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Multi-site programmable functionalization of alkenes via controllable alkene isomerization

Nature Chemistry (2023)Cite this article

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Abstract

Direct and selective functionalization of hydrocarbon chains is a fundamental problem in synthetic chemistry. Conventional functionalization of C=C double bonds and C(sp3)–H bonds provides some solutions, but site diversity remains an issue. The merging of alkene isomerization with (oxidative) functionalization provides an ideal method for remote functionalization, which would provide more opportunities for site diversity. However, the reported functionalized sites are still limited and focus on a specific terminal position and internal site; new site-selective functionalization, including multi-functionalization, remains a largely unmet challenge. Here we describe a palladium-catalysed aerobic oxidative method for the multi-site programmable functionalization, involving the C=C double bond and multiple C(sp3)–H bonds, of terminal olefins via a strategy that controls the reaction sequence between alkene isomerization and oxidative functionalization. Specifically, 1-acetoxylation (anti-Markovnikov), 2-acetoxylation, 1,2-diacetoxylation and 1,2,3-triacetoxylation have been realized, accompanied by controllable remote alkenylation. This method enables available terminal olefins from petrochemical feedstocks to be readily converted into unsaturated alcohols and polyalcohols and particularly into different monosaccharides and C-glycosides.

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Fig. 1: Remote functionalization of alkenes.
Fig. 2: Regioconvergent aerobic 2-hydroxylation and transformations of products.
Fig. 3: Mechanistic studies and proposed catalytic cycles.

Data availability

The data supporting the findings of this study are available within the Article and its Supplementary Information.

References

  1. McDonald, R. I., Liu, G. & Stahl, S. S. Palladium(II)-catalyzed alkene functionalization via nucleopalladation: stereochemical pathways and enantioselective catalytic applications. Chem. Rev. 111, 2981–3019 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mann, S. E., Benhamou, L. & Sheppard, T. D. Palladium(II)-catalysed oxidation of alkenes. Synthesis 47, 3079–3117 (2015).

    Article  CAS  Google Scholar 

  3. Hemric, B. M. Beyond osmium: progress in 1,2-amino oxygenation of alkenes, 1,3-dienes, alkynes, and allenes. Org. Biomol. Chem. 19, 46–81 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. He, J., Wasa, M., Chan, K. S. L., Shao, Q. & Yu, J.-Q. Palladium-catalyzed transformations of alkyl C–H bonds. Chem. Rev. 117, 8754–8786 (2017).

    Article  CAS  PubMed  Google Scholar 

  5. Voica, A.-F., Mendoza, A., Gutekunst, W. R., Fraga, J. O. & Baran, P. S. Guided desaturation of unactivated aliphatics. Nat. Chem. 4, 629–635 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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  PubMed  PubMed Central  Google Scholar 

  7. 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  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chan, H. S. S., Yang, J.-M. & Yu, J.-Q. Catalyst-controlled site-selective methylene C–H lactonization of dicarboxylic acids. Science 376, 1481–1487 (2022).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Janssen-Müller, D., Sahoo, B., Sun, S.-Z. & Martin, R. Tackling remote sp3 C–H functionalization via Ni-catalyzed ‘chain-walking’ reactions. Isr. J. Chem. 60, 195–206 (2020).

    Article  Google Scholar 

  11. Dhungana, R. K., Sapkota, R. R., Niroula, D. & Giri, R. Walking metals: catalytic difunctionalization of alkenes at nonclassical sites. Chem. Sci. 11, 9757–9774 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li, Y., Wu, D., Cheng, H.-G. & Yin, G. Difunctionalization of alkenes involving metal migration. Angew. Chem. Int. Ed. 59, 7990–8003 (2020).

    Article  CAS  Google Scholar 

  13. Fiorito, D., Scaringi, S. & Mazet, C. Transition metal-catalyzed alkene isomerization as an enabling technology in tandem, sequential and domino processes. Chem. Soc. Rev. 50, 1391–1406 (2021).

    Article  CAS  PubMed  Google Scholar 

  14. 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  PubMed  Google Scholar 

  15. Massad, I., Suresh, R., Segura, L. & Marek, I. Stereoselective synthesis through remote functionalization. Nat. Synth. 1, 37–48 (2022).

    Article  Google Scholar 

  16. Seayad, A. et al. Internal olefins to linear amines. Science 297, 1676–1678 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Obligacion, J. V. & Chirik, P. J. Bis(imino)pyridine cobalt-catalyzed alkene isomerization-hydroboration: a strategy for remote hydrofunctionalization with terminal selectivity. J. Am. Chem. Soc. 135, 19107–19110 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Atienza, C. C. H. et al. Bis(imino)pyridine cobalt-catalyzed dehydrogenative silylation of alkenes: scope, mechanism, and origins of selective allylsilane formation. J. Am. Chem. Soc. 136, 12108–12118 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Buslov, I., Becouse, J., Mazza, S., Montandon-Clerc, M. & Hu, X. L. Chemoselective alkene hydrosilylation catalyzed by nickel pincer complexes. Angew. Chem. Int. Ed. 54, 14523–14526 (2015).

    Article  CAS  Google Scholar 

  20. Jia, X. & Huang, Z. Conversion of alkanes to linear alkylsilanes using an iridium–iron-catalysed tandem dehydrogenation–isomerization–hydrosilylation. Nat. Chem. 8, 157–161 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. 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 

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

    Article  PubMed  Google Scholar 

  23. Yang, J. et al. Direct synthesis of adipic acid esters via palladium-catalyzed carbonylation of 1,3-dienes. Science 366, 1514–1517 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Li, X., Jin, J., Chen, P. & Liu, G. Catalytic remote hydrohalogenation of internal alkenes. Nat. Chem. 14, 425–432 (2022).

    Article  CAS  PubMed  Google Scholar 

  25. Masarwa, A. et al. Merging allylic carbon–hydrogen and selective carbon–carbon bond activation. Nature 505, 199–203 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Hamasaki, T., Aoyama, Y., Kawasaki, J., Kakiuchi, F. & Kochi, T. Chain walking as a strategy for carbon–carbon bond formation at unreactive sites in organic synthesis: catalytic cycloisomerization of various 1,n-dienes. J. Am. Chem. Soc. 137, 16163–16171 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. 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  PubMed  Google Scholar 

  28. Kundu, G., Opincal, F., Sperger, T. & Schoenebeck, F. Air-stable PdI dimer enabled remote functionalization: access to fluorinated 1,1-diaryl alkanes with unprecedented speed. Angew. Chem. Int. Ed. 61, e202113667 (2022).

    Article  CAS  Google Scholar 

  29. Xiao, J., He, Y., Ye, F. & Zhu, S. Remote sp3 C–H amination of alkenes with nitroarenes. Chem 4, 1645–1657 (2018).

    Article  CAS  Google Scholar 

  30. Yu, X. et al. Site-selective alkene borylation enabled by synergistic hydrometallation and borometallation. Nat. Catal. 3, 585–592 (2020).

    Article  CAS  Google Scholar 

  31. Lee, C., Seo, H., Jeon, J. & Hong, S. γ-Selective C(sp3)–H amination via controlled migratory hydroamination. Nat. Commun. 12, 5657–5665 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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, 14200–14209 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kohler, D. G., Gockel, S. N., Kennemur, J. L., Waller, P. J. & Hull, K. L. Palladium-catalysed anti-Markovnikov selective oxidative amination. Nat. Chem. 10, 333–340 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kou, X., Shao, Q., Ye, C., Yang, G. & Zhang, W. Asymmetric aza-Wacker-type cyclization of N-Ts hydrazine-tethered tetrasubstituted olefins: synthesis of pyrazolines bearing one quaternary or two vicinal stereocenters. J. Am. Chem. Soc. 140, 7587–7597 (2018).

    Article  CAS  PubMed  Google Scholar 

  37. Liu, J., Yuan, Q., Toste, F. D. & Sigman, M. S. Enantioselective construction of remote tertiary carbon–fluorine bonds. Nat. Chem. 11, 710–715 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Han, C. et al. Palladium-catalyzed remote 1,n-arylamination of unactivated terminal alkenes. ACS Catal. 9, 4196–4202 (2019).

    Article  CAS  Google Scholar 

  39. 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 

  40. Larionov, E., Li, H. & Mazet, C. Well-defined transition metal hydrides in catalytic isomerizations. Chem. Commun. 50, 9816–9826 (2014).

    Article  CAS  Google Scholar 

  41. Frech, C. M., Leitus, G. & Milstein, D. Processes involved in the reduction of a cyclometalated palladium(II) complex. Organometallics 27, 894–899 (2008).

    Article  CAS  Google Scholar 

  42. Henriksen, S. T., Tanner, D., Cacchi, S. & Norrby, P.-O. DFT-based explanation of the effect of simple anionic ligands on the regioselectivity of the Heck arylation of acrolein acetals. Organometallics 28, 6201–6205 (2009).

    Article  CAS  Google Scholar 

  43. Ambrogio, I. et al. Unusual selectivity-determining factors in the phosphine-free Heck arylation of allyl ethers. Organometallics 27, 3187–3195 (2008).

    Article  CAS  Google Scholar 

  44. Sato, S., Sato, F., Gotoh, H. & Yamada, Y. Selective dehydration of alkanediols into unsaturated alcohols over rare earth oxide catalysts. ACS Catal. 3, 721–734 (2013).

    Article  CAS  Google Scholar 

  45. Osborn, H. M. I. (ed.) Best Synthetic Methods: Carbohydrates (Elsevier Science Ltd, 2003).

  46. Frihed, T. G., Bols, M. & Pedersen, C. M. Synthesis of l-hexoses. Chem. Rev. 115, 3615–3676 (2015).

    Article  CAS  PubMed  Google Scholar 

  47. Wong, C.-H. (ed.) Carbohydrate-Based Drug Discovery (Wiley-VCH Verlag GmbH & Co. KGaA, 2003).

  48. Stoltz, B. M. Palladium catalyzed aerobic dehydrogenation: from alcohols to indoles and asymmetric catalysis. Chem. Lett. 33, 362–367 (2004).

    Article  CAS  Google Scholar 

  49. Muzart, J. Progress in the synthesis of aldehydes from Pd-catalyzed Wacker-type reactions of terminal olefins. Tetrahedron 87, 132024 (2021).

    Article  CAS  Google Scholar 

  50. Keith, J. A. & Henry, P. M. The mechanism of the Wacker reaction: a tale of two hydroxypalladations. Angew. Chem. Int. Ed. 48, 9038–9049 (2009).

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful for financial support provided by the National Natural Science Foundation of China (Nos 21620102003, 21831005 and 21991112 to W.Z.), the National Key R&D Program of China (No. 2018YFE0126800 to W.Z.) and the Shanghai Municipal Education Commission (No. 201701070002E00030 to W.Z.). We thank the Instrumental Analysis Center of SJTU for characterization experiments. We are grateful to Q. Ge and C. Xu for their contribution concerning the purification of compounds.

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Authors and Affiliations

  1. Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, China

    Zhengxing Wu, Jingjie Meng, Huikang Liu, Yunyi Li, Xiao Zhang & Wanbin Zhang

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  1. Zhengxing Wu
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Contributions

W.Z. and Z.W. conceived the work and designed the experiments. Z.W. performed the experiments and analysed the data. J.M., Y.L., H.L. and X.Z. performed the experiments. W.Z. and Z.W. wrote the paper. W.Z. guided the project. All the authors checked the paper.

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Correspondence to Wanbin Zhang.

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Supplementary Information

Supplementary Figs. 1–28, Tables 1–6, synthesis and characterization data, supplementary discussion, computational and procedural details, NMR spectra and references.

Supplementary Data 1

Cartesian coordinates (x,y,z) and coupling constants.

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Wu, Z., Meng, J., Liu, H. et al. Multi-site programmable functionalization of alkenes via controllable alkene isomerization. Nat. Chem. (2023). https://doi.org/10.1038/s41557-023-01209-x

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