Cesium carbonate → methyl 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-4-oxo-chromene-6-carboxylate

HRID 41186Notes

Reaction equation

HRID 41186 reaction equation
[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:17])[CH:16]=2)=[CH:13][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=3[C@H:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[F:34][C:32]1[CH:33]=[C:28]([N:23]2[CH2:24][CH2:25][CH2:26][C@@H:22]2[C:10]2[CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=[C:14]3[C:9]=2[O:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16][C:15]3=[O:17])[CH:29]=[C:30]([F:35])[CH:31]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 1363131-Bromo-3,5-difluorobenzeneHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86672411methyl 2-morpholino-4-oxo-8-[(2R)-pyrrolidin-2-yl]chromene-6-carboxylate

Product 1

HCID 86672413methyl 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-4-oxo-chromene-6-carboxylateYield 67.1%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

Diacetoxypalladium (0.028 g, 0.13 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-[(2R)-pyrrolidin-2-yl]chromene-6-carboxylate (0.9 g, 2.51 mmol), 1-bromo-3,5-difluorobenzene (0.361 ml, 3.14 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (145 mg, 0.25 mmol) and cesium carbonate (1.227 g, 3.77 mmol) dissolved in 1,4-dioxane (16 mL). The resulting suspension was degassed with argon and then stirred at 100° C. for 15 h. The reaction mixture was allowed to cool to room temperature, concentrated in presence of silica gel and purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in EtAc. The solvent was evaporated to dryness to afford methyl 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-4-oxo-chromene-6-carboxylate (0.792 g, 67%) as an yellow foam. Mass Spectrum: m/z [M+H]+=471.

Workup

  1. customThe resulting suspension was degassed with argon
  2. temperatureto cool to room temperature
  3. concentrationconcentrated in presence of silica gel
  4. custompurified by flash chromatography on silica gel eluting with 0 to 10% MeOH in EtAc
  5. customThe solvent was evaporated to dryness

Sources & evidence

ORD record
ord-26da521e8eb04474b325ebc89de0bd65
Source dataset
uspto-grants-2013_09
Patent number
US08530470B2

Reaction notes

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