6, 119.7 (C−F, q, 1JC−F = 269.9 Hz), 113.6, 55.2, 52.6. 19F NMR
(377 MHz, CDCl3): δ −54.6. Mp: 124.8−125.3 °C. HRMS (ESI):
[M + H]+ calcd for C19H16F3N2O3 377.1108; found 377.1119.
Methyl 2-(4-Fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imi-
dazole-4-carboxylate (3f). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
raphy (petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title
product 3f as a yellow oily liquid (64.8 mg, 89%).
Scale-up Reaction. Ag2O (927 mg, 4 mmol), Na2CO3 (424 mg, 4
mmol), and 4 Å MS (400 mg) were added to a solution of
azomethine ylide 1a (3 mmol, 1.5 equiv) and trifluoroacetimidoyl
chloride 2e (2 mmol, 1.0 equiv) in CH3CN (20 mL). The mixture
was stirred at 60 °C under an N2 atmosphere for 3 h. After the
reaction was completed, the mixture was slowly cooled to room
temperature and extracted three times with EtOAc (3 × 50 mL). The
extracts were combined and concentrated under vacuum. The residue
was purified by column chromatography on silica gel (petroleum
ether/EtOAc) to yield the product 4e as a white solid (659 mg, 82%).
Methyl 1,2-Diphenyl-5-(trifluoromethyl)-1H-imidazole-4-carbox-
ylate (3a). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate 5/1, Rf = 0.4) to give the title
product 3a as a white solid (65.7 mg, 95%).
1H NMR (400 MHz, CDCl3): δ 7.54−7.45 (m, 3H), 7.34−7.30
(m, 2H), 7.27 (d, J = 8.3 Hz, 2H), 6.91 (t, J = 8.6 Hz, 2H), 3.99 (s,
1
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 163.4 (C−F, d, JC−F
=
251.2 Hz), 162.0, 148.9, 135.4, 134.1, 131.3 (C−F, d, 3JC−F = 8.6 Hz),
2
130.3, 129.7, 127.8, 125.5 (C−F, q, JC−F = 40 Hz), 124.4 (C−F, d,
4JC−F = 3.2 Hz), 120.9 (C−F, q, JC−F = 270.1 Hz), 115.5 (C−F, d,
1
2JC−F = 21.9 Hz), 52.7. 19F NMR (377 MHz, CDCl3): δ −54.7,
1H NMR (400 MHz, CDCl3): δ 7.52−7.42 (m, 3H), 7.33 (d, J =
7.1 Hz, 2H), 7.28 (t, J = 6.5 Hz, 3H), 7.21 (t, J = 7.4 Hz, 2H), 3.99 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 162.1, 149.9, 135.6, 134.1,
−110.0. HRMS (ESI): [M + H]+ calcd for C18H13F4N2O2 365.0908;
found 365.0923.
Methyl 2-(4-Chlorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imi-
dazole-4-carboxylate (3g). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
raphy (petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title
product 3g as a white solid (54.7 mg, 72%).
2
130.1, 129.7, 129.5, 129.2, 128.2, 127.9, 125.4 (C−F, q, JC−F = 39.7
1
Hz), 119.6 (C−F, q, JC−F = 270.1 Hz), 52.6. 19F NMR (377 MHz,
CDCl3): δ −54.7. Mp: 112.4−113.5 °C. HRMS (ESI): [M + H]+
calcd for C18H14F3N2O2 347.1002; found 347.1018.
1H NMR (400 MHz, CDCl3): δ 7.55−7.45 (m, 3H), 7.29−7.25
(m, 4H), 7.20 (d, J = 8.7 Hz, 2H), 4.00 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 162.0, 148.7, 136.0, 135.4, 134.2, 130.4, 130.4,
Methyl 1-Phenyl-2-(p-tolyl)-5-(trifluoromethyl)-1H-imidazole-4-
carboxylate (3b). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title
product 3b as a white solid (69.1 mg, 96%).
2
129.7, 128.6, 127.8, 126.7, 125.6 (C−F, q, JC−F = 39.9 Hz), 119.5
1
(C−F, q, JC−F = 270.2 Hz), 52.7. 19F NMR (377 MHz, CDCl3): δ
1H NMR (400 MHz, CDCl3): δ 7.52−7.41 (m, 3H), 7.27 (d, J =
6.9 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 7.02 (d, J = 8.1 Hz, 2H), 3.99
(s, 3H), 2.27 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 162.2,
150.0, 139.9, 135.7, 134.0, 130.0, 129.5, 129.1, 128.9, 127.9, 125.4,
−54.7. Mp: 109.2−111.3 °C. HRMS (ESI): [M + H]+ calcd for
C18H13ClF3N2O2 381.0612; found 381.0628.
Methyl 2-(2-bromophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imi-
dazole-4-carboxylate (3h). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
raphy (petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title
product 3h as a white solid (56.8 mg, 67%).
2
1
125.2 (C−F, q, JC−F = 39.6 Hz), 119.7 (C−F, q, JC−F = 270.0 Hz),
52.6, 21.3. 19F NMR (377 MHz, CDCl3): δ −54.6. Mp: 135.3−136.2
°C. HRMS (ESI): [M + H]+ calcd for C19H16F3N2O2 361.1158;
found 361.1177.
1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 9.0 Hz, 1H), 7.38−
7.30 (m, 3H), 7.29−7.25 (m, 3H), 7.24−7.15 (m, 2H), 3.99 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 161.7, 149.0, 134.7, 133.6,
Methyl 1-Phenyl-2-(m-tolyl)-5-(trifluoromethyl)-1H-imidazole-4-
carboxylate (3c). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate 5/1, Rf = 0.4) to give the title
product 3c as a white solid (69.1 mg, 96%).
132.6, 132.5, 131.5, 130.3, 129.9, 129.0, 127.3, 126.8, 125.2 (C−F, q,
1
2JC−F = 40.0 Hz), 124.3, 119.6 (C−F, q, JC−F = 270.3 Hz), 52.6. 19F
NMR (377 MHz, CDCl3): δ −54.8. Mp: 116.6−117.6 °C. HRMS
(ESI): [M + H]+ calcd for C18H13BrF3N2O2 425.0107; found
425.0114.
1H NMR (400 MHz, CDCl3): δ 7.53−7.41 (m, 3H), 7.29 (d, J =
12.0 Hz, 3H), 7.10 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.95
(d, J = 7.7 Hz, 1H), 3.99 (s, 3H), 2.23 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 162.2, 150.0, 138.1, 135.8, 134.1, 130.4, 130.2,
Methyl 2-(Naphthalen-2-yl)-1-phenyl-5-(trifluoromethyl)-1H-
imidazole-4-carboxylate (3i). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
raphy (petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title
product 3i as a white solid (55.5 mg, 70%).
2
130.0, 129.5, 128.1, 127.9, 127.9, 126.0, 125.3 (C−F, q, JC−F = 39.5
1
Hz), 119.7 (C−F, q, JC−F = 270.2 Hz), 52.6, 21.2. 19F NMR (377
MHz, CDCl3): δ −54.6. Mp: 134.2−135.7 °C. HRMS (ESI): [M +
1H NMR (400 MHz, CDCl3): δ 7.86 (s, 1H), 7.74 (d, J = 7.9 Hz,
1H), 7.65 (d, J = 8.5 Hz, 2H), 7.53−7.41 (m, 5H), 7.38 (d, J = 10.2
Hz, 1H), 7.31 (d, J = 7.6 Hz, 2H), 4.02 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 162.2, 149.8, 135.7, 134.3, 133.3, 132.5, 130.2,
129.7, 129.6, 128.6, 127.9, 127.9, 127.6, 127.4, 126.6, 125.6 (C−F, q,
H]+ calcd for C19H16F3N2O2 361.1158; found 361.1182.
Methyl 1-Phenyl-2-(o-tolyl)-5-(trifluoromethyl)-1H-imidazole-4-
carboxylate (3d). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate 5/1, Rf = 0.4) to give the title
product 3d as a white solid (64.8 mg, 90%).
1
2JC−F = 39.7 Hz), 125.6, 125.5, 119.7 (C−F, q, JC−F = 270.0 Hz),
1H NMR (400 MHz, CDCl3): δ 7.37−7.29 (m, 3H), 7.21−7.14
(m, 3H), 7.09 (t, 2H), 7.03 (t, J = 7.4 Hz, 1H), 3.98 (s, 3H), 2.17 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 162.0, 150.3, 138.1, 135.0,
133.7, 130.7, 130.1, 129.9, 129.7, 129.1, 128.1, 127.2, 125.2, 124.9
52.7. 19F NMR (377 MHz, CDCl3): δ −54.6. Mp: 135.7−136.6 °C.
HRMS (ESI): [M + H]+ calcd for C22H16F3N2O2 397.1158; found
397.1174.
Methyl 1-Phenyl-2-(pyridin-2-yl)-5-(trifluoromethyl)-1H-imida-
zole-4-carboxylate (3j). Upon completion of the reaction the mixture
was concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate 5/1, Rf = 0.2) to give the title product
3j as a white solid (13.9 mg, 20%).
2
1
(C−F, q, JC−F = 40.0 Hz), 119.7 (C−F, q, JC−F = 270.1 Hz), 52.5,
20.0. 19F NMR (377 MHz, CDCl3): δ −54.7. Mp: 136.8−137.4 °C.
HRMS (ESI): [M + H]+ calcd for C19H16F3N2O2 361.1158; found
361.1176.
1H NMR (400 MHz, CDCl3): δ 8.26 (d, J = 4.7 Hz, 1H), 7.91 (d, J
= 7.9 Hz, 1H), 7.68 (t, J = 8.6 Hz, 1H), 7.49−7.38 (m, 3H), 7.30 (d, J
= 7.4 Hz, 2H), 7.17 (t, 1H), 4.00 (s, 3H). 13C{1H} NMR (101 MHz,
Methyl 2-(4-Methoxyphenyl)-1-phenyl-5-(trifluoromethyl)-1H-
imidazole-4-carboxylate (3e). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
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pubs.acs.org/joc
Note
CDCl3): δ 162.0, 148.8, 148.1, 147.7, 136.4, 136.1, 133.9, 129.5,
128.7, 127.8, 126.2 (C−F, q, 2JC−F = 39.3 Hz), 124.7, 119.5 (C−F, q,
1JC−F = 270.3 Hz), 52.6. 19F NMR (377 MHz, CDCl3): δ −54.8. Mp:
(petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title
product 3q as a yellow oily liquid (33.8 mg, 40%).
1H NMR (400 MHz, CDCl3): δ 7.51−7.41 (m, 5H), 7.40−7.30
(m, 5H), 7.29−7.18 (m, 5H), 5.45 (s, 2H). 13C{1H} NMR (101
MHz, CDCl3): δ 161.8, 149.9, 135.6, 135.5, 134.3, 130.1, 129.7,
102.8−103.4 °C. HRMS (ESI): [M + H]+ calcd for C17H13F3N3O2
348.0954; found 348.0976.
129.5, 129.2, 128.6, 128.5, 128.3, 128.2, 127.9, 125.2 (C−F, q, 2JC−F
=
Methyl 2-(Furan-2-yl)-1-phenyl-5-(trifluoromethyl)-1H-imida-
zole-4-carboxylate (3k). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
raphy (petroleum ether/ethyl acetate 5/1, Rf = 0.2) to give the title
product 3k as a white solid (39.0 mg, 58%).
1
39.6 Hz), 119.7 (C−F, q, JC−F = 269.9 Hz), 67.4. 19F NMR (377
MHz, CDCl3): δ −54.5. HRMS (ESI): [M + H]+ calcd for
C24H18F3N2O2 423.1315; found 423.1328.
Methyl 2-Phenyl-1-(p-tolyl)-5-(trifluoromethyl)-1H-imidazole-4-
carboxylate (4b). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate 5/1, Rf = 0.4) to give the title
product 4b as a yellow oily liquid (64.8 mg, 90%).
1H NMR (400 MHz, CDCl3): δ 7.66−7.53 (m, 3H), 7.40 (d, J =
1.2 Hz, 1H), 7.36 (d, J = 7.5 Hz, 2H), 6.29−6.24 (m, 1H), 5.76 (d, J
= 3.5 Hz, 1H), 3.99 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
161.7, 144.2, 142.5, 142.0, 135.1, 134.3, 130.7, 129.7, 127.8, 125.1
(C−F, q, 2JC−F = 40.1 Hz), 119.5 (C−F, q, 1JC−F = 270.1 Hz), 112.1,
111.3, 52.6. 19F NMR (377 MHz, CDCl3): δ −54.9. Mp: 103.4−
105.2 °C. HRMS (ESI): [M + H]+ calcd for C16H12F3N2O3 337.0795;
found 337.0814.
1H NMR (400 MHz, CDCl3): δ 7.34 (d, J = 7.1 Hz, 2H), 7.29−
7.26 (m, 1H), 7.24−7.19 (m, 4H), 7.13 (d, J = 8.3 Hz, 2H), 3.98 (s,
3H), 2.41 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 162.2,
149.9, 140.3, 134.0, 132.9, 130.1, 129.6, 129.2, 128.3, 128.2, 127.5,
125.4 (q, J(C−F) = 39.6 Hz), 119.7 (q, J(C−F) = 269.9 Hz), 52.6, 21.3.
19F NMR (377 MHz, CDCl3): δ −54.8. HRMS (ESI): [M + H]+
Methyl 2-Isobutyl-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-
carboxylate (3m). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate 5/1, Rf = 0.4) to give the title
product 3m as a white solid (38.5 mg, 59%).
calcd for C19H16F3N2O2 361.1158; found 361.1172.
Methyl 2-Phenyl-1-(m-tolyl)-5-(trifluoromethyl)-1H-imidazole-4-
carboxylate (4c). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate 5/1, Rf = 0.4) to give the title
product 4c as a white solid (71.3 mg, 99%).
1H NMR (400 MHz, CDCl3): δ 7.60−7.51 (m, 3H), 7.31−7.26
(m, 2H), 3.97 (s, 3H), 2.74−2.62 (m, 1H), 1.24 (d, J = 6.9 Hz, 6H).
13C{1H} NMR (101 MHz, CDCl3): δ 162.3, 156.8, 134.9, 133.3,
1H NMR (400 MHz, CDCl3): δ 7.36−7.26 (m, 5H), 7.21 (t, J =
7.4 Hz, 2H), 7.06 (d, J = 7.5 Hz, 2H), 3.98 (s, 3H), 2.35 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 162.1 149.7, 139.7, 135.4,
130.2, 129.6, 127.6, 124.3 (C−F, q, 2JC−F = 39.6 Hz), 119.7 (C−F, q,
1JC−F = 269.8 Hz), 52.6, 26.2, 21.5. 19F NMR (377 MHz, CDCl3): δ
−54.8. Mp: 97.8−98.3 °C. HRMS (ESI): [M + H]+ calcd for
C15H16F3N2O2 313.1158; found 313.1175.
134.0, 130.8, 129.6, 129.2, 129.1, 128.3, 128.2, 128.1, 125.4 (C−F, q,
2JC−F = 39.8 Hz), 124.9, 119.6 (C−F, q, 1JC−F = 270.0 Hz), 52.6, 21.2.
19F NMR (377 MHz, CDCl3): δ −54.7. Mp: 140.3−141.4 °C. HRMS
Methyl 2-(tert-Butyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-
4-carboxylate (3n). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate 5/1, Rf = 0.2) to give the title
product 3n as a white solid (20.2 mg, 31%).
(ESI): [M + H]+ calcd for C19H16F3N2O2 361.1158; found 361.1176.
Methyl 2-Phenyl-1-(o-tolyl)-5-(trifluoromethyl)-1H-imidazole-4-
carboxylate (4d). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate = 20:1, Rf = 0.3) to give the title
product 4d as a yellow oily liquid (63.4 mg, 88%).
1H NMR (400 MHz, CDCl3): δ 7.55 (t, J = 7.4 Hz, 1H), 7.48 (t, J
= 7.5 Hz, 2H), 7.34 (d, J = 7.6 Hz, 2H), 3.94 (s, 3H), 1.20 (s, 9H).
13C{1H} NMR (101 MHz, CDCl3): δ 162.7, 158.0, 136.0, 132.2,
1H NMR (400 MHz, CDCl3): δ 7.42 (t, 1H), 7.40−7.33 (m, 4H),
7.32−7.28 (m, 2H), 7.25−7.20 (m, 2H), 4.01 (s, 3H), 1.91 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 162.1, 149.5, 135.7, 134.7,
130.4, 129.2, 128.8, 125.3 (C−F, q, 2JC−F = 39.0 Hz), 119.6 (C−F, q,
1JC−F = 269.9 Hz), 52.6, 35.0, 30.1. 19F NMR (377 MHz, CDCl3): δ
−55.0. Mp: 122.3−123.8 °C. HRMS (ESI): [M + H]+ calcd for
C16H18F3N2O2 327.1315; found 327.1332.
134.1, 131.3, 130.5, 129.8, 128.7, 128.4, 128.3, 127.0, 125.1 (C−F, q,
1
2JC−F = 39.6 Hz), 119.6 (C−F, q, JC−F = 270.1 Hz), 52.6, 17.1. 19F
Ethyl 1,2-Diphenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxy-
late (3o). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title
product 3o as a white solid (45.4 mg, 63%).
NMR (377 MHz, CDCl3): δ −55.8. HRMS (ESI): [M + H]+ calcd
for C19H16F3N2O2 361.1158; found 361.1176.
Methyl 1-(4-(tert-Butyl)phenyl)-2-phenyl-5-(trifluoromethyl)-1H-
imidazole-4-carboxylate (4e). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
raphy (petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title
product 4e as a white solid (78.0 mg, 97%).
1H NMR (400 MHz, CDCl3): δ 7.52−7.42 (m, 3H), 7.33 (d, J =
7.1 Hz, 2H), 7.28 (t, J = 6.6 Hz, 3H), 7.21 (t, J = 7.4 Hz, 2H), 4.47
(q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 161.9, 149.8, 135.6, 134.6, 130.1, 129.6, 129.5,
1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 8.6 Hz, 2H), 7.36−
7.27 (m, 3H), 7.23−7.15 (m, 4H), 3.99 (s, 3H), 1.34 (s, 9H).
13C{1H} NMR (101 MHz, CDCl3): δ 162.2, 153.5, 149.9, 134.0,
2
129.2, 128.3, 128.2, 127.9, 125.0 (C−F, q, JC−F = 39.6 Hz), 119.7
1
(C−F, q, JC−F = 269.9 Hz), 61.8, 14.1. 19F NMR (377 MHz,
132.8, 129.6, 129.2, 128.4, 128.1, 127.3, 126.4, 125.4 (C−F, q, 2JC−F
=
CDCl3): δ −54.5. Mp: 105.8−106.3 °C. HRMS (ESI): [M + H]+
calcd for C19H16F3N2O2 361.1158; found 361.1176.
39.7 Hz), 119.7 (C−F, q, JC−F) = 270.1 Hz), 52.6, 34.9, 31.2. 19F
NMR (377 MHz, CDCl3): δ −54.7. Mp: 137.6−138.2 °C. HRMS
(ESI): [M + H]+ calcd for C22H22F3N2O2 403.1628; found 403.1646.
Methyl 1-(4-Methoxyphenyl)-2-phenyl-5-(trifluoromethyl)-1H-
imidazole-4-carboxylate (4f). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
raphy (petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title
product 4f as a yellow oily liquid (76.3 mg, 99%).
1
tert-Butyl 1,2-Diphenyl-5-(trifluoromethyl)-1H-imidazole-4-car-
boxylate (3p). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title
product 3p as a white solid (55.9 mg, 72%).
1H NMR (400 MHz, CDCl3): δ 7.52−7.41 (m, 3H), 7.33 (d, J =
7.1 Hz, 2H), 7.26 (t, J = 6.3 Hz, 3H), 7.20 (t, J = 7.4 Hz, 2H), 1.63 (s,
9H). 13C{1H} NMR (101 MHz, CDCl3): δ 161.4, 149.6, 136.2, 135.8,
1H NMR (400 MHz, CDCl3): δ 7.38−7.33 (m, 2H), 7.30 (t, J =
7.4 Hz, 1H), 7.23 (t, J = 7.3 Hz, 2H), 7.18 (d, J = 8.9 Hz, 2H), 6.93
(d, J = 8.9 Hz, 2H), 3.98 (s, 3H), 3.84 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 162.1, 160.4, 150.0, 133.9, 129.6, 129.2, 128.9,
128.3, 128.2, 128.0, 125.4 (C−F, q, 2JC−F = 39.3 Hz), 119.6 (C−F, q,
1JC−F = 270.1 Hz), 114.5, 55.5, 52.6. 19F NMR (377 MHz, CDCl3): δ
2
129.9, 129.5, 129.2, 128.5, 128.2, 127.9, 123.9 (C−F, q, JC−F = 39.2
1
Hz), 119.9 (C−F, q, JC−F = 269.7 Hz), 82.8, 27.9. 19F NMR (377
MHz, CDCl3): δ −54.2. Mp: 132.6−133.2 °C. HRMS (ESI): [M +
H]+ calcd for C21H20F3N2O2 389.1471; found 389.1480.
Benzyl 1,2-Diphenyl-5-(trifluoromethyl)-1H-imidazole-4-carbox-
ylate (3q). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
−54.9. HRMS (ESI): [M + H]+ calcd for C19H16F3N2O3 377.1108;
found 377.1121.
4366
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J. Org. Chem. 2021, 86, 4361−4370

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
2
Methyl 1-(4-Fluorophenyl)-2-phenyl-5-(trifluoromethyl)-1H-imi-
dazole-4-carboxylate (4g). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
raphy (petroleum ether/ethyl acetate = 20:1, Rf = 0.3) to give the title
product 4g as a yellow oily liquid (68.5 mg, 95%).
134.9, 130.3, 129.3, 129.2, 128.6, 127.4, 125.3 (C−F, q, JC−F = 40.4
Hz), 125.0, 119.5 (C−F, q, JC−F = 270.2 Hz), 52.9. 19F NMR (377
MHz, CDCl3): δ −54.2. Mp: 163.4−164.7 °C. HRMS (ESI): [M +
1
H]+ calcd for C18H13F3N3O4 392.0853; found 392.0869.
Methyl 1-(4-Cyanophenyl)-2-phenyl-5-(trifluoromethyl)-1H-imi-
dazole-4-carboxylate (4m). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
raphy (petroleum ether/ethyl acetate 5/1, Rf = 0.2) to give the title
product 4m as a white solid (46.1 mg, 62%).
1H NMR (400 MHz, CDCl3): δ 7.35−7.30 (m, 3H), 7.29−7.23
(m, 4H), 7.14 (t, J = 8.4 Hz, 2H), 3.99 (s, 3H). 13C{1H} NMR (101
1
MHz, CDCl3): δ 163.1 (C−F, d, JC−F = 251.7 Hz), 162.0, 150.0,
134.2, 131.5, (C−F, d, 4JC−F = 3.1 Hz), 129.8, 129.8 (C−F, d, 3JC−F
=
10.0 Hz), 129.2, 128.3, 128.0, 125.4 (C−F, q, 2JC−F = 39.6 Hz), 119.6
1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.4 Hz, 2H), 7.42 (d, J
= 8.4 Hz, 2H), 7.38−7.33 (m, 1H), 7.27 (d, J = 4.4 Hz, 4H), 4.00 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 161.7, 149.8, 139.3, 134.8,
1
2
(C−F, q, JC−F = 270.1 Hz), 116.7 (C−F, d, JC−F = 23.2 Hz), 52.7.
19F NMR (377 MHz, CDCl3): δ −54.7, −109.3. HRMS (ESI): [M +
2
H]+ calcd for C18H13F4N2O2 365.0908; found 365.0925.
133.5, 130.3, 129.3, 129.0, 128.6, 127.5, 125.2 (C−F, q, JC−F = 39.9
Hz), 119.5 (C−F, q, 1JC−F = 270.2 Hz), 117.2, 114.4, 52.8. 19F NMR
(377 MHz, CDCl3): δ −54.2. Mp: 130.7−131.5 °C. HRMS (ESI):
[M + H]+ calcd for C19H13F3N3O2 372.0954; found 372.0971.
Methyl 1-(3,4-Dimethylphenyl)-2-phenyl-5-(trifluoromethyl)-1H-
imidazole-4-carboxylate (4n). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
raphy (petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title
product 4n as a white solid (68.5 mg, 92%).
Methyl 1-(4-Chlorophenyl)-2-phenyl-5-(trifluoromethyl)-1H-imi-
dazole-4-carboxylate (4h). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
raphy (petroleum ether/ethyl acetate 5/1, Rf = 0.4) to give the title
product 4h as a yellow oily liquid (81 mg, 99%).
1H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 8.6 Hz, 2H), 7.36−
7.30 (m, 3H), 7.26 (t, 2H), 7.22 (d, J = 8.6 Hz, 2H), 3.99 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 161.9, 149.9, 136.3, 134.4,
1H NMR (400 MHz, CDCl3): δ 7.39−7.34 (m, 2H), 7.28 (d, J =
6.6 Hz, 1H), 7.22 (t, J = 7.4 Hz, 2H), 7.17 (d, J = 8.0 Hz, 1H), 7.02
(s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H), 2.31 (s, 3H), 2.25 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 162.2, 149.7, 138.9, 138.1,
134.0, 129.9, 129.9, 129.2, 129.2, 128.4, 127.9, 125.3 (C−F, q, 2JC−F
=
1
39.6 Hz), 119.6 (C−F, q, JC−F = 270.2 Hz), 52.7. 19F NMR (377
MHz, CDCl3): δ −54.6. HRMS (ESI): [M + H]+ calcd for
C18H13ClF3N2O2 381.0612; found 381.0632.
133.8, 133.0, 130.4, 129.5, 129.1, 128.4, 128.1, 125.4 (C−F, q, 2JC−F
=
Methyl 1-(4-Bromophenyl)-2-phenyl-5-(trifluoromethyl)-1H-imi-
dazole-4-carboxylate (4i). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
raphy (petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title
product 4i as a yellow oily liquid (84.8 mg, 99%).
1
39.5 Hz), 125.0, 119.6 (C−F, q, JC−F = 270.1 Hz), 52.5, 19.7, 19.5.
19F NMR (377 MHz, CDCl3): δ −54.8. Mp: 87.8−89.0 °C. HRMS
(ESI): [M + H]+ calcd for C20H18F3N2O2 375.1315; found 375.1331.
Methyl 1-(Naphthalen-1-yl)-2-phenyl-5-(trifluoromethyl)-1H-
imidazole-4-carboxylate (4o). Upon completion of the reaction
the mixture was concentrated and purified via flash column
chromatography (petroleum ether/ethyl acetate 5/1, Rf = 0.3) to
give the title product 4o as a yellow oily liquid (83.5 mg, 99%).
1H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 9.0 Hz, 1H), 7.91 (d, J
= 7.5 Hz, 1H), 7.55−7.45 (m, 4H), 7.30−7.26 (m, 3H), 7.17 (t, J =
7.4 Hz, 1H), 7.06 (t, J = 7.6 Hz, 2H), 4.03 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3): δ 162.1, 150.6, 134.2, 133.8, 132.0, 130.9, 130.3,
129.8, 128.6, 128.5, 128.3, 128.2, 128.1, 127.2, 126.5, 126.5 (C−F, q,
1H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 8.6 Hz, 2H), 7.36−
7.31 (m, 3H), 7.27 (d, J = 7.1 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 3.99
(s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 161.9, 149.8, 134.5,
134.3, 132.8, 129.9, 129.4, 129.2, 128.3, 127.9, 125.2 (C−F, q, 2JC−F
=
1
39.8 Hz), 124.3, 119.5 (C−F, q, JC−F = 270.0 Hz), 52.6. 19F NMR
(377 MHz, CDCl3): δ −54.5. HRMS (ESI): [M + H]+ calcd for
C18H13BrF3N2O2 425.0107; found 425.0119.
Methyl 1-(2-Chlorophenyl)-2-phenyl-5-(trifluoromethyl)-1H-imi-
dazole-4-carboxylate (4j). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
raphy (petroleum ether/ethyl acetate 5/1, Rf = 0.4) to give the title
product 4j as a yellow oily liquid (75.6 mg, 99%).
2JC−F = 39.9 Hz), 125.0, 121.6, 119.6 (C−F, q, JC−F = 270.3 Hz),
1
52.7. 19F NMR (377 MHz, CDCl3): δ −55.6. HRMS (ESI): [M +
H]+ calcd for C22H16F3N2O2 397.1158; found 397.1171.
1H NMR (400 MHz, CDCl3): δ 7.48−7.42 (m, 2H), 7.41−7.34
(m, 4H), 7.29 (t, J = 7.4 Hz, 1H), 7.21 (t, J = 7.4 Hz, 2H), 3.97 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 161.8, 150.0, 134.2, 133.5,
132.9, 131.7, 130.5, 130.0, 128.9, 128.3, 128.1, 127.8, 125.6 (C−F, q,
Methyl 5-(Difluoromethyl)-1,2-diphenyl-1H-imidazole-4-carbox-
ylate (4q). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate 5/1, Rf = 0.4) to give the title
product 4q as a white solid (50.0 mg, 77%).
1
2JC−F = 40.0 Hz), 119.5 (C−F, q, JC−F = 270.2 Hz), 52.6. 19F NMR
1H NMR (400 MHz, CDCl3): δ 7.66 (t, J = 52.4 Hz, 1H), 7.48−
7.40 (m, 3H), 7.38−7.30 (m, 4H), 7.28 (d, J = 7.3 Hz, 1H), 7.25−
7.18 (m, 2H), 4.00 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
(377 MHz, CDCl3): δ −56.0. HRMS (ESI): [M + H]+ calcd for
C18H13ClF3N2O2 381.0612; found 381.0624.
Methyl 2-Phenyl-5-(trifluoromethyl)-1-(4-(trifluoromethyl)-
phenyl)-1H-imidazole-4-carboxylate (4k). Upon completion of the
reaction the mixture was concentrated and purified via flash column
chromatography (petroleum ether/ethyl acetate 5/1, Rf = 0.4) to give
the title product 4k as a white solid (80.7 mg, 98%).
2
163.0, 150.1, 136.0, 133.0, 131.5 (C−F, t, JC−F = 22.5 Hz), 129.8,
129.5, 129.3, 129.2, 128.4, 128.2, 128.0, 108.3 (C−F, t, 1JC−F = 235.4
Hz), 52.4. 19F NMR (377 MHz, CDCl3): δ −111.8. Mp: 149.8−150.5
°C. HRMS (ESI): [M + H]+ calcd for C18H15F2N2O2 329.1096;
found 329.1113.
1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.4 Hz, 2H), 7.43 (d, J
= 8.2 Hz, 2H), 7.35−7.23 (m, 5H), 4.00 (s, 3H). 13C{1H} NMR (101
Methyl 5-(Chlorodifluoromethyl)-1,2-diphenyl-1H-imidazole-4-
carboxylate (4r). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title
product 4r as a white solid (60.2 mg, 84%).
2
MHz, CDCl3): δ 161.8, 149.9, 138.6, 134.6, 132.3 (C−F, q, JC−F
=
=
=
3
33.2 Hz), 130.1, 129.3, 128.5, 128.5, 127.7, 126.8 (C−F, q, JC−F
2
1
3.5 Hz), 125.3 (C−F, q, JC−F = 40.0 Hz), 123.2 (C−F, q, JC−F
272.7 Hz), 119.5 (C−F, q, JC−F = 270.0 Hz), 52.7. 19F NMR (377
MHz, CDCl3): δ −54.4, −62.8. Mp: 114.6−115.7 °C. HRMS (ESI):
[M + H]+ calcd for C19H13F6N2O2 415.0876; found 415.0890.
Methyl 1-(4-Nitrophenyl)-2-phenyl-5-(trifluoromethyl)-1H-imi-
dazole-4-carboxylate (4l). Upon completion of the reaction the
mixture was concentrated and purified via flash column chromatog-
raphy (petroleum ether/ethyl acetate 5/1, Rf = 0.2) to give the title
product 4l as a white solid (43.8 mg, 56%).
1
1H NMR (400 MHz, CDCl3): δ 7.52−7.42 (m, 3H), 7.35−7.27
(m, 5H), 7.21 (t, J = 7.4 Hz, 2H), 3.99 (s, 3H). 13C{1H} NMR (101
2
MHz, CDCl3): δ 162.3, 149.6, 135.7, 132.3, 131.5 (C−F, t, JC−F
=
32.4 Hz), 130.1, 129.6, 129.4, 129.2, 128.2, 128.2, 120.4 (C−F, t,
1JC−F = 288.8 Hz), 52.6. 19F NMR (377 MHz, CDCl3): δ −43.4. Mp:
104.8−105.2 °C. HRMS (ESI): [M + H]+ calcd for C18H14ClF2N2O2
363.0706; found 363.0728.
1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 8.5 Hz, 2H), 7.50 (d, J
= 8.7 Hz, 2H), 7.38−7.33 (m, 1H), 7.30−7.25 (m, 4H), 4.01 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 161.7, 149.9, 148.4, 140.8,
Methyl 5-(Perfluoroethyl)-1,2-diphenyl-1H-imidazole-4-carboxy-
late (4s). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
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J. Org. Chem. 2021, 86, 4361−4370

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title product
4s as a white solid (43.1 mg, 55%).
mmol, 2.0 equiv), BHT (88.1 mg, 0.4 mmol, 2.0 equiv), or 1,1-DPE
(72.1 mg, 0.4 mmol, 2.0 equiv), and MeCN (2 mL) (extra dry) were
placed in an oven-dried 15 mL In-Ex tube. Then the tube was sealed
and the mixture was stirred at 60 °C (oil bath) for 3 h. After the
reaction was complete, the mixture was slowly cooled to room
temperature and extracted three times with EtOAc (3 × 10 mL). The
extracts were combined and concentrated under vacuum. The residue
was purified by column chromatography on silica gel (petroleum
ether/EtOAc) to yield the product 4e as a white solid in 93%, trace or
79% yield.
1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 7.2 Hz, 1H), 7.42 (t, J
= 7.5 Hz, 2H), 7.31 (d, J = 7.3 Hz, 2H), 7.28−7.25 (m, 3H), 7.20 (t, J
= 7.5 Hz, 2H), 3.98 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
161.8, 151.3, 136.1, 135.7, 130.1, 129.7, 129.3, 129.1, 128.6, 128.3,
128.1, 123.4 (C−F, t, 3JC−F = 29.3 Hz), 118.6 (C−F, qt, 1JC−F = 287.4
2
Hz, 39.0 Hz), 110.4 (C−F, qt, JC−F = 238.1 Hz, 41.6 Hz), 52.6. 19F
NMR (377 MHz, CDCl3): δ −83.1, −105.3. Mp: 75.2−77.6 °C.
HRMS (ESI): [M + H]+ calcd for C19H14F5N2O2 397.0970; found
397.0986.
Recovery Experiment of Ag Salts (Scheme 5). Under a
nitrogen atmosphere, Ag2O (0.2317 g, 1.0 mmol, 2.0 equiv), Na2CO3
(0.1060 g, 1.0 mmol, 2.0 equiv), 1a (0.75 mmol, 1.5 equiv), 2e (0.5
mmol, 1.0 equiv), 4 Å MS (100 mg), and MeCN (5 mL) (extra dry)
were placed in an oven-dried 15 mL In-Ex tube. Then the tube was
sealed and the mixture was stirred at 60 °C (oil bath) for 3 h. After
the reaction was complete, the mixture was slowly cooled to room
temperature and concentrated under reduced pressure. The residue
was washed three times with CH2Cl2 (3 × 5 mL), and the solid was
dissolved in 25 mL of HNO3 (10%, v/v in H2O). After it was stirred
for 1 h, the reaction mixture was filtered to remove the insoluble
AgCl. To the filtrate was added 25 mL of NaOH (10%, v/v in H2O).
The suspension was filtered and the solid residue washed with water
(3 × 5 mL) to afford 0.148 g of Ag2O (64%) as a brown powder.
Standard Reaction by Using Recycled Ag2O. Under a nitrogen
atmosphere, Ag2O (0.0927 g, 0.4 mmol, 2.0 equiv), Na2CO3 (0.0424
g, 0.4 mmol, 2.0 equiv), 1a (0.3 mmol, 1.5 equiv), 2e (0.2 mmol, 1.0
equiv), 4 Å MS (40 mg), and MeCN (2 mL) (extra dry) were placed
in an oven-dried 15 mL In-Ex tube. Then the tube was sealed and the
mixture was stirred at 60 °C (oil bath) for 3 h. After the reaction was
complete, the mixture was slowly cooled to room temperature and
extracted three times with EtOAc (3 × 10 mL). The extracts were
combined and concentrated under vacuum. The residue was purified
by column chromatography on silica gel (petroleum ether/EtOAc) to
yield the product 4e as a white solid in 65% yield.
Synthetic Utility (Scheme 7). Under a nitrogen atmosphere,
Ag2O (0.0927 g, 0.4 mmol, 2.0 equiv), Na2CO3 (0.0424 g, 0.4 mmol,
2.0 equiv), 1r (0.3 mmol, 1.5 equiv), 2u (0.2 mmol, 1.0 equiv), 4 Å
MS (40 mg), MeCN (2 mL) (extra dry) were placed in an oven-dried
15 mL In-Ex tube. Then the tube was sealed and the mixture was
stirred at 60 °C (oil bath) for 3 h. After the reaction was complete, the
mixture was slowly cooled to room temperature and extracted three
times with EtOAc (3 × 10 mL). The extracts were combined and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel (petroleum ether/EtOAc) to yield the
product 6.
Methyl 5-(Perfluoropropyl)-1,2-diphenyl-1H-imidazole-4-car-
boxylate (4t). Upon completion of the reaction the mixture was
concentrated and purified via flash column chromatography
(petroleum ether/ethyl acetate 5/1, Rf = 0.3) to give the title
product 4t as a yellow oily liquid (50.0 mg, 57%).
1H NMR (400 MHz, CDCl3): δ 7.48−7.39 (m, 3H), 7.32 (d, J =
7.1 Hz, 2H), 7.27 (t, J = 5.7 Hz, 3H), 7.23−7.17 (m, 2H), 3.98 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 161.8, 151.4, 136.5, 135.7,
135.0, 130.1, 129.3, 129.1, 128.6, 128.1, 127.0, 123.3 (C−F, t, 4JC−F
=
1
29.8 Hz), 117.7 (C−F, qt, JC−F = 288.3 Hz, 34.1 Hz), 112.6 (C−F,
2
3
tt, JC−F = 258.5 Hz, 34.0 Hz), 108.5 (C−F, tm, JC−F = 266.64 Hz),
52.6. 19F NMR (377 MHz, CDCl3): δ −80.2, −102.0, −123.1. HRMS
(ESI): [M + H]+ calcd for C20H14F7N2O2 447.0938; found 447.0950.
Procedure for Control Experiments (Scheme 4, eq a). Under
a nitrogen atmosphere, Ag2O (0.092 g, 0.4 mmol, 2.0 equiv), Na2CO3
(0.0424 g, 0.4 mmol, 2.0 equiv), 1a (0.3 mmol, 1.5 equiv), 2e (0.2
mmol, 1.0 equiv), 4 Å MS (40 mg), and MeCN (2 mL) (extra dry)
were placed in an oven-dried 15 mL In-Ex tube. Then the tube was
sealed and the mixture was stirred at 60 °C (oil bath) for 1 h. The
sample of the reaction was tested by GC-MS, and the coupling
product 5 was successfully detected by GC-MS.
Preparation of Intermediate 5. Under a nitrogen atmosphere,
KO-t-Bu (0.0896g, 0.8 mmol, 2.0 equiv), 1a (0.6 mmol, 1.5 equiv), 2e
(0.4 mmol, 1.0 equiv), and MeCN (3 mL) (extra dry) were placed in
an oven-dried 15 mL In-Ex tube. Then the tube was sealed and the
mixture was stirred at 60 °C (oil bath) for 1 h. After the reaction was
complete, the mixture was slowly cooled to room temperature and
extracted three times with EtOAc (3 × 10 mL). The extracts were
combined and concentrated under vacuum. The residue was purified
by column chromatography on silica gel (petroleum ether/EtOAc) to
yield the product 5 as a yellow oily liquid (89.2 mg, 55%).
methyl (Z)-2-(((E)-benzylidene)amino)-3-((4-(tert-butyl)phenyl)-
imino)-4,4,4-trifluorobutanoate (5). Upon completion of the
reaction the mixture was concentrated and purified via flash column
chromatography (petroleum ether/ethyl acetate 5/1, Rf = 0.4) to give
the title product 5 as a yellow oily liquid.
1H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 7.3 Hz, 2H), 7.48−
7.35 (m, 3H), 7.32 (d, J = 8.9 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 6.68
(d, J = 2.5 Hz, 1H), 5.70−5.60 (m, 1H), 3.96 (s, 3H), 1.29 (s, 9H).
13C{1H} NMR (101 MHz, CDCl3): δ 160.8, 156.6, 143.4, 142.8,
Ethyl 2-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-5-(trifluoro-
methyl)-1H-imidazole-4-carboxylate (6). Upon completion of the
reaction the mixture was concentrated and purified via flash column
chromatography (petroleum ether/ethyl acetate 5/1, Rf = 0.4) to give
the title product 6 as a yellow oily liquid (88.1 mg, 87%).
1
137.0, 129.0, 128.9, 126.8, 126.5, 123.6 (C−F, q, JC−F = 284.7 Hz),
1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 2.0 Hz, 1H), 7.45−
7.34 (m, 4H), 7.23 (d, J = 8.6 Hz, 2H), 4.46 (q, J = 7.1 Hz, 2H), 1.42
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 161.2,
149.0, 137.5, 135.0, 133.8, 132.0, 131.8, 130.6, 130.3, 128.4, 126.8,
125.3 (C−F, q, 2JC−F = 39.7 Hz), 124.9, 119.4 (C−F, q, 1JC−F = 270.3
Hz), 61.9, 14.1. 19F NMR (377 MHz, CDCl3): δ −55.7. HRMS
(ESI): [M + H]+ calcd for C19H13BrCl2F3N2O2 506.9484; found
506.9492.
2
113.1, 95.5, 69.6 (C−F, q, JC−F = 33.6 Hz), 53.5, 34.0, 31.4. 19F
NMR (377 MHz, CDCl3): δ −69.0. HRMS (ESI): [M + H]+ calcd
for C22H24F3N2O2 405.1784; found 405.1798.
Procedure for Control Experiments (Scheme 4, eq b). Under
a nitrogen atmosphere, Ag2O (0.0927 g, 0.4 mmol, 2 equiv), Na2CO3
(0.0424 g, 0.4 mmol, 2 equiv), 5 (0.0808 g, 0.2 mmol, 1 equiv), 4 Å
MS (40 mg), and MeCN (2 mL) (extra dry) were placed in an oven-
dried 15 mL In-Ex tube. Then the tube was sealed and the mixture
was stirred at 60 °C (oil bath) for 3 h. After the reaction was
complete, the mixture was slowly cooled to room temperature and
extracted three times with EtOAc (3 × 10 mL). The extracts were
combined and concentrated under vacuum. The residue was purified
by column chromatography on silica gel (petroleum ether/EtOAc) to
yield the product 4e as a white solid (70.8 mg, 88%).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00131.
Procedure for Control Experiments (Scheme 4, eq c). Under
a nitrogen atmosphere, Ag2O (0.0927 g , 0.4 mmol, 2.0 equiv),
Na2CO3 (0.0424 g, 0.4 mmol, 2.0 equiv), 1a (0.3 mmol, 1.5 equiv),
2e (0.2 mmol, 1.0 equiv), 4 Å MS (40 mg), TEMPO (62.5 mg, 0.4
1
Details of the experimental conditions and H, 13C, and
19F NMR spectra for all isolated compounds (PDF)
4368
https://dx.doi.org/10.1021/acs.joc.1c00131
J. Org. Chem. 2021, 86, 4361−4370

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
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AUTHOR INFORMATION
Corresponding Authors
Zhengkai Chen − Department of Chemistry, Zhejiang Sci-
Tech University, Hangzhou 310018, People’s Republic of
China; orcid.org/0000-0002-5556-6461;
■
Email: zkchen@zstu.edu.cn
Xiao-Feng Wu − Dalian National Laboratory for Clean
Energy, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, 116023 Dalian, Liaoning, People’s
Republic of China; Leibniz-Institut für Katalyse e. V,
Universität Rostock, 18059 Rostock, Germany; orcid.org/
0000-0001-6622-3328; Email: xiao-feng.wu@catalysis.de
Authors
Hefei Yang − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China
Shu-Ning Lu − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China
(4) (a) Bunev, A. S.; Vasiliev, M. A.; Statsyuk, V. E.; Ostapenko, G.
I.; Peregudov, A. S. Synthesis of 1-aryl-4-tosyl-5-(trifluoromethyl)-1H-
imidazoles. J. Fluorine Chem. 2014, 163, 34−37. (b) Bunev, A. S.;
Varakina, E. V.; Khochenkov, D. A.; Peregudov, A. S. 1-Imidoyl-1,2,3-
benzotriazoles-Novel Reagents for the Synthesis of 1-Aryl-5-
trifluoromethylimidazoles. Russ. Russ. J. Org. Chem. 2019, 55, 493−
497. (c) Hu, S.; Yang, H.; Chen, Z.; Wu, X.-F. Base-mediated [3 + 2]
annulation of trifluoroacetimidoyl chlorides and isocyanides: An
improved approach for regioselective synthesis of 5-trifluoromethyl-
imidazoles. Tetrahedron 2020, 76, 131168.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00131
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge financial support from the Natural Science
Foundation of Zhejiang Province (LY19B020016).
■
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