Copper(I)-catalyzed direct C-H trifluoromethylation of imidazoheterocycles with Togni's reagent

Article abstract of DOI:10.1016/j.tetlet.2019.01.026

A mild and efficient trifluoromethylation of imidazopyridines with Togni's reagent in the presence of inexpensive base has been realized at room temperature. This methodology has several advantages: (1) using efficient copper(I) as catalyst and inexpensiv

Full text of DOI:10.1016/j.tetlet.2019.01.026

Accepted Manuscript
Copper(I)-Catalyzed Direct C-H Trifluoromethylation of Imidazoheterocycles
with Togni’s Reagent
Ruonan Wang, Jingcai Wang, Qingxuan Tang, Xin Zhao, Junfeng Wang, Yuting
Leng, Yangjie Wu, Junbiao Chang, Yusheng Wu, Zhaoda Zhang, Shiwei Wang
PII:
S0040-4039(19)30038-3
https://doi.org/10.1016/j.tetlet.2019.01.026
TETL 50559
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 November 2018
12 January 2019
14 January 2019
Please cite this article as: Wang, R., Wang, J., Tang, Q., Zhao, X., Wang, J., Leng, Y., Wu, Y., Chang, J., Wu, Y.,
Zhang, Z., Wang, S., Copper(I)-Catalyzed Direct C-H Trifluoromethylation of Imidazoheterocycles with Togni’s
Reagent, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.01.026
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1
Copper(I)-Catalyzed Direct C-H Trifluoromethylation of
Imidazoheterocycles with Togni’s Reagent
Ruonan Wang,1 Jingcai Wang,1 Qingxuan Tang,1 Xin Zhao,1 Junfeng Wang,2 Yuting Leng,1,2* Yangjie
Wu,1* Junbiao Chang,1 Yusheng Wu,1,4 Zhaoda Zhang,2 Shiwei Wang3
1 College of Chemistry and Molecular Engineering, Key Laboratory of Chemical Biology and Organic Chemistry of Henan
Province, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001,
People's Republic of China
2 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149, 13th St.,
Suite 2301, Charlestown, MA 02129, USA
3 School of Mechanics and Engineering Science, Zhengzhou University, Zhengzhou, Henan 450001, People's Republic of China
4 Tetranov Biopharm LLC, Zhengzhou 450052, People's Republic of China
Corresponding Email address: yutingleng@zzu.edu.cn; wyj@zzu.edu.cn.
ABSTRACT
A mild and efficient trifluoromethylation of imidazopyridines with Togni’s reagent in the
presence of inexpensive base has been realized at room temperature. This methodology has
several advantages: (1) using efficient copper(I) as catalyst and inexpensive K3PO4 as base, (2)
no additional oxidants required for this reaction. (3) good functional group tolerance. An array
of trifluoromethylated imidazopyridines with broad functionalities were obtained in acceptable
yields.
Keywords: Imidazopyridines; Togni’s Reagent; Copper; Trifluoromethylation
Introduction
Imidazopyridine and its derivatives exist in a variety of natural products and have
attracted much attention due to their important biological activities and broad utilization in the
pharmaceutical industry.[1] Many commercialized drugs contain this pyridine core such as
alpidem, zolpidem, necopidem, minodronic acid,[2] saripidem,[3] olprinone, zolimidine, etc.
What’s more, imidazopyridines are core ligands in the field of electronic devices and abnormal
N-heterocyclic carbenes.[4] Therefore, a number of efficient processes have been developed for
the synthesis and functionalization of imidazo[1,2-a]pyridines.[5]
The introduction of a trifluoromethyl group into organic molecules can bring unique
alteration of their physical, chemical, and biological properties such as permeability,
bioavailability, and metabolic stability.[6] Therefore, significant attention has been paid to the
developments of versatile and efficacious methodologies to incorporate the trifluoromethyl
group into target molecules in the area of organofluorine chemistry.[7] Recently,
transition-metal-mediated or -catalyzed trifluoromethylation reactions have been developed
intensively to synthesize various CF3-containing compounds.[8]
trifluoromethylation

2
Then photoorganocatalysed
copper-catalyzed trifluoromethylation of imidazopyridines
with Togni’s reagent as a trifluoromethylating reagent in the presence of inexpensive base
K3PO4 at room temperature under air.
Scheme 1 Previous examples and current goals to realize the trifluoromethylation of
imidazopyridines
Results and Discussion
To
optimize
the
reaction
system,
we
examined
the
reaction
of
6-methyl-2-phenylimidazo[1,2-a]pyridine 1a with Togni’s reagent 2 under various conditions,
and the results are summarized in Table 1. We initiated the trifluoromethylation of
6-methyl-2-phenylimidazo[1,2-a]pyridine 1a (0.20 mmol) with Togni’s reagent (0.30 mmol) 2 in
the presence of 10 mol% of CuI and 15 equivalents of NaOH at room temperature in DCM for 6 h,
the desired product 6-methyl-2-phenyl-3-(trifluoromethyl)imidazo[1,2-a]pyridine 3a was isolated
in 43 % yield (entry 1). With the same conditions, we screened various solvents, including EA,
1,4-dioxane, and DMSO (entries 2-4). Among these solvents, 1,4-dioxane was the best one,
affording the desired product in 61% yield (entry 3). To improve the efficiency, different Cu
catalysts such as CuBr, CuCN, [CuIPPh3]4, CuOAc, and Cu(CH3CN)4PF6 were also examined
(entries 5-9). Of these catalysts, [CuIPPh3]4 was the most effective (entry 7). It was found that
3a was obtained in only 39% yield in the absence of Cu catalyst (entry 10). Next, when we
decreased the amount of NaOH to 2 equivalents, the reaction gave 3a in 58% yield (entry 11).
Under the same conditions, reaction was performed with other bases such as Cs2CO3, Na2CO3,
NaHCO3, LiOH, K3PO4 and NaH (entries 12-17), among these bases 3a was isolated in good

3
yield (79%) with K3PO4 (entry 16). The yield of the desired product was dropped by
increasing or decreasing the amount of base (entries 18-19).Decreasing the amount of
[CuIPPh3]4 led to a decrease in the yield (entry 20-21). Only 6% yield of the product was
obtained in the absence of [CuIPPh3]4 (entry 22). This result revealed that copper catalyst is
necessary for our reaction system.
Table 1. Optimization of the reaction conditions a
Entry
1
Catalyst(mol %)
CuI (10)
Base (equiv.)
NaOH (15)
NaOH (15)
NaOH (15)
NaOH (15)
NaOH (15)
NaOH (15)
NaOH (15)
NaOH (15)
Solvent
Yield (%)b
43
DCM
2
CuI (10)
EA
34
3
CuI (10)
1,4-dioxane
DMSO
61
4
CuI (10)
56
5
CuBr (10)
CuCN (10)
[CuIPPh3]4 (5)
CuOAc (10)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
59
6
63
7
67
8
48
9
Cu(CH3CN)4PF6 (10) NaOH (15)
52
10
11
12
13
14
15
16
17
18
19
20
21
22
none
NaOH (15)
NaOH (2)
Cs2CO3 (2)
Na2CO3 (2)
NaHCO3 (2)
LiOH (2)
39
[CuIPPh3]4 (5)
[CuIPPh3]4 (5)
[CuIPPh3]4 (5)
[CuIPPh3]4 (5)
[CuIPPh3]4 (5)
[CuIPPh3]4 (5)
[CuIPPh3]4 (5)
[CuIPPh3]4 (5)
[CuIPPh3]4 (5)
[CuIPPh3]4 (2.5)
[CuIPPh3]4 (1)
none
58
71
65
59
62
K3PO4 (2)
NaH (2)
79
70
K3PO4 (3)
K3PO4 (1)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
67
60
55
24
6
a Reaction conditions: 6-methyl-2-phenylimidazo[1,2-a]pyridine 1a (0.2 mmol, 1.0 equiv.), Togni’s
reagent 2 (0.3 mmol, 1.5 equiv.), catalyst, base, and solvent (1.5 mL) at room temperature for 6 h.
b Isolated yield.
With the optimized reaction conditions in hand (Table 1, entry 16), we set out to
investigate the substrate scope of this trifluoromethylation reaction to show the generality of
this methodology (Table 2). First, imidazo[1,2-a]pyridines substrates bearing methyl group at
different positions efficiently reacted with trifluoromethylating agent under the standard
conditions to give the corresponding trifluoromethylated products in good yield (3a-3c). To our
delight, both electron-donating groups, such as methyl, methoxy, methylthio, and

4
electron-withdrawing groups, such as trifluoromethyl, cyano, fluoro, chloro, bromo, on the
phenyl ring at the 4-position of imidazopyridines were compatible to this reaction system in
satisfactory yields (3e-3i and 3k-3m). The imidazopyridines with meta-substituents on the
phenyl ring underwent the reaction successfully to give the corresponding trifluoromethylated
products
in
modest
to
good
yields
(3n-3p).
Interestingly,
7-methoxy-2-phenylimidazo[1,2-a]pyridine 1q provided the corresponding product 3q in a
higher yield than the product 3r afforded from 6-methoxy-2-phenylimidazo[1,2-a]pyridine 1r.
The imidazopyridines bearing bromo, chloro on the pyridine ring smoothly reacted to give the
desired products (3s and 3t). In addition, 2-(thiophen-2-yl)imidazo[1,2-a]pyridine and
2-phenylimidazo[1,2-a]pyrimidine also reacted well to afford the corresponding products in
good yields. Finally, the C-2 alkyl-substituted imidazo[1,2-a]pyridine and simple
imidazo[1,2-a]pyridine were also investigated under the standard conditions affording the
desired products in the yield of 47% and trace respectively (3w and 3x)
Table 2. The scope of imidazo[1,2-a]pyridinesa,b

5
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv.), Togni’s reagent 2 (0.3 mmol, 1.5 equiv.),
b
[CuIPPh3]4 (5 mol%), K3PO4 (2 equiv.), and 1,4-dioxane (1.5 mL) at room temperature for 6 h.
Isolated yield.
To gain insight into the reaction mechanism, two control experiments were performed
under the optimized conditions (Scheme 2). When the radical scavengers TEMPO and
1,1-diphenylethylene were added separately to the trifluoromethylation reaction mixture, only
19
a small amount of product was isolated, and F NMR analysis showed that the compound 4
was produced (Scheme 2, eqs 1 and 2 ). These results suggested that this reaction possibly
involve a radical pathway.
Scheme 2. Controlled Experiments
On the basis of above control experiments and previous reports[13,14], a plausible
mechanism for this reaction is outlined in Scheme 3. First, the CF3 radical and Cu(II)
intermediate A are generated by a single-electron transfer (SET) from Cu(I) to 2. Subsequently,
the CF3 radical reacts with the imidazopyridine 1 to form the radical intermediate B. The
oxidation of B by Cu(II) intermediate A results in a cationic intermediate C, accompanied by
the regeneration of Cu(I) catalyst. Finally, trifluoromethylated imidazopyridine 3 are generated
from cationic intermediate C via the base-promoted deprotonation.

6
Scheme 3. Plausible mechanism.
Conclusions
In summary, we have developed an efficient copper-catalyzed trifluoromethylation of
imidazopyridines with Togni reagent as a trifluoromethylating reagent at room temperature.
Mechanistic investigations suggested that this reaction possibly involve a radical pathway.
Clean reaction, ease of product isolation, mild reaction conditions, the use of inexpensive
reagent and a simple experimental procedure are the notable advantages of the method and
these features will make this procedure practical and synthetically useful. Further investigation
on the application of this synthetic methodology is currently underway.
Acknowledgements
We gratefully acknowledge National Science Foundation of China(51603192, 21172200) and
Natural Science Foundation of Henan Province (182300410211) for financial support of this
research.
References
1. (a) Baviskar, A. T.; Amrutkar, S. M.; Trivedi, N.; Chaudhary, V.; Nayak, A.; Guchhait, S.
K.; Banerjee, U. C.; Bharatam, P. V.; Kundu, C. N. ACS Med. Chem. Lett., 2015, 6, 481;
(b) Stasyuk, A. J.; Banasiewicz, M.; Cyrański M. K.; Gryko, D. T.; J. Org. Chem., 2012,
77, 5552.
2. (a) Langer, S. Z.; Arbilla, S.; Benavides, J.; Scatton, B. Adv. Biochem. Psychopharmacol.
1990, 46, 61; (b) Mizushige, K.; Ueda, T.; Yukiiri, K.; Suzuki, H. Cardiovasc. Drugs Rev.
2002, 20, 163.
3. (a) Almirante, L.; Polo, L.; Mugnaini, A.; Provinciali, E.; Rugarli, P.; Biancotti, A.;
Gamba, A.; Murmann, W.; J. Med. Chem. 1965, 8, 305. (b) Ma, G. Z.; Leng, Y. T.; Wu, Y.
S., Wu, Y. J. Tetrahedron, 2013, 69, 902.
4. Wan, J.; Zheng, C.-J.; Fung, M.-K.; Liu, X.-K.; Lee, C.-S.; Zhang, X.-H. J. Mater. Chem.
2012, 22, 4502.

7
5. (a) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A. Chem. Commun., 2015, 51, 1555; (b)
Wang, H.; Xu, W.; Xin, L.; Liu, W.; Wang, Z.; Xu, K.; J. Org. Chem., 2016, 81, 3681; (c)
Wu, S.-S.; Feng, C.-T.; Hu, D.; Huang, Y.-K.; Li, Z.; Luoa, Z.-G.; Mac, Si.-T. Org. Biomol.
Chem., 2017, 15, 1680.
6. (a) Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005, 44, 214; (b) Schlosser, M.
Angew. Chem. Int. Ed. 2006, 45, 5432; (c) Mller, K.; Faeh, C.; Diederich, F. Science 2007,
317, 1881; (d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008,
37, 320.
7. (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320;
(b) Mꢀller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881; (c) Liang, T.; Neumann,
C. N.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52, 8214; (d) Alonso, C.; Martínez de
Marigorta, E.; Rubiales, G.; Palacios, F. Chem. Rev. 2015, 115, 1847.
8. (a) Xu, J.; Fu, Y.; Luo, D.-F.; Jiang, Y.-Y.; Xiao, B.; Liu, Z.-J.; Gong, T.-J.;. Liu, L. J. Am.
Chem. Soc. 2011, 133, 15300; (b) Dai, J.-J.; Fang, C.; Xiao, B.; Yi, J.; Xu, J.; Liu, Z.-J.;
Lu, X.; Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 8436; (c) Charpentier, J.; Früh, N.;
Togni, A. Chem. Rev. 2015, 115, 2, 650; (d) Alonso, C.; Martínez de Marigorta, E.;
Rubiales, G.; Palacios, F. Chem. Rev. 2015, 115, 1847; (e) Besset, T.; Schneider, C.;
Cahard, D. Angew. Chem. Int. Ed. 2012, 51, 5048; (f) Wu, X.-F.; Neumann, H.; Beller, M.
Chem. - Asian J. 2012, 7, 1744; (g) Chu, L.-L.; Qing, F.-L. J. Am. Chem. Soc. 2012, 134,
1298; (h) Mu, X.; Chen, S.; Zhen, X.; Liu, G. Chem. - Eur. J. 2011, 17, 6039.
9. Monir, K.; Bagdi, A. K.; Ghosh, M.; Hajra, A. J. Org. Chem. 2015, 80, 1332.
10. Ji, X.-M.; Wei, L.; Chen, F.; Tang, R.- Y. RSC Adv. 2015, 5, 29766.
11. Lefebvre, Q.; Hoffmann, N.; Rueping, M. Chem. Commun., 2016, 52, 2493.
12. Wu, Y.; Zhang, H.-R.; Jin, R.-X.; Lan, Q.; Wang, X.-S. Adv. Synth. Catal. 2016, 358,
3528.
13. (a) Kuninobu, Y.; Nishi, M.; Kanai, M. Org. Biomol. Chem. 2016, 14, 8092; (b) Zhang, Y.;
Guo, D. M.; Ye, S. Y.; Liu, Z. C.; Zhu, G. G. Org. Lett., 2017, 19, 1302.
14. Gao, X. Y.; Geng, Y.; Han, S. J.; Liang, A. P.; Li, J. Y.; Zou D.P.; Wu, Y. S.; Wu, Y. J. Org.
Lett. 2018, 20, 3732.
Supplementary Material
Supplementary data associated with this article can be found in the online version.
1. Cu(I)-catalyzed trifluoromethylation of imidazoheterocycles with Togni’s Reagent.
2. Simple imidazoheterocycles to trifluoromethylation product at room condition.
3. Clean reaction, ease of product isolation and a simple experimental procedure.
Graphical Abstract.

8
Copper(I)-Catalyzed Direct C-H
Trifluoromethylation of Imidazoheterocycles
with Togni’s Reagent
i’s
Ruonan Wang, Jingcai Wang , Qingxuan Tang, Xin Zhao,
Junfeng Wang, Yuting Leng,* Yangjie Wu,* Junbiao Chang,
Yusheng Wu, Zhaoda Zhang, Shiwei Wang
8