Knoevenagel/Michael cascade

A three-component reaction related to the Hantzsch-synthesis of dihydropyrid-ines was recently reported by Yuan and colleagues who developed a domino cascade Knoevenagel/Michael/cyclization sequence converting isatin derivatives 182, malonitrile (183), and symmetrical acyclic 1,3-diketones or (3-ketoesters 184... 

Ten years later, Lubineau et al. reported the direct reaction of unprotected carbohydrates with acetylacetone in aqueous alkali media [11]. By application of this method, an access to different mixtures of furanoid and pyranoid structures of a- and P-configured C-glycosides [12] was obtained. The ratio of the products depends on the conditions of execution for this reaction and the carbohydrates deployed (Eq. 2, Scheme 2.1). This Knoevenagel/Michael/retro-Claisen-aldol cascade is carried out at high temperature (60-90°C) and is associated with the loss of a C2 fragment of the starting 1,3-dicarbonyl component (when used with acetylacetone). 

Based on these findings obtained, a Knoevenagel/ketalization/oxa-Michael cascade reaction can be assumed (Scheme 2.16). In the first step of the reaction cascade, an E -selective Knoevenagel reaction of the carbohydrate takes place (I in Scheme 2.16). This condensation process is followed by a stereoselective ketalization dictated by the configuration of the 2-hydroxy group of the carbohydrate (K). Subsequent Reside attack of the 4-hydroxy group gives an access to fused tetrahydrofiiran structure L. Structure L is identical with that of compound 74, which is obtained when used... 

SCHEME 2.16 Configurative course of Knoevenagel condensation/ketalizatioii/oxa-Michael cascade reactions. 

A further small tweaking of the reaction conditions involves great changes a further new cascade channel is breaking. This is accomplished by modulation of the nucleophilicity of the activated methylene compounds applied. When used with isocyanoacetate 87 instead of cyanoacetates 86 as a methylene-activated component, an Ugi-like multicomponent cascade reaction is observed. This reaction was first detected by deployment of ethyl isocyanoacetate 87 in reactions of ribose and proline. In these experiments, proline—once the catalyst in the Knoevenagel condensation/ketalization/oxa-Michael cascade reactions—is directly incorporated into the product. As a result of that, seven-membered lactone 89 is formed. This sharp difference is demonstrated in Scheme 2.18 [40]. 

In the amine-catalyzed reactions, a Knoevenagel addition/ketalization/ intramolecular retro-Claisen cascade is detected (Scheme 2.32). The retro-Claisen step is enabled by the ketalization of the Knoevenagel addition product Q. The ketalization of the Knoevenagel product (Q S) is initiated by the hydroxyl groups of the carbohydrate moiety, as in-house NMR-experiments suggest (formation of intermediate ketal structure K in Knoevenagel condensation/ketalization/oxa-Michael cascade reaction Scheme 2.16). Products derived from this reaction sequence (Scheme 2.16)... 

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. 

The stoichiometric reaction of aromatic aldehydes with Meldrum s acid at 50°C gave an intermediate melt from which products 139 crystallized quantitatively at the reaction temperature (Scheme 2.47). These Knoevenagel condensations were termed melt reactions with direct crystallization. Similar condensation with dimedone 140 afforded a cascade reaction starting with Knoevenagel condensation, which was followed by elimination and subsequent Michael addition (Scheme 2.48). Unlike the solution synthesis, yields are superior and no wastes was produced. 

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

A mechanism for the piperazine-catalyzed formation of 4//-chromenes is complex cascade of reactions, starting with piperazine acting as a base which activates malononitrile, promoting Knoevenagel condensation, and also formation of an enamine, followed by Michael condensation, proton transfer, intermolecular cycliza-tion via a nucleophilic addition of the enolate oxygen to the nitrile group (hetero-Thorpe-Ziegler), and finally hydrolysis and tautomerization. 

In 2(X)9, Hayashi and co-workers [52] developed a Michael-Knoevenagel cascade reaction between enals and dimethyl-3-oxoglutarate (79) furnishing cyclohexenes (80) in good yields and enantioselectivities. In this case, the absence of base allows the single addition of one molecule of dimethyl-3-oxoglutarate to the enal. 

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

Similar to the mechanism described in Scheme 2.16, a Knoevenagel reac-tion/ketalization cascade of hydroxyacetone with 1,3-dicarbonyl compounds is assumed. In Scheme 2.16, a Knoevenagel condensation/ketalization reaction is depicted. This sequence allows a subsequent oxa-Michael addition, which yields the corresponding C-glycosides. In contrast, a Knoevenagel addition/ketalization occurs under the reaction condition described in Scheme 2.28, which is followed by an intramolecular retro-Claisen step. As a result of that, the corresponding esters were obtained (Scheme 2.29). 

---