3-chloro-4-(difluoromethoxy)phenol

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

Procedure: To a solution of 4-bromo-2-chloro-1-(difluoromethoxy)benzene (Preparation 70, 0.83 g, 3.2 mmol) in THF (16 mL) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.90 g, 3.6 mmol), Pd(dppf)Cl2 (0.12 g, 0.16 mmol), and potassium acetate (0.98 g, 9.7 mmol) under a nitrogen atmosphere and the mixture heated at reflux for 2 hours. The reaction mixture was then concentrated in vacuo, the resulting residue filtered through silica gel pad with arbocel and washed EtOAc. The filtrate was concentrated in vacuo to yield a crude product of 2-[3-chloro-4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A solution of crude 2-[3-chloro-4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 3.3 mmol) in acetone (10 mL) was added to an aqueous oxone solution (2.6 g, 3.9 mmol, 10 mL) dropwise with stirring at 0° C. for 1 hour. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL) and the organic layer was washed with brine, dried over sodium sulphate, filtered, and concentrated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 0 to 40% EtOAc in heptane to afford the title compound as a pale brown oil (0.53 g, 82%): The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL) the organic layer was washed with brine dried over sodium sulphate filtered concentrated in vacuo The resulting crude was purified by silica gel chromatography eluting with 0 to 40% EtOAc in heptane

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

Procedure: To a solution of 4-bromo-2-chloro-1-(difluoromethoxy)benzene (Preparation 70, 0.83 g, 3.2 mmol) in THF (16 mL) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.90 g, 3.6 mmol), Pd(dppf)Cl2 (0.12 g, 0.16 mmol), and potassium acetate (0.98 g, 9.7 mmol) under a nitrogen atmosphere and the mixture heated at reflux for 2 hours. The reaction mixture was then concentrated in vacuo, the resulting residue filtered through silica gel pad with arbocel and washed EtOAc. The filtrate was concentrated in vacuo to yield a crude product of 2-[3-chloro-4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A solution of crude 2-[3-chloro-4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 3.3 mmol) in acetone (10 mL) was added to an aqueous oxone solution (2.6 g, 3.9 mmol, 10 mL) dropwise with stirring at 0° C. for 1 hour. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL) and the organic layer was washed with brine, dried over sodium sulphate, filtered, and concentrated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 0 to 40% EtOAc in heptane to afford the title compound as a pale brown oil (0.53 g, 82%): The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL) the organic layer was washed with brine dried over sodium sulphate filtered concentrated in vacuo The resulting crude was purified by silica gel chromatography eluting with 0 to 40% EtOAc in heptane

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

Procedure: To a solution of 4-bromo-2-chloro-1-(difluoromethoxy)benzene (Preparation 27, 0.83 g, 3.2 mmol) in THF (16 ml) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.90 g, 3.6 mmol), Pd(dppf)Cl2 (0.12 g, 0.16 mmol), and potassium acetate (0.98 g, 9.7 mmol) under N2 and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo and the residue filtered through a silica gel cake with arbocel on top washing through with EtOAc. The filtrate was concentrated in vacuo to give a crude product of 2-[3-chloro-4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A solution of crude of 2-[3-chloro-4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 3.3 mmol) in acetone (10 ml) was added to an aqueous oxone solution (2.6 g, 3.9 mmol, 10 mL) dropwise with stirring at 0° C. for 1 hour. The reaction mixture was partitioned between water (20 ml) and EtOAc (20 ml), the combined organic phase was washed with brine, dried over sodium sulphate, filtered, and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography eluting with 0-40% EtOAc in Heptane to afford the title compound (0.53 g, 82% yield) as a pale brown oil. The reaction mixture was partitioned between water (20 ml) and EtOAc (20 ml) the combined organic phase was washed with brine dried over sodium sulphate filtered concentrated in vacuo to give a crude product, which was purified by silica gel chromatography eluting with 0-40% EtOAc in Heptane

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

Procedure: To a solution of 4-bromo-2-chloro-1-(difluoromethoxy)benzene (Preparation 70, 0.83 g, 3.2 mmol) in THF (16 mL) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.90 g, 3.6 mmol), Pd(dppf)Cl2 (0.12 g, 0.16 mmol), and potassium acetate (0.98 g, 9.7 mmol) under a nitrogen atmosphere and the mixture heated at reflux for 2 hours. The reaction mixture was then concentrated in vacuo, the resulting residue filtered through silica gel pad with arbocel and washed EtOAc. The filtrate was concentrated in vacuo to yield a crude product of 2-[3-chloro-4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A solution of crude 2-[3-chloro-4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 3.3 mmol) in acetone (10 mL) was added to an aqueous oxone solution (2.6 g, 3.9 mmol, 10 mL) dropwise with stirring at 0° C. for 1 hour. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL) and the organic layer was washed with brine, dried over sodium sulphate, filtered, and concentrated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 0 to 40% EtOAc in heptane to afford the title compound as a pale brown oil (0.53 g, 82%): The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL) the organic layer was washed with brine dried over sodium sulphate filtered concentrated in vacuo The resulting crude was purified by silica gel chromatography eluting with 0 to 40% EtOAc in heptane