Magnetic Cu0@HAP@γ-Fe2O3 nanoparticles: An efficient catalyst for one-pot three-component reaction for the synthesis of imidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.jorganchem.2018.07.039

Cu(0) incorporated magnetic hydroxyapatite nanoparticles (Cu⁰@HAP@γ-Fe₂O₃ NPs) was conveniently synthesized via the ion exchange reaction, oxidation, and reduction steps. The structure and composition of the nanohybrid wer

Full text of DOI:10.1016/j.jorganchem.2018.07.039

Accepted Manuscript
0
Magnetic Cu @HAP@γ-Fe O nanoparticles: An efficient catalysts for one-pot
2 3
three-component reactions for the synthesis of imidazo[1,2-a]pyridines
Wei Sun, Wei Jiang, Gan Zhu, Yiqun Li
PII:
S0022-328X(18)30459-5
10.1016/j.jorganchem.2018.07.039
JOM 20526
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 6 June 2018
Revised Date: 9 July 2018
Accepted Date: 31 July 2018
0
Please cite this article as: W. Sun, W. Jiang, G. Zhu, Y. Li, Magnetic Cu @HAP@γ-Fe O
2 3
nanoparticles: An efficient catalysts for one-pot three-component reactions for the synthesis
of imidazo[1,2-a]pyridines, Journal of Organometallic Chemistry (2018), doi: 10.1016/
j.jorganchem.2018.07.039.
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Graphic Abstract
Magnetic Cu0@HAP@γ-Fe2O3
nanoparticles: an efficient catalyst for
one-pot three-component reaction for the
synthesis of imidazo[1,2-a]pyridines
Wei Sun, Wei Jiang, Gan Zhu, and Yiqun
Li*

ACCEPTED MANUSCRIPT
Magnetic Cu0@HAP@γ-Fe2O3 nanoparticles: an efficient
catalysts for one-pot three-component reactions for the
synthesis of imidazo[1,2-a]pyridines
Wei Sun, Wei Jiang, Gan Zhu, Yiqun Li*
Department of Chemistry, Jinan University, Guangzhou 510632, PR China
Abstract
Cu(0) incorporated magnetic hydroxyapatite nanoparticles (Cu0@HAP@γ-Fe2O3 NPs)
was conveniently synthesized via the ion exchange reaction, oxidation, and reduction
steps. The structure and composition of the nanohybrid were confirmed by FT-IR,
SEM, EDS, TEM, XPS, and TGA. The magnetic Cu0@HAP@γ-Fe2O3 hybrid can
efficiently catalyzed a one-pot multicomponent synthesis of imidazo[1,2-a]pyridine
derivatives from 2-aminopyridine, aldehyde or glyoxylic acid, and phenylacetylene or
alkynyl carboxylic acids in excellent yields. The magnetic nanocatalyst was easily
separated from reaction mixture using an external magnet and was successfully
examined for three runs with a slight loss of catalytic activity.
Keywords: imidazo[1,2-a]pyridine, multicomponent reaction, hydroxyapatite, copper,
m
agnetic nanocatalyst
1. Introduction
Among the various categories of nitrogen-containing heterocyclic compounds
endowed with numerous biological activities, imidazo[1,2-a]pyridine as an
indispensable core of the emerging drugs (Fig. 1) have attracted considerable

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attention due to their ring system exists in wide range of bioactive molecules and also
known for their antiviral [1], analgesic [2], antipyretic [2], anti-inflammatory [2,3],
antiulcer [4], antibacterial [5], and anticonvulsant [6]. Commercial drugs such as
zolpidem [7-9], alpidem [7,10,11], olprinone [7,12-14], and minodronic acid [15]
containning imidazo[1,2-a]pyridine framework have already been on the market.
Fig. 1. Examples of imidazo[1,2-a]pyridine-based drug molecules.
In view of their extreme significance, for the synthesis of imidazo[1,2-a]pyridine
scaffold, numerous synthetic methods have been recently documented in the
literature [16,17]. The common methods include: (1) the heterocyclization of
2-aminopyridines with α-halocarbonyl compounds (Scheme 1, Path a)[18,19]; (2)
one-pot multicomponent reaction of 2-aminopyridine, aldehyde, and isonitrile
(Scheme 1, Path b).[20-23] Despite that, it is still a huge demand to synthesize the

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significant imidazopyridines from readily available and easily extensible raw materials
using a simple procedure. Efficiently straightforward protocol for the synthesis of
imidazo[1,2-a]pyridines from conveniently available 2-aminopyridines, aldehydes, and
terminal alkynes has been first developed in 2010 by Gevorgyan et al using
CuCl/Cu(OTf)2 co-catalyst and Lin et al using CuSO4/TsOH catalytic system (Scheme
1, Path c) [24,25].
Path a
O
N
+
+
R
Ar
Ar
Ar
N
N
NH2
Br
H
R
Path b
N
O
O
Ar
N R
C
+
+
N
N
N
NH2
HN
R
Path c
N
Ar
R
+
Ar
H
N
NH2
R
Scheme 1. Syntheses of imidazo[1,2-a]pyridine from 2-aminopyridine.
Subsequently,
various
catalysts
employed
for
the
synthesis
of
imidazo[1,2-a]pyridines from 2-aminopyridines, aldehydes, and terminal alkynes
include InBr3 [26], CuI-NaHSO4·SiO2 [27], CuSO4/glucose [28], Cu-MOFs [28],
magnetic nano-Fe3O4-KHSO4·SiO2 [29], Cu-Mn spinel oxide [30], iodine [31],
Fe3O4@SiO2 [32], CuO-CuAl2O4-D-glucose [33], CuO NPs [34], ZnAlO4 NPs [35] and
so on. In spite of their advantages, most of these catalytic systems suffer from certain

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limitations such as use of homogeneous catalysts, requirements of an inert
atmosphere condition, and need of additives such as glucose, and bisulfate. Hence,
the development of an efficient, high-yielding, and environmentally benign procedure
for the one-pot synthesis of imidazo[1,2-a]pyridine derivatives with diverse bioactivity
is of great interest.
Nowadays the developments of metal nanocatalyst with tunable catalytic
performance in organic synthesis have much significance in academia and industry
[36]. The transition metal-based nanocatalysts are more promising, efficient, and
practical compared to buck catalysts due to their high surface-to-volume ratios and
the high activity of surface atoms. Unfortunately, metal NPs are unstable and easily
aggregate and precipitate to bulk metal, and therefore, decrease their catalytic activity.
Furthermore, the recycling of these nanoctalysts is often tedious because the
recovery of these very tiny particles requires the use of an expensive
ultra-centrifugation technique that has limited their application. This limitation can be
overcome by using magnetic NPs (MPs), which can be simply recovered from the
reaction mixture by magnetic separation. MNPs have recently emerged as an
attractive alternative to immobilize catalytic species for various synthetic
transformations because of their easy recyclability, reusability, high surface area, low
toxicity, and excellent activity [37]. However ultrafine bare MPs always tend to
undergo agglomeration due to the high ratio of surface area-to-volume and the
dipole-dipole attractions between MNPs. To further address the issue of
agglomeration of MNPs, a passive coating of inert inorganic and/or organic materials

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such as carbons, silicas, and polymers on the surfaces of MNPs could be feasible to
prevent their aggregation and improve their stability [38,39]. However, the
surface-coating techniques has some disadvantage of multistep synthetic process,
using expensive reagents and hazardous solvents, harsh condition, and tedious
operation. In order to overcome these defects, hybridization of magnetic MNPs may
be a practical choice. Hydroxyapatite (HAP), i.e. Ca10(PO4)6(OH)2, as the main
inorganic constituent of bone and tooth has unique properties like ion exchange ability,
adsorption capacity, acid–base properties, and high surface area, and good stability
[40]. In the light of the characteristic of ion exchange of Ca2+ with either bivalent or
trivalent cations, we speculative that HAP can be served as an efficient template for
the preparation of HAP-encapsulated Fe2O3 magnetic hybrid material (HAP@γ-Fe2O3)
in which HAP not only is served as coating material to trap Fe2O3 NPs but also acted
as a support to anchor Cu(II) ions via metathesis (CuII@HAP@γ-Fe2O3). Further, the
Cu(II) ions immobilized on HAP can be readily reduced to Cu(0) species to produce
the
magnetic
HAP
encapsulated
Fe2O3-supported
Cu(0)
hybrid
(Cu0@HAP@γ-Fe2O3).
In this paper, we reported a facile and novel methodology for the synthesis of
magnetic Cu0@HAP@γ-Fe2O3 hybrid catalyst and successfully demonstrated its high
catalytic activity and reusability in the synthesis of imidazo[1,2-a]pyridines under mild
condition (Scheme 2). Our careful literature survey at this stage revealed that there is
no report of employing this strategy for the preparation of catalyst for the synthesis of
these target compounds.

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Scheme 2. Synthesis of imidazo[1,2-a]pyridines using magnetic Cu0@HAP@Fe2O3
hybrid catalyst.
2. Results and discussion
Considering the characteristic of ion exchange of Ca2+ of HAP with metal cations,
the HAP can be used as an efficient template for the preparation of both
HAP-encapsulated
Fe3O4
magnetic
hybrid
(HAP@γ-Fe2O3)
[42]
and
Cu0@HAP@Fe2O3 magnetic hybrid. The schematic route for the self-assembly of
Cu0@HAP@Fe2O3 NPs is outlined in Scheme 3.

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Scheme 3. Schematic routes for self-organized fabrication of magnetic
Cu0@HAP@Fe2O3 NPs.
As shown in Scheme 3, the hybrid was prepared with a multistep process. First,

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HAP encapsulated Fe3O4 NPs was easily prepared using the cation-exchange method,
hydrolysis, and oxidation reaction. Subsequent, the resultant HAP@Fe3O4 was
calcined at 130 °C to directly form the desirable reddish-brown powder HAp@γ-Fe2O3.
Next, metathesis of a HAp@γ-Fe2O3 with an aqueous CuSO4 solution at room
temperature yielded the CuII@HAP@γ-Fe2O3. Last, reduction of CuII@HAP@γ-Fe2O3
with an aqueous solution of hydrazine yielded the embedding of the Cu(0) NPs onto
the magnetic nanohybrid (Cu0@HAP@γ-Fe2O3).
To gain insight into the structures of Cu0@HAP@γ-Fe2O3, characterization by
ICP-AES, FT-IR, XRD, FE-SEM, EDS, FE-TEM, and TGA techniques was employed.
Fig. 2 shows the FT-IR spectra of HAP (a), HAP@γ-Fe2O3 (b), and
Cu0@HAP@γ-Fe2O3 (c) in the range of 400–4000 cm−1. The peak at 464 cm-1 can be
assigned to the Fe-O band absoption (curve b and c). The adsorption peak at 1036
cm-1 was attributed to the stretching band of O–P–O. The adsorption peaks at 3412
cm-1 was ascribed to water molecule absorbed on catalysts. The absorption peak at
3566 cm-1 was due to the O–H bond of HAP.

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Fig. 2. FT-IR spectra of HAP (a), HAP@γ-Fe2O3 (b), and Cu0@HAP@γ-Fe2O3 (c).
The XRD of the HAP (a), HAP@γ-Fe2O3 (b), and Cu0@HAP@γ-Fe2O3 (c) which
shown in Fig. 3 depicted the diffraction peaks at 2θ = 25.9°, 31.8°, 32.2°, 32.9°, 34.0°,
39.8°, 46.7°, 49.5°, 50.5°, 53.1° are related to HAP (JCPDF cards, 24-0033) (Fig. 3a).
The peaks at 30.2°, 35.6°, 57.3° and 62.9° correspond to the diffraction of (220), (311),
(511) and (440) of γ-Fe2O3 (curve b) (JCPDF card 39-1346). The peaks at 43.3°, 50.4°,
74.1° corresponding to the (111), (200) and (220) planes of cubic Cu(0) NPs are
consistent with the standard reflection peaks (Fig. 3c) (JCPDF card 04-0836). This
observation identifies the presence of Cu(0) NPs onto the surface of hybrid. The
characteristic diffraction peaks of HAP have not any change after encapsulated Fe2O3
and even the immobilization of Cu(0) species (curve a, b, and c), indicating retention
of the crystalline structure of HAP.

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Fig. 3. XRD patterns of (a)HAP, (b)HAP@γ-Fe2O3, and (c)Cu0@HAP@γ-Fe2O3.
The SEM image of freshly prepared Cu0@HAP@γ-Fe2O3 shows that the hybrid
NPs have morphology with irregular sheet shapes and different sizes (Fig. 4).
Fig. 4. SEM image of Cu0@HAP@γ-Fe2O3 (bar of left image at 5 µm, bar of right
image at 10 µm)

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The existence of metalic element was investigated by EDS along with the SEM.
The EDS spectrum exhibits peaks for Fe, Cu, Ca, P and O in Cu0@HAP@γ-Fe2O3
(Fig. 5).
Fig. 5. EDS analysis of Cu0@HAP@γ-Fe2O3
The corresponding elemental maps based on the SEM images of the catalysts
confirmed the presence of Fe, Cu, P, Ca, and O, indicating these elements were in a
homogenously distribution in the hybrid catalyst. The images show in Fig. 6.
Fig. 6. SEM images and the corresponding elemental mapping images of

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Cu0@HAP@γ-Fe2O3.
TEM of Cu0@HAP@γ-Fe2O3 (Fig. 7a) revealed that the Cu(0) NPs and γ-Fe2O3
had been incorporated in the HAP successfully. Some dark spots in the TEM images
of Cu0@HAP@γ-Fe2O3 can be attributed to the presence of Cu(0) NPs and γ-Fe2O3
NPs in catalyst. The average particle size of the catalyst was measured using image
analysis, and the frequency histogram shows a size of around 40 nm (Fig. 7b).
Fig. 7. TEM images of Cu0@HAP@γ-Fe2O3 (scale of left image in 200 nm, scale of
right image in 500 nm) (a), nanoparticles diameter histogram (b).
XPS was used to investigate the valence state of the elements in catalyst. As
shown in Fig. 8, the binding energies of O1s 531.30 eV indicates the existence of P-O

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bonds in hydroxyapatite [43]. Two intense doublets peaks corresponding to Cu 2p1/2
and Cu 2p3/2 at 932.3 and 952.2eV is typically attributed to Cu0 [44]. These results
indicated that the oxidation state of copper in the catalyst was is zero valence, which
is in good agreement with XRD analysis of pure crystal of Cu NPs (Fig. 3c)
Fig. 8. XPS for Cu0@HAP@γ-Fe2O3 catalyst
The stability of the catalyst was examined by TGA. As shown in Fig. 9, no
significant weight loss was observed in the range of 25 to 800°C, which fully
demonstrated that the catalyst shows good thermal stability in high temperature.

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Fig. 9. TGA curve of Cu0@HAP@γ-Fe2O3.
In order to achieve the optimal conditions, the three-component reaction of
2-aminopyridine, 4-chlorobenzaldehyde, and phenylacetylene was selected as a
model. Typical reaction parameters including several catalysts and its loading, various
solvents, and temperature are screened. The results were shown in Table 1.
Table 1
Optimization of the reaction conditionsa
Entry
1
Catalyst (mol %)
Solvent
i-PrOH
i-PrOH
EtOH
Yield (%)c
N.R.d
25
Temp (°C)b
80
HAP@γ-Fe2O3 (10)
2
CuII@HAP@γ-Fe2O3 (10)
Cu0@HAP@γ-Fe2O3 (10)
Cu0@HAP@γ-Fe2O3 (10)
Cu0@HAP@γ-Fe2O3 (10)
Cu0@HAP@γ-Fe2O3 (10)
Cu0@HAP@γ-Fe2O3 (10)
Cu0@HAP@γ-Fe2O3 (10)
Cu0@HAP@γ-Fe2O3 (10)
Cu0@HAP@γ-Fe2O3 (10)
Cu0@HAP@γ-Fe2O3 (10)
Cu0@HAP@γ-Fe2O3 (5)
Cu0@HAP@γ-Fe2O3 (10)
Cu0@HAP@γ-Fe2O3 (15)
80
3
80
69
4
DMSO
DMF
100
100
100
100
80
22
5
36
6
Dioxane
H2O
53
7
18
8
MeCN
Toluene
t-BuOH
neat
31
9
100
80
23
10
11
12
13
14
67
80
60
i-PrOH
i-PrOH
i-PrOH
100
100
100
71
82
82

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aConditions: 2-aminopyridine (1 mmol), 4-chlorobenzaldehyde (1.2 mmol),
phenylacetylene (1.5 mmol), Cu0@HAP@γ-Fe2O3 (10 mol %), solvent (1 mL),
reaction time 12 h.
bSilicon oil bath temperature.
cIsolated yields.
dNo reaction.
At the beginning, the model reaction was investigated in the presence of various
catalysts such as HAP@γ-Fe2O3, CuII@HAP@γ-Fe2O3, and Cu0@HAP@γ-Fe2O3
separately in refluxing i-PrOH. Among them, Cu0@HAP@γ-Fe2O3 showed the higher
catalytic performance with 69% yield of product (Table 1, entry 3), and
CuII@HAP@γ-Fe2O3 showed low activity (Table 1, entry 2), while HAP@γ-Fe2O3
afford no desired product (Table 1, entry 1). These findings revealed the Cu(0) plays
crucial role in the reaction. Subsequently, we investigated the Cu loading ranging from
5 to 15 mol % in catalyst. Lowering the amount of the Cu to 5 mol% still allowed the
reaction to proceed smoothly, decreasing the desired product in 71% yield
respectively (Table 1, entry 12). However, a further increase of the catalyst to 15 mol%
resulted in no apparently improvement in yield at all (Table 1, entry 14). Next, our
attempts are focused on the screens of the efficiency of various solvents. Moderate
yields are observed when the reaction proceeded in EtOH, dioxane, t-BuOH, and
solvent-free condition (Table 1, entries 3, 6, 10, and 11). DMSO, DMF, H2O, and
toluene provide lower yields (Table 1, entries 4, 5, 7, and 9). Last, the temperature on
reaction was explored. Remarkably, the temperature had an influence on the reaction.
The highest yield of the product was obtained when the reaction was carried out in
i-PrOH at 100°C (Table 1, entry 13), and the yield of the product decreased from 82 to

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69% as the temperature was decreased from 100 to 80 °C (Table 2, entries 13, and
3).
With the optimized reaction conditions in hand, the three-component reactions of
2-aminopridine, a variety of aryl aldehydes, and phenylacetylenes or phenylpropiolic
acid were performed to explore the general effectiveness of the Cu0@HAP@γ-Fe2O3
catalyst. As shown in Table 2, in all cases, the nature of functional groups on the aryl
ring of aldehyde exerted a slight influence on the reaction. All aryl aldehydes
containing electron-donating or electron-withdrawing group proceeded efficiently. In
addition, the heteroaromatic aldehydes are also viable substrates for this type
transformation (Table 2, entries 7, and 8). These successful results clearly indicated
that the present catalytic approach is extendable to a wide scope of substrates. Then
we turned our attention toward phenylpropiolic acid which is a valuable surrogate to
phenylacetylene. The substrate of phenylpropiolic acid reacted well via
decarboxylative coupling under the optimal condition to give the corresponding
imidazo[1,2-a]pyridine
these results of the decarboxylative coupling, we attempt to use phenylglyoxylic
acid as the substrates instead aldehydes to achieve the desired product Fortunately,
s in excellent yields (Table 2, entries 18-21). Encouraged by
.
the target compound was also obtained in good yield (Table 2, entries 22, and
23). To achieve a more universal approach, we further expanded the substrates
to a phenylglyoxylic acid as an aldehyde source and an alkynyl carboxylic acid as a
phenylacetylene source. Surprisingly, the double decarboxylative coupling reaction
afforded the corresponding imidazo[1,2-a]pyridines in good yields (Table 2, entries 24,

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and 25).
Table 2
Scope of reaction of various substrates using Cu0@HAP@γ-Fe2O3 catalytic systema
Entry
Aminopyridine
(1)
Aldehyde/
phenylglyoxylic acid
(2)
Alkyne/alkynyl
carboxylic acid
(3)
Yield Product
(%)b
81
82
79
78
74
85
60
68
80
(4)
4a
4b
4c
4d
4e
4f
1
2
3
4
5
6
7
8
9
4g
4h
4i

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10
11
85
83
4j
4k
12
13
14
83
81
84
4l
4m
4n
15
16
17
18
19
20
21
75
70
76
82
84
80
80
4o
4p
4q
4a
4c
4d
4f
CO2H
CO2H
CO2H
CO2H
22c
63
4f

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23c
24c
25c
70
77
80
4a
4f
CO2H
CO2H
4a
aConditions: 2-aminopyridine (1 mmol), aldehyde/phenylglyoxylic acid (1.2 mmol),
phenylacetylene/alkynyl carboxylic acids (1.5 mmol), Cu0@HAP@γ-Fe2O3 (10 mol%),
solvent (isopropanol, 1mL), temperature 100 °C, reaction time 12h.
bIsolated yields
.
cConducted in solvent (i-PrOH/t-BuOH = 1:1, v/v, 1 mL) at 110 °C for 12h.
Aiming for the practical application, the reusability of catalyst was an indispensable
factor. In order to clarify the recycling abilities of Cu0@HAP@γ-Fe2O3, the model
reactions of 2-aminopyridine, 4-chlorobenzylaldehyde, and phenylacetylene were
chosen under the optimal conditions. After completion of reaction, the catalyst was
recollected using an external magnet from the reaction mixture, washed, dried, and
reused for next cycle. It was found that the catalyst can be reused at least three
consecutive runs with a slight decreasing its activity in the yield of 81%, 79%, and 76%
respectively.
3. Conclusion
In this study, we fabricated a novel nanocatalyst architecture of Cu0 NPs loaded
onto the magnetic hydroxyapatite-encapsulated γ-Fe2O3 (Cu0@HAp@γ-Fe2O3) hybrid
for the synthesis of imidazo[1,2-a]pyridines in excellent yields. The as-prepared

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magnetic nanocatalyst is well characterized by ICP, FTIR, SEM, EDS, TEM, XPS, and
TGA analyses. The experimental results showed that Cu0@HAp@γ-Fe2O3 not only
enhances the activity of MCR of 2-aminopyridine, aryl aldehyde, and phenylacetylene
but also leads to the decarboxylative couplings of alkynyl carboxylic acid and/or
glyoxylic acid for the synthesis of imidazo[1,2-a]pyridines. The alkynyl carboxylic acid
of this coupling reaction shows similar reactivity to that of a terminal alkyne, and the
reactivity of the glyoxylic acid is almost identical to that of an aldehyde. We also found
that both alkynyl carboxylic acids and glyoxylic acids proceed well through a double
decarboxylative coupling with a 2-aminopyridine under the optimal condition.
Moreover, the catalyst can be easily recovered from the reaction mixture by using an
external magnet and reused at least three consecutive runs with a slight loss of
catalytic activity. From a synthetic point of view, the magnetic nanocatalyst owns
salient features of simple isolation, low cost, high catalytic activity, shorter reaction
times, and tolerance of wide scope of substrates which make the process efficient and
practical.
4. Experimental section
4.1. Chemical and characterizations.
All solvents and reagents were purchased from commercial sources and were
used without prior purification. Calcium hydroxyapatite [Ca10(PO4)6(OH)2] was
synthesized according to the literature procedure [41].
Melting pointing was measured by an Electrothermal X6 microscopic digital
melting pointing apparatus. Fourier transform infrared (FT-IR) spectra were recorded

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1
13
from KBr pellets on a Bruker Equinox-55 spectrophotometer. H NMR and C NMR
spectra were recorded on a 300MHz Bruker-300 Advance spectrometer at 25℃ with
CDCl3 as solvent and TMS as internal standard. Scanning electron microscopy (SEM)
and energy disperse spectroscopy (EDS) were conducted with a Philips XL 30ESEM
instrument. Transmission electron microscopy (TEM) was obtained with Philips Tecnai
instrument. The curves obtained from thermo gravimetric analysis (TGA) were
recorded in nitrogen atmosphere using Netzsch STA449F3 in the range of 25-850℃.
High resolution mass spectrometry (HRMS) data were recorded on a MAT 95XP
(Termol) (LCMS-IT-TOF). Qualitative analysis of Cu0@HAP@γ-Fe2O3 MNPs was
performed by using X-ray powder diffraction (XRD) on a MSALXRD2 diffractometer
instrument using Cu Kα radiation in a range of Bragg’s angles (10-80°). X-ray
photoelectron spectroscopy (XPS) analysis was measured by Thermo SCIENTIFIC
ESCALAB 250Xi using a monochromatized Al Kα excitation, pass energy is 1487ev.
The element of copper content of the catalyst was detected by inductively coupled
plasma atomic emission spectrometry (ICP-AES) using PerkinElmer Optima 2000 DV.
4.2. Preparation of magnetic HAP encapsulated Fe2O3-supported Cu(0) hybrid
catalyst (Cu0@HAP@γ-Fe2O3).
4.2.1. Preparation of HAP@γ-Fe2O3 MNPs.
The HAP (1g) was added to a flask containing 100 mL of diluted water with
vigorously stirring to obtain suspension. Afterwards, a solution containing 10 mmol of
FeCl2·4H2O and 1 mmol of KNO3 in 50 mL of water was added into the mixture
solution with constantly stirring at r.t., then 10 mL of a 25wt % NH4OH solution was

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added and keeping the stirring rate for 30 mins. Finally, the suspension aged
overnight. The resultant black solid was collected with an external magnet and
washed by deionized water thoroughly until neutralized. The isolated solid was
dried under vacuum at r.t, then calcined at 130 °C for 12h to provide the
reddish-brown powder (HAP@γ-Fe2O3).
4.2.2. Preparation of Cu0@HAP@γ-Fe2O3 MNPs.
The HAP@γ-Fe2O3 (1g) are introduced into 100 mL aqueous solution of 10 wt%
CuSO4·5H2O with constantly stirring at r.t. for 6 h. The resultant solid was separated
from the solution by suction filtration and washed by deionized water thoroughly until
neutralized, then dried at r.t. under vacuum. Next, the collected powder was
suspended in ethanol and treated with 80% hydrazine hydrate until the suspension
was turned to maroon. The resulting solid was separated by external magnet and
dried under vacuum at r.t. giving the Cu0@HAP@γ-Fe2O3 MNPs. The copper content
was determined to be 2.60 mmol/g by ICP-AES.
4.3. General procedure for the synthesis of imidazo[1,2-a]pyridines catalyzed
by Cu0@HAP@γ-Fe2O3-catalyzed.
2-Aminopyridine (1.0 mmol), aldehyde or glyoxylic acid (1.2 mmol),
phenylacetylene or phenylpropiolic acid (1.5 mmol), and catalytic amount of
Cu0@HAP@γ-Fe2O3 (10 mol%) were added to the sealed tube and stirred at specific
temperature with 1 mL specific solvent (Table 2). The reaction process was monitored
by TLC. Upon the completion of reaction, the catalyst was collected with an external
magnet. The solution was extracted with ethyl acetate (15 mL×3), washed with brine

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(15mL×3), and dried over anhydrous Na2SO4 to afford the crude product which was
further purified by preparative TLC or column chromatography on neutral alumina.
Acknowledgements
We are grateful to the National Natural Science Foundation of China (no. 21372099)
for financial support.
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Highlights
1. Employment of hydroxyapatite as a template to fabrication of magnetic
Cu0@HAP@γ-Fe2O3 nanoparticles.
2. Cu0@HAP@γ-Fe2O3 not only improve the activity of conventional couplings of 2-
aminopyridine, aryl aldehyde, and alkynes but also enhance the decarboxylative
couplings of alkynyl carboxylic acid and/or glyoxylic acid for the synthesis of
imidazo[1,2-a]pyridines.
3. Both alkynyl carboxylic acids and glyoxylic acids proceed well through a double
decarboxylative coupling with a 2-aminopyridine.
4. One-pot multicomponent reaction, broad substrate scope, good functional group
toleration, mild reaction conditions, good to excellent yields, operational simplicity,
high atom-economy.