1-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]methanamine;hydrochloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Bis-(4-fluoro-benzyl)-amine hydrochloride (43 grams, 0.16 mole) was suspended in 200 mL of CH2Cl2. To this was added 730 mL of 1N NaOH. The reaction mixture was stirred vigorously while AcCl (20 mL, 0.28 mole) was slowly added. The reaction was stirred for 0.5 h, then the organic layer separated, washed with 1N HCl, dried over Na2SO4, filtered and the solvent removed under vacuum to yield 24 grams (55% yield) of N,N-bis-(4-fluoro-benzyl)-acetamide as an oil. MS (M+H) calcd for C16H16F2NO: 276.1. found: 276.0. Anal. calcd for C16H15F2NO: C, 69.80; H, 5.49; N, 5.08. found: C, 69.53; H, 5.41; N, 5.06. 1H NMR (500 MHz, DMSO) δ: 2.10 (s, 3), 4.45 (s, 2), 4.50 (s, 2), 7.11–7.27 (overlapping m, 8). 13C NMR (125 MHz, DMSO) δ: 21.34, 50.04, 54.80, 114.90, 115.07, 115.27, 115.45, 128.51, 128.58, 129.57, 129.64, 133.32, 133.34, 133.86, 133.89, 160.25, 160.33, 162.27, 170.22. was slowly added the organic layer separated washed with 1N HCl dried over Na2SO4 filtered the solvent removed under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Bis-(4-fluoro-benzyl)-amine hydrochloride (43 grams, 0.16 mole) was suspended in 200 mL of CH2Cl2. To this was added 730 mL of 1N NaOH. The reaction mixture was stirred vigorously while AcCl (20 mL, 0.28 mole) was slowly added. The reaction was stirred for 0.5 h, then the organic layer separated, washed with 1N HCl, dried over Na2SO4, filtered and the solvent removed under vacuum to yield 24 grams (55% yield) of N,N-bis-(4-fluoro-benzyl)-acetamide as an oil. MS (M+H) calcd for C16H16F2NO: 276.1. found: 276.0. Anal. calcd for C16H15F2NO: C, 69.80; H, 5.49; N, 5.08. found: C, 69.53; H, 5.41; N, 5.06. 1H NMR (500 MHz, DMSO) δ: 2.10 (s, 3), 4.45 (s, 2), 4.50 (s, 2), 7.11–7.27 (overlapping m, 8). 13C NMR (125 MHz, DMSO) δ: 21.34, 50.04, 54.80, 114.90, 115.07, 115.27, 115.45, 128.51, 128.58, 129.57, 129.64, 133.32, 133.34, 133.86, 133.89, 160.25, 160.33, 162.27, 170.22. was slowly added the organic layer separated washed with 1N HCl dried over Na2SO4 filtered the solvent removed under vacuum

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-N-(4-fluoro-benzyl)-benzamide (40.0 grams, 0.16 mole) was dissolved in 240 mL of THF. To this was added BF3.Et2O (7.4 mL. 0.06 mole) and the resulting mixture heated to reflux for 15 min. After cooling to −30° C., BH3.SMe2 (22.3 mL, 0.24 mole) was added using a dropping funnel. The reaction was allowed to warm to room temperature. The reaction flask was fitted with a distillation condenser and solvent removed under reflux for 25 min. The distillation apparatus was replaced with a reflux condenser and the reaction heated to 110° C. for 2 h. After cooling to 0° C., 100 mL of 6N HCl was added and the mixture heated to reflux for 1 hr to yield a thick slurry. 300 mL of 6N NaOH was slowly added at room temperature with intermittent cooling using an ice bath. After all the solid has dissolved Et2O was added and the mixture transferred to a separatory funnel. The organic layer was separated, dried over Na2SO4, filtered and the solvent removed under vacuum to yield an oil. The oil was dissolved in 50 mL of Et2O and 4N HCl (dioxane) added resulting in the formation of a white precipitate which was isolated by filtration to yield 40 grams (93% yield) of bis-(4-fluoro-benzyl)-amine hydrochloride. MS (M+H) calcd for C14H14F2N, 234.1. found: 234.0. Anal. calcd for C14H14F2NCl: C, 62.34; H, 5.23; N, 5.19. found: C, 61.89; H, 5.15; N, 5.27. 1H NMR (500 MHz, DMSO) δ: 4.12 (br s, 4), 7.26 (m, 4), 7.65 (m, 4), 9.91 (br s, 2). the resulting mixture heated to reflux for 15 min to warm to room temperature The reaction flask was fitted with a distillation condenser solvent removed under reflux for 25 min The distillation apparatus was replaced with a reflux condenser the reaction heated to 110° C. for 2 h After cooling to 0° C. 100 mL of 6N HCl was added the mixture heated to reflux for 1 hr to yield a thick slurry with intermittent cooling was added the mixture transferred to a separatory funnel The organic layer was separated dried over Na2SO4 filtered the solvent removed under vacuum to yield an oil resulting in the formation of a white precipitate which was isolated by filtration

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-N-(4-fluoro-benzyl)-benzamide (40.0 grams, 0.16 mole) was dissolved in 240 mL of THF. To this was added BF3.Et2O (7.4 mL. 0.06 mole) and the resulting mixture heated to reflux for 15 min. After cooling to −30° C., BH3.SMe2 (22.3 mL, 0.24 mole) was added using a dropping funnel. The reaction was allowed to warm to room temperature. The reaction flask was fitted with a distillation condenser and solvent removed under reflux for 25 min. The distillation apparatus was replaced with a reflux condenser and the reaction heated to 110° C. for 2 h. After cooling to 0° C., 100 mL of 6N HCl was added and the mixture heated to reflux for 1 hr to yield a thick slurry. 300 mL of 6N NaOH was slowly added at room temperature with intermittent cooling using an ice bath. After all the solid has dissolved Et2O was added and the mixture transferred to a separatory funnel. The organic layer was separated, dried over Na2SO4, filtered and the solvent removed under vacuum to yield an oil. The oil was dissolved in 50 mL of Et2O and 4N HCl (dioxane) added resulting in the formation of a white precipitate which was isolated by filtration to yield 40 grams (93% yield) of bis-(4-fluoro-benzyl)-amine hydrochloride. MS (M+H) calcd for C14H14F2N, 234.1. found: 234.0. Anal. calcd for C14H14F2NCl: C, 62.34; H, 5.23; N, 5.19. found: C, 61.89; H, 5.15; N, 5.27. 1H NMR (500 MHz, DMSO) δ: 4.12 (br s, 4), 7.26 (m, 4), 7.65 (m, 4), 9.91 (br s, 2). the resulting mixture heated to reflux for 15 min to warm to room temperature The reaction flask was fitted with a distillation condenser solvent removed under reflux for 25 min The distillation apparatus was replaced with a reflux condenser the reaction heated to 110° C. for 2 h After cooling to 0° C. 100 mL of 6N HCl was added the mixture heated to reflux for 1 hr to yield a thick slurry with intermittent cooling was added the mixture transferred to a separatory funnel The organic layer was separated dried over Na2SO4 filtered the solvent removed under vacuum to yield an oil resulting in the formation of a white precipitate which was isolated by filtration