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Metal-catalysed azidation of tertiary C–H bonds suitable for late-stage functionalization

Nature volume 517, pages 600–604 (2015)Cite this article

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Abstract

Many enzymes oxidize unactivated aliphatic C–H bonds selectively to form alcohols; however, biological systems do not possess enzymes that catalyse the analogous aminations of C–H bonds1,2. The absence of such enzymes limits the discovery of potential medicinal candidates because nitrogen-containing groups are crucial to the biological activity of therapeutic agents and clinically useful natural products. In one prominent example illustrating the importance of incorporating nitrogen-based functionality, the conversion of the ketone of erythromycin to the –N(Me)CH2– group in azithromycin leads to a compound that can be dosed once daily with a shorter treatment time3,4. For such reasons, synthetic chemists have sought catalysts that directly convert C–H bonds to C–N bonds. Most currently used catalysts for C–H bond amination are ill suited to the intermolecular functionalization of complex molecules because they require excess substrate or directing groups, harsh reaction conditions, weak or acidic C–H bonds, or reagents containing specialized groups on the nitrogen atom5,6,7,8,9,10,11,12,13,14. Among C–H bond amination reactions, those forming a C–N bond at a tertiary alkyl group would be particularly valuable, because this linkage is difficult to form from ketones or alcohols that might be created in a biosynthetic pathway by oxidation15. Here we report a mild, selective, iron-catalysed azidation of tertiary C–H bonds that occurs without excess of the valuable substrate. The reaction tolerates aqueous environments and is suitable for the functionalization of complex structures in the late stages of a multistep synthesis. Moreover, this azidation makes it possible to install a range of nitrogen-based functional groups, including those from Huisgen ‘click’ cycloadditions and the Staudinger ligation16,17,18,19. We anticipate that these reactions will create opportunities to modify natural products, their precursors and their derivatives to produce analogues that contain different polarity and charge as a result of nitrogen-containing groups. It could also be used to help identify targets of biologically active molecules by creating a point of attachment—for example, to fluorescent tags or ‘handles’ for affinity chromatography—directly on complex molecular structures.

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Figure 1: Development of a catalyst for the azidation of aliphatic C–H bonds.
Figure 2: Evaluation of the effect of the steric and electronic environment on site selectivity for the azidation of aliphatic tertiary C–H bonds.
Figure 3: Introduction of a series of nitrogen-containing functionalities via C–H bond azidation.

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Acknowledgements

We thank the US NIH (4R37GM055382 to J.F.H.) and the Swiss National Science Foundation (SNSF; PBGEP2_145544 to AS) for financial support. We thank A. DiPasquale for assistance with crystallographic data and acknowledge US NIH shared instrumentation grant S10-RR027172.

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  1. Department of Chemistry, University of California, Berkeley, 94720, California, USA

    Ankit Sharma & John F. Hartwig

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  1. Ankit Sharma
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Contributions

A.S. conducted the experiments. A.S. and J.F.H. conceived and designed the project, analysed the data and prepared this manuscript. X-ray crystal structures are deposited in the Cambridge Crystallographic Data Centre (CCDC 1027821–1027822).

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Correspondence to John F. Hartwig.

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The authors declare no competing financial interests.

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Sharma, A., Hartwig, J. Metal-catalysed azidation of tertiary C–H bonds suitable for late-stage functionalization. Nature 517, 600–604 (2015). https://doi.org/10.1038/nature14127

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