Pyrrolidine → (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate

Participants

Reaction Steps

To a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (50.64 g, 220.9 mmol) in anhydrous tetrahydrofuran (552 mL) at 2° C. was added 1,1′-carbonyldiimidazole (77.59 g, 460 mmol). The mixture was stirred at room temperature for 2 h, cooled to 10° C. and then pyrrolidine (74 mL, 890 mmol) was added slowly. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and water (200 mL) was added to the residue. The mixture was extracted with ethyl acetate (2×). The combined organics were washed with aqueous hydrochloric acid (200 mL×4, 1N) and with a saturated aqueous solution of sodium bicarbonate (200 mL×2). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate as a white solid (58.82 g). The compound was used for the next step without further purification. 1H NMR (400 MHz, CD3OD) δ 1.39-1.54 (m, 10H) 1.59-1.65 (m, 1H) 1.67 (d, 1H) 1.69-1.77 (m, 1H) 1.80-2.05 (m, 5H) 2.58 (tt, 1H) 2.77 (br s, 1H) 3.33-3.46 (m, 2H) 3.51-3.66 (m, 2H) 3.98-4.12 (m, 2H); MS (AP+) (M+H) 283.3.

Provenance & Evidence