Amine-catalyzed condensations of the Knoevenagel type

CHAPTER 2 REACTIONS OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS 

A procedure in which the iminium salt shown, A, N-dimethyl(methylene) ammonium trifluoroacetate, is isolated and added separately to an enolate ion allows Mannich bases to be prepared by routes other than those involving acidic media. This procedure is exemplified by entry 4. N,iV-Dimethyl(methylene) ammonium iodide is commercially available as Eschenmoser s salt and is sufficiently electrophilic so as to react directly with enol silyl ethers in neutral media. Ketone enolates have been converted to Mannich bases with Eschen-moser s salt (entry 5). 

The importance of the Mannich reaction stems from the synthetic utility of the resulting aminoketones. Thermal decomposition of the amines or the derived quaternary salts leads to a-methylene ketones. The decomposition of the quaternary salts is particularly facile, and they can be used as in situ sources of many a,j3-unsaturated carbonyl compounds. These are useful synthetic intermediates, for 

Schreiber, H. Maag, N. Hashimoto, and A. Eschenmoser, Angew. Chem. Internet. Ed. Engl. 10, 330 (1971). 

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Scheme 2.12. Amine-Catalyzed Condensations of the Knoevenagel Type...

However, more interesting from an application point of view are silylation reactions which introduce new functions into the materials. These can be created either directly or in subsequent further steps after silylation. Most simple is the direct conversion of the silica to a basic material by reaction, for instance, with 3-aminopropyltriethoxysilane [17]. Also two-step processes have been employed to synthesize basic materials, where first chloropropyl groups are anchored to the surface with subsequent conversion of the chloro group into an amine. In order to remove the residual, unreacted silanol groups, a second silylation with hexamethyldisilazane can be used. Such materials were found to be reasonably active in different base-catalyzed reactions, such as Knoevenagel condensations and Michael additions. A survey of the catalyzed reactions and the types of modification used can be found in Ref. [5]. 

The Knoevenagel condensation is a base-catalyzed aldol-type reaction, and the exact mechanism depends on the substrates and the type of catalyst used. The first proposal for the mechanism was set forth by A.C.O. Hann and A. Lapworth Hann-Lapworth mechanism) In 1904." When tertiary amines are used as catalysts, the formation of a p-hydroxydlcarbonyl Intermediate is expected, which undergoes dehydration to afford the product. On the other hand, when secondary or primary amines are used as catalyst, the aldehyde and the amine condense to form an Imlnlum salt that then reacts with the enolate. Finally, a 1,2-ellmlnatlon gives rise to the desired a,p-unsaturated dicarbonyl or related compounds. The final product may undergo a Michael addition with the excess enolate to give a bis adduct. 

A Mannich-type condensation mechanism involving an iminium ion electrophile similar to the aminocatalytic Knoevenagel reaction has recently been proposed for the amine-catalyzed self-aldolization of propionaldehyde (Eq. (6)) [55]. Although this mechanism is not unreasonable it should be... 

The Knoevenagel reaction is a base-catalyzed aldol-type reaction that can occur through two possible mechanisms, depending on the type of base used. When Emil Knoevenagel made his initial discovery of this reaction, it was already known that benzaldehyde could condense with two equivalents of piperidine to provide the benzylidine bispiperidine aminal 1 Therefore, he proposed the intermediacy of an aminal (or imine) in the condensation. 

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