Enantioselective fluorination of β -keto esters using a PEG-bound urea-containing chiral quaternary ammonium salt catalyst

The asymmetric fluorination of β -keto esters with N -fluorobisbenzenesulphonimide (NFSI) catalyzed by a PEG-bound urea-containing chiral quaternary ammonium salt is developed. The corresponding products were obtained in good yields and enantioselectivities. The catalyst structure facilitated its recovery and multiple reuse without any loss of activity.


Introduction
Recently, bifunctional chiral quaternary ammonium salt phase transfer catalysts have received much attention for their powerful catalytic activities and steroselectivities in the asymmetric synthesis. 1Of particular note are the scaffolds of urea, 2-4 thiourea 5 and binaphthols, 6 which produced some leading quaternary ammonium salt molecules that exhibit good catalytic activity and steroselectivity.However, these expensive catalysts suffered from the difficulty of recovery, purification and reuse.Immobilization of the catalyst offers a solution to the problem.Among the polymeric matrixes available, an attractive catalyst support for is polyethylene glycol (PEG), because it is soluble in many organic solvents but can be precipitated with diethyl ether. 7A PEGbound catalyst is not only easy to purify and recycle, but is also able to operate in homogeneous conditions.In 2014, Waser reported a urea-containing quaternary ammonium salt 1 (Figure 1), which can promote the enantioselective fluorination of β-keto esters in high yields and ee values. 8Here, we report a method for the preparation of PEG-supported urea-containing quaternary ammonium salt (3) and its application to the asymmetric fluorination of β-keto esters.

Results and Discussion
To attach compound 1 to the soluble support PEG 8000, we hydrolyzed 1 with aqueous NaOH, followed by acidification with HI, whereby the ester group was completely converted into a carboxyl group The salt 2 was separated from the reaction mixture, and esterified with PEG 8000 in the presence of p-TsOH.After precipitation of the PEG-bound catalyst by diethyl ether, we obtained a catalyst 3 in 78% purity.The synthetic route is outlined in Scheme 1.
Scheme 1. Preparation of the PEG-supported catalyst 3.
To assess the efficacy of the polymer-bound catalyst, we chose the reaction of the β-keto ester 4a with N-fluorobisbenzenesulphonimide (NFSI ) in m-xylene and aqueous K 3 PO 4 (0.5 M) at 0 ºC in the presence of 3 (1 mol %) or 1 (2 mol %), respectively, for 24h.It was found that the catalytic activity and the asymmetric induction of 3 are comparable to the homogeneous 1 under the reaction conditions (Table 1, entries 1 and 2).We focused on the use of 3 for further screening efforts.Dropping the temperature to -10 ºC distinctly improved the enantioselectivity (Table 1, entry 3).The selectivity was not improved further by carrying out the reaction at -20 ºC with a prolonged reaction time (Table 1, entry 4).
When more concentrated aqueous K 3 PO 4 (2 M) was used as an additive, the enantioselectivity observed in the product was slightly increased (Table 1, entry 5).Other solvents were tried, but the results indicated that m-xylene was the best choice.Employing the optimized conditions (Table 1, entry 5), the scope of the method in the fluorination reaction was investigated.The results were summarized in Table 2.The nature of the ester group has a great influence on the ee value of the product.For example, a tertiary butyl ester gave a product ee value of 85% (Table 2, entry 1), while the corresponding methyl ester gave the lower selectivity of 72% ee (Table 2, entry 2).The effect of the substituent identity and substitution pattern on the phenyl ring was also studied.Both electron-withdrawing and electrondonating substituents gave the desired products in high enantioselectivity and reasonable yields (Table 2, entries 3 and 4).The substitution at the 5-or 6-position on the aromatic ring of the substrate did not obviously influence the efficiency of the asymmetric induction (Table 2, entries 3 and 4).Substrates with a six-membered ring also underwent the fluorination reaction smoothly and a good ee value and yield were obtained (Table 2, entry 5).Good results were also obtained when a monocyclic five-membered ring β-keto ester was employed (Table 2, entry 6).However, the acyclic ester ethyl α-benzoylpropionate gave a product in low yield and enantioselectivity (Table 2, entry 7). a Isolated yield.b ee was determined by HPLC analysis.
Recycling of catalyst 3 was also studied.The catalyst 3 already employed in entry 1 of Table 2 was reused a second time in the fluorination of 4a to give the product 5a in 96% yield and 85% ee.The recovered catalyst 3 was recycled 6 times without showing any decrease in the catalytic activity.

Conclusion
In summary, PEG-bound urea-containing quaternary ammonium salt homogeneous catalyst has been successfully applied in the enantioselective fluorination reactions of β-keto esters.The corresponding products could be obtained with good enantioselectivity in excellent yields when NFSI was used as fluorination reagent.The PEG-bound catalyst was proved to facilitate the recovery and reuse without affecting the chemical yield and enantioselectivity.

Experimental Section
General. 1 H NMR, 13 C NMR and 19 F NMR spectra were recorded on a Varian Mercury 400 Plus instrument with TMS as internal standard for 1 H NMR, and CDCl 3 for 13 C NMR. CFCl 3 served as an internal standard for 19 F NMR. High-performance liquid chromatography (HPLC) was conducted on an Agilent 1100 liquid chromatograph; HPLC analysis using Diacel chiralcel OD-H column.The urea-containing quaternary ammonium salt 1 was prepared according to reference 8, in optical purity of 99.7% by recrystallization from EtOH / EtOAc.

Preparation of catalyst 3
A solution of 1 (6 g, 10 mmol) and NaOH (440 mg, 11 mmol, 1 mol•L -1 ) in C 2 H 5 OH (12 mL) was stirred at room temperature for 1.5 h.After adjusting the pH to 3 with aqueous HI solution (1 mol•L -1 ), the mixture was concentrated to dryness under reduced pressure.Dry CH 2 Cl 2 (10 mL) was added to the residue and stirred for 10 min.The solid was filtered off and washed well with more dry CH 2 Cl 2 .The organic phases were combined, and PEG 8000 (8 g, 1 mmol) and ptoluenesulfonic acid (0.14 g) was added.The mixture was placed in a pressure-resistant test tube provided with a magnetic stirring bar.The tube was sealed with a septum, placed in the CEM MW device, and subjected to MW irradiation using a power of 100W at 100 °C for 10 min.Upon completion of the reaction, cold diethyl ether (120 mL) was added to the mixture to precipitate the catalyst 3.This was filtered off, thoroughly washed with ice-cold C 2 H 5 OH, and dried in vacuo.In this way 78 % of the polymer was converted to the desired product (purity of catalyst 3 was determined based on the iodine content, found to be 2.17% by Volhard's method).
General procedure for the asymmetric fluorination of β-keto esters.Aqueous K 3 PO 4 (0.25 mL, 1.2 mmol, 2 mol•L -1 ) was added to a mixture of β-keto ester 4 (1.0 mmol) and catalyst 3 (0.12g, 0.01 mmol) or catalyst 1 (0.01g, 0.02 mmol) in m-xylene (10 mL) and the mixture was cooled to -10 °C.N-Fluorobisbenzenesulphonimide (NFSI, 0.38g, 1.2 mmol) was added portionwise over 1h, and the mixture was vigorously stirred for 48 h under an Ar atmosphere.The mixture was concentrated to ca. 3 mL under reduced pressure.Ten volumes (ca.30 ml) of Et 2 O were slowly added to the residue with stirring.The crystalline polymer was collected by filtration, washing and drying in vacuo, and reused for later reactions.All the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the products 5a-g in the reported yields.

Table 1 .
Effects of additives, temperature and solvents on the fluorination a Isolated yield.b ee was determined by HPLC analysis.