Carbonyl compounds malonic ester synthesis

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Both the malonic ester synthesis and the acetoacetic ester synthesis arc relatively easy to carry out because they involve unusually acidic carbonyl compounds. As a result, relatively mild bases like sodium ethoxide in an alcohol solvent can be used to prepare the necessary enolate ions. Alternatively, it s also possible in many cases to alkylate the a position of monoketones, monoesters, and nitrile. . A strong, sterically hindered base such as LDA is needed, so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

Finally, the synthesis of allenyl ketones is also possible by carbonylation if carbonates 103 are treated with C-H acidic compounds 104 such as /3-diketones or derivatives of malonic ester to yield products of type 105 [143],... 

Application of 7r-allylpalladium chemistry to organic synthesis has made remarkable progress[l]. As described in Chapter 3, Section 3,7r-allylpalladium complexes react with soft carbon nucleophiles such as malonates, /3-keto esters, and enamines in DMSO to form carbon-carbon bonds[2, 3], The characteristic feature of this reaction is that whereas organometallic reagents are considered to be nucleophilic and react with electrophiles, typically carbonyl compounds, 7r-allylpalladium complexes are electrophilic and react with nucleophiles such as active methylene compounds, and Pd(0) is formed after the reaction. 

In contrast, /3-dicarbonyl compounds such as malonic ester and acetoacetic ester are more acidic than alcohols. They are completely deprotonated by alkoxides, and the resulting enolates are easily alkylated and acylated. At the end of the synthesis, one of the carbonyl groups can be removed by decarboxylation, leaving a compound that is difficult or impossible to make by direct alkylation or acylation of a simple ester. 

Corey found the reagent useful for the synthesis of half-esters of a,/3-unsaturated malonic esters. Isopropylidene malonate condenses readily with carbonyl compounds, even with the highly hindered mesitaldehyde (1). Thus the condensation of (I) and (2) was conducted in pyridine solution, and the product (3) on being refluxed with absolute ethanol and a trace of hydrogen chloride afforded ethyl hydrogen mesitylidene malonate (4). 

Malonic acid labeled with carbon-14 at C2 or at Cl,3 and the corresponding mono- and diesters have become important and highly versatile building blocks for the synthesis of a broad range of labeled compounds, such a,/3-unsaturated acids and esters, cycloalkanes, 8-keto esters, a-amino acids, phenols, dihydropyridines/pyridines, pyrimidines and quinolines. In addition, they are widely used as acetic acid synthons ( CH2COOR CHCOOR) for the extension of carbon chains of alkyl, allyl and benzyl halides as well as of saturated and a,)8-unsaturated carbonyl compounds. This Section discusses aU malonates, wherever labeled, and unlabeled malonates used with carbon-14-labeled reaction partners. However, it is the [2- " C]malonates that have been most often used in radiochemical synthesis. 

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