Cyanoacetic acids, decarboxylation

The physical properties of cyanoacetic acid [372-09-8] and two of its ester derivatives are Hsted ia Table 11 (82). The parent acid is a strong organic acid with a dissociation constant at 25°C of 3.36 x 10. It is prepared by the reaction of chloroacetic acid with sodium cyanide. It is hygroscopic and highly soluble ia alcohols and diethyl ether but iasoluble ia both aromatic and aUphatic hydrocarbons. It undergoes typical nitrile and acid reactions but the presence of the nitrile and the carboxyUc acid on the same carbon cause the hydrogens on C-2 to be readily replaced. The resulting malonic acid derivative decarboxylates to a substituted acrylonitrile ... 

The methyl and ethyl esters of cyanoacetic acid are slightly soluble ia water but are completely miscible ia most common organic solvents including aromatic hydrocarbons. The esters, like the parent acid, are highly reactive, particularly ia reactions involving the central carbon atom however, the esters tend not to decarboxylate. They are prepared by esterification of cyanoacetic acid and are used principally as chemical iatermediates. 

Reactions. The chemical properties of cyanoacetates ate quite similar to those of the malonates. The carbonyl activity of the ester function is increased by the cyano group s tendency to withdraw electrons. Therefore, amidation with ammonia [7664-41-7] to cyanoacetamide [107-91-5] (55) or with urea to cyanoacetylurea [448-98-2] (56) proceeds very easily. An interesting reaction of cyanoacetic acid is the Knoevenagel condensation with aldehydes followed by decarboxylation which leads to substituted acrylonitriles (57) such as (29), or with ketones followed by decarboxylation with a shift of the double bond to give P,y-unsaturated nitriles (58) such as (30) when cyclohexanone [108-94-1] is used. 

Malonic acid or cyanoacetic acid can also be used as the nucleophile. With malonic acid or cyanoacetic acid as reactants, the products usually undergo decarboxylation. This may occur as a concerted fragmentation of the adduct.214... 

The submitters prepared o-chlorohydrocinnamonitrile by the following procedure. Ethyl cyanoacetate (3040 g., 27 moles) was added to a solution of 140 g. (6.1 g. atoms) of sodium in 4 1. of absolute ethanol, followed by 970 g. (6 moles) of o.a-dichloro-toluene (Eastman Organic Chemicals), to afford 890 g. (63%) of ethyl 2-(o-chlorobenzyl)cyanoacetate,2 b.p. 117-123° (0.03 mm.). Hydrolysis of this material in 2 1. of 10% aqueous sodium hydroxide at room temperature gave a quantitative yield (790 g.) of 2-(o-chlorobenzyl)cyanoacetic acid, m.p. 129-132° without recrystallization. Decarboxylation of 750 g. of the acid in 750 ml. 

A mixture of 126 g (1.5 mols) of cyclopentanone, 128 g (1.5 mols) cyanoacetic acid, 31 g (0.5 mol) of ammonium acetate and 200 cc of dry benzene is heated under a refluxing condenser and a water trap. The mixture is refluxed for about 12 hours after which time no more water collects in the trap, and the formation of cyclopentylideneacetonitrile is complete. The reaction mixture comprising a mixture of cyclopentylideneacetonitrile and cyclopentylideneacetic acid is washed with about one liter of 2% hydrochloric acid and the benzene layer is separated and the mixture is distilled to cause decarboxylation of the cyclopentylideneacetic acid present. The distillate comprising cyclopentylideneacetonitrile which boils at 172° to 175°C is purified by distillation. 

Cyclohexenylacetonitrile has been prepared by the decarboxylation of cyclohexylidenecyanoacetic acid 4-5 by the dehydration of 1-cyclohexenylacetamide 5 by the condensation of cyclohexanone and cyanoacetic acid in the presence of piperidine 6 by the condensation of cyclohexanone and ethyl cyano-acetate in the presence of sodium ethoxide 4-7 and by the condensation of cyclohexanone and cyanoacetic acid in the presence of ammonium acetate followed by decarboxylation.8 Ammonium acetate also has been used as a catalyst for the condensation of ketones with ethyl cyanoacetate.3-9... 

In a number of instances the decarboxylation of a,/3-unsatu-rated (conjugated) cyanoacetic acids has been found to yield /3,7-unsaturated (unconjugated) nitriles.5-10... 

Cyano acetals, preparation, 598 Cyanoacetic ester condensation, 608 Cyanoacetic ester synthesis, 429, 601 Cyano acids, esterification, 481 preparation, 593, 607, 608 preparations listed in table 74, 622 a-Cyano acids, decarboxylation, 429, 601... 

Cyanoacetic acid reacts readily with aliphatic and aromatic carbonyl compounds to form a-cyanoacrylic acids, which can be decarboxylated by heating to give /3-substituted acrylonitriles. ... 

As work progressed, we desired an acid intermediate that would allow us a broader spectrum of structural variants on the amide nitrogen. We found that the desired vinylogous carbamic acid could be prepared directly from cyanoacetic acid (Figure 5). When R equals (substituted)benzyl, an approximate 1 1 ratio of desired products and decarboxylated products was obtained. When R equals (substituted)phenyl, only the desired carboxylic acid intermediates were obtained. The impure vinylogous carbamic acids could easily be purified by base extraction. These acids were converted to vinylogous ureas via their stable acid chlorides. 

Racemization also occurs on decarboxylation of optically active disub-stituted cyanoacetic acids (which can be regarded as half nitriles of malonic acids), the reaction yielding disubstituted acetonitriles ... 

A closely related variation of the reaction uses cyanoacetic acid or malonic acid, as opposed to the corresponding esters, as the potential nucleophile. The mechanism of the addition phase of the reaction under these circumstances is similar to the previously discussed cases. The addition intermediates, however, are susceptible to decarboxylation. In many instances, the decarboxylation and elimination phases may... 

The nitrile in cyanoacetic acid and cyanoacetic esters makes them more reactive than the corresponding malonic acid or esters. As with malonic acid, cyanoacetic acid can condense to give the alkylidine cyanoacetic acid or the decarboxylated a,P-unsaturated nitriles. Cyanoacetic acid reacts in a similar fashion as malonic acid, and often gives mixtures of the a,P and P,y-... 

Hydrogenolysis of the diallyl alkylmalonate 757 with formic acid in boiling dioxane affords the monocarboxylic acid 758. Allyl ethyl malonates are converted into ethyl carboxylates[471]. The malonic allyl ester TV-allylimide 759 undergoes smooth deallylation in refluxing dioxane to give the simple imide 760(472]. The allyl cyanoacetate 761 undergoes smooth decarboxylation to give... 

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). ... 

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