Toluene → (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)-4-fluorophenyl)acrylate

HRID 1504423Notes

Reaction equation

HRID 1504423 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20].[Br:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28](I)=[CH:27][C:26]=1[Cl:34].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>CCOC(C)=O.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>[CH2:10]([S:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([NH:1][C:28]2[CH:27]=[C:26]([Cl:34])[C:25]([Br:24])=[CH:30][C:29]=2[O:31][CH3:32])=[C:3](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1

Participants

8

Reactant 4

HCID 1140TolueneHCID 10796Cesium carbonateHCID 509978521-Bromo-2-chloro-4-iodo-5-methoxybenzeneHCID 117746832Ethyl (E)-3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate

Product 1

HCID 117746850(E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)-4-fluorophenyl)acrylateYield 67.7%

Reagents, catalysts & solvents 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolvent

Procedure

A RBF was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate (1.60 g, 4.83 mmol), 1-bromo-2-chloro-4-iodo-5-methoxybenzene (2.013 g, 5.79 mmol), xantphos (0.140 g, 0.241 mmol), Pd2(dba)3 (0.111 g, 0.121 mmol), cesium carbonate (2.360 g, 7.24 mmol) and toluene (7.98 ml). The flask was kept under Argon, a reflux condenser was attached and the flask was lowered into a 110° C. heating bath and heated for 4 hours. The mixture was cooled to RT, diluted with EtOAc, and filtered through celite with the aid of EtOAc. The filtrate was concentrated. The oily residue was taken up in 2-PrOH (it remained an oil). The mixture was then concentrated to give a yellow solid with some oily solid present. The mixture was taken up in 2-PrOH to give a suspension, and the suspension was stirred overnight, which broke up the darker, oily solid. The mixture was filtered, and the filtered solid was washed with 2-PrOH (3×). The collected solid was dried on the filter under a flow of N2 (g) for 15 min to give ((E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)-4-fluorophenyl)acrylate (1.8 g, 3.27 mmol, 67.7% yield)as a bright-yellow solid. m/z (ESI) 548.1

Workup

  1. customa reflux condenser was attached
  2. customwas lowered into a 110° C.
  3. temperatureheating bath
  4. temperatureheated for 4 hours
  5. filtrationfiltered through celite with the aid of EtOAc
  6. concentrationThe filtrate was concentrated
  7. concentrationThe mixture was then concentrated
  8. customto give a yellow solid with some oily solid present
  9. customto give a suspension
  10. filtrationThe mixture was filtered
  11. washthe filtered solid was washed with 2-PrOH (3×)
  12. customThe collected solid was dried on the
  13. filtrationfilter under a flow of N2 (g) for 15 min

Sources & evidence

ORD record
ord-656f40d9a15e4185bb97e49d6b2ee785
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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