O. Paliulis, D. Peters, L. Miknius
Feb 1, 2007
Citations
0
Influential Citations
2
Citations
Journal
Organic Preparations and Procedures International
Abstract
Although monosubstituted 3,8-diazabicyclo[3.2. Iloctanes are important starting materials for the preparation of compounds possessing analgesic a~t ivi ty , ' .~ methods for their synthesis remain poorly investigated. 8-Methyl-3,8-diazabicyclo[3.2.1 ]octane (7) has previously been prepared in even-^.^ or eight-step' procedures from diethyl meso-2,5-dibromoadipoate (1) in about 13% and 12% overall yield, respectively. We now describe the preparation of 7 from the same starting material by a four-step procedure in 19% overall yield. Our procedure starts from the preparation of diethyl cis1 -methylpyrrolidine dicarboxylate (2), which was previously obtained in 35% yield by heating diethyl meso-2,5-dibromoadipoate with methylamine in benzene followed by fractional distillation.* We found that compound 2 can be easily synthesized in a similar manner with significantly higher yield (91 5%) if the reaction is carried out in THF instead of benzene. The second and most difficult step of the synthetic route was the cyclization leading to the novel intermediate 3-benzyl-8-methyl-3,8-diazabicyclo[3.2.l]octan-2,4-dione (4). A solution of compound 2 and benzylamine in xylene was refluxed for 16 hours. Amide 3 was identified as the main reaction intermediate. After evaporation of the solvent, the temperature was raised to 210°C. After 18 h of heating, the reaction mixture was allowed to cool to room temperature. The crude product was distilled under vacuum (0.1 mbar, ISOOC) using a Buchi oven. The material obtained solidified and was recrystallized from ethyl acetate-hexane to afford 3-benzyl-8-methyl-3,8-diazabicyclo[3.2.l]octan-2,4-dione (4) in 34% yield. A similar procedure for the synthesis of 3-benzyI-8-ethyl-3,8-diazabicyclo[3.2.l]octan-2,4-dione gave 26% yield.9