Trimethylcyclohexanones, reduction axial alcohols

The method is useful in the preparation of other axial alcohols. Henbest6 has reported the reductions of 3-bbutylcyclohexanone, 3,3,5-trimethylcyclohexanone, and cholestanone to the axial alcohols by this procedure, although for the preparation of 3 a-cholestanol the procedure of Edward7 is preferred by the checkers. Recently8 2,4,4-trimethylcyclohexanone has been reduced to the pure axial alcohol by this method in 90% yield. 

Compared with many other reagents, the amount of axial alcohol is very small (2-11 %) using isobornyloxyaluminum dichloride (1 a) (see Table 1, p 4101) as the reducing agent. The proportion of axial attack, yielding the equatorial alcohol, is also decreased in the reduction of sterically more hindered carbonyl compounds such as 3,3,5-trimethylcyclohexanone and men-thone79. 

With other less-rigid cyclohexanones, the stereochemical course of the reduction is less easy to predict. In general, a mixture of products is obtained in which, with comparatively unhindered ketones, the more stable equatorial alcohol predominates with hindered ketones, the axial alcohol is often the main product. Thus, reduction of 4-tert-butylcyclohexanone 84 with lithium aluminium hydride gives predominantly the equatorial trans-4-/ crt-butylcyclohexanol, whereas the hindered 3,3,5-trimethylcyclohexanone 85 gives a mixture containing mainly the axial alcohol 86 (7.69,7.70). The latter is almost the only product when a more hindered and hence more selective reducing agent such as L-selectride [LiBH( Bu)3] or lithium hydrido-tri-tert-butoxyaluminate [LiAlH(0 Bu)3] is employed. 

The effects of changes in solvent and reducing agent are also profound. This is illustrated in Equation 9.19, where reduction of 3,3,5-trimethylcyclohexanone to the corresponding axial alcohol (from equatorial hydride addition) and equatorial alcohol (from axial hydride addition) is shown. 

Coleman, Kobylecki, and Utley studied the electrochemical reduction of the conformationally fixed ketones 4-tert-butylcyclohexanone and 3,3,5-tri-methylcyclohexanone 82>. Stereochemically, the cleanest reductions took place at a platinum cathode in a mixture of hexamethylphosphoramide and ethanol containing lithium chloride. Under these conditions the equatorial alcohol predominated heavily (95% from 4-fer/-butylcyclohexane and 91% from 3,3,5-trimethylcyclohexanone).In acidic media roughly equal quantities of axial and equatorial alcohol were produced. It was suggested that organo-lead intermediates are involved in the reductions in aqueous media. This is reasonable, based upon the probable mechanism of reduction in acid 83F Reductions in acid at mercury cathodes in fact do result in the formation of... 

Different stereoselectivities caused by solvent effects are demonstrated in the reduction of dihydroisophorone (3,3,5-trimethylcyclohexanone) with sodium borohydride which gave less stable tranj-3,3,5-trimethylcyclohexanol (with axial hydroxyl) by reduction in anhydrous isopropyl alcohol (55-56%), in anhydrous tert-butyl alcohol (55%), in 65% aqeuous isopropyl alcohol (59.5%), in anhydrous ethanol (67%), and in 71% aqueous methanol (73%) (the balance to 100% being the more stable cis isomer with equatorial hydroxyl) [849]. 

---