1-bromo-2-(difluoromethyl)benzene

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: After dissolving 1-bromo-2-difluoromethylbenzene (3.23 g) in tetrahydrofuran (65 ml), the mixture was cooled to −78° C. After then adding n-butyllithium (2.64 M solution in hexane, 6.5 ml) and stirring for 30 minutes, N,N-dimethylformamide (2.4 ml) was added and stirring was continued for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (991 mg). extracted with ethyl acetate The organic layer was washed with water and brine in that order dried over anhydrous magnesium sulfate After filtration the solvent was distilled off under reduced pressure The residue was purified by silica gel column chromatography

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: After dissolving 1-bromo-2-difluoromethylbenzene (3.23 g) in tetrahydrofuran (65 ml), the mixture was cooled to −78° C. After then adding n-butyllithium (2.64 M solution in hexane, 6.5 ml) and stirring for 30 minutes, N,N-dimethylformamide (2.4 ml) was added and stirring was continued for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (991 mg). extracted with ethyl acetate The organic layer was washed with water and brine in that order dried over anhydrous magnesium sulfate After filtration the solvent was distilled off under reduced pressure The residue was purified by silica gel column chromatography

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

Procedure: A solution of n-BuLi (4.2 mL, 10.6 mmol) in THF was added to a solution of 1-bromo-2-(difluoromethyl)benzene 51 (2.0 g, 9.7 mmol) in THF (50 mL) at −78° C. The reaction mixture was stirred for 30 min and DMF (1.4 g, 19.3 mmol) was added. Stirring was continued for 1 h at −40° C. and the reaction was quenched by the addition of sat. aq NH4Cl. The crude mixture was extracted with Et2O, dried (MgSO4) and concentrated to give 52 (1.7 g, 94% yield). Stirring was continued for 1 h at −40° C. the reaction was quenched by the addition of sat. aq NH4Cl The crude mixture was extracted with Et2O dried (MgSO4) concentrated

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Combiblocks PN-8756, 1.9 g, 6.7 mmol), 1-bromo-2-difluoromethyl-benzene (Fluorochem 023878, 1.7 g, 8.1 mmol), cesium fluoride (3.1 g, 20 mmol) and PdCl2(PPh3)2 (142 mg, 0.20 mmol) was prepared in dioxane (20 mL) and water (10 mL) under N2 atmosphere. The resulting mixture was heated at 90° C. for 2 hours. The reaction mixture was diluted with MTBE (60 mL), and then washed with water (2×50 mL) and brine (50 mL). The aqueous layers were extracted with MTBE (50 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, DCM/heptane), the title compound was obtained as a colorless oil (1.4 g, 76%). HPLC (Method A) Rt 5.0 min (purity: 99.1%). 1H NMR (DMSO-d6, 300 MHz) δ 7.93 (s, 1H), 7.84 (dd, J=7.9, 1.4 Hz, 1H), 7.75 (m, 1H), 7.67-7.56 (m, 2H), 7.28 (m, 2H), 6.55 (t, J=55 Hz, 1H), 3.88 (s, 3H), 2.06 (s, 3H). washed with water (2×50 mL) and brine (50 mL) The aqueous layers were extracted with MTBE (50 mL) dried (MgSO4) concentrated under reduced pressure After purification by flash chromatography (silica, DCM/heptane)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-bromo-2-difluoromethyl-benzene (19.8 g, 95.7 mmol) in dry THF (200 ml) at −78° C. under a nitrogen atmosphere was added 2.5 M n-BuLi in hexanes (42 ml, 105 mmol) slowly. After completion of the addition, the resulting dark solution was stirred for an additional hour at −78° C. Subsequently, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25 ml, 123 mmol) was added, and the solution was slowly warmed to room temperature. After stirring overnight at room temperature under a nitrogen atmosphere the solution was poured into 400 ml water. Ethyl acetate (300 ml) was added and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (150 ml and 50 ml respectively), and the combined organic layers were washed with water, dried over Na2SO4, filtered, and evaporated to dryness under reduced pressure. The resulting brown oil (21 g) was purified by bulb-to-bulb-distillation at 3×10−3 mbar at 90-95° C. to yield 2-(2-difluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (14.4 g, 59%) as a slightly yellow oil. After completion of the addition the solution was slowly warmed to room temperature After stirring overnight at room temperature under a nitrogen atmosphere the solution the layers were separated The aqueous layer was extracted twice with ethyl acetate (150 ml and 50 ml respectively), and the combined organic layers were washed with water dried over Na2SO4 filtered evaporated to dryness under reduced pressure The resulting brown oil (21 g) was purified by bulb-to-bulb-distillation at 3×10−3 mbar at 90-95° C.

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

Procedure: A solution of 1-bromo-2-difluoromethylbenzene (9.6 g, 46.8 mmol) and N-bromosuccinimide (24.8 g, 139 mmol) in carbon tetrachloride (100 mL) was irradiated with a sunlamp. After 3 days, the reaction mixture was diluted with hexane, the precipitate was filtered off, and the collected organic filtrate was concentrated in vacuo. Purification by flash chromatography on silica gel (100% hexanes) provided the title compound: 1H NMR (500 M=Hz, CD2Cl2) δ7.74 (d, J=8.0 Hz, 1H), 7.66 (dd, J=8.0, 1.5 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.37 (td, J=7.7, 1.3 Hz, 1H). the precipitate was filtered off the collected organic filtrate was concentrated in vacuo Purification by flash chromatography on silica gel (100% hexanes)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: After dissolving 1-bromo-2-difluoromethylbenzene (3.23 g) in tetrahydrofuran (65 ml), the mixture was cooled to −78° C. After then adding n-butyllithium (2.64 M solution in hexane, 6.5 ml) and stirring for 30 minutes, N,N-dimethylformamide (2.4 ml) was added and stirring was continued for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (991 mg). extracted with ethyl acetate The organic layer was washed with water and brine in that order dried over anhydrous magnesium sulfate After filtration the solvent was distilled off under reduced pressure The residue was purified by silica gel column chromatography

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

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Combiblocks PN-8756, 1.86 g, 6.74 mmol), 1-bromo-2-difluoromethyl-benzene (Fluorochem 023878, 1.67 g, 8.08 mmol), cesium fluoride (3.07 g, 20.2 mmol) and PdCl2(PPh3)2 (142 mg, 0.20 mmol) was prepared in dioxane (20 mL) and water (10 mL) under nitrogen atmosphere. The resulting mixture was heated at 90° C. for 2 hours. The reaction mixture was diluted with MTBE (60 mL), and then washed with water (2×50 mL) and brine (50 mL). The aqueous layers were extracted with MTBE (50 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, DCM/heptane), the title compound was obtained as a colorless oil (1.42 g, 76%). HPLC (Method A) Rt 5.0 min (purity: 99.1%). 1H NMR (DMSO-d6, 300 MHz) δ 7.93 (s, 1H), 7.84 (dd, J=7.9, 1.4 Hz, 1H), 7.75 (m, 1H), 7.67-7.56 (m, 2H), 7.28 (m, 2H), 6.55 (t, J=54.7 Hz, 1H), 3.88 (s, 3H), 2.06 (s, 3H). washed with water (2×50 mL) and brine (50 mL) The aqueous layers were extracted with MTBE (50 mL) dried (MgSO4) concentrated under reduced pressure After purification by flash chromatography (silica, DCM/heptane)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Combiblocks PN-8756, 1.86 g, 6.74 mmol), 1-bromo-2-difluoromethyl-benzene (Fluorochem 023878, 1.67 g, 8.08 mmol), cesium fluoride (3.07 g, 20.2 mmol) and PdCl2(PPh3)2 (142 mg, 0.20 mmol) was prepared in dioxane (20 mL) and water (10 mL) under nitrogen atmosphere. The resulting mixture was heated at 90° C. for 2 hours. The reaction mixture was diluted with MTBE (60 mL), and then washed with water (2×50 mL) and brine (50 mL). The aqueous layers were extracted with MTBE (50 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, DCM/heptane), the title compound was obtained as a colorless oil (1.42 g, 76%). HPLC (Method A) Rt 5.0 min (purity: 99.1%). 1H NMR (DMSO-d6, 300 MHz) δ 7.93 (s, 1H), 7.84 (dd, J=7.9, 1.4 Hz, 1H), 7.75 (m, 1H), 7.67-7.56 (m, 2H), 7.28 (m, 2H), 6.55 (t, J=54.7 Hz, 1H), 3.88 (s, 3H), 2.06 (s, 3H). washed with water (2×50 mL) and brine (50 mL) The aqueous layers were extracted with MTBE (50 mL) dried (MgSO4) concentrated under reduced pressure After purification by flash chromatography (silica, DCM/heptane)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-bromo-2-difluoromethyl-benzene (19.8 g, 95.7 mmol) in dry THF (200 ml) at −78° C. under a nitrogen atmosphere was added 2.5 M n-BuLi in hexanes (42 ml, 105 mmol) slowly. After completion of the addition, the resulting dark solution was stirred for an additional hour at −78° C. Subsequently, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25 ml, 123 mmol) was added, and the solution was slowly warmed to room temperature. After stirring overnight at room temperature under a nitrogen atmosphere the solution was poured into 400 ml water. Ethyl acetate (300 ml) was added and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (150 ml and 50 ml respectively), and the combined organic layers were washed with water, dried over Na2SO4, filtered, and evaporated to dryness under reduced pressure. The resulting brown oil (21 g) was purified by bulb-to-bulb-distillation at 3×10−3 mbar at 90-95° C. to yield 2-(2-difluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (14.4 g, 59%) as a slightly yellow oil. After completion of the addition the solution was slowly warmed to room temperature After stirring overnight at room temperature under a nitrogen atmosphere the solution the layers were separated The aqueous layer was extracted twice with ethyl acetate (150 ml and 50 ml respectively), and the combined organic layers were washed with water dried over Na2SO4 filtered evaporated to dryness under reduced pressure The resulting brown oil (21 g) was purified by bulb-to-bulb-distillation at 3×10−3 mbar at 90-95° C.