Tetrahydrofuran → 4-(4-Chloro-2-fluorophenyl)nicotinaldehyde

Temperature

85 °C

To a mixture of 4-bromonicotinaldehyde (3.00 g, 16.13 mmol), (4-chloro-2-fluorophenyl)boronic acid (2.81 g, 16.13 mmol), cesium carbonate (10.51 g, 32.3 mmol) and Pd(PPh3)4 (0.932 g, 0.806 mmol) was added THF (50 mL) and water (8 mL). Nitrogen gas was bubbled through the stirred suspension for 5 min. The reaction mixture was stirred under nitrogen atmosphere at 85° C. for 6 h. The reaction mixture was then cooled to room temperature and filtered through celite. The filtrate was diluted with ethyl acetate (30 mL) and washed with water (1×25 mL) and brine (1×25 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (ethyl acetate/hexanes) to yield 4-(4-chloro-2-fluorophenyl)nicotinaldehyde (1.5 g, 6.37 mmol, 39% yield for two steps). 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 9.18 (s, 1H), 8.86 (d, J=5.1 Hz, 1H), 7.30 (m, 4H).

1. customNitrogen gas was bubbled through the stirred suspension for 5 min
2. temperatureThe reaction mixture was then cooled to room temperature
3. filtrationfiltered through celite
4. additionThe filtrate was diluted with ethyl acetate (30 mL)
5. washwashed with water (1×25 mL) and brine (1×25 mL)
6. dry with materialThe combined organic extracts were dried over sodium sulfate
7. concentrationconcentrated under reduced pressure
8. customThe crude residue was purified via silica gel chromatography (ethyl acetate/hexanes)

ORD record

ord-ceb94492ba4849798578f855eed54ce6

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08969564B2