Dimethylformamide → (2,5-Difluoro-4-methylphenyl)methanol

Temperature

-78 °C

A mixture of 1-bromo-2,5-difluoro-4-methyl-benzene (3.3 g, 16 mmol) and ether (75 mL) was cooled to −78° C., and a solution of n-butyllithium in hexane (5.4 mL, 2.5 M, 13.5 mmol) was added dropwise. After stirring for 1 hour, dimethylformamide (1.1 mL, 14 mmol) was added, and the mixture was stirred for 1 hour. The mixture was treated with 1M HCl and water, warmed to ambient temperature and was extracted 3× with ether. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was diluted with tetrahydrofuran (50 mL), and the mixture was treated with sodium borohydride (0.50 g, 13.5 mmol) and ethanol (2 mL). After stirring for 30 minutes, the mixture was diluted cautiously with 0.5M aqueous HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization of the residue from hexane afforded 1.24 g (54%) of (2,5-difluoro-4-methyl-phenyl)-methanol as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.05 (dd, 1H, J=6.0, 9.2 Hz), 6.84 (dd, 1H, J=6.4, 10 Hz), 4.68 (d, 2H, J=6.0 Hz), 2.23 (s, 3H), 1.76 (t, 1H, J=6.0 Hz) ppm.

1. stirringthe mixture was stirred for 1 hour
2. temperaturewarmed to ambient temperature
3. extractionwas extracted 3× with ether
4. dry with materialThe combined organic layers were dried over MgSO4
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. additionThe residue was diluted with tetrahydrofuran (50 mL)
8. stirringAfter stirring for 30 minutes
9. extractionextracted 3× with ethyl acetate
10. dry with materialthe combined organic layers were dried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. customRecrystallization of the residue from hexane

ORD record

ord-7745af5b3dcb438996e6cd0486d6699d

Source dataset

uspto-grants-2008_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07405218B2