Cyanoacetic ester, reactions

A major type of reaction in this class is the cyclization of 4-amino- or 4-halo-pyrimidines carrying 5-cyanoethyl or 5-ethoxycarbonylethyl groups, which cyclize to 7-amino or 7-oxo derivatives of 5,6-dihydropyrido[2,3- f]pyrimidine, e.g. (131)->(63). The intermediates may sometimes be prepared by reaction of 4(6)-aminopyrimidines with acrylonitrile, or even via a pyrimidine ring synthesis from an amidine and a cyanoacetic ester or malononitrile derivative, e.g. (132) -> (133) (7lJOC2 85, 72BCJ1127). 

The Guareschi-Thorpe pyridine synthesis is closely related to the Hantzsch protocol. The primary point of difference lies in the use of cyanoacetic esters. This modification assembles pyridine 23 by the condensation of acetoacetic esters 21 with cyanoacetic esters 22 in the presence of ammonia. A second variation of this method involves reaction of cyanoacetic ester 22 with P-diketone 24 in the presence of ammonia to generate the 2-hydroxypyridine 25. 

Guareschi imides are useful synthetic intermediates. They are formed from a ketone reacting with two equivalents of the cyanoacetic esters and ammonia. This transformation is illustrated in the formation of 4,4-dimethylcyclopentenone 30.The synthesis was initiated with the Guareschi reaction of 3-pentanone 27 with 28 to generate imide 29. This product was hydrolyzed to the diacid and esterified. Cyclization of the diester via acyloin condensation followed by hydrolysis and dehydration afforded the desired target 30. 

In order to expand the utility of the reaction, modification of the route to anilidomethylene malonic ester equivalents was developed. Simple condensation of triethyl orthoformate with cyanoacetic ester, acetoacetic ester, or malonic ester in the... 

Dihydrocorynantheine was obtained via similar steps from normal cyanoacetic ester 319 (172). Stereoselective transformation of the alio cyanoacetic ester 315 to the normal stereoisomer 319 was achieved by utilizing a unique epimerization reaction of the corresponding quinolizidine-enamine system (174). Oxidation of alio cyanoacetic ester 315 with lead tetraacetate in acetic acid medium, followed by treatment with base, yielded the cis-disubstituted enamine 317, which slowly isomerized to the trans isomer 318. It has been proved that this reversible eipmerization process occurs at C-15. The ratio of trans/cis enamines (318/317) is about 9 1. The sodium borohydride reduction of 318 furnished the desired cyanoacetic ester derivative 319 with normal stereo arrangement. The details of the C-15 epimerization mechanism are discussed by B rczai-Beke etal. (174). 

Smalley et al. reported the synthesis of the cyano-containing keto ester 98 by reaction of o-azidobenzoyl chloride 97 with cyanoacetic ester in the presence of triethylamine. This keto ester was then heated in acetonitrile for 30 min and gave the ring closed product 99 which was isolated in the fully aromatic tautomeric form 100 <1997S773>. A similar approach to tetrazolo[l,5- ]quinolines has been applied by a Korean research group in this case a reflux of the cyano-azido compound 101 for a longer period was needed in order to accomplish the cyclization to 4-acetoxymethyl-tetrazolo[l,5- ]quinoline 102 <2003JHC1103>. 

Unlike the corresponding reaction of p-keto esters with a,p-unsaturated aldehydes, which produce Michael adducts, a-cyanoacetic esters undergo the aldol reaction forming a-cyanodienoic esters [17]. 

P-keto esters with a,p-unsaturated aldehydes liquidrliquid two-phase conditions [20] but, in contrast, under analogous conditions a-cyanoacetic esters produce aldol adducts with a,p-unsaturated aldehydes [20], Ethyl acetoacetate undergoes a catalysed Michael reaction addition with trans but-2-en-l,4-diones the products are generally insufficiently stable for isolation, but can be converted into furans [21 ]. 

For the synthesis of aminotriacetylpyrans 84 a reaction of 3-bromoace-tylacetone 85 with cyanoacetic ester in ethanolic NaOH was employed. Possibly, it proceeds via the formation of acetylacetone dimer 86... 

Malononitrile and cyanoacetamide only give aminopyrans. However, in reaction with cyanoacetic ester 27b aminopyran 233 has been isolated from the mother liquor and also side product 234 from the cooled mixture. Mechanistic considerations have been proved by the isolation of a deace-tylated intermediate (95M615). Similar transformations occur in the synthesis of spiropyrans 235 from benzothiazole 236 (97G605) (Scheme 90). 

The carbon nucleophiles in amine-catalyzed reaction conditions are usually rather acidic compounds containing two electron-attracting substituents. Malonic esters, cyanoacetic esters, and cyanoacetamide are examples of compounds which undergo condensation reactions under Knoevenagel conditions.115 Nitroalkanes are also effective nucleophilic reactants. The single nitro group sufficiently activates the a hydrogens to permit deprotonation under the weakly basic conditions. Usually, the product that is isolated is... 

Related and equally important reactions are the acetoacetic ester synthesis and the cyanoacetic ester synthesis Here too the initial snbstitnted product can be hydrolyzed and decarboxylated, to yield a ketone 11 (i.e. a substituted acetone) from acetoacetic ester 10, and a snbstitnted acetonitrile 14 from cyanoacetic ester 13 respectively. Fnrthermore a snbstitnted acetoacetic ester can be cleaved into a substituted acetic ester 12 and acetate by treatment with strong alkali ... 

Pimelic acid has been prepared as a by-product of the reaction between trimethylene bromide and sodium cyanoacetic ester 1 by the action of carbon dioxide upon pcntamethylene-... 

Other nucleophiles than amines which have been employed in the reaction are malononitrile and cyanoacetic ester anions. Both of these anions undergo a preliminary reaction with the aryl halide to form the C-aryl derivatives before they attack the ir-allylpalladium intermediate, so that diarylated products are formed (equation 31).86 Phenylmalononitrile anion reacts with iodobenzene and butadiene to give the same product in 70% yield. 

Like / -keto esters, /3-keto nitriles react smoothly with hydrazine the latter give aminopyrazoles.78,310-321 Under the same conditions cyanoacetic ester and its derivatives give aminopyrazolones.322-325 The reaction of malononitrile is more complex, giving 1-substituted 3-cyanomethyl-4-cyano-5-aminopyrazole and products formed by further condensation.328... 

Thiatriazolines are reported as possible transient intermediates in reactions of azide ion with thiobenzophenone (equation 49a) and thiobenzophenone S-oxides (equation 49b) <76ACS(B)997>. l,3-Dithietane-2,4-diylidene bis(cyanoacetic ester) (76) reacts with sodium azide to give a compound assumed to be the sodium salt of alkylidene-1,2,3,4-thiatriazolidine (77). Nitrogen is evolved on acidification of the sodium salt and a hitherto unknown perhydro-l,4,2,5-dithiadiazine (78) is formed (equation 49c) (81ZC102). 

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