Transition-Metal-Free Direct Trifluoromethylation and Perfluoroalkylation of Imidazopyridines under Mild Conditions

Article abstract of DOI:10.1002/adsc.201801541

The first transition-metal-free method for direct C?H trifluoromethylation of imidazo[1,2-a]pyridine derivatives with readily available Ruppert-Prakash reagent TMSCF₃ under mild conditions was described. Moreover, this method could be applied to direct C?H perfluoroalkylation of imidazopyridines, affording a series of novel perfluoroalkylated products in moderate to good yields. Notable advantages of this protocol include easy operation, high-efficiency and wide substrate scope. (Figure presented.).

Full text of DOI:10.1002/adsc.201801541

Title: Transition-Metal-Free Direct Trifluoromethylation and
Perfluoroalkylation of Imidazopyridines under Mild Conditions
Authors: Shuaijun Han, Xianying Gao, Qingsong Wu, jingya Li, Dapeng
Zou, Yangjie Wu, and Yusheng Wu
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801541
Link to VoR: http://dx.doi.org/10.1002/adsc.201801541

Advanced Synthesis & Catalysis
10.1002/adsc.201801541
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Transition-Metal-Free Direct Trifluoromethylation and
Perfluoroalkylation of Imidazopyridines under Mild Conditions
a
a
a
b
a
Shuaijun Han, Xianying Gao, Qingsong Wu, Jingya Li, Dapeng Zou, * Yangjie
a
a, b, c
Wu, * Yusheng Wu
*
a
The College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic
Chemistry, Zhengzhou University, Zhengzhou, People’s Republic of China Fax: (+86)-371-6776-3390; phone: (+86)-
3
71-6776-6865; e-mail: zdp@zzu.edu.cn or wyj@zzu.edu.cn
b
c
Tetranov Biopharm, LLC., and Collaborative Innovation Center of New Drug Research and Safety Evaluation,
Zhengzhou, 450052, People’s Republic of China
Tetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA
Fax: (+ 1)-732-253-7327; phone: (+ 1)-732-253-7326; e-mail: yusheng.wu@tetranovglobal.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
best of our knowledge, transition-metal-free direct C-
trifluoromethylation of nonprefunctionalized
as trifluoromethyl agent
In
addition, compared to trifluoromethylation, efficient
Abstract: The first transition-metal-free method for
direct C-H trifluoromethylation of imidazo[1,2-a]pyridine
H
derivatives with readily available Ruppert-Prakash reagent heterocyles using TMSCF
TMSCF under mild conditions was described. Moreover, near room temperature is less reported.
3
[6b, 6f]
3
this method could be applied to direct C-H
perfluoroalkylation of imidazopyridines, affording a series
of novel perfluoroalkylated products in moderate to good
yields. Notable advantages of this protocol include easy
operation, high-efficiency and wide substrate scope.
and
general
methods
for
nonprefunctionalized
or TMSC are
Thus, expanding the
F2n+1 (n = 1, 2, 3) in the
direct
C-H
perfluoroalkylation
heterocyles with TMSC
comparatively rare.
application of TMSC
of
2
F
5
3 7
F
[5c, 6e, 6f, 7]
n
Keywords: Transition-metal-free; Mild conditions;
Trifluoromethylation; Perfluoroalkylation;
Imidazopyridines;
fluorination of organic compound with higher atom-
efficient as well as getting the useful fluoroalkylated
molecules is still challenging.
CF -containing compounds play a significant role in
3
agricultural and medicinal chemistry and many other
areas due to their unique properties, such as
significant biological activity, remarkable metabolic
stability and high lipophilicity.[1] As a consequence,
the development of efficient methods to construct C-
CF
3
bond has attracted continuous interest in organic
[2]
synthesis. Ruppert-Prakash reagent TMSCF
3
, a
commercially available and relatively inexpensive
material, has emerged as an efficient and economic
reagent for the direct C-H trifluoromethylation of
Scheme 1. Strategies Toward Preparation of
Fluoroalkylated Imidazo[1,2-a]pyridines
[3-6]
[3]
arenes and heteroarenes.
Besides palladium,
copper[ or silver-catalyzed trifluoromethylation of
arenes and heteroarenes with TMSCF have been
reported. Transition-metal-free methods for the
4]
[5]
The imidazo[1,2-a]pyridine moiety has been
frequently found in the frameworks of various
3
[8]
clinical drugs or agricultural chemicals. As a result,
the synthesis of imidazo[1,2-a]pyridine derivatives
with a variety of substituents has gained considerable
attention. Because of the central position of
imidazo[1,2-a]pyridine and trifluoromethyl groups
containing molecules, introduction of trifluoromethyl
substituents into imidazo[1,2-a]pyridine has been of
construction of C-CF
3
bond have also been
developed.[ Despite these advances, toxic metal
catalysts, prerequisite directing groups or the high
temperature may diminish the general application of
such atom-efficient C-H trifluoromethylation. To the
6]
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201801541
considerable significance. The first example on
trifluoromethylation of imidazo[1,2-a]pyridines was
reported by Hajra in 2015, using Langlois’ reagent
15[c] PhI(OAc)
2
2
2
2
2
2
CsF
CsF
CsF
KF
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
CN (1.5)
CN (1.5)
CN (1.5)
CN (1.5)
76
68
72
26
6[d] PhI(OAc)
7[e] PhI(OAc)
1
1
(
NaSO
2
CF
3
) as CF radical source in the presence of
3
[9]
TBHP and AgNO
3
(Scheme 1, a). Subsequently, a
18
PhI(OAc)
PhI(OAc)
PhI(OAc)
copper-catalyzed strategy for the trifluoromethylation
of imidazopyridines was developed with Langlois’
reagent in a recyclable mixed medium of 1-butyl-3-
1
9
0
4
Bu NF
CN (1.5) trace
CN (1.5)
2
NaHCO
3
8
methylimidazoliumtetrafluoroborate
([Bmim]BF
4
)
[a]
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol),
PhI(OAc) (2.0 equiv), base (3.0 equiv), solvent (1.0 mL)
[
10]
and water at room temperature (Scheme 1, a).
2
Moreover,
a
near-UV-light
photocatalysed
°
at 30 C for 3 h. nd = not detected.
trifluoromethylation
of 2-phenylimidazo[1,2-
[b]
HPLC yield.
a]pyridine with readily available benzophenone
derivatives as photosensitisers was developed in
[c]
2
a (0.8 mmol), base (4.0 equiv)
[d]
[e]
2
a (1.0 mmol), base (4.0 equiv)
[11]
batch and flow by Rueping (Scheme 1, a). Recently,
Wang and co-workers demonstrated the first nickel-
catalyzed direct trifluoromethylation reactions of
2
a (0.8 mmol), base (3.0 equiv)
Initially, the reaction was investigated with 2-
phenylimidazo[1,2-a]pyridine 1a as the model
substrate and Ruppert-Prakash reagent TMSCF as
CF source. In the presence of commercially available
oxidant (diacetoxy)iodobenzene (PhI(OAc) ) and
CsF, a series of organic solvents were tested (Table 1,
entries 1-8) and CH CN was found to be the best
choice (Table 1, entry 1). Then, a better result was
obtained in 1.5 mL CH CN affording 57% of the
imidazo[1,2-a]pyridine derivatives using ICF
3
as the
Despite
trifluoromethyl source (Scheme 1, b).[
12]
3
these significant accomplishments, these strategies
usually suffer from expensive and toxic metal
catalysts, which may lead to undesired residual
impurities and hinder their application in
pharmaceutical synthesis. Being energy-efficient and
eco-friendly, a transition-metal-free and mild method
for synthesizing 3-(trifluoromethyl)imidazo[1,2-
a]pyridine derivatives is still highly desirable. As a
part of our ongoing efforts on direct C-H
3
2
3
3
desired product (Table 1, entries 9-11). Other
oxidants either gave lower yields (e.g.,
bis(trifluoroacetoxy)iodobenzene PIFA, entries 12) or
failed to provide any desired product (e.g., K
and TBHP, entries 13 and 14). To our delight, when
.0 equiv of 2a and CsF was used, the yield of
desired product was increased to 76% (Table 1, entry
5). Increasing the amount of 2a to 5.0 equiv did not
improve the yield (Table 1, entry 16). The yield of 3a
was slightly reduced when the amount of CsF
adjusted to 3.0 equiv (Table 1, entry 17). In addition,
a survey of various bases demonstrated that CsF was
a better choice in the reaction process (Table 1,
entries 18-20). Finally, the optimized reaction
conditions for direct C-H trifluoromethylation of 2-
phenylimidazo[1,2-a]pyridine were determined as the
combination of 2-phenylimidazo[1,2-a]pyridine 1a
[13]
functionalization and fluorine chemistry, we herein
report the first transition-metal-free protocol for
2
S
2
O
8
direct
perfluoroalkylation
derivatives with readily available TMSC
, 3) under mild conditions (Scheme 1, c).
C-H
trifluoromethylation
and
4
of imidazo[1,2-a]pyridine
n
F2n+1 (n = 1,
1
2
Table 1. Optimization of the Reaction Conditions.[a]
entry
oxidant
base
solvent (mL) yield
[
b]
(
%)
(
1.0 equiv), TMSCF
equiv), CsF (4.0 equiv) in CH
Table 2. Substrate Scope of Imidazo[1,2-a]pyridines.[a,b]
3
2a (4.0 equiv), PhI(OAc)
2
(2.0
1
2
3
4
5
6
7
8
9
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(TFA)
2
2
2
2
2
2
2
2
2
2
2
2
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CH
3
CN (1.0)
52
34
16
12
51
31
33
28
57
51
28
7
°
3
CN at 30 C for 3 h.
dioxane (1.0)
DME (1.0)
toluene(1.0)
DCM (1.0)
DCE (1.0)
DMF (1.0)
EtOAc (1.0)
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
CN (1.5)
CN (2.0)
CN (3.0)
CN (1.5)
CN (1.5)
CN (1.5)
1
1
1
1
1
0
1
2
3
4
K
S
2 2
O
8
nd
nd
TBHP
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201801541
trifluoromethyl and nitro; 3o-3q) located in phenyl
rings were found to be tolerated in the reaction. The
substrates with halogens groups (fluoro, chloro,
bromo; 3r-3u, 56-71% yields) gave the
corresponding products in moderate to good yield.
The desired 3v could be obtained in 70% yield under
the optimal condition. 2-Methylimidazo[1,2-
a]pyridine was also compatible to this catalytic
system, and gave 3w in 48% yield. In addition, some
heterocycles, such as 2-phenylbenzo[d]imidazo[2,1-
b]thiazole (1x), 2-(p-tolyl)imidazo[1,2-a]pyrimidine
(
1y) and 6-phenylimidazo[2,1-b]thiazole (1z) were
also investigated under the optimal reaction
conditions and the corresponding products were
obtained in 51-75% yields. However, imidazo[1,2-
a]pyridine (1aa) and 1H-indole (1ab) were unreacted
under the optimal reaction conditions.
Table 3. Substrate Scope of Perfluoroalkylation of
[a,b]
Imidazopyridines.
[
a]
Reaction conditions: 1 (0.2 mmol), 2a (0.8 mmol),
PhI(OAc) (2.0 equiv), CsF (4.0 equiv), CH CN (1.5 mL)
at 30 C for 3 h.
2
3
°
[
b]
Isolated yields.
[
a]
Reaction conditions: 1 (0.2 mmol), 2b or 2c (0.8 mmol),
PhI(OAc) (2.0 equiv), CsF (4.0 equiv), CH CN (1.5 mL)
at 30 C for 3 h.
The generality of these conditions was then
2
3
evaluated using a range of imidazo[1,2-a]pyridines
with different substituents on either pyridine or
phenyl ring (Table 2, 3a-3v). For example, substrates
with electron-donating groups, such as methyl and
ethyl, on a pyridyl unit proceed smoothly to give the
desired products in good yields (3b-3d, 63-67%
yield), and no drastic change in efficiency was
observed regarding the position of methyl (3b and 3d,
°
[
b]
Isolated yields.
Notably, many biologically active compounds and
drugs, including the angiotensin II receptor antagonist
[14]
+
(
(
DuP 532), the antihypertensive K channel opener
KC-515)
[15]
[16]
and nucleobases
contain
a
perfluoroalkyl group as an essential motif. To further
evaluate the scope and limitation of our method, and
find an efficient method for direct C-H
6
7% and 63% yield). The iodo-containing substrate
gave the desired product in lower yield than the other
halogen (fluoro, chloro, bromo)-substituted ones (3g
vs. 3e, 3f, 3h). Additionally, 6-bromo-7-methyl-2-
perfluoroethylation
of
nonprefunctionalized
heterocyles, the reactions of imidazo[1,2-a]pyridine
derivatives with TMSC2F5 or TMSC3F7 were
explored (Table 3). Gratifyingly, imidazo[1,2-
a]pyridines with various substituents, such as methyl,
methoxyl and chloro, on either pyridine or phenyl
ring showed higher activities, and the desired
products 4a-4h were isolated in satisfactory yields.
phenylimidazo[1,2-a]pyridine
(1i)
performed
smoothly to deliver the desired product in 61% yield.
Subsequently, the effect of substitients on the phenyl
moiety was explored. Both electron-donating (e.g.,
methyl, tert-butyl, methoxyl and methylthio; 3j-3n)
and
electron-withdrawing groups (e.g., cyano,
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201801541
good yields. In addition, the reaction protocol
features mild conditions and good functional group
tolerance. We believe this metal-free C-H
trifluoromethylation or perfluoroalkylation strategy
will gain much importance in organic synthesis and
medicinal chemistry.
Experimental Section
Scheme 2. Control Experiments.
Preparation
of
Trifluoromethylation
and
Perfluoroalkylation of Imidazopyridines: A dried 25 mL
Schlenk tube equipped with a magnetic stir bar was
To gain preliminary mechanistic information about
this reaction, control experiments were carried out.
When the radical scavengers 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) was added to the reaction
mixture, only trace amoumt of desired product could
2
charged with 1 (0.2 mmol, 1.0 equiv), PhI(OAc) (2.0
equiv), CsF (4.0 equiv), CH
3
CN (0.5 mL), Then, the
CN (1.0 mL) was
mixture 2 (0.8 mmol, 4.0 equiv) and CH
3
added. Subsequently, the tube was sealed and the resulting
mixture was stirred at 30 °C for 3 h. After completion of
the reaction, crude production was diluted by addition of
ethyl acetate, filtered over a pad of Celite and eluted with
ethyl acetate. After the eluent had been concentrated under
vacuum, the residue was purified by silica gel plates to
give the pure products. The products were characterized by
be detected. Meanwhile, the TEMPO-CF adduct was
3
detected by GC-MS (Scheme 2, a). In addition, 4.0
equiv of 2,6-di-tert-butyl-4-methyl phenol (BHT) was
added into the reaction system. As a consequence, the
reaction was inhibited and only 6% of the product
was detected (Scheme 2, b). These results suggested
the radical addition process was probably involved in
our system.
1
13
H NMR, C NMR, LC-MS.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (21172200, 21702191) for financial support.
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