CC BY-NC-ND 4.0 · Synlett 2022; 33(01): 45-47
DOI: 10.1055/a-1695-4516
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A Chiral Sulfoxide-Based C–H Acid

a   Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470, Mülheim an der Ruhr, Germany
,
Karl Kaupmees
b   University of Tartu, Institute of Chemistry, Ravila 14a, 50411 Tartu, Estonia
,
Ivo Leito
b   University of Tartu, Institute of Chemistry, Ravila 14a, 50411 Tartu, Estonia
,
Benjamin List
a   Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470, Mülheim an der Ruhr, Germany
› Author Affiliations
Generous support by the European Research Council (Advanced Grant ‘C–H Acids for Organic Synthesis, CHAOS’) and the Deutsche Forschungsgemeinschaft (Leibniz Award to B.L. and Cluster of Excellence RESOLV, EXC 1069) is gratefully acknowledged. Work at Tartu was supported by the Estonian Research Council grant (PRG690), and by the EU through the European Regional Development Fund under project TK141 (2014-2020.4.01.15-0011).
 


Abstract

We report the design and synthesis of a strong, chiral, enantiopure sulfoxide-based C–H acid. Single-crystal X-ray analysis confirms the proposed structure and its absolute configuration. The new motif shows a high acidity and activity in Brønsted and Lewis acid catalyzed transformations. So far, only little to no enantioselectivities were achieved.


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Zoom Image
Scheme 1 Design (A), synthesis (B), and application (C) of the chiral, enantiopure sulfoxide C–H acid. TMP = 2,2,6,6-tetramethylpiperidine.

Chiral binaphthyl-derived acids have shown great success in asymmetric Lewis and Brønsted acid catalysis,[1] especially confined variants.[2] However, their catalytic activity is inherently limited by the electron-rich binaphthyl system, which also limits their acidity and catalytic reactivity. With both enantiomers readily available, chiral sulfur-stereogenic sulfoxides are attractive ligands in transition-metal catalysis.[3] In organocatalysis, a stereogenic sulfur has been either a contributing factor or exclusively responsible for high enantioselectivities when using weakly acidic chiral urea- or thiourea-derived catalysts.[3] [4] We envisioned a new, tris(triflyl)methane (2)[5]-inspired motif with the acidic proton very close to the stereogenic sulfur atom, which we hypothesized could lead to efficient asymmetric induction. These considerations led to the design of 1, expected to be a very strong C–H acid, with two triflyl (SO2CF3) groups[6] and one chiral sulfoxide moiety (Scheme [1]A). Indeed, a synthesis was developed, from commercially available iodide 3, which was converted into a diastereomeric mixture of two oxazolidinones 6 by following reported procedures.[7] The major diastereomer (6a) was separated by flash chromatography and converted into the desired enantiopure sulfoxide acid 1 by treatment with bis(triflyl)methane in the presence of a strong base followed by H2SO4 acidification.[8] With the desired C–H acid 1 in hand, we were able to assign its absolute configuration by X-ray single-crystal structure analysis of its hydroxonium hydrate (see Supporting Information).[9]

Further, an experimental pK ip value of –12.5 ± 0.5 (in 1,2-dichloroethane, relative to picric acid) was determined for 1. The corresponding free-ion pK a value for a molecule of this size is expected to be essentially the same.[10] This acidity corresponds to a pK a of around 0 in acetonitrile.[11] Therefore, to the best of our knowledge, sulfoxide 1 can be considered to be the strongest enantiopure Brønsted acid that has been prepared so far. We applied acid 1 as a catalyst in a variety of different reactions including two ­Mukaiyama aldolizations and a Hosomi–Sakurai allylation (Scheme [1]C). Although the catalytic activity was promising, little to no enantioselectivity was observed in all cases. In the future, further modifications of this easily accessible motif to increase its enantiodiscrimination are envisioned as well as its potential applications as an anionic ligand in transition-metal catalysis.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We also thank Petra Wedemann, Diana X. Sun, Jonas Aronow, Lucas Schreyer, and Hyejin Kim for experimental assistance, as well as the members of our analytical departments for their excellent service, especially Dr. Christophe Farès, Dr. Richard Goddard, and Nils Nöthling. We acknowledge DESY (Hamburg, Germany), a member of the Helmholtz Association HGF, for the provision of experimental facilities; parts of this research were carried out at PETRA III, and we would like to thank Sofiane Saouane for excellent assistance in using the P11-High-Throughput Macromolecular Crystallography Beamline.

Supporting Information

  • References and Notes

    • 1a Akiyama T. Chem. Rev. 2007; 107: 5744
    • 1b Akiyama T, Mori K. Chem. Rev. 2015; 115: 9277
    • 1c Terada M, Kanomata K. Synlett 2011; 1255
    • 2a Mitschke B, Turberg M, List B. Chem 2020; 6: 2515
    • 2b Schreyer L, Properzi R, List B. Angew. Chem. Int. Ed. 2019; 58: 12761
  • 3 Trost BM, Rao M. Angew. Chem. Int. Ed. 2015; 54: 5026
    • 4a Robak MT, Trincado M, Ellman JA. J. Am. Chem. Soc. 2007; 129: 15110
    • 4b Kimmel KL, Weaver JD, Lee M, Ellman JA. J. Am. Chem. Soc. 2012; 134: 9058 ; corrigendum: J. Am. Chem. Soc. 2012, 134, 11828
  • 5 Turowsky L, Seppelt K. Inorg. Chem. 1988; 27: 2135
    • 6a Höfler D, van Gemmeren M, Wedemann P, Kaupmees K, Leito I, Leutzsch M, Lingnau JB, List B. Angew. Chem. Int. Ed. 2017; 56: 1411
    • 6b Höfler D, Goddard R, Nöthling N, List B. Synlett 2019; 30: 433
    • 6c Gatzenmeier T, van Gemmeren M, Xie Y, Höfler D, Leutzsch M, List B. Science 2016; 351: 949
    • 6d Gheewala CD, Collins BE, Lambert TH. Science 2016; 351: 961
    • 7a Wang X.-J, Liu J.-T. Tetrahedron 2005; 61: 6982
    • 7b Liu L.-J, Chen L.-J, Li P, Li X.-B, Liu J.-T. J. Org. Chem. 2011; 76: 4675
  • 8 1-{[Bis(triflyl)methyl]}sulfinylnonafluorobutane (1) A Schlenk flask was charged with bis(triflyl)methane (0.46 g, 1.6 mmol, 1.0 equiv) and THF (3.5 mL) to give a colorless clear solution that was cooled to −78 °C. A 1.2 M solution of TMP·MgCl·LiCl in THF (3.1 mL, 3.8 mmol, 2.3 equiv) was added dropwise, followed by the diastereomerically pure sulfinyl oxazolidinone 6a (4.3 g, 14 mmol, 1.0 equiv; dr >99:1) in THF (3.5 mL). The mixture was allowed to reach RT overnight. All volatiles were then removed under reduced pressure to give an orange solid that was dissolved in CH2Cl2 (30 mL) and washed with sat. aq. NaHCO3 (3 × 10 mL). The pooled aqueous phases were extracted with CH2Cl2 (2 × 10 mL). The pooled organic phases were washed with concd aq HCl (3 × 30 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting yellowish viscous oil was dissolved in CH2Cl2 (30 mL), washed with concd H2SO4 (3 × 10 mL), stirred over dried BaCl2 for 80 min, and filtered. All volatiles were removed under reduced pressure until 7 mL of liquid remained. This solution was stored at –29 °C overnight, which led to the formation of a precipitate. The mother liquor was removed to give a colorless solid; yield: 0.51 g (57%, 0.93 mmol). LC/MS (chiral): (150 mm Chiralpak IC-3, 4.6 mm i.d., 30:70 MeCN–0.2% TFA, 1.0 mL/min, 20.8 MPa, 298 K): t R,(S)-enantiomer = 21.06 min, t R,(R)-enantiomer = 22.69 min; e.r. = 1:99. 13C NMR (151 MHz, acetone-d 6): δ = 123.74 (t, J = 23.1 Hz, C 6), 120.22 (q, J = ~322.0 Hz, C 7,8), 117.14 (tt, J = 322.7, 36.6 Hz, C 1), 114.51 (qt, J = 287.0, 32.5 Hz, C 4), 111.21 (tp, J = 266.2, 34.0 Hz, C2), 108.76 (th, J = 271.0, ~35 Hz, C 3). 19F NMR (471 MHz, acetone-d 6): δ = –179.16 (br, 3 F, F7,8 ), –80.68 (br, 3 F, F7,8 ), –81.37 to –82.51 (td, J = 9.6, 5.1 Hz, 3 F, F4 ), –103.82 (br d, J = 220.6 Hz, 1 F, F1′ ), –121.02 (dt, J = 221.8, 10.3 Hz, 1 F, F1′′ ), –123.63 [br d (AB system), J = ~300.0 Hz, 1 F, F2′ ], –124.33 [br d (AB system), J = ~300.0 Hz, 1 F, F2′ ], –126.39 [br d (AB system), J = 293.0 Hz, 1 F, F3′ ], –127.19 [br d (AB system), J = 293.0 Hz, 1F, F3′′ ]. MS (ESI–): m/z = 545 [M –H]. HRMS (ESI–): m/z [M –H] calcd for C7F15O5S3: 544.8674; found: 544.8674. Anal.: Calcd for C7HF15O5S3 (546.24 g/mol): C, 15.39; H, 0.18; F, 52.17; S, 17.61; Found: C, 15.42; H, 0.17; F, 52.14; S, 17.60.
  • 9 CCDC 2106642 and 2106643 contain the supplementary crystallographic data for 1 hydroxonium hydrate and 6a. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
  • 10 Paenurk E, Kaupmees K, Himmel D, Kütt A, Kaljurand I, Koppel IA, Krossing I, Leito I. Chem. Sci. 2017; 8: 6964
  • 11 Kütt A, Rodima T, Saame J, Raamat E, Mäemets V, Kaljurand I, Koppel IA, Garlyauskayte RY, Yagupolskii YL, Yagupolskii LM, Bernhardt E, Willner H, Leito I. J. Org. Chem. 2011; 76: 391

Corresponding Author

Benjamin List
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470, Mülheim an der Ruhr
Germany   

Publication History

Received: 17 September 2021

Accepted after revision: 04 November 2021

Publication Date:
12 November 2021 (online)

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  • References and Notes

    • 1a Akiyama T. Chem. Rev. 2007; 107: 5744
    • 1b Akiyama T, Mori K. Chem. Rev. 2015; 115: 9277
    • 1c Terada M, Kanomata K. Synlett 2011; 1255
    • 2a Mitschke B, Turberg M, List B. Chem 2020; 6: 2515
    • 2b Schreyer L, Properzi R, List B. Angew. Chem. Int. Ed. 2019; 58: 12761
  • 3 Trost BM, Rao M. Angew. Chem. Int. Ed. 2015; 54: 5026
    • 4a Robak MT, Trincado M, Ellman JA. J. Am. Chem. Soc. 2007; 129: 15110
    • 4b Kimmel KL, Weaver JD, Lee M, Ellman JA. J. Am. Chem. Soc. 2012; 134: 9058 ; corrigendum: J. Am. Chem. Soc. 2012, 134, 11828
  • 5 Turowsky L, Seppelt K. Inorg. Chem. 1988; 27: 2135
    • 6a Höfler D, van Gemmeren M, Wedemann P, Kaupmees K, Leito I, Leutzsch M, Lingnau JB, List B. Angew. Chem. Int. Ed. 2017; 56: 1411
    • 6b Höfler D, Goddard R, Nöthling N, List B. Synlett 2019; 30: 433
    • 6c Gatzenmeier T, van Gemmeren M, Xie Y, Höfler D, Leutzsch M, List B. Science 2016; 351: 949
    • 6d Gheewala CD, Collins BE, Lambert TH. Science 2016; 351: 961
    • 7a Wang X.-J, Liu J.-T. Tetrahedron 2005; 61: 6982
    • 7b Liu L.-J, Chen L.-J, Li P, Li X.-B, Liu J.-T. J. Org. Chem. 2011; 76: 4675
  • 8 1-{[Bis(triflyl)methyl]}sulfinylnonafluorobutane (1) A Schlenk flask was charged with bis(triflyl)methane (0.46 g, 1.6 mmol, 1.0 equiv) and THF (3.5 mL) to give a colorless clear solution that was cooled to −78 °C. A 1.2 M solution of TMP·MgCl·LiCl in THF (3.1 mL, 3.8 mmol, 2.3 equiv) was added dropwise, followed by the diastereomerically pure sulfinyl oxazolidinone 6a (4.3 g, 14 mmol, 1.0 equiv; dr >99:1) in THF (3.5 mL). The mixture was allowed to reach RT overnight. All volatiles were then removed under reduced pressure to give an orange solid that was dissolved in CH2Cl2 (30 mL) and washed with sat. aq. NaHCO3 (3 × 10 mL). The pooled aqueous phases were extracted with CH2Cl2 (2 × 10 mL). The pooled organic phases were washed with concd aq HCl (3 × 30 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting yellowish viscous oil was dissolved in CH2Cl2 (30 mL), washed with concd H2SO4 (3 × 10 mL), stirred over dried BaCl2 for 80 min, and filtered. All volatiles were removed under reduced pressure until 7 mL of liquid remained. This solution was stored at –29 °C overnight, which led to the formation of a precipitate. The mother liquor was removed to give a colorless solid; yield: 0.51 g (57%, 0.93 mmol). LC/MS (chiral): (150 mm Chiralpak IC-3, 4.6 mm i.d., 30:70 MeCN–0.2% TFA, 1.0 mL/min, 20.8 MPa, 298 K): t R,(S)-enantiomer = 21.06 min, t R,(R)-enantiomer = 22.69 min; e.r. = 1:99. 13C NMR (151 MHz, acetone-d 6): δ = 123.74 (t, J = 23.1 Hz, C 6), 120.22 (q, J = ~322.0 Hz, C 7,8), 117.14 (tt, J = 322.7, 36.6 Hz, C 1), 114.51 (qt, J = 287.0, 32.5 Hz, C 4), 111.21 (tp, J = 266.2, 34.0 Hz, C2), 108.76 (th, J = 271.0, ~35 Hz, C 3). 19F NMR (471 MHz, acetone-d 6): δ = –179.16 (br, 3 F, F7,8 ), –80.68 (br, 3 F, F7,8 ), –81.37 to –82.51 (td, J = 9.6, 5.1 Hz, 3 F, F4 ), –103.82 (br d, J = 220.6 Hz, 1 F, F1′ ), –121.02 (dt, J = 221.8, 10.3 Hz, 1 F, F1′′ ), –123.63 [br d (AB system), J = ~300.0 Hz, 1 F, F2′ ], –124.33 [br d (AB system), J = ~300.0 Hz, 1 F, F2′ ], –126.39 [br d (AB system), J = 293.0 Hz, 1 F, F3′ ], –127.19 [br d (AB system), J = 293.0 Hz, 1F, F3′′ ]. MS (ESI–): m/z = 545 [M –H]. HRMS (ESI–): m/z [M –H] calcd for C7F15O5S3: 544.8674; found: 544.8674. Anal.: Calcd for C7HF15O5S3 (546.24 g/mol): C, 15.39; H, 0.18; F, 52.17; S, 17.61; Found: C, 15.42; H, 0.17; F, 52.14; S, 17.60.
  • 9 CCDC 2106642 and 2106643 contain the supplementary crystallographic data for 1 hydroxonium hydrate and 6a. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
  • 10 Paenurk E, Kaupmees K, Himmel D, Kütt A, Kaljurand I, Koppel IA, Krossing I, Leito I. Chem. Sci. 2017; 8: 6964
  • 11 Kütt A, Rodima T, Saame J, Raamat E, Mäemets V, Kaljurand I, Koppel IA, Garlyauskayte RY, Yagupolskii YL, Yagupolskii LM, Bernhardt E, Willner H, Leito I. J. Org. Chem. 2011; 76: 391

Zoom Image
Scheme 1 Design (A), synthesis (B), and application (C) of the chiral, enantiopure sulfoxide C–H acid. TMP = 2,2,6,6-tetramethylpiperidine.