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The direct arylation of allylic sp3 C–H bonds via organic and photoredox catalysis

Abstract

The direct functionalization of unactivated sp3 C–H bonds is still one of the most challenging problems facing synthetic organic chemists. The appeal of such transformations derives from their capacity to facilitate the construction of complex organic molecules via the coupling of simple and otherwise inert building blocks, without introducing extraneous functional groups. Despite notable recent efforts1, the establishment of general and mild strategies for the engagement of sp3 C–H bonds in C–C bond forming reactions has proved difficult. Within this context, the discovery of chemical transformations that are able to directly functionalize allylic methyl, methylene and methine carbons in a catalytic manner is a priority. Although protocols for direct oxidation and amination of allylic C–H bonds (that is, C–H bonds where an adjacent carbon is involved in a C = C bond) have become widely established2,3, the engagement of allylic substrates in C–C bond forming reactions has thus far required the use of pre-functionalized coupling partners4. In particular, the direct arylation of non-functionalized allylic systems would enable access to a series of known pharmacophores (molecular features responsible for a drug’s action), though a general solution to this long-standing challenge remains elusive. Here we report the use of both photoredox and organic catalysis to accomplish a mild, broadly effective direct allylic C–H arylation. This C–C bond forming reaction readily accommodates a broad range of alkene and electron-deficient arene reactants, and has been used in the direct arylation of benzylic C–H bonds.

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Figure 1: The direct arylation of allylic C–H bonds via the synergistic merger of photoredox and organic catalysis.
Figure 2: Proposed mechanism for the direct arylation of allyli C–H bonds via photoredox and organic catalysis.
Figure 3: Substrate scope for the direct allylic arylation reaction.
Figure 4: Expanding the scope of the direct C–H arylation protocol.

References

  1. He, J. et al. Ligand-controlled C(sp3)–H arylation and olefination in synthesis of unnatural chiral α-amino acids. Science 343, 1216–1220 (2014)

    ADS  CAS  Article  Google Scholar 

  2. Eames, J. & Watkinson, M. Catalytic allylic oxidation of alkenes using an asymmetric Kharasch-Sosnovsky reaction. Angew. Chem. Int. Edn 40, 3567–3571 (2001)

    CAS  Article  Google Scholar 

  3. Johannsen, M. & Jørgensen, K. A. Allylic amination. Chem. Rev. 98, 1689–1708 (1998)

    CAS  Article  Google Scholar 

  4. Trost, B. M. & Van Vranken, D. L. Asymmetric transition metal-catalyzed allylic alkylations. Chem. Rev. 96, 395–422 (1996)

    CAS  Article  Google Scholar 

  5. Borg, R. M., Arnold, D. R. & Cameron, T. S. Radical ions in photochemistry. 15. The photosubstitution reaction between dicyanobenzenes and alkyl olefins. Can. J. Chem. 62, 1785–1802 (1984)

    CAS  Article  Google Scholar 

  6. Hoshikawa, T. & Inoue, M. Photoinduced direct 4-pyridination of C(sp3)–H bonds. Chem. Sci. 4, 3118–3123 (2013)

    CAS  Article  Google Scholar 

  7. Sekine, M., Ilies, L. & Nakamura, E. Iron-catalyzed allylic arylation of olefins via C(sp3)–H activation under mild conditions. Org. Lett. 15, 714–717 (2013)

    CAS  Article  Google Scholar 

  8. Narayanam, J. M. R. & Stephenson, C. R. J. Visible light photoredox catalysis: applications in organic synthesis. Chem. Soc. Rev. 40, 102–113 (2011)

    CAS  Article  Google Scholar 

  9. 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 

  10. Schultz, D. M. & Yoon, T. P. Solar synthesis: prospects in visible light photocatalysis. Science 343, 1239176 (2014)

    Article  Google Scholar 

  11. Nicewicz, D. A. & MacMillan, D. W. C. Merging photoredox catalysis with organocatalysis: the direct asymmetric alkylation of aldehydes. Science 322, 77–80 (2008)

    ADS  CAS  Article  Google Scholar 

  12. Nagib, D. A., Scott, M. E. & MacMillan, D. W. C. Enantioselective α-trifluoromethylation of aldehydes via photoredox organocatalysis. J. Am. Chem. Soc. 131, 10875–10877 (2009)

    CAS  Article  Google Scholar 

  13. Pirnot, M. T., Rankic, D. A., Martin, D. B. C. & MacMillan, D. W. C. Photoredox activation for the direct β-arylation of ketones and aldehydes. Science 339, 1593–1596 (2013)

    ADS  CAS  Article  Google Scholar 

  14. Qvortrup, K., Rankic, D. A. & MacMillan, D. W. C. A general strategy for organocatalytic activation of C–H bonds via photoredox catalysis: direct arylation of benzylic ethers. J. Am. Chem. Soc. 136, 626–629 (2014)

    CAS  Article  Google Scholar 

  15. Khursan, S. L., Mikhailov, D. A., Yanborisov, V. M. & Borisov, D. I. AM1 Calculations of bond dissociation energies. Allylic and benzylic C–H bonds. React. Kinet. Catal. Lett. 61, 91–95 (1997)

    CAS  Article  Google Scholar 

  16. Flamigni, L., Barbieri, A., Sabatini, C., Ventura, B. & Barigelletti, F. Photochemistry and photophysics of coordination compounds: iridium. Top. Curr. Chem. 281, 143–203 (2007)

    CAS  Article  Google Scholar 

  17. Mori, Y., Sakaguchi, Y. & Hayashi, H. Magnetic field effects on chemical reactions of biradical ion pairs in homogeneous fluid solvents. J. Phys. Chem. A 104, 4896–4905 (2000)

    CAS  Article  Google Scholar 

  18. Ogawa, K. A. & Boydston, A. J. Organocatalyzed anodic oxidation of aldehydes to thioesters. Org. Lett. 16, 1928–1931 (2014)

    CAS  Article  Google Scholar 

  19. Jencks, W. P. & Salvesen, K. Equilibrium deuterium isotope effects on the ionization of thiol acids. J. Am. Chem. Soc. 93, 4433–4436 (1971)

    CAS  Article  Google Scholar 

  20. Denisov, E., Chatgilialoglu, C., Shestakov, A. & Denisova, T. Rate constants and transition-state geometry of reactions of alkyl, alkoxyl, and peroxyl radicals with thiols. Int. J. Chem. Kinet. 41, 284–293 (2009)

    CAS  Article  Google Scholar 

  21. McMillen, D. F. & Golden, D. M. Hydrocarbon bond dissociation energies. Annu. Rev. Phys. Chem. 33, 493–532 (1982)

    ADS  CAS  Article  Google Scholar 

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Acknowledgements

Financial support was provided by NIHGMS (R01 GM103558-03), and we also thank Merck and Amgen for funding. J.D.C. thanks Marie Curie Actions for an International Outgoing Fellowship.

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J.D.C. performed and analysed experiments. J.D.C. and D.W.C.M. designed experiments to develop this reaction and probe its utility, and also prepared this manuscript.

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Correspondence to David W. C. MacMillan.

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The authors declare no competing financial interests.

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Cuthbertson, J., MacMillan, D. The direct arylation of allylic sp3 C–H bonds via organic and photoredox catalysis. Nature 519, 74–77 (2015). https://doi.org/10.1038/nature14255

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