Potassium Iodide → 2-Fluoro-4-chloro-5-cyclohexyloxyaniline

HRID 1684314Notes

Reaction equation

HRID 1684314 reaction equation
[NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[C:11]1(C)[CH:16]=[CH:15][C:14](S(OC2CCCCC2)(=O)=O)=[CH:13][CH:12]=1.[I-].[K+].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[F:10][C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([O:8][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][C:2]=1[NH2:1]

Participants

8

Reactant 4

HCID 4875Potassium IodideHCID 13722Cyclohexyl p-toluenesulfonateHCID 14798Sodium HydroxideHCID 1586545-Amino-2-chloro-4-fluorophenol

Product 1

HCID 152793952-Fluoro-4-chloro-5-cyclohexyloxyanilineYield 48.1%

Reagents, catalysts & solvents 3

HCID 74236Tetrabutylammonium BromideCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A round-bottomed flask (100 cc) equipped with a mechanical stirrer was charged with 5-amino-2-chloro-4-fluorophenol (1.03 g, 6.40 mmol), cyclohexyl p-toluenesulfonate (1.69 g, 6.66 mmol), tetrabutylammonium bromide (124 mg, 0.38 mmol) and potassium iodide (100 mg, 0.60 mmol) to prepare a solution in toluene (15 mL). Subsequently, 40% sodium hydroxide in aqueous solution (15 mL) was added slowly and the mixture was stirred under heating at 100° C. for 48 h. After completion of the reaction, the reaction mixture was cooled to room temperature and water (10 mL) was added, followed by extraction with ethyl acetate (20 mL×3). The organic layers were combined, washed with water (10 mL) and saturated brine (10 mL) and dried with anhydrous magnesium sulfate. After the desiccant was removed, the solvent was distilled off under vacuum to give a crude product (1.06 g). The product was separated and purified by silica gel column chromatography (ethyl acetate/hexane=1/9) to give 2-fluoro-4-chloro-5-cyclohexyloxyaniline (0.75 g, 3.08 mmol; yield=48.1%). 1H-NMR(CDCl3,TMS,ppm): δ1.15-2.06(10H,m), 3.46(2H, brs), 3.95-4.25(1H,m), 6.39 (1H,d,JHF =9.0HZ), 6.97(1H,d,JHF =11.5HZ). IR (neat, cm-1): 3500, 3400, 2940, 2860, 1630, 1505, 1240, 1190.

Workup

  1. customA round-bottomed flask (100 cc) equipped with a mechanical stirrer
  2. customAfter completion of the reaction
  3. temperaturethe reaction mixture was cooled to room temperature
  4. extractionfollowed by extraction with ethyl acetate (20 mL×3)
  5. washwashed with water (10 mL) and saturated brine (10 mL)
  6. dry with materialdried with anhydrous magnesium sulfate
  7. customAfter the desiccant was removed
  8. distillationthe solvent was distilled off under vacuum
  9. customto give a crude product (1.06 g)
  10. customThe product was separated
  11. custompurified by silica gel column chromatography (ethyl acetate/hexane=1/9)

Sources & evidence

ORD record
ord-d99531bccd0b4d259d2c0b526b2cdc38
Source dataset
uspto-grants-1997_06
Patent number
US05639915

Reaction notes

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