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Remote carboxylation of halogenated aliphatic hydrocarbons with carbon dioxide

Abstract

Catalytic carbon–carbon bond formation has enabled the streamlining of synthetic routes when assembling complex molecules1. It is particularly important when incorporating saturated hydrocarbons, which are common motifs in petrochemicals and biologically relevant molecules. However, cross-coupling methods that involve alkyl electrophiles result in catalytic bond formation only at specific and previously functionalized sites2. Here we describe a catalytic method that is capable of promoting carboxylation reactions at remote and unfunctionalized aliphatic sites with carbon dioxide at atmospheric pressure. The reaction occurs via selective migration of the catalyst along the hydrocarbon side-chain3 with excellent regio- and chemoselectivity, representing a remarkable reactivity relay when compared with classical cross-coupling reactions. Our results demonstrate that site-selectivity can be switched and controlled, enabling the functionalization of less-reactive positions in the presence of a priori more reactive ones. Furthermore, we show that raw materials obtained in bulk from petroleum processing, such as alkanes and unrefined mixtures of olefins, can be used as substrates. This offers an opportunity to integrate a catalytic platform en route to valuable fatty acids by transforming petroleum-derived feedstocks directly4.

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Figure 1: Switchable site-selective catalytic carboxylation at remote sp3 C–H sites.
Figure 2: Catalytic carboxylation of discrete alkyl halides at remote sp3 C–H sites.
Figure 3: Catalytic carboxylation of feedstock materials by regioconvergent events.
Figure 4: Switchable site-selective carboxylation of unactivated alkyl bromides at remote sp3 C–H sites.

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Acknowledgements

We are grateful for financial support provided by ICIQ, the European Research Council (ERC-StG-277883 and ERC-2015-PoC-713577), MINECO (CTQ2015-65496-R and Severo Ochoa Excellence Accreditation 2014-2018, SEV-2013-0319) and the Cellex Foundation. F.J.-H. and J.C. thank COFUND and Marie Curie Actions for an Intra-European Fellowship (FP7-PEOPLE-2012-IEF-328381).

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Contributions

F.J.-H., T.M. and J.C. performed and analysed the experiments. R.M. wrote the manuscript. All authors commented on the final manuscript and contributed to the analysis and interpretation of the results.

Corresponding author

Correspondence to Ruben Martin.

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A European patent application to ICIQ and ICREA was filed, with application number EP16382336.

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Reviewer Information Nature thanks I. Marek and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

This file contains Supplementary Text and Data, including a detailed description of the methods utilized, characterization of all compounds and spectroscopical data – see contents page for details. (PDF 8338 kb)

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Juliá-Hernández, F., Moragas, T., Cornella, J. et al. Remote carboxylation of halogenated aliphatic hydrocarbons with carbon dioxide. Nature 545, 84–88 (2017). https://doi.org/10.1038/nature22316

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