3-BROMO-2-CHLORO-6-FLUOROTOLUENE

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

Procedure: A mixture of 3-bromo-2-chloro-6-fluoro-toluene (commercially available) (8.0 g), N-bromosuccinimide (“NBS”) (6.42 g) and benzoyl peroxide (catalytic amount) in carbon tetrachloride (40 ml) was heated to reflux. A 500 watt tungsten halogen lamp was used to initiate the reaction. The reaction mixture was heated to reflux and irradiated for 30 minutes. The reaction mixture was allowed to cool to ambient temperature and then filtered. The filtrate was concentrated to give a colorless oil which solidified on standing to give 1-bromo-3-bromomethyl-2-chloro-4-fluoro-benzene as an off-white solid (10.7 g). 1H-NMR (400 MHz, CDCl3): 7.58 (dd, 1H), 6.94 (t, 1H), 4.64 (d, 21-1) ppm. was heated to reflux the reaction The reaction mixture was heated to reflux irradiated for 30 minutes filtered The filtrate was concentrated to give a colorless oil which

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

Procedure: 3-Bromo-2-chloro-6-fluoro-toluene (8.0 g), N-bromosuccinimide (NBS) (6.42 g) and a catalytic amount of benzoyl peroxide in carbon tetrachloride (40 ml) were heated to reflux. A 500 watt tungsten halogen lamp was used to initiate the reaction. The reaction mixture was heated to reflux and irradiated for 30 minutes. The reaction mixture was allowed to cool and then filtered. The filtrate was concentrated to give a colourless oil which solidified on standing to give 1-bromo-3-bromomethyl-2-chloro-4-fluorobenzene as an off-white solid (10.7 g). the reaction The reaction mixture was heated to reflux irradiated for 30 minutes to cool filtered The filtrate was concentrated to give a colourless oil which

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-2-chloro-6-fluorotoluene (7.0 g, 31 mmol), zinc cyanide (3.7 g, 31 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.81 g, 1.56 mmol) was added to a flask under argon atmosphere. Dry DMF (35 mL) was added and the reaction mixture was stirred under argon at 120° C. The reaction was monitored by GC-MS and full conversion was observed after 2 hours. The mixture was diluted with dichloromethane (300 mL), washed with water (100 mL) and 4% magnesium sulfate solution (100 mL), dried over magnesium sulphate, filtered, and evaporated to give a clear oil. The product was further purified by column chromatography on silica gel using n-heptane/ethyl acetate (9:1) giving a white solid (3.79 g, 71%). washed with water (100 mL) and 4% magnesium sulfate solution (100 mL) dried over magnesium sulphate filtered evaporated to give a clear oil The product was further purified by column chromatography on silica gel

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

Procedure: 3-Bromo-2-chloro-6-fluorotoluene 165RL91 (173 mg, 0.78 mmol), zinc cyanide (91 mg, 0.78 mmol) and tetrakis(triphenylphosphine)palladium(0) (27 mg, 23 μmol) was charged in a vial, DMF (1 mL) added, and the mixture irradiated for 150 sec at 200° C. in a microwave oven. Diethyl ether (30 ml) was added and the reaction mixture washed with magnesium sulphate (4% solution, 3×20 mL) followed by brine (20 mL). The organic layer was dried and evaporated. The product was further purified by column chromatography on silica gel using n-heptane/ethyl acetate (9:1) giving a white solid (55 mg, 42%). added the mixture irradiated for 150 sec at 200° C. in a microwave oven the reaction mixture washed with magnesium sulphate (4% solution, 3×20 mL) The organic layer was dried evaporated The product was further purified by column chromatography on silica gel

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

Procedure: 3-Bromo-2-chloro-6-fluorotoluene 165RL91 (173 mg, 0.78 mmol), zinc cyanide (91 mg, 0.78 mmol) and tetrakis(triphenylphosphine)palladium(0) (27 mg, 23 μmol) was charged in a vial, DMF (1 mL) added, and the mixture irradiated for 150 sec at 200° C. in a microwave oven. Diethyl ether (30 ml) was added and the reaction mixture washed with magnesium sulphate (4% solution, 3×20 mL) followed by brine (20 mL). The organic layer was dried and evaporated. The product was further purified by column chromatography on silica gel using n-heptane/ethyl acetate (9:1) giving a white solid (55 mg, 42%). added the mixture irradiated for 150 sec at 200° C. in a microwave oven the reaction mixture washed with magnesium sulphate (4% solution, 3×20 mL) The organic layer was dried evaporated The product was further purified by column chromatography on silica gel

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

Procedure: 2-chloro-6-fluorotoluene (5.00 g, 34.6 mmol) and iron (0.1 g, 0.17 mmol) was stirred in a 100 mL flask. Bromine (6.08 g, 38.1 mmol) was added slowly in 3 portions with 1 min between each addition. The reaction was stirred for additional 15 min. Then dichloromethane (50 ml) was added, the reaction mixture transferred to a separation funnel and washed with a sodium thiosulphate solution (10%, 30 mL) until it had turned colorless. The layers were separated and the organic layer was washed with sat. sodium hydrogen carbonate (30 mL), dried and evaporated to give the title compound as a colorless oil (7.57 g, 98%) containing 15% 3-bromo-5-chloro-2-fluorotoluene (calc. by 1H-NMR). The compound was used in the next step without further purification. the reaction mixture transferred to a separation funnel washed with a sodium thiosulphate solution (10%, 30 mL) until it The layers were separated the organic layer was washed with sat. sodium hydrogen carbonate (30 mL) dried evaporated

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

Procedure: A mixture of 3-bromo-2-chloro-6-fluoro-toluene (8.0 g), N-bromosuccinimide (“NBS”) (6.42 g) and benzoyl peroxide (catalytic amount) in carbon tetrachloride (40 ml) was heated to reflux. A 500 watt tungsten halogen lamp was used to initiate the reaction. The reaction mixture was heated to reflux and irradiated for 30 minutes. The reaction mixture was allowed to cool to ambient temperature and then filtered. The filtrate was concentrated to give a colourless oil which solidified on standing to give 1-bromo-3-bromomethyl-2-chloro-4-fluoro-benzene as an off-white solid (10.7 g). 1H-NMR (400 MHz, CDCl3): 4.64 (d, 2H), 6.94 (t, 1H), 7.58 (dd, 1H) ppm. was heated to reflux the reaction The reaction mixture was heated to reflux irradiated for 30 minutes filtered The filtrate was concentrated to give a colourless oil which

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

Procedure: A mixture of 3-bromo-2-chloro-6-fluoro-toluene (commercially available) (8.0 g), N-bromosuccinimide (“NBS”) (6.42 g) and benzoyl peroxide (catalytic amount) in carbon tetrachloride (40 ml) was heated to reflux. A 500 watt tungsten halogen lamp was used to initiate the reaction. The reaction mixture was heated to reflux and irradiated for 30 minutes. The reaction mixture was allowed to cool to ambient temperature and then filtered. The filtrate was concentrated to give a colorless oil which solidified on standing to give 1-bromo-3-bromomethyl-2-chloro-4-fluoro-benzene as an off-white solid (10.7 g). 1H-NMR (400 MHz, CDCl3): 7.58 (dd, 1H), 6.94 (t, 1H), 4.64 (d, 21-1) ppm. was heated to reflux the reaction The reaction mixture was heated to reflux irradiated for 30 minutes filtered The filtrate was concentrated to give a colorless oil which

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

Procedure: 3-Bromo-2-chloro-6-fluoro-toluene (8.0 g), N-bromosuccinimide (NBS) (6.42 g) and a catalytic amount of benzoyl peroxide in carbon tetrachloride (40 ml) were heated to reflux. A 500 watt tungsten halogen lamp was used to initiate the reaction. The reaction mixture was heated to reflux and irradiated for 30 minutes. The reaction mixture was allowed to cool and then filtered. The filtrate was concentrated to give a colourless oil which solidified on standing to give 1-bromo-3-bromomethyl-2-chloro-4-fluorobenzene as an off-white solid (10.7 g). the reaction The reaction mixture was heated to reflux irradiated for 30 minutes to cool filtered The filtrate was concentrated to give a colourless oil which

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-2-chloro-6-fluorotoluene (7.0 g, 31 mmol), zinc cyanide (3.7 g, 31 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.81 g, 1.56 mmol) was added to a flask under argon atmosphere. Dry DMF (35 mL) was added and the reaction mixture was stirred under argon at 120° C. The reaction was monitored by GC-MS and full conversion was observed after 2 hours. The mixture was diluted with dichloromethane (300 mL), washed with water (100 mL) and 4% magnesium sulfate solution (100 mL), dried over magnesium sulphate, filtered, and evaporated to give a clear oil. The product was further purified by column chromatography on silica gel using n-heptane/ethyl acetate (9:1) giving a white solid (3.79 g, 71%). washed with water (100 mL) and 4% magnesium sulfate solution (100 mL) dried over magnesium sulphate filtered evaporated to give a clear oil The product was further purified by column chromatography on silica gel

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

Procedure: 3-Bromo-2-chloro-6-fluorotoluene 165RL91 (173 mg, 0.78 mmol), zinc cyanide (91 mg, 0.78 mmol) and tetrakis(triphenylphosphine)palladium(0) (27 mg, 23 μmol) was charged in a vial, DMF (1 mL) added, and the mixture irradiated for 150 sec at 200° C. in a microwave oven. Diethyl ether (30 ml) was added and the reaction mixture washed with magnesium sulphate (4% solution, 3×20 mL) followed by brine (20 mL). The organic layer was dried and evaporated. The product was further purified by column chromatography on silica gel using n-heptane/ethyl acetate (9:1) giving a white solid (55 mg, 42%). added the mixture irradiated for 150 sec at 200° C. in a microwave oven the reaction mixture washed with magnesium sulphate (4% solution, 3×20 mL) The organic layer was dried evaporated The product was further purified by column chromatography on silica gel

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

Procedure: 2-chloro-6-fluorotoluene (5.00 g, 34.6 mmol) and iron (0.1 g, 0.17 mmol) was stirred in a 100 mL flask. Bromine (6.08 g, 38.1 mmol) was added slowly in 3 portions with 1 min between each addition. The reaction was stirred for additional 15 min. Then dichloromethane (50 ml) was added, the reaction mixture transferred to a separation funnel and washed with a sodium thiosulphate solution (10%, 30 mL) until it had turned colorless. The layers were separated and the organic layer was washed with sat. sodium hydrogen carbonate (30 mL), dried and evaporated to give the title compound as a colorless oil (7.57 g, 98%) containing 15% 3-bromo-5-chloro-2-fluorotoluene (calc. by 1H-NMR). The compound was used in the next step without further purification. the reaction mixture transferred to a separation funnel washed with a sodium thiosulphate solution (10%, 30 mL) until it The layers were separated the organic layer was washed with sat. sodium hydrogen carbonate (30 mL) dried evaporated