Ethyl cyanoacetate alkylation

Ethyl M-butylcyanoacetate has been prepared by alkylation of the sodium enolate of ethyl cyanoacetate with butyl bromide and by condensation of capronitrile with ethyl carbonate, in addition to the method given above. ... 

Alkyl uracyls have been known for some time to act as diuretic agents in experimental animals. The toxicity of these agents precluded their use in the clinic. Appropriate modification of the molecule did, however, yield diuretic agents with application in man. Reaction of allylamine with ethyl isocyanate affords the urea, 89 (the same product can of course be obtained from the same reagents with reversed functionality). Condensation with ethyl cyanoacetate affords aminotetradine (90). In... 

An early application of this reaction to the preparation of barbiturates starts by the condensation of the ketone, I21, with ethyl cyanoacetate by Knoevenagel condensation. Alkylation of the product (122) with ethyl bromide by means of sodium ethoxide affords 123. Condensation of this intermediate with guanidine in the presence of sodium ethoxide gives the diimino analog of a barbiturate (124). Hydrolysis affords vinbarbital (111). > ... 

Thus, the condensation product of cyclohexanone and ethyl cyanoacetate (125) affords the intermediate (126) for the synthesis of cyclobarbital (112) on alkylation with ethyl bromide. The condensation product of cycloheptanone (127) affords the starting... 

Reaction of ethyl cyanoacetate with ethyl thiol acetate produces a and mixture of the dihydrothiazole derivative 80. This is ji-alkylated with methyl iodide and base (8 ), the active methylene group is brominated (82), and then a displacement with piperidine (83) is performed. Hydrolysis completes the synthesis of the diuretic agent, ozolinone (84). 

Alkyl (or aryl)-6-aminouracils, obtained from A -alkyl or A -arylureas and ethyl cyanoacetate, are reported to be useful for prevention and therapy of diseases caused by viral pathogens [411]. 

Only a few reactions of imidazo[2,l-h][l,3,4]oxadiazoles have been reported. The basicity of these compounds is rather low hydrohalides cannot be isolated (69ZC337). Protonation of 23 with strong acids occurs at position 7, giving, for example, 24 (mp 212°C with explosion ). With aqueous base 24 is converted back to 23 (72BSF3968). On alkylation of 23 the quaternary salts 25 are obtained (72BSF3968). Reaction of 25 (R = Et) with ethyl cyanoacetate (Et3N/EtOH) yields 26, albeit in low yield (3.8%) (72BSF3968). 

The preparation of amides directly from alkyl esters is also feasible but is usually too slow for preparative convenience. Entries 4 and 5 in Scheme 3.6 are successftd examples. The reactivity of ethyl cyanoacetate (entry 4) is higher than that of unsubstituted aliphatic esters because of the inductive effect of the cyano group. 

Catalytic reduction of the 2-nitrophenyIhydrazones (745) and subsequent air oxidation of the tetrahydro-l,2,4-benzotriazines (746) which are formed is used for the synthesis of 3,4-dihydro-1,2,4-benzotriazines (747) (80FES715). In another cyclization of an o-nitro group, which somewhat resembles others (e.g. 736 —> 737) described earlier, treatment of l,l-dialkyl-2-(2-nitrophenyl)hydrazines (748) with acids affords 2-alkyl-1,2,4-benzotriazinium salts (749) (77JCS(P1)478). The 2-nitrophenylbromohydrazone (750) with sodium ethoxide and ethyl cyanoacetate forms 6-bromo-3-phenyl-l,2,4-benzotriazine (751) a mechanism for this interesting transformation, in which the cyanoacetate plays no part, has been proposed (79JHC33). 

IS) By ethyl cyanoacetate. Attempted base-catalyzed condensations of ethyl malonate and ethyl acetoaoetate -with the simple episulfides have been unsuccessful. However, 2-iminothioplianes are obtainable from ethyl cyanoacetate and alkene sulfides.108 In the alkylation of ethyl cyanoacetate with propylene sulfide and isobutylene sulfide, mjcloophilic attack by the carb nion is on the primary carbon atom of the episulfide (Eq. 53). 

Reaction XLIV. (c) Condensation of Alkyl and Acyl Halides with the Sodio-derivatives of Ethyl Cyanoacetate. (B., 20, R., 477 21, R., 353 ... 

Chloro-9-phenylpurine reacts with a variety of nucleophiles including 0-alkyl, 0-aryl, SR, and NHR to produce the 2-substituted purines. The compound also reacts with benzylcyanide and ethyl cyanoacetate to give the corresponding purine-2-CHR(CN) derivative but failed to react with other active methylene derivatives, ketones, or potassium cyanide. In contrast, 9-phenyl-2-methyl-sulfonylpurine reacted readily with active methylene compounds, ketones, and potassium cyanide <87CPB4972>. 

The procedure described here for compound 1 is a scaleup of a published method.6 Phase-transfer catalysis7 and concentrated alkali are used to effect a one-pot conversion of diethyl malonate to the cyclopropane diacid, which is easily obtained by crystallization. Apparently alkylation of the malonate system occurs either at the diester or monocarboxylate, monoester stage since the method fails when malonic acid itself is used as the starting material. This method of synthesizing doubly activated cyclopropanes has been extended to the preparation of 1-cyanocyclopropanecar-boxylic acid (86%) by the use of ethyl cyanoacetate and 1-acetyl-cyclopropanecarboxylic acid (69%) by use of ethyl acetoacetate.6... 

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. 

The condensation of active methylene compounds such as malononitrile, ethyl cyanoacetate, etc., with phenyl isocyanate followed by alkylation and cyclization gives 3-aminothiophenes 304 (Scheme 51) <2003T1557>. Dihydrothienopyrimidine-4(/7T)ones 306 are prepared by the reaction of 305 with a-halo ketones <2006HAC104>. 

Ethyl cyanoacetate is readily alkylated under the usual conditions employed for the malonic and acetoacetic ester syntheses (methods 299 and 213) to yield mono- and di-substituted cyano acetates. These substances may then be hydrolyzed and decarboxylated to furnish mono-carboxylic acids (method 265). In many instances, it is difficult to avoid the formation of the dialkylated ester, the yields may be low. Sev-... 

Few acids have been prepared by this method. It is important in the preparation of diisopropylacetic acid, which is made with difficulty by the malonic ester synthesis. Ethyl cyanoacetate is readily alkylated ... 

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). 

The parent, 8-azapurine, has been made only by nitrosation of 4,5-di-aminopyrimidine, which is an item of commerce. - - The 7- and 8-alkyl derivatives of 8-azapurine, whether with or without further substituents, require 1,2,3-triazole starting materials (Section IV,B), of which the best source is Hoover and Day s historic condensation of benzyl azide with ethyl cyanoacetate or (better) cyanoacetamide. An 8-aralkyl group has been introduced similarly. In favorable cases, an 8-aryl group can be derived from the action of a benzenediazonium chloride on a pyrimidine that bears enough electron-releasing substituents to activate the 5 position (the Benson synthesis Section IV,A). 

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