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:

DMSO-catalysed late-stage chlorination of (hetero)arenes

Nature Catalysis volume 3, pages 107–115 (2020)Cite this article

Subjects

Abstract

The chlorination of a bioactive compound can change its physiological properties and improve its pharmacokinetic and pharmacological profiles. It therefore has been an important strategy for drug discovery and development. However, the direct aromatic chlorination of complex bioactive molecules is too difficult to be practical. In fact, many functional groups such as hydroxyls, amines, amides or carboxylic acids may strongly restrain the reactivity of Cl+ by forming a halogen bond. Here we report a highly efficient aromatic chlorination of arenes that is catalysed by dimethyl sulfoxide with N-chlorosuccinimide as the chloro source. The mild conditions, easy-availability and stability of the catalyst and reagents, as well as good functional-group tolerance, showed the approach to be a versatile protocol for the late-stage aromatic chlorination of complex natural products, drugs and peptides. The multi-gram experiment and low-cost of N-chlorosuccinimide and dimethyl sulfoxide shows great potential for drug discovery and development in industrial applications.

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

Fig. 1: Chlorination of bioactive molecules.
Fig. 2: Mechanistic studies.
Fig. 3: The DFT calculation and proposed mechanism.

Similar content being viewed by others

Data availability

Experimental procedures and characterization of the new compounds are available in the Supplementary Information. The data that support the plots within this paper and other findings of this study are available from the corresponding author on reasonable request.

References

  1. Vogt, P. F. & Gerulis, J. J. in Ullmann’s Encyclopedia of Industrial Chemistry (Wiley-VCH, 2000); https://doi.org/10.1002/14356007.a02_037

  2. Gribble, G. W. Natural organohalogens: a new frontier for medicinal agents. J. Chem. Educ. 81, 1441–1449 (2004).

    CAS  Google Scholar 

  3. Tang, M. L. & Bao, Z. Halogenated materials as organic semiconductors. Chem. Mater. 23, 446–455 (2011).

    CAS  Google Scholar 

  4. Auffinger, P., Hays, F. A., Westhof, E. & Ho, P. S. Halogen bonds in biological molecules. Proc. Natl Acad. Sci. USA 48, 16789–16794 (2004).

    Google Scholar 

  5. Hernandes, M. Z., Cavalcanti, S. M., Moreira, D. R., de Azevedo Junior, W. F. & Leite, A. C. Halogen atoms in the modern medicinal chemistry: hints for the drug design. Curr. Drug Targets 11, 303–314 (2010).

    CAS  PubMed  Google Scholar 

  6. Sun, H., Keefer, C. E. & Scott, D. O. Systematic and pairwise analysis of the effects of aromatic halogenation and trifluoromethyl substitution on human liver microsomal clearance. Drug Metab. Lett. 5, 232–242 (2011).

    CAS  PubMed  Google Scholar 

  7. Raju., T. N. K. The nobel chronicles. Lancet 355, 1022 (2000).

    CAS  PubMed  Google Scholar 

  8. Cernak, T., Dykstra, K. D., Tyagarajan, S., Vachal, P. & Krska, S. W. The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev. 45, 546–576 (2016).

    CAS  PubMed  Google Scholar 

  9. Wencel-Delord, J. & Glorius, F. C–H Bond activation enables the rapid construction and late-stage diversification of functional molecules. Nat. Chem. 5, 369–375 (2013).

    CAS  PubMed  Google Scholar 

  10. Yamaguchi, J., Yamaguchi, A. D. & Itami, K. C–H Bond functionalization: emerging synthetic tools for natural products and pharmaceuticals. Angew. Chem. Int. Ed. 51, 8960–9009 (2012).

    CAS  Google Scholar 

  11. Yamamoto, K. et al. Palladium-catalysed electrophilic aromatic C–H fluorination. Nature 554, 511–514 (2018).

    CAS  PubMed  Google Scholar 

  12. Luca, L. D., Giacomelli, G. & Nieddu, G. A simple protocol for efficient N-chlorination of amides and carbamates. Synlett 2, 223–226 (2005).

  13. Matsuo, J., Iida, D., Yamanaka, H. & Mukaiyama, T. N-tert-Butylbenzenesulfenamide-catalyzed oxidation of alcohols to the corresponding carbonyl compounds with N-chlorosuccinimide. Tetrahedron 59, 6739–6750 (2003).

  14. Liu, W., Christenson, S. D., Standage, S. & Shen, B. Biosynthesis of the enediyne antitumor antibiotic C-1027. Science 297, 1170–1171 (2002).

    CAS  PubMed  Google Scholar 

  15. Lin, S., Van Lanen, S. G. & Shen, B. Regiospecific chlorination of (S)-β-tyrosyl-S-carrier protein catalyzed by SgcC3 in the biosynthesis of the enediyne antitumor antibiotic C-1027. J. Am. Chem. Soc. 129, 12432–12438 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Dong, C. et al. Tryptophan 7-halogenase (PrnA) structure suggests a mechanism for regioselective chlorination. Science 309, 2216–2219 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Payne, J. T., Poor, C. B. & Lewis, J. C. Directed evolution of rebH for site-selective halogenation of large biologically active molecules. Angew. Chem. Int. Ed. 54, 4226–4230 (2015).

    CAS  Google Scholar 

  18. Frese, M. & Sewald, N. Enzymatic halogenation of tryptophan on a gram scale. Angew. Chem. Int. Ed. 54, 298–301 (2015).

    CAS  Google Scholar 

  19. Payne, J. T., Andorfer, M. C. & Lewis, J. C. Regioselective arene halogenation using the FAD-dependent halogenase rebH. Angew. Chem. Int. Ed. 52, 5271–5274 (2013).

    CAS  Google Scholar 

  20. Hering, T., Mîhldorf, B., Wolf, R. & Kçnig, B. Halogenase-inspired oxidative chlorination using flavin photocatalysis. Angew. Chem. Int. Ed. 55, 5342–5345 (2016).

    CAS  Google Scholar 

  21. Podgoršek, A., Zupan, M. & Iskra, J. Oxidative halogenation with “Green” oxidants: oxygen and hydrogen peroxide. Angew. Chem. Int. Ed. 48, 8424–8450 (2009).

    Google Scholar 

  22. Kovacic, P. & Sparks, A. K. Chlorination of aromatic compounds by antimony pentachloride. J. Am. Chem. Soc. 82, 5740–5743 (1960).

    CAS  Google Scholar 

  23. Prakash, G. K. S. et al. N-Halosuccinimide/BF3–H2O, efficient electrophilic halogenating systems for aromatics. J. Am. Chem. Soc. 126, 15770–15776 (2004).

    CAS  PubMed  Google Scholar 

  24. Ben-Daniel, R., de Visser, S. P., Shaik, S. & Neumann, R. Electrophilic aromatic chlorination and haloperoxidation of chloride catalyzed by polyfluorinated alcohols: a new manifestation of template catalysis. J. Am. Chem. Soc. 125, 12116–12117 (2003).

    CAS  PubMed  Google Scholar 

  25. Yang, L., Lu, Z. & Stahl, S. S. Regioselective copper-catalyzed chlorination and bromination of arenes with O2 as the oxidant. Chem. Commun. 42, 6460–6462 (2009).

    Google Scholar 

  26. Mo, F. et al. Gold-catalyzed halogenation of aromatics by N-halosuccinimides. Angew. Chem., Int. Ed. 49, 2028–2032 (2010).

    CAS  Google Scholar 

  27. Qiu, D., Mo, F., Zheng, Z., Zhang, Y. & Wang, J. Gold(iii)-catalyzed halogenation of aromatic boronates with N-halosuccinimides. Org. Lett. 12, 5474–5477 (2010).

    CAS  PubMed  Google Scholar 

  28. Zhang, Y., Shibatomi, K. & Yamamoto, H. Lewis acid catalyzed highly selective halogenation of aromatic compounds. Synlett 18, 2837–2842 (2005).

    Google Scholar 

  29. Samanta, R. C. & Yamamoto, H. Selective halogenation using an aniline catalyst. Chem. Eur. J. 21, 11976–11979 (2015).

    CAS  PubMed  Google Scholar 

  30. Do, H.-Q. & Daugulis, O. A simple base-mediated halogenation of acidic sp 2 C–H bonds under noncryogenic conditions. Org. Lett. 11, 421–423 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kakiuchi, F. et al. Palladium-catalyzed aromatic C–H halogenation with hydrogen halides by means of electrochemical oxidation. J. Am. Chem. Soc. 131, 11310–11311 (2009).

    CAS  PubMed  Google Scholar 

  32. Werf, A. & Selander, N. Para-selective halogenation of nitrosoarenes with copper(ii) halides. Org. Lett. 17, 6210–6213 (2015).

    PubMed  Google Scholar 

  33. Maddox, S. M., Dinh, A. N., Armenta, F., Um, J. & Gustafson, J. L. The catalyst-controlled regiodivergent chlorination of phenols. Org. Lett. 18, 5476–5479 (2016).

    CAS  PubMed  Google Scholar 

  34. Xiong, X. & Yeung, Y.-Y. Highly ortho-selective chlorination of anilines using a secondary ammonium salt organocatalyst. Angew. Chem. Int. Ed. 55, 16101–16105 (2016).

    CAS  Google Scholar 

  35. Xiong, X. & Yeung, Y.-Y. Ammonium salt-catalyzed highly practical ortho-selective monohalogenation and phenylselenation of phenols: scope and applications. ACS Catal. 8, 4033–4043 (2018).

    CAS  Google Scholar 

  36. Wang, M. et al. Story of an age-old reagent: an electrophilic chlorination of arenes and heterocycles by 1-chloro-1,2-benziodoxol-3-one. Org. Lett. 18, 1976–1979 (2016).

    CAS  PubMed  Google Scholar 

  37. Maddox, S. M., Nalbandian, C. J., Smith, D. E. & Gustafson, J. L. A practical lewis base catalyzed electrophilic chlorination of arenes and heterocycles. Org. Lett. 17, 1042–1045 (2015).

    CAS  PubMed  Google Scholar 

  38. Zhang, L. & Hu, X. Room temperature C(sp 2)–H oxidative chlorination via photoredox catalysis. Chem. Sci. 8, 7009–7013 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Tanemura, K., Suzuki, T., Nishida, Y., Satsumabayashi, K. & Horaguchi, T. Halogenation of aromatic compounds by N-chloro-, N-bromo-, and N-iodosuccinimide. Chem. Lett. 32, 932–933 (2003).

    CAS  Google Scholar 

  40. Hering, T. & Konig, B. Photocatalytic activation of N-chloro compounds for the chlorination of arenes. Tetrahedron 72, 7821–7825 (2016).

    CAS  Google Scholar 

  41. Zanka, A. & Kutota, A. Practical and efficient chlorination of deactivated anilines and anilides with NCS in 2-propanol. Synlett 12, 1984–1986 (1999).

    Google Scholar 

  42. Petrone, D. A., Ye, J. & Lautens, M. Modern transition-metal-catalyzed carbon–halogen bond formation. Chem. Rev. 116, 8003–8104 (2016).

    CAS  PubMed  Google Scholar 

  43. Rodriguez, R. A. et al. Palau’chlor: a practical and reactive chlorinating reagent. J. Am. Chem. Soc. 136, 6908–6911 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Fosu, S. C., Hambira, C. M., Chen, A. D., Fuchs, J. R. & Nagib, D. A. Site-selective C–H functionalization of (hetero)arenes via transient, non-symmetric Iodanes. Chem 5, 417–428 (2018).

    PubMed  PubMed Central  Google Scholar 

  45. Denmark, S. E. & Beutner, G. L. Lewis base catalysis in organic synthesis. Angew. Chem. Int. Ed. 47, 1560–1638 (2008).

    CAS  Google Scholar 

  46. Gieuw, M. H., Ke, Z. & Yeung, Y.-Y. Lewis base catalyzed stereo- and regioselective bromocyclization. Chem. Rec. 17, 287–311 (2017).

    CAS  PubMed  Google Scholar 

  47. Landry, M. L. & Burns, N. Z. Catalytic enantioselective dihalogenation in total synthesis. Acc. Chem. Res. 51, 1260–1271 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Snyder, S. A., Treitler, D. S. & Brucks, A. P. Halonium-induced cyclization reactions. Aldrichim. Acta 44, 27–40 (2011).

    CAS  Google Scholar 

  49. Denmark, S. E., Kuester, W. E. & Burk, M. T. Catalytic, asymmetric halofunctionalization of alkenes—a critical perspective. Angew. Chem. Int. Ed. 51, 10938–10953 (2012).

    CAS  Google Scholar 

  50. Martin, D., Weise, A. & Niclas, H. J. The solvent dimethyl sulfoxide. Angew. Chem. Int. Ed. 6, 318–334 (1967).

    CAS  Google Scholar 

  51. Wu, X.-F. & Natte, K. The applications of dimethyl sulfoxide as reagent in organic synthesis. Adv. Synth. Catal. 358, 336–352 (2016).

    CAS  Google Scholar 

  52. Song, S., Sun, X., Li, X., Yuan, Y. & Jiao, N. Efficient and practical oxidative bromination and iodination of arenes and heteroarenes with DMSO and hydrogen halide: a mild protocol for late-stage functionalization. Org. Lett. 17, 2886–2889 (2015).

    CAS  PubMed  Google Scholar 

  53. Majetich, G., Hicks, R. & Reister, S. Electrophilic aromatic bromination using bromodimethylsulfonium bromide generated in situ. J. Org. Chem. 62, 4321–4326 (1997).

    CAS  PubMed  Google Scholar 

  54. Ashikari, Y., Shimizu, A., Nokami, T. & Yoshida, J. Halogen and chalcogen cation pools stabilized by DMSO. Versatile reagents for alkene difunctionalization. J. Am. Chem. Soc. 135, 16070–16073 (2013).

    CAS  PubMed  Google Scholar 

  55. Denmark, S. E. & Burk, M. T. Lewis base catalysis of bromo- and iodolactonization, and cycloetherification. Proc. Natl Acad. Sci. USA 107, 20655–20660 (2010).

    CAS  PubMed  Google Scholar 

  56. Dewick, P. M. Medicinal Natural Products: A Biosynthetic Approach 3rd edn 161, 164–165 (John Wiley & Sons, 2009).

  57. Lazar, C., Kluczyk, A., Kiyota, T. & Konishi, Y. Drug evolution concept in drug design: 1. Hybridization method. J. Med. Chem. 47, 6973–6982 (2004).

    CAS  PubMed  Google Scholar 

  58. Tang, J. et al. Synthesis, characterization, and NF-κB pathway inhibition of 1-halogenated sinomenine derivatives. Chem. Nat. Comp. 48, 1031–1034 (2013).

    CAS  Google Scholar 

  59. Che, Z., Yu, X., Fan, L. & Xu, H. Insight into dihalogenation of E-ring of podophyllotoxins, and their acyloxyation derivatives at the C4 position as insecticidal agents. Bioorg. Med. Chem. Lett. 23, 5592–5598 (2013).

    CAS  PubMed  Google Scholar 

  60. Boutureira, O. & Bernardes, G. J. L. Advances in chemical protein modification. Chem. Rev. 115, 2174–2195 (2015).

    CAS  PubMed  Google Scholar 

  61. Taylor, R. D., MacCoss, M. & Lawson, A. D. G. Rings in drugs. J. Med. Chem. 57, 5845–5859 (2014).

    CAS  PubMed  Google Scholar 

  62. Cresswell, A. J., Eey, S. T.-C. & Denmark, S. E. Catalytic, stereospecific syn-dichlorination of alkenes. Nat. Chem. 7, 146–152 (2015).

    CAS  PubMed Central  Google Scholar 

  63. Samanta, R. C. & Yamamoto, H. Catalytic asymmetric bromocyclization of polyenes. J. Am. Chem. Soc. 139, 1460–1463 (2017).

    CAS  PubMed  Google Scholar 

  64. Sakakura, A., Ukai, A. & Ishihara, K. Enantioselective halocyclization of polyprenoids induced by nucleophilic phosphoramidites. Nature 445, 900–903 (2007).

    CAS  PubMed  Google Scholar 

  65. Seidl, F. J., Min, C., Lopez, J. A. & Burns, N. Z. Catalytic regio- and enantioselective haloazidation of allylic alcohols. J. Am. Chem. Soc. 140, 15646–15650 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Financial support from the National Natural Science Foundation of China (grant nos. 21602005, 21632001, 81821004), the National Basic Research Program of China (973 Program, grant no. 2015CB856600), the Drug Innovation Major Project (grant no. 2018ZX09711-001) and the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China (grant no. KF-GN-201906) are greatly appreciated.

Author information

Authors and Affiliations

  1. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China

    Song Song, Xinyao Li, Jialiang Wei, Weijin Wang, Yiqun Zhang, Lingsheng Ai, Yuchao Zhu, Xiaomeng Shi, Xiaohui Zhang & Ning Jiao

  2. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, China

    Song Song

  3. State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai, China

    Ning Jiao

Authors
  1. Song Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinyao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jialiang Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weijin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yiqun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lingsheng Ai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuchao Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaomeng Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaohui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ning Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.S. and N.J. conceived and designed the experiments. S.S. carried out most of the experiments. X.L. ran the calculations. S.S., X.L., J.W., W.W., Y.Z., L.A., Y.Z., X.S., X.Z. and N.J. analyzed data. S.S. and N.J. wrote the paper. N.J. directed the project.

Corresponding author

Correspondence to Ning Jiao.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Methods, Figs. 1–8, Tables 1–3 and references

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, S., Li, X., Wei, J. et al. DMSO-catalysed late-stage chlorination of (hetero)arenes. Nat Catal 3, 107–115 (2020). https://doi.org/10.1038/s41929-019-0398-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41929-019-0398-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research