Triethylamine → 1-(tert-Butoxycarbonyl)-4-(methanesulfonyloxy)piperidine

Participants

Reaction Conditions

Reaction Steps

To a stirred solution of 4-hydroxy-piperidine hydrochloride monohydrate (10 g, 0.0988 mole) in THF (80 mL) was added triethylamine (11.98 g, 16.48 mL 0.1186 mole) and the resulting mixture was cooled to 10° C. Di-tert-butyl dicarbonate (23.68 g, 0.1086 mole) was added dropwise and stirring was continued at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was acidified with concentrated HCl and extracted with ethyl acetate. The ethyl acetate layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 19.47 g (98%) of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (DMSO-d6): δ 4.7 (d, 1H), 3.7-3.5 (m, 3H), 3.0-2.8 (t, 2H), 1.7-1.6 (m, 2H), 1.4 (s, 9H), 1.3-1.2 (m, 2H). To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10 g, 0.0497 mole) in THF (100 mL), was added triethylamine (6.026 g, 8.29 mL, 0.0596 mole) and the resulting mixture was cooled to 0-5° C. Methane sulfonyl chloride (6.76 g, 0.1086 mole) was then added dropwise over a period of 30 minutes and the mixture was maintained at 0-5° C. for 2 hrs. The reaction mixture was then diluted with cold water and the product extracted with ethyl acetate. The ethyl acetate layer was washed with 1N aqueous HCl solution, followed by saturated aqueous sodium bicarbonate solution and brine solution. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 13.59 g (98%) of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 5.0-4.9 (m, 1H), 3.8-3.6 (m, 2H), 3.4-3.2 (m, 2H), 3.0 (s, 3H), 2.04-1.9 (m, 2H), 1.9-1.74 (m, 2H), 1.5-1.42 (s, 9H).

Provenance & Evidence