Enantioselective Organocatalytic Conjugate Addition of Aromatic Ketones to Nitrodienes

Abstract

The organocatalytic asymmetric nitro-Michael addition of aromatic ketones to nitrodiene using various chiral primary amine thioureas was described. In the presence of 30 mol% of N-[(1R,2R)-2-amino-1,2-diphenylethyl]-N′-benzylthiourea, the Michael adducts were obtained in good yields and excellent enantio­selectivity (94-98% ee).

Key words

organic asymmetric catalysis - aromatic ketones - nitro-Michael additions - nitrodiene - chiral bifunctional thiourea

References and Notes

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All reactions were conducted in solvent (2 mL) using nitrodiene 2a (0.2 mmol) and acetophenone 3a (1 mmol, 5 equiv) in the presence of 10 mol% of catalyst 1d. Results of different solvent: toluene (30% yield, 97% ee), n-hexane (25% yield, 92% ee), i-PrOH (18% yield, 85% ee), EtOH (5% yield, 88% ee), CH₂Cl₂ (15% yield, 97% ee), CHCl₃ (16% yield, 97% ee), THF (5% yield, 95% ee), Et₂O (17% yield, 96% ee).

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General Procedure for Enantioselective Conjugate Addition of Ketone with Nitrodiene
Organocatalyst 1d (43.32 mg, 0.12 mmol) was added to a vial containing acetophenone 3 (4 mmol) and toluene (2 mL) at r.t. The mixture was stirred vigorously for 10 min, and then the corresponding nitrodiene 2 (0.4mmol) was added. The reaction mixture was stirred at r.t. for 96 h. Then the solvent was evaporated, and the residue was purified by flash silica gel chromatography (PE-EtOAc, 10:1) to afford the corresponding product. The ee value was determined by chiral HPLC.
Characterization Data of Representative Compounds Compound 4a: 63% yield, 97% ee, [a]_D ^²0 +3.5 (c 1.0, CHCl₃). HPLC analysis [Chiralpak AD-H column, l = 254 nm, hexane-i-PrOH (90:10), flow rate 1.0 mL/min]: t _R = 16.0 min(major), 18.4 min(minor). ^¹H NMR (500 MHz, CDCl₃): d = 7.96 (d, J = 7.8 Hz, 2 H), 7.61-7.58 (m, 1 H), 7.50-7.47 (m, 2 H), 7.34-7.28 (m, 4 H), 7.25-7.23 (m, 1 H), 6.58 (d, J = 15.8 Hz, 1 H), 6.17 (dd, J = 15.8, 7.6 Hz, 1 H), 4.74-4.70 (m, 1 H), 4.64-4.60 (m, 1 H), 3.76 (m, 1 H), 3.30 (d, J = 6.3 Hz, 2 H). IR (film): n = 2958, 2918, 2850, 1679, 1542, 1450, 1410, 1379, 1365, 1271, 1218, 969, 758, 691 cm^-¹. HRMS: m/z calcd for C₁₈H₁₇NO₃ [M]: 295.1208; found: 295.1210.