Esters cyanomethylation

GLYCINE, N-CARBOXY-, N-BENZYL ESTER, CYANOMETHYL ESTER... 

Mixed carbonic anhydride N-Carboxyanhydride N-Thiocarboxyamino acid anhydride Benzhydroxamic acid ester Cyanomethyl ester 8-Hydroxyquinoline ester p-Nitrophenyl ester Phenylazophenyl ester Pentachlorophenyl ester Pentafluorophenyl ester Phenyl ester... 

In addition to thiodiglycolic acid esters, the use of bis(cyanomethyl)sulfide in the Hinsberg reaction has facilitated the preparation of 5-cyano-thiophene-2-carboxamides. Thus, the condensation of biacetyl with bis(cyanomethyl)sulfide resulted in the efficient preparation of 10 (94% yield). 

A variety of thienopyridine isomers can be generated in low to moderate yields from the reaction of disubstituted pyridines and phenyl isothiocyanate. The pyridine derivatives contain a halogen at position 2 or 3 of the ring, and the other substituent is either a cyanomethyl substituent (CH2CN) or an ester (CH2C02Et) <19978949, 1998S1095>. 

Many such activated acyl derivatives have been developed, and the field has been reviewed [7-9]. The most commonly used irreversible acyl donors are various types of vinyl esters. During the acylation of the enzyme, vinyl alcohols are liberated, which rapidly tautomerize to non-nucleophilic carbonyl compounds (Scheme 4.5). The acyl-enzyme then reacts with the racemic nucleophile (e.g., an alcohol or amine). Many vinyl esters and isopropenyl acetate are commercially available, and others can be made from vinyl and isopropenyl acetate by Lewis acid- or palladium-catalyzed reactions with acids [10-12] or from transition metal-catalyzed additions to acetylenes [13-15]. If ethoxyacetylene is used in such reactions, R1 in the resulting acyl donor will be OEt (Scheme 4.5), and hence the end product from the acyl donor leaving group will be the innocuous ethyl acetate [16]. Other frequently used acylation agents that act as more or less irreversible acyl donors are the easily prepared 2,2,2-trifluoro- and 2,2,2-trichloro-ethyl esters [17-23]. Less frequently used are oxime esters and cyanomethyl ester [7]. S-ethyl thioesters such as the thiooctanoate has also been used, and here the ethanethiol formed is allowed to evaporate to displace the equilibrium [24, 25]. Some anhydrides can also serve as irreversible acyl donors. 

Cyclizative condensations based on aldol-type reactions which conform to the llbd pattern have also been developed. Condensation of bis(alkoxycarbonylmethyl)amines or bis(cyanomethyl)amines with benzil affords 3,4-diarylpyrrole-2,5-dicarboxylic add esters or nitriles. These reactions frequently lead to partial hydrolysis of at least one of the alkoxycarbonyl substituents and if the 3,4-diarylpyrrole is the ultimate objective, work-up involving complete hydrolytic decarboxylation is appropriate (equation 119) (6lLA(639)l02, 65JOC859). 

Aminofuran-2-ones (15) (R = COAr, COMe) could be synthesized by Thorpe-Ziegler cyclization of acylmethyl esters 13 and 14 in the presence of NEt3 and NaOEt, respectively. However, the less acidic ethoxycarbonyl-methyl componds 13 and 14 (R = COOEt) or cyanomethyl esters (R = CN) failed to ring close (84LA1702) (Scheme 4). The starting esters could... 

Finally, lV-(cyanomethyl)iminodiacetic acid was obtained from the ester of iminodiacetic acid and chloroacetonitrile as illustrated in Scheme l.10 The purified ester is hydrolyzed selectively at the methylester groups with zinc perchlorate in a 70% alcoholic solution and formation of the 1 1 complex (3) occurs. The substituted iminodiacetic acid is extracted with ether after zinc separation as ZnS by treatment with H2S, and crystallized in a chloroform ethanol solution. 

Ethyl-2-(sulfonylmethyl)- and 2-(cyanomethyl)-allyl carbonates133 as well as (methoxycarbo-nyl)methylallyl carbonates136 serve as substrates for the [3 + 2] cycloaddition. Oxidative addition into the allylic C—O bond of the carbonate, followed by decarboxylation, gives a 2-substituted allylpalladium al-koxide. The alkoxide then deprotonates the C—H a to the electron-withdrawing substituent at the 2-position of the allyl. This anion then undergoes a Michael addition to an a,(3-unsaturated ketone or ester, followed by intramolecular allylation of the anion of the Michael product (Scheme 2). 

The literature data on the preparation of phosphono-dipeptides from 1-aminoalkanephosphonic acids showed 7-7 that the yields of condensation reactions are usually small or moderate. Moreover,the use of bulky N-blocked amino acids drastically decreased the reaction yield. Thus following Martell s method— we wre unsuccesful in the preparation of dipeptides containing N-terminal valine or leucine,while peptides of phenylalanine were obtained in 5—10% yield.Also the active ester method appeared to give small yields of the desired products. Our studies using p-nitrophenyl- and cyanomethyl esters of N-phtaloyl amino acids confirmed these observations. 

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... 

Cyanomethylation of compounds (3) and (4) was carried out using formaldehyde/potassium cyanide in aqueous ethanol at elevated pressures in the presence of potassium acetate and alumina. Under the conditions of the reaction and subsequent workup, the cyanomethylated products were converted into acetic acid derivatives (e.g., (38)) and isolated as ethyl ester derivatives (e.g., (39)) (Scheme 8) <69TL1909>. No nitrile-containing products were isolated. 

The enamines 132, formed from 7V-(cyanomethyl)-Af-methylaniline and ethyl esters of aliphatic or aromatic carboxylic acids in the presence of sodium hydride, react with hydrazine to yield the pyrazoles 133 (equation 58)78. 

Several new routes involve formation of one carbon-carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of /3-hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahy-droindoles with multiple substituents by formation of the C-3-C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of a-cyanomethyl-/3-ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable A-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoani-lines) <2006OL4473>. 

Ethyl 4-methyl-7-azaindole-3-acetate (155, R = H), obtained from the attempted cyanomethylation of the indole, was hydrolyzed to the 3-acetic acid (156, R = H) (54%), which was treated in succession by thionyl chloride and ammonia to give the 3-acetamide (157) (78%). Reduction with lithium aluminium hydride gave the azatryptamine (150, R = R = R" = H) in 94% yield. The 6-chloro ester (155, R = Cl) was hydrolyzed also to the acid (156, R = Cl.) ... 

Nitriles are directly converted to esters by heating with an alcohol and sulfuric or hydrochloric acid. When water is absent, the imino ester salt is readily isolated (method 402). Aliphatic,aromatic, and heterocycliccyano compounds react in this manner. Most of the aromatic compounds contain a cyanomethyl group although the cyanide radical may be attached directly to the aromatic nucleus. Monosub-stituted malonic esters free from unsubstituted and disubstituted malonic esters are made from the corresponding a-cyano esters by this method. Malonic ester and disubstituted malonic esters have been similarly prepared. ... 

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