Hydrochloric Acid → Ether hydrochloride

Participants

Reaction Conditions

Reaction Steps

To a solution of 1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-one (160 mg; 0.66 mmol) in methanol (20 mL) was added ammonium acetate (5.08 g; 100 equivalent) and NaCNBH3 (332 mg; 5.28 mmol). The mixture was heated to 60° C. and stirred for 2 hours. The reaction mixture was cooled to 10° C., and acidified with 1 N HCl (6 mL) taking care that the flask was vented into a bleach solution due to HCN evolution. The reaction mixture was concentrated at 30° C., and the resulting aqueous layer was diluted with H2O (10 mL). The aqueous layer was then extracted with ethyl acetate (15 mL) to remove nonpolar impurities. The aqueous layer was then adjusted to pH 9 with 1N NaOH, and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to an oily residue. The oil was then dissolved in diethyl ether (5 mL), and the HCl salt was formed by slowly adding HCl/diethyl ether solution (0.5 mL). The slurry was stirred for 30 minutes before filtration. The solids were rinsed with diethyl ether (5 mL) and the compound was quickly transferred to a vacuum dessicator and dried under vacuum for 12 hours to afford a white solid (146 mg; 80%). 1H NMR (400 MHz, Methanol-d4) δ ppm 0.99-1.04 (t, 2 H) 1.24-1.30 (m, 1 H) 1.77-1.89 (m, 3 H) 2.08-2.19 (m, 2H) 2.58-2.78 (m, 3H) 3.97-4.03 (m, 1H) 7.08-7.17 (m, 1 H) 7.32-7.45 (m, 2 H). 13C NMR (100 MHz, Methanol-d4) δ ppm 17.34 (s, 1 C) 24.74 (s, 1 C) 24.92 (s, 1 C) 27.10 (s, 1 C) 32.34 (s, 1 C) 33.18 (s, 1 C) 34.55 (s, 1 C) 36.46 (s, 1 C) 39.32 (s, 1 C) 53.20 (s, 1 C) 125.92 (s, 1 C) 126.41 (s, 1 C) 128.58 (s, 1 C) 130.31 (s, 1 C) 132.01 (s, 1 C) 144.75 (s, 1 C). MS (M+1) 242, HPLC purity 99% (AUC).

Provenance & Evidence