Epoxidation arenes

Toluene has been converted into benzyl chloride (67%) by hypochlorite under phase-transfer conditions, but the procedure does not appear to have been exploited generally, possibly because of competing arene epoxidation [16]. Oxidation of 2,5-di-f-butylfuran yields 2,2,7,7-tetramethyloct-4-en-3,6-dione (83%) [17]. 

Oxidation Aromatic Hydroxylation. Since many drugs contain aromatic rings, this is a very common metabolic transformation. The process tends to be species specific, with human showing a strong tendency to hydroxylation in the para position. This reaction proceeds via an arene epoxide intermediate. The anticonvulsant drug phenytoin is metabolized by being para-hydroxylated in its aromatic rings. 

Another pathway on an isolated surface iron-oxo species rather than the arene-epoxide pathway has also been proposed by DFT calculations as follows ... 

Singlet oxygen reacts with binaphthylphosphine derivatives such as 1, l -binaphthyldi-/-butylphosphine to form the corresponding binaphthyl-2-oxide phosphine oxides. This intramolecular arene epoxidation reaction proceeds with complete retention of stereochemistry. The binaphthyl-2-oxide di-/-butylphosphine oxide undergoes a slow NIH rearrangement to form the corresponding hydroxylated product. A transient phospha-dioxirane intermediate has been directly observed by low-temperature NMR.241... 

In their synthesis of (+)-narciclasine 26, Elango and Yan performed a stereocontrolled epoxide formation via the bromohydrins 25. Following concomitant ring closure and N-piperonylation, treatment with catalytic SnCh affected intramolecular arene-epoxide coupling (Scheme 16) <2002JOC6954>. 

Because the half-life of the epoxide intermediate is short, immediate rearrangement or reaction may lead to a single metabolite or a variety of substituted metabolites. The intermediacy of an epoxide intermediate can be inferred by the identification of para-and meta-hydroxylated and dihydrodiol metabolites, although their relative abundances will vary with substitution and steric considerations. Acetanilide, like phenobarbital discussed previously, exemplifies the aromatic compounds that rearrange rapidly following CYP-mediated arene epoxide formation leading to a single metabolite, as shown in Scheme 11.10. 

The major metabolite of phenytoin is para-hydroxyphenytoin, formed through an arene epoxide intermediate as shown in Scheme 11.11. Microsomal epoxide hydrolase (HYEl) is widely distributed in tissues and serves a protective role in converting longer lasting arene oxide intermediates to diols. The arene epoxide of phenytoin is detoxified through HYEl to form the dihydrodiol (20). 

SCHEME 11.9 Hydroxylation of aromatic carbon atoms often proceeds through a reactive and unstable arene epoxide intermediate. HYLl, Microsomal epoxide hydrolase. 

SCHEME 11.10 Acetanilide, like phenobarbital discussed previously, exemplifies the aromatic compounds that rearrange rapidly following CYP-mediated arene epoxide formation. 

SCHEME 11.11 The metabolism of phenytoin through an unstable arene epoxide results in a triad of oxidized metabolites that is characteristic for this intermediate. 

Dr. Fred Guengerich at Vanderbilt University has published mechanistic schemata for cytochrome P450 involvement in an extensive array of both common and uncommon oxidative reactions and reductive reactions. Some of those are exhibited later in this chapter in a brief consideration of reductive reactions. Mechanisms for carbon hydroxylation, heteroatom oxygenation, N-dealkylation, O-dealkylation, alcohol oxidation, arene epoxidation, phenol formation, oxidation of olefins and acetylenes, reduction of nitro compounds, reductive dehalogenation, and azo reduction, to name a few, are provided. 

In the environmental compartments, PCBs are degraded mainly hy microorganisms. Mono-, di-, and trichlorobiphenyls are broken down relatively quickly, whereas the more highly chlorinated PCBs are much more persistent. Highly chlorinated PCBs are reductively dechlorinated anaerobically with replacement of Cl by H, and the less-chlorinated products are subject to aerobic breakdown processes. The formation of ortho-dioh is thought to involve arene epoxides (Figure 11). 

Although hydroxyl radicals are apparently the active species in oxygenation of benzene [40a], cyclohexane [40a] and even methane [40b] by oxygen-containing derivatives of xenon (which may be generated by dissolution of XeOs or Xep2 in water of aqueous acetonitrile), the mechanism of direct arene epoxidation as the first stage is not excluded [40a] ... 

CYPs are good at epoxidizing aikenes and alkynes as well, which is probably one reason why more drugs don t contain these groups. Then again, just because a reaction can happen doesn t mean that it will. For carbamazepine (Figure 9.18), epoxidation followed by diol formation is the major metabolic route, but for tamoxifen, metabohc epoxidation of the central double bond hardly happens, and other CYP-catalyzed reactions, including arene epoxidation and N-demethylation (discussed in a later section) are much more in evidence. 

Short syntheses of enantiomerically pure narciclasine (68) and lycoricidine based on the intramolecular acid-catalyzed arene-epoxide coupling have been described (288,289). Bromohydroxylation of a protected aminocyclohexenol afforded the corresponding bromohydrin as a mixture of two trans stereoisomers, which was subsequently transformed to link an arylmethyl moiety in basic medium with the concomitant formation of the epoxide ring, thereby setting the stage for the... 

Meesters, R. J. W., M. Duisken, and J. Hollender, 2009, Cytochrome P450-catalysed arene-epoxidation of the bioactive tea tree oil ingredient p cymene Indication for the formation of a reactive allergenic intermediate 59 663-671. 

Epoxides (91), (93), and (95) formed through the normal bromohydrin route are important intermediates in the ultimate synthesis of the polycyclic arene epoxides benz[a]anthracene 8,9-oxide (92), benz[a]pyrene 7,8-oxide (94), and benz[a]pyrene 9,10-oxide (96). Polycyclic arene oxides of the types (92), (94), (96), and (97) were found to bind to DNA and to stimulate DNA synthesis, mutagenesis, and carcinogenesis. ... 

This research group also investigated the intramolecular arene epoxidation of binaphthyl phosphine derivatives. Singlet oxygen reacts with l,l -binaphthyl-2-di-tert-butylphosphine to form the corresponding phosphine oxide-epoxide intermediate with complete retention of stereochemistry. This then undergoes a slow NIH-rearrangement to form the 1-phosphinoxido-l -hydroxy binaphthyl derivative (Scheme 9). °... 

Elango S, Yan TH. A short synthesis of (+)-narciclasine via a strategy derived from stereocontrolled epoxide formation and SnCU-catalyzed arene-epoxide coupling. J. Org. Chem. 2002 67 6954-6959. 

Reactions.—The reaction of sulphonium ylides with carbonyl compounds to form oxirans is now a standard reaction. Among the more unusual examples reported are an intramolecular version directed towards the preparation of arene epoxide (12) (not isolable), the synthesis of the epoxide of 8-phenylthio-methylenecycloheptane, and the direct conversion of a diketone by dimethyl-sulphonium methylide into a doubly homologated hydroxymethyl aldehyde (13) by the rearrangement shown. ... 

---