Verley-Doebner modification, Knoevenagel

The Verley-Doebner Modification of the Knoevenagel Reaction trans-Cinnamic Acid... 

In the formation of the first synthetic intermediate in Sequence D, the very effective Verley-Doebner modification of the fundamental Knoevenagel condensation is used. This modification uses malonic acid in place of the conventional ester to promote enoUzation. In addition, the heterocyclic amine, pyridine, functions as both the base catalyst and the solvent. A cocatalyst, P-alanine (an amino acid), is also introduced. Mechanistically, the reaction closely resembles the aldol condensation in that in both cases a carbanion is generated by abstraction, by base, of a proton alpha to a carbonyl group. The resulting carbanion is stabilized as an enolate anion (see below). 

Verley-Doebner modification of the Knoevenagel condensation. This method was somewhat forgotten for many years, until it was rediscovered by Haley and Maitland in 1951 and Prout in 1953. Prout carried out... 

Interestingly, although Knoevenagel demonstrated the effectiveness of amine bases in promoting aldol-type reactions and though, as noted above, he was particularly interested in pyridine, he overlooked this material s potential application to aldol condensations. It was left to Verley (1899) and Doebner (1900) to introduce successful modifications of the condensation in which pyridine appears to play a number of roles as a solvent, as a base, and assisting in the decarboxylation. 

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