2-(4-CHLOROPHENOXY)ANILINE

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: 2-(4-Chlorophenoxy)aniline (245 mg, 1.118 mmol, 1 eq) and 1-acetyl-N-(3-acetylphenyl)-N-ethylpiperidine-4-carboxamide (250 mg, 1.230 mmol, 1.1 eq) were stirred in dry dichloromethane (DCM) (2 mL) at room temperature for 10 min. Tri-isopropoxytitanium chloride (534 μL, 2.236 mmol, 2 eq) was added to the reaction mixture which was stirred at room temperature for 16 hours. Sodium triacetoxyborohydride (947 mg, 4.472 mmol, 4 eq) was then added to the reaction mixture and was stirred at room temperature for a further 24 h. The reaction mixture was then poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (120 mL). The organic layer was washed with brine (120 mL), dried over MgSO4, filtered and concentrated to give the crude as a yellow oil. Purification of the crude by flash chromatography (ISCO) eluting with a gradient [0-10% MeOH/DCM] gave (437 mg, 91%) as a pale yellow oil. 1H NMR (270 MHz, CDCl3) δ 1.45 (3H, d, J=8.1 Hz, CH3), 2.02-2.18 (2H, m, CH2), 2.58 (2H, t, J=10.8 Hz, CH2), 3.77 (2H, t, J=9.7 Hz, CH2), 4.50 (2H, m, NH and CH), 6.47-6.62 (2H, m, Ar) 6.77-6.96 (4H, m, Ar), 7.09 (1H, d, J=8.1 Hz, Ar), 7.22-7.32 (3H, m, Ar), 7.48 (1H, dd, J=2.4, 8.1 Hz, Ar), 7.59 (1H, m, Ar). LCMS (90% MeOH and 10% H2O; Symmetry C18 reverse phase column) tr=2.73 min; (ES+), m/z 407.2. HPLC 98.56% purity. was stirred at room temperature for a further 24 h extracted with DCM (120 mL) The organic layer was washed with brine (120 mL) dried over MgSO4 filtered concentrated to give the crude as a yellow oil Purification of the crude by flash chromatography (ISCO) eluting with a gradient [0-10% MeOH/DCM] gave (437 mg, 91%) as a pale yellow oil

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

Procedure: 2-(4-Chlorophenoxy)aniline (118 mg, 0.541 mmol, 1 eq) and 1-acetyl-N-(3-acetylphenyl)-N-methylpiperidine-4-carboxamide (180 mg, 0.595 mmol, 1.1 eq) were stirred in dry dichloromethane (DCM) (2 mL) at room temperature for 10 min. Tri-isopropoxytitanium chloride (284 μL, 1.19 mmol, 2 eq) was added to the reaction mixture which was stirred at room temperature for 16 hours. Sodium triacetoxyborohydride (504 mg, 2.38 mmol, 4 eq.) was then added to the reaction mixture and was stirred at room temperature for a further 24 h. The reaction mixture was then poured into aqueous sodium bicarbonate (100 mL) and extracted with DCM (120 mL). The organic layer was washed with brine (120 mL), dried over MgSO4, filtered and concentrated to give the crude as a yellow oil. Purification of the crude by flash chromatography (ISCO) eluting with a gradient [0-10% MeOH/DCM] gave (167 mg, 61%) as a white foam. 1H NMR (270 MHz, CDCl3) δ 1.2-1.38 (2H, m, CH2), 1.50 (3H, d, J=6.1 Hz, CH3), 1.55-1.80 (2H, m, CH2), 1.90 (3H, d, J=6.7 Hz CH3), 2.10-2.30 (2H, m, CH2), 2.39 and 2.65 (1H, m, CH2), 3.15 (3H, s, NCH3), 3.69 and 3.49 (1H, d, J=13.4 Hz, CH), 4.25-4.60 (3H, m, NH and CH), 6.30 (1H, d, J=8.0 Hz, Ar) 6.55 (1H, q, J=7.0 Hz, ArH), 6.75-6.95 (4H, m, ArH), 7.00-7.15 (2H, m, ArH), 7.23-7.51 (4H, m, ArH); LCMS (90% MeOH and 10% H2O; Symmetry C18 reverse phase column) tr=2.15 min; (ES+), m/z 506.4 HRMS (ESI) calcd. for C29H32ClN3O3 (M+H)+ 505.2132, found 506.2193. HPLC 100% purity. was stirred at room temperature for a further 24 h extracted with DCM (120 mL) The organic layer was washed with brine (120 mL) dried over MgSO4 filtered concentrated to give the crude as a yellow oil Purification of the crude by flash chromatography (ISCO) eluting with a gradient [0-10% MeOH/DCM] gave (167 mg, 61%) as a white foam

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

Procedure: 2-(4-Chlorophenoxy)aniline (118 mg, 0.541 mmol, 1 eq) and 1-acetyl-N-(3-acetylphenyl)-N-methylpiperidine-4-carboxamide (180 mg, 0.595 mmol, 1.1 eq) were stirred in dry dichloromethane (DCM) (2 mL) at room temperature for 10 min. Tri-isopropoxytitanium chloride (284 μL, 1.19 mmol, 2 eq) was added to the reaction mixture which was stirred at room temperature for 16 hours. Sodium triacetoxyborohydride (504 mg, 2.38 mmol, 4 eq.) was then added to the reaction mixture and was stirred at room temperature for a further 24 h. The reaction mixture was then poured into aqueous sodium bicarbonate (100 mL) and extracted with DCM (120 mL). The organic layer was washed with brine (120 mL), dried over MgSO4, filtered and concentrated to give the crude as a yellow oil. Purification of the crude by flash chromatography (ISCO) eluting with a gradient [0-10% MeOH/DCM] gave (167 mg, 61%) as a white foam. 1H NMR (270 MHz, CDCl3) δ 1.2-1.38 (2H, m, CH2), 1.50 (3H, d, J=6.1 Hz, CH3), 1.55-1.80 (2H, m, CH2), 1.90 (3H, d, J=6.7 Hz CH3), 2.10-2.30 (2H, m, CH2), 2.39 and 2.65 (1H, m, CH2), 3.15 (3H, s, NCH3), 3.69 and 3.49 (1H, d, J=13.4 Hz, CH), 4.25-4.60 (3H, m, NH and CH), 6.30 (1H, d, J=8.0 Hz, Ar) 6.55 (1H, q, J=7.0 Hz, ArH), 6.75-6.95 (4H, m, ArH), 7.00-7.15 (2H, m, ArH), 7.23-7.51 (4H, m, ArH); LCMS (90% MeOH and 10% H2O; Symmetry C18 reverse phase column) tr=2.15 min; (ES+), m/z 506.4 HRMS (ESI) calcd. for C29H32ClN3O3 (M+H)+ 505.2132, found 506.2193. HPLC 100% purity. was stirred at room temperature for a further 24 h extracted with DCM (120 mL) The organic layer was washed with brine (120 mL) dried over MgSO4 filtered concentrated to give the crude as a yellow oil Purification of the crude by flash chromatography (ISCO) eluting with a gradient [0-10% MeOH/DCM] gave (167 mg, 61%) as a white foam

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

Procedure: 2-(4-Chlorophenoxy)aniline (95 mg, 0.431 mmol, 1 eq) and 1-acetyl-N-(3-acetylphenyl)-N-ethylpiperidine-4-carboxamide (150 mg, 0.474 mmol, 1.1 eq) were stirred in dry dichloromethane (DCM) (2 mL) at room temperature for 10 min. Tri-isopropoxytitanium chloride (206 μL, 1.654 mmol, 2 eq) was added to the reaction mixture which was stirred at room temperature for 16 hours. Sodium triacetoxyborohydride (365 mg, 1.724 mmol, 4 eq) was then added to the reaction mixture and was stirred at room temperature for a further 24 h. The reaction mixture was then poured onto a solution of saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (120 mL). The organic layer was washed with brine (120 mL), dried over MgSO4, filtered and concentrated to give the crude as a yellow oil. Purification of the crude by flash chromatography (ISCO) eluting with a gradient [0-10% MeOH/DCM] gave as a pale yellow oil. 1H NMR (270 MHz, CDCl3) δ 0.98 (3H, dt, J=3.1, 7.0 Hz, CH3), 1.25 (1H, m, CH2), 1.50 (3H, d, J=6.2 Hz CH3), 1.50-1.71 (3H, m, CH2), 1.95 (3H, d, J=7.2 Hz) 2.05-2.20 (2H, m, CH2), 2.40 and 2.65 (1H, m, CH), 3.50-3.72 (3H, m, CH2), 4.30-4.61 (3H, m, CH and NH), 6.32 (1H, d, J=7.8 Hz, ArH), 6.55 (1H, q, J=7.3 Hz, Ar), 6.70-6.90 (4H, m, Ar), 6.95-7.05 (2H, m, Ar), 7.20-7.42 (4H, m, Ar); LCMS (90% MeOH and 10% H2O; Symmetry C18 reverse phase column) tr=2.38 min; (ES+), m/z 520.3; HRMS (ESI) calcd. for C30H35ClN3O3 (M+H)+ 520.2289, found 520.2343. HPLC 99.49% purity. was stirred at room temperature for a further 24 h extracted with DCM (120 mL) The organic layer was washed with brine (120 mL) dried over MgSO4 filtered concentrated to give the crude as a yellow oil Purification of the crude by flash chromatography (ISCO) eluting with a gradient [0-10% MeOH/DCM] gave as a pale yellow oil

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

Procedure: 2-(4-Chlorophenoxy)aniline (137 mg, 0.6237 mmol, 1.1 eq) and 1-acetyl-N-(3-acetylphenyl)piperidine-4-carboxamide (160 mg, 0.5549 mmol, 1 eq) were stirred in dry dichloromethane (DCM) at room temperature for 10 min. Tri-isopropoxytitanium chloride (295 μL, 1.2351 mmol, 2.2 eq) was added to the reaction mixture which was stirred at room temperature for an additional 10 min. Sodium triacetoxyborohydride (590 mg, 2.7838 mmol, 5 eq) and acetic acid (3 drops) were added to the reaction mixture which was stirred at room temperature for 16 h. The reaction mixture was then poured onto a solution of saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (80 mL). The organic layer was washed with brine (100 mL), dried over MgSO4, filtered and concentrated to give the crude as a yellow oil. Purification of the crude by flash chromatography (ISCO) eluting with a gradient [from 100% petroleum ether (PE) to 100% EtOAc] gave the title compound (48 mg, 18%) as a clear oil. was stirred at room temperature for 16 h extracted with DCM (80 mL) The organic layer was washed with brine (100 mL) dried over MgSO4 filtered concentrated to give the crude as a yellow oil Purification of the crude by flash chromatography (ISCO) eluting with a gradient [from 100% petroleum ether (PE) to 100% EtOAc]

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

Procedure: 2-(4-Chlorophenoxy)aniline (137 mg, 0.6237 mmol, 1.1 eq) and 1-acetyl-N-(3-acetylphenyl)piperidine-4-carboxamide (160 mg, 0.5549 mmol, 1 eq) were stirred in dry dichloromethane (DCM) at room temperature for 10 min. Tri-isopropoxytitanium chloride (295 μL, 1.2351 mmol, 2.2 eq) was added to the reaction mixture which was stirred at room temperature for an additional 10 min. Sodium triacetoxyborohydride (590 mg, 2.7838 mmol, 5 eq) and acetic acid (3 drops) were added to the reaction mixture which was stirred at room temperature for 16 h. The reaction mixture was then poured onto a solution of saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (80 mL). The organic layer was washed with brine (100 mL), dried over MgSO4, filtered and concentrated to give the crude as a yellow oil. Purification of the crude by flash chromatography (ISCO) eluting with a gradient [from 100% petroleum ether (PE) to 100% EtOAc] gave the title compound (48 mg, 18%) as a clear oil. was stirred at room temperature for 16 h extracted with DCM (80 mL) The organic layer was washed with brine (100 mL) dried over MgSO4 filtered concentrated to give the crude as a yellow oil Purification of the crude by flash chromatography (ISCO) eluting with a gradient [from 100% petroleum ether (PE) to 100% EtOAc]

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

Procedure: 2-(4-Chlorophenoxy)aniline (25 mg, 0.1138 mmol, 1.1 eq) and 1-acetyl-N-(2-acetylphenyl)piperidine-4-carboxamide (30 mg, 0.1040 mmol, 1 eq) were stirred in dry dichloromethane (DCM) at room temperature for 10 min. Tri-isopropoxytitanium chloride (55 μL, 0.2303 mmol, 2.2 eq) was added to the reaction mixture which was stirred at room temperature for an additional 10 min. Sodium triacetoxyborohydride (110 mg, 0.5190 mmol, 5 eq) and acetic acid (3 drops) were added to the reaction mixture which was stirred at room temperature for 16 h. The reaction mixture was then poured onto a solution of saturated aqueous sodium bicarbonate (50 mL) and extracted with DCM (30 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered and concentrated to give the crude as a yellow oil. Purification of the crude by flash chromatography (ISCO) eluting with a gradient [from 100% petroleum ether (PE) to 100% EtOAc] gave the title compound (5 mg, 10%) as a clear oil. was stirred at room temperature for 16 h extracted with DCM (30 mL) The organic layer was washed with brine (50 mL) dried over MgSO4 filtered concentrated to give the crude as a yellow oil Purification of the crude by flash chromatography (ISCO) eluting with a gradient [from 100% petroleum ether (PE) to 100% EtOAc]