Oppenauer oxidation using aluminium alkoxides

The Oppenauer oxidation with aluminium alkoxides provides an alternative method for the oxidation of secondary (and less commonly primary) alcohols. The reaction is the reverse of the Meerwein-Pondorff-Verley reduction (see Section 7.3). Typically aluminium triisopropoxide (or aluminium tri-tert-butoxide) is used, which serves to form the aluminium alkoxide of the alcohol. This is then oxidized through a cyclic transition state at the expense of acetone (or cyclohexanone or other carbonyl compound). By use of excess acetone, the equilibrium is forced to the right (6.45). 

Oppenauer oxidation, using alkoxides other than aluminium, operates via a hydride transfer mechanism similar to the one depicted in the above Equation, although a complexation of the metal with the carbonyl group may not be present.22d Evidence for a radical mechanism was put forward in the case of the interaction between lithium isopropoxide and benzophenone.24... 

Normally, Oppenauer oxidations are performed employing Al3+ cations as catalyst because aluminium alkoxides possess a good balance of a desired high hydride transfer capability versus a low propensity to promote undesired base-induced reactions, like aldol condensations and Tischtschenko reactions. In the reaction, as originally described by Oppenauer, aluminium t-butoxide is used as catalyst,4 because its high basicity allows a very favourable equilibrium towards the formation of the aluminium alkoxide of the alcohol whose oxidation is desired. However,... 

Aluminium alkoxides very often promote aldol condensations between the aldehyde or ketone, resulting from the oxidation, and the carbonyl compound used as the oxidant. That is why, Oppenauer oxidations are seldom employed for the obtention of aldehydes, as these compounds have a greater tendency than ketones to be involved in aldol condensations. Likewise, although Oppenauer oxidation can be made in the presence of ketones,49 it may be advisable to protect them, for example as semicarbazones.50... 

A common side reaction during Oppenauer oxidations consists of the base-catalyzed condensation of the carbonyl compound, resulting from the oxidation, with the carbonyl compound used as oxidant. Sometimes, advantage is taken from this side reaction for synthetic purposes. For example, oxidation of primary alcohols with an aluminium alkoxide and acetone results in the formation of an intermediate aldehyde that condenses with acetone, resulting in a synthetically useful formation of an enone.59... 

Secondary alcohols may be oxidised to the corresponding ketones by the use of an aluminium alkoxide, frequently the t-butoxide, in the presence of a large excess of acetone (the Oppenauer oxidation). The reaction involves an initial alkoxy-exchange process followed by a hydride ion transfer from the so-formed aluminium alkoxide of the secondary alcohol by a mechanism analogous to that of the Meerwein-Ponndorf-Verley reduction (see Section 5.4.1, p. 520). 

Acetone in conjunction with benzene as a solvent is widely employed. Alternatively cyclohexanone as the hydrogen acceptor, coupled with toluene or xylene as solvent, permits the use of higher reaction temperatures and consequently the reaction time is considerably reduced the excess of cyclohexanone can be easily separated from the reaction product by steam distillation. Usually at least 0.25 mol of aluminium alkoxide per mol of secondary alcohol is employed. However, since an excess of alkoxide has no detrimental effect, the use of 1 to 3 mol of alkoxide is desirable, particularly as water, either present in the reagents or formed during secondary reactions, will remove an equivalent quantity of the reagent. It is recommended that 50 to 200 mol of acetone or 10 to 20 mol of cyclohexanone be employed. Other oxidisable groups are usually unaffected in the Oppenauer oxidation and the reaction has found wide application in the steroid field. 

Rathke and coworkers found that combining this bulky alkoxide again with trifluoroacetic acid leads to a highly efficient catalytic system for the Oppenauer oxidation. For instance, cyclohexanol could be oxidised, at 0 °C within a couple of minutes, to give cyclohexanone in 88% yield, in the presence of 5 mol% of aluminium tri-tert-butoxide activated with 2.5 mol% of trifluoroacetic acid as shown in Scheme 18.5. However, the control provided by this catalytic system in the MPV/Oppenauer reactions leaves some room for improvement and the aluminium-catalysed formation of side products via concurrent aldol reactions (Scheme 18.2) could be observed when enolisable substrates were used. ... 

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