Hydrogen Bromide → 5-Bromo-2-fluoro-2'-(methylthio)biphenyl

HRID 1061791Notes

Reaction equation

HRID 1061791 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH3:16].N([O-])=O.[Na+].[BrH:21]>O1CCOCC1.O.[Cu]Br>[Br:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][CH3:16])[CH:4]=1

Participants

7

Reactant 3

HCID 260Hydrogen Bromide2×HCID 222852932-Fluoro-2'-(methylthio)biphenyl-5-ylamineHCID 23668193Sodium Nitrite2×

Product 1

HCID 222853095-Bromo-2-fluoro-2'-(methylthio)biphenylYield 57%

Reagents, catalysts & solvents 3

HCID 24593copper(I) bromideCatalystHCID 962WaterSolvent3×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
4 °C

Procedure

To a solution of 2-fluoro-2′-(methylthio)biphenyl-5-ylamine (397 mg, 1.70 mmol) in 1,4-dioxane (2.1 mL) was added 48% aqueous hydrobromic acid (8 ml) and the mixture was cooled to 3° C before the dropwise addition of sodium nitrite (137 mg, 1.98 mmol) in water (0.5 mL) over 5 min, while the temperature was kept below 5° C. The resulting mixture was stirred at 4±1° C. for 2 h 40 min then more sodium nitrite (26 mg, 0.37 mmol) in water (0.1 mL) was added dropwise and the mixture was stirred at 3° C. for 50 min. A cooled (3° C.) solution of copper(I) bromide (744 mg, 5.19 mmol) in 48% hydrobromic acid (2.4 mL) was added and the mixture was stirred at 3° C. for 15 min then heated to 50° C. for 1 h. The mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with ethyl acetate (4×35 mL). The combined organics were washed with 1 M aqueous sodium sulphite solution (30 mL), then saturated aqueous ammonium chloride solution (30 mL), dried over anhydrous magnesium sulphate and evaporated to give a brown oil. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (0-2%) gave 5-bromo-2-fluoro-2′-(methylthio)biphenyl as a white solid (287 mg, 57%): δH (360 MHz, CDCl3) 2.40 (3H, s), 7.04 (1H, t, J 9), 7.16-7.24 (2H, m), 7.32 (1H, d, J 8), 7.36-7.51 (4H, m).

Workup

  1. customwas kept below 5° C
  2. stirringthe mixture was stirred at 3° C. for 50 min
  3. additionwas added
  4. stirringthe mixture was stirred at 3° C. for 15 min
  5. temperaturethen heated to 50° C. for 1 h
  6. temperatureThe mixture was cooled to ambient temperature
  7. extractionextracted with ethyl acetate (4×35 mL)
  8. washThe combined organics were washed with 1 M aqueous sodium sulphite solution (30 mL)
  9. dry with materialsaturated aqueous ammonium chloride solution (30 mL), dried over anhydrous magnesium sulphate
  10. customevaporated
  11. customto give a brown oil
  12. customPurification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (0-2%)

Sources & evidence

ORD record
ord-bfa97924f33044f89d7c5d47fba24f40
Source dataset
uspto-grants-2005_11
Patent number
US06960598B2

Reaction notes

Loading…