Acetoacetonitrile

Note This subcategory includes the use of ketones such as 2-butanone, acetylacetone, ethyl acetoacetate, and acetoacetonitrile. 

When 5-methylisoxazole (474) was exposed to two equivalents of LDA in THF at -10 °C the dianion of acetoacetonitrile was generated (78TL4221). Reaction of this dianion (475) with 1.1 equivalents of allyl bromide gave the alkylated product (476) in 60% yield (Scheme 105). The reaction of the dianion with nitriles and aldehydes was also studied. 

The versatility of 5-nitrosopyrimidines in pteridine syntheses was noticed by Pachter (64MI21603) during modification of the Timmis condensation between (262) and benzyl methyl ketone simple condensation leads to 4-amino-7-methyl-2,6-diphenylpteridine (264) but in the presence of cyanide ion 4,7-diamino-2,6-diphenylpteridine (265) is formed (equation 90). The mechanism of this reaction is still uncertain (63JOC1187) it may involve an oxidation of an intermediate hydroxylamine derivative, nitrone formation similar to the Krohnke reaction, or nucleophilic addition of the cyanide ion to the Schiff s base function (266) followed by cyclization to a 7-amino-5,6-dihydropteridine derivative (267), oxidation to a quinonoid-type product (268) and loss of the acyl group (equation 91). Extension of these principles to a-aryl- and a-alkyl-acetoacetonitriles omits the oxidation step and gives higher yields, and forms 6-alkyl-7-aminopteridines, which cannot be obtained directly from simple aliphatic ketones. 

The submitters report that a similar procedure has been used in the preparation of other monosubstituted dibenzyl ketones from a-phenyl-7-(4-substituted phenyl) acetoacetonitriles. 

Acetoacetonitrile dianion (2). This dianion is prepared most conveniently by treatment of 1 with 2 equiv. of LDA in THF at -10°. Reactions with a number of electrophiles have been reported. 

Hydrazine and 3-aminocrotononitrile (286) give the pyrazole (287), which can be reacted with a second molecule of starting material or with acetoacetonitrile to give the pyrazolopyrimidine (288 Scheme 85). A similar reaction sequence is shown in Scheme 86 (74JHC423). 

This reaction has been modified for the use of acetoacetonitriles and Meldrum s acid instead of -ketoesters to afford 4-hydroxyquinolines. 

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