A photochemical dehydrogenative strategy for aniline synthesis

Abstract

Chemical reactions that reliably join two molecular fragments together (cross-couplings) are essential to the discovery and manufacture of pharmaceuticals and agrochemicals1,2. The introduction of amines onto functionalized aromatics at specific and pre-determined positions (ortho versus meta versus para) is currently achievable only in transition-metal-catalysed processes and requires halogen- or boron-containing substrates3,4,5,6. The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (electrophilic halogenation or C–H borylation) so selective targeting of all positions is often not possible. Here we report a non-canonical cross-coupling approach for the construction of anilines, exploiting saturated cyclohexanones as aryl electrophile surrogates. Condensation between amines and carbonyls, a process that frequently occurs in nature and is often used by (bio-)organic chemists7, enables a predetermined and site-selective carbon–nitrogen (C–N) bond formation, while a photoredox- and cobalt-based catalytic system progressively desaturates the cyclohexene ring en route to the aniline. Given that functionalized cyclohexanones are readily accessible with complete regiocontrol using the well established carbonyl reactivity, this approach bypasses some of the frequent selectivity issues of aromatic chemistry. We demonstrate the utility of this C–N coupling protocol by preparing commercial medicines and by the late-stage amination–aromatization of natural products, steroids and terpene feedstocks.

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Fig. 1: Cross-coupling strategies for aniline synthesis.
Fig. 2: Scope of the amine partner in the dehydrogenative amination.
Fig. 3: Scope of the cyclohexanone partner in the dehydrogenative amination.
Fig. 4: Synthesis of complex anilines.

Data availability

Materials and methods, experimental procedures, useful information, mechanistic studies, optimization studies, 1H NMR spectra, 13C NMR spectra and mass spectrometry data are available in the Supplementary Information. Raw data are available from the corresponding author on reasonable request.

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Acknowledgements

D.L. thanks EPSRC for a Fellowship (EP/P004997/1) and the European Research Council for a research grant (758427). S.U.D. thanks the Marie Curie Actions for a Fellowship (791349).

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Contributions

S.U.D. and D.L. designed the project. S.U.D., F.J. and A.L. performed all experiments. All the authors analysed the results. D.L., F.J. and J.J.D. wrote the manuscript.

Corresponding author

Correspondence to Daniele Leonori.

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Peer review information Nature thanks Edward Anderson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

The Supplementary Information file contains the following sections: (1) general experimental details; (2) starting material synthesis; (3) reaction optimization; (4) pictures of reaction set-up; (5) substrate scope; (6) mechanistic considerations; (7) NMR spectra; and (8) references.

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U. Dighe, S., Juliá, F., Luridiana, A. et al. A photochemical dehydrogenative strategy for aniline synthesis. Nature 584, 75–81 (2020). https://doi.org/10.1038/s41586-020-2539-7

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