Knoevenagel condensation/Michael

A Knoevenagel condensation/Michael addition sequence has been reported by Barbas III and coworkers (Scheme 2.70) [158] using benzaldehyde, diethyl malonate, and acetone in the presence of the chiral amine (S)-l-(2-pyrrolidinyl-methyl)-pyrrolidine (2-301). As the final product the substituted malonate 2-302 was isolated in 52% yield with 49% ee. 

Keywords dimedone, aromatic aldehyde, Knoevenagel condensation, Michael addition, uncatalyzed... 

Hantzsch heterocyclization Henry reaction Knoevenagel condensation Michael addition enolate... 

Previous sections have shown that catalysis by solid acids has received much attention due to its importance in petroleum refining and petrochemical processes. Conversely, relatively few studies have focused on catalysis by bases, even if acid and base are paired concepts. Base catalysts, however, play a decisive role in several reactions essential for fine-chemical syntheses [248-251]. Solid-base catalysts have many advantages over liquid bases. Examples of successfijl reactions include isomerization, aldol condensation, Knoevenagel condensation, Michael condensation, oxidation and Si—C bond formation. Various reviews have discussed catalysis by solid bases [248-255]. 

Together with the Knoevenagel condensation, Michael additions constitute a powerful tool for the synthetic chemist, with numerous applications in many fields such as pharmaceuticals [32], perfumes [33], herbicides [34], polymers [35], dispersant agents [36], and anionic surfactants [37], etc. 

Cascade Knoevenagel condensation/Michael addition of dimedone and aromatic aldehydes. 

Knoevenagel condensation, Michael additions, and aldol condensations Homogeneous base catalysts Basic zeolites — [58]... 

Hydrotalcite with Various Anions. Various anions can be incorporated in the interlayers such as t-BuO and F ions by anion exchange or by using memory effect. Hydrotalcite with -BuO ions are highly active for many reactions including Knoevenagel condensation, Michael addition, transesteriflcation, Honor-Wittig, and Henry reactions (23). L-Proline can be intercalated in the interlayers. L-Proline-anchored hydrotalcite is an efficient catalyst for asymmetric syntheses by aldol reactions, Henry reaction, and Michael adition (25-27). 

A silica tungstic acid (STA)-catalyzed Knoevenagel condensation/Michael addition/double Mannich reaction... 

A series of 2-amino-4 /-thiopyrans 268 has been synthesized by one-pot Knoevenagel condensation/Michael addition/cyclization of several p-oxodithioesters 265, active methylene compounds 267, and various aldehydes 266 (Scheme 13.62) [102], The products could be isolated in good to excellent yields (70-93%), after stirring for a few hours in refluxing dichloromethane. Analogous 4-spirothio-pyrans 272 have been prepared by Majumdar et al. [103]. These reactions were conducted without any catalyst in refluxing ethanol, and the products could also be isolated in excellent yields (89-99%). 

Within a sequence of Knoevenagel condensation, Michael addition and condensation, Meldrum s acid can be used as a CHj-C(O) equivalent, through the elimination of acetone and subsequent decarboxylation (Scheme 13.86). In this sequence, other 1,3-dicarbonyl compounds within the reaction mixture serve as nucleophile in the Michael addition. By addition of a nitrogen source to this reaction... 

Horhold et al. and Lenz et al. [94,95]. The polycondensation provides the cyano-PPVs as insoluble, intractable powders. Holmes et al. [96], and later on Rikken et al. [97], described a new family of soluble, well-characterized 2,5-dialkyl- and 2,5-dialkoxy-substituted poly(pflrfl-phenylene-cyanovinylene)s (74b) synthesized by Knoevenagel condensation-polymerization of the corresponding alkyl-or alkoxy-substituted aromatic monomers. Careful control of the reaction conditions (tetra-n-butyl ammonium hydroxide as base) is required to avoid Michael-type addition. 

Examples of commercially applied solid base catalysts are much fewer than for solid acids. Nevertheless, much attention is currently focused on the development of novel solid base catalysts for classical organic reactions such as aldol condensations, Michael additions, and Knoevenagel condensations, to name but a few. 

Barbas, one of the pioneers of enamine catalysis, has incorporated iminium ion intermediates in complex heterodomino reactions. One particularly revealing example that uses the complementary activity of both iminium ion and enamine intermediates is shown in Fig. 12 [188]. Within this intricate catalytic cycle the catalyst, L-proline (58), is actively involved in accelerating two iminium ion catalysed transformations a Knoevenagel condensation and a retro-Michael/Michael addition sequence, resulting in epimerisation. 

The mechanism of the formation of tricyclic intermediates 56 and 57 is also the important and conflicting matter. For example, Quiroga et al. [83] showed that these MCRs, the most probable, proceed via preliminary Knoevenagel condensation and Michael addition (Scheme 26). At the same time they rejected another pathway including the generation of enamine 60, because no reaction was observed between it and aromatic aldehyde when their mixture was refluxed in ethanol. 

Scheme 27 Microwave-assisted Knoevenagel condensation and Michael addition cascade...

The mechanism of these MCRs involving Meldrum s acid should include Knoevenagel condensation and Michael addition cascade process [100, 113] (Scheme 37). To form positional isomeric reaction product, arylliden derivatives of Meldrum s acid are attacked by exocyclic NH2-group instead of endocyclic nucleophilic center. 

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

Interestingly enough, a closely related protocol was successfully proposed for the synthesis of spirooxindoles-containing tetrahydrochromene skeletons when aromatic aldehydes were switched for isatin derivatives. This high-yielded reaction was performed with dimedone, 4-hydroxycoumarin, or barbituric acids in water using triethylbenzylammonium chloride (TEBA) as catalyst (Scheme 36) [125]. A Knoevenagel condensation occurred first between isatin and malonitrile derivative, followed by Michael addition of 1,3-dicarbonyl substrates and cyclization to the cyano moiety. 

In a similar vein, Knoevenagel condensation of nicotinaldehyde (88) with diethyl malonate gives the unsaturated ester Michael addition of dimethylamine... 

C.4. Sti/le Couplings, Knoevenagel Condensations, and Michael Addition Reactions... 

Maraval et al 39) synthesized core- and periphery-functionalized ruthenium and palladium dendritic diphosphines (Fig. 12) that were applied in three reactions (Stille coupling, Knoevenagel condensation, and diastereoselective Michael addition). The catalyst was recovered by using the precipitation strategy. 

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