Development of novel efficient 2D nanocomposite catalyst towards the three-component coupling reaction for the synthesis of imidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.apcata.2017.05.033

Two dimensional (2D) materials such as graphene and functionalized hexagonal boron nitride (h-BN) supported copper catalysts (CuO/rGO, CuO/h-BN, Cu(0)/rGO, Cu(0)/h-BN, CuS/rGO and CuS/h-BN) were prepared, characterized and evaluated their catalytic activity for the synthesis of imidazo[1,2-a]pyridines via one pot three component reaction between 2-aminopyridine, aldehyde and terminal alkynes. The imidazo[1,2-a]pyridines are an imperative class of nitrogen ring containing heterocyclic compounds which has wide range of applications in medicinal chemistry and drug molecule production. The reported synthetic protocol provides a rapid access to substituted imidazo[1,2-a]pyridines with excellent yields. CuO/rGO nanocomposite material was found to be highly active catalyst for the aforementioned reaction. The advantages of our protocol for the preparation of imidazo[1,2-a]pyridines over other previously reported includes shorter reaction times, functional group tolerance, recyclable catalyst and additive-free.

Full text of DOI:10.1016/j.apcata.2017.05.033

Accepted Manuscript
Title: Development of novel efficient 2D nanocomposite
catalyst towards the three-component coupling reaction for the
synthesis of imidazo[1,2-a]pyridines
Authors: Najrul Hussain, Pranjal Gogoi, Manash R. Das,
Pinaki Sengupta, Vladimir E. Fedorov, Igor P. Asanov, Mariia
N. Kozlova, Sofya B. Artemkina
PII:
S0926-860X(17)30242-9
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.apcata.2017.05.033
APCATA 16255
To appear in:
Applied Catalysis A: General
Received date:
Revised date:
Accepted date:
7-4-2017
24-5-2017
27-5-2017
Please cite this article as: Najrul Hussain, Pranjal Gogoi, Manash R.Das, Pinaki
Sengupta, Vladimir E.Fedorov, Igor P.Asanov, Mariia N.Kozlova, Sofya B.Artemkina,
Developmentofnovelefficient2Dnanocompositecatalysttowardsthethree-component
coupling reaction for the synthesis of imidazo[1,2-a]pyridines, Applied Catalysis A,
Generalhttp://dx.doi.org/10.1016/j.apcata.2017.05.033
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Development of novel efficient 2D nanocomposite catalyst
towards the three-component coupling reaction for the synthesis
of imidazo[1,2-a]pyridines
Najrul Hussain,ac Pranjal Gogoi,bc Manash R. Das,ac*, Pinaki Sengupta,ac Vladimir E.
Fedorov,de Igor P. Asanov,de Mariia N. Kozlova,d Sofya B. Artemkinad
aMaterials Sciences & Technology Division, CSIR-North East Institute of Science and Technology,
Jorhat-785006, Assam, India.
bChemical Sciences & Technology Division, CSIR-North East Institute of Science and Technology,
Jorhat-785006, Assam, India.
cAcademy of Scientific and Innovative Research, CSIR-NEIST Campus, India
dNikolaev Institute of Inorganic Chemistry SB RAS, Novosibirsk, Russia
eNovosibirsk National Research State University, Novosibirsk, Russia
*To whom correspondence should be addressed
Dr. Manash R. Das
Materials Sciences & Technology Division,
CSIR−North East Institute of Science and Technology, Jorhat−785006, Assam, India
Tel: +91- 9957178399,
Fax: +91−376−2370011,
E Mail: mnshrdas@yahoo.com, mrdas@neist.res.in
1

Graphical abstract
Highlights
 Development of Cu based 2D nanocomposites using graphene and h-BN
 Cu based nanocomposites used for synthesis of imidazo[1,2-a]pyridines
 The catalysts were well characterized before and after performing the reaction
 Comparative study of the catalytic activity of synthesized materials was performed
 CuO/rGO nanocomposite was found to be more efficient and reusable catalyst
Abstract
Two dimensional (2D) materials such as graphene and functionalized hexagonal boron nitride
(h-BN) supported copper catalysts (CuO/rGO, CuO/h-BN, Cu(0)/rGO, Cu(0)/h-BN,
CuS/rGO and CuS/h-BN) were prepared, characterized and evaluated their catalytic activity
for the synthesis of imidazo[1,2-a]pyridines via one pot three component reaction between 2-
2

aminopyridine, aldehyde and terminal alkynes. The imidazo[1,2-a]pyridines are an
imperative class of nitrogen ring containing heterocyclic compounds which has wide range of
applications in medicinal chemistry and drug molecule production. The reported synthetic
protocol provides a rapid access to substituted imidazo[1,2-a]pyridines with excellent yields.
CuO/rGO nanocomposite material was found to be highly active catalyst for the
aforementioned reaction. The advantages of our protocol for the preparation of imidazo[1,2-
a]pyridines over other previously reported includes shorter reaction times, functional group
tolerance, recyclable catalyst and additive-free.
Keywords: Two dimensional (2D) material, nanoparticles, nanocomposite, graphene oxide,
reduced graphene oxide, functionalized hexagonal boron nitride
1. Introduction
Imidazo[1,2-a]pyridine is one of the most imperative pyridine fused heterocycle found in
various agrochemicals and pharmaceuticals. In pharmaceuticals, they have been used as
analgesic, antiviral, anti-inflammatory, antibacterial, antipyretic, anxioselective and
hypnoselective agents. They are -amyloid formation inhibitors and create a novel class of
orally active nonpeptide bradykinin B2 receptor antagonists. Additionally, they are also used
as benzodiazepine receptor agonists and calcium channel blockers. Several clinical drugs and
agricultural chemicals have this structural unit, such as zolpidem, alpidem, olprinone,
minodronic acid etc. [1-5] (Scheme 1).
Considering enormous applications of various imidazo[1,2-a]pyridine derivatives in different
fields, continuous efforts have been made for their synthesis. Among them some of the
important synthetic routes include one pot condensation of 2-aminopyridine, aldehydes and
3

isonitriles [6,7], coupling reaction of 2-aminopyridines with α-halocarbonyl compounds [8],
one pot three component condensation reaction between 2-aminopyridine, benzyl halide and
isocyanides [9], one pot three component coupling of alkynes, aldehyde and 2-aminopyridine
[10], Suzuki-cross coupling between arylboronic acid with 3-halo-2-arylimidazo[1,2-
a]pyridines [11], tandem cycloisomerization of aryl propargylic alcohols with 2-
aminopyridines [12] etc. Among different types of multicomponent reaction strategy, one pot
three component coupling reactions of aldehyde, alkynes and 2-aminopyridine is the most
convenient and attractive method for the production of imidazo[1,2-a]pyridine derivatives
because of shorter reaction time, higher stability, reusability, availability of substrates and
inexpensive reagents [13].
Until now, a number of catalyst have been recognized towards one pot three component
coupling reaction for the imidazo[1,2-a]pyridines synthesis which includes CuI/Cu(OTf)2
[14], CuCl/Cu(OTf)2 [10,15], CuSO4/TsOH [7], CuSO4/glucose [16] etc. However, these are
associated with issues like use of homogenous catalyst which results difficulties in
separation, need of anhydrous reaction conditions or inert atmosphere, requirement of
additives to enhance the reaction yield. The use of easily separable heterogeneous catalyst
may replace the homogenous catalyst and without the use of any additive is of great
importance in sustainable chemistry. In this regards several efficient heterogeneous catalysts
have been developed by many research groups. For example, Luz et al. reported Cu-MOFs as
heterogeneous catalyst for this three component coupling reaction [17]. Tajbaksh and his co-
workers reported Fe3O4 nanoparticles (NPs) supported biimidazole Cu(I) complex as a
reusable catalyst for this coupling reaction [18]. Guntreddi et al. adapted simple one-pot
imidazo[1,2-a]pyridines synthesis by using magnetic nano-Fe3O4–NaHSO4·SiO2 as reusable
catalyst [19]. Very recently, Mandlimath and his co-workers developed an efficient copper
supported ZnAl2O4 nanocatalyst for the synthesis of imidazo[1,2-a]pyridines [20]. These
4

catalysts are proved to be efficient to yields the desired product but their substrate scope is
limited to only 2-aminopyridine or phenylacetylene. Therefore, there is a high requirement
for the development of an efficient and reusable catalyst for the synthesis of imidazo[1,2-
a]pyridines with wide range of substrates. Here, the reported catalytic system avoids the use
of additives, without inert atmosphere and sufficiently reusable towards the synthesis of
imidazo[1,2-a]pyridines.
Metal and metal oxide NPs are undeniably one of the most exciting functional materials in
catalytic applications due to their different structures and properties. But, due to the strong
interactions between the particles they easily undergo aggregation which in turn greatly
affects the catalytic activity. To resolve this issue, different type of ligands as well as various
stabilizers such as polymers, dendrimers are used to prevent agglomeration of NPs [21-23].
But the use of such kind of capping agents could be ingredient of the catalyst as
contamination and therefore may severely limit their catalytic application. This can be easily
overcome by using support materials. Furthermore, it is well known that the support plays a
crucial role in catalytic activity in case of heterogeneous catalyst. In that case, graphene and
functionalized hexagonal boron nitrides (h-BN) are two excellent 2D materials that are used
as promising support in the synthesis of metal and metal oxide NPs due to their high thermal
conductivity, electric insulation, chemical inertness, great mechanical strength [24,25]. These
2D materials are particularly promising and emerging support for the synthesis of composite
nanomaterial for catalytic applications because of their high surface area and good absorption
capacities. Metal and metal oxidegraphene nanocomposite materials finds wide range of
applications in catalysis which includes oxidation of alcohols, CO oxidation, hydrogenation,
Fishcher-Tropsch synthesis and coupling reactions [26]. But surprisingly, as compared to the
significant progress of metal/metal oxide-graphene nanocomposite materials in catalysis, the
h-BN supported metal/metal oxide NPs have been enduring far behind than that of graphene
5

based nanocomposite materials. Therefore, we have developed metal and metal oxide NPs on
to functionalized h-BN for catalytic application and also report a comparative study of their
catalytic performances with graphene supported metal and metal oxide NPs.
In this study we have chosen Cu due to its availability, low cost and environmental
compatibility nature [27,28]. In spite of these peculiar advantages of using Cu, there is limited
number of reports on Cu based heterogeneous catalyst in organic catalytic reactions and to
the best of our knowledge there is no report on Cu based NPs on graphene and h-BN as a
catalyst towards the synthesis of imidazo[1,2-a]pyridines. Keeping this in mind, we have
developed CuO NPs on to rGO sheets as well as on to h-BN sheets by using hydrothermal
technique. The use of hydrothermal technique for the synthesis of CuO NPs avoids the use of
extra reducing agent and also provides the necessary stability to the composite material for
catalytic conversion. We have also reported here the use of other chalcogenide
nanocomposite material such as CuS/rGO and CuS/h-BN to investigate the effect of the
counterparts of Cu towards the size and shape of the composite materials which will in turn
effects the catalytic activity of the materials towards the reaction. Furthermore, we have also
developed Cu(0) NPs on to rGO sheets and h-BN sheets and investigated their catalytic
activity towards the synthesis of imidazo[1,2-a]pyridines.
2. Experimental
2.1. Materials and Methods
Graphite powder (<20 μm, Sigma-Aldrich), potassium permanganate (>99%, E-Merck,
India), hydrochloric acid (AR grade, Qualigens, India), sulphuric acid (AR grade, Qualigens,
India), H2O2 (30%, Qualigens, India), ascorbic acid (99%, Fisher Scientific, India),
Cu(NO)3.3H2O (99-104%, Sigma-Aldrich), Cu(CH3COO)2.H2O (>99%, E-Merck, India),
6

Na2S2O3 (Qualigens, 99%) and all substrates for organic reactions were used from Sigma
Aldrich, USA.
X-ray diffraction (XRD) analysis were carried out with a scanning rate of 3 deg.min−1 using
ULTIMA IV Rigaku X-ray diffractometer from 5-100o with a Cu Kα X-ray source (λ =
1.54056 Å). Transmission electron microscopy (TEM) as well as high resolution transmission
electron microscopy (HRTEM) images were taken on a JEOL JEM-2011 electron
microscope, Japan functioned at an accelerating voltage of 200 kV. The diffuse reflectance
infrared Fourier transform (DRIFT) spectra of samples were taken by using IR Affinity-1,
Shimadzu, Japan in the range of 4000-400 cm−1. The thermal stability of the synthesized
materials were investigated by TA-SDT (model: Q600DT, TA Instruments, USA) at a
heating rate of 10 °C rise in temperature per minute. Atomic absorption spectroscopy (AAS)
analysis was carried using Perkin Elmer (Model-Analyst-700) spectrometer to determine the
metal content of the composite material. X-ray photoelectron spectroscopy (XPS) analysis
were done by Specs Phoibos 150 instrument using a monochromatized Al Kα excitation at a
9
pressure ~ 3 × 10 mBar, pass energy is 20 eV, electron take off angle is 55°, the full width at
the half maximum of Au4f7/2 is ~ 0.8 eV). Organic reactions were examined by thin-layer
chromatography (TLC) with the help of aluminium-backed silica gel plates; the
chromatograms were envisioned with ultraviolet light (254 nm). Column chromatography
technique was adapted for the purification of the organic products with the help of silica gel
60 (100-200 mesh). All NMR spectra of the products were recorded by using Bruker
Advance DPX 500 MHz NMR spectrometer. Chemical shifts are stated on the δ scale in ppm
downfield from tetramethylsilane of δ = 0.0 ppm using the residual solvent signal at δ = 7.26
ppm (1H) or δ = 77 ppm (13C) as an internal standard.
2.2. Synthesis of the graphene oxide (GO)
7

The detailed synthesis procedure and characterization of GO was reported in our previously
published papers [29, 30].
2.3. Synthesis of functionalized hexagonal boron nitride (h-BN)
Functionalized hexagonal boron nitride samples were prepared by treatment with H2O2 (30%)
as it has been described in our previous work [31]. In the typical procedure 150 mg h-BN
was ground by agate mortar and then pestle for 15 min. After that it was put into a cylindrical
Teflon autoclaves (rated pressure 2–3 atm). 30 mL 30% H2O2 was added to the autoclave and
ultrasonicated for 5 min and then thermostated in a water bath for 25–50 h at 100 °C. After
the reaction, solid phase of the mixture was decanted by centrifugation, washed with water
followed by ethanol and then dried at room temperature.
2.4. Synthesis of the CuO NPs onto reduced graphene oxide sheets (CuO/rGO
nanocomposite)
20 mL of GO suspension (1 g in 100 mL water) was added to the 100 mL round bottom flask
containing 20 mL aqueous solution of Cu(CH3COO)2.H2O (0.2595 g dissolved in 20 mL
water). Then the mixture was stirred for 1 h at 25 °C and then transferred the reaction mixture
to 50 mL autoclave for hydrothermal treatment at 150 °C for 5 h. Finally the solid product
was obtained by centrifugation and then repeatedly washed with ethanol and water. Finally
the solid residue was dried in air oven at 70 °C.
2.5. Synthesis of CuO NPs onto the functionalized hexagonal boron nitride (CuO/h-BN
nanocomposite)
Typically, 20 mL of h-BN-ethanol suspension (20 mg in 40 mL ethanol) was mixed with 20
mL aqueous solution of Cu(CH3COO)2.H2O (0.2595 g dissolved in 20 mL water) and
allowed to stir for 1 h. The reaction mixture was transferred to a 50 mL autoclave and
subjected to hydrothermal treatment at 150 °C for 5 h. After that the solid product was
8

obtained by centrifugation and then repeatedly washed with ethanol and water. Finally the
solid residue was dried in air oven at 70 °C.
2.6. Synthesis of the Cu(0) NPs onto reduced graphene oxide sheets (Cu(0)/rGO
nanocomposite )
The detailed synthesis method of Cu(0)/rGO nanocomposite material and its characterization
was reported in our previously published paper [32].
2.7. Synthesis of Cu(0) NPs onto functionalized hexagonal boron nitride (Cu(0)/h-BN
nanocomposite)
Cu(CH3COO)2.H2O (0.8 g) was dissolved in 10 mL water in a round bottom flask. 20 ml of
h-BN-ethanol suspension (20 mg in 40 ml ethanol) was added to the above solution and
stirred for 1 h followed by addition of ascorbic acid (0.1M, 10 mL) to the reaction mixture
and heated to 80 °C for 3 h. The product was treated with H2O2 to remove the unused
ascorbic acid and after that the solid product was obtained by centrifuge and repeatedly
washed with ethanol and water and then dried at 70 °C in an air oven.
2.8. Synthesis of the CuS NPs onto reduced graphene oxide sheets (CuS/rGO nanocomposite)
The detailed synthesis method of CuS/rGO nanocomposite material and its characterization
was reported in our previously published paper [33].
2.9. Synthesis of CuS NPs onto functionalized hexagonal boron nitride sheets (CuS/h-BN
nanocomposite)
0.164 g Cu(NO)3.3H2O is dissolved in 20 mL water and then 0.248 g of Na2S2O3 was added
to it. The reaction mixture was mechanically stirred until the colour changed to yellowish
green. After that 20 mL of h-BN-ethanol suspension (20 mg in 40 mL ethanol) was added to
the above solution and then the whole reaction mixture was heated to 80 °C with vigorous
stirring for 4h. Finally, the solid product was collected by centrifuge and washed with ethanol
and water and then dried in an air oven at 70 °C.
9

2.10. General experimental procedure for the synthesis of imidazo[1,2-a]pyridines
derivatives:
A mixture of aldehyde (1.2 mmol), alkyne (1.2 mmol) and 2-aminopyridine (1 mmol) were
taken in a 25 mL round bottom flask. Then a suspension of the nanocomposite material (15
mg in 3 mL DMSO) was added to the above reaction mixture. The whole reaction mixture
was ultrasonicated for 2 min followed by heating with continuous stirring at 110 °C for 8 h.
The completion of the reaction was monitored by thin-layer chromatography (TLC). The
product was extracted with ethyl acetate (2×10 mL) followed by drying over Na2SO4 and
concentrated in vacuum. The crude products were purified by column chromatography with
silica gel (60-120 mesh) using EtOAc/hexanes as eluent to get the desired final product. The
products were analysed by 1H and 13C NMR spectroscopy (Details are shown in the
supporting information).
3. Results and Discussions
3.1. Characterization of all the synthesized nanocomposite materials
The detailed characterization of the Cu(0)/rGO and CuS/rGO nanocomposites were
discussed in our previously published paper [32,33]. The formation of CuO and CuS NPs on
to the rGO sheets and h-BN surface was first confirmed by X-ray diffraction (XRD)
technique as shown in the Fig. 1.The XRD pattern of the CuO/rGO nanocomposite revealed
that the peaks at 2θ values of about 32.56o, 35.56o, 38.81o, 48.71o, 53.54o, 58.50o, 61.59o,
65.91o, 68.19o, 72.68o and 75.18o corresponding to d – spacing of 2.74, 2.52, 2.31, 1.86,
1.71, 1.58, 1.50, 1.41, 1.37, 1.31 and 1.26 Å are assigned to the (110), (-111), (111), (-202),
(020), (202), (-113), (-311), (220), (311) and (-222) crystallographic planes of CuO NPs,
respectively [34]. All the diffraction peaks and other lattice parameter found in the XRD are a
= 4.68 Å, b = 3.42 Å, c =5.12 Å with volume cell of 80.90 Å can be indexed in the
10

monoclinic phase of CuO NPs. These values are good agreement with the respective JCPDS
card No 01-070-6830. The average crystallite size of the CuO NPs onto rGO sheets is
determined by using Sherrer equation on PDXL software and found to be 2.50 nm. Similar
crystallographic planes of CuO NPs in CuO/h-BN nanocomposite material were found (Fig.
1b). The formation of CuS NPs on to the h-BN is also confirmed by XRD analysis as shown
in Fig. 1c. Also the formation of Cu(0) NPs on to h-BN was confirmed by XRD as shown in
Fig. 1d. The peaks at 43.30o, 50.43o and 74.13o corresponding to d- spacing of 2.08, 1.80 and
1.27 Å are assigned to the (111), (200) and (220) planes of cubic Cu(0) NPs (JCPDS card No
00-004-0836). The typical diffraction peak at 26.61o corresponds to the (002) plane of h-BN
in these composite materials.
The size, morphologies and microstructures of all the prepared nanocomposites were
examined by using TEM and HRTEM techniques. The TEM images of CuO/rGO
nanocomposite materials as shown in Fig. 2 revealed that the CuO NPs are uniformly
scattered on to the surface of rGO sheets and are spherical in structure. It is observed from the
TEM images as shown in the Fig. 2 that the rGO sheets are irregular and folded and CuO NPs
are wrapped by those folded sheets, which therefore enables unifrom distribution of particles
by preventing from agglomeration [35]. The particle size distribution curve obtained by using
Image J Software shows the average particle size of the CuO NPs at around ~ 5 nm (Fig. 2c).
The HRTEM image as shown in Fig. 2e clearly shows the interplanar spacing of 0.25 nm
which can be indexed with the (-111) plane of cubic CuO NPs. The diffraction dots found in
the SAED pattern proves the crystalline nature of the CuO NPs and the crystal lattices
corresponding to the (111) and (-202) planes of CuO are clearly visible (Fig. 2f). The TEM
image of CuO/h-BN nanocomposite material shows that the CuO nanoparticles are more or
less uniformly distributed on to the surface of h-BN sheets (Fig. 3). The average size of the
CuO NPs on to h-BN sheets is found to be ~ 9 nm which is larger than that onto rGO sheets.
11

The average size of Cu(0) NPs onto h-BN sheets is obtained from particle size distribution
curve and it is found to be 14 nm (Fig. 4(c)). But some of the Cu(0) NPs are susceptible to
undergo agglomeration and also the distribution of the particles are not uniform as compared
to CuO NPs onto rGO and h-BN sheets. The morphology of the Cu(0) NPs on the surface of
rGO sheets are discussed in our previous publication [29] and found that the size of the Cu(0)
NPs is larger onto h-BN sheets than onto the rGO sheets. Further, it is seen from the TEM
images of the synthesized CuS/h-BN nanocomposite (Fig. 4(d-f)) that the CuS NPs are very
large and undergoes agglomeration and therefore forms a cluster type structure. The details of
the surface morphology of the CuS/rGO nanocomposite was given in our previous
publication and observed that synthesized CuS/rGO nanocomposite has crystalline structure
with an average particle size of about 183 nm [33]. TEM and HRTEM images evident that
the particles size and morphology of the Cu NPs are dependent on the support material as
well as on the counterparts of Cu. The sizes of the CuO NPs on to rGO sheets are smaller and
uniformly dispersed than that of h-BN sheets. It can be seen from the TEM images of all the
synthesized copper/h-BN nanocomposite materials that the NPs are distributed in the shape of
irregular structures and are prone to agglomeration and as a result of which a broad particle
size distribution is observed. The regular and uniform distribution of Cu and CuO NPs onto
rGO sheets as compared to functionalized h-BN sheets is because of the presence of adequate
number of oxygen containg functional groups present on rGO surface as compared to
functionalized h-BN. The presence of various oxygen containing functional groups on rGO
sheets can act as active sites for decoration of the NPs with good dispersion than that of
functionalized h-BN sheets where only hydroxyl groups are present [36, 37].
The FTIR spectra of GO, h-BN, CuO/rGO and CuO/h-BN are displayed in Fig. 5. The FTIR
spectra of h-BN (Fig. 5a) displayed two prominent peaks at 1392 cm−1 and 813 cm−1 which
are due to the B–N stretching and B–N bending of h-BN, respectively. The intensity of the
12

peak observed at around 3395 cm−1 of h-BN which is due to the −OH groups is reduced in the
CuO/h-BN nanocomposite material (Fig. 5b) implying that the −OH groups of h-BN served
as the active sites for the formation of CuO NPs on to the h-BN surface. Similar observations
were found in the FTIR spectral analysis of Cu(0)/h-BN and CuS/h-BN nanocomposite
materials (Shown in Fig. S1). As shown in Fig. 5c, the stretching vibrations of OH, C=O,
1
COC of GO is observed at 3130, 1732, and 1052 cm , respectively. The peaks at 1224
1
cm of GO corresponds to the vibration of carboxyl groups. Moreover, the peaks observed
at 1439 cm−1 and 1585 cm−1 corresponds to COH bending of phenolic groups and the C=C
stretching of aromatic rings. These peak intensities of the oxygen containing functional
groups present on GO is decreased in the CuO/rGO nanocomposite material as shown in Fig.
5d, which suggest that the epoxy, carboxyl, hydroxyl and carbonyl groups present in GO are
considerably decreased after formation of the CuO NPs on the rGO sheets. This implies that
these oxygen containing functional groups served as active sites for decoration of CuO NPs.
As a result of which uniform distribution of CuO nanoparticles onto rGO sheets was
obtained.
XPS analysis was performed to study the oxidation state of the Cu, CuO and CuS NPs on the
rGO and h-BN sheets. The high resolution C1s and O1s XPS spectrum of CuO/rGO
nanocomposite is shown in Fig. 6. The C 1s spectrum of CuO/rGO shows the peak at 284.59
eV from sp2 carbon atoms and the less intense components at 286.92 eV (CO bonds) and
288.70 eV (carboxyl group). The weak satellite line at 291.01 eV is related to the inelastic
energy losses at photoionization process. The O1s spectrum can fit into three components at
529.58 eV from CuO, 531.24 eV from C-O bonds and 532.92 eV from water molecules
(shown in Fig. 6). The spectra B1s of CuO/h-BN consists of two components at 189.23 eV
and 190.95 eV with the intensity ratio 0.15. The most intense peak at 190.95 eV comes from
BN and the weak line corresponds to borides (shown in Fig. 7). The N1s spectrum consists of
13

two components at 396.58 eV and 398.23 eV with the intensity ratio 0.19. The most intense
component is related to BN, and the weak component corresponds to the negatively charged
nitrogen atoms (possibly nitride of Cu) (Fig. 7). Although, the XRD spectrum of Cu(0)/h-BN
shows that Cu is in zero oxidation state, the XPS spectra shows that Cu is also in +2
oxidation state in Cu(0)/h-BN nanocomposite material (Fig. S2). This may be due to the fact
that Cu(0) is less stable onto h-BN sheets as compared to rGO sheets and it underwent
oxidation easily in contact with air. But in case of Cu(0)/rGO nanocomposite, Cu is in purely
zero oxidation state and very much stable which is described in our previous publication.
This is because rGO sheets are folded and oriented in different directions and it is assumed
that the Cu(0) NPs are present inside the folded rGO sheets as well as along the basal plane
and the edges of the rGO sheets. The details XPS spectrum analysis of Cu(0)/rGO
nanocomposite is discussed in our previously published paper [32].The S2p XPS spectrum of
CuS/h-BN shows two lines at 162.70 eV and 169.33 eV from sulfide and sulfate groups,
respectively (Fig. S3). The Cu 2p spectrum has an intense line at 931.52 eV from CuS, the
shoulder at 933.54 eV and intensity of the satellite decreases. We can suggest that CuS and
copper sulphate contributes to the surface of Cu NPs in this sample. The details discussion of
the XPS spectra of the CuS/rGO nanocomposite is given in our previous publication [33].
3.2. Catalytic activity of the different Cu based nanocomposites for the synthesis of
imidazo[1,2-a]pyridines
The Cu based nanocomposites as described above were applied to the three component
coupling reaction. First, all catalysts were easily suspended in the appropriate solvent by
ultrasonication. To establish an approximate ranking activity among the synthesized
composite materials, different types of substituted 2-aminopyridine, benzaldehyde and
phenylacetylene were chosen as a standard benchmark reaction for the synthesis of
imidazo[1,2-a]pyridines (Table 1). The highest activity was achieved with CuO/rGO
14

nanocomposite followed by CuO/h-BN, Cu(0)/rGO, Cu(0)/h-BN, CuS/rGO and CuS/h-BN.
Although CuO/h-BN nanocomposite material lead to comparatively good yield of the desired
product, but the activity sharply decreased in the second run of the reaction. The disrupt
change in the activity of reused CuO/h-BN is accompanied by changes in the surface
morphology of the material upon reuse which is supported by TEM images (Fig. 9(d-e)).
Cu(0)/rGO and Cu(0)/h-BN nanocomposites displayed almost same efficiency but afforded
lower yield of the product than that of CuO/rGO and CuO/h-BN nanocomposites. But
surprisingly, both the CuS/rGO and CuS/h-BN nanocomposites displayed lowest activity
among all the synthesized materials. This poor performance is due to the agglomeration of
the CuS NPs onto rGO sheets and h-BN sheets which results lower surface to volume ratio of
these two nanocomposites. On the basis of this findings the highest catalytic activity towards
the synthesis of imidazo[1,2-a]pyridines with the yield of 91-95% is achieved with CuO/rGO
nanocomposite. The higher catalytic activity of CuO/rGO nanocomposite is attributed to the
enhanced interaction between CuO NPs with the substrates resulting from the uniform
distribution of small sized CuO NPs onto rGO sheets.
3.3. Reaction optimization for the CuO/rGO nanocomposite catalyst in one pot three
component coupling reaction of the synthesis imidazo[1,2-a]pyridines
With the optimized catalyst in hand, further we have performed optimization reaction
condition by screening different common solvents as shown in Table 2. At first and foremost,
we tried with evergreen solvents H2O, but unfortunately our catalytic system was unable to
afford the desired product because the catalyst CuO/rGO nanocomposite is not properly
dispersed in water. After that we tried with different organic solvents such as THF, DMF,
acetonitrile, DMSO, toluene and N-methyl-2-pyrrolidone (NMP). Although the solvents
DMF and NMP afforded comparatively good yield of the desired product, but significant
difference in the catalytic activity of the catalyst is found with toluene under our catalytic
15

system. DMSO was found to the best solvent for this catalytic system (Entry 7, Table 2).
Also we have also optimized the reaction temperature and found 110 oC as optimum
temperature for this reaction.
3.4. Scope of the CuO/rGO nanocomposite catalyst in one pot three component coupling
reaction for the synthesis of imidazo[1,2-a]pyridines
After having the optimized reaction conditions with established catalyst, the versatility and
efficiency of the CuO/rGO nanocomposite catalyst is explored for the synthesis of
imidazo[1,2-a]pyridines using different substituted 2-aminopyridines, aldehydes and alkynes.
The results summarised in Table 3 shows that the reactions preceded extraordinarily well in
terms of reaction yields and turn over frequency. The turnover frequency (TOF) of the
synthesized catalyst is found to be higher than the previously reported TOF data for the
imidazo[1,2-a]pyridines synthesis [18]. To investigate the scope and limitation of the
established catalytic system CuO/rGO nanocomposite in the aforementioned reaction, various
substrates containing electron donating, electron withdrawing and neutral groups were
exposed. The benzaldehyde containing electron withdrawing groups such as Cl coupled with
both substituted and un-substituted 2-aminopyridines and phenyl acetylenes to give excellent
yields of the product (entry 5,6,7, 10, 15 table 3). But electron donating groups on
benzaldehyde afforded slightly lower yield of the desired product than that of un-substituted
benzaldehyde as well as benzaldehyde containing electron withdrawing groups (entry 3, 11,
12, 13 Table 3). Further, the phenylacetylenes containing electron donating groups such as
methyl gave slightly higher yields of the product than that of un-substituted phenylacetylenes.
(Entry 2, 8 Table 3). To explore the further scope of the catalyst, we have chosen 2-
aminopyridines containing different substituent at different positions. Surprisingly, it is found
that the effects of electron donating as well as electron withdrawing groups on 2-
16

aminopyridine ring are not pronounced in this three component coupling reaction under the
catalytic system.
The proposed mechanism for the synthesis of imidazo[1,2-a]pyridine by CuO NPs based on
the previous literature on Cu(II) catalytic system is shown in scheme 2 [38]. First,
condensation of 2-aminopyridine and benzaldehyde gives the 2-iminepyridine (2), a Schiff
base followed by Cu(II)-mediated aminomethylation of alkyne (1) with the Schiff base-
copper complex results the formation of propargylamines (3). Then the cyclization of
propargylamines gives intermediate 4 which then went through rearomatization to provide
imidazo[1,2-a]pyridines.
3.5. Stability and reusability of the nanocomposite catalyst
Since several heterogeneous catalysts suffer from leaching of the active species from the
support, and as a result of which the stability and reusability of the catalysts are highly
limited. To check whether the active species CuO leached out from the rGO support during
the reaction, a hot filtration test was performed. In this typical test, a mixture of 2-
aminopyridine, benzaldehyde and phenylacetylene was stirred in presence of the CuO/rGO
nanocomposite catalyst under optimized conditions. After continuing the reaction for 3 h, the
catalyst was separated and the reaction yield was found to be 49% yield. After that, the
filtrate portion was heated further upto 5 h to check the progress of the reaction which shows
no further progress of the reaction. This clearly proves that no CuO NPs was leached from
the catalyst after performing the reaction. These findings enthused us for subsequent
investigation of the reusability of the catalyst. The reusability of the CuO/rGO and CuO/h-
17

BN nanocomposites were investigated for the three component coupling reaction of 2-
aminopyridine, 4-chlorobenzaldehyde and phenylacetylene. After accomplishment of the
reaction, the catalyst were simply recovered through filtration and washed with first water
and then by acetone and dried in air oven. The recovered catalyst was then used for further
reaction without any activation of the catalyst. As shown in Fig. 8, CuO/rGO nanocomposite
catalyst can be consecutively used for five times without loss of significant activity for the
aforementioned reaction. But a significant decrease of the catalytic activity of the CuO/h-BN
nanocomposite is found after first cycle of the reaction as shown in the Fig. 8.
Moreover, to confirm the stability of the catalyst, the size and shape, surface morphology and
the chemical oxidation state of the CuO/rGO and CuO/h-BN nanocomposites catalyst were
investigated by XRD, TEM and XPS after first run of the reaction. The XRD of CuO/rGO
nanocomposite as shown in the Fig. 9 revealed that the crystallinity of the nanocomposite
remain same after performing the catalytic reaction. The average crystallite size of the CuO
NPs for reused catalyst is determined by Sherrer equation using PDXL software in XRD and
found to be 2.7 nm which is very close to the CuO NPs in the CuO/rGO composite before the
catalytic reaction.
The XPS proved that the oxidation state of the Cu in CuO/rGO nanocomposite after
performing the reaction remain same as before the reaction (Fig. 9). The Cu2p spectra in the
CuO/rGO have a specific shape for cupric species containing the doublet Cu2p1/2, 3/2 with the
spin-orbital splitting of 19.80 eV and the maximum of Cu2p3/2 at 932.91 eV and charge
transfer satellites for each component in the doublet. Also the same observation was found in
case of reused CuO/rGO after performing the reaction. This confirms that CuO NPs are well
decorated onto the surface of rGO sheets and are very stable even after its use as catalyst in
the reaction.
18

Furthermore, TEM images of recycled CuO/rGO nanocomposite catalyst showed preserve of
nano structure with uniform distribution of spherical CuO NPs onto rGO sheets as in the
fresh catalyst (Fig. 9(b-c)). Particle size distribution plot obtained from TEM measurements
showed the average size of the CuO NPs at around 5 ± 0.70 nm which is almost similar to
that observed in the fresh catalyst. These results evident that CuO/rGO nanocomposite
catalyst is physically as well as chemically stable. However, the TEM image of the CuO/h-
BN nanocomposite shows a significant change in the morphology compared with the
CuO/rGO nanocomposite ((Fig. 9(d-e)). This is the reason for the rapid decrease in the yield
of the coupled product after the first cycle of the CuO/h-BN nanocomposite catalysed
reaction. This may be due to the instability of the CuO NPs onto h-BN sheets because of the
absence of adequate number of oxygen containing functional groups on h-BN sheets unlike
the rGO sheets where the presence of sufficient amount of oxygen containing functional
groups can act as anchor for the decoration of NPs.
4. Conclusion
In conclusion, we have developed various two dimensional nanocomposite material of Cu
with graphene as well as functionalized hexagonal boron nitride and evaluated their catalytic
efficiency towards the synthesis of imidazo[1,2-a]pyridines. CuO/rGO nanocomposite was
found to be the most efficient catalyst in the three component coupling reaction of various
substituted 2-aminopyridine, aryl aldehyde and terminal alkynes. Unlike the previous
reports, this protocol avoids the need of anaerobic procedures, uses cost effective two
dimensional Cu catalysts and affords excellent yields of expected products with a wide range
of functional groups tolerance. The catalyst morphology remains unaltered even after
performing the reaction that proves the formation of stable composite materials which is an
important parameter in chemical industry. In summarizing, although there have been many
19

report for the development of metal/metal oxide-graphene nanocomposite materials in
different catalysis, the commercial applicability of these catalysts in industrial process is yet
to be explored. However, the main issue in industrial applications is the large scale
productivity of the catalyst and it mainly depends on its activity as well stability. In that case
the present study on developing 2D nanocomposite materials as stable catalyst for the
synthesis of industrially important compounds imidazo[1,2-a]pyridine derivatives will
provide an important platform.
Acknowledgements
The authors are grateful to the Department of Science and Technology, New Delhi for the
financial support (DST Project No. INT/RUS/RFBR/P-193 & CSIR-NEIST Project No. GPP
301). The authors are also thankful to the Director, CSIR−NEIST, Jorhat, for his interest in
this work. VF acknowledges financial support from the Russian Foundation for Basic
Research (Project No. RFBR15-53-45041). We are also thankful to SAIF NEHU, Shillong for
the TEM and HRTEM facility. NH acknowledges UGC, New Delhi, India for SRF Fellowship
grant.
20

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Figures
Fig. 1. XRD pattern of (a) CuO/rGO, (b) CuO/h-BN, (c) CuS/h-BN, (d) Cu(0)/h-BN
nanocomposites
24

35
30
25
20
15
10
5
a
d
b
e
c
0
-5
0
2
4
6
8
10
Diameter (nm)
f
f
Fig. 2. Low magnified TEM images of CuO/rGO nanocomposite (a, b and d), particle size
distribution curve (c), high magnified TEM image of a single nanoparticle (e), SAED pattern
of CuO NPs (f)
25

20
15
10
5
c
b
e
a
d
0
2
4
6
8
10
12
14 16
18
20
Particle size (nm)
f
Fig. 3. Low magnified TEM images of CuO/h-BN nanocomposite (a,b and d), particle size
distribution curve (c), high magnified TEM image of s single particle (e), SAED pattern of
CuO NPs (f)
c
a
b
d
e
f
Fig. 4. TEM images of Cu(0)/h-BN nanocomposite (a-b) along with particle size distribution
curve (c) and TEM images of CuS/h-BN nanocomposite (d-f).
26

Fig. 5. FTIR spectra of (a) h-BN, (b) CuO/h-BN nanocomposite, (c) GO and (d) CuO/rGO
nanocomposite
Fig. 6. High resolution C1s and O1s XPS spectra of CuO/rGO nanocomposite
27

Fig. 7. N1s and B1s XPS spectra of CuO/h-BN nanocomposite
Fig. 8. Reusability of the CuO/rGO and CuO/h-BN nanocomposites in imidazo[1,2-
a]pyridines synthesis
28

a
14
b
c
e
7
0
2
4
6
8
Diameter (nm)
d
29