GENERAL METHODS: NaBH4 (0.6 mol) was added batchwise to a stirred solution of 4,4'-difluorobenzophenone (1.0 mol) in methanol (2 volumes) at room temperature for 45 min. The reaction mixture was stirred at ambient temperature for 2-3 h (progress of the reaction was monitored by TLC), and upon completion of the reaction, the reaction was diluted with water (750 mL), the pH was adjusted to 4 with acetic acid, and the reaction was subsequently extracted with dichloromethane (2 x 400 mL). The organic layer was washed with water (200 mL), dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give pure 4,4'-difluorodiphenylmethanol as a white to off-white solid in 93-97% yield.
To a stirred solution of 4,4'-difluorodiphenylmethanol (1.0 mol) in toluene (370 mL) at room temperature was added concentrated hydrochloric acid (35% aqueous, 370 mL) and tetrabutylammonium bromide (0.01 mol). The mixture was continued to be stirred at 40-45 °C for 6-7 h. After TLC showed that the reaction was complete, the mixture was cooled to room temperature. The organic layer was separated and concentrated under vacuum to give crude 4,4'-difluorodiphenylmethyl chloride as a light brown liquid in 95-97% yield.
Anhydrous piperazine (5.0 mol) was slowly added to a solution of 4,4'-difluorodiphenylmethyl chloride (0.96 mol) in toluene (380 mL) at 60-70 °C for 45-60 minutes. The resulting mixture was heated at 90-100°C for 8-10 hours with stirring. After completion of the reaction the mixture was cooled and water (380 mL) was added to separate the organic layer. The organic layer was washed with a 1:1 mixture of concentrated hydrochloric acid and water (2 x 350 mL) and subsequently neutralized with 20% NaOH solution (750 mL). The aqueous layer was again extracted with toluene (2×300 mL), and the organic layers were combined, dried with anhydrous sodium sulfate, and concentrated in vacuum to afford the pure 4,4'-difluorodiphenylmethylpiperazine derivative as a white to off-white solid in 88% yield.
