Sodium Hydroxide → 4-Fluoro-2,3-dihydro-1H-indole

HRID 1910040Notes

Reaction equation

HRID 1910040 reaction equation
[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2

Participants

5

Reactant 3

HCID 14798Sodium HydroxideHCID 27745024-FluoroindoleHCID 5003444Sodium cyanoborohydride

Product 1

HCID 162444404-Fluoro-2,3-dihydro-1H-indoleYield 52.9%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Conditions

Temperature
12 °C

Procedure

To a stirred solution of 4-fluoro-1H-indole (950 mg, 7.03 mmol) in Acetic Acid (20 mL) at 12° C. under nitrogen was added sodium cyanoborohydride (1458 mg, 23.20 mmol) portionwise. The reaction was stirred at 12° C. for 2 hours, and at room temperature overnight. The reaction was worked up by pouring into sodium hydroxide (10 N). The aqueous was extracted with diethyl ether (3×100 mL), and the combined organics dried over sodium sulfate. LCMS analysis at this point indicated presence of product and some acylated product, along with some acylated starting material. The crude was dissolved in THF (10 mL) and treated with NaOH (6 N, 2 mL), then stirred at r.t. for 2 h. The reaction was stirred overnight, but no change in LCMS was observed, so the organic layer was removed, and the aqueous extracted with diethyl ether (2×10 mL), the combined organics were dried over sodium sulfate. The dried solution was filtered and concentrated, and the residue was purified by flash chromatography (0-25% EtOAc in hexanes, 24-g silica gel column) to afford 4-fluoro-2,3-dihydro-1H-indole (510 mg, 3.72 mmol, 52.9% yield) as a colorless oil. LC-MS (ES) m/z=138 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.94 (t, J=8.59 Hz, 2H), 3.48 (t, J=8.59 Hz, 2H), 5.79 (br. s., 1H), 6.23-6.35 (m, 2H), 6.87-6.99 (m, 1H).

Workup

  1. customat room temperature
  2. customovernight
  3. extractionThe aqueous was extracted with diethyl ether (3×100 mL)
  4. dry with materialthe combined organics dried over sodium sulfate
  5. dissolutionThe crude was dissolved in THF (10 mL)
  6. additiontreated with NaOH (6 N, 2 mL)
  7. stirringstirred at r.t. for 2 h
  8. stirringThe reaction was stirred overnight
  9. customwas removed
  10. extractionthe aqueous extracted with diethyl ether (2×10 mL)
  11. dry with materialthe combined organics were dried over sodium sulfate
  12. filtrationThe dried solution was filtered
  13. concentrationconcentrated
  14. customthe residue was purified by flash chromatography (0-25% EtOAc in hexanes, 24-g silica gel column)

Sources & evidence

ORD record
ord-a449f82533934592a5b5403b9b5bec04
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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