Cyclopentanones polyalkylation

Potassium amyloxide in dimethoxyethane has been recommended as the base for simple monoalkylation of cyclopentanone. Polyalkylation of acyclic and cyclic ketones can be minimized by reaction of the appropriate alkyl iodide and... 

Lithium iodide in refluxing CH2C12 has also been used to convert the oxaspiro-hexanes (169) to polyalkylated cyclopentanones (170) (Table 6)59). 

OL-Alkylation of ketones. Base-catalyzed alkylation of ketones is often unsatisfactory because of polyalkylation and/or formation of isomeric products, particularly in the case of cyclopentanone. A reexamination of this reaction with a variety of bases and solvents indicates that use of potassium t-amyloxide as base and DME as solvent can lead to satisfactory yields, although a large excess of the alkylating... 

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. 

Lithiumlithium triethylaluminum, sodium triethylboron, sodium triethanolamine borate,- potassium triethylboron and tri-n-butyltin cyclohexanone enolates have been successfully monoalkyl-ated. In Scheme 6 the behavior of the lithium enolate of cyclohexanone (11) and the lithium triethylaluminum enolate upon reaction with methyl iodide is compared. The latter enolate gives better results since no dimethylation products were detected, but clearly the cyclohexanone enolate (11) is much less prone to dialkylation than the cyclopentanone enolate (10). Scheme 6 also provides a comparison of the results of alkylation of the potassium enolate of cyclohexanone, where almost equal amounts of mono- and di-alkylation occurred, with the alkylation of the potassium tiiethylboron enolate where no polyalkylation occurred. The employment of more covalently bonded enolates offers an advantage in cyclohexanone monoalkylations but not nearly as much as in the cyclopentanone case. 

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