Malonic Ester Synthesis

The Malonic Ester Synthesis is the alkylation of malonic ester enolates with organic halides followed by thermal decarboxylation of the alkylated products to deliver substituted acetic acid derivatives.

General features:
1. The pKa of the methylene group is usually between 9-11, so relatively weak bases are sufficient for the generation of the enolate.
2. A wide variety of solvents can be used: hydroxylic solvents (alcohols), dipolar aprotic solvents (DMF), or even nonpolar aprotic solvents (benzene) are tolerated.
3. The major drawback of malonic ester synthesis is that the alkylation stage can also produce dialkylated structures. However, C-monoalkyl malonic esters are less acidic than unsubstituted ones, and the alkylation of the corresponding enolates is slower.
4. Saponification of the resulting malonic ester with base affords a 1,3-diacid, which undergoes decarboxylation upon heating with an acid to give substituted acetic acids.

Reaction mechanism:
1. Deprotonation of the carbon alpha to the carbonyl groups by a base.
2. The enolate undergoes nucleophilic substitution on the alkyl halide.
3. Hydrolysis of the di-ester followed by thermal decarboxylation delivers the corresponding acetic acid substituted by the R group.

References:
NROChemistry: https://nrochemistry.com/malonic-synt...