1- Benzoxepin

Pyridazine fV-oxides react with benzyne to give a mbcture of 1-benzoxepin (129) and arylpyridazine (130), while fV-acetylpyridaziniumimide forms a cycloadduct (131) which is further transformed into (132) and (133) (Scheme 44). 

Benzoxepin, 2,3,4,5-tetrahydro-applications, 7, 590 bond fission, 7, 549 synthesis, 7, 577... 

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. 

The reaction of pyridazine 1-oxide or 3- and/or 6-substituted pyridazine 1-oxides with benzyne gives 1 -benzoxepins 2 in variable yield. As byproducts, the respective 3-(2-hydroxyphenyl)pyrid-azines 3 can be isolated in 0-20% yield.88... 

Intramolecular Wittig reaction of [2-hydroxy-3-(2-formylphenoxy)propyl]triphenylphos-phonium bromide with sodium ethoxide gives 1-benzoxepin (2) as minor product only (5%) and 2-(allyloxy)benzaldehyde (40%).96... 

Oxa-4,5-benzotricyclo[4.1.0.02-7]heptene was readily converted to 1-benzoxepin (1) on treatment with silver(I) perchlorate. Dicarbonylrhodium chloride dimer or j3-allylpalladium chloride dimer can also be used as catalyst. Thermolysis of the starting material in carbon tetrachloride solution gives 2a,7b-dihydrocyclobuta[6]benzofuran (2) as a new isomer. Depending on the temperature the proportion of 2 varies from 50% (150°C) to 100% (225°C).110... 

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 dehydrohalogenation reaction has been extended to benzannulated oxepins. Elimination of hydrogen bromide from 3-bromo-4-phenyl-2,3-dihydro-l-benzoxepin with 1,5-diazabicyclo-[4.3.0]non-5-ene gives 4-phenyl-1-benzoxepins 15a15 and 15b16 in low yield. 

Alternatively, the hydroxy group can be converted to the tosyl ester168 or replaced by chlorine108,169 followed by a base-catalyzed elimination. 1-Benzoxepin-5-(4//)-one is reduced with cerium(III) chloride/sodium borohydride to the hydroxy derivative. After conversion to the p-toluenesulfonate, the double bond is formed in 2 upon treatment with potassium tert-pen-toxide.168... 

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 ketones 1 and 3, or compounds with a similar structure, have been used for the preparation of methoxy derivatives of 1-benzoxepin. In the standard procedure for methylation, the 1-benzoxepinone is deprotonated by potassium tert-butoxide and subsequently reacted with methyl fluorosulfonate at low temperature.16 173 - 175 The yields are generally high. 

Phcnyl-l-benzoxepin-3,5(2//,4//)-dione undergoes stepwise acetylation or methylation under appropriate conditions.174 This allows 1-benzoxepins 7 to be synthesized with differently protected oxygen functions. 

Substituted 1-benzoxepins can be obtained by the cycloaddition of activated acetylenes to the benzofuran system. When 2-(Af-mcthylanilino)benzofurans is treated with dimethyl acetylene-dicarboxylate, substituted 1-benzoxepins 1 are obtained in reasonable yield.180,181 This reaction presumably involves a 2a,7b-dihydrocyclobuta[6]bcnzofuran as an intermediate (see Section 4.2).182... 

The 2a,7b-dihydrocyclobuta[7>]benzofuran structure, obtained by addition of activated acetylenes to benzofurans (see Houben-Weyl, Vol.E6b, p 148), isomerizes thermally to a 1-benz-oxepin182 184 185 which reacts further to 1-naphthol derivatives at higher temperature182,185 (see Section 1.2 ). Under photochemical conditions, the 1-benzoxepins undergo ring contraction to the starting material.182 184... 

This reaction can also be used for the synthesis of substituted 1-benzoxepins with one modification instead of the 4/T-benzopyran the 2/7-isomer must be used. 2-[Diazo(phosphoryl)meth-yl]-2//-benzopyrans decompose in the presence of ))3-allylpalladium chloride dimer with elimination of nitrogen to give 1-benzoxepins 2.192 In some cases, the reaction takes a different course and gives 2-methylene-2//-benzopyrans 3.192 In this respect, the bicyclic system behaves differently to the monocyclic diazo(pyranyl)methane. The 2-isomers of the latter structure could not be isolated and gave l//-l,2-diazepines.190 The 4//-benzopyrans do not form benzoxepins but undergo an intramolecular [2+1] cycloaddition to 3,4-dihydro-2,3,4-metheno-2//-ben-... 

Transition-metal complexes such as [Rh(CO)2Cl]2,204 Rh(butadiene)2Cl,205 or Cr(CO)3(NH3)312 have also been used for the deoxygenation of oxepins to give 312,204 205 and benzoxepins to give 4.12,204 Occasionally, substantial amounts of phenolic compounds have been isolated due to the competing NIH shift of the arene oxide.204 1-Benzoxepin and 3-benzoxepin resist oxygen extrusion under these conditions probably due to their inability to form arene oxi-des.133,204... 

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. 

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. 

Benzoxepins are capable of rearranging to naphthalene derivatives 4 and 5 under thermal conditions.182,185,246,247 When 3,5-diacetoxy-4-phenyl-l-benzoxepinis heated to 150°C a mixture of 1- and 2-naphthol derivatives 4a and 5a is obtained due to the intramolecular acetylation of the reactive intermediate.246... 

Some thermal rearrangement reactions of 1-benzoxepins show the participation of the solvent in the formation of stable products, e.g. 6172,247 and 7.177 The synthesis of methoxy-substituted 1-benzoxepins by O-methylation of the anions generated by the deprotonation of the respective oxo derivative with ferf-butoxide is often limited by the rapid aromatization to methoxy-substituted naphthalenes, e.g. 816 and 9,173 under the reaction conditions.16,173... 

The light-induced reaction of pentacarbonyliron with oxepin or 2,7-dimethyloxepin results in the formation of small quantities (3-5 %) of a tricarbonyliron complex of the seven-mem-bered heterocycle.253,251 The main products are benzene (o-xylene) and phenol (2,6-dimethyl-phenol). When 1-benzoxepin is treated with pentacarbonyliron, the tricarbonyliron complex is obtained in 22% yield.254... 

Benzoxepin, 55, 89 Benzoyl chloride, 55, 123 Benzyl chloride [Methyl chloride, phenyl-], 55,94... 

Pyridazine A-oxides undergo 1,3-dipolar addition with benzyne and a number of its analogues to form adducts which, with loss of nitrogen, form 1-benzoxepines and this work has now been extended to 1,2,4-triazine 1-oxides. In this case the product is 1,3-benzoxazepine <96H(43)2091>. 

A tandem palladium-catalysed ort/io-alkylation/intramolecular Heck reaction coupling sequence was used effectively to access in fair yields the tetrahydro 1-benzoxepines 67 from the iodoaryl precursor 66 and the appropriate alkyl bromide. The norbornene plays a relay role in the proposed reaction cycle <06JOC4937>... 

This reaction is directly analogous to that found with 1-benzoxepin and the valence tautomeric cyclobutene product obtained from (46) and was formed by a concerted disrota-tory ring closure mechanism. 

Benzoxepins are frequently synthesized by cyclization of alkyl aryl or diaryl ether precursors. An intramolecular Wittig reaction (equation 48) is used to provide the ring closure step in the synthesis of 1-benzoxepin (28) (68JOC2591). An internuclear cyclization reaction of an aromatic sulfonyl chloride (equation 49) occurred upon heating (250 °C) in the presence of a copper chloride catalyst to yield tribenz[6,d,/]oxepin (175). The analogous thiepin (see equation 71) may also be synthesized by this route (65T1299). 

The acid-catalyzed ring expansion of a spiroepoxide (equation 58) also yielded only the keto tautomer of a 1-benzoxepin. The enolic form of the oxepin in this example however was stabilized by conversion to the diacetate (194) (69CB205). 

A further development of this route (71JOC4028), involving the cyclization of 3-(o-formylphenoxy)propyltriphenylphosphonium salts in methanol, has led to high yields of 2-methylchromene. In the detailed mechanism which has been proposed, an o-quinoneallide is considered to arise by the ring opening of an initially formed benzoxepin derivative. Indeed, 2,3-dihydro-1-benzoxepin is the major product of the reaction in aprotic solvents. 

---