Novel one-pot three component reaction for the synthesis of [2-(alkylsulfanyl)imidazo[1,2-a]pyridin-3-yl](aryl)methanone

Article abstract of DOI:10.1021/cc900103r

A one-pot, three-component reaction between pyridine, phenacyl bromide, and thiocyanate is described. The reaction afforded the corresponding special type of fully substituted imidazo[1,2-a]pyridine derivatives in good yields without using any catalyst or activation.

Full text of DOI:10.1021/cc900103r

J. Comb. Chem. 2010, 12, 41–44
41
Novel One-Pot Three Component Reaction for the Synthesis of
[2-(Alkylsulfanyl)imidazo[1,2-a]pyridin-3-yl](aryl)methanone
Ebrahim Kianmehr,* Mohammad Ghanbari, Mehri Nadiri Niri, and Reza Faramarzi
School of Chemistry, College of Science, UniVersity of Tehran, P.O. Box 14155-6455, Tehran, Iran
ReceiVed July 17, 2009
A one-pot, three-component reaction between pyridine, phenacyl bromide, and thiocyanate is described.
The reaction afforded the corresponding special type of fully substituted imidazo[1,2-a]pyridine derivatives
in good yields without using any catalyst or activation.
1. Introduction
reactions of 2-aminopyridines with glyoxal trimer dehy-
drate,17 R-halocarbonyl compounds,18 and other 1,2-dielec-
trophilic compounds.19 2-Aminopyridines have also been
used in a one-pot condensation reaction with aldehydes and
isonitriles to construct this class of compounds.20 In another
method they have been prepared by reactions of 2-chloro-
pyridines with 1,2,3-triazoles and subsequent elimination of
nitrogens.21 This class of compounds has also been prepared
via pyridinium salts such as 1-[1-substituted 2,2-bis(meth-
ylthio)ethenyl]pyridinum,22 2-halo-1-alkylpyridinium,23 and
2-halo-1-phenacyl pyridinum24 salts. Approaches based on
the use of substituted imidazoles as starting materials to
construct the imidazopyridine nucleus, via cyclization of
1-(2-alkynyl)-2-aminomethylimidazoles and reactions of
(arylacetyl)imidazoles with acetylenedicarboxylic esters, have
also been described.25 However, most of these methods suffer
from lengthy sequences, low overall yields, and limited
ability to vary substituents or use relatively inaccessible
starting materials.
A major challenge of modern drug discovery is the design
of highly efficient chemical reaction sequences that provide
maximum structural complexity and diversity with a mini-
mum number of synthetic steps to assemble compounds with
interesting properties.1 Great efforts have been focused on
synthesizing libraries of small heterocyclic molecules because
of their high degree of structural diversity and extensive
utility as therapeutic agents.2 The development of new, rapid,
and clean synthetic routes toward focused libraries of such
compounds is therefore of great importance to both medicinal
and synthetic chemists.3 Undoubtedly, synthetic strategies
involving multicomponent reactions (MCRs) have manifested
themselves as a powerful tool for the rapid introduction and
expansion of molecular diversity.4 Consequently, the design
and development of new MCR routes for the generation of
heterocycles receives growing interest.5
Synthesis of imidazo[1,2-a]pyridines and their analogues
has attracted significant attention in recent years as this class
of compounds exhibits a broad range of useful pharmaco-
logical activity, including antibacterial,6 antifungal,7 antivi-
ral,8 antiulcer,9 and anti-inflammatory behaviors.10 They have
also been characterized as selective cyclin-dependent kinase
inhibitors,11 calcium channel blockers,12 b-amyloid formation
inhibitors,13 and benzodiazepine receptor agonists,14 and they
constitute a novel class of orally active nonpeptide bradykinin
B2 receptor antagonists.15 Drug formulations containing
imidazo[1,2-a]pyridines such as alpidem (anxiolytic), zolpi-
dem (hypnotic), and zolimidine (anti-ulcer) are currently
available (Figure 1).
Considering the above reports, the development of new
and simple synthetic methods for the efficient preparation
of the heterocycles containing imidazo[1,2-a]pyridine ring
fragments will be a beneficial and interesting challenge. As
part of our current studies on the development of efficient
methods for the preparation of heterocyclic compounds,26
herein, we report a novel one-pot and three-component
synthesis of imidazo[1,2-a]pyridines with 2-alkylsulfanyl and
aroyl substituents at 2 and 3 positions. The notable advan-
tages offered by this method are readily available starting
materials, simple operation, and good yields of the products.
The pharmacological profile of imidazo[1,2-a]pyridines is
shown to be critically dependent on the nature of the
substituents at the 2 and 3 positions.16 Thus, there is a definite
need to develop a more structurally flexible method for the
synthesis of this class of compounds.
So far, several synthetic methods have been reported for
the preparation of imidazo[1,2-a]pyridine ring systems. The
most common approach for the synthesis of imidazo[1,2-
a]pyridines involves construction of the imidazole ring by
* To whom correspondence should be addressed. E-mail: kianmehr@
khayam.ut.ac.ir. Phone: +98-21-61113301. Fax: +98-21-66495291.
Figure 1
10.1021/cc900103r CCC: $40.75  2010 American Chemical Society
Published on Web 11/11/2009

42 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Scheme 1. Model Reaction
Kianmehr et al.
Table 2. Synthesis of Imidazo[1,2-a]pyridine Derivatives 4
entry
yield (%)a
R1
R2
R3
R4
R5
Table 1. Model Reaction, Conditions, and Yielda
4{1,1,1}
4{1,1,2}
4{1,2,1}
4{1,2,2}
4{2,1,1}
4{2,1,2}
4{2,2,1}
4{2,3,1}
4{2,3,3}
4{2,4,1}
4{2,6,1}
4{3,2,1}
4{3,4,1}
4{3,4,2}
4{4,1,1}
4{4,1,2}
4{4,3,1}
4{4,3,3}
4{5,5,1}
4{5,5,2}
78
76
81
74
82
79
77
83
79
86
90
78
84
81
75
74
77
72
78
81
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Cl
Cl
H
H
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
MeO
H
H
H
H
H
H
Me
Et
Me
Et
Me
Et
Me
Me
Bn
Me
Me
Me
Me
Et
Me
Et
Me
Bn
Me
Et
entry
conditions
time (h)
yield (%)
1
2
3
4
5
7
solvent-free (100 °C)
CH3CN (reflux)
water (reflux)
Toluene (reflux)
EtOH (reflux)
12
12
12
12
12
12
42
21
0
78
0
Et
Et
Et
Et
Et
Et
Et
Bn
Bn
Bn
H
H
Cl
Br
Br
MeO
H
Cl
MeO
MeO
H
THF (reflux)
14
a Pyridine (1.2 mmol), phenacyl bromide (1.2 mmol), methyl
thiocyanate (1 mmol), and K2CO3 (2 mmol).
2. Results and Discussion
First, to achieve suitable conditions for the synthesis of
imidazo[1,2-a]pyridines 4, we tested the reaction of pyridine
1{1}, phenacyl bromide 2{1}, and methyl thiocyanate 3{1}
as a simple model substrate in various solvents and under
solvent-free classical heating conditions in the presence of
potassium carbonate (Scheme 1). The results are shown in
Table 1. It was found that toluene is a solvent of choice for
the reaction, and the desired product was obtained in good
yield and high purity (entry 4).
H
H
H
H
H
Br
Br
H
H
Br
Br
H
H
a Isolated yields.
knowledge, this new procedure provides the first example
of an efficient and three-component method for the synthesis
of this class of imidazo[1,2-a]pyridine derivatives.
After optimization of the reaction conditions, to delineate
this approach, particularly in regard to library construction,
this methodology was evaluated by using different pyridines,
phenacyl bromides, and thiocyanates. Five commercially
available pyridines 1{1-5}, six substituted phenacyl bro-
mides 2{1-6}, and three commercially available thiocyan-
ates 3{1-3} were chosen for the library validation, and 20
examples were selected as synthetic targets from 90 (theo-
retical library size) (Figure 2). Corresponding imidazo[1,2-
a]pyridine derivatives 4 were synthesized by the one pot,
three-component condensation of pyridines 1, phenacyl
bromides 2, and thiocyanates 3 in good yields in refluxing
toluene in the presence of potassium carbonate for 12 h. The
reaction can be represented as in Table 2. To the best of our
Given the large number of commercially available py-
ridines and the easy access to phenacyl bromides and
thiocyanates, the present method should be applicable to
synthesis of libraries with high diversity. We expect this
method to find extensive application in the field of combi-
natorial chemistry, diversity-oriented synthesis, and drug
discovery.
Finally, to further explore the potential of this protocol
for heterocyclic synthesis, we investigated a reaction involv-
ing chloroacetonitrile 5 and obtained 2-(methylsulfanyl)imi-
dazo[1,2-a]pyridine-3-yl cyanide derivative 6 in good yield
(Scheme 2). Furthermore, the 2-sulfur atom of 4{2,3,1} can
be oxidized to yield compound 7 and shows the possibility
Figure 2. Diversity of reagents.

Imidazo[1,2-a]pyridine Derivatives
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 43
Scheme 2. Synthesis of 2-(Methylsulfanyl)imidazo[1,2-a]-
pyridine-3-yl Cyanide 6
Acknowledgment. We gratefully acknowledge the finan-
cial support from the Research Council of the University of
Tehran. We thank Dr. Karol Gajewski for helpful advice with
this work.
Note Added after ASAP Publication. This paper
published ASAP November 11, 2009 with an incorrect
version of the Supporting Information; the corrected version
published ASAP November 18, 2009 with revisions to data
strings, compounds, spectra, and additional references were
added.
Scheme 3. Possible Derivatizations of Imidazo[1,2-a]-
pyridine 4
Supporting Information Available. Experimental pro-
1
cedures, H NMR and 13C NMR spectra for compounds 4,
6, and 7. This material is available free of charge via the
Internet at http://pubs.acs.org.
References and Notes
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Although the mechanism of this reaction has not been
established experimentally, a reasonable mechanism is shown
in the Supporting Information. It is worthy of mention that
in the 3-substitued pyridines only the ortho-position of the
substituents was attacked by the imine anion to form an
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Compounds 4, 6, and 7 are stable solids whose structures
1
were established by IR, H NMR, 13C NMR, and EI-MS
spectroscopy.
In conclusion, we have demonstrated an efficient and
simple method for the preparation of imidazo[1,2-a]pyridine
derivatives using readily available starting materials. Promi-
nent among the advantages of this new method are novelty,
operational simplicity, and good yields. Further reactivity
studies and synthetic applications of this methodology are
in progress in our laboratory.
Synthesis of 4{1,1,1}. Caution! SeVere toxicity will occur
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heated or on contact with acids or acid fumes, they emit
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Pyridine (0.097 mL, 1.2 mmol) and phenacyl bromide
(0.239 g, 1.2 mmol) were taken up in toluene (10 mL), and
the mixture was stirred at room temperature (rt) for 1 h. To
this mixture methyl thiocyanate (0.074 g, 1.0 mmol) and
potassium carbonate (0.28 g, 2.0 mmol) were added, and
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completion, the toluene was removed under reduced pressure,
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with dichloromethane (3 × 15 mL). The organic layer was
dried over Na2SO4. Evaporation of the solvent followed by
purification on silica gel (ethyl acetate-hexane, 1-9)
afforded the pure 4{1,1,1} as yellow solid (0.24 g, yield
78%). M.p 140 °C. IR (KBr) (νmax/cm-1): 1490, 1571, 1597,
1
3060. H NMR (500 MHz, CDCl3) δH (ppm): 2.58 (3H, s,
S-CH3), 7.07-7.10 (1H, m), 7.52-7.57 (3H, m), 7.61-7.63
3
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140.33, 148.55, 156.49, 186.05 (CdO). MS, m/z (%): 268
(M+,100), 235 (67), 207 (33), 163 (26), 77 (44), 51 (23).

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CC900103R