Cyanoacetic acid, syntheses

Cyanoacetic acid, syntheses with — 17,903 Cyanoalkylation s. Gyano-ethylation, -methylation N-Cyanoamidines 17, 401 Cyanoazomethines s. Imino-cyanides... 

Uses. In many cases cyanoacetic acid, cyanoacetates, or cyanoacetamide can be used alternatively. The traded cyanoacetic acid is mainly iatended for the synthesis of the cough remedy dextromethorphan [125-71-3] (31) (61) (see Expectorants, antitussives, and related agents) and of the fungicide cymoxanil [57966-95-7] (32) (62) (see Fungicides,agricultural). 

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). 

D A R A P S K I Amino Acid Synthesis (see Curtius) Amino acid synthesis from ethyl cyanoacetates... 

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%. 

The low yield in this reaction might be caused by a number of reasons. First, the overall reaction is only rapid for readily enolizable compounds. 1,3-Dicarbonyl compounds will therefore be a better choice as compared to acetic acid. Second, to prevent oxidation of radical 54, it is advantageous to work with excess diene and therefore speed up trapping of 54 through diene addition. Finally, lactone 55 can, as an enolizable compound itself, also be oxidized by manganese(III) acetate and form various oxidation products. Shorter reaction time and the use of understoichiometric amounts of oxidant might therefore benefit the overall result. All these factors have been taken into account in the synthesis of bicyclic /-lactone 56, which has been obtained from cyanoacetic acid and 1,3-cyclohexadiene in 78% yield within 15 min reaction time (equation 25)60,88. 

As CH-acids in the MCRs with aldehydes and aminoazoles, other classes of organic compounds were used as well. Cyanoacetic acid derivatives, acetoyl(aroyl) acetonitriles, ketosulfones, acetophenones, and other reagents were successfully introduced into these three-component heterocyclizations. For example, synthesis of pyrazolo[3,4-b]pyridine-5-carbonitriles 40 was carried out as the multicomponent treatment of 5-aminopyrazole, aldehyde, and benzoylacetonitriles solvent-free by fusion either in ammonium acetate at 120°C or in boiling ethanol with EtsN (Scheme 17) [69]. The second approach gave the worst results from the viewpoint of yields and purity of the target compounds. 

Substituted-3-aryl[l,6]naphthyridin-2-amines and 7-substituted-3-aryl[l,6]naphthyridin-2(l//)-ones have been prepared by diazotization of 3-aryl[l,6]naphthyridine-2,7-diamines, themselves obtained by the condensation cycli-zation of 4,6-diaminonicotinaldehyde and phenylacetonitrile <2000J(P1)1843>. Derivatives of cyanoacetic acid have rarely been used in the synthesis of naphthyridines, although a recent study has shown that they may be reacted with 4-piperidone derivatives to give [l,6]naphthyridines <2000CHE496>. 

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. 

Another pyrrole synthesis [53] was based on the Ugi-4CR/Knoevenagel condensation between aldehydes, cyclohexyl isocyanide, cyanoacetic acid, and phena-cylamine 68 as the carbonyl input. Also in this case the Ugi products 69 spontaneously cydized to the pyrroles 70 which were methylated with diazomethane to give the 2-methoxy derivatives 71 (Scheme 2.25). 

Cuprous cyanide, 4, 69 Cuprous Hydroxide, 7, 30 Cuprous oxide, 6, 6 7, 33 Cyanoacetic acid, 7, 22 Cyanoacetic ester (ethyl), 7, 21 Cyanohydrin Synthesis, 6, 58 a-CYANO-/3-PlIENYLACRYLIC ACID, 7, 20, 21... 

Solid-phase synthesis is of importance in combinatorial chemistry. As already mentioned RuH2(PPh3)4 catalyst can be used as an alternative to the conventional Lewis acid or base catalyst. When one uses polymer-supported cyanoacetate 37, which can be readily obtained from the commercially available polystyrene Wang resin and cyanoacetic acid, the ruthenium-catalyzed Knoevenagel and Michael reactions can be performed successively [27]. The effectiveness of this reaction is demonstrated by the sequential four-component reaction on solid phase as shown in Scheme 11 [27]. The ruthenium-catalyzed condensation of 37 with propanal and subsequent addition of diethyl malonate and methyl vinyl ketone in TH F at 50 °C gave the adduct 40 diastereoselectively in 40 % yield (de= 90 10). 

Another synthesis of pyrimido[5,4-c]cinnolin-4(3//)-ones (59) via 4-aminocinnolines (56) starts with arylhydrazono-cyanoacetic acid derivatives (58). Upon heating in the presence of A1C13 4-aminocinnolines (56) are formed. Cyclocondensation with formamide or triethyl ort/io-formate affords the pyrimido[5,4-c]cinnolin-4(3/7)-ones (59) (Scheme 10) <92JPS365>. 

Isse, A.A. and Gennaro, A. (2002b) Electrochemical synthesis of cyanoacetic acid from chloroace-tonitrile and carbon dioxide. J. Electrochem. Soc. 149, D113-D117. 

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),... 

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