Reaction with cyanoacetic esters

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 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. 

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... 

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>. 

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... 

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

The reaction of aliphatic, alicyclic, and aromatic aldehydes and ketones with cyanoacetic ester, NCCHjCOjCjH, is general. The products are 0L,/3-olefinic cyanoacetates. The aldehydes are condensed with the ester in the presence of amines or with sodium cyanoacetate in the presence of sodium hydroxide, Similarly, cyanoacetic ester is condensed with ketones by catalysts such as acetamide or the acetates... 

Problem 26.4 (a) Cyclohexanone reacts with cyanoacetic ester (ethyl cyanoace-tate, N CCH2C00C2H5) in the presence of ammonium acetate to yield a product of formula CnHt502N. What is this compound, and how is it formed (This is an example of the Cope reaction. Check your answer in Problem 21.22 (g), p. 714.)... 

When A-benzylidenealkylamines are treated with cyanoacetic esters the reaction proceeds beyond addition and yields monoester monoamide of 1,3-dicyano-2,4-diphenyl-l,3-cyclo butanedicarboxylic acid.243... 

Aminothiophenols have been synthesised from acyclic precursors with yields in the range 83-92%. By the reaction of the substituted thiabenzene shown with cyanoacetic esters, 3-amino-2,4-dicyano-5,6-dialkylthiophenols (R = = alkyl)... 

Menthylethylamine, prepared by the reaction of menthone with cyanoacetic ester followed by reduction of the nitrile obtained by hydrolysis and decarboxylation, is reported to have anti-inflammatory activity. 

When using cyanoacetic esters instead of aldehydes, the Guareschi-Thorpe pyridine synthesis assembles pyridines 155 by the condensation of acetoacetic esters 153 with cyanoacetic esters 154 in the presence of ammonia. A variation of this method involves the reaction of cyanoacetic ester 156 with 3-diketone 157 in the presence of ammonia to generate 2-hydroxypyridine 158." The mechanism of this reaction has been studied, and it was initiated by an ester/amide exchange on cyanoacetic ester 156 with... 

The reaction of aminobutenone with cyanoacetic ester (73IZV2543) and cyanoacetamide affords pyridine derivatives 283 and 284 in 65-76% yield (54IZV47 72JPR353). 

Thorpe worked on the synthesis of polybasic organic acids with cyanoacetic ester, with Perkin on camphor derivatives (see p. 871), and on imino-com-pounds (1904-22), based on his discovery (1904) of the Thorpe reaction involving the condensation of cyanoacetic ester with its sodium compound. 

Similarly, reaction of 321 with cyanoacetic ester and potassium carlxtnate gave the benzopyrane 322. When ketone 321 was treated with monoethyl malonate, triethylamine and phenyl phosphorodichloridate, the required coumarin 323a was obtained and subsequent alkaline hydrolysis gave the acid 323b [179] (Scheme 103). 

Finally, the third method for synthesizing (478), developed by Johnson et al.[577,578], also starts from the Mannich base (496). Its condensation with cyanoacetic ester led to the cyanoke toes ter (493), which, by the Stobbe reaction with dimethyl succinate,formed compound (492). On hydrogenation of the double bond and angular methylation, this was converted into the cyanoester (489) which, in a similar manner to the preceding case, gave the intermediate (478) on treatment with methanolic hydrogen chloride. 

Amongst examples of reactions of 2-thiothiazolines with active methylene groups, their interactions with cyanoacetic ester (see also these Reports, Vol. 1, p. 408) and rhodanines have been studied. 2-Alkylthio-A -thiazolines (129) or their quaternary salts are converted by the former reagents into 2-(ethoxycarbonylcyanomethylene)thia-zolidine (130). Their tetrasubstituted double bond resists catalytic... 

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. 

Reaction with Alkyl Halide. The active methylene group of an Al-acylamino-malonic acid ester or Ai-acylamino cyanoacetic acid ester condenses readily with primary alkyl hahdes. 

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). 

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. 

The synthesis of pyrido[2,3-d]pyrimidin-7(8H)-ones has also been achieved by a microwave-assisted MCR [87-89] that is based on the Victory reaction of 6-oxotetrahydropyridine-3-carbonitrile 57, obtained by reaction of an Q ,/3-unsaturated ester 56 and malonitrile 47 (Z = CN). The one-pot cyclo condensation of 56, amidines 58 and methylene active nitriles 47, either malonitrile or ethyl cyanoacetate, at 100 °C for benzamidine or 140 °C for reactions with guanidine, in methanol in the presence of a catalytic amount of sodium methoxide gave 4-oxo-60 or 4-aminopyridopyrimidines 59, respectively, in only 10 min in a single-mode microwave reactor [87,88]... 

The unusual reaction of cyanoacetic acid esters with s-triazine monoazides afforded derivatives of a novel coupled heterocyclic system 2-[l,3,5]triazin-2-yl-l,2-dihydro[l,2,3,4]tetrazine-5-carboxylic acid esters <06CHE965>. 

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). 

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