A Highly Diastereoselective and Enantioselective Phase-Transfer Catalyzed Epoxidation of β-Trifluoromethyl-β,β-disubstituted Enones with H2O2

Document Type : Research Article


School of Chemical Engineering & the Environment, Beijing Institute of Technology, Haidian District, Beijing 100081, CHINA


Trifluoromethylated organic compounds, especially chiral quaternary alcohols bearing trifluoromethyl group are of important intermediates in drugs, agrochemicals and etc.An efficient epoxidation of β-CF3-β,β-disubstituted unsaturated ketones (6) has been developed with environmental benign hydrogen peroxide as the oxidant and F5-substituted chiral quaternary ammonium salt (1g or 5) derived from cinchona-alkaloid as the catalyst. Using 3 mol% of the catalyst, both enantiomers of(R,R) and (S,S) β-trifluoromethyl-α,β-epoxy ketones (7, 8) were obtained in excellent diastereoselectivities (up to 100:1 d.r.) and enantioselectivities (up to 99.7% ee). The effects of catalyst structure, catalyst loading, substrate structure, the nature of oxidant, and reaction conditions on the catalyst capacities have been discussed in full length. The reaction mechanism was proposed to explain the origin of chiral induction. By subsequent reduction with zinc the epoxides are exhibited to be converted into trifluoromethylated quaternary alcohols without any loss in enantioselectivities. All new compounds are fully characterized by IR, NMR, elemental analysis and or high resolution mass spectrum.


Main Subjects

    (b) Ismail F.M.D., Important Fluorinated Drugs in Experimental and Clinical Use., J. Fluorine Chem., 118: 27-35 (2002).
      (c) Jackson L.M., Hawkey C.J., COX-2 Selective Nonsteroidal Anti-Inflammatory Drugs., Drugs, 59: 1207-1216 (2000).
      (e) Tan L. Chen C.Y., Tillyer R.D., Grabowski E.J.J., Reider P.J., A Novel, Highly Enantioselective Ketone Alkynylation Reaction Mediated by Chiral Zinc Aminoalkoxides., Angew. Chem. Int. Ed., 38: 711-715 (1999).
[2] (a) Prakash G.K.S., Yudin A.K., Perfluoroalkylation with Organosilicon Reagents., Chem. Rev., 97: 757-786(1997).
 (b) Singh R.P., Shreeve J.M., Nucleophilic Trifuoromethylation Reactions of Organic Compounds with (Trifuoromethyl)trimethylsilane., Tetrahedron, 56: 7613-7632 (2000).
       (c) Ma J.-A., Cahard D., Strategies for Nucleophilic, Electrophilic, and Radical Trifluoromethylations.,
J. Fluorine Chem.,
128: 975-996 (2007).
   (e) Wang Y.-F., Wu S., Karmaker P. G., Sohail M., Wang Q., Chen F.-X., Enantioselective Access of Trifluoromethylated Tertiary Thioether though Organocatalytic Sulfa-Michael Reaction of
β-Trifluoromethyl-β,β-Disubstituted enones.
, Synthesis, 47: 1147-1153 (2015).
      (f) Wang Y.-F., Qiu J.-S., Kong D., Chen F.-X., Ag-Mediated Radical Trifluoromethylarylation of Activated Alkenes for the Synthesis of Oxindoles Bearing CF3-Group, Synlett, 25: 1731-1734 (2014).
[3] (a) Rabasseda X., Sorbera L.A., Castaner J., Befloxatone. Antidepressant, MAO-A Inhibitor., Drugs Future, 24: 1057-1067 (1999).
     (b) Choudhury-Mukherjee I., Schenck H.A., Cechova S., Pajewski T.N., Kapur J., Ellena J., Cafiso D.S., Brown M.L., Design, Synthesis, and Evaluation of Analogues of 3,3,3-Trifluoro-2-Hydroxy-2-Phenyl-Propionamide as Orally Available General Anesthetics., J. Med. Chem., 46: 2494-2501 (2003).
[4] (a) Corey E.J., Guzman-Perez A., The Catalytic Enantioselective Construction of Molecules with Quaternary Carbon Stereocenters.,Angew. Chem. Int. Ed., 37: 388-401 (1998).
     (b) Christoffers J., Mann A., Enantioselective Construction of Quaternary Stereocenters., Angew. Chem. Int. Ed., 40: 4591-4597 (2001).
    c) Denissova I., Barriault L., Stereoselective Formation of Quaternary Carbon Centers and Related Functions., Tetrahedron, 59: 10105-10146 (2003).
    (d) Trost B.M., Jiang C., Catalytic Enantioselective Construction of All-Carbon Quaternary Stereocenters., Synthesis, 369-396 (2006).
     (e) Cozzi P.G., Hilgraf R., Zimmermann N., Enantioselective Catalytic Formation of Quaternary Stereogenic Centers., Eur. J. Org. Chem., 5969-5994 (2007).
   (b) Weile G.R., McMorris T.C., Stereoselective Synthesis of 23-deoxyantheridiol., J. Org. Chem., 43: 3942-3946 (1978).
   (c) McChesney J.D., Thompson T.N., Stereochemistry of the Reductive Alkylation of α,β-epoxy Ketones., J. Org. Chem., 50: 3473-3481 (1985).
     (f) Hardouin C., Chevallier F., Rousseau B., Doris E., Cp2TiCl-Mediated Selective Reduction of α,β-Epoxy Ketones., J. Org. Chem., 66: 1046-1048 (2001).
     (g) Hasegawa E., Takizawa S., Seida T., Yamaguchi A., Yamaguchi N., Chiba N., Takahashi T., Ikeda H., Akiyama K., Photoinduced Electron-Transfer Systems Consisting of Electron-Donating Pyrenes or Anthracenes and Benzimidazolines for Reductive Transformation of Carbonyl Compounds., Tetrahedron, 62: 6581-6588 (2006).
     (b) Song J.J., Tan Z., Reeves, J.T. Fandrick D.R., Yee N.K., Senanayake C.H., N-Heterocyclic Carbene-Catalyzed Silyl Enol Ether Formation., Org. Lett., 10: 877-880 (2008).
  (c) Duangdee N., W. Harnying, G. Rulli, J.-M. Neudörfl, H. Gröger, A. Berkessel, Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol Synthesis-A Caveat on Reaction Times and Product Isolation., J. Am. Chem. Soc., 134: 11196-11205 (2012).
    (d) Zheng Y., Xiong H.Y., Nie J., Hua M.-Q., Ma J.-A., Biomimetic Catalytic Enantioselective Decarboxylative Aldol Reaction of β-Ketoacids with Trifluoromethyl Ketones., Chem. Commun., 48: 4308-4310 (2012).
[7] (a) Lauret C., Epoxy Ketones as Versatile Building Blocks in Organic Synthesis., Tetrahedron: Asymmetry, 12: 2359-2383 (2001).
     (b) Curran, D.P. Reduction of Δ2-Isoxazolines. 3. Raney-Nickel Catalyzed Formation of β-Hydroxy Ketones., J. Am. Chem. Soc., 105: 5826-5833 (1983).
     (c) Kozikowski A.P., Adamczyk M., Methods for the Conversion of Isoxazolines to β-Hydroxy Ketones., Tetrahedron Lett., 23: 3123-3126 (1982).
    (d) Porter M.J., Skidmore J., Asymmetric Epoxidation of Electron-Deficient Olefins., Chem. Commun., 1215-1225 (2000).
     (e) Lauret C., Roberts S.M., Asymmetric Epoxidation of α,β-Unsaturated Ketones Catalyzed by Poly(amino acids)., Aldrichim. Acta, 35: 47-51 (2002).
[8] (a) Katsuki J.T., Sharpless K.B., The First Practical Method for Asymmetric Epoxidation., J. Am. Chem. Soc., 102: 5974-5976 (1980).
   (b) Hanson R.M., Sharpless K.B., Procedure for the Catalytic Asymmetric Epoxidation of Allylic Alcohols in the Presence of Molecular Sieves., J. Org. Chem., 51: 1922-1925 (1986).
[9] For recent reviews, see: (a) Wong O.A., Shi Y., Organocatalytic Oxidation. Asymmetric Epoxidation of Olefins Catalyzed by Chiral Ketones and Iminium Salts., Chem. Rev., 108: 3958-3987 (2008).
      (b) McGarrigle E.M., Gilheany D.G., Chromium- and Manganese-salen Promoted Epoxidation of Alkenes., Chem. Rev., 105: 1563-1602 (2005).
   (c) Xia Q.H., Ge H.Q., Ye C.P., Li u Z.M., Su K.X., Advances in Homogeneous and Heterogeneous Catalytic Asymmetric Epoxidation., Chem. Rev., 105: 1603-1662 (2005).
      (d) Lane B.S., Burgess K., Metal-Catalyzed Epoxidations of Alkenes with Hydrogen Peroxide., Chem. Rev., 103: 2457-2474 (2003).
      (f) Zhu Y.G., Wang Q., Cornwall R.G., Shi Y., Organocatalytic Asymmetric Epoxidation and Aziridination of Olefins and Their Synthetic Applications., Chem. Rev., 114: 8199-8256 (2014).
[10] (a) Nemoto T., Ohshima T., Shibasaki M., Catalytic Asymmtrtic Epoxidation of α,β-Unsaturated Carbonyl Compounds ., J. Synth. Org. Chem. Jpn., 60, 94-105 (2002).
[11] (a) Hashimoto T., Maruoka, K. Recent Development and Application of Chiral Phase-Transfer Catalysts., Chem. Rev., 107: 5656-5682 (2007).
       (b) Ooi T., Maruoka K., Recent Advances in Asymmetric Phase-Transfer Catalysis., Angew. Chem. Int. Ed., 46, 4222-4266 (2007).
       (d) Wu S., Guo J., Sohail M., Cao C., Chen F.-X., The Enantioselective Trifluoromethylation of Aromatic Aldehydes by Quaternary Ammonium Bromide and (IPr)CuF at Low Catalyst Loading., J. Fluorine Chem., 148: 19-29 (2013).
[12] (a) Nelson A., Asymmetric Phase-Transfer Catalysis., Angew. Chem. Int. Ed., 38: 1583-1585 (1999).
       (b) Shioiri T., Arai S., In: "Stimulating Concepts in Chemistry", Vögtle F., Stoddart J.F., Shibasaki M., Eds., Wiley-VCH: Weinheim, Germany, 123-143 (2000).
       (c) O’Donnell M.J., In: "Catalytic Asymmetric Syntheses", 2nd ed., Ojima I., Ed., Wiley-VCH: New York, Chapter 10 (2000 ).
[14] Arai S., Tsuge H., Shioiri T., Asymmetric Epoxidation of α,β -Unsaturated Ketones under Phase-Transfer Catalyzed Conditions., Tetrahedron Lett., 39: 7563-7566 (1998).
[16] Jew S.-s., Lee J.-H., Jeong B.-S., Yoo M.-S., Kim M.J., Lee Y.-J., Lee J., Choi S.-H., Lee K., Lah M.-S., Park H.-g., Highly Enantioselective Epoxidation of 2,4-Diarylenones by Using Dimeric Cinchona Phase-Transfer Catalysts: Enhancement of Enantioselectivity by Surfactants., Angew. Chem. Int. Ed., 44: 1383-1385 (2005).
[17] (a) Wang X., Reisinger C.M., List B., Catalytic Asymmetric Epoxidation of Cyclic Enones., J. Am. Chem. Soc., 130: 6070-6071 (2008).
      (b) Ye J., Wang Y., Liu R., Zhang G., Zhang Q., Chen J., Liang X., A Highly Enantioselective Phase-Transfer Catalyzed Epoxidation of Enoneswith a Mild Oxidant, Trichloroisocyanuric Acid., Chem. Commun., 2714-2715 (2003).
      (d) Ooi T., Ohara D., Tamura M., Maruoka K.,Design of New Chiral Phase-Transfer Catalysts with Dual Functions for Highly Enantioselective Epoxidation of α,β-Unsaturated Ketones., J. Am. Chem. Soc., 126: 6844-6845 (2004).
    (f) Chu Y., Liu X., Li W., Hu X. Lin L., Feng X., Asymmetric Catalytic Epoxidation of α,β-Unsaturated Carbonyl Compounds with Hydrogen Peroxide: Additive-Free and Wide Substrate Scope., Chem. Sci., 3: 1996-2000 (2012).
[18] (a) Diez D., Nunez M.G., Anton A.B., Garcia P., Moro R.F., Garrido N.M., Marcos I.S., Basabe P., Urones J.G., Asymmetric Epoxidation of Electron-Deficient Olefins., Curr. Org. Synth., 5: 186-216 (2008).
       (c) Nishikawa Y., Yamamoto H., Iron-Catalyzed Asymmetric Epoxidation of β,β-Disubstituted Enones., J. Am. Chem. Soc., 133: 8432-8435 (2011).
[19] Kawai H., Okusu S., Yuan Z., Tokunaga E., Yamano A., Shiro M., Shibata N., Enantioselective Synthesis of Epoxides Having a Tetrasubstituted Trifluoromethylated Carbon Center: Methylhydrazine-Induced Aerobic Epoxidation of β,β-Disubstituted Enones., Angew. Chem. Int. Ed., 52: 2221-2225 (2013).
[20] (a) Metzger J.O., Solvent-Free Organic Syntheses.,Angew. Chem. Int. Ed., 37: 2975-2978 (1998).
       (b) DeSimone J.M., Practical Approaches to Green Solvents., Science, 297: 799-803 (2002).
[21] (a) Joergensen K.A., Transition-Metal-Catalyzed Epoxidations., Chem. Rev., 89: 431-458 (1989).
    (b) Sanderson W.R., Cleaner Industrial Processes Using Hydrogen Peroxide., Pure Appl. Chem., 72: 1289-1304 (2000).
[23] O’Hagan D., Understanding Organofluorine Chemistry. An Introduction to the C–F Bond., Chem. Soc. Rev., 37: 308-319 (2008).
[24] (a) Ooi T., Takeuchi M., Kameda M., Maruoka K., Practical Catalytic Enantioselective Synthesis of α,α-Dialkyl-α-amino Acids by Chiral Phase-Transfer Catalysis., J. Am. Chem. Soc., 122: 5228-5229 (2000).
       (b) Kim C.-Y., Chandra P.P., Jain A., Christianson D.W.,Fluoroaromatic-Fluoroaromatic Interactions between Inhibitors Bound in the Crystal Lattice of Human Carbonic Anhydrase II., J. Am. Chem. Soc., 123: 9620-9627 (2001).
     (d) Jew S., Yoo M.-S., Jeong B.-S, Park Y., Park H.G., An Unusual Electronic Effect of an Aromatic-F in Phase-Transfer Catalysts Derived from Cinchona-Alkaloid., Org. Lett., 4, 4245-4248 (2002).
[25] (a) Perrard T., Plaquevent J.-C., Desmurs J.-R., Hébrault D., Enantioselective Synthesis of Both Enantiomers of Methyl Dihydrojasmonate Using Solid-Liquid Asymmetric Phase-Transfer Catalysis., Org. Lett., 2: 2959-2962 (2000).
       (d) Palomo C., Oiarbide M., Laso A., López R., Catalytic Enantioselective Aza-Henry Reaction with Broad Substrate Scope., J. Am. Chem. Soc., 127: 17622-17623 (2005).
       (e) Lian M., Li Z., Du J., Meng Q., Gao Z., Asymmetric Direct α-Hydroxylation of β-Oxo Esters by Phase-Transfer Catalysis Using Chiral Quaternary Ammonium Salts., Eur. J. Org. Chem., 6525-6530 (2010).
       (f) Fiandra C.D., Piras L., Fini F., Disetti P., Moccia M., Adamo M.F.A., Phase Transfer Catalyzed Enantioselective Cyclopropanation of 4-Nitro-5-Styrylisoxazoles., Chem. Commun., 3863-3865 (2012).
        (c) Brak K., Jacobsen E.N., Asymmetric Ion-Pairing Catalysis., Angew. Chem. Int. Ed., 52: 534-561 (2013).
[28] Arai S., Nakayama K., Ishida T., Shioiri T., Asymmetric Cyclopropanation Reaction under Phase-Transfer Catalyzed Conditions., Tetrahedron Lett., 40: 4215-4218 (1999).