Reaction Steps
A stirred mixture of 1,2,5,6-hexahydrophthalic anhydride (0.77 grams, 5.0 mmol), methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride (1.38 grams, 5.0 mmol), and sodium acetate (0.40 grams, 4.9 mmol) in 20 mL of acetic acid under N2 was heated to reflux for 20 hours. The cooled reaction mixture was concentrated in vacuo and the residue diluted with 25 mL of methylene chloride and then 25 mL of sat. sodium bicarbonate was added in portions and the resulting mixture stirred for 30 minutes. The organic phase was separated, dried (sodium sulfate), and concentrated to afford the crude product as an oil. The crude product was purified by flash chromatography (silica gel, 1/9 EtOAc/hexanes) to afford 0.72 grams (38%) of methyl 3-(cis-hexahydrophthalimido)-3-(3,4-dimethoxyphenyl)propionate as an off-white solid (wax): mp 92.5°-95° C.; 1H NMR (CDCl3 /TMS) δ 7.02 (m, 2H, Ar), 6.65 (m, 1H, Ar), 5.56 (dd, J=5.5, 10.5 Hz, 1H CHN), 3.86 (2 s, 6H, 2 OCH3), 3.74 (dd, J=16.5, 10.5 Hz, 1H), 3.66 (s, 3H, OCH3), 3.08 (dd, J=5.5, 16.5 Hz, 1H, CHCO), 2.77 (m, 2H, bridgehead Hs), 1.87-1.55 (m, 4H), 1.5-1.2 (m, 4H); 13C NMR (CDCl3 /TMS) δ 179.5, 179.4, 171.1, 148.9, 148.8, 130.9, 120.1, 111.0, 110.9, 55.9, 55.8, 51.8, 51.0, 39.6, 35.2, 23.6, 23.5, 21.6; TLC (1/9 EtOAc/hexanes, UV) Rf =0.36. Anal. Calcd for C20H25NO6. Theory C, 63.99; H, 6.71; N, 3.73. Found C, 63.89; H, 6.81; N, 3.61.
