Malonic esters, Knoevenagel reaction

Malonic Ester Derivatives (Knoevenagel reaction). Malonic acid esters can be condensed with aldehydes through the use of a basic catalyst. The very labile a-H atom of the malonic ester reacts with the catalyst as follows ... 

The prototype of a Knoevenagel reaction shown in the scheme above is the condensation of an aldehyde or ketone 1 with a malonic ester 2, to yield an a ,/3-unsaturated carboxylic ester 4. 

The Knoevenagel reaction is a carbonyl condensation reaction of an ester with an aldehyde or ketone to yield an a,j8-unsaturated product. Show the mechanism of the Knoevenagel reaction of diethyl malonate with benzaldchyde. 

The cz5-aziridine substrate shows, as expected on the basis of this model, predominant formation of the trans-cyclopropane product. The starting materials for this MIRC reaction can readily be obtained from the aziridine esters by reduction to the corresponding aldehyde and a subsequent Knoevenagel reaction with malonate ester (Scheme 25) [34]. 

The carbon nucleophiles in amine-catalyzed reaction conditions are usually rather acidic compounds containing two electron-attracting substituents. Malonic esters, cyanoacetic esters, and cyanoacetamide are examples of compounds which undergo condensation reactions under Knoevenagel conditions.115 Nitroalkanes are also effective nucleophilic reactants. The single nitro group sufficiently activates the a hydrogens to permit deprotonation under the weakly basic conditions. Usually, the product that is isolated is... 

Di-tert-butyl methylenemalonate was originally prepared by phenyl-sulfenylation of di-tert-butyl methylmalonate and thermal elimination of the related sulfoxide.8 Because methylenemalonate esters are customarily prepared by Knoevenagel-type condensation of malonic esters with formaldehyde equivalents, the considerably more convenient procedure described herein was subsequently adapted from Bachman and Tanner s study using paraformaldehyde under metal ion catalysis.39 The approximately 6% di-tert-butyl malonate accompanying the product has presented no interference in the aforementioned reactions with nucleophilic alkenes under neutral or acidic conditions, but its presence should be taken into consideration in other applications. 

Titanium(IV) chloride is used as the catalyst in a Knoevenagel reaction between various 2,2-disubstituted 3-hydroxypropanals and malonic acid or its esters. The products are substituted dihydropyran-2-ones (536) (79LA751). The reaction, which occurs cleanly and in good yield, utilizes an excess of the titanium halide and is thought to involve a cyclic complex which undergoes an ester exchange to a lactone complex (Scheme 198). 

Most C,H-acidic compounds can be condensed with aldehydes or ketones to yield alkenes. Some of these reactions have also been realized on insoluble supports, with either the C,H-acidic (nucleophilic) reactant or the electrophilic reactant linked to the support. Some illustrative examples are listed in Table 5.6. Polystyrene-bound malonic esters or amides, cyanoacetamides, nitroacetic ester [95], and 3-oxo esters undergo Knoevenagel condensation with aromatic or aliphatic aldehydes. Catalytic amounts of piperidine and heating are generally required, although reactive substrates can react at room temperature. 

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

This reaction type leading to oc,/ -unsaturated acids and esters is exemplified in the Perkin reaction (Section 6.12.3, p. 1036) and the Knoevenagel reaction (Section 5.11.6, p. 681). The Doebner reaction, which is illustrated in this section, is the condensation of an aldehyde with malonic acid in pyridine solution, often in the presence of a trace of piperidine. The reaction mechanism involves the addition of a malonate anion to the aldehydic carbonyl carbon atom followed by the elimination of water accompanied by decarboxylation. 

Substituted malonic acids are obtained by alkaline hydrolysis of alkyl-cyano esters prepared either by direct alkylation or by reduction of unsaturated cyano esters from the Knoevenagel reaction. ... 

Olefinic esters may be obtained directly by the Knoevenagel reaction. Alkyl hydrogen malonates are used in place of malonic acid. Decarboxylation then gives the ester directly as in the preparation of ethyl 2-heptenoate (78%) and methyl m-nitrocinnamate (87%). Alkyl hydrogen malonates are readily available by partial hydrolysis of dialkyl malonates. The use of malonic ester in the condensation leads to olefinic diesters, namely, alkylidenemalonates such as ethyl heptylidenemalonate (68%). A small amount of organic acid is added to the amine catalyst since the salts rather than the free amines have been shown to be the catalysts in condensations of this type. Various catalysts have been studied in the preparation of diethyl methylenemalonate. Increased yields are obtained in the presence of copper salts. Trimethylacetalde-hyde and malonic ester are condensed by acetic anhydride and zinc chloride. Acetic anhydride is also used for the condensation of furfural and malonic ester to furfurylidenemalonic ester (82%). ... 

We have been particularly enamored with the development of experiments involving carbon-carbon bond formation, especially as part of tandem reactions occurring in a single container (see the Diels-Alder reaction. Figure 1). One such reaction is the synthesis of simple esters of coumarin-3-carboxylic acids via a Knoevenagel condensation between malonic esters and various a-hydroxybenzaldehydes, followed by intramolecular nucleophilic acyl substitution. This conversion, catalyzed by piperidine, has been carried out under a variety of conditions, for example, at room temperature without solvent... 

Problem 26.3 (a) Malonic ester reacts with benzaldehyde in the presence of piperidine (a secondary amine. Sec. 31.12) to yield a product of formula C14H16O4. What is this compound, and how is it formed (This is an example of the Knoevenagel reaction. Check your answer in Problem 21.22 (f), p. 714.) (b) What compound would be obtained if the product of (a) w ere subjected to the sequence of hydrolysis, acidification, and heating (c) What is another way to synthesize the product of (b) ... 

Knoevenagel Reaction. This involves the reaction of an aldehyde with malonic ester or /3-keto esters. The reaction is catalyzed by amines. 

The Knoevenagel reaction is the condensation of malonic esters or acetoacetic esters (an active methylene) with aldehydes or ketones. The catalysts are mostly organoamines. 

Most aldehydes easily undergo Knoevenagel condensation using secondary amines or their salts as a catalyst. Under standard conditions, reaction of simple unbranched aliphatic aldehydes and of most ketones is difficult. However, the use of TiCWamine allows reaction even of refractory aldehydes and a multitude of ketones in good to very good yields." -" For example, the synthesis of Knoevenagel adducts (72) from 5-formyl-octaethylporphyrin (71) and different malonic esters in the presence of TiCU/pyridine at 0 "C has been achieved in 75-94% yield." ... 

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