Tieqiang Zengab, Wen-Wen Chena, Ciprian M. Cirtiua, Audrey Mooresa, Gonghua Song*b and Chao-Jun Li*a
aDepartment of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, Quebec, Canada H3A 2K6. E-mail: cj.li@mcgill.ca; Fax: (+1)-514-398-3797; Tel: (+1)-514-398-8457
bShanghai Key Laboratory of Chemical Biology, Institute of Pesticides and Pharmaceuticals, East China University of Science and Technology, Shanghai, 200237, P.R. China. E-mail: ghsong@ecust.edu.cn; Fax: +86-21-64252603
First published on 13th January 2010
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.
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.
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 | — | 92b |
12 | THF | 70c |
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).
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).
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 |
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.
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