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Communication

Catalytic Asymmetric Chlorination of β-Ketoesters Using N-PFB-PyBidine-Zn(OAc)2

by
Junma Ma
1,
Takumi Suzuki
1,
Satoru Kuwano
1,2 and
Takayoshi Arai
1,2,3,4,*
1
Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
2
Molecular Chirality Research Center (MCRC), Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
3
Soft Molecular Activation Research Center (SMARC), Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
4
Chiba Iodine Research Innovation Center (CIRIC), Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
*
Author to whom correspondence should be addressed.
Catalysts 2020, 10(10), 1177; https://doi.org/10.3390/catal10101177
Submission received: 21 August 2020 / Revised: 15 September 2020 / Accepted: 30 September 2020 / Published: 13 October 2020
(This article belongs to the Special Issue Multi-Step Syntheses in Biology & Chemistry)
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Abstract

:
A PyBidine-Zn(OAc)2 complex catalyzed asymmetric chlorination of β-ketoesters. With assistance of NaHCO3, a newly developed N-pentafluorobenzyl-PyBidine (N-PFB-PyBidine)-Zn(OAc)2 catalyst promoted the reaction of α-benzyl-β-ketoesters with N-chlorosuccinimide (NCS) to give the chlorinated products with up to 82% ee. Results of a mechanistic study suggested that zinc-enolate of β-ketoesters was formed on the basic (N-PFB-PyBidine)-Zn(OAc)2 catalyst. The α-chlorinated-β-ketoester was successfully transformed into the chiral epoxide through sequential asymmetric chlorination/cyano-epoxidation in a one-pot synthesis.

Graphical Abstract

1. Introduction

Halogenation is an important transformation for producing highly functionalized organic compounds. Characteristics of chlorinated compounds have been evaluated for application in material science, medicinal chemistry, and agrochemistry [1]. Halogenated compounds also are valuable as synthetic intermediates in cross-coupling reactions. Among the wide range of synthetic methods for introducing halogens to the organic compounds, the most reliable is chlorination of the α-position of carbonyl compounds, which has been applied to the catalytic asymmetric version [2].
Asymmetric chlorination of β-ketoesters was described by Togni et al. using a Lewis acid catalyst TiCl2(TADDOLato) in 2000 [3,4]. After seminal work by Jørgensen’s bisoxazoline-copper catalysis [5], various metal-catalyzed enantioselective chlorinations of β-ketoesters have been developed using Cu [6,7,8,9,10,11,12,13], Ni [14], Co [15], Zn [10], Pd [16], and Fe [17]. The use of Cu and Zn salts for a single chiral ligand allows a switch in enantioselectivity [10]. Organocatalyzed reactions also have been reported [18,19,20,21,22,23,24,25,26,27,28,29]. In these reports, formation of enolates from the β-ketoesters has been proposed. Though previously reported metal-catalyzed reactions have involved relatively strong Lewis acids with stable counter anions (e.g., TfO−), increasing the basicity of the metal catalyst should promote formation of the enolate and smooth nucleophilic reaction of the enolate to the chlorinating reagent.
As part of a program for developing advanced halogenated compounds, a series of chiral metal catalysts for iodolactonization were developed [30,31,32,33]. Catalytic asymmetric iodolactonization was achieved using a newly developed chiral bis (imidazolidine) pyridine ligand (PyBidine)-metal complex [30]. The formation of an Ni-carboxylate intermediate from the alkenyl carboxylic acid plays a key role in promoting the iodolactonization. The PyBidine-metal complexes also have been applied successfully to metal enolate chemistry [34,35,36]. For example, generation of metal-enolates from β-ketoesters was achieved with a bis (imidazolidine)pyridine (PyBidine)-CoCl2 complex [36]. The conjugation of the iodolactonization and enolate formation on the PyBidine-metal complex promoted an examination of the asymmetric chlorination of β-ketoesters using basic catalysts.

2. Results

Initially, a study was done to determine the appropriate catalyst for asymmetric chlorination of β-ketoesters.
For asymmetric chlorination of β-ketoester 1a using N-chlorosuccinimide (NCS), various PyBidine(L1)-metal salt complexes possessed catalytic activity to give the α-chlorinated β-ketoester 2a in an enantioselective manner (Table 1). Although L1-Co(II), Ni(II), and Cu(II) complexes, which had been examined previously, were catalytically active, 2a was obtained in low enantiomeric excess. Among the fourth period metal salts examined, the (S,S)-diphenyldiamine-derived PyBidine (L1)-Zn(OAc)2 complex gave (S)-enriched 2a in 60% yield with 60% ee (entry 7). Typically, the weakly basic metal acetate complexes showed greater catalyst activity than those complexes prepared from neutral metal chlorides or Lewis acidic metal salts. Other chiral ligands were also examined for applicability to the Zn(OAc)2-catalyzed reaction (entries 11–14). The trinuclear-aminoiminoBINOL (L2)-Zn3(OAc)4 complex, which possessed outstanding catalytic activity for the iodolactonization reaction, gave 2a in 41% yield with 21% ee (entry 11) [31,32]. Reaction using PyBim (L3) -Zn(OAc)2 gave 2a with low ee (entry 12) [37].
Based on the first screening of catalysts for asymmetric chlorination, the PyBidine-Zn(OAc)2 catalyst system was chosen for further optimization (Table 2).
The substitution effect on the imidazolidine ring of the PyBidine ligand (R-group) was examined (Table 2, entries 1–6). Although the bulky N-trimethylbenzyl-PyBidine (L6)-Zn(OAc)2 catalyst resulted in lower asymmetric induction to give 2a, the catalysts prepared from N-cyclohexylmethyl-PyBidine (L7) and N-1-naphthylmethyl-PyBidine (L8) slightly improved asymmetric induction (entries 3–4). By introducing an electron-withdrawing substituent directly onto the imidazolidine-ring, N-tosyl-PyBidine (L9) reduced the catalytic activity to give 2a in 25% yield, which can be explained by a reduction in basicity of the PyBidine-Zn(OAc)2 complex (entry 5). Finally, the N-pentafluorobenzyl-PyBidine (L10), referred to as N-PFB-PyBidine, improved the Zn(OAc)2-catalyzed reaction to give 2a in 86% yield with 70% ee. For N-PFB-PyBidine (L10)-Zn(OAc)2 catalysis, additional reaction optimization was conducted in entries 7–18. Reactions conducted in a polar solvent tended to reduce asymmetric induction, while the use of cyclohexane improved the asymmetric induction of 2a with up to 79% ee (entry 11). Although other chlorinating reagents were investigated (entries 12–15), reaction using the original NCS provided 2a with the greatest ee value. Based on the weaker basic character of the PyBidine-Zn(OAc)2 complex, some basic additives were also examined (entries 16–18). The best reaction conditions were the addition of 1 equivalent NaHCO3 to the N-PFB-PyBidine (L10)-Zn(OAc)2 catalyst (10 mol%), which gave 2a in 99% yield while maintaining the asymmetric induction of 78% ee (entry 18).
With the optimized reaction conditions in hand, the generality of β-ketoesters was examined in Scheme 1.
The methyl ester 2b and tert-butyl ester 2c were obtained with 76% ee. For the benzyl substituent of β-ketoesters, both electron-donating and -withdrawing substituents on the benzene ring were tolerated to give products ranging from 74% ee to 82% ee. Similarly, the 2-naphthylmethyl substituted product 2i was obtained with 78% ee. However, the simple methyl substituent of the β-ketoester reduced the asymmetric induction to 30% ee in generating 2e. Cyclic β-ketoesters could be used and gave 2m and 2n with 53% ee and 61% ee, respectively. When N-bromosuccinimide (NBS) was used instead of NCS, α-bromo-β-ketoester 2o was obtained in 46% yield and 21% ee. Even in the decreased catalyst loading (5 mol %), 2a was obtained in quantitative yield with 74% ee.
For synthetic application of chiral α-chloro-β-ketoesters, Shibatomi et al. reported the SN2 substitution reaction using azide and thiol nucleophiles [9]. In contrast, when KCN was applied to the chiral α-chloro-β-ketoester 2a, epoxide 3 was obtained in 83% yield, which was generated by 1,2-addition of cyanide to the α-chloro-β-ketoester 2a and subsequent intramolecular epoxide formation (Scheme 2). Although 3 was obtained as a diastereo-mixture, both isomers retained their optical purity of the α-position. Epoxide formation also was possible from sequential asymmetric chlorination/cyano-epoxidation in a one-pot synthesis.

3. Discussion

Figure 1a presents a proposed reaction mechanism. The β-ketoesters coordinate to the PyBidine-Zn complex to form intermediate A. The Zn-enolate B then is generated with assistance of base (e.g., NaHCO3). Enolate B reacts with the chlorinating reagent (NCS) to give the product along with regeneration of the catalyst.
Formation of Zn-enolate B was suggested by 1H-NMR and ESI-MS results. When the N-PFB-PyBidine (L10)-Zn(OAc)2 complex was treated with 1a (1 eq) and NaHCO3 (1 eq) in CH2Cl2, new peaks were observed in the ESI-MS spectrum at 1166.3037 and 1226.3250, corresponding to the [L10-Zn + enolate (1a - H)]+ and [L10-ZnOAc + enolate (1a - H) + H]+, respectively (Figure 2a). Furthermore, in the 1H-NMR study, mixing L10-Zn(OAc)2 complex, 1a (1 eq), NaHCO3 (1 eq), and CD3OD (50 eq) in CDCl3, reduced the intensity of the α-proton of 1a to 0.64 proton, which suggests smooth formation of the enolate 1a under the reaction conditions (Figure 2b).
The PyBim (L3)-Zn(OAc)2 gave (R)-2a with only 6% ee (Table 1, entry 11), and an N,N-Me4-PyBidine)-Zn(OAc)2 resulted in poor asymmetric induction under the optimized reaction conditions (Scheme 3) [36]. These results suggest that the NH-proton of the imidazolidine ring in the N-PFB-PyBidine (L10)-Zn(OAc)2 complex apparently plays a significant role in organizing the appropriate reaction sphere [35].
The reaction model described in Figure 1b explains the formation of (S)-enriched 2a using (S,S)-diphenyldiamine-derived N-PFB-PyBidine (L10)-Zn(OAc)2 catalyst, in which the formation of hydrogen bonding between NCS and the NH-proton of imidazolidine ring is involved.

4. Materials and Methods

N-PFB PyBidine (L10) (0.022 mmol) and Zn(OAc)2 (0.02 mmol) were added to a glass tube equipped with a magnetic stirrer bar under Ar. Then, DCM (1.0 mL) was added to the glass tube and the mixture stirred overnight. After removal of the solvent under reduced pressure, cyclohexane (2.0 mL) was added, followed by the addition of the β-ketoesters (0.2 mmol) at 25 °C and then the addition of NaHCO3 (0.02 mmol) and N-chlorosuccinimide (0.22 mmol). After stirring for 24 h, the reaction mixture was directly purified by silica-gel column chromatography to afford the product. The enantiomeric excess of the products was determined using chiral stationary phase HPLC with Daicel Chiralcel OJ-H and Chiralpak AS-H and IC-3 columns.
The detailed experimental procedure and analytical data are available in the Supporting Information.

5. Conclusions

In conclusion, an efficient Zn-catalyzed enantioselective chlorination reaction of β-ketoesters was developed. The N-PFB-PyBidine (L10)-Zn(OAc)2 complex acts as a basic catalyst to generate the enolate of the β-ketoesters, and to promote α-chlorination in high yield with moderate to good enantioselectivity. Transformation of the α-chlorinated product into chiral epoxide by one-pot sequential asymmetric chrolination/cyano-epoxidation reaction was also achieved.

Supplementary Materials

The following are available online at https://www.mdpi.com/2073-4344/10/10/1177/s1, Detailed experimental procedure, analytical data, Figure S1: nOe experiment of major epoxide 3, Figure S2: ESI-MS analysis of a mixture of N-PFB-PyBidine (L10)-Zn(OAc)2 complex, 1a (1 eq) and NaHCO3 (1 eq) in CH2Cl2, Figure S3: 1H-NMR study of L10-Zn(OAc)2 complex, 1a (1 eq), NaHCO3 (1 eq), and CD3OD (50 eq) in CDCl3.

Author Contributions

Conceptualization and writing—original draft preparation, T.A.; experiment, J.M., T.S., and S.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by JSPS KAKENHI in Grant-in-Aid for Scientific Research (B), grant number 19H02709, and a project of JSPS and DAAD under the Japan–Germany Research Cooperative Program (JPJSBP120193506).

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 10 01177 sch001 550
Scheme 1. General applicability of β-ketoesters. 15 mol % of catalyst were used. 2 N-bromosuccinimide (NBS) was used instead of N-chlorosuccinimide (NCS).
Scheme 1. General applicability of β-ketoesters. 15 mol % of catalyst were used. 2 N-bromosuccinimide (NBS) was used instead of N-chlorosuccinimide (NCS).
Catalysts 10 01177 sch001
Catalysts 10 01177 sch002 550
Scheme 2. Synthesis of chiral epoxide 3: (a) stepwise synthesis; (b) one-pot synthesis.
Scheme 2. Synthesis of chiral epoxide 3: (a) stepwise synthesis; (b) one-pot synthesis.
Catalysts 10 01177 sch002
Catalysts 10 01177 g001 550
Figure 1. Proposed reaction mechanism of asymmetric chlorination of β-ketoesters catalyzed by N-PFB-PyBidine (L10)-Zn(OAc)2 complex: (a) catalytic cycle; (b) reaction model.
Figure 1. Proposed reaction mechanism of asymmetric chlorination of β-ketoesters catalyzed by N-PFB-PyBidine (L10)-Zn(OAc)2 complex: (a) catalytic cycle; (b) reaction model.
Catalysts 10 01177 g001
Catalysts 10 01177 g002 550
Figure 2. (a) ESI-MS analysis and (b) 1H-NMR study in CDCl3.
Figure 2. (a) ESI-MS analysis and (b) 1H-NMR study in CDCl3.
Catalysts 10 01177 g002
Catalysts 10 01177 sch003 550
Scheme 3. Reaction using N,N-Me4-PyBidine-Zn(OAc)2.
Scheme 3. Reaction using N,N-Me4-PyBidine-Zn(OAc)2.
Catalysts 10 01177 sch003
Table
Table 1. First screening of metal catalysts for asymmetric chlorination of β-ketoester.
Table 1. First screening of metal catalysts for asymmetric chlorination of β-ketoester.
Catalysts 10 01177 i001
Catalysts 10 01177 i002
EntryLigandMetal SaltYield (%) ee (%)
1L1FeCl2944
2L1Co(OAc)215442
3L1CoCl23427
4L1Ni(OAc)216428
5L1Cu(OAc)25710
6L1Cu(OTf)22322
7L1Zn(OAc)26060
8L1Zn(OBz)28556
9L1ZnCl213−21
10L1Zn(OTf)22221
11L2Zn(OAc)24121
12L3Zn(OAc)290−6
13L4Zn(OAc)29813
14L5Zn(OAc)25215
1 Tetrahydrate was used.
Table
Table 2. Optimization of asymmetric chlorination of β-ketoester catalyzed by PyBidine-Zn(OAc)2.
Table 2. Optimization of asymmetric chlorination of β-ketoester catalyzed by PyBidine-Zn(OAc)2.
Catalysts 10 01177 i003
Catalysts 10 01177 i004
Catalysts 10 01177 i005
EntryLigandSolventChlorinating ReagentAdditive 1Yield
(%)		Ee
(%)
1L1tolueneNCS-6060
2L6tolueneNCS-6241
3L7toluene NCS-9266
4L8tolueneNCS-6968
5L9toluene NCS-2565
6L10tolueneNCS-8670
7L10EtOAc NCS-8835
8L10Et2ONCS-6757
9L10CH2Cl2NCS-3853
10L10CCl4NCS-7877
11L10cyclohexaneNCS-8579
12L10cyclohexaneNCP-9275
13L10cyclohexaneTCC-4226
14L10cyclohexaneDCH-4723
15L10cyclohexaneChloramine-T-959
16L10cyclohexaneNCSK2CO39659
17L10cyclohexaneNCSTEA9565
18L10cyclohexaneNCSNaHCO39978
1 10 mol % were added.

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Ma, J.; Suzuki, T.; Kuwano, S.; Arai, T. Catalytic Asymmetric Chlorination of β-Ketoesters Using N-PFB-PyBidine-Zn(OAc)2. Catalysts 2020, 10, 1177. https://doi.org/10.3390/catal10101177

AMA Style

Ma J, Suzuki T, Kuwano S, Arai T. Catalytic Asymmetric Chlorination of β-Ketoesters Using N-PFB-PyBidine-Zn(OAc)2. Catalysts. 2020; 10(10):1177. https://doi.org/10.3390/catal10101177

Chicago/Turabian Style

Ma, Junma, Takumi Suzuki, Satoru Kuwano, and Takayoshi Arai. 2020. "Catalytic Asymmetric Chlorination of β-Ketoesters Using N-PFB-PyBidine-Zn(OAc)2" Catalysts 10, no. 10: 1177. https://doi.org/10.3390/catal10101177

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