2-chloro-6-fluoro-3-methylbenzaldehyde

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

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

Procedure: Hydroxylamine hydrochloride (1.1 parts) is added to a solution of 2-fluoro-5-methyl-6-chlorobenzaldehyde in pyridine, and the mixture is stirred for 15 minutes at room temperature. Acetic anhydride (1.3 parts) is then added and the mixture stirred at ambient temperature overnight to effect complete dehydration of the oxime to the nitrile. Most of the pyridine is removed by concentration under vacuum, then the residue is partitioned between ether and water. The organic phase is washed with brine, dried (MgSO4), filtered through silica gel, concentrated, then triturated in hexane to afford 2-fluoro-5-methyl-6-chlorobenzonitrile as light yellow crystals. the mixture stirred at ambient temperature overnight Most of the pyridine is removed by concentration under vacuum the residue is partitioned between ether and water The organic phase is washed with brine dried (MgSO4) filtered through silica gel concentrated triturated in hexane

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:; See reaction.notes.procedure_details.

Procedure: Hydroxylamine hydrochloride (1.1 parts) is added to a solution of 2-fluoro-5-methyl-6-chlorobenzaldehyde in pyridine, and the mixture is stirred for 15 minutes at room temperature. Acetic anhydride (1.3 parts) is then added and the mixture stirred at ambient temperature overnight to effect complete dehydration of the oxime to the nitrile. Most of the pyridine is removed by concentration under vacuum, then the residue is partitioned between ether and water. The organic phase is washed with brine, dried (MgSO4), filtered through silica gel, concentrated, then triturated in hexane to afford 2-fluoro-5-methyl-6-chlorobenzonitrile as light yellow crystals. the mixture stirred at ambient temperature overnight Most of the pyridine is removed by concentration under vacuum the residue is partitioned between ether and water The organic phase is washed with brine dried (MgSO4) filtered through silica gel concentrated triturated in hexane

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:-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:22.01; 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: Hydroxylamine hydrochloride (1.1 parts) is added to a solution of 2-fluoro-5-methyl-6-chlorobenzaldehyde in pyridine, and the mixture is stirred for 15 minutes at room temperature. Acetic anhydride (1.3 parts) is then added and the mixture stirred at ambient temperature overnight to effect complete dehydration of the oxime to the nitrile. Most of the pyridine is removed by concentration under vacuum, then the residue is partitioned between ether and water. The organic phase is washed with brine, dried (MgSO4), filtered through silica gel, concentrated, then triturated in hexane to afford 2-fluoro-5-methyl-6-chlorobenzonitrile as light yellow crystals. the mixture stirred at ambient temperature overnight Most of the pyridine is removed by concentration under vacuum the residue is partitioned between ether and water The organic phase is washed with brine dried (MgSO4) filtered through silica gel concentrated triturated in hexane

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