Organocatalytic Enantioselective Michael Reaction of Aminomaleimides with Nitroolefins Catalyzed by Takemoto’s Catalyst

Known as electrophiles, maleimides are often used as acceptors in Michael additions to produce succinimides. However, reactions with maleimides as nucleophiles for enantioselective functionalization are only rarely performed. In this paper, a series of bifunctional Takemoto’s catalysts were used to organocatalyze the enantioselective Michael reaction of aminomaleimides with nitroolefins. The resulting products were obtained in good yields (76–86%) with up to 94% enantiomer excess (ee). The catalyst type and the substrate scope were broadened using this methodology.

In 2021, Mori's group first reported asymmetric Michael addition of α-aminomaleimides as Michael donors to β-nitroolefins using Cinchona alkaloid as the organocatalyst [31]. Furthermore, density functional theory (DFT) was employed in research to improve the enantioselectivity of the adduct and to reveal the mechanism of stereochemistry. Through DFT calculation, the author predicted that increasing the size of the N substituent of the maleimide could be favorable for stereo control. As expected, the ee value was significantly increased by 16% when N-Me was substituted with an N-i Bu group of the α-aminomaleimide in this asymmetric reaction.

Results and Discussion
We first applied the Takemoto-type catalysts 1a-1h in the Michael reaction of α-aminomaleimide (2a) and β-nitrostyrene (3a) to screen the optimal catalyst. According to the optimized condition reported [31], the reaction was carried out with Et2O as a solvent in the presence of 10 mol% of catalysts at r.t. (Table 1). All catalysts proceeded the reaction smoothly to give the desired product 4a in 69-78% yields with moderate to high enantioselectivities. Among of them, (R,R)-thiourea catalyst 1c was optimal in terms of the yield and enantioselectivity (entry 3). When the thiourea moiety in catalysts 1c was substituted with squareamide moiety in catalyst 1d, the similar stereoselectivity was afforded (entry 4 vs. entry 3). Additionally, N, N-dimethyl tertiary amine of 1c was changed to the steric bulk moieties in catalysts 1e-1h, led to reduction both in the yields and ees (entries 5-8 vs. entry 3). Therefore, N, N-dimethyl tertiary amine proved to be crucial. Although the optical rotation values of the products were not reported in the literature, it indicated that quinine catalyzed the reaction to obtain S configuration of the major product [31]. Therefore, we repeated a quinine-catalyzed Michael reaction of α-aminomaleimide 2a and β-nitrostyrene 3a to obtain the S-adduct 4a (entry 9). Then, the optical rotation data of two products from quinine-or 1c-induced reaction were determined with MeOH as solvent to afford two negative values (entries 3 and 9). Accordingly, the configuration of the major product catalyzed by 1c was proved to be S.

Results and Discussion
We first applied the Takemoto-type catalysts 1a-1h in the Michael reaction of αaminomaleimide (2a) and β-nitrostyrene (3a) to screen the optimal catalyst. According to the optimized condition reported [31], the reaction was carried out with Et 2 O as a solvent in the presence of 10 mol% of catalysts at r.t. (Table 1). All catalysts proceeded the reaction smoothly to give the desired product 4a in 69-78% yields with moderate to high enantioselectivities. Among of them, (R,R)-thiourea catalyst 1c was optimal in terms of the yield and enantioselectivity (entry 3). When the thiourea moiety in catalysts 1c was substituted with squareamide moiety in catalyst 1d, the similar stereoselectivity was afforded (entry 4 vs. entry 3). Additionally, N,N-dimethyl tertiary amine of 1c was changed to the steric bulk moieties in catalysts 1e-1h, led to reduction both in the yields and ees (entries 5-8 vs. entry 3). Therefore, N,N-dimethyl tertiary amine proved to be crucial. Although the optical rotation values of the products were not reported in the literature, it indicated that quinine catalyzed the reaction to obtain S configuration of the major product [31]. Therefore, we repeated a quinine-catalyzed Michael reaction of α-aminomaleimide 2a and β-nitrostyrene 3a to obtain the S-adduct 4a (entry 9). Then, the optical rotation data of two products from quinine-or 1c-induced reaction were determined with MeOH as solvent to afford two negative values (entries 3 and 9). Accordingly, the configuration of the major product catalyzed by 1c was proved to be S. and enantioselective reactions [33][34][35][36][37][38][39][40]. In this paper, we offer the first reports on the enantioselective Michael addition of α-aminomaleimides and nitroolefins by employing Takemoto-type catalysts 1a-1h bearing (thio)urea or squareamide moiety ( Figure 1).

Results and Discussion
We first applied the Takemoto-type catalysts 1a-1h in the Michael reaction of α-aminomaleimide (2a) and β-nitrostyrene (3a) to screen the optimal catalyst. According to the optimized condition reported [31], the reaction was carried out with Et2O as a solvent in the presence of 10 mol% of catalysts at r.t. (Table 1). All catalysts proceeded the reaction smoothly to give the desired product 4a in 69-78% yields with moderate to high enantioselectivities. Among of them, (R,R)-thiourea catalyst 1c was optimal in terms of the yield and enantioselectivity (entry 3). When the thiourea moiety in catalysts 1c was substituted with squareamide moiety in catalyst 1d, the similar stereoselectivity was afforded (entry 4 vs. entry 3). Additionally, N, N-dimethyl tertiary amine of 1c was changed to the steric bulk moieties in catalysts 1e-1h, led to reduction both in the yields and ees (entries 5-8 vs. entry 3). Therefore, N, N-dimethyl tertiary amine proved to be crucial. Although the optical rotation values of the products were not reported in the literature, it indicated that quinine catalyzed the reaction to obtain S configuration of the major product [31]. Therefore, we repeated a quinine-catalyzed Michael reaction of α-aminomaleimide 2a and β-nitrostyrene 3a to obtain the S-adduct 4a (entry 9). Then, the optical rotation data of two products from quinine-or 1c-induced reaction were determined with MeOH as solvent to afford two negative values (entries 3 and 9). Accordingly, the configuration of the major product catalyzed by 1c was proved to be S. To further improve the enantioselectivity of the transformation, a screened catalyst 1c was applied to the Michael reaction of α-aminomaleimide 2a and β-nitrostyrene 3a under the different conditions (Table 2). First, a variety of solvents were investigated. All the reactions proceeded smoothly in the screened solvent. It is noteworthy that aprotic solvents were suitable for the reaction to give 85-93% ees (entries 1-8), while protic MeOH was unfavorable for asymmetric induction (entry 9). Among them, toluene was optimal in terms of the yield and enantioselectivity (entry 7). When the reaction temperature was lowered from r.t. to 0 • C, an improved ee of 93% was afforded (entry 10 vs. entry 7). With further temperature decreases to −10 • C and −20 • C, both enantioselectivities were increased by 1%, but showed significantly lower yields (entries 11, 12 vs. entry 10). Therefore, 0 • C was regarded to be the most suitable reaction temperature. When reducing the catalyst loading to 5 mol%, the enantioselectivity was maintained at an excellent level, but with a relatively low yield (entry 13 vs. entry 10), and 20 mol% loading offered no improvement in the asymmetric induction, albeit with a slightly improved yield (entry 14 vs. entry 10). Furthermore, diluting the reaction concentration by half was detrimental for yield and enantiocontrol (entry 15 vs. entry 10). Adding 4 Å molecular sieves (MS) led to a slightly higher ee value of 94% and increased yield (entry 16 vs. entry 10). Based on these experiments, the optimized conditions were determined to be toluene as the solvent with a 10 mol% loading of catalyst 1c in the presence of 4Å MS (200 mg) at 0 • C.
With the optimized conditions in hand, we explored the scope and general applicability of the protocol. A wide range of substituted α-aminomaleimides and β-nitroolefins were evaluated as shown in Table 3.
All of the substrates reacted smoothly to give the corresponding products in high yields (76-86%) with good ees (81-94%). Therefore, the stereoselectivities were barely affected by the type and position of the substituents on α-aminomaleimide. However, the substituent and position on the β-nitrostyrene was found to have influence on the enantioselectivity. It can be seen that the 2-Br substituent on phenyl of nitrostyrene led to slightly decreased ee values (entries 4,18). Compared with the data of the reported literature listed in parentheses (Table 3) [31], our screened catalyst system showed similar enantioselectivities in most reactions. Exceptionally, in the reaction with N-Bn substituted maleimide as Michael donor, a markedly increased ee value was obtained (entry 17), while in the reaction with β-nitro-1-naphthalene ethylene as Michael acceptor, 10% reduction in enantioselectivity was observed (entry 12) in this paper. To extend the type of Michael acceptor in the reaction of α-aminomaleimide as donor, we tried unsaturated carbonyl compounds such as methyl cinnamate 5 and chalcone 6 to substitute the β-nitroolefin. Surprisingly, neither reaction occurred under the screened condition (Scheme 1). Table 3. Generality of the enantioselective Michael reaction of α-aminomaleimides with β-nitroolefins a .
Molecules 2022, 27, x FOR PEER REVIEW 4 of 12 mized conditions were determined to be toluene as the solvent with a 10 mol% loading of catalyst 1c in the presence of 4Å MS (200 mg) at 0 °C. With the optimized conditions in hand, we explored the scope and general applicability of the protocol. A wide range of substituted α-aminomaleimides and β-nitroolefins were evaluated as shown in Table 3. All of the substrates reacted smoothly to give the corresponding products in high yields (76-86%) with good ees (81-94%). Therefore, the stereoselectivities were barely affected by the type and position of the substituents on α-aminomaleimide. However, the substituent and position on the β-nitrostyrene was found to have influence on the enantioselectivity. It can be seen that the 2-Br substituent on phenyl of nitrostyrene led to slightly decreased ee values (entries 4,18). Compared with the data of the reported literature listed in parentheses (Table 3) [31], our screened catalyst system showed similar enantioselectivities in most reactions. Exceptionally, in the reaction with N-Bn substituted maleimide as Michael donor, a markedly increased ee value was obtained (entry 17), while in the reaction with β-nitro-1-naphthalene ethylene as Michael acceptor, 10% reduction in enantioselectivity was observed (entry 12) in this paper. To extend the type of Michael acceptor in the reaction of α-aminomaleimide as donor, we tried unsaturated carbonyl compounds such as methyl cinnamate 5 and chalcone 6 to substitute the Based on the obtained absolute configuration described above and the previo reported enantioselective Michael addition of α-aminomaleimide 2a and β-nitrosty 3a [31], a proposed transition-state model is depicted in Scheme 2. β-nitrostyrene 3 oriented and activated by the thiourea moiety through hydrogen bonding and the group in 2a is deprotoned and oriented by the tertiary amine of catalyst 1c through Based on the obtained absolute configuration described above and the previously reported enantioselective Michael addition of α-aminomaleimide 2a and β-nitrostyrene 3a [31], a proposed transition-state model is depicted in Scheme 2. β-nitrostyrene 3a is oriented and activated by the thiourea moiety through hydrogen bonding and the NH group in 2a is deprotoned and oriented by the tertiary amine of catalyst 1c through another hydrogen bonding. Then, the reaction proceeds with a Se-face addition of α-aminomaleimide to β-nitrostyrene, affording the desired product S-4a. Scheme 1. Michael reaction of α-aminomaleimide 2a with unsaturated carbonyl compounds.
Based on the obtained absolute configuration described above and the previo reported enantioselective Michael addition of α-aminomaleimide 2a and β-nitrosty 3a [31], a proposed transition-state model is depicted in Scheme 2. β-nitrostyrene oriented and activated by the thiourea moiety through hydrogen bonding and the group in 2a is deprotoned and oriented by the tertiary amine of catalyst 1c through other hydrogen bonding. Then, the reaction proceeds with a Se-face additio α-aminomaleimide to β-nitrostyrene, affording the desired product S-4a. Scheme 2. Proposed stereochemical model.

Chemistry
The 1 H NMR spectra were recorded on a 500 MHz for 1 H and at 125 MHz for NMR, using CDCl3 as a solvent. The chemical shifts were reported in ppm, and th sidual nondeuterated solvent (CHCl3) as internal standard (7.26 and 77.0 ppm, res tively). The splitting patterns of the signals were reported as s, singlet; d, doublet; t plet; q, quartet; dd, doublet of doublets; m, multiplet. High-resolution mass spe (HRMS) were measured on a triple TOF 5600+ mass spectrometer equipped wit electrospray ionization (ESI) source in the negative-ion mode. The enantiomeric ex (ee) values of the products were determined through chiral HPLC, using Daicel ralpak IA columns (4.6 mm × 250 mm). The optical rotation values were determined ing an automatic polarimeter. The reactions were monitored by thin layer chroma raphy (TLC). Purifications by column chromatography were conducted over silica (200-300 mesh). The organocatalysts 1a-1h were purchased from Daicel Chiral T nologies (China) Co.

General Procedure for the Enantioselective Michael Reaction of α-Aminomaleimides and β-Nitrostyrenes
Scheme 2. Proposed stereochemical model.

Chemistry
The 1 H NMR spectra were recorded on a 500 MHz for 1 H and at 125 MHz for 13 C NMR, using CDCl 3 as a solvent. The chemical shifts were reported in ppm, and the residual nondeuterated solvent (CHCl 3 ) as internal standard (7.26 and 77.0 ppm, respectively). The splitting patterns of the signals were reported as s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; m, multiplet. High-resolution mass spectra (HRMS) were measured on a triple TOF 5600+ mass spectrometer equipped with an electrospray ionization (ESI) source in the negative-ion mode. The enantiomeric excess (ee) values of the products were determined through chiral HPLC, using Daicel Chiralpak IA columns (4.6 mm × 250 mm). The optical rotation values were determined using an automatic polarimeter. The reactions were monitored by thin layer chromatography (TLC). Purifications by column chromatography were conducted over silica gel (200-300 mesh). The organocatalysts 1a-1h were purchased from Daicel Chiral Technologies (China) Co.

Conclusions
In summary, we described the first Takemoto-type catalyst to promote the enantioselective Michael addition of α-aminomaleimides and β-nitroolefins. The α-aminomaleimides were used as nucleophiles rather than electrophiles in this transformation to create the desired maleimide-containing adducts with high enantioselectivity (up to 94% ee). Moreover, we used our optimized conditions to expand upon the substrate scope of this reaction. Further study of α-aminomaleimides as donors in Michael additions with other acceptors is under way.