Potassium Carbonate → 6-fluoro-5-(2'-hydroxybiphenyl-4-yl)-1H-indole-3-carbaldehyde

HRID 1054844Notes

Reaction equation

HRID 1054844 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([OH:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)O1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[F:33])[NH:29][CH:28]=[C:27]2[CH:34]=[O:35].C(=O)([O-])[O-].[K+].[K+].S([O-])(O)(=O)=O.[Na+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.C1COCC1.C1(C)C=CC=CC=1>[F:33][C:32]1[CH:31]=[C:30]2[C:26]([C:27]([CH:34]=[O:35])=[CH:28][NH:29]2)=[CH:25][C:24]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])=[CH:13][CH:14]=1

Participants

10

Reactant 4

HCID 11430Potassium CarbonateHCID 516919Sodium BisulfateHCID 592678134'-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-2-olHCID 735543615-Bromo-6-fluoro-1H-indole-3-carbaldehyde

Product 1

HCID 866988376-fluoro-5-(2'-hydroxybiphenyl-4-yl)-1H-indole-3-carbaldehydeYield 24.1%

Reagents, catalysts & solvents 5

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 702EthanolSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
115 °C

Procedure

A glass tube was charged with 4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-ol (73.5 mg, 0.25 mmol), 5-bromo-6-fluoro-1H-indole-3-carbaldehyde (60 mg, 0.25 mmol), toluene (1.2 mL), THF (0.6 mL), EtOH (0.6 mL), and 2.0 M potassium carbonate solution (0.6 mL, 1.2 mmol). Nitrogen was then bubbled through the mixture for 5 minutes then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21.5 mg, 0.025 mmol) was added. The tube was sealed and heated to 115° C. for 2 hours. The reaction was cooled to room temperature, opened, and neutralized with 1.0 M sodium hydrogensulfate then diluted with ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate (×2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in methylene chloride and methanol, silica was added, and the solvent removed in vacuo. The dry-loaded silica gel was then subjected to flash column chromatography (20% to 100% ethyl acetate/heptane) to provide the title compound as a white solid (20 mg, 24%). MS (ES+) 332.3 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.24 (br. s, 1 H) 9.96 (s, 1 H) 9.59 (s, 1 H) 8.36 (s, 1 H) 8.19 (d, 1 H) 7.67 (d, 2 H) 7.58 (d, 2 H) 7.46 (d, 1 H) 7.33 (d, 1 H) 7.18 (t, 1 H) 6.97 (d, 1 H) 6.91 (t, 1 H).

Workup

  1. customNitrogen was then bubbled through the mixture for 5 minutes
  2. customThe tube was sealed
  3. temperatureThe reaction was cooled to room temperature
  4. customThe layers were separated
  5. extractionthe aqueous extracted with ethyl acetate (×2)
  6. dry with materialThe combined organic layers were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. dissolutionThe residue was dissolved in methylene chloride
  10. additionmethanol, silica was added
  11. customthe solvent removed in vacuo

Sources & evidence

ORD record
ord-a92e434d298c4da5969fbfd268ae0c9b
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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