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Step 1: l-Bromo-4,5-difluoro-2-methylbenzene (16). To a ice cooled flask containing 3,4-difluorotoluene 15 (27 g, 210 mmol) and iron powder (600 mg, 10 mmol) was added dropwise Br2 (40 g, 250 mmol). The reaction was stirred for 12 h while it was slowly warmed to RT. Water was added and the resulting mixture was extracted with diethyl ether. The ether layer was washed with sodium thiosulfate solution, brine and dried over Na2S04. Removal of ether gave the desired bromotoluene 16 (36 g, 83percent). -NMR (400MHz, DMSO-d6):D D 8 7.78 (t, 1H), 7.52 (t, 1H), 2.29 (s, 3H).
With potassium carbonate;palladium(0)bis(tricyclohexylphosphine); In 1,4-dioxane; water; at 80 - 85℃; for 19.0h;Inert atmosphere;
4',5'-Difluoro-2'-methyl-biphenyl-4-ol To a stirred solution of 3,4-difluorotoluene (30 g, 234.1 mmol) and iron powder (0.784 g, 14.05 mmol) in methylene chloride (140 mL) in an ice bath was added bromine (12 mL, 155 mmol) slowly over 6.5 hrs. The reaction mixture was warmed to RT and stirred for an additional 60 hrs. The mixture was washed with water (200 mL), 10% Na2SO3 (3*150 mL), saturated (NaHCO3 (100 mL) and saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give 40 g of crude <strong>[875664-38-3]1-bromo-4,5-difluoro-2-methyl-benzene</strong>. Bromo-4,5-difluoro-2-methyl-benzene (30 g, 145 mmol) and 4-hydroxyphenyl-boronic acid (20.99 g, 152.2 mmol) were suspended in 725 ml of dioxane. The mixture was degassed with argon. Potassium carbonate (23.17 g, 166 mmol) in 72.5 ml water solution was added and after stirring for 10 minutes, bis(tricyclohexylphosphine)palladium(0) (2.4 g, 3.62 mmol) was added. The reaction was stirred at 80-85 C. for 19 hrs and concentrated. The mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried and solvents were evaporated. The crude product was purified by flash chromatography, eluting with 0-7% ethyl acetate in hexanes to obtain the crude product which was further recrystallized from hexane to afford 4',5'-difluoro-2'-methyl-biphenyl-4-ol (23.76 g, 74.5%). LR-MS (ES) calculated for C13H10F2O, 220.22. found m/z 219 [M-H].
Step 1: l-Bromo-4,5-difluoro-2-methylbenzene (16). To a ice cooled flask containing <strong>[2927-34-6]3,4-difluorotoluene</strong> 15 (27 g, 210 mmol) and iron powder (600 mg, 10 mmol) was added dropwise Br2 (40 g, 250 mmol). The reaction was stirred for 12 h while it was slowly warmed to RT. Water was added and the resulting mixture was extracted with diethyl ether. The ether layer was washed with sodium thiosulfate solution, brine and dried over Na2S04. Removal of ether gave the desired bromotoluene 16 (36 g, 83%). -NMR (400MHz, DMSO-d6):D D 8 7.78 (t, 1H), 7.52 (t, 1H), 2.29 (s, 3H).
With bromine; iron; In dichloromethane; at 20℃; for 66.5h;Cooling with ice;
4',5'-Difluoro-2'-methyl-biphenyl-4-ol To a stirred solution of <strong>[2927-34-6]3,4-difluorotoluene</strong> (30 g, 234.1 mmol) and iron powder (0.784 g, 14.05 mmol) in methylene chloride (140 mL) in an ice bath was added bromine (12 mL, 155 mmol) slowly over 6.5 hrs. The reaction mixture was warmed to RT and stirred for an additional 60 hrs. The mixture was washed with water (200 mL), 10% Na2SO3 (3*150 mL), saturated (NaHCO3 (100 mL) and saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give 40 g of crude 1-bromo-4,5-difluoro-2-methyl-benzene. Bromo-4,5-difluoro-2-methyl-benzene (30 g, 145 mmol) and 4-hydroxyphenyl-boronic acid (20.99 g, 152.2 mmol) were suspended in 725 ml of dioxane. The mixture was degassed with argon. Potassium carbonate (23.17 g, 166 mmol) in 72.5 ml water solution was added and after stirring for 10 minutes, bis(tricyclohexylphosphine)palladium(0) (2.4 g, 3.62 mmol) was added. The reaction was stirred at 80-85 C. for 19 hrs and concentrated. The mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried and solvents were evaporated. The crude product was purified by flash chromatography, eluting with 0-7% ethyl acetate in hexanes to obtain the crude product which was further recrystallized from hexane to afford 4',5'-difluoro-2'-methyl-biphenyl-4-ol (23.76 g, 74.5%). LR-MS (ES) calculated for C13H10F2O, 220.22. found m/z 219 [M-H].
Preparation 2 (4,5-Difluoro-2-methyl-phenyl)boronic acid n-Butyl lithium (4.6 mL, 11.5 mmol) is added to the mixture of <strong>[875664-38-3]1-bromo-4,5-difluoro-2-methylbenzene</strong> (2.0 g, 9.6 mmol) and trimethyl borate (1.5 g, 14.5 mmol) in anhydrous tetrahydrofuran (30 mL), drop wise, at -78 C. over one hour, under an atmosphere of argon. The reaction mixture is stirred for another hour at the same temperature, quenched and acidified with 1 N HCl. The resulting mixture is extracted with ethyl acetate(3*). The combined organic layer is washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
With trans-bis(triphenylphosphine)palladium dichloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 7.0h;Inert atmosphere;
General procedure: To a solution of o---dibromobenzenes, N---Boc---pyrrole---2---boronic acid 2 and 1.0 M K2CO3aq. in DMF was added PdCl2(PPh3)2 (20%/mol) under a nitrogen atmosphere. Theresulting mixture was heated at 80 C for 7 h. After cooling to room temperature, themixture was extracted with a mixture of EtOAc/hexane (v/v = 1:4). The organic layerwas washed with water and brine, and then dried over Na2SO4. After removal solvent,the residue was purified by silica gel column chromatography and recrystallization todi(N---Boc---pyrrol---2---yl---benzenes).
In 1-methyl-pyrrolidin-2-one; at 160℃; for 12.0h;Sealed tube;
Step 2: 4,5-Difluoro-2-methylbenzonitriIe (17). 1 -Bromo-4,5-difluoro-2- methylbenzene 16 (2 g, 9.6 mmol), CuCN (1.0 g, 1 1 mmol) and NMP (5 mL) were combined in a sealed tube and heated to 160 C with stirring for 12 h. Due to the volatility of the resulting benzonitrile 13, the crude reaction mixture was used as is in the next reaction.
With 1,1'-bis-(diphenylphosphino)ferrocene; bis(benzonitrile)palladium(II) dichloride; N-ethyl-N,N-diisopropylamine; at 135℃; under 7500.75 Torr; for 4.0h;Sealed tube;
1-47: A mixture of <strong>[875664-38-3]2-bromo-4,5-difluorotoluene</strong> (4.00 g, 19.3 mmol), DIPEA (5.2 mL, 30.0 mmol), dichlorobis(benzonitrile)palladium(II) (269 mg, 0.700 mmol) and 1,1- bis(diphenylphosphino)ferrocene (dppf) (482 mg, 0.870 mmol) in absolute ethanol (50 mL) was placed in a sealed bomb with stirring and placed under 10 bars of carbon monoxide and heated to 135C for 4 h. The mixture was then cooled to RT, returned to atmospheric pressure and opened. The rxn mixture was concentrated and diluted with brine (100 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (2x50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by normal phase flash column chromatography on silica gel using 5-20% EtOAc in heptane to afford compound 1-47.