Dimethylamine → 4-Methoxyindole-3-acetonitrile

To a solution of 4-methoxyindole (1.0 g, 6.8 mmol, 1.0 eq.) in a mixture of acetic acid (2 mL) and water (1 mL) were added, at 0° C., formaldehyde (720 μL, 37% in H2O, 8.9 mmol, 1.3 eq) and dimethylamine (1.23 mL, 40% in H2O, 10.9 mmol, 1.6 eq). The mixture was stirred at room temperature for 6 hours and then, quenched with ice and 5 M aqueous sodium hydroxide. The mixture was extracted with dichloromethane and then, the organic layer was dried over MgSO4 and partially evaporated. To the solution gramine in dichloromethane (20 mL) were added, under an argon atmosphere, anhydrous toluene (40 mL) and methyl iodide (845 μL, 13.6 mmol, 2.0 eq.). The mixture was stirred at room temperature for 12 hours and then, concentrated under reduced pressure. To the residue taken up in anhydrous THF (60 mL) were added, under an argon atmosphere, TMSCN (1.28 mL, 10.2 mmol, 1.5 eq.) and TBAF (20.4 mL, 1M, 20.4 mmol, 3.0 eq.). The mixture was stirred at room temperature for 4 hours and then, concentrated under reduced pressure. The crude was taken up in ethyl acetate and the organic layer was washed with aqueous bicarbonate solution and then dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel pad filtration (eluent: EtOAc) to afford (4-methoxy-1H-indol-3-yl)-acetonitrile as a beige solid (0.80 g, 68%).

1. additionwere added, at 0° C.
2. customquenched with ice and 5 M aqueous sodium hydroxide
3. extractionThe mixture was extracted with dichloromethane
4. dry with materialthe organic layer was dried over MgSO4
5. custompartially evaporated
6. additionTo the solution gramine in dichloromethane (20 mL) were added, under an argon atmosphere
7. stirringThe mixture was stirred at room temperature for 12 hours
8. concentrationconcentrated under reduced pressure
9. additionwere added, under an argon atmosphere
10. stirringThe mixture was stirred at room temperature for 4 hours
11. concentrationconcentrated under reduced pressure
12. washthe organic layer was washed with aqueous bicarbonate solution
13. dry with materialdried over MgSO4
14. customThe solvent was removed under reduced pressure
15. filtrationthe residue purified by silica gel pad filtration (eluent: EtOAc)

ORD record

ord-8cccdf165c484e6e97034dab1977b0ee

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09212138B2