Quinone methide intermediates 7-Quinones, oxidation with

The third primary intermediate in the oxidation chemistry of a-tocopherol, and the central species in this chapter, is the orr/zo-quinone methide 3. In contrast to the other two primary intermediates 2 and 4, it can be formed by quite different ways (Fig. 6.4), which already might be taken as an indication of the importance of this intermediate in vitamin E chemistry. o-QM 3 is formed, as mentioned above, from chromanoxylium cation 4 by proton loss at C-5a, or by a further single-electron oxidation step from radical 2 with concomitant proton loss from C-5a. Its most prominent and most frequently employed formation way is the direct generation from a-tocopherol by two-electron oxidation in inert media. Although in aqueous or protic media, initial... 

It was shown that complexes 19 of the zwitterionic precursors of ortho-quinone methides and a bis(sulfonium ylide) derived from 2,5-di hydroxyl 1,4 benzoquinone46 were even more stable than those with amine N-oxides. The bis(sulfonium ylide) complexes were formed in a strict 2 1 ratio (o-QM/ylide) and were unaltered at —78 °C for 10 h and stable at room temperature under inert conditions for as long as 15—30 min (Fig. 6.18).47 The o-QM precursor was produced from a-tocopherol (1), its truncated model compound (la), or a respective ortho-methylphenol in general by Ag20 oxidation in a solution containing 0.50-0.55 equivalents of bis(sulfonium ylide) at —78 °C. Although the species interacting with the ylide was actually the zwitterionic oxidation intermediate 3a and not the o-QM itself, the term stabilized o-QM was introduced for the complexes, since these reacted similar to the o-QMs themselves but in a well defined way without dimerization reactions. 

FIGURE 6.18 Oxidation of ortAo-methylphenols to the corresponding ortho-quinone methide via transient zwitterionic intermediates that are stabilized by forming a complex 19 with the 2,5-dihydroxy[l,4]benzoquinone-derived bis(sulfonium ylide). 

Acolbifene is also metabolized to a QM (Scheme 10.10)64 formed by oxidation at the C-17 methyl group. This QM is considerably more reactive compared to the tamoxifen quinone methide, which indicates that the acolbifene quinone methide is an electrophile of intermediate stability (Table 10.2). In addition, the acolbifene QM was determined to react with deoxynucleosides, with one of the major adducts resulting from reaction with the exocyclic amino group of adenine.64... 

Cholest-4-en-3/3-ol and its 5a-A6- and 5a-A7-isomers gave complex mixtures of oxidation products on treatment with 60Co y-radiation in air. Reaction paths are discussed and compared with those occurring in photosensitized and free-radical oxidations.119 1-Methyl-11-oxo-oestrone (107) is converted by DDQ in 1% aqueous dioxan into the 9/3-hydroxy-derivative (108), apparently by hydration of an intermediate quinone methide.120... 

Chromenes, o-Allylphenols are oxidized to 3-chromenes by potassium dichromate dissolved in benzene in the presence of Adogen 464 in yields of 45-83%. 0 -Quinone methides are postulated intermediates. These heterocycles are also obtained on oxidation of o-allylphenols with DDQ, but in this case ether is preferable to benzene (82-90% yield cf. 2, 116). 

Hydoxyphenyl)-2-(4-hydroxyphenyl)ethane (539) was oxidized with DDQ (1 equiv.) in benzene (room temp., 24 h) to afford both benzofuran (540) and dihydrobenzofuran (541) (27 and 22%, respectively). With 2 equivalents of DDQ the yield of the former increased and that of 541 decreased (Scheme 100). The p-quinone methide 542 is recognized as a plausible reaction intermediate. ... 

Highly reactive quinone methide can be utilized as intermediates in organic synthesis. From the viewpoint of biomimetic synthesis, silybin (782) bearing a benzodioxane skeleton was synthesized in 44.5% yield, together with isosilybin (784) (33.5%), by AgiO-mediated oxidation of equimolar amounts of 27 ,37 -dihydroquercetin (783) and coniferyl alcohol (298) in benzene-acetone. The p-quinone methide 785 must be generated as a reactive intermediate (Scheme 156) °. 

The enzyme vanillyl-alcohol oxidase (VAO, E.C. 1.1.3.38) was examined in detail with respect to mechanism, structural properties, and biotechnological applications by van Berkel and coworkers, giving an excellent example of how detailed biochemical studies provide a basis for preparative biocatalytic applications (for recent reviews see[1, 21). The homooctamer with a monomer mass of 65 kDa was isolated and purified from Penicillium simplicissimum. The catalytic mechanism of VAO-catalyzed oxidation of para-alkyl phenols was studied in detail[3-5 After initial hydride abstraction from the Ca atom, a binary complex of the intermediate para-quinone methide and reduced FAD reacts with molecular oxygen, regenerating the... 

Oxidative C-demethylation of a phenol. Oxidation of the bridged trione (1) with ferric chloride in ethanol (steam bath) unexpectedly gives the 1,2-naphthoquinone derivative (2). A quinone methide is a probable intermediate. This unusually mild demethylation is undoubtedly a result of the bridge system. ... 

There are many other kinds of reactive intermediates, which do not fit into the previous classifications. Some are simply compounds that are unstable for various possible reasons, such as structural strain or an unusual oxidation state, and are discussed in Chapter 7. This book is concerned with the chemistry of carbocations, carbanions, radicals, carbenes, nitrenes (the nitrogen analogs of carbenes), and miscellaneous intermediates such as arynes, ortho-quinone methides, zwitterions and dipoles, anti-aromatic systems, and tetrahedral intermediates. This is not the place to describe in detail the experimental basis on which the involvement of reactive intermediates in specific reactions has been estabhshed but it is appropriate to mention briefly the sort of evidence that has been found useful in this respect. Transition states have no real hfetime, and there are no physical techniques by which they can be directly characterized. Probably one of the most direct ways in which reactive intermediates can be inferred in a particular reaction is by a kinetic study. Trapping the intermediate with an appropriate reagent can also be very valuable, particularly if it can be shown that the same products are produced in the same ratios when the same postulated intermediate is formed from different precursors. 

Although the trypsin-solubilized laccase from M. sexta oxidizes N-)9-alanyldopamine to its o-quinone, the o-quinone does not accumulate to a high concentration (18. Morgan et. al. unpublished data). Instead, an enzyme in the preparation, possibly the laccase itself, appears to catalyze the conversion of the o-quinone to a p-quinone methide or another intermediate which reacts with water to yield the yS - hydroxy lated derivative of... 

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