Imidazo[1,2-a]pyridine A3-Coupling Catalyzed by a Cu/SiO2 Material

Article abstract of DOI:10.21577/0103-5053.20190089

In this work, we report the preparation of a copper-silica material (Cu/SiO₂) by a sol-gel methodology and its characterization concerning composition and textural properties. The Cu/SiO₂ material was successfully applied as a Lewis

Full text of DOI:10.21577/0103-5053.20190089

http://dx.doi.org/10.21577/0103-5053.20190089
J. Braz. Chem. Soc., Vol. 00, No. 00, 1-9, 2019
Printed in Brazil - ©2019 Sociedade Brasileira de Química
Article
Imidazo[1,2-a]pyridine A3-Coupling Catalyzed by a Cu/SiO2 Material
Helena D. de Salles,a Tiago L. da Silva,b Cátia S. Radatz,c Ricardo F. Affeldt,d
Edilson V. Benvenuttia and Paulo H. Schneider *,a
aInstituto de Química, Universidade Federal do Rio Grande do Sul (UFRGS),
Av. Bento Gonçalves 9500, CP 15003, 91501-970 Porto Alegre-RS, Brazil
bInstituto de Química, Universidade Federal do Rio de Janeiro (UFRJ),
Av. Athos da Silveira Ramos 149, Bloco A, Centro de Tecnologia, Cidade Universitária,
21941-909 Rio de Janeiro-RJ, Brazil
cCentro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA),
Universidade Federal de Pelotas (UFPel), 96010-900 Pelotas-RS, Brazil
dDepartamento de Química, Centro de Ciências Físicas e Matemáticas,
Universidade Federal de Santa Catarina (UFSC), 88040-970 Florianópolis-SC, Brazil
In this work, we report the preparation of a copper-silica material (Cu/SiO2) by a sol-gel
methodology and its characterization concerning composition and textural properties. The Cu/SiO2
material was successfully applied as a Lewis acid heterogeneous catalyst for theA3-coupling from
2-aminopyridine, aldehydes and alkynes to imidazo[1,2-a]pyridines (45-82%), which are relevant
pharmacological scaffolds. The synthesis shows a number of advantages, such as easy separation
from the reaction media and the minimal formation of metal aqueous wastes. Investigation of the
mechanism supports the involvement of the formation of reaction intermediates inside the pores
of the mesoporous material prior to 5-exo-dig cyclization.
Keywords: imidazo[1,2-a]pyridines, heterogeneous catalyst, A3-coupling reaction
Introduction
1,3-dipolar CuI-catalyzed alkyne-azide cycloaddition,19-23
Diels-Alder cycloadditions24,25 and Sonogashira cross
coupling.26-29 CuI salts were successfully applied as catalysts
in the synthesis of imidazopyridines from aminopyridine
and nitroolefines.30 Other cyclization methods from
aminopyridines involve the combination of CuI and PdII
salts, as well as CuI and InIII under aerobic conditions.31
Some methods explore the use of CuI and ligands, such
as bipyridine.32
Imidazo[1,2-a]pyridine derivatives are known for their
wide range of applications in pharmaceutics as a result of
their biological properties, including antiviral, antibacterial,
antifungal, antiprotozoal and anti-inflammatory activities.1-4
These heterocycles are also known as gamma-aminobutyric
acid (GABA) and benzodiazepine receptor agonists.5,6
Some of them are well-known commercialized drugs with
sedative, anti-hypnotic and anti-psychotic effects, such as
Alpidem, Zolpidem and Olprinone.7 Recent investigations
showed that imidazo[1,2-a]pyridines are promising drug
candidates in cancer treatment.8,9 The photophysical
properties of these heterocyclic scaffolds have also been
investigated10-12 and their potential as fluorescent probes13
and fluorescent metal sensors has been explored.14
Among the several methods for the synthesis of
imidazo[1,2-a]pyridines,33 the multicomponent reaction
between 2-aminopyridine, aldehyde and alkyne (A3-coupling)
has received considerable attention as a straight route
to products with a wide scope of substituents, with the
advantages of atom economy, lower toxic waste generation
and an environmental friendly method. In this context, a
very mild methodology using a single catalyst as the active
specie was published using iodine in water while the use
of indium bromide as Lewis acid catalyst requires the
presence of triethylamine as additive and molecular sieves
yielding a series of substituted imidazo[1,2-a]pyridines.34,35
One report shows a very clean solvent and catalyst-free
Alternatively, different copper species have received
considerable attention as catalysts for different kinds
of organic transformations involving alkynes, such
as homocoupling (Glaser-Hay coupling),15-18 Huisgen
*e-mail: paulos@iq.ufrgs.br

2
Imidazo[1,2-a]pyridine A3-Coupling Catalyzed by a Cu/SiO2 Material
J. Braz. Chem. Soc.
synthesis of imidazo[1,2-a]pyridines from 2-aminopyridine
and α-bromoacetophenone.36 Copper(II) salts were also
proven useful on intramolecular oxidative cyclization from
haloalkynes and 2-aminopyridines.37
These materials are often prepared by a sol-gel method from
an organosilyl precursor in the presence of metal salts.54,55
In/SiO2 was applied as a heterogeneous catalyst in
a Hantzsch 1,4-dihydropyridine multicomponent
synthesis.56 Later, the same material was employed
and successfully recycled in A3-coupling, leading to
propargylamines.57 Alternatively, a cheaper Cu/SiO2
material was described and employed in a Biginelli
3,4-dihydropyrimidinone multicomponent synthesis by
Russowsky et al.58,59 and more recently, in a 1,2,3-triazole
synthesis by click chemistry.In this work, we prepared and
characterized a Cu/SiO2 material with different conditions
by sol-gel method and investigated their application as
heterogeneous catalysts in the A3-coupling reaction to
produce different substituted imidazo[1,2-a]pyridines,
without using additives.
Catalysis of copper sulfate in the presence of
p-toluenesulfonic acid (10 mol%) leads to moderate to
good yields in three and two-component approaches and
similar results were observed using a mixture of copper
iodide and copper triflate.38,39 Cherniak and Gevorgyan40
described the use of binary CuI and CuII catalysts in toluene
at high temperature.A mixture of CuI-CuII generated in situ
from CuSO4 and glucose was shown to be a useful method
for the 5-exo-dig cycloisomerization.41 Also, glucose was
found an applicable additive for reactions catalyzed by
copper oxide/alumina in heterogeneous strategies.42
It is noteworthy that Mishra and Ghosh43 reported
the use of CuI and NaHSO4.SiO2 as binary catalysts, a
semi-heterogeneous approach.They have also proved
the necessity of both Lewis and Brϕnsted acids in the
reaction media to efficiently perform cycloisomerization.
Another report by Corma and co-workers44 shows the
ability of CuII-MOF (MOF: metal-organic framework)
on catalyzing the same reaction by a combination of
the adsorbed Lewis acid on a microporous and flexible
framework. The use of other copper-MOF has shown
efficiency on catalyzing imidazo[1,2-a]pyridines synthesis
although the preparation of the catalysts usually involves
harsh conditions.45 Recently, copper and porphyrin-MOF
derivatives were successfully applied on the synthesis of
imidazo[1,2-a]pyridines, however a copper solution must
be periodically replaced for zinc exchange on catalyst
preparation.46 In this context the use of small amounts
of copper nanoparticles where also successful, but they
suffer of several steps for preparation or low stability for
storage.47,48 Superparamagnetic iron-copper nanoparticles
leads to higher yields of imidazo[1,2-a]pyridines (75-95%),
but the catalyst preparation involves the use of very high
range of temperature (500-900 ºC) and they also require
the use of euthetic mixture citric acid-dimethyl urea which
favors the imine intermediate formation.49 In addition to
copper, other publications50-52 have reported the use of
heterogeneous magnetic nanoparticles of Fe3O4, which
are easily recovered and recycled from the reaction media.
More recently, a synthesis at mild conditions, involving
CuCl2/nano-TiO2 as the catalyst in the reaction between
2-aminopyridines and unactivated ketones, was also
described. 53
Experimental
General experimental methods
1H and 13C nuclear magnetic resonance (NMR) spectra
in CDCl3 were recorded onVarian or Bruker 400 MHz and
100 MHz respectively, using tetramethylsilane (TMS) as
internal standard. Chemical shifts (d) are expressed in
parts per million referenced to the residual solvent (i.e.,
1H 7.27, 13C 77.16 ppm for CDCl3). Signal multiplicity
is expressed as follows: s (singlet), br s (broad singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), dd (doublet
of doublet), dt (doublet of triplet), td (triplet of doublet).
J values are given in hertz (Hz). For novel compounds, the
high-resolution mass spectrometry (HRMS) measurement,
Bruker Daltonics Micro-TOF instrument was used in
electrospray ionization (ESI) mode.All reactions and purity
of the synthesized compounds were monitored by thin-layer
chromatography (TLC) using silica gel 60 F254 aluminium
plates. Visualization was accomplished by UV light,
exposure to iodine vapor and by treating the plates with
vaniline followed by heating. Unless otherwise indicated,
materials and solvents were purchased and used without
further purification. The images of Cu/SiO2 materials were
obtained using scanning electron microscopy (SEM) on a
JEOL microscope (JSM 5800) connected to a secondary
electron detector and energy dispersive X-ray spectroscopy
(EDS), performed with Cu/SiO2 dispersed on a doubled-
faced conducting tape on a stainless steel support and
coated with gold using Bal-Tec SCD050 Sputter-Coater
apparatus. The N2 adsorption-desorption isotherms of
Cu/SiO2 materials were determined at liquid-nitrogen
boiling point, using Tristar II Krypton 3020 Micromeritics
equipment. The materials were previously degassed at
Metal/silica materials were employed as catalysts in the
synthesis of other types of heterocycles in multicomponent
reactions and they have shown advantages such as easy
preparation, easy handling and the possibility of recovery.

Vol. 00, No. 00, 2019
de Salles et al.
3
120 ºC under vacuum for 10 h. The specific surface areas
were determined by the Brunauer-Emmett-Teller (BET)
multipoint technique and the pore size distribution curves
were obtained by using the Barrett-Joyner-Halenda (BJH)
and density functional theory (DFT) methods.
4.28 (s, 2H), 3.61 (s, 3H); 13C NMR (101 MHz, CDCl3)
d 157.1, 144.9, 141.6, 137.4, 132.3, 129.5, 128.7, 128.1,
126.5, 123.8, 123.6, 120.8, 119.7, 117.7, 111.9, 110.9,
55.2, 30.3.
3‑Benzyl‑2‑(3‑methoxyphenyl)imidazo[1,2‑a]pyridine (4c)49
1
General procedure for the synthesis of Cu/SiO2 material 2
Yield 81% (254.7 mg); H NMR (400 MHz, CDCl3)
d 7.71-7.65 (m, 2H), 7.38-7.19 (m, 6H), 7.18-7.10 (m, 3H),
6.93-6.87 (m, 1H), 6.68 (t, J 6.8 Hz, 1H), 4.48 (s, 2H), 3.78
(s, 3H); 13C NMR (100 MHz, CDCl3) d 159.9, 144.9, 143.9,
136.0, 129.5, 129.0, 127.7, 127.0, 124.2, 123.4, 120.6,
117.9, 117.6, 114.1, 113.3, 112.3, 55.3, 29.9.
In a vial flask adapted with a magnetic bar were added
5 mL of ethanol, 2 mL of deionized water and 1 drop
(circa 50 µL) of hydrofluoric acid. Then, it was added
CuCl2 (1.2 mmol, 0.150 g) and the solution stirred until
complete homogenization. The mixture was poured onto
tetraethyl orthosilicate (TEOS, 22.4 mmol, 5.0 mL), stirred
until complete homogenization and after the formation of
a translucid glassy material (gelation), the vial was closed
and kept under heating (40 ºC) for 7 days. After this time,
the vial cap was removed and kept under mild heating
(30 ºC) for more 7 days for slow solvent evaporation.
The solid was then removed from the vial, powdered and
treated at high temperature (300 ºC) for 4 h while during
this process the material color change from green to dark
brown. After cooling, the green powder was washed with
distilled water (3 × 20 mL) and ethanol (20 mL) and then
dried at 100 ºC for 24 h.
3‑Benzyl‑2‑(4‑methoxyphenyl)imidazo[1,2‑a]pyridine (4d)38
1
Yield 72% (226.4 mg); H NMR (400 MHz, CDCl3)
d 7.72 (d, J 8.7 Hz, 2H), 7.67-7.60 (m, 2H), 7.35-7.20 (m,
3H), 7.18-7.07 (m, 2H), 6.96 (d, J 8.7 Hz, 2H), 6.66 (td,
J 6.8, 2.2 Hz, 1H), 4.45 (s, 2H), 3.82 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 159.3, 144.8, 144.0, 136.9, 129.3,
129.0, 127.7, 127.1, 126.8, 123.9, 123.2, 117.3, 117.0,
114.1, 112.0, 55.3, 29.9.
3‑Benzyl‑2‑(2‑fluorophenyl)imidazo[1,2‑a]pyridine (4e)48
Yield 78% (236.0 mg); 1H NMR (400 MHz, CDCl3) d
7.73 (td, J 7.5, 1.8 Hz, 1H), 7.69-7.62 (m, 2H), 7.34 (m,
1H), 7.28-7.05 (m, 8H), 6.65 (dt, J 6.6, 3.3 Hz, 1H), 4.34
(s, 2H); 13C NMR (100 MHz, CDCl3) d 161.3, 158.8, 145.2,
139.1, 136.8, 132.2, 129.9, 129.8, 128.9, 128.0, 126.8,
124.5, 124.4, 124.2, 123.8, 122.7, 122.5, 119.8, 117.8,
116.1, 115.9, 112.2, 30.1.
General procedure for the A3‑coupling to substituted
imidazo[1,2‑a]pyridines
In a Schlenk tube under inert atmosphere were added
2-aminopyridine (1.1 mmol, 0.112 g), aldehyde (1.0 mmol),
Cu/SiO2 (10 mol%), terminal alkyne (1.5 mmol) and
toluene (0.5 mL). The mixture was heated to 120 °C and
stirred for 48 h. The mixture was then filtered and the
solvent removed under vacuum and the crude product was
purified by column chromatography with hexanes, ethyl
acetate and triethylamine (84:10:4) as eluent.
3‑Benzyl‑2‑(3‑fluorophenyl)imidazo[1,2‑a]pyridine (4f)
1
Yield 71% (214.5 mg); H NMR (400 MHz, CDCl3)
d 7.71-7.64 (m, 2H), 7.54 (d, J 7.5 Hz, 2H), 7.36 (dd,
J 14.2, 7.5 Hz, 1H), 7.32-7.21 (m, 3H), 7.21-7.14 (m, 1H),
7.12 (d, J 7.4 Hz, 2H), 7.06-6.99 (m, 1H), 6.73-6.66 (m,
1H), 4.48 (s, 2H); 13C NMR (100 MHz, CDCl3) d 164.4,
161.9, 145.0, 143.0, 137.0, 136.9, 136.6, 130.2, 130.1,
129.2, 127.7, 126.1, 124.5, 123.8, 123.8, 123.5, 118.2,
117.8, 115.3, 115.1, 114.7, 114.5, 112.5, 29.9; HRMS
(ESI) m/z, calcd. for C20H15N2F [M + H]+: 303.1298,
found: 303.1293.
3‑Benzyl‑2‑phenylimidazo[1,2‑a]pyridine (4a)38
1
Yield 68% (193.3 mg); H NMR (400 MHz, CDCl3)
d 7.79 (d, J 7.4 Hz, 2H), 7.67 (d, J 8.7 Hz, 2H), 7.42 (t,
J 7.5 Hz, 2H), 7.36-7.20 (m, 4H), 7.18-7.10 (m, 3H), 6.67
(t, J 6.9 Hz, 1H), 4.48 (s, 2H); 13C NMR (100 MHz, CDCl3)
d 144.8, 144.1, 136.7, 134.5, 128.9, 128.5, 128.1, 127.6,
126.8, 124.0, 123.3, 117.6, 117.5, 112.1, 29.8.
3‑Benzyl‑2‑(4‑fluorophenyl)imidazo[1,2‑a]pyridine (4g)38
1
Yield 82% (248.0 mg); H NMR (400 MHz, CDCl3)
d 7.77-7.71 (m, 2H), 7.71-7.64 (m, 2H), 7.34-7.24 (m,
3H), 7.21-7.15 (m, 1H), 7.14-7.08 (m, 4H), 6.71 (td, J 6.8,
1.0 Hz, 1H), 4.46 (s, 2H); 13C NMR (100 MHz, CDCl3)
d 163.9, 161.5, 145.0, 143.4, 136.8, 130.8, 130.0, 129.9,
129.2, 127.8, 127.1, 124.3, 123.5, 117.7, 115.8, 115.6,
112.4, 29.9.
3‑Benzyl‑2‑(2‑methoxyphenyl)imidazo[1,2‑a]pyridine (4b)35
1
Yield 64% (201.2 mg); H NMR (400 MHz, CDCl3)
d 7.67-7.61 (m, 3H), 7.35 (td, J 8.3, 1.8 Hz, 1H), 7.26-
7.17 (m, 3H), 7.15-7.10 (m, 3H), 7.05 (td, J 7.5, 0.8 Hz,
1H), 6.95 (d, J 8.2 Hz, 1H), 6.65 (td, J 6.8, 1.0 Hz, 1H),

4
Imidazo[1,2-a]pyridine A3-Coupling Catalyzed by a Cu/SiO2 Material
J. Braz. Chem. Soc.
3‑Benzyl‑2‑(pyridin‑3‑yl)imidazo[1,2‑a]pyridine (4h)
2H), 7.36 (t, J 7.3 Hz, 1H), 7.19-7.13 (m, 1H), 7.05 (d,
J 8.2 Hz, 1H), 6.84 (d, J 8.6 Hz, 2H), 6.71-6.65 (m, 1H),
4.42 (s, 2H), 3.76 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 158.5, 144.8, 143.9, 134.5, 128.7, 128.6, 128.6, 128.2,
127.7, 124.2, 123.5, 118.1, 117.5, 114.4, 112.2, 55.3, 29.0.
1
Yield 80% (228.4 mg); H NMR (400 MHz, CDCl3)
d 9.00 (s, 1H), 8.61-8.54 (m, 1H), 8.14-8.09 (m, 1H),
7.78-7.63 (m, 2H), 7.40-7.04 (m, 8H), 6.72 (m, 1H), 4.47
(s, 2H); 13C NMR (100 MHz, CDCl3) d 148.9, 148.7, 145.2,
140.9, 136.2, 135.5, 130.6, 129.1, 127.6, 127.1, 124.7,
123.6, 123.5, 118.5, 117.6, 112.6, 29.7; HRMS (ESI) m/z,
calcd. for C19H15N3 [M + H]+: 286.1344, found: 286.1363.
4‑((2‑Phenylimidazo[1,2‑a]pyridin‑3‑yl)methyl)benzonitrile
(4n)
1
Yield 14% (43.33mg); H NMR (400 MHz, CDCl3)
3‑Benzyl‑2‑cyclohexylimidazo[1,2‑a]pyridine (4j)38
d 8.06 (d, J 4.4 Hz, 1H), 7.76-7.68 (m, 3H), 7.66-7.58
(m, 3H), 7.48-7.35 (m, 4H), 7.29-7.20 (m, 3H), 6.77 (t,
J 6.8 Hz, 1H), 6.66-6.61 (m, 1H), 6.50 (d, J 8.3 Hz, 1H),
4.56 (s, 2H); 13C NMR (100 MHz, CDCl3) d 148.1, 145.2,
144.8, 142.7, 137.8, 134.2, 133.0, 128.9, 128.6, 128.2,
128.1, 124.6, 123.0, 118.7, 117.9, 116.1, 114.0, 112.7,
111. 1, 108.7, 30.1; HRMS (ESI) m/z, calcd. for C21H15N3
[M + H] +: 310.134, found: 310.1381.
1
Yield 60% (174.1 mg); H NMR (400 MHz, CDCl3)
d 7.63-7.56 (m, 3H), 7.30-7.17 (m, 3H), 7.12-7.02 (m, 3H),
6.60 (td, J 6.8, 0.9 Hz, 1H), 4.28 (s, 2H), 2.89-2.76 (m, 1H),
1.95-1.76 (m, 6H), 1.46-1.30 (m, 4H); 13C NMR (75 MHz,
CDCl3) d 150.0, 144.5, 137.1, 128.8, 127.8, 126.7, 123.2,
123.1, 117.1, 116.3, 111.6, 36.9, 33.3, 29.0, 26.9, 26.0.
3‑(3,5‑Bis(trifluoromethyl)benzyl)‑2‑phenylimidazo
[1,2‑a]pyridine (4k)45
Results and Discussion
1
Yield 75% (315.8 mg); H NMR (400 MHz, CDCl3)
d 7.78 (s, 1H), 7.72 (t, J 7.8 Hz, 3H), 7.64 (d, J 6.9 Hz,
1H), 7.57 (s, 2H), 7.44 (t, J 7.5 Hz, 2H), 7.37 (t, J 7.3 Hz,
1H), 7.27-7.21 (m, 1H), 6.79 (t, J 6.8 Hz, 1H), 4.60 (s,
2H); 13C attached proton test (APT) NMR (100 MHz,
Herein, we propose the preparation and use of Cu/SiO2
as a unique heterogeneous catalyst for the A3-coupling
of 2-aminopyridines, aldehydes and alkynes to obtain
different imidazo[1,2-a]pyridine derivatives. Firstly, by
employing CuCl2 and tetraethylorthosilicate as precursors
in the presence of acid (HCl) or nucleophilic (HF) catalyst
for the sol-gel process, Cu/SiO2 materials 1 and 2 were
obtained, respectively. The glassy-like materials achieved
after complete gelation at room temperature were powdered
and dried to yield pale green solids. These materials were
characterized with regards to composition and textural
properties.
The scanning electron microscopy with energy
dispersive spectroscopy (SEM/EDS) confirm the presence
of copper in the materials and showed the irregular surface
of both materials (Figure 1).
The choice of catalyst had a less pronounced effect
on the material surface area achieved by BET analysis,
leading to 490 and 370 m2 g-1 for the HCl- and HF-catalyzed
materials, respectively materials 1 and 2 (Figure 2).
However, as shown in Figure 2, material 1 has a typical
2
CDCl3) d 145.4, 145.3, 140.0, 134.2, 131.0 (q, JC-F
33.4 Hz), 128.9, 128.3, 128.2, 127.9, 127.3, 124.6, 123.8
(q, 1JC-F 245.2 Hz), 122.8, 121.3, (q, 3JC-F 3.6 Hz), 118.1,
115.5, 112.9, 29.8.
3‑(4‑Methylbenzyl)‑2‑phenylimidazo[1,2‑a]pyridine (4l)38
1
Yield 57% (170.0 mg); H NMR (400 MHz, CDCl3)
d 7.82-7.77 (m, 2H), 7.68 (m, 2H), 7.42 (m, 2H), 7.33 (m,
1H), 7.18-7.12 (m, 1H), 7.10 (d, J 7.9 Hz, 2H), 7.02 (d,
J 7.9 Hz, 2H), 6.67 (t, J 6.7 Hz, 1H), 4.44 (s, 2H), 2.31 (s,
3H); 13C NMR (100 MHz, CDCl3) d 144.7, 143.9, 136.4,
134.4, 133.5, 129.6, 128.6, 128.1, 127.6, 127.5, 124.1,
123.4, 117.9, 117.4, 112.1, 29.3, 21.0.
3‑(4‑Methoxybenzyl)‑2‑phenylimidazo[1,2‑a]pyridine (4m)38
1
Yield 35% (110.0 mg); H NMR (400 MHz, CDCl3)
d 7.84-7.79 (m, 2H), 7.72-7.67 (m, 2H), 7.44 (t, J 7.6 Hz,
Figure 1. SEM micrograph and EDS graph for material 2.

Vol. 00, No. 00, 2019
de Salles et al.
5
microporous profile, while material 2 is predominantly
mesoporous. The results of BJH and DFT calculations
showed that a mesoporous material was obtained using
nucleophilic catalysis (pore size of 5.0 nm), while acid
catalyst resulted in a microporous material (pore size of
0.9 nm, Figure 3). Similar catalyst effects were reported
previously.60
gram of sample. The data concerning pore size, surface area
and copper amount for materials 1 and 2 are summarized
in Table 1.
Table 1. Chemical and textural analyses overview
BET surface Copper amount /
Material
Pore sizea / nm
area / (m2 g-1)
(mg m-1)
1
2
0.9
5.0
490
86
55
3
3
370
aObtained from the maximum of pore distribution curves; BET: Brunauer-
Emmett-Teller multipoint technique.
Materials 1 and 2 were then applied as catalysts in the
three-component reaction between 2-aminopyridine 1,
benzaldehyde 2a and phenylacetylene 3a, as depicted in
Scheme 1.
Table 2 summarizes the yields of product 4a when
comparing the same amount of materials 1 and 2 with
pure SiO2 and the reactions in the absence of a catalyst.
Non-optimized reaction conditions showed that the
higher pore diameter material 2 prepared by HF catalysis
resulted in a better product yield without the need for
molecular sieves in refluxing toluene after 48 h (Table 2,
entry 2). It is worth to mention that the use of free CuCl2
as catalyst leads to similar yields (Table 2, entry 5) but the
work-up produces more wastes and requires more steps
in comparison to simple filtration of the catalyst in our
procedure.
Figure 2. Surface area isotherms of materials 1 and 2.
Table 2. Influence of the catalyst on the imidazo[1,2-a]pyridine synthesis
entry
Catalyst
material 1
material 2
none
Yielda / %
56 (63)b
68 (68)b
n.r.
1
2
3
4
5
SiO2
n.r.
Figure 3. Pore size distribution of materials 1 and 2.
CuCl2 (10 mol%)
64
aIsolated yield; bwith molecular sieves 4 Å; n.r.: no reaction.
The total amount of copper in the material was
determined by flame atomic absorption spectrometry
(FAAS) after acidic digestion of the samples, since
SEM-EDS furnished a Cu:Si atom ratio on the surface
only and not inside the pores of the material. In the case of
material 1, more milligrams of copper were achieved per
After choosing material 2 as the catalyst for the A3-
coupling reaction between 2-aminopyridine, benzaldehyde
and phenylacetylene, a screening of the solvent and
temperature was performed (Table 3). Interestingly,
Scheme 1. Multicomponent A3-coupling synthesis of 3-benzyl-2-phenylimidazo[1,2-a]pyridine.

6
Imidazo[1,2-a]pyridine A3-Coupling Catalyzed by a Cu/SiO2 Material
J. Braz. Chem. Soc.
Table 4. Influence of catalyst load on the imidazo[1,2-a]pyridine synthesis
only toluene was found to be suitable for the cyclization
reaction, although low conversion was achieved in neat
conditions at 120 °C (Table 3, entries 9 and 10). In addition,
investigation of the catalyst load was made by varying the
amount of catalyst from 2.5-20.0 mol% based on the total
amount of copper of the material, as determined by FAAS
in Table 4. It is worth to mention that the use of 10 mol%
of several homogeneous copper species in the absence of
Brϕnsted acid additives does not lead to considerable yield
of imidazo[1,2-a]pyridines under the same conditions, as
described by Liu et al.38
entry
Catalyst load / mol%
Yield / %
1
2
3
4
5
2.5
5.0
10
35
45
68
73
7.5
10.0
20.0
Reaction conditions: 1.0 mmol benzaldehyde, 1.1 mmol 2-aminopyridine,
1.5 mmol phenylacetylene, reflux temperature, inert atmosphere, 0.5 mL
toluene, 48 h.
Table 3. Screening of solvents on the imidazo[1,2-a]pyridine synthesis
Table 5. Scope of the reaction for different substituted imidazo
[1,2-a]pyridines
entry
Solvent
DMFa
Conversion / %
entry
1
R’
R
2-MeO-C6H4
3-MeO-C6H4
4-MeO-C6H4
2-F-C6H4
3-F-C6H4
4-F-C6H4
4-NO2-C6H4
3-Py
Product
4b
4c
Yielda / %
64
1
2
−
trace
−
Ph
DMSOa
water
2
Ph
81
3
3
Ph
4d
4e
72
4
ethanol
toluene/water
THF
−
4
Ph
78
5
trace
−
5
Ph
4f
71
6
6
Ph
Ph
4g
–
82
7
MeCN
DCM
−
7
–
8
−
neata
21
68
8
Ph
4h
4i
80
9
9
Ph
2-Py
trace
60
10
toluene
10
11
12
13
14
Ph
Cy
4j
Reaction conditions: 1.0 mmol benzaldehyde, 1.1 mmol 2-aminopyridine,
1.5 mmol phenylacetylene, 10 mol% Cu/SiO2, reflux temperature, inert
atmosphere, 48 h; a120 °C; DMF: dimethylformamide; DMSO: dimethyl
sulfoxide; THF: tetrahydrofuran; DCM: dichloromethane.
3,5-CF3-C6H3
4-Me-C6H4
4-MeO-C6H4
4-CN-C6H4
Ph
4k
4l
75
Ph
57
Ph
4m
4n
35
With these results in hand, we then studied the
scope of the reaction (Scheme 2). This protocol was
found suitable for a range of aldehydes bearing electron
donating or electron withdrawing groups, giving the
respective imidazo[1,2-a]pyridines with good yields
(64-82%, Table 5, entries 1-6). It is worth mentioning
that no conversion to product was achieved when using
4-nitrobenzaldehyde (entry 7).
Ph
14
Reaction conditions: 1.0 mmol aldehyde, 1.1 mmol 2-aminopyridine,
1.5 mmol acetylene, reflux temperature, inert atmosphere, 0.5 mL toluene,
48 h; aisolated yields; Ph: phenyl.
methyl groups, showed better results than with mesomeric
(donating or withdrawing) effect groups in achieving the
corresponding imidazo[1,2-a]pyridines.
Conversely, heteroaromatic and aliphatic
aldehydes also worked well in this protocol, except for
2-pyridinecarboxaldehyde (entries 8-10). Substituted
aromatic alkynes gave slightly lower yields (entries 11-14)
when compared to phenylacetylene. Substituents with
an inductive effect, such as 3,5-bis-trifluoromethyl and
Concerning the mechanism of the reaction, we believe
that the major role of the catalyst is in the approximation
of the pre-formed imine (I) from 2-aminopiridine and
benzaldehyde and the π-complex of Cu-phenylacetylene (II)
(Scheme 3). This step may occur on the surface but mainly
inside pores of the catalyst, since it was verified that the
Scheme 2. Multicomponent A3-coupling synthesis of different substituted imidazo[1,2-a]pyridines.

Vol. 00, No. 00, 2019
de Salles et al.
7
Scheme 3. Proposed reaction mechanism of the A3-coupling to imidazo[1,2-a]pyridines.
pore size distribution of 0.9 nm for material 2 gave slightly
better yields when compared to material 1 with a higher
surface area and a higher amount of copper per gram of
material. The formation of intermediate III is crucial for
5-exo-dig cyclization, which is also aided by catalyst
complexation. Intermediate I was readily detected by
gas chromatography coupled to mass spectrometry when
analyzing crude reaction mixtures, while intermediate III
was not detected. This result agrees with the mechanistic
proposal made by other authors,35,38,43 with imine formation
from aldehyde and amine as a faster step than the propargyl
alcohol formed between aldehyde and alkyne which was
not observed.
Supplementary Information
Supplementary information (1H and 13C NMR spectra)
is available free of charge at http://jbcs.sbq.org.br as a
PDF file.
Acknowledgments
This research was financially supported in part by
CNPq, INCT-Cat, CAPES and FAPERGS-PRONEX.
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Submitted: January 16, 2019
Published online: May 14, 2019
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