Synthesis
General procedure for the synthesis of 6-fluoro-3,4-dihydronaphthalen-2(1H)-ones from 4-fluorophenylacetic acid: a modified method of Stjernlof, P. et al. was used (J. Med. Chem. 1995, 38, 2202). 4-Fluorophenylacetic acid (10.0 g, 64.9 mmol) and thionyl chloride (11.8 mL, 0.162 mol) were dissolved in 1,2-dichloroethane (150 mL) in a 500 mL round-bottom flask and heated at reflux for 4 hours. Upon completion of the reaction, the solvent was removed by vacuum evaporation. The residue was again dissolved in 1,2-dichloroethane and the solvent was removed by vacuum evaporation to remove excess thionyl chloride. Subsequently, the residue was dissolved in dichloromethane (50 mL) and added dropwise to a pre-cooled suspension of aluminum chloride (21.6 g, 162 mmol) in dichloromethane (250 mL) at -10 to -5°C over 20 minutes. The suspension was stirred at -10°C for 10 minutes. Next, ethylene was rapidly bubbled through the suspension for 20 minutes at -10 to 5°C, followed by continued bubbling at a very slow rate for 2 hours while maintaining -5°C. Upon completion of the reaction, the reaction was quenched with ice (100 g) and the organic layer was separated and washed sequentially twice with water and once with saturated aqueous sodium bicarbonate. The organic layer was dried with magnesium sulfate and the solvent was evaporated by vacuum to give the crude product tetralone (13.2 g) as a yellow solid. The crude product was used directly in the subsequent reaction without further purification. Part of the crude product was recrystallized by hexane to afford purified 3,4-dihydro-6-fluoro-2(1H)-naphthalenone as a colorless solid with about 50% recovery.1H NMR (CDCl3) δ: 2.55 (t, 2H), 3.05 (t, 2H), 3.54 (s, 2H), 6.85-6.97 (m, 2H), 7.05-7.12 (m, 1H). 1H).
References
[1] Patent: US6140354, 2000, A
[2] Synthetic Communications, 2003, vol. 33, # 13, p. 2215 - 2227
[3] Journal of Medicinal Chemistry, 1995, vol. 38, # 12, p. 2202 - 2216
[4] Journal of Medicinal Chemistry, 1993, vol. 36, # 17, p. 2485 - 2493
[5] Australian Journal of Chemistry, 1970, vol. 23, p. 1921 - 1937
