Copper-catalyzed intramolecular oxidative amination of enaminone C-H bond for the synthesis of imidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2016.05.064

The intramolecular C-N bond forming cross coupling reactions on the enaminones has been achieved for the synthesis of imidazole[1,2-a]pyridines via copper-catalyzed C(sp²)-H amination. This protocol provides a new route for the synthesis of 2-u

Full text of DOI:10.1016/j.tetlet.2016.05.064

Accepted Manuscript
Copper-catalyzed intramolecular oxidative amination of enaminone C-H bond
for the Synthesis of imidazo[1,2-a]pyridines
Jie-Ping Wan, Deqing Hu, Ying Liu, Luyao Li, Chengping Wen
PII:
S0040-4039(16)30594-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.064
TETL 47683
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 April 2016
15 May 2016
17 May 2016
Please cite this article as: Wan, J-P., Hu, D., Liu, Y., Li, L., Wen, C., Copper-catalyzed intramolecular oxidative
amination of enaminone C-H bond for the Synthesis of imidazo[1,2-a]pyridines, Tetrahedron Letters (2016), doi:
http://dx.doi.org/10.1016/j.tetlet.2016.05.064
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Tetrahedron Letters
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Copper-catalyzed intramolecular oxidative amination of enaminone C-H bond for the
Synthesis of imidazo[1,2-a]pyridines
Jie-Ping Wana,∗, Deqing Hua, Ying Liu,a Luyao Lia and Chengping Wenb,*
aCollege of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P.R. China
bCollege of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
The intramolecular C-N bond forming cross coupling reactions on the enaminones has been
achieved for the synthesis of imidazole[1,2-a]pyridines via copper-catalyzed C(sp2)-H
Received in revised form
Accepted
amination. This protocol provides a new route for the synthesis of 2-unsubstituted
imidazole[1,2-a]pyridines via easily available starting materials.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Keyword_1 enaminone
Keyword_2 transamination
Keyword_3 C-H bond
Keyword_4 amination
Keyword_5 imidazo[1,2-a]pyridines
The imidazo[1,2-a]pyridine is a typical fused heterocycle moiety
of enriched values in medicinal and synthetic organic chemistry.
As representative examples, the clinical medicines such as
Alpidem, Zolpidem, Saripidem and Necopidem are typical
derivatives of imidazo[1,2-a]pyridine with varied substructures
(Fig. 1).1 During the exploration of the biological function of the
fused heterocyclic scaffold, imidazo[1,2-a]pyridine derivatives
have been disclosed with highly diversified biological profiles
such as antitumor activity,2 antiviral activity,3 antibacterial
activity,4 anti-rhinoviral5 and anti-HIV activity.6 Moreover,
recent researches have revealed that imidazo[1,2-a]pyridine
derivatives are potentially useful in the preparation of functional
materials.7
acids,15 various multicomponent reactions,16 among others,17
have been established for the elegant production of imidazo[1,2-
a]pyridine libraries. While numerous known methods are
presently available, the utilization of starting materials of low
stability and/or substrates requiring tedious prior preparation in
many known protocols remains as challenges. In this context,
designing new synthetic routes to imidazo[1,2-a]pyridines using
stable and easily available starting materials is still an issue of
high significance.
Enaminones are a class of highly stable, easily available and
reactivity versatile compounds with widespread application in
organic synthesis.18 In known literature, the β-enaminones
containing free NH group and additional β-substituent have been
employed for the synthesis of 2,3-disubstituted imidazo[1,2-
a]pyridines.19 However, the synthesis of imidazo[1,2-a]pyridine
without 2-substitution is not accessible with these enaminone-
based protocols as predetermined by the structure of starting
materials. In the progress of our research in enaminone
chemistry,20 we have identified the transamination between N,N-
disubstituted tertiary enaminones as
a facile approach in
generating NH-containing secondary enaminones.21 The results
have enlightened us that this facile transformation can be used for
the preparation of N-pyridinyl secondary enaminones 3 by
employing enaminones 1 and 2-aminopyridines 2, and thereafter
to enable the synthesis of imidazo[1,2-a]pyridines 4 without C-2
substitution via the intramolecular C-H amination (Scheme 1).
Herein, we report this new route toward imidazo[1,2-a]pyridines
synthesis.
Figure 1 Clinical medicines containing imidazo[1,2-a]pyridine core structure
During the past decade, the research interest in the chemistry
and functionality of imidazo[1,2-a]pyridines has driven rapid
progress of the synthetic approaches towards these heterocyclic
entities,8 and a variety of different methodologies have been
successfully devised. For example, the annulation reactions of 2-
aminopyridines with methyl ketones,9 bromoketones,10 enones,11
nitroolefines,12 bromoalkynes,13 formyl alkynes14 or carboxylic
———
∗ Corresponding author. Tel.: +0-791-8812-0380; fax: +0-791-8812-0380; e-mail: wanjieping@jxnu.edu.cn; cpwen.zcmu@yahoo.com

2
Tetrahedron Letters
the synthesis of imidazo[1,2-a]pyridines of different
substructures depending on the employment of corresponding
starting materials. In the aryl ring associated with enaminones 1,
electron donating and withdrawing group such as alkyl, alkoxyl,
fluorinated alkyl, cyano and heteroaryl etc all exhibited good
tolerance to the reaction by affording corresponding imidazo[1,2-
a]pyridines with moderate to excellent yields (4a-4m and 4u,
Table 2). The property of these substituents showed no notable
impact on the yield of corresponding products. On the other hand,
evidently lower yield of product was acquired from the entry
using the substrate containing electron withdrawing group
substitution in the pyridine ring of 3 (4r, Table 2). Notably,
products 4c, 4e, 4f, 4g, 4h, 4i, 4j, 4l, 4o, 4q, 4r, 4s, 4t, 4u are
new compounds that were not reported in previous literature.
Scheme 1 Enaminone-based synthesis of imidazo[1,2-a]pyridines
Originally, the model reaction of N-pyridinyl enaminone 3a
was subjected in the presence of CuI at 120oC, which led to the
production of imidazo[1,2-a]pyridine 4a with moderate yield in
DMSO (entry 1, Table 1). A control experiment without using
catalyst provided no product (entry 2, Table 1). The subsequent
o
examination on the temperature effect proved that 100 C was
most proper for the reaction (entries 3-5, Table 1). Further more,
a class of different copper catalysts were also employed,
respectively. It was found that CuI was the most favored copper
catalyst, and CuCl and Cu(II) salts were not applicable in the
reaction probably because of the specific requirement of active
Cu(I) ion in the reaction (entries 6-9, Table 1). On the other hand,
the comparing experiments employing different organic solvents
suggested that DMSO was the efficient medium, and good yield
was also given in the entry employing DMF. On the other hand,
solvents such as water, ethyl lactate (EL), AcOH, toluene and
DCE (1,2-dichloroethane) were all not practical (entries 10-15,
Table 1). Finally, the optimization on the loading of catalyst
proved that 20 mol% CuI gave even better yield of 4a (entries
16-17, Table 1).
Table 2 Scope of imidazo[1,2-a]pyridines synthesisa,b
N
R2
R2
CuI, DMSO
100 oC, air
N
O
HN
N
R1
R1
O
3
4
N
N
N
N
N
N
N
N
O
O
O
CF3
O
OCH3
4b
, 87%
4a, 89%
4c
, 81%
4d
, 85%
N
N
N
N
N
N
HO
N
N
O
OCH3
OCH3
O
O
O
CN
N
Br
4g
, 61%
4e
4f
, 71%
, 64%
4h
, 76%
N
Table 1 Optimization of reaction conditionsa
N
N
N
N
N
N
N
N
O
O
O
O
O
Cl
O
OCH3
O
Cl
4j
, 85%
4i
, 47%
4k
, 68%
4l
, 75%
4m, 74%
N
N
N
N
N
N
N
N
Entry
1
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
H2O
Catalyst
CuI
T (oC)
120
120
110
100
90
Yield(%)b
O
Cl
O
O
O
Cl
55
nr
Cl
4o
, 88%
4n, 67%
4p, 69%
4q
, 74%
2
-
Cl
N
N
N
N
N
N
3
CuI
62
68
53
nr
N
N
S
O
O
O
Cl
Cl
4
CuI
O
4r
, 43%
4s
4u
, 73%
, 77%
4t
, 69%
aGeneral conditions: N-pyridyl enaminone 3 (0.2 mmol), CuI
(0.04 mmol), DMSO (2 mL), 100 C, 12 h, open air. Yield of
isolated product.
5
CuI
o
b
6
CuCl
CuBr
Cu(OAc)2
CuCl2
CuI
100
100
100
100
100
100
100
100
100
100
100
100
7
10
nr
To investigate the extended application of the system, the N-
pyridinyl enaminone 5 containing a phenyl substitution in the β-
position was also subjected under the standard catalytic condition.
It was found that corresponding product 6 could be provided with
excellent yield (Eq 1).
8
9
nr
10
11
12
13
14
15
16c
17d
nr
EL
CuI
nr
AcOH
toluene
DCE
CuI
nr
CuI
nr
CuI
nr
DMF
CuI
84
89
62
On the basis of the experiments employing different mediuum
(Table 1) and the structure of products, a mechanism involving
the oxidative C(sp2)-H bond amination has been tentatively
proposed for the reaction. As outlined in Scheme 2, enaminone 3
may first react with copper(I) ion to give cuprous intermediate 7
with the assistance of the N-chelating site in the pyridine ring.
Analogous as the case in known literature involving aerobic
oxidation,23 it is possible that Cu(III) intermediate 8 has been
generated via the oxidative addition of 7 in the presence of O2
(air). Finally, the reductive elimination on intermediate 8 gives
the target imidazo[1,2-a]pyridine products 4, and the copper (I)
ion has been simultaneously released to participate further
catalytic process.
DMSO
DMSO
CuI
CuI
aGeneral conditions:N-pyridyl enaminone 3a (0.2 mmol), catalyst
(0.06 mmol) in 2.0 mL solvent, stirred for 12 h. nr = no reaction.
bYield of isolated product. The loading of CuI was 0.04 mmol.
c
dThe loading of CuI was 0.02 mmol.
Following the optimization experiments, the application scope
of the present method for the synthesis of different imidazo[1,2-
a]pyridines was investigated by employing various N-pyridinyl
enaminones.22 The results in this section, as summarized in Table
2, demonstrated that the present method is generally applicable in

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The financial supports from the National Natural Science
Foundation of China (21562025), Natural Science Foundation of
Jiangxi Province (20151BAB203008) and the Jiangxi Provincial
Innovative Fund for Graduate Student (YC2015-S120) are
gratefully acknowledged.
Supplementary Material
Supplementary data (general details, synthetic procedure for 3,
1
characterization data for 3, 4 and 6, H and 13C NMR spectra)
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associated with this article can be found, in the online version, at
http://
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4
Tetrahedron Letters
Copper-catalyzed intramolecular
oxidative amination of enaminone C-H
bond for the Synthesis of imidazo[1,2-
a]pyridines
Jie-Ping Wan,*,a Deqing Hu,a Ying Liu,a Luyao Li,a
and Chengping Wen*,b
aCollege of Chemistry and Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, P.
R. China. Email: wanjieping@jxnu.edu.cn
bCollge of Basic Medical Sciences, Zhejiang
Chinese Medical University, Hangzhou 310053, P.
R. China. E-mail: cpwen.zcmu@yahoo.com

Highlights
1. Easy and facile synthesis of starting materials via
enaminone transamination
2. C(sp2)-H amination for the ring construction
3. Broad tolerance to functional groups in the
substrates