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Iron-catalysed asymmetric carboazidation of styrenes

Abstract

Carboazidation of olefins is an efficient process to convert hydrocarbons directly into nitrogen-containing molecules. Such chemicals find broad applications in medicine and material sciences. Despite the fast development of carboazidation reactions, asymmetric radical carboazidations are still elusive. Here, we report a radical asymmetric carboazidation of olefins via an iron-catalysed group transfer mechanism. The method affords valuable chiral halogenated organoazides from inexpensive industrial chemical feedstocks. This radical azidation reaction is supported by mechanistic studies and should inspire further development of enantioselective radical reactions.

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Fig. 1: Stereocontrol at a radical centre.
Fig. 2: Substrate scope with respective to olefins and carbon sources.
Fig. 3: Mechanistic studies.
Fig. 4: Synthetic use of the chiral azides.

Data availability

Data relating to the characterization data of materials and products, general methods, optimization studies, experimental procedures, mechanistic studies, mass spectrometry, high-performance liquid chromatography and NMR spectra, computational studies are available in the Supplementary Information. Crystallographic data for compounds L2Fe(OTf)2, 63, 72A and 72B are available free of charge from the Cambridge Crystallographic Data Centre (CCDC) under reference numbers 1938900, 1938899, 2003644 and 2015243, respectively.

References

  1. 1.

    Bräse, S. & Banert, K. (eds) Organic Azides: Syntheses and Applications (John Wiley & Sons, Ltd, 2009).

  2. 2.

    Sharma, A. & Hartwig, J. F. Metal-catalysed azidation of tertiary C–H bonds suitable for late-stage functionalization. Nature 517, 600–604 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Renaud, P., Ollivier, C. & Panchaud, P. Radical carboazidation of alkenes: an efficient tool for the preparation of pyrrolidinone derivatives. Angew. Chem. Int. Ed. 41, 3460–3462 (2002).

    CAS  Article  Google Scholar 

  4. 4.

    Wang, F., Qi, X., Liang, Z., Chen, P. & Liu, G. Copper-catalyzed intermolecular trifluoromethylazidation of alkenes: convenient access to CF3-containing alkyl azides. Angew. Chem. Int. Ed. 53, 1881–1886 (2014).

    CAS  Article  Google Scholar 

  5. 5.

    Dagousset, G., Carboni, A., Magnier, E. & Masson, G. Photoredox-induced three-component azido- and aminotrifluoromethylation of alkenes. Org. Lett. 16, 4340–4343 (2014).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Bunescu, A., Ha, T. M., Wang, Q. & Zhu, J. Copper-catalyzed three-component carboazidation of alkenes with acetonitrile and sodium azide. Angew. Chem. Int. Ed. 56, 10555–10558 (2017).

    CAS  Article  Google Scholar 

  7. 7.

    Geng, X., Lin, F., Wang, X. & Jiao, N. Azidofluoroalkylation of alkenes with simple fluoroalkyl iodides enabled by photoredox catalysis. Org. Lett. 19, 4738–4741 (2017).

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Zhu, C.-L. et al. Iron(ii)-catalyzed azidotrifluoromethylation of olefins and N-heterocycles for expedient vicinal trifluoromethyl amine synthesis. ACS Catal. 8, 5032–5037 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Zhang, L. et al. (Salen)Mn(iii)-catalyzed chemoselective acylazidation of olefins. Chem. Sci. 9, 6085–6090 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Xiong, H. et al. Iron-catalyzed carboazidation of alkenes and alkynes. Nat. Commun. 10, 122 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    Wu, K., Liang, Y. & Jiao, N. Azidation in the difunctionalization of olefins. Molecules 21, 352 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 12.

    Jiang, H. & Studer, A. Intermolecular radical carboamination of alkenes. Chem. Soc. Rev. 49, 1790–1811 (2020).

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Ge, L., Chiou, M.-F., Li, Y. & Bao, H. Radical azidation as a means of constructing C(sp3)-N3 bonds. Green Syn. Catal. https://doi.org/10.1016/j.gresc.2020.07.001 (2020).

  14. 14.

    Jacobsen, E. N. Asymmetric catalysis of epoxide ring-opening reactions. Acc. Chem. Res. 33, 421–431 (2000).

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Ding, P.-G., Hu, X.-S., Zhou, F. & Zhou, J. Catalytic enantioselective synthesis of α-chiral azides. Org. Chem. Front. 5, 1542–1559 (2018).

    CAS  Article  Google Scholar 

  16. 16.

    Zhou, P. et al. Iron-catalyzed asymmetric haloazidation of alpha,beta-unsaturated ketones: construction of organic azides with two vicinal stereocenters. J. Am. Chem. Soc. 139, 13414–13419 (2017).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    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  Article  Google Scholar 

  18. 18.

    Li, X., Qi, X., Hou, C., Chen, P. & Liu, G. Palladium(ii)-catalyzed enantioselective azidation of unactivated alkenes. Angew. Chem. Int. Ed. 59, 17239–17244 (2020).

    CAS  Article  Google Scholar 

  19. 19.

    Liu, C., Wang, X., Li, Z., Cui, L. & Li, C. Silver-catalyzed decarboxylative radical azidation of aliphatic carboxylic acids in aqueous solution. J. Am. Chem. Soc. 137, 9820–9823 (2015).

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Krasutsky, A. P., Kuehl, C. J. & Zhdankin, V. V. Direct azidation of adamantane and norbornane by stable azidoiodinanes. Synlett 1995, 1081–1082 (1995).

    Article  Google Scholar 

  21. 21.

    Magnus, P., Lacour, J., Evans, P. A., Roe, M. B. & Hulme, C. hypervalent iodine chemistry: new oxidation reactions using the iodosylbenzene−trimethylsilyl azide reagent combination. direct α- and β-azido functionalization of triisopropylsilyl enol ethers. J. Am. Chem. Soc. 118, 3406–3418 (1996).

    CAS  Article  Google Scholar 

  22. 22.

    Huang, X., Bergsten, T. M. & Groves, J. T. Manganese-catalyzed late-stage aliphatic C–H azidation. J. Am. Chem. Soc. 137, 5300–5303 (2015).

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Chiou, M. F., Xiong, H., Li, Y., Bao, H. & Zhang, X. Revealing the iron-catalyzed beta-methyl scission of tert-butoxyl radicals via the mechanistic studies of carboazidation of alkenes. Molecules 25, 1224 (2020).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  24. 24.

    Sibi, M. P., Manyem, S. & Zimmerman, J. Enantioselective radical processes. Chem. Rev. 103, 3263–3296 (2003).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Wang, K. & Kong, W. Recent advances in transition metal-catalyzed asymmetric radical reactions. Chin. J. Chem. 36, 247–256 (2018).

    CAS  Article  Google Scholar 

  26. 26.

    Wang, F., Chen, P. & Liu, G. Copper-catalyzed radical relay for asymmetric radical transformations. Acc. Chem. Res. 51, 2036–2046 (2018).

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Huang, X. & Meggers, E. Asymmetric photocatalysis with bis-cyclometalated rhodium complexes. Acc. Chem. Res. 52, 833–847 (2019).

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Yang, D., Zheng, B.-F., Gao, Q., Gu, S. & Zhu, N.-Y. Enantioselective PhSe-group-transfer tandem radical cyclization reactions catalyzed by a chiral Lewis acid. Angew. Chem. Int. Ed. 45, 255–258 (2005).

    Article  CAS  Google Scholar 

  29. 29.

    Beeson, T. D., Mastracchio, A., Hong, J. B., Ashton, K. & Macmillan, D. W. Enantioselective organocatalysis using SOMO activation. Science 316, 582–585 (2007).

    CAS  Article  Google Scholar 

  30. 30.

    Herrmann, A. T., Smith, L. L. & Zakarian, A. A simple method for asymmetric trifluoromethylation of N-acyl oxazolidinones via Ru-catalyzed radical addition to zirconium enolates. J. Am. Chem. Soc. 134, 6976–6979 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Zhu, R. & Buchwald, S. L. Enantioselective functionalization of radical intermediates in redox catalysis: copper-catalyzed asymmetric oxytrifluoromethylation of alkenes. Angew. Chem. Int. Ed. 52, 12655–12658 (2013).

    CAS  Article  Google Scholar 

  32. 32.

    Rono, L. J., Yayla, H. G., Wang, D. Y., Armstrong, M. F. & Knowles, R. R. Enantioselective photoredox catalysis enabled by proton-coupled electron transfer: development of an asymmetric aza-pinacol cyclization. J. Am. Chem. Soc. 135, 17735–17738 (2013).

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Hashimoto, T., Kawamata, Y. & Maruoka, K. An organic thiyl radical catalyst for enantioselective cyclization. Nat. Chem. 6, 702–705 (2014).

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Ruiz Espelt, L., McPherson, I. S., Wiensch, E. M. & Yoon, T. P. Enantioselective conjugate additions of alpha-amino radicals via cooperative photoredox and Lewis acid catalysis. J. Am. Chem. Soc. 137, 2452–2455 (2015).

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Murphy, J. J., Bastida, D., Paria, S., Fagnoni, M. & Melchiorre, P. Asymmetric catalytic formation of quaternary carbons by iminium ion trapping of radicals. Nature 532, 218–222 (2016).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Jiang, H., Lang, K., Lu, H., Wojtas, L. & Zhang, X. P. Asymmetric radical bicyclization of allyl azidoformates via cobalt(ii)-based metalloradical catalysis. J. Am. Chem. Soc. 139, 9164–9167 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Poremba, K. E., Kadunce, N. T., Suzuki, N., Cherney, A. H. & Reisman, S. E. Nickel-catalyzed asymmetric reductive cross-coupling to access 1,1-diarylalkanes. J. Am. Chem. Soc. 139, 5684–5687 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Kern, N., Plesniak, M. P., McDouall, J. J. W. & Procter, D. J. Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals. Nat. Chem. 9, 1198–1204 (2017).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Yin, Y. et al. Conjugate addition-enantioselective protonation of N-aryl glycines to alpha-branched 2-vinylazaarenes via cooperative photoredox and asymmetric catalysis. J. Am. Chem. Soc. 140, 6083–6087 (2018).

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Proctor, R. S. J., Davis, H. J. & Phipps, R. J. Catalytic enantioselective Minisci-type addition to heteroarenes. Science 360, 419–422 (2018).

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Li, J. et al. Formal enantioconvergent substitution of alkyl halides via catalytic asymmetric photoredox radical coupling. Nat. Commun. 9, 2445 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. 42.

    Wang, Z., Yin, H. & Fu, G. C. Catalytic enantioconvergent coupling of secondary and tertiary electrophiles with olefins. Nature 563, 379–383 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Dong, X. Y. et al. A general asymmetric copper-catalysed Sonogashira C(sp(3))-C(sp) coupling. Nat. Chem. 11, 1158–1166 (2019).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Biegasiewicz, K. F. et al. Photoexcitation of flavoenzymes enables a stereoselective radical cyclization. Science 364, 1166–1169 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Zheng, D. & Studer, A. Asymmetric synthesis of heterocyclic gamma-amino-acid and diamine derivatives by three-component radical cascade reactions. Angew. Chem. Int. Ed. 58, 15803–15807 (2019).

    CAS  Article  Google Scholar 

  46. 46.

    Goswami, M. & de Bruin, B. Metal-catalysed azidation of organic molecules. Eur. J. Org. Chem. 2017, 1152–1176 (2017).

    CAS  Article  Google Scholar 

  47. 47.

    Huang, X. & Groves, J. T. Taming azide radicals for catalytic C–H azidation. ACS Catal. 6, 751–759 (2015).

    Article  CAS  Google Scholar 

  48. 48.

    Sibi, M. P. & Patil, K. Enantioselective H-atom transfer reactions: a new methodology for the synthesis of beta2-amino acids. Angew. Chem. Int. Ed. 43, 1235–1238 (2004).

    CAS  Article  Google Scholar 

  49. 49.

    Aechtner, T., Dressel, M. & Bach, T. Hydrogen bond mediated enantioselectivity of radical reactions. Angew. Chem. Int. Ed. 43, 5849–5851 (2004).

    CAS  Article  Google Scholar 

  50. 50.

    Zhu, S., Ruppel, J. V., Lu, H., Wojtas, L. & Zhang, X. P. Cobalt-catalyzed asymmetric cyclopropanation with diazosulfones: rigidification and polarization of ligand chiral environment via hydrogen bonding and cyclization. J. Am. Chem. Soc. 130, 5042–5043 (2008).

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Jin, L. M. et al. Effective synthesis of chiral N-fluoroaryl aziridines through enantioselective aziridination of alkenes with fluoroaryl azides. Angew. Chem. Int. Ed. 52, 5309–5313 (2013).

    CAS  Article  Google Scholar 

  52. 52.

    Chen, B., Fang, C., Liu, P. & Ready, J. M. Rhodium-catalyzed enantioselective radical addition of CX4 reagents to olefins. Angew. Chem. Int. Ed. 56, 8780–8784 (2017).

    CAS  Article  Google Scholar 

  53. 53.

    Liang, Y., Wei, J., Qiu, X. & Jiao, N. Homogeneous oxygenase catalysis. Chem. Rev. 118, 4912–4945 (2018).

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Milan, M., Bietti, M. & Costas, M. Enantioselective aliphatic C–H bond oxidation catalyzed by bioinspired complexes. Chem. Commun. 54, 9559–9570 (2018).

    CAS  Article  Google Scholar 

  55. 55.

    Wu, W. et al. Trifluoroacetic anhydride promoted copper(I)-catalyzed interrupted click reaction: from 1,2,3-triazoles to 3-trifluoromethyl-substituted 1,2,4-triazinones. Angew. Chem. Int. Ed. 56, 10476–10480 (2017).

    CAS  Article  Google Scholar 

  56. 56.

    Åhman, J., Birch, M., Haycock-Lewandowski, S. J., Long, J. & Wilder, A. Process research and scale-up of a commercialisable route to maraviroc (UK-427,857), a CCR-5 receptor antagonist. Org. Process Res. Dev. 12, 1104–1113 (2008).

    Article  CAS  Google Scholar 

  57. 57.

    Kanemasa, S. et al. Cationic aqua complexes of the C2-symmetrictrans-chelating ligand (R,R)-4,6-dibenzofurandiyl-2,2‘-bis(4-phenyloxazoline). Absolute chiral induction in Diels–Alder reactions catalyzed by water-tolerant enantiopure Lewis acids. J. Org. Chem. 62, 6454–6455 (1997).

    CAS  Article  Google Scholar 

  58. 58.

    Deng, Q. H., Bleith, T., Wadepohl, H. & Gade, L. H. Enantioselective iron-catalyzed azidation of beta-keto esters and oxindoles. J. Am. Chem. Soc. 135, 5356–5359 (2013).

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Bauer, I. & Knölker, H.-J. Iron catalysis in organic synthesis. Chem. Rev. 115, 3170–3387 (2015).

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Contreras-Garcia, J. et al. NCIPLOT: a program for plotting non-covalent interaction regions. J. Chem. Theor. Comput. 7, 625–632 (2011).

    CAS  Article  Google Scholar 

  61. 61.

    Lee, C., Yang, W. & Parr, R. G. Development of the Colle–Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B. 37, 785–789 (1988).

    CAS  Article  Google Scholar 

  62. 62.

    Becke, A. D. Density‐functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 98, 5648–5652 (1993).

    CAS  Article  Google Scholar 

  63. 63.

    Grimme, S., Antony, J., Ehrlich, S. & Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H–Pu. J. Chem. Phys. 132, 154104 (2010).

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Grimme, S., Ehrlich, S. & Goerigk, L. Effect of the damping function in dispersion corrected density functional theory. J. Comput. Chem. 32, 1456–1465 (2011).

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Weigend, F. Accurate Coulomb-fitting basis sets for H to Rn. Phys. Chem. Chem. Phys. 8, 1057–1065 (2006).

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Weigend, F. & Ahlrichs, R. Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: design and assessment of accuracy. Phys. Chem. Chem. Phys. 7, 3297–3305 (2005).

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Marenich, A. V., Cramer, C. J. & Truhlar, D. G. Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J. Phys. Chem. B. 113, 6378–6396 (2009).

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Frisch, M. J. et al. Gaussian 09, Revision D.01 (Gaussian Inc., 2013).

  69. 69.

    Johnson, E. R. et al. Revealing noncovalent interactions. J. Am. Chem. Soc. 132, 6498–6506 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

We thank K. Ding and X.L. Hou from Shanghai Institute of Organic Chemistry, A. Studer from University of Münster, X. Wang from Lanzhou University, W. Xie from Northwest A&F University and W. Su from our institute for inspiring discussions, D. Yuan and X. Jiang from our institute for X-ray crystallography analysis. We thank G.W.A. Milne for his writing suggestions. Supported by the National Key R&D Programme of China (grant no. 2017YFA0700103), the NSFC (grant nos. 21672213, 21871258 and 21922112), the Strategic Priority Research Programme of the Chinese Academy of Sciences (grant no. XDB20000000), the Haixi Institute of CAS (grant no. CXZX-2017-P01), the Innovative Research Teams Programme II of Fujian Normal University in China (grant no. IRTL1703), the Shenzhen STIC (grant no. JCYJ20170412150343516) and the Shenzhen San-Ming Project (grant no. SZSM201809085).

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Authors

Contributions

H.B. directed the investigations and prepared the manuscript. L.G., H.Z., W.J., C.Y., X.L., X. Zhu and H.X. performed the synthetic experiments and analysed the experimental data. X. Zhang directed the calculation study and M.-F.C. completed the theoretical calculations. H.J. conducted the mass spectra studies, L.S. did the non-covalent bond interaction analysis. Y.L. double checked the data in the Supplementary Information. L.G., H.Z. and M.-F.C. contributed equally.

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Correspondence to Xinhao Zhang or Hongli Bao.

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Supplementary information

Supplementary information

Supplementary Tables 1–4, Methods, Discussion, Figs. 1–8 and references.

Supplementary Data

44 coordinate of optimized structures file as text.

Supplementary Data 1

X-ray crystal structure of iron catalyst A, L2Fe(OTf)2.

Supplementary Data 2

X-ray crystal structure of product 72B.

Supplementary Data 3

X-ray crystal structure of product 72A.

Supplementary Data 4

X-ray crystal structure of product 63.

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Ge, L., Zhou, H., Chiou, MF. et al. Iron-catalysed asymmetric carboazidation of styrenes. Nat Catal 4, 28–35 (2021). https://doi.org/10.1038/s41929-020-00551-4

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