Knoevenagel reaction active methylene compound

Knoevenagel reaction. The condensation of an aldehyde with an active methylene compound (usually malonic acid or its derivatives) in the presence of a base is generally called the Knoevenagel reaction. Knoevenagel found that condensations between aldehydes and malonic acid are effectively catalysed by ammonia and by primary and secondary amines in alcoholic solution of the organic amines piperidine was regarded as the best catalyst. 

Tellurium tetrachloride is an efficient catalyst in the Knoevenagel reaction of non-enoUz-able aldehydes with active methylene compounds. ... 

The Knoevenagel reaction consists in the condensation of aldehydes or ketones with active methylene compounds usually performed in the presence of a weakly basic amine (Scheme 29) [116], It is well-known that aldehydes are much more reactive than ketones, and active methylene substrates employed are essentially those bearing two electron-withdrawing groups. Among them, 1,3-dicarbonyl derivatives are particularly common substrates, and substances such as malonates, acetoacetates, acyclic and cyclic 1,3-diketones, Meldrum s acid, barbituric acids, quinines, or 4-hydroxycoumarins are frequently involved. If Z and Z groups are different, the Knoevenagel adduct can be obtained as a mixture of isomers, but the reaction is thermodynamically controlled and the major product is usually the more stable one. 

The Knoevenagel condensation is a cross-aldol condensation of a carbonyl compound with an active methylene compound leading to C-C bond formation (Scheme 7). This reaction has wide application in the synthesis of fine chemicals and is classically catalyzed by bases in solution (146,147). 

Use of the Knoevenagel reaction (67OR(l5)204), in which a benzaldehyde reacts with an activated methylene compound in the presence of an amine, goes some way to overcoming the inherent difficulties of the Perkin synthesis of coumarins (see later). In order to obtain the coumarin rather than the usual cinnamic acid, a 2-hydroxy substituent must be present... 

Two mechanisms have been proposed for the Knoevenagel reaction. In one, the role of the amine is to form an imine or iminium salt (378) which subsequently reacts with the enolate of the active methylene compound. Under normal circumstances elimination of the amine would give the cinnamic acid derivative (379). However, when an o-hydroxy group is present in the aromatic aldehyde intramolecular ring closure to the coumarin can occur. The timing of the various steps may be different from that shown (Scheme 118). 

Both 1,3- and 1,4- bis[2-(2-arylethenesulfonyl)vinyl]benzenes, synthesized by a Knoevenagel reaction between the appropriate benzenedicarbaldehyde and 2-arylethenesulfonylacetic acid, behave as Michael acceptors and undergo double Michael addition reactions with activated methylene compounds. The products are phenylene-bis(tetrahy-drothiopyran 1,1-dioxides) 460 (Scheme 158) <2005JHC255>. 

A Knoevenagel reaction is a condensation reaction between an active-methylene compound (or the comparably C,I I-acidic nitromethane) and a carbonyl compound. The product of a Knoevenagel reaction is an alkene that contains two geminal acceptor groups (B in Figure 13.52) or one nitro group (B in Figure 13.53). 

Fig. 13.52. Mechanism of the Knoevenagel reaction of active-methylene compounds -H indicates the migration of a proton.

The enolate A or the nitronate A, respectively, initially adds to the C=0 double bond of the aldehyde or the ketone. The primary product in both cases is an atkoxide, D, which contains a fairly strong C,H acid, namely, of an active-methylene compound or of a nitroalkane, respectively. Hence, intermediate D is protonated at the atkoxide oxygen and the C-fi atom is deprotonated to about the same extent as in the case of the respective starting materials. An OH-substituted enolate C is formed (Figures 13.52 and 13.53), which then undergoes an Elcb elimination, leading to the condensation product B. The Knoevenagel condensation and the aldol condensation have in common that both reactions consist of a sequence of an enolate hydroxy alkylation and an Elcb elimination. 

Titanium tetrachloride and a tertiary amine are a useful catalyst for Knoevenagel condensation [149] as shown in Eq. (45) [150]. Because the reaction can be performed under mild conditions, acid-sensitive functional groups survive the reaction conditions and the optically active center at the enolizable position did not racemize (Eq. 45). More examples of the titanium-catalyzed Knoevenagel condensation are shown in Table 5. Alkylation of an (unsaturated) (iV,0)-acetal with active methylene compounds was performed analogously in the presence of TiCU and NEts (Eq. 46) [154]. Depending on the structure of the active methylene compounds, carbon-carbon bond... 

Sonochemistry has been applied to acceleration of the Reformatsky reaction, Diels-Alder reactions, the arylation of active methylene compounds nucleophilic aromatic substitution of haloarenes, and to hydrostannation and tin hydride reduction. " Other sonochemical applications involve the reaction of benzyl chloride and nitrobenzene, a Sr I reaction in liquid ammonia at room temperature, and Knoevenagel condensation of aromatic aldehydes. lodination of aliphatic hydrocarbons can be accelerated, and oxyallyl cations have been prepared from ot,ot -diiodoketones using sonochemistry. Sonochemistry has been applied to the preparation of carbohydrate compounds.When sonochemistry is an important feature of a chemical reaction, this fact will be noted in the reactions presented in Chapters 10-19. 

Simple aliphatic thioketones (6) readily condense with active methylene compounds in a Knoevenagel-type reaction (Scheme 11). The reaction in Scheme 11 proceeds more easily than with ketones, often without catalysts, and involves nucleophilic attack by the X(NC)HC moiety. 

A basic ionic liquid, l-butyl-3-methyl imidazolium hydroxide, [bmImjOH, was found to catalyze the Knoevenagel condensation of aliphatic aldehydes and ketones with active methylene compounds elSciently in the absence of any organic solvent (Scheme 5.58). Coumarins have been obtained in one step from the reaction of o-hydroxy aldehydes following this procedure. ... 

Reactions with Activated Methylene Compounds (Knoevenagel Reactions)... 

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