Sodium Hydroxide → 4-Amino-1-Boc-piperidine

Participants

Reaction Steps

Ammonium formate (300 mg, 4.8 mmol) was added to a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 1.2 mmol) in methanolic ammonia (2.5 mL) followed by 10% Pd/C (50 mg) and stirring was continued at room temperature overnight. The above mixture was filtered through celite, filtrate was collected, and concentrated under reduced pressure to furnish a crude residue. The residue was treated with 2N aqueous NaOH solution, extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure to afford 200 mg (83% yield) of (4-amino-piperidine-1-carboxylic acid tert-butyl ester. Titanium isopropoxide (756 mg, 2.66 mmol) was added to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (293 mg, 1.46 mmol) and adamantan-2-one (200 mg, 1.33 mmol) in EtOH (5 mL) and stirring was continued at room temperature overnight. NaBH4 (100 mg, 2.64 mmol) was added in portionwise and the resulting mixture was stirred at room temperature for 10 hrs. The reaction mixture was quenched with 2N aqueous NH3 solution and filtered. The filtrate was extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure The residue was purified by column chromatography (using neutral alumina and 20% EtOAc in hexane as eluent) to afford 420 mg (94.4% Yield) of 4-(adamantan-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (300 MHz, CDCl3): δ 4.0 (s, 2H), 2.9-2.4 (m, 4H), 2.0-1.6 (m, 9H), 1.7 (s, 4H), 1.6-1.5 (d, 4H), 1.45 (s, 9H), 1.35-1.2 (m, 3H). A mixture of 4-(adamantan-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (420 mg, 1.25 mmol) in dioxane.HCl (20 mL) was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure to get the residue, which was washed with ether to afford 363 mg (93.8% Yield) of 4-(adamantan-2-ylamino)-piperidine dihydrochloride. 1H NMR (300 MHz, DMSO-d6): δ 9.2 (s, 1H), 9.0 (s, 3H), 3.8 (s, 4H), 3.5-3.3 (m, 4H), 3.0-2.8 (m, 2H), 2.4 (d, 2H), 2.3 (d, 3H), 2.0 (t, 2H), 1.9-1.8 (m, 5H), 1.7 (s, 2H), 1.6-1.5 (d, 2H).

Provenance & Evidence