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Brønsted acid-enhanced direct hydrogen atom transfer photocatalysis for selective functionalization of unactivated C(sp3)–H bonds

Nature Synthesis volume 1, pages 794–803 (2022)Cite this article

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Abstract

The manipulation of unactivated aliphatic C–H bonds remains one of the most challenging tasks in synthetic chemistry. Direct hydrogen atom transfer (HAT) photocatalysis is an appealing approach to this goal. However, many methods are constrained due to low catalytic efficiency. Here we report the use of a Brønsted acid to enhance the efficiency of an inexpensive organic HAT photocatalyst, eosin Y. This strategy enables valuable transformations, including alkylation, heteroarylation and fluorination, of a wide array of unactivated C(sp3)–H bonds, using the alkane substrate as the limiting reagent. The process has been applied to the late-stage functionalization of natural products and pharmaceuticals to selectively form C–H-functionalized analogues. Experimental and computational mechanistic studies show that the HAT reactivity is significantly enhanced when the sp3 oxygen atoms on eosin Y are protonated. The method has been shown to be general across different types of direct HAT photocatalysts, demonstrating its potential in native C–H bond functionalization.

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Fig. 1: Development of a strategy to enhance the catalytic efficiency of direct HAT photocatalysis.
Fig. 2: Mechanistic studies on the acid effect.
Fig. 3: Proposed reaction mechanism and computational calculations on the HAT process.
Fig. 4: Effect of Brønsted acids on different direct HAT photocatalysts.

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Data availability

All data supporting the findings of this study are available within the paper and its Supplementary Information. The Cartesian coordinates of the calculated stationary points are provided in the Supplementary Data.

References

  1. Davies, H. M. L., Du Bois, J. & Yu, J.-Q. C–H functionalization in organic synthesis. Chem. Soc. Rev. 40, 1855–1856 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Wencel-Delord, J. & Glorius, F. C–H bond activation enables the rapid construction and late-stage diversification of functional molecules. Nat. Chem. 5, 369–375 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Xue, X. S., Ji, P., Zhou, B. & Cheng, J. P. The essential role of bond energetics in C–H activation/functionalization. Chem. Rev. 117, 8622–8648 (2017).

    Article  CAS  PubMed  Google Scholar 

  4. Sambiagio, C. et al. A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry. Chem. Soc. Rev. 47, 6603–6743 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Oeschger, R. et al. Diverse functionalization of strong alkyl C–H bonds by undirected borylation. Science 368, 736–741 (2020). (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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 

  7. 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 

  8. An, Q. et al. Cerium-catalyzed C–H functionalizations of alkanes utilizing alcohols as hydrogen atom transfer agents. J. Am. Chem. Soc. 142, 6216–6226 (2020).

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. 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 

  11. Cao, H., Tang, X., Tang, H., Yuan, Y. & Wu, J. Photoinduced intermolecular hydrogen atom transfer reactions in organic synthesis. Chem. Cat. 1, 523–598 (2021).

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Ravelli, D., Fagnoni, M., Fukuyama, T., Nishikawa, T. & Ryu, I. Site-selective C–H functionalization by decatungstate anion photocatalysis: synergistic control by polar and steric effects expands the reaction scope. ACS Catal. 8, 701–713 (2018).

    Article  CAS  Google Scholar 

  14. 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 

  15. Shen, Y., Gu, Y. & Martin, R. sp3 C–H arylation and alkylation enabled by the synergy of triplet excited ketones and nickel catalysts. J. Am. Chem. Soc. 140, 12200–12209 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Cao, H. et al. Photoinduced site-selective alkenylation of alkanes and aldehydes with aryl alkenes. Nat. Commun. 11, 1956 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Laudadio, G. et al. C(sp3)–H functionalizations of light hydrocarbons using decatungstate photocatalysis in flow. Science 369, 92–96 (2020).

    Article  CAS  PubMed  Google Scholar 

  18. Wan, T. et al. Accelerated and scalable C(sp3)–H amination via decatungstate photocatalysis using a flow photoreactor equipped with high-intensity LEDs. ACS Cent. Sci. 8, 51–56 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Schultz, D. M. et al. Oxyfunctionalization of the remote C–H bonds of aliphatic amines by decatungstate photocatalysis. Angew. Chem. Int. Ed. 56, 15274–15278 (2017).

    Article  CAS  Google Scholar 

  20. Halperin, S. D., Fan, H., Chang, S., Martin, R. E. & Britton, R. A convenient photocatalytic fluorination of unactivated C–H bonds. Angew. Chem. Int. Ed. 53, 4690–4693 (2014).

    Article  CAS  Google Scholar 

  21. Sarver, P. J., Bissonnette, N. B. & MacMillan, D. W. Decatungstate-catalyzed C(sp3)–H sulfinylation: rapid access to diverse organosulfur functionality. J. Am. Chem. Soc. 143, 9737–9743 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Capaldo, L., Quadri, L. L. & Ravelli, D. Photocatalytic hydrogen atom transfer: the philosopher’s stone for late-stage functionalization? Green Chem. 22, 3376–3396 (2020).

    Article  CAS  Google Scholar 

  23. Guillemard, L., Kaplaneris, N., Ackermann, L. & Johansson, M. J. Late-stage C–H functionalization offers new opportunities in drug discovery. Nat. Rev. Chem. 5, 522–545 (2021).

    Article  CAS  Google Scholar 

  24. Yuan, Z. et al. Electrostatic effects accelerate decatungstate-catalyzed C–H fluorination using [18F]- and [19F]NFSI in small molecules and peptide mimics. ACS Cat. 9, 8276–8284 (2019).

    Article  CAS  Google Scholar 

  25. Gunay, A. & Theopold, K. H. C–H bond activations by metal oxo compounds. Chem. Rev. 110, 1060–1081 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Nam, W., Lee, Y. M. & Fukuzumi, S. Hydrogen atom transfer reactions of mononuclear nonheme metal–oxygen intermediates. Acc. Chem. Res. 51, 2014–2022 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Sacramento, J. J. D. & Goldberg, D. P. Factors affecting hydrogen atom transfer reactivity of metal–oxo porphyrinoid complexes. Acc. Chem. Res. 51, 2641–2652 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen, J. et al. Tuning the reactivity of mononuclear nonheme manganese (IV)–oxo complexes by triflic acid. Chem. Sci. 6, 3624–3632 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jung, J., Kim, S., Lee, Y. M., Nam, W. & Fukuzumi, S. Switchover of the mechanism between electron transfer and hydrogen-atom transfer for a protonated manganese(IV)–oxo complex by changing only the reaction temperature. Angew. Chem. Int. Ed. 55, 7450–7454 (2016).

    Article  CAS  Google Scholar 

  30. Fan, X.-Z. et al. Eosin Y as a direct hydrogen-atom transfer photocatalyst for the functionalization of C–H bonds. Angew. Chem. Int. Ed. 57, 8514–8518 (2018).

    Article  CAS  Google Scholar 

  31. Kuang, Y. et al. Asymmetric synthesis of 1,4-dicarbonyl compounds from aldehydes by hydrogen atom transfer photocatalysis and chiral Lewis acid catalysis. Angew. Chem. Int. Ed. 58, 16859–16863 (2019).

    Article  CAS  Google Scholar 

  32. Yan, J. et al. A radical smiles rearrangement promoted by neutral eosin Y as a direct hydrogen atom transfer photocatalyst. J. Am. Chem. Soc. 142, 11357–11362 (2020).

    Article  CAS  PubMed  Google Scholar 

  33. Shambayati, S. & Schreiber, S. L. in Comprehensive Organic Synthesis Vol. 1 (ed. Trost, B. M.) Ch. 1.10 (Pergamon, 1991).

  34. Arnett, E. M., Quirk, R. P. & Burke, J. J. Weak bases in strong acids. III. Heats of ionization of amines in fluorosulfuric and sulfuric acids. New general basicity scale. J. Am. Chem. Soc. 92, 1260–1266 (1970).

    Article  CAS  Google Scholar 

  35. Arnett, E. M. & Wu, C. Y. Stereoelectronic effects on organic bases. III. The basicities of some saturated ethers in aqueous sulfuric acid. J. Am. Chem. Soc. 82, 4999–5000 (1960).

    Article  CAS  Google Scholar 

  36. Vanzin, D. et al. Experimental and computational studies of protolytic and tautomeric equilibria of erythrosin B and eosin Y in water/DMSO. RSC Adv. 6, 110312–110328 (2016).

    Article  CAS  Google Scholar 

  37. Mchedlov-Petrosyan, N. O., Kukhtik, V. I. & Egorova, S. I. Protolytic equilibria of fluorescein halo derivatives in aqueous-organic systems. Russ. J. Gen. Chem. 76, 1607–1617 (2006).

    Article  CAS  Google Scholar 

  38. Mchedlov-Petrossyan, N. O. Fluorescein dyes in solutions: well studied systems? Kharkov Natl Univ. Bull. Chem. Ser. 626, 221–312 (2004).

    Google Scholar 

  39. Fan, X. et al. Neutral-eosin-Y-photocatalyzed silane chlorination using dichloromethane. Angew. Chem. Int. Ed. 58, 12580–12584 (2019).

    Article  CAS  Google Scholar 

  40. Y. R. Luo, Comprehensive Handbook of Chemical Bond Energies (CRC Press, 2007).

  41. Cismesia, M. A. & Yoon, T. P. Characterizing chain processes in visible light photoredox catalysis. Chem. Sci. 6, 5426–5434 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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 

  43. 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 

  44. Li, G. X., Hu, X., He, G. & Chen, G. Photoredox-mediated Minisci-type alkylation of N-heteroarenes with alkanes with high methylene selectivity. ACS Catal. 8, 11847–11853 (2018).

    Article  CAS  Google Scholar 

  45. Pitre, S. P., Muuronen, M., Fishman, D. A. & Overman, L. E. Tertiary alcohols as radical precursors for the introduction of tertiary substituents into heteroarenes. ACS Catal. 9, 3413–3418 (2019).

    Article  CAS  Google Scholar 

  46. Tabushi, I., Hamuro, J. & Oda, R. Free-radical substitution on adamantane. J. Am. Chem. Soc. 89, 7127–7129 (1967).

    Article  CAS  Google Scholar 

  47. Tabushi, I., Aoyama, Y., Kojo, S., Hamuro, J. & Yoshida, Z. Free-radical halogenation of adamantane. Selectivity and relative lifetime of 1-and 2-adamantyl radicals. J. Am. Chem. Soc. 94, 1177–1183 (1972).

    Article  CAS  Google Scholar 

  48. Hagmann, W. K. The many roles for fluorine in medicinal chemistry. J. Med. Chem. 51, 4359–4369 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Nodwell, M. B. et al. 18F-Fluorination of unactivated C–H bonds in branched aliphatic amino acids: direct synthesis of oncological positron emission tomography imaging agents. J. Am. Chem. Soc. 139, 3595–3598 (2017).

    Article  CAS  PubMed  Google Scholar 

  50. Takahira, Y. et al. Electrochemical C(sp3)–H fluorination. Synlett 30, 1178–1182 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gómez, L. et al. Stereospecific C–H oxidation with H2O2 catalyzed by a chemically robust site-isolated iron catalyst. Angew. Chem. Int. Ed. 48, 5720–5723 (2009).

    Article  Google Scholar 

  52. Renneke, R. F., Kadkhodayan, M., Pasquali, M. & Hill, C. L. Roles of surface protonation on the photodynamic, catalytic, and other properties of polyoxometalates probed by the photochemical functionalization of alkanes. Implications for irradiated semiconductor metal oxides. J. Am. Chem. Soc. 113, 8357–8367 (1991).

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful for the financial support provided by Pfizer (A-0004153-00-00, J.W.), the Ministry of Education (MOE) of Singapore (MOET2EP10120-0014 for J.W. and MOE-MOET2EP10120-0007 for X.L.), NUS (Suzhou) Research Institute, National Natural Science Foundation of China (21871205, 22071170, J.W.; 21702182, 21873081 and 22122109, X.H.), the Fundamental Research Funds for the Central Universities (2020XZZX002-02, X.H.), the State Key Laboratory of Clean Energy Utilization (ZJUCEU2020007, X.H.), the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study (SN-ZJU-SIAS-006, X.H.), Beijing National Laboratory for Molecular Sciences (BNLMS202102, X. H.), CAS Youth Interdisciplinary Team (JCTD-2021-11, X.H.) and the Center of Chemistry for Frontier Technologies and Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province (PSFM 2021-01, X.H.). Calculations were performed on the high-performance computing system at the Department of Chemistry, Zhejiang University. The authors thank P. O’Neill and S. R. Dubbaka (Pfizer) for helpful discussions.

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Authors and Affiliations

  1. Department of Chemistry, National University of Singapore, Singapore, Republic of Singapore

    Hui Cao, Degong Kong, Tao Liu, Linlin Gao & Jie Wu

  2. National University of Singapore (Suzhou) Research Institute, Suzhou, China

    Hui Cao & Jie Wu

  3. School of Chemical Engineering & Technology, Harbin Institute of Technology, Harbin, China

    Degong Kong

  4. Center of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, China

    Li-Cheng Yang & Xin Hong

  5. Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Westlake University, Hangzhou, China

    Li-Cheng Yang & Xin Hong

  6. Beijing National Laboratory for Molecular Sciences, Beijing, China

    Li-Cheng Yang & Xin Hong

  7. Singapore University of Technology and Design, Singapore, Republic of Singapore

    Supphachok Chanmungkalakul & Xiaogang Liu

  8. Chemical Research & Development, Worldwide Research Development & Medical, Pfizer Inc., Groton, MA, USA

    Jared L. Piper & Zhihui Peng

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Contributions

H.C. discovered and developed the reaction. H.C., J.L.P., Z.P., X.H. and J.W. conceived and designed the investigations. H.C., D.K., T.L. and L.G. performed the experiments. L.-C.Y. conducted DFT calculations. S.C. and X.L. performed the flash photolysis experiments. H.C. and J.W. wrote the manuscript.

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Correspondence to Xin Hong or Jie Wu.

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Supplementary Information

Supplementary Tables 1–18, Figs. 1–56, methods, discussions, NMR spectra and references.

Supplementary Data 1

Cartesian coordinates of the calculated stationary points

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Cao, H., Kong, D., Yang, LC. et al. Brønsted acid-enhanced direct hydrogen atom transfer photocatalysis for selective functionalization of unactivated C(sp3)–H bonds. Nat. Synth 1, 794–803 (2022). https://doi.org/10.1038/s44160-022-00125-1

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