Dibenzoxepines

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. 

In 1911, the first dibenzoxepin was obtained in a degradation reaction of morphothebaine,42 but it was not until 1960 that oxepins attracted interest from a chemical point of view (see refs 12 and 43 for a review). 

Substituted 2-phenoxyphenylacetic acids readily cyclize under Friedel-Crafts conditions or acid catalysis to give dibenz[Z>,/]oxepin-10(l l//)-ones.71 85,104- 108 When this reaction is carried out in methanolic hydrochloric acid the 10-methoxy-substituted dibenz[6,/]oxepin system 9a can be isolated.109 5-(Nitro-2-phenoxyphenyl)-2-oxopropanoic acid undergoes cyclization in the presence of polyphosphoric acid yielding the carboxylated dibenzoxepin 9b.107... 

Dihydro-9,10-epoxyphenanthrene and related arene oxides are of considerable interest as carcinogens formed by polycyclic aromatic hydrocarbons in vivo.45 Phenanthrene oxide does not isomerize to the corresponding dibenzoxepin under thermal conditions. Photolysis of... 

The pharmaceutical interest in the tricyclic structure of dibenz[6,/]oxepins with various side chains in position 10(11) stimulated a search for a convenient method for the introduction of functional groups into this position. It has been shown that nucleophilic attack at the carbonyl group in the 10-position of the dibenzoxepin structure renders the system susceptible to water elimination. Formally, the hydroxy group in the enol form is replaced by nucleophiles such as amines or thiols. The Lewis acids boron trifluoride-diethyl ether complex and titanium(IV) chloride have been used as catalysts. 

A palladium-catalysed carbometallation-alkyne cross coupling cascade process has been reported for the stereo- and regio-controlled synthesis of dibenzoxepines with substituted exocyclic alkene functionality <06OL1685>. 

Doxepin Patients with glaucoma or a tendency for urinary retention. Cross-sensitivity may occur among the dibenzazepines (clomipramine, desipramine, imipramine, nortriptyline, and trimipramine). In addition, dibenzoxepines (doxepin, amoxapine) may produce cross-sensitivity. 

Chemical Class Dibenzoxepin derivative tertiary amine... 

A different pathway is followed on irradiation of K-region arene oxides such as 9,10-epoxy-9,10-dihydrophenanthrene (95) the major photoproduct is 2,3 4,5-dibenzoxepin (96), which is believed to arise by a concerted oxygen-walk process, as shown in Scheme 5.83 9-Phenanthrol was also obtained... 

On treatment with a Pd-phosphine complex, allene ethers 54 undergo cyclization (Scheme 17) to the benzox-epines 55, which can be transformed to a dibenzoxepine derivative 56 via Diels-Alder reaction and aromatization <1994JOC4730>. 

Topical doxepin hydrochloride 5% cream (Zonalon) may provide significant antipruritic activity when utilized in the treatment of pruritus associated with atopic dermatitis or lichen simplex chronicus. The precise mechanism of action is unknown but may relate to the potent Hi and H2-receptor antagonist properties of dibenzoxepin tricyclic compounds. Percutaneous absorption is variable and may result in significant drowsiness in some patients. In view of the anticholinergic effect of doxepin, topical use is contraindicated in patients with untreated narrow-angle glaucoma or a tendency to urinary retention. 

The dibenzazepinium salts 81 were prepared in moderate overall yields from the diol 77, via 78, the i ntermediate dibenzoxepine 7 9, a nd the bromo a ldehyde 8 0. New catalysts for catalytic asymmetric epoxidation, for example 82 and 83, were made in this way [02SL580]. 

The sole method of synthesis that has been developed thus far involves the formation of a diGrignard or dilithio reagent from o,o -dibromobi-benzyl. The dibromo derivative is prepared by the coupling of o-bromobenzylbromide with phenyllithium (215). An alternative route that would utilize ring closure at the bridging carbon atoms (i.e., a site remote from the heteroatom) has not yet been explored. The dibenzazepin and dibenzoxepin derivatives have been prepared by this approach 35). The Grignard reactions are summarized in Eq. (97). 

The preparation of this new family of catalysts was achieved by starting from an enantiomerically pure primary amine and 2-[2-(bromomethyl)phenyl]-benzaldehyde (27) (Scheme 5.19). 2-[2-(Bromomethyl)phenyl]benzaldehyde was prepared from the corresponding dibenzoxepine (28), by treatment with molecular bromine in carbon tetrachloride under reflux, following a similar procedure already proven in the dihydroisoquinolinium salt series. The catalysts were synthesized in three steps starting from commercially available 2,2 -biphenyl dimethanol (29). 

The structure of 7 was determined by X-ray crystallographic analysis of its hydrobromide and the structure of cancentrine derived from it by detailed study of the NMR spectra of 1, 3, 4, and 7 (Section II, C). The X-ray data showed that the bond lengths N—C25—C24— C7—0 are consistent with these atoms being a conjugated system—an observation in accord with the carbonyl absorption at 1660 + 5 cm" in the IR spectra of compounds 1-8 and the nonbasicity of this nitrogen atom. The novel UV spectra of all these compounds and their yellow color was attributed to the cis-s-tmns- -aminoenone chromophore which is part of the oxygenated dibenzoxepine. 

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