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

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

• References and Notes

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For recent reviews on enantioselective construction of fluorinated chiral carbon centers, see:
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Selected examples of highly enantioselective fluorination of β-keto esters, see:
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Malonates and β-alkoxylactones:
• 4a Suzuki T, Goto T, Hamashima Y, Sodeoka M. J. Org. Chem. 2007; 72: 246
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β-Keto phosphonates:
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α-Cyano esters, α-cyano phosphonates, and α-cyano sulfones:
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• 6b Kang YK, Cho MJ, Kim SM, Kim DY. Synlett 2007; 1135
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• 6e Kwon BK, Mang JY, Kim DY. Bull. Korean Chem. Soc. 2012; 33: 2481

Oxindoles:
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• 8b Shibatomi K, Soga Y, Narayama A, Fujisawa I, Iwasa S. J. Am. Chem. Soc. 2012; 134: 9836

We confirmed that the optical purity of selected products, 3a, 3c, 3e, 3h, and 5b, does not change even after chromatographic purification using achiral silica gel and subsequent solvent evaporation. For selected papers on the self-disproportionation effect of the enantiomers, see:
• 9a Soloshonok VA, Roussel C, Kitagawa O, Sorochinsky AE. Chem. Soc. Rev. 2012; 41: 4180
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• 9c Han J, Nelson DJ, Sorochinsky AE, Soloshonok VA. Curr. Org. Synth. 2011; 8: 310
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• 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.