Highly regioselective CH bond functionalization of imidazo[1,2-a]pyridines with aryl halides catalyzed by Ru-arene complex

Article abstract of DOI:10.1016/j.catcom.2012.04.032

An effective Ru-catalyzed coupling reaction of imidazo[1,2-a]pyridines and aryl halides is reported for the synthesis of polysubstituted imidazo[1,2-a]pyridines through CH bond cleavages. The current study presents a convenient strategy to synthesize poly

Full text of DOI:10.1016/j.catcom.2012.04.032

Catalysis Communications 26 (2012) 11–14
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Catalysis Communications
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Short Communication
Highly regioselective C\H bond functionalization of imidazo[1,2-a]pyridines with
aryl halides catalyzed by Ru-arene complex
b
a
a
a
a,
Hai Yang a, , Liping Yang , Yuan Li , Fan Zhang , Huajie Liu , Bing Yi
⁎
⁎
a
College of Chemistry and Chemical Engineering, Hunan Institute of Engineering, Xiangtan 411104, PR China
Department of Environmental Engineering, Xiamen University of Technology, Xiamen 361024, PR China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 April 2012
Received in revised form 27 April 2012
Accepted 30 April 2012
Available online 11 May 2012
An effective Ru-catalyzed coupling reaction of imidazo[1,2-a]pyridines and aryl halides is reported for the syn-
thesis of polysubstituted imidazo[1,2-a]pyridines through C\H bond cleavages. The current study presents a
convenient strategy to synthesize polysubstituted imidazo[1,2-a]pyridine, a common structural motif in natural
products and pharmaceuticals. Desired products in considerable yields can be obtained in the presences of
[RuCl2(p-cymene)]2 and Cs2CO3 in DMF at 120 °C after 15 h.
© 2012 Elsevier B.V. All rights reserved.
Keywords:
Imidazo[1,2-a]pyridine
Arylation
Ru-catalyzed
Coupling reaction
1. Introduction
versatile and widely used metals for the direct arylation to synthesize
diaryl compounds [30–32].
Synthesis of polysubstituted imidazo[1,2-a]pyridines has received
great attention because of their broad range of biological activities.
Imidazo[1,2-a]pyridines have been prepared via the efficient C\H
arylation of azole heteroarenes catalyzed by palladium complexes [1].
Later, the synthesis of 2,3-diarylimidazo[1,2-a]pyridines was achieved
through Suzuki cross-coupling reaction followed by a direct arylation
[2]. Cao et al. also reported a convenient method for the copper(I)-
catalyzed arylation of substituted imidazo[1,2-a]pyridines [3].
Morevoer, the imidazo[1,2-a]pyridine derivatives as important fine
chemicals have been found to be key structural units in many na-
tural products and drugs, such as alpidem, necopidem, saripidem,
olprinone, zolpidem and zolimidine (Fig. 1), which are all commercially
available [4,5]. Therefore, exploring new strategies to prepare
imidazo[1,2-a]pyridine derivatives is still important in organic
synthesis.
Transition-metal-catalyzed direct C\H functionalization represents
a powerful strategy for the formation of heteroaromatic molecules via
coupling of two different fragments [6–9]. Significant progress has
been achieved for the direct formation of C\C bonds as biaryls via
C\H activation using various proelectrophiles or pronucleophiles. The
reactions were catalyzed by various transition-metal based complexes,
such as Pd- [10,11], Cu- [12–14], Ni- [15–17], Co- [18–20], Mn- [21,22],
Fe- [23–25], Rh [26–29], or/and Ru [30,31] system. Among transition-
metal-catalyzed cross‐coupling reactions, Pd, Rh, and Ru are the most
In order to explore an efficient catalytic activation system for the
synthesis of polysubstituted imidazo[1,2-a]pyridine derivatives via
arylation reaction, we herein report a highly versatile Ru-catalyzed cou-
pling reaction of imidazo[1,2-a]pyridines and aryl halides for the forma-
tion polysubstituted imidazo[1,2-a]pyridine derivatives as shown in
Scheme 1. This synthetic approach involves the formation of inter-
molecular aryl-aryl bond by Ru-mediated arylation of imidazo[1,2-a]
pyridine with aryl halides in the presences of a suitable ligand and an in-
organic base. And this strategy also addresses issues of synthetic effi-
ciency, in the case of the regioselective Ru-catalyzed C-3 arylation
reaction.
2. Experimental
Typical experimental procedure for the synthesis of 3a: All reac-
tions were performed under air atmosphere in a round bottom flask
equipped with a magnetic stir bar. [RuCl2(p-cymene)]2 (0.05 equiv),
Cs2CO3 (2 equiv), 1a (1 equiv), 2a (1.2 equiv) and 3 mL DMF were
added successively. The mixture was stirred at 120 °C for 15 h. After
the reaction (monitored by TLC), water (10 mL) was then added.
The solution was extracted with ethyl acetate (3×15 mL), and the
combined extract was dried with anhydrous MgSO4. Solvent was
then removed, and the residue was separated by column chromatog-
raphy to yield the pure sample 3a.
1H NMR spectra and 13C NMR spectra were recorded using a
Bruker Avance 400 MHz NMR spectrometer and referenced to
7.26 ppm and 77.0 ppm for chloroform solvent respectively with
TMS as internal standard. Mass spectra were recorded on a Shimadzu
⁎
Corresponding authors. Tel.: +86 731 58680049; fax: +86 731 58680125.
E-mail addresses: yanghai1001@163.com (H. Yang), bingyi2004@126.com (B. Yi).
1566-7367/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2012.04.032

12
H. Yang et al. / Catalysis Communications 26 (2012) 11–14
Fig. 1. Model drug structures containing imidazo[1, 2-a]pyridine.
GCMS–QP5050A at an ionization voltage of 70 eV equipped with a DB‐
WAX capillary column (internal diameter=0.25 mm, length=30 m).
TLC was performed using commercially prepared 100–400 mesh silica
gel plates (GF254), and visualization was effected at 254 nm. All the
other chemicals were purchased from Aldrich Chemicals.
imidazo[1,2-a]pyridine (1a) as the substrate, we carried out the reac-
tions with various types of aryl halides, such as PhX, o-MePhX, m-
MePhX, p-MePhX, o-EtPhX, and p-CNPhX (Table 2, entries 1–6). The
higher isolated yield can be achieved with the para-substitued aryl
halide but the relatively lower with the ortho-substitued aryl halide
as shown in entries 2–4. However, when we replaced the electron-
donating group with a strong electron-withdrawing group like cyan
(see entries 4 and 6), the yield decreased remarkably. The results indi-
cate that electron-withdrawing substituted groups on aryl halides disfa-
vor the reaction. Subsequently, the influence of different substituted
groups on imidazo[1,2-a]pyridine ring was investigated. When we
changed the substrate from 2-methyl-imidazo[1,2-a]pyridine (1a) to
2-(trifluoromethyl)-imidazo[1,2-a] pyridine (1b) by replacing the
methyl group on C-2 position of the imidazole ring with an electron-
withdrawing group ‘trifluoromethyl’ (Table 2, entries 7–10), the sub-
strate of 1b exhibited better performances than 1a if using the same
3. Results and discussion
The potential catalysts and suitable reaction conditions were
screened using the substrates of 2-methyl-imidazo[1,2-a]pyridine
1a and iodobenzene 2a for arylation reaction (Table 1). Firstly, the
coupling reaction does not take place between 1a and 2a without ru-
thenium precursor (Table 1, entry 1). The effect of Ru source was then
investigated. Interestingly, [RuCl2(p-cymene)]2 (5 mol%) shows the
highest activity to give arylation product 3a in good yield under the
following condition: DMF (3.0 mL), 15 h, 120 °C, 1a (0.5 mmol), 2a
(0.6 mmol), Ru-catalyst (5 mol%), and K2CO3 (1.0 mmol) (Table 1,
entry 6). However, relative lower activity was obtained when the
other Ru-catalysts were applied, such as Ru3(CO)12, RuCl2(H2O)n,
RuCl2(PPh3)3 and Ru(acac)2 (Table 1, entries 2–5). Subsequently, by
fixing [RuCl2(p-cymene)]2 and K2CO3 as Ru-catalyst and inorganic
base, the reaction was carried out in different solvents instead of
DMF, such as toluene, dimethyl sulfoxide (DMSO), N-methyl-2-
pyrrolidone (NMP) and dimethyl acetamide (DMAc). Only 22–72%
of the arylation product and the remaining starting materials can be
isolated (Table 1, entries 7–10), indicating that DMF provides the
best performance compared to the other solvents. Next, the effect of
inorganic bases was also studied. Among various inorganic bases ex-
amined, Cs2CO3 is the most efficient. The catalytic efficiency of the in-
organic bases can be arranged in a deceasing order as following:
Cs2CO3, K2CO3, Na2CO3 NaHCO3, KH2PO4 and KOAc (Table 1, entries
6, 11–15). No significant decrease of yields was found when the reac-
tion was protected by N2 atmosphere (Table 1, entry 12). Finally, the
reaction temperature was also tested. It can be seen that the temper-
ature of 120 °C is quite necessary and lower or higher temperature is
not suitable for this transformation (Table 1, entries 16–18).
Table 1
Condition screening for the Ru-catalyzed direct arylation reaction of 1a with 2a.
Entry
Catalyst (mol)a
Base
Solvent
T (°C)
Yield (%)b
1
2
3
4
5
6
7
8
No catalyst
Ru3(CO)12
RuCl2(H2O)n
RuCl2(PPh3)3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
NaHCO3
KH2PO4
KOAc
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
DMSO
NMP
DMAc
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
120
120
120
120
120
120
Reflux
120
120
120
120
120
120
120
120
100
140
reflux
–
43
31
52
51
79
22
61
72
54
59
86/85c
33
21
19
63
41
–
Ru(acac)2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
9
10
11
12
13
14
15
16
17
18
Under optimized conditions (Table 1, entry 12), we then explored
the scope of the catalytic system for arylation reaction of substituted
imidazo[1,2-a]pyridines with aryl halides. Firstly, by fixing 2-methyl-
Cs2CO3
Cs2CO3
Cs2CO3
a
Reaction condition: 1a (0.5 mmol) and 2a (0.6 mmol), Ru-catalyst (5 mol%), sol-
vent (3 mL), 15 h.
b
GC yield.
Reaction under N2 atmosphere.
c
Scheme 1. Ru-catalyzed arylation reaction.

H. Yang et al. / Catalysis Communications 26 (2012) 11–14
13
Table 2
Ru-catalyzed direct arylation of imidazo[1,2-a]pyridines with aryl halides.a
Entry
1
Substituted imidazo[1,2-a]pyridines
ArX
Products
3a
Yield (%)b
1a
X=I, 84
X=Br, 74
R1 =H; R2 =CH3
2
3
1a
1a
X=I, 80
X=Br, 70
3b
X=I, 89
X=Br, 71
3c
4
5
1a
1a
X=I, 93
X=Br, 86
3d
X=I, 84
X=Br, 72
3e
3f
6
7
1a
X=I, 81
X=Br, 70
1b
X=I, 90
X=Br, 77
R1 =H; R2 =CF3
3g
8
1b
X=I, 90
X=Br, 82
3h
3i
9
1b
1b
X=I, 92
X=Br, 85
10
X=I, 86
X=Br, 75
3j
11
12
13
1c
X=I, 87
X=Br, 71
R1 =6-Cl; R2 =CH3
3k
3l
1c
1c
X=I, 80
X=Br, 71
X=I, 84
X=Br, 77
3m
a
Reaction condition: 1 (1 equiv) and 2 (1.2 equiv), Ru‐catalyst (5 mol%), solvent (3 mL), 15 h, 120 °C.
Isolated yield.
b

14
H. Yang et al. / Catalysis Communications 26 (2012) 11–14
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://
dx.doi.org/10.1016/j.catcom.2012.04.032.
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4. Conclusion
In summary, based on C\H activation, an efficient, direct Ru-
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regioselectivity for imidazo[1,2-a]pyridines containing C-2 substitut-
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The authors gratefully acknowledge the generous financial support
from National Natural Science Foundation of China (No. 21172064,
20972045), Provincial Natural Science Foundation of Hunan (No.
10JJ2006), the Key Scientific Research Fund of Hunan Provincial Education
Department (No. 10A022), and the Starting Research Fund for Ph.D from
Hunan Institute Engineering.