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Article

(±)-trans-1,2-Cyclohexanediamine-Based Bis(NHC) Ligand for Cu-Catalyzed Asymmetric Conjugate Addition Reaction

by
Azusa Ishibashi
,
Shun Kamihigashi
,
Yuuki Iwai
and
Satoshi Sakaguchi
*
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan
*
Author to whom correspondence should be addressed.
Catalysts 2019, 9(9), 780; https://doi.org/10.3390/catal9090780
Submission received: 31 August 2019 / Revised: 12 September 2019 / Accepted: 16 September 2019 / Published: 19 September 2019
(This article belongs to the Special Issue Transition Metal Complexes as Catalysts in Organic Chemistry)
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Abstract

:
Bis(NHC) ligand precursors, L1, based on trans-1,2-diaminocyclohexane were designed and synthesized. To introduce chirality at the hydroxyamide side arm on the NHC of L1, a chiral β-amino alcohol, such as enantiopure leucinol, was used. Cu-catalyzed asymmetric conjugate addition reactions of cyclic and acyclic enones with Et2Zn were selected to evaluate the performance of L1 as a chiral ligand. For the reaction of cyclic enone, a combination of [bis(trimethylsilyl)acetylene]-(hexafluoroacetylacetonato)copper(I) (Cu(hfacac)(btmsa)) with a (±)-trans-1,2-cyclohexanediamine-based bis(NHC) ligand precursor, (rac; S,S)-L1, which was prepared from (S)-leucinol, was the most effective. Thus, treating 2-cyclohexen-1-one (3) with Et2Zn in the presence of catalytic amounts of Cu(hfacac)(btmsa) and (rac; S,S)-L1 afforded (R)-3-ethylcyclohexanone ((R)-4) with 97% ee. Similarly, use of (rac; R,R)-L1, which was prepared from (R)-leucinol, produced (S)-4 with 97% ee. Conversely, for the asymmetric 1,4-addition reaction of the acyclic enone, optically pure (−)-trans-1,2-cyclohexanediamine-based bis(NHC) ligand precursor, (R,R; S,S)-L1, worked efficiently. For example, 3-nonen-2-one (5) was reacted with Et2Zn using the CuOAc/(R,R; S,S)-L1 catalytic system to afford (R)-4-ethylnonan-2-one ((R)-6) with 90% ee. Furthermore, initially changing the counterion of the Cu precatalyst between an OAc and a ClO4 ligand on the metal reversed the facial selectivity of the approach of the substrates. Thus, the conjugate addition reaction of 5 with Et2Zn using the Cu(ClO4)2/(R,R; S,S)-L1 catalytic system, afforded (S)-6 with 75% ee.

Graphical Abstract

1. Introduction

Synthesizing efficient chiral ligands for asymmetric catalysis is currently a major challenge in synthetic organic chemistry [1,2,3,4]. In recent years, N-heterocyclic carbenes (NHCs) have become recognized as versatile ligands [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. There have been several recent reports on chiral bis(NHC) ligands (Figure 1) [26,27,28,29,30].
Douthwaite et al. synthesized a chiral bis(NHC)-Pd(II) complex from optically pure trans-1,2-diaminocyclohexane [31,32]. In 2003, Shi et al. developed a bidentate axially chiral bis(NHC)-Rh(III) complex [33]. They succeeded in creating a large variety of asymmetric transformations by using this versatile chiral ligand [34,35,36,37,38,39,40,41,42,43,44,45,46,47]. Nagel et al. showed the enantioselective transfer hydrogenation of ketones catalyzed by Rh(I) and Ir(I) complexes derived from (S)-valinol [48,49]. Iglesias and Sánchez et al. reported the asymmetric hydrogenation of alkenes with bis(NHC) derived from tartaric acid [50,51]. A chiral palladium allyl complex bearing bis(NHC)/cyclophane ligand for 1,4-addition of phenylboronic acid to 2-cyclohexen-1-one was synthesized by Veige et al. [52,53].
To the best of our knowledge, there are two bis(NHC) ligands based on chiral trans-1,2-diaminocyclohexane for asymmetric catalytic transformations (Figure 1). Herrmann and Kühn et al. demonstrated the enantioselective hydrogenation of alkenes catalyzed by Rh(I) complexes derived from 1,2,4-triazole and [54,55]. Zhang et al. reported asymmetric catalytic Suzuki–Miyaura couplings employing a bis(NHC)-Pd(II) complex [56,57,58,59]. However, the appearance of an efficient asymmetric catalytic system using a chiral bis(NHC) ligand remains rare.
Introducing an appropriate hemilabile chiral donor group at the NHC side arm provides a chelating NHC-based ligand [60,61,62,63,64,65,66,67]. As part of our research program on developing chiral NHC ligand precursors, we have reported a Cu-catalyzed enantioselective conjugate addition reaction of enone with Et2Zn, using a chiral hydroxyamide-functionalized azolium ligand precursor [68,69,70,71,72,73,74,75,76]. Much attention has been given to the 1,4-addition reaction [77,78,79,80]. We previously synthesized a new chiral azolium salt, (rac; S,S)-L1, which serves as a bis(NHC) ligand precursor [81]. The (rac; S,S)-L1 was prepared by using (±)-trans-1,2-diaminocyclohexane ((rac)-1) and (S)-leucinol ((S)-2) (Scheme 1). Thus, (rac; S,S)-L1 was obtained as a 1:1 diastereoisomeric mixture and used for the catalytic asymmetric reaction. Importantly, a highly enantioselective Cu-catalyzed conjugate addition reaction of cyclic enone with dialkylzinc in the presence of (rac; S,S)-L1 was successfully achieved [81].
However, the 1,4-addition reaction employing the bis(NHC) ligand precursor derived from an optically active trans-1,2-diaminocyclohexane (1) remains unclarified. In this paper, we show the synthesis of the corresponding bis(NHC) ligand precursor L1 from a single enantiomer of trans-1,2-diaminocyclohexane ((‒)-1 or (+)-1). Systematic studies on the catalytic asymmetric 1,4-addition reaction using this promising class of enantiomerically pure bis(NHC) ligand are described.

2. Results and Discussion

2.1. Catalytic Asymmetric Conjugate Addition Reaction of Cyclic Enone

Enantiomerically pure L1 was synthesized from enantiopure trans-1,2-diaminocyclohexane ((R,R)-1 or (S,S)-1) [81]. To introduce chirality at the hydroxyamide side arm at L1, we chose (S)-leucinol ((S)-2) or (R)-leucinol ((R)-2) as a chiral source. In this study, we wanted to determine the influence of the chirality of the cyclohexanediamine skeleton of L1 on the catalytic asymmetric transformation. Thus, four sets of bis(NHC) azolium ligands were synthesized (Scheme 2).
The previously reported bis(NHC) azolium ligand (rac; S,S)-L1 consists of a 1:1 diastereoisomeric mixture of (R,R; S,S)-L1 and (S,S; S,S)-L1 (Scheme 1) [81]. With a set of diastereomerically and enantiomerically pure azolium salts in hand (Scheme 2), we performed an NMR study of these compounds (Figure 2, Figure 3 and Figure 4). Initially, temperature dependence was observed in the 1H NMR spectrum of the bis(NHC) azolium precursor (Figure 2). For example, 1H NMR signals of (R,R; R,R)-L1 at 25 °C were extremely broad, indicating that several conformers, slowly interconverting on the NMR timescale, were present at room temperature. Conversely, increasing the temperature (to 80 °C) provided sharp, well-defined signals in the NMR spectra (Figure 2). Thus, a fully assignable NMR spectrum was obtained.
Furthermore, the methyl group signals of the isobutyl substituent in the 1H NMR spectra of a series of azolium salts L1 was considered. Figure 3 shows the expanded spectra of the methyl group regions of (rac; S,S)-L1, (R,R; S,S)-L1 and (S,S; S,S)-L1. Their C-H resonances appeared at δ = 0.87/0.82 ppm (J = 6.9 Hz) for (R,R; S,S)-L1 and δ = 0.88/0.83 ppm (J = 6.9 Hz) for (S,S; S,S)-L1. Thus, the methyl group signals in (rac; S,S)-L1 could be assigned, as shown in Figure 3.
Similarly, in the 13C NMR spectrum of (rac; S,S)-L1, two signals were observed in the methine carbon adjacent to the isobutyl substituent (Figure 4). This is because of the presence of a diastereoisomeric mixture. The 13C NMR spectra of the diastereoisomerically pure isomers revealed that the signal at δ 48.6 ppm could be attributed to the methine carbon on (R,R; S,S)-L1 and that at δ 48.5 ppm, it could be attributed to the methine carbon on (S,S; S,S)-L1.
To test the performance of the chiral bis(NHC) ligand precursors L1, the conjugate addition reaction of 2-cyclohexen-1-one (3) with Et2Zn catalyzed by [bis(trimethylsilyl)acetylene](hexafluoro-acetylacetonato)copper(I) (Cu(hfacac)(btmsa)), combined with L1, was examined (Table 1).
In our previous publication, we briefly described a highly stereoselective transformation that was achieved using (rac; S,S)-L1 [81]. Thus, the reaction of 3 with Et2Zn in the presence of catalytic amounts of Cu(hfacac)(btmsa) and (rac; S,S)-L1 in THF at room temperature afforded (R)-3-ethylcyclohexanone ((R)-4) in 99% yield, with excellent enantioselectivity (97% ee) (Table 1, entry 2). We then investigated the 1,4-addition reaction using the diastereomerically and enantiomerically pure ligand. Notably, use of (R,R; S,S)-L1 in place of (rac; S,S)-L1 under these reaction conditions resulted in a lower yield (57%) of (R)-4 with poor enantioselectivity (16% ee) (entry 1). As with (R,R; S,S)-L1, a combination of Cu(hfacac)(btmsa) and (S,S; S,S)-L1 led to (R)-4 in 34% yield with 26% ee (entry 3).
Next, we synthesized (rac; R,R)-L1, (S,S; R,R)-L1 and (R,R; R,R)-L1 (Scheme 2). Clearly, the Cu-catalyzed 1,4-addition reaction of 3 with Et2Zn in the presence of (rac; R,R)-L1 afforded (S)-4 with 97% ee (Table 1, entry 5). Conversely, it was difficult to obtain the desired 1,4-adduct, (S)-4, with high yield and enantioselectivity by using (S,S; R,R)-L1 or (R,R; R,R)-L1 (entries 4 and 6). These results strongly suggest that the chirality of the hydroxyamide side arm plays a critical role in the asymmetric 1,4-addition reaction of 3 with Et2Zn.
It is noteworthy that the asymmetric catalytic 1,4-addition reaction occurred efficiently when using a 1:1 mixture of (R,R; S,S)-L1 and (S,S; S,S)-L1 ((rac; R,R)-L1). To highlight the importance of both components in the catalytic reaction, we then varied the ratio of (R,R; S,S)-L1 and (S,S; S,S)-L1 (Table 2).
We carefully prepared various mixtures of (R,R; S,S)-L1 and (S,S; S,S)-L1 (with (R,R; S,S)-L1/(S,S; S,S)-L1 ratios of 10:0, 9:1, 8:2, 6:4, 5:5, 4:6, 2:8, 1:9 and 0:10). Notably, 3 was reacted with Et2Zn catalyzed by Cu(hfacac)(btmsa) in the presence of a 9:1 mixture to afford (R)-4 in 94% yield with 89% ee (Table 2). Use of (R,R; S,S)-L1 alone resulted in poor enantioselectivity (16% ee) of (R)-4. The best result (99% yield, 97% ee) was obtained at the 5:5 ratio. Furthermore, surprisingly, the yield and stereoselectivity of the 1,4-addition reaction using a 1:9 mixture were comparable to those obtained by using a 9:1 mixture. These results suggest that the presence of a small amount of each component of these two chiral ligands is enough to achieve an optimum asymmetric catalytic performance. This will be discussed later (vide infra; see Table 3).
The same experiment was conducted using (S,S; R,R)-L1 and (R,R; R,R)-L1 to provide (S)-4 in the Cu-catalyzed reaction of 3 with Et2Zn (Table 2). In a similar manner, a 9:1 or 1:9 mixture facilitated the highly enantioselective conjugate addition reaction to afford (S)-4 with 90% or 94% ee, respectively. These results confirm the importance of the presence of both stereoisomers of the cyclohexanediamine moiety in the chiral ligands for reaction efficiency and stereoselectivity.
The relationship between the catalyst ee and the product ee was also investigated (Figure 5). Various mixtures of (rac; S,S)-L1 and (rac; R,R)-L1 were carefully prepared. The enantioselective conjugate addition reaction of cyclic enone 3 with Et2Zn provided sufficient chiral amplification (Figure 5).
As shown in Table 2, we have clearly demonstrated that a 9:1 or 1:9 mixture of (R,R; S,S)-L1 and (S,S; S,S)-L1 promotes the enantioselective catalytic reaction. These reactions were performed in the presence of 6.0 mol % of Cu salt and 4.5 mol % of the chiral ligand mixtures. We assumed that an excess of (R,R; S,S)-L1 would not be needed in the catalytic reaction with a 9:1 mixture of (R,R; S,S)-L1 and (S,S; S,S)-L1 and that a small amount of a 1:1 mixture of these ligands, with respect to the Cu precatalyst, would be sufficient to facilitate the catalytic reaction. This assumption prompted us to study the asymmetric 1,4-addition reaction of 3 with Et2Zn catalyzed by Cu(hfacac)(btmsa), with a reduced amount of the chiral ligand mixtures (Table 3).
As expected, the 1,4-addition reactions with Cu/ligand ratios of 1:0.75, 1:0.3, 1:0.225, and 1:0.15 occurred in a similar manner to afford the corresponding adduct with 97%, 93%, 96%, and 97% ee, respectively (entries 1–4). These results indicate that the same catalytic active species were probably formed. It is also noteworthy that the loading of chiral ligand could be dramatically reduced.
No reaction was observed in the absence of L1. Additionally, two bis(NHC) ligands, L2 and L3, were synthesized to investigate the effect of the ligand structure on the catalytic performance. Changing the alkyl substituent at the chiral carbon center of the ligand from the isobutyl group ((rac; S,S)-L1) to the more sterically hindered tert-butyl group (L2) led to the conjugate adduct, (S)-4, in lower yield and enantioselectivity with the opposite configuration (Table 3, entry 6). This might be due to the highly hindered tert-butyl group blocking the approach of the reagents. Furthermore, L3 was synthesized from 1-aminoethanol. However, it was difficult to react 3 with Et2Zn in the presence of Cu(hfacac)(btmsa) in combination with L3 (entry 7).
The catalytic performance of the Cu(hfacac)(btmsa)/(rac; R,R)-L1 system in the asymmetric 1,4-addition reaction of various cyclic enones was investigated, as described in our previous publication [81].

2.2. Catalytic Asymmetric Conjugate Addition Reaction of Acyclic Enone

In contrast to the conjugate addition reactions of organometallic compounds with cyclic enones, few highly enantioselective reactions of acyclic enones have been reported [71,82,83,84,85,86,87,88,89,90,91,92,93]. We then focused on studying the Cu-catalyzed asymmetric 1,4-addition reaction of acyclic enone with Et2Zn using this promising class of bis(NHC) chiral ligand L1.
In our previous publication, we briefly reported that 3-nonen-2-one (5) was reacted with Et2Zn catalyzed by Cu(hfacac)(btmsa) and (rac; S,S)-L1 at room temperature to afford (R)-4-ethylnonan-2-one ((R)-6) in 90% yield with moderate stereoselectivity (49% ee) (Table 4, entry 1) [81]. Replacing Cu(hfacac)(tmsa) with cyclooctadiene(hexafluoro-2,4-pentanedionato)copper(I) (Cu(hfacac)(cod)) improved the stereoselectivity (61% ee) of the 1,4-addition reaction (entry 2).
Encouraged by this success, we continued to test various Cu precatalysts for further reaction optimization (Table 4). Although the reaction was catalyzed by bis(hexafluoroacetylacetonato)-copper(II) (Cu(hfacac)2) and (rac; S,S)-L1 to afford (R)-6 with moderate enantioselectivity (53% ee), CuOCOCF3 did not work efficiently (entries 3 and 4). The promising result was achieved when the reaction was performed with CuOAc. Thus, the combination of CuOAc and (rac; S,S)-L1 catalyzed the reaction to furnish the corresponding adduct, (R)-6, in 78% yield and with 60% ee (entry 5). Despite achieving the same enantioselectivity (63% ee), Cu(OAc)2 decreased the product yield (entry 6).
Interestingly, during this study, we found that simply changing the copper catalyst precursor with the same ligand reversed the stereochemistry. The reaction of 5 with Et2Zn using the CuCl2/(rac; S,S)-L1 catalytic system afforded (R)-6 in 50% yield and with 39% ee (entry 7). In contrast, Cu(OTf)2 in place of CuCl2 led to the 1,4-adduct, (S)-6, with the opposite configuration with 33% ee (entry 8). Developing a synthetic methodology for switching enantioselectivity is an essential and challenging research topic. Recently, many papers have been published to provide a comprehensive overview of the importance of stereodivergent catalytic transformations [94,95,96,97,98,99,100].
Based on this finding, we decided to evaluate several Cu salts. CuOTf·0.5C6H6 and Cu(NO3)2 resulted in racemic 6 (Table 4, entries 9 and 10). Cu(ClO4)2 led to a marked increase in the enantioselectivity of the 1,4-addition reaction to provide (S)-6 as a major product (entry 11). Previously, we showed that the reversal of enantioselectivity was achieved in the Cu-catalyzed conjugate addition reaction of cyclic enone using a mono-NHC azolium ligand L4 with a chiral hydroxyamide side-arm (Figure 6) [76]. For example, 3 was reacted with Et2Zn catalyzed by Cu(OTf)2/L4 to afford (S)-4, whereas (R)-4 was obtained in the same reaction with the Cu(acac)2/L4 catalytic system [74]. However, no reversal of enantioselectivity was observed in the Cu-catalyzed 1,4-addition reaction of acyclic enone when changing the Cu precatalyst in the presence of L4 [71]. Therefore, to the best of our knowledge, this is the first example of switchable enantioselectivity in a catalytic conjugate addition reaction of acyclic enone, with the same chiral ligand.
The combination of transition metal complex and chiral ligand can provide a chiral environment for the metal, where high enantioselectivity requires only small differences in transition state energies in the catalytic reaction. The transition metal complex consists of a cationic metal and an achiral counter anion. While the chiral ligand design is critical to achieving a highly stereoselective catalytic reaction, the choice of the achiral counter anion of the transition metal complex is also an important factor. In the literature, it appears that changing the achiral counter anion of the metal catalyst precursor has sometimes switched the stereochemistry of the catalytic reaction [76,101,102,103,104,105,106,107].
Table 5 summarizes the switching of enantioselectivity in the asymmetric 1,4-addition reaction of 5 with Et2Zn catalyzed by CuOAc or Cu(ClO4)2 using the chiral bis(NHC) ligand precursor, (rac; S,S)-L1, under selected reaction conditions. To optimize the reaction conditions, various reaction parameters, including the ratio of Cu salt/chiral ligand, solvents and reaction temperatures were screened with CuOAc (entries 1–8) or Cu(ClO4)2 (entries 9–16). Further evaluations of the reaction parameters with both catalytic systems are presented in Tables S1 and S2, respectively (see Supplementary Materials).
In the CuOAc/(rac; S,S)-L1 catalytic system, a 1:1 ratio of Cu/ligand was most effective (entries 1–3). We thus investigated the solvent effect on the reaction in the presence of 4 mol% of a 1:1 mixture of CuOAc and (rac; S,S)-L1 (entries 3–5; also see Table S1). Although slightly lower enantioselectivity was observed in the catalytic reaction with Et2O, a promising result was achieved with 1,2-dimethoxyethane (DME) (entries 4 and 5). Furthermore, a decrease in the reaction temperature to 0 °C improved the enantioselectivity (73–78% ee), even though a longer reaction time was needed (entries 6 and 7). The desired product (R)-6 was obtained in 69% yield with 75% ee when the reaction was performed in DME at −10 °C for 48 h (entry 8). The facial selectivities of the 1,4-addition reaction using the Cu(ClO4)2/(rac; S,S)-L1 catalytic system were reversed, compared to those of the CuOAc-catalyzed reaction (Table 5, entries 9–17). Compound 5 was reacted with Et2Zn catalyzed by 6 mol% of Cu(ClO4)2 and 4.5 mol% of (rac; S,S)-L1 in THF at room temperature to afford (S)-6 in 31% yield with 50% ee (entry 9). Changing the Cu/ligand ratio from 6/4.5 to 4.5/6 decreased the ee value (entry 10). Therefore, the reaction was performed in the presence of a catalytic amount of Cu(ClO4)2/(rac; S,S)-L1 (6/3 mol%) to explore the effect of solvent (entries 11–13). Among the solvents examined, THF gave moderate enantioselectivity, providing (S)-6 with 46% ee (entry 11). Fortunately, performing the catalytic reaction at a lower temperature remarkably increased the stereoselectivity (entries 14–16). Thus, treatment of 5 with Et2Zn in the presence of Cu(ClO4)2 and (rac; S,S)-L1 in THF at 0 °C for 24 h produced (S)-6 in 89% yield with 70% ee (entry 14). Almost the same result was observed for the catalytic 1,4-addition reaction in DME at 0 °C for 24 h (entry 17).
In the Cu-catalyzed conjugate addition reaction of acyclic enone using the bis(NHC) ligand, we described successful enantioselectivity reversal by simply changing of the counter anion of the Cu salt. We then assumed that combining copper chloride with a silver salt facilitates the catalytic reaction and that a silver salt additive would control the setereoselectivity of the 1,4-addition reaction (Table 6).
First, we tested the reaction of 5 with Et2Zn catalyzed by CuCl (4 mol%) in the presence of (rac; S,S)-L1 (4 mol%). This reaction afforded (R)-6 in lower enantioselectivity, compared with the reaction using the CuOAc/(rac; S,S)-L1 catalytic system (entries 1 and 2). As expected, adding AgOAc (4 mol%) to the CuCl-catalyzed reaction led to a remarkable increase in the stereoselectivity (86% ee) (entry 3). This result was comparable to that of the CuOAc-catalyzed reaction, meaning that the acetate anion would play an important role through interaction with a copper ion having the (rac; S,S)-L1 ligand. Based on this assumption, an excess of AgOAc additive, with respect to the CuCl catalyst, was employed. The catalytic 1,4-addition reaction with a 1:1.5 molar ratio of CuCl/AgOAc provided (R)-6 in 54% yield with 85% ee, whereas a greater excess (8 mol%) of AgOAc decreased its catalytic activity (entries 4 and 5).
Next, to test the influence of AgClO4, the reaction of 5 with Et2Zn catalyzed by CuCl2 (6 mol%) in the presence of (rac; S,S)-L1 (3 mol%) was performed as a control experiment. As with the CuCl-catalyzed reaction, the combination of CuCl2 with (rac; S,S)-L1 produced (R)-6 (Table 6, entry 2 vs. entry 7). Interestingly, adding AgClO4 to this catalytic system dramatically affected the facial selectivity of the approach of the substrates to the Cu species. Thus, the reaction of 5 with Et2Zn in the presence of catalytic amounts of CuCl2 (6 mol%), (rac; S,S)-L1 (3 mol%), and AgClO4 (12 mol%) afforded (S)-6 in 93% yield with 68% ee (entry 8). This result was comparable to that of the Cu(ClO4)2-catalyzed reaction, as expected (entry 6 vs. entry 8). Using excess AgClO4 (15 mol%) did not drastically affect the outcome (entry 9). The reversal of enantioselectivity was also achieved in the CuCl2-catalyzed conjugate reaction, using half the amount of AgClO4 (6 mol%) (entry 10).
To evaluate the substrate scope and limitations of the developed catalytic reactions, several α,β-unsaturated enones were investigated (Table 7). The conjugate addition reaction of 5-methyl-3-hexen-2-one (7) with Et2Zn in the presence of catalytic amounts of CuOAc and (rac; S,S)-L1 yielded (S)-4-ethyl-5-methylhexan-2-one ((S)-8) with 69% ee (entry 3). In this reaction, a somewhat lower yield was probably due to steric hindrance in the substrate. In contrast, the 1,4-addition reaction of 7 catalyzed by Cu(ClO4)2 gave reversed enantioselectivity, affording (R)-8 in 44–59% yield with 80–82% ee (entries 4 and 5). Additionally, when 7 was allowed to react with Et2Zn using the combined catalytic system comprising Cu(ClO4)2 and the bis(NHC) azolium ligand having a tert-butyl group, (rac; S,S)-L2, (R)-8 was obtained, with satisfactory enantioselectivity (75% ee) (entry 6).
Switching of stereoselectivity was also observed in the 1,4-addition reaction of benzalacetone (9). Treatment of 9 with Et2Zn in the presence of catalytic amounts of CuOAc and (rac; S,S)-L1 afforded (S)-4-phenylhexan-2-one ((S)-10) in 55% yield and 63% ee (entry 7), whereas (R)-10 was obtained using Cu(ClO4)2 catalyst combined with the same ligand (entry 8). The results of the conjugate addition reaction of chalcone (11) differ from those for the reaction of 9. Although the CuOAc/(rac; S,S)-L1 system catalyzed the reaction of 11 with Et2Zn to produce (S)-1,3-diphenylpentan-1-one ((S)-12) with 55% ee (entry 9), the Cu(ClO4)2/(rac; S,S)-L1 catalytic system gave poor yield and stereoselectivity of (R)-12 (entry 10).
The performance of both catalytic systems for in the Cu-catalyzed conjugate addition of cyclic enone were evaluated (Table 7, entries 11 and 12). As mentioned above, we previously reported successful enantioselectivity reversal of the Cu-catalyzed 1,4-addition reaction of 3 with Et2Zn using the mono-NHC azolium ligand, L4 (Figure 6), by changing the Cu precatalyst from Cu(OTf)2 to Cu(acac)2 [76]. The bis(NHC) azolium ligand, (rac; S,S)-L1, was suitable for achieving the enantioselectivity switch in the 1,4-addition reaction of both acyclic and cyclic enones. The combination of CuOAc and (rac; S,S)-L1 catalyzed the reaction of 3 with Et2Zn to afford the corresponding adduct (R)-4 in 38% yield with 57% ee (entry 11). The facial selectivity of the 1,4-addition reaction using the Cu(ClO4)2/(rac; S,S)-L1 catalytic system was reversed compared to that of the reaction using CuOAc (entry 12).
As shown in Table 2, a mixture of (R,R; S,S)-L1 and (S,S; S,S)-L1 promoted the Cu-catalyzed conjugate addition reaction of cyclic enone with Et2Zn, and using (R,R; S,S)-L1 or (S,S; S,S)-L1 alone led to a poor stereoselectivity. Based on this finding, we next investigated the catalytic reaction of acyclic enone using a set of diastereomerically and enantiomerically pure azolium salts, (R,R; S,S)-L1 and (S,S; S,S)-L1 (Table 8).
Compound 5 was treated with Et2Zn in the presence of catalytic amounts of CuOAc and (R,R; S,S)-L1 in DME at 0 °C for 24 h to afford (R)-6 in good yield and stereoselectivity (79% yield, 88% ee, entry 1). This is in contrast to the catalytic reaction of cyclic enone, where the Cu/(R,R; S,S)-L1 catalytic system was inert (see Table 2). It is noteworthy that (R,R; S,S)-L1 showed a superior catalytic performance compared a diastereomeric mixture of ligands, such as (rac; S,S)-L1, in the 1,4-addition reaction of acyclic enone (entry 1 vs. entry 2). In contrast to the catalytic conjugate addition reaction of 5 using (R,R; S,S)-L1, the reaction using (S,S; S,S)-L1 proceeded, with difficulty, to produce the desired (R)-6 (17% yield and 48% ee, entry 3). These results suggest that (S,S; S,S)-L1 acts as a catalyst poison in the catalytic reaction with (rac; S,S)-L1. Additionally, an excellent ee value of 91% of (R)-6 was obtained in the conjugate addition reaction of 5 with Et2Zn using 4 mol% of CuOAc and 3 mol% of (R,R; S,S)-L1 (entry 4).
Next, in the switchable enantioselective reaction using Cu(ClO4)2 precatalyst to provide (S)-6, the performances of (R,R; S,S)-L1 and (S,S; S,S)-L1 were examined (Table 8, entries 5–7). With 6 mol% of Cu(ClO4)2, 3 mol% of chiral ligand containing (R,R; S,S)-L1 and/or (S,S; S,S)-L1 was employed in the conjugate addition reaction. These experiments showed the formation of the desired (S)-6 with almost the same yields and enantioselectivities (66–75% ee) in each of the catalytic reactions (entries 5–7). These results differed from those of the CuOAc/L1 catalytic system (entries 1–3). It could be assumed that the chiral hydroxyamide side arm of the bis(NHC) ligand would play an important role in the Cu(ClO4)2-catalyzed asymmetric conjugate addition reaction.
Finally, we highlighted the greater reactivity of the 1,2-diaminocyclohexane-based bis(NHC) ligand L1 compared with those of chiral ligands based on other bis(NHC) skeletons. We synthesized three chiral ligands L5, L6 and L7 from 1,2-diaminoethane, 1,3-diaminobenzene and 1,2-benzenedimethanamine, respectively (Table 9).
The reaction of 5 with Et2Zn catalyzed by CuOAc in the presence of 1,2-diaminoethane-based bis(NHC) ligand L5 provided the corresponding 1,4-adduct, (R)-6, in poor yield and stereoselectivity (entry 1). When the same reaction was conducted using the Cu(ClO4)2/L5 catalytic system, the enantioselectivity of the reaction was reversed, affording (S)-6 in 73% yield and 58% ee (entry 2). However, no reversal of enantioselectivity was observed in the catalytic reactions using 1,3-diaminobenzene-based chiral ligand L6 (entries 3 and 4). Additionally, treatment of 5 with Et2Zn catalyzed by CuOAc combined with 1,2-benzenedimethanamine-based ligand L7 gave an almost racemic mixture of conjugate adduct 6 (entry 5). Conversely, the Cu(ClO4)2/L7 catalytic system offered an efficient enantioselective protocol for the 1,4-addition reaction of 5 with Et2Zn to afford (S)-6 in 87% yield and 69% ee (entry 6). Based on the screening test using a series of bis(NHC) ligands, the 1,2-diaminocyclohexane-derived skeleton is critically important for successful enantioselectivity switching.

3. Experimental

3.1. General Procedures

All chemicals were obtained from commercial sources and were used as received. 1H and 13C NMR spectra were recorded on spectrometers at 400 and 100 MHz, respectively. Chemical shifts were reported in ppm relative to TMS for 1H and 13C NMR spectra. CDCl3 and (CD3)2SO were used as the NMR solvent. Thin-layer chromatography (TLC) analysis was performed with glass-backed plates, pre-coated with silica gel and examined under UV (254 nm) irradiation. Flash column chromatography was executed on silica gel 60 (230–400; particle size: 0.040–0.063 nm).

3.2. Procedure for Preparation of Azolium Salt L1

Azoles were synthesized from trans-1,2-cyclohexanediamine (1) according to the literature procedure [47,59]. The reaction mixture of azole (485 mg, 1.5 mmol) and α-chloroacetamide (580 mg, 3.0 mmol), derived from chloroacetyl chloride and luecinol, was heated to 110 °C and stirred for 2 days. After the reaction, the solvent was removed under reduced pressure. The desired product was isolated from the crude residue by column chromatography (SiO2, CH2Cl2/CH3OH = 8/2) to yield the light yellow solution after removing the solvent. The residue was dissolved in methanol, and then activated carbon (ca. 1 g) was added. After 3 h, the activated carbon was removed by filtration. After removing the CH3OH in vacuo from the filtrate, the azolium salt L1 was purified by reprecipitation using CH3OH and CH3CO2C2H5 affording white solid (yield: 710 mg, 62%). Compounds (rac; S,S)-L1, (rac; R,R)-L1, L5 and L6 were reported in our previous publication [81].
(R,R; S,S)-L1. White solid. 1H-NMR ((CD3)2SO, 400 MHz): δ 10.66 (s, 2H, NCHN), 8.60 (d, J = 8.2 Hz, 2H, NCCH), 7.94 (br, 2H, NH), 7.69 (d, J = 7.8 Hz, 2H, NCCH), 7.39–7.33 (m, 4H, NCCHCH), 5.81–5.79 (m, 2H, NCH), 5.31 (d, J = 16.0 Hz, 2H, NCH2CO), 5.23 (d, J = 16.0 Hz, 2H, NCH2CO), 4.69 (br, 2H, OH), 3.86–3.78 (m, 2H, NHCH)), 3.41 (br, 4H, CH2OH), 2.61 (br, 2H), 2.46–2.43 (m, 2H), 2.07–2.05 (m, 2H), 1.87–1.85 (m, 2H), 1.67–1.57 (m, 2H, CHiBu), 1.37 (t, J = 7.1 Hz, 4H, CH2iBu), 0.87 (d, J = 6.9 Hz, 6H, CH3iBu), 0.82 (d, J = 6.9 Hz, 6H, CH3iBu); 13C-NMR (100 MHz): δ 163.1 (CO), 142.5 (NCHN), 130.2, 129.9, 126.3, 126.2, 112.7 (NC), 112.4 (NC), 63.1 (CH2OH), 60.0 (CH2CO), 49.8 (NCH), 48.6 (NHCH), 39.5, 30.7, 23.9 (CH2iBu), 23.5 (CHiBu), 22.6 (CH3iBu), 21.6 (CH3iBu).
(S,S; S,S)-L1. White solid. 1H-NMR ((CD3)2SO, 400 MHz): δ 10.65 (s, 2H, NCHN), 8.63 (d, J = 8.7 Hz, 2H, NCCH), 8.00 (br, 2H, NH), 7.69 (d, J = 7.8 Hz, 2H, NCCH), 7.41–7.34 (m, 4H, NCCHCH), 5.84–5.82 (m, 2H, NCH), 5.30 (d, J = 16.0 Hz, 2H, NCH2CO), 5.25 (d, J = 16.0 Hz, 2H, NCH2CO), 4.68 (br, 2H, OH), 3.85–3.77 (m, 2H, NHCH), 3.39 (br, 4H, CH2OH), 2.61 (br, 2H), 2.46–2.43 (m, 2H), 2.06–2.04 (m, 2H), 1.88–1.86 (m, 2H), 1.70–1.56 (m, 2H, CHiBu), 1.37 (t, J = 7.3 Hz, 4H, CH2iBu), 0.88 (d, J = 6.9 Hz, 6H, CH3iBu), 0.83 (d, J = 6.9 Hz, 6H, CH3iBu); 13C-NMR (100 MHz): δ 163.1 (CO), 142.5 (NCHN), 130.3, 129.8, 126.3, 112.7 (NC), 112.5 (NC), 63.2 (CH2OH), 60.1 (CH2CO), 49.8 (NCH), 48.5 (NHCH), 39.6, 30.7, 24.0 (CH2iBu), 23.5 (CHiBu), 22.6 (CH3iBu), 21.6 (CH3iBu).
(S,S; R,R)-L1. White solid. 1H-NMR ((CD3)2SO, 400 MHz): δ 10.65 (s, 2H, NCHN), 8.59 (d, J = 8.5 Hz, 2H, NCCH), 7.93 (br, 2H, NH), 7.69 (d, J = 7.6 Hz, 2H, NCCH), 7.39–7.32 (m, 4H, NCCHCH), 5.81–5.79 (m, 2H, NCH), 5.30 (d, J = 15.7 Hz, 2H, NCH2CO), 5.22 (d, J = 15.7 Hz, 2H, NCH2CO), 4.68 (br, 2H, OH), 3.86–3.78 (m, 2H, NHCH), 3.42–3.39 (m, 4H, CH2OH), 2.61 (br, 2H), 2.46–2.43 (m, 2H), 2.07–2.05 (m, 2H), 1.87–1.85 (m, 2H), 1.67–1.56 (m, 2H, CHiBu), 1.37 (t, J = 7.0 Hz, 4H, CH2iBu), 0.87 (d, J = 6.7 Hz, 6H, CH3iBu), 0.82 (d, J = 6.7 Hz, 6H, CH3iBu); 13C-NMR (100 MHz): δ 163.1 (CO), 142.5 (NCHN), 130.2, 129.9, 126.3, 126.2, 112.7 (NC), 112.3 (NC), 63.1 (CH2OH), 60.1 (CH2CO), 49.8 (NCH), 48.6 (NHCH), 39.5, 30.8, 23.9 (CH2iBu), 23.5 (CHiBu), 22.6 (CH3iBu), 21.6 (CH3iBu).
(R,R; R,R)-L1. White solid. 1H-NMR ((CD3)2SO, 400 MHz): δ 10.53 (s, 2H, NCHN), 8.52 (d, J = 8.5 Hz, 2H, NCCH), 7.91 (br, 2H, NH), 7.68 (d, J = 8.1 Hz, 2H, NCCH), 7.43–7.34 (m, 4H, NCCHCH), 5.77–5.75 (m, 2H, NCH), 5.26 (d, J = 16.0 Hz, 2H, NCH2CO), 5.22 (d, J = 16.0 Hz, 2H, NCH2CO), 4.63 (br, 2H, OH), 3.86–3.78 (m, 2H, NHCH), 3.43–3.36 (m, 4H, CH2OH), 2.58 (br, 2H), 2.47–2.44 (m, 2H), 2.09–2.06 (m, 2H), 1.86–1.82 (m, 2H), 1.69–1.57 (m, 2H, CHiBu), 1.38 (t, J = 7.0 Hz, 4H, CH2iBu), 0.89 (d, J = 6.7 Hz, 6H, CH3iBu), 0.85 (d, J = 6.7 Hz, 6H); 13C-NMR (DMSO, 100 MHz): δ 163.1 (CO), 142.5 (NCHN), 130.3, 129.8, 126.3, 112.7 (NC), 112.5 (NC), 63.1 (CH2OH), 60.1 (CH2CO), 49.8 (NCH), 48.5 (NHCH), 39.6, 30.7, 24.0 (CH2iBu), 23.5 (CHiBu), 22.6 (CH3iBu), 21.6 (CH3iBu).
L2. White solid. 1H-NMR ((CD3)2SO, 400 MHz): δ 10.69 (br, 2H, NCHN), 8.48 (br, 2H, NCCH), 7.96 (br, 2H, NH), 7.72 (br, 2H, NCCH), 7.35 (br, 4H, NCCHCH), 5.80 (br, 2H, NCH), 5.43–5.31 (m, 4H, NCH2CO), 4.55 (br, 2H, OH), 3.65–3.60 (m, 4H, CH2OH), 3.48–3.45 (m, 2H, NHCH), 2.61 (br, 2H), 2.50–2.44 (m, 2H), 2.02 (br, 2H), 1.85 (br, 2H), 0.88 (m, 18H, CH3tBu). Because of the presence of the diastereoisomeric mixture, so many broad signals appeared in 1H-NMR, that the failure of 13C-NMR measurement in (CD3)2SO was observed. Elemental analysis: Calculated for C36H52Cl2N6O4·3H2O: C, 57.06; H, 7.72; N, 11.09. Found: C, 56.74; H, 7.41; N, 10.86%. M.p. 204-216 °C (decompose).
L3. White solid. 1H-NMR ((CD3)2SO, 400 MHz): δ 10.65 (s, 2H, NCHN), 8.86 (br, 2H, NCCH), 8.00 (br, 2H, NH), 7.70 (d, J = 7.7 Hz, 2H, NCCH), 7.40–7.30 (m, 4H, NCCHCH), 5.83 (br, 2H, NCH), 5.30 (d, J = 16.3 Hz, 2H, NCH2CO), 5.24 (d, J = 16.3 Hz, 2H, NCH2CO), 4.77 (br, 2H, OH), 3.49–3.47 (m, 4H, CH2OH), 3.22–3.19 (m, 4H, NH(CH2)2OH), 2.61 (br, 2H), 2.44–2.41 (m, 2H), 2.03–2.01 (m, 2H), 1.85 (br, 2H). Failure of 13C-NMR measurement in (CD3)2SO was observed. Elemental analysis: Calculated for C28H36Cl2N6O4·3H2O: C, 52.09; H, 6.56; N, 13.02. Found: C, 51.67; H, 6.36; N, 12.88%. M.p. 86.4–89.5 °C.
L7. White solid. 1H-NMR ((CD3)2SO, 400 MHz) δ 9.94 (s, 2H, NCHN), 8.71 (d, J = 8.5 Hz, 2H), 8.02–7.97 (m, 4H, NH), 7.71–7.64 (m, 4H), 7.41–7.38 (m, 2H), 7.16–7.14 (m, 2H), 6.17 (s, 4H, NCH2C), 5.42 (d, J = 16.4 Hz, 2H, NCH2CO), 5.35 (d, J = 16.4 Hz, 2H, NCH2CO), 4.88 (br, 2H, OH), 3.83–3.77 (m, 2H, NHCH), 3.40–3.32 (br, 4H, CH2OH), 1.64–1.57 (m, 2H, CHiBu), 1.36–1.30 (m, 4H, CH2iBu), 0.86 (d, J = 6.4 Hz, 6H, CH3iBu), 0.79 (d, J = 6.4 Hz, 6H, CH3iBu); 13C-NMR (100 MHz) δ 164.0 (CO), 143.9 (NCHN), 132.2, 131.6, 130.8, 129.3, 128.4, 126.9, 126.8, 114.1 (NC), 113.7 (NC), 63.5 (CH2OH), 49.7, 48.8, 47.5, 39.5 (CH2iBu), 24.2 (CHiBu), 23.3 (CH3iBu), 21.8 (CH3iBu). Elemental analysis: Calculated for C38H50Cl2N6O4·1.5H2O: C, 59.91; H, 7.15; N, 11.03. Found: C, 60.13; H, 6.96; N, 10.95%. M.p. 165–174 °C (decompose).

3.3. General Procedure for Cu-Catalyzed Asymmetric Reaction of Enone with Et2Zn

Cu salt and azolium salt were added to anhydrous THF. After stirring at room temperature for 1 h, the mixture was cooled to 0 °C. Then, Et2Zn (3 mmol, 1 M in hexanes, 3 mL) was added to the reaction vessel. After the resulting mixture was stirred at room temperature for 30 min, a solution of enone (1 mmol) in anhydrous THF was added dropwise over a period of 10 min. After stirring at room temperature for 3 h, the reaction was quenched with 10% HCl aq. The product yield was determined by GC using internal standard technique. The enantiomeric excess was measured by the chiral GC (see Supplementary Materials). The conjugate adduct was isolated as follows: After quenching the reaction mixture with 10% HCl aq., the resulting mixture was extracted with diisopropyl ether (3 × 10 mL) and dried over Na2SO4. The product was purified by silica gel column chromatography (hexane/Et2O).

4. Conclusions

We demonstrated that a chiral bis(NHC) ligand precursor L1, which is a dibenzimidazolium salt having a hydroxyamide side arm, efficiently performs Cu-catalyzed asymmetric conjugate addition of Et2Zn to cyclic or acyclic enones. In the catalytic 1,4-addition reaction of cyclic enone 3 with Et2Zn, an excellent enantioselectivity (up to 97% ee) was achieved with the Cu(hfacac)(btmsa)/(rac; S,S)-L1 catalytic system. Further investigations revealed that a 9:1 or 1:9 mixture of (R,R; S,S)-L1 and (S,S; S,S)-L1 promoted the highly enantioselective catalytic reaction. A potential application of the Cu/L1 catalytic system was investigated in the enantioselective 1,4-addition reaction of acyclic enones with Et2Zn. Interestingly, the stereoselectivity switching was observed in the Cu-catalyzed 1,4-addition reaction of 5 with Et2Zn in the presence of L1 when changing the counter anion on the Cu precatalyst.

Supplementary Materials

The following are available online at https://www.mdpi.com/2073-4344/9/9/780/s1: NMR charts; Selected chiral GC and LC traces in the catalytic reactions; Table S1: CuOAc-catalyzed reaction of 5 with E2Zn yielding (R)-6; Table S2: Cu(ClO4)2-catalyzed reaction of 5 with E2Zn yielding (S)-6.

Author Contributions

Conceptualization, Methodology and Writing—original draft preparation, S.S.; Investigation—experiments and analyses, A.I., S.K., and Y.I.; Writing—review and editing, S.S.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 09 00780 g001 550
Figure 1. Selected examples of chiral bis-N-heterocyclic carbenes bis(NHC)s.
Figure 1. Selected examples of chiral bis-N-heterocyclic carbenes bis(NHC)s.
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Catalysts 09 00780 sch001 550
Scheme 1. Previously reported bis(NHC) ligand precursor.
Scheme 1. Previously reported bis(NHC) ligand precursor.
Catalysts 09 00780 sch001
Catalysts 09 00780 sch002 550
Scheme 2. Preparation of a series of chiral ligands L1 used in this study.
Scheme 2. Preparation of a series of chiral ligands L1 used in this study.
Catalysts 09 00780 sch002
Catalysts 09 00780 g002 550
Figure 2. 1H NMR spectrum of (R,R; R,R)-L1 in (CD3)2SO at 25 °C (upper) and 80 °C (lower).
Figure 2. 1H NMR spectrum of (R,R; R,R)-L1 in (CD3)2SO at 25 °C (upper) and 80 °C (lower).
Catalysts 09 00780 g002
Catalysts 09 00780 g003 550
Figure 3. 1H NMR spectrum of the methyl proton on selected L1 (at 80 °C).
Figure 3. 1H NMR spectrum of the methyl proton on selected L1 (at 80 °C).
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Catalysts 09 00780 g004 550
Figure 4. 13C NMR spectrum of the methine carbon adjacent to isobutyl substituent.
Figure 4. 13C NMR spectrum of the methine carbon adjacent to isobutyl substituent.
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Catalysts 09 00780 g005 550
Figure 5. Chiral amplification in the conjugate addition reaction of 3 using (rac; S,S)-L1 and (rac; R,R)-L1.
Figure 5. Chiral amplification in the conjugate addition reaction of 3 using (rac; S,S)-L1 and (rac; R,R)-L1.
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Catalysts 09 00780 g006 550
Figure 6. Previously reported chiral ligand L4.
Figure 6. Previously reported chiral ligand L4.
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Table 1. Effect of chiral ligands L1 in the conjugate addition reaction of cyclic enone 3.
Table
Catalysts 09 00780 i001
Entry a(R,R; S,S)-L1:(S,S; S,S)-L1Yield (%) bee (%) c
11:05716
21:1 ≡ (rac; S,S)-L19997
30:13426
Table
Catalysts 09 00780 i002
Entry a(S,S; R,R)-L1:(R,R; R,R)-L1Yield (%) bee (%) c
41:05912
51:1 ≡ (rac; R,R)-L19197
60:13924
a To a solution of Cu(hfacac)(btmsa) (6.0 mol%) and L1 (4.5 mol%) in THF (9 mL), Et2Zn (3 mmol) was added first, then 3 (1 mmol). The reaction mixture was stirred at room temperature for 3 h. b Determined by GC analysis using the internal standard technique. c Determined by GC analysis of a chiral stationary phase.
Table
Table 2. Influence of the ratio of chiral ligands L1 in the conjugate addition reaction of 3.
Table 2. Influence of the ratio of chiral ligands L1 in the conjugate addition reaction of 3.
Catalysts 09 00780 i007
Table
Table 3. Effect of the amount of chiral ligand and ligand structure on the conjugate addition reaction of 3 a.
Table 3. Effect of the amount of chiral ligand and ligand structure on the conjugate addition reaction of 3 a.
Entry(rac; S,S)-L1 (mol%)Yield (%) bee (%) c
1 d4.59997
21.89793
31.359196
40.98297
50.4513Nd e
6L2, 4.548ent-27
7L3, 4.5180
a To a solution of Cu(hfacac)(btmsa) (6.0 mol%) and (rac; S,S)-L1 (0.45-4.5 mol%) in THF (9 mL), Et2Zn (3 mmol) was added first, then 3 (1 mmol). The reaction mixture was stirred at room temperature for 3 h. b Determined by GC analysis using the internal standard technique. c Determined by GC analysis of a chiral stationary phase. d The same data is shown in Table 1, entry 2. e Not determined.Catalysts 09 00780 i003
Table
Table 4. Switching of stereoselectivity in the conjugate addition reaction of acyclic enone 5 a.
Table 4. Switching of stereoselectivity in the conjugate addition reaction of acyclic enone 5 a.
Catalysts 09 00780 i004
EntryCu SaltProductYield (%) bee (%) c
1 dCu(hfacac)(btmsa)(R)-69049
2 dCu(hfacac)(cod)(R)-68761
3Cu(hfacac)2(R)-68553
4CuOCOCF3(R)-67327
5CuOAc(R)-67860
6Cu(OAc)2(R)-63763
7CuCl2(R)-65039
8Cu(OTf)2(S)-65833
9CuOTf·0.5C6H6(S)-6572
10Cu(NO3)2(S)-6629
11Cu(ClO4)2(S)-63150
a To a solution of Cu salt (6.0 mol%) and (rac; S,S)-L1 (4.5 mol%) in THF (9 mL), Et2Zn (3 mmol) was added first, then 5 (1 mmol). The reaction mixture was stirred at room temperature for 3 h. b Determined by GC analysis using the internal standard technique. c Determined by GC analysis of a chiral stationary phase. d Previously reported data [81].Catalysts 09 00780 i005
Table
Table 5. Switching of stereoselectivity in the conjugate addition reaction of 5 under selected conditions a.
Table 5. Switching of stereoselectivity in the conjugate addition reaction of 5 under selected conditions a.
EntryCu/L1 (mol%)SolvTemp./TimeProductYield (%)ee (%)
1 b,c6/4.5THFr.t./3 h(R)-67860
2 b4.5/6THFr.t./3 h(R)-67256
3 b4/4THFr.t./3 h(R)-67960
4 b4/4Et2Or.t./3 h(R)-64639
5 b4/4DMEr.t./3 h(R)-64370
6 b4/4DME0 °C/24 h(R)-64978
7 b4/4DME0 °C/48 h(R)-67873
8 b4/4DME−10 °C/48 h(R)-66975
9 d,e6/4.5THFr.t./3 h(S)-63150
10 d4.5/6THFr.t./3 h(S)-64434
11 d6/3THFr.t./3 h(S)-63946
12 d6/32-MeTHFr.t./3 h(S)-62643
13 d6/3DMEr.t./3 h(S)-62834
14 d6/3THF0 °C/24 h(S)-68970
15 d6/3THF−5 °C/24 h(S)-68267
16 d6/3THF−10 °C/24 h(S)-69069
17 d,f6/3DME0 °C/24 h(S)-69369
a To a solution of Cu salt and (rac; S,S)-L1 in solvent (9 mL), Et2Zn (3 mmol) was added first, then 5 (1 mmol). b CuOAc was used as a copper precatalyst. c The same data entry is shown in Table 4, as entry 5. d Cu(ClO4)2 was used as a copper precatalyst. e The same data entry is shown in Table 4, as entry 11. f DME (6 mL) was used.
Table
Table 6. Switching of stereoselectivity in the CuCln-catalyzed conjugate addition reaction of 5 in the presence of an additive.
Table 6. Switching of stereoselectivity in the CuCln-catalyzed conjugate addition reaction of 5 in the presence of an additive.
EntryCu saltAdditive(mol%)ProductYield (%)ee (%)
1 a,bCuOAcnone (R)-64978
2 aCuClnone (R)-61235
3 aCuClAgOAc4(R)-64786
4 aCuClAgOAc6(R)-65485
5 aCuClAgOAc8(R)-62174
6 c,dCu(ClO4)2 (S)-68970
7 cCuCl2none (R)-67948
8 cCuCl2AgClO412(S)-69368
9 cCuCl2AgClO415(S)-69066
10 cCuCl2AgClO46(S)-68066
a To a solution of Cu salt (4 mol%) and (rac; S,S)-L1 (4 mol%) in DME (9 mL), Et2Zn (3 mmol) was added first, then 5 (1 mmol). The reaction mixture was stirred at 0 °C for 24 h. b The same data entry is shown in Table 5, as entry 6. c To a solution of Cu salt (6 mol%) and (rac; S,S)-L1 (3 mol%) in THF (9 mL), Et2Zn (3 mmol) was added first, then 5 (1 mmol). The reaction mixture was stirred at 0 °C for 24 h. d The same data entry is shown in Table 5, as entry 14.
Table
Table 7. Exploring substrate scope.
Table 7. Exploring substrate scope.
EntryEnoneConjugate AdductYield (%)ee (%)
1 a,b5(R)-64978
2 c,d5(S)-68970
3 aiPrCH = CHCOMe (7)(S)-81569
4 c7(R)-84482
5 c,e7(R)-85980
6 c,e,f7(R)-86475
7 aPhCH = CHCOMe (9)(S)-105563
8 c9(R)-102157
9 aPhCH = CHCOPh (11)(S)-123355
10 c11(R)-121615
11 a3(R)-43857
12 c3(S)-46447
a To a solution of CuOAc (4 mol%) and (rac; S,S)-L1 (4 mol%) in DME (9 mL), Et2Zn (3 mmol) was added first, then enone (1 mmol). The reaction mixture was stirred at 0 °C for 24 h. b The same data entry is shown in Table 5, as entry 6. c To a solution of Cu(ClO4)2 (6 mol%) and (rac; S,S)-L1 (3 mol%) in THF (9 mL), Et2Zn (3 mmol) was added first, then enone (1 mmol). The reaction mixture was stirred at 0 °C for 24 h. d The same data entry is shown in Table 5, as entry 14. e Reaction was conducted for 48 h. f L2 in place of (rac; S,S)-L1 was used.
Table
Table 8. Effect of chiral azolium ligand L1 in the conjugate addition reaction of 5.
Table 8. Effect of chiral azolium ligand L1 in the conjugate addition reaction of 5.
Entry(R,R; S,S)-L1 (mol%)(S,S; S,S)-L1 (mol%)ProductYield (%)ee (%)
1 a40(R)-67988
2 a,b22(R)-64978
3 a04(R)-61748
4 a30(R)-67091
5 c30(S)-67075
6 c,d1.51.5(S)-68970
7 c03(S)-68266
a To a solution of CuOAc (4 mol%) and L1 in DME (9 mL), Et2Zn (3 mmol) was added first, then 5 (1 mmol). The reaction mixture was stirred at 0 °C for 24 h. b The same data entry is shown in Table 5, as entry 6. c To a solution of Cu(ClO4)2 (6 mol%) and L1 in THF (9 mL), Et2Zn (3 mmol) was added first, then 5 (1 mmol). The reaction mixture was stirred at 0 °C for 24 h. d The same data entry is shown in Table 5, as entry 14.
Table
Table 9. Effect of chiral ligand structure on switching of stereoselectivity in the conjugate addition reaction of 5.
Table 9. Effect of chiral ligand structure on switching of stereoselectivity in the conjugate addition reaction of 5.
EntryCu SaltLigandProductYield (%)ee (%)
1 aCuOAcL5(R)-61227
2 bCu(ClO4)2L5(S)-67358
3 aCuOAcL6(S)-62716
4 bCu(ClO4)2L6(S)-69442
5 aCuOAcL7(S)-6315
6 bCu(ClO4)2L7(S)-68769
a To a solution of CuOAc (4 mol%) and ligand (4 mol%) in DME (9 mL), Et2Zn (3 mmol) was added first, then 5 (1 mmol). The reaction mixture was stirred at 0 °C for 24 h. b To a solution of Cu(ClO4)2 (6 mol%) and ligand (3 mol%) in THF (9 mL), Et2Zn (3 mmol) was added first, then 5 (1 mmol). The reaction mixture was stirred at 0 °C for 24 h.Catalysts 09 00780 i006

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Ishibashi, A.; Kamihigashi, S.; Iwai, Y.; Sakaguchi, S. (±)-trans-1,2-Cyclohexanediamine-Based Bis(NHC) Ligand for Cu-Catalyzed Asymmetric Conjugate Addition Reaction. Catalysts 2019, 9, 780. https://doi.org/10.3390/catal9090780

AMA Style

Ishibashi A, Kamihigashi S, Iwai Y, Sakaguchi S. (±)-trans-1,2-Cyclohexanediamine-Based Bis(NHC) Ligand for Cu-Catalyzed Asymmetric Conjugate Addition Reaction. Catalysts. 2019; 9(9):780. https://doi.org/10.3390/catal9090780

Chicago/Turabian Style

Ishibashi, Azusa, Shun Kamihigashi, Yuuki Iwai, and Satoshi Sakaguchi. 2019. "(±)-trans-1,2-Cyclohexanediamine-Based Bis(NHC) Ligand for Cu-Catalyzed Asymmetric Conjugate Addition Reaction" Catalysts 9, no. 9: 780. https://doi.org/10.3390/catal9090780

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