3-Benzoxepin Explained

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.

Occurrence and synthesis

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%).

Properties

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.

References

  1. J.-H.. Liu. A.. Steigel. E.. Reininger. R.. Bauer. Two new prenylated 3-benzoxepin derivatives as cyclooxygenase inhibitors from Perilla frutescens var. acuta. J. Nat. Prod.. 63. 3. 403–405. 2000. 10.1021/np990362o. 10757731.
  2. A.. Ulubelen. Ayhan Ulubelen. E.. Tuzlaci. N.. Atilan. Oxepine derivatives and anthraquinones from Asphodeline tenuior and A. taurica. Phytochemistry. 28. 2. 649–650. 1989. 10.1016/0031-9422(89)80076-7. 1989PChem..28..649U .
  3. Book: Elsevier's Integrated Review. Pharmacology. NSAIDs. 2011. M.. Kester. K. D.. Karpa. K. E.. Vrana. Elsevier Health Sciences. 9780323074452. 165–166. https://books.google.com/books?id=0A8w30H3gxQC&dq=nsaid+ibuprofen+aspirin+cyclooxygenase&pg=PA165.
  4. US. 20040242799. patent. Process to bromomethylate aromatic compounds. 2004-12-02. 2001-08-29. 2001-08-29. Grabarnick, M.. Sasson, Y.. Grabarnick, M.. Sasson, Y..
  5. Book: A.. Rosowsky. The Chemistry of Heterocyclic Compounds. Seven-Membered Heterocyclic Compounds Containing Oxygen and Sulfur. 26th. II. Oxepin Ring Systems Containing Two Rings. Wiley-Interscience. New York. 1972. 96. 0-471-38210-8. German.
  6. G. R.. Ziegler. Mechanisms of photochemical reactions in solution. LVII. Photorearrangement of 1,4-epoxy-1,4-dihydronaphthalene to benz[''f'']oxepin. J. Am. Chem. Soc.. 91. 2. 446–449. 1969. 10.1021/ja01030a040.
  7. A. M.. Jeffrey. D. M.. Jerina. Autoxidation of 1,4-dihydronaphthalene. Formation of 3-benzoxepin via pyrolysis of 2-hydroperoxy-1,2-dihydronaphthalene. J. Am. Chem. Soc.. 94. 11. 4048–4049 . 1972. 10.1021/ja00766a084.