Pyrrolidine, 2,5-dimethylcyclohexanone enamine from

A valuable feature of the enamine reaction is that it is regioselective. In the alkylation of an unsymmetrical ketone, the product of reaction at the /ess-substituted a-carbon atom is formed in greater amount, in contrast to direct base-mediated alkylation of unsymmetrical ketones, which usually gives a mixture of products. For example, reaction of the pyrrolidine enamine of 2-methylcyclohexanone with iodomethane gives 2,6-dimethylcyclohexanone almost exclusively. This selectivity derives from the fact that the enamine from an unsymmetrical ketone consists mainly of the more-reactive isomer in which the double bond is directed toward the less-substituted carbon atom. In the more-substituted enamine, there is decreased interaction between the nitrogen lone pair and the -ir-system of the double bond because of steric interference between the a-substituent (the methyl group in Scheme 1.33) and the a-methylene group of the amine. 

While it is probably reasonable to draw general trends from this series, it should be kept in mind that most of the data came from different laboratories, as indeed there are four different reports for the simple pyrrolidine enamine that account for the range from 85 to 96%. Some of the factors that contribute to determining the regioisomeric composition of enamines are A -strain, which destabilizes the more substituted isomer, and A - -strain, which destabilizes the less substituted isomer (Scheme 6). The former effect was used by Johnson to effectively convert c/j-2,4-dimethylcyclohexanone to the trans isomer through formation of the less substituted pyrrolidine enamime, where a pseudo-axial orientation of the 2-methyl group reduces the level of A - -strain (equation... 

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