Copper-Catalysed Kinetic Resolution of Cyclic Alkenyl Cyclopropane Malonates with Organoaluminium and Grignard Reagents

Abstract

We report herein the first copper-catalysed kinetic resolution of alkenyl cyclopropane malonates with organoaluminium and Grignard reagents. The conjugate products were exclusively obtained on five- and six-membered-ring substrates. After optimization of the reaction conditions, we observed good conversions and enantiomeric excesses using ferrocene-based ligands on five-membered-ring substrates, and phosphoramidite ligands on six-membered rings.

Key words

kinetic resolution - alkenyl cyclopropane malonates - conjugate addition - Grignard reagents - copper

References and Notes

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16

General Procedure (Chiral Version): In a dried Schlenk tube flushed under nitrogen, was placed the copper catalyst (0.04 mmol) and the specified ligand (0.08 mmol). Anhydrous CH₂Cl₂ (1 mL) was then added and the mixture was stirred at room temperature for 15 min. The Schlenk tube was then placed in a bath at -78 ˚C, and the indicated Grignard reagent (1 equiv) was added. The starting material (1 mmol), solubilised in the indicated solvent (0.5 mL), was added dropwise. The mixture was stirred for 4 h at this temperature. Aq HCl (1N, 1 mL) was added and the reaction was allowed to warm to r.t. The organic layer was separated and the aqueous phase was extracted with Et₂O. The organic phases were dried over MgSO₄ and the solvent was evaporated under reduced pressure. The crude compound was purified by chromatography on silica gel (cyclohexane-Et₂O, 70:30) and the product was isolated as an oil.
Dimethyl 2-(4-ethylcyclopent-2-enyl)malonate (4b): ^¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, J = 7 Hz, 3 H), 1.25-1.45 (m, 2 H), 1.69-1.81 (m, 2 H), 2.62 (br s, 1 H), 3.25 (m, 1 H), 3.36 (br s, 1 H), 3.73 (s, 6 H), 5.62 (d, J = 5 Hz, 1 H), 5.79 (d, J = 5 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 169.4, 169.3, 137.8, 130.9, 57, 52.6, 46.5, 45.2, 34.4, 28.6, 12.3.
Dimethyl 2-(4-ethylcyclohex-2-enyl)malonate (5b): ^¹H NMR (400 MHz, CDCl₃): δ = 0.89 (t, J = 7 Hz, 3 H), 1.20-1.35 (m, 4 H), 1.82-1.95 (m, 3 H), 2.86 (br s, 1 H), 3.24 (d, J = 9 Hz, 1 H), 3.75 (s, 6 H), 5.46 (m, 1 H), 5.64-5.66 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 169.2, 169.1, 134.5, 127.1, 57.1, 52.6, 37.2, 36.4, 29.0, 28.3, 26.9, 11.4.