Tributylamine → tert-butyl 4-(2,5-difluorophenyl)-2-(3-fluorophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

HRID 1394914Notes

Reaction equation

HRID 1394914 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH:13]=[CH:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.[F:21][C:22]1[CH:23]=[C:24](I)[CH:25]=[CH:26][CH:27]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:12]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=2)[CH:13]=1

Participants

9

Reactant 5

HCID 7622TributylamineHCID 11773TriphenylarsineHCID 707251-Fluoro-3-iodobenzeneHCID 516892Sodium BicarbonateHCID 59001787tert-butyl 3-(2,5-difluorophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate

Product 1

HCID 58641279tert-butyl 4-(2,5-difluorophenyl)-2-(3-fluorophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a flame dried flask equipped with stir bar was added tert-butyl 3-(2,5-difluorophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (2-2, 0.088 g, 0.31 mmol), 3-fluoro-1-iodobenzene (0.070 g, 0.31 mmol), triphenylarsine (0.038 g, 0.13 mmol), tributylamine (0.15 mL, 0.62 mmol) and anhydrous DMF (2.0 mL). The resulting solution was purged, and filled with a nitrogen atmosphere. Palladium acetate (0.014 g, 0.06 mmol) was added in one portion, and the reaction was carefully returned to a nitrogen atmosphere. The reaction stirred under nitrogen for 24 h at 65° C. The reaction was then diluted with EtOAc (10 mL) and poured into 5% aq. NaHCO3 in a separatory funnel. The organic layer was washed with brine, separated and dried over magnesium sulfate. The organic layer was then filtered and concentrated to provide crude product. Purification by flash column chromatography (SiO2, 0-20% EtOAc/hexanes gradient) provided tert-butyl 4-(2,5-difluorophenyl)-2-(3-fluorophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4-1). LRMS m/z (M+H) 361.0 found, 361.1 required (M−15). Further transformations followed those described in Scheme 1.

Workup

  1. customTo a flame dried flask
  2. customequipped
  3. customThe resulting solution was purged
  4. additionfilled with a nitrogen atmosphere
  5. stirringThe reaction stirred under nitrogen for 24 h at 65° C
  6. washThe organic layer was washed with brine
  7. customseparated
  8. dry with materialdried over magnesium sulfate
  9. filtrationThe organic layer was then filtered
  10. concentrationconcentrated
  11. customto provide crude product
  12. customPurification by flash column chromatography (SiO2, 0-20% EtOAc/hexanes gradient)

Sources & evidence

ORD record
ord-9203f191437244feba23678d2e805c4d
Source dataset
uspto-grants-2008_03
Patent number
US07348440B2

Reaction notes

Loading…