A - cyanoacetic acid

In another synthesis using a preformed pyridine derivative a cyanoacetic acid ester is condensed in a Guareschi-type reaction with an a-substituted /3-keto carboxylic acid ester and an amine to give a hydroxypyridone (18 Scheme 3). These compounds are suitable precursors for an acid catalyzed cyclization to furo[2,3-6]pyridine-6-ones (19). N-Substituted derivatives may also be prepared by this route (64AP754). The aqueous solutions of these furopyridines show an intensive blue fluorescence. 

Microwave assisted Gewald synthesis of 2-acyl aminothiophenes 13 on solid support has been carried out by Gauvin and co-workers <03SL63>, wherein the solid support was a cyanoacetic acid Wang resin 12 (Scheme 3),... 

Fenpiclonil (1) can be prepared (Scheme 15.2.2) by Knoevenagel condensation of 2,3-dichlorobenzaldehyde (8) with a cyanoacetic acid derivative 9, providing an a-cyanocinnamate intermediate 10 that is then reacted with TosMIC in the presence of a base to produce the desired IH-pyrrole 1 in high yield. 

An atom economic route for the preparation of fludioxonil (2) has been patented [18]. Known 2,2-difluorobenzodioxole 12 is regioselectively lithiated to form 13 (Scheme 15.2.3). In a one-pot reaction intermediate 13 is directly quenched with 14 followed by conversion of the formed intermediate 15 with TosMIC into the desired fludioxonil (2). Alternatively intermediate 13 can be quenched with DMF to form aldehyde 16 which is, similar to the above process, stepwise reacted with a cyanoacetic acid derivative to obtain 15 followed by ring formation using TosMIC to deliver fludioxonil (2). Table 15.2.1 lists the chemical and physical properties of fenpiclonil (1) and fludioxonil (2). 

Since it is known that a-protons of the acylacetonitriles are more acidic than those of the methyl ketones, it was logical to use the acylacetonitrile building blocks during the first stage of the aldol-like condensation for the synthesis of heterocyclic compounds such as the 4H-pyran, 2-pyridone, and furan derivatives [85-95]. Therefore, it was expected that acylacetonitriles would be oxidized by manganese(III) acetate in a similar manner to the oxidation of a-cyanoacetic acid [65,96-99] and 1,3-dicarbonyl compounds [100] to give acylcyanomethyl radicals, CH(COR)CN, which would attack the alkenic double bonds to produce heterocyclic compoimds in one step [73,75,77,80,101-... 

Bossio and coworkers utilized a four-component reaction that included a type ac cyclization for the construction of highly substituted 3-pyrrohn-2-ones (Scheme 64 1999H(50)463). Treatment of a-aminoketone 258, a-cyanoacetic acid (259), cyclohexyl isocyanide (260), and aldehydes 261 with potassium carbonate gives 3-cyano-3-pyrrohn-2-ones 263 via the amide intermediates 262. 

C8H10N4O2. An alkaloid occurring in tea, coffee and guarana, from which it may be prepared by extraction, It is also manufactured by the methylation of theobromine and by the condensation of cyanoacetic acid with urea. Crystallizes with H2O or anhydrous from organic solvents. M.p. (anhydrous) 235"C, sublimes at 176 C. Odourless, and with a very bitter taste. Caffeine acts as a stimulant and diuretic, and is a constituent of cola drinks, tea and coffee. 

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 ... 

Hydrogen Cyanide Process. This process, one of two used for the industrial production of malonates, is based on hydrogen cyanide [74-90-8] and chloroacetic acid [79-11-8]. The intermediate cyanoacetic acid [372-09-8] is esterified in the presence of a large excess of mineral acid and alcohol. 

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. 

Manufacture. Cyanoacetic acid and cyanoacetates are iadustrially produced by the same route as the malonates starting from a sodium chloroacetate solution via a sodium cyanoacetate solution. Cyanoacetic acid is obtained by acidification of the sodium cyanoacetate solution followed by organic solvent extraction and evaporation. Cyanoacetates are obtained by acidification of the sodium cyanoacetate solution and subsequent esterification with the water formed being distilled off. Other processes reported ia the Hterature iavolve the oxidation of partially oxidized propionittile [107-12-0] (59). Higher esters of cyanoacetic acid are usually made through transesterification of methyl cyanoacetate ia the presence of alumiaiumisopropoxide [555-31-7] as a catalyst (60). 

Economic Aspects. In order to avoid the extraction and evaporation steps, most of the cyanoacetic acid derivatives are made directiy from solution therefore, only a small portion of the acid produced is traded. Cyanoacetic acid is produced by Boehringer-Tngelheim and Knoil ia Germany, Juzen ia Japan, as well as Hbls ia the United States. When sold ia tons, the price of cyanoacetic acid was 9/kg ia 1993. 

Analytical and Test Methods. Potentiometic titration is an analytical method for cyanoacetic acid. Methyl and ethyl cyanoacetates are usually analyzed by gas chromatography usiag the same equipment as for the malonates but with a higher column and iajector temperatures, namely 150 and 200°C, respectively. 

Health and Safety Factors. Handling of cyanoacetic acid and cyanoacetates do not present any specific danger or health hazard if handled with the usual precautions. Cyanoacetic acid is classified as a moderate irritant (skin irritation, rabbits) and has an LD q (oral, rats) of 1500 mg/kg. Methyl and ethyl cyanoacetate are both classified as slight irritants (skin irritation, rabbits) and have an LD q (oral, rats) of 3062 and 2820 mg/kg, respectively. Transport classification cyanoacetic acid RID/ADR 8 IMDG-Code 8 lATA/ICAO 6.1. Methyl and ethyl cyanoacetate RID/ADR 6.1 IMDG-Code 6.1 lATA/ICAO 6.1. 

Otherwise cyanoacetic acid is directiy converted as a solution with 1,3-dimethylurea [96-31-1] iato 2-cyano-A/,AT-dimethylcarbamoyl acetamide [39615-79-7] which is further upgraded iato the diuretics theophylline [58-55-9] (33 where R = H) and caffeiae [58-08-2] (33, where R = CH3) (63). 

Beryllium, calcium, boron, and aluminum act in a similar manner. Malonic acid is made from monochloroacetic acid by reaction with potassium cyanide followed by hydrolysis. The acid and the intermediate cyanoacetic acid are used for the synthesis of polymethine dyes, synthetic caffeine, and for the manufacture of diethyl malonate, which is used in the synthesis of barbiturates. Most metals dissolve in aqueous potassium cyanide solutions in the presence of oxygen to form complex cyanides (see Coordination compounds). 

A mixture of 105.6 g. (1.1 moles) of freshly distilled furfural, 87.0 g. (1.0 mole) of 98% cyanoacetic acid (Note 1), 3.0 g. of ammonium acetate, 200 ml. of toluene, and 110 ml. of pyridine is placed in a 1-1. round-bottomed flask equipped with a Stark and Dean water trap and reflux condenser. The mixture is boiled under reflux for 2 days. The theoretical quantity of water is collected in the trap within 1 hour. Upon completion of the reflux period, the solvent is removed under reduced pressure by heating on a water bath. The residue, distilled through a 15-cm. Vigreux column at 11 mm. pressure, yields 88.6-93.3 g. (74.5-78%) of colorless liquid boiling at 95-97°, 1.5823-1.5825. 

The cycloheptenvl-cyanoacetic acid methyl ester so obtained is a colorless liquid boiling at 174°C under a pressure of 20 mm. 

The solution is filtered if not clear, and the cyanoacetic acid is set free (hood) by adding with thorough stirring 600 cc. (a slight excess) of commercial hydrochloric acid (sp. gr. 1.156). The solution is evaporated on a water bath at 60-70° (Note 3) under a pressure of 20 30 mm. and the evaporation continued until practically 110 more distillate (Note 4) comes over. To... 

If the mixture is heated to a higher temperature there is a considerable loss due to decomposition of the cyanoacetic acid. 

Microwave irradiation has been used to accelerate the Gewald reaction for the one-pot synthesis of N-acyl aminothiophenes on solid support [67]. A suspension of cyanoacetic acid Wang resin 35, elemental sulfur, DBU and an aldehyde or ketone 36 in toluene was irradiated for 20 min at 120 °C in a single-mode microwave synthesizer (Scheme 13). Acyl chloride 37 was added, followed by DIPEA, and the mixture was irradiated for 10 min at 100 °C. After cooling to room temperature, the washed resin was treated with a TEA solution to give M-acylated thiophenes 38 in 81-99% yield and purities ranging from 46-99%. 

Ferrocen-l,l -diylbismetallacycles are conceptually attractive for the development of bimetal-catalyzed processes for one particular reason the distance between the reactive centers in a coordinated electrophile and a coordinated nucleophile is self-adjustable for specific tasks, because the activation energy for Cp ligand rotation is very low. In 2008, Peters and Jautze reported the application of the bis-palladacycle complex 56a to the enantioselective conjugate addition of a-cyanoacetates to enones (Fig. 31) [74—76] based on the idea that a soft bimetallic complex capable of simultaneously activating both Michael donor and acceptor would not only lead to superior catalytic activity, but also to an enhanced level of stereocontrol due to a highly organized transition state [77]. An a-cyanoacetate should be activated by enolization promoted by coordination of the nitrile moiety to one Pd(II)-center, while the enone should be activated as an electrophile by coordination of the olefinic double bond to the carbophilic Lewis acid [78],... 

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