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    Home > Green chem.: synthesis of cinnamamide derivatives from aromatic aldehydes, amines and Meldrum acids by three component coupling reaction

    Green chem.: synthesis of cinnamamide derivatives from aromatic aldehydes, amines and Meldrum acids by three component coupling reaction

    • Last Update: 2019-10-24
    • Source: Internet
    • Author: User
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    Cinnamamides are a kind of important compounds, which have a wide range of biological activities, such as anti-cancer, anti malaria, anti Trypanosoma, anti-oxidation, anti diabetes, anti microbial activities and so on In addition, cinnamamide is the key structural unit of many natural products In pharmaceutical chemistry, many cinnamamides with various structures have been prepared to explore their structure-activity relationships At present, the synthesis methods of cinnamamide or piperonamide mainly include (scheme 1a-1c): the coupling reaction between cinnamic acid derivatives and amines, or the oxidation amidation reaction of Cinnamaldehyde and Wittig or Horner Wadsworth Emmons reaction of aromatic aldehydes However, the raw materials of most of the above methods need to be prepared in multiple steps, and there are many by-products Therefore, it is necessary to develop a simple method for the synthesis of cinnamamide Recently, Professor Chandan K Jana's research group of Indian Institute of Technology reported the first one-step method to prepare cinnamamide and piperonamide through the three-component reaction of aldehyde, amine and Meldrum acid, and no additional catalyst or additive is required in this process Relevant research results were published on green chem (DOI: 10.1039/c9gc02937k) (source: Green chem.) the author first studied the three-component reaction of benzylamine, 4-Chlorobenzaldehyde and Meldrum acid (1) at room temperature (Table 1) However, the target CINNAMAMIDE 6A (entry 1) was not obtained when the reaction was carried out at room temperature It is gratifying that the product 6A (entry 2) was obtained in 67% yield when the reaction was carried out in toluene reflux After further screening, the author found that the target product 6A (entry 4) could be obtained by reacting Meldrum acid, 4-Chlorobenzaldehyde and benzylamine in toluene at 110 ℃ for 8 hours with 68% yield (source: Green chem.) under the optimal reaction conditions, the author investigated the scope of application of the substrate (scheme 3) A variety of aromatic aldehydes 2 and amines 7 react with Meldrum acid to obtain the corresponding cinnamamide 6B - 6q in high yield Even the substrates (aldehydes and amines) with electron donor groups (such as methyl, methoxy) and electron acceptor groups (such as fluorine and chlorine) can react efficiently to obtain the needed cinnamamide In addition, noncyclic primary amines and secondary amines can also react smoothly to obtain cinnamamide (6L - 6q) in good yield (source: Green chem.) then, the author also applied the method to the synthesis of natural cinnamamide and piperonamide In the standard reaction system, a series of piperonamide 8A - 8i with various structures can be prepared in one step with high yield (scheme 4) (source: Green chem.) in order to further illustrate the practical application value of this reaction, the author has carried out gram scale preparation and synthesized 1.8g and 6G natural CINNAMAMIDE 8a and 8b (scheme 5) efficiently (source: Green chem.) in order to further understand the mechanism of the three-component reaction, the author conducted a control experiment (scheme 6a) At room temperature, benzylamine reacts with Meldrum acid (1) to obtain malonic acid monoamide 9, which reacts with 4-methoxybenzaldehyde under standard conditions to obtain cinnamamide 6e in 78% yield, while styrene derivative 10 reacts with cinnamic acid 11 and benzylamine to obtain 6e in a lower yield This indicates that the reaction may be carried out by malonic acid derivative 9 (source: Green chem.) according to the experimental results, the author proposed the possible mechanism of the three-component reaction (scheme 6b) At first, amine 4 reacts with Meldrum acid 1 to form monoamide of malonic acid 12 and acetone The product amide 15 can be formed in two possible ways On the one hand, 12 reacts with aromatic aldehydes via aldol condensation to produce β - hydroxy acid 13 On the other hand, 12 and aldehydes can be condensed by Knoevenagel to form benzyl derivative 14 from corresponding alcohol 13; 14 can be decarboxylated and / or alcohol 13 can be decarboxylated to obtain trans cinnamamide 15 with more stable thermodynamics Summary: a three-component reaction involving aldehydes, amines and Meldrum acid was developed, and various cinnamamide and piperonamide were prepared, with better yield than most known methods No other catalyst, oxidant and other by-products are needed in this reaction This method will be helpful for the synthesis of cinnamamide / piperonamide compounds with medicinal value, so as to find more effective drug molecules.
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