Amine-Catalyzed Knoevenagel-Additions

By further expanding the variety of substrates—from methyl ketones to 1,3-dicarbonyl compounds—a chain elongation of the employed carbohydrates instead of a C-glycosylation process was observed. 

SCHEME 2.4 Base-catalyzed Knoevenagel reaction of ribose with ethyl acetoacetate. For a color version of this figure, see the color plate section. 

The degree of internal diastereoselectivity is dictated by the existence and by the relative configuration of the 2,3-hydroxy groups of pentoses deployed. Results of 

SCHEME 2.6 Chain elongation of D-pentoses with ethyl acetoacetate. 

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Jiang et al. described the proline-catalyzed reaction of several amines 143 with alkynes 141, various aldehydes 142, and 1,3-dicarbonyl compounds 144 to afford 1,4-dihydro-pyridines 145 in moderate to good yields (65-85%) (Scheme 13.37) [62]. Mainly three reactions are involved in the production of those products the first one is a proline-catalyzed Knoevenagel reaction between the aldehydes 142 and the 1,3-dicarbonyl compounds 144 to give Michael acceptors. The second one is a hydroamination reaction of the alkyne 141 to yield enamines, which in the third reaction undergo an enamine-Michael addition/cyclization sequence to provide the desired products. 

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)... 

Iminium ions are intermediates in a group of reactions that form ,( -unsaturated compounds having structures corresponding to those formed by mixed aldol addition followed by dehydration. These reactions are catalyzed by amines or buffer systems containing an amine and an acid and are referred to as Knoevenagel condensations,2U The reactive electrophile is probably the protonated form of the imine, since it is a more reactive electrophile than the corresponding carbonyl compound.212... 

However, more interesting from an application point of view are silylation reactions which introduce new functions into the materials. These can be created either directly or in subsequent further steps after silylation. Most simple is the direct conversion of the silica to a basic material by reaction, for instance, with 3-aminopropyltriethoxysilane [17]. Also two-step processes have been employed to synthesize basic materials, where first chloropropyl groups are anchored to the surface with subsequent conversion of the chloro group into an amine. In order to remove the residual, unreacted silanol groups, a second silylation with hexamethyldisilazane can be used. Such materials were found to be reasonably active in different base-catalyzed reactions, such as Knoevenagel condensations and Michael additions. A survey of the catalyzed reactions and the types of modification used can be found in Ref. [5]. 

Since silica is such a common support for immobilization, the effect of the weakly acidic silanol groups has been studied. A cooperative silanol effect is thought to improve the catalytic activity of mesoporous silica-supported amines in base-catalyzed reactions such as the nitroaldol (Henry) condensation [6, 7], Knoevenagel condensation [6, 8,9], and Michael addition [6]. Thus immobilizing amines onto supports with stronger acid groups could be expected to further increase the catalytic activity. 

The Knoevenagel condensation is a base-catalyzed aldol-type reaction, and the exact mechanism depends on the substrates and the type of catalyst used. The first proposal for the mechanism was set forth by A.C.O. Hann and A. Lapworth Hann-Lapworth mechanism) In 1904." When tertiary amines are used as catalysts, the formation of a p-hydroxydlcarbonyl Intermediate is expected, which undergoes dehydration to afford the product. On the other hand, when secondary or primary amines are used as catalyst, the aldehyde and the amine condense to form an Imlnlum salt that then reacts with the enolate. Finally, a 1,2-ellmlnatlon gives rise to the desired a,p-unsaturated dicarbonyl or related compounds. The final product may undergo a Michael addition with the excess enolate to give a bis adduct. 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

H-pyrane] derivatives in the presence of isatins, malononitrile, and acetylacetone/ethyl 3-oxobutanoate [103]. Yan and coworkers showed in 2012 that chiral tertiary amine-thiourea (158) derived from quinine can catalyze a three-component reaction between isatins 118, malononitrile (119), and a-phenyl-isocyanoacetate (217) (Scheme 2.75) [104]. The process affords dihydropyrryl-spirooxindoles 218 and involves an initial Knoevenagel condensation of 118 and 119 followed by the nucleophilic anion attack of 217 (see the key transition state intermediate on Scheme 2.75). Final intramolecular cyclo-addition affords the expected compounds where H bond interactions are supposed to direct the attack of isocyanate anion and, consequently, contfol the enantioselectivity. One year later, Xu s group used a bifunctional cinchona-based squaramide to catalyze multicomponent cascade reaction to synthesize spiro[pyrrolidin-3,2 -oxindoles] via 1,3-proton shift and [3h-2]... 

Knoevenagel CondensatiorL This method can be used to introduce electron-withdrawing groups into conducting polymers by the reaction of an aromatic aldel de with a ben Uc nitrile catalyzed by an amine or amine salt (Fig. 68). Careful optimization of the reaction conditions is needed to reduce unwanted side reactions such as hydrolysis of the nitrile group or Michael addition to the double bond [881-894]. 

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