Butyl vinyl ether → 3-(4-Acetyl-phenyl)-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester

Participants

Reaction Conditions

Reaction Steps

In 100 mL autoclave vessel, a solution of 3-(4-bromo-phenyl)-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (Intermediate from Step 5a; 5 g, 15.142 mmol, 1 eq) in ethanol (17.5 mL) was degassed with nitrogen gas for 30 minutes at room temperature. TEA (3.79 mL, 27.256 mmol, 1.8 eq), butyl vinyl ether (BVE, 3.91 mL, 30.282 mmol, 2 eq), 1,3-bis(diphenylphosphino)propane (DPPP, 0.375 g, 0.909 mmol, 0.06 eq) were added followed by addition of Pd(OAc)2 (0.102 g, 0.454 mmol, 0.03 eq.) at room temperature. Resulting reaction mixture was heated at 96° C. for 16 hours in an autoclave. After complete consumption of starting material, the reaction mixture was quenched with 1N HCl (5 mL, pH˜2-3) and stirred for 2 hours at room temperature. After 2 hours, the pH of reaction mixture was adjusted to 7 by addition of saturated NaHCO3 solution and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (250 mL), dried over sodium sulphate and concentrated under reduced pressure to get crude compound as dark brown sticky oil (6.1 g, Crude). Crude compound was purified by column chromatography on silica gel using 230-400 silica mesh. Desired compound was eluted in 10% ethyl acetate in n-hexane to give product as off white semisolid (2.56 g, 57.66%). 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 9H), 2.61 (s, 3H), 4.20 (dd, J1=0.88 Hz, J2=10.28 Hz, 1H), 4.24 (dd, J1=0.92 Hz, J2=10.36 Hz, 1H), 4.39 (dd, J1=1.28 Hz, J2=10.24 Hz, 1H), 4.44 (dd, J1=1.28 Hz, J2=10.20 Hz, 1H), 7.55 (dd, J1=1.48 Hz, J2=8.48 Hz, 2H), 8.00 (d, J=7.96 Hz, 2H), LC-MS (m/z): 294.1 (M+H).

Provenance & Evidence