4-Bromo-2-fluoroaniline → HCID 18549802, compound

HRID 649825Notes

Reaction equation

HRID 649825 reaction equation
[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1>C1COCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][OH:2])[CH:19]=[CH:18][C:16]=1[NH2:17]

Participants

6

Reactant 2

HCID 1230504-Bromo-2-fluoroanilineHCID 2921892-Formylphenylboronic acid

Product 1

HCID 18549802HCID 18549802, compoundYield 97.6%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolventHCID 10340Sodium CarbonateSolvent

Procedure

Part A: 2-Fluoro-4-((2′-tert-butyldimethylsilyloxymethyl)phenyl)aniline: A solution of 2-formylphenylboronic acid (5 g, 33.3 mmol) and 4-bromo-2-fluoroaniline (4.2 g, 22.2 mmol) in THF (80 mL) and aqueous Na2CO3 solution (2M, 80 mL) was bubbled with nitrogen for 10 minutes. After Pd(PPh3)4 (1.54 g, 1.33 mmol) was added, the resulting mixture was refluxed under nitrogen for 4 hours. The THF layer was separated and filtered through a pad of silica gel. The silica gel was washed with THF. To the combined filtrates containing 2-fluoro-4-(2′-formylphenyl)aniline (65 mL) was portion by portion added NaBH4 (2.2 g, 29.1 mmoL). The resulting mixture was stirred at room temperature for 1 hour, quenched with 1N HCl (10 mL), and washed with 1N HCl (100 mL×3). The combined HCl layers were neutralized with 50% NaOH to pH 12 and extracted with EtOAc (100 mL×3). The EtOAc layers were dried over Na2SO4, concentrated, and purified by column chromatography with a graduate solvent (hexane to EtOAc) to give 2-fluoro-4-(2′-hydroxymethylphenyl)aniline (3.83 g, 97.6%). 1H NMR (CDCl3) δ7.53 (dd, J=6.6 Hz, J=2.2 Hz, 1H), 7.36-7.33 (m, 2H), 7.25 (dd, J=6.6 Hz, J=2.2 Hz, 1H), 7.06 (dd, J=12.1 Hz, J=1.8 Hz, 1H), 6.97 (dd, J=8.0 Hz, J=1.8 Hz, 1H), 6.82 (t, J=8.8 Hz, 1H), 4.63 (s, 2H), 3.79 (bs, 2H); 19F NMR (CDCl3): δ−135.66 (dd, J=12.21 Hz, J=9.2 Hz); CIMS(CI) m/z 218 (M+H, 100%).

Workup

  1. temperaturethe resulting mixture was refluxed under nitrogen for 4 hours
  2. customThe THF layer was separated
  3. filtrationfiltered through a pad of silica gel
  4. washThe silica gel was washed with THF
  5. additionTo the combined filtrates containing 2-fluoro-4-(2′-formylphenyl)aniline (65 mL)
  6. additionadded NaBH4 (2.2 g, 29.1 mmoL)
  7. customquenched with 1N HCl (10 mL)
  8. washwashed with 1N HCl (100 mL×3)
  9. extractionextracted with EtOAc (100 mL×3)
  10. dry with materialThe EtOAc layers were dried over Na2SO4
  11. concentrationconcentrated
  12. custompurified by column chromatography with a graduate solvent (hexane to EtOAc)

Sources & evidence

ORD record
ord-fff3d988d72d4827b1a5ca2f39e34dfa
Source dataset
uspto-grants-2001_08
Patent number
US06271237B1

Reaction notes

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