Unsaturated carboxylic esters condensation

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. 

Because of the mild reaction conditions, and its broad applicability, the Knoevenagel reaction is an important method for the synthesis of a ,/3-unsaturated carboxylic acids. Comparable methods are the Reformatsky reaction, the Perkin reaction, as well as the Claisen ester condensation. The Knoevenagel reaction is of greater versatility however the Reformatsky reaction permits the preparation of a ,/3-unsaturated carboxylic acids that are branched in a-position. 

Reaction of a-sulphinyl carboxylic esters 421 with carbonyl compounds has usually been performed using a Grignard reagent as a base. No condensation products are obtained using t-butyllithium or sodium hydride367,496,497 (equation 251). The condensation products formed are convenient starting materials for the synthesis of a, p-unsaturated esters and /1-ketones497. 

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

Usually the Knoevenagel condensation yields the unsaturated product, but, with appropriate aldehydes, 3-hydroxymalonates can be isolated. The unusual formation of an a-naphthol (74) has been reported from the reaction of diphenylacetaldehyde (73) with diethyl malonate under Knoevenagel conditions." Condensation of stdicyl dehydes and other aromatic o-hydroxy aldehydes with malonates is still in use for the synthesis of the corresponding coumarin-3-carboxylic esters (75). - " Reduction... 

The Claisen condensation is little used for the preparation of <%,/ -unsaturated carboxylic acids since the methods given above are usually preferable. Cinnamic esters have, however, been obtained by Claisen s method from aromatic aldehydes, alkanoic esters, and metallic sodium, e.g., methyl 4-methoxycinna-mate924 and ethyl 5-(2-furyl)-2,4-pentadienoate925 in yields between 70% and 80%. -Substituted cinnamic esters can also be obtained by this method, from higher alkanoic esters.926... 

As the text continues to develop the chemistry of aldehydes and ketones, you will now see how the carbon adjacent to a carbonyl group can become nucleophilic. First, reactions of these new nucleophiles with common electrophiles like haloalkanes will be covered alkylation reactions. More important are reactions of the nucleophilic a-carbons of one carbonyl compound with electrophilic carbonyl carbons of another. They are generically termed carbonyl condensation reactions. You see them here for aldehydes and ketones the aldol condensation. (In a later chapter you will be introduced to the analogous reaction of carboxylic esters the Claisen condensation.) The products of aldol condensations are a, P-unsaturated aldehydes and ketones, which contain additional sites of electrophilic and potential nucleophilic character. 

Ethyne may be condensed first with the alkyl halide to give H3C [CH2]a C=CH or with the difunctional entity to give Hcic(CH2)yY. The carboxyl group can be generated by oxidation of an alcohol or by reaction of halide with cyanide and then with acidic methanol to give a methyl ester. Condensation with acetylene or an ethynyl compound requires the sodium or lithium derivative and is usually conducted in liquid ammonia. Modification of this approach is necessary when the unsaturated centre is close to either end of the molecule. 

Preparation of monomers. Monomers having a N-hydroxy-succinimide ( NHS ) ester group were prepared by a method similar to that reported previously ( 4,5,6 ) The unsaturated carboxylic acids were condensed with NHS in the presence of dicyclohexylcarbodiimide ( DCC ). 

In an aldol reaction, an enolizable carbonyl compound reacts with another carbonyl compound that is either an aldehyde or a ketone. The enolizable carbonyl compound, which must have at least one acidic proton in its a-position, acts as a nucleophile, whereas the carbonyl active component has electrophilic reactivity. In its classical meaning the aldol reaction is restricted to aldehydes and ketones and can occur between identical or nonidentical carbonyl compounds. The term aldol reaction , in a more advanced sense, is applied to any enolizable carbonyl compounds, for example carboxylic esters, amides, and carboxylates, that add to aldehydes or ketones. The primary products are always j5-hydroxycarbonyl compounds, which can undergo an elimination of water to form a,j5-unsaturated carbonyl compounds. The reaction that ends with the j5-hydroxycarbonyl compound is usually termed aldol addition whereas the reaction that includes the elimination process is denoted aldol condensation . The traditional aldol reaction [1] proceeds under thermodynamic control, as a reversible reaction, mediated either by acids or bases. 

Between 1961 and 1967 the electrochemical generation method has been used to obtain, identify, and investigate free radicals derived from about 400 different organic compounds, such as unsaturated acyclic and alicyclic hydrocarbons, condensed and noncondensed polynuclear aromatic hydrocarbons, heterocyclic compounds, quinones, carbonyl compounds, nitriles, nitroso and nitro derivatives, and carboxylic esters. 

Condensation of y-picoline with mesoxalic ester yielded 4-(j8,j8-diethoxycarbonylvinyl)pyridine (35). The unsaturated ester (35) was hydrogenated with platinum catalyst to form 36 which was treated with bromine. 4-(j8-Bromo-j8,j8-diethoxycarbonylethyl)-piperidine (37) was obtained and was cyclized with pyridine to 2,2-die th 0 xycarbony 1 quinuclidine (38). Hydrolysis of 38 and partial decarboxylation gave quinuclidine-2-carboxylic acid (39). 

B as an ester- or lactone-substituted aldehyde enolate. Such enolates undergo condensations with all kinds of aldehydes, including paraformaldehyde. An adduct E is formed initially, acy-lating itself as soon as it is heated. The reaction could proceed intramolecularly via the tetrahedral intermediate D or intermolecularly as a retro-Claisen condensation. In both cases, the result is an acyloxy-substituted ester enolate. In the example given in Figure 13.50, this is the formyloxy-substituted lactone enolate C. As in the second step of an Elcb elimination, C eliminates the sodium salt of a carboxylic acid. The a,/)-unsaturated ester (in Figure 13.50 the 0J,/3-unsaturated lactone) remains as the aldol condensation product derived from the initial ester (here, a lactone) and the added aldehyde (here, paraformaldehyde). 

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