Isopropyl chloroformate → 1-methylethyl 4-[(1R)-1-hydroxyethyl]-1-piperidinecarboxylate

Participants

Reaction Steps

A solution of (1R)-1-(4-piperidinyl)ethanol acetic acid salt (1 g, 5.28 mmol) in water (10 mL) was cooled to 0° C. in an ice bath. A solution of K2CO3 (3.65 g, 26.4 mmol) in water (8 mL) was added, followed by dropwise addition of isopropyl chloroformate (1M in toluene, 21.1 mL, 21.1 mmol). The reaction mixture was stirred from 0° C. to ambient temperature over 2 h, then at ambient temperature overnight, diluted with CH2Cl2 (100 mL), washed with 1N HCl, water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give a brown oil, which was dissolved in MeOH (15 mL). K2CO3 (1 g, 7.24 mmol) and water (5 mL) were added, and the mixture was stirred at ambient temperature overnight and extracted with CH2Cl2. The organic extracts were combined and washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give 1.11 g (98%) of 1-methylethyl 4-[(1R)-1-hydroxyethyl]-1-piperidinecarboxylate as a colorless oil, which was used without further purification (% ee not determined). 1H NMR (400 MHz, CDCl3): δ 4.88 (septet, 1H, J=6.2 Hz), 4.25-4.10 (m, 2H), 3.60-3.50 (m, 1H), 2.75-2.60 (m, 2H), 1.85-1.75 (m, 1H), 1.65-1.55 (m, 1H), 1.50-1.35 (m, 1H), 1.25-1.10 (m, 11H).

Provenance & Evidence