Oppenauer oxidation reactions

Oppenauer reaction is oxidation of secondary alcohols to ketones using aluminium t-butoxide... 

Catalytic reduction of codeine (2) affords the analgesic dihydrocodeine (7) Oxidation of the alcohol at 6 by means of the Oppenauer reaction gives hydrocodone (9)an agent once used extensively as an antitussive. It is of note that treatment of codeine under strongly acidic conditions similarly affords hydrocodone by a very unusual rearrangement of an allyl alcohol to the corresponding enol, followed by ketonization. 

The Oppenauer oxidation makes use of ketones (typically acetone) or alkenes as hydrogen acceptors and this absence of a strong oxidising agent allows to overcome some potential NHC oxidative instability. Reactions consist of an equilibrium between an alcohol and its oxidised form (Scheme 10.9). 

Nortricyclanone has been prepared by oxidation of nortri-cyclanol using chromic acid in acetic acid and using a modified Oppenauer reaction. The present procedure is based on the Jones modification of chromic acid oxidations. 

That specific hydride transfer from carbon to carbon does occur, was established by showing that use of labelled (Me2CDO)3Al led to the formation of RjCDOH. The reaction probably proceeds via a cyclic T.S. such as (47), though some cases have been observed in which two moles of alkoxide are involved—one to transfer hydride ion, while the other complexes with the carbonyl oxygen atom. The reaction has now been essentially superseded by MH reductions, but can sometimes be made to operate in the reverse direction (oxidation) by use of Al(OCMc3)3 catalyst, and with a large excess of propanone to drive the equilibrium over to the left. This reverse (oxidation) process is generally referred to as the Oppenauer reaction. 

Recent advances in alcohol oxidations by rhodium and iridium complexes have mainly focused on Oppenauer-type oxidations or reactions in which this type of oxidation is an intermediate step. An independent result is the oxidation of allyhc (Eq. 9) and benzyUc alcohols with f-BuOOH to the corresponding a,/l-unsaturated ketones [38] with [Rh2(p.-OAc)4]. The reactions were carried out at room temperature in dichloromethane and yields of up to 92% (by GC) in 24-48 h have been described. 

In fact, the production of 5p-steroids from A5-3p-ols, readily available and cheap starting materials, requires preliminar oxidation through the Oppenauer reaction or, more recently, fermentation to the A4-3-keto derivative5. From this one 5p steroids are readily obtained through catalytic hydrogenation4. 

This alcohol is oxidized using an Oppenauer reaction under typical conditions with aluminium isopropoxide and cyclohexanone in boiling toluene. 

An Oppenauer reaction produces the selective oxidation of a secondary alcohol, leading to a (3-hydroxyketone that suffers a retro-aldol condensation under the basic reaction conditions, resulting in the evolution of formaldehyde. 

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). 

Typical for the Oppenauer reaction is high chemoselectivity, even in the presence of other oxidation-sensitive functional groups such as double bonds. Stable anchoring is not a problem with these Si02-based Zr catalysts, which is evident since the surface chemistry of Zr is reminiscent of that of Ti. 

In the second approach, 16-dehydropregnenolone was employed, the double bond of which at the 16,17- position was epoxidised, the epoxide cleaved with hydrogen bromide to the bromohydrin which was reduced and following formation of the 3-formoxy derivative, acetylation of the 17-hydroxy compound gave an intermediate which was oxidised by the Oppenauer reaction to give cortexolone (56) as the diacetate to which the microbiological oxidation could be applied. The process is outlined. 

Oppenauer oxidations, Oppenauer oxidations and Meerwein-Ponndorf-Ver-ley reductions are usually carried out in the presence of aluminum alkoxides in at least stoichiometric amounts. Kagan et al. report that both reactions can be carried... 

Related reactions Meerwein-Ponndorf-Verley reduction, Oppenauer oxidation, Tishchenko reaction ... 

Related reactions Dess-Martin oxidation, Jones oxidation, Ley oxidation, Oppenauer oxidation, PTitzner-Moffatt oxidation, Swern oxidation ... 

Covalent Bonds R Al—0 / D Oxidation (Oppenauer Oxidation) Hydride Transfer (p-Hydride Elimination Meenwein-Ponndorf-Veriey Reduction) C-O Bond Formation (Tischenko Reaction) —Al—0 R... 

The Meerwein-Ponndorf-Verley and Oppenauer reactions are useful when highly selective reduction or oxidations are required, when hydrogenation with molecular H2 is not possible (presence of functional groups) or when suroxidation must be avoided. 

Summary Meerwein-Ponndorf-Verley and Oppenauer reactions (MPVO) are catalysed by metal oxides which possess surface basicity or Lewis acidity. Recent developments include the application of basic alkali or alkaline earth exchanged X-type zeolites and the Lewis-acid zeolites BEA and [Ti]-BEA. The BEA catalysts show high stereoselectivity, as a result of restricted transition state selectivity, in the MPV reduction of substituted alkylcyclohexanones with i-PrOH. 

The cyclization depicted in equation (108) was a key step in a total synthesis of lycopodine. Oppen-auer oxidation of keto alcohol (47) gives keto aldehyde (48), which is cyclized under the reaction conditions to provide dehydrolycopodine (49). The transformation failed with keto diol (50). It was reasoned that, in this case, the tertiary hydroxy group acts as a general acid, protonating the nitrogen and allowing the intermediate p-amino aldehyde to undergo elimination. To remove this side reaction, compound (50) was deprotonated with KH prior to the Oppenauer reaction. Under these modified conditions, enone (51) is obtained in reasonable yield (equation 109). °... 

The stereochemical argument can be closed with the observation that oxidation of dehydroepiandrosterone by the Oppenauer reaction (aluminum isopropoxide in the presence of a ketone) yields the oxidation product androst-4-ene-3,17-dione (14-1) (Scheme 1.14). The same diketone is formed from oxidation of testosterone (14-2). Going in the reverse direction, androst-4-ene-3,17-dione can be converted to testosterone by treatment with fermenting yeast. 

The sequence for preparing the hydroxyketone started by conversion of the acid 15-1 to its chloride with thionyl chloride. Reaction of that acid halide with diazomethane gives the diazoketone 15-2. The hydroxyl group at C3 is then oxidized to the corresponding ketone by means of an Oppenauer reaction. Treatment of the product 15-3 with gaseous hydrogen chloride replaces nitrogen in that intermediate by chlorine. Displacement of chlorine by acetate then leads to the 21-acetate 15-5. Saponification of the ester completes the sequence. 

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