Cyanoacetic ester, addition

In addition to /3-diketones, /3-ketoacids and /3-ketoesters, cyanoacetic ester and related compounds are suitable starting materials. The arylhydrazones 4 thus obtained are of great importance as starting materials for the Fischer indole synthesis, as well as for the preparation of other iV-heterocycles. ... 

P-keto esters with a,p-unsaturated aldehydes liquidrliquid two-phase conditions [20] but, in contrast, under analogous conditions a-cyanoacetic esters produce aldol adducts with a,p-unsaturated aldehydes [20], Ethyl acetoacetate undergoes a catalysed Michael reaction addition with trans but-2-en-l,4-diones the products are generally insufficiently stable for isolation, but can be converted into furans [21 ]. 

The sodium bisulfite purification step may be omitted, and the alkylidene ester purified directly by distillation. Care must be taken to separate the product from ethyl cyanoacetate by fractionation through a moderately efficient column. Purification through the bisulfite addition compound is recommended for alkylidene cyanoacetic esters derived from ketones containing four and five carbon atoms, but not for the higher homologs. 

Alanine has been prepared by the catalytic reduction of cyanoacetic esters 1 or salts 2 by heating acrylonitrile,3 /3-amino-propionitrile,4 iw-(/3-cyanoethyl)-amine,5 /3-hydroxypropionitrile, /3-alkoxypropionitriles,7 u.s-(/3-cyanocthyl) ether,8 or bis-(fi-cyano-ethyl) sulfide 8 with aqueous ammonia at 150-225° by the hydrolysis of /3-aminopropionitrile with concentrated hydrochloric acid and subsequent removal of the acid with anion exchange resins.9 The method as described above has been published.10 Additional references to methods of preparation are given in connection with a procedure for the making of /3-alanine from suc-cinimide through the action of potassium hypobromite.11... 

In addition to malonic, acetoacetic, and cyanoacetic esters, compounds furnishing the active hydrogen atom are nitro paraffins,benzyl cyanide, malononitrile, cyanoacetamide, sulfones, methyl-pyridines, and ketones. ... 

The condensation equilibrium is displaced to the right by removing the unsaturated cyano ester as it is formed by the addition of hydrogen cyanide The effect is analogous to the single-step formation and hydrogenation of a,/S-unsaturated cyanoacetic esters (method 394). The yields are good with most aliphatic ketones and aldehydes (49 75%), but poor results are obtained with aromatic carbonyl compounds and diisopropyl ketone. 

Double addition of diazomethane to cinnamylidene cyanoacetic ester 50 (EWG = COOR ) and corresponding dinitriles (51) (EWG = CN) followed by thermolysis gave rise to pyrazoline-substituted cyclopropanes (52) which upon photolysis and acid treatment afforded biscyclopropanes (53) and tricyclic compounds (54) respectively. ... 

Copper and copper salts also mediate transfer of an alkoxycarbonyl(cyano)methylene unit from a-bromo-a-cyanoacetic esters to certain halogenated 1,3-dienes, e.g. formation of This reaction, which has been carried out with various modifications (including the use of ethyl a-chloro-(x-cyanoacetate), gives access to the acid component of several pyrethroid insecticides. In mechanistic terms, a radical 1,2-addition of the a-halogenated ester to the alkene followed by dehydrohalogenative cyclization takes place (cf. Houben-Weyl Vol.4/3, p369). 

The Michael addition of 6-aminouracils 13 to (arylmethylene)cyanoacetic esters, amides, or nitriles leads to cyclizable adducts, which are subsequently oxidized by air or by a second molecule of the alkenenitrile.228,229 In the case of 6-(hydroxyamino)uracils, aromatization is accomplished by final dehydration. 

The ease of reaction depends both on the CH acidity of the addend and on the polarizability of the ethylenic double bond of the acceptor. Thus, in general, only such compounds function as addend in which a methylene or methine group is activated by two neighboring carbonyl or nitrile groups, as, for example, in malonic esters, malonodinitrile, cyanoacetic esters, 1,3-dioxo compounds and 3-oxo carboxylic esters, and their monoalkyl substitution products. The ethylenic double bond of the acceptor is polarized by conjugation with a polar multiple bond, so that the olefinic component is usually an unsaturated ketone, an, / -unsaturated ester, or an, / -unsaturated nitrile. The addition is catalysed by bases such as potassium hydroxide solution, sodium ethoxide, and amines. 

When A-benzylidenealkylamines are treated with cyanoacetic esters the reaction proceeds beyond addition and yields monoester monoamide of 1,3-dicyano-2,4-diphenyl-l,3-cyclo butanedicarboxylic acid.243... 

Addition to arylidene derivatives of cyanoacetate esters leads to adducts which can be aromatized and decarboxylated to 4-arylpyrrole-3-carbonitriles (Scheme 78) <92Mi 203-03>. 

A cyanoacetate ester, toluene, and half of the catalyst are heated to reflux, and paraformaldehyde slurried in toluene with the rest of the catalyst is slowly added.The catalyst is a mixture of piperidine and 50% aqueous NaOH. The paraformaldehyde is added at a rate which allows control of the exothermic addition reaction. The azeotropic removal of water of condensation is used to monitor the reaction. The choice of solvent is governed by several factors. The use of a water azeotrope allows for continual and efficient drying of the reaction mixture. The viscosity of the solution can be governed by the solvent type and amount. The solvent acts as a heat transfer medium and by refluxing at a desired temperature can prevent the runaway of this exothermic reaction. 

It is an addition reaction between an a,P-unsaturated carbonyl compound and a compound with an active methylene group (e.g., malonic ester, acetoacetic ester, cyanoacetic ester, nitroparaffms etc.) in presence of a base, e.g., sodium ethoxide or a secondary amine (usually piperidine). 

A variant in the production of an intermediate in the Robinson synthesis, the tricyclic ABC diketone (18), was developed by Banerjee and co-workers [635, 636] (Scheme 58). The triester (22) was obtained from a-ethoxycarbonylcyclohexanone (21) by the Michael reaction with methyl acrylate, alkaline cleavage, and esterification, and it was then cyclized by Dieckmann s method with subsequent bromination and dehydrogenation to give the unsaturated keto diester (23). The addition of cyanoacetic ester gave compound (26) from which the keto triester (25) was obtained by methylation, acid hydrolysis, and esterification. The latter, by Dieck-mann cyclization and hydrolysis, gave the BC fragment (24). Selective ketalization, reduction, and hydrolysis of the ketal led to the hydroxy-ketone (27). The trans-B/C linkage present in it required the protection... 

Total syntheses of this group also include the synthesis of 11-oxo-steroids described in the patent literature [1066] (Scheme 118). The starting material used was the cyanoester (413) formed by the condensation of acetoacetic and cyanoacetic esters. The successive addition of hydrogen cyanide and acrylonitrile, hydrolysis, decarboxylation, and esterification of the product led to the tetraester (414). Dieckmann condensation, hydrolysis, decarboxylation, and esterification gave the monocyclic... 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

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). ... 

On evaporating the alcoholic solution under reduced pressure from a water bath held at 50-60° (Note 6) the residue weighs about 540 g. A mixture of 600 cc. of absolute alcohol and 10 cc. of concentrated sulfuric acid (Note 7) is then added. The mixture is then heated on the water bath under a reflux condenser for three hours. The excess of alcohol and some of the water formed are removed by distillation under reduced pressure and the residue again heated for two hours with 300 cc. of absolute alcohol and an additional 4 cc. of concentrated sulfuric acid. The alcohol is removed by distillation under reduced pressure, and when the ester has cooled to room temperature, the sulfuric acid is neutralized with a concentrated solution of sodium carbonate the ester (upper layer) is separated, and the aqueous solution extracted with ether, or preferably benzene about one-tenth of the yield is in the extract. The combined products are placed in a i-l. distilling flask and distilled under reduced pressure after the solvent and alcohol and water have been removed. The ester is collected at 94-990, chiefly at 97-98°/x6 mm. (Note 8). The yield of a product analyzing about 97-98 per cent ethyl cyanoacetate amounts to 474-492 g. (77-80 per cent of the theoretical amount) (Note 9). 

Cuprous -butylmercaptide, 42,22 Cuprous chloride as catalyst for 1,4 addition of Grignard reagents to ar,0-unsaturated esters, 41, 63 Cyanoacetic acid, tert-butyl ester, 41, 5... 

Intermediates such as 224 resulting from the nudeophilic addition of C,H-acidic compounds to allenyl ketones such as 222 do not only yield simple addition products such as 225 by proton transfer (Scheme 7.34) [259]. If the C,H-acidic compound contains at least one carbonyl group, a ring dosure is also possible to give pyran derivatives such as 226. The reaction of a similar allenyl ketone with dimethyl mal-onate, methyl acetoacetate or methyl cyanoacetate leads to a-pyrones by an analogous route however, the yields are low (20-32%) [260], The formation of oxaphos-pholenes 229 from ketones 227 and trivalent phosphorus compounds 228 can similarly be explained by nucleophilic attack at the central carbon atom of the allene followed by a second attack of the oxygen atom of the ketone at the phosphorus atom [261, 262], Treatment of the allenic ester 230 with copper(I) chloride and tributyltin hydride in N-methylpyrrolidone (NMP) affords the cephalosporin derivative 232 [263], The authors postulated a Michael addition of copper(I) hydride to the electron-... 

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