Cheap, abundant but seldom-employed Ca(OH)2 was found khổng lồ be an excellent low-loading (5–10 mol%) catalyst for Claisen-Schmidt condensation of aldehydes with methyl ketones under mild conditions. It was interesting that dilute aqueous ethanol (20 v/v%) was unexpectedly discovered lớn be the optimal solvent. The reaction was scalable at least lớn 100 mmol & calcium could be precipitated by CO2 and removed by filtration. Evaporation of solvent directly afforded the hàng hóa in the excellent 96% yield with high purity, as confirmed by its 1H NMR spectrum.
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α,β-Unsaturated ketones, including dimethylidene acetone derivatives, are not only important building blocks in organic synthesis, but also key chemicals in many fields including perfumery, biochemistry, agriculture, food chemistry, polymer & material science & others1,2,3,4. Therefore, the synthesis of these compounds is of great importance in both academic & industrial circles. Among reported works, Claisen-Schmidt condensation appears to lớn be the most practical method to prepare α,β-unsaturated ketones owing khổng lồ its directness, clean procedures and accessible starting materials. Despite being discovered over 100 years ago, the enthusiasm for Claisen-Schmidt condensations never reduces & in recent years, a series of novel catalysts have been developed for this reaction, such as solid bases5,6, nano catalysts7,8, ionic liquid catalysts9, fluorous based catalysts10,11, metal-organic frame works (MOFs)12 & organocatalysts13,14. Nevertheless, cheap and abundant NaOH would be expected lớn be the most common catalyst for the reaction due to lớn its availability in laboratory and indeed this method is still widely employed up khổng lồ the present15,16,17. But reactions performed in strong alkaline conditions are corrosive lớn equipment and generate unmanageable & corrosive solid waste. These drawbacks have limited the large-scale application of NaOH. Moreover, methods for the synthesis of dimethylidene acetone derivatives, especially for those dissymmetrically substituted compounds, have not been well documented yet. Thus, developing novel alternative synthetic methodologies with broad scope using mild và common base catalysts is not only desirable but timely for the field.
Calcium hydroxide is also a readily accessible base and compared with NaOH, it is much cheaper và less alkaline. Moreover, Ca(OH)2 is easily neutralized & precipitated by CO2, which is beneficial from the point of industrial use. However, despite several well-known applications in industrial production, examples of the employment of Ca(OH)2 as a base catalyst in organic synthesis are rare18. As part of our continuing cooperative research projects with industrial partners to develop green synthetic methodologies19,20,21,22,23,24,25,26,27,28, we reported an organoselenium-catalyzed green oxidation of α,β-unsaturated ketones to lớn prepare vinyl esters, which serve as versatile copolymers in material science24. To facilitate industrial application, a green and practical synthesis of α,β-unsaturated ketones (the starting material for vinyl ester synthesis) was desired. To lớn that end, we investigated the Ca(OH)2-catalyzed Claisen-Schmidt condensations khổng lồ prepare α,β-unsaturated ketones. During this work, dilute aqueous ethanol was unexpectedly found khổng lồ be the optimal solvent and calcium could be precipitated by CO2 và removed by filtration to afford high purity products after solvent evaporation. The method allows comprehensive access khổng lồ versatile α,β-unsaturated ketones, including the challenging dissymmetrically substituted dimethylidene acetone derivatives. Herein, we wish to lớn report our findings.
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We initially chose the Ca(OH)2-catalyzed Claisen-Schmidt condensation of benzaldehyde 1a with acetone 2a as the mã sản phẩm reaction to find optimal conditions (Fig. 1). After heating 1a, 2a and 10 mol% of Ca(OH)2 in EtOH at 50 °C for 20 h, the hàng hóa benzylideneacetone 3a could be isolated in 68% yield (Table 1, entry 1). During the reaction process, we observed Ca(OH)2 precipitation at the bottom of the tube, which implied the low efficiency of alkali utilization. Therefore, water was then added to increase the Ca(OH)2 solubility. When the reaction was performed in EtOH/H2O (80:20), it was significantly accelerated và finished in 16 h, giving 3a in 69% yield (entry 2). The reaction was further accelerated and the hàng hóa yields were enhanced greatly by increasing the proportional of water in the solvent (entries 3–4). Surprisingly, EtOH/H2O (20:80) as solvent gave the highest sản phẩm yield in 85% (entry 4). Increased ratios of water in the solvent only resulted in reduced sản phẩm yield và extended reaction times (entry 5), possibly due lớn the reduced substrate dissolution that inhibited the reaction. When the reactions were taken in highly diluted aqueous EtOH (entry 6) or pure water (entry 7), no hàng hóa 3a was observed. It is notable that the combination of EtOH with water played a key role in this reaction. A series of parallel reactions showed that the effect of EtOH/H2O was not only solvent for both organic substrates & inorganic base, but it also activated the Ca(OH)2. Experiments performed in acetone or acetone/EtOH resulted in very low product yields despite the reaction temperature. For details, please see the Supplementary Information.