Synthesis
General procedure for the synthesis of (6-methoxypyridin-3-yl)boronic acid from 5-bromo-2-methoxypyridine: To a stirred solution of 17.0 mL (0.131 mol) of 5-bromo-2-methoxypyridine dissolved in 130 mL of THF at -78 °C, 79 mL (0.197 mol) of 2.5 M n-butyllithium (dissolved in hexanes) was slowly added. The temperature was maintained at -78 °C and stirring was continued for 2 min. Subsequently, 45 mL (0.197 mol) of triisopropoxyborane [B(OiPr)3] was added to the reaction system and the reaction mixture was allowed to slowly warm up to room temperature over 12 hours. Upon completion of the reaction, the mixture was poured into 300 mL of a 1.0 N aqueous hydrochloric acid solution and stirred vigorously for 30 minutes. The pH of the mixture was adjusted to 7.0 with 3.0 N aqueous sodium hydroxide solution and subsequently extracted with ethyl acetate (3 x 150 mL). The organic phases were combined, washed with 200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in 350 mL of 2.0 M aqueous sodium hydroxide and washed with ethyl acetate (2 x 200 mL). The aqueous phase was adjusted to pH 7.0 with concentrated hydrochloric acid to precipitate a solid. The solid was collected by filtration, washed with water and dried to give 15.01 g (75% yield) of [6-(methoxy)-3-pyridinyl]boronic acid as a white powder. Its 1H NMR (400 MHz, DMSO-d6) data were as follows: δ 8.51 (s, 1H), 8.12 (bs, 2H), 7.95 (d, 1H, J = 7.8 Hz), 6.73 (d, 1H, J = 7.8 Hz), 3.83 (s, 3H).
References
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 224 - 239
[2] Patent: WO2008/28118, 2008, A1. Location in patent: Page/Page column 77
[3] Journal of Organic Chemistry, 2005, vol. 70, # 1, p. 388 - 390
[4] Journal of Organic Chemistry, 2002, vol. 67, # 21, p. 7541 - 7543
[5] Patent: US2006/111394, 2006, A1. Location in patent: Page/Page column 17
