Alkylation, acetoacetic ester nitrile

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

The alkylation of activated halogen compounds is one of several reactions of trialkylboranes developed by Brown (see also 15-16,15-25,18-31-18-40, etc.). These compounds are extremely versatile and can be used for the preparation of many types of compounds. In this reaction, for example, an alkene (through the BR3 prepared from it) can be coupled to a ketone, a nitrile, a carboxylic ester, or a sulfonyl derivative. Note that this is still another indirect way to alkylate a ketone (see 10-105) or a carboxylic acid (see 10-106), and provides an additional alternative to the malonic ester and acetoacetic ester syntheses (10-104). 

Both the malonic ester synthesis and the acetoacetic ester synthesis arc relatively easy to carry out because they involve unusually acidic carbonyl compounds. As a result, relatively mild bases like sodium ethoxide in an alcohol solvent can be used to prepare the necessary enolate ions. Alternatively, it s also possible in many cases to alkylate the a position of monoketones, monoesters, and nitrile. . A strong, sterically hindered base such as LDA is needed, so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

A 1968 patent report has been developed into a practical synthesis of /S-keto-esters by Lewis acid-catalysed condensations of alkyl nitriles with acetoacetates and subsequent acid hydrolysis (Scheme 34). " A new three-step procedure for the alkoxycarbonylation of cyclic ketones consists of an addition of... 

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