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With tetrakis(triphenylphosphine) palladium(0) In toluene at 80℃; Inert atmosphere
To a solution of 4-bromo-2-methylpyridine (10.0 g, 58 mmol) in toluene (100 mL) was added tributyl(l-ethoxyvinyl)stannane (39.7 g, 110 mmol) and Pd(PPh3)4 (5.8 g, 5 mmol). The mixture was stirred at 80 °C under a nitrogen atmosphere overnight. IM HCl was added at 0 °C until the pH of the mixture was adjusted to 1-2. The mixture was stirred for 0.5 h. The pH was adjusted to 6-7 by adding IM NaOH. The mixture was extracted with ethyl acetate (150 mL*3). The organics layer was washed with brine and dried over sodium sulfate. Concentration and purification by column chromatography on silica gel (petroleum ether/ethyl acetate = 30/1-4/1) afforded l-(2-methylpyridin-4-yl)ethanone as light yellow solid (3.0 g, 44percent).
b 4-Bromo-2-picoline A mixture of 4-nitro-2-picoline (1.0 g, 7.2 mmol) and acetyl bromide (3 mL) was heated at reflux under argon for 11 hours. The reaction mixture was poured onto ice and neutralized with sodium bicarbonate. The product was extracted with ethyl acetate and purification by flash chromatography (elution with ethyl acetate-hexanes) afforded the title compound (0.62 g, 50%) as an oil.
50%
b) 4-Bromo-2-picoline A mixture of 4-nitro-2-picoline (1.0 g, 7.2 mmol) and acetyl bromide (3 mL) was heated at reflux under argon for 11 hours. The reaction mixture was poured onto ice and neutralized with sodium bicarbonate. The product was extracted with ethyl acetate and purification by flash chromatography (elution with ethyl acetate-hexanes) afforded the title compound (0.62 g, 50%) as an oil.
EXAMPLE 5 Preparation of 4-Bromo-2-methylpyridine To a cooled (-78° C.) suspension of 4-bromopyridine hydrochloride (5.0 g, 25.7 mmol) in anhydrous THF (90 mL) was added dropwise a solution of MeMgCl (3.0 M in THF, 21 mL, 63.0 mmol). After addition, the reaction mixture was stirred at -78° C. for 15 min. Phenyl chloroformate (3.8 mL, 30 mmol) in THF (10 mL) was added slowly and the mixture was allowed to warm to room temperature. The reaction was quenched with saturated NH4Cl at 0° C. and extracted with Et2O. The combined organic extracts were washed successively with H2O, aqueous 1 N HCl and H2O, dried (MgSO4) and concentrated. The residue was dissolved in andydrous toluene (100 mL) and a solution of o-chloranil (7.8 g, 32 mmol) in glacial AcOH (60 mL) was added dropwise and the mixture was stirred for 22 h. a red suspension was formed and was made basic using 10percent NaOH until a black emulsion was obtained. The mixture was filtered through Celite and washed with H2O. The organic layer was extracted three times with aqueous 1 N HCl. The aqueous layers were basified with aqueous 50percent NaOH and extracted with CH2Cl2. The combined organic extracts were dried (MgSO4) and the solvent was removed under vacuum to give the title compound (2.35 g, 53percent) as an oil. MS (+) EI: 171 M+.
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; water; at 130℃; for 0.333333h;Inert atmosphere; Sealed tube; Microwave irradiation;
To a mixture of 1-Boc-5,6-dihydro-2H-pyridine-3-boronic acid pinacol ester (CAS:885693-20-9; 600 mg, 1.94 mmol) and NaHCO3 (1.94 mL, 3.88 mmol, 2M solution in water) in 1 ,4-dioxane (20 mL), 4-bromo-2-methylpyridine (0.23 mL, 1.94 mmol) andtetrakis(triphenylphosphine)palladium(0) (112 mg, 0.097 mmol) were added at rt while N2 was bubbled through the solution. The mixture was heated at 130 °C for 20 mm in a sealed tube under microwave irradiation. Water and EtOAc were added and the organic layer was separated, dried over MgSO4, filtered and evaporated under vacuum. The residue thus obtained was purified by flash column chromatography (silica; EtOAc in heptane, 1/3 to 4/1) and the desired fractions were concentrated in vacuo affording intermediate 9 (170 mg, 32percent yield).
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