General procedure for the synthesis of 6-bromo-2-methoxycarboxylic acid pyridine from 2-bromo-6-methoxypyridine and carbon dioxide:
Preparation of 2-methoxy-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinamide:
Step 1: Synthesis of 6-bromo-2-methoxynicotinic acid:
A tetrahydrofuran (5 mL) solution of 2,2,6,6-tetramethylpiperidine (0.766 g, 5.32 mmol) was cooled under nitrogen protection to -78°C. A hexane solution of 2.5 M n-butyllithium (2.34 mL, 0.375 g, 5.85 mmol) was slowly added and stirred at -78°C for 30 min. Subsequently, a tetrahydrofuran (5 mL) solution of 2-bromo-6-methoxypyridine (1.00 g, 5.32 mmol) was added dropwise. The reaction mixture was continued to be stirred at -78°C for 1 hour. After that, an excess of dry ice was added to slowly warm the reaction mixture to room temperature for 3 hours. Upon completion of the reaction, water and ethyl acetate were added for layering. The aqueous layer was acidified to pH 4 with hydrochloric acid and then extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give an off-white solid product (0.530 g, 42.9% yield).
1H NMR (500 MHz, DMSO-d6) δ ppm: 2.52 (2H, br.s.), 3.32 (1H, br.s.), 3.90 (1H, d, J = 2.9 Hz), 3.92 (1H, m), 8.03 (1H, d, J = 7.8 Hz).
