1-BROMO-2,5-DIFLUORO-4-METHYLBENZENE

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-bromo-2,5-difluoro-4-methyl-benzene (3.3 g, 16 mmol) and ether (75 mL) was cooled to −78° C., and a solution of n-butyllithium in hexane (5.4 mL, 2.5 M, 13.5 mmol) was added dropwise. After stirring for 1 hour, dimethylformamide (1.1 mL, 14 mmol) was added, and the mixture was stirred for 1 hour. The mixture was treated with 1M HCl and water, warmed to ambient temperature and was extracted 3× with ether. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was diluted with tetrahydrofuran (50 mL), and the mixture was treated with sodium borohydride (0.50 g, 13.5 mmol) and ethanol (2 mL). After stirring for 30 minutes, the mixture was diluted cautiously with 0.5M aqueous HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization of the residue from hexane afforded 1.24 g (54%) of (2,5-difluoro-4-methyl-phenyl)-methanol as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.05 (dd, 1H, J=6.0, 9.2 Hz), 6.84 (dd, 1H, J=6.4, 10 Hz), 4.68 (d, 2H, J=6.0 Hz), 2.23 (s, 3H), 1.76 (t, 1H, J=6.0 Hz) ppm. the mixture was stirred for 1 hour warmed to ambient temperature was extracted 3× with ether The combined organic layers were dried over MgSO4 filtered concentrated in vacuo The residue was diluted with tetrahydrofuran (50 mL) After stirring for 30 minutes extracted 3× with ethyl acetate the combined organic layers were dried over Na2SO4 filtered concentrated in vacuo Recrystallization of the residue from hexane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-bromo-2,5-difluoro-4-methyl-benzene (3.3 g, 16 mmol) and ether (75 mL) was cooled to −78° C., and a solution of n-butyllithium in hexane (5.4 mL, 2.5 M, 13.5 mmol) was added dropwise. After stirring for 1 hour, dimethylformamide (1.1 mL, 14 mmol) was added, and the mixture was stirred for 1 hour. The mixture was treated with 1M HCl and water, warmed to ambient temperature and was extracted 3× with ether. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was diluted with tetrahydrofuran (50 mL), and the mixture was treated with sodium borohydride (0.50 g, 13.5 mmol) and ethanol (2 mL). After stirring for 30 minutes, the mixture was diluted cautiously with 0.5M aqueous HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization of the residue from hexane afforded 1.24 g (54%) of (2,5-difluoro-4-methyl-phenyl)-methanol as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.05 (dd, 1H, J=6.0, 9.2 Hz), 6.84 (dd, 1H, J=6.4, 10 Hz), 4.68 (d, 2H, J=6.0 Hz), 2.23 (s, 3H), 1.76 (t, 1H, J=6.0 Hz) ppm. the mixture was stirred for 1 hour warmed to ambient temperature was extracted 3× with ether The combined organic layers were dried over MgSO4 filtered concentrated in vacuo The residue was diluted with tetrahydrofuran (50 mL) After stirring for 30 minutes extracted 3× with ethyl acetate the combined organic layers were dried over Na2SO4 filtered concentrated in vacuo Recrystallization of the residue from hexane

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,5-difluorotoluene (25 g, 0.20 mol) and iron powder (11 g, 0.2 mol) was cooled to −5° C. Bromine was added dropwise such that the internal temperature of the reaction did not rise above 0° C. After stirring for 3 hours, the mixture was diluted with ether, filtered and washed with aqueous sodium thiosulfate solution. The aqueous layer was extracted with ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Distillation at atmospheric pressure gave 34 g of 1-bromo-2,5-difluoro-4-methyl-benzene as a colorless oil (b.p. 180 oC). 1H NMR (300 MHz, CDCl3) δ 7.20 (dd, 1H, J=6.0, 8.5 Hz), 6.93 (m, 1H), 2.23 (s, 3H) ppm. did not rise above 0° C filtered washed with aqueous sodium thiosulfate solution The aqueous layer was extracted with ether the combined organic layers were dried over MgSO4 filtered concentrated in vacuo Distillation at atmospheric pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-bromo-2,5-difluoro-4-methyl-benzene (3.3 g, 16 mmol) and ether (75 mL) was cooled to −78° C., and a solution of n-butyllithium in hexane (5.4 mL, 2.5 M, 13.5 mmol) was added dropwise. After stirring for 1 hour, dimethylformamide (1.1 mL, 14 mmol) was added, and the mixture was stirred for 1 hour. The mixture was treated with 1M HCl and water, warmed to ambient temperature and was extracted 3× with ether. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was diluted with tetrahydrofuran (50 mL), and the mixture was treated with sodium borohydride (0.50 g, 13.5 mmol) and ethanol (2 mL). After stirring for 30 minutes, the mixture was diluted cautiously with 0.5M aqueous HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization of the residue from hexane afforded 1.24 g (54%) of (2,5-difluoro-4-methyl-phenyl)-methanol as a colorless solid. 1H NMR (400 MHz, CDCl3) δ7.05 (dd, 1H, J=6.0, 9.2 Hz), 6.84 (dd, 1H, J=6.4, 10 Hz), 4.68 (d, 2H, J=6.0 Hz), 2.23 (s, 3H), 1.76 (t, 1H, J=6.0 Hz) ppm. the mixture was stirred for 1 hour warmed to ambient temperature was extracted 3× with ether The combined organic layers were dried over MgSO4 filtered concentrated in vacuo The residue was diluted with tetrahydrofuran (50 mL) After stirring for 30 minutes extracted 3× with ethyl acetate the combined organic layers were dried over Na2SO4 filtered concentrated in vacuo Recrystallization of the residue from hexane

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,5-difluorotoluene (25 g, 0.20 mol) and iron powder (11 g, 0.2 mol) was cooled to −5° C. Bromine was added dropwise such that the internal temperature of the reaction did not rise above 0° C. After stirring for 3 hours, the mixture was diluted with ether, filtered and washed with aqueous sodium thiosulfate solution. The aqueous layer was extracted with ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Distillation at atmospheric pressure gave 34 g of 1-bromo-2,5-difluoro-4-methyl-benzene as a colorless oil (b.p. 180° C.). 1H NMR (300 MHz, CDCl3) δ7.20 (dd, 1H, J=6.0, 8.5 Hz), 6.93 (m, 1H), 2.23 (s, 3H) ppm. did not rise above 0° C filtered washed with aqueous sodium thiosulfate solution The aqueous layer was extracted with ether the combined organic layers were dried over MgSO4 filtered concentrated in vacuo Distillation at atmospheric pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-bromo-2,5-difluoro-4-methyl-benzene (3.3 g, 16 mmol) and ether (75 mL) was cooled to −78° C., and a solution of n-butyllithium in hexane (5.4 mL, 2.5 M, 13.5 mmol) was added dropwise. After stirring for 1 hour, dimethylformamide (1.1 mL, 14 mmol) was added, and the mixture was stirred for 1 hour. The mixture was treated with 1 M HCl and water, warmed to ambient temperature and was extracted 3× with ether. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was diluted with tetrahydrofuran (50 mL), and the mixture was treated with sodium borohydride (0.50 g, 13.5 mmol) and ethanol (2 mL). After stirring for 30 minutes, the mixture was diluted cautiously with 0.5M aqueous HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization of the residue from hexane afforded 1.24 g (54%) of (2,5-difluoro-4-methyl-phenyl)-methanol as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.05 (dd, 1H, J=6.0, 9.2 Hz), 6.84 (dd, 1H, J=6.4, 10 Hz), 4.68 (d, 2H, J=6.0 Hz), 2.23 (s, 3H), 1.76 (t, 1H, J=6.0 Hz) ppm. the mixture was stirred for 1 hour warmed to ambient temperature was extracted 3× with ether The combined organic layers were dried over MgSO4 filtered concentrated in vacuo The residue was diluted with tetrahydrofuran (50 mL) After stirring for 30 minutes extracted 3× with ethyl acetate the combined organic layers were dried over Na2SO4 filtered concentrated in vacuo Recrystallization of the residue from hexane

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,5-difluorotoluene (25 g, 0.20 mol) and iron powder (11 g, 0.2 mol) was cooled to −5° C. Bromine was added dropwise such that the internal temperature of the reaction did not rise above 0° C. After stirring for 3 hours, the mixture was diluted with ether, filtered and washed with aqueous sodium thiosulfate solution. The aqueous layer was extracted with ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Distillation at atmospheric pressure gave 34 g of 1-bromo-2,5-difluoro-4-methyl-benzene as a colorless oil (b.p. 180° C.). 1H NMR (300 MHz, CDCl3) δ 7.20 (dd, 1H, J=6.0, 8.5 Hz), 6.93 (m, 1H), 2.23 (s, 3H) ppm. did not rise above 0° C filtered washed with aqueous sodium thiosulfate solution The aqueous layer was extracted with ether the combined organic layers were dried over MgSO4 filtered concentrated in vacuo Distillation at atmospheric pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-bromo-2,5-difluoro-4-methyl-benzene (3.3 g, 16 mmol) and ether (75 mL) was cooled to −78° C., and a solution of n-butyllithium in hexane (5.4 mL, 2.5 M, 13.5 mmol) was added dropwise. After stirring for 1 hour, dimethylformamide (1.1 mL, 14 mmol) was added, and the mixture was stirred for 1 hour. The mixture was treated with 1M HCl and water, warmed to ambient temperature and was extracted 3× with ether. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was diluted with tetrahydrofuran (50 mL), and the mixture was treated with sodium borohydride (0.50 g, 13.5 mmol) and ethanol (2 mL). After stirring for 30 minutes, the mixture was diluted cautiously with 0.5M aqueous HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization of the residue from hexane afforded 1.24 g (54%) of (2,5-difluoro-4-methyl-phenyl)-methanol as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.05 (dd, 1H, J=6.0, 9.2 Hz), 6.84 (dd, 1H, J=6.4, 10 Hz), 4.68 (d, 2H, J=6.0 Hz), 2.23 (s, 3H), 1.76 (t, 1H, J=6.0 Hz) ppm. the mixture was stirred for 1 hour warmed to ambient temperature was extracted 3× with ether The combined organic layers were dried over MgSO4 filtered concentrated in vacuo The residue was diluted with tetrahydrofuran (50 mL) After stirring for 30 minutes extracted 3× with ethyl acetate the combined organic layers were dried over Na2SO4 filtered concentrated in vacuo Recrystallization of the residue from hexane

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,5-difluorotoluene (25 g, 0.20 mol) and iron powder (11 g, 0.2 mol) was cooled to −5° C. Bromine was added dropwise such that the internal temperature of the reaction did not rise above 0° C. After stirring for 3 hours, the mixture was diluted with ether, filtered and washed with aqueous sodium thiosulfate solution. The aqueous layer was extracted with ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Distillation at atmospheric pressure gave 34 g of 1-bromo-2,5-difluoro-4-methyl-benzene as a colorless oil (b.p. 180 oC). 1H NMR (300 MHz, CDCl3) δ 7.20 (dd, 1H, J=6.0, 8.5 Hz), 6.93 (m,1H), 2.23 (s, 3H) ppm. did not rise above 0° C filtered washed with aqueous sodium thiosulfate solution The aqueous layer was extracted with ether the combined organic layers were dried over MgSO4 filtered concentrated in vacuo Distillation at atmospheric pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-bromo-2,5-difluoro-4-methyl-benzene (3.3 g, 16 mmol) and ether (75 mL) was cooled to −78° C., and a solution of n-butyllithium in hexane (5.4 mL, 2.5 M, 13.5 mmol) was added dropwise. After stirring for 1 hour, dimethylformamide (1.1 mL, 14 mmol) was added, and the mixture was stirred for 1 hour. The mixture was treated with 1M HCl and water, warmed to ambient temperature and was extracted 3× with ether. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was diluted with tetrahydrofuran (50 mL), and the mixture was treated with sodium borohydride (0.50 g, 13.5 mmol) and ethanol (2 mL). After stirring for 30 minutes, the mixture was diluted cautiously with 0.5M aqueous HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization of the residue from hexane afforded 1.24 g (54%) of (2,5-difluoro-4-methyl-phenyl)-methanol as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.05 (dd, 1H, J=6.0, 9.2 Hz), 6.84 (dd, 1H, J=6.4, 10 Hz), 4.68 (d, 2H, J=6.0 Hz), 2.23 (s, 3H), 1.76 (t, 1H, J=6.0 Hz) ppm. the mixture was stirred for 1 hour warmed to ambient temperature was extracted 3× with ether The combined organic layers were dried over MgSO4 filtered concentrated in vacuo The residue was diluted with tetrahydrofuran (50 mL) After stirring for 30 minutes extracted 3× with ethyl acetate the combined organic layers were dried over Na2SO4 filtered concentrated in vacuo Recrystallization of the residue from hexane

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,5-difluorotoluene (25 g, 0.20 mol) and iron powder (11 g, 0.2 mol) was cooled to −5° C. Bromine was added dropwise such that the internal temperature of the reaction did not rise above 0° C. After stirring for 3 hours, the mixture was diluted with ether, filtered and washed with aqueous sodium thiosulfate solution. The aqueous layer was extracted with ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Distillation at atmospheric pressure gave 34 g of 1-bromo-2,5-difluoro-4-methyl-benzene as a colorless oil (b.p. 180 oC). 1H NMR (300 MHz, CDCl3) δ 7.20 (dd, 1H, J=6.0, 8.5 Hz), 6.93 (m, 1H), 2.23 (s, 3H) ppm. did not rise above 0° C filtered washed with aqueous sodium thiosulfate solution The aqueous layer was extracted with ether the combined organic layers were dried over MgSO4 filtered concentrated in vacuo Distillation at atmospheric pressure