Oppenauer oxidation side reactions

Hydrogen transfer reactions from an alcohol to a ketone (typically acetone) to produce a carbonyl compound (the so-caUed Oppenauer-type oxidation ) can be performed under mild and low-toxicity conditions, and with high selectivity when compared to conventional methods for oxidation using chromium and manganese reagents. While the traditional Oppenauer oxidation using aluminum alkoxide is accompanied by various side reactions, several transition-metal-catalyzed Oppenauer-type oxidations have been reported recently [27-29]. However, most of these are limited to the oxidation of secondary alcohols to ketones. 

The so-called Oppenauer oxidation proved to be extremely successful in the oxidation of sterols. On the other hand, its application—in the original formulation—to the obtention of ketones outside the field of steroids and to the preparation of aldehydes met a more limited success because of less favourable thermodynamics and side reactions, induced by the basic character of the aluminium alkoxides. 

The Oppenauer oxidation presents two important limitations on one side it is unable to oxidize certain alcohols because of unfavourable thermodynamics, and on the other side, base-induced reactions between the oxidant and the product may become dominant. That is why, it is seldom employed for the obtention of aldehydes because these compounds react readily under basic conditions. On the other hand, although aluminium alkoxides promote aldol condensations, many base-sensitive functional groups such as most esters but not formates—25 resist its action. 

The aluminium alkoxides present in the Oppenauer oxidation can cause some base-induced side reactions. Thus, quite typically during the oxidation of sterols possessing homoallylic alcohols, a migration of the alkene into conjugation with the resulting ketone is observed (see pages 256 and 259).4... 

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... 

The Oppenauer oxidation is a common side reaction during the condensation of organometallic compounds with aldehydes and ketones, something that very often comes as a surprise for the unaware chemist. This has been observed in condensations of diverse organometallic species, for example chromium,61 Zr62 and Mg63 organometallics. This side reaction... 

The most common side reactions during Oppenauer oxidation consist of base-induced condensations of the aldehyde or ketone, generated during the oxidation, with the carbonyl compound used as oxidant.65 This side reaction is particularly prominent during the obtention of aldehydes because they are generally more reactive in aldol condensations than ketones. Furthennore, aldehydes very often suffer Tischtschenko condensations,66 resulting in the formation of dimeric esters during Oppenauer oxidations. That is why, the Oppenauer oxidation is seldom useful for the preparation of aldehydes. 

Other base-induced side reactions occurring during Oppenauer oxidations include retro-aldol condensations67 and ring-expansions in a-hydro-xyketones.68... 

Sometimes, side reactions during Oppenauer oxidations can be explained by the Lewis acidity of the aluminium atom in aluminium alk-oxides.69... 

Although the Mukaiyama oxidation is not in the top list of the most frequently used alcohol oxidants, the authors of this book have decided to pay full attention to this procedure because it succeeds in very sensitive organometallic compounds, where most other oxidants fail. The Mukaiyama oxidation operates via a somehow unique mechanism involving a hydride transfer from a metal alkoxide to a very good hydride acceptor, which resembles the Oppenauer oxidation. In variance with the Oppenauer oxidation, the Mukaiyama protocol involves much milder conditions and it does not promote as easily base-induced side reactions. 

Zeolite titanium beta has been tested in the liquid- and gas-phase Meerwein-Ponndorf-Verley reduction of cyclohexanones and the Oppenauer oxidation of cyclohexanols. A high selectivity towards the thermodynamically unfavourable cis-alcohol was observed, which has been ascribed to transition-state selectivity in the pores of the zeolite. Under gas-phase conditions the dehydration of alcohols to cycloalkenes is observed as a side reaction. The catalyst was found to be active even in the presence of water and ammonia. 

The most important side reaction in heterogeneously catalysed MPVO reactions is the acid-catalysed aldol condensation. Aldol products are usually observed during the Oppenauer oxidation of alcohols, when a surplus of ketone or aldehyde is used as the oxidizing agent and the solvent. The low amount of by-products formed when Ti-beta was used as the catalyst, demonstrates the advantage of the titanium system over Al-beta. This is probably caused by the much weaker Brpnsted acidity of the solvated titanium site [8] compared with the strong H -acidity of the aluminium site in Al-beta. As we have shown earlier Ti-beta has a high tolerance towards water, which further shows the catalytic potential of Ti-beta in MPVO reactions [9]. 

Since the 4-methylcyclohexene can be formed via dehydration of either of the two alcohols formed, both alcohols were tested in the Oppenauer oxidation, using acetone as the oxidant at 100 °C. It was observed that the cis-dcohol (Fig. 5a) is easily oxidized to the corresponding ketone, while the trans-alcohol showed a much lower activity. This is in accordance with the transition-states assumed for liquid phase MPVO reactions (Fig. 2). It can be observed further that the dehydration of the trans-alcohol only occurred to very limited scale (Fig. 5b) whereas dehydration of the cis-alcohol was an important side-... 

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). °... 

Scheme 18.2 Possible side-reactions of the MPV reduction/Oppenauer oxidation.

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. ... 

The classical Meerwein-Ponndorf-Verley (MPV) process, named after the independent originators, can be illustrated by the reduction of crotonaldehyde (43) by aluminum isopropoxide (44) in isopropyl alcohol (equation 24). Aluminum isopropoxide transfers hydride reversibly to a carbonyl acceptor. Acetone is formed as a volatile side product, which can be removed during reaction. The reaction of equation (24) is forced even further to the right by the use of excess isopropyl alcohol. MPV reactions have been reviewed.In the Oppenauer variant of this reaction an alcohol is oxidized to a ketone, and acetone is used as hydride acceptor in the presence of a strong base like r-butoxide. This reaction was originally developed for the selective oxidation of sterols. The synthetic aspects of this procedure have also been reviewed. ... 

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