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Complementary site selectivity in ortho-alkylative vicinal difunctionalization reactions of iodoarenes enabled by palladium–olefin catalysis

Nature Synthesis volume 5, pages 240–250 (2026)Cite this article

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Abstract

Direct access to multifunctionalized arenes through regioselective vicinal difunctionalization of aryl substrates is a challenging yet highly sought-after process. Palladium–norbornene catalysis enables the synthesis of ipso,ortho-difunctionalized products from haloarenes; however, selective mono-ortho-alkylative vicinal difunctionalization reactions of para-substituted haloarene substrates have remained elusive. Here we report the use of a methyl-modified thio-cycloolefin ligand for the palladium-catalysed ortho-alkylative vicinal difunctionalization of para-substituted iodoarenes. This catalytic system demonstrates compatibility with a variety of para-substituted iodoarenes, alkyl iodides and termination reagents, facilitating ortho-alkylative vicinal difunctionalization unattainable by conventional palladium–norbornene catalysis. In addition, the catalytic system can be used for the selective mono-ortho-arylation of para-substituted iodoarenes, enabling the synthesis of triphenylenes. Mechanistic studies reveal the origins of site selectivity within the catalytic process, through isolation of key intermediates and examination of their stoichiometric reactivity. This work highlights the versatility of palladium–olefin catalysis in addressing the complexities associated with constructing multifunctionalized aromatic frameworks through rational molecular design.

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Fig. 1: Challenges in the site-selective vicinal difunctionalization of haloarenes.
Fig. 2: Ligand design and proof of concept.
Fig. 3: Mechanistic studies on the ligand effect from an intermediate perspective.
Fig. 4: Reaction optimization.
Fig. 5: Substrate scope.
Fig. 6: Synthesis of cyclized products with ligand-enabled site selectivity.

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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 (CCDC), under deposition numbers CCDC 2393060 (Int-8•PPh3), 2393061 (Int-5•PPh3), 2393062 (Int-6•PPh3), 2393063 (Int-3•PPh3), 2393064 (Int-4•PPh3), 2409485 (Int-7•PPh3), 2409488 (Int-5) and 2409562 (Int-3). These data can be obtained free of charge from the CCDC (http://www.ccdc.cam.ac.uk/data_request/cif).

References

  1. 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 

  2. Dupommier, D. & Besset, T. New trends for transition metal-catalyzed ortho/ipso difunctionalizations of arenes. Chem 10, 2651–2665 (2024).

    Article  CAS  Google Scholar 

  3. Catellani, M., Motti, E. & Della Ca, N. Catalytic sequential reactions involving palladacycle-directed aryl coupling steps. Acc. Chem. Res. 41, 1512–1522 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Martins, A., Mariampillai, B. & Lautens, M. Synthesis in the key of Catellani: norbornene-mediated ortho C–H functionalization. Top. Curr. Chem. 292, 1–33 (2010).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Lautens, M. & Piguel, S. A New route to fused aromatic compounds by using a palladium-catalyzed alkylation-alkenylation sequence. Angew. Chem. Int. Ed. 39, 1045–1046 (2000).

    Article  CAS  Google Scholar 

  9. Bressy, C., Alberico, D. & Lautens, M. A route to annulated indoles via a palladium-catalyzed tandem alkylation/direct arylation reaction. J. Am. Chem. Soc. 127, 13148–13149 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Candito, D. A. & Lautens, M. Palladium-catalyzed domino direct arylation/N-arylation: convenient synthesis of phenanthridines. Angew. Chem. Int. Ed. 48, 6713–6716 (2009).

    Article  CAS  Google Scholar 

  11. Dong, Z. & Dong, G.-B. 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 

  12. Huang, Y., Zhu, R., Zhao, K. & Gu, Z. 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 

  13. Sun, F.-G. et al. Cleavage of the C(O)−S bond of thioesters by palladium/norbornene/copper cooperative catalysis: an efficient synthesis of 2-(arylthio)aryl ketones. J. Am. Chem. Soc. 138, 7456–7459 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. 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 

  15. Li, R. & Dong, G. Direct annulation between aryl iodides and epoxides through palladium/norbornene cooperative catalysis. Angew. Chem. Int. Ed. 57, 1697–1701 (2018).

    Article  CAS  Google Scholar 

  16. Cheng, H.-G. et al. Epoxides as alkylating reagents for the catellani reaction. Angew. Chem. Int. Ed. 57, 3444–3448 (2018).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Liu, X., Fu, Y., Chen, Z., Liu, P. & Dong, G. Ortho-C–H methoxylation of aryl halides enabled by a polarity-reversed N–O reagent. Nat. Chem. 15, 1391–1399 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bai, L. et al. Palladium/norbornene-catalyzed C–H alkylation/alkyne insertion/indole dearomatization domino reaction: assembly of spiroindolenine-containing pentacyclic frameworks. Angew. Chem. Int. Ed. 57, 5151–5155 (2018).

    Article  CAS  Google Scholar 

  20. Wang, J. & Gu, Z. Synthesis of 2-(1-Alkoxyvinyl)anilines by Palladium/norbornene-catalyzed amination followed by termination with vinyl ethers. Adv. Synth. Catal. 358, 2990–2995 (2016).

    Article  CAS  Google Scholar 

  21. Botla, V. et al. Closing the cycle as it begins: synthesis of ortho-iodobiaryls via Catellani reaction. Angew. Chem. Int. Ed. 62, e202218928 (2023).

    Article  CAS  Google Scholar 

  22. Jiang, W.-T., Xu, M.-Y., Yang, S., Xie, X.-Y. & Xiao, B. Alkylation-terminated Catellani reactions using alkyl carbagermatranes. Angew. Chem. Int. Ed. 59, 20450–20454 (2020).

    Article  CAS  Google Scholar 

  23. Ye, J.-X. et al. Triple cross-electrophile coupling enabled by palladium/norbornene cooperative catalysis. Sci. Adv. 11, eadu4573 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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 

  25. Ye, R., Liu, X. & Dong, G. Enabling aryl chloride-mediated palladium/norbornene cooperative catalysis. Angew. Chem. Int. Ed. 64, e202500897 (2025).

    Article  CAS  Google Scholar 

  26. Wang, J.-S. et al. ortho C–H alkylation of aryl chlorides by a Catellani strategy. Angew. Chem. Int. Ed. 64, e202509300 (2025).

    Article  CAS  Google Scholar 

  27. Han, M.-L. et al. Palladium/norbornene-catalyzed decarbonylative difunctionalization of thioesters. JACS Au 1, 1877–1884 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li, H. et al. Transformations of aryl ketones via ligand-promoted C–C bond activation. Angew. Chem. Int. Ed. 59, 14388–14393 (2020).

    Article  CAS  Google Scholar 

  29. Tao, K. L. et al. Multisite modifications of arenes using ketones as removable handles enabled by Pd and norbornene cooperative catalysis. Nat. Synth. 4, 209–218 (2025).

    Article  CAS  Google Scholar 

  30. Xie, Y.-H., Zang, L. & Ritter, T. Late-stage cross-electrophile coupling of arylthianthrenium salts with (hetero)aryl (pseudo)halides via palladium catalysis. Angew. Chem. Int. Ed. 64, e202502441 (2025).

    Article  CAS  Google Scholar 

  31. Wang, J. et al. Modular and regioselective synthesis of all-carbon tetrasubstituted olefins enabled by an alkenyl Catellani reaction. Nat. Chem. 11, 1106–1112 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jiao, L. & Bach, T. Palladium-catalyzed direct 2-alkylation of indoles by norbornene-mediated regioselective cascade C–H activation. J. Am. Chem. Soc. 133, 12990–12993 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Jiao, L., Herdtweck, E. & Bach, T. Pd(II)-catalyzed regioselective 2-alkylation of indoles via a norbornene-mediated C–H activation: mechanism and applications. J. Am. Chem. Soc. 134, 14563–14572 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. 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 

  35. Shi, G., Shao, C., Ma, X., Gu, Y. & Zhang, Y. Pd(II)-catalyzed Catellani-type domino reaction utilizing arylboronic acids as substrates. ACS Catal. 8, 3775–3779 (2018).

    Article  CAS  Google Scholar 

  36. Chen, S. et al. The discovery of a palladium(II)-initiated borono-Catellani reaction. Angew. Chem. Int. Ed. 57, 7161–7165 (2018).

    Article  CAS  Google Scholar 

  37. Li, R.-H., Liu, F.-P. & Dong, G.-B. Redox-neutral ortho functionalization of aryl boroxines via palladium/norbornene cooperative catalysis. Chem 5, 929–939 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li, R. & Dong, G. Structurally modified norbornenes: a key factor to modulate reaction selectivity in the palladium/norbornene cooperative catalysis. J. Am. Chem. Soc. 142, 17859–17875 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shen, P.-X., Wang, X.-C., Wang, P., Zhu, R.-Y. & Yu, J.-Q. Ligand-enabled meta-C–H alkylation and arylation using a modified norbornene. J. Am. Chem. Soc. 137, 11574–11577 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dong, Z., Wang, J., 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 

  41. 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 

  42. Wang, J., Li, R., Dong, Z., Liu, P. & Dong, G. Complementary site-selectivity in arene functionalization enabled by overcoming the ortho constraint in palladium/norbornene catalysis. Nat. Chem. 10, 866–872 (2018).

    Article  CAS  PubMed  Google Scholar 

  43. Chen, S.-Q. et al. Construction of axial chirality via palladium/chiral norbornene cooperative catalysis. Nat. Catal. 3, 727–733 (2020).

    Article  Google Scholar 

  44. Wang, J., Zhou, Y., Xu, X., Liu, P. & Dong, G. Entry to 1,2,3,4-tetrasubstituted arenes through addressing the “meta constraint” in the palladium/norbornene catalysis. J. Am. Chem. Soc. 142, 3050–3059 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu, X., Wang, J. & Dong, G. Modular entry to functionalized tetrahydrobenzo(β)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 

  46. Sukowski, V., van Borselen, M., Mathew, S. & Fernández-Ibáñez, M. A. S. O-ligand promoted meta-C–H arylation of anisole derivatives via palladium/norbornene catalysis. Angew. Chem. Int. Ed. 61, e202201750 (2022).

    Article  CAS  Google Scholar 

  47. Zheng, Y.-X. & Jiao, L. Hybrid cycloolefin ligands for palladium–olefin cooperative catalysis. Nat. Synth. 1, 180–187 (2022).

    Article  CAS  Google Scholar 

  48. Wang, F.-Y., Li, Y.-X. & Jiao, L. Functionalized cycloolefin ligand as a solution to ortho-constraint in the Catellani-type reaction. J. Am. Chem. Soc. 145, 4871–4881 (2023).

    Article  CAS  PubMed  Google Scholar 

  49. Wang, X.-X. & Jiao, L. Dual ligand enabled Pd-catalyzed ortho-alkylation of iodoarenes. J. Am. Chem. Soc. 146, 25552–25561 (2024).

    Article  CAS  PubMed  Google Scholar 

  50. Qureshi, Z., Schlundt, W. & Lautens, M. Introduction of hindered electrophiles via C–H functionalization in a palladium-catalyzed multicomponent domino reaction. Synthesis 47, 2446–2456 (2015).

    Article  CAS  Google Scholar 

  51. Gao, Q. et al. Catalytic synthesis of atropisomeric o-terphenyls with 1,2-diaxes via axial-to-axial diastereoinduction. J. Am. Chem. Soc. 143, 7253–7260 (2021).

    Article  CAS  PubMed  Google Scholar 

  52. Stambuli, J. P., Bühl, M. & Hartwig, J. F. Synthesis, characterization, and reactivity of monomeric, arylpalladium halide complexes with a hindered phosphine as the only dative ligand. J. Am. Chem. Soc. 124, 9346–9347 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Sukowski, V., van Borselen, M., Mathew, S., de Bruin, B. & Fernández-Ibáñez, M. A. Meta-C−H arylation of aniline derivatives via palladium/S,O-ligand/norbornene cooperative catalysis. Angew. Chem. Int. Ed. 63, e202317741 (2024).

    Article  CAS  Google Scholar 

  54. Shin, S. S. et al. Preparation of sulfonylaminophenylalkylphenylacrylamide derivatives for use as vanilloid receptor antagonists. WO2009096701 A2 (World Intellectual Property Organization, 2009).

  55. Mehnaz, S. et al. Lahorenoic acids A–C, ortho-dialkyl-substituted aromatic acids from the biocontrol strain Pseudomonas aurantiaca PB-St2. J. Nat. Prod. 76, 135–141 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Mariampillai, B., Alliot, J., Li, M. & Lautens, M. A convergent synthesis of polysubstituted aromatic nitriles via palladium-catalyzed C–H functionalization. J. Am. Chem. Soc. 129, 15372–15379 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Liu, Z.-S. et al. Palladium/norbornene cooperative catalysis to access tetrahydronaphthalenes and indanes with a quaternary center. ACS Catal 8, 4783–4788 (2018).

    Article  CAS  Google Scholar 

  58. Pozo, I., Guitián, E., Pérez, D. & Peña, D. Synthesis of nanographenes, starphenes, and sterically congested polyarenes by aryne cyclotrimerization. Acc. Chem. Res. 52, 2472–2481 (2019).

    Article  CAS  PubMed  Google Scholar 

  59. Yang, Y. et al. Palladium-catalyzed synthesis of triphenylenes via sequential C–H activation and decarboxylation. Org. Lett. 20, 5402–5405 (2018).

    Article  CAS  PubMed  Google Scholar 

  60. Li, S. et al. Palladium-catalyzed annulation reaction of bay-diiodinated arenes with o-chloroaromatic carboxylic acids to access polycyclic aromatic compounds. J. Org. Chem. 89, 15665–15677 (2024).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to the National Natural Science Foundation of China (grant no. 21933007 to L.J.) and the Tsinghua Xuetang Program for financial support. The technology platform of CBMS is acknowledged for providing instrumentation.

Author information

Authors and Affiliations

  1. Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing, China

    Yu-Xiu Li, Cheng-Hao Zong, Yu Meng & Lei Jiao

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  1. Yu-Xiu Li
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  2. Cheng-Hao Zong
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  3. Yu Meng
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Contributions

Y.-X.L. and C.-H.Z. performed ligand synthesis and developed the reaction methods. Y.-X.L. performed mechanistic studies. Y.-X.L. and Y.M. explored the substrate scope. Y.-X.L. and L.J. wrote the paper. L.J. directed the project.

Corresponding author

Correspondence to Lei Jiao.

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The authors declare no competing interests.

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Peer review information

Nature Synthesis thanks Huixiong Dai, Qianghui Zhou 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 information

Supplementary Information (download PDF )

Experimental details, Supplementary Sections 1–4 and Figs. 1–4.

Supplementary Data 1

Crystallographic data for complex Int-8•PPh3, CCDC 2393060.

Supplementary Data 2

Crystallographic data for complex Int-5•PPh3, CCDC 2393061.

Supplementary Data 3

Crystallographic data for complex Int-6•PPh3, CCDC 2393062.

Supplementary Data 4

Crystallographic data for complex Int-3•PPh3, CCDC 2393063.

Supplementary Data 5

Crystallographic data for complex Int-4•PPh3, CCDC 2393064.

Supplementary Data 6

Crystallographic data for complex Int-7•PPh3, CCDC 2409485.

Supplementary Data 7

Crystallographic data for complex Int-5, CCDC 2409488.

Supplementary Data 8

Crystallographic data for complex Int-3, CCDC 2409562.

Source data

Source Data Fig. 3 (download XLSX )

Source data for the kinetic plots in Fig. 3.

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Li, YX., Zong, CH., Meng, Y. et al. Complementary site selectivity in ortho-alkylative vicinal difunctionalization reactions of iodoarenes enabled by palladium–olefin catalysis. Nat. Synth 5, 240–250 (2026). https://doi.org/10.1038/s44160-025-00920-6

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