Synthesis of 9-Bromo-2-fluoro-6,7-dihydro-5H-benzocycloheptene-8-carboxaldehyde

Abstract

Cinnamaldehye is an antioxidant shown to induce apoptotic cell death in a number of human cancer cells. This article reports a synthesis of 9-bromo, 2-fluoro substituted, and Z-ring locked (by a trimethylene bridge at C-8 and C-11) crystalline fluorine-substituted derivative of cinnamaldehyde. The synthon, 8-fluoro-1-benzosuberone was treated with PBr3, dimethylformamide (DMF), and CHCl3 as a solvent to obtain 9-bromo-2-fluoro-6,7-dihydro-5H-benzocycloheptene-8-carboxaldehyde. The one-step trifunctionalization process converts a bicyclic ring–fused ketone into a β-bromo-α,β-unsaturated aldehyde in a chemoselective and regioselective manner. The process also creates a new carbon–carbon bond between C-8 and C-12. The structure of the previously unreported product has been obtained by x-ray crystallographic analysis. It has been characterized spectroscopically by infrared (IR), 1H NMR, 13C NMR, gas chromatography–mass spectrometry (GC-MS), and elemental analysis. It is a structural element found in sterically hindered retinoids and is a useful advanced intermediate in the total synthesis of these naturally occuring bioactive polyenes.