Amine nucleophiles Knoevenagel reaction

The dicyclohexylammonium salt of diethyl l-(hydroxycarbonyl)methylphosphonate and formaldehyde in the presence of EtjN undergoes a Knoevenagel reaction to give the dicyclohexylammonium salt of l-(hydroxycarbonyl)vinylphosphonate (70%) This compound is able to react readily with a variety of secondary amines,-- 1,3-dicarbonyl and monocarbonyl nucleophiles, to give the corresponding Michael adducts. 

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-... 

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). 

On the basis of the proposed catalytic cycle, aldehyde 9 reacts with 1,3-indandione 178 by amine-catalyzed Knoevenagel condensation to provide the benzylidene-indandione B via iminium ion A, which is an excellent organic Lewis acid. This intermediate thns undergoes a Diels-Alder or a double Michael reaction with the soft nucleophile 2-amino-1,3-butadiene C generated in situ from enone 84 and the amine catalyst to produce the... 

To evaluate properties of basic catalysts, the Knoevenagel condensation over aluminophosphate oxynitrides was investigated [13]. In this reaction usually catalysed by amines, the solid catalysts function by abstraction of a proton from an acid methylene group, which is followed by nucleophilic attack on the carbonyl by the resultant carbanion, re-protonation of oxygen and elimination of water. The condensation between benzaldehyde and malononitrile is presented below. 

The carbon nucleophiles in amine-catalyzed reaction conditions are usually rather acidic compounds containing two electron-attracting substituents. Malonic esters, cyanoacetic esters, and cyanoacetamide are examples of compounds which undergo condensation reactions under Knoevenagel conditions.115 Nitroalkanes are also effective nucleophilic reactants. The single nitro group sufficiently activates the a hydrogens to permit deprotonation under the weakly basic conditions. Usually, the product that is isolated is... 

Matsumoto and co-workers reported in 1978 that simply heating a solution of 4-chlorobenzaldehyde (6), methyl a-isocyanoacetate (7), and piperidine (8) in MeOH led to the formation of an amidine (9) in about 50% yield (Scheme 5.6) [19]. The reaction is suggested to be initiated by the Knoevenagel condensation followed by a formal a-addition of the secondary amine to the isocyano group. It is evident from this work that the a-proton of a-isocyanoacetate 7 is relatively acidic and is readily deprotonated under even weakly basic conditions [20]. The nucleophilicity of the a-carbanion of the enolate 12 produced is apparently higher than that of the terminal divalent carbon of the isonitrile, thus initiating the overall reaction sequence by the Knoevenagel condensation. 

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]... 

Like many other MCRs, the Hantzsch protocol usually commences with a condensation reaction that produces an imine from the amine and aldehyde. In this case, however, the Knoevenagel adduct undergoes addition by the nucleophilic p-keto ester, which generates the intermediary dihydropyranol. Ammonium acetate addition then finally initiates the expected cyclocondensation to give the aminal. Although the... 

Xu et al. (2008) studied three-component Knoevenagel nucleophilic aromatic substitution reaction of 4-halobenzaldehydes with cyanoacetic acid esters/cyanoacet-amides, and cyclic secondary amines in alcoholic medium under microwave irradiation giving products in 5 min. This reaction also gave high yield in a short time. The yield of product ranges from 72-90%. 

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