2-chloro-4-fluoro-1-methylbenzene

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: To a solution of 100 g (0.7 mol) of 2-chloro-4-fluorotoluene in 250 ml of concentrated H2SO4 is added portion-wise 85 g (0.875 mol) of KNO3 at 0° C. (addition of the whole amount of KNO3 is finished in about 1 hour). The reddish mixture is slowly warmed-up at room temperature overnight and quenched over crushed ice and extracted with EtOAc. The organic layers are combined, dried over MgSO4 and concentrated. The crude oil is then purified over a large silica plug (eluent: 97/3 hexanes/EtOAc) to afford 2-chloro-4-fluoro-5-nitrotoluene as a pale yellow oil that solidifies upon standing. 1H NMR (CDCl3, 400 Mz): 7.97 (d, J=8.0 Hz, 1H), 7.32 (d, J=10.4 Hz, 1H), 2.43 (s, 3H). quenched over crushed ice extracted with EtOAc dried over MgSO4 concentrated The crude oil is then purified over a large silica plug (eluent: 97/3 hexanes/EtOAc)

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

Procedure: To a solution of 100 g (0.7 mol) of 2-chloro-4-fluorotoluene in 250 ml of concentrated H2SO4 is added portion-wise 85 g (0.875 mol) of KNO3 at 0° C. (addition of the whole amount of KNO3 is finished in about 1 hour). The reddish mixture is slowly warmed-up at room temperature overnight and quenched over crushed ice and extracted with EtOAc. The organic layers are combined, dried over MgSO4 and concentrated. The crude oil is then purified over a large silica plug (eluent: 97/3 hexanes/EtOAc) to afford 2-chloro-4-fluoro-5-nitrotoluene as a pale yellow oil that solidifies upon standing. 1H NMR (CDCl3, 400 Mz): 7.97 (d, J=8.0 Hz, 1H), 7.32 (d, J=10.4 Hz, 1H), 2.43 (s, 3H). quenched over crushed ice extracted with EtOAc dried over MgSO4 concentrated The crude oil is then purified over a large silica plug (eluent: 97/3 hexanes/EtOAc)

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1.3M s-butyl lithium in cyclohexane (75 mL, 98 mmol) is added to a dry-ice/acetone cooled solution of TMEDA (9.67 g, 83 mmol) in THF (90 mL), maintaining the internal reaction temperature <-70° C. The reaction mixture is cooled and maintained at ≤-80° C. with an ether/liquid nitrogen bath while a solution of 2-chloro-4-fluorotoluene (10 g, 69 mmol) in THF (10 mL) is added dropwise. The resulting reaction mixture is stirred with dry-ice/acetone cooling for 1h, then is cannulated into an ether/liquid nitrogen cooled and mechanically stirred solution of DMF (25.1 g, 345 mmol) in THF (50 mL). The resulting mixture is warmed to -30° C. and partitioned between dilute aqueous HCl and ether. The organic solution is washed with aqueous NaHCO3, dried (MgSO4), and concentrated and triturated with hexanes to afford 2-fluoro-5-methyl-6-chlorobenzaldehyde as a crystalline solid. maintaining the internal reaction temperature <-70° C The reaction mixture is cooled is added dropwise The resulting reaction mixture cooled partitioned between dilute aqueous HCl and ether The organic solution is washed with aqueous NaHCO3 dried (MgSO4) concentrated triturated with hexanes

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 in an analogous manner to the compound of Example 15 from 2-chloro-4-fluorophenylacetonitrile, which was itself prepared from 2-chloro-4-fluorotoluene (Aldrich, mp. 238° C.

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

Procedure: This compound was prepared in an analogous manner to the compound of Example 15 from 2-chloro-4-fluorophenylacetonitrile, which was itself prepared from 2-chloro-4-fluorotoluene (Aldrich, mp. 238° C.

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

Procedure: By the method of Example 7, Step C, 141.4 g (0.978 mole) of 2-chloro-4-fluorotoluene, 175.8 g (0.978 mole) of N-bromosuccinimide, and 5.0 g of benzoyl peroxide in 15 liters of carbon tetrachloride were reacted, yielding 165 g of 2-chloro-4-fluorobenzyl bromide as a white solid.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 20.0 g (0.138 mole) of 2-chloro-4fluorotoluene in 50 ml of 1,2-dichloroethane which had been cooled to 0° C. was added 50 ml of concentrated sulfuric acid. While maintaining the temperature below 10° C., 14.0 g (0.138 mole) of potassium nitrate was added slowly to the mixture. After three hours the reaction mixture was poured into ice, and the resulting mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was passed through a silica gel column, eluting with heptane. Appropriate fractions were combined, and the solvent was evaporated under reduced pressure, yielding 13.0 g of 2-chloro-4-fluoro-5-nitrotoluene as a yellow solid. The nmr spectrum was consistent with the proposed structure. was added slowly to the mixture After three hours the reaction mixture was poured into ice the resulting mixture was extracted with methylene chloride The extract was dried over anhydrous magnesium sulfate filtered the solvent was evaporated under reduced pressure eluting with heptane the solvent was evaporated under reduced pressure

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

Procedure: Concentrated sulfuric acid (250 ml) was added to a stirred solution of 2-chloro-4-fluorotoluene (50.0 g, 0.346 mole) in ethylene dichloride (250 ml) at 0° C. Potassium nitrate (35.0 g, 0.346 mole) was then added slowly, maintaining the temperature below 10° C. The reaction was monitored by gas chromatography. Upon the disappearance of 2-chloro-4-fluorotoluene, the reaction mixture was poured into ice and extracted with methylene chloride. The dried organic layer was concentrated under reduced pressure to yield 60.0 g of 2-chloro-4-fluoro-5-nitrotoluene. This reaction was repeated several times. maintaining the temperature below 10° C extracted with methylene chloride The dried organic layer was concentrated under reduced pressure

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

Procedure: This compound was prepared in an analogous manner to the compound of Example 15 from 2-chloro-4-fluorophenylacetonitrile, which was itself prepared from 2-chloro-4-fluorotoluene (Aldrich, mp. 238° C.