Highly regioselective palladium-catalyzed direct cross-coupling of imidazo[1,2-a]pyridines with arylboronic acids

Article abstract of DOI:10.1016/j.catcom.2014.06.028

A highly regioselective method for the palladium-catalyzed direct cross-coupling of imidazo[1,2-a]pyridines with arylboronic acids has been developed by using O₂ as oxidant. This process can be applied to a wide range of imidazo[1,2-a]pyridines and arylboronic acids with excellent C-3-regioselectivity. It provides a new way for developing CC bond-forming processes of multisubstituted imidazo[1,2-a]pyridines, which are common structural motifs in natural products and pharmaceuticals.

Full text of DOI:10.1016/j.catcom.2014.06.028

Highly Regioseletive Palladium-Catalyzed Direct Cross-coupling of
Imidazo[1,2-a]pyridines with Arylboronic Acids
Limin Zhao, Haiying Zhan, Jinqiang Liao, Jianping Huang, Qinlin Chen,
Huifang Qiu, Hua Cao
PII:
DOI:
Reference:
S1566-7367(14)00252-0
doi: 10.1016/j.catcom.2014.06.028
CATCOM 3953
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
18 April 2014
23 June 2014
24 June 2014
Please cite this article as: Limin Zhao, Haiying Zhan, Jinqiang Liao, Jianping Huang,
Qinlin Chen, Huifang Qiu, Hua Cao, Highly Regioseletive Palladium-Catalyzed Direct
Cross-coupling of Imidazo[1,2-a]pyridines with Arylboronic Acids, Catalysis Communica-
tions (2014), doi: 10.1016/j.catcom.2014.06.028
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ACCEPTED MANUSCRIPT
Highly Regioseletive Palladium-Catalyzed Direct Cross-coupling of
Imidazo[1,2-a]pyridines with Arylboronic Acids
Limin Zhao, Haiying Zhan, Jinqiang Liao, Jianping Huang, Qinlin Chen, Huifang Qiu, Hua Cao*
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University,
Guangzhou 510006, P.R. of China
*E-mail: caohua@gdpu.edu.cn
Abstract
A highly regioselective method for the palladium-catalyzed direct cross-coupling of
imidazo[1,2-a]pyridines with arylboronic acids has been developed by using O2 as oxidant. This
process can be applied to a wide range of imidazo[1,2-a]pyridines and arylboronic acids with
excellent C-3-regioselectivity. It provides a new way for developing C-C bond-forming processes
of multisubstituted imidazo[1,2-a]pyridines, which are common structural motifs in natural
products and pharmaceuticals.
Keywords: Regioseletive; Palladium-Catalyzed; Imidazo[1,2-a]pyridines; Cross-coupling;
Arylboronic Acids
Introduction
Transition metal-mediated cross-coupling reactions are one of the most powerful tools for the
formation of carbon-carbon bonds via C-H bonds activation.[1-13] Among transition metals,
Pd-catalyzed[14-21] cross-coupling reactions have become one of the most widely and versatile
used processes for the formation of carbon-carbon bonds due to its high synthetic efficiency. With
the development of chemistry, organic chemists are expected not only to design elegant
transformations for formation of carbon-carbon bonds but also to improve the catalyst system to
maximize resource utilization, especially for environmental benign and safety. Therefore, the
discovery of direct cross-coupling for the formation of C-C bonds has attracted great attention of
organic chemists. Achieving selective transition-metal-catalyzed direct cross-coupling for the
formation of C-C bonds continues to attract research groups worldwide huge attention, especially
in synthesizing bioactive motifs.
On the other hand, imidazo[1,2-a]pyridine derivatives are one of the important class of
heterocyclic compound[22] and exhibit a wide range of biological activities, such as antiviral,[23]
antiprotozoal,[24] antiherpes[25] and anti-apoptotic properties.[26] During the last years,
significant efforts have been made to develop the conventional methods[27-29] for the synthesis of

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these compounds typically containing the condensation of 2-aminopyridines with α-halo
ketones[30-31] , multicomponent reaction[32] ,transition metal-mediated cross-coupling [33-34] ,
cyclization reactions and so on.[35] Despite facile transformations for their preparation have been
developed, arylation of imidazo[1,2-a]pyridine is still highly favourable by using arylboronic
acids as substrates. Herein, we report the development of a general, regiospecific Pd-catalyzed
direct arylation of imidazo[1,2-a]pyridines with arylboronic acids.
Results and discussion
At the outset of our studies, we chose 2-methylimidazo[1,2-a]pyridine 1a and phenylboronic
acid 2a as initial substrates to optimize the reaction conditions. And the results are summarized in
Table1. Interestingly, the reaction of 1a with 2a afforded the desired
2-methyl-3-phenylimidazo[1,2-a]pyridine (3a) in 59% yield (entry 1, Table 1) by using Pd(OAc)2
(5 mol %) as catalyst and Cu(OAc)2 as oxidant in 1,4-dioxane at 120 ℃ for 24 h. Other oxidants,
such as CuCl2 (entry 2, Table 1), AgOAc (entry 3, Table 1), Ag2CO3 (entry 4, Table 1) and O2
(entry 7, Table 1) afforded the desired product 3a in 33-39% yields, respectively. No product was
observed when BQ (entry 5, Table 1) or Oxone (entry 6, Table 1) was used as oxidant or in the
absence of oxidant (entry 8, Table 1). To our delight, a good yield of 85% was obtained, when the
reaction was carried out by using Cu(OAc)2 (10 mol%) and O2 (with oxygen balloon) as
co-oxidant (entry 9, Table 1). Subsequently, our study focused on the arylation of 1a by testing
various ligands, such as pyridine, bipy, DMEDA (Dimethylethylenediamine)(entries 10-12, Table
1). However, the yield was lower than expected. We further explored the reaction in various
solvents (entries 13-17, Table 1), and 1,4-dioxane was demonstrated as the best choice.
Table 1. Optimization of Reaction Conditions. a
N
N
Pd(OAc)2, ligand
CH3+
CH3
PhB(OH)2
N
N
oxidant, 120oC, 24 h
H
Ph
1a
2a
3a
Entry Oxidant
Ligand
Solvent Yield
(%)b
1
2
Cu(OAc)2
CuCl2
Phen
Phen
Dioxane 59%
Dioxane 37

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3
4
5
AgOAc
Ag2CO3
BQ
Phen
Phen
Phen
Phen
Phen
Phen
Dioxane 33
Dioxane 39
Dioxane Trace
Dioxane Trace
Dioxane 36
6
Oxone
7c
8
O2
c
-
Dioxane
Dioxane 85
Cu(OAc)2/O2 pyridine Dioxane 21
Cu(OAc)2/O2 Bipy Dioxane 44
Cu(OAc)2/O2 DMEDA Dioxane 17
-
9
Cu(OAc)2/O2 Phen
10
11
12
13
14
15
16
17
Cu(OAc)2/O2 Phen
Cu(OAc)2/O2 Phen
Cu(OAc)2/O2 Phen
Cu(OAc)2/O2 Phen
Cu(OAc)2/O2 Phen
Toluene 78
DMA
NMP
DMSO
DMF
67
60
10
13
a
Reaction conditions: 2-methylimidazo[1,2-a]pyridine 1a (0.5 mmol), phenylboronic acid (2a)
(1.2 mmol), Pd(OAc)2 (5 mol%), O2 (600 mL), other oxidant (10 mol%), ligand (10 mol%) in 3
mL of solvent at 120 °C for 24 h. b GC yield. c oxygen balloon
Under optimized reaction conditions, the scope of this direct arylation of
imidazo[1,2-a]pyridines with arylboronic acids were further explored. Various 2-sustituted
imidazo[1,2-a]pyridines with different arylboronic acids were firstly examined and the results are
described in Table 2. As shown in Table 2, different substituents on the aromatic ring of
arylboronic acids were suitable partners and gave corresponding products in moderate to good
yields in this process. The position of the substituents on the phenyl ring of arylboronic acids
played a critical role and meta or para substituents gave the good yields, while ortho-substituted
arylboronic acid give 3d in moderate yield. It is noteworthy that this strategy also tolerated
electron-rich and electron-poor groups on the aromatic of boronic acids. As expected, a variety of
2-sustituted imidazo[1,2-a]pyridines were compatible with the direct arylation. Notably, the
substrate containing strong electron-withdrawing group 2-(trifluoromethyl)imidazo[1,2-a]pyridine
was also tested and afforded corresponding products 3f and 3u in moderate yield.
Table 2. Pd-catalyzed Arylation of 2-substituted Imidazo[1,2-a]pyridines a
5 mol%Pd(OAc)2
N
N
Cu(OAc)2/O2
R1
R2
R1
R2
ArB(OH)2
+
N
Phen,120oC
1,4-dioxane
N
Ar
H
1
2
3

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N
N
N
CH3
CH3
CH3
CH3
CH3
N
N
N
Cl
3a 79%
3c 71%
Cl
3b 73%
N
N
N
N
N
CH3
CH3
N
H3C
3d 50%
CH3
F
3e 75 %
3f 78 %
N
N
N
N
CH3
CH3
N
N
CH3
CH3
CH3
Cl
CH3
3i 82%
Cl
3g 77%
3h 78%
CH3
CH3
CH3
N
N
N
CH3
CH3
N
N
N
CH3
CH3
CH3
H3C
Cl
Et
3j 80%
3k 81%
3l 74%
CH3
CH3
CH3
N
CH3
CH3
CH3
N
CH3
CH3
CH3
N
N
N
N
Cl
CH3
H3C
3o 77%
3m 75%
Et
3n 78%
CH3
CH3
CH3
N
N
N
N
Ph
Ph
N
N
3q 75%
OCH3
3p 79%
Cl
3r 78%

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N
N
CF3
CF3
Ph
N
N
N
N
Cl
Cl
3s 78%
a Isolated yields;
3t 55%
3u 65%
Subsequently, regioselective Pd-catalyzed direct arylation was investigated. And the results
were outlined in Table 3. The effect of substituents on the arylboronic acids and
imidazo[1,2-a]pyridine was tested. Seen from Table 3, moderate to good isolated yields could be
achieved under optimized reaction conditions. The results indicated arylboronic acids with
different substituent groups presented on the aromatic ring could react smoothly, and the resulting
corresponding products were obtained in good yields. It should be noted that the present arylation
performed highly regioselectively and the products were obtained as the sole product. All those
cases clearly showed that an efficient and highly regioselective arylation has been developed.
Table 3. Regioselective Pd-catalyzed Direct Arylation of Imidazo[1,2-a]pyridines a
5 mol%Pd(OAc)2
N
N
Cu(OAc)2/O2 R1
H
R1
H
ArB(OH)2
+
N
N
Phen,120oC
1,4-dioxane
Ar
H
1
2
4
N
N
N
N
N
N
CH3
CH3
CH3
4a 75%
CH3
4b 80%
N
Cl
4c 83%
N
N
N
N
N
CH3
CH3
H3C
4f 78 %
Cl
Cl
4d 76%
4e 75%

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N
H3C
N
N
N
N
N
H3C
H3C
F
CH3
4i 78%
4g 70%
4h 73%
N
H3C
N
N
N
N
N
Cl
Cl
CH3
4k 65%b
H3C
Cl
4j 80%
4l 67%b
a
b
Isolated yields; The yields of 4k and 4l are only moderate because part of the
substrate 6-chloroimidazo[1,2-a]pyridine not been fully converted.
A plausible mechanism of Pd-catalyzed direct arylation of imidazo[1,2-a]pyridine with
arylboronic acids has been described in Scheme 1. The mechanism was in consistence with
previous studies on the arylation of heterocycles. First, The C-H bond at 3-position of 1a was
cleaved by Pd(OAc)2 to give the intermediate A. And then the key intermediate B was formed
from immediate A coordinated with 2a, which would then undergo reductive elimination to give
the product 3a and regenerated the palladium catalyst so that it could participate again in the
catalytic cycle.
N
CH3
N
Pd(OAc)2
AcOH
CH3
oxidant
N
Pd 0
N
CH3
Pd OAc
N
L
A
Ph
N
N
PhB(OH)2
CH3
N
Pd Ph
B
L
Scheme 1. Proposal Mechanism

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Conclusions
In summary, we have described an efficient and highly regioselective Pd-catalyzed direct
cross-coupling of imidazo[1,2-a]pyridine with arylboronic acids for the formation of C-C bonds.
This transformation is applicable to a variety of imidazo[1,2-a]pyridines and arylboronic acids and
gives the corresponding products in moderate to good yields. It also provides a new approach to
construct various functionalized imidazo[1,2-a]pyridines core π systems which is broadly
applicable for the synthesis of biologically active molecules. This process has two advantages over
our previous arylation of imidazo[1,2-a]pyridines: 1) no need for pre-functionalization of the
substrate; 2) non-toxic oxygen as oxidant.
Acknowledgments
The work was financially Supported by Foundation for National Natural Science Foundation of
China (21302023 and 21272044)，the Project of Department of Education of Guangdong
Province (2013kjcx0111) and Distinguished Young Talentsin Higher Education of Guangdong,
China (2012LYM_0086).
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Highlights
Pd-catalyzed cross-coupling of imidazo[1,2-a]pyridines with aryl boronic acids;
It represents excellent C-3-regioselectivity direct arylation;
A new method for the formation of C-C bond to prepare imidazo[1,2-a]pyridines;