Organocatalytic aldol and domino Michael-aldol reactions of α,α-difluoro-β-keto esters with acetone

Journal of Fluorine Chemistry 165 (2014) 61–66

Contents lists available at ScienceDirect

Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor

Organocatalytic aldol and domino Michael-aldol reactions of a, a-difluoro-b-keto esters with acetone Yan Zhao, Xiao-Jin Wang, Chen-Xin Cai, Jin-Tao Liu * Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China

A R T I C L E I N F O

A B S T R A C T

Article history: Received 21 April 2014 Received in revised form 11 June 2014 Accepted 13 June 2014 Available online 23 June 2014

Organocatalyzed reactions of a,a-difluoro-b-keto esters with acetone were demonstrated. In the presence of L-proline, the Aldol reaction occurred under mild conditions to give the corresponding tertiary a,a-difluoroalcohols in good yields with high enantioselectivities. Using pyrrolidine as catalyst, the domino Michael-aldol reaction took place readily to give the corresponding addition products in high yields with excellent diastereoselectivities. ß 2014 Elsevier B.V. All rights reserved.

Keywords: a,a-Difluoro-b-keto ester Aldol reaction Domino Michael-aldol reaction Stereoselectivity

1. Introduction In the past decades, fluorinated organic compounds have found widespread applications in many fields such as drugs [1], materials and synthetic chemistry [2,3]. The introduction of a difluoromethylene group into bioactive peptides has led to the discovery of potent protease inhibitors mimicking the transition state for hydrolytic amide bond cleavage. Thus, optically active a,adifluoro-b-hydroxy esters must be among the important chiral building blocks for these bioactive fluorinated compounds [4]. Although many methodologies have been developed for the introduction of difluoromethylene moiety, stereo-controlled synthesis of difluoromethylene-containing compounds still remains a big challenge for chemists [5]. In 1995, Braun et al. reported the Reformatsky reaction of aldehydes with methyl bromodifluoroacetate in the presence of stoichiometric amounts of chiral amino alcohols to afford the corresponding a,a-difluoro-b-hydroxy esters with good enantioselectivities [6]. However, this transformation is less effective with respect to enantioselectivity when using substoichiometric quantities of the chiral ligands. In 1997,Iseki et al. reported that the catalytic, asymmetric Mukaiyama-aldol reaction of difluoroketene ethyl trimethylsilyl acetal could be catalyzed by chiral Lewis acids in a highly enantioselective manner, but forcing conditions were required [7]. In recent years, asymmetric synthesis using metal-free organic molecules as catalysts has attracted increasing attention [8]. The work by List, Barbas III and their co-workers using L-proline to * Corresponding author. Tel.: +86 21 54925188. E-mail address: [email protected] (J.-T. Liu). http://dx.doi.org/10.1016/j.jfluchem.2014.06.010 0022-1139/ß 2014 Elsevier B.V. All rights reserved.

catalyze direct intermolecular aldol reactions has triggered a broad interest in organocatalysis [9]. Subsequently, many proline analogues have been developed for the aldol process aimed at improving reactivity, broadening substrate scope and enhancing stereoselectivity [8]. Since recently, our group is interested in the asymmetric construction of fluorinated building blocks from available substrates by organocatalysis, and has reported the organocatalyzed aldol reaction [10a] and domino Michael-aldol reaction [10b] of a,b-unsaturated trifluoromethyl ketones with acetone. To extend this investigation, we further studied the control of selectivity in the reaction of unsaturated a,a-difluoro-bketo esters with acetone, which resulted in the formation of different chiral multifunctionalized fluorinated building blocks. The results are reported in this paper. 2. Results and discussion Initially, the reaction of a,a-difluoro-b-keto ester 1a and acetone in the presence of L-proline (I) was investigated. When acetone was used as solvent, the reaction afforded the corresponding aldol addition product 2a as the major product, as well as domino Michael-aldol product 3a as a side product, which was not formed in significant amounts in the case of a,b-unsaturated trifluoromethyl ketones under the same conditions [10,11]. Disappointedly, only moderate enantiomeric excess (69% ee) for 2a was obtained. The diastereoselectivity of 3a was quite good as shown by 19F NMR, but poor enantioselectivity was obtained (Table 1, entry 1). The relative conformation of 3a was determined by X-ray crystallography. As shown in Fig. 1, both phenyl and CF2COOEt group are found in the equatorial position [12], the same

Y. Zhao et al. / Journal of Fluorine Chemistry 165 (2014) 61–66

62

Table 1 Catalyst screening and reaction conditions optimization.

(I) (II) III

V

IV

VI

Entry

Cat. (X mol%)

Solvent

Temp. (8C)

Time (h)

Conv. (1a, %)

2a:3aa

Ee (2a, %)b

1 2 3 4 5 6 7 8 9 10 11 12 13

I (20) II (20) III (20) IV (20) V (20) VI (20) I (20) I (20) I (20) I (20) I (10) I (5) I (20)

Acetone Acetone Acetone Acetone Acetone Acetone DMSO Et2O Acetone Acetone:DMSO Acetone:DMSO Acetone:DMSO Acetone:DMSO

rt rt rt rt rt rt rt rt –10 –10 –10 –10 –15

24 10 8 48 6 24 9 48 19 24 36 100 22

100 100 100 50 100 <10 100 50 34 100 100 19 90

72:28 <5:95c <5:95c <5:95c >95:5 – 65:35 >95:5 74:26 >95:5 >95:5 >95:5 >95:5

69 – 30d 26d 44 Nd 65 61 92 91 92 91 92

a b c d

(2:1) (2:1) (2:1) (2:1)

Determined by 19F NMR of the crude product. Determined by chiral HPLC analysis. The dr value of 3a was >95:5. The ee value of product 3a, determined by HPLC analysis.

stereochemistry for the domino product from the reaction of unsaturated trifluoromethyl ketone and acetone [11]. As the modification of the catalyst structure has substantial effect on the regioselectivity and stereoselectivity, a variety of pyrrolidine derivatives were screened to improve the selectivity of the reaction. As shown in Table 1, pyrrolidine (II) only afforded domino Michaelaldol product 3a with 95:5 dr under mild conditions (Table 1, entry 2). Catalyst III and IV also catalyzed the reaction efficiently and gave predominantly the domino Michael-aldol product 3a with high diastereoselectivities but poor enantioselectivities (entries 3–4). On the contrary, N-sulfonyl-amined catalyst V gave the aldol product 2a predominantly, but low enantioselectivity was also obtained (entry 5). In the case of catalyst VI, the reaction became very slow and only trace of product was obtained (entry 6). Furthermore, we screened a range of reaction parameters to find a suitable protocol for the selective formation of aldol product

Fig. 1. ORTEP representation of the crystal structure of 3a.

with high enantioselectivity. Using L-proline as the catalyst, the influence of solvent was examined. The addition reaction of acetone and 1a proceeded faster in DMSO, but the selectivities were not improved (Table 1, entry 7). Although the regioselectivity was high in Et2O, we encountered low reaction rate and conversion (entry 8). Sequentially, we inspected the reaction temperature. By performing the reaction at 10 8C, major product 2a was isolated in good enantioselectivity in spite of low conversion (entry 9). Inspired by the results, we tried using acetone and DMSO as cosolvent, which usually promoted the rate of reaction. To our delight, the combination of acetone and DMSO with a ratio of 2:1 not only increased the conversion obviously, but also led to higher regioselectivity while maintaining the optimal enantioselectivity (entry 10). Further experiments indicated that the catalyst loading could be lowered down to 10 mol% without any erosion in yield and selectivity, but lowering temperature to 15 8C could not improve the selectivity any further (entries 11–13). Therefore, the best result with respects to both regio- and enantio-selectivity was achieved by carrying out the reaction at 10 8C in a mixed solvent of acetone and DMSO with a ratio of 2:1 (entry 12). We next investigated the aldol reaction of various unsaturated ketones with acetone at 10 8C in the presence of 10 mol% Lproline. As shown in Table 2, all reactions gave the expected adducts 2 in good to excellent yields (84–91%) with good enantioselectivities (83–96% ee) [13]. The electronic property of the substituents in aromatic rings had very limited effect on the selectivities of the reaction. Aromatic unsaturated ketones 1, regardless of electro-donating and electro-withdrawing substituents in the phenyl ring, participated in this process with high efficiency (Table 2, entries 1–5). Furthermore, unsaturated keto ester with furyl, naphthyl or alkyl substituents proceeded well under the optimal reaction conditions (Table 2, entries 6–9). Additionally, the bulky isopropyl ester 1j was also investigated under the standard conditions. The reaction gave the desired aldol product 2j in 88% yield with 91% ee (Scheme 1, Eq. 1). To further extend the substrate, butanone was subjected to the reaction; the

Y. Zhao et al. / Journal of Fluorine Chemistry 165 (2014) 61–66

63

Table 2 The scope of ketones 1.

L-proline(10 mol%)

Entrya

1, R

Time (h)

2:3b

Yield (2, %)c

Ee (2, %)d

1 2 3 4 5 6 7 8 9

1a, C6H5 1b, 4-ClC6H4 1c, 4-BrC6H4 1d, 4-MeOC6H4 1e, 2,4-Cl2C6H3 1f, 1-naphthyl 1g, 2-furyl 1h, C6H5(CH2)2 1i, C3H7

36 46 44 40 40 40 24 33 48

>95:5 94:6 >95:5 >95:5 >95:5 90.5:9.5 >95:5 92:8 >95:5

85 81 85 89 89 83 84 90 86

92 95 91 92 89 93 83 93 96

a b c d

Reaction conditions: 1 (0.2 mmol), L-proline (0.02 mmol), acetone (1.4 mL), DMSO (0.7 mL) at -10 8C. Determined by 19F NMR of the crude product. Isolated yield. Determined by chiral HPLC analysis.

L-proline(10 mol%) yield,

L-proline(20 mol%) yield, Scheme 1. The aldol reaction of 1j or butanone.

L-proline(20 mol%) yield,

L-proline(20 mol%) yield,

Scheme 2. The aldol reactions of phenyl and alkyl substituted a,a-difluoro-b-keto ester.

aldol product 2k was obtained with high enantioselectivity (96% ee) but in low yield (Scheme 1, Eq. 2). Finally, to evaluate the effect of the substituent on the a,adifluoro-b-keto esters, phenyl and alkyl substituted a,a-difluorob-keto ester 1l and 1m were examined respectively. Their aldol reactions suffered from slow reaction rate, as well as a decrease of enantioselectivity (Scheme 2). The poor reactivity and selectivity were also reported by London in the case of alkyl substituent [14]. Such a selectivity drop demonstrated that the conjugated system of a,b-unsaturated ketone is an important advantage for achieving high enantioselectivity. Since all these aldol products 2 were oil-like and not qualified for X-ray analysis, it is difficult to determine the absolute configuration of the new generated chiral center. Attempts to get crystal sample by modifying the products without changing the absolute configuration were not successful. Proline-catalyzed aldol reaction has been intensively investigated, and the stereoselectivity can be well explained by the mechanism of the reaction. We have previously reported the aldol reactions of CF3-substitued a,bunsaturated ketones with acetone and gave the absolute configuration of products as S [10a]. Considering the mechanism of aldol reaction and the structural similarity of both substrates, we

tentatively assume that the CF2COOEt substituted aldol products have the same absolute configuration as CF3-substitued ones. The scope of domino Michael-aldol reaction of acetone and a,a-difluoro-b-keto esters 1 using pyrrolidine as the catalyst was also explored. Under mild conditions, the reactions performed smoothly to give the corresponding products 3 in good yields with excellent diastereoselectivities. The results are summarized in Table 3. The reaction showed a wide scope for the structural variation of unsaturated ketones 1. High yields were obtained not Table 3 The domino Michael-aldol reaction of acetone and 1. Entrya

1, R

Time (h)

Yield (3, %)b

Dr (3)c

1 2 3 4 5 6

1a, C6H5 1b, 4-ClC6H4 1d, 4-MeOC6H4 1f, 1-naphthyl 1g, 2-furyl 1i, C3H7

10 11 11 11 14 11

3a, 3b, 3c, 3d, 3e, 3f,

>95:5 >95:5 >95:5 >95:5 >95:5 >95:5

92 95 92 93 83 93

a Reaction conditions: 1 (0.2 mmol), pyrrolidine (0.04 mmol) in acetone (1.0 mL) at room temperature. b Isolated yield. c Determined by 19F NMR of the crude product.

64

Y. Zhao et al. / Journal of Fluorine Chemistry 165 (2014) 61–66

only with aryl substituted a,a-difluoro-b-keto esters (Table 3, entries 1–5), but also with alkyl substituted keto ester 1i (entry 6). 3. Conclusion In summary, the selective organocatalyzed addition reaction of acetone with a,a-difluoro-b-keto esters was achieved by choosing appropriate catalyst. Using L-proline as the catalyst, the aldol reaction occurred under mild conditions to give the corresponding tertiary a,a-difluoroalcohols in good yields with high enantioselectivities. While domino Michael-aldol reaction occurred readily to give the corresponding addition products in high yields with excellent diastereoselectivities when pyrrolidine was used as catalyst, we believe that the current research will provide a significant and convenient synthetic method to introduce difluoromethylene moiety into these molecules in a stereo-controlled manner. 4. Experimental 4.1. General Unless otherwise mentioned, solvents and reagents were purchased from commercial sources and used as received. 1H and 13C NMR spectra were recorded on a Bruker AM-300 or AM400 (100 MHz) spectrometer with TMS as internal standard. 19F NMR spectra were taken on a Bruker AM-300 (282 MHz) spectrometer using CFCl3 as external standard. IR spectra were obtained with a Nicolet AV-360 spectrophotometer. Mass spectra and high-resolution mass spectra (HRMS) were obtained on a Finnigan GC-MS 4021 and a Finnigan MAT-8430 spectrometer, respectively. a,a-Difluoro-b-keto esters 1 were prepared according to the reported method [15]. 4.2. Typical procedure for the Aldol reaction of a,a-difluoro-b-keto esters 1 and acetone A solution of 1 (0.2 mmol) and acetone (1.4 mL) in dry DMSO (0.7 mL) was stirred at 10 8C for 5 min. Then L-proline (0.02 mmol) was added and the mixture was stirred for the time specified in Table 2. After the reaction was completed (monitored by TLC), the mixture was quenched by water. The resulted mixture was extracted with ether (3  10 mL), washed with NaCl solution, and dried over Na2SO4. After removal of solvent, the residue was subjected to flash chromatography (eluent: petroleum ether/ethyl acetate = 8:1) on silica gel to give product 2. The results are given in Table 2. 4.3. Typical procedure for the domino Michael-aldol reaction of a,a-difluoro-b-keto esters 1 and acetone

a,a-Difluoro-b-keto esters 1 (0.2 mmol) and pyrrolidine (3.3 mL, 0.04 mmol) were added to acetone (1 mL). The reaction mixture was stirred at room temperature for the time indicated in Table 3. After removal of the solvent, the crude reaction product was directly charged onto the chromatography column and purified on silica gel (PE:EtOAc = 4:1) to afford compound 3. 4.3.1. Compound 2a 53 mg, 85%; Colorless oil; ½a27 D = +6.8 (c = 1.04 in CHCl3). IR (film): 3404, 2987, 1767, 1704, 1313, 1108 cm1. 1H NMR (300 MHz, CDCl3): 7.41  7.28 (m, 5H), 6.83 (d, J = 15.6 Hz, 1H), 6.20 (d, J = 15.6 Hz, 1H), 5.40 (s, 1H), 4.32  4.26 (m, 2H), 3.32 (J = 16.8 Hz, 1H), 2.72 (J = 16.8 Hz, 1H), 2.24 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H). 19F NMR (282 MHz, CDCl3): –115.70 (s, 2F). 13C NMR (75 MHz, CDCl3): 209.65, 162.77 (t, J = 31.2 Hz), 135.89, 132.67, 128.64, 128.23, 126.86, 125.59, 114.69 (t, J = 259.5 Hz), 76.56 (t, J = 24.7 Hz), 63.05, 44.21, 32.13, 13.91. MS (EI, 70 ev): m/z

(%): 312 (M+, 0.84), 131 (100.00). HRMS: Calcd for C16H18F2O4: 312.1173, found: 312.1169. The chiral HPLC analytical data: chiralpak IC column, detected at 214 nm, eluent: n-hexane/iso-propanol = 95/5, 0.6 mL/min, retention times: tR (minor) = 25.73 min, tR (major) = 26.67 min. 4.3.2. Compound 2b 56 mg, 81%; Colorless oil; ½a25 D = +29.4 (c = 1.94 in CHCl3). IR (film): 3403, 2986, 1767, 1705, 1312, 1096 cm1. 1H NMR (300 MHz, CDCl3): 7.34  7.30 (m, 4H), 6.80 (d, J = 15.9 Hz, 1H), 6.17 (d, J = 15.9 Hz, 1H), 5.46 (s, 1H), 4.31  4.27 (m, 2H), 3.34 (J = 16.8 Hz, 1H), 2.69 (J = 16.8 Hz, 1H), 2.25 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H). 19F NMR (282 MHz, CDCl3): 115.62 (d, J = 4.5 Hz, 2F). 13C NMR (100 MHz, CDCl3): 209.53, 162.67 (t, J = 31.2 Hz), 134.40, 133.94, 131.45, 128.81, 128.05, 126.30, 114.60 (t, J = 259.6 Hz), 76.52 (t, J = 24.7 Hz), 63.06, 44.12, 32.07, 13.91. MS (EI, 70 ev): m/z (%): 346 (M+, 0.98), 165 (100.00). HRMS: Calcd for C16H17ClF2O4: 346.0783, found: 346.0789. The chiral HPLC analytical data: chiralpak OD column, detected at 214 nm, eluent: n-hexane/iso-propanol = 90/10, 0.7 mL/min, retention times: tR (minor) = 10.08 min, tR (major) = 10.68 min. 4.3.3. Compound 2c 66 mg, 85%; Colorless oil; ½a26 D = +26.4 (c = 0.99 in CHCl3). IR (film): 3420, 2986, 1764, 1705, 1313, 1177 cm1. 1H NMR (300 MHz, CDCl3): 7.45 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 6.77 (d, J = 15.9 Hz, 1H), 6.18 (d, J = 15.9 Hz, 1H), 5.47 (s, 1H), 4.32  4.25 (m, 2H), 3.34 (J = 17.1 Hz, 1H), 2.69 (J = 17.1 Hz, 1H), 2.24 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H). 19F NMR (282 MHz, CDCl3): 115.65 (d, J = 2.0 Hz, 2F). 13C NMR (100 MHz, CDCl3): 209.57, 162.60 (t, J = 31.2 Hz), 134.75, 131.71, 131.45, 128.30, 126.29, 122.04, 114.52 (t, J = 259.8 Hz), 76.47 (t, J = 24.6 Hz), 63.04, 43.97, 32.05, 13.87. MS (EI, 70 ev): m/z (%): 390 (M+, 1.46), 209 (100.00). HRMS: Calcd for C16H17BrF2O4: 390.0278, found: 390.0279. The chiral HPLC analytical data: chiralpak OD column, detected at 214 nm, eluent: n-hexane/iso-propanol = 95/5, 0.8 mL/min, retention times: tR (minor) = 13.58 min, tR (major) = 14.58 min. 4.3.4. Compound 2d 61 mg, 89%; Colorless oil; ½a26 D = +26.3 (c = 1.49 in CHCl3). IR (film): 3420, 1766, 1705, 1514, 1251, 1177 cm1. 1H NMR (300 MHz, CDCl3): 7.33 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 15.9 Hz, 1H), 6.05 (d, J = 15.9 Hz, 1H), 5.37 (s, 1H), 4.31  4.26 (m, 2H), 3.81 (s, 3H), 3.29 (J = 16.2 Hz, 1H), 2.73 (J = 16.2 Hz, 1H), 2.24 (s, 3H), 1.26 (t, J = 6.9 Hz, 3H). 19F NMR (282 MHz, CDCl3): –115.78 (d, J = 7.3 Hz, 2F). 13C NMR (100 MHz, CDCl3): 209.59, 162.81 (t, J = 31.2 Hz), 159.71, 132.07, 128.65, 128.26, 123.22, 114.70 (t, J = 258.7 Hz), 114.03, 76.50 (t, J = 24.8 Hz), 62.97, 55.28, 44.34, 32.12, 13.89. MS (EI, 70 ev): m/z (%): 342 (M+, 2.82), 161 (100.00). HRMS: Calcd for C17H20F2O5: 342.1279, found: 342.1285. The chiral HPLC analytical data: chiralpak IC column, detected at 214 nm, eluent: n-hexane/iso-propanol = 98/2, 0.8 mL/min, retention times: tR (minor) = 36.13 min, tR (major) = 38.98 min. 4.3.5. Compound 2e 67 mg, 89%; Colorless oil; ½a25 D = +30.4 (c = 1.23 in CHCl3). IR (film): 3393, 2984, 1765, 1705, 1312, 1103 cm1. 1H NMR (300 MHz, CDCl3): 7.43 (d, J = 8.7 Hz, 1H), 7.37 (s, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 15.9 Hz, 1H), 6.19 (d, J = 15.9 Hz, 1H), 5.48 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 3.34 (J = 16.8 Hz, 1H), 2.74 (J = 16.8 Hz, 1H), 2.27 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). 19F NMR (282 MHz, CDCl3): 114.77, 115.98 (JAB = 249.6 Hz, 2F). 13C NMR (100 MHz, CDCl3): 209.39, 162.57 (t, J = 31.3 Hz), 134.26, 134.00, 132.88, 129.47, 128.06, 128.00, 127.27, 114.53 (t, J = 259.8 Hz), 76.61 (t, J = 24.9 Hz), 63.17, 43.90, 32.08, 13.90. MS (EI, 70 ev): m/z

Y. Zhao et al. / Journal of Fluorine Chemistry 165 (2014) 61–66

65

(%): 380 (M+, 1.19), 199 (100.00). HRMS: Calcd for C16H16Cl2F2O4: 380.0394, found: 380.0385. The chiral HPLC analytical data: chiralpak OD column, detected at 214 nm, eluent: n-hexane/iso-propanol = 95/5, 0.7 mL/min, retention times: tR (major) = 13.26 min, tR (minor) = 14.47 min.

MS (ESI): 279 (M + H+). HRMS: Calcd for C13H21F2O4: 279.1400, found: 279.1402. The chiral HPLC analytical data: chiralpak OB-H column, detected at 214 nm, eluent: n-hexane/ethanol = 95/5, 0.7 mL/min, retention times: tR (major) = 10.66 min, tR (minor) = 11.96 min.

4.3.6. Compound 2f 1 60 mg, 83%; Colorless oil; ½a27 D = +58.3 (c = 1.08 in CHCl3). H NMR (300 MHz, CDCl3): 8.07 (d, J = 15.9 Hz, 1H), 7.85-7.78 (m, 2H), 7.63  7.41 (m, 5H), 6.20 (d, J = 15.9 Hz, 1H), 5.53 (s, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.33 (J = 16.8 Hz, 1H), 2.79 (J = 16.8 Hz, 1H), 2.25 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H). 19F NMR (282 MHz, CDCl3): –115.55 (JAB = 10.2 Hz, 2F). 13C NMR (100 MHz, CDCl3): 209.63, 162.75 (t, J = 31.8 Hz), 133.97, 133.53, 130.34, 129.04, 128.91, 126.48, 126.24, 125.69, 125.49, 125.26, 124.16, 123.80, 114.70 (t, J = 259.3 Hz), 76.70 (t, J = 24.6 Hz), 63.09, 44.23, 32.13, 13.90. IR (film): 3398, 2986, 1766, 1705, 1313, 1109 cm1. MS (EI, 70 ev): m/ z (%): 362 (M+, 12.17), 181 (100.00). HRMS: Calcd for C20H20F2O4: 362.1330, found: 362.1328. The chiral HPLC analytical data: chiralpak IC column, detected at 214 nm, eluent: n-hexane/iso-propanol = 95/5, 0.8 mL/min, retention times: tR (minor) = 19.73 min, tR (major) = 21.13 min

4.3.10. Compound 2j 57 mg, 88%; Colorless oil; ½a26 D = +28.9 (c = 1.36 in CHCl3). IR (film): 3391, 2987, 1763, 1704, 1309, 1099 cm1. 1H NMR (300 MHz, CDCl3): 7.36 – 7.21 (m, 5H), 6.76 (d, J = 15.9 Hz, 1H), 6.15 (d, J = 15.9 Hz, 1H), 5.35 (s, 1H), 5.08 – 5.04 (m, 1H), 3.26 (J = 16.8 Hz, 1H), 2.66 (J = 16.8 Hz, 1H), 2.18 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H). 19F NMR (282 MHz, CDCl3): –115.00, –115.43 (JAB = 253.7, 2F). 13C NMR (100 MHz, CDCl3): 209.58, 162.17 (t, J = 31.3 Hz), 135.85, 132.47, 128.59, 128.16, 126.79, 125.67, 114.53 (t, J = 259.8 Hz), 76.55 (t, J = 25.3 Hz), 71.43, 44.17, 32.12, 21.42. MS (EI, 70 ev): m/z (%): 326 (M+, 1.04), 131 (100.00). HRMS: Calcd for C17H20F2O4: 326.1330, found: 326.1334. The chiral HPLC analytical data: chiralpak OD column, detected at 214 nm, eluent: n-hexane/iso-propanol = 90/10, 0.8 mL/min, retention times: tR (minor) = 8.09 min, tR (major) = 10.49 min.

4.3.7. Compound 2g 51 mg, 84%; Colorless oil; ½a26 D = +7.9 (c = 1.07 in CHCl3). IR (film): 3401, 2986, 1763, 1703, 1313, 1107 cm1. 1H NMR (300 MHz, CDCl3): 7.33 (s, 1H), 6.63 (d, J = 15.9 Hz, 1H), 6.35 (t, J = 3.0 Hz, 1H), 6.26 (d, J = 3.0 Hz, 1H), 6.10 (d, J = 15.9 Hz, 1H), 5.39 (s, 1H), 4.30–4.24 (m, 2H), 3.27 (J = 17.1 Hz, 1H), 2.67 (J = 17.1 Hz, 1H), 2.22 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H). 19F NMR (282 MHz, CDCl3): -115.69 (s, 2F). 13C NMR (100 MHz, CDCl3): 209.79, 162.70 (t, J = 32.0 Hz), 151.66, 142.50, 123.78, 120.95, 114.53 (t, J = 259.8 Hz), 111.43, 109.69, 76.35 (t, J = 25.3 Hz), 63.01, 44.11, 32.09, 13.81. MS (EI, 70 ev): m/z (%): 302 (M+, 3.78), 121 (100.00). HRMS: Calcd for C14H16F2O5: 302.0966, found: 302.0960. The chiral HPLC analytical data: chiralpak OD-H column, detected at 214 nm, eluent: n-hexane/iso-propanol = 90/10, 0.8 mL/min, retention times: tR (minor) = 13.58 min, tR (major) = 15.83 min.

4.3.11. Compound 2k 22 mg, 33%; Colorless oil; ½a24 D = +13.1 (c = 1.42 in CHCl3). IR (film): 3391, 2983, 1766, 1700, 1313, 1119 cm1. 1H NMR (300 MHz, CDCl3): 7.41 – 7.24 (m, 5H), 6.83 (d, J = 15.6 Hz, 1H), 6.20 (d, J = 15.6 Hz, 1H), 5.62 (s, 1H), 4.34 – 4.25 (m, 2H), 3.28 (J = 16.8 Hz, 1H), 2.70 (J = 16.8 Hz, 1H), 2.62 – 2.46 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H). 19F NMR (282 MHz, CDCl3): –115.70 (s, 2F). 13C NMR (100 MHz, CDCl3): 212.40, 162.71 (t, J = 31.5 Hz), 135.93, 132.54, 128.59, 128.15, 126.80, 125.70, 114.73 (t, J = 259.1 Hz), 76.60 (t, J = 25.0 Hz), 62.96, 43.07, 38.15, 13.87, 7.12. MS (EI, 70 ev): m/z (%): 326 (M+, 0.90), 131 (100.00). HRMS: Calcd for C17H20F2O4: 326.1330, found: 326.1332. The chiral HPLC analytical data: chiralpak OD column, detected at 214 nm, eluent: n-hexane/iso-propanol = 80/20, 0.8 mL/min, retention times: tR (minor) = 6.38 min, tR (major) = 7.63 min.

4.3.8. Compound 2h 61 mg, 90%; Colorless oil; ½a27 D = +5.4 (c = 1.30 in CHCl3). IR (film): 3398, 2986, 1763, 1700, 1313 cm1. 1H NMR (300 MHz, CDCl3): 7.19 – 7.07 (m, 5H), 5.90 – 5.82 (m, 1H), 5.42 (d, J = 15.3 Hz, 1H), 5.05 (s, 1H), 4.23 (m, 2H), 2.96 – 2.31 (m, 6H), 2.08 (s, 3H), 1.25 (t, J = 6.6 Hz, 3H). 19F NMR (282 MHz, CDCl3): –115.34 (d, J = 11.3 Hz, 2F). 13C NMR (100 MHz, CDCl3): 209.62, 162.87 (t, J = 32.0 Hz), 141.27, 133.56, 128.38, 128.29, 126.91, 125.86, 114.52 (t, J = 258.3 Hz), 75.92 (t, J = 25.3 Hz), 62.91, 44.13, 35.23, 33.79, 32.06, 13.91. MS (ESI): 363 (M + Na+). HRMS: Calcd for C18H22F2O4Na: 363.1374, found: 363.1378. The chiral HPLC analytical data: chiralpak IC column, detected at 214 nm, eluent: n-hexane/iso-propanol = 95/5, 0.8 mL/min, retention times: tR (major) = 20.87 min, tR (minor) = 25.77 min. 4.3.9. Compound 2i 48 mg, 86%; Colorless oil; ½a26 D = +4.24 (c = 1.55 in CHCl3). IR (film): 3401, 2964, 1766, 1706, 1312, 1132 cm1. 1H NMR (300 MHz, CDCl3): 5.98 – 5.88 (m, 1H), 5.51 (d, J = 15.0 Hz, 1H), 5.10 (brs, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.19 (J = 16.5 Hz, 1H), 2.72 (J = 16.5 Hz, 1H), 2.25 (s, 3H), 2.16 – 2.04 (m, 2H), 1.46 – 1.31 (m, 5H), 0.91 (t, J = 7.2 Hz, 3H). 19F NMR (282 MHz, CDCl3): –115.23, – 115.81 (JAB = 251.4 Hz, 2F). 13C NMR (100 MHz, CDCl3): 209.61, 162.92 (t, J = 32.0 Hz), 134.49, 126.26, 114.54 (t, J = 259.0 Hz), 75.94 (t, J = 24.6 Hz), 62.89, 44.31, 34.12, 32.13, 21.98, 13.88, 13.44.

4.3.12. Compound 2l 52 mg, 91%; Colorless oil; ½a26 D = +21.63 (c = 0.95 in CHCl3). IR (film): 3391, 2983, 1766, 1700, 1313, 1119 cm1. 1H NMR (300 MHz, CDCl3): 7.54 – 7.51 (m, 2H), 7.40 – 7.33 (m, 3H), 5.46 (s, 1H), 4.20 (q, J = 6.9 Hz, 2H), 3.38 (s, 2H), 2.15 (s, 3H), 1.19 (t, J = 6.9 Hz, 3H). 19 F NMR (282 MHz, CDCl3): –113.09, –115.20 (JAB = 249.6 Hz, 2F). 13 C NMR (100 MHz, CDCl3): 209.90, 162.87 (t, J = 31.2 Hz), 138.29, 128.48, 128.35, 126.23, 114.47 (t, J = 258.3 Hz), 77.07 (t, J = 24.8 Hz), 62.94, 45.23, 32.13, 13.70. MS (ESI): 309 (M + Na+). HRMS: Calcd for C14H16F2O4Na: 309.0905, found: 309.0909. The chiral HPLC analytical data: chiralpak IC column, detected at 214 nm, eluent: n-hexane/iso-propanol = 90/10, 0.8 mL/min, retention times: tR (major) = 14.28 min, tR (minor) = 21.38 min. 4.3.13. Compound 2m 59 mg, 94%; Colorless oil; ½a27 D = +2.8 (c = 0.81 in CHCl3). IR (film): 3396, 2983, 1758, 1702, 1311, 1099 cm1. 1H NMR (300 MHz, CDCl3): 7.31 – 7.17 (m, 5H), 5.52 (s, 1H), 4.32 (m, 2H), 3.23 (J = 17.4 Hz, 1H), 2.50 (J = 17.4 Hz, 1H), 2.81 (td, J1 = 12.9 Hz, J2 = 5.4 Hz, 1H), 2.71 – 2.61 (m, 1H), 2.23 (s, 3H), 2.13 (td, J1 = 14.4 Hz, J2 = 5.4 Hz, 1H), 1.87 (td, J1 = 12.9 Hz, J2 = 5.4 Hz, 1H), 1.36 (t, J = 7.2 Hz, 3H). 19F NMR (282 MHz, CDCl3): –112.35, –116.77 (JAB = 251.3 Hz, 2F). 13C NMR (100 MHz, CDCl3): 211.03, 163.43 (t, J = 31.3 Hz), 140.53, 128.49, 128.35, 126.04, 116.05 (t, J = 258.3 Hz), 76.46 (t, J = 23.8 Hz), 65.00, 42.11, 36.48, 31.76, 29.26, 13.87. MS (EI, 70

66

Y. Zhao et al. / Journal of Fluorine Chemistry 165 (2014) 61–66

ev): m/z (%): 314 (M+, 3.35), 91 (100.00). HRMS: Calcd for C16H20F2O4: 314.1330, found: 314.1331. The chiral HPLC analytical data: chiralpak OD column, detected at 214 nm, eluent: n-hexane/iso-propanol = 90/10, 0.8 mL/min, retention times: tR (minor) = 9.42 min, tR (major) = 10.36 min. 4.3.14. Compound 3a 57 mg, 92%; White solid, mp: 103–105 8C. IR (film): 3391, 1764, 1710, 1313 cm1. 1H NMR (300 MHz, CDCl3): 7.38 – 7.24 (m, 5H), 4.36 (q, J = 7.5 Hz, 2H), 3.46 (tt, J1 = 12.3 Hz, J2 = 3.9 Hz, 1H), 3.23 (brs, 1H), 2.81 – 2.50 (m, 4H), 2.29–2.04 (m, 2H), 1.36 (t, J = 7.5 Hz, 3H). 19F NMR (282 MHz, CDCl3): –116.73, –119.02 (JAB = 259.4 Hz, 2F). 13C NMR (100 MHz, CDCl3): 206.79, 162.83 (t, J = 31.8 Hz), 142.58, 134.25, 128.77, 127.05, 126.68, 114.28 (t, J = 259.0 Hz), 76.72 (t, J = 25.4 Hz), 63.42, 48.07, 45.65, 37.60, 36.21. MS (EI): 312 (M+, 29.84), 171 (100.00). HRMS: Calcd for C16H18F2O4: 312.1173, found: 312.1172. 4.3.15. Compound 3b 66 mg, 95%; White solid, mp: 133–135 8C. IR (film) n: 3397, 1759, 1716, 1311 cm1. 1H NMR (300 MHz, CDCl3) d: 7.31 (m, 2H), 7.19 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 3.44 (m, 1H), 3.28 (s, 1H), 2.79 – 2.45 (m, 4H), 2.25 – 2.08 (m, 2H), 1.36 (t, J = 7.2 Hz, 3H). 19F NMR (282 MHz, CDCl3) d: –116.79, –119.46 (JAB = 259.7 Hz, 2F). 13C NMR (100 MHz, CDCl3) d: 206.37, 162.90 (t, J = 31.9 Hz), 141.60, 132.89, 129.03, 120.17, 114.30 (t, J = 258.8 Hz), 76.99 (t, J = 31.9 Hz), 63.61, 48.07, 45.76, 37.16, 36.19, 13.94. MS (70 ev) m/z (%): 346 (M+, 16.49), 205 (100.00). HRMS: Calcd for C16H17ClF2O4: 346.0783, found: 346.0790. 4.3.16. Compound 3c 63 mg, 92%; White solid, mp: 115–117 8C. IR (film) n: 3314, 1768, 1712, 1515 cm1. 1H NMR (300 MHz, CDCl3) d: 7.08 (d, J = 8.1 Hz, 2H), 6.80 (d, J = 8.1 Hz, 2H), 4.28 (q, J = 7.2 Hz, 2H), 3.72 (s, 3 H), 3.33 (t, J = 12.9 Hz, 1H), 3.20 (brs, 1H), 2.71 – 2.37 (m, 4H), 2.17 – 1.96 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H). 19F NMR (282 MHz, CDCl3) d: – 117.04, –119.20 (JAB = 258.8 Hz, 2F). 13C NMR (100 MHz, CDCl3) d: 207.03, 162.93 (t, J = 31.9 Hz), 158.56, 134.89, 129.27, 127.72, 114.45 (t, J = 258.9 Hz), 77.02 (t, J = 31.9 Hz), 63.46, 55.28, 48.47, 45.72, 36.94, 36.56, 13.90. MS (70 ev) m/z (%): 342 (M+, 12.30), 134 (100.00). HRMS: Calcd for C17H20F2O5: 342.1279, found: 342.1286. 4.3.17. Compound 3d 67 mg, 93%; White solid, mp: 93–94 8C. IR (film) n: 3335, 1763, 1712, 1312 cm1. 1H NMR (300 MHz, CDCl3) d: 8.01 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.53 – 7.39 (m, 4H), 4.40–4.29 (m, 3H), 4.10 (m, 1H), 3.73 (s, 1 H), 2.88 – 2.65 (m, 3H), 2.48 – 2.20 (m, 2H), 1.30 (t, J = 7.5 Hz, 3H). 19F NMR (282 MHz, CDCl3) d: –116.96, –119.13 (JAB = 255.2 Hz, 2F). 13C NMR (100 MHz, CDCl3) d: 207.39, 162.93 (t, J = 31.9 Hz), 138.51, 133.95, 130.90, 129.00, 127.64, 126.45, 125.78, 125.45, 122.60, 122.41, 114.55 (t, J = 258.8 Hz), 77.02 (t, J = 31.9 Hz), 63.48, 47.56, 46.16, 36.24, 32.16, 13.86. MS (70 ev) m/z (%): 362 (M+, 22.01), 43 (100.00). HRMS: Calcd for C20H20F2O4: 362.1330, found: 362.1334. 4.3.18. Compound 3e 50 mg, 83%; White solid, mp: 79–82 8C. IR (film) n: 3351, 1769, 1722, 1307 cm1. 1H NMR (300 MHz, CDCl3) d: 7.35 (s, 1H), 6.31 (s, 1H), 6.08 (d, J = 2.7 Hz, 1H), 4.38 (q, J = 7.5 Hz, 2H), 3.57 – 3.50 (m, 2H), 2.76 – 2.50 (m, 4H), 2.41 – 2.04 (m, 2H), 1.37 (t, J = 7.5 Hz, 3H). 19 F NMR (282 MHz, CDCl3) d: –117.04, –119.46 (JAB = 260.0 Hz, 2F). 13 C NMR (100 MHz, CDCl3) d: 206.51, 163.13 (t, J = 32.0 Hz), 156.16, 141.92, 117.19 (t, J = 256.0 Hz), 110.39, 104.89, 76.63 (t, J = 25.5 Hz), 63.76, 46.02, 45.49, 34.23, 31.74, 14.14. MS (70 ev) m/z (%): 302 (M+, 34.78), 161 (100.00). HRMS: Calcd for C14H16F2O5: 302.0966, found: 302.0974.

4.3.19. Compound 3f 52 mg, 93%; White solid, mp: 41-43 8C. IR (film) n: 3386, 1755, 1714, 1309 cm1. 1H NMR (300 MHz, CDCl3) d: 4.40 – 4.33 (m, 2H), 3.23 (s, 1H), 2.65 – 2.47 (m, 3H), 2.20 – 1.98 (m, 3H), 1.61 (t, J = 12.9 Hz, 1H), 1.40 – 1.35 (m, 7H), 0.91 (s, 3H). 19F NMR (282 MHz, CDCl3) d: –117.12, –119.46 (JAB = 259.1 Hz, 2F). 13C NMR (100 MHz, CDCl3) d: 208.00, 162.99 (t, J = 31.9 Hz), 114.59 (t, J = 258.9 Hz), 77.06 (t, J = 26.9 Hz), 63.32, 47.10, 45.92, 38.67, 35.25, 31.78, 19.54, 13.98, 13.88. MS (70 ev) m/z (%): 278 (M+, 4.59), 155 (100.00). HRMS: Calcd for C13H20F2O4: 278.1330, found: 278.1335. Acknowledgements This article is financially supported by National Natural Science Foundation of China (Grant number: 21172243).

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jfluchem.2014. 06.010.

References [1] (a) K. Mu¨ller, C. Faeh, F. Diederich, Science 317 (2007) 1881–1886; (b) S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 37 (2008) 320–330; (c) K.K. Laali (Ed.), Modern Organofluorine Chemistry—Synthetic Aspects, 2, Bentham Science Publishers, San Francisco, 2006; (d) V.A. Soloshonok, K. Mikami, T. Yamazaki, J.T. Welch, J.F. Hoenk (Eds.), Current Fluoroorganic Chemistry: New Synthetic Directions, Technologies, Materials and Biological Applications, American Chemical Society, Washington, DC, 2007; (e) J. Wang, M. Sanchez-Rosello´, J.L. Acen˜a, C.D. Pozo, A.E. Sorochinsky, S. Fustero, V.A. Soloshonok, H. Liu, Chem. Rev. 114 (2014) 2432–2506. [2] (a) W.K. Hagrman, J. Med. Chem. 51 (2008) 4359–4369; (b) A. Berkessel, A.J. Adrio, J. Am. Chem. Soc. 128 (2006) 13412–13420 (and references cited therein). [3] (a) M. Shimizu, T. Hiyama, Angew. Chem. Int. Ed. 44 (2005) 214–231; (b) J.A. Ma, D. Cahard, Chem. Rev. 104 (2004) 6119–6146; (c) Special issue on ‘‘Fluorine in the Life Sciences’’. ChemBioChem 5 (2004) 557–722. (d) P. Kirsch, Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim, 2004; (e) T. Hiyama, Organofluorine Compounds: Chemistry and Applications, Springer, Berlin, 2000. [4] (a) M.H. Gelb, J.P. Svaren, R.H. Abeles, Biochemistry 24 (1985) 1813–1817; (b) M.H. Gelb, J. Am. Chem. Soc. 108 (1986) 3146–3147; (c) T. Poisson, M.C. Belhomme, X. Pannecoucke, J. Org. Chem. 77 (2012) 9277–9285; (d) K.L. Kirk, in: V.P. Kukhar, V.A. Soloshonok (Eds.), Fluorine-containing Amino Acids, John Wiley and Sons Inc., New York, 1995, p. 343. [5] (a) M.J. Tozer, T.F. Herpin, Tetrahedron 52 (1996) 8619–8683; (b) V.A. Soloshonok, H. Ohkura, A. Sorochinsky, N. Voloshin, A. Markovsky, M. Belik, T. Yamazaki, Tetrahedron Lett. 43 (2002) 5445–5448. [6] M. Braun, A. Vonderhagen, D. Waldmfiller, Liebigs Ann. 1995 (1995) 1447– 1450. [7] (a) K. Iseki, Y. Kuroki, D. Asada, Y. Kobayashi, Tetrahedron Lett. 38 (1997) 1447–1448; (b) K. Iseki, Y. Kuroki, D. Asada, M. Takahashi, S. Kishimoto, Y. Kobayashi, Tetrahedron 53 (1997) 10271–10280. [8] (a) B. List, Acc. Chem. Res. 37 (2004) 548–557; (b) W. Notz, F. Tanaka, C.F. Barbas III, Acc. Chem. Res. 37 (2004) 580–591; (c) S. Mukherjee, J.W. Yang, S. Hoffmann, B. List, Chem. Rev. 107 (2007) 5471–5569; (d) A. Dondoni, A. Massi, Angew. Chem. Int. Ed. 47 (2008) 4638–4660. [9] B. List, R.A. Lerner, C.F. Barbas III, J. Am. Chem. Soc. 122 (2000) 2395–2396. [10] (a) X.J. Wang, Y. Zhao, J.T. Liu, Org. Lett. 9 (2007) 1343–1345; (b) X.J. Wang, Y. Zhao, J.T. Liu, Synthesis 2008 (2008) 3967–3973. [11] (a) D.H. Zhang, C.Y. Yuan, Tetrahedron 64 (2008) 2480–2488; (b) G.F. Zhong, J.H. Fan, C.F. Barbas III, Tetrahedron Lett. 45 (2004) 5681– 5684. [12] CCDC-724907 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk. [13] V.A. Soloshonok, Angew. Chem. Int. Ed. 45 (2006) 766–769 (Asymmetric product 2 was chromatographed on silica gel column before determination of ee values by HPLC. No self-disproportionation of enantiomers was observed under the condition of chromatography by examining the ee values of different fractions, and relative reference). [14] G. London, G. Szo¨llo¨si, M. Barto´k, J. Mol. Catal. A: Chem. 267 (2007) 98–101. [15] R.J. Linderman, D.M. Graves, J. Org. Chem. 54 (1989) 661–668.