2,2-Difluoroethanamine → N-(tert-butoxycarbonyl)piperidine

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Reaction Steps

To a stirred solution of 1-Boc-4-piperidone (0.300 g, 1 eq) and 2,2-difluoroethylamine (0.244 g, 2 eq) in 1,2-dichloroethane (6 mL) is added NaBH(OAc)3 (0.640 mg, 2 eq). After 18 h, the solution is diluted with CH2Cl2, washed with NaHCO3 (sat.), brine, dried over Na2SO4 and concentrated. The resulting residue is purified by flash chromatography Hex/EtOAc (1:1) to give the corresponding N-Boc piperidine (0.360 g, 90%). The obtained N-Boc piperidine (29 mg, 1.5 eq) is dissolved in a solution HCl in dioxane (4 M, 0.5 mL) and stirred during 30 min at RT. The solution is concentrated, the resulting residue is dissolved in DMSO (0.5 mL), Et3N (40 μL, 4 eq) is added followed by 50d (35 mg, 1 eq). The solution is heated at 50° C. for 1 h and ammonium acetate (500 mg) is added and the heating is pursued at 140° C. during 4 h. The solution is diluted with H2O/AcOH and purified by prep HPLC to give 5004 (10 mg, 24%).

Provenance & Evidence