Cesium carbonate → (E)-ethyl 3-(5-(benzylthio)-2-((3'-chloro-3-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)amino)phenyl)acrylate

HRID 1504406Notes

Reaction equation

HRID 1504406 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Cl:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33](I)=[C:32]([F:39])[CH:31]=2)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:33]2[C:34]([O:36][CH3:37])=[CH:35][C:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=3)=[CH:31][C:32]=2[F:39])=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 1177370223'-Chloro-3-fluoro-4-iodo-5-methoxy-1,1'-biphenylHCID 117740420(E)-Ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate

Product 1

HCID 117746857(E)-ethyl 3-(5-(benzylthio)-2-((3'-chloro-3-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)amino)phenyl)acrylateYield 53.8%

Reagents, catalysts & solvents 2

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Procedure

A pressure vessel was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (497.91 mg, 1.589 mmol, made via Method 42, Steps 1-2), 3′-chloro-3-fluoro-4-iodo-5-methoxy-1,1′-biphenyl (605 mg, 1.668 mmol), Xantphos (46.0 mg, 0.079 mmol), Pd2(dba)3 (36.4 mg, 0.040 mmol), and cesium carbonate (1035 mg, 3.18 mmol) were added. The vessel was flushed with Ar (g), then toluene (3177 μl) was added. The vessel was sealed and lowered into a 110° C. heating bath for 4 h. The heating bath was turned off, and the vessel was allowed to cool to RT with the bath. In the morning, the mixture was filtered through celite. The filter pad was washed with EtOAc (3×). The filtrate was concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 0-30% EtOAc/Heptane with 5% DCM) to give (E)-ethyl 3-(5-(benzylthio)-2-((3′-chloro-3-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)amino)phenyl)acrylate (468.1 mg, 0.854 mmol, 53.8% yield) as a yellow solid. m/z (ESI) 548.2 (M+H)+.

Workup

  1. additionwere added
  2. customThe vessel was flushed with Ar (g)
  3. additiontoluene (3177 μl) was added
  4. customThe vessel was sealed
  5. customlowered into a 110° C.
  6. temperatureheating bath for 4 h
  7. filtrationIn the morning, the mixture was filtered through celite
  8. washThe filter pad was washed with EtOAc (3×)
  9. concentrationThe filtrate was concentrated
  10. customThe residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 0-30% EtOAc/Heptane with 5% DCM)

Sources & evidence

ORD record
ord-522e64c23b27447286deb6416be964d5
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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