反应详情

温度

60 °C

A solution of 5-bromopyridin-3-ol (146 g, 834 mmol), tetrahydro-2H-pyran-4-ol (128 g, 1250 mmol), and triphenylphosphine (329 g, 1250 mmol) in toluene (2.0 L) was heated to reflux, and 750 mL of distillate was removed via a Dean-Stark trap. The reaction mixture was cooled to 60° C., and 547 g (1.25 mol) of a 40% (w/w) solution of DEAD in toluene was added drop-wise over a 1 hour period. The addition was exothermic with the reactor temperature at the end of addition near 95° C. The reaction mixture was stirred at 115° C. for 18 h, and a portion of the reaction solution was sampled and analyzed by HPLC to establish that the reaction was complete. Upon completion of reaction, 500 mL of solvent was removed by distillation, and the pot residue was cooled to ambient temperature. This organic layer was washed with 10% aqueous sodium hydroxide (2×0.50 L) and concentrated under vacuum to produce a viscous oil, which was dissolved in 2N hydrochloric acid (1.0 L). Diatomaceous earth (100 g) was added with stirring and the resulting suspension was filtered. The pad was rinsed with 2N hydrochloric acid (1.0 L), and the filtrates were combined and extracted with diisopropyl ether (500 mL). The diisopropyl ether layer was discarded, and the aqueous layer was treated with carbon black (10 g) and stirred at 45-50° C. for 1 h. The suspension was filtered through a pad of diatomaceous earth (25 g). The filtrate was collected, cooled to 5° C., and the pH adjusted with 50% aqueous sodium hydroxide (250 mL) to pH=13. The solution was extracted twice with chloroform (1.0 L, 600 mL), and the chloroform extracts were combined and concentrated under vacuum to give 12 as a dark red viscous oil/low melting solid (187 g, 87%), which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 8.29 (s, 1H), 8.24 (s, 1H), 7.38 (s, 1H), 4.52 (m, 1H), 3.98 (m, 2H), 3.60 (m, 2H), 2.05 (m, 2H), 1.81 (m, 2H).

1. temperatureto reflux
2. custom750 mL of distillate was removed via a Dean-Stark trap
3. addition547 g (1.25 mol) of a 40% (w/w) solution of DEAD in toluene was added drop-wise over a 1 hour period
4. additionThe addition
5. additionwas exothermic with the reactor temperature at the end of addition near 95° C
6. aliquota portion of the reaction solution was sampled
7. customUpon completion of reaction, 500 mL of solvent
8. customwas removed by distillation
9. temperaturethe pot residue was cooled to ambient temperature
10. washThis organic layer was washed with 10% aqueous sodium hydroxide (2×0.50 L)
11. concentrationconcentrated under vacuum
12. customto produce a viscous oil, which
13. additionDiatomaceous earth (100 g) was added
14. stirringwith stirring
15. filtrationthe resulting suspension was filtered
16. washThe pad was rinsed with 2N hydrochloric acid (1.0 L)
17. extractionextracted with diisopropyl ether (500 mL)
18. additionthe aqueous layer was treated with carbon black (10 g)
19. stirringstirred at 45-50° C. for 1 h
20. filtrationThe suspension was filtered through a pad of diatomaceous earth (25 g)
21. customThe filtrate was collected
22. temperaturecooled to 5° C.
23. extractionThe solution was extracted twice with chloroform (1.0 L, 600 mL)
24. concentrationconcentrated under vacuum