3-Benzoxepines

Cyclic lactone 125 has been observed as the only minor product of reduction of ketone 124 under thermal conditions. Stepwise reaction under mild conditions 

Pyrrolidinone 126 and salicylic aldehyde in acetic acid under microwave irradiation gives in dioxopyrrolo[3,4-c]benzoxepine 127 as a mixture with phenyl chromeno[2,3- ]pyrrole 128 (8 and 13% yields, correspondingly. Equation (18) 

An alternative method for benzoxepine ring assembly uses the formation of cyclic ethers. Thus, benzoxepino[4,3-f ]indole 130 can be synthesized by the treatment of the keto-alcohol 129 with hot alcoholic base to produce the product in 90% yield as a result of intramolecular nucleophilic substitution (Equation (19) (1993AX(C)2126)). 

The synthesis of cyclic ethers 137 was achieved by a Fischer indole synthesis starting from cyclic keto arylhydrazones generated in situ from 4-(hydroxy-methylene)-3,4-dihydrobenzo[ 7]oxepin-5(2H)-one 136 and the corresponding diazonium salt (Equation (20), 1993JHC1481). 

A peri-fused system can be synthesized by diaryl copper-catalyzed ether coupling accomplished utilizing (CuOTf)2 PhMe in pyridine (Equation (21) (2004JOC4527)). This protocol produces several annulated ring systems and gives 

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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... 

Benzoxepin-4-carbaldehyde, dihydro-from chromones, 3, 713 Benzoxepin-4(3H)-one from isochromanone, 3, 726 [l]Benzoxepino[3,4-d]selenazoles synthesis, 6, 345 Benzoxepins... 

However, the presence of a fused benzene ring was found to hmit the scope of this type of ring expansion severely. Thus the dichloro-carbene adducts of both 2H- (33) and 4H-chromen (34) failed to rearrange to 2,3-benzoxepines (35) on heating. Although some... 

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... 

The reaction of phthalaldehyde and diethyl oxydiacetate in the presence of potassium tert-butoxide gives, with hydrolysis of the ester function, 3-benzoxepin-2,4-dicarboxylic acid (2a).89 The reaction of the dimethyl ester lb gives dimethyl 3-benzoxepin-2,4-dicarboxylate (2 b) when... 

Methylenedioxy)phthalaldehyde was converted with dimethyl oxydiacetate to the corresponding 3-benzoxepin derivative 3.92... 

Benzoxepin (4) was obtained in 55% yield by the reaction of phthalaldehyde with the bis-ylide generated from the bis(triphenylphosphonium) salt prepared from bis(bromomethyl) ether and triphenylphosphane.93,94... 

V-[2-(3-Phenylprop-2-ynyloxy)benzylidene]isopropylamine (the structure in ref 95 is incorrect) undergoes a cyclization reaction to A -isopropyl-4-phenyl-l-benzoxepin-5-amine (1, 52% yield) when treated with butyllithium. 2-(Phenylethynyl)benzofuranis formed as a byproduct (4%).95... 

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... 

When the analogous starting material without the hydroxy group was used, 2,3-dihydro-l-benzoxepin was obtained in low yield (8%). The main product (87%) was 2-methyl-2//-chromene.97... 

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... 

An additional benzannulation over the C6-C7 bond of the oxaquadricyclane also allows this thermal rearrangement to the 3-benzoxepin system.133... 

Direct irradiation of substituted 1,4-dihydro-1,4-epoxy naphthalenes gives small quantities of 3-benzoxepins 16 amongst other products.144 146,256 The primary product of this reaction is probably a 3-oxaquadricyclane derivative which can react to give the benzoxepin under thermal conditions. The formation of benzoylindene compounds as the main products from the photochemical rearrangement of l,4-diphenyl-l,4-dihydro-l,4-epoxynaphthalenes has been shown to proceed via the corresponding 3-benzoxepins.146 The irradiation of naphthalene 1,4-oxides in the presence of a photosensitizer did not lead to benzoxepin derivatives.144... 

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. 

Dichloro- and l,2-dibromo-l,2-dihydro-3-benzoxepins are dehalogenated with zinc in methanol to give 3-benzoxepin (6a) in excellent yield.93 A methoxycarbonyl group in the 2-position, however, diminishes the yield of 6b considerably.91... 

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... 

Irradiation of anft -9,10-epoxy-1.4-dipropyl-l,4-dihydro-l,4-ethanonaphthalene-2,3-dione results in a stepwise loss of two carbonyl groups and the formation of l,5-dipropyl-3-benzoxepin as the major product (25%).171... 

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. 

The different reactivity of the ketone functions has also been demonstrated by the reaction of 2,7-dimethyl-4-phenyl-l-benzoxepin-3,5(2f/,4//)-dione with diazomethane which gives a mixture of the two monomelhylated products 10 and 11. In both compounds, the second methyl group is introduced by deprotonation with potassium tm-butoxide followed by the addition of methyl fluorosulfonate.177... 

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... 

Dimethyl 7-Hydroxy-2-(jV-methylanilino)-l-benzoxepin-3,4-dicarboxylate (1 a) Typical Procedure 181... 

In a similar reaction, but with reversed polarities in the starting materials 3-nitrobenzofuran adds to l-phenyl-2-pyrrolidinoacetylene to afford a mixture of three components, one being 5-nitro-3-phenyl-2-pyrrolidino-l-benzoxepin (3, 27 %).183 In the first step of this reaction, a bond between C2 of the furan and the carbon atom in the a-position to the phenyl group is formed to produce a dipolar intermediate that can react in different directions. 

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... 

The oxidation of 1,4-dihydronaphthalene with oxygen with irradiation gave l,2-dihydro-2-naphthyl hydroperoxide that decomposed thermally to 3-benzoxepin (3).189... 

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-... 

The enamine function in dimethyl 5-pyrrolidino-l-benzoxepin-3,4-dicarboxylate can be hydrolyzed to the corresponding l-benzoxepin-5-ol 1 by treatment with hydrochloric acid.182... 

When dimethyl 3-benzoxepin-2,4-dicarboxylate is reacted under controlled conditions (15 min) with hydrogen it is possible to isolate dimethyl l,2-dihydro-3-benzoxepin-2,4-dicarboxylate.17 Hydrogenation of 2-nitrodibenz[, /]oxepin-10-carboxylic acid in the presence of palladium on potassium carbonate results in the reduction of the nonaromatic C C double bond and the nitro group to give 2-amino-10,l l-dihydrodibenz[i,/]oxepin-10-carboxylic acid.107... 

When 2,7-dimethyloxepin is treated with potassium in liquid ammonia at — 70 C, a mixture of oct-4-en-2-one (1) and octa-4,6-dien-2-one (2) in a ratio of 75 20 is obtained.203 The major product can be separated by preparative gas chromatography in 23% yield. The analogous reaction of 3-benzoxepin gives, in 30% yield, a mixture of (2-cthylphenyl)acetaldehyde (3) and (2-ethynylphenyl)acetaldehyde (4) that resists separation.203 The Latter product can be formed exclusively in 17% yield when 3-benzoxepin is treated with sodium amide in tetra-hydrofuran at 33 C for 210 minutes.203... 

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