[Synthesis]
General procedure for the synthesis of 2-chloro-3-nitrophenol from 2-amino-3-nitrophenol: To a suspension of 2-amino-3-nitrophenol (10 g, 65 mmol) in concentrated hydrochloric acid (10 mL) was added drop-wise an aqueous solution (60 mL) of sodium nitrite (5.1 g, 73.3 mmol) at 0°C. The reaction mixture was stirred for 30 min at 0°C and then stirred for 18 hours. After stirring at 0°C for 30 min, cuprous chloride (12.8 g, 130 mmol) in 10% sulfuric acid (3 mL) was added and the reaction mixture was stirred for 18 hours. The non-homogeneous mixture was filtered and washed with water. The filtrate was extracted three times with 70 mL of ethyl acetate. The ethyl acetate extract was evaporated to give 7 g (62% yield) of pure 2-chloro-3-nitrophenol. 2-Chloro-3-nitrophenol (6 g, 35 mmol) was dissolved in methanol (100 mL) and ammonium chloride (9.4 g, 175.7 mmol) and zinc powder (46 g, 702.8 mmol) were added. The resulting mixture was refluxed for 1 hour. After filtration and evaporation, 2-chloro-3-aminophenol (4.5 g, 90% yield) was collected as a purple solid. To a suspension of 2-chloro-3-aminophenol (4.5 g, 31 mmol) in concentrated hydrochloric acid (10 mL) was added dropwise an aqueous solution (50 mL) of sodium nitrite (2.5 g, 35 mmol) at 0 °C. After stirring at 0°C for 30 min, a solution of iodine (10.4 g, 63 mmol) in 10% sulfuric acid (3 mL) was added dropwise. The reaction was stirred at room temperature for 2 h. The reaction was then filtered, extracted with ethyl acetate and concentrated in vacuo to afford 2-chloro-3-iodophenol as a dark purple solid (6 g, 75% yield). 6-Bromo-2,2,4-trimethyl-1,2-dihydroquinoline (2.3 g, 9.2 mmol) and bis(pinacolato)diborane (4.2 g, 16.5 mmol) were combined in DMSO (2 mL). Potassium acetate (2.7 g, 27.4 mmol) was added, followed by dichlorobis(triphenylphosphine)palladium(II) (100 mg). The contents were placed in a microwave reaction vessel and irradiated at 120°C for 15 minutes. After cooling to room temperature, it was purified by chromatography to afford 2,2,4-trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydroquinoline (2.3 g, 84% yield) as a white crystalline solid. Coupling 2,2,4-trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydroquinoline (308 mg), 2-chloro-3-iodophenol (93 mg), dichloro-bis(triphenylphosphine)palladium(II) (100 mg), and potassium acetate (300 mg) gave 250 mg of 2-chloro-3-(2,2,4 -trimethyl-1,2-dihydroquinolin-6-yl)phenol. Using the method described in Example 7, the product (85 mg) was reacted with N-bromosuccinimide to give 56 mg of 3-(4-bromomethyl-2,2-dimethyl-1,2-dihydroquinolin-6-yl)-2-chlorophenol. The product (50 mg) was coupled with 2-phenylethanethiol (0.04 mL) to give 40 mg of the title compound as an oil. |