Potassium Cyanide → Methyl 3-(cyanomethyl)-1H-indole-4-carboxylate

A solution of methyl indole-4-carboxylate (1.1 g 6.2 mmol) and Eschenmoser's salt [N,N-dimethylmethyleneammonium iodide] (1.3 g, 7 mmol) in acetonitrile (15 ml) is refluxed for 3 hours. The reaction mixture is concentrated, redisolved in dichloromethane (400 ml) and washed with 1M sodium hydroxide (200 ml) and water (200 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated. The resulting methyl 3-(dimethylaminomethyl)indole-4-carboxylate (1.2 g) is methylated with methyl iodide (0.7 ml) in a mixture of dichoromethane (25 ml) and ether (13 ml). The reaction mixture is concentrated, the product dissolved in DMSO (7 ml) and treated with potassium cyanide (700 mg, 10 mmol). After stirring at r.t. overnight the reaction mixture is diluted with ethyl acetate (200 ml) and washed with three portions of water (100 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is chromatographed on silica with ethyl acetate/hexane 2:3 to give methyl 3-(cyanomethyl)indole-4-carboxylate as a dark oil. Hydrogenation in acetic acid over platinum oxide gives the desired intermediate as an orange solid.

1. concentrationThe reaction mixture is concentrated
2. washwashed with 1M sodium hydroxide (200 ml) and water (200 ml)
3. dry with materialThe organic layer is dried over magnesium sulfate
4. filtrationfiltered
5. concentrationconcentrated
6. additionThe resulting methyl 3-(dimethylaminomethyl)indole-4-carboxylate (1.2 g) is methylated with methyl iodide (0.7 ml) in a mixture of dichoromethane (25 ml) and ether (13 ml)
7. concentrationThe reaction mixture is concentrated
8. dissolutionthe product dissolved in DMSO (7 ml)
9. washwashed with three portions of water (100 ml)
10. dry with materialThe organic layer is dried over magnesium sulfate
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. customThe crude material is chromatographed on silica with ethyl acetate/hexane 2:3

ORD record

ord-ad7b016ed511479ab23d1fcab2e4b564

Source dataset

uspto-grants-1998_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05780498