Synthesis of 2-N,N-Dimethylaminomethyl-2,3,3a,12b-tetrahydrodibenzo-[b,f]furo[2,3-d]oxepin Derivatives as Potential Anxiolytic Agents

200430.fm Page 168 Thursday, July 1, 2004 10:50 AM

2004

Multi-membered O,S-heterocycles

Multi-membered O,S-heterocycles R 0691 Synthesis of 2-N,N-Dimethylaminomethyl-2,3,3a,12b-tetrahydrodibenzo[b,f]fuDerivatives as Potential Anxiolytic Agents. — Four diastereoiso30- 160 ro[2,3-d]oxepin mers of cis- and trans-fused tetrahydrodibenzofurooxepines are prepared involving epoxidation of dibenzooxepine (I), epoxide ring opening with allylmagnesium bromide (III), and cyclization of (IV) to form the tetrahydrofuran ring. Different diastereoselectivities are observed under cyclization conditions employed. Bromine or pyridinium bromide perbromate afford good yields and diastereoselectivity. Barluenga's reagent reaches completion in two minutes giving the cyclization products in nearly quantitative yield but with no diastereoselectivity. To obtain all possible isomers and with regard to easier chromatographic separation, MCPBA is used as cyclization agent. Finally, transformation of pure (V) and (VI) into the targets, e.g. (VIII), is carried out. — (TRABANCO*, A. A.; ALONSO, J. M.; ANDRES, J. I.; CID, J. M.; FERNANDEZ, J.; ITURRINO, L.; MEGENS, A.; Chem. Pharm. Bull. 52 (2004) 2, 262-265; Johnson & Johnson Pharm. Res. Dev., Janssen-Cilag S. A., E-45007 Toledo, Spain; Eng.) — H. Hoennerscheid