P-Toluenesulfonamide → 4,7-Difluoro-2-(toluene-4-sulfonyl)isoindoline

HRID 41393

Reaction equation

HRID 41393 reaction equation
[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:15][C:16]1[C:21]([CH2:22]Br)=[C:20]([F:24])[CH:19]=[CH:18][C:17]=1[F:25]>CN(C)C=O>[F:24][C:20]1[CH:19]=[CH:18][C:17]([F:25])=[C:16]2[C:21]=1[CH2:22][N:10]([S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:11])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[CH2:15]2

Participants

5

Reactant 3

HCID 6269P-ToluenesulfonamideHCID 24758Sodium hydrideHCID 593822902,3-Bis-bromomethyl-1,4-difluorobenzene

Product 1

HCID 593822484,7-Difluoro-2-(toluene-4-sulfonyl)isoindolineYield 56%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Conditions

Temperature
110 °C

Procedure

A solution of 4-toluenesulphonamide (2.44 g, 14.28 mmol) in N,N-dimethylformamide (10 ml) was added dropwise to a vigourously stirred suspension of sodium hydride (1.2 g, 60 wt % in mineral oil, 30.0 mmol) in anhydrous N,N-dimethylformamide (60 ml). The mixture was stirred at room temperature for 1 hour, at 110° C. for 1 hour and was then cooled to 60° C. and a solution of 2,3-bis-bromomethyl-1,4-difluorobenzene (4.28 g, 14.28 mmol) in N,N-dimethylformamide (30 ml) was added dropwise. The mixture was stirred at 60° C. for 1 hour and then at room temperature for 16 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane and 1M hydrochloric acid. The organic layer was separated, washed with 5% aqueous potassium carbonate solution, the organics were separated and the solvent removed in vacuo. The residue was rinsed with diethyl ether, filtered and the solids sucked dry under reduced pressure to afford 4,7-difluoro-2-(toluene-4-sulfonyl)isoindoline (2.46 g, 56%) as a pale tan solid. 1H NMR (DMSO-d6) 7.82 (2H, d), 7.43 (2H, d), 7.15 (2H, dd), 4.66 (4H, s), 2.36 (3H, s). MS: [M+H]+ 310.

Workup

  1. temperaturewas then cooled to 60° C.
  2. stirringThe mixture was stirred at 60° C. for 1 hour
  3. waitat room temperature for 16 hours
  4. customThe solvent was removed in vacuo
  5. customthe residue partitioned between dichloromethane and 1M hydrochloric acid
  6. customThe organic layer was separated
  7. washwashed with 5% aqueous potassium carbonate solution
  8. customthe organics were separated
  9. customthe solvent removed in vacuo
  10. washThe residue was rinsed with diethyl ether
  11. filtrationfiltered
  12. customthe solids sucked dry under reduced pressure

Sources & evidence

ORD record
ord-28f6d75c693543f6ad7c911c7f8a0896
Source dataset
uspto-grants-2013_09
Patent number
US08530469B2

Linked notes

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