4-(Tert-Butyl)-2-Ethoxy-1-Iodobenzene synthesis

Yield:-

Reaction Conditions:

with potassium carbonate in ethanol;Heating / reflux;

Steps:

1.a

A solution of 3-tert-butylphenol (100 g, 665.7 mmol, TCI) and potassium hydroxide (37.35 g, 665.7 mmol) in 260 mL of water was added to a vigorously stirred solution of iodine (202.8 g, 798.8 mmol) and potassium hydroxide (89.95 g, 1598 mmol) in 1100 mL of water. The combined solution immediately turned white. It was stirred for 5 min. A small sample of the reaction mixture was removed, acidified and extracted with ethyl acetate. Thin layer chromatography (silica gel, 30% methylene chloride in hexane) showed the product (lower Rf) and some starting material. Methylene chloride (450 mL) was added, and sulfuric acid solution was added until a permanent brown color appeared (pH -7). The layers were separated, and the organic layer was washed with water until it was neutral. The solvents were evaporated to dryness to give a reddish oil (162 g). The crude oil was purified by flash column chromatography (silica gel, eluting with hexane, 5-10% methylene chloride in hexane) to give 5-tert-butyl-2-iodo-phenol (132.7 g) as an amber oil (solidified upon standing). The mixture of 5-tert-butyl-2-iodo-phenol (132.7 g, 480.6 mmol), potassium carbonate (265.7 g, 1923 mmol) and ethyl iodide (76.9 mL, 961.3 mmol) in ethanol (1.125 mL) was heated at reflux overnight. Upon cooling to room temperature, the reaction mixture was diluted with diethyl ether. The white solids were filtered off, and the filtrate was concentrated in vacuo to give 4-tert-butyl-2-ethoxy-1-iodo-benzene (144.7 g) as pale yellow oil. In a 2L pressure reaction flask was placed 4-tert-butyl-2-ethoxy- I -iodo-benzene (142 g, 466.9 mmol), dimethylformamide (275 mL), methanol (500 mL) and triethylamine (130 mL, 933.7 mmol). Argon was bubbled through the mixture for 1 h. Bis(triphenylphosphine)- palladium(II) chloride (19.69 g, 28.05 mmol) was added. The flask was evacuated then pressurized with carbon monoxide (40 psi) five times. The reaction was heated overnight at 65 °C under carbon monoxide pressure (40 psi). Upon cooling to room temperature, the reaction mixture was diluted with ethyl acetate (1400 mL) and washed with water (2 x 600 mL), brine (1 x 200 mL), and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated to dryness to give dark oil (160 g). It was taken in ethyl acetate (160 mL), and hexane (1200 mL) was added while stirring vigorously. After the mixture was settled, the supernatant was removed. The same procedure was repeated two more times with ethyl acetate and hexane. The combined supernatant was treated with charcoal then filtered. The filtrate was concentrated in vacuo. It may be necessary to repeat the same procedure with ethyl acetate and hexane if there are still more solids present. The crude product was purified by flash chromatography (silica gel, eluting with 4% ethyl acetate in hexane) to give 93.5 g of methyl 4-tert-butyl-2-ethoxy-benzoate as a red oil.

References:

WO2005/110996,2005,A1 Location in patent:Page/Page column 21-22