3,5-dibromophenol

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:

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

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Toluene (400 mL) and water (20 mL) were added to a mixture of 3-,5-dibromophenol (5.088 g, 19.85 mmol), phenylboronic acid (2.42 g, 19.85 mmol) and potassium carbonate (5.48 g, 39.7 mmol) in a round bottom flask. This was followed by addition of 1.149 g of tetrakis(triphenylphosphine)palladium(0) under a atmosphere of nitrogen. This mixture was stirred at heated overnight at 90° C. At this time, HCl (2 N aq) was added to the reaction mixture until pH=˜2 and the subsequent two phases were separated; the aqueous phase was extracted and washed three time with ethyl acetate. The combined organic phases were dried with MgSO4, filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo to provide an orange oil. Analysis of the oil by LC/MS indicated a mixture of desired product, starting material and the bis-phenyl coupling product The mixture was carried on to the next aryl boronic acid coupling step 2. the subsequent two phases were separated the aqueous phase was extracted washed three time with ethyl acetate The combined organic phases were dried with MgSO4 filtered washed with ethyl acetate The filtrate was concentrated in vacuo to provide an orange oil

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

Procedure: Example 54 was synthesized in 4 steps from 3-,5-dibromophenol. 2-Methoxy-5-fluorophenyl boronic acid was reacted as described above, step 1. In this manner was isolated 5-bromo-5′-fluoro-2′-methoxy-biphenyl-3-ol, which was then reacted with 3-fluorophenyl boronic reacted as described above, Step 2. In this manner, 3,5″-difluoro-2″-methoxy-[1,1′;3′,1″]terphenyl-5′-ol was obtained.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3,5-dibromophenol (500 mg, 1.98 mmol) in dimethoxyethane (12.5 mL) was stirred for 5 minutes at room temperature under nitrogen atmosphere. Then, the solid tetrakis(triphenylphosphine)palladium(0) (496 mg, 0.43 mmol) was added at room temperature and the resulting light yellow solution was heated to 80° C. and stirred for 5 minutes. At this period, a solution of 1,4-benzodioxane-6-boronic acid (536 mg, 2.98 mmol) in ethanol (12.5 mL) was added followed by a solution of sodium carbonate (421 mg, 3.97 mmol) in water (0.5 mL). The resulting light yellow suspension was stirred for 4 h at reflux. Then, the reaction mixture was cooled to room temperature and diluted with water (20 mL) and ethyl acetate (30 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic extracts were washed with water (100 mL) and brine solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate and filtration of the drying agent and removal of the solvent in vacuo gave the colored residue which was purified by using an ISCO 120 column, eluting with 10-30% ethyl acetate in hexanes to afford 3,5-bis-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-phenol (386 mg, 54%) as an amorphous light brown solid: ES(+)-HRMS m/e calculated for C22H18O5 (M+H)+ 363.1227, found 363.1226. At this period The resulting light yellow suspension was stirred for 4 h at reflux Then, the reaction mixture was cooled to room temperature The two layers were separated the aqueous layer was extracted with ethyl acetate (2×20 mL) the combined organic extracts were washed with water (100 mL) and brine solution (100 mL) The organic layer was dried over anhydrous magnesium sulfate and filtration of the drying agent and removal of the solvent in vacuo gave the colored residue which was purified eluting with 10-30% ethyl acetate in hexanes

Conditions: temp:97.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3,5-dibromophenol (59.54 mmol, 15 g), 3,4-(methylenedioxy) phenylboronic acid (77.40 mmol, 12.84 g), 3-thiopheneboronic acid (62.52 mmol, 8 g), PdCl2(dppf) (6.75 mmol, 4.94 g), and cesium carbonate (240 mmol, 78.19 g) was added dimethoxyethane (550 mL) at room temperature under nitrogen atmosphere. Then, the resulting light brown suspension was heated to 97° C. and stirred for 15 h. Then, the reaction mixture was cooled to room temperature and the solids were filtered-off and the cake was washed with ethyl acetate. The filtrate was diluted with water (300 mL) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2×100 mL) and the combined organic extracts were washed with brine solution (300 mL). The organic layer was dried over anhydrous magnesium sulfate and filtration of the drying agent and removal of the solvent gave the crude dark brown residue which was purified by two times using an ISCO (330 g) column chromatography eluting with 0-20% ethyl acetate in hexanes to afford the desired 3-benzo[1,3]dioxol-5-yl-5-thiophen-3-yl-phenol (7.48 g, 42.5%) as a white low melting solid. HRES(+) m/e calcd for C17H12O3S (M+H)+ 297.0580, found 297.0580 Then, the reaction mixture was cooled to room temperature the cake was washed with ethyl acetate The filtrate was diluted with water (300 mL) the two layers were separated The aqueous layer was extracted with ethyl acetate (2×100 mL) the combined organic extracts were washed with brine solution (300 mL) The organic layer was dried over anhydrous magnesium sulfate and filtration of the drying agent and removal of the solvent gave the crude dark brown residue which was purified by two times eluting with 0-20% ethyl acetate in hexanes

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

Procedure: To a mixture of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (14.54 g, 30.84 mmol), 3,5-dibromophenol (8.55 g, 33.92 mmol), and potassium carbonate (8.53 g, 61.68 mmol) were added N,N-dimethylformamide (210 mL) and acetone (420 mL) at room temperature. The resulting suspension was heated to reflux for 2 days. Then, the reaction mixture was cooled to room temperature and diluted with water (200 mL). The organic compound was extracted into ethyl acetate (2×200 mL) and the combined organic extracts were washed with brine solution (200 mL). The organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the crude product which was purified by using a Biotage column chromatography (FLASH 40L, Silica), eluting with 10% ethyl acetate/hexanes to obtain 4-{3-[6-(3,5-dibromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (19.61 g, 99%) as a colorless oil: ES(+)-HRMS m/e calculated for C29H38O6Br2 (M+H)+ 641.1108, found 641.1101. The resulting suspension was heated to reflux for 2 days The organic compound was extracted into ethyl acetate (2×200 mL) the combined organic extracts were washed with brine solution (200 mL) The organic layers were dried over anhydrous magnesium sulfate filtered concentrated in vacuo to give the crude product which was purified eluting with 10% ethyl acetate/hexanes

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

Procedure: To a suspension of sodium hydride (693 mg, 17.33 mmol, 60%, oil was washed with pentane) in THF (15 mL) was added 3, 5-dibromophenol (3.0 g, 11.55 mmol) at 0° C. and the suspension was stirred for 30 minutes. Then, methoxymethyl chloride (1.4 g, 17.33 mmol) was added at 0° C. The resulting suspension was allowed to warm to room temperature and stirred for 2 days at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was poured into an ice-water (50 mL) and the organic compound was extracted into ethyl acetate (2×100 mL). The combined extracts were washed with brine solution (250 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and the concentration of the solution under reduced pressure gave the crude residue which was purified by using an ISCO 120 g column chromatography, eluting with 5-20% ethyl acetate in hexanes to obtain 1,3-dibromo-5-methoxymethoxy-benzene (2.94 g, 86%) as a white solid: EI(+)-HRMS m/e calcd for C8H8Br2O2 (M)+ 293.8891, found 293.8893. stirred for 2 days at which time TLC analysis of the mixture the organic compound was extracted into ethyl acetate (2×100 mL) The combined extracts were washed with brine solution (250 mL) dried over anhydrous magnesium sulfate Filtration of the drying agent the concentration of the solution under reduced pressure gave the crude residue which was purified eluting with 5-20% ethyl acetate in hexanes