A Domino Azidation/C-H Amination Approach toward Trifluoromethyl Substituted Imidazoles

Article abstract of DOI:10.1021/acs.joc.7b01361

N-Alkyl enamines can be transformed into 2,4,5-trisubsituted imidazoles by reacting with (diacetoxyiodo)benzene and TMSN₃ under the catalysis of a copper salt such as Cu(OAc)₂. Tetrabutyl ammonium iodide was also capable of promoting the reaction. The transformation from N-alkyl enamines into 2,4,5-trisubsituted imidazoles took place in a domino azidation/intramolecular C(sp³)-H amination pattern. The present reaction provides a new efficient method for the preparation of 4-(trifluoromethyl) imidazoles.

Full text of DOI:10.1021/acs.joc.7b01361

Subscriber access provided by UNIV OF NEWCASTLE
Note
A Domino Azidation/C-H Amination Approach
towards Trifluoromethylsubstituted Imidazoles
Haichao Ma, Xiaoyan Zhang, Liangliang Chen, and Wei Yu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01361 • Publication Date (Web): 25 Jul 2017
Downloaded from http://pubs.acs.org on July 25, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A Domino Azidation/C−H Amination Approach towards
Trifluoromethylsubstituted Imidazoles
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Haichao Ma, Xiaoyan Zhang, Liangliang Chen and Wei Yu*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
*Corresponding author: yuwei@lzu.edu.cn
Graphic abstract
Abstract
NꢀAlkyl enamines can be transformed into 2,4,5ꢀtrisubsituted imidazoles by reacting
with (diacetoxyiodo) benzene and TMSN under the catalysis of a copper salt such as
3
Cu(OAc) . Tetrabutyl ammonium iodide was also capable of promoting the reaction.
2
The transformation from Nꢀalkyl enamines into 2,4,5ꢀtrisubsituted imidazoles took
3
place in a domino azidation/intramolecular C(sp )−H amination pattern. The present
reaction provides a new efficient method for the preparation of 5ꢀ(trifluoromethyl)
imidazoles.
Key words: azidation; C−H amination; enamines; 5ꢀ(trifluoromethyl)imidazoles;
diacetoxyiodo) benzene.
(
The C−H amination reactions are of topical interest in the field of current organic
synthesis. In this context, azides have recently emerged as powerful reagents for the
1
2
3
2ꢀ4
amination of both C(sp )−H bond and C(sp )−H bond.
Concurrent with the
insurgence in the azideꢀinvolved amination reactions, many efforts have been made to
5
develop new methods for the azidation of C−H bonds as well as the carbonꢀcarbon
6
double bonds. From the view point of synthetic efficiency, a domino process
combining azidation with the azideꢀbased C−H amination would be highly valuable
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 20
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
for the preparation of nitrogenꢀcontaining compounds because in this way two C−N
bonds can be constructed in one synthetic operation.
To implement this synthetic strategy recently we developed a new method for the
7,8
preparation of quinoxalines from Nꢀarylenamines. This method takes advantage of
3
the oxidative conditions of (diacetoxyiodo) benzene (DIB) and TMSN to azidate the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
electronꢀrich Nꢀarylenamines. The thus formed unstable azidated products then
undergo dinitrogenative cyclization to afford quinoxaline products. The reactions
were believed to follow a free radical mechanism which involves iminyl radicals as
the key intermediates. On the basis of this study, we envisioned that this double
3
amination strategy might be applied as well to realize a domino azidation/ C(sp )−H
amination process (Scheme 1) through which the structurally important imidazole
9
compounds would be generated. It was anticipated that after the iminyl radical was
formed, it would abstract an hydrogen atom from the methylene group adjacent to the
other nitrogen atom to afford a αꢀamino radical. The latter would then be oxidized to
the carbocation and trapped by the imine nitrogen to form the cyclization product. The
10
1,5ꢀhydrogen atom transfer (HAT) reactions,
including those involving
11,12
nitrogenꢀcentered radicals,
have proved to be a powerful tool for C−H
functionalization. However, the iminyl radicalꢀmediated 1,5ꢀHAT reactions are far
1
3
less explored. We hoped that by implementing this strategy, the efficacy of iminyl
radicals to abstract the hydrogen atom from C−H bond could be further evaluated.
Our subsequent investigation showed that the designed reaction did take place, and
the expected imdazole products were obtained in good yields when 3ꢀtrifluromethyl
substituted enamine esters were used as the substrates. Herein we wish to report this
result.
Scheme 1 Designed strategy
Our investigation began by applying the reaction conditions of hypervalent(III) iodine
3
reagent and TMSN to compound 1a. As expected, the desired transformation did take
place when copper salts were used as catalyst, but the yield was low. After extensive
screening of the reaction conditions, we found that by using CuBr as catalyst and
methanol as solvent, the imidazole products 2a-1 and 2a-2 could be obtained in a
2
ACS Paragon Plus Environment

Page 3 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
combined yield of 39% (Scheme 2). Besides 1a, compound 1b was also used as the
substrate, which was transformed into 2b in a moderate yield of 25%. Although these
preliminary results were unsatisfactory, the formation of both compounds 2a and 2b
did demonstrate the practicability of the designed strategy. We hoped that it might
work well with other substrates. Thus compound 1c was tested next, and the
representative reaction conditions being applied to it are listed in Table 1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
PhI(OAc) (3.0 equiv)
2
Ph
TMSN (3.0 equiv)
H
N
3
CO Et
CO Et
2
2
N
CuBr (10 mol%)
Ph
Ph
N
H
Ph
+
MeOH, rt
N
N
H
CO Et
Ph
Ph
2
1a
39%
2a-1
2a-2
PhI(OAc) (3.0 equiv)
2
Ph
TMSN (3.0 equiv)
3
CO Et
2
N
N
CuBr (10 mol%)
MeOH, rt
25%
N
H
CO Et
Ph
2
1b
2b
Scheme 2 Preliminary result with 1a and 1b as the substrates
It can be seen from Table 1 that compound 1c can be converted into the
trifluomethylꢀsubstituted imidazole 2c smoothly in DMF under the conditions of
2 3 2
PhI(OAc) , TMSN and Cu(OAc) (or CuI) . This transformation was also realized in
methanol, but the yield was much lower. Using PhIO as oxidant also effected the
reaction. The yield of 2c can be considerably improved by adding tetrabutyl
ammonium iodide (TBAI) into the reaction system (Table1, entries 4ꢀ9). The optimal
amount of TBAI was found to be 2.0 equiv. As such, when 2.0 equiv. of TBAI was
used along with 3.0 equiv. of PhI(OAc)
2 3
, 3.0 equiv of TMSN and 0.1 equiv
Cu(OAc) , 2c was generated in a yield of 84% in DMF (Table 1, entry 9). The
2
reaction was also conducted by replacing TBAI with 1.0 equiv of CuI, but the yield of
2c was much lower.
a
Table 1 Screening of the reaction conditions for the reaction of compound 1c
Oxidant
TMSN3
catalyst
additive
CF3
H
N
CO Et
2
N
H
CO Et
N
2
CF3
1
c
2c
entry
oxidant
equiv of
cat
additive (equiv)
none
solvent
yield (%)
10
TMSN
3
b
1
PhI(OAc)2
2.0
CuBr2
MeOH
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 20
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
3
4
5
6
7
8
9
1
PhI(OAc)2
PhIO
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.5
3.0
3.0
3.0
3.0
3.0
3.0
CuBr
none
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
19
22
44
46
61
68
63
84
46
51
trace
64
79
70
72
81
66
79
40
Cu(OAc)2
CuCl2
CuBr
none
PhIO
TBAI
TBAI
PhIO
PhIO
Cu(OTf)
2
TBAI
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
PhIO
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
none
TBAI
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
TBAI
TBAI
none
0
1
1
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
2
2
2
2
TBAI
none
c
b
d
12
none
1
3
Cu(OAc)
2
2
TBAI
TBAI
TBAI (0.1)
TBAI (1.0)
TBAI (3.0)
TBAI
TBAI
none
14
Cu(OAc)
1
1
1
1
5
6
7
8
PhI(OAc)2
Cu(OAc)2
PhI(OAc)
PhI(OAc)
PhIO
2
Cu(OAc)
Cu(OAc)
Cu(OAc)
CuI
2
2
2
2
19
PhI(OAc)
2
e
2
0
PhI(OAc)2
CuI
a
The reaction was carried out on a 0.2 mmol scale in 2 mL solvent at room temperature. 3.0 Equiv
of hypervalent iodine reagent, 2.0 equiv. of TABI, and 10 mol% of copper salt were used unless
b
c
otherwise specified. The reaction time was 2−4 h. 2.0 Equiv of PhI(OAc)
was used. Complex
2
d
e
mixture was generated. 3.5 Equiv of PhI(OAc)
2
was used. 1.0 Equiv of CuI was used. TBAI:
tetrabutylammonium Iodide.
The trifluoromethyl group possesses important functions in pharmaceutically and
1
4
medicinally significant compounds.
Despite the intense interest in the
15
trifluoromethylated aromatic compounds, however, the synthesis of trifluoromethyl
16
attached imidazoles have only been scarcely reported. We anticipated that the
current protocol would provide an efficient approach towards this structural moiety.
Thus, the optimal conditions were next applied to a variety of 3ꢀtrifluromethyl
enamine esters, and the results are illustrated in Scheme 3.
4
ACS Paragon Plus Environment

Page 5 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
PhI(OAc)2 (3.0 equiv)
R2
TMSN (3.0 equiv)
3
CF3
H
Cu(OAc)2 (10 mol%)
N
CO Et
2
R1
N
H
TBAI (2.0 equiv)
R1
(or 2u)
CO Et
N
2
DMF, rt
CF3
1
2
H
N
R
R
CO Et
H
N
H
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
CO Et
CO2Et
2
R
N
CF3
N
N
CF3
CF3
R = Me 2l
85%
R = H
2c
84%
R = Me 2j
7
7%
R = F
2m 76%
2n 79%
R = Me 2d
R = OMe 2e
84%
79%
84%
79%
70%c
30%
R = F
2k 71%
R = Cl
H
R = F
R = Cl
R = Br
2f
CO Et
H
N
N
N
2
CO Et
N
2
2g
2h
N
CF3
N
CF3
R = CN 2i
2o
37%
2
p
53%
H
N
CO Et
H
H
2
CO Et
CO Et
N
2
N
2
Bn
N
Et
CF3
N
N
CF3
2r 42%
CF3
2
q
43%
2s 53%
H
N
CO2Et
CF3
CO2Et
CO Et
Me
Ph
N
N
Me
Me
N
N
2
CF3
N
CF3
2
t
80%
2u 52%
2v 0%
2
The Reaction was conducted on a 0.2 mmol scale. R = H except for 1u and 1v.
The structures of 2h and 2l were confirmed by X-ray crystallographic analysis.17
Scheme 3 Examination of the reaction’s scope
From Scheme 3, it can be seen that this protocol is well suitable for the preparation of
2
ꢀphenylꢀ5ꢀ(trifluoromethyl)ꢀimidazoles, the yields were generally good except for
those bearing a strong electron withdrawing group at the phenyl ring (2i). This result
suggests that the benzyl position would bear some positive charge at certain stages
during the reaction. Substituting an electronꢀdeficient pyridyl ring for the phenyl ring
lowered the yield as well (2o and 2p). 2ꢀAlkyl and 2ꢀvinyl substituted imidazoles can
also be prepared with this method, albeit in lower yields (2qꢀ2s). When reactants
bearing two substituents at the amino’s αꢀposition was used, the reaction delivered
mixed result: while compound 2u was generated in a yield of 52%, compound 2v
cannot be obtained in this way. The current conditions were also applied to
compounds 1a and 1b, but the results were inferior to those shown in Scheme 2.
As shown in Scheme 1, our design was based on the assumption that the initial
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 20
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
azidation would produce a vinyl azide intermediate, which would be further oxidized
to afford iminyl radicals. To verify this radical mechanism, some preliminary
investigations were conducted. The results are shown in Schemes 4 and 5. It was
found the commonly used radical scavenger TEMPO (4ꢀOHꢀTEMPO was used in this
case) had no inhibiting effect on the reaction, and when compound 1w was used as the
substrate, the imidazole product 2w was obtained in a yield of 50%. In the latter case,
no ringꢀopening product was obtained. These results did not support the assumed
radical mechanism, but they also did not point to other alternative pathways. Further
studies are needed to elucidate the mechanistic issues.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4 Reactions conducted in the presence of 4ꢀOHꢀTEMPO
Scheme 5 Reaction of Nꢀcyclopropylmethyl enamine 1w
3
In summary, a tandem azidation/C(sp )−H amination strategy has been developed to
gain access to 2,4,5ꢀtrisubsituted imidazoles from the enamine precursors by using
3
(diacetoxyiodo)benzene as oxidant and TMSN as an azide source. This protocol is
highly efficient for the preparation of 5ꢀ(trifluoromethyl)imidazoles. A copper salt or
tetrabutyl ammonium iodide is required for the reaction to take place, and
5
ꢀ(trifluoromethyl)imidazoles can be obtained in high yields when both of them were
present in the reaction system. The present result demonstrates the synthetic value of
6
ACS Paragon Plus Environment

Page 7 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
the domino azidation/C−H amination strategy in the synthesis of nitrogen
heterocycles.
Experimental section
General information
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
13
The H and C NMR spectra were recorded in CDCl , DMSOꢀd or acetoneꢀd on a
3
6
6
4
00 MHz spectrometer or a 300 MHz spectrometer. NMR data are represented as
follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), coupling constants in hertz (Hz), and integration. The
1
chemical shifts in H NMR spectra were determined with Si(CH
3
)
4
as the internal
13
standard (δ = 0.00 ppm). The chemical shifts in C NMR spectra were determined
3 6
based on the chemical shift of CDCl (δ = 77.00 ppm), DMSOꢀd (δ = 39.60 ppm) or
1
3
acetoneꢀd (206.5 ppm). All the CNMR spectra measured in this study were
6
protonꢀdecoupled. The high resolution mass spectra (HRMS) were measured on a
TOFꢀMS instrument with an ESI source. Xꢀray crystallographic analysis was
performed with a SMART CCD and a P4 diffractometer. Melting points were
uncorrected. Flash column chromatography was carried out on silica gel (200ꢀ300
mesh) with petroleum ether (PE) and ethyl acetate as the eluent.
General procedure for the synthesis of
1
Compounds (Z)ꢀethyl
3
ꢀ((arylmethyl)amino)ꢀ4,4,4ꢀtrifluorobutꢀ2ꢀenoate (1cꢀ1w) were prepared according
1
8
to the literature methods.
As a typical procedure, to a 50 mL roundꢀbottom flask equipped with a magnetic
stirring bar were added benzylamine (5.5 mmol, 1.1 equiv), CH COOH (5.5 mmol,
3
1.1 equiv) and CHCl
minutes. A solution of ethyl 4,4,4ꢀtrifluoroacetoacetate (5 mmol, 1.0 equiv) in CHCl
10 mL) was then added into the mixture. After stirring for 5h under reflux, the
3
(8 mL). The mixture was stirred at room temperature for 5
3
(
solution was evaporated under reduced pressure, and the residual was filtered through
a short silica column (PE/ethyl acetate) to give the 1c.
19, 20
Compounds 1a, 1b were prepared according to the literature methods.
General procedure for the reactions of 1 Into a 10 mL roundꢀbottom flask equipped
with a magnetic stirring bar were added sequentially 1 (0.2 mmol, 1.0 equiv),
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 20
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Cu(OAc)
2
(3.6 mg, 0.02 mmol, 0.1 equiv), DMF (5 mL) , tetrabutyl ammonium
iodide (147 mg, 0.4 mmol, 2.0 equiv), TMSN (78.9 ꢁL, 0.6 mmol, 3.0 equiv), and
3
2
finally PhI(OAc) (193 mg, 0.6 mmol, 3.0 equiv). The mixture was stirred at room
temperature until the reaction was complete as indicated by TLC (generally 2ꢀ4 h).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The reaction mixture was then poured into a saturated aqueous NaHCO solution (20
3
mL), and was then extracted with ethyl acetate (4×10 mL). The combined organic
2 4
layers were washed with brine (4×30 mL) and dried with anhydrous Na SO . The
solvent was removed under reduced pressure, and the residual was treated with silica
gel chromatography (PE/ethyl acetate) to give product 2.
Compounds 2a and 2b are obtained by a similar operation as described above.
Warning!
Under the present reaction conditions of TMSN /PhI(OAc) /CuCl , HN and Cu(N )
3 2
3
2
2
3
might be formed as the byꢀproducts. These compounds are toxic and explosive; the
reactions must be handled carefully with sufficient protection.
1
8
(Z)-Ethyl 3-(benzylamino)-4,4,4-trifluorobut-2-enoate (1c): 75% yield (0.806 g),
1
Colorless liquid; R = 0.25 (PE : EtOAc = 95 : 5); H NMR (CDCl , 400 MHz, δ ppm):
f
3
8
7
1
.45 (s, 1H), 7.36−7.26 (m, 5H), 5.17 (s, 1H), 4.46 (d, J = 6.4 Hz, 2H), 4.13 (q, J =
13
.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H); C NMR (CDCl
3
, 100 MHz, δ ppm): 169.8,
48.1, 137.7, 128.8, 127.7, 127.2, 120.3 (q, J = 275 Hz), 85.2, 59.7, 48.0, 14.2.
1
8
(Z)-Ethyl 4,4,4-trifluoro-3-((4-methylbenzyl)amino)but-2-enoate (1d): 75% yield
1
(0.859 g), Yellow liquid; R
f
= 0.26 (PE : EtOAc = 20 : 1); H NMR (CDCl
3
, 400 MHz,
δ ppm): 8.40 (s, 1H), 7.19−7.13 (m, 4H), 5.15 (s, 1H), 4.41 (d, J = 6.4 Hz, 2H), 4.14
1
3
(q, J = 7.2 Hz, 2H), 2.33 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H); C NMR (CDCl
MHz, δ ppm): 169.8, 148.1, 137.5, 134.6, 129.5, 127.4, 120.3 (q, J = 275 Hz), 85.0,
9.6, 47.8, 21.0, 14.2.
3
, 100
5
18
(Z)-Ethyl 4,4,4-trifluoro-3-((4-methoxybenzyl)amino)but-2-enoate (1e): 80% yield
1
(0.980 g), Orange oil; H NMR (CDCl
3
, 400 MHz, δ ppm): 8.34 (s, 1H), 7.22 (d, J =
8
.8 Hz, 2H), 6.88 (d, J = 9.2 Hz, 2H), 5.14 (s, 1H), 4.39 (d, J = 6.0 Hz, 2H), 4.12 (q, J
13
=
3
7.2 Hz, 2H), 3.79 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H); C NMR (CDCl , 100 MHz, δ
ppm): 169.8, 159.2, 148.0, 129.7, 128.7, 120.3 (q, J = 275 Hz), 114.2, 84.9, 59.6, 55.2,
8
ACS Paragon Plus Environment

Page 9 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4
7.5,14.3.
(Z)-Ethyl 4,4,4-trifluoro-3-((4-fluorobenzyl)amino)but-2-enoate (1f): 49% yield
1
(0.713 g), Colorless liquid; R
f
= 0.64 (PE : EtOAc = 20 : 1); H NMR (CDCl
3
, 400
MHz, δ ppm): 8.39 (s, 1H), 7.28−7.25 (m, 2H), 7.07−7.02 (m, 2H), 5.17 (s, 1H), 4.44
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
(d, J = 6.4 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H); C NMR
CDCl , 100 MHz, δ ppm): 169.8, 162.4 (d, J = 244 Hz), 148.0 (d, J = 31 Hz), 133.5,
29.0, 120.3 (q, J = 275 Hz), 115.8, 85.6, 59.8, 47.4, 14.3; HRMS (ESIꢀTOF) m/z: [M
(
3
1
+
+
14 4 2
H] Calcd for C13H F NO 292.0955; found 292.0952.
18
(
Z)-Ethyl 3-((4-chlorobenzyl)amino)-4,4,4-trifluorobut-2-enoate (1g): 78% yield
1
(
1.214 g); H NMR (CDCl
3
, 400 MHz, δ ppm): 8.43 (s, 1H), 7.33−7.31 (m, 2H),
7
1
.23−7.21 (m, 2H), 5.18 (s, 1H), 4.43 (d, J = 6.4 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H),
1
3
.26 (t, J = 7.2 Hz, 3H); C NMR (CDCl , 100 MHz, δ ppm): 169.8, 147.9, 136.3,
3
133.6, 129.0, 128.5, 120.3 (q, J = 275 Hz), 85.8, 59.8, 47.3, 14.2.
(Z)-Ethyl 3-((4-bromobenzyl)amino)-4,4,4-trifluorobut-2-enoate (1h): 47% yield
1
(
0.828 g), Colorless liquid; R = 0.44 (PE : EtOAc = 20 : 1); H NMR (CDCl , 400
f
3
MHz, δ ppm): 8.44 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 5.18 (s,
13
1
H), 4.41 (d, J = 6.4 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); C
NMR (CDCl
3
, 100 MHz, δ ppm): 169.7, 147.9, 136.8, 131.9, 128.8, 121.6, 120.3 (q, J
+
=
275 Hz), 85.8, 59.8, 47.3, 14.2; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
C
13 14 3 2
H F BrNO 352.0155; found 352.0150.
(Z)-ethyl 3-((4-cyanobenzyl)amino)-4,4,4-trifluorobut-2-enoate (1i): 55% yield (0.819
1
g), yellow liquid; R
f
= 0.20 (PE : EtOAc = 20 : 1); H NMR (CDCl
3
, 400 MHz, δ
ppm): 8.55 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 5.23 (s, 1H),
1
3
4
.54 (d, J = 6.8 Hz, 2H), 4.17 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H); C NMR
(
CDCl , 100 MHz, δ ppm): 169.7, 147.7, 143.4, 132.6, 127.5, 120.3 (q, J = 275 Hz),
3
+
1
18.5, 111.6, 86.7, 60.0, 47.4, 14.2; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
14 14 3 2 2
C H F N O 299.1002; found 299.0995.
(
Z)-Ethyl 4,4,4-trifluoro-3-((3-methylbenzyl)amino)but-2-enoate (1j): 49% yield
1
(0.703 g), yellow liquid; R
f
= 0.56 (PE : EtOAc = 20 : 1); H NMR (CDCl
3
, 400 MHz,
δ ppm): 8.40 (s, 1H), 7.25−7.22 (m, 2H), 7.11−7.08 (m, 2H), 5.16 (s, 1H), 4.43 (d, J =
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 20
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
6
.4 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); C NMR
(
CDCl , 100 MHz, δ ppm): 169.8, 148.1, 138.5, 137.5, 128.7, 128.6, 128.1, 124.3,
3
+
1
20.3 (q, J = 275 Hz), 85.0, 59.7, 48.1, 21.4, 14.3; HRMS (ESIꢀTOF) m/z: [M + H]
Calcd for C14 NO 288.1206; found 288.1203.
H
17
F
3
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Z)-Ethyl 4,4,4-trifluoro-3-((3-fluorobenzyl)amino)but-2-enoate (1k): 88% yield
1
(1.285 g), colorless liquid; R
f
= 0.65 (PE : EtOAc = 20 : 1); H NMR (CDCl
3
, 400
MHz, δ ppm): 8.47 (s, 1H), 7.34−7.29 (m, 1H), 7.08−7.06 (m, 1H), 7.01−6.96 (m,
2
H), 5.19 (s, 1H), 4.46 (d, J = 6.4 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2
13
Hz, 3H); C NMR (CDCl
3
, 100 MHz, δ ppm): 169.8, 163.0 (d, J = 245 Hz), 147.9.
1
40.4, 130.3, 122.6, 120.3 (q, J = 275 Hz), 121.6, 114.7, 114.1, 85.9, 59.8, 47.5, 14.2;
+
HRMS (ESIꢀTOF) m/z: [M + H] calcd. for C13
H
14
F
4
NO
2
292.0955; found 292.0952.
(
Z)-Ethyl 4,4,4-trifluoro-3-((2-methylbenzyl)amino)but-2-enoate (1l): 61% (0.876 g),
1
f 3
colorless liquid; R = 0.48 (PE : EtOAc = 20 : 1); H NMR (CDCl , 400 MHz, δ ppm):
8.27 (s, 1H), 7.25−7.17 (m, 4H), 5.17 (s, 1H), 4.43 (d, J = 6.0 Hz, 2H), 4.11 (q, J =
13
7
.2 Hz, 2H), 2.33 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H); C NMR (CDCl , 100 MHz, δ
3
ppm): 169.8, 148.1, 136.3, 135.4, 130.6, 128.2, 128.1, 126.4, 120.3 (q, J = 275 Hz),
+
8
5.1, 59.7, 46.2, 18.8, 14.2; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C14
17 3 2
H F NO
2
88.1206; found 288.1203.
(
Z)-Ethyl 4,4,4-trifluoro-3-((2-fluorobenzyl)amino)but-2-enoate (1m): 87% yield
1
(1.274 g), colorless liquid; R
f
= 0.68 (PE : EtOAc = 20 : 1); H NMR (CDCl
3
, 400
MHz, δ ppm): 8.46 (s, 1H), 7.33−7.26 (m, 2H), 7.17−7.12 (m, 1H), 7.09−7.05 (m,
1H), 5.17 (s, 1H), 4.53 (d, J = 6.4 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2
13
Hz, 3H); C NMR (CDCl
3
, 100 MHz, δ ppm): 169.8, 160.6 (d, J = 246 Hz), 147.9,
1
29.5. 129.1, 124.9, 124.4, 120.3 (q, J = 275 Hz), 115.5, 85.7, 59.8, 41.9, 14.3;
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H F NO 292.0955; found 292.0957.
1
3
14
4
2
18
(
Z)-Ethyl 3-((2-chlorobenzyl)amino)-4,4,4-trifluorobut-2-enoate (1n): 81% yield
1
(1.242 g); H NMR (CDCl
3
, 400 MHz, δ ppm): 8.53 (s, 1H), 7.40−7.34 (m, 1H),
7
.34−7.32 (m, 1H), 7.29−7.23 (m, 2H), 5.19 (s, 1H), 4. 57 (d, J = 6.8 Hz, 2H), 4.16 (q,
13
3
J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H); C NMR (CDCl , 100 MHz, δ ppm): 169.8,
148.0, 135.4, 133.2, 129.7, 129.1, 128.8, 127.2, 120.3 (q, J = 275 Hz), 85.7, 59.8, 45.8,
10
ACS Paragon Plus Environment

Page 11 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
4.3.
(Z)-Ethyl 4,4,4-trifluoro-3-((pyridin-2-ylmethyl)amino)but-2-enoate (1o): 39% yield
1
(0.534 g), pale yellow liquid; R
f
= 0.22 (PE : EtOAc = 3 : 1); H NMR (CDCl
3
, 400
MHz, δ ppm): 9.09 (s, 1H), 8.64−8.63 (m, 1H), 7.70−7.66 (m, 1H), 7.26−7.20 (m,
2H), 5.21 (s, 1H), 4. 64 (d, J = 5.6 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
Hz, 3H); C NMR (CDCl
3
, 100 MHz, δ ppm): 169.4, 156.0, 149.3, 147.4, 136.7,
1
22.4, 121.0, 120.3 (q, J = 275 Hz), 85.6, 59.6, 48.4, 14.2; HRMS (ESIꢀTOF) m/z: [M
+
+
14 3 2 2
H] Calcd for C12H F N O 275.1002; found 275.1004.
(
Z)-Ethyl 4,4,4-trifluoro-3-((pyridin-3-ylmethyl)amino)but-2-enoate (1p): 84% yield
1
(
1.156 g), pale yellow liquid; R
f
= 0.17 (PE : EtOAc = 3 : 1); H NMR (CDCl
3
, 400
MHz, δ ppm): 8.57−8.56 (m, 2H), 8.47 (s, 1H), 7.65−7.63 (m, 1H), 7.32−7.29 (m,
H), 5.22 (s, 1H), 4. 50 (d, J = 6.4 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2
1
1
3
3
Hz, 3H); C NMR (CDCl , 100 MHz, δ ppm): 169.7, 149.2, 148.8, 147.8, 134.8,
133.3, 123.6, 120.3 (q, J = 275 Hz), 86.4, 59.9, 45.5, 14.2; HRMS (ESIꢀTOF) m/z: [M
+
+
H] Calcd for C H F N O 275.1002; found 275.0999.
12 14
3
2
2
1
8
(
Z)-ethyl 4,4,4-trifluoro-3-(phenethylamino)but-2-enoate (1q): 53% yield (0.758 g,
1
5
2
2
.0 mmol scale); H NMR (CDCl
3
, 400 MHz, δ ppm): 8.23 (s, 1H), 7.34−7.30 (m,
H), 7.26−7.20 (m, 3H), 5.09 (s, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.52 (d, J = 7.2 Hz,
13
H), 2.88 (t , J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); C NMR (CDCl
3
, 100 MHz, δ
ppm): 169.8, 137.9, 128.7, 128.7, 126.7, 120.3 (q, J = 275 Hz), 84.7, 59.6, 45.6, 37.2,
14.3.
(Z)-ethyl 4,4,4-trifluoro-3-(propylamino)but-2-enoate (1r): 58% yield (0.658 g),
1
colorless liquid; R
f
= 0.76 (PE : EtOAc = 20 : 1); H NMR (CDCl
3
, 400 MHz, δ ppm):
8
.20 (s, 1H), 5.06 (s, 1H), 4.15 (q, J = 9.6 Hz, 2H), 3.26 (q, J = 9.2 Hz, 2H), 1.68ꢀ1.56
13
(
m, 2H), 1.28 (t , J = 9.6 Hz, 3H), 0.99 (t, J = 10.0 Hz, 3H); C NMR (CDCl , 100
3
MHz, δ ppm): 170.1, 148.7, 120.3 (q, J = 275 Hz), 83.8, 59.5, 45.7, 23.7, 14.3, 11.1;
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C
9
H F
15 3
NO
2
; found 226.1050.
21
(
Z)-Ethyl 3-(allylamino)-4,4,4-trifluorobut-2-enoate (1s): 73% yield (0.818 g),
1
colorless liquid; H NMR (CDCl , 400 MHz, δ ppm): 8.25 (s, 1H), 5.95−5.83 (m, 1H),
3
5
.29−5.18 (m, 2H), 5.12 (s, 1H), 4.16 (q, J = 9.6 Hz, 2H), 3.91 (t, J = 7.6 Hz, 2H),
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 20
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
1
.28 (t , J = 9.6 Hz, 3H); C NMR (CDCl
3
, 100 MHz, δ ppm): 169.9, 148.2, 133.9,
+
1
20.3 (q, J = 275 Hz), 116.8, 85.0, 59.7, 46.4, 14.3. HRMS (ESIꢀTOF) m/z: [M + H]
Calcd for C
9 13 3 2
H F NO 224.0893; found 224.0891.
(Z)-Ethyl 4,4,4-trifluoro-3-((naphthalen-1-ylmethyl)amino)but-2-enoate (1t): 89%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
yield (1.438 g), white solid, m.p. = 65−66 C; H NMR (CDCl
8.41 (s, 1H), 7.95−7.93 (m, 1H), 7.88−7.86 (m, 1H), 7.82−7.80 (m, 1H), 7.57−7.41 (m,
H), 5.21 (s, 1H), 4. 89 (d, J = 5.6 Hz, 2H), 4.07 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2
3
, 400 MHz, δ ppm):
4
1
3
Hz, 3H); C NMR (CDCl
3
, 100 MHz, δ ppm): 169.7, 148.0, 133.8, 132.8, 131.1,
1
5
28.9, 128.8, 126.7, 126.0, 125.9, 125.4, 124.6, 122.8, 120.3 (q, J = 275 Hz), 85.5,
+
9.7, 46.0, 14.2; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C17
H
17
F
3
2
NO 324.1206;
found 324.1203.
2
2,23
(
Z)-Ethyl 4,4,4-trifluoro-3-((1-phenylethyl)amino)but-2-enoate (1u):
53% yield
1
(0.758 g); H NMR (CDCl
3
, 400 MHz, δ ppm): 8.66 (d, J = 9.6 Hz, 1H), 7.35−7.22
(m, 5H), 5.13 (s, 1H), 4.77−4.73 (m, 1H), 4.20−4.14 (m, 2H), 1.53 (d, J = 6.8 Hz, 3H),
1
3
1
.28 (t, J = 7.2 Hz, 3H); C NMR (CDCl , 100 MHz, δ ppm): 169.9, 147.6, 143.9,
3
1
28.7, 127.3, 125.3, 124.4, 120.3 (q, J = 275 Hz), 85.4, 59.7, 53.9, 24.9, 14.3.
2
3
(
Z)-Ethyl 4,4,4-trifluoro-2-(isopropylamino)but-2-enoate (1v): 56% yield (0.660
1
g); H NMR (CDCl
3
, 400 MHz, δ ppm): 8.09 (s, 1H), 5.03 (s, 1H), 4.15 (q, J = 7.2 Hz,
13
2
H), 3.82−3.71 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.23 (d, J = 6.4 Hz, 6H); C NMR
(
3
CDCl , 100 MHz, δ ppm): 170.1, 147.9, 120.4 (q, J = 275 Hz), 83.8, 59.5, 46.6, 24.6,
14.3.
(Z)-Ethylꢀ3-((cyclopropylmethyl)amino)-4,4,4-trifluorobut-2-enoate (1w): 59% yield
(0.695 g), colorless liquid, R = 0.61 (PE : EtOAc = 10 : 1); 1H NMR (CDCl , 400
MHz, δ ppm): 8.27 (s, 1H), 5.07 (s, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.15 (t, J = 6.4 Hz,
f
3
2
2
5
2
H), 1.28 (t , J = 7.2 Hz, 3H), 1.08−1.03 (m, 1H), 0.61−0.57 (m, 2H), 0.28−0.24 (m,
H); 13C NMR (CDCl3, 100 MHz, δ ppm): 169.9, 148.2, 120.3 (q, J = 275 Hz), 84.0,
+
9.5, 49.0, 14.3, 11.4, 3.3; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C10
15 3 2
H F NO
38.1049; found 238.1046.
Ethyl 2,4-diphenyl-1H-imidazole-5-carboxylate (2a-1), ethyl 2,5-diphenyl-1H
2
4
1
6
-imidazole-4-carboxylate (2a-2): 39% yield (23 mg); H NMR (DMSOꢀd , 400
12
ACS Paragon Plus Environment

Page 13 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
MHz, δ ppm): 13.22−13.10 (d, 1H), 8.22−8.08 (m, 2H), 7.92−7.68 (m, 2H), 7.51−7.43
13
(
m, 6H), 4.30−4.18 (m, 2H), 1.28−1.17 (m, 3H); C NMR (DMSOꢀd
6
, 100 MHz, δ
ppm): 163.0, 160.0, 147.9, 147.1, 145.9, 138.2, 133.9, 129.7, 129.5, 129.3, 129.0,
128.8, 128.5, 128.0, 127.9, 127.6, 126.5, 125.7, 60.4, 59.6, 14.2.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 2,2-dimethyl-5-phenyl-2H-imidazole-4-carboxylate (2b): 25% yield (12 mg),
1
pale yellow liquid, R = 0.39 (PE : EtOAc = 5 : 1); H NMR (CDCl , 400 MHz, δ
f
3
ppm): 7.70−7.68 (m, 2H), 7.42−7.35 (m, 3H), 4.36 (q, J = 7.2 Hz, 2H), 1.55 (s, 1H),
1
3
1
1
.30 (t, J = 7.2 Hz, 3H); C NMR (CDCl
3
, 100 MHz, δ ppm): 163.3, 162.1, 156.9,
+
31.1, 130.8, 128.5, 128.4, 103.3, 62.5, 23.3, 14.0; HRMS (ESIꢀTOF) m/z: [M + H]
17 2 2
Calcd for C14H N O
245.1285; found 245.1293.
1
6a
Ethyl 2-phenyl-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2c): 84% yield (48
1
mg); H NMR (DMSOꢀd
6
, 400 MHz, δ ppm): 14.07 (br, 1H), 8.17−8.15 (m, 2H), 7.52
1
3
(d, J = 6.8 Hz, 3H), 4.39 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H); C NMR
(DMSOꢀd , 100 MHz, δ ppm): 158.0, 147.9, 134.1, 130.1, 128.9, 128.4, 126.7, 122.5,
21.3 (q, J = 266 Hz), 61.4, 14.0.
Ethyl 2-(p-tolyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2d): 84% yield (50
6
1
o
1
mg), white solid, m.p. = 190−192 C; H NMR (DMSOꢀd
6
, 400 MHz, δ ppm): 13.90
(br, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H),
13
2
1
6
.33 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); C NMR (DMSOꢀd , 100 MHz, δ ppm): 158.1,
48.1, 140.0, 134.1, 129.5, 126.6, 125.8, 122.2, 121.4 (q, J = 266 Hz), 61.4, 21.0, 14.0;
+
HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for C14
13 3 2 2
H F N O Na 321.0821; found
321.0819.
1
6a
Ethyl 2-(4-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2e):
o
1
7
9% yield (50 mg), white solid, m.p. = 194−197 C; H NMR (DMSOꢀd , 400 MHz, δ
6
ppm): 13.80 (br, 1H), 8.08 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 4.34 (q, J =
13
7
.2 Hz, 2H), 3.80 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); C NMR (DMSOꢀd
6
, 100 MHz, δ
ppm): 160.8, 158.2, 148.1, 134.4, 128.3, 122.0, 121.4 (q, J = 267 Hz), 121.1, 114.3,
+
6
1.3, 55.4, 14.0; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C14
H
14
F
3
N
2
O
3
315.0951,
found: 315.0948.
Ethyl 2-(4-fluorophenyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2f): 84%
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 20
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
yield (51 mg) white solid, m.p. = 191−193 C; H NMR (DMSOꢀd
6
, 400 MHz, δ ppm):
1
4.03 (br, 1H), 8.19−8.15 (m, 2H), 7.34−7.29 (m, 2H), 4.35 (q, J = 7.2 Hz, 2H), 1.31
1
3
(
6
t, J = 7.2 Hz, 3H); C NMR (DMSOꢀd , 100 MHz, δ ppm): 163.2 (d, J = 246 Hz),
158.1, 147.1, 134.1, 129.1, 125.1, 121.3 (q, J = 267 Hz), 116.0, 61.4, 14.0; HRMS
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(ESIꢀTOF) m/z: [M + H] Calcd for C H F N O 303.0751; found 303.0748.
13
11
4
2
2
Ethyl 2-(4-chlorophenyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2g): 79%
o
1
yield (50 mg), white solid, m.p. = 206−208 C; H NMR (Acetoneꢀd , 400 MHz, δ
6
ppm): 8.15−8.11 (m, 2H), 7.55−7.52 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2
13
Hz, 3H); C NMR (Acetoneꢀd
6
, 100 MHz, δ ppm): 158.5, 147.5, 136.3, 129.8, 128.8,
+
1
28.2, 123.6, 122.0 (q, J = 266 Hz), 62.0, 14.2; HRMS (ESIꢀTOF) m/z: [M + H]
Calcd for C13 ClN 319.0456; found 319.0451.
H
11
F
3
2 2
O
1
6a
Ethyl 2-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2h):
1
70% yield (50 mg); H NMR (DMSOꢀd
6
, 400 MHz, δ ppm): 14.11 (br, 1H), 8.06 (d, J
= 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 4.35 (q, J = 6.8 Hz, 2H), 1.31 (t, J = 7.2 Hz,
1
3
3
H); C NMR (DMSOꢀd , 100 MHz, δ ppm): 158.0, 146.9, 134.1, 131.9, 128.6,
6
1
27.7, 122.8, 122.5, 121.2 (q, J = 267 Hz), 61.5, 14.0.
Ethyl 2-(4-cyanophenyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2i): 30%
o
1
yield (19 mg), white solid, m.p. = 244−246 C; H NMR (DMSOꢀd
6
, 400 MHz, δ
ppm): 14.36 (br, 1H), 8.28 (d, J = 8.0 Hz, 2H), 7.94 (d, J = 7.6 Hz, 2H), 4.36 (q, J =
13
6
6
.8 Hz, 2H), 1.32 (t, J = 6.8 Hz, 3H); C NMR (DMSOꢀd , 100 MHz, δ ppm): 157.9,
146.1, 134.5, 132.9, 132.5, 127.2, 123.7, 121.1 (q, J = 267 Hz), 118.5, 112.3, 61.6,
+
14.0; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H F N O 310.0798; found
14
11
3
3
2
310.0804.
Ethyl 2-(m-tolyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2j): 77% yield (46
o
1
mg), white solid, m.p. = 138−139 C; H NMR (DMSOꢀd
6
, 400 MHz, δ ppm): 13.99
(
br, 1H), 7.98 (s, 1H), 7.93 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.26 (d, J =
13
7
.2 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 2.34 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H); C NMR
(DMSOꢀd
6
, 100 MHz, δ ppm): 158.1, 148.1, 138.3, 134.4, 130.8, 128.8, 128.4, 127.2,
1
23.8, 122.4, 121.3 (q, J = 266 Hz), 61.4, 21.0, 14.0; HRMS (ESIꢀTOF) m/z: [M +
+
H] Calcd for C14
H
14
F
3
N
2
O
2
299.1002; found 299.0998.
14
ACS Paragon Plus Environment

Page 15 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Ethyl 2-(3-fluorophenyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2k): 71%
o
1
yield (43 mg), white solid, m.p. = 176−179 C; H NMR (DMSOꢀd
6
, 400 MHz, δ
ppm): 14.13 (br, 1H), 7.98−7.93 (m, 2H), 7.54−7.48 (m, 1H), 7.30−7.25 (m, 1H), 4.35
1
3
6
(q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H); C NMR (DMSOꢀd , 100 MHz, δ ppm):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
162.4 (d, J = 242 Hz), 158.0, 146.6, 134.6, 131.1, 130.6, 122.8, 121.3 (q, J = 267 Hz),
+
1
16.9, 113.3, 61.5, 14.0; HRMS (ESIꢀTOF) m/z: [M + H] Calcd. for C13
H
11
F
4
N
2
O
2
3
03.0751; found 303.0747.
Ethyl 2-(o-tolyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2l): 85% yield (51
o
1
mg), white solid, m.p. = 103−104 C; H NMR (DMSOꢀd , 400 MHz, δ ppm): 13.91
6
(br, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.41−7.29 (m, 3H), 4.35 (q, J = 7.2 Hz, 2H), 2.44 (s,
1
3
3
1
6
H), 1.32 (t, J = 7.2 Hz, 3H); C NMR (DMSOꢀd , 100 MHz, δ ppm): 158.1, 148.5,
37.2, 133.8, 131.0, 130.1, 129.9, 128.6, 125.9, 121.9, 121.3 (q, J = 267 Hz), 61.3,
+
20.4, 14.0; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C14
14 3 2 2
H F N O 299.1002;
found 299.0997.
Ethyl 2-(2-fluorophenyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2m): 76%
o
1
yield (46 mg), white solid, m.p. = 106−108 C; H NMR (DMSOꢀd , 400 MHz, δ
6
ppm): 14.01 (br, 1H), 7.87−7.83 (m, 1H), 7.59−7.54 (m, 1H), 7.41−7.32 (m, 2H), 4.36
13
(
q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H); C NMR (DMSOꢀd
6
, 100 MHz, δ ppm):
1
59.5 (d, J = 250 Hz), 157.9, 143.4, 134.0, 132.5, 132.4, 130.9, 124.9, 122.6, 121.3 (q,
+
J = 266 Hz), 117.1, 116.4, 61.5, 14.0; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
303.0751; found 303.0748.
Ethyl 2-(2-chlorophenyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2n): 79%
13 11 4 2 2
C H F N O
o
1
yield (50 mg), white solid, m.p. = 91−92 C; H NMR (DMSOꢀd
6
, 400 MHz, δ ppm):
1
4.16 (br, 1H), 7.68−7.66 (m, 1H), 7.64−7.62 (m, 1H), 7.57−7.53 (m, 1H), 7.49−7.46
13
(
m, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H); C NMR (DMSOꢀd , 100
6
MHz, δ ppm): 157.9, 145.8, 133.8, 132.6, 132.3, 131.8, 130.1, 128.6, 127.3, 122.4,
+
1
21.3 (q, J = 266 Hz), 61.5, 14.0; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
C
13
H
11
3 2 2
F ClN O 319.0456; found 319.0450.
Ethyl 2-(pyridin-2-yl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2o): 37%
o
1
yield (21 mg), white solid, m.p. = 138−140 C; H NMR (DMSOꢀd , 400 MHz, δ
6
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 20
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ppm): 14.35 (br, 1H), 8.72−8.70 (m, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.00−7.96 (m, 1H),
13
7
.54−7.51 (m, 1H), 4.33 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H); C NMR
(DMSOꢀd
6
, 100 MHz, δ ppm): 157.9, 149.5, 147.4, 147.0, 137.8, 131.6, 128.8, 125.0,
+
121.6, 121.3 (q, J = 267 Hz), 61.4, 13.9; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
C H F N O 286.0798; found 286.0801.
12
11
3
3
2
Ethyl 2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2p): 53%
o
1
6
yield (30 mg), pale yellow solid, m.p. = 204−205 C; H NMR (DMSOꢀd , 400 MHz,
δ ppm): 9.26 (s, 1H), 8.63 (d, J = 4.0 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.52−7.49 (m,
13
1
H), 4.35 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); C NMR (DMSOꢀd
6
, 100
MHz, δ ppm): 158.1, 150.7, 147.7, 145.7, 134.4, 134.0, 124.8, 123.9, 122.6, 121.3 (q,
+
J = 267 Hz), 61.5, 14.0; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C12
H
11
F
3
N
3
O
2
2
86.0798; found 286.0792.
Ethyl 2-benzyl-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2q): 43% yield (26
o
1
mg), white solid, m.p. = 143−144 C; H NMR (DMSOꢀd
6
, 400 MHz, δ ppm): 13.73
(br, 1H), 7.32−7.22 (m, 4H), 7.21−7.19 (m, 1H), 4.30 (q, J = 7.2 Hz, 2H), 4.06 (s, 2H),
1
3
1
1
6
.28 (t, J = 7.2 Hz, 3H); C NMR (DMSOꢀd , 100 MHz, δ ppm): 157.9, 149.8, 137.3,
33.5, 128.7, 128.6, 126.7, 121.3 (q, J = 267 Hz), 121.1, 61.2, 14.0; HRMS (ESIꢀTOF)
+
m/z: [M + H] Calcd for C14
H
14
F
3
N
2
O
2
299.1002; found 299.0999.
Ethyl 2-ethyl-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2r): 42% yield (20 mg),
o
1
white solid, m.p. = 160−162 C; H NMR (DMSOꢀd
6
, 400 MHz, δ ppm): 13.42 (br,
1H), 4.30 (q, J = 6.8 Hz, 2H), 3.35 (s, 1H), 2.68 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2
13
Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H); C NMR (DMSOꢀd , 100 MHz, δ ppm): 158.0,
6
152.4, 133.1, 121.3 (q, J = 266 Hz), 120.7, 61.1, 21.0, 14.0, 12.4; HRMS (ESIꢀTOF)
+
m/z: [M + H] Calcd for C
9
H
12
F
3
N
2
O
2
237.0845; found 237.0842.
Ethyl 4-(trifluoromethyl)-2-vinyl-1H-imidazole-5-carboxylate (2s): 53% yield (25 mg),
o
1
white solid, m.p. > 300 C; H NMR (DMSOꢀd , 400 MHz, δ ppm): 13.82 (br, 1H),
6
6
4
.63 (dd, J = 17.6 Hz, 7.2Hz, 1H), 6.27 (d, J = 17.6 Hz, 1H), 5.61 (d, J = 11.6 Hz, 1H),
13
.33 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); C NMR (DMSOꢀd
6
, 100 MHz, δ
ppm): 157.9, 147.0, 134.0, 124.5, 121.6, 121.4, 121.3 (q, J = 267 Hz), 61.4, 14.0;
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C
9
H F
10 3
N
2
O
2
235.0689; found 235.0687.
16
ACS Paragon Plus Environment

Page 17 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Ethyl 2-(naphthalen-1-yl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2t): 80%
o
1
yield (53 mg), white solid, m.p. = 194−195 C; H NMR (Acetoneꢀd , 400 MHz, δ
6
ppm): 12.98 (br, 1H), 8.71−8.69 (m, 1H), 8.06−8.04 (m, 1H), 8.00−7.89 (m, 1H),
7.88−7.87 (m, 1H), 7.63−7.55 (m, 3H), 4.41 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
3H); C NMR (Acetoneꢀd , 100 MHz, δ ppm): 158.6, 148.5, 135.6, 135.3, 134.6,
6
1
31.6, 131.4, 129.1, 128.9, 127.8, 127.1, 126.8, 126.5, 125.7, 123.2, 122.2 (q, J = 266
+
Hz), 62.0,14.2; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C17
14 3 2 2
H F N O 335.1002;
found 335.0995.
Ethyl 2-methyl-2-phenyl-5-(trifluoromethyl)-2H-imidazole-4-carboxylate (2u): 52%
1
yield (31 mg), pale yellow liquid, R
DMSOꢀd
H), 1.88 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H); C NMR (DMSOꢀd , 100 MHz, δ ppm):
f
= 0.31 (PE : EtOAc = 20 : 1); H NMR
(
6
, 400 MHz, δ ppm): 7.69−7.66 (m, 2H), 7.39−7.31 (m, 3H), 4.52−4.46 (m,
13
2
6
159.5, 153.8, 153.5, 136.6, 128.7, 128.6, 127.1, 118.6 (q, J = 272 Hz), 108.5, 63.1,
+
26.4, 13.8; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C14
14 3 2 2
H F N O 299.1002;
found 299.0999.
Ethyl 2-cyclopropyl-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2w): White
o
1
solid, 50% yield (25 mg), m.p. = 99−102 C; H NMR (DMSOꢀd
6
, 400 MHz, δ ppm):
1
1
1
3.48 (s, 1H), 4.30 (q, J = 7.2 Hz, 2H), 2.05−2.01 (m, 1H), 1.28 (t , J = 7.2 Hz, 3H),
13
.01−0.95 (m, 2H), 0.94−0.90 (m, 2H); C NMR (DMSOꢀd , 100 MHz, δ ppm):
6
57.8, 152.9, 133.8, 133.1, 120.3 (q, J = 266 Hz), 61.0, 14.0, 8.44, 8.39; HRMS
+
(ESIꢀTOF) m/z: [M + H] Calcd for C10
H
12
F
3
N
2
O
2
249.0845; found 249.0844.
Acknowledgements
The authors thank the National Natural Science Foundation of China (No. 21372108)
for financial support.
Notes
The authors declare no competing financial interest.
Associated content
The Supporting Information:
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 20
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
13
H and C NMR spectra for the reactants and products, Xꢀray crystal data (CIF) for
compounds 2h and 2l. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
. Fore reviews, see: (a) Barman, D. N.; Nicholas, K. M. Eur. J. Org. Chem. 2011,
908. (b) Stokes, B. J.; Driver, T. G. Eur. J. Org. Chem. 2011, 4071. (c) Collet, F.;
Lescot, C.; Dauban, P. Chem. Soc. Rev. 2011, 40, 1926. (d) Ramirez, T. A.; Zhao,
B.; Shi, Y. Chem. Soc. Rev. 2012, 41, 931. (e) Jeffrey J. L.; Sarpong, R. Chem. Sci.
2
013, 4, 4092. (f) Louillat, M.ꢀL.; Patureau, F. W. Chem. Soc. Rev. 2014, 43, 901.
g) Jiao, J.; Murakami, K.; Itami, K. ACS Catal. 2016, 6, 610.
. For reviews, see: (a) Intrieri, D.; Zardi, P.; Caselli, A.; Gallo, E. Chem. Commun.
(
2
3
2
014, 50, 11440. (b) Shin, K.; Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48,
1
040.
2
. For examples of amination of C(sp )−H bonds, see: (a) Stokes, B. J.; Dong, H.;
Leslie, B. E.; Pumphrey, A. L.; Driver, T. G., J. Am. Chem. Soc. 2007, 129, 7500.
(b) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.; Chang, S. J. Am.
Chem. Soc. 2012, 134, 9110. (c) Ryu, J.; Shin, K.; Park, S. H.; Kim, J. Y.; Chang,
S. Angew. Chem., Int. Ed. 2012, 51, 9904. (d) Alt, I. T.; Plietker, B. Angew. Chem.
Int. Ed. 2016, 55, 1519. (e) Hermann, G. N.; Becker, Bolm, P. C. Angew. Chem.
Int. Ed. 2016, 55, 3781. (f) Wang, X.; Jiao, N. Org. Lett. 2016, 18, 2150. (g) Li, Y.;
Feng, Y.; Xu, L.; Wang, L.; Cui, X. Org. Lett. 2016, 18, 4924. (h) Kim, H.; Park,
G.; Park, J.; Chang, S. ACS Catal. 2016, 6, 5922.
3
4
. For examples of amination of C(sp )−H bonds, (a) Ruppel, J. V.; Kamble, R. M.;
Zhang, X. P. Org. Lett. 2007, 9, 4889. (b) Liu, Y.; Wei. J.; Che, C.ꢀM. Chem.
Commun. 2010, 46, 6926. (c) Nguyen, Q.; Sun, K.; Driver, T. G. J. Am. Chem.
Soc. 2012, 134, 7262−7265. (d) Hennessy, E. T.; Betley, T. A. Science 2013, 340,
5
91. (e) Villanueva, O.; Weldy, N. M.; Blakey, S. B.; MacBeth, C. E. Chem. Sci.
2
015, 6, 6672. (f) Tona, V.; de la Torre, A.; Padmanaban, M.; Ruider, S.;
González, L.; Maulide, N. J. Am. Chem. Soc. 2016, 138, 8348.
18
ACS Paragon Plus Environment

Page 19 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
5
. For reviews, see: (a) Song, W.; Kozhushkov, S. I.; Ackermann, L. Angew. Chem.
Int. Ed. 2013, 52, 6576. (b) Vita, M. V.; Waser, J. Angew. Chem. Int. Ed. 2015, 54,
5290. (c) Huang, X.; Groves, J. T. ACS Catal. 2016, 6, 751.
6. For reviews, see: (a) Panchaud, P.; Chabaud, L.; Landais, Y.; Ollivier, C.; Renaud,
P.; Zigmantas, S. Chem. Eur. J. 2004, 10, 3606. (b) Waser, J.; Carreira, E. M.
Jimeno, C.; Renaud, P. Azides by Olefin Hydroazidation Reactions, in: Organic
Azides: Syntheses and Applications, Bräse, S; Banert, S. K. Ed.; John Wiley &
Sons: Chichester, 2010, pp95−111. (c) Jimeno, C.; Renaud, P. Radical Chemistry
with Azides, in: Organic Azides: Syntheses and Applications, Bräse, S; Banert, S.
K. Ed.; John Wiley & Sons: Chichester, 2010, 239. (d) Wu, K.; Liang, Y.; Jiao, N.
Molecules 2016, 21, 352.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
. Ma, H.; Li, D.; Yu, W. Org. Lett. 2016, 18, 868.
8. Similar studies have been reported independently by others, see: (a) Chen, T.;
Chen, X.; Wei, J.; Lin, D.; Xie, Y.; Zeng, W. Org. Lett. 2016, 18, 2078. (b) Sagar,
A.; Vidaycharan, S.; A. Shinde, H.; Sharada, D. S. Org. Biomol. Chem. 2016, 14,
4018.
9
1
1
. Kumar, D.; Kommi, D. N.; Bollineni. N.; Patel, A. R.; Chakraborti, A. K. Green
Chem. 2012, 14, 2038.
0. (a) Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095. (b) Robertson, J.;
Pillai, J.; Lush, R. K. Chem. Soc. Rev. 2001, 30, 94.
1. For reviews, see: (a) Wolff, M. E. Chem. Rev. 1963, 63, 54. (b) Stella, L.
NitrogenꢀCentered Radicals, in Radicals in Organic Synthesis Vol. 2, Ed.: Renaud,
P.; Sibi, M. P. John Wiley & Sons, Ltd. 2001, pp407–426.
1
2. For recent examples, see: (a) Chen, K., Richter, J. M.; Baran, P. S. J. Am. Chem.
Soc. 2008, 130, 7247. (b) Choi, G. J.; Zhu, Q.; Miller, D. C.; Gu, C. J.; Knowles,
R. R. Nature 2016, 539, 268. (c) Chu, J. C. K.; Rovis, T. Nature 2016, 539, 272.
3. (a) Leardini, R.; McNab, H.; Minozzi, Matteo, Nanni, D.; Reed, D.; Wright, A. G.
J. Chem. Soc. Perkin trans 1 2001, 2704. (b) Zhang, L.; Ang, G. Y.; Chiba, S.
Org.Lett. 2011, 13, 1622. (c) Shu, W.; Nevado, C. Angew. Chem. Int. Ed. 2017, 56,
1
1881. (d) Shu, W.; Lorente, A.; Go´mezꢀBengoa, E.; Nevado, C. Nat Commun.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 20
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
017, 8, 13832.
1
4. (a) Hiyama, T. Organofluorine Compounds: Chemistry and Applications,
Springer, Berlin, 2000. (b) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317,
1881. (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev.
2008, 37, 320; (d) Cametti, M.; Crousse, B.; Metrangolo, P.; Milani, R.; Resnati,
G. Chem. Soc. Rev. 2012, 41, 31. (e) Wang, J.; SánchezꢀRoselló, M.; Aceña, J. L.;
del Pozo, Sorochinsky, C. A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem.
Rev. 2014, 114, 2432.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
5. (a) Petrov, V. A. Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and
Applications, John Wiley & Sons, Inc., Hoboken, NJ, 2009. (b) Tomashenko, O.
A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475.
6. (a) Honey, M. A.; Pasceri, R.; Lewis, W.; Moody, C. J. J. Org. Chem. 2012, 77,
1396. (b) Bunev, A. S.; Vasiliev, M. A.; Statsyuk, V. E.; Ostapenko, G. I.;
Peregudov, A. S. J. Fluor. Chem. 2014, 163, 34.
1
7. CCDC No. for 2h: 1548483; CCDC No. for 2l: 1548482.
1
8. Kenis, S.; D’hooghe, M.; Verniest, G.; Thi, T. A. D.; The, C. P.; Nguyen, T. V.;
Kimpe, N. D. J. Org. Chem. 2012, 77, 5982.
1
9. Sano, T.; Horiguchi, Y.; Toda, J.; Imafuku, K.; Tsuda, Y. Chem. Pharm. Bull. 1984,
32, 497.
20. Wu, X.; Li, Y.; Wang, C.; Zhou, L.; Lu, X.; Sun, J. Chem. Eur. J. 2011, 2846.
2
1. Ohkura, H.; Berbasov, D. O.; Soloshonok, V. A. Tetrahedron 2003, 59, 1647.
2. Sato, J.; Kawamura, Y.; Fukuda, K.; Ito, K.; Kita, H. Jpn. Kokai Tokkyo Koho
2
1993, JP 05140060 A.
2
3. Prie, G.; Richard, S.; Parrain, J.ꢀL.; Duchene, A.; Abarbri, M. J. Fluor. Chem.
2002, 117, 35.
24. Rolfs, A.; Liebscher, J. J. Org. Chem. 1997, 62, 3480.
20
ACS Paragon Plus Environment