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

Abstract

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.

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1. Introduction

The core–shell magnetic nanoparticles (NPs) are of special interest since the heterogeneous nanostructures offer opportunities 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 enhancement 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 applications.⁶ In contrast to the difficulty observed in recovering and reusing most solid catalysts, magnetic catalysts can be recycled by external magnetic field 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 separation, is decreasing of catalytic activities with time, due to the formation of dimeric species.¹⁰

To overcome this disadvantage, the metal complex catalysts are coated on Fe₃O₄ and providing the corresponding heterogeneous 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-flammable, cheap and easily available, it is attractive media for not only the development of inexpensive and harmless chemical reactions, but also simple purification 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 zolimidine (4),^14e and minodronic acid (5)^14f (Scheme 1). They also show antivirus,^15a antibacterial,^15b anti-inflammatory,^15c antipyretic and analgesic activities.^15d

Scheme 1 Imidazo[1,2-a]pyridine-based drugs.

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

Recently, a strategic approach has been documented from a three component coupling (TCC) reaction of 2-aminopyridines 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 aldehydes 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 significant loss of activity.

2. Experimental

2.1. Reagents and materials

Chemical materials were purchased from Merck and Aldrich Chemical Companies in high purity. All the solvents were distilled, dried and purified by standard procedures.

2.2. Instrumentation

Melting points were measured on an Electrothermal 9100 apparatus. The samples were analyzed using FT-IR spectroscopy (Bruker Vector in KBr matrix). The X-ray powder diffraction (XRD) of the catalyst was carried out on a Philips PW 1830 X-ray diffractometer with CuKα source (λ = 1.5418 Å) in a range of Bragg's angle (5–80°) at room temperature. Scanning electron microscope (SEM) pictures-EDS analyses were taken using VEGA//TESCAN KYKY-EM3200 microscope (acceleration voltage 26 kV). Transmission electron microscopy (TEM) experiments were conducted on a Philips EM 208 electron microscope. ¹H, ¹³C NMR spectra were recorded on a BRUKER DRX-400 AVANCE 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 Redcraft STA-780 (London, UK). Magnetic measurements were performed 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.

2.3. General procedure

2.3.1. Preparation of 2,2′-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 filtered and then washed with distilled water (3 × 20 mL) and acetone (3 × 20 mL) to give a crude product. The brown solid was dissolved in 130 mL of hot ethylene glycol, and decolorized with activated carbon. After hot filtration, 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 left 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. Afterward silica coated MNPs (MNP@SiO₂) was magnetically 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 reflux condition for 48 h.²⁶ The CPS functionalized magnetic nanoparticles (MNP@CPS) was washed with 30 mL of toluene and ethanol before being dried at 60 °C for 12 h.

2.3.3. Preparation of MNP@BiimCu catalyst. Sodium hydride 2.4 g (0.06 mol) was suspended in 15 mL of dry DMF under inert atmosphere. To this suspension, 6.7 g of biimidazole (0.05 mol) was added and stirred for 30 more minutes at room temperature. The MNP@CPS (1.8 g) was then added to this suspension and mixture was stirred at 65 °C for 2 days. The dark brown precipitate formed was filtered, washed with water and methanol and then soxhlet extraction by hot methanol to remove unreacted species and dried under vacuum at 70 °C. A mixture of MNP@Biim (2 g), copper iodide (500 mg) and dry acetonitrile (30 mL) was stirred at room temperature under nitrogen atmosphere for 48 h. The resulting solid was then separated by an external magnet and washed with acetonitrile and acetone for several times. The residue was dried for 24 h in air to afford the Nano Fe₃O₄ supported biimidazole Cu(I) complex (MNP@BiimCu).

2.3.4. General procedure for the synthesis of imidazo[1,2-a]pyridine derivatives. In a 10 mL round bottomed flask, a mixture of 2-aminopyridine (1 mmol) and benzaldehyde (1 mmol) was stirred. After 20 min, phenylacetylene (1.1 mmol), MNP@BimCu (0.01 g, 1.3 mol%), 0.005 g CTAB and 2 mL H₂O were added to the above mixture and the resulting mixture was allowed to stir under reflux conditions for specified period of time. The progress of the reaction was monitored by thin-layer chromatography (TLC). After completion of the reaction the catalyst was magnetically separated. The residue was extracted with EtOAc (2 × 10 mL) followed by drying with anhydrous Na₂SO₄. After evaporation of the solvent, the residue was purified by flash chromatography to afford the desired product. The products were characterized with IR, ¹HNMR and ¹³CNMR spectroscopies.
3-Benzyl-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine (Table 2, entry 7). White solid; mp 138–141 °C. ¹H NMR (400 MHz, CDCl₃) δ = 7.89 (d, J = 8.2 Hz, 2H), 7.68–7.78 (m, 4H), 7.24–7.36 (m, 3H), 7.19 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 6.76 (t, J = 7.2 Hz, 1H), 4.49 (s, 2H). ¹³C NMR (100 MHz, CDCl₃) δ = 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 = 154–156 °C. ¹H NMR (400 MHz, CDCl₃) δ = 8.03 (t, J = 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 = 6.80 Hz, 2H), 6.76 (td, J = 6.8 Hz, J = 6.80 Hz, J = 1.2 Hz, 1H), 4.51 (s, 2H). ¹³C NMR (100 MHz, CDCl₃) δ = 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†).

3. Results and discussion

At first, 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 successfully coated by silica. Next, MNP@SiO₂ was functionalized with 3-(chloropropyl)triethoxysilane (CPTES), Afterward, biimidazole, was immobilized on MNP@CPS, then CuI was anchored on the functionalized beads to obtain final heterogonous catalyst.

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 cm⁻¹ corresponds to Fe–O stretching and 3450 cm⁻¹ corresponding to broad OH groups on magnetite surface (Fig. 1a). From the IR spectra presented in Fig. 1b, the absorption peak at 634 cm⁻¹ belonged to the stretching vibration mode of Fe–O bonds in MNP@SiO₂, the absorption peak presented at 1062 cm⁻¹ most probably due to stretching vibration of framework and Si–O–Si groups. MNP@CPS (Fig. 1c) exhibits basic characteristic peak at 651 cm⁻¹, which attributed to the presence of Fe–O stretching vibration, the band at 1068 cm⁻¹ is assigned to the asymmetric vibrations of (Si–O–Si), the band at 3440 cm⁻¹ is assigned to the symmetric and asymmetric stretching vibration of the OH groups. The observed C–H stretching band 2955 cm⁻¹ in the coated magnetic nanoparticles reveal the presence of CPTES on the surface of the magnetic nanoparticles. Fig. 1d shows the FT-IR spectrum of free ligand of biimidazole, the regions of the spectrum corresponding to stretching vibrations C=N and C–N exhibit at 1681 cm⁻¹ and 1546 cm⁻¹ respectively, while in the MNP@BiimCu (Fig. 1e), these bands shift to lower frequencies and appear at 1644 and 1542 cm⁻¹ due to the coordination of the nitrogen with the copper. Also the presence of vibration bands at 630, 1029 and 3450 cm⁻¹, which are due to Fe–O, Si–O–Si, and OH respectively, demonstrates the existence of Fe₃O₄ and SiO₂ components in MNP@BiimCu.

Fig. 1 FTIR spectra of MNP s (a), MNP@SiO₂ (b), MNP@CPS (c), Bim (d), MNP@BiimCu (e).

Fig. 2 shows the X-ray diffraction pattern of MNPs (Fig. 2a) and MNP@BiimCu (Fig. 2b). The patterns at 2θ values 30.1°, 35.4°, 43.1°, 53.4°, 57° and 62.6° 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 modification 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 confirmed the complexation of copper iodide with biimidazole on MNP@Biim surface.

Fig. 2 XRD patterns of MNPs (a) and MNP @BiimCu (b).

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 loss occurs (30.17%, 1.4 mmol g⁻¹) at 250–600 °C which attributes to the decomposition of biimidazolylpropyl groups grafted 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 nanocatalysts (30%).

Fig. 3 The TGA thermogram of (a) MNP@SiO₂ (b) MNP@BiimCu 10 °C min⁻¹ under N₂ atmosphere.

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 g⁻¹. The Cu loading of catalyst was confirmed by ICP and was found to be 1.26 mmol g⁻¹, consistent with the TGA result (Fig. 3) that indicating the deposition of CuI species on MNP@Biim nanosphere support. Further to support the above observation, the EDX analysis of magnetic nanocatalyst indicates that CuI was chelated on the surface of MNP@Biim nanoparticles (Fig. 4).

Table 1 Elemental analysis for MNP@SiO₂, MNP@CPS and MNP@BiimCu

Samples	C%	H%	N%	Cu%
a The amount of copper was determined using AAS.b The amount of copper was determined using ICP.c Recycled after ten times.
MNP@SiO2	0.10	0.21	—	—
MNP@CPS	5.85	1.50	—	—
MNP@BiimCu	14.59	2.17	8.21	7.3^a, 7.97^b,7.92^b^,^c

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Fig. 4 EDS pattern of MNP@BiimCu.

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.

Fig. 5 SEM images of synthesized MNP@BiimCu (left), used (right).

Fig. 6 Transmission electron microscopy (TEM) image of MNP@BiimCu.

The magnetic hysteresis measurements of both MNP@SiO₂ and MNP@BiimCu nanocrystallites obtained by VSM at 300 K, with the field 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 g⁻¹ and 47.4 emu g⁻¹ respectively. The hysteresis loop for the particles was completely reversible, showing that the nanoparticles exhibit superparamagnetic 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 sufficient for magnetic separation with a conventional magnet (Fig. 7c). The reversibility in the graph confirms that no aggregation imposes to the nanoparticles in the magnetic fields.

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.

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.

Scheme 2 TCC reaction of 2-aminopyridine, p-chloro benzaldehyde, and phenylacetylene.

Table 2 Screening of reaction conditions^a,c

Entry	Catalyst (g)	Surfactant	Solvent	Time (h)	Yield^b (%)
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), reflux.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.
1	—	—	H2O	24	N.R
2	MNP@BiimCu	—	H2O	7	75
3	MNP@BiimCu		Toluene	24	90
4	MNP@BiimCu		MeCN	24	45
5	MNP@BiimCu		EtOH	24	30
6	MNP@BiimCu		—	7	70
7	MNP@BiimCu	CTAB	H2O	5	90
8	MNP@BiimCu	SDS	H2O	7	75
9	MNP@BiimCu (0.02)	CTAB	H2O	5	90
10	MNP@BiimCu(0.005)	CTAB	H2O	5	70
11	MNP@BiimCu^d	CTAB	H2O	5	90
12	MNP@BiimCu^e	CTAB	H2O	5	90
13	—	CTAB	H2O	24	N.R
14	Fe3O4	CTAB	H2O	24	Trace
15	CuI	CTAB	H2O	24	Trace
16	CuI(0.03)	CTAB	H2O	24	20
17	Biim/CuI	CTAB	H2O	24	60

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It can be seem that when the model reaction was carried out at 100 °C in aqueous medium in the absence of any catalyst, no desired product was formed after 24 h (Table 2, entry 1), but in the presence of 0.01 g MNP@BiimCu after 7 h a good yield of the expected imidazo[1,2-a]pyridine (1) was obtained showing the role of catalyst in this reaction (Table 2, entry 2). Screening the solvent in this reaction showed that under aqueous media, highest yield of the product is obtained compared with other solvents (entries 2–5). When the reaction was performed under solvent-free condition, higher yield of the product was obtained in shorter reaction time compared with reaction in ethanol, toluene and acetonitrile (Table 2, entry 6). In order to increase the solubility of the substrates in aqueous media, anionic (SDS) and cationic (CTAB) surfactants were used (Table 2, entries 7 and 8) and reaction rate was increased in the presence of CTAB (entry 7). Further increasing the amount of catalyst does not improve the yield of the product any further, whereas decreasing the amount of catalyst leads to decrease in the product yield (entries 9 and 10). Addition of additives such as p-TSA and Et₃N did not show any significant 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 significant 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 reaction conditions and results are presented in Table 3. As it is clear from this table, aromatic and hetero aromatic aldehydes tolerated well in this reaction. Appreciable lower yields were obtained for aliphatic aldehydes which might be due to the low boiling-point aliphatic aldehydes^22b (entries 15 and 16). Reaction of 5-methyl-2-aminopyridine and 3-methyl-2-amino pyrimidine with benzaldehyde afforded corresponding imidazo[1,2-a]pyridines with 82 and 78% yields, respectively (entries 17 and 18). However, it was observed that existing of the dimethylamino, or nitro substituent groups on the aromatic rings of the aldehydes interferes in the reaction which led to no product. This is likely due to deactivation by the coordination NMe₂ and NO₂ groups with catalyst.^22b

Table 3 Synthesis of imidazo[1,2-a]pyridines^a

Entry	Product	Time (h)	Yield^b (%)	M. P. (°C)^Ref.	TON^c/TOF^d
a Reaction conditions: aldehyde : amine : phenylacetylene (1 : 1 : 1.1), MNP@BiimCu (0.01 g), CTAB(5 mg), H2O (2.0 mL), reflux.b Isolated yield.c TON: turn over number (mol of product/mol of catalyst).d TOF: turn over frequency [mol of product/(mol of catalyst × reaction time)].
1		5	90	146 (ref. 22a)	75/0.25
2		5	92	119–120 (ref. 22a)	77/0.25
3		5.7	85	130–132 (ref. 21b)	70/0.2
4		5	90	160–162 (ref. 22b)	75/0.25
5		6	78	160 (ref. 22h)	65/0.18
6		5.5	95	135–136 (ref. 22b)	79/0.24
7		5	90	138–141 (ref. 22b)	75/0.25
8		6	95	82 (ref. 22c)	79/0.22
9		7.5	80	Semisolid^22c	67/0.15
10		5.5	87	116 (ref. 21b)	72/0.23
11		6	82	154–156 (ref. 22h)	68/0.18
12		5.4	85	141–142 (ref. 22a)	71/0.21
13		7.25	78	163–165 (ref. 22d)	65/0.14
14		7.2	90	99–101 (ref. 21b)	75/0.17
15		6	65	Oil^22a	54/0.15
16		6	76	82–83 (ref. 22e)	63/0.17
17		8.5	82	207–209 (ref. 22b)	68/0.13
18		8	78	126–127 (ref. 22a)	65/0.13

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Besides after completion of the reaction, catalyst was easily removed by an external magnet as shown in Fig. 7c and recovered simply by washing with organic solvent (EtOAc), and vacuum drying, and then reused for at least 10 times without observation significant decrease in activity. For example the reaction of 2-aminopyridine, p-chlorobenzaldehyde and phenylacetylene gave corresponding of imidazo[1,2-a]pyridine in sequenced ten times (Fig. 8). In addition, the SEM image of catalyst after recycling did not show a significant change in the morphology (Fig. 5 right), which clearly indicated that the MNP@BiimCu is robust, recyclable and was not affected under the reaction conditions of this MCR protocol. At the end, to determine the catalyst leaching into solution, the model reaction was carried out in the presence of MNP@BiimCu, and separated solution was tested by the AAS measurement and showed no significant Cu⁺. This was further confirmed by ICP analysis which did not show pronounced Cu⁺ leaching after the first run. The amount of Cu⁺ leaching after 10 repeated recycling was analyzed with ICP to be only 0.6%. These observations confirmed the heterogeneous character of the catalytically active species.

Fig. 8 Reusability of the MNP@BiimCu for the reaction of 2-aminopyridine, p-chlorobenzaldehyde and phenylacetylene under optimized conditions at 5 h.

To show the merit of the present protocol for imidazo[1,2-a]pyridines synthesis via one-pot three component coupling reaction between alkynes, aldehydes and amines, the results obtained with MNP@BiimCu were compared with some of those reported in the literature (Table 4). Although, all the methods are effective and there is one report in water, but the present procedure comparatively affords high yield of the product with the catalyst reusability for at least 10 consecutive runs without loss of activity.

Table 4 Evaluation of the introduced methodology in comparison with some of other reported methods^a

Entry	Catalyst (mol%)	Reaction conditions	Yield (%)/Time (h)	Ref.
a TCC reaction between 2-aminopyridine, benzaldehyde and phenylacetylene.b This work.
1	CuCl(5)/Cu(OTf)2(5)	Toluene, 120 °C	92/16	22a
2	InBr3(10)/Et3N	Dry toluene, reflux,	82/12	22d
3	Cu-MOFs (10)	Toluene, 120 °C, N2	97/30	22g
4	Cu(SO4)(10)/p-TSA(10)	Toluene, reflux	60/18	22b
5	Cu(SO4)(10)/D-glucose	EtOH, 100 °C	79/10	22e
6	Cu–Mn(10)	Water, 100 °C	85/4	22i
7	CuI(5)–NaHSO4·SiO2	Toluene, reflux, N2	91/12	22c
8	Fe3O4(10)/KHSO4·SiO2	Dry toluene, 110 °C	89/24	22h
9	Fe3O4–SiO2(5)/K2CO3(5)	EtOH, reflux	86/3	22j
10	MNP@BiimCu (1.2)	Water, 100 °C	92/5	—^b

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4. Conclusions

A clean and safe protocol was developed for preparation of imidazo[1,2-a]pyridine by three-component reaction of 2-aminopyridines, aldehydes, and phenylacetylene using magnetic catalyst in water. The advantages of the present method are: (a) easy and simple work up, (b) green reaction conditions, (c) short reaction times, and (d) excellent yields and makes present protocol worthy and highly compliant as compared to the other heterogeneous catalytic system. It is worth to note that catalyst is stable and requires no special handling precaution and it is easily recovered by magnet and reused without any significant loss of its activity after at least 10 successive runs. Thus, this approach could find industrial applications in synthesis of this class of compounds.

Acknowledgements

We are grateful to Mazandaran University for support of our research.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra03333g

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