Phenols spontaneous isomerization

The NIH shift has been found to occur during aromatic hydroxylations catalyzed by enzymes present in plants, animals, fungi and bacteria. It is thus evident that the acid catalyzed (or spontaneous) isomerization of oxepins-arene oxides is a very important type of in vivo reaction. It should be emphasized that the NIH shift may occur under either acid-catalyzed or neutral (spontaneous) conditions (76ACR378). The direct chemical oxidation of aromatic rings has also yielded both phenols (obtained via the NIH shift) and arene oxides (80JCS(P1)1693>. 

The products of epoxidation in vivo depend on the reactivity of the particular epoxide. Stabilized epoxides react with nucleophiles and undergo further enzymic reactions, whereas destabilized ones undergo spontaneous isomerization to phenols. Epoxides are generally reactive intermediates, however, and in a number of cases are known to be responsible for toxicity by reaction with cellular constituents. 

As has been stated before, oxirane derivatives are formed as intermediates during metabolic oxidations at carbon-carbon double bonds. These epoxides (arene oxides) undergo spontaneous isomerization to phenols, or enzymic hydration via epoxide hydrase to trans- dihydrodiols, or reaction with reduced glutathione (GSH) via specific GSH-transferases to the corresponding conjugates (Scheme 11), which eventually appear in urine... 

Fig. 10.1. Simplified mechanisms of the spontaneous and acid-catalyzed isomerization of arene oxides to phenols via a carbonium ion intermediate (benzene oxide (10.1) as the... 

The most widely studied aspect of arene-oxide chemistry is the aromatization reaction to yield phenols. The acid-catalyzed, spontaneous, and thermal rearrangements of epoxides to ketones have a parallel in the isomerization of arene oxides to dienone intermediates with subsequent aromatization to phenols. Prior to their availability by chemical synthesis, arene oxides were postulated as initial inter-... 

Figure 11. Pathways involved in the acid-catalyzed and spontaneous (k i isomerization of arene oxides to phenols.

In Scheme 26.24, examples of an RCM/isomerization/tautomerization sequence by Yoshida et al. are shown [30]. After RCM of 4-methylene-l,7-octadien-3-ones 81, synthesis of phenols 83 was accomplished by Rh-catalyzed isomerization of the carbon-carbon double bond of the RCM products 82 from exo to endo, followed by spontaneous tautomerization. The same group also showed that the Mizoroki-Heck reaction could be used as an alternative to the isomerization described above (Scheme 26.25) [30]. In the presence of a catalytic amount of Pd(OAc)2, RCM product 82... 

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