Sodium Carbonate → (2-Cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methanol

HRID 530985Notes

Reaction equation

HRID 530985 reaction equation
Br[C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=O)[C:5]([O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[CH:22]1(B(O)O)[CH2:24][CH2:23]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>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].O.C1(C)C=CC=CC=1>[CH:22]1([C:2]2[CH:7]=[C:6]([CH2:8][OH:10])[C:5]([O:12][CH2:13][CH3:14])=[CH:4][C:3]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:24][CH2:23]1

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 2760897Cyclopropylboronic acidHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 117992268Methyl 2-bromo-5-ethoxy-4'-fluorobiphenyl-4-carboxylate

Product 1

HCID 117992311(2-Cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methanolYield 91.5%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

A mixture of methyl 2-bromo-5-ethoxy-4′-fluorobiphenyl-4-carboxylate (7.62 g), cyclopropylboronic acid (5.56 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (1.33 g), a 2 M aqueous sodium carbonate solution (32.4 mL), tris(dibenzylideneacetone)dipalladium(0) (1.38 g), and toluene (50 mL) was stirred at 100° C. for 2 hours in an argon atmosphere. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto. The reaction mixture was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. A THF (50 mL) solution of the obtained residue was added to a THF (50 mL) suspension of lithium aluminum hydride (0.819 g) under ice cooling. After stirring at the same temperature as above for 30 minutes, water (1 mL) and a 15% aqueous sodium hydroxide solution (1 mL) were added thereto, and the mixture was stirred for 5 minutes. Water (3 mL) was further added to the reaction mixture, and the mixture was stirred for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (5.65 g).

Workup

  1. washThe reaction mixture was washed with saturated saline
  2. dry with materialdried over anhydrous magnesium sulfate
  3. distillationthe solvent was distilled off under reduced pressure
  4. additionA THF (50 mL) solution of the obtained residue was added to a THF (50 mL) suspension of lithium aluminum hydride (0.819 g) under ice cooling
  5. additiona 15% aqueous sodium hydroxide solution (1 mL) were added
  6. stirringthe mixture was stirred for 5 minutes
  7. additionWater (3 mL) was further added to the reaction mixture
  8. stirringthe mixture was stirred for 30 minutes
  9. filtrationfiltered
  10. concentrationThe filtrate was concentrated under reduced pressure
  11. customThe obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate)

Sources & evidence

ORD record
ord-c61404acbe014a47ab278d14a3da1974
Source dataset
uspto-grants-2016_05
Patent number
US09353108B2

Reaction notes

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