Knoevenagel condensations of 1,3-dicarbonyl compounds with aldehydes catalyzed by heterogeneous Ps-AlCl₃ without solvents

Abstract

A simple, efficient procedure is proposed for Knoevenagel condensations of 1,3-dicarbonyl compounds with aldehydes catalyzed by heterogeneous polystyrene-supported aluminum chloride (Ps-AlCl₃) under solvent-free conditions. The condensations are carried out smoothly with high yields (87–98%) at 60 °C for 2–4 h in the presence of the Ps-AlCl₃ catalyst. The catalyst is characterized by Fourier transfer-infrared spectroscopy (FT-IR). The catalyst is applicable to a wide range of aldehydes, and has excellent recyclability and can be reused several times without loss of activity.

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Introduction

Knoevenagel condensation is a well-known reaction for carbon–carbon bond formation in organic synthesis. The adducts such as α,β-unsaturated carbonyl compounds and α,β-unsaturated esters have been used as intermediates in cosmetics and perfumes, natural products, functional polymers, and pharmaceutical applications.^1–3 Due to its wide applications, many homogeneous catalyst systems^4–11 have been developed for this reaction. Because of the difficulty in separation of catalysts from products and/or solvents and high Chemical Oxygen Demand (COD) in wastewater generated, industrial utilization of those catalysts on a large scale is still unfavorable.

In recent years, the growing public concerns about environmental pollution have caused the chemical industry to minimize wastes generated during chemical manufacturing. Heterogeneous catalysis is a more clean and environmentally-friendly catalytic method. Many heterogeneous catalysts such as basic MCM-41,^12,13 amine-functionalized materials,^14–17 montmorillonite KSF,¹ cationic coordination cage,¹⁸ zeolites,^19,20 enzymes,^21,22 and ionic liquids^23–26 have been developed to catalyze Knoevenagel condensations. These heterogeneous catalysts have higher atom efficiency, stability, operational simplicity, selectivity and recyclability.

With the development of science and the progress of human society, there is an increasing demand to minimize the usage of toxic volatile solvents and use water as an alternative solvent in chemical reactions. Although numerous clean procedures for Knoevenagel reactions have been practised in water or under solvent-free conditions, most of the condensations are reactions of nitrile compounds with aldehydes.^27,28 The existing green technologies are not well suited for the condensations of 1,3-dicarbonyl compounds since these compounds have an inherent tendency to form a stable six-membered enolate which makes it less reactive.^29,30 Only a few groups have undertaken trials, with insignificant progress.^19,31,32 Therefore, it is desirable to develop and characterize highly efficient and reusable heterogeneous catalysts for Knoevenagel condensations between aldehydes and 1,3-dicarbonyl compounds either without solvents or in water.

In this paper, we report in detail a study using Ps-AlCl₃^33–35 as an efficient heterogeneous catalyst for Knoevenagel condensations of 1,3-dicarbonyl compounds (Scheme 1) with various aromatic aldehydes under solvent-free and mild conditions. The experimental results indicate high yields. The water stable Ps-AlCl₃ catalyst can be easily recycled from the reaction system using simple filtration and can be reused several times without loss of activity, which provides a green route for Knoevenagel reactions.

Scheme 1 Knoevenagel condensations of 1,3-dicarbonyl compounds with aldehydes catalyzed by Ps-AlCl₃.

Results and discussion

Characterization

Polystyrene-supported aluminum chloride (Ps-AlCl₃) was prepared by immobilizing anhydrous aluminum chloride on polystyrene (8% divinylbenzene) according to a procedure reported in the literature.³⁶ Although free AlCl₃ is hygroscopic and corrosive, polystyrene supported AlCl₃ is nonhygroscopic, stable, and can be stored in air for a few months without significant loss of activity. Ps-AlCl₃ was characterized by FT-IR and pyridine-adsorbed FT-IR.

The infrared spectra of polystyrene and Ps-AlCl₃ are shown in Fig. 1. The IR spectrum of polystyrene is nearly the same before and after the immobilization of AlCl₃. The successful immobilization of AlCl₃ onto Ps was demonstrated by a new band at 1637 cm⁻¹ in the IR spectrum of Ps-AlCl₃.³⁶

Fig. 1 FT-IR spectra of Ps and Ps-AlCl₃.

The IR spectra of pyridine adsorbed on two Ps-Lewis acids samples in Fig. 2 shows the characteristic band at 1450 cm⁻¹, which was attributed to Lewis acid sites,³⁷ but no band at the same wavelength was observed for the Ps sample. Again this proved that the Lewis acids were successfully immobilized on polystyrene.

Fig. 2 Pyridine-adsorbed FT-IR of Ps and Ps-AlCl₃.

Catalytic studies

Generally, liquid-phase Knoevenagel condensations are carried out in the presence of weak bases or Lewis acids. For a variety of Lewis acids, TiCl₄ is a powerful and effective catalyst for the condensations,^4,38 but it is water unstable and reacts with water severely, therefore strictly anhydrous conditions and stoichiometric amounts or more are required in order to achieve good yields. Moreover, several molar equivalents of triethylamine to titanium tetrachloride are also needed to improve the reaction yields. To overcome these drawbacks, we proposed using aluminum chloride instead of titanium tetrachloride as the catalyst for the condensation of benzaldehyde with acetylacetone. Experiments indicated that 22 mol% AlCl₃ was sufficient for the condensation with 100% conversion at room temperature (Table 1).

Table 1 Reaction conditions optimization for Knoevenagel condensations

Entry	Catalyst	T (°C)	Time (h)	Conversion (%)^c
a Reaction conditions for free AlCl3: benzaldehyde (4 mmol), acetylacetone (4.5 mmol). b Reaction conditions for Ps-AlCl3: benzaldehyde (1.5 mmol), acetylacetone (10 mmol). c Conversion determined by GC. d Ps-AlCl3 was reused five times.
1	100 mol% AlCl3^a	rt	1	100
2	50 mol% AlCl3	rt	1	100
3	22 mol% AlCl3	rt	1	100
4	15 mol% AlCl3	rt	2.5	89
5	15 mol% AlCl3	40	2.5	76
6	15 mol% AlCl3	50	2.5	63
7	15 mol% AlCl3	60	2.5	61
8	20 mol% Ps-AlCl3^b	70	2.2	100
9	20 mol% Ps-AlCl3	60	2.2	100
10	20 mol% Ps-AlCl3	50	3	87
11	20 mol% Ps-AlCl3	40	3	62
12	20 mol% Ps-AlCl3	rt	5	35
13	15 mol% Ps-AlCl3	60	2.5	100, 100, 98, 92, 83^d
14	10 mol% Ps-AlCl3	60	3	81
15	5 mol% Ps-AlCl3	60	4	42

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Given the promising results in Table 1, we continued to prepare Ps-AlCl₃ and test it as a heterogeneous catalyst for the condensation, which could avoid tedious extra work after completion of the reaction and reduce the amount of acidic wastewater generated. The initial reaction was carried out using 20 mol% Ps-AlCl₃ (with respect to the AlCl₃ content in Ps-AlCl₃) relative to benzaldehyde under solvent-free conditions at room temperature. After 5 h, a sample of the reaction mixture was analyzed by GC. The reaction conversion was 35% at rt, and increased with increasing temperature. The optimal temperature was found to be 60 °C with a conversion of 100%. The reason for requiring a higher temperature was that the acidity of Ps-AlCl₃ was weaker than that of anhydrous AlCl₃. In addition, mesoporous pores and channels of polystyrene were unfavorable for the molecular mass transfer process. At the same time, the GC-MS of the reaction mixture indicated that no Michael adducts or other byproducts were generated. After completion of the condensation, Ps-AlCl₃ was filtered out, excess acetylacetone was recycled under reduced pressure, and the residue was almost pure product as confirmed by ¹H NMR spectroscopy. The amount of Ps-AlCl₃ was also an important factor for the condensation, 5 mol% Ps-AlCl₃ gave a conversion of 42% after 4 h while 15 mol% Ps-AlCl₃ was sufficient to give a conversion of 100% after 2.5 h, but the reaction did not occur in the absence of the catalyst or only with polystyrene present. To further confirm that the reaction was not catalyzed by free AlCl₃ released from the support, Ps-AlCl₃ was stirred in acetylacetone for 1 h and filtered out, then benzaldehyde was added to the filtrate and stirred for 2 h at 60 °C, and no reaction was observed.

The generality of the heterogeneous catalyst was also tested in the above optimized Ps-AlCl₃-catalyzed system. We tried various substituted benzaldehydes to condense with acetylacetone and ethyl acetoacetate in the presence of 15 mol% Ps-AlCl₃. The results are summarized in Table 2 and Table 3. Most condensations proceeded smoothly to give the corresponding adducts in good to excellent yields. The electronic effects of substrates had some impact on the condensation. Aromatic aldehydes bearing electron-withdrawing groups exhibited higher reactivity than those possessing electron-donating groups. Products of ethyl acetoacetate were E and Z configuration isomers and the assignment of stereochemistry of different isomers was made on the basis of the chemical shifts of CH=C, which migrated to lower field for the E isomers as confirmed by ¹H NMR.³⁹ Furthermore, acid and base sensitive heteroaromatic aldehydes reacted with acetylacetone and ethyl acetoacetate perfectly, and excellent yields were obtained using our method.

Table 2 Knoevenagel condensations of aromatic aldehydes with acetylacetone^a

Entry	Aldehyde	Time (h)	Yield (%)^b
a Reaction conditions: aldehyde (1.5 mmol), acetylacetone (10 mmol), Ps-AlCl3 (0.5 g, 0.225 mmol AlCl3), 60 °C. b Isolated yield after column chromatography.
1		2.5	98
2		2.0	96
3		2.8	93
4		2.1	98
5		3.5	96
6		3.5	95
7		3.7	96
8		2.3	98
9		2.8	98
10		3.0	97

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Table 3 Knoevenagel condensations of aromatic aldehydes with ethyl acetoacetate^a

Entry	Aldehyde	Time (h)	Yield (%)^b	Z : E^c
a Reaction conditions: aldehyde (1.5 mmol), ethyl acetoacetate (10 mmol), Ps-AlCl3 (0.5 g, 0.225 mmol AlCl3), 60 °C. b Isolated yield after column chromatography. c The Z : E geometry was determined by ^1H NMR.
1		2.5	98	9.9 : 5.5
2		2.1	87	1 : 0
3		3.2	90	5 : 1
4		4.0	95	6.3 : 3.9
5		4.0	96	6.4 : 3.5
6		4.0	95	6.4 : 4.1
7		2.7	97	8.4 : 9.4
8		3.0	96	3.0 : 1.6
9		3.4	95	5.8 : 4.0

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Heterogeneous catalysts also have the advantages of easy separation as well as reusability, therefore the recyclability and reusability of Ps-AlCl₃ was investigated. The Ps-AlCl₃ catalyst was separated by simple filtration after reaction, then washed with plenty of ethyl acetate to remove any physisorbed reagents, dried and used in the next reaction under the same reaction conditions. The results showed that 92% conversion was still achieved at the fourth operation.

Continuing on, we also compared the Ps-AlCl₃ catalyst with some homogeneous or heterogeneous catalysts reported in the literature for the Knoevenagel condensation (Table 4). As shown in Table 4, in terms of reaction conditions, yields and costs, etc., Ps-AlCl₃ has many advantages over reported catalysts.

Table 4 Comparisons of Ps-AlCl₃ with various homogeneous or heterogeneous catalysts in Knoevenagel condensations^a

Entry	Catalyst	Solvent	T (°C)	Time (h)	Yield (%)
a Substrate: benzaldehyde and acetylacetone.
1	Ps-AlCl3	Neat	60	2	98
2	Yb(OPf)3^40	FBS	80	8	80
3	Organobismuth complex^41	[Bmin]BF4	rt	6	95
4	Silica sulfuric acid^32	Neat	rt	10	66
5	Silica functionalized with amino groups^42	Toluene	rt	—	35
6	Zeolites^19	Neat	140	6	32.2
7	Magnetic Fe2O3 functionalized with ionic liquids^43	Water	80	9	91.1
8	Perfluoroalkylated pyridine^44	n-Octane	80	8	82
9	Piperidine AcOH^4	Benzene	Reflux	18	60
10	L-Tryptophan^5	DMSO	rt	16	82
11	NbCl5^45	Neat	rt	1	85
12	Magnesium perchlorate^30	Neat	rt	70	55

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Encouraged by the results above, we then investigated the reaction mechanism. Based on Fontana and Re’s investigation of TiCl₄,³⁸ we hypothesized the mechanism of Ps-AlCl₃-catalyzed Knoevenagel condensation (Scheme 2). First, the addition of Ps-AlCl₃ to acetylacetone results in the formation of an aluminum enolate anion and a hydrion. Second, the hydrion simultaneously polarizes the aldehyde and aluminum enolate anion attacking the carbonyl carbon atom to form a carbon–carbon bond. Finally, the dehydration takes place on the intermediate, then the dissociation of Ps-AlCl₃ resulting in the formation of the Knoevenagel adduct.

Scheme 2 The proposed mechanism of Knoevenagel condensation catalyzed by Ps-AlCl₃.

Conclusion

Ps-AlCl₃ was an efficient catalyst for Knoevenagel condensation of less active 1,3-dicarbonyl compounds with aldehydes. The condensations were carried out smoothly with high yields under solvent-free and mild reaction conditions in the presence of the Ps-AlCl₃ catalyst. After completion of the reaction, Ps-AlCl₃ could be easily separated from the reaction system via filtration, showing better recyclability and reusability without loss of activity. We believe that this new methodology has contributions to the environmentally-friendly synthesis of substituted electrophilic alkenes.

Experimental

General

All the chemicals used were of analytical grade and were used without further purification. Polystyrene (8% divinylbenzene) was purchased from Nanjing Microspheres Hi-Efficiency Isolation Carrier Co., Ltd. IR spectra were recorded on a Shimadzu FTIR-8400S spectrophotometer. GC profiles were recorded on FuLi 9790 with a SE-54 column (30 m × 0.32 mm × 0.5 μm). GC-MS was recorded on Hewlett-Packard system HP 6890 gas chromatograph. ¹H and ¹³C NMR spectra were recorded in CDCl₃ using TMS as an internal standard on a Bruker spectrophotometer at 500 and 125 MHz respectively. High resolution mass spectrum of the new compound was recorded on GCTPremier at 70 eV.

Catalyst preparation

0.9 g anhydrous AlCl₃ was added to polystyrene (8% divinylbenzene, 3.5 g) in carbon disulfide (25 ml). The mixture was stirred under reflux for 2 h, cooled to room temperature and then cold water was cautiously added to hydrolyze the excess aluminum chloride. The mixture was stirred until the deep orange color disappeared and the catalyst became light yellow, then it was filtered, and the polymer beads were collected, washed with water (250 ml), then with ether, finally it was dried to a constant weight under vacuum. The capacity of Ps-AlCl₃ based on its chloride content, which was determined by the Mohr titration method, was 0.45 AlCl₃ mmol per g of catalyst.³⁶

Catalyst characterization

Polystyrene and Ps-AlCl₃ were dehydrated in an infrared (IR) cell at 100 °C for 2 h under vacuum before pyridine adsorption. Pyridine was added to the IR cell at 100 °C. Pyridine adsorption IR spectra of polystyrene and Ps-AlCl₃ were measured at room temperature after pyridine desorption at 100 °C for 2 h.

Knoevenagel condensation

In a typical experiment, a mixture of aldehyde (1.5 mmol), acetylacetone (10 mmol) and Ps-AlCl₃ (0.5 g, 0.225 mmol AlCl₃) was stirred at 60 °C for 2.5 h. After completion of the reaction, Ps-AlCl₃ was filtered and washed with ethyl acetate (3 × 10 ml). The filtrate was concentrated to give the almost pure crude product, which was purified further by column chromatography (petroleum ether/ethyl acetate) if necessary.

Selected spectral data

3-Benzylidenepentane-2,4-dione. ¹H NMR (CDCl₃, 500 MHz): δ 7.49 (s, 1H), δ 7.40 (s, 5H), δ 2.43 (s, 3H), δ 2.29 (s, 3H).

3-(2-Nitrobenzylidene)pentane-2,4-dione. ¹H NMR (CDCl₃, 500 MHz): δ 8.22–8.24 (d, 1H), δ 7.92 (s, 1H), δ 7.65–7.68 (t, 1H), δ 7.58–7.61 (t, 1H), δ 7.39–7.40 (d, 1H), δ 2.49 (s, 3H), δ 2.12 (s, 3H).

3-(Furan-2-ylmethylene)pentane-2,4-dione. ¹H NMR (CDCl₃, 500 MHz): δ 7.72–7.75 (m, 1H), δ 7.42–7.44 (d, 1H), δ 7.33 (s, 1H), δ 7.25–7.27 (t, 1H), δ 2.46 (s, 3H), δ 2.44 (s, 3H).

3-(p-Tolyl)pentane-2,4-dione. ¹H NMR (CDCl₃, 500 MHz): δ 7.46 (s, 1H), δ 7.29–7.30 (d, 2H), δ 7.18–7.19 (d, 2H), δ 2.41 (s, 3H), δ 2.36 (s, 3H), δ 2.29 (s, 3H).

3-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)methylene)pentane-2,4-dione (new compound). Yellow oil, ¹H NMR (CDCl₃, 500 MHz): δ 7.35 (s, 1H), δ 6.90–6.93 (m, 2H), δ 6.84–6.86 (d, 2H), δ 4.28–4.29 (t, J = 3.5 Hz, 2H), δ 4.25–4.26 (t, J = 1.5 Hz, 2H), δ 2.39 (s, 3H), δ 2.32 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ = 206.17, 196.68, 146.25, 143.89, 141.18, 139.74, 126.27, 124.09, 118.95, 118.04, 64.74, 64.27, 31.80, 26.51 ppm. HRMS: m/z calcd for C₁₄H₁₄O₄: 246.0892, found: 246.0890.

Acknowledgements

The authors would like to thank Dr Zhengbao Wang for infrared spectra and pyridine-adsorbed IR, Nanjing Microspheres Hi-Efficiency Isolation Carrier Co., Ltd for providing polystyrene. This work was supported by the NSFC (No: 21176213), and Zhejiang Key Innovation Team of Green Pharmaceutical Technology (No: 2010R50043).

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Footnote

† Electronic supplementary information (ESI) available: ¹H NMR spectra, ¹³C NMR spectrum, GC-MS profile, HRMS profile. See DOI: 10.1039/c2ra21571c

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