Direct arylation of imidazo[1,2-a ]pyridine at C-3 with aryl iodides, bromides, and triflates via copper(I)-catalyzed C-H bond functionalization

Article abstract of DOI:10.1021/ol300232a

A convenient method for the copper(I)-catalyzed arylation of substituted imidazo[1,2-a]pyridine has been developed. This method is applicable to a variety of aryl electrophiles, including bromides, iodides, and triflates. It represents the first general p

Full text of DOI:10.1021/ol300232a

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1688–1691
Direct Arylation of Imidazo[1,2-a]pyridine
at C-3 with Aryl Iodides, Bromides, and
Triflates via Copper(I)-Catalyzed CꢀH
Bond Functionalization
Hua Cao,*,† Haiying Zhan,† Yuanguang Lin,† Xiulian Lin,† Zuodong Du,† and
Huanfeng Jiang*,‡
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University,
Guangzhou 510006, P. R. China, and School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou 510640, P. R. China
hua.cao@mail.scut.edu.cn; jianghf@scut.edu.cn
Received January 29, 2012
ABSTRACT
A convenient method for the copper(I)-catalyzed arylation of substituted imidazo[1,2-a]pyridine has been developed. This method is applicable to
a variety of aryl electrophiles, including bromides, iodides, and triflates. It represents the first general process for C-3 arylation of substituted
imidazo[1,2-a]pyridine by Cu(I) catalysis to construct various functionalized imidazo[1,2-a]pyridine core π-systems.
Transition-metal-catalyzed direct CꢀH functionaliza-
tion represents a powerful tool for the formation of
heteroaromatic molecules via coupling of two different
fragments in organic synthesis1 and has attracted consider-
able interest2 among chemists. These heteroaromatic mol-
ecules play an important role in predominant structural
motifs of many natural products and bioactive molecules.3
In recent decades, a variety of direct arylation reactions to
synthesize these compounds have been developed by CꢀH
bond functionalization due to its high efficiency. In partic-
ular, Pd-,4 Rh-,5and Ru-6catalyzed direct CꢀH arylations
of heteroaromatic compounds have been extensively stud-
ied. Compared with those expensive catalysts, inexpensive
Cu,7 Fe,8 and Ni9 salts proved to be highly effective for
direct arylation but showed more potential in future
development. Although a variety of heterocyclic com-
pounds, such as imidazo[2,1-b]thiazole, indolizines, imidazo
[1,5-a]pyrazines, xanthines, and thiazoles, have been devel-
oped to construct heteroaromatic molecules via several
metal-catalyzed direct arylations, there is still an intrinsic
need to develop and construct new heteroaromatic mole-
cules by Cu-catalyzed direct CꢀH functionalization under
much milder conditions and simpler catalytic system.10
† Guangdong Pharmaceutical University.
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H. A.; Koutentis, P. A. Org. Lett. 2011, 13, 1510–1513. (c) Tamba, S.;
Okubo, Y.; Tanaka, S.; Monguchi, D.; Mori, A. J. Org. Chem. 2010, 75,
6998–7001. (d) Caron, L.; Campeau, L.-C.; Fagnou, K. Org. Lett. 2008,
10, 4533–4536. (e) McClure, M. S.; Glover, B.; McSorley, E.; Millar, A.;
Osterhout, M. H.; Roschangar, F. Org. Lett. 2001, 3, 1677–1680. (f)
Kobayashi, K.; Sugie, A.; Takahashi, M.; Masui, K.; Mori, A. Org. Lett.
2005, 7, 5083–5085. (g) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int.
Ed. 2005, 44, 4046–4048. (h) Campeau, L. C.; Rousseaux, S.; Fagnou, K.
J. Am. Chem. Soc. 2005, 127, 18020–18021. (i) Lane, B. S.; Brown, M. A.;
Sames, D. J. Am. Chem. Soc. 2005, 127, 8050–8057. (j) Leclerc, J. P.;
Fagnou, K. Angew. Chem., Int. Ed. 2006, 45, 7781–7786. (k) Nadres,
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‡ South China University of Technology.
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42, 1074–1086. (c) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219,
211–241. (d) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174–238.
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1193. (b) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 3850–3850. (c)
Wang, X.; Leow, D.; Yu, J. Q. J. Am. Chem. Soc. 2011, 133, 13864–
13867.
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Chem. Rev. 2002, 102, 1359–1469. (b) Corbet, J. P.; Mignani, G. Chem.
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r
10.1021/ol300232a
Published on Web 03/14/2012
2012 American Chemical Society

In contrast, imidazo[1,2-a]pyridine derivatives as impor-
tant fine chemicals have been found to be key structural
units in many natural products and drugs and exhibited a
wide range of biological activities,11 such as zolpidem,
zolimidine, and alpidem. Thus, the development of an
efficient transformation to form novel imidazo[1,2-
a]pyridine derivatives is a long-standing and challenging
goal of organic chemists. To the best of our knowledge,
there has been no report of a Cu(I)-catalyzed example of
direct arylation of the imidazo[1,2-a]pyridine.
Table 1. Optimization of Reaction Conditions a
yield
(%)c
entry
cat.
ligandb
base
solvent
2-Methylimidazo[1,2-a]pyridine 1a and iodobenzene 2a
were chosen as model substrates to optimize the reaction
conditions. Without any ligand, treatment of 1a with 2a
using Cs2CO3 as the base and CuCl as the copper source in
DMF afforded very poor conversion, yielding only 5% of
3aa (Table 1, entry 1). In the absence of base, reaction fails
completely (entry 2). The desired product 3aa was ob-
tained in 25% yield, when the reaction was carried out in
the presence of CuCl as the catalyst, PPh3 as the ligand,
and Cs2CO3 as the base at 140 °C for 24 h (entry 3). Other
Cu(I) catalysts, such as CuBr, CuI, CuCN, were examined
at 140 °C for 24 h (entries 4ꢀ6). Excitingly, CuI proved to
be an ideal choice among the catalysts investigated. Sub-
sequently, our study focused on the arylation of 1a by
testing various ligands, such as PBu3, Phen, pyridine, Bpy,
DMEDA, TMEDA, and DABCO (entries 7ꢀ13).The use
of Phen as a ligand significantly improved the catalytic
1
CuCl
CuCl
CuCl
CuBr
CuI
ꢀ
Cs2CO3
ꢀ
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
NMP
toluene
5
2
PPh3
ꢀ
3
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
t-BuOLi
t-BuOK
K3PO4
t-BuOK
t-BuOK
t-BuOK
25
22
39
35
36
70
43
58
56
21
17
73
86
92(87)d
41
86
85
74
4
PPh3
5
PPh3
6
CuCN
CuI
PPh3
7
PBu3
8
CuI
Phen
9
CuI
pyridine
Bpy
10
11
12
13
14
15
16
17
18
19
20
CuI
CuI
DMEDA
TMEDA
DABCO
Phen
CuI
CuI
CuI
CuI
Phen
CuI
Phen
CuI
Phen
CuI
Phen
CuI
Phen
CuI
Phen
(5) (a) Berman, A. M.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2008, 130, 14926–14927. (b) Lewis, J. C.; Berman,
A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2493–
2500. (c) Wiedemann, S. H.; Lewis, J. C.; Ellman, J. A.; Bergman, R. G.
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Bergman, R. G.; Ellman, J. A. Angew. Chem., Int. Ed. 2006, 45, 1589–
1591.
a Reaction conditions: 1a (1 mmol), 2a (1.5 mmol), CuI (5 mol %),
ligand (10 mol %), and base (2.5 mmol) in 2 mL of solvent at 140 °C for
24 h. b Phen = 1,10-phenanthroline; Bpy = 2,20-bipyridine; DMEDA =
N,N0-dimethylethylene diamine; TMEDA = N,N,N,N0-tetramethy-
lethylene diamine; DABCO = 1,4-diazabicyclo[2.2.2]octane. c GC yield.
d Isolated yield.
ꢁ
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3474–3481. (b) Arockiam, P.; Poirier, V.; Fischmeister, C.; Bruneau, C.;
€
Dixneuf, P. H. Green Chem. 2009, 11, 1871–1875. (c) Ozdemir, I.; Demir,
efficiency. Bases such as Cs2CO3, K2CO3, t-BuOLi, t-
BuOK, and K3PO4 were found to facilitate this coupling
reaction, and among them t-BuOK was the best (entries
14ꢀ17). After a variety of solvents were examined, such
as DMF, NMP, DMA, and toluene, DMF was clearly the
best solvent system (entries 18ꢀ20). These preliminary
results revealed that Phen acts as a good ligand with
optimum conditions which includethe presenceoft-BuOK
and CuI as the copper source in DMF solvent at 140 °C for
24 h. The results proved that the conditions previously
reported by Daugulis are optimal for direct arylation.
With the establishment of a viable reaction system, the
scope of this coupling reaction was further expanded and
the results are summarized in Table 2. To explore the scope
of the arylation reaction, a variety of different imidazo[1,2-
a]pyridines (1aꢀ1d) and diverse aryl iodides (2aꢀ2p) were
examined under optimal conditions to form the corre-
sponding product. First, by using 1a as a fixed substrate,
we carried out the arylation of 1a with various types of aryl
iodides. From Table 2, it was found that the reaction
conditions were useful for 2aꢀ2o and in most cases the
corresponding products 3aaꢀ3ao were obtained in mod-
erate to good yields (entries 1ꢀ15). The results clearly
indicate that this protocol is general and applicable for
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P. H. J. Am. Chem. Soc. 2008, 130, 1156–1157. (d) Ackermann, L. Org.
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Chem. Soc. 2011, 133, 13577–13586. (c) Popov, I.; Lindeman, S.;
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Savic, V. Org. Lett. 2011, 13, 2286–2289. (b) Trapani, G.; Franco, M.;
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Org. Lett., Vol. 14, No. 7, 2012
1689

Table 2. Direct Arylation of Substituted Imidazo[1,2-a]pyridine with Aryl Iodidesa
a Reaction conditions: 1 (1 mmol), 2 (1.5 mmol), CuI (5 mol %), 1,10-phenanthroline (10 mol %), and t-BuOK (2.5 mmol) in DMF (2 mL) at 140 °C
for 24 h. b Isolated yield.
reactions of a wide variety of electron-rich and -deficient
aryl iodides. It is noteworthy that the present strategy was
tolerant of many other functional groups including o-F, m-
F, p-F, and p-CN, (entries 9ꢀ11, 15). Also this arylation is
less sensitive to steric factors and gives good yields which
has been evident in all ortho-substituted iodoarenes
(entries 2, 7, 13). Furthermore, other different substituted
imidazo[1,2-a]pyridines, such as 2-(trifluoromethyl)imi-
dazo[1,2-a]pyridine (1b), 6-chloro-2-methylimidazo[1,
2-a]pyridine (1c), ethyl 5-methylimidazo[1,2-a]pyridine-2-
carboxylate (1d), ethyl imidazo[1,2-a]pyridine-2-carboxy-
late (1e), and 2-phenylimidazo[1,2-a]pyridine (1f), were
also tested and coupled with aryl iodides to give the
corresponding products in good yields. From Table 2, it
is observed that this transformation occurs smoothly. Also
this process is applicable for arylation of a variety of electron-
deficient groups at C-2, such as ꢀCF3 and ꢀCO2Et. How-
ever, the corresponding product 3fr was not detected, when
the arylation of 1f with 2r was carried out.
We also applied these direct arylation conditions to
other phenyl electrophiles, such as aryl bromides, triflates.
As shown in Table 3, we are pleased to find that the aryl
bromides coupled with 1a, 1b, or 1c smoothly to afford the
expected products in good yields under the optimal condi-
tions (entries 1ꢀ11). To our surprise, the arylation of the
triflates, such as phenyl triflate and p-tolyl triflate, with 1a or
1b also reacted to give the corresponding product 3aa, 3ad,
3bc in moderate to good yields (entries 1, 3, 8). All of these
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Org. Lett., Vol. 14, No. 7, 2012

Table 3. Arylation of 1 with Aryl Bromides or Triflatesa
Scheme 1. Arylation of 1a with Aryl Dihalides
entry
1
ArX
product
yield (%)b
1
2
3
4
5
7
7
8
9
10
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
X = Br, OTf
X = Br
3aa
3ac
3ad
3af
81 (76)c
79
X = Br, OTf
X = Br
84 (81)
77
X = Br
3ag
3ah
3ak
3bc
3be
3cc
72
X = Br
85
X = Br
81
X = Br, OTf
X = Br
78 (75)c
76
Scheme 2. Proposed Mechanism for CuI-Catalyzed Arylation
X = Br
83
a Reaction conditions: 1 (1 mmol), 2 (1.5 mmol), CuI (5 mol %),1,10-
phenanthroline (10 mol %), and t-BuOK (2.5 mmol) in DMF (2 mL) at
140 °C for 24 h. b Isolated yield. c Using triflates as substrates.
results in Tables 2 and 3 demonstrate clearly that this
copper(I) catalytic systems are applicable to a variety of
aryl electrophiles, including bromides, iodides, and triflates.
Finally, we attempted to construct more complex imida-
zo[1,2-a]pyridine derivatives by coupling 1a with 1,4-
diiodobenzene, 1,4-dibromobenzene, 1,2-diiodobenzene,
and 1,2-dibromobenzene (Scheme 1). Interestingly, the
desired product 1,4-bis(2-methylimidazo[1,2-a]pyridin-3-yl)-
benzene 4a was formed, when the reaction was carried out by
using 1,4-diiodobenzene or 1,4-dibromobenzene as the sub-
strate. However, when 1,2-diiodobenzene or 1,2-dibromo-
benzene was used as the substrate, the target compound 4b
was not detected and trace amounts of product 4c was
detected by GC-MS.
A proposed mechanism is described in Scheme 2. The
mechanism was consistent with previous studies on the
arylation of heterocycles.12 First, deprotonation utilizing t-
BuOK would generate intermediate A. And then transme-
talation to copper formed the intermediate B, which
possibly would then undergo PhI reversible oxidative
addition to give the intermediate C. Finally intermediate
C underwent reductive elimination to give the product 3aa
and released the Cu(I) catalyst.
bond-forming processes of multisubstituted imidazo[1,2-a]
pyridine which is a common structural motif in natural
products and pharmaceuticals. The advantage of this
arylation is the usage of inexpensive copper, rather than
expensive palladium, as a catalyst with better yields.
Acknowledgment. The work was financially supported
by the Foundation for Distinguished Young Talentsin High-
er Education of Guangdong, China (LYM11083), National
Natural Science Foundation of China (20932002 and
21172076), National Basic Research Program of China (973
Program) (2011CB808600), Doctoral Fund of the Ministry
of Education of China (20090172110014), and Guangdong
Natural Science Foundation (10351064101000000).
In conclusion, we have developed an inexpensive
copper(I) catalytic system for the efficient direct arylation
ofsubstituted imidazo[1,2-a]pyridines(1aꢀ1f) withdiverse
aryl iodides, aryl bromides, and triflates to give rise to
the corresponding π-conjugated compounds. This trans-
formation provides a new avenue for developing CꢀC
Supporting Information Available. Scheme 1, experi-
mental procedure and characterization of compounds
3aaꢀ3fg, 4a. This material is available free of charge via
the Internet at http://pubs.acs.org.
(12) Do, H. Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 15185–15192.
The authors declare no competing financial interest.
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