Iodine → 2-Methoxy-pyrrolidine-1-carboxylic acid benzyl ester

Participants

Reaction Steps

To a solution of (S)-(−)-N-benzyloxycarbonylproline (10 g, 40 mmol) in CH2Cl2 (500 mL) was added iodobenzene diacetate (26 g, 80 mmol, 2.0 equiv) and iodine (5.2 g, 20 mmol, 0.50 equiv). The resulting mixture was stirred at rt for 5 h. Methanol (20 mL) was added and the reaction mixture was stirred at rt for 1.5 h. The reaction was then quenched by the addition of 10% Na2S2O3 (200 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic extracts were washed with 10% Na2S2O3 (200 mL), brine (200 mL), dried (Na2SO4) and concentrated under reduced pressure to give the crude product (28 g) as a yellow oil. Purification by flash chromatography (silica gel, 10-30% EtOAc/hexane) provided the expected product (9.41 g, 77%) as a yellow oil along with the corresponding hydroxy product (8.85 g, 11%) as a white solid: mp 44-46° C. The hydroxy product could subsequently be quantitatively recycled to the desired methoxy compound by treatment with pyridinium p-toluene sulfonate (PPTS) in MeOH at rt for 20 h. Data for step 1 compound: HPLC (Phenominex 4.6×50 mm) retention time 2.94 min; LC/MS m/z 236 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.27-7.39 (m, 5H), 5.15-5.29 (m, 3H), 3.52 (td, 1H, J=8.8, 1.3 Hz), 3.32-3.48 (m, 3H), 3.26 (s, 1H), 1.99-2.15 (m, 1H), 1.84-1.98 (m, 2H), 1.67-1.82 (m, 1H). Data for compound 3: LC/MS m/z 222 [M+H]+; 1 H NMR (CDCl3, 400 MHz) δ 7.30-7.40 (m, 5H), 5.47-5.55 (m, 1H), 5.15 (s, 2H), 3.55-3.65 (m, 1H), 3.30-3.42 (m, 1H), 1.78-2.02 (m, 4H).

Provenance & Evidence