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Stage #1: With hydrogen bromide; bromine In water at -10℃; for 0.0833333 h; Stage #2: With sodium nitrite In water at 0 - 10℃; for 3.5 h; Stage #3: With sodium hydroxide In water at 0℃;
Bromine (0.35 mL, 6.8 mmol) was added dropwise to a solution of 3-bromo-4-methyl-pyridin-2-ylamine (0.44 g, 2.4 mmol) in 48percent HBr (3 mL) at -10° C. to give an orange slurry. After 5 minutes NaNO2 (0.47 g, 6.8 mmol), dissolved in water (1.5 mL), was added dropwise over 5 minutes. The dark brown mixture was slowly warmed to 10° C. over 3.5 h and then cooled to 0° C. and quenched with 10N NaOH until pH~12. The resulting orange slurry was extracted with CH2Cl2 (3*50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an orange/brown solid. Purification by column chromatography on silica gel (Hexanes:Et2O, 7:3, v/v) yielded 2,3-dibromo-4-methyl-pyridine (0.28 g, 47percent) as a pale yellow solid. 1H NMR (CDCl3) δ 2.48 (s, 3H), 7.11 (d, 1H, J=6.0 Hz), 8.16 (d, 1H, J=6.0 Hz).
Bromine (0.35 mL, 6.8 mmol) was added dropwise to a solution of 3-bromo-4-methyl-pyridin-2-ylamine (0.44 g, 2.4 mmol) in 48% HBr (3 mL) at -10 C. to give an orange slurry. After 5 minutes NaNO2 (0.47 g, 6.8 mmol), dissolved in water (1.5 mL), was added dropwise over 5 minutes. The dark brown mixture was slowly warmed to 10 C. over 3.5 h and then cooled to 0 C. and quenched with 10N NaOH until pH~12. The resulting orange slurry was extracted with CH2Cl2 (3*50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an orange/brown solid. Purification by column chromatography on silica gel (Hexanes:Et2O, 7:3, v/v) yielded 2,3-dibromo-4-methyl-pyridine (0.28 g, 47%) as a pale yellow solid. 1H NMR (CDCl3) delta 2.48 (s, 3H), 7.11 (d, 1H, J=6.0 Hz), 8.16 (d, 1H, J=6.0 Hz).
With bis(tri-t-butylphosphine)palladium(0); In tetrahydrofuran; at 60℃; for 12h;Inert atmosphere;
In a 250 ml four-necked flask, 0.01 mol of 1a, 0.011 mol of M1 was added.5*10-5 mol Pd(PtBu3)2 [bis(tri-tert-butylphosphine) palladium], 100 ml THF, protected by nitrogen,The temperature was raised to 60 C, and the reaction was stirred for 12 hours, and the reaction was confirmed to be complete by spotting.The reaction solution was suction filtered, and the filtrate was evaporated and evaporated to silica gel column to afford white powder 1b, purity 99.40%, yield 82.0%.
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