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The reductive C3 functionalization of pyridinium and quinolinium salts through iridium-catalysed interrupted transfer hydrogenation

Abstract

Aromatic rings are ubiquitous in organic chemistry and form the basis of many commercial products. Despite the numerous routes available for the preparation of aromatic compounds, there remain few methods that allow their conversion into synthetically useful partially saturated derivatives and even fewer that allow new C–C bonds to be formed at the same time. Here we set out to address this problem and uncover a unique catalytic partial reduction reaction that forms partially saturated azaheterocycles from aromatic precursors. In this reaction, methanol and formaldehyde are used for the reductive functionalization of pyridines and quinolines using catalytic iridium; thus, inexpensive and renewable feedstocks are utilized in the formation of complex N-heterocycles. By harnessing the formation of a nucleophilic enamine intermediate, the C–C bond-forming process reverses the normal pattern of reactivity and allows access to the C3 position of the arene. Mechanistic investigations using D-labelling experiments reveal the source of hydride added to the ring and show the reversible nature of the iridium-hydride addition.

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Fig. 1: State-of-the-art methods used to access substituted tetrahydropyridines.
Fig. 2: Deuterium labelling studies and proposed mechanism for the pyridinium salts.
Fig. 3: Deuterium labelling studies and proposed mechanism for the quinolinium salts.

Data availability

Supplementary information, chemical compound information and copies of spectra are available in the online version of this paper.

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Acknowledgements

The EPSRC (grant no. EP/L023121/1 and a DTP award) and Eli-Lilly provided financial support for this project.

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Contributions

A.G. and T.J.D. conceived and designed the study. A.G., H.B.H., P.J.S. and H.K.P. performed the experiments and A.G., H.B.H., P.J.S., H.K.P., P.J.L.-S. and T.J.D. analysed the data for the compounds. A.G., H.B.H. and T.J.D. co-wrote the paper.

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Correspondence to Timothy J. Donohoe.

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Full synthetic protocols for the synthesis of all starting materials and products, full characterization data and spectra for all novel starting materials and products, additional screening information and additional mechanistic experiments

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Grozavu, A., Hepburn, H.B., Smith, P.J. et al. The reductive C3 functionalization of pyridinium and quinolinium salts through iridium-catalysed interrupted transfer hydrogenation. Nature Chem 11, 242–247 (2019). https://doi.org/10.1038/s41557-018-0178-5

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