Esters amidomalonic

Using esters instead of acids reduces the rate of formation of lactones and gives rise to trapping by solvent as well as the formation of overall diene substitution products. Oxidation of amidomalonic ester 57, for example, yields as major products the acetic acid trapping product 58 and the diene substitution product 59, but only 5% of lactone 60 (equation 26). The oxidation of the initially formed amidomalonic ester radical, of increased importance in this case due to the amide substituent, could be largely reduced through addition of sodium acetate or trifluoroacetic acid, which are known to reduce the oxidation potential of the Mn(III) acetate. 

A more general method for preparation of a-amino acids is the amidomalonate synthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by 5 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to yield an a-amino acid. For example, aspartic acid can be prepared from ethyl bromoacetate, BrCH2C02Et ... 

Simplest of all the laboratory methods, in concept, are those general methods based on the alkylation of glycine derivatives shown in Scheme 6.3, particularly 2-acyl-amidomalonate esters (1), Schiff bases (2), oxazol-5(4H)-ones (alias azlactones , 3) and piperazin-2,5-diones (4). 

The process involves the same three steps used in the malonic ester synthesis (1) deprotonation, (2) alkylation, and (3) hydrolysis and decarboxylation. During the hydrolysis step, the amide is hydrolyzed as well. As an example, consider the synthesis of phenylalanine via the amidomalonate synthesis. 

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