Copper-Catalyzed Kinetic Resolution of 1,3-Cyclohexadiene Monoepoxide with Grignard Reagents

Abstract

Chiral ferrocenyl-based diphosphines lead to kinetic ­resolution of 1,3-cyclohexadiene monoepoxide with moderate to good enantioselectivity (up to 90% ee) and good regioselectivity with various Grignard reagents through an anti-S_N2′ pathway.

Key words

epoxides - asymmetric synthesis - Grignard reagents - catalysis - copper

References and Notes

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12

Et₂O is purified by filtration over Al₂O₃, whereas MTBE has to be distilled over Na/benzophenone.

13

Typical Procedure: In a dried Schlenk tube under N₂ atmosphere were placed CuBr (1.4 mg, 0.01 mmol) and (R,S)-L11 (7.0 mg, 0.011 mmol). Et₂O was added (6 mL) and the mixture was stirred at r.t. for 20 min. The tube was cooled to -78 °C and 1,3-cyclohexadiene monoepoxide (1; 100 µL, 1 mmol) was added. BuMgCl (250 µL, 2.0 M in Et₂O, 0.5 mmol) was added dropwise over a period of 3 min. The reaction was stirred for 1 h and quenched with MeOH and (NH₄)₂SO₄ before being allowed to reach r.t. The aqueous phase was extracted with Et₂O and the organic layers were dried over Na₂SO₄ and the solvent was removed on a rotary evaporator (45% conversion, 90% ee). The crude was poured in Ac₂O (1 mL, 10 mmol) in the presence of Et₃N (100 µL) and DMAP (a few mg). The mixture was stirred overnight at r.t. The reaction was quenched with MeOH (100 µL) and diluted with Et₂O (5 mL). The organic phase was washed with 1 M NaOH (1 mL) and the aqueous phase with Et₂O (2 × 1 mL). The organic layer was dried over Na₂SO₄ and the solvent was removed on a rotary evaporator. The crude residue was purified by flash chromatography on silica gel (cyclohexane-EtOAc 19:1) yielding the pure product (69 mg, 35% yield). ¹H NMR (400 MHz, CDCl₃): δ = 5.79 (m, 1 H), 5.58 (m, 1 H), 5.28 (m, 1 H), 2.08 (m, 1 H), 2.05 (s, 3 H), 1.87 (m, 1 H), 1.56 (m, 1 H), 1.30 (br, 7 H), 0.89 (t, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171, 136.9, 125.9, 77.2, 35.4, 35.1, 29.2, 27.7, 26.5, 22.9, 21.5, 14.0. [α]_D ²⁰ -167° (c = 15.2, CHCl₃, ee = 90%).