Visible-Light-Promoted Metal-Free C-H Trifluoromethylation of Imidazopyridines

Article abstract of DOI:10.1002/ejoc.201901860

A metal-free photo redox C–H trifluorometlylation of imidazopyridines is described. The reaction is operationally simple and the easy-handling CF₃SO₂Na serves as an effective fluoroalkyl radical precursor. Various functional groups were tolerated under blue LED light to access the desired products in satisfied yields at room temperature.

Full text of DOI:10.1002/ejoc.201901860

A Journal of
Accepted Article
Title: Visible-Light-Promoted Metal-Free C-H Trifluoromethylation of
Imidazopyridines
Authors: Xia Mi, Yuanfang Kong, Huaixia Yang, Jingyu Zhang, Chao
Pi, and Xiuling Cui
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901860
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10.1002/ejoc.201901860
European Journal of Organic Chemistry
COMMUNICATION
Visible-Light-Promoted Metal-Free C-H Trifluoromethylation of
Imidazopyridines
Xia Mi,[a] Yuanfang Kong,[a] Huaixia Yang,[a] Jingyu Zhang,*[a] Chao Pi,[b] Xiuling Cui*[b]
Abstract: A metal-free photo redox C-H trifluorometlylation of
imidazopyridines is described. The reaction is operationally simple
and the easy-handling CF3SO2Na serves as an effective fluoroalkyl
radical precursor. Various functional groups were tolerated under blue
LED light to access the desired products in satisfied yields at room
temperature.
As a privileged heterocyclic scaffold, imidazopyridine is found
in diverse bioactive natural products and pharmaceuticals.[10]
Numerous methods have been developed for the synthesis and
medication of this core.[11] Some methods have been reported for
the trifluoromethylation of imidazo[1,2-a]pyridine and its
derivatives (Scheme 1a).[12] However, only a few reports involved
visible-light-induced trifluoromethylation of imidazopyridines.[13] In
2015, Rueping’s group first showed the trifluoromethylation of
imidazopyridine using benzophenone derivative as photo redox
catalyst under near-UV irradiation (λ = 350 nm), however only one
example was involved and afforded moderate yield. Recently,
Zhang and coworkers reported trifluoromethylation of
imidazo[1,2-a]pyridines by employing anthraquinone-2-carboxylic
acid as the photo-organo catalyst with the addition of base and
acid (Scheme 1b). Herein we present a mild and photo redox
protocol for trifluoromethylation of imidazo[1,2-a]pyridine
derivatives with mesityl acridinium as photo redox catalyst and
CF3SO2Na as a CF3 radical source under transition-metal-free
condition at room temperature (Scheme 1c).
The trifluoromethyl group plays an important role in
pharmaceuticals, agrochemicals, and functional materials.[1]
Hence, the research of selective introduction of a trifluoromethyl
group into organic molecules has become a hot topic in modern
organic chemistry.[2] Trifluoromethylation,[3] especially via photo
redox catalysis, represents an attractive alternative for a mild and
efficient method to produce active CF3 radical.[4] In this strategy,
a
variety of CF3 radical precursors, such as CF3I,[4c]
CF3SO2Cl,[4e,4i] TMSCF3,[4k] Togni reagent,[4g] Umemoto
reagent,[4h] Langlois reagent (CF3SO2Na),[4f] and Baran’s
reagent,[4d] have been used for the incorporation of a CF3 group
into diverse skeletons. Trifluoromethylation starting from
commercially available, low cost, and easy-handling Langlois
reagent is more appealing. The redox potential of the Langlois
reagent is 1.05 V (vs. SCE).[5] Generally, it requires transition
metal iridium complexes or stoichiometry oxidant, such as K2S2O8,
TBHP, PhI(OAc)2, to oxidize the Langlois reagent, which is not
compatible with sensitive functional groups. Several organic dyes
such as rose bengal, methylene blue, and Nile red have proven
to be efficient in visible-light-promoted trifluoromethylation and
show the advantages of efficiency, cheapness and non-toxicity.[6]
Mesitylacridinium species have known as the photo redox catalyst
to realize hydrotrifluromethylation,[5] vicinal difunctionalization of
alkenes[7] and cascade radical trifluromethylation of
isocyanides.[8] However, there is no report on the
trifluorometlylation of (hetero)-arenes using the acridinium /
CF3SO2Na system. We proposed that
a high oxidizing
mesitylacridinium (Ered 1/2 > 1.8 V vs. SCE) [9] would be an effective
photo oxidant to generate reactive CF3 radicals from the Langlois
reagent to achieve C-H trifluorometlylation of imidazopyridines
with visible-light irradiation.
Scheme 1. Trifluoromethylation of imidazo[1,2-a]pyridines.
Our investigation was commenced with imidazo[1,2-a]pyridine
(1a) and CF3SO2Na (2) as starting materials under the irradiation
of a 3 W blue LED (Table 1). No desired product was obtained
using Ir(ppy)3, Ru(bpy)3Cl2, Eosin Y as the catalyst (entries 1-3).
A high oxidation potential acridinium A showed good reactivity
and the desired C-H trifluromethylated product 3a was afforded in
42% yield (entry 4). The effect of solvent was explored with
[a]
Dr. X. Mi, Dr. Y. F. Kong, Prof. H. X. Yang, Prof. Dr. J. Y. Zhang
College of Pharmacy
Henan University of Chinese Medicine
Zhengzhou 450046, P. R. China
E-mail: jyzhang2004@hactcm.edu.cn
Dr. C. Pi, Prof. Dr. X. L. Cui
[b]
acridinium
A as catalyst. The result revealed that 1,2-
College of Chemistry
dichloroethane (DCE) was a suitable medium compared to other
solvents, such as tetrahydrofuran (THF), MeCN, and CHCl3
(entries 5-8). To further improve yield of target product, other
acridiniums with counter anions or substitutions were tested
(entries 9-10). The desired product 3a could be formed in 53%
yield when acridinium C was employed as a catalyst (entry 10).
Henan Key Laboratory of Chemical Biology and Organic Chemistry
Key Laboratory of Applied Chemistry of Henan Universities
Zhengzhou University
Zhengzhou 450052, P. R. China
E-mail: cuixl@zzu.edu.cn.
Supporting information for this article is given via a link at the end of
the document. ((Please delete this text if not appropriate))
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10.1002/ejoc.201901860
European Journal of Organic Chemistry
COMMUNICATION
Table 2. Scope of imidazopyridines.[a]
Working at lower concentration (from 1.0 mL to 2.0 mL DCE) gave
63% yield. However, when 3.0 mL of solvent was loaded, the
reaction decreased its efficiency (entries 11-12). Increased the
loading of 1a afforded a yield of 74% (entry 14), while the product
yield was decreased with higher loading of CF3SO2Na (entry 13).
A similar yield of 75% was achieved after irradiation for 36 hours
(entry 15). Inferior results were obtained when the loading of
acridinium C was decreased (entry 16). Trace amount of product
was provided in absence of photo catalyst or in the dark (entries
17-18).
Table 1. Screening the reaction conditions.[a]
entry
catalyst
solvent/v (mL)
yield (%)[b]
1
Ir(ppy)3
DCE/1
DCE/1
DCE/1
DCE/1
DMSO/1
THF/1
ND
ND
ND
42
[a] Reaction conditions: 1a (0.3 mmol), 2 (0.2 mmol), C (5 mol %), DCE (2.0
mL), 3 W blue LED for 24 h. Isolated yields.
2
Ru(bpy)3Cl2
With the optimized reaction conditions in hand (Table 1, entry
14), we next explored the scope of this C-H trifluoromethylation of
imidazopyridines. As shown in Table 2, imidazo[1,2-a]pyridines
bearing -Me, -OMe or halogen substituents on pyridine ring at
different position efficiently reacted with CF3SO2Na to afford the
desired products with moderate to good yields (3b-3q).
Imidazo[1,2-a]pyridines with methyl ester at C-6 was tolerated
and resulted in 64% yield (3g). Then we examined the effect of
substituents in C-2 position of imidazo[1,2-a]pyridines (3r-3af).
Imidazopyridine moiety with electron-donating groups, such as -
CH3 and -OCH3 on the phenyl ring, afforded the desired products
with good yields (3r, 3s, 3aa, 3ab and 3af). The crystal structure
of 3s was confirmed by X-ray single crystal diffraction, as shown
in supporting information. Halogens were also well tolerated (3t-
3w and 3ac-3ae). Strong electron-withdrawing groups, for
example -CF3 in a phenyl ring, successfully afforded the desired
products 3y. To our delight, thiophene- and pyridine-substituted
imidazo[1,2-a]pyridines also furnished the products with 71% and
34% yields, respectively (3ag, 3ah). In addition, imidazo[2,1-
b]thiazole and phenylimidazo[1,2-a]pyrimidine were found to be
effective for this reaction (3ai, 3aj). However, unsubstituted
imidazopyridine and indoles did not work in this catalytic system.
To probe the mechanism of this transformation, we attempted
to perform the reaction in the presence of radical scavenger
TEMPO (2,2,6,6-tetramethylpiperidinooxyl) under standard
reaction conditions (Scheme 2). The formation of
trifluoromethylated imidazopyridine was totally suppressed and
TEMPO-CF3 adduct 4 was detected in 14% yield by 19F NMR
spectroscopy.[5] This result suggested that CF3 radical was
involved in this reaction.
3
Eosin Y
4
A
A
A
A
A
B
C
C
C
C
C
C
C
C
C
5
11
6
18
7
MeCN/1
CHCl3/1
DCE/1
DCE/1
DCE/2
DCE/3
DCE/2
DCE/2
DCE/2
DCE/2
DCE/2
DCE/2
22
8
36
9
11
10
53
11
63
12
59
13 [c]
14 [d]
15 [d], [e]
16 [d], [f]
17 [d]
18[d], [g]
39
74
75
66
trace
trace
[a] 1a (0.2 mmol), 2 (0.3 mmol), photocatalyst (5 mol %), solvent (1.0 mL), 3
W blue LED. [b] Isolated yields. [c] 2 (0.4 mmol) [d] 1a (0.3 mmol), 2 (0.2
mmol). [e] 36 h. [f] catalyst C (2 mol %). [g] Dark. [h] ND = not detected.
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10.1002/ejoc.201901860
European Journal of Organic Chemistry
COMMUNICATION
This work was financially supported by the National Natural
Science Foundation of China (No. 21602046), the MOST of China
(No. 2016YFE0132600) and the Doctor’s Scientific Research
Foundation of Henan University of Chinese Medicine (No.
BSJJ2016-12).
Scheme 2. Radical capture experiment in the presence of TEMPO.
Keywords: C-H trifluorometlylation • photochemistry •
organocatalysis • imidazopyridines • radical reaction • metal-free
A plausible mechanism for the C-H trifluoromethylation of
imidazo[1,2-a]pyridines is shown in Scheme 3. Under the
photocatalytic conditions, electron transfer from CF3SO2- to the
excited-state acridinium [PC]* is expected to efficiently generate
CF3SO2 and [PC]*- radicals. The cleavage of CF3SO2 radical
products CF3 radical and SO2. Subsequently, the CF3 radical
reacted with imidazo[1,2-a]pyridine 1a to produce the
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In conclusion, we have developed an efficient and photoredox-
based protocol for the C-H trifluoromethylation of imidazo[1,2-
a]pyridines using acridinium as the photo redox catalyst and
CF3SO2Na as CF3 source. A series of the desired products were
afforded in satisfied yields under the transition-metal-free
condition, which displays potential for further application in
medicinal and agrochemical research.
Experimental Details.
Under N2 atmosphere, a reaction tube (25 mL) equipped with a magnetic
stirrer bar was charged with imidazo[1,2-a]pyridine (1, 0.3 mmol),
CF3SO2Na (2, 0.2 mmol), acridinium (0.01 mmol, 5 mol %) and 1,2-DCE
(2.0 mL). The reaction mixture was stirred with a 3 W blue LED irradiation
at room temperature for 24 h, filtered through a pad of celite and then
washed with CH2Cl2 (10 mL×3). The solvent was removed under reduced
pressure and the residue was purified by chromatography on silica gel
(elute: EA/PE) to give the desired product 3.
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Xia Mi, Yuanfang Kong, Huaixia Yang,
Jingyu Zhang,* Chao Pi, Xiuling Cui*
Page No. – Page No.
Visible-Light-Promoted Metal-Free C-
H Trifluoromethylation of
Imidazopyridines
C-H Trifluoromethylation: An efficient, mild and photo redox-based protocol for the
C-H trifluoromethylation of imidazo[1,2-a]pyridines has been developed using
acridinium as photo redox catalyst and the easy-handling CF3SO2Na as CF3 source.
A series of desired products were afforded in satisfied yields under transition-metal-
free condition, which displays potential for further application in synthetic research.
This article is protected by copyright. All rights reserved.