Cesium carbonate → 2-Bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]-indolizin-2(1H)-yl)benzyl acetate

HRID 1024091Notes

Reaction equation

HRID 1024091 reaction equation
[C:1]([O:4][CH2:5][C:6]1[C:11]([Br:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[C:15]1(=[O:28])[C:20]2[CH:21]=[C:22]3[N:27]([C:19]=2[CH2:18][CH2:17][NH:16]1)[CH2:26][CH2:25][CH2:24][CH2:23]3.C(=O)([O-])[O-].[Cs+].[Cs+].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>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].O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:16]2[CH2:17][CH2:18][C:19]3[N:27]4[C:22]([CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:21][C:20]=3[C:15]2=[O:28])=[CH:8][C:9]([F:13])=[CH:10][C:11]=1[Br:12])(=[O:3])[CH3:2]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 580442873,4,6,7,8,9-Hexahydropyrido[3,4-b]indolizin-1(2H)-oneHCID 670165932,6-Dibromo-4-fluorobenzyl acetate

Product 1

HCID 866837002-Bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]-indolizin-2(1H)-yl)benzyl acetateYield 48.4%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (60 mL), 2,6-dibromo-4-fluorobenzyl acetate (1.9 g, 6.0 mmol), 120d (400 mg, 2.0 mmol), and cesium carbonate (1.3 g, 4.0 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, Xantphos (120 mg, 0.2 mmol) and tris(dibenzylideneacetone)dipalladium(0) (180 mg, 0.2 mmol) were added, and the reaction mixture was heated at 100° C. for 12 h. After this time the reaction was cooled to room temperature, partitioned between ethyl acetate (40 mL) and water (40 mL), and filtered. The aqueous layer was separated and extracted with ethyl acetate (3×70 mL). The combined organic layer was washed with brine (30 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flush column eluting with 2:1 petroleum ether/ethyl acetate to afford 120e (421 mg, 46%) as yellow solid. MS: [M+H]+ 435. 1H NMR (500 MHz, MeOD) δ 7.52-7.50 (m, 1H), 7.23-7.20 (m, 1H), 6.14 (s, 1H), 5.20-5.10 (m, 2H), 4.09-4.06 (m, 1H), 3.95-3.92 (m, 1H), 3.88-3.85 (m, 1H), 3.78-3.75 (m, 1H), 3.07-2.97 (m, 2H), 2.81-2.77 (m, 2H), 2.03-2.00 (m, 5H), 1.87-1.84 (m, 2H).

Workup

  1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser
  3. customAfter bubbling nitrogen through the resulting mixture for 30 minutes
  4. temperatureAfter this time the reaction was cooled to room temperature
  5. custompartitioned between ethyl acetate (40 mL) and water (40 mL)
  6. filtrationfiltered
  7. customThe aqueous layer was separated
  8. extractionextracted with ethyl acetate (3×70 mL)
  9. washThe combined organic layer was washed with brine (30 mL)
  10. dry with materialdried over sodium sulfate
  11. customThe drying agent was removed by filtration
  12. concentrationthe filtrate was concentrated under reduced pressure
  13. customThe residue was purified
  14. customon flush column
  15. washeluting with 2:1 petroleum ether/ethyl acetate

Sources & evidence

ORD record
ord-1af238f2b7c14deebee75d62522d520e
Source dataset
uspto-grants-2014_05
Patent number
US08722676B2

Reaction notes

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