Dimethylformamide → 2,5-Difluorobenzaldehyde

Temperature

-65 °C

A solution of 1,4-difluorobenzene (10 g, 87.6 mmol, 1 wt) in THF (175 mL, 17.5 vol) was stirred under nitrogen and cooled to −75 to −78° C. n-Butyllithium (82 mL of 1.6 M solution in hexanes, 131.4 mmol, 1.5 eq) was added to the reaction mixture over approximately 20 minutes while maintaining the temperature at <−65° C. After a further hour, DMF (10.16 mL, 131.4 mmol, 1.5 eq) was added over approximately 10 minutes while maintaining the temperature<−65° C. The reaction mixture was quenched after 10 minutes by the addition of acetic acid (17.5 mL, 1.75 mL) directly followed by water (440 mL, 36.4 vol). This caused the reaction to exotherm to 5° C. The cold bath was then removed, TBME (220 mL, 22 vol) added and the reaction stirred for 5 minutes. The phases were separated and the aqueous phase extracted with TBME (2×220 mL, 22 vol). The organic phases were combined, washed with 0.2 M HCl (220 mL, 22 vol), 2 M Na2CO3 (220 mL, 22 vol) then saturated brine (220 mL, 22 vol), dried over magnesium sulphate (50 g, 5 wt) and concentrated on a rotary evaporator to afford the crude product (11.07 g). Purification by Kugelrohr distillation gave the product as a clear, colourless oil (7.52 g, 60%)

1. additionwas added to the reaction mixture over approximately 20 minutes
2. temperaturewhile maintaining the temperature at <−65° C
3. waitAfter a further hour
4. customThe reaction mixture was quenched after 10 minutes by the addition of acetic acid (17.5 mL, 1.75 mL)
5. customthe reaction
6. customto exotherm to 5° C
7. customThe cold bath was then removed
8. additionTBME (220 mL, 22 vol) added
9. customThe phases were separated
10. extractionthe aqueous phase extracted with TBME (2×220 mL, 22 vol)
11. washwashed with 0.2 M HCl (220 mL, 22 vol), 2 M Na2CO3 (220 mL, 22 vol)
12. dry with materialsaturated brine (220 mL, 22 vol), dried over magnesium sulphate (50 g, 5 wt)
13. concentrationconcentrated on a rotary evaporator
14. customto afford the crude product (11.07 g)
15. customPurification
16. distillationby Kugelrohr distillation

ORD record

ord-491392500f7441f7b9563ac3630ea375

Source dataset

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08852937B2