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With chloro-trimethyl-silane; sodium iodide In 1,4-dioxane at 80℃;
Example 230; (3 -Fluoropyridin-2-vi)but-3 -vnyDbenzo [d] oxazole; 230(A) 3 -Fluoro-2-iodopyridine ;To a solution of 2-chloro-3-fluoropyridine (400 mg, 3 mmol) in dioxane (6 mL, 0.5M) was added in one portion chlorotrimethylsilane (652 mg, 6 mmol) and sodium iodide (2.20 g, 15 mmol). The resulting mixture was stirred at 80°C overnight. The reaction mixture was concentrated to afford 660 mg of 3-fluoro-2-iodopyridine (Yield : 98percent) as a yellow oil which was used in the next step without further purification
A solution of 2-chloro-3-fluoropyridine (2 mmol) in anhydrous THF (10ml) was cooled to -780C. To this solution was added a solution of lithium diisopropylamide (LDA; 2.2 mmol) in hexane slowly at same temperature. After 2h at -780C, to the mixture was added trimethoxyborane (0.48ml) and stirred for 2h, followed by an addition of peracetic acid (0.72 ml; 32% in dilute acetic acid). The mixture was allowed to warm to O0C under stirring for Ih, then cooled to -2O0C, sodium dithionite (0.8g in 2ml water) was added dropwise. The mixture was extracted with ethyl acetate and the extract was <n="24"/>dried and concentrated. The residue was purified by chromatography, eluting with 1:19 MeOH:DCM to give the expected product as a white solid (80%).
80%
2-Chloro-3-fluoro-4-hydroxypyridine (10): A solution of 2-chloro-3-fluoropyridine (2 mmol) in anhydrous THF (10 ml) wascooled to 78 8C. To this solution was added a solution of lithiumdiisopropylamide (LDA; 2.2 mmol) in hexane slowly at sametemperature. After 2 h at 78 8C, to the mixture was addedtrimethoxyborane (0.48 ml) and stirred for 2 h, followed by anaddition of peracetic acid (0.72 ml; 32% in dilute acetic acid). Themixture was allowed to warm to 0 8C under stirring for 1 h. Afterthe mixture was cooled to 20 8C, sodium dithionite (0.8 g in 2 mlwater) was added dropwise. The mixture was extracted with ethylacetate and the extract was dried and concentrated. The residuewas purified by chromatography, eluting with 1:19 MeOH:DCM togive the expected product as a white solid [19] (80%). 1H NMR (d6-DMSO): d 11.86 (brs, 1H, OH), 7.89 (d, J = 5.3 Hz, 1H, C6-H), 6.95 (t,J = 5.8 Hz, 1H, C5-H). 19F NMR (d6-DMSO): d 141.29 (s). ESI-MS:148 (M+1)+.
78%
n-BuLi (2 M in cyclohexane, 6 mL, 12.0 mmol) was added to a solution of diisopropylamine (1.8 mL, 12.8 mmol) in dry THF (50 mL) at -78 C. Next, 2-chloro-3-fluoropyridine (1 mL, 10.058 mmol, CAS 17282-04-1) was added dropwise and the reaction mixture was stirred for 2 h at -78 C. Then, trimethylborate (2.4 mL, 21.3 mmol) was added dropwise and the mixture was stirred another 2 h. Then, peracetic acid (39% in acetic acid, 3.0 mL, 17.7 mmol) was added together with water (0.5 mL) and the mixture was allowed to warm to 0 C and stirred for 1 h. The clear solution turned turbid. An aq. saturated Na 2S 2O 3 solution was added, and the org layer was separated. The aq. layer was extracted with EtOAc multiple times, the combined organic layers were dried over MgSO 4, filtered and concentrated. The residue was purified by flash column chromatography (120 g silica, redisep Gold, gradient DCM/MeOH 99:1 to 95:5). After concentration of the product fractions, intermediate 35?? was obtained as white solid (1.16 g, 78%).
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