Base-mediated [3+2] annulation of trifluoroacetimidoyl chlorides and isocyanides: An improved approach for regioselective synthesis of 5-trifluoromethyl-imidazoles

Article abstract of DOI:10.1016/j.tet.2020.131168

A t-BuOK-mediated [3 + 2] cycloaddition reaction of trifluoroacetimidoyl chlorides and active methylene isocyanides for the synthesis of 5-trifluoromethyl-imidazoles has been developed. Under mild reaction conditions, the transformation proceeds smoothly

Full text of DOI:10.1016/j.tet.2020.131168

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Base-mediated [3þ2] annulation of trifluoroacetimidoyl chlorides and
isocyanides: An improved approach for regioselective synthesis of
5-trifluoromethyl-imidazoles
, b, *
Sipei Hu a, Hefei Yang a, Zhengkai Chen a, Xiao-Feng Wu a
a Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, 310018, People’s Republic of China
b
€
Leibniz-Institut für Katalyse e. V. an der Universitat Rostock, Albert-Einstein-Stra
b
e 29a, 18059, Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A t-BuOK-mediated [3 þ 2] cycloaddition reaction of trifluoroacetimidoyl chlorides and active methylene
isocyanides for the synthesis of 5-trifluoromethyl-imidazoles has been developed. Under mild reaction
conditions, the transformation proceeds smoothly in the presence of t-BuOK to afford an array of
structurally diverse 5-trifluoromethyl-imidazoles with high efficiency.
Received 3 March 2020
Received in revised form
27 March 2020
Accepted 30 March 2020
Available online xxx
© 2020 Elsevier Ltd. All rights reserved.
Keywords:
Base-mediated
[3þ2] annulation
Imidazoles
Trifluoroacetimidoyl chlorides
Isocyanides
1. Introduction
isocyanides to construct trisubstituted imidazoles [7]. As an option,
the [3 þ 2] cycloaddition of isocyanides with trifluoromethyl syn-
Imidazoles, especially multi-functionalized imidazoles, as a kind
of highly privileged structural motifs, are much prevalent in bio-
logical and pharmaceutical fields, ligand chemistry as well as
functional materials [1]. Imidazole motifs exist in several com-
mercial drugs, such as losartan, eprosartan, etomidate, flumazenil,
econazole and clotrimazole [2]. Therefore, a great amount of efforts
have been devoted to investigate the synthetic methods for imid-
azoles over the past decades [3]. In this context, the mainstream
and frequently-used pathways to imidazoles lie in the [3 þ 2]
cycloaddition of active methylene isocyanides and “C]N” subunits,
including imines (Scheme 1a), carbodiimides/isothiocynates/kete-
nimines (Scheme 1b), benzothiazoles (Scheme 1c), and isocyanides
(Scheme 1d) [4,5]. Isocyanides are identified as a kind of important
and powerful building blocks for the synthesis of diverse hetero-
cyclic compounds [6]. Besides that, there are several seminal multi-
component reactions and visible-light-induced reactions involving
thons represents an interesting pathway for the construction of
trifluoromethyl-substituted imidazoles. Although Bunev and co-
workers realized NaH-promoted synthesis of 5-trifluoromethyl-
imidazoles from trifluoroacetimidoyl chlorides and isocyanides,
limited imidazole products (only 9 examples) were obtained with
moderate yields [8]. The development of more general and efficient
routes for the rapid construction of trifluoromethyl substituted
imidazoles is still desirable.
The significance of trifluoromethyl-substituted nitrogen-con-
taining heterocycles has aroused considerable attention due to
their extensive applications in the fields of organic synthesis,
pharmaceuticals, agrochemicals, and materials science [9]. The
existence of the trifluoromethyl group could greatly improve the
properties of the parent molecule. The efficient and atom-
economical methods for the synthesis of trifluoromethyl-
substituted N-heterocycles mostly focus on the reaction of
diverse trifluoromethyl-containing synthons with suitable
coupling substrates. It is worth mentioning that tri-
fluoroacetimidoyl chloride has been applied as a versatile synthon
to construct trifluoromethyl-substituted N-heterocycles, and
numerous related works have been reported [10]. Very recently, our
group developed a metal-free approach for the assembly of 5-
* Corresponding author. Department of Chemistry, Zhejiang Sci-Tech University,
Hangzhou, 310018, People’s Republic of China.
E-mail addresses: zkchen@zstu.edu.cn (Z. Chen), xiao-feng.wu@catalysis.de
(X.-F. Wu).
https://doi.org/10.1016/j.tet.2020.131168
0040-4020/© 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: S. Hu et al., Base-mediated [3þ2] annulation of trifluoroacetimidoyl chlorides and isocyanides: An improved approach
for regioselective synthesis of 5-trifluoromethyl-imidazoles, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131168

2
S. Hu et al. / Tetrahedron xxx (xxxx) xxx
Table 1
Optimization of reaction conditionsa.
Entry
Base (equiv)
Solvent (mL)
Temp (ꢀC)
Yield (%)b
1
2
3
4
5
6
7
8
Cs2CO3
K2CO3
Ag2CO3
DBU
t-BuONa
t-BuOK
NaOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
CH3CN
1,4-dioxane
DMSO
THF
DMF
DMF
DMF
80
80
80
80
80
80
80
80
80
80
80
80
80
RT
60
100
83
37
70
67
79
90
72
ND
trace
80
trace
88
85
83
98
89
/
9
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
10
11
12
13
14
15
16
Scheme 1. Isocyanides-“C]N” [3 þ 2] Cycloaddition for the Synthesis of Imidazole
Derivatives.
trifluoromethyl-1,2,4-triazoles from I2-mediated annulation of tri-
fluoroacetimidoyl chlorides and hydrazones [10b]. Inspired by the
relevant impressive achievement and our continuous efforts on the
synthesis of diverse nitrogen-containing heterocycles [11], we
herein disclosed a t-BuOK-mediated [3 þ 2] cycloaddition reaction
of active methylene isocyanides and trifluoroacetimidoyl chlorides
for the direct formation of 5-trifluoromethyl-imidazoles with broad
substrate scope and high efficiency (Scheme 1e).
Bold indicated It the optimized conditions.
a
Reaction conditions: 1b (0.45 mmol), 2a (0.3 mmol), and base (1.2 equiv) in
solvent (2.0 mL) under air at specified temperature for 1 h.
b
Isolated yields. ND ¼ No detection of the product.
that the halogen atoms, strong electron-withdrawing groups as
well as di-substituted substrates were all smoothly tolerated under
the standard conditions (Table 2, 3j-3r), implying the good
compatibility of the reaction. Furthermore, the naphthalene ring
could be attached into the trifluoromethyl-substituted imidazole
product 3s in 79% yield. Gratifyingly, trifluoroacetimidoyl chloride
derived from aliphatic amine was also employed as a reactive
substrate to furnish the target product 3t in acceptable yield.
However, in the case of low molecular weight amines, we failed to
get the desired imidoyl chlorides which might due to the low
boiling point after substituted with fluoro group. As for other
different fluorinated imidoyl chlorides, the transformation pro-
ceeded well to lead to the corresponding fluoroalkyl-imidazoles
3u-3y with high efficiency. In addition, the scope of active methy-
lene isocyanides under the current reaction conditions was next
examined. Undoubtedly, alkyl isocyanoacetates were viable reac-
tive substrates to react with trifluoroacetimidoyl chloride 1b to
enable the formation of ester-substituted imidazoles 3z-3aa in
reasonable yields. Benzylisocyanide could also participate in the
reaction to give the corresponding imidazole products 3 ab in 73%
yield upon the replacement of t-BuOK with NaH. The exact struc-
ture of the obtained 5-trifluoromethyl-imidazole 3l was unam-
biguously confirmed by single X-ray diffraction analysis (Fig.1) [12].
In order to gain better understanding of the mechanism, a series
of control experiments were conducted (Scheme 2). The radical
trapping experiments were carried out by the addition of different
radical scavengers. The yield of the reaction was not sharply
decreased with the addition of 2.0 equiv. of TEMPO (2,2,6,6-
tetramethylpiperidine 1-oxyl) or BHT (2,4-di-tert-butyl-4-
methylphenol) into the reaction (Scheme 2a), which indicated
that a single electron transfer (SET) pathway was not involved in
the transformation. Furthermore, the reaction in the presence of 2.0
equiv. of D2O resulted in the deuterated imidazole [D]-3b in 84%
yield with moderate deuterium incorporation (60%) (Scheme 2b).
This result implied that the hydrogen atom of imidazole partly
came from trace amount of water in DMF. However, we can not
2. Results and discussion
We chose 2,2,2-trifluoro-N-(p-tolyl)acetimidoyl chloride 1b and
tosylmethylisocyanide (TosMIC) 2a as the model substrates to
initiate the investigations. The reaction proceeded smoothly with
1b and 2a in the presence of Cs2CO3 in DMF at 80 ꢀC for 1 h. To our
delight, the 5-trifluoromethyl-imidazole product 3b was obtained
in 83% yield (Table 1, entry 1). A series of bases were next screened,
and the results indicated that t-BuOK showed the best reactivity to
give rise to the desired product 3b in 90% yield (Table 1, entries
2e7). Noteworthy was that the reaction did not occur in the
absence of base (Table 1, entry 8). The study towards different
solvents revealed the reaction proceeded well in CH3CN, DMSO or
THF and only trace of product was detected with respect to toluene
or 1,4-dioxane (Table 1, entries 9e13). When the reaction was
carried out at room temperature, 83% yield of 3b was afforded,
whereas the optimal reaction temperature was 60 ꢀC, which could
enable the desired product in the highest yield (Table 1, entries
14e15). Further increasing the reaction temperature to 100 ꢀC
resulted in the reduced efficiency (Table 1, entry 16).
With the optimized reaction conditions in hand, the scope and
generality of this [3 þ 2] annulation reaction was surveyed by the
employment of a range of fluorinated imidoyl chlorides to react
with TosMIC (Table 2). To our delight, broad substrate scope of the
protocol was shown, as demonstrated by the obtained good to
excellent yields with regard to N-aryl-trifluoroacetimidoyl chlo-
rides bearing electron-donating or -withdrawing groups (Table 2,
3a-3r). The steric hindrance of trifluoroacetimidoyl chlorides had a
slightly impact on the reaction (Table 2, 3b-3d). It was found that
the electronic factors did not exert an obvious influence on the
transformation and comparable reactivity was observed upon the
trifluoroacetimidoyl chlorides (Table 2, 3a-3r). Noteworthy was
Please cite this article as: S. Hu et al., Base-mediated [3þ2] annulation of trifluoroacetimidoyl chlorides and isocyanides: An improved approach
for regioselective synthesis of 5-trifluoromethyl-imidazoles, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131168

S. Hu et al. / Tetrahedron xxx (xxxx) xxx
3
Table 2
Scope of fluorinated imidoyl chlorides and isocyanidesa,b
.
Scheme 2. Control experiments.
Scheme 3. Scale-up reaction.
Scheme 4. Plausible reaction mechanism.
imidazole product 3b could be isolated in 87% yield, highlighting
the great synthetic potential of the reaction.
On the basis of the preliminary experimental results and related
literatures [4d,13], a plausible mechanistic pathway is proposed as
outlined in Scheme 4. At first, the active carbanionic intermediate A
was formed upon base-mediated deprotonation of TosMIC 2a. The
nucleophilic addition of intermediate A into 1a could give inter-
mediate B, followed by the elimination of chloride ion to lead to C.
Subsequently, a 5-endo-dig cyclization of intermediate C and the
following 1,3-H shift or protonation occurred to afford the final
imidazole product 3a. Of note, the hydrogen atom of imidazole
product possibly originated from active methylene of isocyanides
or trace amount of water in DMF. In addition, a concerted [3 þ 2]-
cycloaddition [14] of base-promoted isocyanides with tri-
fluoroacetimidoyl chlorides cannot be entirely excluded because
the attempt to isolate or detect the coupling product C during the
reaction process failed.
Fig. 1. The X-ray structure of product 3l.
exclude that the hydrogen was exchanged after the reaction in the
presence of base as the proton is quite reactive.
3. Conclusions
To further illustrate the practical utility of the methodology, the
gram-scale reaction of 1b and 2a was conducted under the stan-
dard reaction conditions in 5.0 mmol scale (Scheme 3). Notably, the
In conclusion, we have disclosed a facile and practical catalyst-
free approach for the preparation of 5-trifluoromethyl-imidazoles
through base-mediated [3 þ 2] annulation of active methylene
Please cite this article as: S. Hu et al., Base-mediated [3þ2] annulation of trifluoroacetimidoyl chlorides and isocyanides: An improved approach
for regioselective synthesis of 5-trifluoromethyl-imidazoles, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131168

4
S. Hu et al. / Tetrahedron xxx (xxxx) xxx
isocyanides with trifluoroacetimidoyl chlorides. Notable features of
the current methodology include mild reaction conditions, readily
accessible reagents, broad substrate scope, high efficiency and
scalability. The present protocol offers an efficient alternative for
the synthesis of trifluoromethyl-substituted imidazoles. Further
investigations of the application of trifluoromethyl synthons to
construct more trifluoromethyl-containing heterocyclic com-
pounds are in progress.
water and extracted with ethyl acetate (3 ꢁ 15 mL). The extract was
dried over anhydrous Na2SO4 and the solvent was removed in
vacuo to provide a crude product, which was purified by column
chromatography on silica gel with petroleum ether/EtOAc as eluent
to afford the imidazole product [D]-3b as white solid in 84% yield
with 60% deuterium incorporation.
4.4. General procedure for the scale-up reaction
4. Experimental details
t-BuOK (672 mg, 6 mmol) was added to a solution of 2,2,2-
trifluoro-N-(p-tolyl)acetimidoyl chloride 1b (7.5 mmol) and tosyl-
methylisocyanide 2a (5 mmol) in DMF (20 mL). The mixture was
stirred at 60 ꢀC under air for 1 h. After the completion of the re-
action (monitored by TLC), the reaction mixture was cooled to
ambient temperature, quenched by water and extracted with ethyl
acetate (3 ꢁ 50 mL). The extract was dried over anhydrous Na2SO4
and the solvent was removed in vacuo to provide a crude product,
which was purified by column chromatography on silica gel with
petroleum ether/EtOAc as eluent to afford the imidazole product 3b
as white solid in 87% yield (1.653 g).
Unless otherwise stated, all reactions were performed under air
in a flame-dried reaction flask. Toluene, THF, 1,4-Dioxane, CH3CN
and DMF were dried by calcium hydride and freshly distilled. DMSO
was used without further purification. The isocyanides, other ma-
terials and solvents were purchased from Adamas-beta and other
commercial suppliers and used without additional purification. For
chromatography, 200e300 mesh silica gel (Qingdao, China) was
employed. 1NMR spectra were recorded on a Bruker Avance oper-
ating at for 1H NMR at 400 MHz, 13C NMR at 100 MHz and 19F NMR
at 377 MHz using TMS as internal standard. Mass spectroscopy data
of the products were collected on an HRMS-TOF instrument or
Waters TOFMS GCT Premier using EI or ESI ionization. Melting
points were measured with WRR digital point apparatus and not
corrected. The trifluoroacetimidoyl chlorides were synthesized
according to the previous literatures [15].
4.4.1. Characterization data of the corresponding products
4.4.1.1. 1-Phenyl-4-tosyl-5-(trifluoromethyl)-1H-imidazole
(3a).
Yield: 89%; 98.2 mg, white solid; m.p ¼ 146e148 ꢀC; 1H NMR
(CDCl3, 400 MHz)
(m, 3H), 7.36 (d, 2H, J ¼ 8.0 Hz), 7.31 (d, 2H, J ¼ 7.2 Hz), 2.44 (s, 3H).
d
7.98 (d, 2H, J ¼ 8.4 Hz), 7.60 (s, 1H), 7.57e7.48
13C NMR (CDCl3, 100 MHz)
d
145.0, 143.9, 139.7, 137.0, 134.5, 130.6,
4.1. General procedure for the synthesis of 5-trifluoromethyl-
imidazoles (3)
129.8, 129.7, 128.7, 126.2, 122.6 (q,
J
¼
41.2 Hz), 119.0 (q,
J ¼ 268.9 Hz), 21.7. 19F NMR (CDCl3, 377 MHz)
d
ꢂ53.1. HRMS (EI-
TOF) calcd for C17H14F3N2O2Sþ (M þ H) þ: 367.0723, found:
t-BuOK (40.3 mg, 0.36 mmol) were added to a solution of
fluorinated imidoyl chlorides 1 (0.45 mmol) and isocyanides 2
(0.3 mmol) in DMF (2.0 mL). The mixture was stirred at 60 ꢀC under
air for 1 h. After the completion of the reaction (monitored by TLC),
the reaction mixture was cooled to ambient temperature, quenched
by water and extracted with ethyl acetate (3 ꢁ 15 mL). The extract
was dried over anhydrous Na2SO4 and the solvent was removed in
vacuo to provide a crude product, which was purified by column
chromatography on silica gel with petroleum ether/EtOAc as eluent
to afford the imidazole products 3.
367.0737.
4.4.1.2. 1-(p-tolyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazole
(3b).
Yield: 98%; 111.8 mg, white solid; m.p ¼ 197e199 ꢀC; 1H NMR
(CDCl3, 400 MHz)
d
7.97 (d, 2H, J ¼ 8.0 Hz), 7.57 (s, 1H), 7.36 (d, 2H,
J ¼ 8.0 Hz), 7.29 (d, 2H, J ¼ 8.0 Hz), 7.18 (d, 2H, J ¼ 8.0 Hz), 2.43 (s,
3H), 2.42 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d
145.0, 143.9, 141.0,
139.8, 137.1, 131.9, 130.3, 129.8, 128.7, 126.0, 122.6 (q, J ¼ 41.0 Hz),
119.0 (q, J ¼ 268.8 Hz), 21.7, 21.2. 19F NMR (CDCl3, 377 MHz)
ꢂ53.2.
d
HRMS (EI-TOF) calcd for C18H15F3N2O2SNaþ (M þ Na) þ: 403.0699,
found: 403.0714.
4.2. General procedure for the radical trapping experiments
4.4.1.3. 1-(m-tolyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazole
(3c).
t-BuOK (40.3 mg, 0.36 mmol) was added to a solution of 2,2,2-
trifluoro-N-(p-tolyl)acetimidoyl chloride 1b (0.45 mmol) and
tosylmethylisocyanide 2a (0.3 mmol) in DMF (2.0 mL). Then, the
radical scavenger TEMPO (93.6 mg, 0.6 mmol) or BHT (132 mg,
0.6 mmol) was added into the reaction, respectively. The mixture
was stirred at 60 ꢀC under air for 1 h. After the completion of the
reaction (monitored by TLC), the reaction mixture was cooled to
ambient temperature, quenched by water and extracted with ethyl
acetate (3 ꢁ 15 mL). The extract was dried over anhydrous Na2SO4
and the solvent was removed in vacuo to provide a crude product,
which was purified by column chromatography on silica gel with
petroleum ether/EtOAc as eluent to afford the imidazole product 3b
as white solid in 84% or 86% yield, respectively.
Yield: 92%; 105.5 mg, white solid; m.p ¼ 189e191 ꢀC; 1H NMR
(CDCl3, 400 MHz)
d
7.97 (d, 2H, J ¼ 8.0 Hz), 7.59 (s, 1H), 7.39e7.33
(m, 4H), 7.11e7.09 (m, 2H), 2.43 (s, 3H), 2.40 (s, 3H). 13C NMR (CDCl3,
100 MHz) 145.0, 143.9, 140.1, 139.7, 137.1, 134.4, 131.3, 129.8, 129.4,
d
128.9, 128.7, 126.7, 123.2, 122.5 (q, J
¼
40.8 Hz), 119.0 (q,
J ¼ 265.6 Hz), 21.7, 21.2. 19F NMR (CDCl3, 377 MHz)
d
ꢂ53.1. HRMS
(EI-TOF) calcd for C18H16F3N2O2Sþ (M þ H) þ: 381.0879, found:
381.0898.
4.4.1.4. 1-(o-tolyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazole
(3d).
Yield: 75%; 86.0 mg, white solid; m.p ¼ 179e181 ꢀC; 1H NMR
(CDCl3, 400 MHz)
d
7.99 (d, 2H, J ¼ 8.0 Hz), 7.51 (s, 1H), 7.44 (t, 1H,
J ¼ 7.6 Hz), 7.39e7.34 (m, 3H), 7.31 (t, 1H, J ¼ 7.6 Hz), 7.20 (d, 1H,
J ¼ 7.6 Hz), 2.45 (s, 3H), 2.04 (s, 3H). 13C NMR (CDCl3, 100 MHz)
4.3. General procedure for the deuterium labelling experiments
d 145.0, 143.8, 139.7, 137.1, 135.2, 131.3, 130.9, 129.8, 128.7, 127.4,
127.0, 122.7 (q, J ¼ 41.0 Hz), 119.0 (q, J ¼ 268.9 Hz), 21.7, 17.0. 19F
t-BuOK (40.3 mg, 0.36 mmol) and D2O (12 mg, 0.6 mmol) were
added to a solution of 2,2,2-trifluoro-N-(p-tolyl)acetimidoyl chlo-
ride 1b (0.45 mmol) and tosylmethylisocyanide 2a (0.3 mmol) in
DMF (2.0 mL). The mixture was stirred at 60 ꢀC under air for 1 h.
After the completion of the reaction (monitored by TLC), the re-
action mixture was cooled to ambient temperature, quenched by
NMR (CDCl3, 377 MHz)
d
ꢂ54.5. HRMS (EI-TOF) calcd for
C
18H16F3N2O2Sþ (M þ H) þ: 381.0879, found: 381.0898.
4.4.1.5. 1-(4-ethylphenyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazole
(3e). Yield: 94%; 111.2 mg, white solid; m.p ¼ 195e197 ꢀC; 1H NMR
(CDCl3, 400 MHz)
d
7.97 (d, 2H, J ¼ 8.4 Hz), 7.58 (s, 1H), 7.36 (d, 2H,
Please cite this article as: S. Hu et al., Base-mediated [3þ2] annulation of trifluoroacetimidoyl chlorides and isocyanides: An improved approach
for regioselective synthesis of 5-trifluoromethyl-imidazoles, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131168

S. Hu et al. / Tetrahedron xxx (xxxx) xxx
5
J ¼ 8.4 Hz), 7.31 (d, 2H, J ¼ 8.4 Hz), 7.20 (d, 2H, J ¼ 8.4 Hz), 2.27e2.69
(m, 2H), 2.43 (s, 3H), 1.26 (t, 3H, J ¼ 7.6 Hz). 13C NMR (CDCl3,
4.4.1.12. 1-(4-bromophenyl)-4-tosyl-5-(trifluoromethyl)-1H-imid-
azole (3l). Yield: 82%; 109.9 mg, white solid; m.p ¼ 194e195 ꢀC; 1H
100 MHz)
d
147.1, 145.0, 143.9, 137.1, 132.0, 129.6, 129.1, 128.7, 126.1,
NMR (CDCl3, 400 MHz)
d
7.97 (d, 2H, J ¼ 8.0 Hz), 7.65 (d, 2H,
122.6 (q, J ¼ 41.2 Hz),119.0 (q, J ¼ 268.9 Hz), 28.5, 21.7, 15.2. 19F NMR
J ¼ 8.4 Hz), 7.59 (s, 1H), 7.57 (d, 2H, J ¼ 8.0 Hz), 7.20 (d, 2H,
(CDCl3, 377 MHz)
C
d
ꢂ53.2. HRMS (EI-TOF) calcd for
J ¼ 8.0 Hz), 2.44 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d 145.2, 144.4,
19H18F3N2O2Sþ(M þ H) þ: 395.1036, found: 395.1050.
139.5, 136.9, 133.4, 133.1, 129.7, 128.8, 127.8, 124.9, 122.5 (q,
J ¼ 41.3 Hz), 119.0 (q, J ¼ 268.7 Hz), 21.8. 19F NMR (CDCl3, 377 MHz)
þ
4.4.1.6. 1-(4-isopropylphenyl)-4-tosyl-5-(trifluoromethyl)-1H-imid-
azole (3f). Yield: 87%; 107.1 mg, white solid; m.p ¼ 200e201 ꢀC; 1H
d
ꢂ53.0. HRMS (EI-TOF) calcd for C17H13BrF3N2O2Sþ(M þ H)
:
444.9828, found: 444.9836.
NMR (CDCl3, 400 MHz)
d
8.01 (d, 2H, J ¼ 8.0 Hz), 7.62 (s, 1H), 7.39 (t,
4H, J ¼ 8.4 Hz), 7.25 (d, 2H, J ¼ 8.4 Hz), 3.03e2.98 (m, 1H), 2.47 (s,
4.4.1.13. 1-(4-iodophenyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazole
(3m). Yield: 85%; 125.7 mg, white solid; m.p ¼ 200e201 ꢀC; 1H
3H),1.30 (d, 6H, J ¼ 6.8 Hz). 13C NMR (CDCl3,100 MHz)
d 151.7,145.0,
143.9, 139.8, 137.1, 132.0, 129.8, 128.7, 127.7, 126.1, 122.6 (q,
NMR (CDCl3, 400 MHz)
d
7.97 (d, 2H, J ¼ 8.4 Hz), 7.85 (d, 2H,
J ¼ 40.9 Hz), 119.0 (q, J ¼ 269.1 Hz), 33.9, 23.8, 21.7. 19F NMR (CDCl3,
J ¼ 8.8 Hz), 7.58 (s, 1H), 7.37 (d, 2H, J ¼ 8.0 Hz), 7.06 (d, 2H,
377
C
MHz)
d
ꢂ53.2.
HRMS
(EI-TOF)
calcd
for
J ¼ 8.4 Hz), 2.44 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d 145.1, 144.5,
20H20F3N2O2Sþ(M þ H) þ: 409.1192, found: 409.1209.
139.4, 139.0, 136.9, 134.1, 129.8, 128.7, 127.9, 122.4 (q, J ¼ 41.6 Hz),
119.0 (q, J ¼ 269.0 Hz), 96.5, 21.7. 19F NMR (CDCl3, 377 MHz)
ꢂ53.0.
d
4.4.1.7. 1-(4-(tert-butyl)phenyl)-4-tosyl-5-(trifluoromethyl)-1H-
imidazole (3g). Yield: 76%; 97.1 mg, white solid; m.p ¼ 196e197 ꢀC;
HRMS (EI-TOF) calcd for C17H13F3IN2O2Sþ(M þ H) þ: 492.9689,
found: 492.9699.
1H NMR (CDCl3, 400 MHz)
d
8.02 (d, 2H, J ¼ 8.4 Hz), 7.63 (s, 1H), 7.54
(d, 2H, J ¼ 8.8 Hz), 7.40 (d, 2H, J ¼ 8.0 Hz), 7.27 (d, 2H, J ¼ 8.8 Hz),
4.4.1.14. 4-Tosyl-5-(trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-
1H-imidazole (3n). Yield: 72%; 93.6 mg, white solid;
2.48 (s, 3H), 1.38 (s, 9H). 13C NMR (CDCl3, 100 MHz)
d
154.0, 145.0,
143.9, 139.8, 137.1, 131.8, 129.8, 128.7, 126.6, 125.7, 122.6 (q,
m.p ¼ 185e186 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.97 (d, 2H,
J ¼ 41.1 Hz), 119.0 (q, J ¼ 268.9 Hz), 35.0, 31.2, 21.7. 19F NMR (CDCl3,
J ¼ 8.4 Hz), 7.80 (d, 2H, J ¼ 8.8 Hz), 7.64 (s, 1H), 7.49 (d, 2H,
377 MHz)
d
ꢂ53.1. HRMS (EI-TOF) calcd for C21H22F3N2O2Sþ(M þ H)
J ¼ 8.4 Hz), 7.37 (d, 2H, J ¼ 8.4 Hz), 2.45 (s, 3H). 13C NMR (CDCl3,
þ: 423.1349, found: 423.1358.
100 MHz)
d
145.3, 144.7, 139.4, 137.4, 136.7, 132.8 (q, J ¼ 33.1 Hz),
129.9,128.7,127.1,126.9,123.2(q, J ¼ 271.0 Hz),122.4 (q, J ¼ 41.4 Hz),
4.4.1.8. 1-(4-methoxyphenyl)-4-tosyl-5-(trifluoromethyl)-1H-imid-
azole (3h). Yield: 97%; 115.8 mg, white solid; m.p ¼ 193e194 ꢀC; 1H
119.0 (q,
J
¼
269.1 Hz), 21.7. 19F NMR (CDCl3, 377 MHz)
d
ꢂ53.2, ꢂ55.4. HRMS (EI-TOF) calcd for C18H13F6N2O2Sþ(M þ H) þ
:
NMR (CDCl3, 400 MHz)
d
8.04 (d, 2H, J ¼ 8.0 Hz), 7.64 (s, 1H), 7.43 (d,
435.0596, found: 435.0613.
2H, J ¼ 8.0 Hz), 7.29 (d, 2H, J ¼ 8.0 Hz), 7.05 (d, 2H, J ¼ 8.0 Hz), 3.92
(s, 3H), 2.50 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d
161.0,145.0, 143.9,
4.4.1.15. 1-(2-chlorophenyl)-4-tosyl-5-(trifluoromethyl)-1H-imid-
azole (3o). Yield: 80%; 96.6 mg, white solid; m.p ¼ 187e188 ꢀC; 1H
140.0, 137.1, 129.8, 128.7, 127.5, 127.0, 122.7 (q, J ¼ 41.1 Hz), 119.0 (q,
J ¼ 269.0 Hz), 114.8, 55.7, 21.8. 19F NMR (CDCl3, 377 MHz)
d
ꢂ53.3.
NMR (CDCl3, 400 MHz)
d
7.98 (d, 2H, J ¼ 8.4 Hz), 7.58e7.50 (m, 3H),
HRMS (EI-TOF) calcd for C18H16F3N2O3Sþ (M þ H) þ:397.0828,
7.42 (t, 1H, J ¼ 7.6 Hz), 7.38e7.36 (m, 3H), 2.44 (s, 3H). 13C NMR
found: 397.0837.
(CDCl3, 100 MHz) d 145.1, 143.6, 139.8, 137.0, 132.3, 132.1, 132.0,
130.6, 129.9, 128.9, 128.7, 127.9, 122.8 (q, J ¼ 41.7 Hz), 119.0 (q,
4.4.1.9. 4-Tosyl-1-(4-(trifluoromethoxy)phenyl)-5-(trifluoromethyl)-
J ¼ 269.2 Hz), 21.7. 19F NMR (CDCl3, 377 MHz)
d
ꢂ53.2. HRMS (EI-
1H-imidazole
(3i). Yield:81%;
109.1
mg,
white
solid;
TOF) calcd for C17H13ClF3N2O2Sþ(M þ H) þ: 401.0333, found:
m.p ¼ 185e187 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
8.03 (d, 2H,
401.0346.
J ¼ 8.4 Hz), 7.65 (s, 1H), 7.44e7.42 (m, 6H), 2.50 (s, 3H). 13C NMR
(CDCl3, 100 MHz)
d
150.5, 145.2, 144.5, 139.6, 136.8, 132.6, 130.0,
4.4.1.16. 1-(2-iodophenyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazole
(3p). Yield: 77%; 113.7 mg, white solid; m.p ¼ 195e196 ꢀC; 1H NMR
128.9, 128.1, 121.9, 120.2 (q, J ¼ 258.2 Hz), 118.9 (q, J ¼ 271.2 Hz),
21.7. 19F NMR (CDCl3, 377 MHz)
d
ꢂ53.0, ꢂ57.9. HRMS (EI-TOF) calcd
(CDCl3, 400 MHz) d 7.99e7.94 (m, 3H), 7.53 (s, 1H), 7.49 (t, 1H,
for C18H13F6N2O3Sþ (M þ H) þ: 451.0546, found: 451.0551.
J ¼ 7.6 Hz), 7.37e7.34 (m, 3H), 7.27e7.25 (m, 1H), 2.44 (s, 3H). 13
C
NMR (CDCl3, 100 MHz)
d 145.0, 143.8, 140.0, 139.7, 137.1, 132.2,
4.4.1.10. 1-(4-fluorophenyl)-4-tosyl-5-(trifluoromethyl)-1H-imid-
azole (3j). Yield: 80%; 91.8 mg, white solid; m.p ¼ 188e189 ꢀC; 1H
129.8, 129.4, 128.6, 128.3, 122.6 (q, J ¼ 41.0 Hz), 119.0 (q,
J ¼ 269.2 Hz), 97.0, 21.8. 19F NMR (CDCl3, 377 MHz)
d
ꢂ53.9. HRMS
NMR (CDCl3, 400 MHz)
d
7.96 (d, 2H, J ¼ 8.4 Hz), 7.60 (s, 1H), 7.36 (d,
(EI-TOF) calcd for C17H13F3IN2O2Sþ(M þ H) þ: 492.9689, found:
2H, J ¼ 8.0 Hz), 7.33e7.30 (m, 2H), 7.22e7.17 (m, 2H, J ¼ 8.0 Hz), 2.43
492.9690.
(s, 3H). 13C NMR (CDCl3, 100 MHz)
d
163.5 (d, J ¼ 250 Hz), 145.1,
144.2, 139.8, 136.9, 130.3, 129.8, 128.7, 128.4 (d, J ¼ 9.0 Hz), 122.6 (q,
4.4.1.17. 1-(2,5-dimethylphenyl)-4-tosyl-5-(trifluoromethyl)-1H-
imidazole (3q). Yield: 72%; 85.2 mg, white solid; m.p ¼ 189e190 ꢀC;
J ¼ 41.3 Hz), 119.0 (q, J ¼ 268.9 Hz), 116.8 (d, J ¼ 23.4 Hz), 21.7. 19
F
NMR (CDCl3, 377 MHz)
C
d
ꢂ53.1, ꢂ108.8. HRMS (EI-TOF) calcd for
1H NMR (CDCl3, 400 MHz)
d
7.98 (d, 2H, J ¼ 8.0 Hz), 7.49 (s, 1H), 7.36
17H13F4N2O2Sþ (M þ H) þ: 385.0628, found: 385.0643.
(d, 2H, J ¼ 8.4 Hz), 7.23e7.21 (m, 2H), 6.99 (s, 1H), 2.44 (s, 3H), 2.33
(s, 3H),1.97 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d
145.0, 143.6, 139.7,
4.4.1.11. 1-(4-chlorophenyl)-4-tosyl-5-(trifluoromethyl)-1H-imid-
azole (3k). Yield: 78%; 92.1 mg, white solid; m.p ¼ 199e200 ꢀC; 1H
137.1, 133.4, 131.9, 131.6, 131.0, 129.8, 128.6, 127.8, 122.7 (q,
J ¼ 40.7 Hz), 119.0 (q, J ¼ 269.1 Hz), 21.7, 20.6, 16.5. 19F NMR (CDCl3,
NMR (CDCl3, 400 MHz)
d
7.97 (d, 2H, J ¼ 8.4 Hz), 7.59 (s, 1H), 7.49 (d,
377 MHz)
d
ꢂ54.5. HRMS (EI-TOF) calcd for C19H18F3N2O2Sþ(M þ H)
2H, J ¼ 8.8 Hz), 7.37 (d, 2H, J ¼ 8.0 Hz), 7.28e7.26 (m, 2H), 2.45 (s,
þ:395.1036, found: 395.1051.
3H). 13C NMR (CDCl3, 100 MHz)
d
145.1, 144.4, 139.5, 136.9, 136.8,
132.9, 130.0, 129.8, 128.7, 127.6, 122.5 (q, J ¼ 41.2 Hz), 119.0 (q,
4.4.1.18. 1-(3,4-dimethylphenyl)-4-tosyl-5-(trifluoromethyl)-1H-
imidazole (3r). Yield: 84%; 99.4 mg, white solid; m.p ¼ 181e182 ꢀC;
J ¼ 269.0 Hz), 21.7. 19F NMR (CDCl3, 377 MHz)
d
ꢂ53.0. HRMS (EI-
TOF) calcd for C17H13ClF3N2O2Sþ(M þ H) þ: 401.0333, found:
1H NMR (CDCl3, 400 MHz)
d
7.97 (d, 2H, J ¼ 8.4 Hz), 7.56 (s, 1H), 7.36
401.0347.
(d, 2H, J ¼ 8.0 Hz), 7.23 (d, 1H, J ¼ 8.0 Hz), 7.06e7.03 (m, 2H), 2.44 (s,
Please cite this article as: S. Hu et al., Base-mediated [3þ2] annulation of trifluoroacetimidoyl chlorides and isocyanides: An improved approach
for regioselective synthesis of 5-trifluoromethyl-imidazoles, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131168

6
S. Hu et al. / Tetrahedron xxx (xxxx) xxx
3H), 2.32 (s, 3H),2.29 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d
145.0,
467.0667.
143.8, 139.8, 139.5, 138.5, 137.2, 132.1, 130.6, 129.8, 128.7, 127.0,
123.4, 122.6 (q, J ¼ 41.2 Hz), 119.0 (q, J ¼ 269.0 Hz), 21.7, 19.8, 19.6.
4.4.1.25. 5-(perfluorobutyl)-1-phenyl-4-tosyl-1H-imidazole
(3y).
19F NMR (CDCl3, 377 MHz)
d
ꢂ53.2. HRMS (EI-TOF) calcd for
Yield: 82%; 127.0 mg, white solid; m.p ¼ 205e207 ꢀC; 1H NMR
C
19H18F3N2O2Sþ(M þ H) þ: 395.1036, found: 395.1049.
(CDCl3, 400 MHz)
d
7.99 (d, 2H, J ¼ 8.0 Hz), 7.60 (s, 1H), 7.55 (t, 1H,
J ¼ 7.6 Hz), 7.48 (t, 2H, J ¼ 7.6 Hz), 7.37 (d, 2H, J ¼ 8.4 Hz), 7.29 (d, 2H,
J ¼ 7.6 Hz), 2.45 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d 146.7, 145.0,
4.4.1.19. 1-(Naphthalen-2-yl)-4-tosyl-5-(trifluoromethyl)-1H-imid-
azole (3s). Yield: 79%; 98.7 mg, white solid; m.p ¼ 179e181 ꢀC; 1H
141.5, 137.3, 134.5, 130.7, 129.7, 129.2, 128.9, 127.5, 120.6 (t,
NMR (CDCl3, 400 MHz)
d
8.00 (d, 2H, J ¼ 8.4 Hz), 7.97 (d, 1H,
J ¼ 31.8 Hz), 118.7 (t, J ¼ 33.3 Hz), 115.5 (q, J ¼ 19.6 Hz), 113.0 (t,
J ¼ 35.1 Hz), 110.4, 21.7. 19F NMR (CDCl3, 377 MHz)
d
ꢂ80.9 (t, 3F,
J ¼ 8.8 Hz), 7.94e7.87 (m, 2H), 7.81 (s,1H), 7.70 (s,1H), 7.64e7.59 (m,
2H), 7.38e7.34 (m, 3H), 2.44 (s, 3H). 13C NMR (CDCl3, 100 MHz)
J ¼ 9.2 Hz), ꢂ100.3 (t, 2F, J ¼ 15.6 Hz), ꢂ119.0 (m, 2F), ꢂ125.9 (m, 2F).
HRMS (EI-TOF) calcd for C20H14F9N2O2Sþ(M þ H) þ: 517.0627,
found: 517.0634.
d
145.1, 144.2, 140.0, 1371, 133.5, 132.7, 131.8, 130.0, 129.9, 128.7,
128.3, 128.1, 128.0, 127.9, 125.4, 123.2, 122.8 (q, J ¼ 40.9 Hz), 119.0 (q,
J ¼ 269.0 Hz), 21.8. 19F NMR (CDCl3, 377 MHzþ) d ꢂ53.0. HRMS (EI-
TOF) calcd for
417.0890.
C
21H16F3N2O2Sþ(M
þ
H)
: 417.0879, found:
4.4.1.26. Methyl 1-(p-tolyl)-5-(trifluoromethyl)-1H-imidazole-4-
carboxylate
(3z). Yield:
71%;
60.5
mg,
white
solid;
m.p ¼ 172e174 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.59 (s, 1H), 7.29 (d,
2H, J ¼ 8.4 Hz), 7.21 (d, 2H, J ¼ 8.4 Hz), 3.95 (s, 3H), 2.42 (s, 3H). 13
C
4.4.1.20. 1-(1-phenylethyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazole
(3t). Yield: 54%; 63.9 mg, white solid; m.p ¼ 169e171 ꢀC; 1H NMR
NMR (CDCl3, 100 MHz)
d 161.6, 140.5, 140.0, 134.7, 132.5, 130.1,
125.9, 124.8 (q, J ¼ 39.8 Hz), 119.6 (q, J ¼ 268.3 Hz), 52.5, 21.2. 19
F
(CDCl3, 400 MHz)
d
7.91 (d, 2H, J ¼ 8.0 Hz), 7.56 (s, 1H), 7.38e7.32
(m, 5H), 7.18e7.16 (m, 2H), 5.64e5.59 (m, 1H), 2.43 (s, 3H), 1.88 (d,
NMR (CDCl3, 377 MHz)
d
ꢂ54.7. HRMS (EI-TOF) calcd for
3H, J ¼ 6.8 Hz). 13C NMR (CDCl3, 100 MHz)
d 144.8, 143.7, 138.6,
C
13H11F3N2O2 Naþ (M þ Na) þ: 307.0665, found: 307.0685.
137.3, 137.1, 129.7, 129.3, 129.2, 129.0, 128.7, 126.2, 120.9 (q,
J ¼ 41.3 Hz), 119.0 (q, J ¼ 268.5 Hz), 57.5, 22.4, 21.7. 19F NMR (CDCl3,
4.4.1.27. Ethyl 1-(p-tolyl)-5-(trifluoromethyl)-1H-imidazole-4-
carboxylate (3aa). Yield: 61%; 54.6 mg, white solid;
377 MHz)
d
ꢂ54.2. HRMS (EI-TOF) calcd for C19H18F3N2O2Sþ(M þ H)
þ: 395.1036, found: 395.1042.
m.p ¼ 188e189 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.59 (s, 1H), 7.29 (d,
2H, J ¼ 8.4 Hz), 7.20 (d, 2H, J ¼ 8.4 Hz), 4.42 (q, 2H, J ¼ 6.8 Hz), 2.43
(s, 3H), 1.40 (t, 3H, J ¼ 7.2 Hz). 13C NMR (CDCl3, 100 MHz)
d
161.3,
4.4.1.21. 5-(difluoromethyl)-1-phenyl-4-tosyl-1H-imidazole
(3u).
Yield: 80%; 83.6 mg, white solid; m.p ¼ 194e195 ꢀC; 1H NMR
140.5, 140.0, 135.1, 132.5, 130.1, 125.9, 124.6 (q, J ¼ 39.8 Hz), 119.6 (q,
J ¼ 268.5 Hz), 61.6, 21.2, 14.1. 19F NMR (CDCl3, 377 MHz)
d
ꢂ54.6.
(CDCl3, 400 MHz)
d
7.98 (d, 2H, J ¼ 8.4 Hz), 7.65 (t, 1H, J ¼ 52 Hz),
7.61 (s, 1H), 7.54e7.48 (m, 3H), 7.39e7.37 (m, 4H), 2.44 (s, 3H). 13
C
HRMS (EI-TOF) calcd for C14H14F3N2O2þ(M þ H) þ: 299.1002,
NMR (CDCl3,100 MHz) d 145.1,140.8,137.1,135.0,130.2,130.0,129.5,
found: 299.1010.
128.3, 127.2 (t, J ¼ 24.3 Hz), 126.4, 107.6 (t, J ¼ 235.0 Hz), 21.7. 19
F
NMR (CDCl3, 377 MHz)
d
ꢂ110.8 (d, J ¼ 56.0 Hz). HRMS (EI-TOF)
4.4.1.28. 4-Phenyl-1-(p-tolyl)-5-(trifluoromethyl)-1H-imidazole
(3 ab). Yield: 73%; 66.2 mg, white solid; m.p ¼ 167e169 ꢀC; 1H
calcd for C17H15F2N2O2Sþ(M þ H) þ: 349.0817, found: 349.0832.
NMR (CDCl3, 400 MHz) d 7.66e7.65 (m, 3H), 7.46e7.40 (m, 3H), 7.31
(s, 4H), 2.45 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d 145.0, 140.2, 139.8,
4.4.1.22. 5-(chlorodifluoromethyl)-1-phenyl-4-tosyl-1H-imidazole
(3v). Yield: 83%; 81.8 mg, white solid; m.p ¼ 191e192 ꢀC; 1H NMR
133.2, 132.9, 130.0, 19.0, 128.5, 128.2, 126.0, 121.5 (q, J ¼ 266.7 Hz),
117.7 (q, J ¼ 37.4 Hz), 21.2. 19F NMR (CDCl3, 377 MHz)
d
ꢂ53.5. HRMS
(CDCl3, 400 MHz)
d
7.97 (d, 2H, J ¼ 8.0 Hz), 7.55e7.48 (m, 4H),
7.37e7.34 (m, 4H), 2.43 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d 145.0,
(EI-TOF) calcd for C17H14F3N2þ(M þ H) þ: 303.1104, found: 303.1112.
Declaration of competing interest
141.8, 139.5, 137.2, 134.5, 130.6, 129.8, 129.6, 128.7, 127.4 (t,
J ¼ 34.8 Hz), 126.7, 119.8 (t, J ¼ 287.4 Hz), 21.7. 19F NMR (CDCl3,
377
C
MHz)
d
ꢂ42.3.
HRMS
(EI-TOF)
calcd
for
17H14ClF2N2O2Sþ(M þ H) þ: 383.0427, found: 383.0444.
We have no conflict of interest to declaration!
Acknowledgements
4.4.1.23. 5-(perfluoroethyl)-1-phenyl-4-tosyl-1H-imidazole
(3w).
Yield: 89%; 111.2 mg, white solid; m.p ¼ 190e191 ꢀC; 1H NMR
(CDCl3, 400 MHz)
d
8.00 (d, 2H, J ¼ 8.4 Hz), 7.60 (s, 1H), 7.55 (t, 1H,
We acknowledge financial support from the Natural Science
Foundation of Zhejiang Province (LY19B020016) and the Funda-
mental Research Funds of Zhejiang Sci-Tech University (2019Q065).
J ¼ 7.6 Hz), 7.48 (t, 2H, J ¼ 7.6 Hz), 7.38 (d, 2H, J ¼ 8.4 Hz), 7.29 (d, 2H,
J ¼ 7.6 Hz), 2.45 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d 146.2, 145.0,
141.4, 137.3, 134.5, 130.7, 129.8, 129.2, 128.9, 127.4, 118.4 (q,
J ¼ 251.8 Hz) 116.7 (t, J ¼ 251.8 Hz), 110.0 (t, J ¼ 41.4 Hz), 21.7. 19
F
Appendix A. Supplementary data
NMR (CDCl3, 377 MHz)
d
ꢂ82.7, ꢂ104.0. HRMS (EI-TOF) calcd for
C
18H14F5N2O2Sþ(M þ H) þ: 417.0691, found: 417.0702.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131168.
4.4.1.24. 5-(perfluoropropyl)-1-phenyl-4-tosyl-1H-imidazole
(3x).
Yield: 82%; 114.7 mg, white solid; m.p ¼ 201e202 ꢀC; 1H NMR
References
(CDCl3, 400 MHz)
d
7.99 (d, 2H, J ¼ 8.4 Hz), 7.61 (s, 1H), 7.54 (t, 1H,
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J ¼ 7.6 Hz), 2.44 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d 146.5, 145.0,
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ꢂ80.0
d
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Please cite this article as: S. Hu et al., Base-mediated [3þ2] annulation of trifluoroacetimidoyl chlorides and isocyanides: An improved approach
for regioselective synthesis of 5-trifluoromethyl-imidazoles, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131168

S. Hu et al. / Tetrahedron xxx (xxxx) xxx
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Please cite this article as: S. Hu et al., Base-mediated [3þ2] annulation of trifluoroacetimidoyl chlorides and isocyanides: An improved approach
for regioselective synthesis of 5-trifluoromethyl-imidazoles, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131168