Diisopropylamine → Tert-butyl 4-cyano-4-(cyclopropylmethyl)piperidine-1-carboxylate

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Reaction Steps

n-Butyllithium in hexanes (1.6M, 11.2 mL, 17.9 mmol) was added dropwise to diisopropylamine (2.5 mL, 17.8 mmol) in THF (20 mL) cooled in an ice bath. After stirring for 0.5 h, the solution was cooled in a dry-ice bath and a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (I-1) (2.50 g, 11.9 mmol) in THF (20 mL) was added dropwise. The solution was stirred in a dry-ice bath for 1 h then cyclopropylmethyl bromide (1.27 mL, 13.1 mmol) was added. The reaction mixture was allowed to warm to room temperature over 2 h then quenched with water. The mixture was extracted with DCM (3×). The combined organic phase was washed with brine, dried (MgSO4) and the solvent removed in vacuo. Biotage chromatography (5-10% ethyl acetate-hexanes) afforded tert-butyl 4-cyano-4-cyclopropylmethylpiperidine-1-carboxylate (I-2) as a colourless oil. 1H NMR (500 MHz, CDCl3): δ 4.12 (br s, 2H), 3.05 (br s, 2H), 2.02 (m, 2H), 1.52 (d, J=7.0, 2H), 1.46 (s, 9H), 0.89 (m, 1H), 0.58 (m, 2H), 0.19 (m, 2H).

Provenance & Evidence