REACTIONS OF ENOLATE ANIONS WITH ELECTROPHILES

There are two major reactions of enolates (1) displacement reactions with alkyl halides or other suitable electrophiles and (2) nucleophilic addition to carbonyl compounds. Reaction of 58 with butanal to give 59 and reaction of 61 with bromopentane to give 62 are simple examples of each process. Enolate anions function as carbon nucleophiles and their reactions are fundamentally the same as those discussed in Section 8.3.C for acetylides. Although there are interesting differences, treating an enolate anion as a carbon nucleophile is very reasonable. 

An enolate anion is a nucleophile and, unlike Grignard reagents and organolithium reagents, reacts easily with the electrophilic carbon of an alkyl halide. Although both the oxygen and the carbon are nucleophilic (sec. 9.3.B), the carbon is usually the most nucleophilic site in the enolate. As with other carbon nucleophiles, such as acetylides (sec. 8.3), the electron rich carbon attacks the electrophilic carbon of the halide to form a new carbon-carbon bond, with lithium iodide (Lil) as the byproduct. 

There are many synthetic applications that involve enolate alkylation. In the Yamada and co-workers synthesis of dysidiolide, cyclohexenone 66 was treated with LDA to generate the enolate anion.Addition of TBDMS protected 3-iodo-l-propanol gave the alkylated product 67 in 76% yield. Notice that HMPA 

In the conversion of 66 to 67, we saw that HMPA was used as an additive. Another useful ingredient in many alkylation reactions is hexamethylphosphorus triamide [HMPT, (Me2N)3P], which coordinates with the enolate anion, diminishing the aggregate state and increasing reactivity. This additive also enhances the polarity of the solvent and thereby enhances the facility of the Sn2 alkylation step (sec. 2.7.A.i). The use of an additive such as HMPA or HMPT is very common when the enolate anion reacts slowly and/or the halide is relatively unreactive. Other acid derivatives such as lactones can react with LDA to give an enolate anion, which then reacts with alkyl halides in the usual manner. 

Enolates derived from acid derivatives can also be alkylated. When ester 79 was treated with 3 equivalents of KN(TMS)2 in a toluene-THF mixture, in the presence of 4 equivalents of iodomethane, a quantitative yield of 80 was obtained, as part of Tadano s synthesis of (-)-mniopetal 

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The reaction of enolate anions with electrophiles is one of the most important and most widely used C-C bond forming reactions. Compared to its immense importance there are relatively few reviews dealing with this subject1-5. 

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