1-bromo-3,4-difluoro-2-methylbenzene

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

Procedure: To 1,2-difluoro-3-methylbenzene (5 g, 39.0 mmol, commercially available from e.g. Sigma-Aldrich, Apollo or Fluorochem) containing iron (0.131 g, 2.342 mmol) was added bromine (2.011 ml, 39.0 mmol) dropwise maintaining a temperature of <30° C. with ice cooling. The mixture was stirred at room temperature overnight. The mixture was partitioned between water (50 mL) and diethyl ether (100 mL). The aqueous phase was extracted with diethyl ether (3×50 mL), combined organic extracts were washed with water (50 mL), 5% sodium thiosulfate solution (50 mL), water (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford product in 8.07 g. (Caution: by of product=68-70° C. @ 57 mBar). dropwise maintaining a temperature of <30° C. with ice cooling The mixture was partitioned between water (50 mL) and diethyl ether (100 mL) The aqueous phase was extracted with diethyl ether (3×50 mL) were washed with water (50 mL), 5% sodium thiosulfate solution (50 mL), water (50 mL), brine (50 mL) dried over anhydrous magnesium sulfate concentrated in vacuo to afford product in 8.07 g (Caution: by of product=68-70° C. @ 57 mBar)

Conditions: temp:-105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-3,4-difluoro-2-methylbenzene (4.14 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.37 in EtOAc/hexane 3:7) to give (2R)-1-(3,4-difluoro-2-methylphenyl)propan-2-ol (2.64 g, 71%) as pale oil. 1H NMR (300 MHz, CDCl3): δ 6.85-7.26 (m, 2H), 3.98 (m, 1H), 2.73 (m, 2H), 2.25 (m, 3H), 1.45 (d, J=3.75 Hz, 1H), 1.26 (d, J=6.21 Hz, 3H). The mixture was stirred at −100° C. to −90° C. for 2 h the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C The mixture was stirred warmed to 0° C. overnight Then 20 mL of water was added mixture was extracted with EtOAc (2×60 mL) the extract was dried over Na2SO4 evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.37 in EtOAc/hexane 3:7)

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

Procedure: The acid was synthesised as reported in US 2005/0054733A1 and described below 1-bromo-3,4-difluoro-2-methylbenzene (I67) (8.07 g, 39.0 mmol) was cooled to 0° C. in tetrahydrofuran (THF) (40 mL). Isopropylmagnesium chloride (29.2 mL, 58.5 mmol) was added dropwise and the solution stirred at room temperature overnight. The solution was cooled to 0° C. and gassed slowly with Carbon dioxide (excess) for 1 hour. The cooling was removed and gassing continues for 4 hours before allowing the solution to stand at room temperature overnight. Water (10 ml) was added and the solvents removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and 2N Hydrochloric acid (25 mL). The aqueous phase was extracted with ethyl acetate (5×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to a crude solid that was recrystalised from cyclohexane to afford product in 4.68 g. The acid was synthesised The solution was cooled to 0° C. The cooling was removed gassing continues for 4 hours to stand at room temperature overnight Water (10 ml) was added the solvents removed in vacuo The residue was partitioned between ethyl acetate (50 mL) and 2N Hydrochloric acid (25 mL) The aqueous phase was extracted with ethyl acetate (5×50 mL) The combined organic extracts were washed with water (50 mL), brine (50 mL) dried over anhydrous magnesium sulfate concentrated in vacuo to a crude solid that was recrystalised from cyclohexane to afford product in 4.68 g

Conditions: temp:-105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-3,4-difluoro-2-methylbenzene (4.14 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silicagel, EtOAc/hexane 1:9, Rf=0.37 in EtOAc/hexane 3:7) to give (2R)-1-(3,4-difluoro-2-methylphenyl)propan-2-ol (2.64 g, 71%) as pale oil. 1H NMR (300 MHz, CDCl3): 6.85-7.26 (m, 2H), 3.98 (m, 1H), 2.73 (m, 2H), 2.25 (m, 3H), 1.45 (d, J=3.75 Hz, 1H), 1.26 (d, J=6.21 Hz, 3H). The mixture was stirred at −100° C. to −90° C. for 2 h the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C The mixture was stirred warmed to 0° C. overnight Then 20 mL of water was added mixture was extracted with EtOAc (2×60 mL) the extract was dried over Na2SO4 evaporated to give crude oil, which was purified by column (silicagel, EtOAc/hexane 1:9, Rf=0.37 in EtOAc/hexane 3:7)