Cesium fluoride → 1-(3-(Cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone

HRID 1056132Notes

Reaction equation

HRID 1056132 reaction equation
Br[C:2]1[C:3]([F:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][CH:13]1[CH2:15][CH2:14]1)[C:8]([CH3:16])=[N:7]2.C([Sn](CCCC)(CCCC)[C:23]([O:25]CC)=[CH2:24])CCC.[F-].[Cs+]>O1CCOCC1.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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH:13]1([NH:12][C:9]2[C:8]([CH3:16])=[N:7][C:6]3[C:11]([N:10]=2)=[C:2]([C:23](=[O:25])[CH3:24])[C:3]([F:17])=[CH:4][CH:5]=3)[CH2:15][CH2:14]1

Participants

7

Reactant 3

HCID 25953Cesium fluorideHCID 619414Stannane, tributyl(1-ethoxyethenyl)-HCID 897819328-bromo-N-cyclopropyl-7-fluoro-3-methylquinoxalin-2-amine

Product 1

HCID 897822001-(3-(Cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanoneYield 87.4%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A 150-mL round bottomed flask was charged with 8-bromo-N-cyclopropyl-7-fluoro-3-methylquinoxalin-2-amine (283a) (1.60 g, 5.40 mmol), tributyl(1-ethoxyvinyl)tin (Sigma-Aldrich) (2.74 mL, 8.10 mmol), Pd2dba3 (Strem Chemicals) (0.15 g, 0.16 mmol), Xphos (Strem Chemicals) (0.15 g, 0.32 mmol), Cut (Strem Chemicals) (0.21 g, 1.08 mmol) and cesium fluoride (Sigma-Aldrich) (2.46 g, 16.21 mmol) in dioxane (27.0 mL). The flask was purged with argon for 3 min, placed into a pre-heated (80° C.) bath and stirred 2.5 h while under inert atmosphere. The progress of the reaction was monitored by LCMS, which showed desired material. The mixture was removed from the heat bath and cooled to RT. The mixture was treated with 1 N HCl (20 mL) and stirred at RT 30 min. The mixture was filtered through AW Standard Super-Celt NF (Sigma-Aldrich). The filter cake was washed with EtOAc and water. The aq. layer was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography through a SiliCycle SiliaSep HP pre-packed silica-gel column (SiliCycle, Quebec City, Canada; 40 gram), eluting with a gradient of 0-20% EtOAc in DCM, to provide 1-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (283b) (1.22 g, 4.72 mmol, 87% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.82 (dd, J=9.00, 6.06 Hz, 1H), 7.51 (dd, J=2.74, 0.39 Hz, 1H), 7.23 (t, J=9.29 Hz, 1H), 2.78-2.97 (m, 1H), 2.76 (s, 3H), 2.46 (s, 3H), 0.70-0.83 (m, 2H), 0.52-0.70 (m, 2H). m/z (ESI, +ve) 260 (M+H).

Workup

  1. customThe flask was purged with argon for 3 min
  2. customThe mixture was removed from the heat bath
  3. temperaturecooled to RT
  4. additionThe mixture was treated with 1 N HCl (20 mL)
  5. stirringstirred at RT 30 min
  6. filtrationThe mixture was filtered through AW Standard Super-Celt NF (Sigma-Aldrich)
  7. washThe filter cake was washed with EtOAc and water
  8. extractionThe aq. layer was extracted with EtOAc (3×)
  9. dry with materialThe combined organic extracts were dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe crude material was purified by chromatography through a SiliCycle SiliaSep HP pre-packed silica-gel column (SiliCycle, Quebec City, Canada; 40 gram)
  13. washeluting with a gradient of 0-20% EtOAc in DCM

Sources & evidence

ORD record
ord-1a06cf51e8e64c54bcdcb3a12fff8df2
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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