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Practical and innate carbon–hydrogen functionalization of heterocycles


Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition-metal-mediated cross-coupling have simplified the synthesis of such molecules; however, C–H functionalization of medicinally important heterocycles that does not rely on pre-functionalized starting materials is an underdeveloped area1,2,3,4,5,6,7,8,9. Unfortunately, the innate properties of heterocycles that make them so desirable for biological applications—such as aqueous solubility and their ability to act as ligands—render them challenging substrates for direct chemical functionalization. Here we report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild (moderate temperature, 50 °C or less), direct and operationally simple formation of medicinally relevant C–C bonds while reacting in a complementary fashion to other innate C–H functionalization methods2,3,4,5,6 (Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated C–H insertion and C–H deprotonation). We prepared a toolkit of these reagents and studied their reactivity across a wide range of heterocycles (natural products, drugs and building blocks) without recourse to protecting-group chemistry. The reagents can even be used in tandem fashion in a single pot in the presence of water and air.

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Figure 1: Development of a reagent toolkit for an innate C–H functionalization of heterocycles.
Figure 2: Chemoselectivity, rapid diversity and complexity generation, and practical utility.


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We thank D.-H. Huang and L. Pasternack for NMR spectroscopic assistance, A. Schuyler and W. Uritboonthai for mass spectrometry assistance and D. Cayer for the analysis of the β-lactamase activity. Financial support for this work was provided by the US NIH/NIGMS (GM-073949), the Uehara Memorial Foundation (postdoctoral fellowship for Y.F.), the US–UK Fulbright Commission (postdoctoral fellowship for F.O.), Aarhus University, OChem Graduate School, CDNA, CFIN and NABIIT (fellowship for E.D.F.), the US NIH (graduate fellowship for R.A.R.) and Pfizer Inc. (postdoctoral fellowship for R.D.B.).

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Y.F., J.A.D., D.D.D., R.A.R. and P.S.B. conceived the work; Y.F., J.A.D., F.O., E.D.F., D.D.D., R.A.R., R.D.B., B.H., N.S. and M.R.C. performed the experiments; Y.F., J.A.D., F.O., E.D.F., D.D.D., R.A.R., R.D.B., B.H., N.S., M.R.C. and P.S.B. designed the experiments and analysed the data; and F.O., R.A.R., Y.I. and P.S.B. wrote the manuscript.

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Correspondence to Phil S. Baran.

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Fujiwara, Y., Dixon, J., O’Hara, F. et al. Practical and innate carbon–hydrogen functionalization of heterocycles. Nature 492, 95–99 (2012).

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