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Energy transfer-enabled unsymmetrical diamination using bifunctional nitrogen-radical precursors

Nature Catalysis volume 5, pages 1120–1130 (2022)Cite this article

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Abstract

Vicinal diamines, especially unsymmetrical ones, are among the most common structural motifs in biologically active molecules, natural products and pharmaceuticals. While the catalytic diamination of carbon–carbon double bonds provides rapid access to diamines, these reactions are often limited to installation of undifferentiated amino functionalities through transition metals or hypervalent iodine reagent catalysis. Herein we disclose a metal-free, photosensitized dearomative unsymmetrical diamination of various electron-rich (hetero)arenes with bifunctional diamination reagents, producing a series of previously inaccessible vicinal diamines with excellent regio- and diastereoselectivity. A class of bifunctional nitrogen-radical precursors was developed to simultaneously generate two N-centred radicals with different reactivity via an energy transfer process. In addition, the protocol was also found suitable for a wide range of alkenes. Notably, the formed vicinal diamines bear two differentiated amino functionalities, and either imine or amide units could readily and orthogonally be converted to unprotected amines, thereby facilitating selective downstream transformations.

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Fig. 1: Development of nitrogen-radical precursors.
Fig. 2: Reaction development.
Fig. 3: Mechanistic investigations.
Fig. 4: Dearomative unsymmetrical diamination of (hetero)arenes.
Fig. 5: Unsymmetrical diamination of alkenes.
Fig. 6: Synthetic applications.

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Data availability

Materials and methods, experimental procedures, mechanistic studies, computational studies, sensitivity assessment and nuclear magnetic resonance (NMR) spectra are available in the Supplementary Information. Crystallographic information data files and xyz coordinates of the optimized structures are available as Supplementary files. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre under deposition nos. CCDC 2145161 (21) and 2145162 (66). Copies of crystallographic data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data are available from the authors upon reasonable request.

References

  1. Ricci, A. Amino Group Chemistry: From Synthesis to the Life Sciences (Wiley, 2008).

  2. Lucet, D., Le Gall, T. & Mioskowski, C. The chemistry of vicinal diamines. Angew. Chem. Int. Ed. Engl. 37, 2580–2627 (1998).

    Article  CAS  Google Scholar 

  3. Newhouse, T., Lewis, C. A., Eastman, K. J. & Baran, P. S. Scalable total syntheses of N-linked tryptamine dimers by direct indole-aniline coupling: psychotrimine and kapakahines B and F. J. Am. Chem. Soc. 132, 7119–7137 (2010).

    Article  CAS  Google Scholar 

  4. Kizirian, J.-C. Chiral tertiary diamines in asymmetric synthesis. Chem. Rev. 108, 140–205 (2008).

    Article  CAS  Google Scholar 

  5. Cardona, F. & Goti, A. Metal-catalysed 1,2-diamination reactions. Nat. Chem. 1, 269–275 (2009).

    Article  CAS  Google Scholar 

  6. Jong, S., de, Nosal, D. G. & Wardrop, D. J. Methods for direct alkene diamination, new & old. Tetrahedron 68, 4067–4105 (2012).

    Article  Google Scholar 

  7. Chong, A. O., Oshima, K. & Sharpless, K. B. Synthesis of dioxobis(tert-alkylimido)osmium(VIII) and oxotris(tert-alkylimido)osmium(VIII) complexes. Stereospecific vicinal diamination of olefins. J. Am. Chem. Soc. 99, 3420–3426 (1977).

    Article  CAS  Google Scholar 

  8. Becker, P. N., White, M. A. & Bergman, R. G. A new method for 1,2-diamination of alkenes using cyclopentadienylnitrosylcobalt dimer/NO/LiAlH4. J. Am. Chem. Soc. 102, 5676–5677 (1980).

    Article  CAS  Google Scholar 

  9. Bar, G. L. J., Lloyd-Jones, G. C. & Booker-Milburn, K. I. Pd(II)-catalyzed intermolecular 1,2-diamination of conjugated dienes. J. Am. Chem. Soc. 127, 7308–7309 (2005).

    Article  CAS  Google Scholar 

  10. Zhao, B., Du, H., Cui, S. & Shi, Y. Synthetic and mechanistic studies on Pd(0)-catalyzed diamination of conjugated dienes. J. Am. Chem. Soc. 132, 3523–3532 (2010).

    Article  CAS  Google Scholar 

  11. Röben, C., Souto, J. A., González, Y., Lishchynskyi, A. & Muñiz, K. Enantioselective metal-free diamination of styrenes. Angew. Chem. Int. Ed. Engl. 50, 9478–9482 (2011).

    Article  Google Scholar 

  12. Zhao, B. et al. Cu(I)-catalyzed diamination of conjugated dienes. Complementary regioselectivity from two distinct mechanistic pathways involving Cu(II) and Cu(III) species. J. Am. Chem. Soc. 133, 20890–20900 (2011).

    Article  CAS  Google Scholar 

  13. Zhu, Y., Cornwall, R. G., Du, H., Zhao, B. & Shi, Y. Catalytic diamination of olefins via N–N bond activation. Acc. Chem. Res. 47, 3665–3678 (2014).

    Article  CAS  Google Scholar 

  14. Fumagalli, G., Rabet, P. T. G., Boyd, S. & Greaney, M. F. Three-component azidation of styrene-type double bonds: light-switchable behavior of a copper photoredox catalyst. Angew. Chem. Int. Ed. Engl. 54, 11481–11484 (2015).

    Article  CAS  Google Scholar 

  15. Yuan, Y.-A., Lu, D.-F., Chen, Y.-R. & Xu, H. Iron-catalyzed direct diazidation for a broad range of olefins. Angew. Chem. Int. Ed. Engl. 55, 534–538 (2016).

    Article  CAS  Google Scholar 

  16. Fu, N., Sauer, G. S., Saha, A., Loo, A. & Lin, S. Metal-catalyzed electrochemical diazidation of alkenes. Science 357, 575–579 (2017).

    Article  CAS  Google Scholar 

  17. Muñiz, K., Barreiro, L., Romero, R. M. & Martínez, C. Catalytic asymmetric diamination of styrenes. J. Am. Chem. Soc. 139, 4354–4357 (2017).

    Article  Google Scholar 

  18. Shen, S.-J., Zhu, C.-L., Lu, D.-F. & Xu, H. Iron-catalyzed direct olefin diazidation via peroxyester activation promoted by nitrogenbased ligands. ACS Catal. 8, 4473–4482 (2018).

    Article  CAS  Google Scholar 

  19. Fu, N., Sauer, G. S. & Lin, S. A general, electrocatalytic approach to the synthesis of vicinal diamines. Nat. Protoc. 13, 1725–1743 (2018).

    Article  CAS  Google Scholar 

  20. Siu, J. C., Parry, J. B. & Lin, S. Aminoxyl-catalyzed electrochemical diazidation of alkenes mediated by a metastable charge-transfer complex. J. Am. Chem. Soc. 141, 2825–2831 (2019).

    Article  CAS  Google Scholar 

  21. Cai, C.-Y., Shu, X.-M. & Xu, H.-C. Practical and stereoselective electrocatalytic 1,2-diamination of alkenes. Nat. Commun. 10, 4953–4959 (2019).

    Article  Google Scholar 

  22. Tao, Z., Gilbert, B. B. & Denmark, S. E. Catalytic, enantioselective syn-diamination of alkenes. J. Am. Chem. Soc. 141, 19161–19170 (2019).

    Article  CAS  Google Scholar 

  23. Minakata, S., Miwa, H., Yamamoto, K., Hirayama, A. & Okumura, S. Diastereodivergent intermolecular 1,2-diamination of unactivated alkenes enabled by iodine catalysis. J. Am. Chem. Soc. 143, 4112–4118 (2021).

    Article  CAS  Google Scholar 

  24. Southgate, E. H., Pospech, J., Fu, J., Holycross, D. R. & Sarlah, D. Dearomative dihydroxylation with arenophiles. Nat. Chem. 8, 922–928 (2016).

    Google Scholar 

  25. Wertjes, W. C., Okumura, M. & Sarlah, D. Palladium-catalyzed dearomative syn-1,4-diamination. J. Am. Chem. Soc. 141, 163–167 (2019).

    Article  CAS  Google Scholar 

  26. Wu, J., Dou, Y., Guillot, R., Kouklovsky, C. & Vincent, G. Electrochemical dearomative 2,3-difunctionalization of indoles. J. Am. Chem. Soc. 141, 2832–2837 (2019).

    Article  CAS  Google Scholar 

  27. Wang, D., Yu, H., Sun, S. & Zhong, F. Intermolecular vicinal diaminative assembly of tetrahydroquinoxalines via metal-free oxidative [4+2] cycloaddition strategy. Org. Lett. 22, 2425–2430 (2020).

    Article  CAS  Google Scholar 

  28. Liu, J. et al. Diastereoselective 2, 3-diazidation of indoles via copper(II)-catalyzed dearomatization. Chin. Chem. Lett. 31, 1332–1336 (2020).

    Article  CAS  Google Scholar 

  29. Wang, M.-M., Nguyen, T. V. T. & Waser, J. Diamine synthesis via the nitrogen-directed azidation of σ- andπ‑C-C Bonds. J. Am. Chem. Soc. 143, 11969–11975 (2021).

    Article  CAS  Google Scholar 

  30. Li, G., Wei, H.-X., Kim, S. H. & Carducci, M. D. A novel electrophilic diamination reaction of alkenes. Angew. Chem. Int. Ed. Engl. 40, 4277–4280 (2001).

    Article  CAS  Google Scholar 

  31. Jiang, H., Nielsen, J. B., Nielsen, M. & Jørgensen, K. A. Organocatalysed asymmetric β-amination and multicomponent syn-selective diamination of α,β-unsaturated aldehydes. Chem. Eur. J. 13, 9068–9075 (2007).

    Article  CAS  Google Scholar 

  32. Simmons, B., Walji, A. M. & MacMillan, D. W. C. Cycle-specific organocascade catalysis: application to olefin hydroamination, hydro-oxidation, and amino-oxidation, and to natural product synthesis. Angew. Chem. Int. Ed. Engl. 48, 4349–4353 (2009).

    Article  CAS  Google Scholar 

  33. Iglesias, A. ́, Pérez, E. G. & Muñiz, K. An intermolecular palladium-catalyzed diamination of unactivated alkenes. Angew. Chem. Int. Ed. Engl. 49, 8109–8111 (2010).

    Article  CAS  Google Scholar 

  34. Martínez, C. & Muñiz, K. Palladium-catalyzed vicinal difunctionalization of internal alkenes: diastereoselective synthesis of diamines. Angew. Chem. Int. Ed. Engl. 51, 7031–7034 (2012).

    Article  Google Scholar 

  35. Zhang, H. et al. Copper-catalyzed intermolecular aminocyanation and diamination of alkenes. Angew. Chem. Int. Ed. Engl. 52, 2529–2533 (2013).

    Article  CAS  Google Scholar 

  36. Zhang, B. & Studer, A. Copper-catalyzed intermolecular aminoazidation of alkenes. Org. Lett. 16, 1790–1793 (2014).

    Article  CAS  Google Scholar 

  37. Olson, D. E., Su, J. Y., Roberts, D. A. & Du Bois, J. Vicinal diamination of alkenes under Rh-catalysis. J. Am. Chem. Soc. 136, 13506–13509 (2014).

    Article  CAS  Google Scholar 

  38. Ciesielski, J., Dequirez, G., Retailleau, P., Gandon, V. & Dauban, P. Rhodium-catalyzed alkene difunctionalization with nitrenes. Chem. Eur. J. 22, 9338–9347 (2016).

    Article  CAS  Google Scholar 

  39. Govaerts, S. et al. Photoinduced olefin diamination with alkylamines. Angew. Chem. Int. Ed. Engl. 59, 15021–15028 (2020).

    Article  CAS  Google Scholar 

  40. Makai, S., Falk, E. & Morandi, B. Direct synthesis of unprotected 2-azidoamines from alkenes via an iron-catalyzed difunctionalization reaction. J. Am. Chem. Soc. 142, 21548–21555 (2020).

    Article  CAS  Google Scholar 

  41. Fan, Z., Wang, Z., Shi, R. & Wang, Y. Dirhodium(II)-catalyzed diamination reaction via a free radical pathway. Org. Chem. Front. 8, 5098–5104 (2021).

    Article  CAS  Google Scholar 

  42. Xuan, J. & Xiao, W.-J. Visible-light photoredox catalysis. Angew. Chem. Int. Ed. Engl. 51, 6828–6838 (2012).

    Article  CAS  Google Scholar 

  43. Narayanam, J. M. R. & Stephenson, C. R. J. Visible light photoredox catalysis: applications in organic synthesis. Chem. Soc. Rev. 40, 102–113 (2011).

    Article  CAS  Google Scholar 

  44. Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).

    Article  CAS  Google Scholar 

  45. Skubi, K. L., Blum, T. R. & Yoon, T. P. Dual catalysis strategies in photochemical synthesis. Chem. Rev. 116, 10035–10074 (2016).

    Article  CAS  Google Scholar 

  46. Stephenson, C. R. J., Yoon, T. & MacMillan, D. W. C. Visible Light Photocatalysis in Organic Chemistry (Wiley, 2018).

  47. Zard, S. Z. Recent progress in the generation and use of nitrogen-centred radicals. Chem. Soc. Rev. 37, 1603–1618 (2008).

    Article  CAS  Google Scholar 

  48. Chen, J.-R., Hu, X.-Q., Lu, L.-Q. & Xiao, W.-J. Visible light photoredox-controlled reactions of N-radicals and radical ions. Chem. Soc. Rev. 45, 2044–2056 (2016).

    Article  CAS  Google Scholar 

  49. Kärkäs, M. D. Photochemical generation of nitrogen-centered amidyl, hydrazonyl, and imidyl radicals: methodology developments and catalytic applications. ACS Catal. 7, 4999–5022 (2017).

    Article  Google Scholar 

  50. Jackman, M. M., Cai, Y. & Castle, S. L. Recent advances in iminyl radical cyclizations. Synthesis 49, 1785–1795 (2017).

    Article  CAS  Google Scholar 

  51. Zhao, Y. & Xia, W. Recent advances in radical-based C–N bond formation via photo-/electrochemistry. Chem. Soc. Rev. 47, 2591–2608 (2018).

    Article  CAS  Google Scholar 

  52. Davies, J., Morcillo, S. P., Douglas, J. J. & Leonori, D. Hydroxylamine derivatives as nitrogen-radical precursors in visible-light photochemistry. Chem. Eur. J. 24, 12154–12163 (2018).

    Article  CAS  Google Scholar 

  53. Strieth-Kalthoff, F., James, M. J., Teders, M., Pitzer, L. & Glorius, F. Energy transfer catalysis mediated by visible light: principles, applications, directions. Chem. Soc. Rev. 47, 7190–7202 (2018).

    Article  CAS  Google Scholar 

  54. Zhou, Q.-Q., Zou, Y.-Q., Lu, L.-Q. & Xiao, W.-J. Visible-light-induced organic photochemical reactions through energy-transfer pathways. Angew. Chem. Int. Ed. Engl. 58, 1586–1604 (2019).

    Article  CAS  Google Scholar 

  55. Strieth-Kalthoff, F. & Glorius, F. Triplet energy transfer photocatalysis: unlocking the next level. Chem 6, 1888–1903 (2020).

    Article  CAS  Google Scholar 

  56. Jiang, H. & Studer, A. Amidyl radicals by oxidation of α-amido-oxy acids: transition-metal-free amidofluorination of unactivated alkenes. Angew. Chem. Int. Ed. Engl. 57, 10707–10711 (2018).

    Article  CAS  Google Scholar 

  57. Jiang, H., Seidler, G. & Studer, A. Carboamination of unactivated alkenes through three-component radical conjugate addition. Angew. Chem. Int. Ed. Engl. 58, 16528–16532 (2019).

    Article  CAS  Google Scholar 

  58. Patra, T., Das, M., Daniliuc, C. G. & Glorius, F. Metal-free, photosensitized oxyimination of unactivated alkenes with bifunctional oxime carbonates. Nat. Catal. 4, 54–61 (2021).

    Article  CAS  Google Scholar 

  59. Pitzer, L., Schäfers, F. & Glorius, F. Rapid assessment of the reaction-condition-based sensitivity of chemical transformations. Angew. Chem. Int. Ed. Engl. 58, 8572–8576 (2019).

    Article  CAS  Google Scholar 

  60. Nikitas, N. F., Gkizis, P. L. & Kokotos, C. G. Thioxanthone: a powerful photocatalyst for organic reactions. Org. Biomol. Chem. 19, 5237–5253 (2021).

    Article  CAS  Google Scholar 

  61. Fische, H. The persistent radical effect: a principle for selective radical reactions and living radical polymerizations. Chem. Rev. 101, 3581–3610 (2001).

    Article  Google Scholar 

  62. Leifert, D. & Studer, A. The persistent radical effect in organic synthesis. Angew. Chem. Int. Ed. Engl. 59, 74–108 (2020).

    Article  CAS  Google Scholar 

  63. Huang, C.-Y. et al. Widely applicable deprotection method of 2,2,2-trichloroethoxycarbonyl (Troc) group using tetrabutylammonium fluoride. J. Carbohydr. Chem. 29, 289–298 (2010).

    Article  CAS  Google Scholar 

  64. Jiang, H., Yu, X., Daniliuc, C. G. & Studer, A. Three-component aminoarylation of electron-rich alkenes by merging photoredox with nickel catalysis. Angew. Chem. Int. Ed. Engl. 60, 14399–14404 (2021).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank P. Bellotti, X. Yu, X. Zhang (all WWU) and H. Keum (KAIST) for helpful assistance and discussions. Generous financial support provided by the Alexander von Humboldt Foundation (G.T.), Fonds der Chemischen Industrie (R.K., Kekulé Scholarship no. 106151) and Deutsche Forschungsgemeinschaft (no. SFB 858) is gratefully acknowledged.

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Authors and Affiliations

  1. Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Münster, Germany

    Guangying Tan, Mowpriya Das, Roman Kleinmans, Felix Katzenburg, Constantin Daniliuc & Frank Glorius

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  1. Guangying Tan
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Contributions

F.G. and G.T. conceived the project. G.T. and R.K. performed the initial screening experiments. G.T. and M.D. performed synthetic experiments. F.K. conducted computations. C.D. analysed X-ray structures. G.T. and F.G. supervised research and wrote the manuscript with contributions from all authors.

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Correspondence to Frank Glorius.

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Nature Catalysis thanks Wujiong Xia, Fangrui Zhong and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Methods, Figs. 1–16 and Tables 1–4.

Supplementary Data 1

Crystallographic data for compound 21.

Supplementary Data 2

Crystallographic data for compound 66.

Supplementary Data 3

Cartesian coordinates for all calculated structures.

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Tan, G., Das, M., Kleinmans, R. et al. Energy transfer-enabled unsymmetrical diamination using bifunctional nitrogen-radical precursors. Nat Catal 5, 1120–1130 (2022). https://doi.org/10.1038/s41929-022-00883-3

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