Bu4NI-catalyzed synthesis of imidazo[1,2- a ]pyridines via oxidative coupling of aminopyridines with nitroolefins

Article abstract of DOI:10.1055/s-0033-1340485

A metal-free method for the synthesis of imidazo[1,2-a]pyridines via double C-N oxidative coupling of aminopyridines with nitroolefins using TBAI as the catalyst and TBHP as oxidation agent has been developed. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340485

718▌
LETTER
letter
Bu4NI-Catalyzed Synthesis of Imidazo[1,2-a]pyridines via Oxidative Coupling
of Aminopyridines with Nitroolefins
Metal-Free Oxidative Coupling
Xiangsheng Xu,* Peizhu Hu, Wubin Yu, Guo Hong, Yucai Tang, Mingwu Fang, Xiaoqing Li*
College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
Fax +86(571)88320799; E-mail: future@zjut.edu.cn; E-mail: xqli@zjut.edu.cn
Received: 31.10.2013; Accepted after revision: 04.12.2013
them provided better results. Control experiments indicat-
Abstract: A metal-free method for the synthesis of imidazo[1,2-
ed that both TBAI and TBHP were required for this trans-
a]pyridines via double C–N oxidative coupling of aminopyridines
formation (Table 1, entries 14 and 15). The amount of
TBAI was also optimized; reducing the amount of TBAI
with nitroolefins using TBAI as the catalyst and TBHP as oxidation
agent has been developed.
to10 mol% decreased the yield of 3aa (Table 1, entry 16).
Key words: TBAI, imidazo[1,2-a]pyridines, oxidative coupling,
aminopyridines, nitroolefins
Table 1 Optimization of Reaction Conditionsa
NO2
N
conditions
+
The imidazo[1,2-a]pyridines are an important class of het-
erocycles which widely exist in medicinal chemistry1 and
material science.2 Traditional approaches for the forma-
tion of imidazo[1,2-a]pyridines rely on condensation re-
action of 2-aminopyridines with α-halocarbonyl
compounds.3 Recently, the direct transition-metal-cata-
lyzed oxidative coupling of unfunctionalized starting ma-
terials, including ketones,4 alkynes,5 nitroolefins,6 β-keto
esters7 with 2-aminopyridines has attracted much atten-
tion. In particular, Huang demonstrated CuBr-catalyzed
synthesis of imidazo[1,2-a]pyridine by mild oxidative
double C–N coupling of nitroolefins with 2-aminopyri-
dines using air as oxidative agent.8 In addition, an alterna-
tive metal-free method has also been developed. Han and
co-workers reported TBAI-catalyzed synthesis of imid-
azo[1,2-a]pyridine though tandem oxidative C–N cou-
pling/condensation of 2-aminopyridines with β-keto
esters and 1,3-diones using tert-butyl hydroperoxide
(TBHP) as the oxidant.9 However, there is still no pub-
lished report on metal-free double C–N coupling protocol
for the construction of imidazo[1,2-a]pyridines. As a part
of our continuing research on the TBAI-catalyzed trans-
formation,10 we herein report the first metal-free, TBAI-
catalyzed oxidative coupling of 2-aminopyridines with ni-
troolefins, representing a new method for the construction
of imidazo[1,2-a]pyridines.
N
N
1a
NH2
2a
NO2
3aa
Entry
Catalyst
Oxidant
Solvent
Yield (%)b
1
2
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
KI
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBPB
H2O2
MeCN
DMF
DCE
75
83
72
23
0
3
4
DMSO
H2O
5
6
EtOAc
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
32
53
46
48
39
20
0
7
8
I2
9
NaI
10
11
12
13
14
15
TBAI
TBAI
TBAI
TBAI
–
K2S2O8
MCPBA
TBHP
–
0
0
We commenced our reaction with pyridin-2-amine (1a)
and (E)-(2-nitrovinyl)benzene (2a) as model substrates
TBAI
TBAI
0
(Table 1). Gratifyingly, the desired 3-nitro-2-phenylimid- 16c
TBHP
56
azo[1,2-a]pyridine (3aa) was obtained in 75% yield under
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), TBAI (20
mol%), oxidant (2 equiv), solvent (2 mL) at 80 °C for 4 h.
b Isolated yield.
the standard conditions established in our previous work
(Table 1, entry 1).10b When various solvents were exam-
ined, DMF gave 3aa in the highest yield (Table 1, entry
2). Various iodine reagents (Table 1, entries 7–9) and ox-
idants (Table 1, entries 10–13) were also used, but none of
c Amount of catalyst used was 10 mol%.
Under the optimal reaction conditions, we investigated the
substrate scope of the oxidative coupling (Table 2).11
First, the reaction of substituted aminopyridines 1 and β-
nitrostyrene 2a proceeded smoothly. Both the steric hin-
SYNLETT 2014, 25, 0718–0720
Advanced online publication: 10.01.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340485; Art ID: ST-2013-W1018-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Metal-Free Oxidative Coupling
719
Table 2 Synthesis of Imidazo[1,2-a]pyridines 3a
dergo the cyclization oxidative coupling due to the steric
effect. Finally, heterocyclic substituted nitroolefins 2
could also be employed in this reaction to afford the cor-
responding products.
R1
N
1
NH2
NO2
TBAI (20 mol%)
TBHP (2 equiv)
N
On the basis of the results described above and in previous
reports,8 a plausible mechanism has been proposed
(Scheme 1). Initially, the reaction of aminopyridine with
β-nitrostyrene in the presence of TBHP affords enamine C
via Michael addition of intermediate A and imine B.8 The
hydrogen abstraction of enamine C by the tert-butoxyl or
tert-butylperoxy radicals, generated by TBAI-catalyzed
decomposition of TBHP,12 produces intermediate D. Fi-
R2
R1
+
N
DMF, 80 °C
R2
NO2
2
3
Entry
1
R1
2
R2
Product Yield
(%)b
1
2
1a
1b
1c
1d
1e
1f
H
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
Ph
Ph
Ph
Ph
Ph
Ph
3aa
3ba
3ca
3da
3ea
3fa
83
73
74
46
33
33
43
62
50
80
43
31
25
52
38
45
0
13
nally, the oxidation of intermediate D by I2 and subse-
quent intramolecular nucleophilic addition of nitrenium
ion E affords intermediate F, which converts to products
3 by proton elimination.
3-Me
4-Me
6-Me
4-Cl
5-Cl
H
3
4
t-BuOOH
H2O
+
t-BuOO•
t-BuOOH
5
1
I–
/
2 I2
6
t-BuO•
+
–OH
7
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
4-MeC6H4
4-i-PrC6H4
4-MeOC6H4
4-FC6H4
3ab
3ac
3ad
3ae
3af
H
N
Ar
8c
9
H
NO2
+
Ar
N
H
N
NH2
2
NO2
A
1
10
11
12
13
14
15
16
17
18
19
20
H
[O]
N
t-BuO•
or
t-BuOO•
H
4-ClC6H4
4-BrC6H4
4-F3CC6H4
H
N
•
Ar
Ar
N
Ar
H
2g
2h
2i
3ag
3ah
N
N
N
H
NO2
NO2
NO2
t-BuOH
or
D
C
B
H
4-MeO2CC6H4 3ai
t-BuOOH
1
/
2 I2
H
2j
3-BrC6H4
3-MeC6H4
2-BrC6H4
2-MeOC6H4
2-thienyl
2-furyl
3aj
I–
H
2k
2l
3ak
3al
H
N
N
Ar
Ar
N
Ar
– H+
H
+
N
N
+
N
NO2
NO2
H
2m
2n
2o
3am
3an
3ao
0
NO2
F
E
3
H
56
90
Scheme 1 Proposed mechanism
H
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), TBAI (20 mol%),
TBHP (2 equiv, 70% aq solution), DMF (2 mL) at 80 °C for 4 h.
b Isolated yield.
In summary, we have reported a metal-free process for the
oxidative double C–N coupling of aminopyridines with
nitroolefins by using TBAI as catalyst and TBHP as oxi-
dation agent. It provides simple and economical access to
imidazo[1,2-a]pyridines.
c Reaction time: 6 h.
drance and the electronic nature of the substituents on the
aminopyridines ring had a pronounced effect on the effi-
ciency of the oxidative coupling. For example, aminopyr-
idine with 6-methyl and electron-withdrawing chloride
substituents are less effective. Then, the reactions of ami-
nopyridine 1a with nitroolefin 2 were screened. Both elec-
tron-donating Me, i-Pr, OMe substituents and electron-
withdrawing halide, CF3, CO2Me substituents at para and
meta position were compatible with the optimal condi-
tions, whereas ortho-substituted nitroolefin 2 did not un-
Acknowledgment
We thank the National Natural Science Foundation of China
(21102130) and the Key Innovation Team of Science & Technology
in Zhejiang Province (2010R50018 and 2011R50017) for financial
support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 718–720

720
X. Xu et al.
LETTER
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Synlett 2014, 25, 718–720
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