Hydrogen Bromide → 3-(5-Bromo-2-fluorophenyl)pyridine

HRID 1180220Notes

Reaction equation

HRID 1180220 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.N([O-])=O.[Na+].[OH-].[NH4+].[BrH:21]>O1CCOCC1.O>[Br:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:4]=1

Participants

7

Reactant 4

HCID 260Hydrogen Bromide2×HCID 14923Ammonium HydroxideHCID 222853304-Fluoro-3-(pyridin-3-yl)anilineHCID 23668193Sodium Nitrite

Product 1

HCID 115433553-(5-Bromo-2-fluorophenyl)pyridine

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 3-(2-fluoro-5-aminophenyl)pyridine (22.4 g, 119 mmol) in 1,4-dioxane (40 ml) was treated with a solution of 48% aqueous hydrobromic acid (500 ml). The resulting suspension was cooled to 0° C. before being treated dropwise over 20 min with an aqueous solution of NaNO2 (9.5 g, 137 mmol) in water (30 ml) keeping the internal temperature <5° C. After stirring at 0° C. for 2 h, a cooled (0° C.) solution of CuBr (25.6 g, 179 mmol) in 48% aqueous hydrobromic acid (150 ml) was added to the reaction which was then stirred at 0° C. for 10 min before heating at 50° C. for 20 min. The reaction was cooled to ambient temperature, diluted with ice-cold water (500 ml), then treated with ice-cold aqueous 33% ammonium hydroxide solution until pH 8-9 (ca. 750 ml). After stirring for 20 min the product was extracted into EtOAc (600 ml), the organics were washed with water, brine (300 ml), dried over anhydrous NaSO4, filtered and pre-adsorbed onto silica. Purification by column chromatography [silica; 20-50% EtOAc/isohexane (containing 1% MeOH and 1% triethylamine)] gave 3-(5-bromo-2-fluorophenyl)pyridine as a white solid (22 g, 73% for sequence): 8H (360 MHz, CDCl3) 7.09 (1H, dd, J 9 and 1), 7.37-7.40 (1H, m), 7.46-7.51 (1H, m), 7.56-7.59 (1H, m), 7.83-7.86 (1H, m), 8.63-8.65 (1H, m), 8.77-8.79 (1H, m).

Workup

  1. customthe internal temperature <5° C
  2. additionwas added to the reaction which
  3. stirringwas then stirred at 0° C. for 10 min
  4. temperaturebefore heating at 50° C. for 20 min
  5. temperatureThe reaction was cooled to ambient temperature
  6. stirringAfter stirring for 20 min the product
  7. extractionwas extracted into EtOAc (600 ml)
  8. washthe organics were washed with water, brine (300 ml)
  9. dry with materialdried over anhydrous NaSO4
  10. filtrationfiltered and pre-adsorbed onto silica
  11. customPurification by column chromatography [silica; 20-50% EtOAc/isohexane (containing 1% MeOH and 1% triethylamine)]

Sources & evidence

ORD record
ord-9492eb7dc75b436cba667040e58d9bec
Source dataset
uspto-grants-2007_10
Patent number
US07279580B2

Reaction notes

Loading…