Synthesis of Imidazo[1,2-a]pyridines using fe3o 4@sio2 as an efficient Nanomagnetic catalyst via a one-pot Multicomponent reaction

Article abstract of DOI:10.1002/hlca.201300244

A one-pot multicomponent synthesis of imidazo[1,2-a]pyridine derivatives by using pyridin-2-amines, aldehydes, and terminal alkynes in the presence of a catalytic amount of silica-supported iron oxide (Fe₃O ₄@SiO₂) nanopar

Full text of DOI:10.1002/hlca.201300244

Helvetica Chimica Acta – Vol. 97 (2014)
587
Synthesis of Imidazo[1,2-a]pyridines Using Fe3O4@SiO2 as an Efficient
Nanomagnetic Catalyst via a One-Pot Multicomponent Reaction
by Ali Maleki*
Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran
(phone: þ 98-21-77240640-50; fax: þ 98-21-77491204; e-mail: maleki@iust.ac.ir)
A one-pot multicomponent synthesis of imidazo[1,2-a]pyridine derivatives by using pyridin-2-
amines, aldehydes, and terminal alkynes in the presence of a catalytic amount of silica-supported iron
oxide (Fe3O4@SiO2) nanoparticles in refluxing EtOH in good-to-excellent yields is reported.
Introduction. – Imidazo[1,2-a]pyridines have been the object of intense investiga-
tions in medicinal chemistry, because of their remarkable central nervous system
activity, and are now one of the most widely prescribed classes of psychotropics. They
constitute a class of biologically active compounds such as potent anti-inflammatory
[1 – 3] and antibacterial agents [4], inhibitors of gastric acid secretion [5], selective
cyclin-dependent kinase inhibitors [6], calcium channel blockers [7][8], b-amyloid
formation inhibitors [9], and bradykinin B2 receptor antagonists [10]. Furthermore,
they represent the main framework of several established drugs [11 – 17] such as
sedative-hypnotic drugs zolpidem and alpidem [11][12]: zolpidem (A), for the
treatment of insomnia; alpidem (B), an anxiolytic agent; olprinone (C) [13][14] for
the treatment of acute heart failure; minodronic acid (D) [13][14] for the treatment of
osteoporosis; zolimidine (E) [15], an anti-ulcer agent; necopidem (F) [16] and
saripidem (G) [17] as anxiolytic drugs; and further biologically and pharmaceutically
active agents (Fig. 1) [13][14].
In recent years, several methods for the synthesis of imidazo[1,2-a]pyridine
scaffolds have been developed, but most of them are limited in scope or require multi-
step preparation of the starting materials [18 – 20]. Among them, due to significant
advantages of multicomponent reactions (MCRs) over conventional linear syntheses,
such as shorter time, saving energy, and inexpensive raw materials, thus resulting in
both economic and environmental benefits [21 – 23], the reaction of pyridine-2-amines,
aldehydes, and terminal alkynes is the most attractive method for the synthesis of
imidazo[1,2-a]pyridines, which has been carried out using metal-based catalysts such as
CuCl/Cu(OTf)2 [24], CuSO4/TsOH · H2O [25], InBr3 [26], CuIꢀNaHSO4 · SiO2 [27],
and CuSO4ꢀglucose [28].
In this work, a new protocol for the one-pot three-component synthesis of
imidazo[1,2-a]pyridine derivatives 4a – 4j has been introduced starting from simple and
readily available compounds including a pyridin-2-amine 1, an aldehyde 2, and a
terminal alkyne 3 in the presence of a catalytic amount of silica-supported iron oxide,
Fe3O4@SiO2, nanoparticles and K2CO3 in refluxing EtOH in good-to-excellent yields
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Fig. 1. Structures of some important drugs containing the imidazopyridine cores
(Scheme 1). This new approach has a potential to access an important field by using
economically and environmentally efficient Fe3O4@SiO2 nanoparticles in the synthesis
of heterocyclic compounds.
Scheme 1. Synthesis of Imidazo[1,2-a]pyridines 4a – j in the Presence of Fe3O4@SiO2 Nanocatalyst
Results and Discussion. – Silica-supported iron oxide (Fe3O4@SiO2) nanoparticles
were readily prepared according as described in [29], by the addition of Fe3O4
nanoparticles, dispersed in H2O, to a basic solution of tetraethylorthosilicate (TEOS)
and stirring overnight. After heating the resulted gel, the magnetic material was
isolated by centrifugation and vacuum-dried to obtain Fe3O4@SiO2 nanoparticles,
which were stable under reaction conditions.
The particle size was studied by transmission electron microscopy (TEM), and the
identification of Fe3O4@SiO2 nanoparticles was based on the analysis of TEM images.
The obtained TEM images of nanoparticles showed clearly a monodispersed spherical
shape in which Fe3O4 nanoparticles were supported on silica (Fig. 2).
To optimize the conditions, a model reaction was carried out with pyridin-2-amine,
PhCHO, and phenylacetylene stirred in refluxing EtOH in the presence of Fe3O4@SiO2
nanocatalyst and K2CO3 as a base. The progress of the reaction was monitored by TLC.
After completion of the reaction, a physical magnetic filtration of the catalyst, followed
by an aqueous workup afforded compound 4a in 86% yield.

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589
Fig. 2. TEM Image of the Fe3O4@SiO2 nanoparticles
The results showed that the efficiency and the yield of the model reaction in EtOH
was higher than those obtained in other solvents, such as H2O, MeOH, MeCN, CH2Cl2,
and toluene, or under solvent-free conditions.
The above mentioned reaction was also carried out in the presence of various protic
solid acids (Amberlyst-21 and Montmorillonite-K10), liquid acids (HCl, H2SO4, and
AcOH), Lewis acid (AlCl3), Fe3O4, SiO2, and K2CO3 under the same reaction
conditions. The best yield was obtained with Fe3O4@SiO2 nanoparticles. To illustrate
the need of the catalyst for this reaction, an experiment was conducted in the absence of
Fe3O4@SiO2. The yield in this case was marginal after 8 h. Obviously, Fe3O4@SiO2 is
essential for the reaction.
To explore the scope and limitations, various substituted pyridin-2-amines,
aldehydes, and terminal alkynes were examined in this MCR. The reaction proceeded
very cleanly under mild conditions, and no undesirable side reactions were observed.
As compiled in the Table, the reaction proceeded efficiently in all of the investigated
cases.
An important aspect of this MCR was the high purity of the product. All of the
products were sufficiently pure after workup, but they were crystallized from hot EtOH
to give highly pure crystalline products.
It was shown that the Fe3O4@SiO2 catalyst could be recovered and reused in
subsequent reactions several times without considerable loss of catalytic activity. Thus,
this MCR process could be interesting for large-scale syntheses. The catalyst is very
active, non-toxic, economically efficient, and environmentally benign. One of the
advantages of the heterogeneous catalysts is their reusability. The Fe3O4@SiO2
nanoparticles were adsorbed onto the magnetic stirring bar, when the magnetic stirring
was stopped. The nanoparticles were then washed with EtOH, air-dried, and used
directly for the next round of reactions without further purification (Table, Entry 1).
A plausible mechanism for the formation of products 4a – 4j is outlined in Scheme 2.
It is conceivable that the initial event is the formation of imine 5 by condensation of

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Table. Synthesis of Imidazo[1,2-a]pyridines 4a – 4j in the Presence of Fe3O4@SiO2 Nanoparticles
Entry
R1
R2
R3
Product
Time [h]
Yield [%]a)
1
2
3
4
5
6
7
8
9
H
Br
H
H
H
H
H
Me
Br
Br
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
3
4
4
3
5
6
6
6
3
4
86b)
89
88
83
79
85
77
84
90
78
4-MeꢀC6H4
4-ClꢀC6H4
4-O2NꢀC6H4
Naphthalen-2-yl
Pentyl
Thiophen-2-yl
Thiophen-2-yl
4-CNꢀC6H4
Ph
4-MeꢀC6H4
Ph
Ph
Ph
10
4j
a) Yields of the isolated products. b) Yields of the five subsequent runs by using the same recovered
catalyst were 85, 83, 84, 82, and 80%, respectively.
Scheme 2. Proposed Mechanism for the Formation of the Products 4a – 4j
pyridin-2-amines 1 and aldehydes 2 in the presence of a catalytic amount of
Fe3O4@SiO2 and K2CO3. Then, intermediate 6 formed from nucleophilic attack of
the carbanion form of the terminal alkynes 3 to complex 5. Cyclization leads to
intermediate 7 by intramolecular nucleophilic reaction. Finally, isomerization of
compound 7 furnishes the imidazo[1,2-a]pyridine derivatives 4a – 4j.
In summary, a new protocol for the one-pot multicomponent synthesis of
imidazo[1,2-a]pyridines starting from simple and readily available precursors including
pyridin-2-amines, aldehydes, and terminal alkynes using magnetically recoverable
Fe3O4@SiO2 nanocatalyst in the presence of K2CO3 as a base has been introduced. This
new and efficient MCR approach for the preparation of synthetically, biologically, and
pharmaceutically relevant imidazo[1,2-a]pyridine derivatives presents some important
advantages such as the easy workup procedure, reusability of catalyst, high atom
economy, excellent yields, and mild reaction conditions.

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591
The author gratefully acknowledges the financial support from the Iran National Science Foundation
(INSF) and the Research Council of the Iran University of Science and Technology (IUST), and the
reviewer for valuable comments and suggestions.
Experimental Part
General. All solvents, chemicals, and reagents were purchased from Merck, Fluka, and Sigma-
Aldrich. M.p.: Electrothermal 9100 apparatus; uncorrected. IR Spectra: Shimadzu IR-470 spectrometer;
.
˜n in cmꢀ1 1H- and 13C-NMR spectra: at 500 and 125 MHz, resp., on Bruker DRX-500 Avance
spectrometer; d in ppm rel. to Me4Si as internal standard, J in Hz. MS: Finnigan-MAT 8430 mass
spectrometer operating at an ionization potential of 70 eV; in m/z. Elemental analyses: Elementar
Analysensysteme GmbH VarioEL. TEM: Philips EM208.
Preparation of Silica-Supported Fe3O4 Nanoparticles. Dispersion of Fe3O4 (< 50-nm particle size
(TEM), ꢁ 98%) in H2O (10 ml) was adjusted to pH 11 with NaOH (1m). Then, tetraethyl orthosilicate
(TEOS; 2.10 ml) was added, and the mixture was stirred overnight. Then, the resulting gel was heated at
608 during 30 min. The magnetic material was isolated by centrifugation (8,000 rpm, 15 min) and
vacuum-dried during 24 h to obtain the Fe3O4@SiO2 nanoparticles.
Representative Synthesis of Compound 4a. To a reaction tube containing a magnetic stirring bar and
Fe3O4@SiO2 nanoparticles (5 mol-%) and K2CO3 (5 mol-%) in 5 ml of EtOH, pyridin-2-amine (1a;
0.094 g, 1 mmol), PhCHO (2a; 0.106 g, 1 mmol) and phenylacetylene (3a; 0.102 g, 1 mmol) were added.
The mixture was stirred for 3 h under reflux. After completion of the reaction (TLC (AcOEt/hexane
4:1)), stirring was stopped, and the Fe3O4@SiO2 catalyst became attached to the magnetic stir bar. The
Fe3O4@SiO2 nanoparticles were then washed with EtOH, air-dried, and used directly for the next round
of reactions without further purification. Then, the reaction soln. was filtered off, and the residue was
purified by washing with H2O, and then crystallized from EtOH to give 3-benzyl-2-phenylimidazo[1,2-
a]pyridine (4a; 0.245 g, 86%) Light-yellow crystals. M.p. 123 – 1248. IR (KBr): 3035, 2946, 2850, 1635,
1540, 1440. 1H-NMR (CDCl3): 4.48 (s, CH2); 6.96 (t, J ¼ 6.8, 1 arom. H); 7.08 (d, J ¼ 8.4, 2 arom. H); 7.30 –
7.90 (m, 10 arom. H); 8.16 (d, J ¼ 9.0, 1 arom. H). 13C-NMR (CDCl3): 29.8; 112.2; 117.4; 123.4; 124.2;
126.9; 127.6; 127.8; 128.2; 128.5; 128.8; 129.0; 129.3; 135.6; 138.8; 144.3. MS: 284 (Mþ), 194, 117, 91, 77.
Anal. calc. for C20H16N2: C 84.48, H 5.67, N 9.85; found: C 84.51, H 5.55, N 9.79.
3-Benzyl-6-bromo-2-(4-methylphenyl)imidazo[1,2-a]pyridine (4b). Yellow crystals. M.p. 207 – 2098.
IR (KBr): 3055, 2926, 2853, 1625, 1530, 1480. 1H-NMR (CDCl3): 2.36 (s, Me); 4.43 (s, CH2); 7.05 (d, J ¼
7.1, 2 arom. H); 7.20 – 7.45 (m, 6 arom. H); 7.56 (d, J ¼ 9.2, 1 arom. H); 7.64 (d, J ¼ 8.2, 2 arom. H); 7.83 (s, 2
arom. H). 13C-NMR (CDCl3): 21.5; 29.8; 107.2; 117.4; 123.4; 126.9; 127.1; 127.6; 128.1; 129.1; 129.4; 131.2;
135.6; 137.8; 143.3; 145.2; 148.1. MS: 378 (Mþ, 81Br), 376 (Mþ, 79Br), 194, 117, 91, 77. Anal. calc. for
C21H17BrN2: C 66.85, H 4.54, N 7.43; found: C 66.81, H 4.48, N 7.50.
3-Benzyl-2-(4-chlorophenyl)imidazo[1,2-a]pyridine (4c). Yellow crystals. M.p. 170 – 1728. IR (KBr):
3045, 2944, 2855, 1636, 1545, 1442. 1H-NMR (CDCl3): 4.45 (s, CH2); 6.50 – 6.70 (m, 2 arom. H); 7.06 (d,
J ¼ 6.1, 1 arom. H); 7.10 – 7.30 (m, 4 arom. H); 7.36 (d, J ¼ 8.5, 2 arom. H); 7.60 – 7.70 (m, 4 arom. H).
13C-NMR (CDCl3): 29.8; 112.2; 117.4; 123.4; 124.2; 127.6; 127.8; 128.2; 128.5; 128.8; 129.0; 129.3; 132.6;
133.5; 136.8; 144.5. MS: 320 (Mþ, 37Cl), 318 (Mþ, 35Cl), 194, 117, 112, 91, 77. Anal. calc. for C20H15ClN2: C
75.35, H 4.74, N 8.79; found: C 75.40, H 4.67, N 8.72.
3-Benzyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (4d). Yellow crystals. M.p. 1578. IR (KBr): 3055,
2946, 2850, 1630, 1540, 1490, 1350. 1H-NMR (CDCl3): 4.52 (s, CH2); 6.78 (t, J ¼ 6.7, 1 arom. H); 7.12 (d,
J ¼ 6.8, 2 arom. H); 7.22 (s, 1 arom. H); 7.25 – 7.40 (m, 3 arom. H); 7.72 (d, J ¼ 8.9, 1 arom. H); 7.78 (d, J ¼
6.8, 1 arom. H); 7.98 (d, J ¼ 8.9, 2 arom. H); 8.26 (d, J ¼ 8.9, 2 arom. H). 13C-NMR (CDCl3): 29.9; 112.8;
118.1; 119.5; 123.6; 124.2; 125.4; 127.5; 127.8; 128.6; 128.8; 136.2; 139.8; 141.8; 145.3; 147.2. MS: 340
([M þ 1]þ), 194, 123, 117, 91, 77. Anal. calc. for C20H15N3O2: C 72.94, H 4.59, N 12.76; found: C 72.89, H
4.54, N 12.60.
3-Benzyl-2-(naphthalen-2-yl)imidazo[1,2-a]pyridine (4e). Yellow crystals. M.p. 164 – 1668. IR
(KBr): 3072, 3045, 2946, 2850, 1635, 1540, 1440. 1H-NMR (CDCl3): 4.28 (s, CH2); 6.70 (t, J ¼ 6.7, 1
arom. H); 7.06 (d, J ¼ 7.4, 2 arom. H); 7.10 – 7.60 (m, 8 arom. H); 7.80 (d, J ¼ 7.7, 2 arom. H); 7.87 (d, J ¼

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Helvetica Chimica Acta – Vol. 97 (2014)
7.8, 2 arom. H); 8.16 (d, J ¼ 8.0, 1 arom. H). 13C-NMR (CDCl3): 29.7; 112.2; 117.4; 123.5; 124.2; 125.2;
125.8; 126.3; 126.5; 127.0; 127.8; 128.2; 128.5; 128.9; 129.1; 129.2; 130.3; 135.9; 136.3; 138.4; 141.2; 142.5.
MS: 334 (Mþ), 194, 127, 117, 91, 77. Anal. calc. for C24H18N2: C 86.20, H 5.43, N 8.38; found: C 86.12, H
5.34, N 8.45.
3-Benzyl-2-pentylimidazo[1,2-a]pyridine (4f). Colorless crystals. M.p. 127 – 1288. IR (KBr): 3038,
2945, 2855, 1635, 1540, 1440, 1346. 1H-NMR (CDCl3): 1.01 (t, J ¼ 6.8, Me); 1.60 – 1.90 (m, 3 CH2); 2.83 (t,
J ¼ 6.8, CH2); 4.28 (s, CH2); 6.64 (t, J ¼ 7.8, 1 arom. H); 7.10 – 7.30 (m, 6 arom. H); 7.65 (t, J ¼ 8.9, 2 arom.
H). 13C-NMR (CDCl3): 14.3; 23.2; 24.1; 24.2; 29.2; 29.8; 110.3; 111.6; 117.2; 119.2; 123.1; 123.7; 125.8;
126.3; 127.1; 128.8; 137.8. MS: 278 (Mþ), 194, 117, 91, 77, 71, 43. Anal. calc. for C19H22N2: C 81.97, H 7.97, N
10.06; found: C 81.85, H 7.81, N 10.15.
3-(4-Methylbenzyl)-2-(thiophen-2-yl)imidazo[1,2-a]pyridine (4g). Colorless crystals. M.p. 126 – 1278.
IR (KBr): 3095, 2940, 2852, 1573, 1538, 1492, 1382. 1H-NMR (CDCl3): 2.31 (s, Me); 4.48 (s, CH2); 6.68
(dd, J ¼ 4.4, 4.2, 1 arom. H); 7.05 (d, J ¼ 4.7, 2 arom. H); 7.10 – 7.20 (m, 4 arom. H); 7.35 (d, J ¼ 3.1, 1 arom.
H); 7.42 (d, J ¼ 2.8, 1 arom. H); 7.66 (d, J ¼ 5.4, 1 arom. H); 7.75 (d, J ¼ 4.1, 1 arom. H). 13C-NMR
(CDCl3): 21.2; 29.7; 112.3; 117.4; 117.8; 123.4; 124.5; 124.7; 125.7; 127.6; 127.8; 129.9; 133.3; 136.4; 137.8;
138.6; 144.9. MS: 304 (Mþ), 194, 117, 105, 91, 83. Anal. calc. for C19H16N2S: C 74.97, H 5.30, N 9.20; found:
C 75.17, H 5.35, N 9.26.
3-Benzyl-6-methyl-2-(thiophen-2-yl)imidazo[1,2-a]pyridine (4h). Yellow crystals. M.p. 184 – 1868. IR
(KBr): 3106, 3055, 2916, 2858, 1575, 1539, 1490, 1432, 1385. 1H-NMR (CDCl3): 2.25 (s, Me); 4.52 (s, CH2);
7.00 – 7.10 (m, 2 arom. H); 7.16 (d, J ¼ 7.2, 2 arom. H); 7.30 – 7.40 (m, 7 arom. H). 13C-NMR (CDCl3): 19.2;
29.9; 112.0; 117.4; 118.0; 121.5; 123.0; 125.2; 126.1; 127.6; 128.5; 128.8; 129.8; 130.8; 137.4; 138.3; 144.6.
MS: 304 (Mþ), 194, 131, 117, 105, 91, 83, 77. Anal. calc. for C19H16N2S: C 74.97, H 5.30, N 9.20; found: C
74.84, H 5.34, N 9.28.
3-Benzyl-6-bromo-2-(4-cyanophenyl)imidazo[1,2-a]pyridine (4i). Light-yellow crystals. M.p. 195 –
1
1988. IR (KBr): 3065, 2946, 2850, 2360, 2220, 1615, 1520, 1486, 1412. H-NMR (CDCl3): 4.48 (s, CH2);
7.12 (t, J ¼ 6.8, 1 arom. H); 7.28 (d, J ¼ 4.7, 2 arom. H); 7.30 – 7.40 (m, 3 arom. H); 7.58 (d, J ¼ 9.4, 1 arom.
H); 7.72 (d, J ¼ 8.3, 2 arom. H); 7.80 – 7.90 (m, 3 arom. H). 13C-NMR (CDCl3): 29.8; 107.8; 111.3; 118.4;
118.9; 119.4; 123.4; 127.5; 127.6; 128.5; 129.3; 132.6; 135.5; 138.7; 142.8; 143.5; 152.1. MS: 389 (Mþ, 81Br),
387 (Mþ, 79Br), 194, 117, 102, 91, 77. Anal. calc. for C21H14BrN3: C 64.96, H 3.63, N 10.82; found: C 65.12,
H 3.70, N 10.75.
3-Benzyl-6-bromo-2-phenylimidazo[1,2-a]pyridine (4j). Colorless crystals. M.p. 210 – 2128. IR
1
(KBr): 3085, 2910, 2858, 1575, 1530, 1490, 1450, 1388. H-NMR (CDCl3): 4.48 (s, CH2); 7.15 (d, J ¼ 7.2,
2 arom. H); 7.20 – 7.50 (m, 7 arom. H); 7.56 (d, J ¼ 9.4, 1 arom. H); 7.76 (d, J ¼ 7.4, 2 arom. H); 7.85 (s, 1
arom. H). 13C-NMR (CDCl3): 29.8; 107.1; 118.1; 118.3; 123.4; 127.3; 127.7; 128.1; 128.3; 128.8; 129.1;
129.3; 134.1; 136.2; 143.3; 145.1. MS: 364 (Mþ, 81Br), 362 (Mþ, 79Br), 194, 117, 91, 77. Anal. calc. for
C20H15BrN2: C 66.13, H 4.16, N 7.71; found: C 66.20, H 4.09, N 7.82.
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Received June 15, 2013