Oxepin ring system

In their prominent synthesis of brevetoxin B, Nicolaou et al. have investigated, among some other methods for construction of oxepine ring system, the reductive cyclization of keto alcohol 37 with triethylsilane and trimethylsilyl triflate giving oxepane 38 (Equation 12) <1995JA1173>. 

Ch. 3. Oxepin Ring Systems Containing Three Rings... 

Six-membered carbocycles often play the role of starting materials in the construction of the oxepin ring system however, for many syntheses rather stable intermediates of a different nature are known, for example those with fused six-membered carbocycles and three-membered oxygen heterocycles. The use of such systems is described in the next section. Here, several other transformations are mentioned. Some of them also may have heterocycles as intermediates but the latter are unstable under normal conditions or their structures were not studied in detail. 

The preference of 2,7-disubstituted oxepins for this tautomeric form at equilibrium may be rationalized in terms of a steric substituent effect. The eclipsing interactions of the 2,7-substituents in the arene oxide form will be diminished by isomerization to the oxepin. When the 2,7-substituents form part of an annelated ring system, e.g. (22)-(24), the tautomeric preference will be determined by the size of the methylene bridge (67AG(E)385). Thus when n = 5 the annelated oxepin (24) was present in approximately equal proportions with the arene oxide form. However with n =4. (23) tetralin 9,10-oxide was dominant. The... 

Oxepin (25) was not observed since this structure would incorporate the antiaromatic cyclobutadiene ring system, i.e. the arene oxide tautomer appeared to be formed exclusively <74AG(E)277>. 

Thiepin (44), like oxepin (Section 5.17.1.2), is a member of the 87r-electron series. While oxepin (7) has been synthesized, isolated and characterized at ambient temperature, the sulfur analogue, thiepin, is a highly unstable structure which has not been detected to date. The thiepin ring system may be stabilized by formation of the 1,1-oxide (45), or by fusion to an aromatic ring (e.g. 46). 

Chemical study of a marine-derived Penicillium brocae, obtained from a tissue sample of a Fijian Zyzzya sp. sponge, resulted in the isolation and characterization of three novel cytotoxic polyketides, brocaenols A-C 136, 137a, and 137b, possessing an unusual enolized oxepine lactone ring system <2003JOC2014>. 

Leyhane and Snapper have epoxidized a series of fused cyclobutenes, and the adducts were subject to thermal rearrangement leading to oxepine-containing bicyclo[5.3.0] ring systems (e.g., Scheme 13) <20060L5183>. 

Structural information in the crystalline state can be obtained directly by x-ray diffraction studies, but this method has not been used extensively in the arene oxide-oxepin series since the majority of the monocyclic arene oxide-oxepins synthesized to date have been liquids and since chemical instability at ambient temperature is a common feature of many mono- and polycyclic arene oxides. X-ray crystal structure analysis has been carried out on the relatively stable K-region arene oxides 2-4. ° Similarly, an x-ray analysis of 5, a crystalline annelated benzene oxide (which, however, exists in both arene oxide and oxepin form in solution), has been reported and indicates that the six-membered ring is almost planar. The oxepin ring in compound 6 has been shown to exist in the boat conformation both in solution and in the crystalline state. The structural information thus obtained in the crystalline state is totally consistent with the spectroscopic data and the chemical reactivity of the arene oxides in solution and has been used in theoretical studies of the arene oxide-oxepin system. ... 

In addition to the temperature, solvent, and substituent effects, a preference for either the arene oxide or oxepin form may be achieved by localization of one double bond as part of an aromatic ring system. Thus the reluctance to form a cyclobutadiene ring causes 10 to exist preponderantly as its oxide form. Naphthalene 1,2-oxide 11 is the simplest arene-oxide member in the polycyclic aromatic hydrocarbon (PAH) series and exists exclusively in that tautomeric form. In contrast, naphthalene 2,3-oxide exists exclusively as the oxepin form 12 since the C4-CS bond in the oxepin ring forms part of an aromatic ring. ... 

The cyclopropane system is a tool for inserting a methylene unit into a ring system to form a larger ring structure. Even densely functionalized pyranoids such as 161 [130,131] and cyclohexanes [132] expand into heptanoids and cycloheptanes, respectively. 1,2-C-dibromomethy-lene sugar 163 expands its pyranose ring to give oxepine 164 [133] (O Scheme 39). 

Dibenzo[h./]oxepins and dibenzo[hJ]thiepins have important medicinal uses and can be prepared by irradiation of halogeno-substituted acetophones in liquid ammonia in the presence of bases (Nagaoka). A novel 1,9-hydrogen atom abstraction occurs on irradiation of 47 to give ultimately the keto ether 48 (Mizuno et al.) and previously unknown polycyclic ring systems such as 49,... 

Benzazepine and benzoxepine ring systems showed high CNS activity and their syntheses have been reported [142]. The key step in this synthesis exploited an alternative route to form oxepine or thiepine ring systems 61 via a Pd-catalyzed cyclo-amination of 60. Overall, the best yields were achieved with Pd2(dba)3 as the palladium source, P(Z-Bu)3 as the ligand, Z-BuONa alone or with K2CO3, in toluene [142]. 

Gunther, H. P.M.R. Spectroscopy of unsaturated ring systems. II. Detection and kinetics of benzene oxide-oxepine equilibrium. Tetrahedron Lett. 1965, 6, 4085. 

The presence of oxepin rings in the aranotin structures is best explained Nieuss et al, 1968a,b) by the intervention of an arene oxide (Fig. 8) capable rapid valence tautomerism (see also Section III,B). The close biosynthetic lationship between the aranotin and gliotoxin ring systems is conveniently iiplayed in the structure of apoaranotin (24), a metabolite of A. aureus. 

The thiepin system 31 is formed quantitatively by ring expansion of the diazoacetate derivative 30 via carbene formation catalyzed by 7r-allylpalladium chloride and its intramolecular insertion[31], The 4-diazomethyl-4//-pyrane 32 is expanded to the oxepine 33 in quantitative yield with the same catalyst[32]. 

Diene moieties, reactive in [2 + 4] additions, can be formed from benzazetines by ring opening to azaxylylenes (Section 5.09.4.2.3). 3,4-Bis(trifluoromethyl)-l,2-dithietene is in equilibrium with hexafluorobutane-2,3-dithione, which adds alkenes to form 2,3-bis-(trifluoromethyl)-l,4-dithiins (Scheme 17 Section 5.15.2.4.6). Systems with more than two conjugated double bonds can react by [6ir + 2ir] processes, which in azepines can compete with the [47t + 27t] reaction (Scheme 18 Section 5.16.3.8.1). Oxepins prefer to react as 47t components, through their oxanorcaradiene isomer, in which the 47r-system is nearly planar (Section 5.17.2.2.5). Thiepins behave similarly (Section 5.17.2.4.4). Nonaromatic heteronins also react in orbital symmetry-controlled [4 + 2] and [8 + 2] cycloadditions (Scheme 19 Section 5.20.3.2.2). 

Thiepin, as a seven-membered conjugated system with sulfur as heteroatom, is a member of the 8 7t-electron heteroannulenes which are antiaroinatic according to Hiickel s rule. In contrast to oxepin, thiepin is not stable at room temperature and no valence isomerism with an arene sulfide has been observed. Stable thiepins are obtained only when two bulky substituents, e.g. /ert-butyl, are introduced into positions 2 and 7. In benzothiepins the annellation effect of the aromatic rings contributes decisively to the stability of these compounds stability increases with an increasing number of fused benzene rings. 

Eberbach has shown that pyrolysis of the system 39, in which both A and B represent benzene rings, the product is the stable dihydrodibenzo[c,e]oxepine 40, (A,B = benzo), in which the intermediate ylide undegoes a 1,7-electrocyclisation followed by a [1,5] H shift (Scheme 9) <85CB4035>. This work has now been extended by Sharp to include systems where B is a thiophene or pyridine, offering a route to the corresponding thieno- and pyrido-benzoxepines <96JCS(P1)515>. 

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