METHYL 3-CHLORO-5-IODOBENZOATE

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of L-proline (1.553 g, 13.49 mmol, CAS RN 147-85-3) in dimethylsulfoxide (80 mL) was added sodium hydroxide (0.54 g, 13.49 mmol) and the reaction mixture was stirred at 25° C. for 30 min. Then copper(I) iodide (2.568 g, 13.49 mmol), 3-chloro-5-iodo-benzoic acid methyl ester (5.0 g, 16.86 mmol, CAS RN 289039-85-6) and sodium methanesulfinate (13.77 g, 134.9 mmol, CAS RN 20277-69-4) were added to the reaction mixture and the reaction mixture was heated at 120° C. for 2 h. The reaction mixture was allowed to cool down, poured on saturated aqueous sodium bicarbonate solution (500 mL) and ethyl acetate (500 mL) and filtered through celite. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (200 mL each). The combined organic layers were washed with cold water (200 mL) and brine (100 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography over silica gel (100-200 mesh) with a gradient of ethyl acetate:n-hexane (1:10 to 2:10) to get the desired compound as a colorless solid (2.31 g, 55%). MS (EI): m/z=248 ([M]). the reaction mixture was heated at 120° C. for 2 h to cool down filtered through celite The organic layer was separated the aqueous layer was extracted twice with ethyl acetate (200 mL each) The combined organic layers were washed with cold water (200 mL) and brine (100 mL) dried over anhydrous sodium sulfate evaporated The residue was purified by column chromatography over silica gel (100-200 mesh) with a gradient of ethyl acetate:n-hexane (1:10 to 2:10)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of L-proline (77.7 mg, 675 μmol) in DMSO (4 mL) was added sodium hydride (27.0 mg, 675 μmol, 60% dispersion in mineral oil) and the mixture was stirred at room temperature for 30 minutes before copper(I)iodide (128 mg, 675 μmol), methyl 3-chloro-5-iodobenzoate (0.25 g, 843 μmol) and sodium methanesulfinate (689 mg, 6.75 mmol) were added. The reaction mixture was heated to 120° C. in a sealed tube to give a turbid blue solution. After 2 hours the reaction mixture was allowed to cool down and was poured on saturated aqueous NaHCO3 solution and EtOAc and filtered. The filtrate layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered and evaporated. Light brown solid (0.135 g; 64%). MS (EI): m/z=248 [M]. were added to give a turbid blue solution to cool down filtered The filtrate layers were separated the aqueous layer was extracted twice with EtOAc The organic layers were washed once with brine dried over MgSO4 filtered evaporated

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of L-proline (77.7 mg, 675 μmol) in DMSO (4 mL) was added sodium hydride (27.0 mg, 675 μmol, 60% dispersion in mineral oil) and the mixture was stirred at room temperature for 30 minutes before copper(I)iodide (128 mg, 675 μmol), methyl 3-chloro-5-iodobenzoate (0.25 g, 843 μmol) and sodium methanesulfinate (689 mg, 6.75 mmol) were added. The reaction mixture was heated to 120° C. in a sealed tube to give a turbid blue solution. After 2 hours the reaction mixture was allowed to cool down and was poured on saturated aqueous NaHCO3 solution and EtOAc and filtered. The filtrate layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered and evaporated. Light brown solid (0.135 g; 64%). MS (EI): m/z=248 [M]. were added to give a turbid blue solution to cool down filtered The filtrate layers were separated the aqueous layer was extracted twice with EtOAc The organic layers were washed once with brine dried over MgSO4 filtered evaporated

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 3-chloro-5-iodobenzoate (0.5 g, 1.69 mmol) in THF (5 mL) were added cyclopropylzinc(II)bromide (3.71 mL, 1.86 mmol), PEPPSI-IPr (22.9 mg, 33.7 μmol, CAS RN 905459-27-0) and 1,3-dimethyl-2-imidazolidinone (DMI) (1 mL) and the turbid light brown solution was stirred at 50° C. for 2.25 hours. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 50 g column using an MPLC (Flasmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30). The obtained fraction (light yellow oil, 315 mg) was dissolved in THF (5 mL), to the clear solution were added cyclopropylzinc(II) bromide (3.71 mL, 1.86 mmol), PEPPSI-IPr (22.9 mg, 33.7 μmol, CAS RN 905459-27-0) and 1,3-dimethyl-2-imidazolidinone (DMI) (1 mL) and the reaction mixture was heated at 50° C. for 2.25 hours. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 40:60) to give the title compound as a light brown oil (0.225 g; 63%) containing 3,5-dicyclopropyl-benzoic acid methyl ester. the layers were separated The aqueous layer was extracted twice with EtOAc The organic layers were washed with brine dried over MgSO4 filtered treated with silica gel evaporated The compound was purified by silica gel chromatography on a 50 g column eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30) The obtained fraction (light yellow oil, 315 mg) was dissolved in THF (5 mL), to the clear solution the reaction mixture was heated at 50° C. for 2.25 hours the layers were separated The aqueous layer was extracted twice with EtOAc The organic layers were dried over MgSO4 filtered treated with silica gel evaporated The compound was purified by silica gel chromatography on a 10 g column eluting with a gradient of n-heptane:EtOAc (100:0 to 40:60)

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 3-chloro-5-iodobenzoate (0.5 g, 1.69 mmol) in THF (5 mL) were added cyclopropylzinc(II)bromide (3.71 mL, 1.86 mmol), PEPPSI-IPr (22.9 mg, 33.7 μmol, CAS RN 905459-27-0) and 1,3-dimethyl-2-imidazolidinone (DMI) (1 mL) and the turbid light brown solution was stirred at 50° C. for 2.25 hours. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 50 g column using an MPLC (Flasmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30). The obtained fraction (light yellow oil, 315 mg) was dissolved in THF (5 mL), to the clear solution were added cyclopropylzinc(II) bromide (3.71 mL, 1.86 mmol), PEPPSI-IPr (22.9 mg, 33.7 μmol, CAS RN 905459-27-0) and 1,3-dimethyl-2-imidazolidinone (DMI) (1 mL) and the reaction mixture was heated at 50° C. for 2.25 hours. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 40:60) to give the title compound as a light brown oil (0.225 g; 63%) containing 3,5-dicyclopropyl-benzoic acid methyl ester. the layers were separated The aqueous layer was extracted twice with EtOAc The organic layers were washed with brine dried over MgSO4 filtered treated with silica gel evaporated The compound was purified by silica gel chromatography on a 50 g column eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30) The obtained fraction (light yellow oil, 315 mg) was dissolved in THF (5 mL), to the clear solution the reaction mixture was heated at 50° C. for 2.25 hours the layers were separated The aqueous layer was extracted twice with EtOAc The organic layers were dried over MgSO4 filtered treated with silica gel evaporated The compound was purified by silica gel chromatography on a 10 g column eluting with a gradient of n-heptane:EtOAc (100:0 to 40:60)

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of L-proline (1.553 g, 13.49 mmol, CAS RN 147-85-3) in dimethylsulfoxide (80 mL) was added sodium hydroxide (0.54 g, 13.49 mmol) and the reaction mixture was stirred at 25° C. for 30 min. Then copper(I) iodide (2.568 g, 13.49 mmol), 3-chloro-5-iodo-benzoic acid methyl ester (5.0 g, 16.86 mmol, CAS RN 289039-85-6) and sodium methanesulfinate (13.77 g, 134.9 mmol, CAS RN 20277-69-4) were added to the reaction mixture and the reaction mixture was heated at 120° C. for 2 h. The reaction mixture was allowed to cool down, poured on saturated aqueous sodium bicarbonate solution (500 mL) and ethyl acetate (500 mL) and filtered through celite. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (200 mL each). The combined organic layers were washed with cold water (200 mL) and brine (100 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography over silica gel (100-200 mesh) with a gradient of ethyl acetate:n-hexane (1:10 to 2:10) to get the desired compound as a colorless solid (2.31 g, 55%). MS (EI): m/z=248 ([M]). the reaction mixture was heated at 120° C. for 2 h to cool down filtered through celite The organic layer was separated the aqueous layer was extracted twice with ethyl acetate (200 mL each) The combined organic layers were washed with cold water (200 mL) and brine (100 mL) dried over anhydrous sodium sulfate evaporated The residue was purified by column chromatography over silica gel (100-200 mesh) with a gradient of ethyl acetate:n-hexane (1:10 to 2:10)

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of L-proline (1.553 g, 13.49 mmol, CAS RN 147-85-3) in dimethylsulfoxide (80 mL) was added sodium hydroxide (0.54 g, 13.49 mmol) and the reaction mixture was stirred at 25° C. for 30 min. Then copper(I) iodide (2.568 g, 13.49 mmol), 3-chloro-5-iodo-benzoic acid methyl ester (5.0 g, 16.86 mmol, CAS RN 289039-85-6) and sodium methanesulfinate (13.77 g, 134.9 mmol, CAS RN 20277-69-4) were added to the reaction mixture and the reaction mixture was heated at 120° C. for 2 h. The reaction mixture was allowed to cool down, poured on saturated aqueous sodium bicarbonate solution (500 mL) and ethyl acetate (500 mL) and filtered through celite. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (200 mL each). The combined organic layers were washed with cold water (200 mL) and brine (100 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography over silica gel (100-200 mesh) with a gradient of ethyl acetate:n-hexane (1:10 to 2:10) to get the desired compound as a colorless solid (2.31 g, 55%). MS (EI): m/z=248 ([M]). the reaction mixture was heated at 120° C. for 2 h to cool down filtered through celite The organic layer was separated the aqueous layer was extracted twice with ethyl acetate (200 mL each) The combined organic layers were washed with cold water (200 mL) and brine (100 mL) dried over anhydrous sodium sulfate evaporated The residue was purified by column chromatography over silica gel (100-200 mesh) with a gradient of ethyl acetate:n-hexane (1:10 to 2:10)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 3-chloro-5-iodobenzoate was dissolved in anhydrous THF and cooled to 0° C. 1M DIBAL in toluene (13 mL) was added slowly to the reaction solution at that temperature. The reaction mixture was stirred overnight at room temperature. Next morning, another 10 mL of 1M DIBAL in toluene was added and stirred for additional 4 h. When the reaction was complete, the reaction mixture was quenched with saturated solution of potassium sodium tartrate. The reaction mixture wad then extracted with ethyl acetate (×3). The combined organic extracts were dried over Na2SO4 and concentrated to afford the desired (3-chloro-5-iodo-phenyl)-methanol (2.7 g, 98%). stirred for additional 4 h the reaction mixture was quenched with saturated solution of potassium sodium tartrate The reaction mixture wad then extracted with ethyl acetate (×3) The combined organic extracts were dried over Na2SO4 concentrated

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of L-proline (77.7 mg, 675 μmol) in DMSO (4 mL) was added sodium hydride (27.0 mg, 675 μmol, 60% dispersion in mineral oil) and the mixture was stirred at room temperature for 30 minutes before copper(I)iodide (128 mg, 675 μmol), methyl 3-chloro-5-iodobenzoate (0.25 g, 843 μmol) and sodium methanesulfinate (689 mg, 6.75 mmol) were added. The reaction mixture was heated to 120° C. in a sealed tube to give a turbid blue solution. After 2 hours the reaction mixture was allowed to cool down and was poured on saturated aqueous NaHCO3 solution and EtOAc and filtered. The filtrate layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered and evaporated. Light brown solid (0.135 g; 64%). MS (EI): m/z=248 [M]. were added to give a turbid blue solution to cool down filtered The filtrate layers were separated the aqueous layer was extracted twice with EtOAc The organic layers were washed once with brine dried over MgSO4 filtered evaporated

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 3-chloro-5-iodobenzoate (0.5 g, 1.69 mmol) in THF (5 mL) were added cyclopropylzinc(II)bromide (3.71 mL, 1.86 mmol), PEPPSI-IPr (22.9 mg, 33.7 μmol, CAS RN 905459-27-0) and 1,3-dimethyl-2-imidazolidinone (DMI) (1 mL) and the turbid light brown solution was stirred at 50° C. for 2.25 hours. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 50 g column using an MPLC (Flasmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30). The obtained fraction (light yellow oil, 315 mg) was dissolved in THF (5 mL), to the clear solution were added cyclopropylzinc(II) bromide (3.71 mL, 1.86 mmol), PEPPSI-IPr (22.9 mg, 33.7 μmol, CAS RN 905459-27-0) and 1,3-dimethyl-2-imidazolidinone (DMI) (1 mL) and the reaction mixture was heated at 50° C. for 2.25 hours. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 40:60) to give the title compound as a light brown oil (0.225 g; 63%) containing 3,5-dicyclopropyl-benzoic acid methyl ester. the layers were separated The aqueous layer was extracted twice with EtOAc The organic layers were washed with brine dried over MgSO4 filtered treated with silica gel evaporated The compound was purified by silica gel chromatography on a 50 g column eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30) The obtained fraction (light yellow oil, 315 mg) was dissolved in THF (5 mL), to the clear solution the reaction mixture was heated at 50° C. for 2.25 hours the layers were separated The aqueous layer was extracted twice with EtOAc The organic layers were dried over MgSO4 filtered treated with silica gel evaporated The compound was purified by silica gel chromatography on a 10 g column eluting with a gradient of n-heptane:EtOAc (100:0 to 40:60)