Magnetic silica supported copper: a modular approach to aqueous Ullmann-type amination of aryl halides

Abstract

One-pot synthesis of a magnetic silica supported copper catalyst has been described via in situ generated magnetic silica (Fe₃O₄@SiO₂); the catalyst can be used for the efficacious amination of aryl halides in aqueous medium under microwave irradiation.

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Introduction

Amination of aryl halides is a very important transformation and a method of choice for the synthesis of fascinating motifs containing the N-aryl moiety;¹ they are widely present in many biologically important natural products and pharmaceuticals. Buchwald–Hartwig amination using a palladium catalyst has been well explored.² However, this method requires phosphine, N-heterocyclic carbenes, and many other complex organic ligands. The main limitation of this amination reaction is that these ligands are often air-sensitive, and many of them are expensive and often require long reaction times.^1,2 In recent years, there has been significant progress in the discovery of copper-catalyzed coupling reaction of aryl halides with amines,³ a pathway that has been highly dependent on the use of organic ligands.⁴ Although these ligands have been very important for accelerating the copper-catalyzed coupling of aryl halides with amines, none of them have displayed general efficiency for promoting copper-catalyzed N-arylation.

Thus, the development of a mild and efficient method for the amination of aryl halides under eco-friendly conditions that can circumvent the extravagant use of stoichiometric reagents is highly desirable. Magnetic nanoparticles have emerged as a robust, high-surface area heterogeneous catalyst support.⁵ Magnetic recoverability, which eliminates the necessity of catalyst filtration after completion of the reaction is an additional positive attribute of these materials⁶ compared to most of the heterogeneous catalysts deployed. These catalysts work well but suffer from the following drawback: the synthesis of the catalyst is an elaborate and tedious procedure that involves three steps, (i) synthesis of nano ferrite, (ii) post-synthetic modification via anchoring of the ligand, which may be toxic and (iii) immobilization of catalytically active metal. To overcome these drawbacks and to avoid the use of toxic ligands and reagents we have developed a one-step procedure for the synthesis of magnetic silica supported CuSO₄ as a magnetically retrievable catalyst and have demonstrated its application for the amination of aryl halides in benign aqueous media, which circumvents the use of organic solvents.

Results and discussion

The first step in the accomplishment of this goal was the facile synthesis of a magnetic silica supported copper catalyst (Scheme 1) through the sequential addition of reagents in one-pot. The magnetic nano ferrite (Fe₃O₄) was generated in-situ via a hydrolysis method by stirring the solution of FeSO₄·7H₂O and Fe₂(SO₄)₃ in water in a 1 : 1 ratio at pH 10 (adjusted using (25%) ammonia (NH₃) solution) followed by heating in a water bath at 50 °C for 1 h. The reaction mixture was cooled down to room temperature and tetraethyl orthosilicate (TEOS) was added to this solution under vigorous stirring, which was continued for 18 h under ambient conditions. The supernatant liquid was decanted and fresh water added, then, to this solution CuSO₄ was added and stirring was continued for another 24 h (Scheme 1).

Scheme 1 Synthesis of the magnetic silica supported copper catalyst.

The magnetic silica supported CuSO₄ catalyst was separated using an external magnet, washed with water followed by acetone and dried under vacuum at 50 °C for 8 hours. The catalyst was characterized by transmission electron microscopy (TEM) (Fig. 1a) and X-ray diffraction (XRD) (Fig. 1b), which confirmed the formation of single-phase silica coated Fe₃O₄ nanoparticles Fe₃O₄@SiO₂Cu, with spherical morphology and a size range of 5–30 nm. The weight percentage of Cu was found to be 4.92% by inductively coupled plasma-atomic emission spectroscopy (ICP-AES) analysis.

Fig. 1 (a) TEM image of Fe₃O₄@SiO₂Cu. (b) XRD image of Fe₃O₄@SiO₂Cu.

The application of the magnetic silica supported copper catalyst was then demonstrated in a heterogeneous catalyzed amination of aryl halides in aqueous medium as a benign solvent under microwave (MW) irradiation conditions (Scheme 2). MW-assisted chemistry was used due to the efficiency of the interaction of the polar nano catalysts and water molecules with microwaves, further the reaction mixture can be rapidly heated to the requisite temperatures under MW irradiation with precise control of the reaction temperature.⁷ Initially, experiments were performed to optimize the reaction conditions for the amination of 4-nitro bromobenzene by pyrrolidine in aqueous medium (Table 1).

Scheme 2 Amination of 4-nitro bromobenzene using Fe₃O₄@SiO₂Cu.

Table 1 Optimization of reaction conditions

Entry	Catalyst	Time	Temperature (°C)	Yield
a Reactions were performed under conventional heating.b Reactions were performed under MW irradiation.
1^a	Fe3O4	24 h	100	—
2^b	Fe3O4	60 min	100	—
3^b	Fe3O4	60 min	150	—
4^b	Fe3O4@SiO2Cu	60 min	100	96%
5^a	Fe3O4@SiO2Cu	24 h	100	Trace

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First, the reaction was conducted using nanoferrite (nano-Fe₃O₄). The amination reaction did not proceed under conventional heating (24 h, 100 °C, Table 1, entry 1), or under MW irradiation at 100 °C or at 150 °C, even after 60 min of MW exposure (Table 1, entries 2–3). The magnetic silica supported copper catalyst Fe₃O₄@SiO₂Cu was then tested for the amination of 4-nitro bromobenzene with pyrrolidine at 100 °C using MW and conventional heating. Under conventional heating, it gave trace amounts of product, whereas MW exposure for 1 h at 100 °C leads to a nearly quantitative conversion of 4-nitro bromobenzene to the corresponding aryl amines (Table 1, entry 4). The variation in base did not influence the outcome of the reaction; results with Cs₂CO₃ were similar to those obtained using K₂CO_3. Using the above optimized conditions, the scope of the magnetic silica supported copper catalyst, Fe₃O₄@SiO₂Cu, was then explored for the amination of a variety of aryl halides (Table 2). The catalyst displayed high activity for amination of aryl bromide and iodide using primary, secondary, cyclic, and acyclic amines in pure water (Table 2 entries 1–17). The rates were hardly influenced by the electronic effects of the substituents on the aromatic ring of the aryl halides (Table 2 entries 1–15). The cyclic (Table 2, entries 1–10 and entries 16–17) and acyclic amines (Table 2, entries 11–15) did not show any difference in reactivity. Primary and secondary amines reacted efficiently. It was interesting to observe that 1-bromo-4-iodo benzene can be selectively converted to the corresponding bromo aryl amines (Table 2 entry 16) after 60 min exposure to MW at 100 °C with 1 equivalent of pyrrolidine. The reaction of aryl halides bearing both halide (Br) and boronic acid functional groups with amines led to the formation of the corresponding aryl amines along with the removal of a boronic acids moiety (Table 2, entry 17). The aryl chlorides were not reactive enough to be converted into the corresponding amines, however. We did not observe any product formation when a similar reaction was performed with benzene chloride and pyrrolidine (Table 2 entry 18). The TON and TOF of the reactions (Table 2) clearly indicates that the method will be very useful for aryl amine synthesis.

Table 2 Amination of aryl halides

Entry	Aryl halides	Amines	Time	Product	Yield^a^,^b	TON/TOF^c
a Reaction conditions: (1)Fe3O4@SiO2Cu (25 mg), amine (1.1 mmol), K2CO3 (2 mmol), water (4 mL), MW, 100 °C, 60 min.b Isolated yield.c TON/TOF calculated based on 10 mmol reaction, reaction time 4 h.
1			60 min		95%	772/193
2			60 min		96%	780/195
3			60 min		94%	764/191
4			60 min		95%	772/193
5			60 min		92%	747/186
6			60 min		92%	747/186
7			60 min		86%	699/174
8			60 min		84%	682/170
9			60 min		89%	723/180
10			60 min		90%	731/182
11			60 min		83%	674/168
12			60 min		82%	666/166
13			60 min		85%	691/172
14			60 min		95%	772/193
15			60 min		97%	788/197
16			60 min		78%	634/158
17			60 min		74%	601/150
18			90 min	N.R	N.R	—

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The lifetime of the catalyst and its level of reusability are important considerations in terms of practical applications. To clarify this issue, a set of experiments for the amination of 4-nitro-1-bromobenzene with pyrrolidine using a Fe₃O₄@SiO₂Cu catalyst were established. After the completion of the first reaction to afford the corresponding aryl amine, the catalyst was recovered magnetically, washed with acetone, and dried at 50 °C. A new reaction was then performed with fresh 4-nitro-1-bromobenzene under similar conditions. The magnetic silica supported copper catalyst Fe₃O₄@SiO₂Cu could be reused at least three times without any change in the activity (ESI, Table 1†). Metal leaching was studied by ICP-AES analysis of the catalyst before and after the three reactions. The Cu concentration was found to be 4.92% before the reaction and 4.87% after the reaction. The TEM image of the catalyst taken after the third cycle of the reaction did not show any significant change in the morphology or in the size of the catalyst nanoparticles (ESI, Fig. 1†), which indicates the retention of the catalytic activity after recycling. No Cu metal was detected in the reaction solvent (water) after completion of the reaction. This confirms the fact that the nano magnetic silica held the copper catalyst very tightly, minimizing the deterioration of the catalyst and thus metal leaching and facilitating efficient catalyst recycling.

Conclusion

A novel one-step procedure for the synthesis of magnetic silica-supported copper catalyst has been developed, which can be readily prepared in gram quantities in aqueous media. It catalyzed the amination of aryl halides and the desired reactions proceeded smoothly to deliver the corresponding aryl amines in very good yields. Because of the magnetic nature of the catalyst, it could be separated using an external magnet, which eliminates the requirement of catalyst filtration after completion of the reaction, an additional attribute of the catalyst.

Experimental section

Synthesis of magnetic silica supported ruthenium hydroxide nanoparticles

FeSO₄·7H₂O (1.39 g) and Fe₂(SO₄)₃ (2.0 g) were dissolved in 100 mL water in a 250 mL beaker. Ammonia solution (25%) was added slowly to adjust the pH of the solution to 10. The reaction mixture was then continually stirred for 1 h at 50 °C. The reaction mixture was cooled down to room temperature, tetraethyl orthosilicate (TEOS, 10 mL) was added and vigorous stirring was continued for 18 h at ambient conditions. The supernatant liquid was decanted and fresh water added, to this CuSO₄ (400 mg) was added and stirring was continued for another 24 h (Scheme 1). The magnetic silica supported CuSO₄ catalyst was separated using an external magnet, washed with water followed by acetone and dried under vacuum at 50 °C for 8 hours. Catalyst characterization using X-ray diffraction (XRD) (Fig. 1a MS) and transmission electron microscopy (TEM) (Fig. 1b, MS) confirmed the formation of single-phase silica coated Fe₃O₄ nanoparticles Fe₃O₄@SiO₂Cu, with spherical morphology and a size range of 5–30 nm. The weight percentage of Cu was found to be 4.92% using inductively coupled plasma-atomic emission spectroscopy (ICP-AES).

Amination of aryl halides

Aryl halide (1.0 mmol), amine (1.1 mmol), K₂CO₃ (2.0 mmol) and Fe₃O₄@SiO₂Cu (25 mg) were placed in a crimp-sealed thick-walled glass tube equipped with a pressure sensor and a magnetic stirrer. Water (4 mL) was added to the reaction mixture. The reaction tube was placed inside the cavity of a CEM Discover focused microwave synthesis system, operated at 100 °C (temperature monitored by a built-in infrared sensor), 100 Watts for 60–90 min. After completion of the reaction, the catalyst was easily removed from the reaction mixture using an external magnet. The products were extracted using ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure and purified using column chromatography.

Acknowledgements

R. B. Nasir Baig was supported by the Postgraduate Research Program at the National Risk Management Research Laboratory administered by the Oak Ridge Institute for Science and Education through an inter-agency agreement between the U.S. Department of Energy and the U.S. Environmental Protection Agency. We thank Dr M. Nadagouda for recording XRD data and valuable suggestions.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra45606d

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