Chapter 27: Amino Acids, Peptides and Proteins

Alkylation of an Acetamidomalonate

Reaction type: Nucleophilic Substitution then amide and ester hydrolysis and finally decarboxylation (!)

Summary

• Reagents : (1) NaOEt, (2) alkyl halide, then (3) aq. acid / heat
• Although this looks complex, it is an application of reactions seen previously:
• alkylation of an enolate
• hydrolysis of an amide
• hydrolysis of an ester
• decarboxylation of a b-dicarboxylic acid
• The malonate derivative is treated with a base to form the nucleophilic enolate that then reacts with the alkyl halide.
• Note that the same acetamido malonate can be used to form any primary a-amino acid.
• Hydrolysis of the malonate ester and the amide forms an intermediate amino dicarboxylic acid that decarboxylates to give the a-amino acid.

• Why was ethoxide used as the base to form the enolate ? 
• Is diethyl acetamidomalonate an active methylene compound  ? 
• Could a proline type system be made this way  ? 

• Malonic ester synthesis
• Nucleophilic substitution of a-halocarboxylic acids
• Strecker synthesis