Enolates molecular oxygen

The ff-oxidation of carbonyl compounds may be performed by addition of molecular oxygen to enolate anions and subsequent reduction of the hydroperoxy group, e.g. with triethyl phosphite (E.J. Bailey, 1962 J.N. Gardner, 1968 A,B). If the initially formed a-hydroperoxide possesses another enolizable a-proton, dehydration to the 1,2-dione occurs spontaneously, and further oxidation to complex product mitctures is usually observed. 

Ketones and carboxylic esters can be a hydroxylated by treatment of their enolate forms (prepared by adding the ketone or ester to LDA) with a molybdenum peroxide reagent (MoOs-pyridine-HMPA) in THF-hexane at -70°C. The enolate forms of amides and estersand the enamine derivatives of ketones can similarly be converted to their a hydroxy derivatives by reaction with molecular oxygen. The M0O5 method can also be applied to certain nitriles. Ketones have also been Qc hydroxylated by treating the corresponding silyl enol ethers with /n-chloroperoxy-... 

Although ketones are essentially inert to molecular oxygen, enolates are susceptible to oxidation. The combination of oxygen and a strong base has found some utility in the introduction of an oxygen function at carbanionic sites.200 Hydroperoxides are the initial products of such oxidations, but when DMSO or some other substance capable of reducing the hydroperoxide is present, the corresponding alcohol is isolated. A procedure that has met with considerable success involves oxidation in the presence of a trialkyl phosphite.201 The intermediate hydroperoxide is efficiently reduced by the phospite ester. 

Attempts to use molecular oxygen as the oxidant failed except in solvents that undergo efficient autoxidation to the corresponding hydroperoxide (e.g., THF). Mechanistic studies, including isotopic labeling studies, indicate that fBuOOH is the source of the oxygen atom incorporated into the product, and the reaction proceeds via a hydride-shift pathway that avoids formation of an enol intermediate (Scheme 12). 

In some cases, where enolate oxygoiation with molecular oxygen failed, it has been reported that quenching with 90% hydrogen peroxide allows efficioit ctmversion to the hydroxy ketone, e.g. (49) to (50). Similarly violate oxidation with organic peracids is possible (vide it a). a-Hydroxylation via preformed enolates comprises one of most synthetically expedimit approaches for achieving this transformation. 

Just as ketones and esters may be derivatized by the action of molecular oxygen on the corresponding enolates, the same is true of amides. Generation of the lithio enolate (clearly not as facile as the previous substrates) and quenching with oxygen produce the a-hydroperoxyamide, which after in situ reduction, (P(OEt)3), or reductive work-up, (NaHSOs), gives good yields of the required material. 

It has long been realized that the enol form of ketones can react with molecular oxygen to generate the a-hydroperoxy ketone from which a-hydroxy ketones are readily obtained by reductive work-up. The oxidation was thought to arise either fiom direct attack of the enol on molecular oxygen or through a radical-mediated process (vide infra). Necessarily the oxidation is most efficient where the proportion of... 

The diastereoselectivity in these oxidations can generally be predicted assuming that the MoOPH reagent approaches the enolate from the less hindered direction. In one example, the diastereoselectivity was improved from 26% to 66% by addition of 18-crown-648. Where a comparison was made, MoOPH gave higher diastereomcric excesses than did molecular oxygen, 38% versus 0%, respectively (see Table 1, entry 7 and I able 3, entry 6). A limitation of MoOPH is that it can apparently not be used for the oxygenation of stabilized enolates derived from /3-dicarbonyl compounds. 

Table 10. Asymmetric 2-Oxygenation of Enolates with Molecular Oxygen Using. V-(4-Trifluoromethylphcnylmethyl)dnchoninium Bromide as Chiral Catalyst102...

The reaction of lithium enolates with molecular oxygen has been used for the a-hydroxylation of several substrates. The carbanion generated in the reaction of N,N-dialkylamides or esters with alkyl lithium reagents undergoes rapid oxidation under mild conditions when treated with molecular oxygen. The reaction produces an a-hydroperoxide intermediate which is cleanly reduced with sodium sulphite to the a-hydroxo derivatives" (equation 1). 

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