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Photochemical diversification of strong C(sp3)–H bonds enabled by allyl bromide and sodium fluoride

Nature Synthesis volume 2, pages 766–777 (2023)Cite this article

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Abstract

The development of practical approaches for the selective functionalization of strong, neutral C(sp3)–H bonds, such as those in petroleum-derived hydrocarbons, is of general interest but remains a remarkable challenge in synthetic chemistry. We here report a convenient approach that employs allyl bromides as the reagents and sodium fluoride as an activator in photochemical processes. Diverse C(sp3)–H functionalizations of alkanes, cycloalkanes and other relatively unreactive substances were enabled by using a stoichiometric or catalytic amount of allyl bromides as initiators in the presence of NaF, which furnished various allylated, heteroarylated, alkylated, hydrazinated and aminated products in good yields with high chemoselectivity and site selectivity. Binary NaF–allyl bromide adducts generated in situ appear to play essential roles in the reaction as light-active species, initiators for radical-mediated C–H cleavage and potential functionalization reagents. We expect that this transition-metal- and photosensitizer-free strategy will offer new opportunities for the C–H diversification of hydrocarbon feedstocks and the late-stage modification of lead compounds.

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Fig. 1: Overview of this work.
Fig. 2: Optimization of reaction conditions.
Fig. 3: Mechanistic studies.
Fig. 4: Extension of this method to C(sp3)–H heteroarylation, alkylation and hydrazination reactions.
Fig. 5: Synthetic utility of the method initiated by a catalytic amount of 1a.
Fig. 6: Studies of the mechanism of the C(sp3)–H hydrazination reaction enabled by a catalytic amount of 1a.

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Data availability

All relevant data supporting the findings of this study, including experimental procedures, compound characterization, computational study details, NMR spectra and other spectroscopic analysis, are available within the article and its Supplementary Information.

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Davies, H. M. L. & Liao, K. Dirhodium tetracarboxylates as catalysts for selective intermolecular C–H functionalization. Nat. Rev. Chem. 3, 347–360 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kariofillis, S. K. & Doyle, A. G. Synthetic and mechanistic implications of chlorine photoelimination in nickel/photoredox C(sp3)–H cross-coupling. Acc. Chem. Res. 54, 988–1000 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fazekas, T. J. et al. Diversification of aliphatic C–H bonds in small molecules and polyolefins through radical chain transfer. Science 375, 545–550 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Le, C., Liang, Y., Evans, R. W., Li, X. & MacMillan, D. W. C. Selective sp3 C-H alkylation via polarity-matchbased cross-coupling. Nature 547, 79–83 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Capaldo, L., Ravelli, D. & Fagnori, M. Direct photocatalyzed hydrogen atom transfer (HAT) for aliphatic C–H bonds elaboration. Chem. Rev. 122, 1875–1924 (2022).

    Article  CAS  PubMed  Google Scholar 

  7. Goldberg, K. I. & Goldman, A. S. Large-scale selective functionalization of alkanes. Acc. Chem. Res. 50, 620–626 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Feng, K. et al. Late-stage oxidative C(sp3)–H methylation. Nature 580, 621–627 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Perry, I. B. et al. Direct arylation of strong aliphatic C–H bonds. Nature 560, 70–75 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hu, A., Guo, J.-J., Pan, H. & Zuo, Z. Selective functionalization of methane, ethane, and higher alkanes by cerium photocatalysis. Science 361, 668–672 (2018).

    Article  CAS  PubMed  Google Scholar 

  11. Sharma, A. & Hartwig, J. F. Metal-catalysed azidation of tertiary C–H bonds suitable for late-stage functionalization. Nature 517, 600–604 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Huang, H.-M., Bellotti, P., Chen, P.-P., Houk, K. N. & Glorius, F. Allylic C(sp3)–H arylation of olefins via ternary catalysis. Nat. Synth. 1, 59–68 (2022).

    Article  Google Scholar 

  13. Mukherjee, S., Maji, B., Tlahuext-Aca, A. & Glorius, F. Visible-light-promoted activation of unactivated C(sp3)–H bonds and their selective trifluoromethylthiolation. J. Am. Chem. Soc. 138, 16200–16203 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Tsuji, T. et al. α-Amino acid and peptide synthesis using catalytic cross-dehydrogenative coupling. Nat. Synth. 1, 304–312 (2022).

    Article  Google Scholar 

  15. Sarver, P. J. et al. The merger of decatungstate and copper catalysis to enable aliphatic C(sp3)–H trifluoromethylation. Nat. Chem. 12, 459–467 (2020).

    Article  CAS  PubMed  Google Scholar 

  16. Chu, J. C. K. & Rovis, T. Amide-directed photoredox-catalysed C–C bond formation at unactivated sp3 C–H bonds. Nature 539, 272–275 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Liao, K., Negretti, S., Musaev, D. G., Bacsa, J. & Davies, H. M. L. Site-selective and stereoselective functionalization of unactivated C–H bonds. Nature 533, 230–234 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Liao, K. et al. Site-selective and stereoselective functionalization of non-activated tertiary C–H bonds. Nature 551, 609–613 (2017).

    Article  CAS  PubMed  Google Scholar 

  19. Shu, C., Noble, A. & Aggarwal, V. K. Metal-free photoinduced C(sp3)–H borylation of alkanes. Nature 586, 714–719 (2020).

    Article  CAS  PubMed  Google Scholar 

  20. Rohe, S., Morris, A. O., McCallum, A. O. & Barriault, L. Hydrogen atom transfer reactions via photoredox catalyzed chlorine atom generation. Angew. Chem. Int. Ed. 57, 15664–15669 (2018).

    Article  CAS  Google Scholar 

  21. Jia, P. et al. Light-promoted bromine-radical-mediated selective alkylation and amination of unactivated C(sp3)–H bonds. Chem 6, 1766–1776 (2020).

    Article  CAS  Google Scholar 

  22. Silvi, M. & Melchiorre, P. Enhancing the potential of enantioselective organocatalysis with light. Nature 554, 41–49 (2018).

    Article  CAS  PubMed  Google Scholar 

  23. Strieth-Kalthoff, F. & Glorius, F. Triplet energy transfer photocatalysis: unlocking the next level. Chem 6, 1888–1903 (2020).

    Article  CAS  Google Scholar 

  24. Fu, M.-C., Shang, R., Zhao, B., Wang, B. & Fu, Y. Photocatalytic decarboxylative alkylations mediated by triphenylphosphine and sodium iodide. Science 363, 1429–1434 (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Saux, E. L., Zanini, M. & Melchiorre, P. Photochemical organocatalytic benzylation of allylic C–H bonds. J. Am. Chem. Soc. 144, 1113–1118 (2022).

    Article  PubMed  Google Scholar 

  26. Li, Y., Lei, M. & Gong, L. Photocatalytic regio- and stereoselective C(sp3)–H functionalization of benzylic and allylic hydrocarbons as well as unactivated alkanes. Nat. Catal. 2, 1016–1026 (2019).

    Article  CAS  Google Scholar 

  27. Cao, S., Hong, W., Ye, Z. & Gong, L. Photocatalytic three-component asymmetric sulfonylation via direct C(sp3)–H functionalization. Nat. Commun. 12, 2377 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li, Y. et al. Copper(II)-catalyzed asymmetric photoredox reactions: enantioselective alkylation of imines driven by visible light. J. Am. Chem. Soc. 140, 15850–15858 (2018).

    Article  CAS  PubMed  Google Scholar 

  29. Li, Y. et al. Organophotocatalytic selective deuterodehalogenation of aryl or alkyl chlorides. Nat. Commun. 12, 2894 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cao, S. et al. Nickel-catalyzed regiodivergent asymmetric cycloadditions of α,β-unsaturated carbonyl compounds. CCS Chem. 3, 3329–3340 (2021).

    Google Scholar 

  31. Zhang, S. et al. Photocatalyzed site-selective C(sp3)–H sulfonylation of toluene derivatives and cycloalkanes with inorganic sulfinates. Chin. J. Catal. 43, 564–570 (2022).

    Article  CAS  Google Scholar 

  32. Katsuto, H., Okamoto, R., Sumi, T. & Koga, K. Ion size dependences of the salting-out effect: reversed order of sodium and lithium ions. J. Phys. Chem. B 125, 6296–6305 (2021).

    Article  CAS  PubMed  Google Scholar 

  33. Daniele, P. G., Rigano, C. & Sammartano, S. Studies on sulphate complexes. Part I. Potentiometric investigation of Li+, Na+, K+, Rb+ and Cs+ complexes at 37 °C and 0.03 ⩽ I ⩽ 0.5. Inorg. Chim. Acta 63, 267–272 (1982).

    Article  CAS  Google Scholar 

  34. Wang, L.-T. & Su, T.-M. Molecular complexes between sodium and carbonyl compounds: photoionization and ab initio molecular orbital studies. J. Phys. Chem. A 104, 10825–10833 (2000).

    Article  CAS  Google Scholar 

  35. Zhang, G.-Z., Fu, M.-C., Zhao, B. & Shang, R. Photocatalytic decarboxylative alkylations of C(sp3)–H and C(sp2)–H bonds enabled by ammonium iodide in amide solvent. Sci. China Chem. 64, 439–444 (2021).

    Article  Google Scholar 

  36. Struss, J. A., Sadeghipour, M. & Tanko, J. M. Radical additions to allyl bromides. A synthetically useful, ‘tin-free’ method for carbon–carbon bond formation. Tetrahedron Lett. 50, 2119–2120 (2009).

    Article  CAS  Google Scholar 

  37. Ghosh, M. et al. Formation of a room temperature stable FeV(O) complex: reactivity toward unactivated C–H bonds. J. Am. Chem. Soc. 136, 9524–9527 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Fu, J., Ren, Z., Bacsa, J., Musaev, D. G. & Davies, H. M. L. Desymmetrization of cyclohexanes by site- and stereoselective C–H functionalization. Nature 564, 395–399 (2018).

    Article  CAS  PubMed  Google Scholar 

  39. Heitz, D. R., Rizwan, K. & Molander, G. A. Visible-light-mediated alkenylation, allylation, and cyanation of potassium alkyltrifluoroborates with organic photoredox catalysts. J. Org. Chem. 81, 7308–7313 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chen, C.-H. & Gabbaï, F. P. Fluoride anion complexation by a triptycene-based distiborane: taking advantage of a weak but observable C−H⋅⋅⋅F interaction. Angew. Chem. Int. Ed. 56, 1799–1804 (2017).

    Article  CAS  Google Scholar 

  41. Lu, T. & Chen, F. Multiwfn: a multifunctional wavefunction analyzer. J. Comput. Chem. 33, 580–592 (2012).

    Article  PubMed  Google Scholar 

  42. Zhao, Y., Bordwell, F. G., Cheng, J.-P. & Wang, D. Equilibrium acidities and homolytic bond dissociation energies (BDEs) of the acidic H−N bonds in hydrazines and hydrazides. J. Am. Chem. Soc. 119, 9125–9129 (1997).

    Article  CAS  Google Scholar 

  43. Kato, T. & Maruoka, K. Design of bowl-shaped N-hydroxyimide derivatives as new organoradical catalysts for site-selective C(sp3)–H bond functionalization reactions. Angew. Chem. Int. Ed. 59, 14261–14264 (2020).

    Article  CAS  Google Scholar 

  44. Tlahuext-Aca, A., Garza-Sanchez, R. A., Schäfer, M. & Glorius, F. Visible-light-mediated synthesis of ketones by the oxidative alkylation of styrenes. Org. Lett. 20, 1546–1549 (2018).

    Article  CAS  PubMed  Google Scholar 

  45. Wegner, E. E. & Adamson, A. W. Photochemistry of complex ions. III. Absolute quantum yields for the photolysis of some aqueous chromium(III) complexes. Chemical actinometry in the long wavelength visible region. J. Am. Chem. Soc. 88, 394–404 (1966).

    Article  CAS  Google Scholar 

  46. Tlahuext-Aca, A., Candish, L., Garza-Sanchez, R. A. & Glorius, F. Decarboxylative olefination of activated aliphatic acids enabled by dual organophotoredox/copper catalysis. ACS Catal. 8, 1715–1719 (2018).

    Article  CAS  Google Scholar 

  47. Buzzetti, L., Crisenza, G. E. M. & Melchiorre, P. Mechanistic studies in photocatalysis. Angew. Chem. Int. Ed. 58, 3730–3747 (2019).

    Article  CAS  Google Scholar 

  48. Lee, W., Jung, S., Kim, M. & Hong, S. Site-selective direct C–H pyridylation of unactivated alkanes by triplet excited anthraquinone. J. Am. Chem. Soc. 143, 3003–3012 (2021).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We gratefully acknowledge funding from the National Natural Science Foundation of China (grant nos. 22071209 and 22071206), the National Youth Talent Support Program, the Natural Science Foundation of Fujian Province of China (grant no. 2017J06006) and the Fundamental Research Funds for the Central Universities (grant no. 20720190048).

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Author notes

  1. These authors contributed equally: Ziqi Ye, Ying Yu.

Authors and Affiliations

  1. Key Laboratory of Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China

    Ziqi Ye, Ying Yu, Yu-Mei Lin, Yuehua Chen, Silin Song & Lei Gong

  2. Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM), Xiamen, China

    Lei Gong

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Contributions

L.G. conceived and designed the project. Z.Y., Y.Y., Y.C. and S.S. conducted the experiments, Z.Y. designed and performed the DFT calculations, and with L.G., analysed and interpreted the experimental data. L.G. and Y.-M.L. prepared the manuscript, and Z.Y. and Y.Y. prepared the Supplementary Information.

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Correspondence to Lei Gong.

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Nature Synthesis thanks Rui Shang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Ye, Z., Yu, Y., Lin, YM. et al. Photochemical diversification of strong C(sp3)–H bonds enabled by allyl bromide and sodium fluoride. Nat. Synth 2, 766–777 (2023). https://doi.org/10.1038/s44160-023-00291-w

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