Cesium carbonate → (2-Bromo-4-fluoro-6-{7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl}phenyl)methyl acetate

HRID 1919149Notes

Reaction equation

HRID 1919149 reaction equation
[CH:1]12[CH2:14][CH:11]([CH2:12][CH2:13]1)[C:10]1[CH:9]=[C:8]3[N:3]([CH2:4][CH2:5][NH:6][C:7]3=[O:15])[C:2]2=1.[C:16]([O:19][CH2:20][C:21]1[C:26]([Br:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=1Br)(=[O:18])[CH3:17].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>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]>[C:16]([O:19][CH2:20][C:21]1[C:22]([N:6]2[C:7](=[O:15])[C:8]3[N:3]([C:2]4[CH:1]5[CH2:14][CH:11]([C:10]=4[CH:9]=3)[CH2:12][CH2:13]5)[CH2:4][CH2:5]2)=[CH:23][C:24]([F:28])=[CH:25][C:26]=1[Br:27])(=[O:18])[CH3:17]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 580438163,4,6,7,8,9-Hexahydro-6,9-methanopyrazino[1,2-a]indol-1(2H)-oneHCID 670165932,6-Dibromo-4-fluorobenzyl acetate

Product 1

HCID 68096577(2-Bromo-4-fluoro-6-{7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl}phenyl)methyl acetateYield 72.7%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

Into a sealed tube was charged with 334f (800 mg, 4 mmol) and 197c (3.8 g, 12 mmol) in dioxane (25 mL), and cesium carbonate (2.6 g, 8 mmol). After bubbling nitrogen through the resulting solution for 30 min, XantPhos (230 mg, 0.4 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (362 mg, 0.4 mmol) were added, and the reaction mixture was heated at 100° C. for 4 h. After this time the reaction was cooled to room temperature, and partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL×3). The organic layers were combined, washed with brine (20 mL×3), and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 1:5 ethyl acetate/petroleum ether to give 334g as a brown solid (1.3 g, 72%). MS: [M+H]+ 447.

Workup

  1. customAfter bubbling nitrogen through the resulting solution for 30 min
  2. temperatureAfter this time the reaction was cooled to room temperature
  3. custompartitioned between ethyl acetate (100 mL) and water (100 mL)
  4. customThe aqueous layer was separated
  5. extractionextracted with ethyl acetate (50 mL×3)
  6. washwashed with brine (20 mL×3)
  7. dry with materialdried over sodium sulfate
  8. customThe drying agent was removed by filtration
  9. concentrationthe filtrate was concentrated under reduced pressure
  10. customThe residue was purified by column chromatography
  11. washeluting with 1:5 ethyl acetate/petroleum ether

Sources & evidence

ORD record
ord-618a3fef866d44c7ba584a9b210c5979
Source dataset
uspto-grants-2013_12
Patent number
US08618107B2

Reaction notes

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