Benzoxepin reaction

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... 

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... 

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... 

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. 

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... 

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. 

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-... 

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... 

Benzoxepin undergoes addition of bromine and chlorine to give l,2-dibromo-l,2-dihydro-3-benzoxepin (2 a) and 1,2-dichloro-l, 2-dihydro-3-benzoxepin (2b), respectively.93 The bromination reaction of dimethyl 3-benzoxepin-2,4-dicarboxylate takes the same course to give 2c.91... 

The reaction of 3-benzoxepin with methyllithium results in the addition of two equivalents of the organometallic reagent and cleavage of the heterocycle. After hydrolysis l-[2-(Z)-prop-l-enyl)phenyl]propan-2-ol can be isolated, but no experimental data is available.216 Occasionally, a small amount of the tran.v-isomcr is obtained (less than 10% of the product).12... 

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. 

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... 

Benzoxepins require drastic conditions for the thermal rearrangement to naphthols. When 3-benzoxepin-2,4-dicarboxylic acid is heated to 300 C, a decarboxylation reaction takes place and 3-hydroxynaphthalene-2-carboxylic acid (10) is formed in 44% yield.91... 

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... 

A new and useful route to the 3-benzoxepin-2-one 64 involved coupling of the Fischer carbene 65 to the epoxy phenylacetylene 62 to give 64 (46%) via 63. An epoxyvinylcarbene complex is proposed for the initiation of the reaction followed by CO insertion and cyclisation <06H(67)233>. 

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). 

Benzoxepin (27) has been synthesized from phthalaldehyde and a bis-phosphonium salt by a double Wittig condensation reaction as shown in equation (50) (66CB634). 

The palladium catalysed sequential alkylation-alkenylation of 5-iodoquinoline leads to the formation of the quinolooxepin ring system (5.20.), The process, closely related to the Catellani reaction,19 runs through an ort/zo-alkylation - Heck reaction sequence. The preparation of a series of benzoxepines has also been achieved in this manner, starting from such iodobenzene derivatives, where one of the or/7 o-positions was blocked by substitution.20... 

The synthesis of the benzoxepin (167) involves an intramolecular Wittig reaction (Scheme 19) (68JOC2591). 

Z)-Styryloxiranes 154 undergo a thermal ring expansion reaction to give carbonyl ylides 155, which cyclize to 2,7-dihydro-3,4-benzoxepines 156 (Scheme 47) (79TL4049 85CB4035). 

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. 

The halogens in o-bromo- or o-iodo-veratric acids are replaced by ketone enolates to give primary products which on lactonization or lactamization lead to benzazepines or benzoxepines respectively.126 There would appear to be no reason why this reaction could not be extended to reactions of o-halo-phenylacetic acids in general. 

Iodobenzyl propargyl ether 57 cyclizes with 7t-allylpalladium (Scheme 18) to form after trapping by a secondary amine tetrahydro-2-benzoxepines 58 in 70% yield. The piperidino derivative 58 (R2 = (CH2)5) undergoes Diels-Alder reaction with 4-phenyl-l,2,4-triazole-3,5-dione as dienophile to give a spiro derivative 59 in 44% yield <1996TL6565>. 

Benzoxepin-5-ones are formed (Scheme 44) by the insertion of a two-carbon fragment into phthalides by reaction with prop-2-ynylmagnesium bromide <1996CC19>. 

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