4-methoxy-3-propan-2-ylphenol

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

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

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Isopropyl-4-methoxyphenol (197.2 g, 1.19 moles) was dissolved in dimethylformamide (4 L). The mixture was stirred while the reaction vessel was cooled in an icewater bath. Sodium hydroxide (1.278 L of 1.0M aqueous solution, 1.278 moles) was added while maintaining the temperature of the reaction mixture below 35° C. 1,3-Dibromo-2-iodo-5-nitrobenzene (400.0 g, 0.983 moles) dissolved in dimethylformamide (portion of 4 L) was added to the reaction mixture over approximately 45 min. The reaction mixture was stirred at 20° to 25° C. for 24 h. Deionized water (2 L) was added over 2 h and the reaction mixture was cooled to 5° C. The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (405.4 g, 92.6%) were recovered by filtration and dried for 48 h by evaporation under air flow at room temperature. was cooled in an icewater bath while maintaining the temperature of the reaction mixture below 35° C was added to the reaction mixture over approximately 45 min The reaction mixture was stirred at 20° to 25° C. for 24 h The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (405.4 g, 92.6%) were recovered by filtration dried for 48 h by evaporation under air flow at room temperature

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

Procedure: A 22 L jacketed vessel equipped with mechanical stirring and a nitrogen inlet adapter was charged with dimethylformamide (4 L) and 3-isopropyl-4-methoxyphenol (462.8 g, 2.59 moles). The solution was cooled to 0° C., and KHMDS (5.50 L of 0.5M toluene solution, 2.25 moles) was added over 1.5 h while maintaining the temperature of the mixture below 2° C. The reaction mixture was stirred for 30 min at 2° C., then 1,3-dibromo-2-iodo-5-nitro-benzene (798.6 g, 1.96 moles) was added in portions, still maintaining temperature of the mixture below 2° C. After the addition was complete, the reaction mixture was allowed to stir at room temperature for 2 h or until the reaction was complete as assayed by HPLC. The reaction mixture was cooled once more to 2° C. and ethyl acetate (4.5 L) was added, followed by slow addition of saturated aqueous sodium bicarbonate (6 L) while maintaining the temperature of the reaction mixture below 28° C. The organic layer was washed with saturated aqueous sodium chloride solution, then concentrated by rotary evaporation. The black, oily residue was taken up in acetone (3.87 L). Water (0.77 L) was added to the solution over 30 min with heating to 42° C. The solution was seeded with crystals of the product, cooled to 0° C., and stirred for 15 min. The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (665 g, 76.1%) were recovered by filtration and dried for 48 h by evaporation under air flow at room temperature. equipped while maintaining the temperature of the mixture below 2° C The reaction mixture was stirred for 30 min at 2° C. still maintaining temperature of the mixture below 2° C After the addition to stir at room temperature for 2 h or until the reaction The reaction mixture was cooled once more to 2° C. while maintaining the temperature of the reaction mixture below 28° C The organic layer was washed with saturated aqueous sodium chloride solution concentrated by rotary evaporation Water (0.77 L) was added to the solution over 30 min with heating to 42° C cooled to 0° C. stirred for 15 min The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (665 g, 76.1%) were recovered by filtration dried for 48 h by evaporation under air flow at room temperature

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

Procedure: A 22 L three-necked round bottom flask equipped with mechanical agitation was charged with hydroxy-(3-isopropyl-4-methoxyphenyl)methanesulfonic acid, sodium salt (1300 g, 4.61 moles), p-toluenesulfonic acid monohydrate (908 g, 4.77 moles), and methanol (10.4 L), and the mixture was cooled to 0° to 5° C. Hydrogen peroxide (30% aqueous, 1.625 L, 16.12 moles) was added slowly to the reaction mixture over about 2 h. The reaction mixture was stirred overnight and allowed to return to room temperature. The completeness of the reaction was assayed by HPLC; if the reaction was incomplete, further hydrogen peroxide was added to the reaction mixture. The reaction mixture was cooled once more to 0° to 5° C. and then quenched by addition of an aqueous slurry of sodium dithionite (1860 g, 10.68 moles, stirred 1 h at room temperature in 6.5 L deionized water). After stirring at least 0.5 h, the reaction mixture was filtered, and the white solids were washed with ethyl acetate (8 L). The ethyl acetate and the aqueous filtrate were combined, agitated, and allowed to separate. Cyclohexane was added if necessary to facilitate separation. The organic phase was washed with sodium bicarbonate (4 L, 10% aqueous solution), then with saturated aqueous sodium chloride solution (4 L). The solvent was removed by vacuum distillation to afford 3-isopropyl-4-methoxyphenol (510 g, 66.7%). A 22 L three-necked round bottom flask equipped with mechanical agitation the mixture was cooled to 0° to 5° C to return to room temperature The reaction mixture was cooled once more to 0° to 5° C. After stirring at least 0.5 h the reaction mixture was filtered the white solids were washed with ethyl acetate (8 L) agitated to separate Cyclohexane was added if necessary separation The organic phase was washed with sodium bicarbonate (4 L, 10% aqueous solution) The solvent was removed by vacuum distillation

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

Procedure: To a solution of 3-isopropyl-4-methoxybenzaldehyde (12.5 g, 70 mmol) in MeOH(140 mL) was added concentrated sulfuric acid (1.2 mL) followed by dropwise addition of 30% by wt aqueous hydrogen peroxide(6 g, 20 mL, 176 mmol). The mixture was left to stir at ambient room temperature. After 3 hours, the mixture was concentrated in vacuo to about ⅓ of the reaction volume. The concentrate was partitioned between EtOAc (100 mL) and brine (50 mL). The EtOAc extract was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give 13.5 g of dark oil as crude product. The crude product was purified by chromatography (250 g silica gel, 10% EtOAc in hexane) to afford 10.1 g (86%) of compound 1c as a thick oil that eventually solidified. The mixture was left the mixture was concentrated in vacuo to about ⅓ of the reaction volume The concentrate was partitioned between EtOAc (100 mL) and brine (50 mL) The EtOAc extract was washed with brine (50 mL) dried (Na2SO4) filtered concentrated in vacuo

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

Procedure: 4-Chloro-3,5-dimethylnitrobenzene (2.12 g), 1.9 g of 3-isopropyl-4-methoxyphenol, and 1.74 g of potassium carbonate are heated 18 hrs at 125° in 25 ml dimethylsulfoxide. The mixture is poured into ethyl acetate and extracted once with water and five times with brine. The ethyl acetate is dried, filtered, and stripped to yield an oil which is chromatographed on silica gel with 97:3 hexane:ethyl acetate to afford 3,5-dimethyl-4-(3'-isopropyl-4'-methoxyphenoxy)-nitrobenzene. NMR (CDCl3): δ1.1 (6H,d), 2.2 (6H,s), 3.3 (1H,m), 3.7 (3H,s) 6.3 (1H,d of d), 6.6 (1H,d), 6.7 (1H,d), 8.0 (2H, s). extracted once with water and five times with brine The ethyl acetate is dried filtered to yield an oil which is chromatographed on silica gel with 97:3 hexane

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

Procedure: A mixture of 3-isopropyl-4-methoxyphenol (200 mg), 4-chloro-3-cyano-5-methylnitrobenzene (200 mg) and potassium carbonate (211 mg) in methylethylketone (8 mL) was refluxed for 18 h. The dark mixture was concentrated in vacuo, partitioned between ethyl acetate/water, the organic layer washed with about 2N sodium hydroxide, brine, dried over sodium sulfate and concentrated to a dark oil. Flash chromatography (10% ethyl acetate/hexanes) afforded 2-(3-isopropyl-4-methoxy-phenoxy)-3-methyl-5-nitrobenzonitrile as a yellow oil (300 mg). was refluxed for 18 h The dark mixture was concentrated in vacuo partitioned between ethyl acetate/water the organic layer washed with about 2N sodium hydroxide, brine dried over sodium sulfate concentrated to a dark oil

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

Procedure: A mixture of 3-isopropyl-4-methoxyphenol (200 mg), 4-chloro-3-cyano-5-methylnitrobenzene (200 mg) and potassium carbonate (211 mg) in methylethylketone (8 mL) was refluxed for 18 h. The dark mixture was concentrated in vacuo, partitioned between ethyl acetate/water, the organic layer washed with about 2N sodium hydroxide, brine, dried over sodium sulfate and concentrated to a dark oil. Flash chromatography (10% ethyl acetate/hexanes) afforded 2-(3-isopropyl-4-methoxy-phenoxy)-3-methyl-5-nitrobenzonitrile as a yellow oil (300 mg). was refluxed for 18 h The dark mixture was concentrated in vacuo partitioned between ethyl acetate/water the organic layer washed with about 2N sodium hydroxide, brine dried over sodium sulfate concentrated to a dark oil

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Isopropyl-4-methoxyphenol (197.2 g, 1.19 moles) was dissolved in dimethylformamide (4 L). The mixture was stirred while the reaction vessel was cooled in an icewater bath. Sodium hydroxide (1.278 L of 1.0M aqueous solution, 1.278 moles) was added while maintaining the temperature of the reaction mixture below 35° C. 1,3-Dibromo-2-iodo-5-nitrobenzene (400.0 g, 0.983 moles) dissolved in dimethylformamide (portion of 4 L) was added to the reaction mixture over approximately 45 min. The reaction mixture was stirred at 20° to 25° C. for 24 h. Deionized water (2 L) was added over 2 h and the reaction mixture was cooled to 5° C. The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (405.4 g, 92.6%) were recovered by filtration and dried for 48 h by evaporation under air flow at room temperature. was cooled in an icewater bath while maintaining the temperature of the reaction mixture below 35° C was added to the reaction mixture over approximately 45 min The reaction mixture was stirred at 20° to 25° C. for 24 h The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (405.4 g, 92.6%) were recovered by filtration dried for 48 h by evaporation under air flow at room temperature

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Isopropyl-4-methoxyphenol (197.2 g, 1.19 moles) was dissolved in dimethylformamide (4 L). The mixture was stirred while the reaction vessel was cooled in an icewater bath. Sodium hydroxide (1.278 L of 1.0M aqueous solution, 1.278 moles) was added while maintaining the temperature of the reaction mixture below 35° C. 1,3-Dibromo-2-iodo-5-nitrobenzene (400.0 g, 0.983 moles) dissolved in dimethylformamide (portion of 4 L) was added to the reaction mixture over approximately 45 min. The reaction mixture was stirred at 20° to 25° C. for 24 h. Deionized water (2 L) was added over 2 h and the reaction mixture was cooled to 5° C. The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (405.4 g, 92.6%) were recovered by filtration and dried for 48 h by evaporation under air flow at room temperature. was cooled in an icewater bath while maintaining the temperature of the reaction mixture below 35° C was added to the reaction mixture over approximately 45 min The reaction mixture was stirred at 20° to 25° C. for 24 h The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (405.4 g, 92.6%) were recovered by filtration dried for 48 h by evaporation under air flow at room temperature

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

Procedure: A 22 L jacketed vessel equipped with mechanical stirring and a nitrogen inlet adapter was charged with dimethylformamide (4 L) and 3-isopropyl-4-methoxyphenol (462.8 g, 2.59 moles). The solution was cooled to 0° C., and KHMDS (5.50 L of 0.5M toluene solution, 2.25 moles) was added over 1.5 h while maintaining the temperature of the mixture below 2° C. The reaction mixture was stirred for 30 min at 2° C., then 1,3-dibromo-2-iodo-5-nitro-benzene (798.6 g, 1.96 moles) was added in portions, still maintaining temperature of the mixture below 2° C. After the addition was complete, the reaction mixture was allowed to stir at room temperature for 2 h or until the reaction was complete as assayed by HPLC. The reaction mixture was cooled once more to 2° C. and ethyl acetate (4.5 L) was added, followed by slow addition of saturated aqueous sodium bicarbonate (6 L) while maintaining the temperature of the reaction mixture below 28° C. The organic layer was washed with saturated aqueous sodium chloride solution, then concentrated by rotary evaporation. The black, oily residue was taken up in acetone (3.87 L). Water (0.77 L) was added to the solution over 30 min with heating to 42° C. The solution was seeded with crystals of the product, cooled to 0° C., and stirred for 15 min. The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (665 g, 76.1%) were recovered by filtration and dried for 48 h by evaporation under air flow at room temperature. equipped while maintaining the temperature of the mixture below 2° C The reaction mixture was stirred for 30 min at 2° C. still maintaining temperature of the mixture below 2° C After the addition to stir at room temperature for 2 h or until the reaction The reaction mixture was cooled once more to 2° C. while maintaining the temperature of the reaction mixture below 28° C The organic layer was washed with saturated aqueous sodium chloride solution concentrated by rotary evaporation Water (0.77 L) was added to the solution over 30 min with heating to 42° C cooled to 0° C. stirred for 15 min The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (665 g, 76.1%) were recovered by filtration dried for 48 h by evaporation under air flow at room temperature