4-bromo-2-fluoro-1-iodobenzene

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: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: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:0.00; pressure:0.00; stir:

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2.106 g of bis(triphenylphosphine) palladium(II)chloride (Merck Schuchart, Art. No. 804 174) were suspended in 20.0 ml tetrahydrofurane (Merck KGaA, Art. No.108 107) in a 50 ml, four necked vessel and heated to 55° C. Now 0.113 g sodiumboric hydride (Merck Schuchart, Art. Nr. 806 372) were added slowly while the suspension was stirred with a magnetic stirrer. The dark mixture was heated under reflux for 30 minutes and then allowed to cool to 40° C. 49.648 g of 1-bromo-3-fluoro-4-iodo-benzene (Wychem, Art. No. 45 570 300/12) 35.60 g of 4-n-butyl-phenylboronic acid, prepared in house), 330 ml toluene (Merck KGaA, Art. No.108 325), 130 ml ethanol (Merck KGaA, Art. No.100 983) and 170 ml of a solution of sodium carbonate (Merck KGaA, Art. No.106 384) were placed in an 1 I, four necked vessel at ambient temperature and heated to 50° C. Now the freshly prepared 40° C. warm solution of the Pd0-catalyst was rapidly added dropwise to the vigorously stirred reaction mixture. The brown mixture was stirred at 50° C. for 16 hours. The completeness of the reaction was confirmed by thin sheet chromatography. The reaction mixture was cooled to ambient temperature. Then distilled water and methyl-t-butyl ether were added and the phases separated. The aquous phase was extracted twice with methyl-t-butyl ether. The combined organic phases were washed twice with distilled water, dried over Na2SO4 filtered and the solvent evaporated. The crude product of 74 g of 4-bromo-4′-n-butyl-2-fluoro-biphenyl was purified over 3 I silica gel with 1-chloro-butane. The resultant 61.4 g of crude product were distilled under reduced pressure. Thus 45.4 g of 4-bromo-4′-n-butyl-2-fluoro-biphenyl with a purity of 90.6% by GC were obtained. The dark mixture was heated under reflux for 30 minutes to cool to 40° C were placed in an 1 I, four necked vessel at ambient temperature heated to 50° C Now the freshly prepared 40° C. warm solution of the Pd0-catalyst was rapidly added dropwise to the vigorously stirred reaction mixture The brown mixture was stirred at 50° C. for 16 hours The reaction mixture was cooled to ambient temperature the phases separated The aquous phase was extracted twice with methyl-t-butyl ether The combined organic phases were washed twice with distilled water dried over Na2SO4 filtered the solvent evaporated The crude product of 74 g of 4-bromo-4′-n-butyl-2-fluoro-biphenyl was purified over 3 I silica gel with 1-chloro-butane The resultant 61.4 g of crude product were distilled under reduced pressure

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 1.75 g (5.78 mmol) 1-bromo-3-fluoro-4-iodo-benzene in 12 ml dry tetrahydrofuran were added at −78° C. 3.61 ml (5.78 mmol) of a 1.6M butyl lithium solution in hexanes. After 1 h 0.600 g (1.65 mmol) rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) were added and stirred at −78° C. fur further 4 h. Then the reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution, warmed to ambient temperature and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by flash-chromatography over silica gel with a heptane/AcOEt gradient starting with pure heptane: rac-[2-(4-bromo-2-fluoro-phenyl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester was obtained as a colorless viscous oil: MS (ISP): 476.0 and 477.9 (M+H)+. Then the reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution warmed to ambient temperature extracted with ethyl acetate The combined extracts were washed with brine dried over Na2SO4 filtered evaporated The crude product was purified by flash-chromatography over silica gel with a heptane/AcOEt gradient