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Stage #1: 2-bromo-1-fluoro-3-methyl-4-nitrobenzene; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal In 1,4-dioxane; 1-methyl-pyrrolidin-2-one at 100℃; for 18h;
Stage #2: With iron; acetic acid for 2h; Reflux;
Step 2
To a stirring solution of 2-bromo-1-fluoro-3-methyl-4-nitrobenzene (3.0 g, 12.68 mmol, 1 eq) in 1,4-dioxane (25 mL) were slowly added N,N-dimethylformamide dimethylacetal (7.6 g, 64.10 mmol, 5 eq) and pyrrolidine (0.9 g, 12.82 mmol, 1eq), and the reaction mixture was stirred for 18 h at 100°C. The reaction mixture was then concentrated and to the residue were added acetic acid (30 mL) and iron powder (7.17 g, 128 mmol, 10 eq). The reaction mixture was refluxed for 2 h, cooled to room temperature and filtered through a celite bed. The filtrate was neutralised by 50% sodium hydroxide solution and extracted by ethyl acetate (2 x 250 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The cmde residue was purified by column chromatography (230-400 mesh silica gel; 20% ethyl acetate/hexane) to afford compound 4-bromo-5-fluoro-1H-indole (1.7 g, 63%) as a brown liquid.
Stage #1: 4-bromo-5-fluoro-1H-indole With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h;
Stage #2: 2-(tert-butyldimethylsilyloxy)ethyl bromide In N,N-dimethyl-formamide at 20℃; for 2h;
Step 3
To a solution of 4-bromo-5-fluoro-1H-indole (0.5 g, 2.336 mmol, 1 eq.) in DMF (5 mL) was added sodium hydride (0.130 g, 2.80 mmol, 1.2 eq) at 0°C, and the solution was stirred at RT for half an hour, followed by addition of (2-bromoethoxy)(tert-butyl)dimethylsilane (1.17 g, 4.67 mmol, 2.0 eq) and the reaction mixture was stirred at RT for 2 h. After completion (monitored by LCMS), the reaction mixture was diluted with ethyl acetate (20 mL) and the organic layer was washed with cold water (5 x 10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The cmde residue was purified by column chromatography to afford 4-bromo-1-{2-[(tert- butyldimethylsilyl)oxy]ethyl}-5-fluoro-1H-indole (0.85 g, 98%) as a brown liquid.