1-chloro-4-fluoro-2-methylbenzene

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

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

Procedure: To a stirred solution of 2-chloro-5-fluorotoluene (10.356 g, 71.628 mmol, Lancaster, used as received) in conc. H2SO4 (70 mL) at 0° C., KNO3 (7.252 g, 71.72 mmol) was added in four equal portions. The resulting pale yellow solution was allowed to warm to room temperature and was stirred overnight at room temperature. It was then poured into ice water (350 g) and extracted with ether (3×100 mL). Ether was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil was dried further under vacuum to afford 12.277 g (90%). of the title compound as an oil, which was used as such for the next reaction; 1H NMR (CDCl3); δ 2.459 (s, 2H), 7.193 (d, 1H, J1=11.1 Hz), 8.083 (d, 1H, J1=6.6 Hz). extracted with ether (3×100 mL) Ether was dried over anhydrous Na2SO4 removed under vacuum the resulting oil was dried further under vacuum to afford 12.277 g (90%)

Conditions: temp:28.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-chloro-5-fluorotoluene (0.500 g, 3.46 mmol, Lancaster, used as received) in conc. H2SO4 (5.0 mL) at 0° C., KNO3 (0.350 g, 3.46 mmol) was added in one lot. The resulting pale yellow solution was allowed to warm to 28° C. and stirred overnight at 28° C. It was then poured into ice (50 g) and extracted with ether (2×50 mL). The ether was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil was dried further under vacuum to afford 0.616 g (94%) of the title compound as an oil, which was used as such for the next reaction; 1H NMR (CDCl3): δ 2.459 (s, 3H), 7.193 (d, 1H, J1=11.1 Hz), 8.083 (d, 1H, J1=6.6 Hz). extracted with ether (2×50 mL) The ether was dried over anhydrous Na2SO4 removed under vacuum the resulting oil was dried further under vacuum

Conditions: temp:28.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-chloro-5-fluorotoluene (0.500 g, 3.46 mmol, Lancaster, used as received) in conc. H2SO4 (5.0 mL) at 0° C., KNO3 (0.350 g, 3.46 mmol) was added in one lot. The resulting pale yellow solution was allowed to warm to 28° C. and stirred overnight at 28° C. It was then poured into ice (50 g) and extracted with ether (2×50 mL). The ether was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil was dried further under vacuum to afford 0.616 g (94%) of the title compound as an oil, which was used as such for the next reaction; 1H NMR (CDCl3): δ 2.459 (s, 3H), 7.193 (d, 1H, J1=11.1 Hz), 8.083 (d, 1H, J1=6.6 Hz). extracted with ether (2×50 mL) The ether was dried over anhydrous Na2SO4 removed under vacuum the resulting oil was dried further under vacuum

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

Procedure: (5-Chloro-2-fluoro-4-methyl-phenyl)-methanol was prepared in analogous fashion to (2,5-difluoro-4-methyl-phenyl)-methanol using 2-chloro-5-fluorotoluene as starting material. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 1H, J=6.8 Hz), 6.92 (d, 1H, J=10 Hz), 4.69 (s, 2H), 2.34 (s, 3H) ppm.

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

Procedure: To concentrated sulfuric acid (23.81 g), cooled to 0° C., under a nitrogen atmosphere, was added concentrated nitric acid (27.5 g) dropwise. 2-Chloro-5-fluorotoluene (9 g) was added dropwise and the reaction was stirred for 2 hours. The reaction was poured into ice and extracted with ethyl acetate. The organic phase was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography [eluting with ethyl acetate/heptane (1:2)] to yield the title compound (9.4 g). The reaction was poured into ice extracted with ethyl acetate The organic phase was washed with aqueous sodium hydrogen carbonate dried over sodium sulfate concentrated under reduced pressure The residue was purified by silica column chromatography [eluting with ethyl acetate/heptane (1:2)]

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

Procedure: To concentrated sulfuric acid (23.81 g), cooled to 0° C., under a nitrogen atmosphere, was added concentrated nitric acid (27.5 g) dropwise. 2-Chloro-5-fluorotoluene (9 g) was added dropwise and the reaction was stirred for 2 hours. The reaction was poured into ice and extracted with ethyl acetate. The organic phase was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography [eluting with ethyl acetate/heptane (1:2)] to yield the title compound (9.4 g). The reaction was poured into ice extracted with ethyl acetate The organic phase was washed with aqueous sodium hydrogen carbonate dried over sodium sulfate concentrated under reduced pressure The residue was purified by silica column chromatography [eluting with ethyl acetate/heptane (1:2)]

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

Procedure: A solution of 2-chloro-5-fluorotoluene (5.0 g) in acetic anhydride (40 ml) was treated dropwise with concentrated sulfuric acid (40 ml) with cooling on ice. Subsequently, a solution of chromic anhydride (9.3 g) in acetic anhydride (40 ml) was added dropwise over a period of 2 hours. At the same temperature, the mixture was stirred for 1 hour, and added to an ice-water. The mixture was extracted with diethyl ether and the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 ml), combined with water (4 ml) and concentrated sulfuric acid (4 ml), and heated with stirring at 100° C. for 30 minutes. After allowed to stand to cool, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to a column chromatography on a silica gel to obtain 2-chloro-5-fluorobenzaldehyde (1.6 g). with cooling on ice The mixture was extracted with diethyl ether the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine dried over magnesium sulfate The solvent was distilled off under reduced pressure the residue was dissolved in tetrahydrofuran (10 ml) heated with stirring at 100° C. for 30 minutes to cool the reaction mixture was extracted with ethyl acetate the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine dried over magnesium sulfate The solvent was distilled off

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

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

Procedure: A solution of 2-chloro-5-fluorotoluene (5.0 g) in acetic anhydride (40 ml) was treated dropwise with concentrated sulfuric acid (40 ml) with cooling on ice. Subsequently, a solution of chromic anhydride (9.3 g) in acetic anhydride (40 ml) was added dropwise over a period of 2 hours. At the same temperature, the mixture was stirred for 1 hour, and added to an ice-water. The mixture was extracted with diethyl ether and the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 ml), combined with water (4 ml) and concentrated sulfuric acid (4 ml), and heated with stirring at 100° C. for 30 minutes. After allowed to stand to cool, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to a column chromatography on a silica gel to obtain 2-chloro-5-fluorobenzaldehyde (1.6 g). with cooling on ice The mixture was extracted with diethyl ether the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine dried over magnesium sulfate The solvent was distilled off under reduced pressure the residue was dissolved in tetrahydrofuran (10 ml) heated with stirring at 100° C. for 30 minutes to cool the reaction mixture was extracted with ethyl acetate the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine dried over magnesium sulfate The solvent was distilled off

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

Procedure: 3-Fluoro-4,6-dichlorotoluene is prepared with reduced formation of 3-fluoro-2,6-dichlorotoluene by chlorinating 3-fluorotoluene in the presence of a catalyst system to give a mixture containing 3-fluoro-6-chlorotoluene and 3-fluoro-4-chlorotoluene and chlorinating this in the presence of another catalyst system to give 3-fluoro-4,6-dichlorotoluene. to give a mixture

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

Procedure: 3-Fluoro-4,6-dichlorotoluene is prepared with reduced formation of 3-fluoro-2,6-dichlorotoluene by chlorinating 3-fluorotoluene in the presence of a catalyst system to give a mixture containing 3-fluoro-6-chlorotoluene and 3-fluoro-4-chlorotoluene and chlorinating this in the presence of another catalyst system to give 3-fluoro-4,6-dichlorotoluene. to give a mixture