Cesium carbonate → (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate

HRID 1504493Notes

Reaction equation

HRID 1504493 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].[Br:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27](I)=[CH:26][C:25]=1[Cl:33].C(=O)([O-])[O-].[Cs+].[Cs+].COC1CCCC1>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.C(O)(C)C>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:27]2[CH:26]=[C:25]([Cl:33])[C:24]([Br:23])=[CH:29][C:28]=2[O:30][CH3:31])=[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 10796Cesium carbonateHCID 138539Cyclopentyl methyl etherHCID 509978521-Bromo-2-chloro-4-iodo-5-methoxybenzeneHCID 117740420(E)-Ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate

Product 1

HCID 117746875(E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylateYield 90%

Reagents, catalysts & solvents 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
90 °C

Procedure

A flask was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (50.0 g, 160 mmol), 1-bromo-2-chloro-4-iodo-5-methoxybenzene (66.5 g, 191 mmol), xantphos (4.62 g, 7.98 mmol), Pd2(dba)3 (3.65 g, 3.99 mmol), and cesium carbonate (72.8 g, 223 mmol). A reflux condenser was attached and the reaction placed under nitrogen atmosphere. CPME (319 ml) was added and the reaction was heated at 90° C. for 36 h. The mixture was cooled to rt and partitioned between 1000 mL of EtOAc and 1000 mL of water. The layers were separated and the aqueous layer was extracted with 200 mL of EtOAc. The combined organic layers were poured through a silica plug to provide a brown solution. The solution was concentrated until about 100 mL of solvent was left, giving a heterogeneous brown sludge. Isopropanol (500 mL) was added to the solution and a yellow solid precipitated. The yellow solid was collected by vacuum filtration (rinsing with 200 mL isopropanol) to provide desired product (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate (76.4 g, 143 mmol, 90% yield) as a yellow solid. m/z (ESI) 531.9 (M−H)−.

Workup

  1. customA reflux condenser was attached
  2. temperatureThe mixture was cooled to rt
  3. custompartitioned between 1000 mL of EtOAc and 1000 mL of water
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with 200 mL of EtOAc
  6. additionThe combined organic layers were poured through a silica plug
  7. customto provide a brown solution
  8. concentrationThe solution was concentrated until about 100 mL of solvent
  9. waitwas left
  10. customgiving a heterogeneous brown sludge
  11. customa yellow solid precipitated
  12. filtrationThe yellow solid was collected by vacuum filtration (rinsing with 200 mL isopropanol)

Sources & evidence

ORD record
ord-5b344905359047e0add38761b46fd6a3
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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