Transition-metal-free, visible-light-mediated regioselective C–H trifluoromethylation of imidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2019.02.003

A transition-metal-free, visible-light-induced trifluoromethylation of imidazo[1,2-a]pyridines has been developed at mild conditions by employing cheap and commercially available anthraquinone-2-carboxylic acid (AQN-2-CO₂H) as the photo-organocatalyst, and Langlois reagent as the trifluoromethylating reagent. A series of 3-(trifluoromethyl)imidazo[1,2-a]pyridine derivatives with broad functionalities could be conveniently and efficiently obtained by direct regioselective functionalization.

Full text of DOI:10.1016/j.tetlet.2019.02.003

Accepted Manuscript
Transition-Metal-Free, Visible-Light-Mediated Regioselective C–H Trifluoro-
methylation of Imidazo[1,2-a]pyridines
Qiguang Zhou, Song Xu, Ronghua Zhang
PII:
S0040-4039(19)30111-X
https://doi.org/10.1016/j.tetlet.2019.02.003
TETL 50597
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
22 December 2018
21 January 2019
1 February 2019
Please cite this article as: Zhou, Q., Xu, S., Zhang, R., Transition-Metal-Free, Visible-Light-Mediated Regioselective
C–H Trifluoromethylation of Imidazo[1,2-a]pyridines, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/
j.tetlet.2019.02.003
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1
Tetrahedron Letters
jo u r n a l h o m e p a g e : w w w . e ls e v ie r . c o m
Transition-Metal-Free, Visible-Light-Mediated Regioselective C–H
Trifluoromethylation of Imidazo[1,2-a]pyridines
Qiguang Zhou a, b, Song Xu a, b and Ronghua Zhang a, b,

a School of Chemical Science and Engineering, Tongji University, 1239 Siping Road, Shanghai 200092, China
b Shanghai Key Lab of Chemical Assessment and Sustainability, Tongji University, 1239 Siping Road, Shanghai 200092, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A transition-metal-free, visible-light-induced trifluoromethylation of imidazo[1,2-a]pyridines
has been developed at mild conditions by employing cheap and commercially available
anthraquinone-2-carboxylic acid (AQN-2-CO2H) as the photo-organocatalyst, and Langlois
reagent as the trifluoromethylating reagent. A series of 3-(trifluoromethyl)imidazo[1,2-
a]pyridine derivatives with broad functionalities could be conveniently and efficiently obtained
by direct regioselective functionalization.
Available online
Keywords:
transition-metal-free
visible-light
2009 Elsevier Ltd. All rights reserved.
trifluoromethylation
imidazo[1,2-a]pyridines
Introduction
id, etc [16]. Thus, substantial methods for the synthesis and
modification of imidazoheterocycles have been extensively
Fluorine-containing organic molecules have gained increasing
attentions [1]. Fluorine can alter the physicochemical properties
of organic molecules [2], and wide applications in medicinal
chemistry, agrichemicals, and materials science [3]. Recently,
impressive achievements have been covered about the
trifluoromethylation of organic molecules [4], using electrophilic
[5], nucleophilic [6], and radical [7] trifluoromethylating
reagents. Among the developed methods of radical
reported [17]. In the midst of them, there are a few reports about
a) Previous work
Hajra, 2015 (ref. 18):
trifluoromethylation,
trifluoromethylations have attracted significant notice [8].
photoredox-catalyzed
radical
Wang, 2016 (ref. 19):
Visible light is an abundant, eco-friendly and accessible
energy source [9]. Over the past decade, visible-light photoredox-
catalyzed organic synthesis has achieved great progress [10].
Since 2008, when MacMillan and coworkers reported visible
light photoredox catalysis for organic synthesis by Ru(bpy)3Cl2
[11], numerous photocatalysts have entered this field, such as
noble metal polypyridine and phenylpyridyl complexes [12],
organic dyes [13]. In recent years, many photo-organocatalysts as
inexpensive and nontoxic substitution have gained more favor
[14]. In 2013, Itoh reported the direct trifluoromethylation of
arenes and heteroarenes under visible light irradiation by using
CF3SO2Na as the source of trifluoromethyl group and
anthraquinone-2-carboxylic acid (AQN-2-CO2H) as photoredox-
catalyst [15].
Rueping, 2016 (ref. 20):
b) This work: trifluoromethylation with visible light
Imidazoheterocycles as an important nitrogen-containing
compound, are the core of many drug molecules, such as
Alpidem, Zolimidine, Saripidem, Zolpidem, and Minodronic Ac-
———
Scheme 1. Trifluoromethylation of imidazo[1,2-a]pyridines
 Corresponding author. E-mail: rhzhang@tongji.edu.cn

2
Tetrahedron Letters
the
introduction
of
trifluoromethyl
groups
into
etic acid, 0.06 equiv.) in DMSO solvent at room temperature
imidazoheterocycles that are very valuable means of
modification. In 2015, Hajra reported silver-catalyzed
under N2 balloon atmosphere with 3 W blue LED irradiation.
When the photo-organocatalyst AQN-2-CO2H was replaced with
AQN-2-CH3, a remarkable decline in the yield of 3a was
recorded (54%, entry 2). Similarly, when the reaction was carried
out by employing AQN-2-Cl (entry 3), Na Eosin Y (entry 4) or
Ru(bpy)3Cl2•6H2O (entry 5) instead of AQN-2-CO2H, the yield
of 3a has no improvement. Control experiments demonstrated
that the yield was reduced when AQN-2-CO2H was absent from
the reaction mixture (entry 6) and no desired product was
observed without light (entry 7). The yield of 3a was also
decreased without TFA or K2CO3 (entry 8 and 9). Furthermore,
various solvents, including DMF, MeCN, THF and MeOH, were
also investigated (entries 10-13). However, no higher yield was
gained by altering the solvent. In addition, a series of bases,
Cs2CO3, (i-Pr)2NEt and DBU (entries 14-16), were screened, but
all led to lower product yields. Fortunately, a modicum of
improvement of the yield was observed, with double the amount
of K2CO3 (entry 17). Lastly, the oxygen was adverse to the
reaction (entry 18).
With the optimal reaction conditions in hand, we then
investigated the scope of substrates, and the results are shown in
Table 2. A wide range of substituted imidazo[1,2-a]pyridines
reacted with CF3SO2Na to generate desired products with
satisfactory yields. Imidazopyridines substituted with a methyl
group at different positions gave moderate yields (3b-d).
Imidazopyridine with another electron-donating group was also
successfully trifluoromethylated (3e). The polyphenyl-substituted
substrates also performed well under the optimal conditions, and
the corresponding trifluoroethylated products (3f-g) were
obtained in reasonable yields. Electron-withdrawing groups, such
as fluoro, chloro, bromo, trifluoromethyl, on the phenyl ring at
different position of imidazopyridines were well tolerated in this
regioselective
imidazoheterocycles
oxidative
trifluoromethylation
Langlois’ reagent
of
as
with
trifluoromethylating reagent [18]. In 2016, Wang reported nickel-
catalyzed C-H trifluorometylation of imidazoheterocycles with
trifluoromethyl iodide (ICF3) as trifluoromethylating reagent
[19]. In 2016, Rueping reported photo-organocatalysed
trifluoromethylation of imidazoheterocycles in batch and
continuous flow with UV light [20]. For all we know, there is no
method of transition-metal-free direct C-H trifluoromethylation
of imidazoheterocycles using photo-organocatalyst in visible
light. Herein, we report
trifluoromethylation of
a
direct method for the
imidazo[1,2-a]pyridines using
anthraquinone-2-carboxylic acid (AQN-2-CO2H) as photo-
organocatalyst in visible light.
Results and discussion
Initially, we chose 2-phenylimidazo[1,2-a]pyridine (1a) and
CF3SO2Na (Langlois reagent) as the model substrates to optimize
the reaction conditions (Table 1). It is gratifying that the desired
product was obtained in 74% yield (entry 1) when the reaction
was conducted in photo-organocatalyst AQN-2-CO2H (2 mol%),
CF3SO2Na (4.0 equiv.), K2CO3 (0.5 equiv.) and TFA (trifluoroac-
Table 1. Optimization of reaction conditions a
Entry
1
Photocatalyst
AQN-2-CO2H
AQN-2-CH3
AQN-2-Cl
Base
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yield (%) b
reaction
system,
2-(4-bromophenyl)imidazo[1,2-a]pyridine
especially gave a good yield (81%). The antiulcer drug
Zolimidine was also smoothly trifluoromethylated with moderate
yield (3o). Substrates with methyl or halogen atom on the
pyridine ring were compatible under the standard conditions, as
well. 2-thienylimidazo[1,2-a]pyridine also reacted well to afford
corresponding product (3s). It is delightful that alkenyl, methyl or
no group containing imidazopyridines also afforded the desired
products in standard conditions.
To further expand the substrate scope of this methodology,
other imidazoheterocycles like imidazo[2,1-b]thiazole and
benzo[d]imidazo[2,1-b]thiazole were explored, and the results
are shown in Table 3. The corresponding trifluoroethylated
products (5a-b) were nevertheless afforded in moderate to good
yields under the developed conditions.
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
74
54
55
26
41
29
0
2
3
4
Na Eosin Y
5
Ru(bpy)3Cl2•6H2O
—
6
7 c
8 d
9
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
55
30
65
40
8
To gain insight into the mechanism of this reaction, a few
controlled experiments were carried out. No trifluoroethylated
product was observed when the radical scavenger TEMPO was
added into the system, and the desired product was detected by
GC-MS (see the Supporting information for details), which
indicated that a free radical process would be involved. From the
experiments and literature reports [15, 18], the probable
mechanism of the reaction is described in Scheme 2. At first, the
CF3 radical is generated from the photoredox-catalyzed
cyclization. The ground and excited redox states of AQN are
important for this process. In the cyclization, CF3SO2ˉ would
transfer electron to the excited state of AQN (AQN*) to generate
10
11
12
13
14
15
16
17 e
18 f
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
(i-Pr)2NEt
DBU
CH3CN
THF
MeOH
DMSO
DMSO
DMSO
DMSO
DMSO
46
41
24
26
81
39
K2CO3
K2CO3
•
CF3SO2 and AQN•ˉ radical based on their redox potentials.
AQN•ˉwould be facile oxidized by SO2 produced by cleavage of
•
a Reaction conditions: 1a (0.2 mmol), 2 (4.0 equiv.), photocatalyst (2 mol%),
base (0.5 equiv. ), TFA (0.06 equiv.) and solvent (2.5 mL), irradiation with 3
W blue LEDs for 24 h, N2 balloon, rt.
b Isolated yield, based on 1a.
CF3SO2 to regenerated AQN. Subsequently, the CF3 radical
reacted with imidazopyridines to form the radical intermediate A.
The intermediate A was oxidized by the CF3 radical to give the
carbocation intermediate B. Finally, the intermediate B afforded
the product by eliminating H+.
c In the dark.
d TFA (0 equiv.) was added.
e Base (1 equiv.) was added.
f In oxygen balloon.

3
Table 2. Substrate Scope of Imidazopyridines a
3b, 54%
3c, 50%
3d, 49%
3e, 66%
3h, 54%
3f, 63%
3i, 65%
3g, 56%
3j, 81%
3k, 73%
3n, 77%
3q, 47%
3t, 29%
3l, 67%
3o, 55%
3r, 45%
3u, 50%
3m, 50%
3p, 67%
3s, 71%
3v, 11%
a Reaction conditions: 1 (0.2 mmol), 2 (4.0 equiv.), AQN-2-CO2H (2 mol%), K2CO3 (1.0 equiv. ), TFA (0.06 equiv.) and DMSO (2.5
mL), irradiation with 3 W blue LEDs, N2 balloon, rt.
Table 3. Substrate Scope of Imidazoheterocycles a
5a, 51%
5b, 70%
a
Reaction conditions: 4 (0.2 mmol), 2 (4.0 equiv.), AQN-2-CO2H (2 mol%), K2CO3 (1.0 equiv. ), TFA (0.06 equiv.) and DMSO
(2.5 mL), irradiation with 3 W blue LEDs, N2 balloon, rt.
Conclusions
In conclusion, we have developed an efficient and mild method for trifluoromethylation of imidazopyridines by employing
Langlois reagent as the source of trifluoromethyl group in visible light. This method is a transition-metal-free, dir-

3
Scheme 2. Plausible reaction mechanism.
ect trifluoromethylation by employing cheap trifluoromethyl-ating agent under visible light irradiation. A series of 3-
(trifluoromethyl)imidazo[1,2-a]pyridine derivatives with broad functionalities could be conveniently and efficiently obtained in
moderate to good yields. Other imidazoheterocycles like imidazo[2,1-b]thiazole and benzo[d]imidazo-[2,1-b]thiazole were also well
tolerated to this protocol. We believe this method is of great value in introducing trifluoromethyl group into imizazopyridine
derivatives to strengthen their physiochemical properties.
Acknowledgments
We thank the National Natural Science Foundation of China (No. 20972113/B020502) and the Fundamental Research Funds for
the Central Universities for financial support.
Supplementary Material
Supplementary data to this article can be found online at …
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Graphical Abstract
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Transition-Metal-Free, Visible-Light-
Mediated Regioselective C–H
Trifluoromethylation of Imidazo[1,2-
a]pyridines
Leave this area blank for abstract info.
Qiguang Zhou, Song Xu and Ronghua Zhang

Tetrahedron Letters
6
Highlights
Transition-metal-free visible-light-induced
trifluoromethylation of imidazopyridines.
Anthraquinone-2-carboxylic acid as the photo-organocatalyst.
Photoredox catalyzed cyclization generate trifluoromethyl
radical.