Dialkylated malonic ester

The rate of the alkylation reaction depends on the enolate concentration, since it proceeds by a SN2-mechanism. If the concentration of the enolate is low, various competitive side-reactions may take place. As expected, among those are E2-eliminations by reaction of the alkyl halide 2 with base. A second alkylation may take place with mono-alkylated product already formed, to yield a -alkylated malonic ester however such a reaction is generally slower than the alkylation of unsubstituted starting material by a factor of about 10. The monoalkylation is in most cases easy to control. Dialkylated malonic esters with different alkyl substituents—e.g. ethyl and isopropyl—can be prepared by a step by step reaction sequence ... 

On heating with aqueous hydrochloric acid, the alkylated (or dialkylated) malonic ester undergoes hydrolysis of its two ester groups followed by decarboxylation (loss of C02) to yield a substituted monoacid. 

The carbanions are involved in a number of substitutaion reactions. The example are the formation of mono and dialkyl malonic esters. 

Both acidic H atoms of a malonic ester can be replaced by alkyl groups. These dialkylated malonic esters are formed by successively removing the acidic protons with sodium alkoxide... 

Both acidic H atoms of a malonic ester can be replaced by alkyl groups. These dialky-lated malonic esters are formed by successively removing the acidic protons with sodium alkoxide and treatment of the enolates with an alkylating reagent. The subsequent hydrolysis and decarboxylation of these dialkylated malonic esters affords a,a-dialkylated acetic acids as another class of products accessible via the malonic ester synthesis. 

The alkylmalonic ester has a second acidic proton that can be removed by a base. Removing this proton and alkylating the enolate with another alkyl halide gives a dialkylated malonic ester. Hydrolysis and decarboxylation lead to a disubstituted derivative of acetic acid. 

The preparation of a number of 1,4-diazepines with two carbonyl functions has been reported. A variety of alkyl and dialkyl malonic esters have been reacted with ethylenediamine to give 161.170 71... 

The first enantioselective total synthesis of (+)-macbecin I was accomplished by R. Baker and co-workers. A key vinyl iodide precursor was prepared stereoselectively using the malonic ester synthesis. Diethyl methylmalonate was treated with in situ generated diiodocarbene in ether at reflux to afford diiodomethylmethylmalonate in good yield. This dialkylated malonic ester then was converted to ( )-3-iodo-2-methyl-2-propenoic acid by reacting it with aqueous KOH. The saponification was accompanied by a concomitant decarboxylation. 

The barbiturate series of hypnotics are easily and cheaply made from phosgene [577]. Typically, a dialkyl malonic ester is treated with strong aqueous ammonia to give the diamide of the substituted malonic acid. Equation (4.14). This substance is then heated in an autoclave with phosgene for several hours at about 100 C to give the corresponding dialkyl barbituric acid [577]. 

The alkylation reaction mixtures are usually separated either by chromatographic methods or fractional distillation, which may prove difficult when boiling points are close. A recently introduced separation technique (Figure 6.99) ° exploits the fact that, presumably owing to steric reasons, the saponification rates of labeled mono- and dialkylated malonic esters differ significantly. For example, it was shown that refluxing with aqueous 2 M KOH completely saponified the monoalkylated species without affecting the dialkylated by-product. 

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