Acetone cardice → Di-tert-butyl 3,3'-carbonylbis(azetidine-1-carboxylate)

Participants

Reaction Steps

n-BuLi (1.60 M in hexane, 0.752 mL, 0.12 mmol) was added dropwise under argon to a slurry of 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (51.8 mg, 0.12 mmol, Intermediate 12: step d) in diethyl ether (0.8 mL) at ˜−70° C. with stirring. The grey slurry was immediately transferred to an ice bath for ˜30 seconds at which point a homogeneous dark amber solution formed. The reaction was then immediately transferred back to the dry ice/acetone bath and after stirring for 2 minutes was treated with a solution of di-tert-butyl 3,3′-carbonylbis(azetidine-1-carboxylate) (42.7 mg, 0.125 mmol, Intermediate 85: step b) in toluene (0.4 mL) over 50 seconds. After 5 minutes stirring at ˜−70° C., the reaction was removed from the cold bath and stirred under ambient conditions for 1 minute and then transferred to an ice bath and stirred for 30 minutes. The homogeneous yellow reaction was then quenched with 5 M aqueous NH4Cl (0.035 mL), diluted with EtOAc (3 mL), dried (Na2SO4), filtered, and concentrated. The residue was flash chromatographed (0-100% EtOAc in heptane over 16 column volumes) to provide a 65/35 mol fraction ratio of the title compound/di-tert-butyl 3,3′-carbonylbis(azetidine-1-carboxylate) as a thick yellow oil. This mixture was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=2.02 Hz, 1H), 7.83 (d, J=8.59 Hz, 1H), 7.58 (dd, J=2.02, 9.09 Hz, 1H), 7.51 (d, J=8.59 Hz, 2H), 7.40 (d, J=8.08 Hz, 2H), 4.36 (s, 2H), 4.03-4.16 (m, 5H), 3.92 (t, J=8.59 Hz, 2H), 3.54-3.67 (m, 4H), 3.11-3.21 (m, 2H), 1.39 (s, 18H); MS m/e 692.2 [M+H]+.

Provenance & Evidence