Knoevenagel and Doebner Condensations

Knoevenagel type condensation reactions generally include the condensation of a-cyano-eslers (and some other malonate analogs) with an aldehyde or ketone. An 

Enolate anions derived from cyano-esteis can also be reacted with alkyl halides, as in the conversion of 4.3 to 4.4 via reaction with sodium hydroxide and 1-bromo-butane.3 Catalytic hydrogenation gave ethyl 2-butyl-2-methyl-3-aminopropanoate, 4.5. Similarly prepared were 2,2-dimethyl-3-aminopropanoate, 2-methyl-2-ethyl-3-aminopropanoate, and 2-methyl-3-propyl-3-aminobutanoate in 64%, 71%, and 69% yield, respectively.  

Cyano-esters can also be condensed with other nitriles, as in the reaction of methyl a-cyano acetate and a-amino acetonitrile to give 4.6. Initial condensation of the cyano-ester enolate with the other nitrile moiety gave an iminium salt. Subsequent reaction with aqueous acid led to an imine, which isometizes to the 

When malonic acid is used as the enolate partner, with pyridine as the base, the condensation reaction with aldehydes is known as the Doebner condensation. This is an important route to non-a-amino acids. An example of this condensation when 

Both aldehydes or ketones can be condensed with malonate derivatives, but ammonia can be used as a base rather than pyridine. Reaction of butanal with ammonia in the presence of the half-ester of malonic acid, for example, gave ethyl 

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