N,N,N',N'-Tetramethylethylenediamine → Tert-butyl 2-(2-fluoropyridin-3-yl)piperidine-1-carboxylate

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Reaction Steps

To a −78° C. solution of tert-butyl piperidine-1-carboxylate (1.0 mL, 5.20 mmol), dry ether (20 mL) and TMEDA (0.82 mL, 5.47 mmol) was added sec-butyllithium, 1.4M in cyclohexane (3.90 mL, 5.46 mmol) dropwise over 5 minutes. After 2 hours, a solution of zinc chloride, 0.5M in ether (6.8 mL, 6.80 mmol) was added over 7 minutes. After 30 minutes, the mixture was warmed to ambient temperature and stirred for a further 30 minutes then 2-fluoro-3-iodopyridine (1511 mg, 6.78 mmol), palladium(ii) acetate (127 mg, 0.566 mmol), tri-t-butylphosphonium tetrafluoroborate (268 mg, 0.924 mmol) was added in one portion. After 18 hours, NH4OH (10 mL, 10% aqueous solution) was added dropwise, followed by Et2O (10 mL). The organic layer was extracted, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with 0% to 40% EtOAc in hexane, to provide tert-butyl 2-(2-fluoropyridin-3-yl)piperidine-1-carboxylate (70 mg, 0.250 mmol) as a colorless oil. [M+Na]=303.2.

Provenance & Evidence