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Remote carboxylation of halogenated aliphatic hydrocarbons with carbon dioxide


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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  1. Colacot, T. New Trends in Cross-coupling: Theory and Applications (RSC Catalysis Series, 2015)

  2. Kambe, N., Iwasaki, T. & Terao, J. Pd-catalyzed cross-coupling reactions of alkyl halides. Chem. Soc. Rev. 40, 4937–4947 (2011)

    Article  CAS  Google Scholar 

  3. Vasseur, A., Bruffaerts, J. & Marek, I. Remote functionalization through alkene isomerization. Nat. Chem. 8, 209–219 (2016)

    Article  CAS  Google Scholar 

  4. Szilagyi, M. in Patty’s Toxicology Vol. 3 (eds Bingham, E. & Cohrssen, B. ) Ch. 48 (Wiley, 2012)

  5. Netherton, M. R., Dai, C., Neuschutz, K. & Fu, G. C. Room-temperature alkyl-alkyl Suzuki cross-coupling of alkyl bromides that possess β hydrogens. J. Am. Chem. Soc. 123, 10099–10100 (2001)

    Article  CAS  Google Scholar 

  6. Devasagayaraj, A., Studemann, T. & Knochel, P. A new nickel-catalyzed cross-coupling reaction between sp3 carbon centers. Angew. Chem. Int. Ed. Engl. 34, 23–24 (1995)

    Google Scholar 

  7. Tasker, S. Z., Standley, E. A. & Jamison, T. F. Recent advances in homogeneous nickel catalysis. Nature 509, 299–309 (2014)

    Article  ADS  CAS  Google Scholar 

  8. Owston, N. A. & Fu, G. C. Asymmetric alkyl-alkyl cross-couplings of unactivated secondary alkyl electrophiles: stereoconvergent Suzuki reactions of racemic acylated halohydrins. J. Am. Chem. Soc. 132, 11908–11909 (2010)

    Article  CAS  Google Scholar 

  9. Zuo, Z. et al. Merging photoredox with nickel catalysis: coupling of α-carboxyl sp3-carbons with aryl halides. Science 345, 437–440 (2014)

    Article  ADS  CAS  Google Scholar 

  10. White, M. C. Adding aliphatic C–H bond oxidations to synthesis. Science 335, 807–809 (2012)

    Article  ADS  CAS  Google Scholar 

  11. He, Y., Cai, Y. & Zhu, S. Mild and regioselective benzylic C–H functionalization: Ni-catalyzed reductive arylation of remote and proximal olefins. J. Am. Chem. Soc. 139, 1061–1064 (2017)

    Article  CAS  Google Scholar 

  12. Choi, G. J., Zhu, Q., Miller, D. C., Gu, C. J. & Knowles, R. R. Catalytic alkylation of remote C–H bonds enabled by proton-coupled electron transfer. Nature 539, 268–271 (2016)

    Article  ADS  CAS  Google Scholar 

  13. Chu, J. C. K. & Rovis, T. Amide-directed photoredox-catalysed C–C bond formation at unactivated sp3 C–H bonds. Nature 539, 272–275 (2016)

    Article  ADS  Google Scholar 

  14. Mei, T.-S., Patel, H. H. & Sigman, M. S. Enantioselective construction of remote quaternary stereocentres. Nature 508, 340–344 (2014)

    Article  ADS  CAS  Google Scholar 

  15. Vasseur, A., Perrin, L., Eisenstein, O. & Marek, I. Remote functionalization of hydrocarbons with reversibility enhanced stereocontrol. Chem. Sci. 6, 2770–2776 (2015)

    Article  CAS  Google Scholar 

  16. Correa, A., León, T. & Martin, R. Ni-catalyzed carboxylation of C(sp2)– and C(sp3)–O bonds with CO2 . J. Am. Chem. Soc. 136, 1062–1069 (2014)

    Article  CAS  Google Scholar 

  17. Moragas, T., Cornella, J. & Martin, R. Ligand-controlled regiodivergent Ni-catalyzed reductive carboxylation of allyl esters with CO2 . J. Am. Chem. Soc. 136, 17702–17705 (2014)

    Article  CAS  Google Scholar 

  18. Liu, Q., Wu, L., Jackstell, R. & Beller, M. Using carbon dioxide as a building block in organic synthesis. Nat. Commun. 6, 5933 (2015)

    Article  ADS  Google Scholar 

  19. Dupuy, S., Zhang, K.-F., Goutierre, A.-S. & Baudoin, O. Terminal-selective functionalization of alkyl chains by regioconvergent cross-coupling. Angew. Chem. Int. Ed. 55, 14793–14797 (2016)

    Article  CAS  Google Scholar 

  20. Johnson, L. K., Killian, C. M. & Brookhart, M. New Pd(II)- and Ni(II)-based catalysts for polymerization of ethylene and α-olefins. J. Am. Chem. Soc. 117, 6414–6415 (1995)

    Article  CAS  Google Scholar 

  21. Bair, J. S. et al. Linear-selective hydroarylation of unactivated terminal and internal olefins with trifluoromethyl-substituted arenes. J. Am. Chem. Soc. 136, 13098–13101 (2014)

    Article  CAS  Google Scholar 

  22. Behr, A. et al. Highly selective tandem-isomerization hydroformylation reaction of trans-4-octene to n-nonanal with rhodium-BIPHEPHOS catalysis. J. Mol. Catal. Chem. 206, 179–184 (2003)

    Article  CAS  Google Scholar 

  23. Wu, X.-F. et al. Transition metal-catalyzed carbonylation reactions of olefins and alkynes: a personal account. Acc. Chem. Res. 47, 1041–1053 (2014)

    Article  CAS  Google Scholar 

  24. Chou, R. T. & Bendler, H. V. Polyamide composition containing ionomer. WO patent WO/2013/101891 (2013)

  25. Liu, Y., Cornella, J. & Martin, R. Ni-catalyzed carboxylation of unactivated primary alkyl bromides and sulfonates with CO2 . J. Am. Chem. Soc. 136, 11212–11215 (2014)

    Article  CAS  Google Scholar 

  26. Singh, S., Bruffaerts, J., Vasseur, A. & Marek, I. A unique Pd-catalysed Heck arylation as a remote trigger for cyclopropane selective ring-opening. Nat. Commun. 8, 14200 (2017)

    Article  ADS  Google Scholar 

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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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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.

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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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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).

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