4-bromo-2-(chloromethyl)-1-methylbenzene

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

Procedure: In a three-necked round-bottom flask 9.50 g (0.413 mol) of sodium metal was dissolved in 260 ml of dry ethanol. To the resulting solution 72.0 g (0.413 mol) of diethyl methylmalonate was added. This mixture was stirred for 15 min, then 5-bromo-2-methylbenzyl chloride prepared above was added by vigorous stirring at such a rate as to maintain gentle reflux. This mixture was refluxed for an additional 2 h and then cooled to room temperature. A solution of 85 g of KOH in 250 ml of water was added. The resulting mixture was refluxed for 4 h to saponificate the ester formed. Ethanol and water were distilled off until temperature reached 95° C., and 1000 ml of water and then 12 M HCl (to pH 1) were added to the residue. The precipitated substituted methylmalonic acid was filtered off, washed with 3×100 ml of water, and then decarboxylated at 180° C. to give 3-(5-bromo-2-methylphenyl)-2-methylpropanoic. A mixture of this acid and 105 ml of SOCl2 was stirred at room temperature for 24 hours. After evaporation of an excess of thionyl chloride, the residue was distilled in vacuum to give 85.3 g (75% from 5-bromo-2-methylbenzaldehyde) 3-(5-bromo-2-methylphenyl)-2-methylpropanoyl chloride, b.p. 115° C./1 mm Hg. above was added by vigorous stirring at such a rate as to maintain gentle reflux This mixture was refluxed for an additional 2 h The resulting mixture was refluxed for 4 h formed Ethanol and water were distilled off until temperature reached 95° C. 1000 ml of water and then 12 M HCl (to pH 1) were added to the residue The precipitated substituted methylmalonic acid was filtered off washed with 3×100 ml of water decarboxylated at 180° C. to give 3-(5-bromo-2-methylphenyl)-2-methylpropanoic was stirred at room temperature for 24 hours After evaporation of an excess of thionyl chloride the residue was distilled in vacuum

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 80.9 g (0.406 mol) of 5-bromo-2-methylbenzaldehyde and 7.80 g (0.206 mol) of NaBH4 in 300 ml of THF 200 ml of methanol was added dropwise by vigorous stirring for 5 h at 0-5° C. This mixture was stirred overnight at room temperature and then added to 1 liter of cold water. The resulting mixture was acidified by 2 M HCl to pH˜1, and the formed (5-bromo-2-methylphenyl)methanol was extracted with 3×250 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. To the residue dissolved in 450 ml of dichloromethane 37 ml of SOCl2 was added dropwise at +5° C. The resulting solution was stirred overnight at room temperature, evaporated to dryness, the residue was dissolved in 500 ml CH2Cl2, and the obtained solution was washed with 500 ml of water. The organic layer was separated, the aqueous layer was additionally extracted with 2×100 ml of dichloromethane. The combined organic extract was passed through a short pad of silica gel 60 (40-63 um), the filtrate was evaporated to dryness, and the residue was dried in vacuum to yield 5-bromo-2-methylbenzyl chloride as a slightly yellowish liquid which was further used without an additional purification. was added dropwise This mixture was stirred overnight at room temperature the formed (5-bromo-2-methylphenyl)methanol was extracted with 3×250 ml of dichloromethane The combined organic extract was dried over Na2SO4 evaporated to dryness To the residue dissolved in 450 ml of dichloromethane 37 ml of SOCl2 was added dropwise at +5° C The resulting solution was stirred overnight at room temperature evaporated to dryness the residue was dissolved in 500 ml CH2Cl2 the obtained solution was washed with 500 ml of water The organic layer was separated the aqueous layer was additionally extracted with 2×100 ml of dichloromethane The combined organic extract the filtrate was evaporated to dryness the residue was dried in vacuum

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 80.9 g (0.406 mol) of 5-bromo-2-methylbenzaldehyde and 7.80 g (0.206 mol) of NaBH4 in 300 ml of THF 200 ml of methanol was added dropwise by vigorous stirring for 5 h at 0-5° C. This mixture was stirred overnight at room temperature and then added to 1 liter of cold water. The resulting mixture was acidified by 2 M HCl to pH˜1, and the formed (5-bromo-2-methylphenyl)methanol was extracted with 3×250 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. To the residue dissolved in 450 ml of dichloromethane 37 ml of SOCl2 was added dropwise at +5° C. The resulting solution was stirred overnight at room temperature, evaporated to dryness, the residue was dissolved in 500 ml CH2Cl2, and the obtained solution was washed with 500 ml of water. The organic layer was separated, the aqueous layer was additionally extracted with 2×100 ml of dichloromethane. The combined organic extract was passed through a short pad of silica gel 60 (40-63 um), the filtrate was evaporated to dryness, and the residue was dried in vacuum to yield 5-bromo-2-methylbenzyl chloride as a slightly yellowish liquid which was further used without an additional purification. was added dropwise This mixture was stirred overnight at room temperature the formed (5-bromo-2-methylphenyl)methanol was extracted with 3×250 ml of dichloromethane The combined organic extract was dried over Na2SO4 evaporated to dryness To the residue dissolved in 450 ml of dichloromethane 37 ml of SOCl2 was added dropwise at +5° C The resulting solution was stirred overnight at room temperature evaporated to dryness the residue was dissolved in 500 ml CH2Cl2 the obtained solution was washed with 500 ml of water The organic layer was separated the aqueous layer was additionally extracted with 2×100 ml of dichloromethane The combined organic extract the filtrate was evaporated to dryness the residue was dried in vacuum

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

Procedure: In a three-necked round-bottom flask 9.50 g (0.413 mol) of sodium metal was dissolved in 260 ml of dry ethanol. To the resulting solution 72.0 g (0.413 mol) of diethyl methylmalonate was added. This mixture was stirred for 15 min, then 5-bromo-2-methylbenzyl chloride prepared above was added by vigorous stirring at such a rate as to maintain gentle reflux. This mixture was refluxed for an additional 2 h and then cooled to room temperature. A solution of 85 g of KOH in 250 ml of water was added. The resulting mixture was refluxed for 4 h to saponificate the ester formed. Ethanol and water were distilled off until temperature reached 95° C., and 1000 ml of water and then 12 M HCl (to pH 1) were added to the residue. The precipitated substituted methylmalonic acid was filtered off, washed with 3×100 ml of water, and then decarboxylated at 180° C. to give 3-(5-bromo-2-methylphenyl)-2-methylpropanoic. A mixture of this acid and 105 ml of SOCl2 was stirred at room temperature for 24 hours. After evaporation of an excess of thionyl chloride, the residue was distilled in vacuum to give 85.3 g (75% from 5-bromo-2-methylbenzaldehyde) 3-(5-bromo-2-methylphenyl)-2-methylpropanoyl chloride, b.p. 115° C./1 mm Hg. above was added by vigorous stirring at such a rate as to maintain gentle reflux This mixture was refluxed for an additional 2 h The resulting mixture was refluxed for 4 h formed Ethanol and water were distilled off until temperature reached 95° C. 1000 ml of water and then 12 M HCl (to pH 1) were added to the residue The precipitated substituted methylmalonic acid was filtered off washed with 3×100 ml of water decarboxylated at 180° C. to give 3-(5-bromo-2-methylphenyl)-2-methylpropanoic was stirred at room temperature for 24 hours After evaporation of an excess of thionyl chloride the residue was distilled in vacuum

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 80.9 g (0.406 mol) of 5-bromo-2-methylbenzaldehyde and 7.80 g (0.206 mol) of NaBH4 in 300 ml of THF 200 ml of methanol was added dropwise by vigorous stirring for 5 h at 0-5° C. This mixture was stirred overnight at room temperature and then added to 1 liter of cold water. The resulting mixture was acidified by 2 M HCl to pH˜1, and the formed (5-bromo-2-methylphenyl)methanol was extracted with 3×250 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. To the residue dissolved in 450 ml of dichloromethane 37 ml of SOCl2 was added dropwise at +5° C. The resulting solution was stirred overnight at room temperature, evaporated to dryness, the residue was dissolved in 500 ml CH2Cl2, and the obtained solution was washed with 500 ml of water. The organic layer was separated, the aqueous layer was additionally extracted with 2×100 ml of dichloromethane. The combined organic extract was passed through a short pad of silica gel 60 (40-63 um), the filtrate was evaporated to dryness, and the residue was dried in vacuum to yield 5-bromo-2-methylbenzyl chloride as a slightly yellowish liquid which was further used without an additional purification. was added dropwise This mixture was stirred overnight at room temperature the formed (5-bromo-2-methylphenyl)methanol was extracted with 3×250 ml of dichloromethane The combined organic extract was dried over Na2SO4 evaporated to dryness To the residue dissolved in 450 ml of dichloromethane 37 ml of SOCl2 was added dropwise at +5° C The resulting solution was stirred overnight at room temperature evaporated to dryness the residue was dissolved in 500 ml CH2Cl2 the obtained solution was washed with 500 ml of water The organic layer was separated the aqueous layer was additionally extracted with 2×100 ml of dichloromethane The combined organic extract the filtrate was evaporated to dryness the residue was dried in vacuum