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

: A PyBidine-Zn(OAc) 2 complex catalyzed asymmetric chlorination of β -ketoesters. With assistance of NaHCO 3 , 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.


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].
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)-CoCl 2 complex [36]. 2 of 9 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.

Results
Initially, a study was done to determine the appropriate catalyst for asymmetric chlorination of β-ketoesters.

Results
Initially, a study was done to determine the appropriate catalyst for asymmetric chlorination of β-ketoesters.
Catalysts 2020, 10, x FOR PEER REVIEW 2 of 9 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.

Results
Initially, a study was done to determine the appropriate catalyst for asymmetric chlorination of β-ketoesters.
With the optimized reaction conditions in hand, the generality of β-ketoesters was examined in Scheme 1.
With the optimized reaction conditions in hand, the generality of β-ketoesters was examined in Scheme 1.

Scheme 1.
General applicability of β-ketoesters. 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 βketoester 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. 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.
Catalysts 2020, 10, x FOR PEER REVIEW 5 of 9 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 1,2addition 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.  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.  (Figure 2a). Furthermore, in the 1 H-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).  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., NaHCO 3 ). Enolate B reacts with the chlorinating reagent (NCS) to give the product along with regeneration of the catalyst.

Discussion
Catalysts 2020, 10, x FOR PEER REVIEW 5 of 9 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 1,2addition 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.  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.   The PyBim (L3)-Zn(OAc) 2 gave (R)-2a with only 6% ee (Table 1, entry 11), and an N,N-Me 4 -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].

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.

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.

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 NaHCO 3 (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.

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.