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Synlett 2013; 24(3): 375-378
DOI: 10.1055/s-0032-1318027
letter
© Georg Thieme Verlag Stuttgart · New York

Copper(II)-Catalyzed Enantioselective Fluorination of β-Keto Esters Using Chiral Spiro Oxazoline Ligands

Akira Narayama
Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi 441-8580, Japan   Fax: +81(532)485833   Email: shiba@ens.tut.ac.jp
,
Kazutaka Shibatomi*
Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi 441-8580, Japan   Fax: +81(532)485833   Email: shiba@ens.tut.ac.jp
,
Yoshinori Soga
Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi 441-8580, Japan   Fax: +81(532)485833   Email: shiba@ens.tut.ac.jp
,
Tsubasa Muto
Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi 441-8580, Japan   Fax: +81(532)485833   Email: shiba@ens.tut.ac.jp
,
Seiji Iwasa
Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi 441-8580, Japan   Fax: +81(532)485833   Email: shiba@ens.tut.ac.jp
› Author Affiliations
Further Information

Publication History

Received: 25 November 2012

Accepted after revision: 17 December 2012

Publication Date:
10 January 2013 (online)

 
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Abstract

Highly enantioselective fluorination of α-alkyl-β-keto esters was performed using a chiral Lewis acid catalyst prepared from Cu(OTf)2 and chiral spiro oxazoline ligands. The fluorination proceeded in a highly enantioselective manner both when cyclic and acyclic substrates were applied to the reaction. Fluorination of α-alkyl­malonates was also performed to afford the corresponding products in good enantioselectivity.


#

Key words

asymmetric catalysis - fluorination - chiral ligands - ­spiro compounds - Lewis acid

Organofluorine compounds are of considerable interest in both medicinal and agricultural chemistry owing to the unique properties of the fluorine atom.[ 1 ] In particular, chiral compounds with fluorinated stereogenic center(s) are fascinating building blocks for new drug candidates. Therefore, developing a catalytic method for the construction of a fluorinated stereogenic center is obviously an important task.[ 2 ] The first breakthrough related to this issue was made by Togni and Hintermann in 2000. They achieved the enantioselective α-fluorination of β-keto esters with up to 90% ee using a taddol–titanium complex as a Lewis acid catalyst.[ 3a ] Following Togni and Hintermann’s study, a number of catalyst systems for the enantioselective fluorination of active methine compounds have been reported.[3] [4] [5] [6] [7] However, only a few catalysts that can achieve high enantioselectivity for both cyclic and acyclic β-keto esters are known to date.[ 3b,e ] Recently, we have developed a new type of chiral oxazoline ligand 1, which we call SPYMOX, and successfully used it for catalytic asymmetric transformations such as the Pd-catalyzed Tsuji–Trost allylation,[ 8a ] the Cu(II)-catalyzed gem-chlorofluorination of active methylene compounds,[ 3n ] and the Cu(II)-catalyzed α-chlorination of β-oxo esters.[ 8b ] Herein, we describe the application of 1 (Figure [1]) to the enantioselective α-fluorination of α-alkyl-β-keto esters to form a fluorinated quaternary stereogenic center.

Zoom Image
Figure 1 Structures of the chiral spiro oxazoline ligands

Table 1 Optimization of Reaction Conditionsa

Entry

Lewis acid

Ligand

Solvent

Yield (%)b

ee (%)c

 1d

Ni(ClO4)2

1a

CH2Cl2

79

45 (S)

 2

Mg(ClO4)2

1a

CH2Cl2

71

12 (S)

 3

Mn(ClO4)2

1a

CH2Cl2

33

28 (S)

 4

Zn(OTf)2

1a

CH2Cl2

72

41 (S)

 5

Cu(ClO4)2

1a

CH2Cl2

98

84 (S)

 6

Cu(OTf)2

1a

CH2Cl2

95

88 (S)

 7

Cu(OTf)2

1a

THF

97

86 (S)

 8

Cu(OTf)2

1a

benzene

93

94 (S)

 9

Cu(OTf)2

1a

toluene

95

95 (S)

10

Cu(OTf)2

1b

toluene

94

93 (S)

11

Cu(OTf)2

1c

CH2Cl2

94

18 (R)

12

Cu(OTf)2

1d

CH2Cl2

92

 9 (R)

a All reactions were carried out using 1.5 equiv of NFSI in the presence of a Lewis acid catalyst prepared from 12 mol% chiral ligand and 10 mol% Cu(OTf)2.

b Isolated yield.

c Determined by chiral HPLC analysis.

d Hexahydrate of nickel salt was used.

To begin with, several Lewis acidic metal salts were screened in the α-fluorination of 2a with N-fluoro­benzenesulfonimide (NFSI, Table [1]).[9] [10] As shown in entries 1–6, we found that a chiral catalyst prepared from Cu(OTf)2 and 1a gave the desired product 3a with high enantioselectivity. Screening of the reaction solvents showed that the reactions in aromatic solvents afforded the best enantioselectivity (Table [1], entries 8 and 9). Low enantioselectivity was observed when monosubstituted 2-(oxazolinyl)pyridine ligands 1c and 1d were used in the same reaction (Table [1], entries 11 and 12). These results indicate that a binaphthyl backbone attached to an oxazoline ring through a spiro linkage is advantageous for the asymmetric induction.

Table 2 Enantioselective α-Fluorination of β-Keto Estersa

Entry

Product

Ligand

Time (h)

Yield (%)b

ee (%)c

 1
 2

3b

1a
1b

 1
 1

94 (92)d
93

89 (90)d
87

 3
 4

3c

1a
1b

 1
 1 (3)e

77
82 (82)e

75
99 (99)e

 5
 6

3d

1a
1b

 1
 1 (3)e

76
86 (85)e

86
99 (99)e

 7
 8

3e

1a
1b

20
20

76
81

85
99

 9

3f

1b

18

93

90

10

3g

1b

30

90

90

11
12

3h

1a
1b

36
36

83
81

92 (S)
90 (S)

13

3i

1a

16

86

 8

14

3j

1a

42

83

88

a All reactions were carried out using 1.5 equiv of NFSI in the presence of a Lewis acid catalyst prepared from 12 mol% 1 and 10 mol% Cu(OTf)2.

b Isolated yield.

c Determined by chiral GC or HPLC analysis.

d Reaction was carried out in benzene.

e Reactions were carried out with 6 mol% 1b and 5 mol% Cu(OTf)2.

Using the optimized reaction conditions, we attempted to expand the range of possible substrates. As shown in Table [2], various cyclic and acyclic β-keto esters were successfully fluorinated with high enantioselectivity (Table [2]).[9] [10] [11] [12] [13] Oxygen-containing substituent such as an additional ketone and furan ring were well tolerated (Table [2], entries 10 and 14). It was found that a bulky ester substituent is essential for obtaining high selectivity (Table [2], entry 11 vs. entry 13). The pyridine-derived ligand 1a and the quinoline-derived ligand 1b complement each other in this fluorination. For instance, the fluorination of 2c, 2d, and 2e with 1b proceeded with much higher enantioselectivity than was the case for the reactions with 1a. On the other hand, the use of 1a resulted in slightly higher enantioselectivity in the fluorination of 2a, 2b, and 2h than did the use of 1b.

We then carried out the enantioselective α-fluorination of α-alkylmalonates.[ 4b ] The reaction of methyl tert-butyl 2-methylmalonate (4a) in the presence of 30 mol% 1b/Cu(OTf)2 complex afforded the desired α-fluoromalonate 5a with 71% ee (Scheme [1]). The fluorination of methyl di(1-naphthyl)methyl 2-methylmalonate (4b) ­proceeded with higher enantioselectivity (83% ee).

Zoom Image
Scheme 1 Enantioselective α-fluorination of α-alkylmalonates[ 14 ]

A plausible asymmetric induction model is proposed in Figure [2]. The bulky tert-butyl ester would be located on the side opposite the binaphthyl backbone. One of the naphthyl rings on the ligand shields the upper side of the enol complex; thus, the face of nucleophilic attack is ­properly controlled.

Zoom Image
Figure 2 Plausible asymmetric induction model (the ligating solvent and counteranion are omitted for clarity)

In conclusion, we were successful in the highly enantioselective α-fluorination of α-alkyl-β-keto esters and α-alkylmalonates with a Cu(II) complex of chiral spiro oxazoline ligands. Our catalyst works efficiently for the fluorination of both cyclic and acyclic substrates, yielding the corresponding products with high enantioselectivity.


#

Acknowledgment

This study was supported by a Grant-in-Aid for Young Scientists (B) (23750111) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan. We thank the Nippon Synthetic Chemical Industry Co., Ltd. for supplying ethyl iso­cyanoacetate used in the synthesis of chiral ligands.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.
  • Supporting Information

  • References and Notes


      • β-Keto phosphonates:
    • 5a Bernardi L, Jørgensen KA. Chem. Commun. 2005; 1324
    • 5b Hamashima Y, Suzuki T, Shimura Y, Shimizu T, Umebayashi N, Tamura T, Sasamoto N, Sodeoka M. Tetrahedron Lett. 2005; 46: 1447
      CrossrefSearch in Google Scholar
    • 5c Kim SM, Kim HR, Kim DY. Org. Lett. 2005; 7: 2309 ; see also ref. 3f and 3n
      CrossrefSearch in Google Scholar

      α-Cyano esters, α-cyano phosphonates, and α-cyano sulfones:
    • 6a Kim HR, Kim DY. Tetrahedron Lett. 2005; 46: 3115
      Search in Google Scholar
    • 6b Kang YK, Cho MJ, Kim SM, Kim DY. Synlett 2007; 1135
      Thieme Connect
    • 6c Moriya K, Hamashima Y, Sodeoka M. Synlett 2007; 1139
      Thieme Connect
    • 6d Jacquet O, Clément ND, Blanco C, Belmonte MM, Benet-Buchholz J, van Leeuwen PW. N. M. Eur. J. Org. Chem. 2012; 4844
    • 6e Kwon BK, Mang JY, Kim DY. Bull. Korean Chem. Soc. 2012; 33: 2481
      CrossrefSearch in Google Scholar
  • 10 General Procedure for the Asymmetric Fluorination of 2 A flame-dried flask under argon was charged with ligand 1 (0.024 mmol), Cu(OTf)2 (0.020 mmol), activated 4 Ǻ MS (140 mg), and toluene (6 mL). After the mixture was stirred for 1 h at 80 °C, β-keto ester 2 (0.20 mmol), and N-fluorobenzenesulfonimide (0.30 mmol) were added successively, and the mixture was stirred at ambient temperature. The reaction mixture was diluted with sat. NaHCO3 solution and extracted with Et2O. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give the desired product 3. All spectroscopic data of 3a–e, 3h–i, and 5a are in good agreement with those of reported previously. See Supporting Information for details. Spectroscopic characterization data of new compounds are given in the following references.
  • 11 tert-Butyl 2-Fluoro-2-benzyl-3-oxobutanoate (3f) The crude mixture was purified by silica gel column chromatography (hexane–EtOAc = 10:1) to give 93% yield of 3f. 1H NMR (500 MHz, CDCl3): δ = 7.31–7.20 (m, 5 H), 3.38 (dd, 1 H, J = 34.0, 14.9 Hz), 3.33 (dd, 1 H, J = 34.8, 14.9 Hz), 2.13 (d, 3 H, J = 4.9 Hz), 1.41 (s, 9 H). 13C NMR (126 MHz, CDCl3): δ = 202.6 (d, J = 29.3 Hz), 164.7 (d, J = 25.3 Hz), 133.5, 130.5, 128.4, 127.4, 100.1 (d, J = 198.4 Hz), 84.1, 39.5 (d, J = 20.7 Hz), 27.8, 26.1. 19F NMR (470 MHz, CDCl3): δ = –163.6. [α]D 23 +37.9 (c 0.8, CHCl3). FTIR (neat): 2980, 2932, 1750, 1496, 1456, 1424, 1395, 1370, 1286, 1252, 1155, 1086, 839, 742, 701, 526, 442, 420, 410 cm–1. Anal. Calcd (%) for C15H19FO3: C, 67.65; H, 7.19. Found: C, 67.48; H, 7.18. The ee of 3f was determined by HPLC (hexane–2-PrOH = 100:1, 1.0 mL/min) using a CHIRALCEL OJ-H column (0.46 cm × 25 cm): t R (major isomer) = 8.4 min; t R (minor isomer) = 12.0 min.
  • 12 tert-Butyl 2-Acetyl-2-fluoro-4-oxo-4-phenylbutanoate (3g) The crude mixture was purified by silica gel column chromatography (hexane–EtOAc = 5:1) to give 90% yield of 3g. 1H NMR (500 MHz, CDCl3): δ = 7.93 (d, 2 H, J = 8.4 Hz), 7.59 (dd, 1 H, J = 8.4, 7.6 Hz), 7.47 (dd, 2 H, J = 8.0, 7.6 Hz), 3.95 (dd, 1 H, J = 38.2, 18.3 Hz), 3.90 (dd, 1 H, J = 28.3, 18.3 Hz), 2.52 (d, 3 H, J = 5.0 Hz), 1.50 (s, 9 H). 13C NMR (126 MHz, CDCl3): δ = 203.5 (d, J = 28.8 Hz), 194.0, 164.5 (d, J = 24.0 Hz), 135.7, 133.8, 128.7, 128.1, 97.5 (d, J = 201.5 Hz), 84.3, 43.7 (d, J = 20.4 Hz), 27.6, 25.5. 19F NMR (470 MHz, CDCl3): δ = –163.7. [α]D 24 +38.9 (c 1.0, CHCl3). FTIR (neat): 3064, 2980, 2933, 2355, 1745, 1362, 1298, 1252, 1156, 1074, 992, 841, 756, 690, 624, 578, 526, 416 cm–1. Anal. Calcd (%) for C16H19FO4: C, 65.29; H, 6.51. Found: C, 65.27; H, 6.52. The ee of 3g was determined by HPLC (hexane–2-PrOH = 100:1, 1.0 mL/min) using a CHIRALPAK IC column (0.46 cm × 25 cm): t R (major isomer) = 26.1 min; t R (minor isomer) = 23.3 min.
  • 13 tert-Butyl 2-Fluoro-3-(furan-2-yl)-2-methyl-3-oxopropanoate (3j) The crude mixture was purified by silica gel column chromatography (hexane–EtOAc = 10:1) to give 83% yield of 3j. 1H NMR (500 MHz, CDCl3): δ = 7.70–7.67 (m, 1 H), 7.48–7.45 (m, 1 H), 6.59–6.56 (m, 1 H), 1.80 (d, 3 H, J = 22.6 Hz), 1.42 (s, 9 H). 13C NMR (126 MHz, CDCl3): δ = 180.4 (d, J = 26.4 Hz), 166.6 (d, J = 25.2 Hz), 148.9, 147.8, 121.7, 112.5, 96.1 (d, J = 193.1 Hz), 84.0, 27.7, 19.9 (d, J = 24.0 Hz). 19F NMR (470 MHz, CDCl3): δ = –154.2 (q, J = 22.9 Hz). [α]D 23 +76.3 (c 0.2, CHCl3). FTIR (neat): 3141, 2982, 2937, 1748, 1687, 1565, 1462, 1380, 1303, 1264, 1137, 1028, 989, 936, 845, 771, 588, 517, 428 cm–1. Anal. Calcd (%) for C12H15FO4: C, 59.50; H, 6.24. Found: C, 59.50; H, 6.26. The ee of 3j was determined by HPLC (hexane–2-PrOH = 100:1, 1.0 mL/min) using a CHIRALPAK IE column (0.46 cm × 25 cm): t R (major isomer) = 13.8 min; t R (minor isomer) = 14.6 min.
  • 14 Di(naphthalen-1-yl)methyl Methyl 2-chloro-2-methylmalonate (5b) The crude mixture was purified by silica gel column chromatography (hexane–CH2Cl2 = 1:1) to give 81% yield of 5b. 1H NMR (500 MHz, CDCl3): δ = 8.48 (s, 1 H), 8.00–7.94 (m, 1 H), 7.94–7.82 (m, 5 H), 7.55–7.36 (m, 7 H), 7.34–7.30 (m, 1 H), 3.52 (s, 3 H), 1.80 (d, 3 H, J = 22.1 Hz). 13C NMR (126 MHz, CDCl3): δ = 166.8 (d, J = 25.2 Hz), 165.8 (d, J = 26.4 Hz), 133.8, 133.8, 133.5, 133.5, 131.0, 130.8, 129.5, 129.4, 129.0, 128.9, 126.8, 126.8, 126.3, 126.0, 125.9, 125.9, 125.2, 125.2, 123.2,123.1, 92.4 (d, J = 195.5 Hz), 73.3, 53.0, 20.6 (d, J = 22.8 Hz). 19F NMR (470 MHz, CDCl3): δ = –157.6 (q, J = 22.9 Hz). [α]D 23 +1.90 (c 1.0, CHCl3). FTIR (neat): 2980, 2932, 1750, 1496, 1456, 1424, 1395, 1370, 1286, 1252, 1155, 1086, 839, 742, 701, 526, 442, 420, 410 cm–1. Anal. Calcd (%) for C26H21FO4: C, 74.99; H, 5.08. Found: C, 75.01; H, 5.08. The ee of 5b was determined by HPLC (hexane–CH2Cl2 = 3:1, 1.0 mL/min) using a CHIRALPAK IC column (0.46 cm × 25 cm): t R (major isomer) = 7.9 min; t R (minor isomer) = 10.2 min.

  • References and Notes


      • β-Keto phosphonates:
    • 5a Bernardi L, Jørgensen KA. Chem. Commun. 2005; 1324
    • 5b Hamashima Y, Suzuki T, Shimura Y, Shimizu T, Umebayashi N, Tamura T, Sasamoto N, Sodeoka M. Tetrahedron Lett. 2005; 46: 1447
      CrossrefSearch in Google Scholar
    • 5c Kim SM, Kim HR, Kim DY. Org. Lett. 2005; 7: 2309 ; see also ref. 3f and 3n
      CrossrefSearch in Google Scholar

      α-Cyano esters, α-cyano phosphonates, and α-cyano sulfones:
    • 6a Kim HR, Kim DY. Tetrahedron Lett. 2005; 46: 3115
      Search in Google Scholar
    • 6b Kang YK, Cho MJ, Kim SM, Kim DY. Synlett 2007; 1135
      Thieme Connect
    • 6c Moriya K, Hamashima Y, Sodeoka M. Synlett 2007; 1139
      Thieme Connect
    • 6d Jacquet O, Clément ND, Blanco C, Belmonte MM, Benet-Buchholz J, van Leeuwen PW. N. M. Eur. J. Org. Chem. 2012; 4844
    • 6e Kwon BK, Mang JY, Kim DY. Bull. Korean Chem. Soc. 2012; 33: 2481
      CrossrefSearch in Google Scholar
  • 10 General Procedure for the Asymmetric Fluorination of 2 A flame-dried flask under argon was charged with ligand 1 (0.024 mmol), Cu(OTf)2 (0.020 mmol), activated 4 Ǻ MS (140 mg), and toluene (6 mL). After the mixture was stirred for 1 h at 80 °C, β-keto ester 2 (0.20 mmol), and N-fluorobenzenesulfonimide (0.30 mmol) were added successively, and the mixture was stirred at ambient temperature. The reaction mixture was diluted with sat. NaHCO3 solution and extracted with Et2O. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give the desired product 3. All spectroscopic data of 3a–e, 3h–i, and 5a are in good agreement with those of reported previously. See Supporting Information for details. Spectroscopic characterization data of new compounds are given in the following references.
  • 11 tert-Butyl 2-Fluoro-2-benzyl-3-oxobutanoate (3f) The crude mixture was purified by silica gel column chromatography (hexane–EtOAc = 10:1) to give 93% yield of 3f. 1H NMR (500 MHz, CDCl3): δ = 7.31–7.20 (m, 5 H), 3.38 (dd, 1 H, J = 34.0, 14.9 Hz), 3.33 (dd, 1 H, J = 34.8, 14.9 Hz), 2.13 (d, 3 H, J = 4.9 Hz), 1.41 (s, 9 H). 13C NMR (126 MHz, CDCl3): δ = 202.6 (d, J = 29.3 Hz), 164.7 (d, J = 25.3 Hz), 133.5, 130.5, 128.4, 127.4, 100.1 (d, J = 198.4 Hz), 84.1, 39.5 (d, J = 20.7 Hz), 27.8, 26.1. 19F NMR (470 MHz, CDCl3): δ = –163.6. [α]D 23 +37.9 (c 0.8, CHCl3). FTIR (neat): 2980, 2932, 1750, 1496, 1456, 1424, 1395, 1370, 1286, 1252, 1155, 1086, 839, 742, 701, 526, 442, 420, 410 cm–1. Anal. Calcd (%) for C15H19FO3: C, 67.65; H, 7.19. Found: C, 67.48; H, 7.18. The ee of 3f was determined by HPLC (hexane–2-PrOH = 100:1, 1.0 mL/min) using a CHIRALCEL OJ-H column (0.46 cm × 25 cm): t R (major isomer) = 8.4 min; t R (minor isomer) = 12.0 min.
  • 12 tert-Butyl 2-Acetyl-2-fluoro-4-oxo-4-phenylbutanoate (3g) The crude mixture was purified by silica gel column chromatography (hexane–EtOAc = 5:1) to give 90% yield of 3g. 1H NMR (500 MHz, CDCl3): δ = 7.93 (d, 2 H, J = 8.4 Hz), 7.59 (dd, 1 H, J = 8.4, 7.6 Hz), 7.47 (dd, 2 H, J = 8.0, 7.6 Hz), 3.95 (dd, 1 H, J = 38.2, 18.3 Hz), 3.90 (dd, 1 H, J = 28.3, 18.3 Hz), 2.52 (d, 3 H, J = 5.0 Hz), 1.50 (s, 9 H). 13C NMR (126 MHz, CDCl3): δ = 203.5 (d, J = 28.8 Hz), 194.0, 164.5 (d, J = 24.0 Hz), 135.7, 133.8, 128.7, 128.1, 97.5 (d, J = 201.5 Hz), 84.3, 43.7 (d, J = 20.4 Hz), 27.6, 25.5. 19F NMR (470 MHz, CDCl3): δ = –163.7. [α]D 24 +38.9 (c 1.0, CHCl3). FTIR (neat): 3064, 2980, 2933, 2355, 1745, 1362, 1298, 1252, 1156, 1074, 992, 841, 756, 690, 624, 578, 526, 416 cm–1. Anal. Calcd (%) for C16H19FO4: C, 65.29; H, 6.51. Found: C, 65.27; H, 6.52. The ee of 3g was determined by HPLC (hexane–2-PrOH = 100:1, 1.0 mL/min) using a CHIRALPAK IC column (0.46 cm × 25 cm): t R (major isomer) = 26.1 min; t R (minor isomer) = 23.3 min.
  • 13 tert-Butyl 2-Fluoro-3-(furan-2-yl)-2-methyl-3-oxopropanoate (3j) The crude mixture was purified by silica gel column chromatography (hexane–EtOAc = 10:1) to give 83% yield of 3j. 1H NMR (500 MHz, CDCl3): δ = 7.70–7.67 (m, 1 H), 7.48–7.45 (m, 1 H), 6.59–6.56 (m, 1 H), 1.80 (d, 3 H, J = 22.6 Hz), 1.42 (s, 9 H). 13C NMR (126 MHz, CDCl3): δ = 180.4 (d, J = 26.4 Hz), 166.6 (d, J = 25.2 Hz), 148.9, 147.8, 121.7, 112.5, 96.1 (d, J = 193.1 Hz), 84.0, 27.7, 19.9 (d, J = 24.0 Hz). 19F NMR (470 MHz, CDCl3): δ = –154.2 (q, J = 22.9 Hz). [α]D 23 +76.3 (c 0.2, CHCl3). FTIR (neat): 3141, 2982, 2937, 1748, 1687, 1565, 1462, 1380, 1303, 1264, 1137, 1028, 989, 936, 845, 771, 588, 517, 428 cm–1. Anal. Calcd (%) for C12H15FO4: C, 59.50; H, 6.24. Found: C, 59.50; H, 6.26. The ee of 3j was determined by HPLC (hexane–2-PrOH = 100:1, 1.0 mL/min) using a CHIRALPAK IE column (0.46 cm × 25 cm): t R (major isomer) = 13.8 min; t R (minor isomer) = 14.6 min.
  • 14 Di(naphthalen-1-yl)methyl Methyl 2-chloro-2-methylmalonate (5b) The crude mixture was purified by silica gel column chromatography (hexane–CH2Cl2 = 1:1) to give 81% yield of 5b. 1H NMR (500 MHz, CDCl3): δ = 8.48 (s, 1 H), 8.00–7.94 (m, 1 H), 7.94–7.82 (m, 5 H), 7.55–7.36 (m, 7 H), 7.34–7.30 (m, 1 H), 3.52 (s, 3 H), 1.80 (d, 3 H, J = 22.1 Hz). 13C NMR (126 MHz, CDCl3): δ = 166.8 (d, J = 25.2 Hz), 165.8 (d, J = 26.4 Hz), 133.8, 133.8, 133.5, 133.5, 131.0, 130.8, 129.5, 129.4, 129.0, 128.9, 126.8, 126.8, 126.3, 126.0, 125.9, 125.9, 125.2, 125.2, 123.2,123.1, 92.4 (d, J = 195.5 Hz), 73.3, 53.0, 20.6 (d, J = 22.8 Hz). 19F NMR (470 MHz, CDCl3): δ = –157.6 (q, J = 22.9 Hz). [α]D 23 +1.90 (c 1.0, CHCl3). FTIR (neat): 2980, 2932, 1750, 1496, 1456, 1424, 1395, 1370, 1286, 1252, 1155, 1086, 839, 742, 701, 526, 442, 420, 410 cm–1. Anal. Calcd (%) for C26H21FO4: C, 74.99; H, 5.08. Found: C, 75.01; H, 5.08. The ee of 5b was determined by HPLC (hexane–CH2Cl2 = 3:1, 1.0 mL/min) using a CHIRALPAK IC column (0.46 cm × 25 cm): t R (major isomer) = 7.9 min; t R (minor isomer) = 10.2 min.

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Zoom Image
Figure 1 Structures of the chiral spiro oxazoline ligands
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Scheme 1 Enantioselective α-fluorination of α-alkylmalonates[ 14 ]
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Figure 2 Plausible asymmetric induction model (the ligating solvent and counteranion are omitted for clarity)