Cesium carbonate → (E)-ethyl 3-(5-(benzylthio)-2-((6-(3-fluorophenyl)-4-methoxypyridin-3-yl)amino)phenyl)acrylate

HRID 1504371Notes

Reaction equation

HRID 1504371 reaction equation
Br[C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][C:19]=1/[CH:32]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35].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)([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].CCOC(C)=O>[CH2:25]([S:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)=[CH:4][C:3]=2[O:15][CH3:16])=[C:19](/[CH:32]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:20]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)2×HCID 1177372915-Bromo-2-(3-fluorophenyl)-4-methoxypyridineHCID 117740420(E)-Ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate

Product 1

HCID 117739607(E)-ethyl 3-(5-(benzylthio)-2-((6-(3-fluorophenyl)-4-methoxypyridin-3-yl)amino)phenyl)acrylateYield 80.3%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

A 40-mL vial containing 5-bromo-2-(3-fluorophenyl)-4-methoxypyridine (0.420 g, 1.489 mmol), (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (0.560 g, 1.787 mmol), Xantphos (0.172 g, 0.298 mmol), cesium carbonate (0.679 g, 2.084 mmol), and Pd2(dba)3 (0.136 g, 0.149 mmol) was flushed with N2 and charged with CPME (3 mL). After stirring overnight at 90° C., additional Pd2(dba)3 (0.136 g, 0.149 mmol) and Xantphos (0.172 g, 0.298 mmol) was added. After stirring an additional 4 h, the reaction was cooled to rt, quenched with H2O and extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a brown-black oil. Column chromatography (50 g Snap Ultra column, 0% to 80% EtOAc/hept) afforded (E)-ethyl 3-(5-(benzylthio)-2-((6-(3-fluorophenyl)-4-methoxypyridin-3-yl)amino)phenyl)acrylate (0.615 g, 1.195 mmol, 80% yield) as a yellow oil. m/z (ESI) 515.2 (M+H)+.

Workup

  1. customwas flushed with N2
  2. additioncharged with CPME (3 mL)
  3. stirringAfter stirring an additional 4 h
  4. temperaturethe reaction was cooled to rt
  5. customquenched with H2O
  6. extractionextracted thrice with EtOAc
  7. washwashed with brine
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo to a brown-black oil

Sources & evidence

ORD record
ord-7bbda308461e406b93d5167405f7d74c
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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