To a solution of N,N,N',N'-tetramethylethylenediamine (6.1 mL, 40.5 mmol) in diethyl ether (100 mL) was added n-butyllithium (26 mL, 1.6 M in hexane, 41.6 mmol) dropwise at 0° C. After 30 min the reaction mixture was cooled to -78° C., 1,2-dimethoxybenzene (5.0 g, 36.4 mmol) and stirred for 3 h at this temperature. Subsequently, trimethyl borate (9.7 mL, 86.4 mmol) was added, the cold bath was removed and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, the mixture was cooled to 0 °C, 150 mL of aqueous 2 M hydrochloric acid was added and stirred for 3 hours. The mixture was extracted with ethyl acetate (3 x 20 mL), the organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuum to afford 2,3-dimethoxyphenylboronic acid (1 g, 37% yield) as white crystals.
6-Bromo-2,2,4-trimethyl-1,2-dihydroquinoline (256 mg, 1.02 mmol) and 2,3-dimethoxyphenylboronic acid (370 mg, 2.03 mmol) were dissolved in DMSO (2 mL), and 2 M aqueous K3PO4 (1 mL) was added, followed by PdCl2 (dppf) (50 mg). The mixture was transferred to a microwave reaction tube and microwave irradiated at 120 °C for 15 min. After completion of the reaction, it was cooled to room temperature and the crude product was purified by column chromatography to afford 6-(2,3-dimethoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (190 mg, 61% yield) as a white solid.
The product was brominated with N-bromosuccinimide, followed by a coupling reaction with 2-phenylethanethiol as described in Example 7 to give 45 mg of 2,3-dimethoxyphenylboronic acid as an oil.
