Synthesis of imidazo[1,2-a]pyridine in the presence of iodine-water catalytic system

Article abstract of DOI:10.1016/j.tetlet.2013.12.088

We have devised an expedient, cleaner, and environmentally friendly approach for 'on water' mediated synthesis of imidazo[1,2-a]pyridine derivatives. The synthesis involves in situ formation of imines followed by addition of alkyne to give the desired pro

Full text of DOI:10.1016/j.tetlet.2013.12.088

Tetrahedron Letters 55 (2014) 1159–1163
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of imidazo[1,2-a]pyridine in the presence of iodine–water
catalytic system
⇑
I. R. Siddiqui , Pragati Rai, Rahila, Anushree Srivastava, Shayna Shamim
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:
We have devised an expedient, cleaner, and environmentally friendly approach for ‘on water’ mediated
synthesis of imidazo[1,2-a]pyridine derivatives. The synthesis involves in situ formation of imines
followed by addition of alkyne to give the desired products in excellent yield.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 19 October 2013
Revised 20 December 2013
Accepted 24 December 2013
Available online 9 January 2014
Keywords:
Imidazo[1,2-a]pyridine
Iodine
Aqueous medium
Eco-friendly
Multicomponent reaction
The use of multicomponent reactions (MCR) to form several
bonds via single step synthesis and to integrate different fragments
into one molecule has made a big advancement in the field of
chemical research in recent decade.1 Due to increasing concerns
over hazardous effect of organic solvents on environment and hu-
man beings, various types of MCR have been successfully investi-
gated in aqueous medium. Reactions in aqueous environment
have attracted attention due to its unique reactivity and selectivity
that are difficult to achieve in conventional organic solvents.
Water, probably due to its unique abilities such as hydrogen bond-
ing, high dielectric constant, and polarity appears to be a more effi-
cient medium for organic transformation.2,3 In this context water is
preferable solvent and a remarkable contributor in the field of
organic synthesis.
identified as selective cyclin-dependent kinase inhibitors,8 calcium
channel blockers,9 and beta-amyloid formation inhibitors10 and
also constitute orally active non-peptide bradykinin B2 receptor
antagonists.11
All these bioactivities make imidazo[1,2-a]pyridine an interest-
ing scaffold for organic chemists. Numerous methodologies have
been enumerated for the synthesis of imidazo [1,2-a]pyridines by
using transition metal salts and other catalysts.12–16 Among these,
the three-component coupling of aldehyde, 2-aminopyridine, and
alkyne is one of the most preferable method for the synthesis of
imidazo[1,2-a]pyridine.17,18 The disadvantages of all these investi-
gations are requirement of expensive and huge amount of catalyst,
long reaction time, use of metal catalyst which is separated after
complex process, unsatisfactory yield of the product, and harsh
reaction conditions.13 During recent years molecular iodine has re-
ceived considerable interest due to its low price, sustainability,
ready availability, non toxicity, and eco-friendly properties.19 The
use of iodine as Lewis acid has increased substantially due to its
quality of high tolerance to air, moisture, and high catalytic activity
in dilute as well as in highly concentrated condition.20 Recently, it
has been successfully employed to synthesize indoles and oxaz-
oles. Encouraged by these advances, we sought to investigate the
application of this reagent in imidazo[1,2-a]pyridine synthesis.
The considerations described above inspired us to investigate
the three-component conversion of 2-aminopyridine, aldehyde,
and alkyne, in imidazo[1,2-a]pyridine by employing iodine as a
catalyst in aquatic condition (Scheme 1). To the best of our knowl-
edge, this is the first approach for the synthesis of imidazo[1,2-
a]pyridine in water by using molecular iodine.
Over the years, the pharmacological potential of imidazo[1,2-
a]pyridine has attracted extensive interest from both medicinal
and synthetic chemists because of their presence in broad spec-
trum of natural and synthetic organic molecules with diverse bio-
logical properties.
A wide range of compounds possessing
imidazo[1,2-a]pyridine scaffold have been employed as antibacte-
rial, antiviral, anti-inflammatory, antiulcer, immunomodulatory,
and anticonvulsant.4–6 Further imidazo[1,2-a]pyridine also consti-
tutes the core structure of various drugs7 like zolpidem which is
used in the treatment of insomnia, alpidem as an anxiolytic agent,
olprinone for the treatment of acute heart failure, and zolimidine
used for the treatment of peptic ulcer (Fig. 1). They have also been
⇑
Corresponding author. Tel.: +91 9335153359.
E-mail address: dr.irsiddiqui@gmail.com (I.R. Siddiqui).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.088

1160
I. R. Siddiqui et al. / Tetrahedron Letters 55 (2014) 1159–1163
Table 2
N
Screening of reaction condition with respect to solvent and temperature for the
O
O
N
Cl
N
synthesis of 5ea
S
Cl
N
O
N
NH2
N
Zolimidine
CHO
N
I2 (10mol%)
solvent /temp
N
Alpidem
N
1a
2e
3a
5e
N
N
N
HN
Entry
Solvent
Catalyst (10 mol %)
Temp
Time (h)
Yieldb (%)
O
1
2
3
4
5
6
7
8
DCM
THF
H2O
Toluene
CH3NO2
C2H5OH
CH3OH
CH3CN
DMF
Iodine
Iodine
Iodine
Iodine
Iodine
Iodine
Iodine
Iodine
Iodine
Iodine
Iodine
Iodine
Reflux
Reflux
60 °C
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
rt
8
12
6
12
12
12
12
6
12
12
12
6
55
21
85
15
68
40
34
84
17
—
O
CN
N
Zolpidem
Olprinone
Figure 1. Drugs containing imidazo[1,2-a]pyridine ring.
R2
NH2
9
N
CHO
R1
I2 (10mol%)
10
11
12
H2O
H2O
H2O
N
N
30 °C
Reflux
25
85
water /600C
6.0-6.5h
R1
R2
R3
R3
5(a-m)
1(a-d)
a
2(a-h)
3(a-b)
Reaction condition: All reactions were carried out using 2-aminopyridine
(1 mmol), aldehyde (1 mmol), phenylacetylene (1 mmol), and iodine (10 mol %), in
different solvents, at different temperatures.
Scheme 1. Single-pot synthesis of imidazo[1,2-a]pyridine.
b
Yield of isolated products.
Table 1
and water afforded the product in high yield in short time period.
But from economical and environmental point of view water was
selected as the reaction medium for all further conversions.21 For
scrutinizing the appropriate temperature the same reaction was
carried out under different temperatures ranging from 30 °C to
60 °C with water as solvent. It was observed that reaction did not
proceed at room temperature (Table 2, entry 10) and the yield
was also found to be low at low temperature (Table 2, entry 11).
60 °C was found to be optimum temperature for maximum conver-
sion in minimum time.
To investigate the superiority of iodine, a comparative study of
various catalysts was conducted. For this, the model reaction has
been scrutinized with various catalysts and iodine was found to
be the best. All the details are listed in Table 3.
We observed that the reaction did not occur in the presence of
VB1, b-cyclodextrin, and SnCl2 (Table 3, entries 3, 4, and 7), how-
ever TfOH and CAN were found to be less effective and the yield
of desired product was not satisfactory (Table 3, entries 5 and
6).From these optimization results, the iodine–water pairing
proved to be the best catalyst–reaction medium combination
Effect of amount of iodine on the synthesis of 5ea
NH2
N
CHO
iodine
N
N
water / 60oC
1a
2e
3a
5e
Entry
Iodine (mol %)
Time (h)
Yieldb (%)
1
2
3
4
5
10
15
20
7
6
6
6
60
85
85
85
a
Reaction condition: All reactions were carried out using 2-aminopyridine
(1 mmol), aldehyde (1 mmol), phenylacetylene (1 mmol), and iodine in water.
b
Yield of isolated products.
When the reaction mixture was stirred at 60 °C for 12 h in the
absence of iodine, no desired product was generated. However in
the presence of iodine the reaction proceeded to completion giving
excellent yield of the desired product. After the above observation,
we first examined the suitable reaction condition by using differ-
ent loadings of iodine. It was found that the amount of catalyst
plays a vital role- an increase in the amount of catalyst from 5 to
10 mol % not only decreases the reaction time but also enhances
the reactivity and the yield of product from 60 to 85% (Table 1,
entry 2).
Inspired by this interesting result we further increased the
amount of catalyst to 15 and 20 mol %. It was observed that using
greater amount of catalyst shows no effect on the yield of product
and reaction time (Table 4, entries 3 and 4). We next set out to ex-
plore the influence of solvents on this iodine catalyzed conversion.
The reaction was carried out in various solvent systems such as
non polar (nitromethane, dichloromethane, toluene), polar aprotic
(acetonitrile, tetrahydrofuron, DMF), and polar protic (water,
methanol, ethanol) in the presence of iodine (Table 2). When the
reaction was carried out in THF, toluene, and DMF very low yield
of the product (Table 2, entries 2, 4, and 9, respectively) was ob-
tained. It is remarkable that the reaction performed in acetonitrile
Table 3
Screening of various catalysts for the synthesis of 5ea
N
NH2
CHO
catalyst (10mol%)
water / 60oC
N
N
1a
2e
3a
5e
Entry
Catalyst (10 mol %)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
—
Iodine
VB1
Cyclodextrin
TfOH
CAN
12
6.0
12
12
12
12
12
0
85
0
0
44
31
—
SnCl2
a
Reaction condition: 2-aminopyridine (1 mmol), benzaldehyde (1 mmol) phen-
ylacetylene (1 mmol), catalyst (10 mol %), water (5 mL), 60 °C, 6.0 h.
b
Yield of isolated products.

I. R. Siddiqui et al. / Tetrahedron Letters 55 (2014) 1159–1163
1161
Table 4
Scope of various substrates for the synthesis of imidazo[1,2-a]pyridine derivatives
R2
NH2
N
CHO
R1
I2 (10mol%)
N
N
water /600C
R1
R2
R3
6.0-6.5h
R3
1(a-d)
2(a-h)
3(a-b)
5(a-m)
Entry
a
2-Amino pyridine
Aldehyde
Alkyne
Producta
Time (h)
6.5
Yieldb (%)
NH2
N
CHO
N
N
N
85
85
82
Cl
Cl
NH2
N
CHO
CH
N
N
N
O2N
b
c
6.0
6.5
NO2
CN
F
NH2
N
NC
N
N
NH2
N
CHO
F
d
e
f
6.0
6.0
6.0
85
85
83
NH2
N
CHO
N
N
N
N
NH2
N
CHO
Br
Br
NH2
N
CHO
N
N
g
6.5
6.5
84
81
NH2
N
CHO
N
N
h
NH2
N
CHO
N
N
N
N
i
j
6.5
6.0
65
NH2
N
CHO
86
(continued on next page)

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I. R. Siddiqui et al. / Tetrahedron Letters 55 (2014) 1159–1163
Table 4 (continued)
Entry
2-Amino pyridine
Aldehyde
Alkyne
Producta
Time (h)
6.0
Yieldb (%)
NH2
CHO
Br
N
N
Br
N
k
l
83
NH2
N
CHO
N
N
NC
6.0
6.5
87
84
CN
NH2
CHO
Cl
N
N
Cl
N
m
a
Reaction condition: 2-aminopyridine (1 mmol), benzaldehyde (1 mmol) phenylacetylene (1 mmol), iodine (10 mol %), water (5 mL), 60 °C, 6.0 h.
Yield of isolated products.
b
H
R2
I2
N
N
R3
N
R2
I2
O
NH2
N
-H2O
dehydration
H
N
N
R2
R1
-I2
R1
2
1
R3
3
R2
N
R2
N
H
N
tautomerisation
4
R3
R3
5
Scheme 2. Plausible mechanism for the synthesis of imidazo[1,2-a]pyridine derivatives.
which was applied to various examples (Table 4) by using different
types of aldehydes, alkynes, and 2-aminopyridines to afford the
corresponding products in good to excellent yield.
reaction in each step. First of all iodine polarizes and activates
the carbonyl group of aldehyde22 as it behaves as mild Lewis acid
to give iodine–aldehyde complex and thus increases the electro-
philic character of carbonyl carbon of aldehyde (2) and facilitates
dehydration which leads to the formation of Schiff base (3), result-
ing in the formation of new (C@N). It further activates the C@N
bond of Schiff base (3) which leads to addition of alkyne followed
by intramolecular cyclization to afford the desired product (5)23 in
excellent yield (Scheme 2). Moreover, unlike previously reported
methods, this approach could possibly facilitate the use of environ-
mentally-friendly solvent and catalyst product (5) in excellent
yield (Scheme 2). Moreover, unlike previously reported methods,
this approach could possibly facilitate the use of environmentally
friendly solvent and catalyst.
In summary, we have successfully uncovered a facile, cost
effective, and efficient synthesis of various types of imidazo[1,2-
a]pyridine derivatives via iodine promoted MCR in aquatic envi-
ronment. This modified procedure gave better results and shows
its superiority over previously reported methods. From a syn-
thetic point of view, this protocol is very simple, the conversion
took place under mild reaction conditions, in the presence of air
and moisture, without expensive, harsh, highly acidic, or sensitive
catalysts, yielding imidazo[1,2-a]pyridine in good to excellent
yield.
A variety of aldehydes containing electron withdrawing and
electron donating substituents (Table 4) participated well in this
three-component conversion. Interestingly, aldehyde containing
polycyclic substituent such as 1-naphthaldehyde also proved to
be effective to produce corresponding products in 84% yield
(Table 4, entry g) when treated with 2-aminopyridine and alkyne
under optimized conditions. Additionally, aliphatic aldehyde, for
example 1-hexanaldehyde (Table 4, entry i) also survived the mild
reaction condition and gave the desired product in good yield. In
continuation, different types of alkynes were also examined in this
iodine catalyzed conversion. It was found that all underwent
smooth transformation to afford the corresponding products in
excellent yield. The reaction has also been performed with ali-
phatic terminal alkyne, however, the yield obtained was very low
and in case of acetylene the desired product was not obtained.
The structures of all the products were elucidated with the help
of 1HNMR, 13CNMR, and elemental analysis. Based on the experi-
mental results and together with literature survey19f,g we thought
that iodine catalyzes the reaction as a mild Lewis acid. Thus we
propose the possible mechanism as shown in Scheme 2. The
important feature of the mechanism is that iodine catalyzes the

I. R. Siddiqui et al. / Tetrahedron Letters 55 (2014) 1159–1163
1163
12. (a) Mehdi Adib; Mohammad Mahdavi; Mahsa Alizadeh Noghania Peiman
Mirzaei Tetrahedron Lett. 2007, 48, 7263; (b) Reddy, B. V. S.; Reddy, P. S.; Reddy,
Y. J.; Yadav, J. S. Tetrahedron Lett. 2011, 52, 5789.
13. Ramesha, A. B.; Raghavendra, G. M.; Nandeesh, K. N.; Rangappa, K. S.;
Mantelingu, K. Tetrahedron Lett. 2013, 54, 95.
14. (a) Ueno, M.; Nabana, T.; Togo, H. J. Org. Chem. 2003, 68, 6424; (b) Adib, M.;
Mahdavi, M.; Abbasi, A.; Jahromia, A. H.; Bijanzadeh, H. R. Tetrahedron Lett.
2007, 48, 3217.
15. (a) Parenty, A. D. C.; Croni, L. Synthesis 2008, 1479; (b) Koubachi, J.; Berteina-
Raboin, S.; Mouaddib, A.; Guillaumet, G. Synthesis 2009, 271; (c) Adiba, M.;
Sheibani, E.; Zhub, L. G.; Mirzaei, P. Tetrahedron Lett. 2008, 49, 5108.
16. (a) Guchhait, S. K.; Madaan, C. Org. Biomol. Chem. 2010, 8, 3631; (b) Shaabani,
A.; Soleimani, E.; Maleki, A.; Moghimi, J. Synth. Commun. 2008, 38, 1090.
17. Liua, P.; Fanga, Li-song; Lei, X.; Lin, Guo-qiang Tetrahedron Lett. 2010, 51, 4605.
18. (a) Chernyak, N.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2743; (b) Yadav,
J. S.; Reddy, B. V. S.; Rao, Y. G.; Srinivas, M.; Narsaia, A. V. Tetrahedron Lett. 2007,
48, 7717; (c) Bakherad, M.; Isfahani, H. N.; Keivanloo, A.; Doostmohammadi, N.
Tetrahedron Lett. 2008, 49, 3819.
Acknowledgments
We gratefully acknowledge the financial support from the
Council of Scientific and Industrial Research and the University
Grant Commission. The authors also gratefully acknowledge the
SAIF, Punjab University, Chandigarh for providing all the spectro-
scopic and analytical data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.12.
088.
19. (a) Yadav, J. S.; Reddy, V. B. S.; Hashim, S. R. J. Chem. Soc. Perkin Trans. 1 2000,
3025; (b) Yadav, J. S.; Reddy, B. V. S.; Premalatha, K.; Swamy, T. Tetrahedron
Lett. 2005, 46, 2687; (c) Yadav, J. S.; Reddy, V. B. S.; Rao, C. V.; Chand, P. K.;
Prasad, A. R. Synlett 2001, 1638; (d) Bandyopadhyay, D.; Mukherjee, S.; Banik,
B. K. Molecules 2010, 15, 2520; (e) Mphahlele, M. J. Molecules 2009, 14, 5308; (f)
Li, X.; Mao, Z.; Wang, Y.; Chen, W.; Lin, X. Tetrahedron 2011, 67, 3858; (g) Khan,
A. T.; Das, D. K.; Islam, K.; Das, P. Tetrahedron Lett 2012, 53, 6418.
20. (a) Khan, A. T.; Khan, M. M.; Bannuru, K. K. R. Tetrahedron 2010, 66, 7762; (b)
Khan, A. T.; Ghosh, A.; Khan, M. M. Tetrahedron Lett. 2012, 53, 2622; (c) Jin, G.;
Zhao, J.; Han, J.; Zhu, S.; Zhang, J. Tetrahedron 2010, 66, 913; (d) Wang, X.-S.;
Zhou, J.; Yin, M. Y.; Yang, K.; Tu, S. J. J. Comb. Chem. 2010, 12, 266; (e) Jareb, M.;
Vrazic, D.; Zupan, M. Tetrahedron 2010, 67, 1355; (f) Togo, H.; Iida, H. Synlett
2006, 2159.
References and notes
1. (a) Domling, A. Chem. Rev. 2006, 106, 17; (b) Orru, R. A. V.; De greef, M. Synthesis
2003, 1471; (c) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51; (d) Montagne,
C.; Shiers, J. J.; Shipman, M. Tetrahedron Lett. 2006, 47, 9207.
2. Li, C.-J.; Chan, T. H. Organic Reactions in Aqueous Media; Wiley: New York, 1997.
Organic Synthesis in Water; P. A., Ed. Grieco. Thomson Science: Glasgow:
Scotland, 1998; Li, C. J. Chem. Rev. 2005, 105, 3095.
3. Potewar, T. M.; Ingale, S. A.; Srinivasan, K. V. Tetrahedron 2008, 64, 5019.
4. Lhassani, M.; Chavignon, O.; Chezal, J. M.; Teulade, J. C.; Chapat, J. P.; Snoeck, R.;
Andrei, G.; Balzarini, J.; De Clercq, E.; Gueiffier, A. Eur. J. Med. Chem. 1999, 34,
271.
5. Ruper, K. C.; Henry, J. R.; Dodd, J. H.; Wadsworth, S. A.; Cavender, D. E.; Olini, G.
C.; Fahmy, B.; Siekierka, J. Bioorg. Med. Chem. Lett. 2003, 13, 347.
6. Trapani, G.; Franco, M.; Latrofa, A.; Ricciardi, L.; Carotti, A.; Serra, M.; Sanna, E.;
Biggio, G.; Liso, G. J. Med. Chem. 1999, 42, 3934.
7. Enguehard-Gueiffier, C.; Gueiffier, A. Mini Rev. Med. Chem. 2007, 7, 888.
8. Hamdouchi, C.; Zhong, B.; Mendoz, J.; Collins, E.; Jaramillo, C.; De Diego, J. E.;
Robertson, D.; Spencer, C. D.; Anderson, B. D.; Watkins, S. A.; Zhanga, F.; Brooks,
H. B. Bioorg. Med. Chem. Lett. 2005, 15, 1943.
9. Roger Tully, W.; Gardner, Colin R.; Gillespie, Roger J.; Robert Westwood J. Med.
Chem. 1991, 34, 2060.
21. Liu, J.; Lei, M.; Hu, L. Green Chem. 2012, 14, 840.
22. Wang, Y.-H.; Li, L.; Chen, X.-S. Chem. Res. Chin. Univ. 2008, 24, 520.
23. General procedure for the synthesis of imidazo[1,2-a]pyridine. A mixture of 2-
aminopyridine (1 mmol), aldehyde (1 mmol), in 5 mL of water was taken in a
25 mL flask. Then phenylacetylene (1 mmol) and iodine (10 mol %) were added
successively into the above reaction mixture. The reaction mixture was stirred
at 60 °C until the reaction was completed which was monitored by TLC from
time to time. The reaction mixture was diluted with H2O and then extracted
twice with EtOAc. The organic layer was washed successively with 10%
NaHCO3 and H2O and dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure to give the product. The product was purified using
silica gel column chromatography.
10. Goodacre, Simon C.; Street, Leslie J.; Hallett, David J.; Crawforth, James M.;
Sarah Kelly; Owens, Andrew P.; Blackaby, Wesley P.; Lewis, Richard T.; Joanna
Stanley, ; Smith, Alison J.; Pushpinder Ferris; Bindi Sohal; Cook, Susan M.;
Andrew Pike; Nicola Brown; Wafford, Keith A.; George Marshall; Castro, José L.;
Atack, John R. J. Med. Chem. 2006, 49, 35.
11. Yoshito Abe; Hiroshi Kayakiri; Shigeki Satoh; Takayuki Inoue; Yuki Sawada;
Keisuke Imai; Noriaki Inamura; Masayuki Asano; Chie Hatori; Akira Katayama;
Teruo Oku; Hirokazu Tanak J. Med. Chem. 1998, 41, 564.
Characterization of compound 5a: 3-Benzyl-2-(4-chlorophenyl) imidazo[1,2-
a]pyridine, White solid: mp 147À149 °C; IR (KBr)
mmax 3072, 2851, 1634, 1601,
1488, 1453, 1360, 1247, 1093 cmÀ1
;
1H NMR (400 MHz, CDCl3) d = 7.73À7.66
(m, 4H), 7.39 (d, J = 8.6 Hz, 2H), 7.33À7.27 (m, 3H), 7.22À7.18 (m, 1H), 7.12 (d,
J = 8.2 Hz, 2H), 6.73 (dt, J = 6.8 Hz, J = 1.1 Hz, 1H), 4.48 (s, 2H); 13C NMR
(100 MHz, CDCl3) d = 144.9, 143.0, 136.5, 133.7, 133.0, 129.4, 129.1, 128.9,
127.6, 127.0, 124.5, 123.4, 117.8, 117.6, 112.4, 29.8; Anal. Calcd for C20H15ClN2:
C, 75.35; H, 4.74; Cl, 11.12; N, 8.79. Found: C, 75.37; H, 4.75; Cl, 11.11; N, 8.80.