Bromide ion → 1,1-Dimethylethyl 4-fluoro-3-[(methylamino)methyl]benzoate

HRID 1633844Notes

Reaction equation

HRID 1633844 reaction equation
[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:15].Br[N:17]1C(=O)CC[C:18]1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br-].CN>C1COCC1.[W].C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:17][CH3:18]

Participants

9

Reactant 5

HCID 259Bromide ionHCID 6329MethylamineHCID 7187Benzoyl PeroxideHCID 67184N-bromobutanimideHCID 11042021Tert-butyl 4-fluoro-3-methylbenzoate

Product 1

HCID 117912751,1-Dimethylethyl 4-fluoro-3-[(methylamino)methyl]benzoateYield 43.2%

Reagents, catalysts & solvents 3

HCID 23964TungstenCatalystHCID 5943Carbon TetrachlorideSolventHCID 8028TetrahydrofuranSolvent

Procedure

A mixture of tert-butyl 4-fluoro-3-methylbenzoate (9.85 g, 46.9 mmole), N-bromosuccinimide (10 g, 56 mmole), benzoyl peroxide (0.6 g, 2.5 mmole), and CCl4 (100 mL) was heated to reflux with the aid of a 150 W tungsten flood lamp. After refluxing for 24 h, the reaction was cooled to RT and filtered, and the filter pad was washed with CCl4 (25 mL). The filtrate was concentrated to give the crude benzylic bromide (15.11 g, 59% pure by GC, containing 32% dibromide) as a yellow oil. To a solution of this crude bromide in THF (150 mL) was added with stirring at 0° C. a solution of methylamine (40 wt % in H2O, 20 mL, 232 mmole) in one portion. The reaction was allowed to warm to RT and stirred for 18 h, then was concentrated to half its volume. The residue was diluted with H2O (250 mL) and extracted with Et2O (2×150 mL). The combined organic layers were washed sequentially with 1.0 N NaOH (150 mL) and brine (150 mL), dried (Na2SO4), and concentrated. The remaining residue was purified by flash chromatography on silica gel (10% MeOH in 1:1 EtOAc/CHCl3) to give the title compound (4.85 g, 43%) as a yellow oil: MS (ES) m/e 240.0 (M+H)+.

Workup

  1. temperaturewas heated
  2. temperatureAfter refluxing for 24 h
  3. filtrationfiltered
  4. washthe filter pad was washed with CCl4 (25 mL)
  5. concentrationThe filtrate was concentrated
  6. customto give the crude benzylic bromide (15.11 g, 59% pure by GC, containing 32% dibromide) as a yellow oil
  7. temperatureto warm to RT
  8. concentrationwas concentrated to half its volume
  9. additionThe residue was diluted with H2O (250 mL)
  10. extractionextracted with Et2O (2×150 mL)
  11. washThe combined organic layers were washed sequentially with 1.0 N NaOH (150 mL) and brine (150 mL)
  12. dry with materialdried (Na2SO4)
  13. concentrationconcentrated
  14. customThe remaining residue was purified by flash chromatography on silica gel (10% MeOH in 1:1 EtOAc/CHCl3)

Sources & evidence

ORD record
ord-734f5b53850446a6a7e437181a06b545
Source dataset
uspto-grants-2003_01
Patent number
US06503903B1

Reaction notes

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