5-bromo-2,3-difluorobenzaldehyde

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-bromo-2,3-difluorobenzaldehyde (17.38 g, 78.6 mmol), O-methylhydroxylamine hydrochloride (7.23 g, 86.46 mmol), and K2CO3 (13 g, 94.32 mmol) in DME (80 mL) was heated at 40° C. for 14 h. Work-up: the reaction mixture was filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (0˜2% EtOAc in petroleum ether), to give (E)-5-bromo-2,3-difluorobenzaldehyde O-methyl oxime (19.65 g). 1H NMR (CDCl3, 300 MHz): δ 8.20 (s, 1H), 7.76-7.73 (m, 1H), 7.35-7.29 (m, 1H), 4.01 (s, 3H). the reaction mixture was filtered The filtrate was concentrated in vacuo the residue was purified by column chromatography on silica gel (0˜2% EtOAc in petroleum ether)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,3-difluorobenzaldehyde (42 g, 0.296 mol) in H2SO4 (150 mL), was added NBS (63 g, 0.354 mol) in three portions over a period of 30 minutes at 60° C. The resulting mixture was heated for 6 hours at this temperature under N2. Work-up: the reaction mixture was poured into ice water. Petroleum ether (300 mL) was added, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with more petroleum ether (300 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜0.5% EtOAc in petroleum ether) to give 5-bromo-2,3-difluorobenzaldehyde (17.4 g). 1H NMR (300 MHz, CDCl3): δ 10.32 (s, 1H), 7.81-7.79 (m, 1H), 7.65-7.60 (m, 1H). The resulting mixture was heated for 6 hours at this temperature under N2 The organic layer was separated the aqueous layer was extracted with more petroleum ether (300 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo The residue was purified by column chromatography on silica gel (0˜0.5% EtOAc in petroleum ether)

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 10.0 g of 5-bromo-2,3-difluorobenzaldehyde in 40.0 mL of 1-methyl-2-pyrrolidone was added 4.26 g of copper cyanide (I) at room temperature and stirred at 170° C. for 8 hours. Adding ethyl acetate and water, the solution was stirred, and insoluble substances were filtered out through celite. The organic layer of filtrate was washed successively with saturated aqueous ammonium chloride, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:20), to afford 2.64 g of the title compound as colorless crystals. insoluble substances were filtered out through celite The organic layer of filtrate was washed successively with saturated aqueous ammonium chloride, water and saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography (ethyl acetate:n-hexane=1:20)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 18.0 g of 5-bromo-2,3-difluoro-4-trimethylsilanyl benzaldehyde in 20 mL of N,N-dimethylformamide and 2 mL of water was added 1.63 g of cesium fluoride at room temperature, and stirred at this temperature for 1 hour. After diluting with ethyl acetate, the organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to afford 10.26 g of the title compound as a colorless oil. the organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated

Conditions: temp:22.01; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 10.0 g of 5-bromo-2,3-difluorobenzaldehyde in 40.0 mL of 1-methyl-2-pyrrolidone was added 4.26 g of copper cyanide (I) at room temperature and stirred at 170° C. for 8 hours. Adding ethyl acetate and water, the solution was stirred, and insoluble substances were filtered out through celite. The organic layer of filtrate was washed successively with saturated aqueous ammonium chloride, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:20), to afford 2.64 g of the title compound as colorless crystals. insoluble substances were filtered out through celite The organic layer of filtrate was washed successively with saturated aqueous ammonium chloride, water and saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography (ethyl acetate:n-hexane=1:20)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 18.0 g of 5-bromo-2,3-difluoro-4-trimethylsilanyl benzaldehyde in 20 mL of N,N-dimethylformamide and 2 mL of water was added 1.63 g of cesium fluoride at room temperature, and stirred at this temperature for 1 hour. After diluting with ethyl acetate, the organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to afford 10.26 g of the title compound as a colorless oil. the organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated