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Connecting remote C–H bond functionalization and decarboxylative coupling using simple amines

Abstract

Transition metal-catalysed C–H functionalization and decarboxylative coupling are two of the most notable synthetic strategies developed in the past 30 years. Here, we connect these two reaction pathways using bases and a simple Pd-based catalyst system to promote a para-selective C–H functionalization reaction from benzylic electrophiles. Experimental and computational mechanistic studies suggest a pathway that involves an uncommon Pd-catalysed dearomatization of the benzyl moiety followed by a base-enabled rearomatization through a formal 1,5-hydrogen migration. This reaction complements ‘C–H activation’ strategies that convert inert C–H bonds into C–metal bonds prior to C–C bond formation. Instead, this reaction exploits an inverted sequence and promotes C–C bond formation prior to deprotonation. These studies provide an opportunity to develop general para-selective C–H functionalization reactions from benzylic electrophiles and show how new reactive modalities may be accessed with careful control of the reaction conditions.

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Fig. 1: C–H functionalization versus decarboxylative cross-coupling.
Fig. 2: Brønsted basicity controls selectivity.
Fig. 3: General reaction mechanism.
Fig. 4: Mechanistic experiments.
Fig. 5: Energetics of key steps.

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Data availability

All data supporting the findings of this study are available within the paper and its Supplementary Information files.

References

  1. Johansson Seechurn, C. C. C., Kitching, M. O., Colacot, T. J. & Snieckus, V. Palladium-catalyzed cross-coupling: a historical contextual perspective to the 2010 Nobel prize. Angew. Chem. Int. Ed. 51, 5062–5085 (2012).

    Article  CAS  Google Scholar 

  2. Labinger, J. A. & Bercaw, J. E. Understanding and exploiting C–H bond activation. Nature 417, 507–514 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Hartwig, J. F. Evolution of C–H bond functionalization from methane to methodology. J. Am. Chem. Soc. 138, 2–24 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. Gensch, T., Hopkinson, M. N., Glorius, F. & Wencel-Delord, J. Mild metal-catalyzed C–H activation: examples and concepts. Chem. Soc. Rev. 45, 2900–2936 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Yamaguchi, J., Yamaguchi, A. D. & Itami, K. C–H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals. Angew. Chem. Int. Ed. 51, 8960–9009 (2012).

    Article  CAS  Google Scholar 

  6. Engle, K. M., Mei, T.-S., Wasa, M. & Yu, J.-Q. Weak coordination as a powerful means for developing broadly useful C–H functionalization reactions. Acc. Chem. Res. 45, 788–802 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Neufeldt, S. R. & Sanford, M. S. Controlling site selectivity in palladium-catalyzed C–H bond functionalization. Acc. Chem. Res. 45, 936–946 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang, F. & Spring, D. R. Arene C–H functionalisation using a removable/modifiable or a traceless directing group strategy. Chem. Soc. Rev. 43, 6906–6919 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Yang, J. Transition metal catalyzed meta-C–H functionalization of aromatic compounds. Org. Biomol. Chem. 13, 1930–1941 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Dey, A., Agasti, S. & Maiti, D. Palladium catalysed meta-C–H functionalization reactions. Org. Biomol. Chem. 14, 5440–5453 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Ciana, C.-L., Phipps, R. J., Brandt, J. R., Meyer, F.-M. & Gaunt, M. J. A highly para-selective copper(ii)-catalyzed direct arylation of aniline and phenol derivatives. Angew. Chem. Int. Ed. 50, 458–462 (2011).

    Article  CAS  Google Scholar 

  12. Wang, X., Leow, D. & Yu, J.-Q. Pd(ii)-catalyzed para-selective C–H arylation of monosubstituted arenes. J. Am. Chem. Soc. 133, 13864–13867 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ball, L. T., Lloyd-Jones, G. C. & Russell, C. A. Gold-catalyzed direct arylation. Science 337, 1644–1648 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Wu, Z. et al. Palladium-catalyzed para-selective arylation of phenols with aryl iodides in water. Chem. Commun. 49, 7653–7655 (2013).

    Article  CAS  Google Scholar 

  15. Yu, Z. et al. Highly site-selective direct C–H bond functionalization of phenols with α-aryl-α-diazoacetates and diazooxindoles via gold catalysis. J. Am. Chem. Soc. 136, 6904–6907 (2014).

    Article  CAS  PubMed  Google Scholar 

  16. Berzina, B., Sokolovs, I. & Suna, E. Copper-catalyzed para-selective C–H amination of electron-rich arenes. ACS Catal. 5, 7008–7014 (2015).

    Article  CAS  Google Scholar 

  17. Marchetti, L., Kantak, A., Davis, R. & DeBoef, B. Regioselective gold-catalyzed oxidative C–N bond formation. Org. Lett. 17, 358–361 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Xu, H., Shang, M., Dai, H.-X. & Yu, J.-Q. Ligand-controlled para-selective C–H arylation of monosubstituted arenes. Org. Lett. 17, 3830–3833 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Yang, Z., Qiu, F.-C., Gao, J., Li, Z.-W. & Guan, B.-T. Palladium-catalyzed oxidative arylation of tertiary benzamides: para-selectivity of monosubstituted arenes. Org. Lett. 17, 4316–4319 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Sokolovs, I. & Suna, E. Para-selective Cu-catalyzed C–H aryloxylation of electron-rich arenes and heteroarenes. J. Org. Chem. 81, 371–379 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. Ma, B. et al. Highly para-selective C−H alkylation of benzene derivatives with 2,2,2-trifluoroethyl α-aryl-α-diazoesters. Angew. Chem. Int. Ed. 56, 2749–2753 (2017).

    Article  CAS  Google Scholar 

  22. Luan, Y.-X. et al. Amide-ligand-controlled highly para-selective arylation of monosubstituted simple arenes with arylboronic acids. J. Am. Chem. Soc. 139, 1786–1789 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Bag, S. et al. Remote para-C–H functionalization of arenes by a D-shaped biphenyl template-based assembly. J. Am. Chem. Soc. 137, 11888–11891 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Patra, T. et al. Palladium-catalyzed directed para C−H functionalization of phenols. Angew. Chem. Int. Ed. 55, 7751–7755 (2016).

    Article  CAS  Google Scholar 

  25. Maji, A. et al. Experimental and computational exploration of para-selective silylation with a hydrogen-bonded template. Angew. Chem. Int. Ed. 56, 14903–14907 (2017).

    Article  CAS  Google Scholar 

  26. Li, M. et al. Remote para-C–H acetoxylation of electron-deficient arenes. Org. Lett. 21, 540–544 (2019).

    Article  CAS  PubMed  Google Scholar 

  27. Nakao, Y., Yamada, Y., Kashihara, N. & Hiyama, T. Selective C-4 alkylation of pyridine by nickel/Lewis acid catalysis. J. Am. Chem. Soc. 132, 13666–13668 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Tsai, C.-C. et al. Bimetallic nickel aluminum mediated para-selective alkenylation of pyridine: direct observation of η21-pyridine Ni(0)−Al(iii) intermediates prior to C−H bond activation. J. Am. Chem. Soc. 132, 11887–11889 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Saito, Y., Segawa, Y. & Itami, K. Para-C–H borylation of benzene derivatives by a bulky iridium catalyst. J. Am. Chem. Soc. 137, 5193–5198 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. Okumura, S. et al. Para-selective alkylation of benzamides and aromatic ketones by cooperative nickel/aluminum catalysis. J. Am. Chem. Soc. 138, 14699–14704 (2016).

    Article  CAS  PubMed  Google Scholar 

  31. Berger, F. et al. Site-selective and versatile aromatic C−H functionalization by thianthrenation. Nature 567, 223–228 (2019).

    Article  CAS  PubMed  Google Scholar 

  32. Yang, M.-H., Hunt, J. R., Sharifi, N. & Altman, R. A. Palladium catalysis enables benzylation of α,α-difluoroketone enolates. Angew. Chem. Int. Ed. 55, 9080–9083 (2016).

    Article  CAS  Google Scholar 

  33. Recio, I. I. I. A., Heinzman, J. D. & Tunge, J. A. Decarboxylative benzylation and arylation of nitriles. Chem. Commun. 48, 142–144 (2012).

    Article  CAS  Google Scholar 

  34. Mendis, S. N. & Tunge, J. A. Decarboxylative dearomatization and mono-α-arylation of ketones. Chem. Commun. 52, 7695–7698 (2016).

    Article  CAS  Google Scholar 

  35. Jaeger, C. W. & Kornblum, N. New type of substitution at a saturated carbon atom. J. Am. Chem. Soc. 94, 2545–2547 (1972).

    Article  CAS  Google Scholar 

  36. Bao, M., Nakamura, H. & Yamamoto, Y. Facile allylative dearomatization catalyzed by palladium. J. Am. Chem. Soc. 123, 759–760 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Lu, S., Xu, Z., Bao, M. & Yamamoto, Y. Carbocycle synthesis through facile and efficient palladium-catalyzed allylative de-aromatization of naphthalene and phenanthrene allyl chlorides. Angew. Chem. Int. Ed. 47, 4366–4369 (2008).

    Article  CAS  Google Scholar 

  38. Peng, B., Zhang, S., Yu, X., Feng, X. & Bao, M. Nucleophilic dearomatization of chloromethyl naphthalene derivatives via η3-benzylpalladium intermediates: a new strategy for catalytic dearomatization. Org. Lett. 13, 5402–5405 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Ueno, S., Komiya, S., Tanaka, T. & Kuwano, R. Intramolecular SN′-type aromatic substitution of benzylic carbonates at their para-position. Org. Lett. 14, 338–341 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Zhang, S., Wang, Y., Feng, X. & Bao, M. Palladium-catalyzed amination of chloromethylnaphthalene and chloromethylanthracene derivatives with various amines. J. Am. Chem. Soc. 134, 5492–5495 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Zhang, S., Yu, X., Feng, X., Yamamoto, Y. & Bao, M. Palladium-catalyzed regioselective allylation of five-membered heteroarenes with allyltributylstannane. Chem. Commun. 51, 3842–3845 (2015).

    Article  CAS  Google Scholar 

  42. Arlow, S. I. & Hartwig, J. F. Synthesis, characterization, and reactivity of palladium fluoroenolate complexes. J. Am. Chem. Soc. 139, 16088–16091 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Bordwell, F. G. Equilibrium acidities in dimethyl sulfoxide solution. Acc. Chem. Res. 21, 456–463 (1988).

    Article  CAS  Google Scholar 

  44. Trost, B. M., Xu, J. & Schmidt, T. Palladium-catalyzed decarboxylative asymmetric allylic alkylation of enol carbonates. J. Am. Chem. Soc. 131, 18343–18357 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Weaver, J. D., Recio, A., Grenning, A. J. & Tunge, J. A. Transition metal-catalyzed decarboxylative allylation and benzylation reactions. Chem. Rev. 111, 1846–1913 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Xie, H., Zhang, H. & Lin, Z. DFT studies on the palladium-catalyzed dearomatization reaction between chloromethylnaphthalene and the cyclic amine morpholine. Organometallics 32, 2336–2343 (2013).

    Article  CAS  Google Scholar 

  47. Boga, C., Del Vecchio, E., Forlani, L. & Tozzi, S. Evidence of reversibility in azo-coupling reactions between 1,3,5-tris(N,N-dialkylamino)benzenes and arenediazonium salts. J. Org. Chem. 72, 8741–8747 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Forlani, L., Boga, C., Del Vecchio, E., Ngobo, A.-L. T. D. & Tozzi, S. Reactions of Wheland complexes: base catalysis in re-aromatization reaction of σ complexes obtained from 1,3,5-tris(N,N-dialkylamino)benzene and arenediazonium salts. J. Phys. Org. Chem. 20, 201–205 (2007).

    Article  CAS  Google Scholar 

  49. Simmons, E. M. & Hartwig, J. F. On the interpretation of deuterium kinetic isotope effects in C–H bond functionalizations by transition-metal complexes. Angew. Chem. Int. Ed. 51, 3066–3072 (2012).

    Article  CAS  Google Scholar 

  50. Ma, S., Villa, G., Thuy-Boun, P. S., Homs, A. & Yu, J.-Q. Palladium-catalyzed ortho-selective C–H deuteration of arenes: evidence for superior reactivity of weakly coordinated palladacycles. Angew. Chem. Int. Ed. 53, 734–737 (2014).

    Article  CAS  Google Scholar 

  51. Ariafard, A. & Lin, Z. DFT studies on the mechanism of allylative dearomatization catalyzed by palladium. J. Am. Chem. Soc. 128, 13010–13016 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the donors of the Herman Frasch Foundation for Chemical Research (701-HF12), the National Science Foundation (NSF, CHE-1455163) and the National Institute of General Medical Sciences (R35 GM124661) for supporting this work. NMR instrumentation was provided by NIH (S10OD016360, S10RR024664 and P20GM103418) and NSF Grants (9977422 and 0320648). P.H.-Y.C. acknowledges financial support from the Bert and Emelyn Christensen Professorship and the Vicki & Patrick F. Stone family. P.H.-Y.C., T.F., M.A.G. and A.C.B. acknowledge the NSF (CHE-1352663) and the computing infrastructure in part provided by the NSF Phase-2 CCI, Center for Sustainable Materials Chemistry (NSF, CHE-1102637). T.F. acknowledges the Summer Fellowship Award from the department of Chemistry at Oregon State University.

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Contributions

F.d.A. and M.-H.Y. contributed equally. R.A.A. and M.-H.Y. created the project. R.A.A., M.-H.Y., F.d.A., M.S. and S.K. designed the experiments. M.-H.Y., M.S. and S.K. optimized the reaction conditions. M.-H.Y., F.d.A., M.S. and S.K. explored the substrate scope. F.d.A. designed and conducted the mechanistic experiments. R.A.A. supervised the synthetic and mechanistic portions of the experimental work. T.F. used density functional theory (DFT) to compute the key transition states and intermediates in the different proposed mechanisms, which ultimately led to pinpointing the operative pathway; A.C.B. performed the initial DFT computations; M.A.G. performed energy refinements at various levels of theory to verify that the DFT results were in line with experimental results. P.H.-Y.C. supervised the computational aspect of the work and also contributed to the DFT energy refinements. All the authors contributed to the writing and editing of the manuscript.

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Correspondence to Paul Ha-Yeon Cheong or Ryan A. Altman.

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Supplementary information

Supplementary Information

Experimental details for synthetic chemistry, including: general synthetic information and procedures, data for reaction optimization, characterization of substrates and products, data supporting mechanistic investigations. Computational details, including: complete authorship of Gaussian 09 and Gaussian 16, computational procedure, reaction coordinate diagram with higher-in-energy intermediates, exploration of para-selectivity of arylation process, reaction coordinate diagram with dimethyl substrate, coordinates for relevant computed structures. NMR spectra supporting the characterization of substrates and products and mechanistic studies

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de Azambuja, F., Yang, MH., Feoktistova, T. et al. Connecting remote C–H bond functionalization and decarboxylative coupling using simple amines. Nat. Chem. 12, 489–496 (2020). https://doi.org/10.1038/s41557-020-0428-1

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