Transamidation of primary carboxamides, phthalimide, urea and thiourea with amines using Fe(OH)₃@Fe₃O₄ magnetic nanoparticles as an efficient recyclable catalyst

Abstract

The highly efficient transamidation of primary amides, phthalimide, urea and thiourea with amines catalyzed by magnetic Fe(OH)₃@Fe₃O₄ nanoparticles is described. This magnetic nanocomposite is able to catalyze transamidation reactions of a wide range of the above-mentioned substrates with amines, generating a new amide bond in moderate to good yields. The catalyst exhibited very good recyclability and reusability up to five runs without significant loss of its catalytic activity.

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Introduction

The amide bond formation is an important functional group in chemistry and nature due to its presence in polymers, dyes, peptides, and protein structures.¹ Consequently, the construction of amide bonds has been one of the most studied transformations in organic synthesis. The conventional way to make an amide bond involves the use of either a carboxylic acid (or derivatives) or coupling reagents in stoichiometric quantities,² resulting in a poor atom-efficiency and formation of a significant amount of chemical waste. To circumvent these drawbacks, numerous alternative amide formation protocols have been explored.³ Among them, transamidation of amides with amines is potentially an attractive alternative method for exchanging the constituents of two different amide groups. Due to the high reaction temperatures required to break the amide bond, transamidation under thermal conditions⁴ is considered as an unfavorable method for amide formation. Alternatively, enzyme mediated transamidation reactions have been reported,⁵ whereas they have limited scope and require development of task specific enzymes as well as long reaction times. In order to overcome these drawbacks, new homogeneous and heterogeneous catalysts have recently been reported.

Stahl,⁶ Myers,⁷ Beller,⁸ Williams,⁹ and other groups¹⁰ reported elegant methods for transamidation by employing homogeneous catalytic systems. Yet, despite the advances achieved, these homogeneous catalysts suffer from difficulty in recovery and recycling of the catalyst, resulting in poor atom economy and possess potential environmental problems due to the production of a significant amount of waste.

Recently, heterogeneous catalysts such as CeO₂,¹¹ Fe³⁺-exchanged montmorillonite (Fe-mont),¹² mesoporous niobium oxide spheres (MNOS)¹³ and sulfated tungstate¹⁴ have been deployed in transamidation reactions.

Although, these heterogeneous-catalytic systems for transamidation, promote the drawbacks existing with the homogeneous-catalytic systems, the efficiency and easy separation of the product and catalysts from the reaction mixture can be challenging in these catalytic methodologies.

Due to the high stability and easy separation of the catalyst from the reaction mixture by using an external magnet, magnetic nanoparticles-supported catalysts have been successfully deployed in a variety of important organic reactions.¹⁵ As part of our continuing interest in using magnetic nanoparticles as catalyst supports in organic reactions, we have recently reported the results obtained for the tandem oxidative amidation of alcohols with amine hydrochloride salts using superparamagnetic Fe(OH)₃@Fe₃O₄ nanoparticle catalysts.¹⁶ To further establish other organic transformations with our catalyst, herein, we describe an inexpensive, magnetically recoverable and environmentally friendly catalytic system (Fe(OH)₃@Fe₃O₄) for the transamidation of primary carboxamides, phthalimide, urea and thiourea with amines (Scheme 1).

Scheme 1 Fe(OH)₃@Fe₃O₄ catalyzed transamidation of primary carboxamides, phthalimide, urea and thiourea with amines.

Results and discussion

As can be seen in Scheme 2, the Fe(OH)₃@Fe₃O₄ catalyst was prepared through a simple pathway (for details see the Experimental section).

Scheme 2 Preparation of magnetic Fe(OH)₃@Fe₃O₄ nanoparticles.

The prepared catalyst was characterized using some instrumental techniques, such as XRD, SEM, TEM, TGA, and VSM. The XRD pattern of this catalyst is shown in Fig. 1. In particular, seven characteristic peaks at 2θ equal 21.5°, 35.4°, 41.7°, 50.9°, 63.7°, 68.0°, and 75.1°, which correspond to the Miller indices values {hkl} of {111}, {220}, {311}, {400}, {422}, {511}, and {440}, respectively. The XRD pattern resembles that of Fe₃O₄ nanoparticles and no signal is observed from the Fe(OH)₃ phase, indicating that the Fe(OH)₃ compound is amorphous. Nanoparticle morphology was evaluated by TEM (Fig. 2) and SEM (Fig. 3) images. Core–shell structure and spherical in shape with a smooth surface morphology of the particles are clearly seen in these images. On the other hand, the particle size distribution, obtained from the generated histogram using the TEM image, revealed the Fe(OH)₃@Fe₃O₄ MNPs with a mean size of 18 nm (Fig. 4). TGA recorded under a nitrogen atmosphere for Fe₃O₄ (Fig. 5A) and Fe(OH)₃@Fe₃O₄ MNPs (Fig. 5B) determined this catalyst consisted of 9.4 wt% of Fe(OH)₃ and 90.6 wt% of Fe₃O₄. The magnetic feature of the catalyst was confirmed by vibrating sample magnetometry (VSM). Magnetization (emu g⁻¹) as a function of applied field (Oe) is depicted in Fig. 6. The magnetization curve demonstrates that these Fe(OH)₃@Fe₃O₄ nanoparticles (possessed magnetic saturation (M_s) about 40.0 emu g⁻¹) have superparamagnetic properties which accounts for the easy recovery of this catalyst.

Fig. 1 XRD pattern of Fe₃O₄ and Fe(OH)₃@Fe₃O₄.

Fig. 2 TEM image of the catalyst.

Fig. 3 SEM image of the catalyst.

Fig. 4 Histograms generated from the sizes of the catalyst using the TEM images.

Fig. 5 TGA results of Fe₃O₄ and Fe(OH)₃@Fe₃O₄.

Fig. 6 Magnetization curve of Fe₃O₄ and the catalyst.

Transamidation of benzylamine with formamide using Fe(OH)₃@Fe₃O₄ magnetic nanoparticles as catalyst was chosen as a model reaction under the following conditions: benzylamine 1a (1.0 mmol), formamide 2a (1.0 mmol), H₂O (1.0 mL), under an Ar atmosphere at reflux conditions. Unfortunately, after 10 h of reaction time, the corresponding product, N-benzylformamide 3a, was formed in just 16% yield (Table 1, entry 1). To increase the yield of the product, a series of experiments were carried out to screen the effect of various reaction parameters and these results are summarized in Table 1. Screening organic solvents (CH₃CN, toluene, p-xylene, THF, EtOH, and DMSO) indicated that p-xylene is the best (Table 1, entries 1–7). Further study showed that the catalyst is essential for this transamidation reaction. In the absence of the catalyst, transamidation did not occur (Table 1, entry 8). Finally, the effect of catalyst loading on the efficiency was studied and 30 mg per 1.0 mmol of benzylamine was found to be the best (Table 1, entries 9–11). Furthermore, the low efficiency of the reaction in the presence of Fe₃O₄ nanoparticles showed that iron(III) hydroxide, coated on the magnetic nanoparticles, plays a major role as catalyst (Table 1, entry 12). Therefore, the optimum conditions were obtained when we performed the reaction by using 30 mg of Fe(OH)₃@Fe₃O₄ at 135 °C with the respective p-xylene as the solvent (Table 1, entry 4).

Table 1 Optimization of the reaction conditions^a

Entry	Cat. (mg)	Solvent	Yield^b (%)
a Reaction conditions: benzylamine (1.0 mmol), formamide (1.0 mmol), solvent (1.0 mL) under Ar atmosphere, 10 h.b Yield of the isolated product is based on the amine.c Reaction performed at 140 °C.d 30 mg of Fe3O4 nanoparticles were used.
1	30	H2O	16
2	30	CH3CN	58
3	30	Toluene	81
4	30	p-Xylene	92
5	30	THF	53
6	30	EtOH	66
7	30	DMSO^c	28
8	—	p-Xylene	—
9	20	p-Xylene	68
10	25	p-Xylene	74
11	35	p-Xylene	92
12	30^d	p-Xylene	31

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The above optimized catalytic system was extended to the transamidation reaction. So, a wide range of amines with amides, urea, thiourea and phthalimide were subjected to the reaction conditions and the corresponding transamidation products were obtained in moderate to good yields (Table 2). Subsequently, we have applied the optimized reaction conditions for different amides, where acetamide, formamide, and N,N-dimethylformamide could be successfully converted to the corresponding products when reacted with different amines.

Table 2 Fe₃O₄@Fe(OH)₃ catalyzed transamidation of primary amides, phthalimide, urea and thiourea with amines^a,b

a Reaction conditions: amine (1.0 mmol), amide (1.0 mmol), p-xylene (1.0 mL) under Ar atmosphere, 10 h.b Isolated yields; the yields of the transamidation of N,N-dimethylformamide with amines are given in parentheses.c Amine (2.0 mmol), amide (1.0 mmol).

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Generally speaking, anilines bearing electron-donating groups such as methyl- or methoxy-, were better than those bearing electron withdrawing groups, such as fluoro-, bromo-, or nitro- (Table 2, 3d, 3e vs. 3f–h). Worthy of note is that transamidation of formamide or N,N-dimethylformamide with amines gave the corresponding N-formylated products in excellent yields (Table 2, entries 3a–g). To further extend the scope of this methodology, the Fe(OH)₃@Fe₃O₄ catalyzed transamidations of urea and thiourea were examined with amines and the corresponding target products obtained in moderate to good yields (Table 2, entries 3o–v). Finally, our study was focused on the transamidation of phthalimide with several primary amines such as aniline, benzylamine, and 4-methylaniline and the corresponding N-substituted phthalimides were obtained in good yields (Table 2, entries 3w–y).

Based on the results and literature reports,^6d,10a,17 we propose a plausible mechanism for this transformation as shown in Scheme 3. In the proposed mechanism, the Fe(OH)₃ shell played a dual role: (i) as a hydrogen bond donor by H-bonds formation with the nitrogen atom of amide 1: (ii) as a Lewis acid at the iron atom by coordination to the oxygen atom of the amide. This double activation would be followed by addition of amine 2 to the amide (Scheme 2, intermediate (II)). Subsequently, this generated intermediate can undergo reversible proton exchange to form intermediate (III). Finally, the catalytic cycle ends with removal of amine 3 and the dissociation of amide 4 from Fe(OH)₃@Fe₃O₄ catalyst.

Scheme 3 Proposed mechanism for the Fe(OH)₃@Fe₃O₄ catalyzed transamidation reaction.

After establishing the activity and versatility of the Fe(OH)₃@Fe₃O₄ catalyst for transamidation, its recyclability was examined in the preparation of compound 3a under the optimized reaction conditions. For this, after completion of the reaction, the catalyst was easily removed from the reaction mixture by using an external magnet, washed with ethanol, dried at ambient temperature and subjected to the next cycle. The Fe(OH)₃@Fe₃O₄ catalyst could be reused up to five cycles without any significant loss of its catalytic activity (Fig. 7).

Fig. 7 Recyclability study of the catalyst in the preparation of compound 3a.

To compare the efficiency of the Fe(OH)₃@Fe₃O₄ catalyst with the previously reported ones, we have tabulated the corresponding data for promotion of N-benzylformamide (product 3a) (Table 3). It is clear that our catalyst worked remarkably well to give the desired product in 92% yield in a shorter reaction time.

Table 3 Comparison of different catalysts in the formation of N-benzylformamide

Entry	Catalyst	Condition	Time (h)	Yield (%)	Ref.
1	Fe(NO3)3·9H2O	Toluene/reflux	30	93	18
2	Chitosan	Neat/150 °C	36	83	19
3	B(OH)3	H2O/100 °C	16	81	10a
4	H2NOH·HCl	Toluene/reflux	16	86	9a
5	L-Proline	Neat/150 °C	36	94	20
6	Fe(OH)3@Fe3O4	p-Xylene/reflux	10	92	—

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Experimental

All experiments were carried out under argon. All chemicals and solvents were purchased from commercial suppliers and used without further purification. FT-IR spectra were obtained over the region 400–4000 cm⁻¹ with a Nicolet IR100 FT-IR spectrometer with spectroscopic grade KBr. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker Avance (DRX 400 MHz and DRX 500 MHz) spectrometer in pure deuterated CDCl₃, and DMSO-d₆ solvents with tetramethylsilane (TMS) as internal standard.

Preparation of Fe(OH)₃@Fe₃O₄ catalyst

The synthesis of the Fe(OH)₃@Fe₃O₄ catalyst was conducted according to the procedure previously reported.¹⁶ In a typical preparation procedure, the mixture of FeCl₃·6H₂O (4.0 mmol) and FeCl₂·4H₂O (2.0 mmol) salts in deionized water (40.0 mL) was placed in a two-necked flask under vigorous stirring. An ammonia solution (25% (w/w)) was added in a dropwise manner over 5 min to the stirring mixture to maintain the reaction pH at about 11. The resulting black dispersion was stirred vigorously for 1 h at room temperature and then was refluxed for 1 h. Fe₃O₄ nanoparticles were magnetically gathered and the residue was repeatedly washed with water and ethanol. Subsequently, the as-prepared Fe₃O₄ nanoparticles and 15.0 mmol of FeCl₃·6H₂O were ultrasonically dispersed in 10.0 mL of ethanol. After total dissolution and dispersion, the nanoparticles were separated from the ethanol solution by magnetic decantation and dried at 80 °C for 4 h. Fe(OH)₃@Fe₃O₄ nanoparticles were obtained by dropwise addition of aqueous ammonia (25% (w/w), 5 mL) to the dried brown nanoparticles under vigorous stirring. Finally, the products of Fe(OH)₃@Fe₃O₄ were magnetically separated, washed with water, and dried in an oven at 373 K overnight for further usage.

General procedure for the synthesis of products 3a–3y

To a mixture of catalyst (30.0 mg, 2.6 mol%) and amine (1.0 mmol) in p-xylene (1.0 mL) was added amide (1.0 mmol) under an argon atmosphere, and the mixture was refluxed for 10 h. After completion, the reaction mixture was allowed to cool to room temperature. It was then diluted with EtOAc and the catalyst was separated from the reaction mixture by using an external magnet and washed twice with EtOAc, all volatiles were removed under vacuum, and the resulting residue was purified by column chromatography on silica gel to afford the desired product.

Conclusions

In conclusion we have demonstrated an environmentally friendly, inexpensive and magnetically separable Fe(OH)₃@Fe₃O₄ catalytic system for transamidation. This catalyst exhibited high catalytic activity for transamidation of amines with amides, urea, thiourea and phthalimide. By using this catalytic system, all corresponding target products were obtained in moderate to good yields. Due to its straightforward preparation, facial separation from the reaction medium and recyclability, the Fe(OH)₃@Fe₃O₄ catalytic system described here, represents a good compliment to the previously reported protocols.

Acknowledgements

This article is dedicated to the memory of Mohammad Ebrahim Hemmat. We acknowledge Tarbiat Modares University for partial support of this work. The authors express their gratitude to Dr Dariush Saberi for revising the English language of the manuscript.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra27680b

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