Retro-Knoevenagel reaction

The rate of the hydrolytic cleavage of Knoevenagel products (retro-Knoevenagel reaction) strongly depends on the pH of the aqueous solution - as well as on cosolvents such as DMSO and additional nucleophiles such as amines. The hydrolysis of these alkenes to CH2XY can be presented by equation (3) at pH < and by equation (4) at pH > Although the kinetics are related to the na-... 

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. 

Knoevenagel adduct 239 of oxohomophthalimide 240 with malononitrile 27a in reactions with CH-acids behaves ambiguously (82CPB1215). Reactions of 239 with acetylacetone, ethyl esters of acetoacetic and ben-zoylacetic acids, as well as methyl pyruvate led to the formation of the desired spiropyrans 241. However, benzoylacetone, dibenzoylmethane, cyanacetamide, and oxindole always gave the same 242. Authors explain this feature in terms of a retro-cleavage of adducts of Michael product 239... 

Malononitrile reacts with acetone in water in the presence of KF-alumina to give 2-aza[2.2.2]octane in high yield via Knoevenagel condensation followed by double cyclization [15]. The bicyclo adduct heated directly or refluxed in tetralin releases 2-methylpropene (retro Diels-Alder reaction), giving the corresponding pyridine derivative. 

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). 

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). 

This transformation was successfully extended to reactions of unprotected dihy-droxyacetone 141 with acetylacetone 5 or benzoylacetone 138. The expected products derived from a Knoevenagel/ketalization/retro-Claisen cascade were isolated in high yields (Scheme 2.30). 

To explain the high selectivity, which is detected in these cascade reactions, the possible products and reaction paths for reaction with L-erythrulose 146 and acety-lacetone 5 are depicted in Scheme 2.32. The stereoselective Knoevenagel addition to intermediate Q is favored and determines simultaneously the configuration of the tertiary alcohol. A subsequent ketalization step to ketone S followed by the final intramolecular retro-Claisen step yields the isolated product 147 as a single stereoisomer. 

These results differ considerably from those obtained by Lubineau reactions. In the Lubineau series, a Knoevenagel condensation followed by an oxa-Michael/intermolecular retro-Claisen process is proposed. As a result of the Lubineau sequence, the loss of an acetate-fragment occurs in reactions with acetylacetone. 

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)... 

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