Highly Enantioselective Organocatalytic Michael Addition of Ketones to Nitroolefins in the Presence of Water

Abstract

Chiral pyrrolidine-based organocatalysts, in combination with ionic-liquid-supported Brønsted acids, catalyze the enantioselective Michael addition of ketones and aldehyde to nitroolefins in high yields with high enantioselectivities (ee ≤ 96%) and diastereoselectivities (syn/anti ratio ≤ 98:2). This novel process provides synthetically useful γ-nitrocarbonyl compounds, which can be easily transformed into other invaluable precursors of biologically active compounds. In addition, the synthetic procedure presented is simple and practical.

Key words

organocatalysts - asymmetric synthesis - Michael addition - ketones - nitroolefins

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• 18 Typical Procedure for the Asymmetric Michael Addition To a solution of the amine catalyst 1e ¹⁹ (8.5 mg, 0.04 mmol) and ILS sulfonic acid 3a ²⁰ (16.4 mg, 0.04 mmol) in H₂O (0.8 mL) was added ketone (2.0 mmol) at r.t. The reaction mixture was stirred for 20 min, and then nitroolefin (0.4 mmol) was added. The reaction mixture was stirred until complete conversion of the nitroolefin (monitored by TLC) and then extracted with CH₂Cl₂ (2 × 2 mL). The combined organic phase was concentrated under vacuum to give the crude residue, which was purified by flash column chromatography (silica gel, hexane–EtOAc) to afford the Michael adduct 5. The syn/anti ratio was determined by ¹H NMR spectroscopy of the crude mixture and the ee was determined by chiral HPLC. Analytic Data of 5a ¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.22 (m, 3 H), 7.17 (d, J = 7.2 Hz, 2 H), 4.95 (dd, J = 12.4, 4.4 Hz, 1 H), 4.64 (dd, J = 12.4, 10.0 Hz, 1 H), 3.77 (dt, J = 14.4, 4.8 Hz, 1 H), 2.74–2.64 (m, 1 H), 2.54–2.33 (m, 2 H), 2.14–2.04 (m, 1 H), 1.83–1.50 (m, 4 H), 1.30–1.18 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 211.9, 137.7, 128.9, 128.2, 127.8, 78.9, 52.5, 43.9, 42.7, 33.2, 28.5, 25.0. HPLC (Chiralpak AD-H, i-PrOH–hexane = 10:90, flow rate = 0.5 mL/min, λ = 254 nm): t _R (minor) = 19.4 min; t _R (major) = 24.7 min; ee = 92%.
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