4-bromo-2-iodo-1-methylbenzene

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:-35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A dry flask was charged with 4-bromo-2-iodo-1-methyl-benzene (6.85 g, 23.1 mmol) and the flask was evaporated and then filled with argon and this process repeated twice. Dry THF (20 mL) was added, and the solution cooled to −35° C.; then isopropylmagnesium chloride (11.5 mL, 2.0 M in diethyl ether, 23 mmol) was added slowly over 40 min keeping the temperature below −35° C. On completion of the addition the reaction mixture was stirred at −35° C. for 30 min. A THF solution of ZnCl2 (3.93 g, 28.9 mmol, 0.7 M) was added dropwise over 20 min. The reaction mixture was stirred at 0° C. for 20 min; then 2-chloro-4-nitro-benzoyl chloride (5.33 g, 24.2 mmol) and Cu(OAc)2 (92 mg, 0.46 mmol) were added and the reaction mixture was allowed to warm to room temperature. After 16 h the reaction mixture was poured into a mixture of EtOAc/water, then shaken and separated. The aqueous phase was extracted with more EtOAc. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by flash chromatography using EtOAc/petroleum ether 1:14 as the eluent to give the title compound as almost white solid. the flask was evaporated filled with argon Dry THF (20 mL) was added the temperature below −35° C On completion of the addition the reaction mixture The reaction mixture was stirred at 0° C. for 20 min to warm to room temperature shaken separated The aqueous phase was extracted with more EtOAc dried (MgSO4) filtered concentrated in vacuo to afford the crude product The crude product was purified by flash chromatography

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3-iodo-4-methyl-phenylamine (5.0 g, 21 mmol) and 48% hydrobromic acid (30 ml) was heated at 90° C. for 30 minutes. After cooling in an ice bath, a solution of sodium nitrite (1.7 g, 25.2 mmol) in water (5 ml) was added and stirred for 15 minute. This mixture was added to a mixture of copper bromide (I) (3.6 g, 25.2 mmol), 48% hydrobromic acid (20 ml) and ice (50 g) cooled in an ice bath. After stirring for 20 minutes, the mixture was heated at 90° C. for 1 hour. After stirring at room temperature for 16 hours, the mixture was treated with water (350 ml) and extracted with dichloromethane (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 ml), washed with saturated aqueous sodium chloride solution (100 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane to give 5-bromo-2-methyl-1-iodo-benzene (4.4 g, 71% yield). 1H NMR (acetone-d6) δ 2.40 (s, 3H, CH3), 7.30 (d, 1H, J=8.2 Hz, Ar), 7.50 (dd, 1H, J=8.2 Hz, J=2.0 Hz, Ar), 8.00 (d, 1H, J=2.0 Hz, Ar). After cooling in an ice bath cooled in an ice bath After stirring for 20 minutes the mixture was heated at 90° C. for 1 hour After stirring at room temperature for 16 hours extracted with dichloromethane (100 ml) The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 ml) washed with saturated aqueous sodium chloride solution (100 ml) dried over magnesium sulfate concentrated under reduced pressure The residue was purified by flash chromatography eluting with hexane

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

実験手順: To a solution of 2-methyl-5-bromo-iodobenzene (12 g, 40.4 mmol) in tetrahydrofuran (75 ml), cooled to −78° C., was added a solution of isopropylmagnesium chloride (4.6 g, 44.5 mmol) in tetrahydrofuran (22.2 ml) dropwise over 20 minutes. After stirring at −78° C. for 30 minutes, the mixture was warmed slowly to −20° C. and stirred for 1 hour. After cooling again to −78° C., trimethylborate (8.4 g, 80.8 mmol) was added dropwise. After warming to 0° C., the mixture was stirred for 2 hours, treated with 1 M hydrochloric acid (35 ml), and extracted with ethyl acetate (2×50 ml). The combined extracts were washed with water (50 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residual solid was suspended in hexane (50 ml), filtered, washed with hexane (30 ml) and dried under reduced pressure to provide 2-methyl-5-bromo-phenylboronic acid (7.32 g, 84% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.92 (s, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 2.59 (s, 3H). the mixture was warmed slowly to −20° C. stirred for 1 hour After cooling again to −78° C. After warming to 0° C. the mixture was stirred for 2 hours extracted with ethyl acetate (2×50 ml) The combined extracts were washed with water (50 ml) dried over sodium sulfate concentrated under reduced pressure filtered washed with hexane (30 ml) dried under reduced pressure

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

実験手順: 2-Methyl-5-bromo-iodobenzene was synthesized according to the method described by Lulinski, P., Skulski, L., Bull. Chem. Soc. Jpn. 2000 73:951-956. To a mixture of acetic acid (100 ml) and acetic anhydride (50 ml), cooled in an ice bath, was added sodium periodate (15.4 g, 72 mmol) and iodine (12.2 g, 48 mmol). While stirring vigorously, concentrated sulfuric acid (21 ml) was added slowly followed by 4-bromotoluene (23.1 g, 135 mmol). After stirring for 2 hours, the ice bath was removed and the mixture was protected from light. After stirring for 16 hours, the mixture was poured into a mixture of 10% aqueous sodium sulfite solution (250 ml) and ice (250 g), and extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (100 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residual oil was purified by distillation (87-92° C., 1 mm) to provide 2-methyl-5-bromo-iodobenzene (28.2 g, 70% yield) as colorless oil. 1H NMR (DMSO-d6) δ 7.99 (s, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 2.33 (s, 3H). 2-Methyl-5-bromo-iodobenzene was synthesized cooled in an ice bath After stirring for 2 hours the ice bath was removed After stirring for 16 hours the mixture was poured into a mixture of 10% aqueous sodium sulfite solution (250 ml) and ice (250 g) extracted with dichloromethane (3×100 ml) The combined extracts were washed with water (100 ml) dried over sodium sulfate concentrated under reduced pressure The residual oil was purified by distillation (87-92° C., 1 mm)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3-iodo-4-methyl-phenylamine (5.0 g, 21 mmol) and 48% hydrobromic acid (30 ml) was heated at 90° C. for 30 minutes. After cooling in an ice bath, a solution of sodium nitrite (1.7 g, 25.2 mmol) in water (5 ml) was added and stirred for 15 minute. This mixture was added to a mixture of copper bromide (I) (3.6 g, 25.2 mmol), 48% hydrobromic acid (20 ml) and ice (50 g) cooled in an ice bath. After stirring for 20 minutes, the mixture was heated at 90° C. for 1 hour. After stirring at room temperature for 16 hours, the mixture was treated with water (350 ml) and extracted with dichloromethane (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 ml), washed with saturated aqueous sodium chloride solution (100 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane to give 5-bromo-2-methyl-1-iodo-benzene (4.4 g, 71% yield). 1H NMR (acetone-d6) δ 2.40 (s, 3H, CH3), 7.30 (d, 1H, J=8.2 Hz, Ar), 7.50 (dd, 1H, J=8.2 Hz, J=2.0 Hz, Ar), 8.00 (d, 1H, J=2.0 Hz, Ar). After cooling in an ice bath cooled in an ice bath After stirring for 20 minutes the mixture was heated at 90° C. for 1 hour After stirring at room temperature for 16 hours extracted with dichloromethane (100 ml) The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 ml) washed with saturated aqueous sodium chloride solution (100 ml) dried over magnesium sulfate concentrated under reduced pressure The residue was purified by flash chromatography eluting with hexane

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

実験手順: To a solution of 2-methyl-5-bromo-iodobenzene (12 g, 40.4 mmol) in tetrahydrofuran (75 ml), cooled to −78° C., was added a solution of isopropylmagnesium chloride (4.6 g, 44.5 mmol) in tetrahydrofuran (22.2 ml) dropwise over 20 minutes. After stirring at −78° C. for 30 minutes, the mixture was warmed slowly to −20° C. and stirred for 1 hour. After cooling again to −78° C., trimethylborate (8.4 g, 80.8 mmol) was added dropwise. After warming to 0° C., the mixture was stirred for 2 hours, treated with 1 M hydrochloric acid (35 ml), and extracted with ethyl acetate (2×50 ml). The combined extracts were washed with water (50 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residual solid was suspended in hexane (50 ml), filtered, washed with hexane (30 ml) and dried under reduced pressure to provide 2-methyl-5-bromo-phenylboronic acid (7.32 g, 84% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.92 (s, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 2.59 (s, 3H). the mixture was warmed slowly to −20° C. stirred for 1 hour After cooling again to −78° C. After warming to 0° C. the mixture was stirred for 2 hours extracted with ethyl acetate (2×50 ml) The combined extracts were washed with water (50 ml) dried over sodium sulfate concentrated under reduced pressure filtered washed with hexane (30 ml) dried under reduced pressure

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

実験手順: 2-Methyl-5-bromo-iodobenzene was synthesized according to the method described by Lulinski, P., Skulski, L., Bull. Chem. Soc. Jpn. 2000 73:951-956. To a mixture of acetic acid (100 ml) and acetic anhydride (50 ml), cooled in an ice bath, was added sodium periodate (15.4 g, 72 mmol) and iodine (12.2 g, 48 mmol). While stirring vigorously, concentrated sulfuric acid (21 ml) was added slowly followed by 4-bromotoluene (23.1 g, 135 mmol). After stirring for 2 hours, the ice bath was removed and the mixture was protected from light. After stirring for 16 hours, the mixture was poured into a mixture of 10% aqueous sodium sulfite solution (250 ml) and ice (250 g), and extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (100 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residual oil was purified by distillation (87-92° C., 1 mm) to provide 2-methyl-5-bromo-iodobenzene (28.2 g, 70% yield) as colorless oil. 1H NMR (DMSO-d6) δ 7.99 (s, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 2.33 (s, 3H). 2-Methyl-5-bromo-iodobenzene was synthesized cooled in an ice bath After stirring for 2 hours the ice bath was removed After stirring for 16 hours the mixture was poured into a mixture of 10% aqueous sodium sulfite solution (250 ml) and ice (250 g) extracted with dichloromethane (3×100 ml) The combined extracts were washed with water (100 ml) dried over sodium sulfate concentrated under reduced pressure The residual oil was purified by distillation (87-92° C., 1 mm)

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

実験手順: N-Bromosuccinimide (NBS) (1.1 molar equivalents, 66.5 g, 373 mmol) and benzyl peroxide (0.006 molar equivalent, 450.7 mg, 1.9 mmol) are added to a solution of 2-iodo-4-bromotoluene 6 (1 molar equivalent, 100.3 g, 338 mmol) in chlorobenzene (1200 ml). The batch is then stirred under reflux overnight. After the solvent has been removed in a rotary evaporator, ethyl acetate and water are added. The aqueous phase is extracted by shaking with ethyl acetate. The organic phase is washed by shaking with water, dried and evaporated in a rotary evaporator. The product 7 (30.7 g, 24%) is obtained in the form of a white powder by recrystallisation from ethanol (50 ml). under reflux overnight After the solvent has been removed in a rotary evaporator, ethyl acetate and water are added The aqueous phase is extracted by shaking with ethyl acetate The organic phase is washed by shaking with water dried evaporated in a rotary evaporator

反応条件: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium periodate (0.5 molar equivalent, 102.5 g, 0.48 mol) and iodine (0.3 molar equivalent, 81.6 g, 0.32 mol) are suspended in acetic acid (700 ml) and acetic anhydride (340 ml). The batch is then cooled to 10° C., and sulfuric acid (2.9 molar equivalents, 142 ml, 2.66 mol) is slowly added dropwise at this temperature. 4-Bromotoluene 5 (1 molar equivalent, 160.7 g, 0.94 mol) is subsequently slowly added dropwise at room temperature, and the batch is stirred overnight. After addition of cooled water (1000 ml) and a solution of Na2SO3 (169 g in 1000 ml), the mixture is extracted by shaking with dichloromethane (DCM). The organic phase is washed with water, dried and evaporated in a rotary evaporator. The product 6 (188.0 g, 67%) is obtained in the form of a liquid by vacuum distillation. a solution of Na2SO3 (169 g in 1000 ml), the mixture is extracted by shaking with dichloromethane (DCM) The organic phase is washed with water dried evaporated in a rotary evaporator