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

HRID 1504446Notes

Reaction equation

HRID 1504446 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]([CH3:30])[C:27](I)=[CH:26][C:25]=1[F:32].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:27]2[CH:26]=[C:25]([F:32])[C:24]([Br:23])=[CH:29][C:28]=2[CH3:30])=[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 121872165-Bromo-4-fluoro-2-iodotolueneHCID 117740420(E)-Ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate

Product 1

HCID 117746868(E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methylphenyl)amino)phenyl)acrylateYield 86.5%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
110 °C

Procedure

A pressure tube was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (2.31 g, 7.37 mmol), 1-bromo-2-fluoro-4-iodo-5-methylbenzene (2.79 g, 8.84 mmol, Oakwood Chemicals), XantPhos (0.213 g, 0.369 mmol), Pd2(dba)3 (0.169 g, 0.184 mmol), and cesium carbonate (6.00 g, 18.43 mmol). The whole was purged with argon. Then toluene (14.74 ml) was added. The tube was sealed and heated in the heating block at 110° C. for 17 h. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through celite with an aid of EtOAc. The filtrate was concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 0% to 30% EtOAc in heptane, to provide (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methylphenyl)amino)phenyl)acrylate (3.19 g, 86% yield) as yellow solid. m/z (ESI) [M+H]+=500.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.09 Hz, 3 H) 2.04 (s, 3 H) 4.04 (q, J=7.11 Hz, 2 H) 4.16 (s, 2 H) 6.27 (d, J=11.05 Hz, 1 H) 6.47 (d, J=15.94 Hz, 1 H) 6.78 (d, J=8.41 Hz, 1 H) 7.09-7.26 (m, 6 H) 7.34 (dd, J=8.02, 0.68 Hz, 1 H) 7.53-7.66 (m, 3 H).

Workup

  1. customThe whole was purged with argon
  2. additionThen toluene (14.74 ml) was added
  3. customThe tube was sealed
  4. temperatureThe mixture was cooled to room temperature
  5. additiondiluted with EtOAc
  6. filtrationfiltered through celite with an aid of EtOAc
  7. concentrationThe filtrate was concentrated
  8. customThe crude material was absorbed onto a plug of silica gel
  9. custompurified by chromatography through a Redi-Sep pre-packed silica gel column (80 g)
  10. washeluting with a gradient of 0% to 30% EtOAc in heptane

Sources & evidence

ORD record
ord-4a94347e4b0b4a67afe8886042bd3ac0
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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