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Molecular editing

Converting benzene to pyridine

Nature Reviews Chemistry volume 7, page 71 (2023)Cite this article

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Functional-group interconversion is a fundamental technique for chemists to construct new molecules and expand the accessible chemical space. However, such transformations are usually restricted to changing specific substituents on the periphery of a molecular scaffold, with only a limited number of examples enabling the modification of a molecule’s backbone architecture. Among them, converting a carbocyclic arene to its nitrogen-containing heterocyclic analogue by swapping a single carbon for a nitrogen is highly sought-after, owing to the prevalence of nitrogen-containing heterocycles in biologically active compounds. Such a unique transformation, that might look like a typographical error on paper, allows the direct access to pyridine analogues without having to resort to de novo synthesis.

The team took inspiration from a pioneering report by Sundberg and co-workers, in which the photolysis of phenyl azide was reported. However, limited functional group tolerance and the complex mixture of products in low yield hampered the utility of the method. Patel and Burns identified a 3H-azepine as a key intermediate. To improve the transformation, the nitrogen insertion and carbon deletion steps were investigated separately. Extensive optimization of the individual steps enabled the authors to combine them into a convenient one-pot protocol, using acenaphthylene as an unusual sensitizer for the generation of singlet oxygen under mild visible light irradiation.

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References

Original article

  • Patel, S. C. & Burns, N. Z. Conversion of aryl azides to aminopyridines. J. Am. Chem. Soc. 144, 17797–17802 (2022)

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Related article

  • Sundberg, R. J., Suter, S. R. & Brenner, M. Photolysis of ortho-substituted aryl azides in diethylamine. Formation and autoxidation of 2-diethylamino-1 H-azepine intermediates. J. Am. Chem. Soc. 94, 513–520 (1972)

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

    Elisa Y. Lai & Lucas Guillemard

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  1. Elisa Y. Lai
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  2. Lucas Guillemard
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Correspondence to Elisa Y. Lai or Lucas Guillemard.

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The authors declare no competing interests.

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Lai, E.Y., Guillemard, L. Converting benzene to pyridine. Nat Rev Chem 7, 71 (2023). https://doi.org/10.1038/s41570-023-00465-2

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