Nano Fe3O4 supported biimidazole Cu(i) complex as a retrievable catalyst for the synthesis of imidazo[1,2-a]pyridines in aqueous medium

Article abstract of DOI:10.1039/c4ra03333g

A novel magnetically recoverable nano-catalyst based on a biimidazole Cu(i) complex has been synthesized by covalent grafting of biimidazole on chloride-functionalized silica@magnetite nanoparticles, followed by metalation with CuI. The synthesized catalyst was characterized by various techniques such as CHN, NMR, FT-IR, TG/DTG, SEM, TEM, EDS, XRD, AAS, ICP-OES and VSM which revealed the superparamagnetic nature of the particles. The amount of Cu in the catalyst was measured to be 1.2 mmol g^-1 by ICP-OES and AAS. From electron microscopy (SEM and TEM) studies it can be inferred that the particles are mostly spherical in shape and have an average size of 20 nm. Elemental and thermo gravimetric analysis (CHN and TG) results indicate the loading amount of functionalized organic groups on the magnetic material was 1.4 mmol g ^-1. The prepared nanocatalyst was shown to have excellent and green catalytic activity in the synthesis of imidazo[1,2-a]pyridines in aqueous media. The catalyst can be easily recovered by applying an external magnetic field and reused for atleast 10 times without deterioration in catalytic activity.

Full text of DOI:10.1039/c4ra03333g

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Nano Fe3O4 supported biimidazole Cu(I) complex
as a retrievable catalyst for the synthesis of
imidazo[1,2-a]pyridines in aqueous medium†
Cite this: RSC Adv., 2014, 4, 23116
*
Mahmood Tajbakhsh, Maryam Farhang, Rahman Hosseinzadeh and Yaghoub Sarrafi
A novel magnetically recoverable nano-catalyst based on a biimidazole Cu(I) complex has been synthesized
by covalent grafting of biimidazole on chloride-functionalized silica@magnetite nanoparticles, followed by
metalation with CuI. The synthesized catalyst was characterized by various techniques such as CHN, NMR,
FT-IR, TG/DTG, SEM, TEM, EDS, XRD, AAS, ICP-OES and VSM which revealed the superparamagnetic nature
of the particles. The amount of Cu in the catalyst was measured to be 1.2 mmol gꢀ1 by ICP-OES and AAS.
From electron microscopy (SEM and TEM) studies it can be inferred that the particles are mostly spherical in
shape and have an average size of 20 nm. Elemental and thermo gravimetric analysis (CHN and TG) results
Received 12th April 2014
Accepted 13th May 2014
indicate the loading amount of functionalized organic groups on the magnetic material was 1.4 mmol gꢀ1
.
The prepared nanocatalyst was shown to have excellent and green catalytic activity in the synthesis of
imidazo[1,2-a]pyridines in aqueous media. The catalyst can be easily recovered by applying an external
magnetic field and reused for atleast 10 times without deterioration in catalytic activity.
DOI: 10.1039/c4ra03333g
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separation, is decreasing of catalytic activities with time, due to
the formation of dimeric species.10
1. Introduction
To overcome this disadvantage, the metal complex catalysts
are coated on Fe3O4 and providing the corresponding hetero-
geneous catalysts. A number of such supported nano magnetic
Fe3O4 have been synthesized and applied in many organic
reaction as catalyst.11,12 The use of water as a solvent in organic
transformations and transition-metal catalyzed reactions has
been gradually expanding.13 Since water is non-toxic, non-
ammable, cheap and easily available, it is attractive media for
not only the development of inexpensive and harmless chemical
reactions, but also simple purication and separation
processes. Moreover, reactions in water usually occur even more
effectively and selectively than in organic solvents and in most
cases, products can be separated easily by extraction.13
On the other hand, many imidazo[1,2-a]pyridines are
important pharmacophore and clinically applied drugs,14a for
example olprinone (1),14b zolpidem (2),14c alpidem (3),14d zoli-
midine (4),14e and minodronic acid (5)14f (Scheme 1). They also
show antivirus,15a antibacterial,15b anti-inammatory,15c antipy-
retic and analgesic activities.15d
The core–shell magnetic nanoparticles (NPs) are of special
interest since the heterogeneous nanostructures offer oppor-
tunities for developing devices and cluster assembled materials
with new functions for chemistry,1 magnetic recording, bio, and
medical applications.2 Other uses of magnetic NPs are in
magnetic biosensing,3 cell separation,4 and contrast enhance-
ment in magnetic resonance imaging.5 Among magnetite
nanoparticles, nano Fe3O4 have attracted much attention due to
unique physical properties including the high surface area,
superparamagnetism, low toxicity and their potential applica-
tions.6 In contrast to the difficulty observed in recovering and
reusing most solid catalysts, magnetic catalysts can be recycled
by external magnetic eld and reused in subsequent reactions.
Owing to these properties, recently, use of catalysts supported
Fe3O4 nanoparticles has been the subject of many researches as
shown in literature.7
2,2-Biimidazole (H2Biim) is one of the most important
derivatives of imidazole and plays a considerable role in crystal
engineering due to the coordinative versatility of metal cations.8
Some metal complexes of H2Biim have been used as efficient
homogeneous catalyst in organic transformation reactions.9
The major drawback of complexes, in addition of their tedious
To date, several synthetic approaches for the synthesis of
these important frameworks have been published.16,17 Some of
these reported methods suffer from drawbacks such as limited
to only 3-amino imidazo[1,2-a]pyridines,18 sequential synthetic
steps,19a,b long reaction times (more than a week),19c low yields
under harsh reaction conditions,20 and use of toxic solvents or
reagents.18–21
Department of Organic Chemistry, Faculty of Chemistry, Mazandaran University,
Babolsar, 47415, Iran. E-mail: Tajbaksh@umz.ac.ir; Fax: +981125242002
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra03333g
Recently, a strategic approach has been documented from a
three component coupling (TCC) reaction of 2-aminopyridines
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spectrometer. Mass spectra were recorded on a FINNIGAN-
MATT 8430 mass spectrometer operating at an ionization
potential of 20 eV. Elemental analyses for C, H and N were
performed using a Heraeus CHN–O-Rapid analyzer. Thermo
gravimetric analysis (TGA) was recorded on a Stanton Redcra
STA-780 (London, UK). Magnetic measurements were per-
formed using vibration sample magnetometry (VSM, MDK,
Model 7400) analysis. A simultaneous ICP-OES (Varian Vista-
Pro, Springvale, Australia) coupled to a V-groove nebulizer and
equipped with a charge coupled device (CCD) was applied for
determination of the trace amounts of copper.
Scheme 1 Imidazo[1,2-a]pyridine-based drugs.
2.3. General procedure
with aldehydes and alkynes.22 For this cascade reaction (TCC
Protocol), various catalytic species, such as CuCl/Cu(OTf)2,22a
CuSO4/p-TsOH,22b CuI/NaHSO4–SiO2,22c InBr3/Et3N,22d CuSO4/
glucose,22e CuI/Cu(OTf)2,22f Cu-MOFs,22g Fe3O4/NaHSO4–SiO2,22h
Cu–MnO22i and Fe3O4–SiO2,22j have been employed. Although all
of these methods are relatively good yielding reactions, but
most of them still have some disadvantages, for example long
reaction times, using toluene which is a toxic solvent and
moisture sensitivity. To the best of our knowledge, there is only
one report about TCC reaction for synthesis of imidazo[1,2-a]-
pyridines in water medium using Cu–Mn oxide as catalyst.22i
Therefore, the development of a green, highly efficient, clean
and safe method for synthesis of this valuable class of
compounds is highly desirable. In continuation of our studies
on the development of green and sustainable methods for
organic transformations,23 we report herein from three
component coupling reaction of 2-aminopyridines with alde-
hydes and phenylacetylene by using biimidazole Cu(I) complex
immobilized onto the surface of Fe3O4 NPs as efficient and
reusable nanomagnetic catalyst for synthesis of imidazo[1,2-a]
pyridines. The catalyst could be conveniently separated by an
external magnet from the reaction mixture and reused without
signicant loss of activity.
2.3.1. Preparation of 2,20-biimidazole (Biim) I. To a mixture
of ammonium acetate (0.46 mol, 35.4 g) and H2O (6.5 mL) was
added dropwise glyoxal (0.173 mol, 10.0 g) solution (20%) at
40 ꢁC over a period of 3 h then the mixture was allowed to stir for
an additional 5 h at room temperature. The reaction mixture
was ltered and then washed with distilled water (3 ꢂ 20 mL)
and acetone (3 ꢂ 20 mL) to give a crude product. The brown
solid was dissolved in 130 mL of hot ethylene glycol, and
decolorized with activated carbon. Aer hot ltration, the
product precipitated instantly to provide 3.2 g (42%) of white
crystalline I24 (refer to ESI†).
2.3.2. Preparation
of
3-chloropropyl-functionalized
magnetic nanoparticles (MNP@CPS). A mixture of FeCl3$6H2O
(2.35 g, 8.7 mmol) and FeCl2$4H2O (0.86 g, 4.3 mmol) were
dissolved in 40 mL deionized water. The resultant solution was
le to be stirred for 30 min at 80 ꢁC. Then 5 mL of NH4OH
solution was added with vigorous stirring to produce a black
solid and the reaction was continued for another 30 min. The
black magnetite nanoparticles were isolated by magnetic
decantation, washed several times with deionized water and
ꢁ
then dried at 80 C for 10 h.0.5 g of dried Fe3O4 nanoparticles
were suspended in a mixture of 50 mL ethanol and 5 mL of
NH3$H2O (25%). Then, 0.2 mL of tetraethoxysilane (TEOS) was
added to solution and the mixture was ultrasonicated for 2 h.
Aerward silica coated MNPs (MNP@SiO2) was magnetically
2. Experimental
2.1. Reagents and materials
ꢁ
separated, washed three times with ethanol and dried at 80 C
for 10 h.25 MNP@SiO2 (100 mg) was dispersed in 15 mL of dry
toluene by ultrasonication under nitrogen atmosphere. Next, 3-
chloropropyltriethoxysilane (0.2 mL, 0.8 mmL) was dropwise
added into the MNP@SiO2 solution under reux condition for
48 h.26 The CPS functionalized magnetic nanoparticles
Chemical materials were purchased from Merck and Aldrich
Chemical Companies in high purity. All the solvents were
distilled, dried and puried by standard procedures.
2.2. Instrumentation
(MNP@CPS) was washed with 30 mL of toluene and ethanol
ꢁ
Melting points were measured on an Electrothermal 9100 before being dried at 60 C for 12 h.
apparatus. The samples were analyzed using FT-IR spectroscopy
2.3.3. Preparation of MNP@BiimCu catalyst. Sodium
(Bruker Vector in KBr matrix). The X-ray powder diffraction hydride 2.4 g (0.06 mol) was suspended in 15 mL of dry DMF
(XRD) of the catalyst was carried out on a Philips PW 1830 X-ray under inert atmosphere. To this suspension, 6.7 g of biimida-
˚
diffractometer with CuKa source (l ¼ 1.5418 A) in a range of zole (0.05 mol) was added and stirred for 30 more minutes at
Bragg's angle (5–80ꢁ) at room temperature. Scanning electron room temperature. The MNP@CPS (1.8 g) was then added to
microscope (SEM) pictures-EDS analyses were taken using this suspension and mixture was stirred at 65 ꢁC for 2 days. The
VEGA//TESCAN KYKY-EM3200 microscope (acceleration voltage dark brown precipitate formed was ltered, washed with water
26 kV). Transmission electron microscopy (TEM) experiments and methanol and then soxhlet extraction by hot methanol to
1
ꢁ
were conducted on a Philips EM 208 electron microscope. H, remove unreacted species and dried under vacuum at 70 C. A
13C NMR spectra were recorded on a BRUKER DRX-400 AVANCE mixture of MNP@Biim (2 g), copper iodide (500 mg) and dry
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acetonitrile (30 mL) was stirred at room temperature under spectra presented in Fig. 1b, the absorption peak at 634 cmꢀ1
nitrogen atmosphere for 48 h. The resulting solid was then belonged to the stretching vibration mode of Fe–O bonds in
separated by an external magnet and washed with acetonitrile MNP@SiO2, the absorption peak presented at 1062 cmꢀ1 most
and acetone for several times. The residue was dried for 24 h in probably due to stretching vibration of framework and Si–O–Si
air to afford the Nano Fe3O4 supported biimidazole Cu(I) groups. MNP@CPS (Fig. 1c) exhibits basic characteristic peak at
complex (MNP@BiimCu).
651 cmꢀ1, which attributed to the presence of Fe–O stretching
2.3.4. General procedure for the synthesis of imidazo[1,2- vibration, the band at 1068 cmꢀ1 is assigned to the asymmetric
a]pyridine derivatives. In a 10 mL round bottomed ask, a vibrations of (Si–O–Si), the band at 3440 cmꢀ1 is assigned to the
mixture of 2-aminopyridine (1 mmol) and benzaldehyde symmetric and asymmetric stretching vibration of the OH
(1 mmol) was stirred. Aer 20 min, phenylacetylene (1.1 mmol), groups. The observed C–H stretching band 2955 cmꢀ1 in the
MNP@BimCu (0.01 g, 1.3 mol%), 0.005 g CTAB and 2 mL H2O coated magnetic nanoparticles reveal the presence of CPTES on
were added to the above mixture and the resulting mixture was the surface of the magnetic nanoparticles. Fig. 1d shows the FT-
allowed to stir under reux conditions for specied period of IR spectrum of free ligand of biimidazole, the regions of the
time. The progress of the reaction was monitored by thin-layer spectrum corresponding to stretching vibrations C]N and C–N
chromatography (TLC). Aer completion of the reaction the exhibit at 1681 cmꢀ1 and 1546 cmꢀ1 respectively, while in the
catalyst was magnetically separated. The residue was extracted MNP@BiimCu (Fig. 1e), these bands shi to lower frequencies
with EtOAc (2 ꢂ 10 mL) followed by drying with anhydrous and appear at 1644 and 1542 cmꢀ1 due to the coordination of
Na2SO4. Aer evaporation of the solvent, the residue was puri- the nitrogen with the copper. Also the presence of vibration
ed by ash chromatography to afford the desired product. The bands at 630, 1029 and 3450 cmꢀ1, which are due to Fe–O, Si–O–
products were characterized with IR, 1HNMR and 13CNMR Si, and OH respectively, demonstrates the existence of Fe3O4
spectroscopies.
and SiO2 components in MNP@BiimCu.
3-Benzyl-2-(4-(triuoromethyl)phenyl)imidazo[1,2-a]pyridine
(Table 2, entry 7). White solid; mp 138–141 ꢁC. 1H NMR (400
MHz, CDCl3) d ¼ 7.89 (d, J ¼ 8.2 Hz, 2H), 7.68–7.78 (m, 4H),
7.24–7.36 (m, 3H), 7.19 (t, J ¼ 8.0 Hz, 1H), 7.15 (d, J ¼ 8.0 Hz,
2H), 6.76 (t, J ¼ 7.2 Hz, 1H), 4.49 (s, 2H). 13C NMR (100 MHz,
CDCl3)
d
¼
145.6(C2), 143.5(C4), 137.6(C10), 136.2(C17),
129.1(C23), 128.3(C18, 22), 127.6(C13), 127.2(C11, 15),
125.7(C19, 21), 125.8(C5), 125.5(C20), 124.8(C12, 14), 124.2(C6),
118.8(C8), 116.7(C9), 112.6(C7), 29.8(C16) (refer to ESI†).
3-Benzyl-2-(3-bromophenyl)h-imidazo[1,2-a]pyridine (Table 2,
entry 11). White solid; mp ¼ 154–156 C. H NMR (400 MHz,
CDCl3) d ¼ 8.03 (t, J ¼ 2 Hz, 1H), 7.67–7.75 (m, 3H), 7.49–7.51
(m, 1H), 7.30–7.34 (m, 4H), 7.21–7.26 (m, 1H), 7.15 (d, J ¼ 6.80
Hz, 2H), 6.76 (td, J ¼ 6.8 Hz, J ¼ 6.80 Hz, J ¼ 1.2 Hz, 1H), 4.51 (s,
2H). 13C NMR (100 MHz, CDCl3) d ¼ 144.7(C2), 144.2(C4),
136.4(C17), 136.3(C10), 134.6 (C18, 22), 129.8(C11), 129.4(C14),
128.1(C19, 21), 127.9(C15), 127.3(C13), 126.9(C5), 126.7(C20),
124.2(C6), 123.4(C8), 118.1(C12), 117.6(C9), 112.3(C7), 29.8(C16)
(refer to ESI†).
1
ꢁ
3. Results and discussion
Fig. 1 FTIR spectra of MNP s (a), MNP@SiO2 (b), MNP@CPS (c), Bim (d),
At rst, magnetite nanoparticles were synthesized by a typical
chemical co-precipitation of FeCl3 and FeCl2 in an ammonia
solution. To improve the reliable chemical stability and
biocompatibility of magnetite NPs, their surface was success-
fully coated by silica. Next, MNP@SiO2 was functionalized with
3-(chloropropyl)triethoxysilane (CPTES), Aerward, biimida-
zole, was immobilized on MNP@CPS, then CuI was anchored
on the functionalized beads to obtain nal heterogonous
catalyst.
MNP@BiimCu (e).
The FT-IR spectra of MNPs (a), MNP@SiO2 (b), MNP@CPS
(c), Bim (d) and MNP@BiimCu (e) were shown in Fig. 1. Pure
magnetic nanoparticles demonstrate peaks at 624 cmꢀ1 corre-
sponds to Fe–O stretching and 3450 cmꢀ1 corresponding to
broad OH groups on magnetite surface (Fig. 1a). From the IR Fig. 2 XRD patterns of MNPs (a) and MNP @BiimCu (b).
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Fig. 2 shows the X-ray diffraction pattern of MNPs (Fig. 2a)
RSC Advances
Table
MNP@BiimCu
1
Elemental analysis for MNP@SiO2, MNP@CPS and
and MNP@BiimCu (Fig. 2b). The patterns at 2q values 30.1ꢁ,
35.4ꢁ, 43.1ꢁ, 53.4ꢁ, 57ꢁ and 62.6ꢁ can be assigned to (220), (311),
(400), (422), (511) and (440) crystal planes in Fe3O4 cubic lattice
which agrees with the standard Fe3O4 (JCPDS 19-0629), were
also observed for MNP@BiimCu (Fig. 2b). This revealed that the
surface modication of the Fe3O4 nanoparticles do not lead to
their phase change. However, the weaker peak intensities in
pattern Fig. 2b compared to Fig. 2a can be attributed to the
shielding effect of shell on magnetite. The sharp peaks of
copper complex were observed in the XRD pattern of
MNP@BiimCu (Fig. 2b). The peaks conrmed the complexation
of copper iodide with biimidazole on MNP@Biim surface.
The TGA analyses for MNP@SiO2 (Fig. 3a) and
MNP@BiimCu (Fig. 3b) are shown in Fig. 3. For MNP@SiO2, the
weight loss around 200 ꢁC is attributed exclusively to the
physically adsorbed water molecules and surface hydroxyl
groups on magnetite surface.27 For MNP@BiimCu, three stage
weight losses are observed. The weight loss within 100–200 ꢁC is
due to physically adsorbed moisture whereas the major weight
Samples
C%
0.10
5.85
14.59
H%
N%
Cu%
MNP@SiO2
MNP@CPS
MNP@BiimCu
0.21
1.50
2.17
—
—
8.21
—
—
7.3a, 7.97b,7.92b,c
a
b
The amount of copper was determined using AAS. The amount of
c
copper was determined using ICP. Recycled aer ten times.
loss occurs (30.17%, 1.4 mmol gꢀ1) at 250–600 C which attri-
ꢁ
butes to the decomposition of biimidazolylpropyl groups graf-
ted to the MNP@SiO2 surface. The third weight loss is quite
large and could be assigned to the sublimation of iodine
(melting point of CuI: 602 ꢁC).28 These results prove not only the
attachment of biimidazole moiety onto the surface of
MNP@SiO2 but also show the Cu content of magnetic nano-
catalysts (30%).
Fig. 4 EDS pattern of MNP@BiimCu.
Elemental analysis for MNP@SiO2, MNP@CPS and
MNP@BiimCu were carried out and the data were tabulated in
Table 1 which is shown to be in good agreement with the result
obtained from TGA (Fig. 3). The results displayed that contents
of C, H and N for MNP@BiimCu are 14.59, 2.17 and 8.21,
respectively. The content of nitrogen shows that chloro groups
in the MNP@CPS were effectively displaced by biimidazole. The
content ratio of C/N (1.77) is very near to theoretical calculation
(1.92). Amount of metal was determined by Inductively Coupled
Plasma (ICP) and atomic absorption spectrophotometer (AAS).
According to the AAS measurement, the Cu content in the
magnetic nanocatalyst is about 1.16 mmol gꢀ1. The Cu loading
of catalyst was conrmed by ICP and was found to be 1.26 mmol
gꢀ1, consistent with the TGA result (Fig. 3) that indicating the
Fig. 5 SEM images of synthesized MNP@BiimCu (left), used (right).
deposition of CuI species on MNP@Biim nanosphere support.
Further to support the above observation, the EDX analysis of
Fig. 3 The TGA thermogram of (a) MNP@SiO2 (b) MNP@BiimCu 10 ꢁC Fig.
6
Transmission electron microscopy (TEM) image of
minꢀ1 under N2 atmosphere.
MNP@BiimCu.
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magnetic nanocatalyst indicates that CuI was chelated on the
surface of MNP@Biim nanoparticles (Fig. 4).
Scanning electron microscopy (SEM) analysis (Fig. 5) of the
nano-magnetic catalyst showed uniform-sized particles with
spherical morphology with an average size range of 20–25 nm.
Fig. 6 displays HRTEM image of MNP@BiimCu nanoparticles.
As may be seen in the TEM image, the size of particles is around
15 nm and the particles are spherical in shape with some
agglomeration, which is obvious because of the magnetic
nature of the particles.
The magnetic hysteresis measurements of both MNP@SiO2
and MNP@BiimCu nanocrystallites obtained by VSM at 300 K,
with the eld sweeping from ꢀ8000 to +8000 Oe. As shown in
Fig. 7 the magnetic saturation values for the MNP@SiO2 and
biimidazole
Cu(I)
complex
coated
on
MNP@SiO2
(MNP@BiimCu) reached to be 57.2 emu gꢀ1 and 47.4 emu gꢀ1
respectively. The hysteresis loop for the particles was completely
reversible, showing that the nanoparticles exhibit super-
paramagnetic characteristics and the particles did not show any
coercivity. Lower magnetic saturation of later nanoparticles
suggests that the successful coating of biimidazole Cu(I)
complex on the MNP@SiO2 nanoparticles. The relatively high
saturation magnetization of synthesized nanoparticles is suffi-
cient for magnetic separation with a conventional magnet
(Fig. 7c). The reversibility in the graph conrms that no aggre-
gation imposes to the nanoparticles in the magnetic elds.
The catalytic activity of MNP@BiimCu was investigated in
synthesis of imidazopyridines via the one-pot reaction of 2-
aminopyridines, aldehydes and phenylacetylene. In order to
optimize the reaction conditions, we examined the reaction of
2-aminopyridine (1 mmol) with of p-chloro benzaldehyde
(1 mmol) and phenylacetylene (1.1 mmol) at 100 ꢁC under
different conditions as a model reaction (Scheme 2) and the
results are presented in Table 2.
Fig. 7 VSM curve of MNP@SiO2 (a) vs. MNP@BiimCu (b) and (c)
MNP@BiimCu ability to effective recovery at the end of reaction.
Scheme 2 TCC reaction of 2-aminopyridine, p-chloro benzaldehyde,
and phenylacetylene.
Table 2 Screening of reaction conditionsa,c
Entry
Catalyst (g)
Surfactant
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
—
—
—
H2O
H2O
Toluene
MeCN
EtOH
—
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
24
7
24
24
24
7
5
7
5
5
N.R
75
90
45
30
70
90
75
90
70
90
90
N.R
Trace
Trace
20
MNP@BiimCu
MNP@BiimCu
MNP@BiimCu
MNP@BiimCu
MNP@BiimCu
MNP@BiimCu
MNP@BiimCu
MNP@BiimCu (0.02)
MNP@BiimCu(0.005)
MNP@BiimCud
MNP@BiimCue
—
CTAB
SDS
9
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
10
11
12
13
14
15
16
17
5
5
24
24
24
24
24
Fe3O4
CuI
CuI(0.03)
Biim/CuI
60
a
Reaction conditions: p-chloro-benzaldehyde (1 mmol), 2-aminopyridine (1 mmol), catalyst (0.01 g), phenylacetylene (1.1 mmol), surfactant (5 mg)
and solvent (2 mL), reux. b Isolated yield. c The ratio for the acetylene versus aldehyde or amine (1 mmol: 75%, 1.1 mmol 95%, 1.2 mmol 95%).
d
Addition p-TSA (1 mmol) or. e NEt3 (1 mmol) as additive.
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Table 3 Synthesis of imidazo[1,2-a]pyridinesa
Entry
1
Product
Time (h)
5
Yieldb (%)
90
M. P. (ꢁC)Ref.
146 (ref. 22a)
TONc/TOFd
75/0.25
2
5
92
119–120 (ref. 22a)
77/0.25
3
4
5
5.7
5
85
90
78
130–132 (ref. 21b)
160–162 (ref. 22b)
160 (ref. 22h)
70/0.2
75/0.25
65/0.18
6
6
7
8
9
5.5
5
95
90
95
80
135–136 (ref. 22b)
138–141 (ref. 22b)
82 (ref. 22c)
79/0.24
75/0.25
79/0.22
67/0.15
6
7.5
Semisolid22c
10
11
12
5.5
6
87
82
85
116 (ref. 21b)
72/0.23
68/0.18
71/0.21
154–156 (ref. 22h)
141–142 (ref. 22a)
5.4
13
7.25
78
163–165 (ref. 22d)
65/0.14
14
15
7.2
6
90
65
99–101 (ref. 21b)
75/0.17
54/0.15
Oil22a
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Table 3 (Contd.)
Entry
16
Product
Time (h)
Yieldb (%)
M. P. (ꢁC)Ref.
TONc/TOFd
63/0.17
6
76
82
82–83 (ref. 22e)
207–209 (ref. 22b)
17
8.5
68/0.13
18
8
78
126–127 (ref. 22a)
65/0.13
a
b
Reaction conditions: aldehyde : amine : phenylacetylene (1 : 1 : 1.1), MNP@BiimCu (0.01 g), CTAB(5 mg), H2O (2.0 mL), reux. Isolated yield.
TON: turn over number (mol of product/mol of catalyst). d TOF: turn over frequency [mol of product/(mol of catalyst ꢂ reaction time)].
c
It can be seem that when the model reaction was carried out tolerated well in this reaction. Appreciable lower yields were
at 100 ꢁC in aqueous medium in the absence of any catalyst, no obtained for aliphatic aldehydes which might be due to the low
desired product was formed aer 24 h (Table 2, entry 1), but in boiling-point aliphatic aldehydes22b (entries 15 and 16). Reac-
the presence of 0.01 g MNP@BiimCu aer 7 h a good yield of tion of 5-methyl-2-aminopyridine and 3-methyl-2-amino
the expected imidazo[1,2-a]pyridine (1) was obtained showing pyrimidine with benzaldehyde afforded corresponding
the role of catalyst in this reaction (Table 2, entry 2). Screening imidazo[1,2-a]pyridines with 82 and 78% yields, respectively
the solvent in this reaction showed that under aqueous media, (entries 17 and 18). However, it was observed that existing of the
highest yield of the product is obtained compared with other dimethylamino, or nitro substituent groups on the aromatic
solvents (entries 2–5). When the reaction was performed under rings of the aldehydes interferes in the reaction which led to no
solvent-free condition, higher yield of the product was obtained product. This is likely due to deactivation by the coordination
in shorter reaction time compared with reaction in ethanol, NMe2 and NO2 groups with catalyst.22b
toluene and acetonitrile (Table 2, entry 6). In order to increase
Besides aer completion of the reaction, catalyst was easily
the solubility of the substrates in aqueous media, anionic (SDS) removed by an external magnet as shown in Fig. 7c and recov-
and cationic (CTAB) surfactants were used (Table 2, entries 7 ered simply by washing with organic solvent (EtOAc), and
and 8) and reaction rate was increased in the presence of CTAB vacuum drying, and then reused for at least 10 times without
(entry 7). Further increasing the amount of catalyst does not observation signicant decrease in activity. For example the
improve the yield of the product any further, whereas reaction of 2-aminopyridine, p-chlorobenzaldehyde and phe-
decreasing the amount of catalyst leads to decrease in the nylacetylene gave corresponding of imidazo[1,2-a]pyridine in
product yield (entries 9 and 10). Addition of additives such as p- sequenced ten times (Fig. 8). In addition, the SEM image of
TSA and Et3N did not show any signicant effect in the reaction
rate (entries 11 and 12). To show the impact of the supported
catalyst (MNP@BiimCu), the model reaction was studied in the
presence of CTAB (entry 13), Fe3O4 (entry 14), different amount
of CuI (entries 15 and 16) and biimidazole/CuI complex (entry
17) in aqueous media, which did not give any signicant effect
in reaction yield. The result in Table 2, clearly show that treating
2-aminopyridine (1 mmol) and p-chloro-benzaldehyde (1 mmol)
with phenylacetylene (1.1 mmol) using of MNP@BiimCu (0.01
g) and CTAB (5 mg) in water (2 mL) at 100 ꢁC, an excellent yield
of the desired imidazo[1,2-a]pyridine can be achieved (entry 7).
In order to explore the generality and applicability of this
catalyst a variety of aliphatic and aromatic aldehydes reacted
with 2-aminopyridine and phenylacetylene under the optimal
Fig. 8 Reusability of the MNP@BiimCu for the reaction of 2-amino-
reaction conditions and results are presented in Table 3. As it is
clear from this table, aromatic and hetero aromatic aldehydes
pyridine, p-chlorobenzaldehyde and phenylacetylene under opti-
mized conditions at 5 h.
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Table 4 Evaluation of the introduced methodology in comparison with some of other reported methodsa
Entry
Catalyst (mol%)
Reaction conditions
Toluene, 120 ꢁ
Yield (%)/Time (h)
Ref.
1
2
3
4
5
CuCl(5)/Cu(OTf)2(5)
InBr3(10)/Et3N
Cu-MOFs (10)
Cu(SO4)(10)/p-TSA(10)
Cu(SO4)(10)/D-glucose
Cu–Mn(10)
C
92/16
82/12
97/30
60/18
79/10
85/4
22a
22d
22g
22b
22e
22i
Dry toluene, reux,
Toluene, 120 ꢁC, N2
Toluene, reux
EtOH, 100 ꢁC
6
Water, 100 ꢁ
C
7
8
9
10
CuI(5)–NaHSO4$SiO2
Fe3O4(10)/KHSO4$SiO2
Fe3O4–SiO2(5)/K2CO3(5)
MNP@BiimCu (1.2)
Toluene, reux, N2
91/12
89/24
86/3
22c
22h
22j
Dry toluene, 110 ꢁ
C
EtOH, reux
b
Water, 100 ꢁ
C
92/5
—
TCC reaction between 2-aminopyridine, benzaldehyde and phenylacetylene. b This work.
a
catalyst aer recycling did not show a signicant change in the
morphology (Fig. 5 right), which clearly indicated that the
References
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Acknowledgements
We are grateful to Mazandaran University for support of our
research.
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