Citric Acid → 2-(Benzamido)-4-(2-(benzofuran-5-yl)ethyl)benzoic acid

HRID 1673428Notes

Reaction equation

HRID 1673428 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([NH:25][C:26]1[CH:38]=[C:37]([CH:39]=[CH2:40])[CH:36]=[CH:35][C:27]=1[C:28]([O:30]C(C)(C)C)=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:17]([NH:25][C:26]1[CH:38]=[C:37]([CH2:39][CH2:40][C:2]2[CH:3]=[CH:4][C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=2)[CH:36]=[CH:35][C:27]=1[C:28]([OH:30])=[O:29])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1

Participants

9

Reactant 4

HCID 311Citric AcidHCID 10796Cesium carbonateHCID 90015Benzofuran, 5-bromo-HCID 67343635Tert-butyl 2-(benzamido)-4-vinylbenzoate

Product 1

HCID 578794852-(Benzamido)-4-(2-(benzofuran-5-yl)ethyl)benzoic acidYield 7.2%

Reagents, catalysts & solvents 4

HCID 74236Tetrabutylammonium BromideCatalystHCID 86634613dicyclohexylphenylphosphine palladium(II)CatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

0.12 g of 5-bromobenzofuran, 0.20 g of cesium carbonate, 30 mg of tetrabutylammonium bromide and 48 mg of polymer supported di(acetato)dicyclohexylphenylphosphine palladium(II) were added to 2.0 mL of toluene solution containing 0.10 g of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, 48 mg of polymer supported di(acetato) dicyclohexylphenyl-phosphine palladium(II) was added and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 2.4 mL of tetrahydrofuran, 0.6 mL of water, 0.44 mL of acetic acid, 0.42 g sodium formate and 50 mg of 3.9% palladium-carbon (ethylenediamine complex) were added to the obtained residue and stirred at 50° C. for 12 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 10 mL of trifluoroacetic acid was added to the obtained residue and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 8.6 mg of 2-(benzamido)-4-(2-(benzofuran-5-yl)ethyl)benzoic acid as white solid.

Workup

  1. temperatureAfter the reaction mixture was cooled to room temperature
  2. additionwas added
  3. stirringstirred at 110° C. for 24 hours
  4. temperatureAfter the reaction mixture was cooled to room temperature
  5. customThe organic layer was separated
  6. dry with materialdried over anhydrous magnesium sulfate
  7. washafter washed with 10% citric acid aqueous solution
  8. customa saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure
  9. addition2.4 mL of tetrahydrofuran, 0.6 mL of water, 0.44 mL of acetic acid, 0.42 g sodium formate and 50 mg of 3.9% palladium-carbon (ethylenediamine complex) were added to the obtained residue
  10. stirringstirred at 50° C. for 12 hours
  11. temperatureAfter the reaction mixture was cooled to room temperature
  12. additionethyl acetate and 10% citric acid aqueous solution were added
  13. customThe organic layer was separated
  14. dry with materialdried over anhydrous magnesium sulfate
  15. washafter washed with 10% citric acid aqueous solution
  16. customa saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure
  17. addition10 mL of trifluoroacetic acid was added to the obtained residue
  18. stirringstirred at room temperature for 1 hour
  19. customThe solvent was evaporated under reduced pressure
  20. customthe obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution]

Sources & evidence

ORD record
ord-3aae3adc88864c60a8684da47e0f26be
Source dataset
uspto-grants-2011_08
Patent number
US07999132B2

Reaction notes

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