Knoevenagel reaction heterocycles

Keywords 1,3-Dicarbonyls, Biginelh reaction, Hantzsch reaction, Heterocyclic chemistry, Knoevenagel condensation, Mannich reaction, Michael addition, Multi-component reactions... 

The base facilitated Knoevenagel reaction has been used on an oxindole scaffold as indicated in Fig. 17 49 Position 3 of this heterocycle consists of an activated methylene function, which lends itself to classic... 

A one-pot reaction between the phosphonodithioacetate 58 and a,P-unsaturated aldehydes proceeds via a Knoevenagel reaction and a 1,6-electrocyclisation and leads to a 277-thiopyran-5-yl phosphonate (Scheme 42). When 5-membered heterocyclic aldehydes are used, the intermediate is obtained admixed with the thiopyran or as the only product <07EJO4948>. 

The Knoevenagel reaction is a synthetic method with a broad scope. The educts are simple and cheap, reaction conditions are mild, and a wide variety of solvents can be used. In addition, the Knoevenagel products are reactive compounds and may be employed in sequential transformations (see also Section 1.1.1.4). This is why the Knoevenagel reaction is widely employed, especially in the formation of heterocycles. The most used active methylene in these reactions is malonodinitrile. In many syntheses of natural products, drugs, dyes and other compounds, the condensation of a carbonyl group with an activated methylene compound is found. It is beyond the scope of this review to discuss all examples described in the literature, so only a few recent examples are given in this section. 

Knoevenagel reactions are used in the synthesis of a wide variety of O- and N-heterocycles. In the typical Knorr pyrrole synthesis, a 1,3-dicarbonyl compound is condensed with an oximino- or azimino-1,3-dicarbonyl compound followed by reductive cyclization. Thus, catalytic hydrogenation of benzyl acetoacetate (243) and diethyl oximinoacetonedicarboxylate (242) affords pyrrole (244), which is transformed to (245) by another Knoevenagel reaction (Scheme 49). A rational synthesis of all four uropor-phyrines has been achieved by cyclization of appropriate pyrroles such as (245). ° Another typical preparation of a heterocycle that involves a Knoevenagel condensation is the Hantzsch 1,4-dihydro-pyridine synthesis. Here, an aldehyde and two molecules of a 1,3-dicarl30nyl compound react in the... 

Piperidoius. The Knoevenagel reaction of aryl or heterocyclic aldehydes with ethyl 4-nitrobutanoate in the presence of ammonium acetate has been used for the synthesis of 2-piperidones (equation I). 

The exchange of the heterocyclic component by a phosphine led to phosphonium based zwitterionic salts [179]. Catalytic pyrrolidine and benzoic acid act as mediators for the Knoevenagel reaction generating the 2-aUcylidene Meldrum s acids. The formed zwitterionic salts can easily be transformed into highly substituted furan derivatives utilizing carboxylic acid chlorides. 

Keywords Ninhydrin, malononitrile, aryl isothiocyanates, primary aliphatic amines, ethanol, triethylamine, room temperature, one-pot multicomponent synthesis, thio-Michael and Knoevenagel reactions, sulfur-nitrogen heterocycles, oxathiaaza[3.3.3]-propellanes, che-moselectivity, regioselectivity... 

The butenolides are another class of bioactive furan heterocycles that involve a base-catalyzed transesterification, followed by a Knoevenagel reaction in their synthesis [88]. Villemin et al. reported the high yielding synthesis of butenolides 33 by reaction of ethyl cyanoacetate with several a-hydroxyketones using recyclable [BMIM][Bp4] in a molar ratio of 1 1.5 (reactant/IL) (Scheme 7) [89]. 

Subsequent to Hantzsch s communication for the construction of pyridine derivatives, a number of other groups have reported their efforts towards the synthesis of the pyridine heterocyclic framework. Initially, the protocol was modified by Beyer and later by Knoevenagel to allow preparation of unsymmetrical 1,4-dihydropyridines by condensation of an alkylidene or arylidene P-dicarbonyl compound with a P-amino-a,P-unsaturated carbonyl compound. Following these initial reports, additional modifications were communicated and since these other methods fall under the condensation approach, they will be presented as variations, although each of them has attained the status of named reaction . 

Tietze L. F. Domino-Reactions the Tandem-Knoevenagel-Hetero-Diels-Alder Reaction and Its Application in Natural Product Synthesis J. Heterocycl. Chem. 1990 27 47-69... 

Scheme 2.167. Synthesis of diversified heterocycles by domino Knoevenagel/hetero-Diels-Alde reaction.

Tietze LF (1990) Domino-reactions - the tandem-Knoevenagel-hetero-Diels-Alder reaction and its application in natural product synthesis. J Heterocycl Chem 27 47-69... 

Aldehydes will condense with pyridinium ylides in a manner similar to the Knoevenagel condensation (Scheme 66) (53AG617). However, the corresponding condensation of aromatic nitroso compounds results in the elimination of the parent heterocycle, the product being a nitrone. The reaction is illustrated with phenacylisoquinolinium bromide (71 Scheme 66). 

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