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A new prenylated 3-benzoxepin derivative, elsholtzioxin (1), together with fifteen known compounds (2–16) were isolated from the whole parts of Elsholtzia penduliflora. Their structures were elucidated on the basis of various spectroscopic techniques and chemical evidences. The antiviral activities of these compounds were evaluated in vitro. The new compound (1) exhibited potential anti-influenza virus activity against strain A/WSN/33/2009 (H1N1) with inhibition rate of 47.19%. Compounds 2, 9 and 12 exhibited significant inhibitory activities with IC50 value of 26.16, 34.66 and 20.81 μM, respectively.

A short and efficient method was developed for the synthesis of 2-benzoxepin-3(1H)-ones. The synthetic sequence comprises of initial intermolecular Heck coupling, followed by reduction of the carbonyl functionality of the Heck product and finally base-induced intramolecular condensation. Notably, the final condensation may proceed by an interesting oxy-Michael addition, cycloreversion via double bond isomerization and intramolecular condensation.

A one-pot synthesis of multisubstituted 2,3-dihydro-1H-2-benzazepin-1-ones and 3H-2-benzoxepin-1-ones by an I-MCR/Wittig sequence was developed. The reaction of phosphonium salt 3, arylglyoxals 4, amine 5 (or without), and isocyanide 6 produced the 2,3-dihydro-1H-2-benzazepin-1-ones 8 or 3H-2-benzoxepin-1-ones 10 in good yields via a sequential Ugi or Passerini condensation and intramolecular Wittig reaction in the presence of NEt3.

In this study, the synthesis of a series of novel four-fused-ring chromeno-benzoxepinones is described. The reaction of 1-benzoxepin-5-ones with salicylaldehydes mediated by 1,4diazabicyclo[2,2,2]octane (DABCO) involves domino reactions including an oxa-Michael reaction, an aldol condensation and dehydration in a one-pot sequence to yield the target compounds in fairly good yields.

Several methods for the preparation of 3,4-dihydro-1-benzoxepin-5 (2H)-ones are described. In addition to the desired ketones, a variety of novel by-products have been isolated

Thiophenol-mediated 7- endo radical cyclization for the synthesis of seven-membered cyclic ethers is described. This method can be successfully applied to synthesize various benzoxepin derivatives, which are present in many natural products as building blocks. Alkenyl radicals are generated from easily available terminal alkynes and thiophenol.

The estrogen receptors ERα and ERβ are recognized as important pharmaceutical targets for a variety of diseases including osteoporosis and breast cancer. A series of novel benzoxepin-derived compounds are described as potent selective modulators of the human estrogen receptor modulators (SERMs). We report the antiproliferative effects of these compounds on human MCF-7 breast tumor cells. These heterocyclic compounds contain the triarylethylene arrangement as exemplified by tamoxifen, conformationally restrained through the incorporation of the benzoxepin ring system. The compounds demonstrate potency at nanomolar concentrations in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity together with low nanomolar binding affinity for the estrogen receptor. The compounds also demonstrate potent antiestrogenic properties in the human uterine Ishikawa cell line. The effect of a number of functional group substitutions on the ER binding properties of the benzoxepin molecular scaffold is examined through a detailed docking and 2D-QSAR computational investigation. The best QSAR model developed for ERαβ selectivity yielded R2 of 0.84 with an RMSE for the training set of 0.30. The predictive quality of the model was Q2 of 0.72 and RMSE of 0.18 for the test set. One particular compound (26b) bearing a 4-fluoro substituent, exhibits 15-fold selectivity for ERb and both our docking and QSAR studies converge on the correlation between enhanced lipophilicity and enhanced ERb binding for this benzoxepin ring scaffold. Refereed/Peer-reviewed

[structures: see text] Two naturally occurring 3-methyl-2,5-dihydro-1-benzoxepin carboxylic acids, 6-hydroxy-3-methyl-8-(phenylethyl)-2,5-dihydro-1-benzoxepin-9-carboxylic acid (radulanin E) (1) and 9-hydroxy-3-methyl-2,5-dihydro-1-benzoxepin-7-carboxylic acid (2), were synthesized using Stille coupling followed by Mitsunobu cyclization.

The first unambiguous observation of an oxepin-2,3-oxide is reported. Between 5 and 10 °C it rearranges rapidly to its isomer 1H-2-benzopyran-1-carboxaldehyde. In contrast, 2,3-oxides of monocyclic oxepins rearrange to stable, ring-opened dialdehydes or diketones.

The synthesis and pharmacological evaluation of cis- and trans-6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ols 4a-c and 5a-c and cis- and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ols 4d-f and 5d-f were carried out. Chemo- and stereoselective synthesis of 5a-f was achieved by reduction of corresponding alpha-amino ketones 3a-f with LiAl(t-BuO)3H. cis-4-Amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 4d and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 5d exhibited marked anorexigenic activity in mice at a dose of LD50 800 and 500 mg/kg and ED50 75 and 55 mg/kg, respectively, while the analog cis-2,3-dihydroxy-6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol 8 showed typical alpha-sympathomimetic activity.

The chlorinated 1-benzoxepin derivative pterulone ( 1a ), a potent antifungal metabolite isolated from a Pterula species, was synthesised from 4,5-dihydro-2 H -benzoxepin-3-one 6 by the oxidation of 6 to 3(2 H )-oxepinone 7 , a Wittig reaction that transformed the keto functionality of 7 to a chlorovinyl group, and a Friedel Craft's acetylation. The mixture of E and Z isomers ( 1a and 1b ) obtained could transformed to pure pterulone ( 1a ) by photochemical isomerisation and separation by chromatography. The yield was 23% starting from 6 .

By treatment of sodium nitronate salts of 5-glyco-4-nitrocyclohexenes with hydrochloric acid, five new bicyclic ethers with six-membered rings fused to five-, seven-, or eight-membered rings have been synthesized; also a mechanism for their formation is proposed. Structural elucidation of the new compounds is based on spectroscopic data, as well as on their comparison with those of closely related substances.

Bioisosteric replacement of the C-6 carbon atom in piperidine I and piperazine II with S, O, and N heteroatoms is described. Amide and cyanoguanidine derivatives of these compounds were evaluated in vitro and found to be good inhibitors of farnesyl-protein transferase. An improved method of preparing the 5,11-dihydro-[1]-benzthiepin nucleus 6 was accomplished in high yield and with excellent regioselectivity using an AlCl3 melt protocol.

International audience; A series of novel benzoxepins 6 was designed and prepared as rigid-isoCA-4 analogues according to a convergent strategy using the coupling of N-tosylhydrazones with aryl iodides under palladium catalysis. The most potent compound 6b, having the greatest resemblance to CA-4 and isoCA-4 displayed antiproliferative activity at nanomolar concentrations against various cancer cell lines and inhibited tubulin assembly at a micromolar range. In addition, benzoxepin 6b led to the arrest of HCT116, K562, H1299 and MDA-MB231 cancer cell lines in the G2/M phase of the cell cycle, and strongly induced apoptosis at low concentrations. Docking studies demonstrated that benzoxepin 6b adopt an orientation similar to that of isoCA-4 at the colchicine binding site on -tubulin.

Nine 1,3,4,5-tetrahydro-2-benzoxepin derivatives have been prepared as mimics of the folded (gauche) conformation of cyclamenaldehyde (1) and related compounds, but none of them showed the typical lily-of-the valley (muguet) odour activity. However, conversion of these substances to previously unknown analogues of 1 having a Me substituent on the aromatic ring in an ortho position to the side chain led to new fragrance substances with remarkable properties. The results indicate that the extended (anti) conformation is more likely to be the ‘bioactive’ one at the receptor site(s).

A series of N-hydroxyurea derivatives based on substituted benzoxepin and benzothiepin templates was prepared and the compounds were evaluated for their ability to inhibit 5-lipoxygenase in vitro and ex vivo.

Syntheses of spiro[2,3-dihydro-4H-1-benzopyran-4,1'-cyclohexan]-2-one derivatives by reaction sequences including a radical reaction and a total synthesis of (±)-lycoramine (2) are described. Radical reactions (Bu 3 SnH, AIBN) of 1-[(1'-cyclohexenylmethyl)oxy]-2-halobenzenes 23b-d in boiling benzene gave the corresponding spiro[2,3-dihydrobenzofuran-3,1'-cyclohexanes] 26a,b in good yields, whereas the reaction of 1-(1'-cyclohexenylethoxy)-2-bromobenzene (25) under similar conditions afforded a mixture of spiro[2,3-dihydro-4H-1-benzopyran-4,1'-cyclohexane] 27 and benzoxepin 28. Furthermore, the radical reaction of ethyl 2-[(2'-bromoaryl)oxy]-1-cyclohexenylacetate 37a produced ethyl 2-spiro[2,3-dihydrobenzofuran-3,1'-cycloexane]carboxylate 38 in good yield. Compound 38 was converted to spiro[2,3-dihydro-4H-1-benzopyran-4,1'-cyclohexane]-2,4'-dione 40 by treatment with SmI 2 and then with 3 N HCl. Spiro[2,3-dihydro-4H-1-benzopyran-4,1'-cyclohexane]-2,4'-dione 40 was transformed to (±)-lycoramine (2) in four steps in 43% overall yield

By treatment of ethyl 4- or 5-substituted 2-acetylphenoxyacetates 1 with potassium hydroxide in dry dioxane, benzofurans 2–7 and 2,3,4,5-tetrahydro-1-benzoxepin-3,5-diones 8 were obtained. The relative yields of benzofurans 2–7 and 2,3,4,5-tetrahydro-1-benzoxepin-3,5-diones 8 varied with the types of 4- or 5-substituents. The electron-donating 4-methoxyl group favored the formation of benzoxepins. On the other hand, electron-withdrawing substituents such as the 4-nitro group favored the formation of benzofurans. When esters 1 were treated with sodium amide, 2,3-dihydrobenzofurans 2 were obtained exclusively regardless of 4- or 5-substituents.

cis - and trans - amino alcohols 1a and 2a and their derivatives have been synthesised and their stereochemistry studied. Stereochemical studies have shown that cis -isomer is thermodynamically more favoured than the trans -isomer.

The photochemical reactions of 2-acylphenyl methacrylates (= 2-acylphenyl 2-methylprop-2-enoates) 1 were investigated. Irradiation of 2-acylphenyl methacrylates 1a–d in MeCN gave the tricyclic lactones 2a–d in good yields, together with a small amount of OCO bond cleavage product, the 2-acylphenols 3a–d (Scheme 2, Table). The formation of the tricyclic lactones 2 probably follows a mechanism involving a 1,7-diradical through ζ-H abstraction (1,8-H transfer) by the excited carbonyl O-atom (Scheme 3). Irradiation of 2-acylphenyl tiglate (= 2-acylphenyl (2E)-2-methylbut-2-enoate) 1e and 2-acylphenyl methacrylates 1g–i, substituted by a MeO group (δ-H) at the 3,5-positions of the phenyl group, also gave the tricyclic lactones 2e and 2g–i, but in low yields. On the other hand, no H-abstraction products were observed on irridation of 2-(ethoxycarbonyl)phenyl methacrylate 1f, of 2-acylphenyl methacrylate 1j which is substituted by a Me group (γ-H) at the 3,5-positions of the phenyl group, and of 1k with an OH group at the 3-position of the phenyl group.

A series of functionalized 1-benzoxepins were synthesized by way of a tandem ring-opening/cyclocondensation of aldehyde-containing 3-bromoisoxazoles.

Two novel prenyl 3-benzoxepin derivatives, perilloxin (1) and dehydroperilloxin (2), were isolated from the dichloromethane extract of the stems of Perilla frutescens var. acuta. Their structures were elucidated as (-)-(R)-5-methoxy-2,3-dihydrofuro[2, 3-g][3]benzoxepin and 5-methoxyfuro[2,3-g][3]benzoxepin, respectively, based on UV, MS, (1)H and (13)C NMR, NOE, (1)H-(13)C COSY, and HMBC spectral data. They were isolated following bioassay-guided fractionation, using an in vitro cyclooxygenase-1 test. Compounds 1 and 2 possess inhibitory activities, with IC(50) values of 23.2 microM and 30.4 microM, respectively.

Two novel monochlorinated 2,3-dihydro-1-benzoxepin derivatives were isolated from the ethyl acetate extracts of the stipes of Mycena galopus. The structures were established on the basis of their spectral data.

Three preparative procedures of seven-membered O-heterocyclic 3-methyl-2,5-dihydro-l-benzoxepin derivatives are summarized. For the Z-selective formation of C=C double bond, the first approach used the Grubbs ring-closing methathesis, the second approach used the intramolecular Mitsunobu cyclization of corresponding Z-diols prepared using Stille coupling of the benzyl bromide with (Z)-vinylstannane, and the third approach used the revised synthesis of the Z-diols using Z-selective Ando-Homer-Emmons condensation and the following DIBAL-H reduction. Some naturally occurring 3-methyl-2,5-dihydro-1-benzoxepin derivatives were synthesized using these procedures. In these studies, some preparations of 3-methyl-2,5-dihydrooxepin derivatives were also developed.

A series of 2-phenyl-2,3,4,5-tetrahydro-1-benzoxepin-5-ones were synthesized by 2 steps from flavones through 3,4-benzo-5-oxo-2-oxabicyclo[4.1.0]heptanes.

A novel rearrangement of dithianylcyclobutachromanol derivative 3a on treatment with mercuric oxide and fluoroboric acid in aqueous tetrahydrofuran leads to 1,2,2a,8,9,9a-hexahydro-2a,9a-dimethylcyclobuta[b]-[1]benzoxepin-8,9-dione whose structure is established by X-ray analysis.

A series of 2-phenyl-2,3,4,5-tetrahydro-1-benzoxepin-5-ones were synthesized by 2 steps from flavones through 3,4-benzo-5-oxo-2-oxabicyclo[4.1.0]heptanes.

2,3,4,5-Tetrahedro-1-benzoxepin (8) and its 3-substituted derivatives (9–13) have been studied by 1H and 13C dynamic nuclear magnetic resonance in a few solvent systems. The results show that, while 8 and its methyl derivative 9 exist solely in chair forms (C for 8 and Ce:Ca (96:4) for 9), the twist-boat (TB) conformation contributes significantly to the conformational equilibria of the derivatives 3-methoxy 10 (Ca:Ce:TB, 70:20:10), 3,3-dimethyl 11 (C:TB, 90:10), 3,3-methylmethoxy 12(Ca:Ce:TB, 89:4:7), and 3,3-dimethoxy 13 (C:TB, 92:8). The analysis of several factors (steric, electrostatic, and electronic) on the conformational behaviour of these molecules shows why the TB form is a viable conformational alternative to destabilized chair forms in this benzoxepin system.

Base induced isomerization of 1-benzoxepin-5(2H )-one (1a ) yields 1-benzoxepin-5(4H )-one (4a) which gives the unsaturated alcohol 5a on treatment with Ce(III)chloride/sodiumboranate. Subsequent reaction of 5a with p-toluenesulfonylchloride and then, without isolation of the intermediate, with base yields 1-benzoxepine (6 a). With tetracyanoethylene 6a forms the corresponding diene-adduct. The same reaction sequence was realized in the analogous sulfur series, yielding 1-benzothiepine (6 b).

Some 5-aryl-4,5-dihydro[1]benzoxepin-3(2H)-ones and 5-aryl-5,6,8,9-tetrahydro-7H-benzocyclohepten-7-ones were synthesized by hydrogenolytic cleavage of the isoxazole ring of 4-aryl-3-oxo-3,3a,4,10-tetrahydro[1]-benzoxepino[3,4-c]isoxazoles or 4-aryl-3-oxo-3a,4,9,10-tetrahydro-3H-benzo[4,5]cyclohepta[1,2-c]isoxazoles which in turn were prepared from ethyl 3-oxo-4-phenoxybutanoate or ethyl 3-oxo-5-phenylpentanoate by simple methods.

Near-UV irradiation of the photosynthetic electron transport quinone, plastoquinone-9, in the presence of methanol and water, gave rise to mixtures of diastereoisomers of the dihydrobenzofurans 2a and 2c , respectively, as the major products. In both cases minor amounts of the plastochromenol-8 4a and the benzoxepin 6a were isolated and characterized.