Enantioselectivity switch in copper-catalyzed conjugate addition reactions under the influence of a chiral N-heterocyclic carbene–silver complex

Abstract

The asymmetric 1,4-addition of Et₂Zn to 2-cyclohexen-1-one using a Cu(I) salt/N-heterocyclic carbene (NHC)–Ag complex catalytic system afforded optically active 3-ethylcyclohexanone. The reversal of enantioselectivity using the same catalytic system was achieved by changing the order of the addition of substrates.

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Asymmetric catalysis is an efficient tool for the synthesis of enantiomerically enriched compounds using chiral catalysts. In this regard, it is important to develop novel chiral ligands for efficient asymmetric transformations. Despite enormous progress, it is a significant challenge to develop asymmetric catalytic methods that afford both the enantioenriched products using a single chiral source.¹ Hence, in recent years, much attention has been paid to study the induction of both enantiomers without using the antipode of the chiral source.²

Enantioselective conjugate addition reaction is one of the most important tools for the synthesis of valuable optically active compounds. Recently, several efficient chiral ligands have been developed for this transformation.³ Over the last decades, N-heterocyclic carbenes (NHCs) have been developed as useful ligands for the Cu-catalyzed 1,4-addition of organometallic reagents to α,β-unsaturated carbonyl compounds.^4,5 One of the most attractive features of NHC ligands is the easy access to their precursors; thus, diverse NHC ligands can be obtained for efficient metal-catalyzed asymmetric reactions.⁴ The common methods for catalytic asymmetric conjugate addition (ACA) reactions involve in situ generated catalysts from azolium salts (a precursor of NHC) and a Cu species.⁵

Recently, we designed and synthesized a chiral hydroxyamide-functionalized azolium salt that acts as the precursor of NHC from an α-amino acid.⁶ To our delight, the combination of a Cu catalyst precursor and the chiral azolium salt thus obtained promoted the enantioselective 1,4-addition of dialkylzinc reagents to enones.⁷ Alexakis and Roland reported that the use of an NHC–Ag complex instead of an azolium salt carbene precursor in the Cu-catalyzed ACA reaction of cyclic enone with Et₂Zn (4) increased the stereoselectivity.⁸ Thus, we envisioned that the stereoselectivity of an ACA reaction would be enhanced by using a “Cu precatalyst/NHC–Ag complex” catalytic system. During the course of our study, we discovered that the enantioselectivity of the reaction was reversed by varying the order of the addition of the substrates such as the enone and dialkylzinc. When dialkylzinc was added to a mixture of Cu(I) precatalyst, NHC–Ag complex and enone, the 1,4-addition reaction afforded the corresponding adduct with good enantioselectivity. Surprisingly, the conjugate adduct with the opposite configuration was obtained as the major product by adding the enone as the last component to the mixture of Cu(I) salt, NHC–Ag complex and dialkylzinc. Herein, we report our findings on the switching of enantioselectivity with the in situ generated NHC–Cu species by using a single chiral source.

This study commenced with the synthesis of an NHC–Ag complex (Scheme 1). The ethylene-bridged, hydroxyamide-functionalized azolium salt 1 was synthesized in two steps from a β-amino alcohol according to a previously reported procedure.^7b In this study, the chiral ligand precursors 1a, 1b and ent-1b derived from (+)-leucinol, (+)-2-amino-1-butanol and (−)-2-amino-1-butanol, respectively, were selected. The NHC–Ag complexes were easily synthesized using the Ag₂O method.⁹ The treatment of precursor 1a with 0.5 equiv. of Ag₂O in CH₂Cl₂ at room temperature under open-air conditions afforded the corresponding monodentate NHC–Ag complex 2a in 92% yield. NHC–Ag complexes 2b and ent-2b were synthesized in a similar manner. Notably, these newly synthesized Ag complexes were air and moisture stable; thus, they could be easily handled under air atmosphere and stored as solids without any special precaution. These compounds were completely characterized by ¹H and ¹³C NMR spectroscopies in DMSO-d₆ and elemental analysis. In the ¹H NMR spectra of azolium salt 1a and NHC–Ag complex 2a, the signal at δ 9.1 ppm for the azolium proton was observed in azolium salt 1a, but not in NHC–Ag complex 2a. Furthermore, the signals at approximately δ 7.8 and 4.5 ppm corresponding to the N–H and O–H protons, respectively, in salt 1a were still present in the spectrum of complex 2a, indicating that no anionic amidato- and alkoxy-tethered NHC–Ag complex was formed.^6c In the ¹³C NMR spectra of compounds 1a and 2a, the signal of the carbene C shifted to a higher frequency by ∼40 ppm upon deprotonation. The characteristic carbene C signal at δ 191.0 ppm was observed in NHC–Ag complex 2a.

Scheme 1 Preparation of NHC–Ag complexes.

The reaction of 2-cyclohexen-1-one (3) with Et₂Zn (4) in the presence of catalytic amounts of “(CuOTf)₂·C₆H₆/NHC–Ag complex” in THF was selected as the model reaction. Table 1 summarizes the 1,4-addition of Et₂Zn (4) to enone 3 under the influence of NHC–Ag complex 2a or 2b under selected reaction conditions, affording 3-ethylcyclohexanone (5). The reaction was conducted by adding enone 3 first, followed by 4, to a THF solution of (CuOTf)₂·C₆H₆ (6 mol%) and NHC–Ag complex 2a (4 mol%) under Ar atmosphere (method A). The reaction conducted using method A at room temperature afforded (R)-5 as the major product in 78% yield and with 67% ee (entry 1). Under air atmosphere, the corresponding 1,4-adduct was obtained in a low yield and with moderate enantioselectivity (entry 2). When the reaction temperature was decreased to −20 °C, a slight improvement in the enantioselectivity was observed, affording (R)-5 with 72% ee (entry 3).

Table 1 Switching of enantioselectivity in ACA reaction^a

Entry	Cu salt (mol%)	NHC–Ag (mol%)	Method^b	Product	Yield^c (%)	ee^d (%)
a Reaction conditions: 3 (0.5 mmol), 4 (1.5 mmol), (CuOTf)2·C6H6 (2–6 mol%), 2 (4–10 mol%), in THF (7–9 mL) at room temperature for 3 h under Ar.b Method A: to a solution of Cu precatalyst and 2 in THF, 3 was added first, then 4. Method B: 4 was added first, then 3.c Determined by GC using the internal standard method.d Determined by GC on a chiral stationary phase.e Under air.f At −20 °C.g Almost no reaction occurred.
1	6	2a (4)	A	(R)-5	78	67
2^e	6	2a (4)	A	(R)-5	46	51
3^f	6	2a (4)	A	(R)-5	87	72
4^g	6	2a (4)	B
5	4	2a (6)	B	(S)-5	30	10
6	4	2a (10)	B	(S)-5	84	79
7^e	4	2a (10)	B	(S)-5	75	88
8^e	2	2a (6)	B	(S)-5	74	82
9	6	2b (4)	A	(R)-5	99	61
10^e	6	2b (4)	A	(R)-5	65	45
11^f	6	2b (4)	A	(R)-5	84	74
12^g	6	2b (4)	B
13	4	2b (6)	B	(S)-5	49	58
14	4	2b (10)	B	(S)-5	97	75
15^e	4	2b (10)	B	(S)-5	84	87
16	4	2a (10)	A	(R)-5	89	18

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Next, Et₂Zn (4) was added to a THF solution of (CuOTf)₂·C₆H₆ and NHC–Ag complex 2a; after stirring for 30 min, enone 3 was added to the resulting reaction mixture (method B). The reaction conducted using method B under the influence of (CuOTf)₂·C₆H₆ (6 mol%) and NHC–Ag complex 2a (4 mol%) failed (entry 4). However, the reaction using 4 mol% Cu precatalyst and 10 mol% chiral ligand precursor afforded the conjugate adduct with the opposite configuration compared to the product obtained in the ACA reaction using method A (entry 6). A high ee value of 88% was obtained for (S)-5 in the ACA reaction catalyzed by (CuOTf)₂·C₆H₆/2a system using method B under air atmosphere, even though the reason for the effect of air is unclear at this stage (entry 7). Moreover, a decrease in the catalyst loading (Cu/NHC–Ag = 2/6 mol%) did not decrease the product yield and ee significantly (entry 8). The ability of the reversal of enantiocontrol in ACA reaction using NHC–Ag complex 2b derived from (+)-2-amino-1-butanol was also investigated. The results obtained in the ACA reaction with (CuOTf)₂·C₆H₆/2b system were similar to those obtained with (CuOTf)₂·C₆H₆/2a system (Table 1, entries 1–7 vs. entries 9–15).‡

At this stage, the ratio of the Cu salt and NHC–Ag complex used in method A differs from that used in method B. Therefore, the ACA reaction using method A under the influence of (CuOTf)₂·C₆H₆ (4 mol%) and NHC–Ag complex 2a (10 mol%) was finally examined (Table 1, entry 16). This reaction afforded (R)-5 with low enantioselectivity. These results indicate that the ratio of Cu/NHC is also an important factor for achieving the dual enantiocontrol with high enantioselectivity. In the literature, the enantioselectivity switch in the Cu-catalyzed ACA reaction using dipeptide phosphine ligand was reported by changing the reaction temperature.^3e

The higher performance of the combined catalytic system of a Cu salt and 2b prompted us to study the ability of the chiral NHC ligand with the opposite configuration. As expected, when Et₂Zn (4) was added to a THF solution of (CuOTf)₂·C₆H₆, ent-2b and enone 3 (method A), the corresponding 1,4-adduct such as (S)-5 was preferentially obtained in 82% yield and with 78% ee. In stark contrast, when Et₂Zn (4) was added first followed by enone 3 (method B), (R)-5 was obtained as the major product (85% yield and 85% ee) (see Scheme S1 in ESI†).

With a set of both the enantiomers of NHC–Ag complex in hand, the relationship between catalyst ee (ee_cat) and product ee (ee_pro) in both the asymmetric reaction systems (methods A and B) was investigated (Fig. 1, see also ESI†). Kagan reported that a plot of ee_pro vs. ee_cat is a simple method to obtain the information on the enantioselectivity of a catalytic reaction.¹⁰ Various mixtures of NHC–Ag complexes 2b and ent-2b were carefully prepared. The ACA reaction using method A provided sufficient chiral amplification to reach an enantiopure end state. Moreover, in the reaction using method B, the chiral amplification phenomenon was also observed. These results probably indicate that only one molecule of the chiral auxiliary is not involved in both the active catalyst species, even though we have no experimental evidence to elucidate the reaction mechanism at this stage.

Fig. 1 Chiral amplification phenomenon in ACA reaction.

Finally, the switching of enantioselectivity in the conjugate addition of dialkylzinc reagents to other cyclic enones was investigated using this protocol (Table 2). The catalytic systems were suitable for the reaction of 2-cyclohepten-1-one (6) with dialkylzinc (entries 1–6). The 1,4-addition reaction of 6 with Et₂Zn (4) proceeded efficiently under the influence of (CuOTf)₂·C₆H₆/2b system using method A, affording (R)-3-ethylcycloheptanone ((R)-7) in an excellent yield (96%) and with 83% ee (entry 2). The use of the same catalyst under the reaction conditions using method B afforded (S)-7 with the opposite configuration in 91% yield and with 86% ee (entry 4). In the reaction of enone 6 with Me₂Zn (8) using method A catalyzed by (CuOTf)₂·C₆H₆/2b system, most of 6 was recovered (entry 5). In contrast, (S)-9 was obtained in an excellent yield (96%) and enantioselectivity (95% ee) using method B (entry 6). Although the ACA reaction of 8 to 3 proceeded with difficulty using method A (entry 7), a highly enantioselective reaction was achieved by adding 3 as the last component to a mixture of Cu(I) salt, 2a and 8 (method B), affording (S)-10 in 90% yield and with 95% ee (entry 8).

Table 2 Evaluation of several cyclic enones^a

Entry	Substrates^c	NHC–Ag	Method	Adduct	Yield^b (%)	ee (%)
a Method A: reaction was run as under the same reaction conditions as shown in Table 1, entry 3 or entry 11. Method B: reaction was run as under the same reaction conditions as shown in Table 1, entry 7 or entry 15.b Isolated yield.c 6: 2-Cyclohepten-1-one; 4: Et2Zn; 8: Me2Zn; 3: 2-cyclohexen-1-one; 11: 4,4-dimethyl-2-cyclohexen-1-one; 13: 2-cyclopenten-1-one.d For 24 h.
1	6 + 4	2a	A	(R)-7	84	85
2	6 + 4	2b	A	(R)-7	96	83
3	6 + 4	2a	B	(S)-7	79	83
4	6 + 4	2b	B	(S)-7	91	86
5	6 + 8	2b	A	9	Trace	—
6	6 + 8	2b	B	(S)-9	96	95
7	3 + 8	2a	A	10	Trace	—
8	3 + 8	2a	B	(S)-10	90	95
9	3 + 8	2b	B	(S)-10	88	95
10^d	11 + 4	2a	A	(S)-12	42	71
11^d	11 + 4	2b	A	(S)-12	52	60
12^d	11 + 4	2a	B	(R)-12	41	95
13^d	11 + 4	2b	B	(R)-12	32	96
14	13 + 4	2b	A	(S)-14	79	9
15	13 + 4	2b	B	(S)-14	63	80

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A dual enantioselective control was also observed in the reactions of 4,4-dimethyl-2-cyclohexen-1-one (11) with Et₂Zn (4), affording 3-ethyl-4,4-dimethylcyclohexanone (12) (entries 10–13). Despite a good yield, the reaction of 2-cyclopenten-1-one (13) and 4 using method A afforded 1,4-adduct 14 with a poor enantioselectivity (entry 14). This is probably because of the conformational difference between the five-membered ring in 13 and six-membered ring in 3.¹¹ Furthermore, the ACA reaction of acyclic enone was examined. Although the switching of enantioselectivity was observed in the reactions of 3-nonen-2-one with Et₂Zn, the 1,4-adducts were obtained with low enantioselectivities (see Scheme S2 in ESI†).¹²

Mauduit and Alexakis proposed a reaction mechanistic model in the NHC–Cu-catalyzed ACA of a Grignard reagent to an enone. The enantioselectivity of the reaction was significantly affected by the order of addition of the substrates.^5d,13 The present Cu-catalyzed ACA reaction may have proceeded through a similar reaction pathway. When dialkylzinc was added to a mixture of Cu salt, chiral ligand and enone in the ACA reaction of enone 3 and Et₂Zn (4) (method A), an alkylcuprate species A might be generated, affording 1,4-adduct with R-configuration. In contrast, when the enone is added as the last component (method B), a higher-order cuprate B might be formed, probably because of the presence of an excess amount of dialkylzinc. Presumably, the reaction of dialkylzinc with NHC–Cu species in the presence of an enone affords cuprate A, whereas higher-order cuprate B is produced in the absence of enone. The resulting higher-order cuprate B would promote the ACA reaction, affording 1,4-adduct with the opposite configuration.

In summary, a switchable enantioselectivity was achieved in a Cu-catalyzed ACA reaction. The hydroxyamide-functionalized NHC–Ag complex, readily accessible from a chiral β-amino alcohol, was found to be a versatile chiral ligand precursor for a dual enantioselective control.

Acknowledgements

This work was financially supported by a Grant-in-Aid for Scientific Research (C) (26410127) from Japan Society for the Promotion of Science (JSPS).

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Experimental details, Scheme S1, S2, data for Fig. 1 and spectral data. See DOI: 10.1039/c5ra25926f

‡ Procedure for method A: the reaction was performed under argon atmosphere. A flask, under argon atmosphere, was charged with (CuOTf)₂·C₆H₆ (15 mg, 0.03 mmol) and NHC–Ag complex 2b (23 mg, 0.04 mmol). Then, a solution of 3 (96 mg, 1 mmol) in anhydrous THF (9 mL) was added. The resulting mixture was stirred at room temperature for 1 h. After the mixture was cooled to −20 °C, a solution of 4 (3 mmol, 1 M in hexanes, 3 mL) was added dropwise over a period of 10 min. The reaction mixture was stirred at −20 °C for 3 h. The reaction was quenched by adding 10% aq. HCl. The resulting mixture was extracted with diisopropyl ether and dried over Na₂SO₄. The product was purified by silica gel column chromatography using a mixture of (hexane/EtOAc). The enantiomeric excess was measured using a chiral GLC. Procedure for method B: the reaction was performed under open-air conditions. (CuOTf)₂·C₆H₆ (10 mg, 0.02 mmol) and 2b (59 mg, 0.10 mmol) were added to anhydrous THF (5.5 mL). After stirring at room temperature for 1 h, the mixture was cooled to 0 °C. Then, 4 (3 mmol) was added to the reaction vessel. After the resulting mixture was stirred at room temperature for 30 min, a solution of 3 (1 mmol) in anhydrous THF (1.5 mL) was added dropwise over a period of 10 min. The reaction mixture was stirred at room temperature for 3 h.

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