Dimethylformamide → 1-(4-methoxybenzyl)-1H-indole-4-carbonitrile

HRID 2190065Notes

Reaction equation

HRID 2190065 reaction equation
Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[NH:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH:13]=[CH:12]1.[H-].[Na+].CN(C=O)C>O>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=3[CH:13]=[CH:12]2)=[CH:4][CH:5]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 699934-Methyloxybenzyl chlorideHCID 38176024-Cyanoindole

Product 1

HCID 687632391-(4-methoxybenzyl)-1H-indole-4-carbonitrileYield 99.4%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

1-(Chloromethyl)-4-methoxybenzene (30.3 g, 193 mmol) was added to a slurry of 1H-indole-4-carbonitrile (25.0 g, 176 mmol) and NaH (7.74 g, 193 mmol) in DMF (586 mL, 176 mmol) at 0° C., and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organic layers were washed with water and brine, dried (Na2SO4) and concentrated to afford a crude residue, which was purified by column chromatography eluting with an ethyl acetate/hexanes gradient to give 1-(4-methoxybenzyl)-1H-indole-4-carbonitrile (46.0 g, 175 mmol, 99%). 1H NMR (400 MHz, CDCl3) 7.89 (d, J=8.2 Hz, 1H), 7.81 (d, J=3.1 Hz, 1H), 7.54 (d, J=7.4 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.21 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 6.64 (d, J=2.7 Hz, 1H), 5.44 (s, 2H), 3.70 (s, 3H).

Workup

  1. extractionextracted with ethyl acetate (3×)
  2. washThe combined organic layers were washed with water and brine
  3. dry with materialdried (Na2SO4)
  4. concentrationconcentrated
  5. customto afford a crude residue, which
  6. customwas purified by column chromatography
  7. washeluting with an ethyl acetate/hexanes gradient

Sources & evidence

ORD record
ord-20ae1a732d42479e9eb95c914ddcc1d3
Source dataset
uspto-grants-2012_12
Patent number
US08324221B2

Reaction notes

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