Ethyl cyanoacetate, benzaldehyde

Formal oxidation of pyrrolidine to the succinimide stage affords a series of compounds used as anticonvulsant agents for treatment of seizures in petit mal epilepsy. Knoevnagel condensation of benzaldehyde with ethyl cyanoacetate affords the unsaturated ester, 9. Conjugate addition of cyanide ion leads to the di-nitrile ester (10). Hydrolysis in mineral acid affords the succinic acid (11), presumably by decarboxylation of the intermediate tricarboxyllie acid. Lactamization with methylamine gives phensuximide (12). ... 

Uncharged styryl (methine) disperse dyes were originally introduced to provide greenish yellow colours on cellulose acetate fibres. One such dye still in use is Cl Disperse Yellow 31 (6.226), which is made by condensing 4-(N-butyl-N-chloroethylamino)benzaldehyde with ethyl cyanoacetate. Suitable compounds for polyester usually contain the electron-accepting dicyanovinyl group, introduced with the aid of malononitrile. An increased molecular size leads to improved fastness to sublimation, as in the case of Cl Disperse Yellow 99 (6.227). A novel polymethine-type structure of great interest is present in Cl Disperse Blue 354 (6.228), which is claimed to be the most brilliant blue disperse dye currently available [85]. 

Because a base-catalyzed reaction involves the abstraction of a proton by the catalyst, one approach to measurement of the total number of basic sites and also the base strength distribution is to use the reactions of molecules with various values (96-100). For instance, the basic site distribution in calcined MgAl hy-drotalcites was determined by Corma et al. (99), who used the Knoevenagel condensation (Scheme 7) between benzaldehyde and methylene active compounds with various pKa values, i.e., ethyl cyanoacetate (pKa = 9), diethyl malonate (pKa = 13.3), and ethyl bromoacetate (pKa = 16.5). The authors found that this material has basic sites with pKa values up to 16.5, although most of the basic sites... 

Padwa et al. (44) studied the diazo-decomposition of 119 and found that the cyclic ylide 120 could be trapped by a variety of heterodipolarophiles such as ethyl cyanoacetate (Mander s reagent) to provide aminal 121 or with benzaldehyde to generate the bicyclic acetal 122. In both cases, only a single isomer was formed, with the regiochemistry easily predicted from frontier orbital considerations. Nair et al. (45) were able to employ the highly functionalized o-quinone 125 for the trapping of carbonyl ylide 124 to provide the highly complex cycloadduct 126 in 76% yield. 

Microwave-assisted multicomponent reaction of 6-amino- or hydroxy-aminouracil derivatives with benzaldehyde and malononitrile or ethyl cyanoacetate in the solid state in the absence or presence of Et3N for 5-8 min afforded the pyridopyrimidine derivatives 463 <2003TL8307>. Similarly, 6-aminouracil derivatives or 6-hydroxyamino analogues were reacted with HC(OEt)3 and active methylene compounds [CH2(CN)2 or NCCH2C02Et] in the presence of AcOH under microwave-assisted conditions to give the pyrido[2,3-r7 pyrimidines 464 and their iV-oxides 465 within 2 or 8 min, respectively. The reaction proceeded under thermal conditions in ethanol or without solvent for 1—4h to give 464 and 465 in 45-70% and 35-50% yield, respectively <2004SL283>. 

The condensation of benzaldehyde with ethyl cyanoacetate, ethyl malonate and ethyl acetoacetate were carried out with high rates and selectivity promoted by lithium-, sodium, potassium-, and caesium-exchanged X and Y zeolites and on sodium-Germanium substituted faujasite. 

TABLE 2.- Comparative activity of pyridine and piperidine as catalyst and X Zeolite for the condensation of benzaldehyde and ethyl cyanoacetate. 

The results in Table 2 show that the pyridine is less active than any of the X zeolites and Ge faujasite except the lithium form which shows slightly lower activity, whereas all Y zeolites show lower activity than pyridine. Piperidine, however, is more active than any of the zeolite samples studied here. From this comparison, it appears that, most of the basic sites of the zeolites must have pK<10.3. However, the fact that zeolites are also active for catalyzing the condensation of benzaldehyde with ethyl malonate, indicate that these samples have some basic sites with pK< 13.3. On a quantitative bases, and comparing the activity of zeolites for condensation with ethyl cyanoacetate, ethyl acetoacetate and ethyl malonate (Fig. 2), we can conclude that most of the basic sites of the zeolite have pK<9.0 with a sensible amount with 9.0basic strength of different solid base catalysts. 

Fig. 2. Condensation of equimolar amounts of benzaldehyde and ethyl cyanoacetate, ethyl aceioaceiatc and ethyl malonate at 140°C using 1 %wt of zeolite. NaGeX (left) and ZXCs (right).

Kappe et al. reported the microwave-assisted synthesis of pyrido[2,3-ri ]pyrimidines via a one-pot three component cyclocondensation of a,(3-unsaturated esters, amidines and malonitrile (or ethyl cyanoacetate) (Scheme 3.45)71. Quiroga et al. reported a similar three component cyclocondensation to synthesise regiospecif-ically 5,8-dihydropyrido[2,3-ri ]pyrimidines under solvent-free conditions, starting from a combination of aminopyrimidin-4-ones, benzoylacetonitrile and benzaldehyde (Scheme 3.45)72. 

Scheme 2 shows Rapoport s synthesis [15]. The cinnamic acid derivative 3 prepared from m-methoxy benzaldehyde [20] was ethylated by diethyl sulfate to give ethyl cinnamate derivative 4, followed by Michael addition with ethyl cyanoacetate to afford compound 5. Compound 5 was converted to lactam 6 by the reduction of the cyano group and subsequent cyclization. Selective reduction of the lactam moiety of 6 was achieved by treatment with trimethy-loxonium fluorob orate followed by sodium borohydride reduction. Amine 8 was obtained by the reductive methylation of amine 7. Amine 8 was converted to compound 9 by methylene lactam rearrangement [21], followed by selenium dioxide oxidation to provide compound 10. Allylic rearrangement of compound 10 and subsequent hydrolysis gave compound 12. The construction of the decahydroisoquinoline structure began with compound 12,... 

Hybrid organic/mineral solid base catalysts bearing primary and tertiary amino functions have been used as catalysts in the Knoevenagel condensation of benzaldehyde and ethyl cyanoacetate at 375 K in the presence of DMSO as solvent. Both catalysts exhibited a selectivity of approximately 100 % in ethyl trans-a-cyanocinnamate and could be recycled several times, after filtration and washing, without decrease in their catalytic performance.11711 The activity was found to be... 

Diamines grafted on MCM-41 revealed higher base catalytic activity because they were able to catalyse condensation between benzaldehyde and ethyl malonate which is usually less active than ethyl cyanoacetate. The catalytic activity was also high with less reactive carbonyl derivatives, such as cyclic or aliphatic ketones. Moreover, aldolization between acetone and aromatic aldehyde was also possible.11721... 

The catalytic properties were checked in the transesterification of ethyl propionate with n-butanol and in the Knoevenagel condensation of benzaldehyde with ethyl cyanoacetate ... 

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) ... 

Excellent results were also obtained using activated hydrotalcite as a solid base catalyst in the Knoevenagel condensation of benzaldehyde with ethylcya-noacetate [110], ethylacetoacetate [111] or malononitrile [112] (see Fig. 2.34). Similarly, citronitrile, a perfumery compound with a citrus-like odor, was synthesized by hydrotalcite-catalyzed condensation of benzylacetone with ethyl-cyanoacetate, followed by hydrolysis and decarboxylation (Fig. 2.34) [113]. 

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]. 

Of more synthetic interest is the Cs-X catalyzed liquid phase condensation of benzaldehyde with active methylene compounds such as ethyl cyanoacetate, ethyl malonate and ethyl acetoacetate but the yields in these reactions were only in the 40%-70% region. Higher yields were obtained using a germanium substituted faujasite 2 06 or a nitrided aluminophosphate as the basic catalyst. 

The catalytic activity of proton sponge in the Knoevenagel reaction has been studied227. It was shown that benzaldehyde, in the presence of 2 mol% of 1, reacts with ethyl cyanoacetate and ethyl acetoacetate (equation 22). The condensation is accelerated in polar solvents (especially in DMSO) and does not occur in the case of diethyl malonate, as its CH-acidity is too low (pK = 13.3). 

An interesting comparison of the activity of primary and tertiary amino groups linked to MTS silicas in the reaction of benzaldehyde with ethyl cyanoacetate (Scheme 3.21, R = CN, R ElOCO, Ph, II) was reported. The results showed that catalysis induced by tertiary amine was relevant to classical base activation of the methylene group followed by nucleophilic attack to the carbonyl function, whereas primary amines could activate the carbonyl group by imine formation followed by Mannich-like nucleophilic attack by the activated ethyl cyanoacetate, as shown in Scheme 3.9. 

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