Retrosynthesis of Carboxylic Acids Disconnect at Carbonyl

The retrosynthesis of a carboxylic acid TM can involve a disconnection between the alpha carbon and the carbonyl carbon. This bond can either be formed via a Grignard reaction (alpha carbon is the nucleophile, reacting with CO2) or via Sn2 with cyanide (alpha carbon is the electrophile as an alkyl halide, reacting with NaCN, followed by conversion of -ON to -CO2H). Not all TMs can be effectively prepared by either method. An Sn2 mechanism requires an unhindered alkyl halide (methyl, 1°, or 2°), so the nitrile approach is unsuitable for a highly substituted TM or for a benzoic acid derivative since there cannot be an Sn2 mechanism on an sp -hybridized carbon. 

CARBOXYLIC ACIDS VIA a-ALKYLATION MALONIC ESTER SYNTHESIS 

Deprotonation of the alpha carbon of acetic acid with LDA would be impossible since the carboxylic acid proton is more acidic than the alpha proton. 

Protection as an ester overcomes this problem, but the resulting ester enolate is not particularly stable and its reactions can be low yielding. Addition of a second ester to the alpha carbon serves as an activating group and allows the formation of a stabilized enolate. As seen with the acetoacetic ester synthesis, this ester group can be eventually removed by a decarboxylation reaction. The malonic ester synthesis starts with commercially available diethyl malonate. Deprotonation, alkylation of the resulting enolate with an alkyl haUde, and hydrolysis followed by decarboxylation furnishes a carboxylic acid product. 

If desired, the two-step alkylation process can be repeated before hydrolysis to give a wide variety of acetic acid derivatives after decarboxylation. 

---