4'-Hydroxyacetophenone → 2-(4-Hydroxyphenyl)indole

HRID 565433Notes

Reaction equation

HRID 565433 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[OH-].[Na+]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:11]3[C:16]([CH:9]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 74694'-HydroxyacetophenoneHCID 7516Phenylhydrazine

Product 1

HCID 112872602-(4-Hydroxyphenyl)indoleYield 57.4%

Reagents, catalysts & solvents 1

HCID 14798Sodium HydroxideSolvent

Conditions

Temperature
150 °C

Procedure

To 47.2 g of polyphosphoric acid was added 13.62 g (0.10 mol) of 4′-hydroxyacetophenone and 10.0 mL (0.10 mol) of phenylhydrazine at room temperature. The mixture was heated at 150° C. (oil bath temp) for 1 h. After cooling to room temperature an ice-cold H2O (250 mL) was added and the dark brown mixture was stirred overnight. This was then neutralized with 5.0 N NaOH (100 mL) and extracted with EtOAc (1 L×4) which was washed with saturated aqueous NaHCO3 and brine (500 mL each). Organic layers were dried over MgSO4, filtered through a pad of diatomaceous earth, and concentrated to ca. 200-300 mL. This was treated with charcoal, filtered and concentrated. The crude 2-(4-hydroxyphenyl)indole 12.02 g (57%) was obtained. The crude phenolic indole (10.7 g; 51 mmol) was treated with 33.32 g (0.10 mol) of Cs2CO3 and 6.7 mL (56 mmol) of benzyl bromide in ca. 250 mL of DMF at room temperature overnight. The mixture was filtered through a pad of diatomaceous earth with thorough EtOAc rinse. The filtrate was taken up in to 1 L of EtOAc and washed with H2O (500 mL×2) and brine (500 mL) which were back-extracted with EtOAc (1 L×3). Combined organic layers were dried over MgSO4, concentrated and purified by PrepLC with 10:90 benzene-hexanes and 10:10:80 benzene-Et2O-hexanes to obtain 5.34 g (27%) of N,O-dibenzylated product and 1.94 g (13%) of the named benzyl ether.

Workup

  1. additionwas added
  2. extractionextracted with EtOAc (1 L×4) which
  3. washwas washed with saturated aqueous NaHCO3 and brine (500 mL each)
  4. dry with materialOrganic layers were dried over MgSO4
  5. filtrationfiltered through a pad of diatomaceous earth
  6. concentrationconcentrated to ca. 200-300 mL
  7. additionThis was treated with charcoal
  8. filtrationfiltered
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-864a6bf638e345fc85cab94b4b204a6f
Source dataset
uspto-grants-2001_01
Patent number
US06172100B2

Reaction notes

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