Polyethylene gylcol (PEG-400) as an efficient and recyclable reaction medium for one-pot three-component synthesis of imidazo[1,2-a]pyridine derivatives

Article abstract of DOI:10.14233/ajchem.2016.20061

Polyethylene glycol (PEG) was found to be an inexpensive nontoxic and effective medium for the one-pot three-component synthesis of imidazo[1,2-a]pyridine derivatives under catalyst-free conditions in excellent yields. Environmental acceptability, low cost, high yields and recyclability of the polyethylene glycol are the important features of this protocol.

Full text of DOI:10.14233/ajchem.2016.20061

Asian Journal of Chemistry; Vol. 28, No. 11 (2016), 2517-2520
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.20061
Polyethylene Gylcol (PEG-400) as an Efficient and Recyclable Reaction Medium for
One-Pot Three-Component Synthesis of Imidazo[1,2-a]pyridine Derivatives
*
P. RAMESH and K. BHASKAR
Department of Chemistry, Nizam College, Osmania University, Hyderabad-500 001, India
*Corresponding author: E-mail: kuthatibhaskar@gmail.com
Received: 3 May 2016;
Accepted: 12 July 2016;
Published online: 10 August 2016;
AJC-18030
Polyethylene glycol (PEG) was found to be an inexpensive nontoxic and effective medium for the one-pot three-component synthesis of
imidazo[1,2-a]pyridine derivatives under catalyst-free conditions in excellent yields. Environmental acceptability, low cost, high yields
and recyclability of the polyethylene glycol are the important features of this protocol.
Keywords: Imidazo[1,2-a]pyridine, 2-Aminopyridines, Aldehydes, Nitroalkane, Polyethylene glycol, Catalyst-free conditions.
fluorides [12], Strecker-Type reaction between 2-amino-
pyridines, a cyanide and a limited number of aldehydes [12,13]
or by use of benzotriazole as an auxiliary group [14]. Most of
these methods involve three or more sequential synthetic steps,
the use of harsh reaction conditions that give low yields and
in some cases, the use of hazardous or expensive starting
materials. Multi-component reactions (MCRs) are useful for
the construction of diverse chemical libraries of ‘drug-like’
molecules. The isocyanide-based multi-component reactions
are especially important in this area [15]. New variants of
the multi-component reactions were described by Ugi [16]
Blackburn [17], Bienaymé [18] and Groebke [19], which
enabled simple syntheses of imidazo[1,2-a]azines. Reactions
of an aldehyde, an isocyanide and 2-aminoazine in methanolic
solution containing a catalyst such as Sc(OTf)3 [17], perchloric
acid [18] or glacial acetic acid [19] were performed at room
temperature. However, these methods required long reaction
times and the work-ups were complicated. Imidazo[1,2-a]azine
syntheses have also been carried out under microwave irradia-
tion in the presence of a solid acid, montmorillonite K10 [20]
and Sc(OTf)3 [21] and using a non-polar solvent [22] or in the
presence of an ionic liquid [23]. Improved conditions have
been reported in recent years [24]. However, most of the reported
methodologies still have certain limitations such as expensive
and air sensitive nature of catalysts, toxicity of solvents, restric-
tions for large scale applications, critical product isolation
procedures, difficulty in recovery of high boiling solvents,
excessive amounts of catalysts and generation of large amounts
of toxic wastes in scaling up for industrial applications leading
to environmental issues. Thus, the development of a simple
INTRODUCTION
Imidazo[1,2-a] pyridines are pharmaceutically important
scaffolds widely found in naturally occurring, as well as
synthetic biologically active, molecules [1]. Moreover, the
pyrimidine ring system have been shown to possess, anti-
protozoal [2], antiviral [3] and antiapoptotic [4] activities and
have attracted attention to possess a broad range of useful
pharmacological properties, including antibacterial, antifungal,
anthelmintic, antiviral, antiprotozoal, anti-inflammatory,
anticonvulsant, anxiolytic, hypnotic (e.g., zolpidem, Fig. 1),
gastrointestinal, antiulcer and immunomodulatory activities
[5,6]. Furthermore, several pyrimidines are used in polymer
and supramolecular chemistry [7,8].
N
Me
N
Me
CH2CONMe2
Fig. 1. Zolpidem, a pharmacologically important imidazo[1,2-a]pyridine
Several synthetic methods have been reported for the
preparation of 2- or 3-substituted imidazo[1,2-a]pyridines with
the majority relying on the condensation of 2-aminopyridine
with α-bromoketones to form the five-membered cyclic system
[9,10]. Particularly interesting are those structures that contain
an amino group at C-2 or C-3. There are well established methods
for the preparation of 3-aminoimidazo[1,2-a]pyridines; these
include nitration at C-3 of the already formed heterocycle and
subsequent reduction [11], preparation from pyridinium

2518 Ramesh et al.
Asian J. Chem.
and efficient method under catalyst free conditions for cons-
tructing these heterocyclic has been advocated. In recent years,
polyethylene glycol (PEG) has emerged as a powerful phase-
transfer catalyst and performs many useful organic trans-
formations under mild reaction conditions. Moreover, PEG is
inexpensive, easy to handle, thermally stable, nontoxic and
recyclable in various organic transformations. In continuation
of our interest in the field of the PEG-catalyzed synthesis of
heterocyclic compounds under catalyst-free conditions [25].
As a part of our continuing studies into the synthesis of hetero-
cycles, we paid attention to designing a new strategy for straight-
forward access to imidazo[1,2-a]pyridine rings through a de
nitration reaction catalyzed by PEG-400 PEG-catalyzed one-
pot three-component reaction, involving the assembly of the
scaffold from [3+1+1] atom fragments. The method is facile,
simple to undertake, uses commercially available starting
materials, is environmentally benign and shows functional
group tolerance. Herein, we wish to present this simple one pot
synthesis of imidazo[1,2-a]pyridine derivatives, using PEG-
400 as a recyclable medium without additional organic solvent
and catalyst (Scheme-I).
Hz, 1H), 7.43 (t, J = 7.6 Hz, 2 H), 7.34–7.30 (m, 1 H), 7.16–
7.12 (m, 1H), 6.74 (t, J = 6.8 Hz, 1 H) ppm. C NMR (100
MHz, CDCl3): δ 165.6, 15105, 147.8, 138.5, 134.2, 132.2,
129.0, 129.9, 128.4, 127.2, 125.9, 119.9, 114.2 ppm. Mass
(ESI): m/z 193 [M+H]+.
13
2-(4-Nitrophenyl)imidazo[1,2-a]pyridine (2):Yield: 295
mg (90 %); White solid, m.p. 106–08 °C. IR (neat, cm-1); 3134,
2909, 2849, 1726, 1457, 1397, 1369, 1265, 1216, 1063, 1002,
849, 816, 728, 498. 1H NMR (400 MHz, CDCl3): δ = 8.12 (d,
J = 6.8 Hz, 1H), 7.95 (d, J = 7.2 Hz, 2 H), 7.82 (s, 1 H), 7.62
(d, J = 9.2 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1 H), 7.34–7.30 (m, 1
H), 7.16–7.12 (m, 1H), 6.79 (t, J = 6.8 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 145.7, 144.7, 132.7, 131.8,
127.5, 125.5, 124.9, 121.9, 117.6, 112.6, 108.1 ppm. Mass
(ESI): m/z 238 [M+H]+.
2-(4-Bromophenyl)imidazo[1,2-a]pyridine (14): Yield:
285 mg (70 %);Yellow solid, m.p.104–106 °C. IR (neat, cm-1);
3145, 2909, 2849, 2361, 1720, 1457, 1260, 1117, 728, 580,
526. 1H NMR (400 MHz, CDCl3): δ = 8.13–8.12 (m, 2 H), (s,
1 H), 7.86 (s, 1 H), 7.63 (d, J = 9.2 Hz, 1 H), 7.45 (dd, J = 8.0,
J = 0.8 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.22–7.18 (m, 1H),
6.81 (td, J = 6.8, J = 0.8 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 145.7, 144.2, 135.8, 130.8, 130.2, 128.9, 125.7,
125.1,124.5, 122.9, 117.6, 112.7, 108.5 ppm. Mass (ESI): m/z
270 [M+H]+.
CHO
NO2
PEG-400 (5 mL)
or
N
+
+
N
R
85 °C, 8 h
2-(2-Bromophenyl)imidazo[1,2-a]pyridine (16): Yield:
280 mg (70 %);Yellow solid, m.p.104–106 °C. IR (neat, cm-1);
3156, 3106, 3057, 2926, 2854, 1928, 1676, 1638, 1561, 1534,
1495, 1457, 1424, 1364, 1315, 1276, 1205, 1019, 942, 915,
N
NH2
Me-NO2
Scheme-I
1
739, 641. H NMR (400 MHz, CDCl3): δ = 8.13–8.12 (m, 2
EXPERIMENTAL
All the chemicals employed in this study were procured
H), (s, 1 H), 7.86 (s, 1 H), 7.63 (d, J = 9.2 Hz, 1 H), 7.45 (dd,
J = 8.0, J = 0.8 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.22–7.18
13
(m, 1H), 6.81 (td, J = 6.8, J = 0.8 Hz, 1 H) ppm. C NMR
from Sigma Aldrich and Alfaesear. In present study, all the
synthetic reactions were monitored by TLC and synthesized
compounds were confirmed by various spectroscopic methods.
The IR spectra were recorded using KBr pellets on a Perkin
Elmer IR spectrophotometer. 1H NMR spectra were recorded
on Brucker 300 MHz Avance NMR spectrophotometer using
CdCl3 as solvent and TMS as internal standard (chemical shifts
in δ ppm). The mass spectra were recorded on Agilent 6300
series ion trap.
General procedure: A mixture of the requisite 2-amino-
pyridine (0.5 mmol), benzaldehyde (0.6 mmol), MeNO2 or
EtNO2 (15 equiv) was taken in PEG (5 mL) and stirred at 90 °C
for the appropriate time. After completion of the reaction, as
monitored by TLC, the reaction mixture was poured into H2O
and extracted with EtOAc. The organic layer was removed
under reduced pressure and the crude product was purified by
column chromatography. The recovered PEG could be reused
for a number of cycles without significant loss of activity.
(100 MHz, CDCl3): δ = 144.5, 143.2, 134.4, 133.6, 128.9,
127.5, 125.7, 124.8, 121.5, 117.6, 112.5, 112.0 ppm. Mass
(ESI): m/z 270 [M+H]+.
RESULTS AND DISCUSSION
To the best of our knowledge there are no previous reports
for the synthesis of imidazo[1,2-a]pyridine derivatives by using
PEG-400 as a reaction medium under catalyst-free conditions.
In general, all the reactions were very clean and the imidazo-
[1,2-a]pyridine derivatives were obtained in high yields. We
pleased to note that the transformation is very general for a
wide range of aldehydes. Aryl and alkyl aldehydes revealed
good reactivity in this reaction. A variety of electron-donating
(Me, OMe; Table-1, entries 3, 7) and electron-withdrawing
substituents (Cl, Br, F, NO2; Table-1, entries 2, 4, 11 and 14)
at the aromatic ring of the aldehyde were tolerated. In addition,
a bulky naphthyl substituent did not hamper the process and
also gave desired product albeit in lower yields (Table-1, entry
13). Heteroaryl-substituted substrate furan-2-carbaldehyde
could be converted into target product in 57 % yield (Table-1,
entry 12). The structures of all the products were determined
from their analytical and spectroscopic (IR, 1H NMR and 13C
NMR) data and by direct comparison with authentic samples
[26,27].
Characterization data of imidazo[1,2-a]pyridine derivatives
2-Phenylimidazo[1,2-a]pyridine (1): Yield: 275 mg
(70 %); White solid, m.p. 106–08 °C. IR (neat, cm-1); 3374,
3063, 2920, 2849, 1726, 1676, 1578, 1550, 1523, 1424, 1369,
1309, 1260, 1232, 1145, 1084, 1073, 991. 904, 772, 706, 613,
1
520. H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 6.8 Hz,
1H), 7.95 (d, J = 7.2 Hz, 2 H), 7.82 (s, 1 H), 7.62 (d, J = 9.2

Vol. 28, No. 11 (2016)
One-Pot Three-Component Synthesis of Imidazo[1,2-a]pyridine Derivatives 2519
TABLE-1
PEG-400 MEDIATED SYNTHESIS OF IMIDAZO[1,2-a]PYRIDINE DERIVATIVES
Entry
1
Aminopyridine
Aldehyde
CHO
Product
Yield (%)
70
N
N
N
N
N
N
N
NH2
NH2
NH2
NH2
CHO
2
3
4
90
50
55
NO2
N
O2N
CHO
N
N
N
CHO
Cl
N
Cl
Cl
Cl
Cl
N
CHO
5
6
7
8
9
50
40
55
60
70
N
N
N
NH2
NH2
Cl
CHO
CHO
N
N
OMe
OMe
MeO
MeO
N
N
N
N
N
NH2
NH2
NH2
CHO
N
N
MeO
Cl
CHO
OMe
N
N
Cl
N
CHO
10
70
Cl
N
N
NH2
Cl
F
F
N
CHO
CHO
11
12
85
50
N
N
N
NH2
NH2
N
O
N
O
O
CHO
N
13
14
50
70
N
N
NH2
NH2
N
CHO
N
Br
N
Br

2520 Ramesh et al.
Asian J. Chem.
Yield (%)
Entry
Aminopyridine
Aldehyde
CHO
Product
Br
Br
N
15
70
N
N
NH2
Br
Br
N
CHO
16
60
N
NH2
N
aThe reaction was carried out by using 2-aminopyridine (0.5 mmol), benzeldehyde (0.6 mmol) and nitro methane (10 equiv.) with catalyst, PEG (5
mL), 85 °C. bYield of isolated product.
9. A.S. Howard, in eds.: A.R. Katritzky, C.W. Rees and E.V.F. Scriven, In
Conclusion
Comprehensive Heterocyclic Chemistry II; Pergamon Press: London,
We have developed an efficient and facile method for the
synthesis of imidazo[1,2-a]pyridine derivatives by treatment
of 2-aminopyridine, benzaldehyde and EtNO2 using PEG as a
recyclable medium without the addition of any additive or
organic co-solvent. Mild reaction conditions, inexpensive
reaction medium, operational simplicity and high yields are
the advantages of the protocol.
vol. 8, Chap. 10, pp 262 (1996).
10. R. Goel, V. Luxami and K. Paul, RSC Adv., 5, 81608 (2015).
11. C. Blackburn, B. Guan, P. Fleming, K. Shiosaki and S. Tsai, Tetrahedron
Lett., 39, 3635 (1998)
12. C. Roubaud, P. Vanelle, J. Maldonado and M.P. Crozet, Tetrahedron,
51, 9643 (1995).
13. A. Kiselyov, Tetrahedron Lett., 46, 4487 (2005).
14. N.W. Bristow, P.T. Charlton, D.A. Peak and W.F. Short, J. Chem. Soc.,
616 (1954).
15. A.R. Katritzky, Y.-J. Xu and H. Tu, J. Org. Chem., 68, 4935 (2003).
16. (a) A. Dömling, Chem. Rev., 106, 17 (2006); (b) A. Dömling and I.
Ugi, Angew. Chem. Int. Ed., 39, 3168 (2000).
17. I. Ugi and R. Meyr, Chem. Ber., 94, 2229 (1961).
18. C. Blackburn, Tetrahedron Lett., 39, 5469 (1998).
19. H. Bienaymé and K. Bouzid, Angew. Chem. Int. Ed., 37, 2234 (1998).
20. K. Groebke, L. Weber and F. Mehlin, Synlett, 661 (1998).
21. R.S. Varma and D. Kumar, Tetrahedron Lett., 40, 7665 (1999).
22. S.M. Ireland, H. Tye and M. Whittaker, Tetrahedron Lett., 44, 4369
(2003).
ACKNOWLEDGEMENTS
The authors are thankful to UGC-CSIR, India and Indian
Institute of Chemical Technology (IICT) Hyderabad, India for
their constant support and encouragement.
REFERENCES
1. J.P. Michael, Nat. Prod. Rep., 16, 675 (1999).
2. (a) T. Biftu, D. Feng, M. Fisher, G.-B. Liang, X. Qian, A. Scribner, R.
Dennis, S. Lee, P.A. Liberator, C. Brown, A. Gurnett, P.S. Leavitt, D.
Thompson, J. Mathew, A. Misura, S. Samaras, T. Tamas, J.F. Sina,
K.A. McNulty, C.G. McKnight, D.M. Schmatz and M. Wyvratt, Bioorg.
Med. Chem. Lett., 16, 2479 (2006); (b) A. Scribner, R. Dennis, S. Lee,
G. Ouvry, D. Perrey, M. Fisher, M. Wyvratt, P. Leavitt, P. Liberator, A.
Gurnett, C. Brown, J. Mathew, D. Thompson, D. Schmatz and T. Biftu,
Eur. J. Med. Chem., 43, 1123 (2008).
23. V.Z. Parchinsky, O. Shuvalova, O. Ushakova, D.V. Kravchenko and
M. Krasavin, Tetrahedron Lett., 47, 947 (2006).
24. A. Shaabani, E. Soleimani and A. Maleki, Tetrahedron Lett., 47, 3031
(2006).
25. (a) L.R. Odell, M.T. Nilsson, J. Gising, O. Lagerlund, D. Muthas, A.
Nordqvist, A. Karlen and M. Larhed, Bioorg. Med. Chem. Lett., 19,
4790 (2009); (b) M.C. Pirrung, S. Ghorai and T.R. Ibarra-Rivera, J.
Org. Chem., 74, 4110 (2009); (c) S.K. Guchhait and C. Madaan, Synlett,
628 (2009); (d) M. Nayak, S. Batra and S. Kanojiya, Synthesis, 431
(2009); (e) A. Shaabani, E. Soleimani, A. Maleki and J. Moghimi-
Rad, Synth. Commun., 38, 1090 (2008); (f) F. Mert-Balci, J. Conrad,
U. Beifuss, K. Meindl, T. Schulz and D. Stalke, Synthesis, 3649 (2008);
(g) A.L. Rousseau, P. Matlaba and C.J. Parkinson, Tetrahedron Lett.,
48, 4079 (2007); (h) A. Shaabani, A. Maleki, J. Moghimi Rad and E.
Soleimani, Chem. Pharm. Bull. (Tokyo), 55, 957 (2007); (i) V.G.
Nenajdenko, A. Reznichenko, L. Balenkova and E.S. Russ, Chem. Bull,
56, 560 (2007).
3. K.S. Gudmundsson and B.A. Johns, Bioorg. Med. Chem. Lett., 17,
2735 (2007).
4. C. Enguehard-Gueiffier, F. Fauvelle, J.C. Debouzy, A. Peinnequin, I.
Thery, V. Dabouis and A. Gueiffier, Eur. J. Pharm. Sci., 24, 219 (2005).
5. A.S. Howard, in eds.: A.R. Katritzky, C.W. Rees and E.V.F. Scriven, In
Comprehensive Heterocyclic Chemistry II; Pergamon Press: London,
Chap. 10, p. 262 (1996).
6. F. Couty and G. Evano, in eds.: A.R. Katritzky, C.A. Ramsden, E.V.F.
Scriven and R.J.K. Taylor, In Comprehensive Heterocyclic Chemistry
III; Elsevier Science: Oxford, vol. 11, Chap. 11, p. 409 (2008).
7. R. Gompper, H.J. Mair and K. Polborn, Synthesis, 696 (1997); T.
Kanbara, T. Kushida, N. Saito, I. Kuwajima, K. Kubota and T.Yamamoto,
Chem. Lett., 583 (1992).
26. L. Nagarapu, R. Mallepalli, L. Yeramanchi and R. Bantu, Tetrahedron
Lett., 52, 3401 (2011).
27. H. Yan, Y. Wang, C. Pan, H. Zhang, S. Yang, X. Ren, J. Li and G. Huang,
Eur. J. Org. Chem., 2014, 2754 (2014).
8. G.S. Hanan, D. Volkmer, U.S. Schubert, J.-M. Lehn, G. Baum and D.
Fenske, Angew. Chem. Int. Ed. Engl., 36, 1842 (1997); A. Semenov, J.P.
Spatz, M. Möller, J.-M. Lehn, B. Sell, D. Schubert, C.H. Weidl and
U.S. Schubert, Angew. Chem. Int. Ed., 38, 2547 (1999).