Arene oxide reactions aromatization

Fig. 2. Reactions of arene oxides. Spontaneous aromatization into phenols and nucleophilic addition reactions by amines and thiols...

Synthesis of Arene Oxides. Reaction of (Me2N)3P with aromatic dialdehydes provides arene oxides such as benz[a]anthracene 5,6-oxide (2a) (eq 5). These compounds, also known as oxiranes, are relatively reactive, undergoing thermal and acid-catalyzed rearrangement to phenols and facile hydrolysis to dihydrodiols. Consequently, their preparation and purification requires mild reagents and condition.s. The importance of this is underlined by successful synthesis of the reactive arene oxide (2b) in 75% yield using appropriate care, despite a previous report of failure of the method. While compound (2b) is a relatively potent mutagen, it is rapidly detoxified by mammalian cells. The principal limitation of the method is the unavailability of the dialdehyde precursors, which are obtained through oxidation of the parent hydrocarbons, e.g. by ozonolysis. 

Phenolic compounds are commonplace natural products Figure 24 2 presents a sampling of some naturally occurring phenols Phenolic natural products can arise by a number of different biosynthetic pathways In animals aromatic rings are hydroxylated by way of arene oxide intermediates formed by the enzyme catalyzed reaction between an aromatic ring and molecular oxygen... 

Numerous reactions have been described in which the oxygen of the oxepin system is removed to give benzene derivatives. The formation of the aromatic products can be rationalized by an arene oxide as intermediate. A suitable reagent for the elimination of an oxygen atom from this heterocycle is triphenylphosphane, e.g. formation of l,24 2a,12 and 2b.1,9... 

The reductive transformation of arene carboxylates to the corresponding aldehydes under aerobic conditions has already been noted. In addition, aromatic aldehydes may undergo both reductive and oxidative reactions, with the possibility of decarboxylation of the carboxylic acid formed ... 

Oxidative carbonylation can also be achieved by metal-assisted C - H activation. The Pd(II)-promoted oxidative carbonylation of arenes to give aromatic acids has been reported to occur under stoichiometric [127,128] as well as catalytic [129-138] conditions (Eqs. 28-30). In the case of alkylben-zenes, the Pd-catalyzed reaction shows only a moderate selectivity towards the para position. Better p-selectivilics have however been attained by employing Rh(III) or Ir(III) catalysts [139-146]. 

In rearrangement reactions that lead to isomerization, an important discrimination must be made between epoxides of aromatic compounds, e.g., benzene oxide (10.1, Fig. 10.1), and epoxides of alkenes. As a class, epoxides of aromatic compounds (also known as arene oxides) are markedly un-... 

Another isomerization reaction of arene oxides is equilibrium with oxe-pins [5], Here, the fused six-membered carbocycle and three-membered oxirane merge to form a seven-membered heterocycle, as shown in Fig. 10.2. An extensive computational and experimental study involving 75 epoxides of monocyclic, bicyclic, and polycyclic aromatic hydrocarbons has revealed much information on the structural factors that influence the reaction rate and position of equilibrium [11], Thus, some compounds were stable as oxepins (e.g., naphthalene 2,3-oxide), while others exhibited a balanced equilibrium... 

A clever application of this reaction has recently been carried out to achieve a high yield synthesis of arene oxides and other dihydroaromatic, as well as aromatic, compounds. Fused-ring /3-lactones, such as 1-substituted 5-bromo-7-oxabicyclo[4.2.0]oct-2-en-8-ones (32) can be readily prepared by bromolactonization of 1,4-dihydrobenzoic acids (obtainable by Birch reduction of benzoic acids) (75JOC2843). After suitable transformation of substituents, mild heating of the lactone results in decarboxylation and formation of aromatic derivatives which would often be difficult to make otherwise. An example is the synthesis of the arene oxide (33) shown (78JA352, 78JA353). 

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 arene oxide valence tautomer of oxepins in principle should undergo nucleophilic substitution reactions (Sn2) which are characteristic of simple epoxides. In reality oxepin-benzene oxide (7) is resistant to attack by hard nucleophiles such as OH-, H20, NH2- and RNH2. Attempts to obtain quantitative data on the relative rates of attack of nucleophiles on (7) in aqueous solution hqye been thwarted by competition from the dominant aromatization reaction. 

Nitrogen heterocycles continue to be valuable reagents and provide new synthetic approaches such as NITRONES FOR INTRAMOLECULAR -1,3 - DIPOLAR CYCLOADDITIONS HEXAHYDRO-1,3,3,6-TETRAMETHYL-2,l-BENZISOX AZOLINE. Substituting on a pyrrolidine can be accomplished by using NUCLEOPHILIC a - sec - AM IN O ALKYL ATION 2-(DI-PHENYLHYDROXYMETHYL)PYRROLIDINE. Arene oxides have considerable importance for cancer studies, and the example ARENE OXIDE SYNTHESIS PHENANTHRENE 9,10-OXIDE has been included. An aromatic reaction illustrates RADICAL ANION ARYLATION DIETHYL PHENYLPHOSPHONATE. 

Isoquinolines have been prepared on insoluble supports by radical-mediated cycli-zations and by intramolecular Heck reaction (Table 15.25). Entry 1 in Table 15.25 is a rare example of the formation of a biaryl by intramolecular addition of an aryl radical to an arene. Oxidative aromatization was achieved by using a large excess of AIBN. 

Aromatic hydrocarbons are mainly hydroxylated to phenolic products. Complex (12) hydroxylated benzene in MeCN at 20 °C into phenol in ca. 55% yield, and no isotope effect was found for this reaction. Hydroxylation of toluene mainly occurs at the ring positions, with minor amounts of benzylic oxidation products. Hydroxylation of 4-deuterotoluene by (12) occurred with 70% retention and migration of deuterium in the formation of p-cresol. This high NIH shift value is in the same range as that found for liver microsome cytochrome P-450 hydroxylase, and suggests the transient formation of arene oxide intermediates. 

The NIH shift has been recognized to be so general that whenever a 1,2-shift occurs in aromatic hydroxylation reactions, it is assumed that arene oxides are involved. This need not be so. That the 1,2-shift could take place without the... 

Two important reactions of arene oxides in animal tissue are (1) detoxification and (2) formation of conjugates of arene oxides with purine pyrimidine bases of DNA. For both of these reactions to take place, the arene oxide should have a certain intrinsic stability to survive an aromatization reaction. Reaction with the thiolate bond of glutathione is responsible for detoxification, whereas the extent of involvement of arene oxides in the nucleophilic reactions with nonpolarized nitrogen bases of DNA is directly related to their carcinogenic activity. 

What is remarkable, however, is the stereochemical influence of a 13-hydroxyl group, p-hydroxycarbocations such as 31 are formed not only from arene oxide as precursors but from arene dihydrodiols. As shown for the parent benzene dihydrodiols in Scheme 23, arene dihydrodiols exist as cis-and /ra/rv-isomers. The m-isomers are obtained as products of the action on the aromatic molecule of dioxygenase enzymes and have been prepared on a large scale by fermentation.92 The trans-isomers are normally accessible by straightforward synthesis, for example, from the arene oxide. Both isomers undergo acid-catalyzed dehydration to the parent aromatic molecule, as is also shown in Scheme 23. It is clear that their reactions should involve a common carbocation intermediate,163 164 and in so far as there is little difference in the stabilities of the isomers,165 their difference in reactivities might have been expected to be small. 

Epoxidation and Aromatic Hydroxylation. Epoxidation is an extremely important microsomal reaction because not only can stable and environmentally persistent epoxides be formed (see aliphatic epoxidations, below), but highly reactive intermediates of aromatic hydroxylations, such as arene oxides, can also be produced. These highly reactive intermediates are known to be involved in chemical carcinogenesis as well as chemically induced cellular and tissue necrosis. 

Cytochromes P-450 also catalyze the hydroxylation of aromatic rings. In most cases, these reactions involve the intermediate formation of arene oxides derived from the epoxidation of a double bond of the aromatic compound and an isomerization of these very reactive epoxides into the corresponding phenols. 

We suggest that electron transfer and electrophilic substitutions are, in general, competing processes in arene oxidations. Whether the product is formed from the radical cation (electron transfer) or from the aryl-metal species (electrophilic substitution) is dependent on the nature of both the metal oxidant and the aromatic substrate. With hard metal ions, such as Co(III), Mn(III), and Ce(IV),289 reaction via electron transfer is preferred because of the low stability of the arylmetal bond. With soft metal ions, such as Pb(IV) and Tl(III), and Pd(II) (see later), reaction via an arylmetal intermediate is predominant (more stable arylmetal bond). For the latter group of oxidants, electron transfer becomes important only with electron-rich arenes that form radical cations more readily. In accordance with this postulate, the oxidation of several electron-rich arenes by lead(IV)281 289 and thallium(III)287 in TFA involve radical cation formation via electron transfer. Indeed, electrophilic aromatic substitutions, in general, may involve initial charge transfer, and the role of radical cations as discrete intermediates may depend on how fast any subsequent steps involving bond formation takes place. 

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