1-bromo-4-(diethoxymethyl)benzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve 1-bromo-4-(diethoxymethyl)-benzene (6.1 g, 23.55 mmol) in anhydrous THF (150 mL) and cool the solution to −78° C. Add n-butyllithium (11.3 mL, 28.26 mmol, 2.5M solution in hexane) and stir the mixture for 30 min. Add 3,3-dimethylbutyraldehyde (4.7 mL, 35.33 mmol) and stir the mixture for 1 h. Add water and EtOAc. Warm the solution to room temperature and extract the aqueous layer three times with EtOAc. Dry the combined organic extracts with Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (93:7) to give the desired intermediate as a colorless oil (3.8 g, 58%). Warm the solution to room temperature extract the aqueous layer three times with EtOAc Dry the combined organic extracts with Na2SO4 filter concentrate in vacuo Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (93:7)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve 1-bromo-4-(diethoxymethyl)-benzene (6.1 g, 23.55 mmol) in anhydrous THF (150 mL) and cool the solution to −78° C. Add n-butyllithium (11.3 mL, 28.26 mmol, 2.5M solution in hexane) and stir the mixture for 30 min. Add 3,3-dimethylbutyraldehyde (4.7 mL, 35.33 mmol) and stir the mixture for 1 h. Add water and EtOAc. Warm the solution to room temperature and extract the aqueous layer three times with EtOAc. Dry the combined organic extracts with Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (93:7) to give the desired intermediate as a colorless oil (3.8 g, 58%). Warm the solution to room temperature extract the aqueous layer three times with EtOAc Dry the combined organic extracts with Na2SO4 filter concentrate in vacuo Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (93:7)

反応条件: temp:12.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of magnesium turnings (5.11 g) in anhydrous tetrahydrofuran (40 mL) is added 1,2-dibromoethane (0.106 mL; 1.2 mmol). The suspension is cooled to 12° C. and 6 mL of a solution of 1-bromo-4-(diethoxymethyl)benzene (53.6 g; 200 mmol) in anhydrous tetrahydrofuran (120 mL) and a second portion of 1,2-dibromoethane (0.106 mL; 1.2 mmol) are added. After the reaction starts the remainder of the solution of 1-bromo-4-(diethoxymethyl)benzene is added over 90 minutes. The resulting mixture is further stirred at 20 to 25° C. for 2.5 hours. The mixture is diluted with anhydrous tetrahydrofuran to a total volume of 250 mL. The concentration of 4-(diethoxymethyl)phenylmagnesium bromide in the solution above the excess of magnesium turnings is about 0.78 M. In another flask are added to dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.012 g; 0.015 mmol) a 0.5 M zinc chloride solution in tetrahydrofuran (0.6 mL; 0.30 mmol) and a solution of a mixture of 5-(2-bromophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole and 5-(2-bromophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazole (4.99 g; 14.3 mmol) in tetrahydrofuran (30 mL). To the stirred resulting yellow-orange solution is added at room temperature 22.2 mL of the above 0.78 M 4-(diethoxymethyl)phenylmagnesium bromide solution (17.3 mmol) over two hours. The resulting orange solution is further stirred at room temperature for 18 hours. After that, no more starting material could be detected by thin layer chromatography. The mixture is cooled to about 0° C. and a solution of sodium hydrogencarbonate (2.0 g) in water (25 mL) and ethyl acetate (30 mL) are added. The aqueous phase is separated and extracted with ethyl acetate (40 mL). The combined organic phases are washed with a solution of sodium hydrogencarbonate (2.0 g) in water (25 mL) and twice with water (25 mL) before they are evaporated in vacuo. The resulting orange oil is purified by column chromatography on silica gel eluting with a 1:4 mixture of ethyl acetate and hexane (in the presence of 0.3 volume-% of triethylamine) to afford the main isomer (N2-isomer) 5-(4′-diethoxymethyl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)-2H-tetrazole as a pale yellow oil. is added over 90 minutes To the stirred resulting yellow-orange solution The resulting orange solution is further stirred at room temperature for 18 hours The mixture is cooled to about 0° C. The aqueous phase is separated extracted with ethyl acetate (40 mL) The combined organic phases are washed with a solution of sodium hydrogencarbonate (2.0 g) in water (25 mL) and twice with water (25 mL) before they are evaporated in vacuo The resulting orange oil is purified by column chromatography on silica gel eluting with a 1:4 mixture of ethyl acetate and hexane (in the presence of 0.3 volume-% of triethylamine)

反応条件: temp:12.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of magnesium turnings (5.11 g) in anhydrous tetrahydrofuran (40 mL) is added 1,2-dibromoethane (0.106 mL; 1.2 mmol). The suspension is cooled to 12° C. and 6 mL of a solution of 1-bromo-4-(diethoxymethyl)benzene (53.6 g; 200 mmol) in anhydrous tetrahydrofuran (120 mL) and a second portion of 1,2-dibromoethane (0.106 mL; 1.2 mmol) are added. After the reaction starts the remainder of the solution of 1-bromo-4-(diethoxymethyl)benzene is added over 90 minutes. The resulting mixture is further stirred at 20 to 25° C. for 2.5 hours. The mixture is diluted with anhydrous tetrahydrofuran to a total volume of 250 mL. The concentration of 4-(diethoxymethyl)phenylmagnesium bromide in the solution above the excess of magnesium turnings is about 0.78 M. In another flask are added to dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.012 g; 0.015 mmol) a 0.5 M zinc chloride solution in tetrahydrofuran (0.6 mL; 0.30 mmol) and a solution of a mixture of 5-(2-bromophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole and 5-(2-bromophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazole (4.99 g; 14.3 mmol) in tetrahydrofuran (30 mL). To the stirred resulting yellow-orange solution is added at room temperature 22.2 mL of the above 0.78 M 4-(diethoxymethyl)phenylmagnesium bromide solution (17.3 mmol) over two hours. The resulting orange solution is further stirred at room temperature for 18 hours. After that, no more starting material could be detected by thin layer chromatography. The mixture is cooled to about 0° C. and a solution of sodium hydrogencarbonate (2.0 g) in water (25 mL) and ethyl acetate (30 mL) are added. The aqueous phase is separated and extracted with ethyl acetate (40 mL). The combined organic phases are washed with a solution of sodium hydrogencarbonate (2.0 g) in water (25 mL) and twice with water (25 mL) before they are evaporated in vacuo. The resulting orange oil is purified by column chromatography on silica gel eluting with a 1:4 mixture of ethyl acetate and hexane (in the presence of 0.3 volume-% of triethylamine) to afford the main isomer (N2-isomer) 5-(4′-diethoxymethyl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)-2H-tetrazole as a pale yellow oil. is added over 90 minutes To the stirred resulting yellow-orange solution The resulting orange solution is further stirred at room temperature for 18 hours The mixture is cooled to about 0° C. The aqueous phase is separated extracted with ethyl acetate (40 mL) The combined organic phases are washed with a solution of sodium hydrogencarbonate (2.0 g) in water (25 mL) and twice with water (25 mL) before they are evaporated in vacuo The resulting orange oil is purified by column chromatography on silica gel eluting with a 1:4 mixture of ethyl acetate and hexane (in the presence of 0.3 volume-% of triethylamine)

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

実験手順: Magnesium metal (0.200 g, 8.23 mmol) was activated using a crystal of iodine followed by the addition of THF (4 mL). 1-Bromo-4-(diethoxymethyl)-benzene (2.0 g, 7.72 mmol) was added and the mixture allowed to sit without stirring for 5 minutes. Gas evolution was observed and the colour of the iodine mostly disappeared. Stirring was then initiated and additional dry THF (20 mL) was added. After stirring for 2 hours, the mixture was allowed to settle. The supernatant was added to a solution of (S,E)-2-methyl-N-((3-(trifluoromethyl)-pyridin-2-yl)methylene)propane-2-sulfinamide (0.450 g, 1.617 mmol) in dry THF (10 mL). The resulting reaction mixture was stirred overnight. Saturated aqueous NH4Cl (10 mL) was added followed by H2O (80 mL) and EtOAc (100 mL). The phases were mixed and separated. The organic layer was dried with MgSO4 and evaporated to dryness under reduced pressure. The acetal was further dried under high vacuum. The acetal was dissolved in EtOAc (50 mL) and treated with 50% TFA in H2O (50 mL). The solution was stirred vigorously for 20 minutes. Water (200 mL), EtOAc (100 mL), and Et2O (100 mL) were then added and the phases separated. The aqueous layer was removed, and the organic layer was washed with additional H2O (2×200 mL). The organic layer was then washed with saturated aqueous NaHCO3 (3×100 mL, strong gas evolution) followed by H2O (100 mL) and finally brine (100 mL). The organic layer was dried with MgSO4 and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave the desired (S)—N—((S)-(4-formylphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide as an oil. Stirring After stirring for 2 hours The resulting reaction mixture was stirred overnight The phases were mixed separated The organic layer was dried with MgSO4 evaporated to dryness under reduced pressure The acetal was further dried under high vacuum The acetal was dissolved in EtOAc (50 mL) treated with 50% TFA in H2O (50 mL) The solution was stirred vigorously for 20 minutes Water (200 mL), EtOAc (100 mL), and Et2O (100 mL) were then added the phases separated The aqueous layer was removed the organic layer was washed with additional H2O (2×200 mL) The organic layer was then washed with saturated aqueous NaHCO3 (3×100 mL, strong gas evolution) The organic layer was dried with MgSO4 evaporated to dryness under reduced pressure Purification

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

実験手順: Magnesium metal (0.200 g, 8.23 mmol) was activated using a crystal of iodine followed by the addition of THF (4 mL). 1-Bromo-4-(diethoxymethyl)-benzene (2.0 g, 7.72 mmol) was added and the mixture allowed to sit without stirring for 5 minutes. Gas evolution was observed and the colour of the iodine mostly disappeared. Stirring was then initiated and additional dry THF (20 mL) was added. After stirring for 2 hours, the mixture was allowed to settle. The supernatant was added to a solution of (S,E)-2-methyl-N-((3-(trifluoromethyl)-pyridin-2-yl)methylene)propane-2-sulfinamide (0.450 g, 1.617 mmol) in dry THF (10 mL). The resulting reaction mixture was stirred overnight. Saturated aqueous NH4Cl (10 mL) was added followed by H2O (80 mL) and EtOAc (100 mL). The phases were mixed and separated. The organic layer was dried with MgSO4 and evaporated to dryness under reduced pressure. The acetal was further dried under high vacuum. The acetal was dissolved in EtOAc (50 mL) and treated with 50% TFA in H2O (50 mL). The solution was stirred vigorously for 20 minutes. Water (200 mL), EtOAc (100 mL), and Et2O (100 mL) were then added and the phases separated. The aqueous layer was removed, and the organic layer was washed with additional H2O (2×200 mL). The organic layer was then washed with saturated aqueous NaHCO3 (3×100 mL, strong gas evolution) followed by H2O (100 mL) and finally brine (100 mL). The organic layer was dried with MgSO4 and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave the desired (S)—N—((S)-(4-formylphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide as an oil. Stirring After stirring for 2 hours The resulting reaction mixture was stirred overnight The phases were mixed separated The organic layer was dried with MgSO4 evaporated to dryness under reduced pressure The acetal was further dried under high vacuum The acetal was dissolved in EtOAc (50 mL) treated with 50% TFA in H2O (50 mL) The solution was stirred vigorously for 20 minutes Water (200 mL), EtOAc (100 mL), and Et2O (100 mL) were then added the phases separated The aqueous layer was removed the organic layer was washed with additional H2O (2×200 mL) The organic layer was then washed with saturated aqueous NaHCO3 (3×100 mL, strong gas evolution) The organic layer was dried with MgSO4 evaporated to dryness under reduced pressure Purification

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: Under an atmosphere of nitrogen, a solution of 900 mg of 4-bromobenzaldehyde diethylacetal in 1.8 ml of tetrahydrofuran was added dropwise to 83 mg of magnesium at 50° to 60° C., and the mixture was stirred at that temperature for 10 minutes, and then diluted with 2 ml of tetrahydrofuran. The solution, thus obtained, was added dropwise to a solution of 280 mg of 4-methyl-3-formylpyridine [prepared as described in J. Org. Chem., 25, 560(1960)] in 7 ml of tetrahydrofuran at 0° C., and the mixture was stirred at the same temperature for one hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (7:3) a eluent to give 406 mg of the title compound having the following physical characteristics: The solution, thus obtained the mixture was stirred at the same temperature for one hour The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride concentrated under reduced pressure To the residue was added a saturated aqueous solution of sodium bicarbonate the mixture was extracted with ethyl acetate The extract was washed with water dried over magnesium sulphate concentrated under reduced pressure The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (7:3) a eluent

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 4-bromobenzaldehyde diethyl acetal (107 g, 0.41 mol) in anhydrous THF (750 mL) was added n-BuLi (1.6 M in hexanes, 268 mL, 0.43 mol) dropwise at −78° C. After stirring for 1 h at −78° C., a solution of 15 (97.6 g, 0.34 mol) in THF (750 mL) was cannulated into the reaction mixture portionwise. The mixture was stirred overnight at RT, H2O (500 mL) was added, and the volatiles were removed under reduced pressure. The residue was extracted with Et2O (3×500 mL) and the combined extracts washed with H2O (500 mL) and brine (500 mL). The mixture was dried over MgSO4 and concentrated to afford 194 g of 16 that was used without further purification. 1HNMR (400 MHz, DMSO-d6): δ 0.58 (t, J=7.3 Hz, 3H), 1.12 (m, 6H), 1.52 (m, 1H), 1.70 (m, 1H), 3.23 (s, 3H), 3.40-3.65 (m, 5H), 4.98 (s, 2H), 5.41 (s, 1H), 5.51 (s, 1H), 6.62 (d, J=8.8 Hz, 2H), 6.96-7.06 (m, 3H), 7.17-7.23 (m, 4H), 7.31 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H). The mixture was stirred overnight at RT the volatiles were removed under reduced pressure The residue was extracted with Et2O (3×500 mL) the combined extracts washed with H2O (500 mL) and brine (500 mL) The mixture was dried over MgSO4 concentrated