2,2-difluoro-2-phenylethanol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred mixture of 0.23 g of g of cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester, 0.54 g of 1.1′-(azodicarbonyl)-dipiperidine and 20 mL of benzene was added 0.4 g of tri-n-butyl-phosphine and 1.3 g (8 equivalents) of 2,2-difluoro-2-phenyl-ethanol. The mixture was heated to 60° C. overnight, then an additional 0.5 g of 1.1′-(azodicarbonyl)-dipiperidine and 0.4 g of tri-n-butyl-phosphine was added and heating continued for another 24 h. The mixture was cooled, diluted with 25 mL of toluene, filtered and the filter pad washed with 5 mL of toluene. The filtrate was purified by chromatography on silica gel eluting with a gradient of 0%-20% ethyl acetate in hexane gave 0.15 g of product as a resin: 1H NMR (400 MHz, CDCl3) 7.5 (m, 5H), 3.95 (m, 2H), 3.4 (m, 1H), 1.95 (m, 2H), 1.6 (m, 6H), 1.45 (s, 9H). heating The mixture was cooled filtered the filter pad washed with 5 mL of toluene The filtrate was purified by chromatography on silica gel eluting with a gradient of 0%-20% ethyl acetate in hexane

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred mixture of 0.23 g of g of cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester, 0.54 g of 1.1′-(azodicarbonyl)-dipiperidine and 20 mL of benzene was added 0.4 g of tri-n-butyl-phosphine and 1.3 g (8 equivalents) of 2,2-difluoro-2-phenyl-ethanol. The mixture was heated to 60° C. overnight, then an additional 0.5 g of 1.1′-(azodicarbonyl)-dipiperidine and 0.4 g of tri-n-butyl-phosphine was added and heating continued for another 24 h. The mixture was cooled, diluted with 25 mL of toluene, filtered and the filter pad washed with 5 mL of toluene. The filtrate was purified by chromatography on silica gel eluting with a gradient of 0%-20% ethyl acetate in hexane gave 0.15 g of product as a resin: 1H NMR (400 MHz, CDCl3) 7.5 (m, 5H), 3.95 (m, 2H), 3.4 (m, 1H), 1.95 (m, 2H), 1.6 (m, 6H), 1.45 (s, 9H). heating The mixture was cooled filtered the filter pad washed with 5 mL of toluene The filtrate was purified by chromatography on silica gel eluting with a gradient of 0%-20% ethyl acetate in hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred mixture of 2.2 g of difluoro-2-phenyl acetic acid ethyl ester (W. J. Middleton, E. M. Bingham, J. Org. Chem., 45, 2883-2887 (1980)), and 0.6 g of sodium borohydride in 75 mL of ethanol was kept at room temperature overnight, concentrated to near dryness under reduced pressure carefully acidified with 20 mL of 5% HCl and extracted into 3×50 mL of dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave 1.7 g of product as an oil: 1H NMR (400 MHz, CDCl3) 7.5 (m, 5H), 4.0 (t, 2H). concentrated extracted into 3×50 mL of dichloromethane The combined extracts were dried over magnesium sulfate concentrated under reduced pressure Drying under vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred mixture of 2.2 g of difluoro-2-phenyl acetic acid ethyl ester (W. J. Middleton, E. M. Bingham, J. Org. Chem., 45, 2883-2887 (1980)), and 0.6 g of sodium borohydride in 75 mL of ethanol was kept at room temperature overnight, concentrated to near dryness under reduced pressure carefully acidified with 20 mL of 5% HCl and extracted into 3×50 mL of dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave 1.7 g of product as an oil: 1H NMR (400 MHz, CDCl3) 7.5 (m, 5H), 4.0 (t, 2H). concentrated extracted into 3×50 mL of dichloromethane The combined extracts were dried over magnesium sulfate concentrated under reduced pressure Drying under vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add triflic anhydride (1.28 mL, 2.14 g) dropwise to a stirred solution of 2,2-difluoro-2-phenyl-ethanol (0.8 g, 5.06 mmol) and 2,6-di-tert-butyl-4-methylpyridine (1.556 g, 7.59 mmol) in anhydrous dichloromethane (25 mL) at −78° C. Stir the reaction overnight while the temperature warms up. Dilute the mixture with pentane and filter the precipitate over Celite®b. Concentrate the filtrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (95:5) to provide the title compound (946 mg, 64%). the reaction overnight while the temperature filter the precipitate over Celite®b Concentrate the filtrate in vacuo purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (95:5)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add triflic anhydride (1.28 mL, 2.14 g) dropwise to a stirred solution of 2,2-difluoro-2-phenyl-ethanol (0.8 g, 5.06 mmol) and 2,6-di-tert-butyl-4-methylpyridine (1.556 g, 7.59 mmol) in anhydrous dichloromethane (25 mL) at −78° C. Stir the reaction overnight while the temperature warms up. Dilute the mixture with pentane and filter the precipitate over Celite®b. Concentrate the filtrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (95:5) to provide the title compound (946 mg, 64%). the reaction overnight while the temperature filter the precipitate over Celite®b Concentrate the filtrate in vacuo purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (95:5)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add lithium aluminum hydride (5.18 mL, 5.18 mmol, 1M solution in THF) to a solution of methyl difluorophenylethanoate (0.964 g, 5.18 mmol, prepared by following the procedure described in J. Org. Chem. 1995, 60, 5174-5179) in anhydrous THF (10 mL) at 0° C. Stir the mixture at room temperature for 45 min. Cool to 0° C. and quench with EtOAc and then water. Separate the organic phase and extract twice the aqueous phase with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to provide the desired intermediate (0.8 g, 98%) that was used without any further purification. prepared at 0° C Cool to 0° C. quench with EtOAc Separate the organic phase extract twice the aqueous phase with EtOAc Dry the combined organic extracts over Na2SO4 filter concentrate in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Obtained from Intermediate 6 (1.0 g, 6.3 mmol) by the procedure described for the Intermediate 13. The title compound was obtained (0.88 g, 86%) as oil.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Obtained from Intermediate 6 (1.0 g, 6.3 mmol) by the procedure described for the Intermediate 13. The title compound was obtained (0.88 g, 86%) as oil.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Obtained from Intermediate 6 (6.88 g, 43.5 mmol) by the procedure described in Intermediate 3. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (10:1) as eluent gave the title compound (10.9 g, 78%) as oil. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (10:1) as eluent

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Obtained from Intermediate 6 (6.88 g, 43.5 mmol) by the procedure described in Intermediate 3. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (10:1) as eluent gave the title compound (10.9 g, 78%) as oil. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (10:1) as eluent