Diastereo‐ and Enantioselective Conjugate Addition of α‐Substituted Cyanoacetates to Maleimides Catalyzed by Binaphthyl‐based Thiourea

Abstract

The Michael addition reaction is widely recognized as one of the most efficient and powerful methods for the C-C bonds formation in organic synthesis.1 To date, various asymmetric Michael addition reactions have been developed.2 Chiral α-cyanoacetates bearing a quaternary stereogenic center are an important class of substrates that serve as precursors of the highly functionalized chiral compounds such as amino acids and amino alcohols with simple functional group transformation.3 Recently, organocatalytic enantioselective conjugate addition reactions of α-substituted cyanoacetates with various Michael acceptors have been reported. 4 Until now, there are a few reports for the catalytic conjugate addition of α-substituted cyanoacetates to maleimides using organocatalysts.5 Although these methods are satisfyingly efficient in some extent, new organocatalytic conjugate addition of α-substituted cyanoacetates to maleimides is highly desired.As part of our research program related to the development of synthetic methods for the enantioselective construction of stereogenic carbon centers, 6 we recently reported the asymmetric Michael addition reactions of active methines using chiral catalysts.7 Herein, we wish to describe the conjugate addition of α-substituted cyanoacetates with maleimide promoted by binaphthyl-based organocatalysts.To determine suitable reaction conditions for the catalytic enantioselective Michael addition of α-substituted cyanoacetates, we initially investigated the reactions with N-phenylmaleimide (2a) in the presence of 10 mol % binaphthyl-based organocatalysts I-IV bearing both central and axial chiral elements ( Figure. 1). As shown in Table 1, binaphthyl-based (thio)urea catalysts I-III effectively promoted the reaction in toluene with high enantioselectivities (entries 1-3, Table 1). Replacement of urea function with squaramide (catalyst IV) slightly decreased the enantioselectivity (entry 4, - Table 1), and the highest enantioselectivities obtained with the binaphthyl-based thiourea catalyst II. For further improvement of selectivity, different solvents were then tested in the presence of 10 mol % of catalyst II. Aprotic solvents such as toluene, benzene, diethyl ether, THF, and dichloromethane were well tolerated in this Michael addition without a significant decrease of enantioselectivities (76-96% enantiomeric excesses [ee], entries 2 and 5-9, Table 1). Among the solvents probed, toluene provided the best results (79% yield, 9:1 dr, 96% ee, entry 2, Table 1). The present catalytic system tolerates catalyst loading down to 5 mol %, and both the yields and enantioselectivities were retained (entries 4 and 10-11, Table 1).With the optimized conditions in hand, we proceeded to investigate the scope of the enantioselective conjugate addition of various α-substituted cyanoacetates 1 and N-phenylmaleimide (2a) in the presence of 5 mol % of binaphthylbased thiourea-tertiary amine catalyst II in toluene at room temperature. The results of conjugate addition reaction are summarized in Table 2. A ra...

Recent Advancement on the Organocatalyzed Asymmetric Conjugate Addition using Maleimide as a Potential Substrate

“…In 2015, Kim et al developed chiral trans-cyclohexane-1,2diamine based binaphthyl attached thiourea catalyst 1 o as an efficient catalyst for the asymmetric conjugate addition of αsubstituted cyanoacetates 55 with maleimides 3 (Scheme 37). [54] The products 56 were obtained by using 5 mol % of the catalyst loading in very high yields, diastereoselectivities and enantioselectivities (up to 97 % yield, 20 : 1 d.r., 98 % ee). It is presumed that the reaction proceeded via the activation of maleimides through the hydrogen bonding with NÀ H of thiourea unit and enolized cyanoacetates with tertiary amine group.…”