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N-heterocyclic carbene- and organic photoredox-catalysed meta-selective acylation of electron-rich arenes

Nature Synthesis volume 2, pages 1037–1045 (2023)Cite this article

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Abstract

meta-Selective functionalization of electron-rich arenes provides a complementary route to that of traditional organic synthesis. In classical electrophilic aromatic substitution reactions of electron-donating group-pendant arenes, C–H functionalization occurs at the ortho- or para-positions. There have been numerous efforts to overcome this selectivity, and various synthetic methods have been developed, typically using transition metal catalysis. Here we report a combined N-heterocyclic carbene- and organic photoredox-catalysed method for meta-selective acylation of electron-rich arenes, using acyl imidazoles as acylating reagents. This approach proceeds without directing groups or steric factors required in transition metal-catalysed processes, resulting in the opposite regioselectivity to conventional approaches such as Friedel–Crafts acylation. Mechanistic studies reveal the process involves a sequence of single-electron oxidation of an electron-rich arene followed by the radical–radical coupling between a ketyl radical and an arene radical cation.

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Fig. 1: Regioselective functionalization of arenes.
Fig. 2: Mechanistic study.
Fig. 3: Energy profiles for the proposed pathway.

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Data availability

Details on the procedures, optimization and characterization, including spectra of new compounds and compounds made using the reported method, are available in Supplementary Information.

References

  1. Friedel, C. & Crafts, J.-M. Sur une méthode générale nouvelle de synthèse d’hydrocarbures d’acetones. Compt. Rend. 84, 1450–1454 (1877).

    Google Scholar 

  2. Crafts, J. M. & Ador, E. Ueber die Einwirkung des Chlorkohlenoxyds auf Toluol in Gegenwart von Chloraluminium. Ber. Dtsch. Chem. Ges. 10, 2173–2176 (1877).

    Article  Google Scholar 

  3. Leitch, J. A. & Frost, C. G. Ruthenium-catalysed σ-activation for remote meta-selective C–H functionalisation. Chem. Soc. Rev. 46, 7145–7153 (2017).

    Article  CAS  PubMed  Google Scholar 

  4. Gandeepan, P. & Ackermann, L. Transient directing groups for transformative C–H activation by synergistic metal catalysis. Chem 4, 199–222 (2018).

    Article  CAS  Google Scholar 

  5. Mihai, M. T., Genov, G. R. & Phipps, R. J. Access to the meta position of arenes through transition metal catalysed C–H bond functionalisation: a focus on metals other than palladium. Chem. Soc. Rev. 47, 149–171 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Dey, A., Sinha, S. K., Achar, T. K. & Maiti, D. Accessing remote meta‐ and para‐C(sp2)−H bonds with covalently attached directing groups. Angew. Chem. Int. Ed. 58, 10820–10843 (2019).

    Article  CAS  Google Scholar 

  7. Phipps, R. J. & Gaunt, M. J. A meta-selective copper-catalysed C–H bond arylation. Science 323, 1593–1597 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Leow, D., Li, G., Mei, T.-S. & Yu, J.-Q. Activation of remote meta-C–H bonds assisted by an end-on template. Nature 486, 518–522 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang, X.-C. et al. Ligand-enabled meta-C–H activation using a transient mediator. Nature 519, 334–338 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kuninobu, Y., Ida, H., Nishi, M. & Kanai, M. A meta-selective C–H borylation directed by a secondary interaction between ligand and substrate. Nat. Chem. 7, 712–717 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Shi, H., Herron, A. N., Shao, Y., Shao, Q. & Yu, J.-Q. Enantioselective remote meta-C–H arylation and alkylation via a chiral transient mediator. Nature 558, 581–585 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ramadoss, B., Jin, Y., Asako, S. & Ilies, L. Remote steric control for undirected meta-selective C–H activation of arenes. Science 375, 658–663 (2022).

    Article  CAS  PubMed  Google Scholar 

  13. Cao, H., Cheng, Q. & Studer, A. Radical and ionic meta-C–H functionalization of pyridines, quinolines, and isoquinolines. Science 378, 779–785 (2022).

    Article  CAS  PubMed  Google Scholar 

  14. Ishii, T., Nagao, K. & Ohmiya, H. Recent advances in N-heterocyclic carbene-based radical catalysis. Chem. Sci. 11, 5630–5636 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ohmiya, H. N-heterocyclic carbene-based catalysis enabling cross-coupling reactions. ACS Catal. 10, 6862–6869 (2020).

    Article  CAS  Google Scholar 

  16. Liu, K., Schwenzer, M. & Studer, A. Radical NHC catalysis. ACS Catal. 12, 11984–11999 (2022).

    Article  CAS  Google Scholar 

  17. Bay, A. V. & Scheidt, K. A. Single-electron carbene catalysis in redox processes. Trends Chem. 4, 277–290 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ishii, T., Kakeno, Y., Nagao, K. & Ohmiya, H. N-heterocyclic carbene-catalysed decarboxylative alkylation of aldehydes. J. Am. Chem. Soc. 141, 3854–3858 (2019).

    Article  CAS  PubMed  Google Scholar 

  19. Ishii, T., Ota, K., Nagao, K. & Ohmiya, H. N-heterocyclic carbene-catalysed radical relay enabling vicinal alkylacylation of alkenes. J. Am. Chem. Soc. 141, 14073–14077 (2019).

    Article  CAS  PubMed  Google Scholar 

  20. Davies, A. V., Fitzpatrick, K. P., Betori, R. C. & Scheidt, K. A. Combined photoredox and carbene catalysis for the synthesis of ketones from carboxylic acids. Angew. Chem. Int. Ed. 59, 9143–9148 (2020).

    Article  Google Scholar 

  21. Kakeno, Y., Kusakabe, M., Nagao, K. & Ohmiya, H. Direct synthesis of dialkyl ketones from aliphatic aldehydes through radical N-heterocyclic carbene catalysis. ACS Catal. 10, 8524–8529 (2020).

    Article  CAS  Google Scholar 

  22. Zuo, Z., Daniliuc, C. G. & Studer, A. Cooperative NHC/photoredox catalysed ring‐opening of aryl cyclopropanes to 1‐aroyloxylated‐3‐acylated alkanes. Angew. Chem. Int. Ed. 60, 25252–25257 (2021).

    Article  CAS  Google Scholar 

  23. Matsuki, Y. et al. Aryl radical-mediated N-heterocyclic carbene catalysis. Nat. Commun. https://doi.org/10.1038/s41467-021-24144-2 (2021).

  24. Liu, K. & Studer, A. Direct α-acylation of alkenes via N-heterocyclic carbene, sulfinate, and photoredox cooperative triple catalysis. J. Am. Chem. Soc. 143, 4903–4909 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Meng, Q.-Y., Lezius, L. & Studer, A. Benzylic C−H acylation by cooperative NHC and photoredox catalysis. Nat. Commun. https://doi.org/10.1038/s41467-021-22292-z (2021).

  26. Sato, Y. et al. Light-driven N-heterocyclic carbene catalysis using alkylborates. ACS Catal. https://doi.org/10.1021/acscatal.1c04153 (2021).

  27. Ren, S.-C. et al. Carbene and photocatalyst-catalyzed decarboxylative radical coupling of carboxylic acids and acyl imidazoles to form ketones. Nat. Commun. https://doi.org/10.1038/s41467-022-30583-2 (2022).

  28. Bay, A. V., Farnam, E. J. & Scheidt, K. A. Synthesis of cyclohexanones by a tandem photocatalyzed annulation. J. Am. Chem. Soc. 144, 7030–7037 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yu, X., Meng, Q. Y., Daniliuc, C. G. & Studer, A. Aroyl fluorides as bifunctional reagents for dearomatizing fluoroaroylation of benzofurans. J. Am. Chem. Soc. https://doi.org/10.1021/jacs.2c01735 (2022).

  30. Han, Y.-F. et al. Photoredox cooperative N-heterocyclic carbene/palladium-catalysed alkylacylation of alkenes. Nat. Commun. 13, 5754 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yang, W., Hu, W., Dong, X., Li, X. & Sun, J. N-heterocyclic carbene catalyzed γ-dihalomethylenation of enals by single-electron transfer. Angew. Chem. Int. Ed. 55, 15783–15786 (2016).

    Article  CAS  Google Scholar 

  32. DiRocco, D. A. & Rovis, T. Catalytic asymmetric α-acylation of tertiary amines mediated by a dual catalysis mode: N-heterocyclic carbene and photoredox catalysis. J. Am. Chem. Soc. 134, 8094–8097 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  34. Ohkubo, K., Mizushima, K., Iwata, R. & Fukuzumi, S. Selective photocatalytic aerobic bromination with hydrogen bromidevia an electron-transfer state of 9-mesityl-10-methylacridinium ion. Chem. Sci. 2, 715–722 (2011).

    Article  CAS  Google Scholar 

  35. Romero, N. A., Margrey, K. A., Tay, N. E. & Nicewicz, D. A. Site-selective arene C–H amination via photoredox catalysis. Science 349, 1326–1330 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Fukuzumi, S. et al. Electron-transfer state of 9-mesityl-10-methylacridinium ion with a much longer lifetime and higher energy than that of the natural photosynthetic reaction center. J. Am. Chem. Soc. 126, 1600–1601 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Margrey, K. A., McManus, J. B., Bonazzi, S., Zecri, F. & Nicewicz, D. A. Predictive model for site-selective aryl and heteroaryl C–H functionalisation via organic photoredox catalysis. J. Am. Chem. Soc. 139, 11288–11299 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yan, H., Song, J., Zhu, S. & Xu, H.-C. Synthesis of acridinium photocatalysts via site-selective C–H alkylation. CCS Chem. 3, 317–325 (2021).

    Article  CAS  Google Scholar 

  39. Truong, C. C., Kim, J., Lee, Y. & Kim, Y. J. Well-defined cesium benzotriazolide as an active catalyst for generating disubstituted ureas from carbon dioxide and amines. ChemCatChem 9, 247–252 (2017).

    Article  CAS  Google Scholar 

  40. Ji, P. et al. Selective skeletal editing of polycyclic arenes using organophotoredox dearomative functionalization. Nat. Commun. https://doi.org/10.1038/s41467-022-32201-7 (2022).

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Acknowledgements

This work was supported by JSPS KAKENHI grant numbers JP21H04681, JP23H04912 and JST, PRESTO grant number JPMJPR19T2 to H.O. We thank K. Nagao (Kyoto University) for helpful discussion about computational study.

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Authors and Affiliations

  1. Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan

    Yamato Goto & Masaki Sano

  2. Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan

    Yuto Sumida

  3. Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto, Japan

    Hirohisa Ohmiya

  4. JST, PRESTO, Kawaguchi, Saitama, Japan

    Hirohisa Ohmiya

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  1. Yamato Goto
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Contributions

Y.G., M.S., Y.S. and H.O. designed, performed and analysed the experiments. Y.S. and H.O. co-wrote the paper. All authors contributed to discussions.

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Correspondence to Yuto Sumida or Hirohisa Ohmiya.

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Nature Synthesis thanks Wei Wang, Song Ye and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary Figs. 1–11 and Tables 1–3.

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Goto, Y., Sano, M., Sumida, Y. et al. N-heterocyclic carbene- and organic photoredox-catalysed meta-selective acylation of electron-rich arenes. Nat. Synth 2, 1037–1045 (2023). https://doi.org/10.1038/s44160-023-00378-4

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