Methyl cyano acetate

The reaction of dimedone-derived enamines 110, methyl (2-cyano)acetate 109, and formaldehyde 72 mediated by lithium perchlorate led to the formation of a Knoevenagel/ enamine-Michael addition product (Scheme 13.33) [52], This could be cyclized in a one-pot procedure with substoi-chiometric amounts of triphenyl phosphine to provide... 

Johnson and Lockard found that (114) could be dehydrated, and the resulting olefin (115) behaved very much like vinyl sulphonium salts, undergoing addition of dibasic acids. Thus, reaction with methyl cyano-acetate afforded the cyclopropane (116) in 80% yield, presumably via addition of the cyanoacetate carbanion to the olefin, then a prototropic shift to form a new cyanomethoxycarbonyl carbanion which displaced... 

Then, ethyl methyl(3-benzoylphenyl)cyanoacetate employed as an intermediate material is prepared as follows The sodium derivative of ethyl (3-benzoylphenyl)cyanoacetate (131 g) is dissolved in anhydrous ethanol (2 liters). Methyl iodide (236 g) is added and the mixture is heated under reflux for 22 hours, and then concentrated to dryness under reduced pressure (10 mm Hg). The residue is taken up in methylene chloride (900 cc) and water (500 cc) and acidified with 4N hydrochloric acid (10 cc). The methylene chloride solution is decanted, washed with water (400 cc) and dried over anhydrous sodium sulfate. The methylene chloride solution is filtered through a column containing alumina (1,500 g). Elution is effected with methylene chloride (6 liters), and the solvent is evaporated under reduced pressure (10 mm Hg) to give ethyl methyl(3-benzoylphenyl)cyano-acetate (48 g) in the form of an oil. 

In the final production preparation, a mixture of ethyl methyl(3-benzoylphenyl)cyano-acetate (48 g), concentrated sulfuric acid (125 cc) and water (125 cc) is heated under reflux under nitrogen for 4 hours, and water (180 cc) is then added. The reaction mixture is extracted with diethyl ether (300 cc) and the ethereal solution is extracted with N sodium hydroxide (300 cc). The alkaline solution is treated with decolorizing charcoal (2 g) and then acidified with concentrated hydrochloric acid (40 cc). An oil separates out, which is extracted with methylene chloride (450 cc), washed with water (100 cc) and dried over anhydrous sodium sulfate. The product is concentrated to dryness under reduced pressure (20 mm Hg) to give a brown oil (33.8 g). 

A solution of 69g of sodium in 1,380 ccof absolute alcohol is mixed with 257.4 g of /3-methyl-thioethyl-d -methyl)-n-butvl-cyano-acetic acid ethyl ester and 114 g of thiourea and the whole mass boiled under reflux with stirring for six hours. After concentration under vacuum the residue is taken up in 1.5 liters of water and shaken up thrice, each time with 300 cc of ether. The aqueous alcoholic layer is stripped, under vacuum, of the dissolved ether and mixed with 300 cc of 30% acetic acid under stirring and ice cooling. The precipitated material is sucked off, washed with water, dried and recrystallized from isopropyl alcohol. The thus obtained j3-methvl-thioethyl-(1 -methyD-n-butyl-cyano-ecetyl thiourea forms yellowish green crystals having a melting point of 229°C to 230°C. 

The one-step condensation to convert 2-butanone, ethyl cyano-acetate, and hydrocyanic acid to ethyl 2,3-dicyano-3-methyl-pentanoate is a modification of the procedure described by Smith and Horowitz 6 in which pyridine acetate was employed as the catalyst. Higson and Thorp 6 employed a two-step procedure in which butanone was converted to its cyanohydrin, which in turn was condensed with ethyl cyanoacetate. 

Lappin s publication, 1,8-naphthyridine (72 R = NH2) was obtained under similar conditions from the 6-amino derivative of 70 by Adams et al.127 The special behavior of the 6-substituted derivatives of 70 was ascribed by Lappin126 to the steric hindrance effect of the 6-substituent. Some later results,29 128 however, contradicted Lappin s concept. On vacuum distillation of the 2-(6-methyl-2-pyridylaminomethylene)acetoacetate and -cyano-acetate, Antaki did not obtain the 1,8-naphthyridines but instead the 3-substituted 6-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidines.29 By the thermal ring closure of 70 (R = 5-CONH2) Richardson and McCarty128 obtained a product described as a 1,8-naphthyridine of type 72. 

Head-to-tail dimerisation of methyl acrylate to the dimethyl ester of 2-methylenepentane-dioic acid (126) occurred in 82-85% yield in the presence of catalytic amounts of P(RNCH2CH2)3N with R = PP, Bu or Bz but the less sterically hindered proazaphosphatrane with R = Me, gave oligomer or pol-ymer. The proazaphosphatrane, P(RNCH2CH2)3N with R = Bu also acts as an effective ligand for the palladium-catalyzed direct arylation of ethyl cyano-acetate (127) with aryl bromides (e.g. 128) to form (129) in high yield. ... 

Hexobarbital is prepared by reacting together methyl urea and methyl-a-methyl-a-cyclo-hexen-1-yl-a-cyano acetate when an open-chain ureide is formed as an intermediate with the elimination of a molecule of methanol. This upon hydrolysis affords spontaneous closure of the ring thereby resulting into the formation of hexobarbital. 

It is prepared by the interaction of urea with methyl-2-ethyl-a-cyclo-hexene-l-yl-a-cyano acetate in the presence of sodium ethoxide when a molecule of methanol is eliminated with the formation of an open-chain ureido which upon hydrolysis results into spontaneous ring closure and gives rise to cyclobarbital. 

Ethyl ethylcyanoacetate, 26, 33 Ethyl ethylidene-frw-acetoacetate, 27,24 Ethyl (1-ethylpropenYl)-methyl-cyanoacetate, 25, 44 Ethyl (1-ethylpropylidene)-cyano-acetate, 26,46 Ethyl formate, 3A, 12 26, 29 Ethtyl 1,16-hexadecanedicarboxyl-ate, 21, 48... 

Ethyl (1-methyl-A]-buteny )cyano-acetic acid ethyl ester Vinbarbital sodium 1-Ethyl-6,7-methylenedioxy-4-(1H)-oxocinnoline-3-carbonitrile Cinoxacin... 

A soln. of 2-methylimidazole, ethyl 2-cyano-3-ethoxyacrylate, and ethyl cyano-acetate in ethanol refluxed 4 days diethyl 3 amino-2-cyano-4-[(2-methyl-l-imidazolyl)methylene]glutaconate. Y 91%. F. e., mostly with benzimidazole derivatives, s. R. K. Howe, J. Org. Chem. 34, 2983 (1969). 

Cyano-esters can also be condensed with other nitriles, as in the reaction of methyl a-cyano acetate and a-amino acetonitrile to give 4.6. Initial condensation of the cyano-ester enolate with the "other" nitrile moiety gave an iminium salt. Subsequent reaction with aqueous acid led to an imine, which isometizes to the... 

In this manuscript we disclose new synthetic methodology to prepare a member of a class of tetrasubstituted imidazole p38 inhibitors. The optimal route involves a thiazolium catalyzed cross acyloin-type condensation of a pyridinealdehyde with an iV-acylimine. The pyridinealdehyde was prepared in 3 steps and 68% yield from 2-chloro-4-cyano pyridine. The tosylamide precursor to the iV-acyl imine was prepared in two steps and 93% yield from isonipecotic acid. We have demonstrated the scope and some preliminary mechanistic studies concerning this new reaction. The resulting a-keto-amide is then cyclized with methyl ammonium acetate to provide the desired tetrasubstituted imidazole. Cbz deprotection and formation of a pharmaceutically acceptable salt completes the synthesis in 6 steps and 38% overall yield. 

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