Thiourea-Catalyzed Asymmetric Michael Addition of Activated Methylene Compounds to α,β-Unsaturated Imides:  Dual Activation of Imide by Intra- and Intermolecular Hydrogen Bonding

Abstract

A thiourea-catalyzed asymmetric Michael addition of activated methylene compounds to alpha,beta-unsaturated imides derived from 2-pyrrolidinone and 2-methoxybenzamide has been developed. In the case of 2-pyrrolidinone derivatives, the reaction with malononitrile proceeded in toluene with high enantioselectivity, providing the Michael adducts in good yields. However, the nucleophiles that could be used for this reaction were limited to malononitrile due to poor reactivity of the substrate. Further examination revealed that N-alkenoyl-2-methoxybenzamide was the best substrate among the corresponding benzamide derivatives bearing different substituents on the aromatic ring. Indeed, several activated methylene compounds such as malononitrile, methyl alpha-cyanoacetate, and nitromethane could be employed as a nucleophile to give the Michael adducts in good to excellent yields with up to 93% ee. The results of spectroscopic experiments clarified that this enhanced reactivity can be attributed to the intramolecular hydrogen-bonding interaction between the N-H of the imide and the methoxy group of the benzamide moiety. Thus, the key to the success of the catalytic enantioselective Michael addition is dual activation of the substrate by both intramolecular hydrogen bonding in the imide and intermolecular hydrogen bonding with thiourea 1a, as well as the activation of a nucleophile by the tertiary amine of the bifunctional thiourea.

Development of Chiral Thiourea Catalysts and Its Application to Asymmetric Catalytic Reactions

“…Although the catalyst efficiently accelerated a variety of asymmetric reactions such as Michael addition, aza-Henry reaction, Mannich reaction, and hydrazination as a result of dual activation of electrophile and nucleophile, [81][82][83][84][85][86][87][88][89][90] the scope of suitable nucleophiles for catalysts 2a was mainly limited to active methylene compounds. We therefore turned our attention toward the development of new catalysts having coordinating or chelating functionality, which might activate metallic nucleophiles.…”

“…In this review, we provide a comprehensive overview of our recent studies on bifunctional thiourea-mediated asymmetric nucleophilic reactions. [81][82][83][84][85][86][87][88][89][90] …”

Organocatalytic Michael–Alkylation Cascade: The Enantioselective Nitrocyclopropanation of Oxindoles

“…The use of a bifunctional catalyst capable of simultaneously activating the oxindole and halonitroalkane was fundamental; it is well established that thioureas are excellent activators of the imide moiety through hydrogen bonds, [11] whereas tertiary amines efficiently promote the conjugate addition of bromonitroalkanes to suitable Michael acceptors. [9b, 12] Therefore, we focused our attention on catalysts 1 a-1 d, which incorporate these functionalities within their structures.…”

Organocatalysis in Enantioselective α‐Functionalization of 2‐Cyanoacetates

“…[20] Michael addition of methyl 2-cyanoacetate to aliphatic imides in toluene at room temperature and in the presence of 10 mol% of the organocatalyst led to the corresponding Michael adducts as a 60/40 mixture of diastereoisomers with high yield and high enantioselectivity. With aromatic imides the reaction at room temperature was very slow and it was necessary to increase the temperature up to 80 8C.…”