Catalytic functionalization of unactivated primary C–H bonds directed by an alcohol

Abstract

New synthetic methods for the catalytic functionalization of C–H bonds have the potential to revolutionize the synthesis of complex molecules1,2,3,4. However, the realization of this synthetic potential requires the ability to functionalize selectively one C–H bond in a compound containing many such bonds and an array of functional groups. The site-selective functionalization of aliphatic C–H bonds is one of the greatest challenges that must be met for C–H bond functionalization to be used widely in complex-molecule synthesis1,3,5,6, and processes catalysed by transition-metals provide the opportunity to control selectivity7,8. Current methods for catalytic, aliphatic C–H bond functionalization typically rely on the presence of one inherently reactive C–H bond9,10, or on installation and subsequent removal of directing groups that are not components of the desired molecule8. To overcome these limitations, we sought catalysts and reagents that would facilitate aliphatic C–H bond functionalization at a single site, with chemoselectivity derived from the properties of the catalyst and site-selectivity directed by common functional groups11 contained in both the reactant and the desired product. Here we show that the combination of an iridium-phenanthroline catalyst and a dihydridosilane reagent leads to the site-selective γ-functionalization of primary C–H bonds controlled by a hydroxyl group, the most common functional group in natural products12. The scope of the reaction encompasses alcohols and ketones bearing many substitution patterns and auxiliary functional groups; this broad scope suggests that this methodology will be suitable for the site-selective and diastereoselective functionalization of complex natural products.

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Figure 1: Hydroxyl-directed γ-oxygenation of secondary and tertiary alcohols and ketones.
Figure 2: Functional-group tolerance of hydroxyl-directed γ-oxygenation.
Figure 3: Directed aliphatic C–H functionalization of natural products.

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Acknowledgements

We thank the US National Science Foundation (CHE-0910641 to J.F.H.) and the US National Institutes of Health (GM087901 to E.M.S.) for funding this work, and Johnson Matthey for a gift of [Ir(cod)OMe]2.

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E.M.S. and J.F.H. conceived the work and designed the experiments. E.M.S. performed the experiments. Both authors analysed the data and wrote the manuscript.

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Correspondence to John F. Hartwig.

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The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Materials and Method, Supplementary Experimental Procedures and Spectral Data , 1H and 13 C NMR Spectra and additional references. (PDF 3547 kb)

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Simmons, E., Hartwig, J. Catalytic functionalization of unactivated primary C–H bonds directed by an alcohol. Nature 483, 70–73 (2012). https://doi.org/10.1038/nature10785

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