2,5-Dibromothiophene → (4R*,5R*)-5-[(1S*)(5-bromo(2-thienyl))hydroxymethyl]-1-methyl-4-phenylpyrrolidin-2-one

Participants

Reaction Steps

To a −78° C. solution of 2,5-dibromothiophene (7.2 g, 29.6 mmol, 1.02 equiv) in anhyd. THF (100 mL) was added dropwise a solution of n-BuLi (1.6M in hexane, 18.5 mL, 29.6 mmol, 1.02 equiv) keeping the reaction temperature below −70° C. The resulting brown solution was stirred for 2.5 h. A solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 5.9 g, 29.1 mmol) in benzene (30 mL) was added, keeping the reaction temperature below −70° C. The reaction mixture was diluted with THF (30 mL) and after 30 min was treated with a saturated NH4Cl solution (150 mL). The resulting mixture was extracted with EtOAc (200 mL) and CH2Cl2 (2×200 mL) and dried (Na2SO4). The combined organic layers were concentrated under reduced pressure. The crude product was triturated (MeOH) to give (±)-(4R*,5R*)-5-[(1S*)(5-bromo(2-thienyl))hydroxymethyl]-1-methyl-4-phenyl-pyrrolidin-2-one (6.2 g) as a white solid. The filtrate was treated with silica gel (15 g), concentrated under reduced pressure and purified by flash chromatography to afford an additional 0.92 g of product (total 7.12 g, 67%) as an off-white solid: TLC (60% EtOAc/hex) Rf 0.39; 1H NMR (CDCl3) δ 2.24 (dd, J=6.2, 15.1 Hz, 1H), 2.42 (s, 3H), 2.95 (t, J=13.8 Hz, 1H), 3.76-3.85 (m, 1H), 4.15 (d, J=8.0 Hz, 1H), 4.36 (d, J=4.5 Hz, 1H), 6.06 (d, J=5.6 Hz, 1H), 6.70-7.15 (m, 1H), 7.02 (dd, J=1.9, 4.0 Hz, 1H), 7.22-7.44 (m, 5H).

Provenance & Evidence