Valence oxepin/benzene oxide

Since both oxepin and its valence isomer benzene oxide contain a x-tb-diene structure they are prone to Diels-Alder addition reactions. The dienophiles 4-phenyl- and 4-methyl-4//-l,2,4-triazole-3,5-dione react with substituted oxepins at room temperature to give the 1 1 adducts 7 formed by addition to the diene structure of the respective benzene oxide.149 190,222... 

Oxidation of the 2,2 -biphenyldiol (218, Scheme 56) by one molar equivalent of lead tetraacetate affords the oxepinobenzofuran 219. With two molar equivalents of lead tetraacetate the initial product is converted to the acetate 221, which on reductive acetylation, involving oxepin-benzene oxide isomerization, affords the dibenzofuran 222. Treatment of the oxepinobenzofuran 219 with ethanolic 2,4-dinitrophenylhydrazine yields the azo compound 220. On boiling with methanol in air, compound 219 is converted to the dibenzofuranone 223, again involving valence isomerization. Reductive acetylation then affords the dibenzofuran 224. ... 

A feature of 1//-azepine chemistry that intrigued early researchers (B-69MI51600, 71 AG(E)ll) was the possibility of azepine-benzeneimine (or azanorcaradiene) valence isomerism (67AG(E)402) akin to that in the oxepin-benzene oxide system. 

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. 

O ) By formation of seven-from three-membered rings This is the most widely used synthetic route to monocyclic oxepins. The key step in the synthesis of oxepin-benzene oxide (7) is the dehydrohalogenation of a dibromoepoxide precursor (64AG(E)S10). Since the benzene oxide valence tautomer is formed initially the valence tautomerization of the latter to oxepin (equation 51) may be considered as a ring expansion reaction. 

Valence tautomers, benzene oxide 1 and oxepine 2 (Equation 1), as well as relative tautomeric systems, benzene sulfide-thiepine and o-xylene-2,7-dimethyloxepine, have been studied by a post-Hartree-Fock (HF) ab initio QCISD(r)/6-31G //MP2/6-31G method. In particular, the enthalpy calculated for a benzene oxide-oxepine system is 0.59 kj moF1 <1997PCA3371>. The calculated molecular orbital (MO) energies are in linear relationship to those from the photoelectron (PE) spectra <1996JCF1447>. Barrier to tautomerization for a benzene oxide-oxepine system is 29.4 kj mol-1. Protonation stabilizes the oxide form versus the oxepine <1997PCA3371>. 

P(0)(0Me)2] gives the pyrans 65a-b and the diazepines 67a-b. Diazepines 67a-b are formed by spontaneous isomerization of the intermediate 2-(diazomethyl)-2//-pyrans 66a-b (87JOC3851). In contrast, the analogous reactions of 4-methyl-2,6-diphenylpyrylium tetrafluoroborate 63b with 64a-b give only 68a-b. The allylpalladium chloride-catalyzed decomposition of 65a-b and 68a-b in benzene solution gives 92-98% of oxepines 69a-b,d. Oxepines 69a-b,d react with triazolinedione 55 to form the Diels-Alder adducts 70a-b,d (83-89%), which are derived from the valence tautomeric benzene oxides. The corresponding reaction of 69c with 55 under otherwise identical conditions proceeds differently in that an isomer with structure 70 c (66%) is formed along with 70c (23%). 

Furthermore, it was also found that the dissociation of the Fe+-complex of the valence tautomers benzene oxide oxepin proceeds via a [phenol-Fe+] complex 65 rather than via the [2,4-cyclohexadien-l-one-Fe+] species 66 (see also Section VII.C). 

A study of Diels-Alder reactions of three oxepines differing in the positions of oxepin-benzene oxide equilibria, namely unsubstituted oxepin (considerable amounts of both valence isomers), 2,7-dimethyloxepin (principally in the oxepin form), and indene oxide (predominantly benzene oxide form), has shown that all three compounds act exclusively in [4 + 2] cycloaddition reactions as benzene oxides, giving endo-adducts with anti-configuration relative to the bridge oxygen atom <91CJC1337>. 

Oxepin and its derivatives have attracted attention for several reasons. Oxepin is closely related to cycloheptatriene and its aza analog azepine and it is a potential antiaromatic system with 871-elcctrons. Oxepin can undergo valence isomerization to benzene oxide, and the isomeric benzene oxide is the first step in the metabolic oxidation of aromatic compounds by the enzyme monooxygenase. 

Three decades ago the preparation of oxepin represented a considerable synthetic challenge. The theoretical impetus for these efforts was the consideration that oxepin can be regarded as an analog of cyclooctatetraene in the same sense that furan is an analog of benzene. The possibility of such an electronic relationship was supported by molecular orbital calculations suggesting that oxepin might possess a certain amount of aromatic character, despite the fact that it appears to violate the [4n + 2] requirement for aromaticity. By analogy with the closely related cycloheptatriene/norcaradiene system, it was also postulated that oxepin represents a valence tautomer of benzene oxide. Other isomers of oxepin are 7-oxanorbornadiene and 3-oxaquadricyclane.1 Both have been shown to isomerize to oxepin and benzene oxide, respectively (see Section 1.1.2.1.). 

The knowledge of the valence tautomerization of benzene oxides to oxepins12 prompted several groups to synthesize oxepins by dehydrohalogenation of 7-oxabicyclo[4.1.0]heptane derivatives. Numerous examples have been described for the base-catalyzed elimination of hydrogen bromide from the 3,4-dibromo-7-oxabicyclo[4.1.0]heptane system. The reaction products are usually obtained as mixtures of oxepin 1 and benzene oxide 2. The 2,7-bis(hydroxy-methyl)oxepin 1 p obtained by this route can be converted to the 2,7-dicarbaldehyde with man-ganese(IV) oxide.23... 

When the valence tautomeric mixture of oxepin and benzene oxide is treated with singlet oxygen, the primary product is the 1,4-endoperoxide 3 which has proven to be too labile for isolation.219 Its formation can be rationalized by a 1,4-addition across the diene system of the benzene oxide structure 3 then rearranges to ba s-3,6,9-trioxatetracyclo[6.1.0.02 4.05 ]nonane (transbenzene trioxide, 4). 

The molecules taking part in a valence tautomerization need not be equivalent. Thus, NMR spectra indicate that a true valence tautomerization exists at room temperature between the cycloheptatriene 110 and the norcaradiene (111). In this case one isomer (111) has the cw-l,2-divinylcyclopropane structure, while the other does not. In an analogous interconversion, benzene oxide and oxepin exist in a tautomeric equilibrium at room temperature. 

In connection with the chemistry of the reactive transient species, nitrene, the chemistry of azepines is well documented u. Also, the chemistry of oxepins has been widely developed due to the recent interest in the valence isomerization between benzene oxide and oxepin and in the metabolism of aromatic hydrocarbons 2). In sharp contrast to these two heteropins, the chemistry of thiepins still remains an unexplored field because of the pronounced thermal instability of the thiepin ring due to ready sulfur extrusion. Although several thiepin derivatives annelated with aromatic ring(s) have been synthesized, the parent thiepin has never been characterized even as a transient species3). 

The parent structure, oxepin (7), exists in a state of spontaneous equilibration with the valence bond isomer benzene oxide at ambient temperature. 

Some of the reagents used in olefin epoxidation can be applied in the direct oxidation of arenes to arene oxides. Benzene oxide, however, like other arene oxides, exists in equilibrium with oxepin, its valence tautomer, and has not been isolated. Existence of benzene oxides as intermediates can be concluded from observations like the NIH shift discussed above.752,753... 

One of the important features of the structure and reactivity of arene oxides is the possibility of their involvement in valence tautomerism with the oxepin system. In benzene oxide (86) the two n bonds and the C—C a bond undergo facile disrotatory electrocyclic reaction to give a 6rc-oxepin system (96). 

For the benzene sulfide-thiepine system, the rate of valence isomerization is predicted to be much slower than that in the benzene oxide-oxepine system, as the enthalpy of activation for 10 —> 1 is 20.5 kcal mol 1 (7.03 kcal mol for benzene oxide-oxepine). 

Many arene oxides are in dynamic equilibrium with their oxepin forms. The parent molecules, benzene oxide la and oxepin lb, are related as valence tautomers that interconvert by an allowed disrotatory electrocyclic reaction. Structural identification of la and lb was based initially upon spectroscopic evidence and chemical transformation to stable products of known structure. Thus the arene-oxide structure was inferred from its typical dienoid (4 + 27t cycloaddition) and epoxide (ring-opening, aromatization) reactions, while the oxepin structure was deduced by catalytic hydrogenation of the triene oxepin to form oxepane. 

While the isomerization of benzene oxides to oxepins occurs spontaneously at low temperature, the analogous mobile valence tautomerization of m-benzene dioxide 143 (Figure 10) to the 10-tt-heterocycle, 1,4-dioxocin, was only evident at temperatures > 50°The latter process is symmetry-allowed and is formally equivalent to a retro-Diels-Alder reaction. The mobile equilibrium at 60°C appeared... 

Oxepins and their bicyclic valence tautomers, arene oxides are discussed in <95CHE(42)197>. Particularly noteworthy is the synthesis of a stable benzene oxide (63) which surprisingly shows little tendency to isomerize to the corresponding oxepin (64) in spite of the expectation that the fluorines would greatly destabilize the three-membered ring in the bicyclic structure (63) (Scheme 10) <90JA6715>. 

The reaction of oxepin (228 R = H) was complicated by the simultaneous photochemical reaction of benzene oxide, the valence isomer of oxepin.26 The results varied with solvent, temperature, and wavelength.269 The reaction proceeded with high selectivity to 2-oxa-bicyclo[3.2.0]hepta-3,6-diene (229 R = H) upon irradiation (A >310 nm) at room temperature. In most other cases the reaction was attended with the formation of phenol, probably from benzene oxide via Dewar benzene oxide, as this compound is known to isomerize photo-... 

Benzene oxide (7-oxabicyclo[4.1.0]hepta-2,4-diene) was obtained in an equilibrium mixture with the valence isomer oxepine (see p 459) (Vogel 1967) ... 

The possibility of valence isomerization also affects the reactions of the oxepins [5]. For instance, cycloadditions involve the benzene oxide, as shown by the Diels-Alder reaction with activated al-kynes, and give the epoxybicyclo[2.2.2]octatriene 9 or, in the presence of singlet oxygen, afford the peroxide 10. The latter isomerizes thermally yielding the ra .s-benzene trioxide 11 ... 

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