Iron(III)-catalyzed three-component domino strategy for the synthesis of imidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2014.07.094

An efficient, one-pot, three-component domino strategy has been demonstrated for the synthesis of imidazo[1,2-a]pyridines using a catalytic amount of Fe(III) chloride in high yields in air. A library of imidazo[1,2-a]pyridines was synthesized by the reaction of easily available aldehydes and 2-aminopyridines in a mixture of nitroalkane and DMF (2:1). This transformation presumably occurs by a sequential aza-Henry reaction/cyclization/denitration. The use of readily available chemicals as starting materials, inexpensive metal catalyst, aerobic reaction conditions, tolerance of a wide range of functional groups, and operational simplicity are the notable advantages of this present protocol.

Full text of DOI:10.1016/j.tetlet.2014.07.094

Tetrahedron Letters 55 (2014) 5151–5155
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iron(III)-catalyzed three-component domino strategy for the
synthesis of imidazo[1,2-a]pyridines
⇑
Sougata Santra, Shubhanjan Mitra, Avik Kumar Bagdi, Adinath Majee, Alakananda Hajra
Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, one-pot, three-component domino strategy has been demonstrated for the synthesis of
imidazo[1,2-a]pyridines using a catalytic amount of Fe(III) chloride in high yields in air. A library of
imidazo[1,2-a]pyridines was synthesized by the reaction of easily available aldehydes and 2-
aminopyridines in a mixture of nitroalkane and DMF (2:1). This transformation presumably occurs by
a sequential aza-Henry reaction/cyclization/denitration. The use of readily available chemicals as starting
materials, inexpensive metal catalyst, aerobic reaction conditions, tolerance of a wide range of functional
groups, and operational simplicity are the notable advantages of this present protocol.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 21 May 2014
Revised 20 July 2014
Accepted 23 July 2014
Available online 30 July 2014
Keywords:
Ferric chloride
Domino reaction
Denitration
Imidazo[1,2-a]pyridines
Recently, significant interest has focused on the development of
new protocols for environmentally benign processes that are both
economically and technologically practical. Particularly the use of
nonhazardous, inexpensive metals has attracted interest in organic
synthesis. Iron-based catalysts have been shown to promote a
broad range of organic transformations, such as cross-couplings,
allylations, hydrogenations, and direct CAH bond functionaliza-
tions owing to their low cost, sustainability, ready availability,
nontoxicity, and environmental friendliness.1
aldehydes, and alkynes7/nitromethane.8 Recently a few methodolo-
gies have also been developed employing CAH amination.9 How-
ever, most of these methodologies have been developed using
expensive reagents, commercially less available alkynes, and
a-halocarbonyl compounds which have lachrymatory properties.
Therefore, finding new methodology for the synthesis of
a
imidazo[1,2-a]pyridines in terms of using basic chemicals as
starting materials, increasing efficiency, operational simplicity,
and economic practicability is highly desirable.
Fused imidazoles have proven to be an important structural
scaffold in many pharmaceuticals. Interestingly, the fused imidaz-
ole containing an embedded pyridine, that is, imidazo[1,2-a]pyri-
dine derivatives, have been shown to have a diverse range of
biological activities, for instance antiviral, antimicrobial, antitu-
mor, anti-inflammatory, antiparasitic, hypnotic etc.2 They are also
b-amyloid formation inhibitors, GABA and benzodiazepine recep-
tor agonists, and cardiotonic agents.3 Imidazo[1,2-a]pyridine scaf-
folds, in particular, constitute the core structure of many currently
marketed drugs4 such as zolpidem, alpidem, olprinone, zolimidine,
necopidem, and saripidem (Fig. 1).
Multicomponent domino reactions are one of the best options
to generate complex heterocycles and natural products with sev-
eral degrees of structural diversity by the reaction of three or more
simple starting materials in one-pot.10 In addition, multicompo-
nent reactions (MCRs) are accepted as efficient chemical processes
since they avoid time-consuming and costly purification processes,
as well as protection–deprotection steps.11 In recent years, MCRs
have emerged as a powerful synthetic tool for generating structur-
ally complex molecular entities12 with fascinating biological prop-
erties through the formation of several carbonAcarbon and
carbonAheteroatom bonds in a one pot operation.13 For these
reasons, MCRs are particularly well suited for diversity oriented
synthesis and library synthesis of drug like compounds, which
are an essential part of the research performed in agrochemical
and pharmaceutical companies.
As
a consequence, a number of methods to synthesize
imidazo[1,2-a]pyridines have been developed in recent times. The
most important approaches are the condensation of 2-aminopyri-
dine with
a
-halocarbonyl compounds,5 one-pot condensation of
aldehydes, isonitriles, and 2-aminopyridines,6 and the copper-
catalyzed three-component reaction of 2-aminopyridines,
Our group is actively researching multicomponent reactions.14
Recently, we reported a one-pot methodology for the synthesis of
b-nitroamines via a three-component coupling of an amine, an
aldehyde, and
Furthermore, our previous studies revealed that the in situ
a
nitroethane using an aza-Henry reaction.15
⇑
Corresponding author. Tel./fax: +91 3463 261526.
E-mail address: alakananda.hajra@visva-bharati.ac.in (A. Hajra).
http://dx.doi.org/10.1016/j.tetlet.2014.07.094
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

5152
S. Santra et al. / Tetrahedron Letters 55 (2014) 5151–5155
N
N
N
Cl
Me
Cl
N
N
N
HN
Me
O
O
O
CN
N
N
nPr
Me
Me
Prn
Olprinone (III)
Zolpidem (I)
Alpidem (II)
N
N
N
Cl
N
Et
SO2Me
Me
N
N
Me
N
Me
N
Zolimidine (IV)
nPr
Saripidem (VI)
iBu
O
O
Necopidem (V)
Figure 1. Imidazo[1,2-a]pyridine containing drugs.
generated nitro compounds could be transformed into a cyclic
compound via a denitration process.16 These results suggested that
an amine having two nucleophilic sites such as 2-aminopyridine
could afford a cyclic structure via a sequential aza-Henry reac-
tion/cyclization/denitration process (Scheme 1a). Very recently
we reported the synthesis of imidazo[1,2-a]pyridines by a cascade
reaction between nitroolefins and 2-aminopyridines.16a However,
this method is only applicable for the synthesis of 3-unsubstituted
imidazopyridines (Scheme 1b). Herein we report a FeCl3-catalyzed
one-pot protocol for the synthesis of substituted imidazo[1,2-
a]pyridines by a three-component coupling of 2-aminopyridines,
aldehydes, and nitroalkanes (Scheme 1).
We started by choosing 2-aminopyridine 1a and 4-chlorobenz-
aldehyde 2a as the model substrates for this reaction using
20 mol % FeCl3 as the catalyst in nitromethane as solvent for 5 h
at 110 °C. Gratifyingly, the expected product was obtained in 36%
yield (entry 1, Table 1). Inspired by this result, we tested various
iron salts in different solvents as well as varying the temperature
(see Table 1). The use of a mixture of nitromethane and DMF
(2:1 v/v) as the solvent yielded 5aaa in 72% (entry 2, Table 1). It
indicated that the binary solvent system might play an important
role for this conversion.17 So, we examined the model reaction
with various binary solvent systems such as nitromethane with
DMSO, toluene, and CH3CN. It was found that the use of a mixture
of nitromethane and DMF (2:1) afforded the product 5aaa in max-
imal yield (entry 6, Table 1). Increasing the temperature did not
improve the yield whereas decreasing the temperature lowered
the yield to 64%. FeCl3 (20 mol %) was found to be a more effective
catalyst compared to other iron salts like FeBr3 and Fe(OTf)3. In this
case FeBr3 and Fe(OTf)3 make strong complexes with 2-aminopyr-
idine which probably suppressed the formation of product.
Increasing the amount of catalyst (30 mol %) did not improve the
yield noticeably (entry 13, Table 1) whereas decreasing the amount
of catalyst (10 mol %) decreased the yield (entry 14, Table 1). In the
absence of catalyst no product was observed. Furthermore, the use
of other additives, such as piperidine and acetic acid, did not
improve the yield of this transformation (entries 7 and 8, Table 1).
However, other common Lewis acids like AlCl3 and ZnCl2 were not
effective for this reaction (entries 16 and 17, Table 1). Thus, opti-
mal reaction conditions were obtained using 2-aminopyridine
(1a, 1 mmol), 4-chlorobenzaldehyde (2a, 1.1 mmol) in presence
of 20 mol % of FeCl3 in a mixture of nitromethane (3a) and DMF
(2:1) at 110 °C (entry 6, Table 1) in air.
With the optimized reaction conditions in hand, we explored
the scope of this reaction (Table 2). Our attention was focused on
the use of substituted aldehydes and 2-aminopyridines to prove
the general applicability of the reaction conditions (5aaa–5eba).
It can be seen that electron-rich and electron-deficient aldehydes
reacted efficiently with various 2-aminopyridines to afford the
desired products with good yields under the optimized reaction
conditions without any additives.18 The chloro- and iodo-substi-
tuted benzaldehydes gave the corresponding 5aaa and 5bja in
78% and 76% yields respectively. We were pleased to notice that
under the stated conditions, aminopyridines substituted with
halogens such as –Cl, and –I (5dba and 5eba) smoothly reacted
with benzaldehyde without forming any dehalogenated products.
The aldehyde containing an electron donating OMe group on
the aromatic ring also showed good efficiency (5ada and 5bda).
H
(a) Synthetic strategy:
N
R2
X = CH
R1
R1
R3
NO2
Our Previous Work
Ref. 15
NO2
4
R1
R2 CHO
R3
+
NH2
+
H
N
R2
X
1
X = N
This Work
N
2
3
R3
NO2
N
R1
R2
N
R3
R3 = H, Me, Et
R1
5
(b) Our previous method (Ref 16a):
NH2
FeCl3 (20 mol%)
DMF, 80 0C
N
R2
R2
NO2
R1
N
N
H
Scheme 1. Synthesis of imidazo[1,2-a]pyridine derivatives.

S. Santra et al. / Tetrahedron Letters 55 (2014) 5151–5155
5153
Table 1
Optimization of the reaction conditionsa
NH2
+
Catalyst
N
Cl
CHO
Cl
N
N
Air, Temp.
MeNO2 / Solvent
1a
2a
3a
5aaa
Entry
Catalyst (mol %)
Solvent
Temp. (°C)
Yieldb (%)
1c
2
3
4
5
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeBr3 (20)
Fe(OTf)3 (20)
FeCl3 (30)
FeCl3 (10)
—
MeNO2 (3 mL)
110
110
110
110
110
110
110
110
90
130
110
110
110
110
110
110
110
36
72
28
33
26
78
76
74
64
72
42
37
79
64
MeNO2/DMF (1.5/1.5 mL)
MeNO2/Toluene (1.5/1.5 mL)
MeNO2/DMSO (1.5/1.5 mL)
MeNO2/CH3CN (1.5/1.5 mL)
MeNO2/DMF (2/1 mL)
MeNO2/DMF (2/1 mL)
MeNO2/DMF (2/1 mL)
MeNO2/DMF (2/1 mL)
MeNO2/DMF (2/1 mL)
MeNO2/DMF (2/1 mL)
MeNO2/DMF (2/1 mL)
MeNO2/DMF (2/1 mL)
MeNO2/DMF (2/1 mL)
MeNO2/DMF (2/1 mL)
MeNO2/DMF (2/1 mL)
MeNO2/DMF (2/1 mL)
6
7d
8e
9
10
11
12
13
14
15
16
17
NDf
Trace
Trace
AlCl3 (20)
ZnCl2 (20)
Entry 6 is the optimized reaction conditions.
a
Reaction conditions: Carried out with 1 mmol of 1a and 1.1 mmol of 2a in solvent (3 mL) for 5 h.
Isolated yields.
Reaction carried out under reflux conditions.
20 mol % piperidine was used as an additive.
20 mol % AcOH was used as an additive.
b
c
d
e
f
Yields are not determined by TLC.
heteroaryl aldehydes such as furfural and thiophene-2-carboxalde-
hyde could also participate in the multicomponent reaction to pro-
duce the desired products in moderate yields without affecting the
heterocyclic moieties (5aga and 5bka). We were delighted to find
that the –SMe substituted benzaldehyde was also tolerated under
our catalytic conditions with 72% isolated yield (5aea). Aliphatic
aldehyde isobutyraldehyde also afforded the desired product with
moderate yield (5aha). This methodology is also applicable on a
gram-scale synthesis. We have successfully prepared the imidazo-
pyridine 5aaa in 72% yield by the reaction of 2-aminopyridine (1a,
20 mmol) with 4-chlorobenzaldehyde (2a, 22 mmol).
Our synthesized compound 5aea can be utilized for the synthe-
sis of the marketed drug zolimidine by oxidation employing the
reported method.9b We have also successfully synthesized this
drug under our present reaction conditions with good yield
(Scheme 2).
Table 2
Scope of the iron(III)-catalyzed three-component reactiona
NH2
+
N
FeCl3 (20 mol%)
R1
R1
R2
R2 CHO
N
N
Air, 110 oC
MeNO2 / DMF (2:1)
3a
1
2
5
N
N
N
Cl
Me
N
N
N
5aaa, 78% (72%)b
5aba, 76%
5aca, 72%
HO
N
N
N
OMe
SMe
Me
N
N
N
5ada, 78%
5aea, 72%
5afa, 68%
N
N
N
N
N
N
S
5aga, 58%
5aha, 35%
5bba, 73%
By virtue of our method, we are able to synthesize substituted
imidazo[1,2-a]pyridines at the C-3 position. The synthesis of
3-substituted imidazo[1,2-a]pyridines is possible by changing
nitromethane to other nitroalkanes (Scheme 3). Both nitroethane
and nitropropane worked well under the present reaction
conditions. The desired 3-substituted imidazo[1,2-a]pyridines
were obtained in good yields (6aab–7bbc). An aliphatic aldehyde
also reacted under the optimized reaction conditions (6bhb).
To understand the reaction mechanism, a few experiments
were performed which are represented in Scheme 4. First of all,
we synthesized the corresponding imine A by reacting with
2-aminopyridine (1a) and 4-chlorobenzaldehyde (2a) in ethanol.
When the imine A was subjected to the optimized reaction
conditions, the corresponding imidazo[1,2-a]pyridine 5aa was
obtained in quantitative yield (Eq. 1). Furthermore, the imine A
has been isolated from the reaction mixture by quenching the reac-
tion after 30 min. Moreover, the formation of nitrostyrene was not
observed in the reaction. This suggests that the imine A is the key
intermediate for this reaction. No significant decrease in yield was
observed when the reaction was carried out in the presence of a
NO2
Me
Me
N
N
OMe
N
N
5bda, 75%
5bia, 70%
Me
I
Me
N
N
N
Me
N
N
N
O
Me
5bja, 76%
5bka, 62%
5cca, 68%
N
N
N
N
Cl
I
5dba, 68%
5eba, 70%
a
Reaction conditions: 1 (1.0 mmol), 2 (1.1 mmol), FeCl3 (20 mol %), MeNO2 (3a,
2.0 mL), DMF (1.0 mL) at 110 °C for 5 h. All are isolated yields.
b 1a (20.0 mmol), 2a (22.0 mmol), FeCl3 (20 mol %), MeNO2 (3a, 40.0 mL), DMF
(20.0 mL) at 110 °C for 5 h.
2-Hydroxybenzaldehyde afforded the corresponding product 5afa
which is very useful for photophysical studies and displays
excited-state intramolecular proton transfer (ESIPT).5a In addition,

5154
S. Santra et al. / Tetrahedron Letters 55 (2014) 5151–5155
NH2
+
present reaction most likely occurs via a sequential aza-Henry
FeCl3 (20 mol%)
N
OHC
SO2Me
SO2Me
N
reaction/cyclization/denitration. Readily available chemicals as
starting materials, an inexpensive metal catalyst, aerobic reaction
conditions, tolerance of a wide range of functional groups, and
operational simplicity are the notable advantages of this present
approach. These advantages render this protocol facile and suitable
to create a diversified library of imidazo[1,2-a]pyridine derivatives.
N
Air, 110 oC, 5 h
MeNO2 / DMF (2:1)
3a
Zolimidine
5ala (68%)
1a
2l
Scheme 2. One-pot synthesis of the drug zolimidine.
NH2
+
FeCl3 (20 mol%)
N
Acknowledgments
R1
R2 CHO
R1
R2
N
Air, 110 oC, 5 h
N
R3CH2NO2 / DMF (2:1)
R3
A.H. is pleased to acknowledge the financial support from CSIR,
India (Grant No. 02(0168)/13/EMR-II). We are thankful to DST-FIST
and UGC-SAP. S.S. and A.K.B. thank UGC and CSIR for fellowship.
1
2
3
R1 = H, R2 = 4-Cl-C6H4, R3 = Me, 6aab, 76%
R1 = H, R2 = C6H5, R3 = Me, 6abb, 78%
R1 = 4-Me, R2 = (CH3)2CH, R3 = Me, 6bhb, 38%
R1 = H, R2 = C6H5, R3 = Et, 7abc, 75%
R1 = 4-Me, R2 = C6H5, R3 = Et, 7bbc, 74%
Supplementary data
Scheme 3. Synthesis of 3-substituted imidazo[1,2-a]pyridines.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014
.07.094.
Cl
N
FeCl3 (20 mol%)
N
Cl
(Eq. 1)
References and notes
N
MeNO2 / DMF (2:1)
Air, 110 oC, 5 h
N
N
5aaa, Quantitative yield
A
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NH2
N
N
FeCl3 (20 mol%)
Cl
Cl
+
CHO
TEMPO (1.5 equiv)
Air, 110 oC, 5 h
(Eq. 2)
MeNO2 / DMF (2:1)
1a
2a
3a
5aaa, 76% yield
Scheme 4. Mechanistic experiments.
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CHO
CH3NO2
H
N
N
N
O
N
O
FeCl3
3a
+
NH2
FeCl3
aza-Henry
H
N
N
Cl
Cl
Cl
B
FeCl3
H
1a
A (Isolable)
2a
N
H
N
N
N
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Cl
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HO
Cl
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FeCl3
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Cl
5aaa
FeCl3
D
C
Scheme 5. Probable mechanism for the three-component reaction.
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radical scavenger, TEMPO (1.5 equiv) (Eq. 2) which favors the
formation of imidazo[1,2-a]pyridines through the non-radical
mechanistic pathway.
From the results of the above experiments, a probable mecha-
nism for the reaction is represented in Scheme 5. Initially, imine
A is formed by the condensation between 2-aminopyridine and
aldehyde. The next step is the formation of the aza-Henry product
B through the addition of nitromethane to the imine.15 Likely, FeCl3
assisted these two steps by increasing the electrophilicity of both
the aldehyde and the imine. Intermediate B then tautomerizes to
intermediate C, which undergoes an intramolecular cyclization
affording intermediate D. The final product results from a subse-
quent elimination of both water and nitroxyl (HNO).16,19 FeCl3
may further act as a Lewis acid to facilitate the intramolecular
cyclization.
In summary, we have developed an iron(III)-catalyzed one-pot
three-component domino strategy for the expedient synthesis of
imidazo[1,2-a]pyridines under ambient atmosphere. Furthermore,
the present methodology is also applicable to the synthesis of
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