Green synthesis of imidazo[1,2-a]pyridines using calix[6]arene-SO3H surfactant in water

Article abstract of DOI:10.1016/j.tetlet.2018.04.075

In this research, green synthesis of imidazo[1,2-a]pyridines in the presence of calix[n]arenes-SO₃H as a Br?nsted acid catalyst and surfactant is described. Using of calix[n]arenes in water provided a hydrophobic cavity that successfully carried out the synthesis reactions at short times with high yields. This catalyst system is recoverable with a simple extraction using an organic solvent and reusable for at least for 5 cycles without any losses of its activity.

Full text of DOI:10.1016/j.tetlet.2018.04.075

Accepted Manuscript
Green synthesis of imidazo[1,2-a]pyridines using calix[6]arene-SO3H surfac-
tant in water
Mahshid Esmaielzade Rostami, Banafsheh Gorji, Reza Zadmard
PII:
S0040-4039(18)30561-6
https://doi.org/10.1016/j.tetlet.2018.04.075
TETL 49938
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 March 2018
20 April 2018
27 April 2018
Please cite this article as: Rostami, M.E., Gorji, B., Zadmard, R., Green synthesis of imidazo[1,2-a]pyridines using
calix[6]arene-SO3H surfactant in water, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.04.075
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Graphical Abstract

Title:
Green synthesis of imidazo[1,2-a]pyridines using calix[6]arene-SO3H surfactant in
water
Author names and affiliation:
Mahshid Esmaielzade Rostamia, Banafsheh Gorjia,*, Reza Zadmardb,*
a Department of Chemistry, Islamic Azad University, South Tehran Branch, Tehran, Iran
b
Chemistry and Chemical Engineering Research Center of Iran (CCERCI), PO Box
14335-186, Tehran, Iran
*Corresponding authors: E-mail: Banafsheh.gorji@gmail.com; Tel: +98 21 33722831;
Fax: +98 21 33717140 and zadmard@ccerci.ac.ir; Tel: +98 21 44787719; Fax: +98 21
44787785

Abstract
In this research, green synthesis of imidazo[1,2-a]pyridines in the presence of calix[n]arenes-
SO3H as a Brønsted acid catalyst and surfactant is described. Using of calix[n]arenes in water
provided a hydrophobic cavity that successfully carried out the synthesis reactions at short
times with high yields. This catalyst system is recoverable with a simple extraction using an
organic solvent and reusable for at least for 5 cycles without any losses of its activity.
Keywords: imidazo[1,2-a]pyridine, calix[n]arene, surfactant, hydrophobic cavity
Introduction
Imidazopyridines are considered as important class of fused heterocyclic compounds
possessing interesting biological and pharmacological properties as antiviral [5], antifungal
[1], anti varicella-zoster [2], antibacterial [4] and anti-cancer agents [6]. Specifically,
imidazo[1,2-a]pyridine framework has been found in several marketed drugs such as
Olprinone (heart failure drug) [7], Alpidem (a nonsedative anxiolytic agent) [8], Zolimidine
(treatment of peptic ulcers) [9] and Zolpidem (treatment of insomnia) [8,10] .
Up to now, various methods have been utilized for the synthesis of imidazo[1,2-a]pyridine
scaffold. In this context, Groebke–Blackburn–Bienaymé (GBB) multicomponent reaction is
one of the simplest synthesis routes of this important class of heterocyclic systems [11]. This
reaction is based on the condensation of 2-aminoazine, an aldehyde and an isocyanide in the
presence of Lewis acids like ZnCl2 [12], Sc(OTf)3 [13], ZrCl4 [14], MgCl2 [15], RuCl3 [16],
LaCl3 [17], and Brønsted acids like cellulose sulfuric acid [11], AcOH [18], HClO4 [11c], 4-
toluene sulfonic acid [19]. Moreover, the GBB reaction has been carried out under solvent-
free [20] or microwave irradiation conditions [21]. However, many of these methods suffer
from some drawbacks, such as the use of toxic or expensive reagents, long reaction times,
tedious work-up procedures, low yields, requirement for an inert atmosphere, and in some
cases harsh reaction conditions. Thus, the development of an efficient and convenient method
for the synthesis of imidazo[1,2-a]pyridines would be valuable.
The development of organic reactions in water has been of considerable interest in organic
synthesis, because of the many advantageous properties of water as an environmentally
friendly and nontoxic reaction medium. The main disadvantage of water as a solvent is that

many organic compounds are hydrophobic and insoluble in water. However, the use of water-
soluble supramolecular catalysts in aqueous reaction systems can potentially overcome this
issue [22-25]. Calix[n]arenes, are a class of macrocyclic molecules, which have been used
extensively as supramolecular catalysts [26]. Specifically, p-sulfonic acid calix[n]arenes
showed to be the most efficient catalysts for different multicomponent reactions such as
Mannich-type [27, 28], Povarov [24, 25] and Biginelli [29].
Herein we report an efficient and straightforward method for synthesis of 3-amino-
imidazo[1,2-a]pyridines via the GBB three-component reaction protocol in the presence of
sulfonated calix[n]arenes (n= 4 or 6) in water. The sulfonated calix[n]arenes as water soluble
organocatalyst provide a new green catalyst system to accelerate the GBB reaction. From
environmental point of view, using water as solvent in the organic transformations simplify
the experimental and reaction workup in compared to reactions utilizing organic solvent and
also decrease the waste and handling costs.
Scheme 1. Synthesis of the imidazo[1,2-a]pyridines in the presence of calix[n]arenes
Results and discussion
In our efforts to design a green and facile method for synthesis of imidazo[1,2-a]pyridines
based on sulfonated calix[n]arenes as catalyst, the reaction of 2-aminopyridine, benzaldehyde
and cyclohexyl isocyanide was chosen as model reaction and water as the greenest solvent for
initial investigation. As seen in the Table 1, the model reaction was examined using 0.1
equivalent of calix[4]arene and calix[6]arene in water in different temperatures that the

desired product N-cyclohexyl-2-phenylimidazo[1,2-a]pyridin-3-amine 4a was formed with
38% and 88% yields at room temperature, respectively. There was a question "what is the
difference between the sulfonated calix[4]arene and calix[6]arene?". We found the best
answer based on the previous report on the catalytic activity of calix[n]arenes for alkylation
of alcohols in water, which sulfonated calix[n]arenes provide hydrophobic cavity in water as
the surfactants, and calix[6]arene is the most effective surfactant [30]. Accordingly, It can be
concluded that calix[n]arenes have a doul roles as Brønsted acid and surfactant. When the
calix[n]arenes were used as a catalyst, the reaction was carried out in the hydrophobic cavity
under high microscopic temperature and pressure, which the calix[6]arene provide
hydrophobic cavity more effective than calix[4]arene. In order to prove the surfactant role of
the calix[n]arenes, the para-toluene sulfonic acid (PTSA) was used in the model reaction
under same reaction conditions, and the desired product 4a was synthesized with 28% yield.
These results confirmed that the reaction was accelerated in the hydrophobic cavity. As
complementary study, the model reaction was examined with different amount of the
calix[6]arene in water and in two various solvents such as ethanol and acetonitrile (see Table
1). In the cases of organic solvent, 4a was formed with low yields. Finally, the calix[6]arene,
water and room temperature were chosen as best catalyst, solvent and temperature,
respectively.
Table 1. Optimization of the reaction conditionsa.
Yieldb
Entry
Catalyst (mol%)
Solvent
Temperature (oC)
Time (h)
calix[4]arene (10)
calix[6]arene (10)
calix[6]arene (10)
calix[6]arene (10)
calix[6]arene (5)
calix[6]arene (15)
PTSA (20)
water
water
water
water
water
25
25
50
100
25
25
25
25
25
3
3
3
4
3
3
10
3
38
88
90
24
51
90
28
57
46
1
2
3
4
5
6
7
8
9
water
water
calix[6]arene (10)
calix[6]arene (10)
ethanol
acetonitrile
3
aReaction condition: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.1 mmol) and solvent (10 mL).bIsolated yield.
With the optimized conditions in hand, scope and generality of the reaction were investigated
using three derivatives of 2-aminopyridines, five various aldehydes and two isocyanides. As

seen in the Table 2, in the all cases the products were synthesized with good to excellent
yields at relative short times.
Table 2. Calix[6]arene sulfonic acid-catalyzed the GBB reaction in water
Entry
Aldehyde
2-aminopyridine isocyanides
Product
Yieldb(%)
1
88
2
3
90
83
4
93
5
6
75
96

7
8
81
88
92
82
9
10
b Isolated yield
As parallel study, some alternative compounds that used instead of 2-aminopyridine in the
previous reports were chosen to establish the efficiently of this catalyst system. 2-
aminobenzoimidazole, 2-aminobenzothiazole and 2-aminopyrazine were applied in the model
reaction with benzaldehyde and cyclohexyl isocyanide. Fortunately, all reactions led to the
creation of the corresponding fused imidazole rings in the good yields (Scheme 2).

Scheme 2. Synthesis of some fused imidazole rings
Table 3. Calix[6]arene-SO3H catalyzed Synthesis of some fused imidazole rings in water
Entry
Aldehyde
2-aminopyridine
isocyanides
Product
Yieldc(%)
1
79
2
3
75
81
c Isolated yield
The possible mechanism for synthesis of imidazo[1,2-a]pyridine 4a has been schematically
shown below. Although we have not experimentally established the mechanism of this reaction,
it is reasonable to assume that the calix[6]arene could provide the micelles (hydrophobic
cavities) in the water medium that played the role of reactors in this protocol. Also the
production of imine intermediate A is catalyzed by the acidic character of this system and then
the reaction was accomplished by participation of isocyanide as C1 source in the formal [1+4]
cycloaddition reaction with imini A as diene. This reaction is three molecular condensation
(decreasing the reaction entropy), so this process is potentially accelerated in the micelle system
under high pressure conditions (scheme 3).

Scheme 3. Proposed mechanism
In summary, we have developed a new approach for synthesis of imidazo[1,2-a]pyridines and
some other fused imidazole rings based on GBB protocol in the presence of calix[6]arene as a
dual roles catalyst in water. This approach is a green and efficient method for high-yielding
synthesis of these heterocycles at room temperature without using any metal catalyst.
Experimental section
Preparation of calix[n]arenes (4 and 6): The hexasodium salt of calix[n]arene-p-hexa or
tetrasulfonate (2 mmol) was poured in the solution of NaOH (58.8 mmol) in water (15 mL) and
resulted solution was mixed with solution of butyl bromide (59.2 mmol) in dimethyl sulfoxide
o
(60 mL), and the reaction mixture was stirred at 80 C for 72 h. After that, the solution was
diluted with methanol and cooled to give a solid, which was filtered and dissolved in water (10

mL). After the insoluble material was removed by filtration, the solid was precipitated again by
adding ethanol. After dried under vacuum at 60 oC, a white powder was obtained.
Typical procedure for synthesis of the imidazo[1,2-a]pyridine 4a using calix[6]arene in
water:2-aminopyridine (1.0 mmol), benzaldehyde (1.0 mmol) and cyclohexyl isocyanide (1.1
mmol) was added to the mixture of calix[6]arene (0.1 mmol) in water (10 mL) and magnetically
stirred for 3 h at ambient temperature. After completion the reaction that indicated by thin layer
chromatography (mixture of ethyl acetate and n-hexane), the reaction mixture was extracted by
ethyl acetate (3×2 mL) and the solvent or organic layer was evaporated and recrystallized in
ethanol. All of the known compounds were identified by physical properties, and some of them
were characterized by 1H and 13C NMR spectroscopy.
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Highlights:
1- Synthesis of imidazo[1,2-a]pyridines in water
2- Using of sulfonated calix[4]arene and calix[6]arene as a reusable catalyst
3- Simple procedure, short reaction time with good yield.