Methylene compounds aldehydes

A highly efficient access to diversely substituted indolizines using a new three-component condensation of activated methylene compounds, aldehydes, and isonitriles is described <2006QSAR504>. 

Keywords active methylene compound, aldehyde, Knoevenagel condensation, ZnCl2, styrene... 

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. 

Aldol Addition and Related Reactions. Procedures that involve the formation and subsequent reaction of anions derived from active methylene compounds constitute a very important and synthetically useful class of organic reactions. Perhaps the most common are those reactions in which the anion, usually called an enolate, is formed by removal of a proton from the carbon atom alpha to the carbonyl group. Addition of this enolate to another carbonyl of an aldehyde or ketone, followed by protonation, constitutes aldol addition, for example... 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

Another important synthetic method for the reduction of ketones and aldehydes to the corresponding methylene compounds is the Woljf-Kishner reduction. This reaction is carried out under basic conditions, and therefore can be applied for the reduction of acid-sensitive substrates it can thus be regarded as a complementary method. The experimental procedure for the Clemmensen reduction is simpler however for starting materials of high molecular weight the Wolff-Kishner reduction is more successful. 

Condensation of an aldehyde or ketone with an active methylene compound... 

The term Knoevenagel reaction however is used also for analogous reactions of aldehydes and ketones with various types of CH-acidic methylene compounds. The reaction belongs to a class of carbonyl reactions, that are related to the aldol reaction. The mechanism is formulated by analogy to the latter. The initial step is the deprotonation of the CH-acidic methylene compound 2. Organic bases like amines can be used for this purpose a catalytic amount of amine usually suffices. A common procedure, that uses pyridine as base as well as solvent, together with a catalytic amount of piperidine, is called the Doebner modification of the Knoevenagel reaction. 

Virtually any aldehyde or ketone and any CH-acidic methylene compound can be employed in the Knoevenagel reaction however the reactivity may be limited due to steric effects. Some reactions may lead to unexpected products from side-reactions or from consecutive reactions of the initially formed Knoevenagel product. 

A large number of aldehydes and structurally different CH-acidic methylene compounds can be employed in such a domino-Knoevenagel + hetero-Diels-Alder reaction. 

The imide nitrogen atom was also most reactive to a variety of electrophilic species (hydrogen halides, pseudohalogens, and alkyl halides) in the parent Rimidophosphazenes, R(C—NH)-N=PPh3. With t-butyl hypochlorite the /V-chloro-derivatives, R(C=NCl)-N=PPh3, were obtained. R/ -Vinyl-phenylphosphazenes have been prepared by condensation of aldehydes with active methylene compounds ... 

Classical Aldol. Aldol reaction is an important reaction for creating carbon-carbon bonds. The condensation reactions of active methylene compounds such as acetophenone or cyclohexanone with aryl aldehydes under basic or acidic conditions gave good yields of aldols along with the dehydration compounds in water.237 The presence of surfactants led mainly to the dehydration reactions. The most common solvents for aldol reactions are ethanol, aqueous ethanol, and water.238 The two-phase system, aqueous sodium hydroxide-ether, has been found to be excellent for the condensation reactions of reactive aliphatic aldehydes.239... 

Peterson methylenation (10, 433 11, 581). Methylenation with trimethyl-silylmethyllithium, (CH3),SiCH2Li, is not widely used in synthesis because of lack of selectivity and moderate yields. However, a modified reagent prepared from (CH3)3SiCH2Li and CeCl, adds to aldehydes or ketones (even enolizable ones) to form adducts in generally high yield, particularly in the presence of TMEDA. The 2-hydroxysilanes are converted into methylene compounds by aqueous HF (with or without pyridine).4... 

Finally, Nikishin and coworkers have reported that the mediated oxidations of doubly activated methylene compounds can be used to synthesize cyclopropane derivatives (Scheme 17) [30]. Reactions using dimethyl malonate, ethyl cyanoacetate, and malononitrile were studied. Metal halides were used as mediators. When the activated methylene compound was oxidized in the absence of a carbonyl compound, three of the substrate molecules were coupled together to form the hexasubstituted product. Interestingly, when the ethyl cyanoacetate substrate was used the product was formed in a stereoselective fashion (18b). In an analogous reaction, oxidation of the activated methylene compounds in the presence of ketones and aldehydes led to the formation of cyclopropane products that had incorporated the ketone or aldehyde (20). In the case of 19a, the reactions typically led to a mixture of stereoisomers. 

Reduction of aldehydes and ketones to the corresponding methylene compounds using amalgamated zinc and hydrogen chloride. 

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

The condensation between an aldehyde, an amine and an active methylene compound, named after Carl Mannich, was first published in 1912 [4]. The products of the reaction, a-amino ketones or Mannich bases are important compounds with numerous applications in the synthesis of pharmaceuticals and of natural products [7]. 

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. 

Quantitative Knoevenagel condensations of aldehydes with active methylene compounds are most desirable due to the frequent use of the electron-poor alkenes that arise [107]. But previous techniques use catalysts and produce dangerous wastes even if highly energy-consuming microwave irradiation upon polar solid supports is additionally used. 

The aldehyde moiety of 50 can be condensed with either amines or active methylene compounds. In the case of reactions with amines, the aldehyde 50 (presumably obtained by reduction of the cyano group with diisobutyl-aluminium hydride (DIBAL-H)) forms simple Schiff bases 51 (Equation 20) <1998J(P1)3557>. 

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