Sodium hydride → 6-(2,4-Difluorophenyl)-2-naphthyl hydrosulfide

Temperature

0 °C

Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.25 mmol) was added to a solution of triisopropylsilyl sulfide (1.2 mL, 5.59 mmol) in tetrahydrofuran (15 mL) at 0° C. The reaction was stirred at 0° C. for 5 minutes then at room temperature for 20 minutes. 2-Bromo-6-(2,4-difluorophenyl)naphthalene (Step 1, 1.63 g, 5.11 mmol) in toluene (30 mL) and tetrakis(triphenylphosphine)palladium(0) (310 mg) were added and the mixture degassed. The reaction was heated to reflux for 3 hours. The cooled reaction mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was suspended in isohexane and silica added. The mixture was filtered, washing the silica with isohexane. The filtrate was evaporated in vacuo and the residue dissolved in tetrahydrofuran (6 mL) and cooled to 0° C. A solution of tetrabutylammonium fluoride (1M in tetrahydrofuran, 3 mL) was added and the reaction stirred at 0° C. for 30 minutes. Water was added then 2M hydrochloric acid. The reaction mixture was extracted with diethyl ether. The combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by filtration through a plug of silica, eluting with 10% dichloromethane/isohexane, to give 6-(2,4-difluorophenyl)-2-naphthyl hydrosulfide (0.78 g, contains some impurities). 1H NMR (500 MHz, CDCl3) δ 7.89 (1H, s), 7.77-7.74 (3H, m), 7.62-7.59 (1H, m), 7.52-7.46 (1H, m), 7.37 (1H, dd, J=1.8, 8.5 Hz), 7.01-6.93 (2H, m), 3.62 (1H, s).

1. waitat room temperature for 20 minutes
2. customthe mixture degassed
3. temperatureThe reaction was heated
4. temperatureto reflux for 3 hours
5. customThe cooled reaction mixture
6. customwas partitioned between water and ethyl acetate
7. washThe combined organic layers were washed with brine
8. dry with materialdried over MgSO4
9. customevaporated in vacuo
10. additionsilica added
11. filtrationThe mixture was filtered
12. washwashing the silica with isohexane
13. customThe filtrate was evaporated in vacuo
14. dissolutionthe residue dissolved in tetrahydrofuran (6 mL)
15. temperaturecooled to 0° C
16. additionA solution of tetrabutylammonium fluoride (1M in tetrahydrofuran, 3 mL) was added
17. stirringthe reaction stirred at 0° C. for 30 minutes
18. additionWater was added
19. extractionThe reaction mixture was extracted with diethyl ether
20. washThe combined organic layers were washed with brine
21. dry with materialdried over MgSO4
22. customevaporated in vacuo
23. filtrationThe residue was purified by filtration through a plug of silica
24. washeluting with 10% dichloromethane/isohexane

ORD record

ord-2e63b97efaed40d486de6d196b024dc3

Source dataset

uspto-grants-2009_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07592456B2