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

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.

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.

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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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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.

Corresponding authors

Correspondence to Xin Hong or Jie Wu.

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Supplementary information

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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