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Ortho-C–H methoxylation of aryl halides enabled by a polarity-reversed N–O reagent

Nature Chemistry volume 15, pages 1391–1399 (2023)Cite this article

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Abstract

Oxygen-substituted arenes widely exist in biologically important molecules and can serve as versatile handles to install other functional groups. However, direct and site-selective installation of oxygen groups to common aromatic compounds remains challenging, especially when additional arene functionalization is simultaneously required. Current arene C−H oxidation strategies generally require directing groups or precisely prefunctionalized substrates to control site-selectivity. While palladium/norbornene cooperative catalysis is promising for site-specific arene vicinal difunctionalization through simultaneous reactions with an electrophile and a nucleophile, the electrophile scope has been limited to species based on relatively ‘soft’ elements, such as carbon, nitrogen and sulfur. Here we report the development of an ortho oxygenation reaction with common aryl halides to rapidly deliver diverse aryl ethers. The coupling of the ‘hard’ oxygen electrophile is enabled by a stable, polarity-reversed, conformationally predistorted N−O reagent and facilitated by a C7-bromo-substituted norbornene mediator. Mechanistic studies reveal a unique SN2-type pathway between the N−O reagent as the oxygen electrophile and an electron-rich Pd(II) nucleophile.

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Fig. 1: Alkyl aryl ethers and their preparations.
Fig. 2: Computational study of the Pd/NBE-catalysed ortho-C–H oxygenation reaction.
Fig. 3: Synthetic applications.
Fig. 4: Rapid access to challenging substitution patterns of benzenoids via a relay C–H functionalization strategy.

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Data availability

The data supporting the findings of this study are available within the Article and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre under deposition numbers CCDC 2209874 (4m) and 2209875 (2a). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  1. Scott, K. A., Cox, P. B. & Njardarson, J. T. Phenols in pharmaceuticals: analysis of a recurring motif. J. Med. Chem. 65, 7044–7072 (2022).

    Article  CAS  PubMed  Google Scholar 

  2. Qiu, Z. H. & Li, C. J. Transformations of less-activated phenols and phenol derivatives via C–O cleavage. Chem. Rev. 120, 10454–10515 (2020).

    Article  CAS  PubMed  Google Scholar 

  3. Liu, B. & Shi, B. F. Transition-metal-catalyzed etherification of unactivated C—H bonds. Tetrahedron Lett. 56, 15–22 (2015).

    Article  CAS  Google Scholar 

  4. Yang, F. Z., Zhang, H., Liu, X. R., Wang, B. & Lutz, A. Transition metal-catalyzed regio-selective aromatic C—H bond oxidation for C—O bond formation. Chin. J. Org. Chem. 39, 59–73 (2019).

    Article  CAS  Google Scholar 

  5. Mann, G., Incarvito, C., Rheingold, A. L. & Hartwig, J. F. Palladium-catalyzed C–O coupling involving unactivated aryl halides. Sterically induced reductive elimination to form the C–O bond in diaryl ethers. J. Am. Chem. Soc. 121, 3224–3225 (1999).

    Article  CAS  Google Scholar 

  6. Torraca, K. E., Huang, X. H., Parrish, C. A. & Buchwald, S. L. An efficient intermolecular palladium-catalyzed synthesis of aryl ethers. J. Am. Chem. Soc. 123, 10770–10771 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Qiao, J. X. & Lam, P. Y. in Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials Vol. 1–2, 2nd edn (ed. Hall, D. G.) Ch. 6 (Wiley-VCH, 2011).

    Google Scholar 

  8. Terrett, J. A., Cuthbertson, J. D., Shurtleff, V. W. & MacMillan, D. W. C. Switching on elusive organometallic mechanisms with photoredox catalysis. Nature 524, 330–334 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang, Q., Zhao, Y. S. & Ma, D. W. Cu-mediated Ullmann-type cross-coupling and industrial applications in route design, process development, and scale-up of pharmaceutical and agrochemical processes. Org. Process Res. Dev. 26, 1690–1750 (2022).

    Article  CAS  Google Scholar 

  10. Ye, J. T. & Lautens, M. Palladium-catalysed norbornene-mediated C–H functionalization of arenes. Nat. Chem. 7, 863–870 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Della Ca', N., Fontana, M., Motti, E. & Catellani, M. Pd/norbornene: a winning combination for selective aromatic functionalization via C–H bond activation. Acc. Chem. Res. 49, 1389–1400 (2016).

  12. Wang, J. C. & Dong, G. Palladium/norbornene cooperative catalysis. Chem. Rev. 119, 7478–7528 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dong, S. C. & Luan, X. J. Catellani reaction: an enabling technology for vicinal functionalization of aryl halides by palladium(0)/norbornene cooperative catalysis. Chin. J. Chem. 39, 1690–1705 (2021).

    Article  CAS  Google Scholar 

  14. Zhao, K., Ding, L. L. & Gu, Z. H. Development of new electrophiles in palladium/norbornene-catalyzed ortho-functionalization of aryl halides. Synlett 30, 129–140 (2019).

    Article  Google Scholar 

  15. Catellani, M., Frignani, F. & Rangoni, A. A complex catalytic cycle leading to a regioselective synthesis of o,o′-disubstituted vinylarenes. Angew. Chem. Int. Ed. 36, 119–122 (1997).

    Article  CAS  Google Scholar 

  16. Catellani, M., Motti, E. & Baratta, S. A novel palladium-catalyzed synthesis of phenanthrenes from ortho-substituted aryl iodides and diphenyl- or alkylphenylacetylenes. Org. Lett. 3, 3611–3614 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Lautens, M. & Piguel, S. A new route to fused aromatic compounds by using a palladium-catalyzed alkylation – alkenylation sequence. Angew. Chem. Int. Ed. 39, 1045–1056 (2000).

    Article  CAS  Google Scholar 

  18. Dong, Z., Wang, J. C., Ren, Z. & Dong, G. Ortho C—H acylation of aryl iodides by palladium/norbornene catalysis. Angew. Chem. Int. Ed. 54, 12664–12668 (2015).

    Article  CAS  Google Scholar 

  19. Huang, Y. Z., Zhu, R., Zhao, K. & Gu, Z. H. Palladium-catalyzed Catellani ortho-acylation reaction: an efficient and regiospecific synthesis of diaryl ketones. Angew. Chem. Int. Ed. 54, 12669–12672 (2015).

    Article  CAS  Google Scholar 

  20. Zhou, P. X. et al. Palladium-catalyzed acylation/alkenylation of aryl iodide: a domino approach based on the Catellani–Lautens reaction. ACS Catal. 5, 4927–4931 (2015).

    Article  CAS  Google Scholar 

  21. Liu, C. et al. Synthesis of indolines via a palladium/norbornene-catalyzed reaction of aziridines with aryl iodides. Chem. Commun. 54, 3407–3410 (2018).

    Article  CAS  Google Scholar 

  22. Ding, Y. N. et al. Palladium-catalyzed ortho-C–H glycosylation/ipso-alkenylation of aryl iodides. J. Org. Chem. 85, 11280–11296 (2020).

    Article  CAS  PubMed  Google Scholar 

  23. Lv, W. W., Chen, Y. H., Wen, S., Ba, D. & Cheng, G. L. Modular and stereoselective synthesis of C-aryl glycosides via Catellani reaction. J. Am. Chem. Soc. 142, 14864–14870 (2020).

    Article  CAS  PubMed  Google Scholar 

  24. Dong, Z. & Dong, G. Ortho vs ipso: site-selective Pd and norbornene-catalyzed arene C–H amination using aryl halides. J. Am. Chem. Soc. 135, 18350–18353 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Cai, W. Q. & Gu, Z. H. Selective ortho thiolation enabled by tuning the ancillary ligand in palladium/norbornene catalysis. Org. Lett. 21, 3204–3209 (2019).

    Article  CAS  PubMed  Google Scholar 

  26. Li, R. H., Zhou, Y., Yoon, K. Y., Dong, Z. & Dong, G. Sulfenamide-enabled ortho thiolation of aryl iodides via palladium/norbornene cooperative catalysis. Nat. Commun. 10, 3555 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Qi, X. T., Wang, J. C., Dong, Z., Dong, G. & Liu, P. Compatibility score for rational electrophile selection in Pd/NBE cooperative catalysis. Chem 6, 2810–2825 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dong, X., Liu, Q., Dong, Y. H. & Liu, H. Transition-metal-catalyzed electrophilic amination: application of O-benzoylhydroxylamines in the construction of the C–N bond. Chem. Eur. J. 23, 2481–2511 (2017).

    Article  CAS  PubMed  Google Scholar 

  29. Korch, K. M. & Watson, D. A. Cross-coupling of heteroatomic electrophiles. Chem. Rev. 119, 8192–8228 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Berman, A. M. & Johnson, J. S. Copper-catalyzed electrophilic amination of diorganozinc reagents. J. Am. Chem. Soc. 126, 5680–5681 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Yoo, E. J., Ma, S., Mei, T. S., Chan, K. S. L. & Yu, J. Q. Pd-catalyzed intermolecular C–H amination with alkylamines. J. Am. Chem. Soc. 133, 7652–7655 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Rucker, R. P., Whittaker, A. M., Dang, H. & Lalic, G. Synthesis of hindered anilines: copper-catalyzed electrophilic amination of aryl boronic esters. Angew. Chem. Int. Ed. 51, 3953–3956 (2012).

    Article  CAS  Google Scholar 

  33. Zhu, S. L., Niljianskul, N. & Buchwald, S. L. Enantio- and regioselective CuH-catalyzed hydroamination of alkenes. J. Am. Chem. Soc. 135, 15746–15749 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. McDonald, S. L. & Wang, Q. Copper-catalyzed α-amination of phosphonates and phosphine oxides: a direct approach to α-amino phosphonic acids and derivatives. Angew. Chem. Int. Ed. 53, 1867–1871 (2014).

    Article  CAS  Google Scholar 

  35. Canty, A. J., Denney, M. C., Skelton, B. W. & White, A. H. Carbon–oxygen bond formation at organopalladium centers: the reactions of PdMeR(L2) (R = Me, 4-tolyl; L2= tmeda, bpy) with diaroyl peroxides and the involvement of organopalladium(IV) species. Organometallics 23, 1122–1131 (2004).

    Article  CAS  Google Scholar 

  36. Liu, X., Wang, J. C. & Dong, G. Modular entry to functionalized tetrahydrobenzo[b]azepines via the palladium/norbornene cooperative catalysis enabled by a C7-modified norbornene. J. Am. Chem. Soc. 143, 9991–10004 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Patel, B. et al. In search of a new class of stable nitroxide: synthesis and reactivity of a peri-substituted N,N-bissulfonylhydroxylamine. Org. Biomol. Chem. 9, 2336–2344 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Xie, Y., Lee, C. L., Yang, Y. P., Rettig, S. J. & James, B. R. Mono- and dinuclear palladium complexes containing 2-pyridylphosphine ligands, including X-ray characterization of Pd2I2(µ-PPh2py)2 and a dimethylacetylenedicarboxylate A-frame complex Pd2Cl2(µ-Ppy3)2(µ-MeO2C•C=C•CO2Me); py = 2-pyridyl. Can. J. Chem. 70, 751–762 (1992).

    Article  CAS  Google Scholar 

  39. Dong, Z., Lu, G., Wang, J. C., Liu, P. & Dong, G. Modular ipso/ortho difunctionalization of aryl bromides via palladium/norbornene cooperative catalysis. J. Am. Chem. Soc. 140, 8551–8562 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cheng, J. J. et al. Design and discovery of functionally selective serotonin 2C (5-HT2C) receptor agonists. J. Med. Chem. 59, 9866–9880 (2016).

    Article  CAS  PubMed  Google Scholar 

  41. Gao, S. J., Qian, G. Y., Tang, H., Yang, Z. & Zhou, Q. H. Three-step total synthesis of ramelteon via a Catellani strategy. ChemCatChem 11, 5762–5765 (2019).

    Article  CAS  Google Scholar 

  42. Bai, Y. J. et al. Polygala tenuifolia-Acori tatarinowii herbal pair as an inspiration for substituted cinnamic α-asaronol esters: design, synthesis, anticonvulsant activity, and inhibition of lactate dehydrogenase study. Eur. J. Med. Chem. 183, 111650 (2019).

    Article  CAS  PubMed  Google Scholar 

  43. Farina, A., Ferranti, C., Marra, C., Guiso, M. & Norcia, G. Synthesis of hydroxystilbenes and their derivatives via Heck reaction. Nat. Prod. Res. 21, 564–573 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Nilova, A., Campeau, L. C., Sherer, E. C. & Stuart, D. R. Analysis of benzenoid substitution patterns in small molecule active pharmaceutical ingredients. J. Med. Chem. 63, 13389–13396 (2020).

    Article  CAS  PubMed  Google Scholar 

  45. Catellani, M., Motti, E. & Minari, M. Symmetrical and unsymmetrical 2,6-dialkyl-1,1′-biaryls by combined catalysis of aromatic alkylation via palladacycles and Suzuki-type coupling. Chem. Commun. 2000, 157–158 (2000).

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

    Article  CAS  Google Scholar 

  47. Ye, C. Q., Zhu, H. & Chen, Z. Y. Synthesis of biaryl tertiary amines through Pd/norbornene joint catalysis in a remote C–H amination/Suzuki coupling reaction. J. Org. Chem. 79, 8900–8905 (2014).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge the financial support from the University of Chicago, the National Institute of General Medical Sciences (R01GM124414, G.D.) and the National Science Foundation (CHE-2247505, P.L.). We thank J. Huo (University of Chicago) for checking the experimental procedure. We thank Z. Wu and Y. Xue (University of Chicago) for helpful discussions. We acknowledge Z. Zhang and S. Ochi (University of Chicago) for the X-ray crystallography. Density functional theory calculations were performed at the Center for Research Computing of the University of Pittsburgh and the Extreme Science and Engineering Discovery Environment (XSEDE) supported by the National Science Foundation grant number ACI-1548562 (P.L.).

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Authors and Affiliations

  1. Department of Chemistry, University of Chicago, Chicago, IL, USA

    Xin Liu, Zhijie Chen & Guangbin Dong

  2. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

    Yue Fu & Peng Liu

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Contributions

X.L. and G.D. conceived and designed the experiments. X.L. and Z.C. performed the experiments. Y.F. and P.L. designed and conducted the density functional theory calculations. X.L., Y.F., P.L. and G.D. wrote the manuscript. P.L. and G.D. directed the research.

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Correspondence to Peng Liu or Guangbin Dong.

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Nature Chemistry thanks Wei Guan 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 Figs. 1–11, Tables 1–3, experimental procedures and NMR spectra.

Supplementary Data 1

Crystallographic data for compound 2a; CCDC reference no. 2209875.

Supplementary Data 2

Crystallographic data for compound 4m; CCDC reference no. 2209874.

Supplementary Data 3

Computational data including xyz coordinates.

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Liu, X., Fu, Y., Chen, Z. et al. Ortho-C–H methoxylation of aryl halides enabled by a polarity-reversed N–O reagent. Nat. Chem. 15, 1391–1399 (2023). https://doi.org/10.1038/s41557-023-01312-z

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