Enolate alkylation

Ketones, esters, nitriles, and carboxylic acids may be alkylated at the alpha position in strongly basic conditions. Typical bases for this reaction include Et₂NLi, LDA (lithium diisopropyl amide), t-BuOK, NaNH₂, and KH. This reaction can very useful for creating carbon-carbon bonds. However, it is usually not as general as the scheme above might suggest. The main limitations to the scope of this reaction are as follows:

The nature of the R group: From the standpoint of the alkyl halide, the reaction follows an SN2 mechanism. Therefore, the alkyl halide should preferably be primary, allylic, or benzylic. Secondary halides sometimes work, but may give predominant elimination (E2). Tertiary halides do not work at all. However, there is an alternative method which permits the use of tertiary halides: the silyl enol ether derived from an aldehyde, ketone or ester may be alkylated using a Lewis acid as catalyst.
Overalkylation: Another problem is the fact that the alkylated ketone is just as acidic (or more) than the starting material. Therefore it can be alkylated also, so di- and trialkylation may be common. An alternative method to avoid this problem is to use the Stork Enamine Reaction, in which th ketone is first transformed into an enamine and then alkylated. This method works only with active halides such as allylic, benzylic, and propargillic, but primary and secondaty halides may be alkylated if the enamine is first transformed into a salt.
Regioselectivity: The last problem is whether the desired side of an unsymmetric ketone may be alkylated selectively. Sometimes this can be solved by using kinetic versus thermodynamic control when forming the enolate: for example, under kinetic control the least substituted enolate is obtaines; while the thermodinamic enolate is the more substituded one. This requires the use of preformed enolates. Another way is to use a precursor with two electron-withdrawing groups such as acetoacetic acid instead of a ketone, and then decarboxylate. Also, it is possible to introduce a blocking group in one side of the ketone and then remove it after the alkylation.

Stereoselectivity: this reaction may be carried out stereoselectively by using a chiral auxiliary group such as oxazolidinone derivatives.

References

March, J. Advanced Organic Chemistry, 4th ed., reactions 0-95, 0-94, 0-96, 2-19

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Enolate alkylation

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