Basic ionic liquid promoted heterocyclization to access fused imidazopyridines

Article abstract of DOI:10.1016/j.tetlet.2013.07.054

A single step access to fused imidazopyridine involving [bmIm]OH promoted click cyclocondensation of N-methylisatin with 2-aminopyridine has been achieved. The title heterocyclic scaffolds were obtained in excellent yield with high purity. [bmIm]OH was found to be more attractive as it plays the role of solvent, base, and catalyst.

Full text of DOI:10.1016/j.tetlet.2013.07.054

Tetrahedron Letters 54 (2013) 5083–5086
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Basic ionic liquid promoted heterocyclization to access fused
imidazopyridines
⇑
I. R. Siddiqui , Shireen, Shayna Shamim, Malik Abdul Waseem, Afaf A. H. Abumhdi, Arjita Srivastava,
Anjali Srivastava
Laboratory of Green Synthesis, Department of Chemistry, University of Allahabad, Allahabad 211002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A single step access to fused imidazopyridine involving [bmIm]OH promoted click cyclocondensation of
N-methylisatin with 2-aminopyridine has been achieved. The title heterocyclic scaffolds were obtained in
excellent yield with high purity. [bmIm]OH was found to be more attractive as it plays the role of solvent,
base, and catalyst.
Received 23 May 2013
Revised 4 July 2013
Accepted 7 July 2013
Available online 15 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Ionic liquid
Imidazopyridine
Heterocyclization
Room temperature
Mild reaction conditions
Nitrogen-containing heteroaromatics and their analogous are
pharmaceutically attractive scaffolds and are broadly present in
naturally occurring and synthetic biologically active molecules.
Fused imidazo[1,2-a]heterocycles such as benzimidazo[2,1-a]iso-
quinolines (I)1 and pyrido[1,2-c]purines (II) are anticancer agents2,
pyridino[1,2-a]imidazo[5,4-b]indol (III)(Fig. 1) and dimeric ana-
logues of 2 aminodipyrido[1,2-a:30,20-d]imidazole, are potent anti-
hypertensive compounds.3,4 They possibly interact with DNA and
display biological and pharmaceutical activity.5 Moreover, drugs
like zolpidem which is clinically used for the treatment of insom-
nia, olprinone which is used for the treatment of acute heart fail-
ure, minodronic acid for the treatment of osteoporosis, and
zolimidine as an anti-ulcer agent (Fig. 2) have imidazo[1,2-a]pyri-
dine as the core structure.6
A number of synthetic routes have been reported for the syn-
thesis of imidazo[1,2-a]pyridine.7 The synthesis of imidazopyri-
dines containing pyrrole as an auxiliary group also suffered
limitations like scope, generality, substrate availability, hazardous
catalysts, carcinogenic VOLs (volatile organic liquids), and
unavoidable need of bases. Furthermore these synthetic protocols
involved time consuming sequential multistep processes with
harsh reaction conditions. Because of strong requirement of fused
imidazo[1,2-a]pyridine scaffolds in medicament, there is a demand
for developing a straightforward, simple, high yielding, and conve-
nient facile methodology for the synthesis of imidazo[1,2-a]pyri-
dine from simple and readily available precursors.
The pressing need is the use of alternative reaction medium that
circumvents the problems associated with many traditional organ-
ic solvents. Operations resulting in the construction of highly func-
tionalized heterocycles remain a great scientific challenge. This has
prompted us to utilize [bmIm]OH in intermolecular cyclization to
facilitate the synthesis of fused imidazopyridine. Buoyed from
the green credentials of task specific basic ionic liquids (TSBIL)8–10
as well as part of our ongoing endeavors for the development of
simple, efficient, and versatile synthetic methodologies for the syn-
thesis of biodynamic heterocyclic scaffolds,11–16 we report herein a
single step methodology using 2-aminopyridine and N-methyl
isatin as reactants catalyzed by [bmIm]OH (1-butyl-3-methylimi-
dazolium hydroxide) to furnish fused imidazopyridine scaffolds
(Scheme 1).17
We have successfully developed an efficient method to prepare
a number of fused imidazopyridine derivatives via basic ionic li-
quid promoted cyclocondensation of N-methylisatin and 2-amino-
pyridine at room temperature. The selection of base, catalyst, and
solvent system is a main issue as per importance of environmental
purity. However, in the previously reported work, catalysts like Cu,
Pd, Rh, solvents such as DMF, ethanol, toluene, and bases like NaOH
have already been used in standard reaction conditions. We have
replaced toxic catalysts, hazardous bases, and carcinogenic volatile
organic solvents with recyclable and non hazardous [bmIm]OH
and achieved better yield of the product (89%).
⇑
Corresponding author. Tel.: +91 532 2461236; fax: +91 532 2461157.
E-mail address: dr.irsiddiqui@gmail.com (I.R. Siddiqui).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.054

5084
I. R. Siddiqui et al. / Tetrahedron Letters 54 (2013) 5083–5086
Table 2
Influence of catalyst on the synthesis of 4aa
N
N
NR1R2
Z
V
N
N
N
R
O
N
Y
N
H
N
H2N
Catalyst, NaOH, DCM
r.t., 4-6h
38-68%
N
X
N
N
N
N
R
O
R
I
II
III
Entry
Catalyst (10%)
Solvent
Catalyst (10%)
Time (h)
Yieldb (%)
Figure 1.
1
2
3
4
CuI
DCM
DCM
DCM
DCM
NaOH
NaOH
NaOH
NaOH
4
5
6
5
63
45
38
46
CuBr
ZnCl2
InCl3
O
N
H2N
[bmIm]OH
N
r.t., 2-5h
75-89%
N
N
a
N
R
Reaction conditions: N-methylisatin (2.0 mmol), 2-aminopyridine (2.0 mmol).
Isolated yields.
O
R
b
Scheme 1. Basic ionic liquid catalyzed synthesis of fused imidazo-pyridine.
Table 3
Influence of Ionic liquid on the synthesis of 4aa
Table 1
Influence of various solvents on the synthesis of 4a using NaOH as base and CuI as
O
catalysta
N
H2N
Ionic liquid
N
r.t., 3-6h
N
N
R
N
71-86%
R
O
O
N
H2N
Solvent, CuI, NaOH
r.t., 4-7h, 21-53%
Entry
Ionic liquid
Time (h)
Yieldb (%)
N
N
N
N
R
O
R
1
2
[bmIm]OH
[bmIm]Br
3
6
86
71
Entry
Solvent
Base (10%)
Catalyst (10%)
Time (h)
Yieldb (%)
a
Reaction conditions: N-methylisatin (2.0 mmol), 2-aminopyridine (2.0 mmol).
Isolated yields.
b
1
2
3
4
5
H2O
NaOH
NaOH
NaOH
NaOH
NaOH
CuI
CuI
CuI
CuI
CuI
7
5
4
5
6
21
37
53
43
48
Ethanol
DCM
THF
Table 4
DMF
Influence of different mol (%) of [bmIm]OH on 4aa
a
Reaction conditions: N-methylisatin (2.0 mmol), 2-aminopyridine (2.0 mmol).
Isolated yields.
b
O
N
H2N
[bmIm]OH, mol%
N
r.t.
N
N
N
R
O
R
In order to explore the generality and feasibility of the strategy
we attempted to investigate the optimization of reaction
conditions using 2-aminopyridine and N-methyl isatin as model
reactants. Various solvents were used in the presence of NaOH as
a base and CuI as a catalyst to afford desirable products and the re-
sults are summarized in Table 1.
It was inferred from Table 1 that the best solvent in terms of
product yield and reaction time was DCM (Table 1, entry 3) while
ethanol, THF, CH2Cl2, and H2O proved less effective as lower yield
of product was obtained and longer reaction time was needed (Ta-
ble 1, entries 2, 4, and 5). To achieve high product conversion the
reaction was carried out in DCM with different catalysts like CuI,
CuBr, ZnCl2, and InCl3 and it was found that CuI turns out to be
the best catalyst for the transformation of reactants into products
(Table 2, entry 1).
Reports regarding heterocyclization reactions in ionic liquid
encouraged us to perform the reaction in this versatile reaction
medium which in most of the cases acted also as a promoter and
additionally sometimes as base. So this reaction involving model
reactants was carried using ionic liquids [bmIm]OH and [bmIm]Br
without inorganic base, organic solvent, and metal halide as
catalyst and the results are summarized in Table 3. From Table 3
[bmIm]OH was found to be the most efficient as there was no need
to use additional catalyst and base. Further the suitable work-up
process for the reaction is an additional advantage of the protocol.
The effect of mol % of [bmIm]OH on product yield and reaction
time was also optimized for the synthesis of fused imidazopyridine
by using different mol % of the ionic liquid (Table 4). From the
results shown in Table 4, entry 1 it was inferred that 20 mol % of
[bmIm]OH proved to be the optimum catalyst loading for intermo-
Entry
[bmIm]OH (mol %)
Time (h)
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
20
15
25
20
20
20
3
3
3
4
2
3
rt
rt
rt
rt
rt
60
86
71
86
86
78
86
a
Reaction conditions: N-methylisatin (2.0 mmol), 2-aminopyridine (2.0 mmol).
Isolated yields.
b
lecular heterocyclization with the product yield of 86%. By decreas-
ing the amount of catalyst to 15 from 20 mol % relative to
substrate, the yield of product 4a decreased (Table 4, entry 2)
but by increasing the amount of catalyst from 20 to 25 mol %, no
appreciable change in the yield of product was observed (Table 4,
entry 3). It was also observed that when [bmIm]OH was used as
solvent and catalyst, at higher reaction temperature no appreciable
effect on the yield was observed (Table 4, entry 6).
The task specific basic ionic liquid was synthesized according to
a reported procedure.18 Ionic liquid [bmIm]OH was recovered
completely and recycled twice for the synthesis with no apprecia-
ble decrease in the efficiency of the process (Fig. 3). The procedure
for the synthesis of [bmIm]OH, and procedure for its recycling are
given in the experimental section (Fig. 3).17
The formation of 4a may be rationalized by the condensation of
the carbonyl group of N-methyl isatin with 2-aminopyridine which
on cyclization gives imidazopyridine intermediate 3. This interme-
diate undergoes tautomerization and dehydration under the reac-

I. R. Siddiqui et al. / Tetrahedron Letters 54 (2013) 5083–5086
5085
N
Table 5
Cl
Ionic liquid [bmIm]OH promoted synthesis of products 4(a–j)a
N
N
Cl
N
N
N
O
HN
O
N
O
O
N
O
H2N
[bmIm]OH
r.t., 2-5h
75-89%
N
CN
N
N
N
N
R
R
Alpidem
Zolpidem
Olprinone
N
N
N
O
N
P
OH
OH
HN
O
HO
P
O
OH
HO
Entry
1
R
Product
Time (h) Yieldb (%)
CN
N
Zolimidine
Minodronic acid
3
4
86
76
N
NH2
NH2
N
N
N
Figure 2.
N
N
2
3
N
N
Cl
100
80
N
N
N
NH2
3
5
4
81
75
86
60
40
20
0
Cl
N
1
2
3
N
NH2
N
N
N
N
4
5
Reaction cycles
Figure 3. Recycling of [bmIm]OH.
Br
N
N
NH2
NH2
Br
N
N
N
N
H N
O
O
2
OH
N
NC
N
N
O
δ
N
N
N
N
6
7
3
5
89
83
δ
H
N
N
CN
N
OH
H3CO
N
NH2
N
N
N
N
N
H
-H2O
N
N
H3CO
N
N
OH
N
N
8
9
3
4
5
78
85
77
Scheme 2. Plausible mechanism for fused imidazopyridine promoted by
[bmIm]OH.
N
NH2
OCH3
N
N
N
N
N
N
N
NH2
N
OCH3
tion conditions to afford 5-methyl-5H-4a,5,10-triaza-indeno
[2,1-a]indene derivatives (Scheme 2).
The presence of both electron donating and electron withdraw-
ing groups present in the benzene ring of imidazopyridine has
been well studied and they have been found to have pronounced
effect on product yield and reaction time. It was observed from
Table 5 that fused imidazopyridines bearing electron withdrawing
groups were obtained at a faster rate and with better yield, than
those containing electron releasing groups.
NH2
10
a
Reaction conditions: N-methylisatin (2.0 mmol), 2-aminopyridine (2.0 mmol).
Isolated yields.
b
From Table 5 it was also inferred that reactants bearing electron
withdrawing groups on the benzene ring of o-alkynylphenol react
faster with better yield than those having electron donating
groups.
efficiency, generality, short reaction time, and clean reaction
profiles are the advantages of the protocol.
In summary, we have developed a novel [bmIm]OH mediated
protocol for the synthesis of 5-methyl-5H-4a,5,10-triaza-inde-
no[2,1-a]indene derivatives without using VOL as reaction
medium, transition metal halide catalyst, and any inorganic base.
The strategy could be applied to various available substrates with
a one-step synthetic procedure in moderate to good yields. High
Acknowledgements
The authors gratefully acknowledge UGC, New Delhi and the
Department of Chemistry, University of Allahabad, Allahabad. The
authors would also like to thank SAIF, Chandigarh for spectral
analysis.

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17. Genereal procedure for synthesis of 4a:
A mixture of N-methyl-isatin 1
(2.0 mmol), 2-aminopyridine 2a (2.0 mmol) and [bmIm]OH (0.4 mmol) was
stirred at room temperature for 2–5 h. After completion of reaction as
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