3-Benzoxepin is an annulated ring system with an aromatic benzene ring and a non-aromatic, unsaturated, oxygen-containing seven-membered heterocyclic oxepin. The first synthesis was described by Karl Dimroth and coworkers in 1961. It is one of the three isomers of the benzoxepins.
3-Benzoxepin itself is a non-natural compound, but the bicyclic ring system is part of the naturally occurring compounds perilloxin (I) from Perilla frutescens (variant acuta)[1] and tenual (II) and tenucarb (III) from Asphodeline tenuior.[2] Perilloxin inhibits the enzyme cyclooxygenase with an IC50 of 23.2 μM. Non-steroidal anti-inflammatory drugs like aspirin and ibuprofen also work by inhibiting the cyclooxygenase enzyme family.[3]
Unsubstituted 3-benzoxepin can be synthesized through a double Wittig reaction from o-phthalaldehyde with bis-(α,α′-triphenylphosphonium)-dimethylether-dibromide. The latter compound can be synthesized from α,α′-dibromodimethyl ether (bis(bromomethyl)ether or BBME) which is accessible from hydrobromic acid, paraformaldehyde,[4] and triphenylphosphine. The reaction is performed in dry methanol with sodium methoxide, and the product is obtained in 55% yield.[5]
The compound can also be obtained through UV-irratiation of certain naphthalene derivatives such as 1,4-epoxy-1,4-dihydronaphthalene.[6]
It can also be obtained by photooxidation of 1,4-dihydronaphthalene, followed by pyrolysis of the formed hydroperoxides.[7]
The latter syntheses give 3-benzoxepins in low yields (4–6%).
3-Benzoxepin is a bright yellow solid that crystallizes in platelets, with a smell similar to naphthalene. The material is soluble in apolar, organic solvents. Like naphthalene, it can be purified through sublimation. The solid is relatively acid-resistant, only under refluxing in concentrated, acidic alcohol solutions an unsaturated aldehyde is formed (likely an indene-3-aldehyde). Catalytic hydrogenation with a palladium catalyst results in 1,2,4,5-tetrahydro-3-benzoxepin.