Oxepin structure

Another application of this method is the synthesis of 5,10-epoxy[10]annulene (7) from 2,3.6,7-tetrabromo-4a,8a-epoxydecahydronaphthalene.152-154 The byproduct is 1-benzoxepin (8). The 5,10-cpoxyannulcnc (7) incorporates the oxepin structure. The annulene can be converted to 1-benzoxepin by proton catalysis.153154... 

The oxidation of diethyl 3,6-hexanooxepin-4,5-dicarboxylate with a mixture of sodium periodate and potassium permanganate as oxidizing agent gives diethyl 3-[(formyioxy)methylene]-l 0-oxocyclodec-l-en-l,2-dicarboxylate (2) in 91 % yield.130 A minor modification of the reaction conditions gives two products 2 (35 %) and a product which retains the oxepin structure (23 %) identified as the same lactone described in Section 1.2.1.1.129... 

Bromine can also undergo addition to the nonaromatic double bond of dibenz[ft,/]oxe-pin.160,161 Oxygen-bridged annulenes that incorporate an oxepin structure have been shown to undergo 1,4-addition of bromine at — 78°C.159... 

Benzoxepin with a stabilized oxepin structure also undergoes addition of singlet oxygen to give the endoperoxide 5,220 which is stable and can be isolated in good yield. 

In 1-benzoxepins the benzene oxide form is energetically unfavorable. Thus, the adducts 5 formed with dienophiles such as ethenetetracarbonitrile arise from the oxepin structure with the nonaromatic double bonds as diene fragment.233 The yields of these reactions arc almost quantitative. 

The aromatization of the oxepin structure can be accompanied by other acid-catalyzed reactions such as the hydrolysis of ketals. Dimethyl 11 -oxo-6-oxabicyclo[5.4.0]undeca-l (7),2,4-triene-2,3-dicarboxylate ethylene ketal reacts in the presence of trifluoroacetic acid to give the tetralone system 3.133... 

For compound (151 R = Me or Ph), the base peak arises from an [M-HI]t ion. The molecular ion from the parent compound is not observed. Metastable ion peaks aided the elucidation of the fragmentation pathways which are outlined in Scheme 25. The [M—HI] ion (151a) may possess either a methylene pyran or an oxepin structure. Further decomposition of this ion occurs by loss of a hydrogen radical. Expulsion of a methyl radical from (151a) generates (151b) which decomposes as shown (Scheme 25). 

When attempts were made to prepare 102, a red brown 2-acetyloxepin (158) was obtained. The NMR spectrum showed very little change with temperature and was consistent only with oxepin structure 158. ... 

Compound 162 is colorless and in isooctane possesses a UV spectrum of the cyclohexa-1,3-diene type, with a maximum at 258 nm (e = 4900). The reference for the oxepin structure is 157, which has a broad band at 297 nm (e = 1800) in isooctane. When the solvent polarity is increased or the temperature is lowered, the equilibrium shifts clearly from the oxepin to the epoxide form.8... 

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. 

Amongst natural products, the oxepin structure occurs only in senoxepin 19, a norsesquiterpene lactone of the groundsel Senecio platiphylla its structure has been established by synthesis [8]. Hydrogenated oxepins and oxepanones are often found in natural products, e.g. in the alkaloids strychnine (20, R = H) and brucine (20, R = OCH3), and in the brassinosteroids, e.g. the growth regulator brassinolid 21. 

Amongst natural products, the oxepin structure occurs only in senoxepin (23), a norsesquiterpene lactone of the groundsel Senecio platiphylla its structure has been established by synthesis [10]. 

Two reactions dominate the chemistry of arene oxides the first which has been discussed above is their facile conversion to phenols and the second is their valence bond tautomerism to oxepins. Circumstantial evidence for the role of an aromatic epoxide type of intermediate (119) in the biosynthesis is provided by the location of two oxepin structural units in the related metabolite arantoin (113). The origin of these rings has been plausibly attributed to valence bond tautomerism of an L-phenylalanine epoxide Figure 4.18) and some experimental data to support this suggestion has been obtained by Brannon, Mabe, Molloy and Day . These workers showed that [ Hs]-L-phenylalanine was readily incorporated into acetylarantoin in Aspergillus terreus and contributed seven (or fourteen) hydrogen atoms to the molecule. In this case, in... 

The fluorescence spectrum of dibenz[7>,/]oxepin shows that this molecule adopts a planar structure in the excited state whereas the ground state has bent geometry as expected.19 The emission spectrum is similar to that of anthracene. 

An acetyl group in the 2-position favors the monocyclic structure presumably because of the resonance stabilization.12 The same observation was made with oxepin-2,7-dicarbaldehyde, oxepin-2,7-dicarboxylic acid, and oxepin-2,7-dicarbonitrile.23 Substituents in the 4- and 5-positions of the oxepin such as methyl or methoxycarbonyl groups shift the equilibrium towards the epoxide.12 24 Low temperature 1H NMR studies on 7-ethyloxepin-2-carbonitrile and ethyl 7-ethyloxepin-2-carboxylate established a nonplanar boat geometry with a ring-inversion harrier of 6.5 kcal mol-1.25... 

X-ray structures of 2,7-uiphenyloxepin,34 3,7-di-te/7-butyl-5-phenyl-2-(4-tolyl)oxepin,35 and tert-butyl oxepin-2-carboxylate25 and various 3,6-alkanooxepin derivatives36-38 confirmed a nonplanar boat geometry that had already been assumed from spectroscopic data. 

Oxepin is the Hantzsch-Widman name for a seven-membered unsaturated heterocycle with one oxygen atom and the numbering follows the convention for monocyclic heterocycles. However, the isomeric benzene oxide has different numbering in agreement with the 7-oxabi-cyclo[4.1.0]hepta-2,4-diene structure, position 1 now corresponds to position 2 in the oxepin. 

The three different benzoxepins are simply assigned by the position of the oxygen 1 -benzoxepin, 2-benzoxepin, 3-benzoxepin. Among the four possible dibenzoxepins only dibenz[6,d]oxepin and dibenz[6,/]oxepin are of importance whereas the two other isomers are only of theoretical interest because they contain unfavorable o-quinoid structures. Benzannulation across all of the C-C double bonds leads to tribenz[6,rf,/]oxepin. 

Thermolysis of 3-oxaquadricyclanes in which the bond between Cl and C2 is part of a cyclohexane structure gives a,/J-annulated oxepins 11 in good yield.133 The enlargement of the an-nulated ring favors the arene oxide structure.134... 

Direct acid-catalyzed dehydration of 2,3,6-trimethoxy-6,l l-dihydrodibenz[6,/]oxepin-1()-ol leads to a mixture of the corresponding dibenz[b,/]oxepin and the rearranged alcohol with a 9/7-xanthene structure.262... 

Due to the nonaromatic character of the oxepin system the oxepinones do not usually form stable enol structures. By O-acylation or O-alkylation, however, the enol forms can be stabilized as enol esters and ethers, respectively. A large number of substituted 1-benzoxepins have been synthesized by this route. Acetylation of l-benzoxepin-3(2//)-ones 1 and l-benzoxepin-5(2/T)-ones 3 was readily achieved with acetic anhydride in the presence of an appropriate base such as pyridine, triethylamine or sodium acetate.t5,t6 t72 176... 

The pharmaceutical interest in the tricyclic structure of dibenz[6,/]oxepins with various side chains in position 10(11) stimulated a search for a convenient method for the introduction of functional groups into this position. It has been shown that nucleophilic attack at the carbonyl group in the 10-position of the dibenzoxepin structure renders the system susceptible to water elimination. Formally, the hydroxy group in the enol form is replaced by nucleophiles such as amines or thiols. The Lewis acids boron trifluoride-diethyl ether complex and titanium(IV) chloride have been used as catalysts. 

The nonaromatic character of oxepins makes this structure susceptible to the reduction of one or more double bonds. 10-[(2-Aminoethyl)sulfanyl]-substituted dibenz[b,/]oxepins with various substituents in position 2 smoothly react to give the 10,1 l-dihydrodibenz[b,/]oxepin system 1 on treatment with magnesium in methanol.71 202 The advantage of this method is the possibility of reducing dibenz[b,/]oxepins with various heteroatoms such as sulfur, oxygen or nitrogen in the side chain. 

A variety of substituted oxepins and 1-benzoxepins can be converted to 2-oxabicyclo[3.2.0]hep-tadiene structures 2208 and 388-174.i82,i92.208-2ii irracjiation. 

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). 

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... 

Occasionally, addition products of 4//-l,2,4-triazole-3,5-diones or diazenedicarboxylic esters and oxepins have been obtained whose formation can be rationalized by an addition to the 2,4-diene system in the oxepin, e.g. formation of 10.190191 In these cases, the primary adduct usually cannot be isolated, because it undergoes a hetero-Cope rearrangement to a tricyclic or bicyclic structure in which the oxepin oxygen has become part of a carbonyl function.190 191,227... 

Methyl-7-(trimethylsilyl)oxepin and 4-methyl-4//-l,2,4-triazole-3,5-dione as dienophile undergo a Diels-Alder reaction in which the 4,6-diene structure of the seven-membered ring react. Contrary to the aforementioned reactions, the primary adduct 12 is stable and does not rearrange to a carbonyl compound.222... 

The equilibrium between oxepin and benzene oxide created interest in performing Diels-Alder reactions trapping one or both isomeric structures.1 The reaction of maleic anhydride or maleic imide with oxepin and substituted derivatives gives products 1 derived from the addition of the dienophile to the benzene oxide structure.2-l4-126 14 9 156 158 228 231-259... 

Irradiation of 3,6-bridged oxepins with ester functions in the 4- and 5-positions gives tricyclic structures 3 in which the oxepin oxygen becomes part of an aldehyde function.248-250 When chiral esters are used, it has been shown that the irradiation in solid state proceeds with a high degree of diastereoselectivity.249,251,252... 

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