An efficient magnetic copper ferrite nanoparticle catalysed ligand and solvent free synthesis of N-aryl amide from aldoximes and iodobenzene

Abstract

A simple, efficient, and environmentally benign method has been reported for the synthesis of N-aryl amides using aldoximes and iodobenzene under ligand free and solvent free conditions and using magnetically separable copper ferrite nanoparticles as catalyst. The catalyst was characterised using XRD, FEG-SEM, EDAX, ICP-AES and TEM and tested for recyclability for up to five cycles.

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Introduction

N-Aryl amides are important moieties in medicinal chemistry which are the backbone of many pharmaceutical and biologically active natural products.¹ The medicinal chemistry database indicates that the amide bond appears in more than 25% of known pharmaceutical active ingredients.² Additionally, amides are very useful building blocks in organic synthesis, and are precursors for many valuable compounds such as agrochemicals, polymers and organic materials.³ Over time, amide bond formation reactions have begun to play an important role in organic synthesis for green chemistry applications.⁴ However, traditional trans amide formation reactions are usually carried out by using coupling reactions between corresponding acids or acid chlorides with amines.⁵ The rearrangement of ketoximes in the presence of strong acids, gives the straightforward product of trans amide.⁶ Both the above traditional methods have some drawbacks such as high temperature, strong acidic conditions, and hazardous waste.⁷ There are various methods of synthesis of N-aryl amide using the aryl halide (Scheme 1). Aldoximes on sequential reaction of hydration and dehydration in the presence of transition metals, give primary amides.⁸ Recently Panda et al. reported the copper catalysed homogeneous coupling reaction of aldoximes and aryl halides to afford N-aryl amides directly.⁹ There are many reports on the formation of trans amide using a coupling reaction between primary amides and aryl halides, with various homogenous and heterogeneous catalytic systems.¹⁰ In situ hydration of benzonitrile and coupling reactions with aryl halide were also reported.¹¹ Green and heterogeneous catalytic coupling reactions of amides and amines for the synthesis of N-aryl amides were also reported.¹² Most of the above reported reactions take place in solvent medium. However, reaction in solvent free conditions has great importance in the area of green chemistry.¹³ Magnetically separable nanoparticles as catalysts have attracted much attention for organic reactions .¹⁴ These nanoparticles have shown a large surface area to volume ratio, good activity and reusability.¹⁵ Particularly, copper ferrite nanoparticles possess good catalytic activity when employed in various organic transformations.¹⁶ Here, we propose solvent and ligand free, magnetically separable copper ferrite nanoparticles, as catalyst for the coupling reactions between aldoximes and aryl halides to get N-arylated amides.¹⁷ This protocol overcomes the drawback of regioselectivity and moreover it is the first report on the said reaction using heterogeneous catalyst.

Scheme 1 Various methods of N-aryl amide formation using aryl halides.

Experimental

The catalyst was prepared using a known simple co-precipitation followed by thermal decomposition method.^15b Copper(II) nitrate (4.1 mmol) and iron(III) nitrate (8.2 mmol) were taken in stoichiometric proportions and 100 mL of deionised water was added to produce clear solution. 1 M NaOH solution was added drop wise under stirring to the above solution until the pH became 10. A reddish-black precipitate of copper ferrite was formed. The reaction mixture was warmed to 90 °C and stirred for 2 h which on cooling gave magnetic particles. The catalyst was then washed with water and ethanol and separated using a magnet. It was kept in an air oven at 80 °C for 12 h. Then the catalyst was ground in a mortar-pestle and kept in a furnace at 700 °C for 5 h. It was then cooled to room temperature slowly to get the magnetic copper ferrite NPs.

Characterization of material

The synthesized catalyst was characterized using various techniques such as X-ray diffraction (XRD), field emission gun scanning electron microscopy (FEG-SEM) and transmission electron microscopy (TEM). The XRD analysis was performed on a Shimadzu XRD 2400 instrument using Cu Kα radiation (λ = 1.5406 Å) with a scanning rate of 2 degrees per minute. TEM analysis was performed using a PHILIPS 2200 instrument. FEG-SEM analysis was performed using a 25 TESCAN MIRA instrument. The energy dispersive X-ray spectral analysis (EDS) image was recorded with an Oxford instrument at 10 kV. Beam intensity was kept high to get a good response from the detector. GC analysis was performed using a PerkinElmer Clarus 480 instrument. GC-MS spectra were recorded using a Shimadzu QP-2010 instrument. 1H spectra were recorded on an Agilent 400 MHz.

Result and discussion

The XRD analysis showed peaks at 2θ = 30.1, 35.14, 43.41, 54.601, 57.0671 and 63.6651 which represent the Bragg reflections from the (220), (311), (400), (422), (511) and (440) planes respectively (Fig. 1A). The XRD pattern of the prepared copper ferrite nanoparticles shows the tetragonal structure with good crystallinity (JCPDS card no. 034-0425).¹⁵ We found the same XRD pattern of the recycled copper ferrite nanoparticles after the fifth cycle of reaction (Fig. 1B). An elemental analysis of the nano CuFe₂O₄ was performed using EDS (Fig. 2E) and ICP-AES. The elemental analysis gave the copper–iron ratio as 1 : 2 approximately. The ICP-AES study shows 0.00026 mmol g⁻¹ of copper and 0.00056 mmol g⁻¹ of iron in the catalyst. The particle size of the nano-copper ferrite measured using the TEM was found to be between 11–14 nm (Fig. 2B). The FEG-SEM analysis shows the crystalline nature of the copper ferrite nanoparticles. The FEG-SEM analysis shows the same morphology of the nanoparticles after the fifth cycle of the reaction (Fig. 2A–C). The FEG-SEM analysis of the reaction mass clearly shows the homogenisation of the catalyst (Fig. 2D).

Fig. 1 X-ray diffraction spectrum of fresh copper ferrite nanoparticles (A) and after the fifth cycle (B).

Fig. 2 Scanning electron microscopy images of copper ferrite nanoparticles before (A), and after five cycles (C) and after the reaction without washing of organic compounds (D). Transmission electron microscopy of copper ferrite nanoparticles (B). EDAX of copper ferrite nanoparticles (E).

We started the optimisation of the reaction parameters by considering the reaction between benzaldoxime and iodobenzene. It is treated as a model reaction. Initially we carried out the reaction without using the catalyst which gave benzamide as the major product instead of the desired product (Table 2 entry 7). Various copper and iron based catalysts were employed to get the best catalytic system (Table 1). Copper ferrite NPs were found to be the most effective catalyst for the model reaction in the presence of K₂CO₃ under solvent free conditions (Table 1 entry 8). We also tried the model reaction with various bases. Triethylamine and Na-tert-butoxide did not even initiate the reaction and the starting materials remained unchanged (Table 2 entry 2–3). The model reaction carried out using sodium carbonate, KOH and potassium phosphate afforded moderate yield, whereas K₂CO₃ gave 88% yield of N-phenyl benzamide (Table 2 entry 4–6). Hence K₂CO₃ was used as a base throughout the optimisation of reaction conditions (Table 2 entry 1). The reaction was also carried out in various solvents, where a greater amount of benzamide was obtained decreasing the yield of the coupling product N-phenyl benzamide (Table 2 entry 11–15). When the reaction was carried out at 100 °C, it afforded only 40% yield. The reaction carried out at 160 °C did not show any significant increase in the product yield. The optimised catalyst concentration was found to be 10 mol%. The model reaction carried out using 5 and 7.5 mol% of the catalyst, offered 48% and 65% yield respectively whereas 12% catalyst loading did not show a significant increase in the product yield (Table 2 entry 7–9).

Table 1 Synthesis of N-aryl amides using different Cu and Fe based catalysts^a

Entry	Catalyst	Yield^b
a Reaction conditions: a mixture of iodobenzene (1 mmol), benzaldoxime (2 mmol), 10 mol% catalyst and K2CO3 (2 eq.) at 150 °C for 12 h.b Isolated yield.
1	CuI	43
2	CuO (bulk)	45
3	CuSO4	ND
4	Cu2O (nano)	68
5	FeCl3·6H2O	53
6	Fe3O4	55
7	FeSO4	ND
8	Copper ferrite NPs	88

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Table 2 Optimisation of reaction conditions^a

Entry	Solvent	Base	Mol%	Yield^b
a Reaction conditions: iodobenzene (1 mmol), benzaldoxime (2 mmol), copper ferrite NPs, base (2 eq.), neat, 150 °C for 12 h.b Isolated yield.c Solvent as medium.d Without catalyst.
1	Neat	K2CO3	10	88
2	Neat	TEA	10	ND
3	Neat	Na-tert-butoxide	10	ND
4	Neat	KOH	10	68
5	Neat	Na2CO3	10	73
6	Neat	K3PO4	10	56
7	Neat	K2CO3	—	ND^d
8	Neat	K2CO3	5	48
9	Neat	K2CO3	7.5	65
10	Neat	K2CO3	12	90
11	Toluene	K2CO3	10	54^c
12	DMF	K2CO3	10	45^c
13	NMP	K2CO3	10	43^c
14	H2O	K2CO3	10	36^c
15	Ethanol	K2CO3	10	30^c

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We applied these optimised reaction conditions to various derivatives of the aldoximes and iodobenzene to explore and to check the stability of functional groups. We have used different substrates having electron donating groups as well as bulkier groups at various positions. We observed that the compound containing an electron donating group on aldoximes gave a good yield of the product (Table 3). The bulkier group also gave a moderate yield of the desired product (Table 3 entry 7). Aryl halides bearing fluoride, methyl, methoxy, chloride, bromide and –CF₃ groups gave moderate to good yield of the respective products (Table 4). We observed that reaction of benzaldoximes with 2-bromoiodobenzene gave a mixture of 2-phenyl benzaoxazole and 2 bromo-N-phenylbenzamide products (Table 4 entry 10). Reaction of chlorobenzene and bromobenzene with the benzaldoximes did not give the desired product under the present reaction conditions.

Table 3 Reactions of aldoximes with iodobenzene^a

Sr no.	Aldoxime R1	Product	Yield^b
a Reaction conditions: iodobenzene (1 mmol), aldoxime (2 mmol), copper ferrite NPs (10 mol%), K2CO3 (2 eq.) neat, 150 °C for 12 h.b Isolated yield.
1			88
2			76
3			86
4			84
5			82
6			83
7			73

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Table 4 Reactions of aryl halides with benzaldoximes^a

Sr no.	Aryl halide R2	Product	Yield^b
a Reaction conditions: aryl halides (1 mmol), benzaldoxime (2 mmol), copper ferrite NPs catalyst (10 mol%) and K2CO3 (2 eq.) neat, 150 °C for 12 h.b Isolated yield.
1			85
2			84
3			80
4			73
5			79
6			86
7			83
8			77
9			85
10			35
			45

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Based on literature reports⁸ and our present experimental results a plausible reaction mechanism has been proposed. We carried out the control reaction to check the mechanism. In the absence of iodobenzene and optimised reaction conditions the benzaldoximes get converted to benzamide and benzonitrile. We carried out the reaction with benzonitrile and iodobenzene under the same reaction conditions but we did not obtain the desired product. It was confirmed that the dehydration and hydration of benzaldoxime take place in the presence of copper ferrite nanoparticles. Here, in situ formed benzamide then coupled with iodobenzene on the surface of copper ferrite NPs to give N-arylated amides (Fig. 3).

Fig. 3 Plausible reaction mechanism.

In a leaching test, it is very difficult to remove the catalyst from the reaction to study the leaching of copper and iron. We did an ICP-AES study of the filtrate of the reaction mass after the completion of the reaction. The ICP-AES study revealed leaching of 0.029 ppm copper and 0.021 ppm iron in the filtrate which is negligible. It confirms the heterogeneous nature of the nanoparticles. At the end of the reaction, the catalyst was separated from the crude reaction mixture using a magnet, washed with ethyl acetate and water, dried at 100 °C, and reused as such for successive experiments (up to a fifth cycle) under similar reaction conditions. A slight decrease in the product yield indicates that the catalyst can be reused for up to five cycles (Fig. 4).

Fig. 4 Recyclability study of the copper ferrite NP catalyst.

Conclusions

In conclusion, we have developed a simple and green protocol for the one pot synthesis of N-aryl amide using aldoxime and iodobenzene as starting materials and nano-copper ferrite as a catalyst. The protocol is applicable to various substrates and afforded moderate to good yields. Solvent free reaction and reusability as well as a magnetically separable heterogeneous catalyst are the main advantages of the protocol.

Acknowledgements

The authors are thankful to the UGC-SAP, New Delhi, India for the award of a fellowship.

Notes and references

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17. General procedure for N-arylation of amide. An oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with benzaldoxime (2 mmol), iodobenzene (1 mmol), copper ferrite NPs (10 mol%), and K₂CO₃ (2 mmol). The reaction mixture was heated in an oil bath at 150 °C and was stirred for 12 h. The reaction was monitored by GC and TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and the reaction mass was diluted with ethyl acetate. The catalyst was separated using a magnet. The resulting filtrate was washed with water and 20% brine solution. The organic layer was separated and dried over anhydrous sodium sulphate. The solvent was removed under vacuum to get the crude product, which was purified by column chromatography on silica gel eluting with the mixture of pet ether/EtOAc (80 : 20) to afford the pure product. The purity and identity of known products are confirmed by ¹H NMR and GC-MS spectroscopic techniques.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra22777a

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