2-bromo-4,5-difluorophenol

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

Procedure: A mixture of 79.4 gm (0.38 mole) 2-bromo-4,5-difluorophenol and 79 gm (0.57 mole) potassium carbonate in 200 mL dimethylformamide was stirred at room temperature for 30 minutes. At this point 33 mL (0.38 mMol) allyl bromide were added and the resulting mixture was stirred for 18 hours at room temperature. The reaction mixture was then diluted with diethyl ether and washed with water followed by saturated aqueous sodium chloride. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure to provide 90 gm (96%) of the desired compound. the resulting mixture was stirred for 18 hours at room temperature washed with water The remaining organics were dried over magnesium sulfate concentrated under reduced pressure

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

Procedure: Beginning with 5 gm (23.9 mMol) 2-bromo-4,5-difluorophenol, 7.05 gm (91%) 2-(2-bromo-4,5-difluorophenoxy)-acetaldehyde diethyl acetal were prepared essentially as described in Preparation IV. were prepared essentially

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-4,5-difluoro-phenol (1 g, 4.78 mmol) in N,N-dimethylformamide were added K2CO3 and 2-fluoropyridine (0.46 g, 4.78 mmol) and heated at 120° C. for overnight. One more equivalent of 2-fluoropyridine was added and heated at 150° C. for 12 h. The reaction mixture was dissolved in ethyl acetate, washed with 1M NaHCO3, concentrated and purified by flash column chromatography using 0%, 5% and 10% of ethyl acetate in hexanes to yield 0.8 g (59%) of product. MS (ESI+) m/z 286 (M+H)+. heated at 150° C. for 12 h washed with 1M NaHCO3 concentrated purified by flash column chromatography

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-4,5-difluoro-phenol (1 g, 4.78 mmol) in N,N-dimethylformamide were added K2CO3 and 2-fluoropyridine (0.46 g, 4.78 mmol) and heated at 120° C. for overnight. One more equivalent of 2-fluoropyridine was added and heated at 150° C. for 12 h. The reaction mixture was dissolved in ethyl acetate, washed with 1M NaHCO3, concentrated and purified by flash column chromatography using 0%, 5% and 10% of ethyl acetate in hexanes to yield 0.8 g (59%) of product. MS (ESI+) m/z 286 (M+H)+. heated at 150° C. for 12 h washed with 1M NaHCO3 concentrated purified by flash column chromatography

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromo-4,5-difluoro-phenol (1.0 g, 4.8 mmol), 1,1,1-trifluoro-2-iodo-ethane (706 mg, 7.2 mmol) and CsF (882 mg, 5.8 mmol) in DMSO (20 mL) was heated at 120° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using hexane/ethyl acetate (10:1) to give the title compound (697 mg, 50%). 1HNMR (500 MHz, CDCl3) δ ppm 4.36 (q, J=7.93 Hz, 2 H) 6.85 (dd, J=10.98, 7.02 Hz, 1 H) 7.43 (t, J=8.85 Hz, 1 H). extracted with ethyl acetate (2×) The solvent was removed the resulting residue was chromatographed

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromo-4,5-difluoro-phenol (1.0 g, 4.8 mmol), 1,1,1-trifluoro-2-iodo-ethane (706 mg, 7.2 mmol) and CsF (882 mg, 5.8 mmol) in DMSO (20 mL) was heated at 120° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using hexane/ethyl acetate (10:1) to give the title compound (697 mg, 50%). 1HNMR (500 MHz, CDCl3) δ ppm 4.36 (q, J=7.93 Hz, 2 H) 6.85 (dd, J=10.98, 7.02 Hz, 1 H) 7.43 (t, J=8.85 Hz, 1 H). extracted with ethyl acetate (2×) The solvent was removed the resulting residue was chromatographed

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

Procedure: Potassium carbonate (1.38 g, 10.0 mmol) and propargyl bromide (0.414 mL, 5.50 mmol) were added to a solution (25 mL) of 2-bromo-4,5-difluorophenol (1.05 g, 5.00 mmol) in DMF, and stirred at room temperature overnight. The solvent was distilled away under reduced pressure, and after diluted with ethyl acetate, the resultant was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away, and the residue was purified by silica gel chromatography (hexane/ethyl acetate). To the resulting compound (1.18 g, 4.78 mmol), cesium fluoride (872 mg, 5.74 mmol) and dimethylaniline (7 mL) were added, and stirred at 170° C. overnight. To the reaction solution, ethyl acetate and a 2 N hydrochloric acid aqueous solution were added and stirred. After the insoluble material was filtered off, extraction was performed with ethyl acetate. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane) to thus obtain the title compound. The solvent was distilled away under reduced pressure after diluted with ethyl acetate the resultant was washed with water and saturated brine dried over anhydrous magnesium sulfate The solvent was distilled away the residue was purified by silica gel chromatography (hexane/ethyl acetate) stirred at 170° C. overnight stirred After the insoluble material was filtered off extraction The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine dried over anhydrous magnesium sulfate The solvent was distilled away under reduced pressure The resulting residue was purified by silica gel chromatography (hexane)

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

Procedure: An operation similar to that in Step 1 of Example 12 was performed using 2-bromo-4,5-difluorophenol (1.05 g, 5.00 mmol) in place of 2-bromo-4-fluorophenol, and bromoacetone (0.504 mL, 6.00 mmol) in place of bromoacetaldehyde dimethyl acetal to thus obtain the title compound.