Ethyl cyanoacetate: Knoevenagel-Michael

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

CsX is useful for the simple Knoevenagel reaction of benzaldehyde with ethyl cyanoacetate even a simple NaY is sufficiently basic to form carbamates starting from primary aromatic amines and dialkyl carbonates (35, 36). At contrast CsjO-MCM-41 can also be used for the addition of C02 to epoxides, or for Michael addition of one or two molecules of diethyl malonate on neopentylglycol diacrylate (37, 38) ... 

The first reaction is easier not only because it is a Knoevenagel reaction and not a Michael process, but also because the C-H bond in ethyl cyanoacetate is considerably more acidic than in diethyl malonate. It should be noted that there are few, if any, examples of shape-selectivity with such base catalysts. 

In contrast with the widespread application of zeolites as solid acid catalysts (see earlier), their use as solid base catalysts received scant attention until fairly recently [121]. This is probably because acid-catalyzed processes are much more common in the oil refining and petrochemical industries. Nonetheless, basic zeolites and related mesoporous molecular sieves can catalyze a variety of reactions, such as Knoevenagel condensations and Michael additions, which are key steps in the manufacture of flavors and fragrances, pharmaceuticals and other specialty chemicals [121]. Indeed, the Knoevenagel reaction of benzaldehyde with ethyl cyanoacetate (Fig. 2.36) has become a standard test reaction for solid base catalysts [121]. 

Cesium-exchanged zeolite X was used as a solid base catalyst in the Knoevenagel condensation of benzaldehyde or benzyl acetone with ethyl cyanoacetate [121]. The latter reaction is a key step in the synthesis of the fragrance molecule, citronitrile (see Fig. 2.37). However, reactivities were substantially lower than those observed with the more strongly basic hydrotalcite (see earlier). Similarly, Na-Y and Na-Beta catalyzed a variety of Michael additions [122] and K-Y and Cs-X were effective catalysts for the methylation of aniline and phenylaceto-nitrile with dimethyl carbonate or methanol, respectively (Fig. 2.37) [123]. These procedures constitute interesting green alternatives to classical alkylations using methyl halides or dimethyl sulfate in the presence of stoichiometric quantities of conventional bases such as caustic soda. 

Alkali-exchanged mesoporous molecular sieves are suitable solid base catalysts for the conversion of bulky molecules which cannot access the pores of zeolites. For example, Na- and Cs-exchanged MCM-41 were active catalysts for the Knoevenagel condensation of benzaldehyde with ethyl cyanoacetate (pKa=10.7) but low conversions were observed with the less acidic diethyl malonate (pKa=13.3) [123]. Similarly, Na-MCM-41 catalyzed the aldol condensation of several bulky ketones with benzaldehyde, including the example depicted in Fig. 2.38, in which a flavonone is obtained by subsequent intramolecular Michael-type addition [123]. 

Lasperas et al. [73,74,78] have studied the Knoevenagel condensation between benzaldehyde (1) and ethyl cyanoacetate (2) in the presence of over-exchanged CsY zeolites. The reaction was performed under a nitrogen atmosphere in dimethyl sulfoxide (DMSO), the best solvent for eliminating interference from the non-catalyzed reaction. The use of equimolar amounts of each reactant suppressed successive Michael addition between ethyl cyanoacetate and ethyl cyanocinna-mate (3) to give compound 4 (Scheme 5) this resulted in high selectivity for the Knoevenagel product (3) (95 % at 90 % conversion). 

The COj species in the HT interlayer could be exchanged with OH ions by calcination at 723 K and hydration at room temperature. A spinel phase of Mg-Al mixed oxide obtained after the calcination transforms into the original layered structure during the hydration. This reconstruction is known as the memory effect of HT materials. The reconstructed HT catalyzed the Knoevenagel condensation of various aldehydes with nitriles in the presence of water [119]. The reconstracted HT also showed an aqueous Michael reaction of nitriles with a,p-unsaturated compounds. The layered double-hydroxide-supported diisopropylamine catalyzed the Knoevenagel condensation of aromatic carbonyl compounds with malononitrile or ethyl cyanoacetate [120]. This solid base could be recycled at least four times, and exhibited activity for aldol, Henry, Michael, transesterification, and epoxidation of alkenes. 

Vinyl ketones, ethyl cyanoacetate and atnncaiixin acetate give 4,6-disubsti-tuted 3-cyano-2-pyridones (XU-142) by a reaction path that includes a Michael addition and a dehydrogenation. The intermediate 3,4-dihydro-2-pyridones were not detected. When benzylideneacetophenone was used in benzene, the reaction proceeded by a Knoevenagel condensation and it was possible to isolate the intermediate 3-cyano-5,6-dihydro-4,6-diphenyl-2-pyridone, which was dehydrogenated to MI-142 by boiling in acetone. ... 

Aminopropylated functionalized hexagonal mesoporous silicas (HMS) and SBA-15 materials with different amino-loadings (5-30 wt. % NH ) were synthesized by Pineda et al. (2013). These play important role as catalyst in the microwave-assisted Knoevenagel condensation of cyclohexanone and ethyl cyanoacetate as well as in the Michael reaction between 2-cyclohexen-l-one and nitromethane. The low loaded HMS-5%NH2 and higher loaded SBA-15-20% NH were found to give the best activities in the reactions. High activities and selectivities to the condensation product could be achieved in short times of microwave irradiation for both these base-catalyzed processes. 

Mettler and colleagues reported an alternative synthesis of malonate 16 in the same paper (Griffiths et al., 1991) in which they condensed cyclohexanone with ethyl cyano-acetate instead of diethyl malonate in the Knoevenagel reaction to give ethyl cyano(cyclohexylidene)-acetate (18). In the presence of a catalytic amount of sodium cyanide, the Michael addition of HCN to cyanoacetate 18 proceeded in good yield at room temperature to generate the dicyanoester 19. Intermediate 19 was selectively converted to malonate 16 with pressurized HCI treatment in ethanol (Scheme 16.4). 

P-, and S-Heterocycles The reaction of two similar or dissimilar aryl aldehydes 250/251 with malonodi-nitrile 21 or ethyl 2-cyanoacetate 175 catalyzed by Af-hetero-cyclic carbenes (NHCs) has been demonstrated to provide fully substituted furans 252 in good to high yields (74-90%), within short reaction times up to 5 h under solvent-free conditions (Scheme 13.59) [97]. This transformation is based on the umpolung of one of the aldehydes by the NHC, while the other one undergoes a Knoevenagel condensation with the CH-acidic reaction partner. The Breslow intermediate then attacks the condensation product in fashion of a Michael addition. After elimination of the NHC, base-catalyzed cyclization provides the desired products. Five different NHCs have been tested catalyzing this reaction. 

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]. 

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