Nitriles, condensation with malonate esters

The nitrile group is one of the most reactive electron withdrawing groups in the active methylene component, and with two nitriles, malononitrile is very reactive and condenses with almost all aldehydes and many ketones under mild conditions.Even sterically hindered ketones such as pinacolone condense with malononitrile in 48% yield using P-alanine as a catalyst. Formation of the bis-adduct is less of a problem with malononitrile than with malonic esters. 

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. 

Catalytic reduction of the nitrile 79 in the presence of semicarbazide affords initially the semicarbazone of 80. Hydrolysis-interchange, for example in the presence of pyruvic acid, gives the aldehyde 80. Condensation with the half ester of malonic acid leads to the acrylic ester 81 the double bond is then removed by means of catalytic reduction (82). Base catalyzed reaction of the... 

The condensation of enolates derived from malonic esters and other active methylene compounds with a,p-unsaturated aldehydes, ketones, esters, or nitriles proceeds exclusively by 1,4-addition. The conjugate addition to a,(3-unsaturated compounds, often called Michael acceptors, is promoted by treatment of the active methylene species with either an excess of a weak base (e.g., Et3N or piperidine) or using a stronger base in catalytic amounts (e.g., 0.1-0.3 equivalents NaH, NaOEt, or r-BuOK). 

Pyrido[2,3-(7]pyrimidincs 23, unsubstituted in the 2,4-positions, have been synthesized by condensation of ethyl 4-aminopyrimidine-5-carboxylate with several esters, phenylacetonitrile, phenylacetamide, or malonic ester chloride.173 In the first step, the 4-amino group reacts with the ester, nitrile, or acid chloride function of the cyclization partner, ring closure then being effected by a Dieckmann-type cyclization. 

Pyridines having a 3-nitroso substituent in combination with a 2-amino group can be condensed with methylene-active compounds such as malonic esters, / -oxo esters, ketones, or nitriles.18... 

The nitrile in cyanoacetic acid and cyanoacetic esters makes them more reactive than the corresponding malonic acid or esters. As with malonic acid, cyanoacetic acid can condense to give the alkylidine cyanoacetic acid or the decarboxylated a,P-unsaturated nitriles. Cyanoacetic acid reacts in a similar fashion as malonic acid, and often gives mixtures of the a,P and P,y-... 

Cyclobutanedicarboxylic acid has been prepared by hydrolysis of the ethyl ester,1 or of the half nitrile, 1-cyano-l-car-boxycyclobutane.2 The ethyl ester has been prepared by condensation of ethyl malonate with trimethylene bromide1 or chloro-bromide.3 The half nitrile has been prepared by condensation of trimethylene bromide with ethyl cyanoacetate followed by hydrolysis of the ester to the acid.2... 

The synthesis of one of the agents begins with nucleophilic aromatic displacement of bromine by cyanide in the highly fluorinated compound 78. Acid hydrolysis of the nitrile (79), followed by esterification of the newly formed acid, affords ester 80. Base-catalyzed condensation of the intermediate with diethyl malonate leads to the tricarbonyl derivative 81. 

Amino-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbaldehydes have been treated with activated methylene compounds such as malonic acid derivatives, fi-oxo esters, or -nitriles. The Knoevenagel condensation between the aldehyde function and the activated methylene group to build up the side chain is followed by cyclization. 

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