| 91% |
With palladium diacetate; sodium carbonate; triphenylphosphine; In ethanol; water; toluene; at 20 - 100℃; for 24.1667h;Inert atmosphere; Sealed tube; |
A solution containing triphenylphosphine (84.1 mg, 0.320 mmol), ethanol (4.8 mL) , toluene (4.8 mL) and Pd(OAc)2 (14.4 mg, 0.0641 mmol) was stirred under nitrogen at room temperature for 10 min. Then, commercially available 5-bromo-l-fluoro-2-methyl-3-nitrobenzene (500 mg, 2.14 mmol), an aqueous sodium carbonate solution (4.8 mL, 2 M) and phenylboronic acid (417 mg, 3.42 mmol) were added and the resulting mixture was heated at 100C for 24 h under stirring in a sealed vial. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine and concentrated under vacuum, leaving a crude residue that was purified by flash column chromatography (n-hexane) to afford the correponding intermediate "M" as a white solid (500 mg, 91% yield) [Scheme 5, R3 and R5 = H; NMR (CDC13) : delta 2.51 (d, 3H, J = 2.2 Hz), 7.39-7.71 (m, 6H) , 7.98 (t, 1H, J = 1.8 Hz)] |
| 91% |
With palladium diacetate; sodium carbonate; triphenylphosphine; In ethanol; toluene; at 100℃; for 3h;Inert atmosphere; Sealed tube; |
Example 51 A solution containing triphenylphosphine (84.1 mg, 0.320 mmol), ethanol (4.8 mL), toluene (4.8 mL) and Pd(OAc)2 (14.4 mg, 0.0641 mmol) was stirred under nitrogen at room temperature for 10 min. Then, commercially available <strong>[502496-34-6]5-bromo-1-fluoro-2-methyl-3-nitrobenzene</strong> (500 mg, 2.14 mmol), an aqueous sodium carbonate solution (4.8 mL, 2 M) and phenylboronic acid (417 mg, 3.42 mmol) were added and the resulting mixture was heated at 100 C. for 24 h under stirring in a sealed vial. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine and concentrated under vacuum, leaving a crude residue that was purified by flash column chromatography (n-hexane) to afford the corresponding intermediate "M" as a white solid (500 mg, 91% yield) [Scheme 5, R3 and R5=H; 1H NMR (CDCl3): delta 2.51 (d, 3H, J=2.2 Hz), 7.39-7.71 (m, 6H), 7.98 (t, 1H, J=1.8 Hz)]. Subsequently, a solution of intermediate "M" (318 mg, 1.38 mmol) and dimethyl oxalate (812 mg, 6.88 mmol) in anhydrous THF (2.0 mL) was added dropwise under nitrogen to a cooled (0 C.) 30% solution of sodium methoxide in MeOH (1.3 mL). The resulting reddish suspension was stirred at room temperature for 18 h. The reaction mixture was then cooled to 0 C. and quenched with ice and 1N aqueous HCl until pH 5 was reached. Then the mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine and concentrated under vacuum evaporated to give a crude residue that was purified by flash column chromatography (n-hexane/EtOAc 8:2), affording the corresponding intermediate "N" (264 mg, 60% yield) as an yellow oily product [Scheme 5, R3 and R5=H. 1H NMR (CDCl3): delta 3.97 (s, 3H), 4.62 (s, 2H), 7.45-7.68 (m, 6H), 8.20 (s, 1H)]. Finally, intermediate "N" (145 mg, 0.457 mmol) was dissolved in dry DME (0.4 mL) and the resulting solution was added dropwise under nitrogen to a cooled (0 C.) solution of anhydrous SnCl2 (217 mg, 1.14 mmol) in dry DME (0.5 mL) containing activated 4 A molecular sieves. The reaction mixture was stirred at room temperature for 72 h, then it was filtered and concentrated under vacuum to afford a crude residue that was purified by flash chromatography (n-hexane/EtOAc 85:15) to give methyl 4-fluoro-1-hydroxy-6-phenyl-1H-indole-2-carboxylate (Example 51) as a light yellow solid (98.3 mg, 75% yield). |
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