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Practical and regioselective amination of arenes using alkyl amines

Abstract

The formation of carbon–nitrogen bonds for the preparation of aromatic amines is among the top five reactions carried out globally for the production of high-value materials, ranging from from bulk chemicals to pharmaceuticals and polymers. As a result of this ubiquity and diversity, methods for their preparation impact the full spectrum of chemical syntheses in academia and industry. In general, these molecules are assembled through the stepwise introduction of a reactivity handle in place of an aromatic C–H bond (that is, a nitro group, halogen or boronic acid) and a subsequent functionalization or cross-coupling. Here we show that aromatic amines can be constructed by direct reaction of arenes and alkyl amines using photocatalysis, without the need for pre-functionalization. The process enables the easy preparation of advanced building blocks, tolerates a broad range of functionalities, and multigram scale can be achieved via a batch-to-flow protocol. The merit of this strategy as a late-stage functionalization platform has been demonstrated by the modification of several drugs, agrochemicals, peptides, chiral catalysts, polymers and organometallic complexes.

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Fig. 1: Amination of aromatics.
Fig. 2: Development of a photocatalytic strategy for direct aromatic C–H amination.
Fig. 3: Late-stage diversification of bioactive molecules via photoredox C–H amination.
Fig. 4: Applications of the aromatic C–H amination reaction.

Data availability

All data supporting the findings of this study are available within the Supplementary Information. These include reaction procedures, products characterization, the batch-to-flow experiment procedure, the microscale parallel screening procedure, cyclic voltammograms and UV–vis, density functional theory and NMR spectra.

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Acknowledgements

The authors thank M. Simonetti and F. Juliá-Hernandez for useful discussions. D.L. thanks EPSRC for a Fellowship (EP/P004997/1) and the European Research Council for a research grant (758427). A.R. thanks the Marie Curie Actions for a Fellowship (703238).

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A.R., F.J. and D.L. designed the project. A.R., F.J., T.D.S. and A.J.M. performed all the synthetic experiments. J.J.D. performed the batch-to-flow optimization and scale-up. All authors analysed the results and wrote the manuscript.

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Correspondence to Daniele Leonori.

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Supplementary Information

Synthetic procedures; products characterization; electrochemical, UV–vis, emission quenching and DFT studies; NMR spectra.

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Ruffoni, A., Juliá, F., Svejstrup, T.D. et al. Practical and regioselective amination of arenes using alkyl amines. Nat. Chem. 11, 426–433 (2019). https://doi.org/10.1038/s41557-019-0254-5

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