Novel DABCO Based Ionic Liquids: Green and Efficient Catalysts with

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Novel DABCO Based Ionic Liquids: Green and Efficient Catalysts with Dual Catalytic Roles for Aqueous Knoevenagel Condensation Anguo Ying,‡ Yuxiang Ni,† Songlin Xu,†,* Shuo Liu,† Jianguo Yang,‡ and Rongrong Li‡ †

School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People’s Republic of China School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou 318000, People’s Republic of China

‡

S Supporting Information *

ABSTRACT: Four novel basic ionic liquids (ILs), based on 1,4-diazobicyclo[2.2.2]octane (DABCO) and 3-chloro-1,2propanediol, have been introduced as catalysts for Knoevenagel condensation. These catalysts are applicable to a wide range of aromatic/heteroaromatic aldehydes with α-aromatic (heteroaromatic or polyaromatic)-substituted methylene compounds in water at room temperature, and they afford the products in excellent yields within short times. These reactions are operationally simple, and the desired products can be separated directly from the reaction mixture without further purification. A possible reaction mechanism was proposed, and the relevant evidence was given. In addition, the ionic liquids used can be regenerated and recycled several times without significant loss of activity. Furthermore, the novel ILs could be efficiently used in a step of atorvastatin synthesis.

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INTRODUCTION In recent years, ionic liquids (ILs) have attracted significant attention as potentially benign media for a wide range of applications in chemistry, electrochemistry, and materials sciences.1−4 Although the ionic liquid was initially introduced as an alternative green reaction medium, today it has marched far beyond, showing its significant role in controlling the reaction as catalyst. The large number of cations and anions allow a wide range of physical and chemical characteristics to be achieved, including volatile and involatile systems, and thus the terms “designer” and “task-specific’’ ILs have been developed.5−8 The prospects for ionic liquid use are vast. And many functional ILs have been synthesized and utilized as catalysts for different reactions.9−11 All these functional ILs possess physicochemical properties that make them improved media able to increase reactivity, selectivity, catalyst recyclability, and so on. Knoevenagel condensation is one of the most important reactions in organic synthesis for carbon−carbon bond formation. It has been used for the synthesis of important chemical intermediates, pharmaceuticals, polymers, cosmetics, and perfumes.4,12−15 Traditionally, Knoevenagel condensation is performed in organic solvents in the presence of common bases, such as ammonia, primary or secondary amines, and their salts.16−18 However, the tedious recovery of these catalysts reaction solutions imposed an environmental barrier upon their further application on an industrial scale. Recently, a wide array of catalysts have been used in the Knoevenagel condensation, such as Lewis acids,19,20 solid bases,21−23 supported heterogeneous catalysts,24−27 and “task-specific” ionic liquids.28−31 However, there are still a lot of disadvantages associated with these new catalysts, such as long reaction time, harsh reaction conditions, use of hazardous organic solvents, and difficulty in catalyst recovery. In most cases, the range of methylene compounds was limited to malononitrile and ethyl cyanoacetate,9,32−34 and few examples used α-aromatic (heteroaromatic © 2014 American Chemical Society

or polyaromatic)-substituted methylene compounds at room temperature with excellent yields, in which the active carbon exhibits relatively weak nucleophilicity because of the steric hindrance of the aryl group. In this work, we report on the synthesis and application of four novel basic ionic liquids with dual catalytic roles based on 1,4-diazobicyclo[2.2.2]octane (DABCO) and 3-chloro-1,2propanediol (Figure 1), which can highly catalyze the

Figure 1. Structures of the [DABCO-PDO][X] ionic liquids.

Knoevenagel condensation reactions of aromatic or heteroaromatic aldehydes and α-aromatic (heteroaromatic or polyaromatic)-substituted methylene compounds (Scheme 1). Moreover, the catalysis can be performed in water, which is compatible with “green chemistry”, because, in comparison with organic solvents, water is inexpensive and safe and leads to the development of environmentally friendly chemical processes.35,36 Another advantage is that the catalysts can be recycled many times without loss of activity, offering a greener route to Knoevenagel condensation products. Received: Revised: Accepted: Published: 5678

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Scheme 1

Scheme 2. Synthesis of the [DABCO-PDO][X] Ionic Liquids

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EXPERIMENTAL SECTION General. 1H and 13C NMR were recorded on a Bruker Avance DPX 400 spectrometer at 400 and 100 MHz, respectively. Chemical shifts were reported in parts per million (δ), relative to the internal standard of tetramethylsilane (TMS). All the materials in reactions are commercially available and were used without further purification. Preparation of the Catalysts [DABCO-PDO][X]. To a solution of 1,4-diazobicyclo[2.2.2]octane (DABCO) (11.2 g, 0.1 mol) in ethanol (50 mL) was added 3-chloro-1,2propanediol (8.4 mL, 0.1 mol), and the mixture was refluxed for 24 h. The solvent was removed by rotatory evaporation under reduced pressure, and the intermediate 1 was obtained without any purification. Then, the ion exchange reagent (potassium acetate/sodium fluoroborate/potassium hexafluorophosphate/potassium trifluoromethanesulfonate) (0.02 mol) was added to a solution of 1 (4.45g, 0.02 mol) in methanol (20 mL). The mixture was refluxed for 8 h and evaporated under reduced pressure to give the corresponding IL catalyst. General Procedure for the Knoevenagel Condensation Catalyzed by [DABCO-PDO][OAc]. A mixture of aromatic/heteroaromatic aldehydes (1.0 mmol), α-aromatic (heteroaromatic or polyaromatic)-substituted methylene compounds (1.0 mmol), and catalyst (15 mol %) was stirred at room temperature in water (2 mL). The formation of the products was monitored by TLC. After completion of the reaction, the product solidified from the reaction mixture. Then it was filtered and purified with recrystallization using ethanol. The products were characterized by 1H NMR and 13C NMR. The ionic liquid catalysts were recovered by removing the water of the filtrate and reused in the reaction seven times. Selected data for typical compounds are given in the Supporting Information (SI).

Table 1. Effect of Catalyst on the Knoevenagel Condensation of Benzaldehyde and Benzothiazole-2acetonitrile in Watera

entry

catalyst (mol %)

time

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12

[DABCO-PDO][OAc] [DABCO-PDO][BF4] [DABCO-PDO][PF6] [DABCO-PDO][CF3SO3] triethylamine no catalyst [DABCO-PDO][OAc] (10 mol %) [DABCO-PDO][OAc] (5 mol %) [DABCO-PDO][OAc] (1 mol %) [DABCO-PDO][OAc] (0.2 mol %) [DABCO-PDO][OAc] (20 mol %) [DABCO-PDO][OAc] (25 mol %)

3 min 10 min 10 min 30 min 1h 6h 15 min 30 min 1h 3h 3 min 3 min

96 82 86 85 73 trace 89 86 61 53 96 95

a Unless otherwise shown, the reaction was performed with benzaldehyde (1.0 mmol), benzothiazole-2-acetonitrile (1.0 mmol), catalyst (15 mol %), and water (1 mL), and at room temperature. b Isolated yield based on benzaldehyde.

PDO][BF4], [DABCO-PDO][PF6], or [DABCO-PDO][CH3SO3] proceeded efficiently and gave the desired product in good to excellent yields within 30 min (Table 1, entries 1− 4). The ionic liquid containing the acetate anion showed higher catalytic activity than those containing tetrafluoroborate, hexafluorophosphate, or methylsulfonic anion. For comparison, we used triethylamine as the catalyst, and the reaction mixture solidified in 1 h with 73% yield (Table 1, entry 5). When reacted without the addition of catalyst, only a trace amount of product was detected even after 6 h of reaction (Table 1, entry 6). So in our further study, catalyst [DABCO-PDO][OAc] was used as the optimal choice for further investigation. To investigate the effect of catalyst loading on Knoevenagel condensation, the model reaction was carried out in the presence of different amounts of catalyst. When we reduced the amount of the catalyst to 10 mol % and 5 mol %, the yields were also very high, while the reaction rates were decreased (Table 1, entries 7−8). When the catalyst amount was further reduced to 1 mol % and 0.2 mol %, the desired product with moderate yield after a certain long reaction time was obtained (Table 1, entries 9−10). While the amount of IL was increased over 20 mol % and 25 mol % equivalent, neither the yield nor the reaction time was improved (Table 1, entries 11−12).

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RESULTS AND DISCUSSION The novel DABCO based ionic liquids were synthesized from commercially available 1,4-diazobicyclo[2.2.2]octane (DABCO) and 3-chloro-1,2-propanediol, followed by anion exchange (Scheme 2). The specific method of synthesis of [DABCO-PDO][X] is described in the Experimental Section. In order to test the catalytic activity of four different novel basic ILs, the Knoevenagel condensation of benzaldehyde and benzothiazole-2-acetonitrile in water was selected as model reaction and the results are summarized in Table 1. From Table 1, we found that the condensation reaction of benzaldehyde with benzothiazole-2-acetonitrile in water catalyzed by any one of [DABCO-PDO][OAc], [DABCO5679

dx.doi.org/10.1021/ie500440w | Ind. Eng. Chem. Res. 2014, 53, 5678−5682

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act as a suitable catalyst with respect to reaction time and yield of the product. A plausible mechanism for the reaction between benzaldehyde and benzothiazole-2-acetonitrile catalyzed by [DABCOPDO][OAc] is shown in Scheme 3. On the one hand, the lone pair electrons on the N atom of the IL can take away the hydrogen atom of active methylene to form a corresponding active carbon anion. On the other hand, the hydrogen bonding interactions between the hydroxyl groups of the IL and the carbonyl group of the aldehyde increase the electrophilicity of the aldehyde carbon atom. Due to this dual catalysis, the condensation reactions could offer excellent yields in short times. This plausible mechanism could be verified by comparison of the 13C NMR spectra of the benzaldehyde and benzaldehyde[DABCO-PDO][OAc] mixture (SI Figure S1), and the results are shown in Table 3. It was found that the chemical shift of

These experiments show that the rational amount of the catalyst [DABCO-PDO][OAc] was 15 mol %. To evaluate the scope and limitations of this methodology, we extended our studies to the reaction of benzothiazole-2acetonitrile with a variety of structurally diverse aromatic aldehydes under the optimized conditions. The results are summarized in Table 2 (SI Table S1, entries 1−9). All the Table 2. Comparison Results with Different Catalysts and Conditions in the Synthesis of 2-(Benzothiazol-2-yl)-3phenylacrylonitrile entry

catalyst

1

free

2 3

triethylamine TMSCl

4

[DABCOPDO][OAc]

conditions

time

yield (%)

microwave irradiation, solvent-free ethanol DMF, pressure tube, water bath water, room temperature

15 min

7037

1h 2h

9838 9739

3 min

96 (present work)

Table 3. 13C NMR Data of Benzaldehyde and the Benzaldehyde−[DABCO-PDO][OAc] Mixture

reactions proceeded smoothly to afford good to excellent yields, and there is a common reaction phenomenon that aromatic aldehydes bearing with electron-withdrawing groups (NO2, Cl, and CF3) reacted a little faster than aldehydes bearing with electron-donating (CH3, OCH3, and N(CH3)2) substituents. Benzimidazolylacetonitrile is also an efficient substrate to undergo with aromatic aldehydes to give the corresponding products within 10 min in 87−95% yields (SI Table S1, entries 10−17). Moreover, benzimidazolylacetonitrile can also react with heteroaromatic aldehydes and give excellent reaction yields (SI Table S1, entries 18−19). To our pleasure, the catalyst [DABCO-PDO][OAc] was also compatible with phenylacetonitrile and indole-2-acetonitrile, and the desired products were obtained in excellent yields when we prolonged the reaction time to 60 min (SI Table S1, entries 20−29). These reactions need more time to finish, most probably due to their relatively low C−H acidity. It is noteworthy that all products obtained are E-geometry exclusively. This is a very simple and mild reaction, which is readily amenable to largescale synthesis. Using this procedure, we tried the reaction out on a 1 mol scale (reaction of benzaldehyde and benzothiazole2-acetonitrile), and the desired product was prepared in 97% yield. To show the merit of the present work, we compared the result regarding the reaction of 2-(benzothiazol-2-yl)-3-phenylacrylonitrile with the reported results in the literature. As shown in Table 2, the [DABCO-PDO][OAc] ionic liquid can

carbonyl in benzaldehyde is 193.28, while it is 193.38 in the mixture. The chemical shift is offset by 0.1, which indicates an interaction between the hydroxyl groups of the IL and the carbonyl group of the aldehyde. To further demonstrate that the hydroxyl groups of the IL can activate the carbonyl of benzaldehyde, a [DABCO][OAc] ionic liquid (see Scheme 4) was prepared and used as catalyst Scheme 4. Structures of [DABCO-PDO][OAc] and [DABCO][OAc]

Scheme 3. Plausible Mechanism for the Reaction between Benzaldehyde and Benzothiazole-2-acetonitrile Catalyzed by [DABCO-PDO][OAc]

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products, which solidified from the system in a few minutes, did not need to be purified. The catalysts can be recycled seven times without significant loss of catalytic activity, offering a green route to Knoevenagel condensation products. Furthermore, the novel IL [DABCO-PDO][OAc] could be efficiently used in a step of atorvastatin synthesis, which would greatly contribute to an industrially feasible manufacturing process for atorvastatin.

in the reaction of benzaldehyde with benzothiazole-2acetonitrile. Under the same conditions, the reaction yield was only 77%, far below the yield catalyzed by [DABCOPDO][OAc] (96%) (see Scheme 4) . The comparative experiments also show that the hydroxyl groups play an important role in the process of the catalytic reaction. For practical applications of ionic liquids, the recyclability of the catalyst is a very important factor. To clarify this issue, one of the most effective functionalized ILs, [DABCO-PDO][OAc], was selected to investigate the recyclability and the reaction of benzothiazole-2-acetonitrile, with benzaldehyde used as a model. Once product had been filtered from the mixture, excess water was evaporated from the IL [DABCOPDO][OAc] under vacuum, and the catalyst was reused for the same reaction. The results demonstrated in SI Figure S2 indicate that the catalyst showed no substantial reduction in activity even after the seventh reuse. All reactions were completed within 3 min and afford excellent yields. Encouraged by the exciting results of cyano-substituted methylene compounds, we have also studied the reaction of acetylacetone with benzaldehyde under the same optimized conditions (Scheme 5). The reaction was completed within 1 h,

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ASSOCIATED CONTENT

S Supporting Information *

Table for Knoevenagel condensation of various substituted aldehydes and methylene active compounds, spectral data and copies of 1H and 13C NMR for novel ILs and representative condensation products, and the intermediate for preparation of Atorvastatin calcium. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Tel/Fax: 86-22-87402107. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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Scheme 5. Reaction of Acetylacetone with Benzaldehyde Catalyzed by [DABCO-PDO][OAc]

ACKNOWLEDGMENTS We are grateful for the financial supports of this research by the National Natural Science Foundation of China (Grant Nos. 21106090, 21176170 and 21272169), and Foundation of Low Carbon Fatty Amine Engineering Research Center of Zhejiang Province (2012E10033).

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and excellent yield of product was obtained (95%). We continued to investigate the reaction of benzaldehyde with 4methyl-3-oxo-N-phenylpentanamide (2), which is an important step in atorvastatin synthesis (Scheme 6). To our pleasure, the synthesis of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide (3) can proceed at room temperature using [DABCO-PDO][OAc] as catalyst, and gives 83% yield within 3 h. Compared to the traditional procedure,40 the method we used can avoid the use of organic solvent and greatly shorten the reaction time, which would greatly contribute to the industrially feasible manufacturing process for atorvastatin

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CONCLUSIONS In summary, we have developed four novel DABCO based ionic liquids which can be used as efficient and recyclable catalysts for the Knoevenagel condensation reactions of aromatic/heteroaromatic aldehydes with α-aromatic (heteroaromatic or polyaromatic)-substituted methylene compounds at room temperature in water. The reactions proceed smoothly and afford the desired products in good to excellent yields. The Scheme 6. Route of Atorvastatin Synthesis

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