Asymmetric Direct Michael Reactions of Cyclohexanone with Aromatic Nitroolefins in Water Catalyzed by Novel Axially Unfixed Biaryl-Based Bifunctional Organocatalysts

Abstract

A new family of axially unfixed biaryl-based water-compatible bifuctional organocatalysts were designed and synthesized for the asymmetric direct Michael reaction of cyclohexanone with various nitroolefins in water. One of the organocatalysts incorporates pyrrolidine and arylsulfonamide motifs as active organocatalytic sites, and axially unfixed biaryl as a skeleton; with this organocatalyst, the direct Michael reactions proceeded readily, furnishing the desired Michael adducts in high yields (up to 99% yield) with high levels of stereocontrol (up to >99:1 dr and 94% ee).

Key words

biaryl compounds - aqueous chemistry - organocatalysts - asymmetric Michael reaction - stereoselectivity

• References and Notes


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• 9 Asymmetric Michael Addition; General Procedure: A suspension of catalyst 2a (4.2 mg, 0.01 mmol), PhCO₂H (1.2 mg, 0.01 mmol) and cyclohexanone (104 μL, 1.0 mmol) in water (0.5 mL) was stirred at r.t. for 30 min. Nitroolefin (0.1 mmol) was added and the mixture was stirred for the time indicated in the tables. The mixture was extracted with CH₂Cl₂ (2 × 5 mL) and the organic layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo. A mixture of syn- and anti-Michael products was obtained through flash chromatography on silica gel (petroleum–EtOAc, 5:1). The dr and ee values were determined by chiral HPLC analysis [Chiralcel AS-H; hexane–2-propanol, 85:15; 1.0 mL/min; λ = 210 nm; t_R = 13.91 (minor), 23.41 (major) min]. (S)-2-[(R)-2-Nitro-1-phenylethyl]cyclohexanone (Table 2, entry 1): Reaction time: 12 h. Yield: 85%; dr = 97:3 (syn/anti); ee = 89% (syn).¹H NMR (400 MHz, CDCl₃): δ = 7.28–7.32 (m, 3 H), 7.16–7.17 (m, 2 H), 4.94 (dd, J = 12.4, 4.0 Hz, 1 H), 4.60–4.66 (m, 1 H), 3.76 (d, J = 4.0 Hz, 1 H), 2.69 (s, 1 H), 2.38–2.49 (m, 2 H), 2.07 (d, J = 3.2 Hz, 1 H), 1.55–1.80 (m, 4 H), 1.19–1.28 (m, 1 H).