l-Proline-Catalyzed Asymmetric Michael Addition of 2-Oxindoles to Enones: A Convenient Access to Oxindoles with a Quaternary Stereocenter

Abstract

A new organocatalytic approach for 1,4-conjugate addition of 2-oxindoles to α,β-unsaturated ketones using the combination of readily available and nonexpensive l-proline and achiral trans-2,5-dimethylpiperazine as catalytic system is provided. The reaction results in oxindole derivatives with vicinal quaternary and tertiary carbon centers in up to 99% yield and 91% ee.

l-proline - organocatalysis - 2-oxindoles - quaternary stereocenters - Michael addition

References and Notes

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9

We also introduced defined amounts of H₂O into the reaction system while using CHCl₃ as solvent, with negative results. An increase in the reaction time was observed with increasing amounts of H₂O, accompanied by a decrease in the enantioselectivity.

10

Besides, when both the proline and additive loadings were reduced, a somewhat decreased enantioselectivity was observed, along with increased reaction time.

11

General Procedure To a suspension of l-proline (0.3 equiv) and trans-2,5-dimethylpiperazine (1 equiv) in CHCl₃ (c _base = 0.2 M) 2-oxindole (1 equiv) was added, followed by the α,β-unsatured ketone (1 equiv). The reaction mixture was stirred at ambient temperature, until the conversion was judged complete by TLC, and transferred directly to purification by column or flash chromatography (over SiO₂). For more details, see Supporting Information.