Methyl iodide → [5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetonitrile

Participants

Reaction Conditions

Reaction Steps

5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (780 mg, 3.94 mmol) and Eschenmoser's Salt (1.46 g, 7.88 mmol) were combined in acetonitrile:acetic acid (19:1, 12.3 ml and 700 uL, respectively) and heated for 5 hours at 40° C. Next, 4N potassium hydroxide was added until pH>9. The solution was transferred to a separatory funnel and extracted with copious amount of ethyl acetate. The organic layer was dried over Na2SO4 and concentrated down. Next methyl iodide (246 uL, 3.94 mmol) in ethanol (11 mL) was added to the crude gramine and the solution was stirred at room temperature overnight. The solution was concentrated under vacuum and redissolved in dimethylformamide (10 mL) and water (2 mL). This was then heated to 70° C. for 3 hours. The reaction was allowed to return to room temperature, transferred to a separatory funnel with ethyl acetate (250 mL) and washed with water (2×200 mL). The aqueous layers were combined and back extracted with ethyl acetate (200 mL). The organic layer was dried over Na2SO4 and concentrated down to afford the crude [5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetonitrile. This material was then dissolved in methanol (6 mL) and 4N potassium hydroxide (8 mL) and heated at 90° C. overnight. The solution was then acidified with 1N hydrochloric acid (aq) until precipitate formed. The precipitate was then filtered and washed with water to afford the crude product. The product was purified by flash chromatography (0-15% methanol/dichloromethane gradient) to afford the title compound (284 mg, 28%). MS m/z=257 [M+H+]+

Provenance & Evidence