1-methoxy-2-propan-2-ylbenzene

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

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

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

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

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: 2-Isopropylphenol was reacted with methyl iodide in the presence of potassium carbonate to yield 1-isopropyl-2-methoxybenzene, which in turn was reacted with the solution of unisolated intermediate (CF3CO2)3 I described above to form the bis-[3-isopropyl-4-methoxyphenyl] iodonium salt in 40-70% yield. The bis-[3-isopropyl-4-methoxyphenyl] iodonium salt precipitated as a gummy solid, making purification impracticable and contributing to the unpredictability of the yield.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 L three-necked round bottom flask was equipped with mechanical agitation and provided with an inert gas blanket. The flask was charged with 1-isopropyl-2-methoxybenzene (859 g, 5.85 moles) and dimethylformamide (1584 mL, 20.46 moles), and the mixture was heated to 80° C. Phosphorus oxychloride (2690 g, 17.54 moles) was added to the reaction mixture over approximately 3 h while maintaining the temperature of the reaction mixture between 80° C. and 90° C. The addition of POCl3 caused an immediate color change with continuous darkening over the course of the reaction. The reaction mixture was maintained at 80° C. for approximately 16 h, then checked by HPLC for presence of unreacted starting materials. The reaction mixture was quenched by slow addition over approximately 2 h to icewater (8 kg total, 5 kg ice); alternatively the reaction mixture was added over approximately 3 h to deionized water (10 L) in a jacketed 30 L reactor whose cooling bath was maintained between 0° and 5° C. Ethyl acetate (12 L) was added to the quenched reaction with stirring. After settling, the layers were separated, and the aqueous layer was washed with additional ethyl acetate (4 L). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (4 L) and saturated aqueous sodium chloride (4 L). The ethyl acetate was removed by vacuum distillation to yield 3-isopropyl-4-methoxybenzaldehyde (881 g, 86.5%). A 5 L three-necked round bottom flask was equipped with mechanical agitation provided with an inert gas blanket while maintaining the temperature of the reaction mixture between 80° C. and 90° C over the course of the reaction The reaction mixture was maintained at 80° C. for approximately 16 h The reaction mixture was quenched by slow addition over approximately 2 h to icewater (8 kg total, 5 kg ice) alternatively the reaction mixture was added over approximately 3 h to deionized water (10 L) in a jacketed 30 L reactor whose cooling bath was maintained between 0° and 5° C Ethyl acetate (12 L) was added to the quenched reaction the layers were separated the aqueous layer was washed with additional ethyl acetate (4 L) The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (4 L) and saturated aqueous sodium chloride (4 L) The ethyl acetate was removed by vacuum distillation

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 stirring was charged with KOH (1154 g, 20.56 moles), tetrabutylammonium hydrogen sulfate (140 g, 0.411 mole), and deionized water (5.6 L). The mixture was cooled to a temperature of approximately 20° C. to 25° C. Methylene chloride (5.6 L) was added to the flask, then 2-isopropylphenol (590 g, 4.33 moles). The mixture was stirred for 0.5 h before iodomethane (741 g, 5.22 moles) was added. The stirring was continued at room temperature until the reaction was observed to be complete by HPLC, typically after approximately 5 h. Stirring was discontinued and the reaction mixture was allowed to settle into aqueous and organic layers, which were then separated. Triethylamine (185 mL, 1.33 moles) was added to the organic phase with stirring for at least 15 min. Solvent was then removed by vacuum distillation to afford a white solid. Cyclohexane (41) was added to the white solid, which was filtered and washed with further cyclohexane to remove the reaction product as a solvate. The cyclohexane solution was washed with aqueous HCl (2N), then half-saturated aqueous NaCl, and finally saturated aqueous NaCl. The cyclohexane was removed by vacuum distillation to afford 1-isopropyl-2-methoxybenzene as a light yellow oil of medium viscosity (612 g, 94% yield). A 22 L three-necked round bottom flask equipped The mixture was cooled to a temperature of approximately 20° C. to 25° C was added was continued at room temperature until the reaction Stirring were then separated with stirring for at least 15 min Solvent was then removed by vacuum distillation to afford a white solid was filtered washed with further cyclohexane to remove the reaction product as a solvate The cyclohexane solution was washed with aqueous HCl (2N) The cyclohexane was removed by vacuum distillation

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

Procedure: To a solution of 2-isopropylanisole (0.40 g, 2.66 mmol) in CH2Cl2 (9 mL) cooled with an ice water bath was added slowly chlorosulfonic acid (4 mL). After 1.5 h of cooling, the mixture was poured into a flask containing ice (25 g). The product was extracted with CH2Cl2 (50 mL). The organic extract was washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford 0.62 g of grayish oil as crude product. The crude product was purified by chromatography using the ISCO Combiflash SQ16x system (0 to 20% EtOAc in hexane, 20 min gradient, 35 g Redisep silica gel column) to give 0.56 g (84%) of compound 50a as a clear oil. After 1.5 h of cooling the mixture was poured into a flask The product was extracted with CH2Cl2 (50 mL) The organic extract was washed with brine (25 mL) dried (Na2SO4) filtered concentrated in vacuo

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

Procedure: To a solution of 2-isopropylphenol (30 g, 220.3 mmol) in CH2Cl2 (300 mL) was added tetrabutylammonium hydrogen sulfate (7.5 g, 22.1 mmol). After the entire solid was dissolved, a solution of potassium hydroxide (61.8 g, 1.1 mol in 300 mL H2O) was added to the previous mixture. After 15 minutes of stirring, methyl iodide (47 g, 20.6 mL, 331 mmol) was added. The mixture was left to stir overnight (ca. 15 hours). The organic layer was separated and then washed with brine (2×100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The solid material in the concentrate was removed by filtration. The precipitate was washed with hexane (100 mL). The filtrate was concentrated in vacuo to give 32.15 g of yellow oil as a crude product. The crude product was filtered through a pad of silica gel (250 g) and washed with 5% EtOAc in hexane to give 30.7 g (93%) of compound 1a as a colorless oil. After the entire solid was dissolved The mixture was left to stir overnight (ca. 15 hours) The organic layer was separated washed with brine (2×100 mL) dried (Na2SO4) filtered concentrated in vacuo The solid material in the concentrate was removed by filtration The precipitate was washed with hexane (100 mL) The filtrate was concentrated in vacuo

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