Trimethylsilyl triflate → 2-Bromo-1-(5-fluorothiophen-2-yl)ethanone

Temperature

0 °C

To a stirred clear amber solution of 1-(5-fluorothiophen-2-yl)ethanone (9.70 g, 67.3 mmol) in dichloromethane (224 mL) at 0° C. under nitrogen is added diisopropylethylamine (14.7 mL, 84.1 mmol) followed by the drop wise addition of trimethylsilyl trifluoromethanesulfonate (13.8 mL, 74.0 mmol) over 10 minutes while maintaining the internal temperature below 5° C. The resulting solution is stirred at 0° C. for 90 minutes. N-bromosuccinimide (13.17 g, 74.0 mmol) is added in one portion and the resulting orange solution is stirred at 0° C. for 1 hour. Dilute aqueous sodium bicarbonate (200 mL of a 1:1 water/saturated aqueous sodium bicarbonate solution) and dichloromethane (50 mL) are added. The phases are separated and the aqueous phase is re-extracted with dichloromethane (150 mL). The combined organic extracts are dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a red oily/amorphous residue. The residue is diluted with hexanes (50 mL) and dichloromethane (5 mL) and filtered to remove solids. The solids are washed with a solution of hexanes/dichloromethane (˜50 mL, 7:3). The combined filtrates are concentrated under reduced pressure and the residue is purified by silica gel chromatography eluting with hexanes/dichloromethane (two-step gradient from 70:30 to 60:40 to 50:50) to give the title compound (13.33 g, 89%). 1H NMR (CDCl3) δ 4.27 (s, 2H), 6.58 (dd, J=1.3, 4.4 Hz, 1H), 7.52 (dd, J=1.5, 4.2 Hz, 1H).

1. temperaturewhile maintaining the internal temperature below 5° C
2. stirringthe resulting orange solution is stirred at 0° C. for 1 hour
3. customThe phases are separated
4. extractionthe aqueous phase is re-extracted with dichloromethane (150 mL)
5. dry with materialThe combined organic extracts are dried over sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated under reduced pressure
8. customto give a red oily/amorphous residue
9. filtrationfiltered
10. customto remove solids
11. washThe solids are washed with a solution of hexanes/dichloromethane (˜50 mL, 7:3)
12. concentrationThe combined filtrates are concentrated under reduced pressure
13. customthe residue is purified by silica gel chromatography
14. washeluting with hexanes/dichloromethane (two-step gradient from 70:30 to 60:40 to 50:50)

ORD record

ord-b8ea40e551fc4bb59f3dd5a48fe524eb

Source dataset

uspto-grants-2014_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08889856B2