4-chloro-2-(difluoromethoxy)phenol

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

Procedure: To an ice cold suspension of 2-(difluoromethoxy)phenol (6.54 g, 0.00408 mol), aluminum trichloride (0.0544 g, 0.000408 mol) and 1,1′-thiodibenzene (0.068 mL, 0.000408 mol) was added sulfuryl dichloride (3.61 mL, 0.0449 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction was diluted in dichloromethane (10.0 mL) and purified using silica gel column chromatography eluting with 0-20% EtOAc in heptane. The title compound was isolated as a colourless oil (2.33 g, 0.01195 mol, 29%). purified eluting with 0-20% EtOAc in heptane

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

Procedure: To an ice cold suspension of 2-(difluoromethoxy)phenol (6.54 g, 0.00408 mol), aluminum trichloride (0.0544 g, 0.000408 mol) and 1,1′-thiodibenzene (0.068 mL, 0.000408 mol) was added sulfuryl dichloride (3.61 mL, 0.0449 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction was diluted in dichloromethane (10.0 mL) and purified using silica gel column chromatography eluting with 0-20% EtOAc in heptane. The title compound was isolated as a colourless oil (2.33 g, 0.01195 mol, 29%). purified eluting with 0-20% EtOAc in heptane

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

Procedure: To an ice cold suspension of 2-(difluoromethoxy)phenol (6.54 g, 0.00408 mol), aluminum trichloride (0.0544 g, 0.000408 mol) and 1,1′-thiodibenzene (0.068 mL, 0.000408 mol) was added sulfuryl dichloride (3.61 mL, 0.0449 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction was diluted in dichloromethane (10.0 mL) and purified using silica gel column chromatography eluting with 0-20% EtOAc in heptane. The title compound was isolated as a colourless oil (2.33 g, 0.01195 mol, 29%). purified eluting with 0-20% EtOAc in heptane

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

Procedure: To a solution of 4-chloro-2-(difluoromethoxy)bromobenzene (Preparation 27, 200 mg, 0.63 mmol) in THF (6 mL) was added bis-neopentylglycolatodiboron (149 mg, 0.660 mmol), potassium acetate (191 mg, 1.88 mmol) and Pd(dppf)Cl2 (23 mg, 0.031 mmol). The reaction mixture was heated to reflux for 4 hours before cooling and diluting with EtOAc and water. The organic layer was collected, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in acetone (6 mL) and treated with a solution of oxone (1.64 g, 2.54 mmol) in water (6 mL). The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with diethyl ether (10 mL) and water (5 mL). The organic layer was collected, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-15% diethyl ether in DCM to afford the title compound. The reaction mixture was heated to reflux for 4 hours before cooling The organic layer was collected washed with brine dried over Na2SO4 concentrated in vacuo The residue was dissolved in acetone (6 mL) The organic layer was collected washed with brine dried over Na2SO4 concentrated in vacuo The residue was purified eluting with 0-15% diethyl ether in DCM