2,4,6-trifluorobenzaldehyde

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

Procedure: To a solution of 2,4,6-trifluorobenzaldehyde (0.80 g, 5.0 mmol) in 1,2-dimethoxyethane (10 mL) were added potassium carbonate (1.04 g, 7.5 mmol) and O-methylhydroxylamine hydrochloride (438 mg, 5.25 mmol). The reaction mixture was heated at 50° C. for 5 h then cooled to room temperature and filtered, rinsing with dichloromethane. The filtrate was concentrated. The residue was dissolved in 1,2-dimethoxyethane (10 mL) and hydrazine (0.17 mL, 5.5 mmol) was added. The reaction mixture was heated at 100° C. for 1.5 h. Additional hydrazine (0.17 mL, 5.5 mmol) was added and heating was continued for 30 min. Thereaction was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with sat LiCl and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane to provide 358 mg (47%) of 4,6-difluoro-1H-indazole as a light yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 13.47 (br. s., 1H), 8.19 (s, 1H), 7.22 (d, J=9.1 Hz, 1H), 6.96 (td, J=10.0, 1.9 Hz, 1H). then cooled to room temperature filtered rinsing with dichloromethane The filtrate was concentrated The residue was dissolved in 1,2-dimethoxyethane (10 mL) The reaction mixture was heated at 100° C. for 1.5 h heating Thereaction was cooled to room temperature extracted with ethyl acetate The organic layer was washed with sat LiCl and brine then dried over MgSO4 concentrated The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,4,6-trifluorobenzaldehyde (0.80 g, 5.0 mmol) in 1,2-dimethoxyethane (10 mL) were added potassium carbonate (1.04 g, 7.5 mmol) and O-methylhydroxylamine hydrochloride (438 mg, 5.25 mmol). The reaction mixture was heated at 50° C. for 5 h then cooled to room temperature and filtered, rinsing with dichloromethane. The filtrate was concentrated. The residue was dissolved in 1,2-dimethoxyethane (10 mL) and hydrazine (0.17 mL, 5.5 mmol) was added. The reaction mixture was heated at 100° C. for 1.5 h. Additional hydrazine (0.17 mL, 5.5 mmol) was added and heating was continued for 30 min. Thereaction was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with sat LiCl and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane to provide 358 mg (47%) of 4,6-difluoro-1H-indazole as a light yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 13.47 (br. s., 1H), 8.19 (s, 1H), 7.22 (d, J=9.1 Hz, 1H), 6.96 (td, J=10.0, 1.9 Hz, 1H). then cooled to room temperature filtered rinsing with dichloromethane The filtrate was concentrated The residue was dissolved in 1,2-dimethoxyethane (10 mL) The reaction mixture was heated at 100° C. for 1.5 h heating Thereaction was cooled to room temperature extracted with ethyl acetate The organic layer was washed with sat LiCl and brine then dried over MgSO4 concentrated The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane

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

Procedure: To a suspension of 2,4,6-trifluorobenzaldehyde (5.00 g, 31.2 mmol) and potassium carbonate (5.61 g, 40.6 mmol) in N,N-dimethylformamide (63 mL) was added ethyl thioglycolate (3.40 g, 28.3 mmol) at 0° C. The mixture was stirred at room temperature overnight, and then heated to stir at 60° C. for 6 hours. The mixture was cooled to room temperature, and then to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→93:7) to give ethyl 4,6-difluoro-1-benzothiophene-2-carboxylate (1.95 g, 29%) as a pale yellow solid. heated to stir at 60° C. for 6 hours The mixture was cooled to room temperature the mixture was extracted with ethyl acetate The organic layer was washed with water and saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→93:7)

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

Procedure: To the solution of ethyl[bis(methyloxy)phosphoryl]acetate (1.980 mL, 11.99 mmol) in THF-DMF (60 mL, v/v=5:1) at 0° C. was added t-BuOK (1.458 g, 12.99 mmol) portion wise. The resultant mixture was stirred at room temperature for 30 minutes, then mixed with a solution of 2,4,6-trifluorobenzaldehyde (1.6 g, 9.99 mmol) in THF (10 mL) at 0° C. It was allowed to warm to room temperature and the mixture was stirred for 45 min. It was mixed with aqueous ammonium chloride and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by a flash column chromatography to give the title compound as a pale yellow oil (2.0 g, 87% yield). LCMS: rt=3.52 min, [M+H+]=231.1 extracted with ethyl acetate The organic layer was washed with brine dried over Na2SO4 filtered concentrated The residue was purified by a flash column chromatography

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

Procedure: To the solution of ethyl[bis(methyloxy)phosphoryl]acetate (1.980 mL, 11.99 mmol) in THF-DMF (60 mL, v/v=5:1) at 0° C. was added t-BuOK (1.458 g, 12.99 mmol) portion wise. The resultant mixture was stirred at room temperature for 30 minutes, then mixed with a solution of 2,4,6-trifluorobenzaldehyde (1.6 g, 9.99 mmol) in THF (10 mL) at 0° C. It was allowed to warm to room temperature and the mixture was stirred for 45 min. It was mixed with aqueous ammonium chloride and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by a flash column chromatography to give the title compound as a pale yellow oil (2.0 g, 87% yield). LCMS: rt=3.52 min, [M+H+]=231.1 extracted with ethyl acetate The organic layer was washed with brine dried over Na2SO4 filtered concentrated The residue was purified by a flash column chromatography

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

Procedure: To the solution of ethyl[bis(methyloxy)phosphoryl]acetate (1.980 mL, 11.99 mmol) in THF-DMF (60 mL, v/v=5:1) at 0° C. was added t-BuOK (1.458 g, 12.99 mmol) portion wise. The resultant mixture was stirred at room temperature for 30 minutes, then mixed with a solution of 2,4,6-trifluorobenzaldehyde (1.6 g, 9.99 mmol) in THF (10 mL) at 0° C. It was allowed to warm to room temperature and the mixture was stirred for 45 min. It was mixed with aqueous ammonium chloride and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by a flash column chromatography to give the title compound as a pale yellow oil (2.0 g, 87% yield). LCMS: rt=3.52 min, [M+H+]=231.1 extracted with ethyl acetate The organic layer was washed with brine dried over Na2SO4 filtered concentrated The residue was purified by a flash column chromatography

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

Procedure: A solution of 2,4,6-Trifluoro-benzaldehyde (3 g, 18.74 mmol) and methyl hydrazine (40% in water, 2.6 ml, 18.74 mmol) in 20 ml anhydrous ethanol was stirred at room temperature for 1 hour. Solvent was evaporated to give the title compound as a white solid which was used in the next step without purification (3.95 g, 100%). LCMS (method B): [MH]+=189, tR=2.16 min. Solvent was evaporated

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

Procedure: A solution of 2,4,6-Trifluoro-benzaldehyde (3 g, 18.74 mmol) and methyl hydrazine (40% in water, 2.6 ml, 18.74 mmol) in 20 ml anhydrous ethanol was stirred at room temperature for 1 hour. Solvent was evaporated to give the title compound as a white solid which was used in the next step without purification (3.95 g, 100%). LCMS (method B): [MH]+=189, tR=2.16 min. Solvent was evaporated