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A general strategy for the amination of electron-rich and electron-poor heteroaromatics by desaturative catalysis

Nature Catalysis (2024)Cite this article

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Abstract

The introduction of alkylamines onto heteroaromatics is integral to the preparation of high-value molecules. Typical methods rely on heteroaromatic pre-functionalization by halogenation or nitration, followed by metal-catalysed cross-coupling or multi-step manipulation of the nitrogen functionality. This results in often unselective or low-yielding synthetic routes. Here we show an alternative approach in which saturated heterocyclic ketones are used as aryl surrogates for desaturative coupling with amines. The process operates under mild photochemical conditions, is compatible with complex amines and delivers both electron-poor and -rich heteroaromatics that are difficult to access by other methods. As ketones are readily decorated by carbonyl chemistry, this retrosynthetic tactic escapes the rules and limitations of aromatic reactivity and metal-catalysed cross-couplings. Our process uses enamine formation to create the key carbon–nitrogen bond, followed by two rounds of photoredox oxidation and cobalt-catalysed desaturation. The two desaturation steps are distinct, as the cobaloxime first acts as a hydrogen atom abstractor and then an oxidant.

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Fig. 1: Relevance and preparation of aminated heteroaromatics.
Fig. 2: Design and development of a desaturative approach to 4-aminopyridines.
Fig. 3: Substrate scope for the synthesis of 4-aminopyridines.
Fig. 4: Substrate scope for the synthesis of 3-amino-pyridines, pyrroles, furans, thiophenes and pyrazoles.
Fig. 5: Proposed mechanism for the desaturative aminations.

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The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information or from the authors upon reasonable request.

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Acknowledgements

D.L. thanks the European Research Council for a research grant (101086901). H.P.C. thanks AstraZeneca for a PhD CASE Award. J.C. thanks the EU funding from an MSCA Postdoctoral Fellowship (101104383-DES-B-CAT). L.M.A. is a Ramón y Cajal fellow (ref. RYC2021-030994-I) and thanks MCIN/AEI and NextGenerationEU/PRTR for support and the KAUST Supercomputer Laboratory (KSL) for providing the computational resources (Shaheen II). We thank C. Vermeeren (RWTH Aachen University) for help with the purification of some of the products.

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Authors and Affiliations

  1. Institute of Organic Chemistry, RWTH Aachen University, Aachen, Germany

    Javier Corpas, Ester Maria Di Tommaso, Alessandro Ruffoni & Daniele Leonori

  2. Department of Chemistry, University of Manchester, Manchester, UK

    Henry P. Caldora

  3. XChem Inc., Montreal, Quebec, Canada

    Augusto César Hernandez-Perez

  4. Oncology R&D Medicinal Chemistry, AstraZeneca, Cambridge, UK

    Oliver Turner

  5. Instituto de Estudios Ambientales y Recursos Naturales (i-UNAT), Campus Universitario de Tafira, Universidad de Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, Spain

    Luis Miguel Azofra

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A.R. and D.L. designed the project and directed the work. J.C., H.C. and E.M.d.T. performed all the synthetic and mechanistic experiments. L.M.A. performed the computational studies. All the authors analysed the results and wrote the paper.

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Corpas, J., Caldora, H.P., Di Tommaso, E.M. et al. A general strategy for the amination of electron-rich and electron-poor heteroaromatics by desaturative catalysis. Nat Catal (2024). https://doi.org/10.1038/s41929-024-01152-1

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