Knoevenagel condensation, Doebner modification

Knoevenagel condensation Doebner modification. Condensation of aldehydes or ketones with active methylene compounds (specifically malonic ester) in the presence of ammonia or amines the use of malonic acid and pyridine is known as the Doebner modification. 

When the reactant is of the form ZCH2Z, aldehydes react much better than ketones and few successful reactions with ketones have been reported. However, it is possible to get good yields of alkene from the condensation of diethyl malonate, CH2(COOEt)2, with ketones, as well as with aldehydes, if the reaction is run with TiCU and pyridine in THF. In reactions with ZCH2Z, the catalyst is most often a secondary amine (piperidine is the most common), though many other catalysts have been used. When the catalyst is pyridine (to which piperidine may or may not be added) the reaction is known as the Doebner modification of the Knoevenagel reaction. Alkoxides are also common catalysts. 

The Doebner Modification (or Knoevenagel Condensation), which is possible in the presence of carboxylic acid groups, includes a pyridine-induced decarboxylation. 

Malonic acid undergoes Knoevenagel condensations with nearly every type of aldehyde and with very reactive ketones. If condensations with malonic acid are performed in ethanolic ammonia below 70 C, the methylenemalonic acids are usually obtained. If, however, the condensations are performed in pyridine (Doebner modification), decarboxylation normally takes place and the acrylic or cinnamic acid is... 

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). 

The condensation of aldehydes or ketones, with active methylene compounds (especially malonic ester) in presence of a weak base like ammonia or amine (primary or secondary) is known as Knoevenagel reaction. However, when condensation is carried out in presence of pyridine as a base, decarboxylation usually occurs during the condensation. This is known as Doebner modification. Some examples are given (Scheme 37). 

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... 

The Doebner condensation (or reaction) is a slight modification of the Knoevenagel reaction and consists in warming a solution of the aldehyde and... 

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. 

---