Asymmetric Michael Addition of Arylthiols to α,β-Unsaturated Carbonyl Compounds Catalyzed by Bifunctional Organocatalysts

Abstract

Bifunctional chiral organocatalysts comprising thiourea and tertiary amine groups were synthesized. They act as efficient catalysts for asymmetric Michael addition of arylthiols to α,β-unsaturated carbonyl compounds. Enantioselectivity up to 85% has been achieved. Asymmetric α-protonation reaction (up to 60% ee) can be obtained in the presence of the bifunctional catalyst.

bifunctional organocatalyst - thiourea - hydrogen bonding - asymmetric Michael addition - asymmetric protonation

References

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HRMS data of new organocatalysts: 1a, 564.1770 (calcd 564.1782); 1b, 564.1781 (calcd 564.1782); 1f, 501.1853 (calcd 501.1861); 1g, 701.1728 (calcd 701.1734).

15

General Experimental Procedure for ( S , S )-1d-Catalyzed Asymmetric Michael Addition. Phenylthiol (12 µL, 0.11 mmol) was added to the stirred solution of α,β-unsaturated imide 7a (25.1 mg, 0.1 mmol) and 1d (4.2 mg, 0.01 mmol) in 0.5 mL CH₂Cl₂ at -40 °C. The reaction was stirred for 72 h. Flash chromatography eluting with petroleum ether-EtOAc (10:1) gave the product as a white solid (35.3 mg, 98%). ¹H NMR (400 MHz, CDCl₃): δ = 9.47 (s, NH), 7.78-7.76 (m, 2 H), 7.62-7.59 (m, 1 H), 7.51-7.47 (m, 2 H), 7.36-7.32 (m, 4 H), 7.29-7.19 (m, 6 H), 4.85 (dd, J = 1.6, 8.4 Hz, 1 H), 3.77 (dd, J = 8.4, 15.6 Hz, 1 H), 3.62 (dd, J = 8.4, 15.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.3, 165.6, 140.8, 133.9, 133.3, 133.1, 132.4, 128.9, 128.8, 128.4, 127.8, 127.7, 127.6, 127.4, 48.2, 43.8. ESI-MS: m/z = 360.1 [M - H]^-; ee was determined by HPLC on Daicel Chiralcel OD (20% 2-propanol in hexane, 0.5 mL/min, t _S = 10.8 min, t _R = 12.1 min, 75% ee).

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18

The absolute configuration was determined by the rotation after conversion to ethyl ester.^8c