1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine) → (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)-acrylate

HRID 1504401Notes

Reaction equation

HRID 1504401 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].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.CC(C)([O-])C.[Na+].[Br:71][C:72]1[CH:77]=[C:76]([O:78][CH3:79])[C:75](I)=[CH:74][C:73]=1[F:81]>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].C1(C)C=CC=CC=1>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:75]2[CH:74]=[C:73]([F:81])[C:72]([Br:71])=[CH:77][C:76]=2[O:78][CH3:79])=[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

8

Reactant 4

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 23676156Sodium t-butoxideHCID 716561571-Bromo-2-fluoro-4-iodo-5-methoxybenzeneHCID 117740420(E)-Ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate

Product 1

HCID 117746844(E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)-acrylateYield 48.6%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
130 °C

Procedure

A screw cap vial was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (0.500 g, 1.595 mmol), xantphos (0.185 g, 0.319 mmol), Pd2(dba)3 (0.146 g, 0.160 mmol), sodium tert-butoxide (0.153 g, 1.595 mmol) and toluene (7.98 ml). The vial was purged with Argon, sealed and heated to 130° C. for 10 minutes. The reaction was cooled to RT and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (0.581 g, 1.755 mmol) was added and the reaction was continued heating at 100° C. for an additional 30 minutes. The reaction was cooled to RT, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 0.40 g of (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (0.400 g, 0.775 mmol, 48.6% yield). m/z (ESI) 471.0

Workup

  1. customA screw cap vial
  2. customThe vial was purged with Argon
  3. customsealed
  4. temperatureThe reaction was cooled to RT
  5. temperaturethe reaction was continued heating at 100° C. for an additional 30 minutes
  6. temperatureThe reaction was cooled to RT
  7. extractionextracted with DCM (3×)
  8. washThe combined organics were washed with water and brine
  9. dry with materialdried over magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. concentrationThe resulting material was concentrated
  13. dissolutiondissolved in minimal DCM
  14. custompurified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane)

Sources & evidence

ORD record
ord-3ccdbba5f82e4fd4ab5fbad0fa98ac27
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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