Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Catalytic asymmetric trifluoromethylthiolation via enantioselective [2,3]-sigmatropic rearrangement of sulfonium ylides

Nature Chemistry volume 9, pages 970–976 (2017)Cite this article

Subjects

Abstract

The trifluoromethylthio (SCF3) functional group has been of increasing importance in drug design and development as a consequence of its unique electronic properties and high stability coupled with its high lipophilicity. As a result, methods to introduce this highly electronegative functional group have attracted considerable attention in recent years. Although significant progress has been made in the introduction of SCF3 functionality into a variety of molecules, there remain significant challenges regarding the enantioselective synthesis of SCF3-containing compounds. Here, an asymmetric trifluoromethylthiolation that proceeds through the enantioselective [2,3]-sigmatropic rearrangement of a sulfonium ylide generated from a metal carbene and sulfide (Doyle–Kirmse reaction) has been developed using chiral Rh(II) and Cu(I) catalysts. This transformation features mild reaction conditions and excellent enantioselectivities (up to 98% yield and 98% e.e.), thus providing a unique, highly efficient and enantioselective method for the construction of C(sp3)–SCF3 bonds bearing chiral centres.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Catalytic asymmetric trifluoromethylthiolation.
Figure 2: Assignment of the absolute configuration of the product 3f.
Figure 3: Mechanistic experiments.

Similar content being viewed by others

References

  1. Bégué, J.-P. & Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine (Wiley, 2008).

  2. Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology (Blackwell, 2009).

    Google Scholar 

  3. Cametti, M., Crousse, B., Metrangolo, P., Milani, R. & Resnati, G. The fluorous effect in biomolecular applications. Chem. Soc. Rev. 41, 31–42 (2012).

    CAS  PubMed  Google Scholar 

  4. Nakajima, T. Fluorine compounds as energy conversion materials. J. Fluorine Chem. 149, 104–111 (2013).

    CAS  Google Scholar 

  5. Wang, J. et al. Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001–2011). Chem. Rev. 114, 2432–2506 (2014).

    CAS  PubMed  Google Scholar 

  6. Chu, L. & Qing, F.-L. Oxidative trifluoromethylation and trifluoromethylthiolation reactions using (trifluoromethyl) trimethylsilane as a nucleophilic CF3 source. Acc. Chem. Res. 47, 1513–1522 (2014).

    CAS  PubMed  Google Scholar 

  7. Toulgoat, F., Alazet, S. & Billard, T. Direct trifluoromethylthiolation reactions: the “renaissance” of an old concept. Eur. J. Org. Chem. 2415–2428 (2014).

  8. Shao, X., Xu, C., Lu, L. & Shen, Q. Shelf-stable electrophilic reagents for trifluoromethylthiolation. Acc. Chem. Res. 48, 1227–1236 (2015).

    CAS  PubMed  Google Scholar 

  9. Shen, C. et al. Recent advances in C–S bond formation via C–H bond functionalization and decarboxylation. Chem. Soc. Rev. 44, 291–314 (2015).

    CAS  PubMed  Google Scholar 

  10. Xu, X.-H., Matsuzaki, K. & Shibata, N. Synthetic methods for compounds having CF3–S units on carbon by trifluoromethylation, trifluoromethylthiolation, triflylation, and related reactions. Chem. Rev. 115, 731–764 (2015).

    CAS  PubMed  Google Scholar 

  11. Yang, X., Wu, T., Phipps, R. J. & Toste, F. D. Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev. 115, 826–870 (2015).

    CAS  PubMed  Google Scholar 

  12. Zhang, K., Xu, X. & Qing, F. Recent advances of direct trifluoromethylthiolation. Chin. J. Org. Chem. 35, 556–569 (2015).

    CAS  Google Scholar 

  13. Chachignon, H. & Cahard, D. State-of-the-art in electrophilic trifluoromethylthiolation reagents. Chin. J. Chem. 34, 445–454 (2016).

    CAS  Google Scholar 

  14. Bootwicha, T., Liu, X., Pluta, R., Atodiresei, I. & Rueping, M. N-Trifluoromethylthiophthalimide: a stable electrophilic SCF3-reagent and its application in the catalytic asymmetric trifluoromethylsulfenylation. Angew. Chem. Int. Ed. 52, 12856–12859 (2013).

    CAS  Google Scholar 

  15. Rueping, M., Liu, X., Bootwicha, T., Pluta, R. & Merkens, C. Catalytic enantioselective trifluoromethylthiolation of oxindoles using shelf-stable N-(trifluoromethylthio) phthalimide and a cinchona alkaloid catalyst. Chem. Commun. 50, 2508–2511 (2014).

    CAS  Google Scholar 

  16. Wang, X., Yang, T., Cheng, X. & Shen, Q. Enantioselective electrophilic trifluoromethylthiolation of β-ketoesters: a case of reactivity and selectivity bias for organocatalysis. Angew. Chem. Int. Ed. 52, 12860–12864 (2013).

    CAS  Google Scholar 

  17. Deng, Q.-H., Rettenmeier, C., Wadepohl, H. & Gade, L. H. Copper–boxmi complexes as highly enantioselective catalysts for electrophilic trifluoromethylthiolations. Chem. Eur. J. 20, 93–97 (2014).

    CAS  PubMed  Google Scholar 

  18. Zhu, X.-L. et al. In situ generation of electrophilic trifluoromethylthio reagents for enantioselective trifluoromethylthiolation of oxindoles. Org. Lett. 16, 2192–2195 (2014).

    CAS  PubMed  Google Scholar 

  19. Liu, X., An, R., Zhang, X., Luo, J. & Zhao, X. Enantioselective trifluoromethylthiolating lactonization catalyzed by an indane-based chiral sulfide. Angew. Chem. Int. Ed. 55, 5846–5850 (2016).

    CAS  Google Scholar 

  20. Kirmse, W. & Kapps, M. Reaktionen des diazomethans mit diallylsulfid und allyläthern unter kupfersalz-katalyse. Chem. Ber. 101, 994–1003 (1968).

    CAS  Google Scholar 

  21. Doyle, M. P., Griffin, J. H., Chinn, M. S. & van Leusen, D. Highly effective catalytic methods for ylide generation from diazo compounds. Mechanism of the rhodium-and copper-catalyzed reactions with allylic compounds. J. Org. Chem. 46, 5094–5102 (1981).

    CAS  Google Scholar 

  22. Li, A.-H., Dai, L.-X. & Aggarwal, V. K. Asymmetric ylide reactions: epoxidation, cyclopropanation, aziridination, olefination, and rearrangement. Chem. Rev. 97, 2341–2372 (1997).

    CAS  PubMed  Google Scholar 

  23. Braverman, S. & Cherkinsky, M. [2,3]-Sigmatropic rearrangements of propargylic and allenic systems. Top. Curr. Chem. 275, 67 (2007).

    CAS  PubMed  Google Scholar 

  24. Reggelin, M. [2,3]-Sigmatropic rearrangements of allylic sulfur compounds. Top. Curr. Chem. 275, 1–65 (2007).

    CAS  PubMed  Google Scholar 

  25. Wang, J. in Comprehensive Organometallic Chemistry III Vol. 11 (eds Mingos, D. M. P. & Crabtree, R. H.) 151–178. (Applications II: Transition Metal Compounds In Organic Synthesis 2, Elsevier, 2007).

    Google Scholar 

  26. Zhang, Y. & Wang, J. Catalytic [2,3]-sigmatropic rearrangement of sulfur ylide derived from metal carbene. Coord. Chem. Rev. 254, 941–953 (2010).

    CAS  Google Scholar 

  27. West, T. H., Spoehrle, S. S. M., Kasten, K., Taylor, J. E. & Smith, A. D. Catalytic stereoselective [2,3]-rearrangement reactions. ACS Catal. 5, 7446–7479 (2015).

    CAS  Google Scholar 

  28. Nishibayashi, Y., Ohe, K. & Uemura, S. The first example of enantioselective carbenoid addition to organochalcogen atoms: application to [2,3]-sigmatropic rearrangement of allylic chalcogen ylides. Chem. Commun. 1245–1246 (1995).

  29. Fukuda, T. & Katsuki, T. Co(III)-salen catalyzed carbenoid reaction: stereoselective [2,3]-sigmatropic rearrangement of S-ylides derived from allyl aryl sulfides. Tetrahedron Lett. 38, 3435–3438 (1997).

    CAS  Google Scholar 

  30. Itoh, K., Fukuda, T., Kitajima, H. & Katsuki, T. New aspect of carbenoid reaction: exploitation of new asymmetric synthesis using chiral carbenoid species. Yuki Gosei Kagaku Kyokaishi 55, 764–773 (1997).

    CAS  Google Scholar 

  31. Fukuda, T., Irie, R. & Katsuki, T. Catalytic and asymmetric [2,3]-sigmatropic rearrangement: Co(III)-salen catalyzed S-ylide formation from allyl aryl sulfides and their rearrangement. Tetrahedron 55, 649–664 (1999).

    CAS  Google Scholar 

  32. McMillen, D. W., Varga, N., Reed, B. A. & King, C. Asymmetric copper-catalyzed [2,3]-sigmatropic rearrangements of alkyl- and aryl-substituted allyl sulfides. J. Org. Chem. 65, 2532–2536 (2000).

    CAS  PubMed  Google Scholar 

  33. Kitagaki, S., Yanamoto, Y., Okubo, H., Nakajima, M. & Hashimoto, S. Enantiocontrol in tandem allylic sulfonium ylide generation and [2,3]-sigmatropic rearrangement catalyzed by chiral dirhodium(II) complexes. Heterocycles 54, 623–628 (2001).

    CAS  Google Scholar 

  34. Zhang, X. et al. Catalytic asymmetric [2,3]-sigmatropic rearrangement of sulfur ylides generated from copper(I) carbenoids and allyl sulfides. J. Org. Chem. 67, 5621–5625 (2002).

    CAS  PubMed  Google Scholar 

  35. Zhang, X., Ma, M. & Wang, J. Catalytic asymmetric [2,3]- sigmatropic rearrangement of sulfur ylides generated from carbenoids and propargyl sulfides. Tetrahedron: Asymm. 14, 891–895 (2003).

    CAS  Google Scholar 

  36. Zhang, X., Ma, M. & Wang, J. Catalytic asymmetric [2,3]-sigmatropic rearrangement of sulfur ylides generated from carbenoids and allenic 2-methylphenyl sulfide. Chin. J. Chem. 21, 878–882 (2003).

    CAS  Google Scholar 

  37. Ma, M., Peng, L., Li, C., Zhang, X. & Wang, J. Highly stereoselective [2,3]-sigmatropic rearrangement of sulfur ylide generated through Cu(I) carbene and sulfides. J. Am. Chem. Soc. 127, 15016–15017 (2005).

    CAS  PubMed  Google Scholar 

  38. Liao, M. & Wang, J. Highly efficient [2,3]-sigmatropic rearrangement of sulfur ylide derived from Rh(II) carbene and sulfides in water. Green Chem. 9, 184–188 (2007).

    CAS  Google Scholar 

  39. Zhang, H., Wang, B., Yi, H., Zhang, Y. & Wang, J. Rh (II)-catalyzed [2, 3]-sigmatropic rearrangement of sulfur ylides derived from cyclopropenes and sulfides. Org. Lett. 17, 3322–3325 (2015).

    CAS  PubMed  Google Scholar 

  40. Tyagi, V., Sreenilayam, G., Bajaj, P., Tinoco, A. & Fasan, R. Biocatalytic synthesis of allylic and allenyl sulfides through a myoglobin-catalyzed Doyle–Kirmse reaction. Angew. Chem. Int. Ed. 55, 13562–13566 (2016).

    CAS  Google Scholar 

  41. Doyle, M. P. & Forbes, D. C. Recent advances in asymmetric catalytic metal carbene transformations. Chem. Rev. 98, 911–935 (1998).

    CAS  PubMed  Google Scholar 

  42. Davies, H. M. L. & Beckwith, R. E. J. Catalytic enantioselective C-H activation by means of metal-carbenoid-induced C-H insertion. Chem. Rev. 103, 2861–2903 (2003).

    CAS  PubMed  Google Scholar 

  43. Davies, H. M. L. & Nikolai, J. Catalytic and enantioselective allylic C–H activation with donor–acceptor-substituted carbenoids. Org. Biomol. Chem. 3, 4176–4187 (2005).

    CAS  PubMed  Google Scholar 

  44. Aggarwal, V. K., Ferrara, M. & Hainz, R. [2,3]-Sigmatropic rearrangement of allylic sulfur ylides derived from trimethylsilyldiazomethane (TMSD). Tetrahedron Lett. 40, 8923–8927 (1999).

    CAS  Google Scholar 

  45. Li, Z., Parr, B. T. & Davies, H. M. L. Highly stereoselective C−C bond formation by rhodium-catalyzed tandem ylide formation/[2,3]-sigmatropic rearrangement between donor/acceptor carbenoids and chiral allylic alcohols. J. Am. Chem. Soc. 134, 10942–10946 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Li, Z. et al. Scope and mechanistic analysis of the enantioselective synthesis of allenes by rhodium-catalyzed tandem ylide formation/[2,3]-sigmatropic rearrangement between donor/acceptor carbenoids and propargylic alcohols. J. Am. Chem. Soc. 134, 15497–15504 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Parr, B. T. & Davies, H. M. L. Highly stereoselective synthesis of cyclopentanes bearing four stereocentres by a rhodium carbene-initiated domino sequence. Nat. Commun. 5, 4455 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Trost, B. M. & Hammen, R. F. New synthetic methods. Transfer of chirality from sulfur to carbon. J. Am. Chem. Soc. 95, 962–964 (1973).

    CAS  Google Scholar 

  49. Trost, B. M. & Biddlecom, W. G. Asymmetric induction in a [2,3]-sigmatropic rearrangement. J. Org. Chem. 38, 3438–3439 (1973).

    CAS  Google Scholar 

  50. Davies, H. M. L. & Morton, D. Guiding principles for site selective and stereoselective intermolecular C–H functionalization by donor/acceptor rhodium carbenes. Chem. Soc. Rev. 40, 1857–1869 (2011).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge financial support from the National Basic Research Program of China (973 programme no. 2015CB856600) and Natural Science Foundation of China (grant no. 21332002). We thank Y. Wang and Z. Yu (Peking University) for the discussion on the reaction mechanism. We greatly appreciate W.-X. Zhang and N. Wang (Peking University) for the assistance in obtaining X-ray crystallographic structures.

Author information

Authors and Affiliations

  1. Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing, 100871, China

    Zhikun Zhang, Zhe Sheng, Weizhi Yu, Guojiao Wu, Rui Zhang, Wen-Dao Chu, Yan Zhang & Jianbo Wang

Authors
  1. Zhikun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhe Sheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Weizhi Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guojiao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wen-Dao Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jianbo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Z.Z., Z.S., W.Y., G.W. and R.Z. performed the experiments. W.-D.C. and Y.Z. participated in the discussion and helped the measurement of optical purities. J.W. conceived and supervised the project. Z.Z. and J.W. wrote the manuscript.

Corresponding author

Correspondence to Jianbo Wang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 9487 kb)

Supplementary information

Crystallographic data for compound 8 (CIF 37 kb)

Supplementary information

Crystallographic data for compound 10j (CIF 36 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Z., Sheng, Z., Yu, W. et al. Catalytic asymmetric trifluoromethylthiolation via enantioselective [2,3]-sigmatropic rearrangement of sulfonium ylides. Nature Chem 9, 970–976 (2017). https://doi.org/10.1038/nchem.2789

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.2789

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing