Polyalkylation equilibration

Enolate equilibration and di- and poly-alkylation are the major side reactions, which lead to reduced yields of desired products in ketone alkylations. These processes occur as a result of equilibration of the starting enolate (or enolate mixture) with the neutral monoalkylation product(s) via proton transfer reactions. Polyalkylation may also occur when bases, in addition to the starting enolate, which are capable of deprotonating the monoalkylated ketone are present in the medium. With symmetrical ketones, e.g. cyclopentanone and cyclohexanone, the problem of regioselectivity does not arise. However, except under special conditions, polyalkylation occurs to a significant extent during enolate alkylations of more kinetically acidic ketones such as cyclobutanone, cyclopentanone and acyclic ketones, particularly methyl ketones. Polyalkylation is also a troublesome side reaction with less acidic ketones such as cyclohexanone. 

Finally like methyllithium (ref. 121) ammonium fluoride (ref. 122), tris-(dialkylamino)sulfonium salts (ref. 123) or alkali alkoxides (ref. 124), alkali amides in liquid ammonia are able to cleave the silicium-oxygen bond of silyl enol ethers (refs. 125, 126) leading to enolates. The sodium enolate obtained (Fig. 27) by treatment of a silyl enol ether with NaNH2 can be equilibrated in the medium, leading to two alkylated products, nevertheless no polyalkylated species is detected. With the use of LiNH2 only the expected reaction product is prepared but the use of KNH2 leads to a mixture of C-mono and dialkylated and O-alkylted products (ref. 125). 

These limitations include the ability to regioselectively form an enolate from an unsymmetrical ketone, polyalkylation via enolate equilibration, and the necessity to use simple electrophiles hinder both chiral and achiral enolate alkylations. Additionally, this alkylation usually requires specific enolate geometry for chirality of the product and since the origin of enatioselectivity is defined by a combination of enolate geometry and facial selectivity of the alkylation, chirality in this reaction is difficult while maintaining atom economical practices. 

From this, we must conclude that selectivity will not be achieved without considerable care in establishing optimum reaction conditions. In addition, if there is the possibility of proton exchange between enolate and ketone, polyalkylation may occur (Figure 17.43). Numerous approaches to this problem have been developed. The classical solution is to form the enolate completely (so that there is no ketone present to equilibrate) at low temperature (to ensure formation of a kinetic enolate) and then add the enolate to an excess of RX, so that it is all quenched immediately, and... 

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