4-(2-chlorophenoxy)piperidine

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

Procedure: Sodium iodide (19 mg; 0.13 mmol) was added to a solution of chloroacetamide 6 (40 mg; 0.12 mmol), piperidine 7.6 (31 mg; 0.15 mmol) and DIPEA (30 μL; 0.17 mmol) in 3:1 acetonitrile:THF (2 mL). After 22 h the reaction was filtered through a short plug of silica gel with THF as a wash. The solution was concentrated in vacuo then purified on silica gel (20 mL) with 10:1 EtOAc:i-PrOH yielding a hard white foam (59.2 mg; 98%). LC (method B) tR=12.9 min; 1H NMR (200 MHz, CDCl3) δ 9.51 (s, 1H), 8.37 (m, 2H), 7.47 (m, 3H), 7.38 (m, 1H), 7.31-7.14 (m, 2H), 7.02-6.86 (m, 2H), 6.72 (brs, 1H), 5.69 (brt, J=5.6 Hz, 1H), 4.48 (m, 1H), 3.67 (m, 2H), 3.53 (m, 2H), 3.19 (s, 2H), 2.90 (m, 2H), 2.56 (m, 2H), 2.20-2.00 (m, 4H), 1.86 (s, 3H). ESIMS 523.0/525.0 (100/42) [MH+], 262 (58), 198 (75). After 22 h the reaction was filtered through a short plug of silica gel with THF as a wash The solution was concentrated in vacuo then purified on silica gel (20 mL) with 10:1 EtOAc

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

Procedure: Sodium iodide (19 mg; 0.13 mmol) was added to a solution of chloroacetamide 6 (40 mg; 0.12 mmol), piperidine 7.6 (31 mg; 0.15 mmol) and DIPEA (30 μL; 0.17 mmol) in 3:1 acetonitrile:THF (2 mL). After 22 h the reaction was filtered through a short plug of silica gel with THF as a wash. The solution was concentrated in vacuo then purified on silica gel (20 mL) with 10:1 EtOAc:i-PrOH yielding a hard white foam (59.2 mg; 98%). LC (method B) tR=12.9 min; 1H NMR (200 MHz, CDCl3) δ 9.51 (s, 1H), 8.37 (m, 2H), 7.47 (m, 3H), 7.38 (m, 1H), 7.31-7.14 (m, 2H), 7.02-6.86 (m, 2H), 6.72 (brs, 1H), 5.69 (brt, J=5.6 Hz, 1H), 4.48 (m, 1H), 3.67 (m, 2H), 3.53 (m, 2H), 3.19 (s, 2H), 2.90 (m, 2H), 2.56 (m, 2H), 2.20-2.00 (m, 4H), 1.86 (s, 3H). ESIMS 523.0/525.0 (100/42) [MH+], 262 (58), 198 (75). After 22 h the reaction was filtered through a short plug of silica gel with THF as a wash The solution was concentrated in vacuo then purified on silica gel (20 mL) with 10:1 EtOAc

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

Procedure: Trifluoroacetic acid (4 mL) was added to crude carbamate 10.6 (1.030 g). After 20 min at rt most of the volatiles were removed in vacuo and 1 M HCl (10 mL) was added, whereupon an oil separated. This was washed with DCM (3×3 mL). The aqueous portion was basified to pH>12 with 5 M NaOH, extracted with DCM (3×4 mL), dried (MgSO4), filtered and concentrated to an oil (10 mg). The initial DCM washing was dried (MgSO4), filtered and concentrated to a pale yellow oil (1.26 g), whose 1H NMR was consistent with being the piperidinium trifluoroacetate. This material, plus the initial collected free base (10 mg) was dissolved in ether (30 mL) and washed with 5 M NaOH (10 mL), 1 M NaOH (2×10 mfL), water (10 mL) and saturated NaCl (2×10 mL), then dried (MgSO4) and filtered. HCl—saturated ether (35 mL) was added and the turbid solution was extracted with 1 M HCl (3×10 mL). The acidic portion was basified with 5 M NaOH, extracted with DCM (3×8 mL) and the organic portion dried (MgSO4), filtered and concentrated to a pale yellow oil (457 mg; 62% from 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester). LC (method B) tR=8.2 min; 1H NMR (200 MHz, CDCl3) δ 7.37 (dd, J=1.6, 8.0 Hz, 1H), 7.19 (ddd, J=1.5, 7.3, 8.6 Hz, 1H), 7.0-6.8 (m, 2H), 4.42 (tt, J=3.9, 3.9 Hz, 1H), 3.18 (ddd, J=4.0, 6.3, 12.0 Hz, 2H), 2.73 (ddd, J=3.7, 8.6, 12.3 Hz, 2H), 2.00 (m, 2H), 1.77 (m, 2H); ESIMS (free base) 212.0/213.9 (100/37) [MH+]. After 20 min at rt most of the volatiles were removed in vacuo and 1 M HCl (10 mL) was added, whereupon an oil separated This was washed with DCM (3×3 mL) extracted with DCM (3×4 mL) dried (MgSO4) filtered concentrated to an oil (10 mg) The initial DCM washing was dried (MgSO4) filtered concentrated to a pale yellow oil (1.26 g), whose 1H NMR This material, plus the initial collected free base (10 mg) was dissolved in ether (30 mL) washed with 5 M NaOH (10 mL), 1 M NaOH (2×10 mfL), water (10 mL) and saturated NaCl (2×10 mL) dried (MgSO4) filtered HCl—saturated ether (35 mL) was added the turbid solution was extracted with 1 M HCl (3×10 mL) extracted with DCM (3×8 mL) the organic portion dried (MgSO4) filtered concentrated to a pale yellow oil (457 mg; 62% from 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester)

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