A mild and novel synthesis of functionalized fused imidazole analogues under environmentally benign reaction media

Article abstract of DOI:10.1016/j.tetlet.2014.04.080

A mild and novel approach is described for the synthesis of functionalized fused imidazole analogues in solvent-free and catalyst-free condition in ionic liquid. The short reaction time, good isolated yields, generality and environmentally benign reaction media are the significant features of this protocol.

Full text of DOI:10.1016/j.tetlet.2014.04.080

Accepted Manuscript
A mild and novel synthesis of functionalized fused imidazole analogues under
environmentally benign reaction media
B. Madhu Babu, G. Santosh Kumar, Pramod B. Thakur, Vikas M. Bangade,
H.M. Meshram
PII:
S0040-4039(14)00705-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.080
TETL 44542
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 April 2014
22 April 2014
22 April 2014
Please cite this article as: Madhu Babu, B., Santosh Kumar, G., Thakur, P.B., Bangade, V.M., Meshram, H.M., A
mild and novel synthesis of functionalized fused imidazole analogues under environmentally benign reaction media,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.080
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A mild and novel synthesis of functionalized
fused imidazole analogues under
environmentally benign reaction media
B. Madhu Babu, G. Santosh Kumar, Pramod B. Thakur, Vikas M. Bangade, H. M. Meshram.*
N
N
R1
N
NH2
OR2
NO2
O
O
[Hbim]BF4
50 min, rt
S
R1
OR2
R
N
S
N
R
OR2
NH2
N
R1
O
t
R1= CH3, Ph
R2= CH3, Et, Bu

Tetrahedron Letters
1
A mild and novel synthesis of functionalized fused imidazole analogues under
environmentally benign reaction media
B. Madhu Babu, G. Santosh Kumar, Pramod B. Thakur, Vikas M. Bangade, H. M. Meshram*
Medicinal Chemistry and pharmacology division
Indian Institute of Chemical Technology, Hyderabad – 500 007, India
Tel.: +91-40-27191643, Fax: +91-40-27193275, E-mail address- hmmeshram@yahoo.com
Abstract— A mild and novel approach is described for the synthesis of functionalized fused imidazole analogues in solvent-free and
catalyst-free condition in ionic liquid. The short reaction time, good isolated yields, generality and environmentally benign reaction media
are the significant features of this protocol.
Keywords: β-Nitroacrylate, 2-Aminopyridine, Fused heterocycles, Ionic liquid, Green synthesis.
Fused imidazo-heterocycles containing ring-junction nitrogen
atoms plays an important role in the area of medicinal
chemistry.1 Particularly, five membered nitrogen containing
imidazo[1,2-a]pyridine scaffolds have been shown to possess
Numerous methods have been reported for the synthesis of
fused imidazo-heterocycles framework under different
reaction conditions.14 The classical approach includes, the
reaction of heteroamine such as 2-aminopyridine with α-
halocarbonyl compounds,15 and three-component reaction of
aromatic amidines with isocyanide and aromatic aldehydes.16
Other classical methods have been developed by using acid
catalysts,1a,17 solid supported p-toluenesulfonic acid,18a
glyoxalic acid,18b Montmorillonite clay K10,18c Sc(OTf)3,18d
ZnCl2,19 in polar solvents,19,20a,20b as well as ionic liquid.20c
One example of catalyst-free20d synthesis of fused imidazole
framework is also reported. However, most of the methods
rely on the use of α-halocarbonyl compound or isocyanide
which are difficult to handle and require an excess amount of
expensive catalyst.16f,16h Additionally, a few of the methods
require longer reaction time,1a,16f,16h,20d harsh reaction
conditions and cumbersome work-up procedure.18c,18d
Although some of the protocols are satisfactory, still there is a
scope to develop general and convenient protocols for the
synthesis of a new diversely functionalized fused imidazoles
under environmentally benign reaction media.
a
wide range of biological activity such as anti-
inflammatory,2 antiprotozoal,3 antiviral,1c,4 antiulcer,5
antibacterial6 and antifungal agents.7a Moreover, this
framework is a core structure of many commercially available
drugs such as zolimidine (antiulcer),7b alpidem (anxiolytic),7c
zolpidem (hypnotic),8 olprinone (to treat heart failure),9a
necopidem (sedative) and saripidem (anxiolytic)9b (Fig. 1). In
addition
to
this,
fused
imidazothiazole
and
imidazobenzothiazole analogues also serve as antibacterial,10
antifungal,11 antihelmintic12 and antitumor agents.13 Due to
such prominence and prevalence of fused imidazole
frameworks
in the arena of medicinal chemistry,
development of efficient protocol for the synthesis of this
motif is desirable.
N
N
N
Cl
Cl
Et
N
N
N
Cl
O
Me
N
Me
N
In recent years development of an eco-friendly synthetic
protocols for the assembly of new chemical entities is gaining
great importance.21 In this context, ionic liquids (ILs, Fig. 2)
have attracted more attention as benign reaction media in
organic synthesis because of their special and unique
properties like non-volatility, high thermal stability,
negligible flammability and recyclability.22 The main
advantage of ionic liquid is to eliminate the use of hazardous,
volatile and toxic solvents,23a which satisfy the requirements
of modern green chemistry.23b Moreover, some of the ionic
liquids also promotes the organic transformations without the
use of any additional catalyst or solvent,24 because of their
high polarity and the ability to solubilize both inorganic and
N
nPr
iBu
O
O
Alpidem
Sarpidem
Necopidem
CN
N
N
O
CH3
H3C
N
N
HN
N
S
O
CH3
N
N
CH3
H3C
Levamisole
Olprinone
Zolpidem
Fig. 1: Representative examples of bioactive molecules
containing fused imidazole structural framework.

2
Tetrahedron Letters
organic compounds, which can accelerate the rate of
reactions.
temperature and progress of the reaction was monitored
continuously by TLC. After completion of the reaction (50
min) the reaction mixture was extracted from ionic liquid
using diethyl ether to get crude reaction mass and subjected
to 1H NMR analysis. On analysis of 1H NMR spectrum of
Table 2: Synthesis of fused imidazole derivatives.a
Fig. 2: Chemical structure of representative ionic liquid
1-n-butylimidazolium tetrafluoroborate [Hbim]BF4.
NO2
O
[Hbim]BF4
50min, rt
N
N
In the last few years, β-nitroacrylates have been emerged as a
versatile class of electron-poor alkenes26 in chemical
synthesis.27,28 Although β-nitroacrylates are less readily
available compared to 2-halocarbonyl compounds, they
display a significantly higher reactivity and efficiency
towards aminopyridine compared to the halocarbonyl
compounds. Due to this β-nitroacrylates have been explored
in the synthesis of a variety of heterocycles29 by replacing
highly toxic and lachrymatory 2-halocarbonyl compounds. In
this context, recently we have explored β-nitroacrylates in the
synthesis of thiazol-2-imine derivatives using ionic liquid
under solvent-free and catalyst-free condition.25a In
continuation of our ongoing interest in the application of ionic
liquids25 in the synthesis of biologically active molecules, we
envisaged the possible utilization of β-nitroacrylates in the
synthesis of fused imidazole frame work using suitable ionic
liquid. To the best of our knowledge, there is no report on
ulitization of β-nitroacrylates in the synthesis of fused
imidazole molecular framework by the reaction of amidines
with β-nitroacrylates. Herein we wish to report a catalyst-free,
solvent-free, efficient and general method for the preparation
of diversely functionalized fused imidazo-heterocycles by the
reaction of β-nitroacrylates with amidine in the presence of
ionic liquid as a reusable reaction media.
R1
OR2
N
NH2
R1
OR2
O
2a
1a
3aa
Yieldb(%)
Entry
Amino pyridine
R1
R2
Product
OEt
N
N
1
Me
Et
74
75
71
O
N
NH2
Me
3aa
1a
N
OMe
O
Me
2
3
Me
Et
N
N
N
NH2
Me 3ab
1a
OEt
N
Ph
O
N
NH2
Ph
3ac
1a
N
O
4
5
tBu
73
86
Me
Me
N
N
O
3ad
N
NH2
1a
Me
Me
Me
OEt
N
Et
O
3ba
N
NH2
Me
1b
Me
Me
Me
OMe
N
Me
Ph
Me
Initially, we attempted the reaction of 2-aminopyridine 1a (1
mmol) and β–nitroacrylate, ((Z)-ethyl 3-nitrobut-2-enoate) 2a
(1 mmol) in 5 mL ionic liquid [Hbim]BF4 (Scheme 1) at room
6
7
84
83
N
N
O
3bb
N
NH2
Me
1b
Me
N
OEt
O
Et
N
NH2
Ph 3bc
NO2
O
Ionic liquid
rt
OEt
N
1b
N
O2N
N
NH2
OEt
N
OEt
Me
Me
Et
8
9
71
74
N
N
O
2a
O
3ca
1a
N
N
O2N
3aa
NH2
Me
1c
Scheme 1: Optimization of the reaction conditions.
Table 1: Screening of reaction mediaa
O2N
OMe
N
Me
O
O2N
NH2
Me
3cb
1c
Yieldb(%)
Entry
Reaction media
Time (min)
O2N
OEt
N
Ph
10
11
Et
1
2
70
72
50
50
74
59
[Hbim]BF4
[bmim]BF4
N
N
O
3cc
O2N
N
N
NH2
Ph
1c
O2N
O
O
N
3
4
[bmim]PF6
[emim]BF4
-
50
50
61
tBu
Me
O2N
NH2
1c
65
Me 3cd
24 h
tracec
5
a All products exhibited physical and spectral (NMR, Mass, HRMS
and IR) properties in accordance with the assigned structure.
Isolated Yield.
a
Reaction condition: 2-aminopyridine 1a (1 mmol), β-nitroacrylate,
(Z)-ethyl 3-nitrobut-2-enoate 2a (1 mmol) in 5 mL ionic liquid.
b Isolated Yield, c under neat reaction condition.
b

Tetrahedron Letters
3
crude mass, it was observed that the reaction of 2-amino
pyridine 1a with β-nitroacrylate ((Z)-ethyl 3-nitrobut-2-
enoate) 2a in ionic liquid affords only regioselective product
ethyl 3-methyl H-imidazo[1,2-a]pyridine-2-carboxylate (3aa)
(Table 2, entry 1). As a part of the study, the scope of the
reaction was also tested in different ionic liquids such as, 1-
butyl-3-methylimidazolium tetrafluoroborate [bmim]BF4, 1-
butyl-3-methylimidazolium hexafluoro phosphate [bmim]PF6,
1-ethyl-3-methylimidazolium tetrafluoroborate [emim]BF4.
After screening results, we found that ionic liquid [Hbim]BF4
as a most suitable reaction media for optimum conversion in
terms of reaction time and isolated yield (Table 1, entry 1).
The results evaluating the merits of various ionic liquids are
presented in Table 1.
substituted 2-aminopyridines under optimized condition. In
this context, we screened 2-aminopyridine with various β-
nitroacrylates which reacted smoothly in the standard reaction
condition to furnish the expected product in very good yield
(Table 2, entries 1-4). Further the scope was tested with
substituted 2-aminopyridine like 4-methyl 2-aminopyridine
and 5-nitro 2-aminopyridine. We were delighted to observe
that, the reaction of 5-nitro 2-aminopyridine led to excellent
yields of the desired products (Table 2, entries 8-11). The
reaction of 4-methyl 2-aminopyridine with β-nitroacrylates
also afforded the corresponding products in good to moderate
yields (Table 2, entries 5-7).
The efficiency of the reaction was further strengthened by the
participation of 2-aminothiazole with β-nitroacrylates. For
example the reaction of 2-aminothiazole 1d with β-
Table 3: Synthesis of fused imidazothiazole derivatives.a
nitroacrylates
proceeded
efficiently
and
afforded
S
corresponding products 3da, 3db, 3dc in good yield (Table 3,
entries 1-3). To further extend the substrate scope of the
reaction, we intended to study the reaction of fused ring
heteroamines with β-nitroacrylates. In this regard, we treated
aminobenzothiazoles with β-nitroacrylates in the presence of
[Hbim]BF4. It is worthy to mention that, aminobenzothiazoles
also reacted with β-nitroacrylates in similar fashion to afford
the respective product in good yield (Table 3, entries 4-6).
S
NO2
O
R
[Hbim]BF4
50 min, rt
N
NH2
R
N
OR2
R1
OR2
N
R1
O
R1
R2
Product
S
Yieldb(%)
Entry
Thiazole
S
N
N
78
Et
NH2
Me
Me
1
2
OEt
N
1d
Me
O
3da
Other
substituted
aminobenzothiazoles
like
6-
S
S
methoxyaminobenzothiazoles also participated effectively
under same reaction conditions to furnish corresponding
products in good to moderate yields (Table 3, entries 4-9).
N
N
74
NH2
Me
N
OMe
N
1d
Me
S
3db
O
S
N
71
76
3
4
NH2
Ph
Et
Et
OEt
[Hbim]BF
4
N
S
1d
Ph
S
O
O
3dc
N
NH2
..
NH2
Me
R1
O
N
N
N
N
N
H
N
R2
N
R1
N
N
OEt
1e
O
R2
NO2 O
Me
S
3ea
N
NO2 O
N
A
R2
S
R1
NH2
80
72
76
5
6
Me
Ph
Me
Et
O
N
N
D
OMe
O
1e
-HNO
-H
Me
S
3eb
O
O
O
2O
S
NH2
N
N
N
H
N
O
1e
OEt
R1
O
N
R1
2
R
Ph
S
3ec
N
H3CO
H3CO
N
S
H3CO
H3CO
N
HO
O
OH
B
NH2
Me
Me
7
8
Et
OH
O
R2
O
N
N
C
1f
OEt
Me
S
3fa
Scheme 2: Plausible mechanistic pathway for the formation
of substituted imidazo[1,2-a]pyridine in the presence of
[Hbim]BF4.
S
Me
79
73
NH2
N
N
1f
OMe
Me
3fb
O
O
H3CO
H3CO
S
S
Keeping the green chemistry criteria in mind, we have tested
the reusability of ionic liquid. After completion of reaction,
the product was isolated from reaction mixture simply by
extraction with ether (3x15 mL). Then the residual
[Hbim]BF4 was dried under vacuum and used for subsequent
three cycles without any appreciable loss in the catalytic
activity. It was noticed that the yield of the product 3aa
gradually decreased from first to third cycle (74%, 73% and
70%), respectively.
Ph
NH2
Et
9
N
N
N
OEt
1f
Ph
3fc
a All products exhibited physical and spectral (NMR, Mass, HRMS
and IR) properties in accordance with the assigned structure.
Isolated Yield.
b
Further to determine the scope of this reaction, we planned to
examine the reaction of various β-nitroacrylates with

4
Tetrahedron Letters
G.; Chavignon, O.; Teulade, J.-C.; Kerbal, A.;
Essassi, E. M.; Debouzy, J.-C.; Witvrouw, M.;
Blache, Y.; Balzarini, J.; Clercq, E. D.; Chapat, J.-P.
J. Med. Chem. 1996, 39, 2856; (e) Elhakmoui, A.;
Gueiffier, A.; Milhavet, J. C.; Blache, Y.; Chapat, J.
P. Bioorg. Med. Chem. Lett. 1994, 4, 1937.
The plausible mechanism for the formation of desired product
was given in Scheme 2. Initially, the Michael addition of 2-
aminopyridine occurs on to β-nitroacrylate to form Michael
adduct A. Then the adduct A tautomerizes into the reactive
species B (aci-nitro tautomer),25a which is promptly attacked
by the nitrogen atom of pyridine ring, with the formation of
the five membered ring C. Finally, elimination of water and
nitroxyl molecules, lead to the formation of the target
imidazo[1,2-a]pyridine D.
5. (a) Kaminsky, J. J.; Doweyko, A. M. J. Med. Chem.
1997, 40, 427; (b) Katsura, Y.; Nishino, S.; Inoue,
Y.; Tomoi, M.; Takasugi, H. Chem. Pharm. Bull.
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J.; Lovey, R. G.; Guzik, H.; Chui, P. J. S.; Long, J.
F. J. Med. Chem. 1989, 32, 1686.
6. (a) Rival, Y.; Grassy, G.; Michel, G. Chem. Pharm.
Bull. 1992, 40, 1170; (b) Teulade, J. C.; Grassy, G.;
Girard, J. P.; Chapat, J. P.; de Buochberg, M. M. S.
Eur. J. Med. Chem. 1978, 13, 271; (c) Rewankar, G.
R.; Matthews, J. R.; Robins, R. K. J. Med. Chem.
1975, 18, 1253.
7. (a) Rival, Y.; Grassy, G.; Taudou, A.; Ecalle, R. Eur.
J. Med. Chem. 1991, 26, 13; (b) Trapani, G.; Franco,
M.; Latrofa, A.; Ricciardi, L.; Carotti, A.; Serra, M.;
Sanna, E.; Biggio, G.; Liso, G. J. Med. Chem. 1999,
42, 3934; (c) Okubo, T.; Yoshikawa, R.; Chaki, S.;
Okuyama, S.; Nakazato, A. Bioorg. Med. Chem.
2004, 12, 4.
8. Goodacre, S. C.; Street, L. J.; Hallett, D. J.;
Crawforth, J. M.; Kelly, S.; Owens, A. P.; Blackaby,
W. P.; Lewis, R. T.; Stanley, J.; Smith, A. J.; Ferris,
P.; Sohal, B.; Cook, S. M.; Pike, A.; Brown, N.;
Wafford, K. A.; Marshall, G.; Castro, J. L.; Atack, J.
R. J. Med. Chem. 2006, 49, 35.
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Cardiovasc. Drugs Rev. 2002, 20, 163; (b) Boerner,
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145.
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Med. Chem. 2010, 45, 63; (b) Gadad, A. K.;
Mahajanshetti, C. S.; Nimbalkar, S.; Raichurkar, A.
Eur. J. Med. Chem. 2000, 35, 853; (c) Kiran, J. M.
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In conclusion, we have demonstrated novel and efficient
synthesis of new diversely functionalized fused imidazole
analogues. The developed protocol is operationally simple,
mild and provide direct access for regioselective synthesis of
fused imidazo-heterocyclics. Moreover, reusable reaction
media and generality of the procedure are the important
features of present protocol.
Acknowledgments
The authors B M B, G S K, P B T and V M B thank CSIR-
UGC for the award of a fellowship and to Dr. Ahmed Kamal,
Outstanding Scientist and Head, MCP Division, IICT, for his
support and encouragement.
The authors thank CSIR, New Delhi for financial support as
part of XII Five Year plan programme under title ACT (CSC-
0301).
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