4-Methyloxybenzyl chloride → Tert-butyl (3-bromo-2-chloro-5-(difluoromethyl)phenyl)(4-methoxybenzyl)carbamate

HRID 921619Notes

Reaction equation

HRID 921619 reaction equation
[Br:1][C:2]1[C:3]([Cl:19])=[C:4]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[C:6]([CH:8]([F:10])[F:9])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1.[Li+].[Cl-]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([Cl:19])=[C:4]([N:11]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH:5]=[C:6]([CH:8]([F:10])[F:9])[CH:7]=1

Participants

7

Reactant 4

HCID 699934-Methyloxybenzyl chlorideHCID 433294Lithium ChlorideHCID 2724254Sodium bis(trimethylsilyl)amideHCID 86708469tert-Butyl (3-bromo-2-chloro-5-(difluoromethyl)phenyl)carbamate

Product 1

HCID 86708468Tert-butyl (3-bromo-2-chloro-5-(difluoromethyl)phenyl)(4-methoxybenzyl)carbamateYield 94.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

tert-Butyl (3-bromo-2-chloro-5-(difluoromethyl)phenyl)carbamate (1.82 g, 5.10 mmol) was dissolved in DMF (11.1 mL) at room temperature. NaHMDS (6.12 mL, 6.12 mmol) was added dropwise and the reaction was stirred for 30 minutes before the addition of 4-methoxybenzyl chloride (0.904 mL, 6.64 mmol) and stirring overnight. The reaction mixture was diluted with EtOAc causing a ppt to form. 10% aq. LiCl solution was added and the two layers became clear with stirring. The mixture was poured into a separatory funnel and the organic layer was washed with an extra equivalent of 10% aq. LiCl solution. The organic layer was dried over Na2SO4 and concentrated. Column chromatography (220 g SiO2, 0 to 8% EtOAc-hexane, gradient elution) afforded the expected product tert-butyl (3-bromo-2-chloro-5-(difluoromethyl)phenyl)(4-methoxybenzyl)carbamate (2.29 g).

Workup

  1. customto form
  2. stirringwith stirring
  3. additionThe mixture was poured into a separatory funnel
  4. washthe organic layer was washed with an extra equivalent of 10% aq. LiCl solution
  5. dry with materialThe organic layer was dried over Na2SO4
  6. concentrationconcentrated
  7. washColumn chromatography (220 g SiO2, 0 to 8% EtOAc-hexane, gradient elution)

Sources & evidence

ORD record
ord-81bc282ff1ad44e0b280c0f78537508a
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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