2-bromo-4-(bromomethyl)-1-fluorobenzene

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

Procedure: This compound was prepared from 3-bromo-4-fluorobenzyl bromide and 2,2-dimethylpropan-1,3-diol using the method of Example 1.

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Pyridine (0.7 cm3) and a solution of 3-bromo-4-fluorobenzyl alcohol (5 g) in dry toluene (50 cm3) were added to a stirred solution of phosphorus tribromide (2.64 g) in dry toluene (50 cm3) under an atmosphere of nitrogen, the temperature of the reaction mixture being maintained at -10° C. during the addition. The mixture was allowed to warm to the ambient temperature (ca. 20° C.) and was stirred for one hour. The mixture was poured into ice and the products extracted into diethyl ether. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulphate to give an orange-red oil, shown by thin layer chromatography to contain two components. NMR spectroscopy of the mixture suggested the presence of a phosphite intermediate and the required product. The oil was redissolved in dry toluene (50 cm3) and further phosphorus tribromide (0.2 g) and pyridine (0.7 cm3) added. The mixture was stirred at 50° C. for 4 hours and then stood at the ambient temperature for 17 hours. The mixture was poured into ice and sodium bicarbonate solution added to neutralise the resulting acid mixture. The products were extracted into diethyl ether, and the combined organic extracts washed with brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent gave a white solid which was purified by flash column chromatography on a silica gel support, eluting with petroleum ether containing 5% by volume diethyl ether, to give the title compound (4.6 g) as a colourless crystalline solid. to warm to the ambient temperature (ca. 20° C.) The mixture was poured into ice the products extracted into diethyl ether The combined organic extracts were washed with brine dried over anhydrous magnesium sulphate to give an orange-red oil

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

Procedure: The title compound was prepared from (S,E)-N—((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide and 2-bromo-4-(bromomethyl)-1-fluorobenzene using a method analogous to that described in Examples 509 and 510.

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

Procedure: (3-Bromo-4-fluorophenyl)methanol (0.264 g, 1.29 mmol) was dissolved in DCM (3 mL). The solution was cooled to 0 deg, and tribromoborane (1.0 M in DCM, 0.863 ml, 0.863 mmol) was added. The mixture was stirred at 0 deg for 1 h, then rt for 1 h. The reaction was quenched with water, and the mixture was transferred to a separatory funnel with half-saturated NaHCO3 (15 mL), and the aqueous phase was extracted with DCM (3×20 mL). The organics were combined, washed with half-saturated brine (5 mL), dried over sodium sulfate and concentrated. Purification of the residue through silica gel (40 mL) using 5% EtOAc-hexane afforded the title compound. The solution was cooled to 0 deg rt for 1 h The reaction was quenched with water the mixture was transferred to a separatory funnel with half-saturated NaHCO3 (15 mL) the aqueous phase was extracted with DCM (3×20 mL) washed with half-saturated brine (5 mL) dried over sodium sulfate concentrated Purification of the residue through silica gel (40 mL)

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

Procedure: (3-Bromo-4-fluorophenyl)methanol (0.264 g, 1.29 mmol) was dissolved in DCM (3 mL). The solution was cooled to 0 deg, and tribromoborane (1.0 M in DCM, 0.863 ml, 0.863 mmol) was added. The mixture was stirred at 0 deg for 1 h, then rt for 1 h. The reaction was quenched with water, and the mixture was transferred to a separatory funnel with half-saturated NaHCO3 (15 mL), and the aqueous phase was extracted with DCM (3×20 mL). The organics were combined, washed with half-saturated brine (5 mL), dried over sodium sulfate and concentrated. Purification of the residue through silica gel (40 mL) using 5% EtOAc-hexane afforded the title compound. The solution was cooled to 0 deg rt for 1 h The reaction was quenched with water the mixture was transferred to a separatory funnel with half-saturated NaHCO3 (15 mL) the aqueous phase was extracted with DCM (3×20 mL) washed with half-saturated brine (5 mL) dried over sodium sulfate concentrated Purification of the residue through silica gel (40 mL)

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

Procedure: A mixture of magnesium turnings (880 mg, 37 mmol) and 2-bromo-4-(bromomethyl)-1-fluorobenzene (1.0 g, 3.7 mmol) in anhydrous diethyl ether (15 ml) was treated with a piece of iodine. The mixture was then heated to gentle reflux until the color of the mixture disappeared, after which the heating continued for additional hour. The suspension was cooled to room temperature, and cannulated into a solution of dimethylpyridine-2,3-dicarboxylate (1.0 g, 5.1 mmol) in tetrahydrofuran (50 ml) at −78° C. The reaction mixture was maintained at the same temperature for 30 minutes, and was quenched with addition of water. After warming up to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (15% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 353 (M+H)+. The mixture was then heated to gentle reflux until the color of the mixture after which the heating continued for additional hour The reaction mixture was maintained at the same temperature for 30 minutes was quenched with addition of water After warming up to room temperature the reaction mixture was partitioned between ethyl acetate and brine The organic phase was washed with brine concentrated The residue was purified by flash chromatography (15% ethyl acetate in hexane)