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Practical and regioselective amination of arenes using alkyl amines

Abstract

The formation of carbon–nitrogen bonds for the preparation of aromatic amines is among the top five reactions carried out globally for the production of high-value materials, ranging from from bulk chemicals to pharmaceuticals and polymers. As a result of this ubiquity and diversity, methods for their preparation impact the full spectrum of chemical syntheses in academia and industry. In general, these molecules are assembled through the stepwise introduction of a reactivity handle in place of an aromatic C–H bond (that is, a nitro group, halogen or boronic acid) and a subsequent functionalization or cross-coupling. Here we show that aromatic amines can be constructed by direct reaction of arenes and alkyl amines using photocatalysis, without the need for pre-functionalization. The process enables the easy preparation of advanced building blocks, tolerates a broad range of functionalities, and multigram scale can be achieved via a batch-to-flow protocol. The merit of this strategy as a late-stage functionalization platform has been demonstrated by the modification of several drugs, agrochemicals, peptides, chiral catalysts, polymers and organometallic complexes.

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Fig. 1: Amination of aromatics.
Fig. 2: Development of a photocatalytic strategy for direct aromatic C–H amination.
Fig. 3: Late-stage diversification of bioactive molecules via photoredox C–H amination.
Fig. 4: Applications of the aromatic C–H amination reaction.

Data availability

All data supporting the findings of this study are available within the Supplementary Information. These include reaction procedures, products characterization, the batch-to-flow experiment procedure, the microscale parallel screening procedure, cyclic voltammograms and UV–vis, density functional theory and NMR spectra.

References

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

  2. Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).

    CAS  Article  Google Scholar 

  3. Roughley, S. D. & Jordan, A. M. The medicinal chemist’s toolbox: an analysis of reactions used in the pursuit of drug candidates. J. Med. Chem. 54, 3451–3479 (2011).

    CAS  Article  Google Scholar 

  4. Ruiz-Castillo, P. & Buchwald, S. L. Applications of palladium-catalyzed C−N cross-coupling reactions. Chem. Rev. 116, 12564–12649 (2016).

    CAS  Article  Google Scholar 

  5. Hartwig, J. F. Evolution of a fourth generation catalyst for the amination and thioetherification of aryl halides. Acc. Chem. Res. 41, 1534–1544 (2008).

    CAS  Article  Google Scholar 

  6. Corcoran, E. B. et al. Aryl amination using ligand-free Ni(ii) salts and photoredox catalysis. Science 353, 279–283 (2016).

    CAS  Article  Google Scholar 

  7. Creutz, S. E., Lotito, K. J., Fu, G. C., Peters, J. C. & Ullmann, C. –N. Photoinduced coupling: demonstrating the viability of a radical pathway. Science 338, 647–651 (2012).

    CAS  Article  Google Scholar 

  8. Santanilla, A. B. et al. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules. Science 347, 44–49 (2015).

    Article  Google Scholar 

  9. Jiao, J., Murakami, K. & Itami, K. Catalytic methods for aromatic C–H amination: an ideal strategy for nitrogen-based functional molecules. ACS Catal. 6, 610–633 (2016).

    CAS  Article  Google Scholar 

  10. Allen, L. J., Cabrera, P. J., Lee, M. & Sanford, M. S. N-Acyloxyphthalimides as nitrogen radical precursors in the visible light photocatalyzed room temperature C–H amination of arenes and heteroarenes. J. Am. Chem. Soc. 136, 5607–5610 (2014).

    CAS  Article  Google Scholar 

  11. Foo, K., Sella, E., Thomé, I., Eastgate, M. D. & Baran, P. S. A mild, ferrocene-catalyzed C–H imidation of (hetero)arenes. J. Am. Chem. Soc. 136, 5279–5282 (2014).

    CAS  Article  Google Scholar 

  12. Boursalian, G. B., Ham, W. S., Mazzotti, A. R. & Ritter, T. Charge-transfer-directed radical substitution enables para-selective C–H functionalization. Nat. Chem. 8, 810–815 (2016).

    CAS  Article  Google Scholar 

  13. 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).

    CAS  Article  Google Scholar 

  14. Morofuji, T., Shimizu, A. & Yoshida, J. Direct C–N coupling of imidazoles with aromatic and benzylic compounds via electrooxidative C–H functionalization. J. Am. Chem. Soc. 136, 4496–4499 (2014).

    CAS  Article  Google Scholar 

  15. Paudyal, M. P. et al. Dirhodium-catalyzed C-H arene amination using hydroxylamines. Science 353, 1144–1147 (2016).

    CAS  Article  Google Scholar 

  16. Legnani, L., Cerai, G. P. & Morandi, B. Direct and practical synthesis of primary anilines through iron-catalyzed C−H bond amination. ACS Catal. 6, 8162–8165 (2016).

    CAS  Article  Google Scholar 

  17. An, X.-D. & Yu, S. Photoredox-catalyzed C(sp 2)–N coupling reactions. Tetrahedron Lett. 59, 1605 (2018).

    CAS  Article  Google Scholar 

  18. Chow, Y. L., Danen, W. C., Nelsen, S. F. & Rosenblatt, D. H. Nonaromatic aminium radicals. Chem. Rev. 78, 243–274 (1978).

    CAS  Article  Google Scholar 

  19. Svejstrup, T. D., Ruffoni, A., Julia, F., Aubert, V. M. & Leonori, D. Synthesis of arylamines via aminium radicals. Angew. Chem. Int. Ed. 56, 14948–14952 (2017).

    CAS  Article  Google Scholar 

  20. Margrey, K. A., Levens, A. & Nicewicz, D. A. Direct aryl C–H amination with primary amines using organic photoredox catalysis. Angew. Chem. Int. Ed. 56, 15644–15648 (2017).

    CAS  Article  Google Scholar 

  21. Goldberg, F. W., Kettle, J. G., Kogej, T., Perry, M. W. D. & Tomkinson, N. P. Designing novel building blocks is an overlooked strategy to improve compound quality. Drug Discov. Today 20, 11–17 (2015).

    Article  Google Scholar 

  22. Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).

    CAS  Article  Google Scholar 

  23. Lee, S. J., Terrazas, M. S., Pippel, D. J. & Beak, P. Mechanism of electrophilic chlorination: experimental determination of a geometrical requirement for chlorine transfer by the endocyclic restriction test. J. Am. Chem. Soc. 125, 7307–7312 (2003).

    CAS  Article  Google Scholar 

  24. Xiong, X. & Yeung, Y.-Y. Highly ortho-selective chlorination of anilines using a secondary ammonium salt organocatalyst. Angew. Chem. Int. Ed. 55, 16101–16105 (2016).

    CAS  Article  Google Scholar 

  25. Minisci, F. Novel applications of free-radical reactions in preparative organic chemistry. Synthesis 1973, 1–24 (1973).

    Article  Google Scholar 

  26. Cosgrove, S. C., Plane, J. M. C. & Marsden, S. P. Radical-mediated direct C–H amination of arenes with secondary amines. Chem. Sci. 9, 6647–6652 (2018).

    CAS  Article  Google Scholar 

  27. 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).

    CAS  Article  Google Scholar 

  28. Musacchio, A. J. et al. Catalytic intermolecular hydroaminations of unactivated olefins with secondary alkyl amines. Science 355, 727 (2017).

    CAS  Article  Google Scholar 

  29. Citterio, A. et al. Polar effects in fee radical reactions. homlytic aromatic amination by the amino radical cation, •+NH3: reactivity and selectivity. J. Org. Chem. 49, 4479–4482 (1984).

    CAS  Article  Google Scholar 

  30. Colomer, I., Chamberlain, A. E. R., Haughey, M. B. & Donohoe, T. J. Hexafluoroisopropanol as a highly versatile solvent. Nat. Rev. Chem. 1, 0088 (2017).

    CAS  Article  Google Scholar 

  31. Tang, R.-J., Milcent, T. & Crousse, B. Regioselective halogenation of arenes and heterocycles in hexafluoroisopropanol. J. Org. Chem. 83, 930–938 (2018).

    CAS  Article  Google Scholar 

  32. Nguyen, J. D., Reiß, B., Dai, C. & Stephenson, C. R. J. Batch to flow deoxygenation using visible light photoredox catalysis. Chem. Commun. 49, 4352–4354 (2013).

    CAS  Article  Google Scholar 

  33. Cambié, D., Bottecchia, C., Straathof, N. J. W., Hessel, V. & Noël, T. Applications of continuous-flow photochemistry in organic synthesis, material science, and water treatment. Chem. Rev. 116, 10276–10341 (2016).

    Article  Google Scholar 

  34. Wang, H.-W. et al. Ligand-promoted rhodium(iii)-catalyzed ortho-C−H amination with free amines. Angew. Chem. Int. Ed. 56, 7449–7453 (2017).

    CAS  Article  Google Scholar 

  35. Rosane, J. & Daugulis, O. A general method for aminoquinoline-directed, copper-catalyzed sp 2 C–H bond amination. J. Am. Chem. Soc. 138, 4601–4607 (2016).

    Article  Google Scholar 

  36. 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).

    CAS  Article  Google Scholar 

  37. Carreira, E. M. & Fessard, T. C. Four-membered ring-containing spirocycles: synthetic strategies and opportunities. Chem. Rev. 114, 8257–8322 (2014).

    CAS  Article  Google Scholar 

  38. Willcox, D. et al. A general catalytic β-C–H carbonylation of aliphatic amines to β-lactams. Science 354, 851–857 (2016).

    CAS  Article  Google Scholar 

  39. Wanka, L., Iqbal, K. & Schreiner, P. R. The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives. Chem. Rev. 113, 3516–3604 (2013).

    CAS  Article  Google Scholar 

  40. Immel, O. et al. Catalyst for the preparation of aniline. US patent 5,304,525A (1994).

  41. Krska, S. W., DiRocco, D. A., Dreher, S. D. & Shevlin, M. The evolution of chemical high-throughput experimentation to address challenging problems in pharmaceutical synthesis. Acc. Chem. Res. 50, 2976–2985 (2017).

    CAS  Article  Google Scholar 

  42. Gesmundo, N. J. et al. Nanoscale synthesis and affinity ranking. Nature 557, 228–232 (2018).

    CAS  Article  Google Scholar 

  43. Vinogradova, E. V., Zhang, C., Spokoyny, A. M., Pentelute, B. L. & Buchwald, S. L. Organometallic palladium reagents for cysteine bioconjugation. Nature 526, 687–691 (2025).

    Article  Google Scholar 

  44. Bloom, S. et al. Decarboxylative alkylation for site-selective bioconjugation of native proteins via oxidation potentials. Nat. Chem. 10, 205–211 (2018).

    CAS  Article  Google Scholar 

  45. Osberger, T. J., Rogness, D. C., Kohrt, J. T., Stepan, A. F. & White, M. C. Oxidative diversification of amino acids and peptides by small-molecule iron catalysis. Nature 537, 214–219 (2016).

    CAS  Article  Google Scholar 

  46. deGruyter, J. N., Malins, L. R. & Baran, P. S. Residue-specific peptide modification: a chemist’s guide. Biochemistry 56, 3863–3873 (2017).

    CAS  Article  Google Scholar 

  47. Boutureira, O. & Bernardes, G. J. L. Advances in chemical protein modification. Chem. Rev. 115, 2174–2195 (2015).

    CAS  Article  Google Scholar 

  48. Blasco, E., Sims, M. B., Goldmann, A. S., Sumerlin, B. S. & Barner-Kowollik, C. Polymer functionalization. Macromolecules 50, 5215–5252 (2017).

    CAS  Article  Google Scholar 

  49. Bomben, P. G., Robson, K. C. D., Sedach, P. A. & Berlinguette, C. P. On the viability of cyclometalated Ru(ii) complexes for light-harvesting applications. Inorg. Chem. 48, 9631–9643 (2009).

    CAS  Article  Google Scholar 

  50. Ma, D. L. et al. Antagonizing STAT3 dimerization with a rhodium(iii) complex. Angew. Chem. Int. Ed. 53, 9178–9182 (2014).

    CAS  Article  Google Scholar 

  51. Gagliardo, M. et al. Organic transformations on σ-aryl organometallic complexes. Angew. Chem. Int. Ed. 46, 8558–8573 (2007).

    CAS  Article  Google Scholar 

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Acknowledgements

The authors thank M. Simonetti and F. Juliá-Hernandez for useful discussions. D.L. thanks EPSRC for a Fellowship (EP/P004997/1) and the European Research Council for a research grant (758427). A.R. thanks the Marie Curie Actions for a Fellowship (703238).

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A.R., F.J. and D.L. designed the project. A.R., F.J., T.D.S. and A.J.M. performed all the synthetic experiments. J.J.D. performed the batch-to-flow optimization and scale-up. All authors analysed the results and wrote the manuscript.

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Correspondence to Daniele Leonori.

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Supplementary Information

Synthetic procedures; products characterization; electrochemical, UV–vis, emission quenching and DFT studies; NMR spectra.

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Ruffoni, A., Juliá, F., Svejstrup, T.D. et al. Practical and regioselective amination of arenes using alkyl amines. Nat. Chem. 11, 426–433 (2019). https://doi.org/10.1038/s41557-019-0254-5

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