Trifluoroacetic anhydride → N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide

HRID 384602Notes

Reaction equation

HRID 384602 reaction equation
Br[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+].ClC1C=CC(N)=CC=1F>CCOCC.CCCCCC>[Cl:9][C:6]1[CH:5]=[CH:4][C:3]([NH:10][C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])=[CH:2][C:7]=1[F:8]

Participants

7

Reactant 4

HCID 9845Trifluoroacetic anhydrideHCID 10340Sodium CarbonateHCID 27365114-Chloro-3-fluoroanilineHCID 86643278N-(2-bromo-4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide

Product 1

HCID 63374789N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8058HexaneSolvent

Procedure

N-(2-bromo-4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide: 2,2,2-trifluoroacetic anhydride (5.77 mL, 41.2 mmol) was added dropwise to a stirring mixture of sodium carbonate (6.19 g, 58.4 mmol) and 4-chloro-3-fluoroaniline (5.0 g, 34.3 mmol) in Et2O (50 mL) at −10° C. After 1 h, hexane (30 mL) was added and the reaction mixture filtered. The filtrate was washed with ice-water, 10% aq. NaHCO3 solution, and then brine. The organic phase was treated with activated charcoal, dried over sodium sulfate, filtered through a plug of Celite®, and concentrated to give N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide as a white solid. A solution of tert-Butyllithium (1.7M in pentane) (40.4 mL, 68.7 mmol) was added dropwise to N,N,N′,N′-tetramethylethylenediamine (10.37 mL, 68.7 mmol) in THF (60 mL) at −78° C. After 1 h, N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide in THF (40 mL) was added drop-wise to this yellow solution. After stirring for an additional hour, bromine (2.12 mL, 41.2 mmol) was slowly added and the complete mixture stirred for 1.5 h before quenching and neutralized with 1.0N HCl solution (final pH ˜6-7). The mixture was brought to rt, treated with brine (100 mL), and THF evaporated. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with water, saturated NaHCO3 solution, brine, dried over sodium sulfate, filtered and dry-loaded onto silica gel. Purification by flash chromatography (120 g column; (hexane/EtOAc solvent system) gave Intermediate 7A (3.95 g, 36%) as a slowly solidifying tan solid. 1H NMR (400 MHz, CDCl3) δ: 8.42 (1H, br. s.), 8.13 (1H, dd, J=9.09, 1.77 Hz), 7.43-7.49 (1H, m) ppm.

Workup

  1. filtrationthe reaction mixture filtered
  2. washThe filtrate was washed with ice-water, 10% aq. NaHCO3 solution
  3. additionThe organic phase was treated with activated charcoal
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered through a plug of Celite®
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-7b491cd63b4c4fa19fc5ff61bbeafb51
Source dataset
uspto-grants-2013_02
Patent number
US08367709B2

Reaction notes

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