Dimethylformamide → (R)-1-(2-chloropropanoyl)-3,3-dimethylindoline-6-carbonitrile

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Reaction Steps

To a stirred solution of 2-chloro-1-propionic acid (0.11 mL, 1.16 mmol) in DCM (20 mL) was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (0.55 g, 1.45 mmol). The mixture was stirred for 30 minutes then triethylamine (0.48 mL, 3.44 mmol), 3,3-dimethyl-2,3-dihydro-1H-indole-6-carbonitrile (0.2 g, 1.16 mmol) and a drop of DMF was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with DCM and washed with water. The organic phases were separated, dried with Na2SO4 and concentrated. The crude product was washed with diethyl ether and the filtrate was concentrated and purified by flash column chromatography eluting with 10% EtOAc in heptane to give (R)-1-(2-chloropropanoyl)-3,3-dimethylindoline-6-carbonitrile (0.133 g) [M+H]+=263. A solution of this material, (R)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.13 g, 0.51 mmol) and potassium carbonate (0.10 g, 0.51 mmol) in acetonitrile (2.5 mL) was heated at 60° C. for 48 h. The reaction mixture was then diluted with EtOAc and washed with water. The organic phase was separated, dried with Na2SO4 and concentrated. The residue was purified by flash column chromatography eluting with 15% EtOAc in heptane to give the title compound (33.5 mg), [M+H]+=427.

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