1-bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with 1-bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (0.149 g, 0.47 mmol) and tert-butyl 4-(2-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.112 g, 0.36 mmol) in tetrahydrofuran (2 mL) at 0° C. The reaction was treated with potassium tert-butoxide (0.41 mg, 0.36 mmol), stirred at 0° C. for 20 min, and treated with another aliquot of potassium tert-butoxide (0.41 mg, 0.36 mmol). The reaction was allowed to warm to room temperature and was stirred for 16 h. The reaction mixture was evaporated in vacuo and the crude oil was purified by silica gel chromatography (5% ethyl acetate/95% hexanes→30% ethyl acetate/70% hexanes) to afford 0.138 g (70%) of the desired ether. Mass spec.: 546.03 (MH)+ LC tr=4.501 min. (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min). to warm to room temperature was stirred for 16 h The reaction mixture was evaporated in vacuo the crude oil was purified by silica gel chromatography (5% ethyl acetate/95% hexanes→30% ethyl acetate/70% hexanes) to afford 0.138 g (70%) of the desired ether

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.2 g, 3.78 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.96 g, 3.2 mmol) were combined in dimethylformamide (10 mL) and cooled to 0° C. The reaction was treated with sodium hydride (151 mg, 6.3 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 1.1 g (61%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.61 (s, 1H), 7.35 (s, 1H), 7.30-7.31 (m, 2H), 7.26 (s, 1H), 7.03-7.07 (m, 2H), 4.36 (s, 2H), 3.72-3.75 (m, 2H), 3.38 (s, 2H), 3.01-3.06 (m, 2H), 2.13-2.16 (m, 2H), 1.81-1.87 (m, 2H), 1.43 (s, 9H). 13C-NMR (CDCl3, 126 MHz) δ 161.6 (d, J=245.7 Hz), 152.0, 141.9, 138.3, 133.3, 132.4 (q, J=32.6 Hz), 128.8, 127.5 123.2 (q, J=273.5 Hz), 122.8, 122.4, 115.5, 115.3, 79.7, 79.5, 71.7, 68.0, 41.4, 32.2, 28.5, 25.7. Mass spec.: 548.16 (MH)+. at room temperature for 30 min extracted with ethyl acetate (2×) washed with brine (2×) dried over sodium sulfate concentrated Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 1.1 g (61%) as a clear oil

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.0 g, 3.14 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.70 g, 2.4 mmol) were combined in dimethylformamide (8 mL) and cooled to 0° C. The reaction was treated with sodium hydride (115 mg, 4.8 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.6 g (96%). 1H-NMR (CDCl3, 500 MHz) δ 7.61 (s, 1H), 7.39 (s, 1H), 7.34-7.37 (m, 4H), 7.25-7.28 (m, 2H), 4.35 (s, 2H), 3.75-3.77 (m, 2H), 3.41 (s, 2H), 3.01-3.06 (m, 2H), 2.19-2.22 (m, 2H), 1.83-1.89 (m, 2H), 1.44 (s, 9H). Mass spec.: 530.21 (MH)+. at room temperature for 30 min extracted with ethyl acetate (2×) washed with brine (2×) dried over sodium sulfate concentrated Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.6 g (96%)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (3-Bromo-5-(trifluoromethyl)phenyl)methanol (1.6 g, 6.3 mmol) and triphenylphosphine (3.3 g, 12.6 mmol) were combined in tetrahydrofuran (30 mL) and cooled to 0° C. N-Bromosuccinimide (2.4 g, 13.2 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (100% hexanes) gave 1.53 g (76%) as a light brown oil. 1H-NMR (CDCl3, 500 MHz) δ 7.73 (s, 1H), 7.70 (s, 1H), 7.58 (s, 1H), 4.44 (s, 2H). to warm to room temperature washed with concentrated sodium bicarbonate (2×), brine (2×) dried over sodium sulfate concentrated Column chromatography on silica gel (100% hexanes) gave 1.53 g (76%) as a light brown oil

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (220 mg, 0.67 mmol) and 1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (450 mg, 1.41 mmol) were combined in tetrahydrofuran (2 mL) and cooled to 0° C. The reaction was treated with sodium tert-butoxide (75 mg, 0.355 mmol) and stirred at 0° C. for 20 min. The reaction was treated with another aliquot of sodium tert-butoxide (75 mg, 0.355 mmol), allowed to warm to room temperature, and stirred for 30 min. The reaction was diluted with 10% sodium bicarbonate and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (1×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (0%→25% ethyl acetate/hexanes) gave 200 mg (50%). Mass spec.: 586.04 (MH)+ LC tr=2.552 min. (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min). to warm to room temperature stirred for 30 min extracted with ethyl acetate (2×) washed with brine (1×) dried over sodium sulfate concentrated Column chromatography on silica gel (0%→25% ethyl acetate/hexanes) gave 200 mg (50%)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with 1-bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (0.149 g, 0.47 mmol) and tert-butyl 4-(2-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.112 g, 0.36 mmol) in tetrahydrofuran (2 mL) at 0° C. The reaction was treated with potassium tert-butoxide (0.41 mg, 0.36 mmol), stirred at 0° C. for 20 min, and treated with another aliquot of potassium tert-butoxide (0.41 mg, 0.36 mmol). The reaction was allowed to warm to room temperature and was stirred for 16 h. The reaction mixture was evaporated in vacuo and the crude oil was purified by silica gel chromatography (5% ethyl acetate/95% hexanes→30% ethyl acetate/70% hexanes) to afford 0.138 g (70%) of the desired ether. Mass spec.: 546.03 (MH)+ LC tr=4.501 min. (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min). to warm to room temperature was stirred for 16 h The reaction mixture was evaporated in vacuo the crude oil was purified by silica gel chromatography (5% ethyl acetate/95% hexanes→30% ethyl acetate/70% hexanes) to afford 0.138 g (70%) of the desired ether

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.2 g, 3.78 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.96 g, 3.2 mmol) were combined in dimethylformamide (10 mL) and cooled to 0° C. The reaction was treated with sodium hydride (151 mg, 6.3 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 1.1 g (61%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.61 (s, 1H), 7.35 (s, 1H), 7.30-7.31 (m, 2H), 7.26 (s, 1H), 7.03-7.07 (m, 2H), 4.36 (s, 2H), 3.72-3.75 (m, 2H), 3.38 (s, 2H), 3.01-3.06 (m, 2H), 2.13-2.16 (m, 2H), 1.81-1.87 (m, 2H), 1.43 (s, 9H). 13C-NMR (CDCl3, 126 MHz) δ 161.6 (d, J=245.7 Hz), 152.0, 141.9, 138.3, 133.3, 132.4 (q, J=32.6 Hz), 128.8, 127.5 123.2 (q, J=273.5 Hz), 122.8, 122.4, 115.5, 115.3, 79.7, 79.5, 71.7, 68.0, 41.4, 32.2, 28.5, 25.7. Mass spec.: 548.16 (MH)+. at room temperature for 30 min extracted with ethyl acetate (2×) washed with brine (2×) dried over sodium sulfate concentrated Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 1.1 g (61%) as a clear oil

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.0 g, 3.14 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.70 g, 2.4 mmol) were combined in dimethylformamide (8 mL) and cooled to 0° C. The reaction was treated with sodium hydride (115 mg, 4.8 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.6 g (96%). 1H-NMR (CDCl3, 500 MHz) δ 7.61 (s, 1H), 7.39 (s, 1H), 7.34-7.37 (m, 4H), 7.25-7.28 (m, 2H), 4.35 (s, 2H), 3.75-3.77 (m, 2H), 3.41 (s, 2H), 3.01-3.06 (m, 2H), 2.19-2.22 (m, 2H), 1.83-1.89 (m, 2H), 1.44 (s, 9H). Mass spec.: 530.21 (MH)+. at room temperature for 30 min extracted with ethyl acetate (2×) washed with brine (2×) dried over sodium sulfate concentrated Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.6 g (96%)