Iron(II)-catalyzed denitration reaction: Synthesis of 3-methyl-2- arylimidazo[1,2-a]pyridine derivatives from aminopyridines and 2-methylnitroolefins

Article abstract of DOI:10.1055/s-0032-1317685

A variety of ways to synthesize imidazo[1,2-a]pyridines have been reported and many approaches are devoted to the functionalization of imidazo[1,2-a] pyridines. However, the use of a denitration reaction in the synthesis of imidazo[1,2-a]pyridines has not

Full text of DOI:10.1055/s-0032-1317685

LETTER
▌2961
lIertteor n(II)-Catalyzed Denitration Reaction: Synthesis of 3-Methyl-2-arylimida-
zo[1,2-a]pyridine Derivatives from Aminopyridines and 2-Methylnitroolefins
Iron(II)-Catalyzed Denitration Reaction
Hao Yan, Sizhuo Yang, Xiai Gao, Kang Zhou, Chao Ma, Rulong Yan,* Guosheng Huang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: hgs@lzu.edu.cn
Received: 04.09.2012; Accepted after revision: 31.10.2012
N
n-Pr
Abstract: A variety of ways to synthesize imidazo[1,2-a]pyridines
Me
N
have been reported and many approaches are devoted to the func-
tionalization of imidazo[1,2-a]pyridines. However, the use of a de-
nitration reaction in the synthesis of imidazo[1,2-a]pyridines has
not been reported. We report here the iron-catalyzed synthesis of 3-
methyl-2-arylimidazo [1,2-a] pyridine derivatives from aminopyri-
dines and 2-methyl-nitroolefins. The procedure, using FeCl2 as cat-
alyst, is simple and inexpensive. Various functional groups are
tolerated and provide the products in good yields.
N
N
O
N
O
Cl
N
CN
saripidem (I)
olprinone (II)
Me
Me
N
O
Key words: iron catalysis, denitration, heterocycles, cyclization,
imidazo[1,2-a]pyridines
N
N
SO2Me
N
N
zolimidine (III)
zolpidem (IV)
The imidazopyridine1 nucleus is an important pharmaco-
phore which is widely found in many bioactive com-
pounds. In particular, the imidazo[1,2-a]pyridine core is
one of the most significant heterocycles. Imidazo[1,2-a]-
pyridines are 5,6-fused bicyclic compounds with one ring
junction nitrogen atom and one nitrogen atom in the five-
membered ring. They have found widespread application
in medicinal chemistry2 and materials science.3 They are
also found in many pharmaceutical compounds (Figure
1), such as saripidem4 (anxiolytic, I), olprinone5 (to treat
acute heart failure, II), zolimidine6 (antiulcer, III), and
zolpidem7 (hypnotic, IV), which exhibit antifungal,8 anti-
inflammatory,9 antitumor,10 antiviral,11 antibacterial,12
antiprotozoal,13 antipyretic,14 analgesic,15 antiapoptotic,16
hypnoselective, and anxioselective activities.17 Conse-
quently, there is considerable interest from the pharma-
ceutical industry, synthetic chemists and this has
stimulated the development of numerous methods for
their preparation.18 Recently, several new approaches
based on multicomponent19 coupling reactions and dehy-
drogenations through C–H activation catalyzed by transi-
tion metals20 have been reported.21 However, there is still
a need for easy and efficient methods to construct hetero-
cycles using environmentally friendly reagents with sim-
ple and readily accessible substrates. As part of our
continuing study on the utilization of oxygen in organic
chemistry, 22 we paid attention to developing a strategy for
the synthesis of 3-methyl-2-arylimidazo[1,2-a]pyridine
derivatives through denitration catalyzed by FeCl2. Here-
in, we wish to report this simple synthesis of 3-methyl-2-
arylimidazo[1,2-a]pyridine derivatives.
Figure 1 Selected examples of imidazo[1,2-a]pyridines with biolog-
ical activities in pharmaceutical compounds
At the beginning of our study, pyridin-2-amine (1a) and
(E)-(2-nitroprop-1-en-1-yl)benzene (2a) were chosen as
the model substrates for the reaction, as shown in Table 1.
Firstly, the reaction was carried out with CuI at 150 °C for
seven hours. We were pleased to note the formation of 3-
methyl-2-arylimidazo[1,2-a]pyridine (3aa) as the sole
product in 30% yield (Table 1, entry 1). Attempts to im-
prove the yield using different copper salts were evaluat-
ed, but were unsuccessful under these reaction conditions
(Table 1, entries 2–8). Interestingly, iron salts, (Table 1,
entries 9–13) and in particular FeCl2, afforded the product
in good yield (Table 1, entry 9). As expected, in the ab-
sence of a catalyst, no target product was obtained (Table
1, entry 20). Switching the reaction solvent from DMF to
DMA, DMSO or NMP did not further improve the yield
of the reaction (Table 1, entries 14–16). When the reaction
time was changed to four or ten hours, the yields also de-
creased (Table 1, entries 17 and 18). The yield of 3aa was
also influenced by the reaction temperature; when the re-
action was performed at 130 °C, the yield of 3aa reduced
to 50% (Table 1, entry 19). Ultimately, the optimized con-
ditions were identified (Table 1, entry 9).
Under the optimized reaction conditions, we investigated
the scope of substituted aminopyridines that could be em-
ployed. This resulted in the formation of 3-methyl-2-ary-
limidazo[1,2-a]pyridines, as shown in Table 2. Generally,
the reaction of substituted aminopyridines with (E)-(2-ni-
troprop-1-en-1-yl)benzene proceeded smoothly and led to
the formation of the desired products in moderate to good
yields, although the nature of the substituent on the pyri-
dine ring had some influence on the yields of the products.
SYNLETT 2012, 23, 2961–2964
Advanced online publication: 27.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317685; Art ID: ST-2012-W0740-L
© Georg Thieme Verlag Stuttgart · New York

2962
H. Yan et al.
LETTER
Table 1 Optimization of the Reaction Conditionsa
Table 2 Substrate Scope of Aminopyridinesa,23
R
N
N
N
N
catalyst, solvent
FeCl2 (10 mol%)
R
+
+
NH2
DMF, 150 °C, 7 h
NO2
N
NH2
NO2
N
1a
2a
1
2a
3
3aa
Entry
R
Product
Yield (%)
Entry
Catalyst
Solvent
Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
3-Me (1b)
5-Me (1c)
6-Me (1d)
5-F (1e)
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
26
62
47
62
78
76
51
68
80
1
2
CuI
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
NMP
DMF
DMF
DMF
DMF
7
7
30
42
44
41
46
30
24
31
80
50
31
33
42
41
34
28
54
61
50b
0
CuBr
3
CuCl
7
4
CuBr2
7
4-Cl (1f)
5
Cu(OAc)2
Cu(acac)2
Cu(OTf)2
7
5-Cl (1g)
5-Br (1h)
6-Br (1i)
6
7
7
7
8
CuOTf
7
FeCl2
4-COOEt (1j)
3ja
9
7
a Reactions were carried out using 1 (0.34 mmol), 2a (0.41 mmol),
and catalyst (0.03 mmol) in DMF (2 mL) for 7 h at 150 °C.
10
11
12
13
14
15
16
17
18
19
20
FeCl3
7
FeSO4
7
Fe(acac)3
7
Subsequently, the substrate scope of 2-methylnitroolefins
was further investigated, as summarized in Table 3. To
our delight, we found the transformation to be very gener-
al for a wide range of 2-methylnitroolefins, with all of the
substrates tested affording the desired 3-methyl-2-ary-
limidazo[1,2-a]pyridine. It was observed that the nature
of the substituent on the aromatic rings had some influ-
ence on the yields of the products. In general, the aromatic
ring with electron-withdrawing groups, such as chloro,
bromo and cyano groups (Table 3, entries 7–11, 15 and
16) gave higher yields than those with electron-donating
groups, such as methyl and methoxy groups (Table 3, en-
tries 2–6). Moreover, a sterically bulky naphthyl substitu-
ent did not hamper the efficiency of the process and also
gave the desire product (Table 3, entry 12). Heteroaromat-
ic substituted 2-methylnitroolefins also underwent this
transformation, albeit in lower yields (Table 3, entries 13
and 14). Finally, when (E)-(2-nitro but-1-en-1-yl)benzene
(2a′) reacted with pyridin-2-amine, the expected 3-ethyl-
2-phenylimidazo[1,2-a]pyridine (3aa′) was obtained in
60% yield (Scheme 1).
FeCl2–AgOAc
FeCl2
7
7
FeCl2
7
FeCl2
7
FeCl2
4
FeCl2
10
7
FeCl2
–
7
a Reaction condition: The reaction was carried out using 1a (0.34
mmol), 2a (0.41 mmol), and catalyst (0.03 mmol) in DMF (2 mL) for
7 h at 150 °C.
b The reaction was carried out at 130 °C.
Aminopyridines substituted with electron-withdrawing
groups (Table 2, entries 4–9) generally gave higher yields
than those with electron-donating groups (Table 2, entries
1–3); with aminopyridines with substituents at position 4
giving products in highest yield (Table 2, entries 5 and 9).
Furthermore, different 2-amino heterocycles were also
tested. When 2-aminobenzimidazole was subjected to the
reaction conditions, no separable product was formed. 2-
Aminopyrimidine was also tested, however, it may be not
suitable for the process as the desired product was not iso-
lated, and only a trace amount of product was detected on
the silica gel.
FeCl2 (10 mol%)
N
+
N
DMF, 150 °C, 7 h
60%
NO2
N
NH2
1a
2a'
3aa'
Scheme 1 Synthesis of 3-ethyl-2-phenylimidazo[1,2-a]pyridine
Synlett 2012, 23, 2961–2964
© Georg Thieme Verlag Stuttgart · New York

LETTER
Iron(II)-Catalyzed Denitration Reaction
2963
Table 3 Substrate Scope of 2-Methylnitroolefinsa,23
R1
Michael addition
R1
R2
N
NH
FeCl2 (10 mol%)
+
NO2
R
+
N
NH2
R2
NO2
N
N
R
DMF, 150 °C, 7 h
1
2
N
NH2
N
1a
2
– O
+
FeCl
O
4
3
Entry
R
Product
Yield (%)
R1
R1
5-exo-trig
elimination
N
N
N
N
N
1
2
Ph (2a)
3aa
3ab
3ac
3ad
3ae
3af
80
66
67
51
49
53
74
83
95
65
77
76
61
63
76
68
H
R2
3-MeC6H4 (2b)
4-MeC6H4 (2c)
3,4-Me2C6H3 (2d)
2-MeOC6H4 (2e)
4-MeOC6H4 (2f)
2-ClC6H4 (2g)
3-ClC6H4 (2h)
4-ClC6H4 (2i)
O
R2
O
5
FeCl
3
3
Scheme 2 Proposed reaction mechanism
4
5
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
6
r
t
iornat
7
3ag
3ah
3ai
8
References and Notes
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Acknowledgment
We thank the Fundamental Research Funds for the Central Univer-
sities (lzujbky-2012-74) and the National Science Foundation
(NSF-21202067) for financial support.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2961–2964

2964
H. Yan et al.
LETTER
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arylimidazo[1,2-a]pyridine: A test tube was charged with
1a (0.34 mmol), 2a (0.41 mmol) and FeCl2 (3.81 mg, 0.03
mmol). Then DMF (2 mL) was added to the reaction system.
The reaction was stirred at 150 °C for 7 h. After cooling to
r.t., the solvent was diluted with EtOAc (10 mL) and washed
with brine (5 mL) and dried over anhyd Na2SO4. After the
solvent was evaporated in vacuo, the residues were purified
by column chromatography, eluting with PE–EtOAc to
afford pure 3aa (57 mg, 80%) as a white solid; mp 140–142
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(m, 1 H), 7.11–7.15 (m, 1 H), 6.78 (t, J = 6.8 Hz, 1 H), 2.58
(s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 144.2, 142.2,
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Synlett 2012, 23, 2961–2964
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