Ketone reductions, homogeneous systems

In this chapter, we do not attempt to give a comprehensive overview of the field, but we would rather concentrate on results where both enantioselectivity and catalyst activity are relevant to preparative application. In the first section, results obtained with cinchona-mediated homogeneous systems for the reduction of ketones are briefly reviewed. Then, heterogeneous cinchona-modified Pt catalysts applied to the hydrogenation of a-functionalized ketones and cinchona-modified Pd catalysts for the hydrogenation of activated C=C bonds are discussed from a synthetic point... 

Borohydride reduction of NiCl2 in dimethylformamide or dimethyl-acetamide leads to very active catalysts, thought to be homogeneous, for hydrogenation of monoolefins, unsaturated fats, cyclic dienes to monoenes, and saturated aldehydes and ketones (165, 538, 539). Cobaltous chloride systems have also been used (540). 

The dispersity or homogeneity of the reductant in a reaction system sometimes plays a decisive role. It is also important for synthetic practice. Crandall and Mualla (1986) compared reduction of 7-methylocta-5,6-diene-2-one [H3C-C(CH3)=C=CH-CH2-CH2-C(0)-CH3] in THF by the action of naphthalene-sodium, on the one hand and, by sonically activated sodium on the other. In both the cases, one-electron transfer yields the anion-radical salt of the allenic ketone with sodium. However, only in the case of sonicated sodium is this salt stabilized, eventually giving H3C-C(CH3)=C=CH-CH2-CH2-C(0H)-CH3 along with cyclic products (l-methyl-2-isopropylidene cyclopentanol and l-methyl-2-isopropylcyclopent-2-enol). If naphthalene-sodium is used, only the cyclic alcohols are obtained as mentioned earlier. 

According to these, for purely aliphatic ketones the highest enantioselectivities are achieved for methyl ketones with a second, branched-chained alkyl substituent (84-94% ee). The value of 75 % ee obtained with the straight-chain hexan-2-one is, to the best of our knowledge, in any case better than anything achieved to date with nonenzymatic systems and homogeneous catalysis. Higher selectivities have been reported for reductions with stoichiometric amounts of chiral borohydrides (e.g. 80 % ee for the reduction of octan-2-one) [20]. 

The scope of cinchona-based chiral auxiliary or chirality transmitters for enantioselective reductions is at the moment restricted to heterogeneous Pt and Pd catalysts and primarily to the reduction of a-functionalized ketones and to a lesser degree of activated C=C bonds. Up to now, very few homogeneous catalysts have been described, and with the exception of a transfer hydrogenation system, none shows any promise. 

Knoevenagel condensation of aldehydes/ketones with malonitrile and ethyl cyanoacetate. The reactions were carried out under homogeneous and biphasic conditions, including the use of liquid-silica supported IL, with the biphasic system employing cyclohexene as the second phase. Although supported ILs showed a reduced initial activity, in general an excellent recyclability was observed, with the reaction repeated over five times without leaching of the IL into the extractant phase or reduction in activity. 

The reduction of the C=0 function is relatively unusual among homogeneous hydrogenation catalysts. [Rh(cod)(PPh3)]A-based systems reduce various ketones, both in the native cationic form, where H2O is a cocatalyst,and in the deprotonated form. This does not necessarily occur via the enol, since Ph2CO can be reduced by the neutral system in this way. 

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