Fe₃O₄ nanoparticles: a robust and magnetically recoverable catalyst for three-component coupling of aldehyde, alkyne and amine

Abstract

A robust, safe and magnetically recoverable Fe₃O₄ nanoparticle catalyzed three-component coupling of aldehyde, alkyne, and amine (A³-coupling) was developed. A diverse range of propargylamines were obtained in moderate to high yield under mild conditions in air. The separation and reuse of the magnetic Fe₃O₄ nanoparticles were very simple, effective and economical.

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Environmentally benign, economical, practical, and efficient processes for catalyst separation and reuse have been increasingly important goals in the chemical community from economic, safety, and environmental points of view.¹ The strategy of magnetic separation, taking advantage of magnetic nanoparticles, is typically more effective than filtration or centrifugation as it prevents loss of the catalyst.² Magnetic separation of the magnetic nanoparticles is simple, economical and promising for industrial applications.³ In recent years, Fe₃O₄ nanoparticles (magnetite nanoparticle) have attracted worldwide attention.³ Various strategies have successfully demonstrated the applications of Fe₃O₄ nanoparticle-immobilized or -supported catalysts.⁴ However, the direct use of Fe₃O₄ nanoparticles without modification as magnetically recoverable catalysts for organic reactions is very rare.⁵

Propargylic amines, products of the three-component aldehyde–alkyne–amine coupling (A³-coupling), are useful building blocks and important skeletons of biologically active compounds.⁶ During the past decade, significant efforts have been made in order to develop one-pot multi-component reactions to make new carbon–carbon bonds.⁷ In the past few years, we⁸ and others⁹ have reported highly efficient couplings catalyzed by various metals such as copper, silver, gold, iridium, and indium to afford various propargylamines. Recently, we¹⁰ and others¹¹ also reported that such a coupling can also be catalyzed by iron salts. In these studies, we also observed that iron powder could catalyze the reaction. To rationalize this result, we speculated that the iron-powder reaction was due to the catalytic activities of iron oxides on the surface of the powder. Consequently, we were intrigued by the possibility of using Fe₃O₄ nanoparticles as catalysts for the A³-coupling reaction, featuring both a much greater surface area than iron powder and magnetic recoverability. Herein, we wish to report the robust and magnetically recoverable Fe₃O₄ and Fe₂O₃ nanoparticles catalyzed three-component coupling of aldehyde, alkyne and amine (Fig. 1). It was found that good yields were obtained and the magnetic recovery of Fe₃O₄ nanoparticles was simple and efficient. The catalyst was directly reused 12 times without the need for activation. Fe₂O₃ nanoparticles were also effective as catalysts.

Fig. 1 Photo of 1-1: Fe₃O₄ nanoparticles in THF; 1-2: Fe₃O₄ nanoparticle dispersion in THF; 1-3: Fe₃O₄ nanoparticles adsorbed on the magnetic stirring bar; 1-4: a magnet attracted the magnetic stirring bar and Fe₃O₄ nanoparticles; 2-1: Fe₂O₃ nanoparticles in THF; 2-2: Fe₂O₃ nanoparticle dispersion in THF; 2-3: Fe₂O₃ nanoparticles adsorbed on the magnetic stirring bar; 2-4: a magnet attracted the magnetic stirring bar and Fe₂O₃ nanoparticles.

We used cyclohexanecarbaldehyde, piperidine, and phenylacetylene as standard substrates to search for a suitable solvent for the Fe₃O₄ nanoparticle (<50 nm) catalyzed A³-coupling (Table 1). Among the solvents tested, tetrahydrofuran was the most effective reaction medium for this three-component coupling reaction (Table 1, entry 1). The use of tetrahydrofuran effected not only the coupling reaction of aldehyde, alkyne, and amine in good yield, but also performed well in the process of magnetic separation of nanoparticle catalysts, by reducing the viscosity of the reaction mixture and facilitating the congregation of magnetic catalyst, when the reaction was complete. Slightly lower yields were obtained when using acetonitrile or ethyl acetate as the solvent (Table 1, entries 2 and 3). Ethanol, dichloromethane, water, acetone and dimethyl sulfoxide (DMSO) afforded the products in only low or moderate yields (Table 1, entries 4–8). No desired product was detected by NMR when the reaction was carried out in N,N-dimethylformamide (DMF) (Table 1, entry 9). The corresponding product was also obtained in good yield under neat conditions (Table 1, entry 10). However, the mixture was viscous in the absence of a solvent and made the separation of catalyst from products difficult magnetically unless an extraction solvent such as ether was added. No significant difference was observed when slightly increasing the catalyst loading (Table 1, entry 11). It is worth noting that γ-Fe₂O₃ nanoparticles (<50 nm) also catalyzed the reaction, affording the corresponding propargylamine products in a lower yield (Table 1, entry 12). The gamma-form iron oxide nanoparticles can also be separated easily by magnetic method and reused. No desired product was obtained in the absence of Fe₃O₄ nanoparticles or Fe₂O₃ nanoparticles. The optimized reaction conditions include 1.0 equiv of aldehyde, 1.2 equiv of amine, 1.5 equiv of alkyne, and 5 mol % of Fe₃O₄ nanoparticles in THF at 80 °C in air. Buchwald and Bolm recently found that the results of FeCl₃-catalyzed reactions may be due to trace quantities of copper.¹² To preclude such a possibility in the present case, we tested 99.99% Fe₃O₄ powder (from Aldrich) to catalyze the three-component coupling of Cu-free cyclohexanecarbaldehyde, piperidine, and phenylacetylene under the optimized reaction conditions, which gave 57% NMR yield.¹³ In comparison, a 54% NMR yield was obtained when 600 ppm Cu₂O was added into this 99.99% Fe₃O₄ powder, which indicated that trace quantity of copper has no obvious effect on this reaction. Considering Fe₃O₄ nanoparticles have a much larger surface area than their powder form, we conclude that the reaction was catalyzed by Fe₃O₄ nanoparticles rather than by trace copper impurities.

Table 1 Three-component coupling of cyclohexanecarbaldehyde, piperidine, and phenylacetylene catalyzed by a magnetic iron oxide catalyst^a

Entry	Solvent	NMR Yield(%)
a All reactions were carried out with cyclohexanecarbaldehyde (0.5 mmol), piperidine (0.6 mmol), phenylacetylene (0.75 mmol) and Fe3O4 nanoparticles (0.025 mmol) at 80 °C (oil bath) at 24 h.b (0.05 mmol) Fe3O4 nanoparticles was used as catalyst.c (0.025 mmol) Fe2O3 nanoparticles was used as catalyst.
1	THF	89
2	CH3CN	86
3	Ethyl acetate	84
4	CH3CH2OH	69
5	CH2Cl2	42
6	H2O	39
7	Acetone	29
8	DMSO	10
9	DMF	0
10	—	89
11	—	92^b
12	THF	70^c

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To expand the scope of this A³-coupling, various aldehydes and amines were used as substrates under the optimized reaction conditions, and the results are summarized in Table 2. In general, both aromatic and aliphatic aldehydes underwent the addition reaction smoothly to provide the desired product in moderate to good yields (Table 2, entries 1–14). However, similar to the FeCl₃-catalyzed A³-coupling,¹⁰ the reaction was found to be strongly influenced by the nature of the aldehyde. As shown in Table 2, aliphatic aldehydes were more reactive than the aromatic aldehyde. The reactions involving aliphatic aldehydes such as cyclohexanecarboxaldehyde, valeraldehyde, isobutyraldehyde, 2-methylbutanal, and 3-phenylpropanal all provided higher yields than benzaldehyde (Table 2, entries 1, 2, 4, 5, 6 and 10). Formaldehyde (37 wt% in water) afforded the desired products also in good yield (Table 2, entry 3). Moderate to good yields were observed when cyclic dialkylamines such as pyrrolidine, morpholine and azepane were used (Table 2, entries 7, 8, 12, 13 and 14).

Table 2 Three-component coupling of aliphatic aldehyde, amine, and alkyne catalyzed by iron oxide nanoparticles^a

Entry	Aldehyde	Amine	Isolated yield (%)
a All reactions were carried out with aldehyde (0.5 mmol), amine (0.6 mmol), alkyne (0.75 mmol) and Fe3O4 nanoparticles (0.025 mmol) at 80 °C (oil bath) in THF for 24 h.
1			82
2			45
3	HCHO		80
4	CH3(CH2)3CHO		74
5			51
6			83
7			63
8			84
9			86
10			53
11			50
12			89
13			78
14			52

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The magnetic Fe₃O₄ or Fe₂O₃ nanoparticles were adsorbed onto the magnetic stirring bar when the magnetic stirring was stopped. The nanoparticles were then washed with ethyl acetate, air-dried and used directly for the next round of reactions without further purification. It was shown that the Fe₃O₄ nanoparticle catalyst could be recovered and reused 12 times without significant loss of catalytic activity (Table 3).

Table 3 The reuse of Fe₃O₄ nanoparticles in A³-coupling^a

Cycle	NMR Yield(%)	Cycle	NMR Yield(%)
a All reactions were carried out with 0.5 mmol cyclohexanecarbaldehyde, 0.6 mmol piperidine, 0.75 mmol phenylacetylene and 0.025 mmol Fe3O4 nanoparticles (for cycle 1) or recovered Fe3O4 nanoparticles (for other cycles) at 80 °C (oil bath) in THF for 24 h.
1	89	7	73
2	85	8	74
3	82	9	79
4	83	10	78
5	80	11	80
6	77	12	82

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In summary, we have demonstrated a robust and magnetically recoverable Fe₃O₄ nanoparticle catalyzed three-component coupling of aldehyde, alkyne, and amine (A³-coupling). A diverse range of propargylamines were obtained in moderate to high yield under mild conditions in air. The separation and reuse of the magnetic Fe₃O₄ nanoparticles were very simple, effective and economical. In addition, the use of iron oxides as catalysts is also more environmentally friendly and safer than other transition-metal catalysts. We also showed that the efficiency of the catalytic activity is also affected by the different forms of iron oxides. The direct use and recycling of magnetic Fe₃O₄ and Fe₂O₃ nanoparticles to catalyze other reactions by the same strategy are under investigation in our laboratory.

Experimental section

Fe₃O₄ (<50 nm particle size (TEM), ≥98%) and Fe₂O₃ (<50 nm particle size) were purchased from Sigma-Aldrich. To a reaction tube charged with a magnetic stir bar and Fe₃O₄ nanoparticles (0.05 mmol, 5 mol %) in air, aldehyde (0.5 mmol), amine (0.6 mmol), and alkyne (0.75 mmol) were added. The tube was then stoppered. The reaction mixture was stirred at 80 °C (oil bath temperature) for 24 h. The Fe₃O₄ nanoparticles were adsorbed on to the magnetic stirring bar when the stirring was stopped. After cooling to room temperature, the reaction solution was filtered through Celite in a pipette eluting with ethyl acetate. The volatile liquid was removed in vacuo and the residue was purified by flash column chromatography on silica gel (eluent: hexane–ethyl acetate = 15 : 1) to give the corresponding product. Fe₃O₄ nanoparticles were washed with ethyl acetate, air-dried and used directly for the next round of reactions without further purification.

Acknowledgements

We are grateful to the Canada Research Chair foundation (to CJL and AM), the CFI, NSERC and McGill University for support of our research. TQZ thanks the China Scholarship Council for a Visiting Scholarship. We thank Prof. Eric D. Salin, David A. Duford and Yongqing Xi of the Chemistry Department at McGill University for the ICP-AES and AAS analysis.

Notes and references

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13. Fe₃O₄ powder (99.99%), cyclohexanecarbaldehyde, piperidine, and phenylacetylene were purchased from Sigma-Aldrich. Cyclohexanecarbaldehyde and piperidine were distilled before use. Analysis by using Perkin-Elmer 603 atomic absorption spectrophotometer showed that 99.99% Fe₃O₄ powder and phenylacetylene were Cu-free (below detecting limit).

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