One-pot three-component synthesis of 3-nitro-2-arylimidazo[1,2-a]pyridine derivatives using air as an oxidant

Article abstract of DOI:10.1002/asia.201200319

A novel one-pot three-component synthesis of 3-nitro-2-arylimidazo[1,2-a] pyridines has been easily achieved with 2-aminopyridines, aromatic aldehydes, and MeNO₂, and is catalyzed by CuBr under air. The procedure, using air as an oxidative agent, is simple, low cost, and sustainable. Various functional groups are tolerated in this reaction system, and it proceeds well with moderate to good yields. Copyright

Full text of DOI:10.1002/asia.201200319

DOI: 10.1002/asia.201200319
One-Pot Three-Component Synthesis of 3-nitro-2-arylimidazo
Derivatives Using Air as an Oxidant
ACHTUNGTREN[NGNU 1,2-a]pyridine
Hao Yan,[a, b] Rulong Yan,*[a, b] Sizhuo Yang,[a, b] Xiai Gao,[a, b] Yuling Wang,[a, b]
Guosheng Huang,*[a, b] and Yongmin Liang[a, c]
In modern drug discovery, to design a highly efficient
chemical reaction, which provides structural diversity with
few synthetic steps and simple compounds is a major chal-
lenge. One of the ways to achieve this goal is to develop
multicomponent reactions.[1] Multicomponent reactions have
received considerable interest, because they not only allow
more than two reactants to combine sequentially, which is
timesaving, highly efficient, and atom economic, but also
can give rise to complex structures by simultaneous forma-
tion of two or more bonds. Therefore, developing multicom-
ponent reactions has been recognized as one of the most im-
portant topics in recent years.
Imidazopyridine[2] as an important pharmacophore is
widely found in many bioactive compounds. Especially,
imidazoACHTUNGTRENNUNG[1,2-a]pyridines are one of the most important heter-
ocyclic compounds. They have tremendous applications in
material science,[3] medicinal chemistry,[4] and drug synthe-
sis.[5] They are found in many pharmacological compounds,
such as the clinical antiulcer compound soraprazan
(Figure 1, I), alpidem (a nonsedative anxiolytic, II),[6] and
Figure 1. Selected examples of imidazo
tivities.
ACHTUNGTRENN[UNG 1,2-a]pyridines with biological ac-
zolpidem (a hypnotic drug, III).[7] Imidazo
ACTHNUTRGNE[NUG 1,2-a]pyridines
show antiinflammatory, antiviral,[8] antibacterial,[9] antipyret-
ic,[10] analgesic,[11] hypnoselective, and anxioselective activi-
ties. Therefore, they have attracted significant attention
from organic chemists. Recently, with the development of
transition metal catalyst tandem reactions[12] and multicom-
substituted imidazoACTHNGUTERNNUG
[1,2-a]pyridine rings.[15] Although syn-
thetic methods for the synthesis of these important struc-
tures have been reported, most of them are limited because
of expensive oxidants or multistep preparation of the start-
ing materials.[16] As a result, a simple and efficient way to
ponent[13] reactions, new approaches based on N H and C
H activations[14] have been developed to gain access to the
construct imidazoACTHNUTRGNE[NUG 1,2-a]pyridine is still necessary.
À
À
The development of a green oxidant is extremely impor-
tant for future industrial applications, therefore using an en-
vironmentally friendly oxidant to construct heterocycles
with simple and readily accessible substrates is highly desira-
ble and urgent. Air is the ideal oxidant owing to its abun-
dance, low cost, and sustainability. As a part of our continu-
ing study on the utilization of oxygen in organic chemis-
try,[17] we paid attention to developing a new strategy for the
[a] H. Yan, Dr. R. Yan, S. Yang, X. Gao, Y. Wang, Prof. Dr. G. Huang,
Prof. Dr. Y. Liang
State Key Laboratory of Organic Chemistry
Lanzhou University
Lanzhou, 730000 (P. R. China)
Fax : (+86)931-8912582
E-mail: hgs@lzu.edu.cn
synthesis of 3-nitro-2-arylimidazoACTHUNTGRNEUNG[1,2-a]pyridine derivatives
yanrl@lzu.edu.cn
through a one-pot three-component reaction (Scheme 1).
Herein, we wish to report this simple one-pot synthesis of 3-
nitro-2-aryl-imidazoACTHNUTRGNE[NUG 1,2-a]pyridines in the presence of air.
In the initial experiment, pyridin-2-amine (1a) with ben-
zaldehyde (2a) and MeNO2 (3) were chosen as the model
substrates for the reaction, as shown in Table 1. Firstly, the
reaction was carried out with CuI in air at 808C for 8 hours,
[b] H. Yan, Dr. R. Yan, S. Yang, X. Gao, Y. Wang, Prof. Dr. G. Huang
Key Laboratory of Nonferrous Metal Chemistry and Resources Uti-
lization of Gansu Province
Lanzhou, 730000 (P. R. China)
[c] Prof. Dr. Y. Liang
State Key Laboratory of Solid Lubrication
Lanzhou, Institute of Chemical Physics
Chinese Academy of Science
the desired 3-nitro-2-phenylimidazo
was isolated in 78% yield (Table 1, entry 1). Then different
ACHTUNGERTN[NUNG 1,2-a]pyridine (4aa)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200319.
Chem. Asian J. 2012, 00, 0 – 0
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COMMUNICATION
Table 2. Synthesis of 3-nitro-2-arylimidazo
from aminopyridines, aromatic aldehydes and MeNO2
ACHTUNGTNER[NUNG 1,2-a]pyridine derivatives
[a]
Scheme 1. Retrosynthesis of imidazoACTHNUTRGNEUNG[1,2-a]pyridines.
Entry
R1
R2
Product
Yield [%]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1 f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2 f
2g
2h
2i
Ph
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
80
86
82
88
84
78
73
67
75
62
52
50
44
30
60
78
78
58
67
73
copper salts were evaluated, CuBr was superior to CuCl,
CuBr2, Cu(OAc)2, Cu(OTf)2, CuOTf, and Cu(OAc)2·H2O,
3-Me-Ph
4-Me-Ph
3,4-diMe-Ph
2-MeO-Ph
4-MeO-Ph
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
2-Br-Ph
3-Br-Ph
4-Br-Ph
1-naphthyl
piperonyl
2-furyl
Ph
G
R
ACHTUNGTRENNUNG
and showed the highest activity for this reaction, affording
the desired product in 80% yield (Table 1, entries 2–8). In
addition, without metal copper salts as the catalyst, no de-
sired product was obtained (Table 1, entry 9). When the re-
action time was reduced to 4 hours, the product 4aa was ob-
tained in only 50% yield (Table 1, entry 10). Meanwhile,
when the temperature changed to 608C or 1008C, the yields
also decreased (Table 1, entries 11 and 12). When O2 was
employed as the oxidant, there was no improvement in the
yield (Table 1, entry 13). Therefore, the optimized condi-
tions were identified (Table 1, entry 2).
Having established the optimal reaction conditions, the
scope of this one-pot three-component reaction was exam-
ined, the results are illustrated in Table 2. Generally, the re-
action of 2-aminopyridines with aromatic aldehydes and
MeNO2 mostly proceeded smoothly and led to the desired
product in moderate to good yields. To our delight, we
found this transformation to be very general for a wide
range of aromatic aldehydes and 2-aminopyridines, thus pro-
9
10
11
12
13
14
15
16
17
18
19
20
2j
2k
2l
4aj
4ak
4al
2m
2n
2o
2a
2a
2a
2a
2a
4am
4an
4ao
4ba
4ca
4da
4ea
4 fa
3-Me
5-Me
6-Me
5-Cl
4-COOEt
Ph
Ph
Ph
Ph
[a] The reaction was carried out using 1 (0.3 mmol), 2 (0.36 mmol), and 3
(20 equiv) in the presence of air at 808C for 8 h catalyzed by CuBr.
the products. The aromatic aldehydes with electron-donating
groups, such as methyl and methoxy groups (Table 2, en-
tries 2–6) gave higher yields than those with electron-with-
drawing groups, such as chloro and bromo groups (Table 2,
entries 7–12). To our disappointment, when other
electron-withdrawing groups such as o-NO2, p-NO2,
and CN were tested, only a complex mixture was
detected and no desired products were obtained.
Furthermore, the reaction of the aromatic aldehyde
(Table 2, entry 13) and heteroatom-containing aro-
matic aldehydes also proceeded efficiently (Table 2,
entries 14 and 15). Additionally, the substrate scope
of 2-aminopyridines was further investigated 1b–1 f,
viding easy access to 3-nitro-2-arylimidazoACTHUNRTGNEUNG[1,2-a] pyridine
derivatives. It is observed that the nature of the substituent
on the aromatic rings had some influence on the yields of
Table 1. Optimization of reaction conditions.[a]
and similar results were observed. These results in-
dicated that electron-rich 2-aminopyridines were
successfully employed (Table 2, entries 16 and 17),
and gave higher yields than those with electron-de-
ficient substituents (Table 2, entries 19 and 20).
However, 1d reacted with 2a to produce 4da in
only 58% (Table 2, entry 18); this may be owing to
the steric hindrance on the pyridine ring. Further-
more, different 2-amino heterocycles were also
tested. When 2-aminopyrimidine was subjected to
the reaction system, no reaction was observed. 2-
Aminobenzimidazole was also tested, however, the
desired product was not isolated, and only a trace
amount of product was detected. Several aliphatic
Entry
Catalyst
t [h]
T [8C]
Yield [%]
1
2
3
4
5
6
7
8
CuI
8
8
8
8
8
8
8
8
8
4
8
8
8
80
80
80
80
80
80
80
80
80
80
60
100
80
78
80
78
74
76
75
77
76
0
50
60
78
70[b]
CuBr
CuCl
CuBr2
Cu
Cu(OT f)2
CuOTf
Cu(OAc)2·H2O
ACHTUNGTRENNUNG(OAc)2
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
9
–
10
11
12
13
CuBr
CuBr
CuBr
CuBr
[a] The reaction was carried out using 1a (0.30 mmol), 2a (0.36 mmol), and
(20 equiv) with catalyst (0.03 mmol) under air. [b] The oxidant is O2 (1 atm).
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Synthesis of 3-nitro-2-arylimidazoACTHUNTGRNEUNG[1,2-a]pyridine derivatives
Scheme 2. Plausible reaction mechanism.
Experimental Section
aldehydes, such as n-butyraldehyde and iso-butyraldehyde
were unsuitable substrates to produce 3-nitro-2-arylimidazo-
ACHTUNGTRENNUNG
A
tube was charged with 1 (0.30 mmol), 2 (0.36 mmol), and CuBr
(4.3 mg, 0.03 mmol). Then 3 (20 equiv) was added to the reaction system.
The reaction was stirred at 80oC under air for 8 h. After cooling to room
temperature, the residues were purified by silica-gel column chromatog-
raphy, eluting with petroleum ether/EtOAc to afford pure 4.
has been proposed (Scheme 2). The first step involves the
reaction of substrates 1 and 2 to produce the imine 5. Then
3 reacts with imine 5 by Michael addition to form intermedi-
ate 6. Intermediate 6 is then oxidized into the radical cation
7 by the copper catalyst, and subsequent hydride-atom ab-
straction with oxidant forms nitrenium ion 8. The intermedi-
ate 9 that is produced by proton elimination from nitrenium
ion 8 isomerizes into enamine 10 easily. Similarly, intermedi-
ate 10 generates radical cation 11 by losing one electron to
the copper catalyst. A hydride-atom abstraction of radical
cation 11 with oxidant forms the imino nitronate ion 12,
which undergoes nucleophilic addition to produce 13. Final-
ly, intermediate 13 undergoes proton elimination and affords
product 4.
Acknowledgements
We thank the financial supported by the Fundamental Research Funds
for the Central Universities (lzujbky-2012-74).
Keywords: copper
· green chemistry · heterocycles ·
multicomponent reactions · oxidation
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a] pyridine derivatives. In this system, the starting materials
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moderate to good yields.
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Rulong Yan, Guosheng Huang et al.
COMMUNICATION
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Received: April 10, 2012
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COMMUNICATION
Multicomponent Reactions
Hao Yan, Rulong Yan,* Sizhuo Yang,
Xiai Gao, Yuling Wang,
Guosheng Huang,*
Yongmin Liang
&&&& — &&&&
One-Pot Three-Component Synthesis
of 3-nitro-2-arylimidazo[1,2-a]pyridine
Derivatives Using Air as an Oxidant
A novel one-pot three-component syn-
thesis of 3-nitro-2-arylimidazoACTHNUTRGNEUG[N 1,2-
a]pyridines has been easily achieved
with 2-aminopyridines, aromatic alde-
hydes, and MeNO2, and is catalyzed by
CuBr under air. The procedure, using
air as an oxidative agent, is simple, low
cost, and sustainable. Various func-
tional groups are tolerated in this reac-
tion system, and it proceeds well with
moderate to good yields.
AHCTUNGTRENNUNG
Chem. Asian J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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