Formaldehyde → (1H-Pyrrolo[2,3-b]pyridin-3-yl)acetonitrile

To a solution of 1H-pyrrolo[2,3-b]pyridine (1.5 g, 12.7 mmol, 1.0 eq.) and paraformaldehyde (0.46 g, 15.2 mmol, 1.2 eq.) in isopropanol (20 mL) was added dimethylamine hydrochloride (1.24 g, 15.2 mmol, 1.2 eq). The mixture was stirred at reflux temperature for 20 minutes and then, quenched with ice and 5 M aqueous sodium hydroxide after cooling to room temperature. The mixture was extracted with ethyl acetate and the organic layer was dried over MgSO4 and evaporated under reduced pressure. The gramine residue was taken up in a mixture of anhydrous dichloromethane (40 mL) and toluene (80 mL) and then, methyl iodide (1.26 mL, 20.3 mmol, 1.6 eq.) was added under an argon atmosphere. The mixture was stirred at room temperature for 12 hours and concentrated. To the residue taken up in anhydrous THF (120 mL) were added, under an argon atmosphere, TMSCN (2.39 mL, 19.1 mmol, 1.5 eq.) and TBAF (38.1 mL, 1M, 38.1 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 a saturated aqueous sodium bicarbonate solution and then, dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel flash-column chromatography (eluent: heptane/EtOAc, 50:50) to afford 2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-acetonitrile as a white solid (0.56 g, 28%).

1. temperatureat reflux temperature for 20 minutes
2. customquenched with ice and 5 M aqueous sodium hydroxide
3. extractionThe mixture was extracted with ethyl acetate
4. dry with materialthe organic layer was dried over MgSO4
5. customevaporated under reduced pressure
6. additionThe gramine residue was taken up in a mixture of anhydrous dichloromethane (40 mL) and toluene (80 mL)
7. stirringThe mixture was stirred at room temperature for 12 hours
8. concentrationconcentrated
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 a saturated aqueous sodium bicarbonate solution
13. dry with materialdried over MgSO4
14. customThe solvent was removed under reduced pressure
15. customthe residue purified by silica gel flash-column chromatography (eluent: heptane/EtOAc, 50:50)

ORD record

ord-63a18d8322ef4b29a5d8c53ef6b0b8e9

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08703808B2