Ethyl cyanoacetate, reaction with

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 condenses with ketones and ammonia in absolute ethanol at 0-5° to give 44-73% yields of cyclic dicyanoimides. Endocyclic ketones may be used, giving imides in which the two radicals are p>art of an alicyclic ring. The imides are hydrolyzed and decarboxylated in almost theoretical yields to yS,/S-disubstituted glutaric acids. A similar reaction takes place between aldehydes or ketones and cyanoacetamide, NCCHjCONHj, in the presence of piperidine or potassium hydroxide. When aldehydes are used, the condensation products are dicyanoamides, RCH[CH(CN)CONHj]j, rather than cyclic imides. 

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. 

Cs+- and Na+-exchanged MCM-41 type materials also have basic character and have been found to be active towards the base catalysed Knoevenagel condensation of benzaldehyde with ethyl cyanoacetate (Reaction 4).32 The Cs+-and Na+-exchanged samples were prepared by repeated exchange of the hydrogen form of MCM-41 with an aqueous solution of appropriate chloride salt (0.5 mol dm-3) at room temperature. The Cs+-exchanged sample was considerably more basic and therefore more active than the Na+-exchanged sample. 

Choudary et al. have investigated the Knoevenagel reaction by use of diamine-functionalized MCM-41 [47]. This grafted material was effective in the condensation of several aldehydes with both ethyl cyanoacetate and with malononitrile. In-... 

Cyclopropanation. The reaction of ethyl cyanoacetate (1) with cupric chloride and cupric acetate in the presence of an olefin such as cyclohexene at 100-110° in DMF leads to a mixture of two cyclopropanes and some unsaturated products of addition. The latter are eliminated by oxidation with KMuOa. The cyclopropanes were identified as exo- and endo-isomers (2) and (3). Cyclopropanes were also obtained under similar conditions from styrene and from decene-1. 

Stirred ethyl cyanoacetate treated with phenyl isocyanate and triethylamine, and allowed to stand 1 hr. -> ethyl 2-cyanomalonanilate. Y 88%. F. e. and reactions of the products s. L. Capuano and R. Zander, B. 106, 3670 (1973) pyrrolidine-2,3,5-triones s. ibid. 106, 3677. 

The formation of ethyl isopropylidene cyanoacetate is an example of the Knoevenagel reaction (see Discussion before Section IV,123). With higher ketones a mixture of ammonium acetate and acetic acid is an effective catalyst the water formed is removed by azeotropic distillation with benzene. The essential step in the reaction with aqueous potassium cyanide is the addition of the cyanide ion to the p-end of the ap-double bond ... 

Into a 500 nil. round-bottomed flask, provided with a double surface condenser, place 50 g. (63 ml.) of pure, dry acetone, 50 g. (47 ml.) of ethyl cyanoacetate (Section 111,131) and 0 -5 g. of piperidine. Allow to stand for 60 hours and heat on a water bath for 2 hours. Treat the cold reaction mixture with 100 ml. of ether, wash with dilute hydrochloric acid, then with water, and dry over anhydrous sodium or magnesium sulphate. Distil under diminished pressure and collect the ethyl fsopropylidene cyanoacetate (ethyl a-cyano-pp-dimethylacrylate) at 114-116°/14mm.(l). The yield is 39 g. 

The preparation of ethyl cyanoacetate proceeds via ethyl chloroacetate and begins with acetic acid Wnte a sequence of reactions descnbmg this synthesis... 

If the substituent at the 3-position is a group that can be eliminated as an anion (such as Cr, CN and NJ), the reaction proceeds without the cleavage of the C(3)—C(4) bond in the isoxazole ring and involves the ejection of the 3-substituent as an anion. For example, 3-cyanoisoxazole (114) reacted with sodium ethoxide at room temperature to give ethyl cyanoacetate (115) via an intermediate cyanoketene (32G436). 

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. 

CN/CC replacements were also observed when the pyrimidine ring is part of a bicyclic system. Reaction of quinazoline with active methylene compounds, containing the cyano group (malonitrile, ethyl cyanoacetate, phenylacetonitrile) gave 2-amino-3-R-quinoline (R = CN, C02Et, Ph) (72CPB1544) (Scheme 12). The reaction has to be carried out in the absence of a base. When base is used, no ring transformation was observed only dimer formation and SnH substitution at C-4 was found. 

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). > ... 

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). 

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