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Catalytic remote hydrohalogenation of internal alkenes

Nature Chemistry volume 14, pages 425–432 (2022)Cite this article

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Abstract

Primary alkyl halides have broad utility as fine chemicals in organic synthesis. The direct halogenation of alkenes is one of the most efficient approaches for the synthesis of these halides. Internal alkenes, in particular mixtures of isomers from refineries, constitute readily available and inexpensive feedstock and are the most attractive starting materials for this synthesis. However, the hydrohalogenation of alkenes generally affords branched alkyl halides; there are no catalytic methods to prepare linear alkyl halides directly from internal alkenes, let alone from a mixture of alkene isomers. Here we report the remote oxidative halogenation of alkenes under palladium catalysis via which both terminal and internal alkenes yield primary alkyl halides efficiently. Engineering pyridine-oxazoline ligands by introducing a hydroxyl group is essential for achieving excellent chemo- and regioselectivity. The catalytic system is also good for the mixture of alkene isomers generated from dehydrogenation of alkanes, providing a window to investigate the high-value utilization of inexpensive alkanes.

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Fig. 1: Catalytic hydrohalogenation of alkenes for the synthesis of primary alkyl halides.
Fig. 2: Palladium-catalysed oxidative hydrochlorination of unactivated alkenes.
Fig. 3: Site selectivity and synthetic applications of the hydrohalogenation process.

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Data availability

The data supporting the finding of this study are available in this article and the Supplementary Information. Crystallographic data for structures Pd(L6)Cl2, Pd(L6)2Cl2 and Pd(L9)Cl2 have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2026831, CCDC 2026793 and CCDC 2076726, respectively. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/

References

  1. Weissermel, K. & Arpe, H.-J. Industrial Organic Chemistry 4th edn (Wiley-VCH, 2003).

  2. Larock, R. C. Comprehensive Organic Transformations: A Guide to Functional Group Preparations 3rd edn, 1231−1467 (Wiley-VCH, 2018).

  3. Gribble, G. W. in Progress in the Chemistry of Organic Natural Products Vol. 91 (Springer, 2010).

  4. Hernandes, M. Z. et al. Halogen atoms in the modern medicinal chemistry: hints for the drug design. Curr. Drug Targets. 11, 303–314 (2010).

    Article  CAS  Google Scholar 

  5. Tang, M. L. & Bao, Z. Halogenated materials as organic semiconductors. Chem. Mater. 23, 446–455 (2011).

    Article  CAS  Google Scholar 

  6. Luh, T.-Y., Leung, M.-K. & Wong, K.-T. Transition metal-catalyzed activation of aliphatic C−X bonds in carbon−carbon bond formation. Chem. Rev. 100, 3187–3204 (2000).

    Article  CAS  Google Scholar 

  7. Petrone, D. A., Ye, J. T. & Lautens, M. Modern transition-metal catalyzed carbon–halogen bond formation. Chem. Rev. 116, 8003–8104 (2016).

    Article  CAS  Google Scholar 

  8. Varenikov, A., Shapiro, E. & Gandelman, M. Decarboxylative halogenation of organic compounds. Chem. Rev. 121, 412–484 (2021).

    Article  CAS  Google Scholar 

  9. Agarwal, V. et al. Enzymatic halogenation and dehalogenation reactions: pervasive and mechanistically diverse. Chem. Rev. 117, 5619–5674 (2017).

    Article  CAS  Google Scholar 

  10. El-Qisairi, A. K. & Henry, P. M. New palladium(II)-catalyzed asymmetric 1,2-dibromo synthesis. Org. Lett. 5, 439–441 (2003).

    Article  CAS  Google Scholar 

  11. Denmark, S. E. & Carson, N. Reinvestigation of a catalytic, enantioselective alkene dibromination and chlorohydroxylation. Org. Lett. 17, 5728–5731 (2015).

    Article  CAS  Google Scholar 

  12. Herron, A. N. & Yu, J.-Q. δ-C−H Mono- and dihalogenation of alcohols. J. Am. Chem. Soc. 142, 2766–2770 (2020).

    Article  CAS  Google Scholar 

  13. Zhu, Y. & Yu, W. Visible-light-driven remote C−H chlorination of aliphatic sulamides with sodium hypochlorite. Asian J. Org. Chem. 9, 1650–1654 (2020).

    Article  CAS  Google Scholar 

  14. Kharasch, M. S. & Kleiman, M. Synthesis of polyenes. III. A new synthesis of diethylstilbestrol. J. Am. Chem. Soc. 65, 11–15 (1943).

    Article  CAS  Google Scholar 

  15. Kharasch, M. S. & Mayo, F. R. The peroxide effect in the addition of reagents to unsaturated compounds. I. The addition of hydrogen bromide to allyl bromide. J. Am. Chem. Soc. 55, 2468–2496 (1933).

    Article  CAS  Google Scholar 

  16. Mayo, F. R. Free radical addition and transfer reactions of hydrogen chloride with unsaturated compounds. J. Am. Chem. Soc. 76, 5392–5396 (1954).

    Article  CAS  Google Scholar 

  17. Wilger, D. J., Grandjean, J. M., Lammert, T. R. & Nicewicz, D. A. The direct anti-Markovnikov addition of mineral acids to styrenes. Nat. Chem. 6, 720–726 (2014).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Sommer, H., Juliá-Hernández, F., Martin, R. & Marek, I. Walking metals for remote functionalization. ACS Cent. Sci. 4, 153–165 (2018).

    Article  CAS  Google Scholar 

  20. Bonfield, H. E., Valette, D., Lindsay, D. M. & Reid, M. Stereoselective remote functionalization via palladium-catalyzed redox-relay Heck methodologies. Chem. Eur. J. 27, 158–174 (2021).

    Article  CAS  Google Scholar 

  21. Wu, L., Fleischer, I. & Beller, M. Ruthenium-catalyzed hydroformylation/reduction of olefins to alcohols: extending the scope to internal alkenes. J. Am. Chem. Soc. 135, 14306–14312 (2013).

    Article  CAS  Google Scholar 

  22. Yuki, Y., Takahashi, K., Tanaka, Y. & Nozaki, K. Tandem isomerization/ hydroformylation/hydrogenation of internal alkenes to n-alcohols using Rh/Ru dual- or ternary-catalyst systems. J. Am. Chem. Soc. 135, 17393–17400 (2013).

    Article  CAS  Google Scholar 

  23. Zhang, L., Peng, D., Leng, X. & Huang, Z. Iron-catalyzed, atom economical, chemo- and regioselective alkene hydroboration with pinacolborane. Angew. Chem. Int. Ed. 52, 3676–3680 (2013).

    Article  CAS  Google Scholar 

  24. Sun, S.-Z., Borjesson, M., Martin-Montero, R. & Martin, R. Site-selective Ni-catalyzed reductive coupling of α-haloboranes with unactivated olefins. J. Am. Chem. Soc. 140, 12765–12769 (2018).

    Article  CAS  Google Scholar 

  25. Juliá-Hernández, F., Moragas, T., Cornella, J. & Martin, R. Remote carboxylation of halogenated aliphatic hydrocarbons with carbon dioxide. Nature 545, 84–88 (2017).

    Article  Google Scholar 

  26. Bhunia, A., Bergander, K. & Studer, A. Cooperative palladium/Lewis acid-catalyzed transfer hydrocyanation of alkenes and alkynes using 1-methylcyclohexa-2,5-diene-1-carbonitrile. J. Am. Chem. Soc. 140, 16353–16359 (2018).

    Article  CAS  Google Scholar 

  27. Werner, E. W., Mei, T.-S., Burckle, A. J. & Sigman, M. S. Enantioselective Heck arylations of acyclic alkenyl alcohols using a redox-relay strategy. Science 338, 1455–1458 (2012).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Ho, G.-M., Jiudkele, L., Bruffaerts, J. & Marek, I. Metal-catalyzed remote functionalization of ω-ene unsaturated ethers as a new entry to functionalized vinyl species. Angew. Chem. Int. Ed. 57, 8012–8016 (2018).

    Article  CAS  Google Scholar 

  30. Sehnal, P., Taylor, R. J. K. & Fairlamb, I. J. S. Emergence of palladium(IV) chemistry in synthesis and catalysis. Chem. Rev. 110, 824–889 (2010).

    Article  CAS  Google Scholar 

  31. Hickman, A. J. & Sanford, M. S. High-valent organometallic copper and palladium in catalysis. Nature 484, 177–185 (2012).

    Article  CAS  Google Scholar 

  32. Yin, G., Mu, X. & Liu, G. Palladium-catalyzed oxidative difunctonalization of alkenes: bond forming at a high-valent palladium center. Acc. Chem. Res. 49, 2413–2423 (2016).

    Article  CAS  Google Scholar 

  33. Qi, X. et al. Enantioselective Pd(II)-catalyzed intramolecular oxidative 6-endo-amino-acetoxylation of unactivated alkenes. J. Am. Chem. Soc. 140, 7415–7419 (2018).

    Article  CAS  Google Scholar 

  34. Tian, B., Chen, P., Leng, X. & Liu, G. Palladium-catalyzed enantioselective diactoxylation of terminal alkenes. Nat. Catal. 4, 172–179 (2021).

    Article  CAS  Google Scholar 

  35. Garces, K. et al. Iridium-catalyzed hydrogen production from hydrosilanes and water. ChemCatChem 6, 1691–1697 (2014).

    Article  CAS  Google Scholar 

  36. Pendleton, I. M., Pérez-Temprano, M. H., Sanford, M. S. & Zimmerman, P. M. Experimental and computational assessment of reactivity and mechanism in C(sp3)−N bond-forming reductive elimination from palladium(iv). J. Am. Chem. Soc. 138, 6049–6060 (2016).

    Article  CAS  Google Scholar 

  37. Cai, Y. F. et al. Highly enantioselective α-chlorination of cyclic β-ketoesters catalyzed by N,N-dioxide using NCS as the chlorine source. Chem. Commun. 46, 1250–1252 (2010).

    Article  CAS  Google Scholar 

  38. Saikia, I., Borah, A. J. & Phukan, P. Use of bromine and bromo-organic compounds in organic synthesis. Chem. Rev. 116, 6837–7042 (2016).

    Article  CAS  Google Scholar 

  39. 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 

  40. Wang, W. et al. Migratory arylboration of unactivated alkenes enabled by nickel catalysis. Angew. Chem. Int. Ed. 58, 4612–4616 (2019).

    Article  CAS  Google Scholar 

  41. Liu, F. & Goldman, A. S. Efficient thermochemical alkane dehydrogenation and isomerization catalyzed by an iridium pincer complex. Chem. Commun. 655−656 (1999).

Download references

Acknowledgements

Financial Support was provided by the National Key R&D Program of China (No. 2021YFA1500100), the National Natural Science Foundation of China (numbers 91956202, 21971255, 21790330 and 21821002), the Science and Technology Commission of Shanghai Municipality (numbers 20JC1417000, 21520780100 and 19590750400), the International Partnership Program (number 121731KYSB20190016), and the Key Research Program of Frontier Science (number QYZDJSSW-SLH055) of the Chinese Academy of Sciences. P.C. also thanks the Youth Innovation Promotion Association of the Chinese Academy of Sciences (number 2018292).

Author information

Author notes

  1. These authors contributed equally: Xiang Li, Jianbo Jin.

Authors and Affiliations

  1. State Key Laboratory of Organometallic Chemistry and Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Xiang Li, Jianbo Jin, Pinhong Chen & Guosheng Liu

  2. Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, China

    Xiang Li & Guosheng Liu

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Contributions

X.L., J.J. and G.L. conceived the work and designed the experiments. X.L. and J.J. performed the laboratory experiments. X.L., P.C. and G.L. analysed the data and wrote the manuscript.

Corresponding author

Correspondence to Guosheng Liu.

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Extended data

Extended Data Fig. 1 The function of NEt3.

a. The side reactions when L9 was employed in the reaction. b. The possible mechanism for the side product formation. The oxygenation and amination product were formed via reductive elimination from PdIV. c. NEt3 acted as a liable ligand to accelerate the dissociation chloride from Pd IV intermediate, which was helpful for the formation of C–Cl bond.

Supplementary information

Supplementary Information

Supplementary Tables 1–8, Figs. 1–6, methods, mechanism experiments, data and references.

Supplementary Data 1

Crystallographic data for compound (L6)2PdCl2. CCDC reference 2026793.

Supplementary Data 2

Crystallographic data for compound (L6)PdCl2. CCDC reference 2026831.

Supplementary Data 3

Crystallographic data for compound (L9)PdCl2. CCDC reference 2076726.

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Li, X., Jin, J., Chen, P. et al. Catalytic remote hydrohalogenation of internal alkenes. Nat. Chem. 14, 425–432 (2022). https://doi.org/10.1038/s41557-021-00869-x

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