Cyclohexanones, alkylation conformational preference

Endocyclic cyclohexanone enolates with 2-alkyl groups show a small preference (1 1-5 1) for approach of the electrophile from the direction that permits the chair conformation to be maintained. ... 

The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the reaction which is crucial in many cases is the stereoselectivity. The alkylation step has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, since the electrons which are involved in bond formation are the n electrons. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile will approach from the less hindered of the two faces, and the degree of stereoselectivity depends upon the steric differentiation. For simple, conformationally based cyclohexanone enolates such as that from 4 - /- b u ty I eye I o h cx an o ne, there is little steric differentiation. The alkylation product is a nearly 1 1 mixture of the cis and trans isomers. 

Alkylations of enolates, enamines, and silyl enol ethers of cyclohexanone usually show substantial preference for axial attack. The enamine of 4-f-butylcyclohexanone, which has a fixed conformation because of the i-butyl group, gives 90% axial alkylation and only 10% equatorial alkylation with n-Prl. 

Enolates derived from cyclic compounds such as cyclohexane carboxylic acid or cyclohexane carboxalde-hyde generate enolates that are unique. These enolates have an exocyclic double bond that can exist as ( ) and (Z) isomers. The facial and orientational bias in alkylation and condensation reactions of such enolates is influenced by the conformation of the ring it is attached to. Alkylidene cyclohexane enolates show a preference for equatorial attack, just as cyclohexanone derivatives do (sec. 4.7.C,D). 

As regards product stabilities the axial methoxy-ketone (125) might be expected to be less stable than the equatorial isomer (126). It exhibits an axial preference of ca. 0.85 kcalmol" on the basis of AG° for methoxycyclohexanes and with account taken of the 3-alkyl ketone effect for (125) (126). Precedent exists for a number of 4-substituted cyclohexanones where the axial conformer or isomer is atypically the more stable, and in these instances dipole-dipole interactions between the carbonyl group and the polar substituent are postulated in order to rationalize the results. It is suggested that analogous dipole-dipole interactions may stabilize (125) with the reservation that it is difficult to quantify this effect in the present instance, on account of different rotamers with respect to the C—0(Me) bond. The possibility is also mentioned that the anomeric effect is also capable of rationalizing the greater stability of (125). 

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