Benzo oxepines

Synthesis of an antifungal natural benzo[ ]oxepine derivative, pterulone 17 (Scheme 6), demonstrates some reactions of dihydrooxepines. The target product is formed as a mixture of (E)- and (Z)-isomers (1 3) however, the latter... 

Benzoxepine derivatives, perilloxin 143 and dehydroperilloxin 144, were isolated from the plant Perilla frutescens var. acuta <2000JNP403>. Suitably designed mono- and bis-benzo[ ]oxepines were described as nonsteroidal estrogens <2003BMC5025>. 

Scheme 21 2,3-Dihydrobenzofurans, chromans, and 2,3,4,5-tetrahydro-benzo[ ]oxepines by sequential ort/zo-alkylation-vinylations [75,76]...

Oxo-benzo[b] benzofurano[26-e] oxepin Sulfuric acid Fumaric acid... 

The mixture was heated under reflux and a solution of 0.2 g of ethyl iodide in 5 ml of dry tetrahydrofuran was allowed to flow into the reaction medium. When the reaction started, a solution of 6.2 g of 7heated under reflux until the complete disappearance of the magnesium turnings. The reaction medium was then cooled in an ice bath, after which there was added thereto a solution in 45 ml of tetrahydrofuran of 7 g of 6-oxo-benzo[b] -benzofurano[2,3-e] oxepin. The reaction mixture was allowed to stand for 20 hours at a temperature of 20°C, and was then poured into a saturated aqueous solution of ammonium chloride maintained at a temperature of 5°C. The mixture was extracted with ether and the organic portion was washed and dried over anhydrous sodium sulfate. After evaporation of the solvent, 9.4 g of crude product were obtained, which after recrystallization from isopropanol, provided 6.7 g of pure 6-(3-dimethylam nopropyl)-8-hydroxybenzo[b] benzofurano-[2,3-e] oxepin, melting point 160°C (yield, 71 %). 

Benzo-annulated dihydrooxepinones are readily accessible (see Houben-Weyl, Vol. 6/4, pp453) and can be converted to the corresponding hydroxy derivatives by reduction of the ketone function. The elimination of water from 10,ll-dihydrodibenz[fc,/]oxepin-10-ol to give 1 was accomplished with /t-toluenesulfonic acid.165-167... 

Hydrogen usually adds to benzo-annulated oxepins in the presence of noble-metal catalysts such as platinum or palladium with saturation of the nonbenzenoid C-C double bonds to give 6152,154 and 7.17-89-93... 

Substituted and benzo-annulated oxepins readily undergo addition of bromine across the nonaromatic double bond. Bromination of 3,6-bridged oxepins can occur in two different ways, either as a 1,2-addition164 or as formal 1,4-addition to the diene system of the corresponding benzene oxide to give products i.129 138-140 164... 

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>. 

Bromomethyl-3,4-dibromo-3,4-dihydrocoumarin 1 (Fig. 11.4) and its chloro-methylated analogue 2b rapidly and progressively inactivate a-chymotrypsin and also the activities of a series of trypsin-like proteases. A benzyl substituent characteristic of good substrates of a-chymotrypsin was introduced at the 3-position to make inhibition more selective. This substituted dihydrocoumarin 3 irreversibly inhibited a-chymotrypsin and other proteases. These functionalized six-membered aromatic lactones, and their five- and seven-membered counterparts, 3//-benzofuran-2-ones 2a26 and 4,5-dihydro-3//-benzo[b]oxepin-2-ones 2c,27 were the first efficient suicide inhibitors of serine proteases. Their postulated mechanism of action is shown in Scheme 11.2. 

Another photocyclization to a benzo[c]phenanthridine was reported (127). Oppenauer oxidation of ( )-ophiocarpine (92) with potassium fm-butoxide and benzophenone in dioxane effected C-6—N bond cleavage to afford the hydroxyisoquinoline 219 via berberinephenolbetaine (121) (Scheme 39). Although photolysis of 219 gave only the oxepine 221, that of its methyl ether 220 furnished directly norchelerythrine (222) through electrocyclization followed by spontaneous elimination of methanol. 

Summary of synthetic routes to benzo-, mono- and di-substituted Oxepins 583... 

Oxepanes, Oxepins, Thiepanes and Thiepins Table 8 Synthetic Routes to Benzo-, Mono- and Di-substituted Oxepins... 

Kormniiller et al., 1997 b). For example, in the ozonation of the five ring condensed benzo(e)pyrene this was confirmed by the oxidation products being formed a secondary ozonide and oxepinone (hydroxytriphenylenol[4,5-cde]oxepin-6(4H)-one), which are specific for an ozonolysis (Kornmuller and Wiesmann, 1999). 

HMO calculations, based on localized polyenes instead of isolated alkenes, can account for the heats of atomization of furan (41.64 observed, 41.69 eV) and of dibenzofuran (109.09 observed, 108.92 eV). For resonance energies (quoted as resonance energy per electron, REPE) they give furan, 0.007 oxepin, -0.006 benzo[6]furan, 0.036 benzo[c]furan, 0.002 and dibenzofuran, 0.047 /3 (72T3657). That furan emerges as hardly more aromatic than a diene while pyrrole (REPE 0.039/3) is clearly aromatic is in line with other results, including those from MINDO/3 and topological methods (see Section... 

The very low aromaticity of benzo[c]furan is also in line with other estimates, and the antiaromaticity of oxepin is not surprising. However, charge distributions and dipole moments remain inaccurate. 

Benzofnran 3-Methy -l-methylen-1,3-dihydro- VI/3, 644 Benzo-7-oxa-bicyclo 4.1.0 hept-2-en E13/2, 1267 (Epoxygenierung) E21e, 4679 (Epoxygenierung) 2H-l-Benzopyran, 2-Methylen-3,4-dihydro- E15/1, 149/152 [R-COOR + Ti CH2 —Al] l-Ben/oxepin 2,3-Dihydro- VI/4,465 1,2-Bntadien... 

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