Ethyl cyanoacetate, addition

The Michael Addition Reaction consists in the addition of the sodio-derivative of ethyl acetoacetate, ethyl malonate or ethyl cyanoacetate to an olefine group... 

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. ... 

Kinetics of the reaction of p-nitrochlorobenzene with the sodium enolate of ethyl cyanoacetate are consistent with this mechanism. Also, radical scavengers have no effect on the reaction, contrary to what would be expected for a chain mechanism in which aryl radicals would need to encounter the enolate in a propagation step. The reactant, /i-nitrophenyl chloride, however, is one which might also react by the addition-elimination mechanism, and the postulated mechanism is essentially the stepwise electron-transfer version of this mechanism. The issue then becomes the question of whether the postulated radical pair is a distinct intermediate. 

A convenient method leading to pyrans (38) consists in the nucleophilic addition of R anions to 2,6-disubstituted pyrjdium salts, in which the y-position (secondary carbonium ion) is more reactive than the a-positions (tertiary carbonium ions), in opposition to the reactivity of 2,4,6-trisubstituted pyrylium salts.Krohnke and Dickore as well as Dimroth and WolH showed that 2,6-diphenyl-pyrylium salts add the anions R of nitromethane, 1,3-diketones, malonodinitrile, ethyl cyanoacetate, and benzoylacetonitrile. Similar reactions are known in the flavylium series. -Nonactivated R ... 

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). 

Coupling of the diazotetrazole with ethyl cyanoacetate gave 1034. Its cyclization in boiling acetic acid or pyridine afforded 1035 as the major product in addition to 1036. Mass spectral fragmentation of 1035 confirmed that the azole ring is more stable than the 1,2,4-triazine ring on electron impact [76JCS(P1) 1496] (Scheme 194). 

The above is an example of the Guareschi reaction. It is applicable to most dialkyl ketones and to alicyclic ketones (e.., cj/clohexanone, cyclopentanone, etc.). The condensation product (I) is probably formed by a simple Knoe-venagel reaction of the ketone and ethyl cyanoacetate to yield ethyl a-cyano-pp dimethylacrylate (CH3)2C=C(CN)COOC2Hj, followed by a Michael addition of a second molecule of ethyl cyanoacetate finally, the carbethoxyl groups are converted to the cyclic imide structure by the action of ammonia. 

A distantly related acid with a more highly functionalized ring shows choleretic rather than antiinflammatory activity. That is, the compound is useful in those conditions in which the flow of bile is to be increased. Construction of the thiazolone ring is accomplished by a method analogous to that used above to build the thiazole ring. Thus, condensation of ethyl mercaptoacetate with ethyl cyanoacetate leads to the thiazolinone (203) an intermediate such as 202, involving addition of mercaptide to the nitrile function, can be reasonably invoked. 

Ethylbenzoic acid was converted to the acid chloride, which was treated with AICI3 and benzene to give 4-ethylbenzophenone in 90% yield overall. Condensation with ethyl cyanoacetate afforded ethyl 4-ethyl-a-cyano-B-phenylcinnamate as an essentially 50/50 mixture of the Z- and E-isomers. The yield of the condensation was highly sensitive to reaction conditions, and was optimized at 75% with portionwise addition of the ammonium acetate catalyst. Bromination and dehydrobromination as described earlier then completed the preparation. The overall yield of ethyl 4-vinyl-a-cyano-p-phenylcinnamate was 20%. 

Diazotised 5-aminotetrazole is unstable under the conditions recommended for its use as a biochemical reagent. While the pH of the diazotised material (the cation of which contains 87% nitrogen) at 0°C was being reduced to 5 by addition of potassium hydroxide, a violent explosion occurred [1], This may have been caused by a local excess of alkali causing the formation of the internal salt, 5-diazoniotetrazolide, which will explode in concentrated solution at 0°C [2], The diazonium chloride is also very unstable in concentrated solution at 0°C. Small-scale diazotisation (2 g of amine) and susequent coupling at pH 3 with ethyl cyanoacetate to prepare ethyl 2-cyano-(l//-tetrazol-5-ylhydrazono)acetate proceeded uneventfully, but on double the scale a violent explosion occurred [3], The importance of adequate dilution of the reaction media to prevent explosions during diazotisation is stressed [4]. 

Potassium cyanide (71.6 g., 1.1 moles, u.s.p.) and 100 ml. of 95% ethanol are placed in a 2-1. round-bottomed flask having a ground joint and arranged with a Hershberg stirrers (Note 1). A solution of 113 g. (106 ml., 1 mole) of ethyl cyanoacetate, 79 g. (98 ml., 1.1 moles) of 2-butanone, and 66 ml. of.glacial acetic acid is added to the stirred solution over a period of 1 hour. The mixture is stirred for an additional hour, the stirrer is removed, and the mixture is allowed to stand at room temperature for 7 days (Note 2). 

Thus, the unsubstituted starting compound 69 was treated with resorcinol in the presence of trifluoroacetic acid (TFA) to yield 70. Then, reaction of 69 with the cyclic a,/3-unsaturated ketone in the presence of lithium hydride gave the 7-substituted heteroaromatic compound 71, and ethyl cyanoacetate afforded the cross-conjugated product 72, whereas reaction with pyrimidine-2,4,6-trione in the presence of triethylamine yielded the addition product 73. Indole also been reacted with 69, and heating of the dichloromethane solution for 90 min in the presence of TFA yielded the addition product 74 in excellent yield (95%) <1998ZOR450> (Scheme 12). 

The same hyperbranched polyglycerol modified with hydrophobic palmitoyl groups was used for a noncovalent encapsulation of hydrophilic platinum Pincer [77]. In a double Michael addition of ethyl cyanoacetate with methyl vinyl ketone, these polymer supports indicated high conversion (81 to 59%) at room temperature in dichloromethane as a solvent. The activity was stiU lower compared with the noncomplexed Pt catalyst. Product catalyst separation was performed by dialysis allowing the recovery of 97% of catalytic material. This is therefore an illustrative example for the possible apphcation of such a polymer/catalyst system in continuous membrane reactors. 

Ethyl (6-Methoxy-l,2-naphthoquinonyl-6) Cyanoacetate. The above naphthoquinone (21.7 g) is added to a solution of 500 cc of ethanol and 14 cc of ethyl cyanoacetate, followed by the addition of 32 cc triethylamine. A deep purple color will develop and the mixture should be swirled for 4 min to dissolve the quinone completely. A solution of 75.9 g of potassium ferricyanide in 320 cc of water is then added to the solution, causing a thick dark complex to form and separate. Redissolve by adding a soluhon of 24 g of sodium carbonate in 1,600 cc of water. Swirl or stir and filter through diatomaceous filter aid. Acidify the filtrate with 100 cc of 6 M sulfuric acid to precipitate 34.8 g of red-orange powder, which is oven dried at 70°. Reciystallize from ethyl acetate to get 19.3 g, mp 157-158.5°. The remaining filtrate is evaporated to a small bulk and reciystallization from ethyl acetate gives an additional 2.8 g of product. 

The phosphine-containing ruthenium dihydride dendrimer 33 was found to be an active catalyst for the diastereoselective Michael addition of ethyl cyanoacetate to diethyl ethylidenemalonate in THF (Scheme 12). The dendritic catalyst showed an activity and selectivity similar to those of the reference compound RuH2(PPh3)4 (100% conversion after 24 h and a diastereoselectivity of 7/3) (40). The dendritic catalyst was recycled twice by precipitation with diethyl ether without loss of activity or selectivity. Complex 34 showed similar activity and recoverability over three runs like that of complex 33. 

An alternative form of reactivity of pyrimidines also assisted by electron donating substituents is the nucleophilicity of a ring carbon atom towards various electrophiles. For example, the reaction of 69 with aryl aldehydes 70 in the presence of ethyl cyanoacetate produced 71, presumably fi om the conjugate addition of 69 to the in situ generated double bond formed in the Rnoevenagel condensation of 70 and ethyl cyanoacetate <99JHC113>. 

The addition of a mercaptide to a nitrile provides the key reaction to the preparation of a thiazolidinone that shows diuretic activity. The hrst step in the reaction of ethyl 2-mercaptoacetate (105-2) with ethyl cyanoacetate (105-1) thus probably leads hrst to the formation of the addition product (105-3). The imino... 

Ethyl ethoxymethylenecyanoacetate can be prepared in the laboratory from ethyl cyanoacetate and ethyl orthoformate according to the directions of de Bellemont.2 The submitters and checkers used a commercial product, m.p. 45-50°, obtained from Kay-Fries, Inc., New York. The liquefied product is weighed and poured into the dropping funnel. An infrared heating lamp is used to keep it liquid during the addition. 

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