Cyanoacetate , ethyl ester, reaction with

Pyridinitrile is prepared by the reaction of cyanoacetic acid ethyl ester (3) with ammonia, followed by the coupling of two molecules of the cyanoacetic amide (4) formed with benzaldehyde (5) and by the chlorination of the product, 3,5-dicyano-... 

The synthesis of pyrido[2,3-d]pyrimidin-7(8H)-ones has also been achieved by a microwave-assisted MCR [87-89] that is based on the Victory reaction of 6-oxotetrahydropyridine-3-carbonitrile 57, obtained by reaction of an Q ,/3-unsaturated ester 56 and malonitrile 47 (Z = CN). The one-pot cyclo condensation of 56, amidines 58 and methylene active nitriles 47, either malonitrile or ethyl cyanoacetate, at 100 °C for benzamidine or 140 °C for reactions with guanidine, in methanol in the presence of a catalytic amount of sodium methoxide gave 4-oxo-60 or 4-aminopyridopyrimidines 59, respectively, in only 10 min in a single-mode microwave reactor [87,88]... 

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. 

In the presence of sodamide the anionic form of 2-amino-l-ethylbenzimidazole is substituted by alkyl halides on both the annular and exocyclic nitrogens. With butyl and isopropyl iodides the proportion of dialkylated product is increased. The synthetic utility of such nucleophilic reactions of 2-aminobenzimidazole is exemplified by reactions with ethyl cyanoacetate, acetoacetic ester and ethyl benzoylacetate, when subsequent cyclization of the initial products also gives pyrimidobenzimidazole derivatives (Scheme 117). 

Derivation Esterification of cyanoacetic acid with ethanol reaction of an alkali cyanide and chloroa-cetic ethyl ester. 

Rann et al. reported the dramatic influence of a new tailor-made, task-specific, and stable ionic liquid, butyl methyl imidazolium hydroxide ([bmim][OH]), in Michael addition. They have discovered that a task-specific ionic liqnid [bmim][OH] efficiently promoted the Michael addition of 1,3-dicarbonyl compounds, cyano esters, and nitro alkanes to a variety of conjugated ketones, carboxylic esters, and nitriles withont reqniring any other catalyst and solvent (Fig. 12.21) [16]. Very interestingly, all open-chain 1,3-dicarbonyl componnds such as acetylacetone, ethyl ace-toacetate, diethyl malonate, and ethyl cyanoacetate reacted with methyl vinyl ketone and chalcone to give the usual monoaddition products, whereas the same reactions with methyl acrylate or acrylonitrile provided exclusively bis-addition products. 

The moisture- and air-stable ionic liquids, l-butyl-3-methylimidazolium tetra-lluoroborate [bmim]BF and l-butyl-3-methylimidazolium hexafluorophosphate [bmim]PFg, were used as green recyclable alternatives to volatile organic solvents for the ethylenediaimnonium diacetate-catalyzed Knoevenagel condensation between aldehydes or ketones with active methylene compounds. As described by Su et al. [57], the ionic hquids containing a catalyst were recycled several times without decrease in yields and reaction rates. In the case of 2-hydroxybenzaldehyde, the reactions led to the formation of 3-substituted coumarin derivatives in high yields of up to 95% (Scheme 17.11). When ethyl cyanoacetate was used, 2-imino-27f-l-benzopyran-3-carboxyhc acid ethyl ester was formed. 

Arylidenebarbituric and thiobarbituric acids react with compounds containing an active methylene group under Michael reaction conditions.246,247 Compounds 69 (R = H, p-N02, p-Cl X = O, S) have been obtained in the reaction of 5-arylidenebarbituric or thiobarbituric acids with cyclohexanone, benzyl phenyl ketone, camphor, ethyl ester of phenylacetic acid, or nitromethane. The reaction with ethyl cyanoacetate or ethyl... 

Other synthons for 1,3-dicarbonyl compounds that have been successfully applied include p-chloro-a,P-unsaturated ketones and aldehydes, P-dimethylamino-a,P-unsaturated ketones (easily obtained from ketones by reaction with DMFDMA), P-alkoxy-enones"" and vinyl-amidinium salts."" Alkynyl-ketones react with 5-alkyl-isothioureas, giving 2-alkylthio-pyrimidines" and propiolic acid reacts with urea to give uracil directly in about 50% yield. "" 1,3-Keto-esters with formamidine produce 4-pyrimidinones"" and C-substituted formamidines with ethyl cyanoacetate give 2-substituted-6-amino -pyrimidinones. In analogy, pyrimidines fused to other rings, for example as in quinazolines, can be made from ortho-aminonitriles " and in general, from P-enamino esters. ... 

Reactions using highly acidic active methylene compounds (pAa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer and Harada have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aptotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of 3-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce p-phenylalanine (88) in high yield (equation 14). This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

The electron-rich character of keten acetals (36) means that they undergo cycloaddition with ketens with judicious choice of reactants, this results in the formation of dihydropyran-2-ones, e.g. (37), which are hydrolysed to the dioxo-derivative (38). /3-Keto-esters are cyclized by their reaction with 3-hydroxy-aldehydes and titanium(rv) chloride to form 5,6-dihydropyran-2-ones. Aroylarylacetylenes condense with either ethyl cyanoacetate or aceto-acetate in the presence of a base to form 4,6-diarylpyran-2-ones (39)." ... 

Aldol and Michael reactions. Active methylene compounds such as ethyl cyanoacetate and malonic esters react with aldehydes and electron-deficient alkenes in the aldol and Michael mode, respectively. 

In another variation, keto-ester 7.14 reacted with ethyl a-cyanoacetate to give 7.143. Subsequent reaction with ammonium hydroxide led to 7.116 in good yield.85 Amines were also reacted with 7.143 to give N-alkyl derivatives of 7.116. 

Alkylation and Arylation. The 5-methylation of thioamides by diazomethane is catalysed by silica gel. 5-Phenyl derivatives of thiobenzanilides are obtained in high yield by radical arylation with nitrosoacetanilide or phenylazotriphenyl-methane. Thiols are made from alkyl (or cycloalkyl, or aralkyl) halides by their reaction with dimethylthioformamide and treatment of the imidium ester with methanol other methods of hydrolysis lead to side-reactions, giving impure products. Mono- and bi-protic thiocarboxamides condense with ethyl bromo-cyanoacetate and one equivalent of NaOEt with spontaneous separation of sulphur and the formation of ff-amino-cr-cyano-acrylates, as shown in reaction (5). The... 

Oxo- and amino-substituted [2,3-b]-TTs (202 and 204) result from the reaction of 3-keto esters, malononitrile, ethyl cyanoacetate, or 3-ketonitriles, with alkylating agents such as ethyl bromoacetate and bromoacetonitrile, as exemplified in Scheme 49 [75],... 

Numerous CH insertion reactions of isocyanates involve substrates with a CH2CO group. For example, dialkyl malonates, malonitrile , ethyl cyanoacetate and oxaloacetic esters react with alkyl and aryl isocyanates at room temperature, in the presence of triethylamine, to give products resulting from insertion into the activated C-H bond as... 

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