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Diverse sp3 C−H functionalization through alcohol β-sulfonyloxylation

Nature Chemistry volume 7, pages 829–834 (2015)Cite this article

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Abstract

Site-selective C−H functionalization has emerged as an attractive tool for derivatizing complex synthetic intermediates, but its use for late-stage diversification is limited by the functional groups that can be introduced, especially at unactivated sp3-hybridized positions. To overcome this, we introduce a strategy that directly installs a sulfonyloxy group at a β-C−H bond of a masked alcohol and subsequently employs nucleophilic substitution reactions to prepare various derivatives. Hydroxyl groups are widely found in bioactive molecules and are thus readily available as synthetic handles. A directing group is easily added (and subsequently removed) from the alcohols such that a formal site-selective β-C−H sulfonyloxylation of these alcohols is achieved. Substitution reactions with carbon, nitrogen, oxygen and other nucleophiles then lead to diverse functionalizations that may help to streamline the synthesis of complex analogues for drug discovery.

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Figure 1: A LG-based strategy for late-stage diversification using C−H activation.
Figure 2: Cleavage of the DG.
Figure 3: Late-stage diversification via an LG-based strategy.

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Change history

  • 09 September 2015

    In the original graphical abstract for this Article, an in-house error meant that the product structures were incorrect. This has now been corrected in all versions of the article.

References

  1. Thompson, L. A. & Ellman, J. A. Synthesis and applications of small molecule libraries. Chem. Rev. 96, 555–600 (1996).

    CAS  PubMed  Google Scholar 

  2. Bryan, M. C. et al. Sustainable practices in medicinal chemistry: current state and future directions. J. Med. Chem. 56, 6007–6021 (2013).

    CAS  PubMed  Google Scholar 

  3. Nicolaou, K. C. The chemistry–biology–medicine continuum and the drug discovery and development process in academia. Chem. Biol. 21, 1039–1045 (2014).

    CAS  PubMed  Google Scholar 

  4. Wencel-Delord, J. & Glorius, F. C–H bond activation enables the rapid construction and late-stage diversification of functional molecules. Nature Chem. 5, 369–375 (2013).

    CAS  Google Scholar 

  5. Dai, H.-X., Stepan, A. F., Plummer, M. S., Zhang, Y.-H. & Yu, J.-Q. Divergent C–H functionalizations directed by sulfonamide pharmacophores: late-stage diversification as a tool for drug discovery. J. Am. Chem. Soc. 133, 7222–7228 (2011).

    CAS  PubMed  Google Scholar 

  6. Rosen, B. R. et al. C–H functionalization logic enables synthesis of (+)-hongoquercin A and related compounds. Angew. Chem. Int. Ed. 52, 7317–7320 (2013).

    CAS  Google Scholar 

  7. He, G. & Chen, G. A practical strategy for the structural diversification of aliphatic scaffolds through the palladium-catalyzed picolinamide-directed remote functionalization of unactivated C(sp3)–H bonds. Angew. Chem. Int. Ed. 50, 5192–5196 (2011).

    CAS  Google Scholar 

  8. Newhouse, T. & Baran, P. S. If C–H bonds could talk: selective C–H bond oxidation. Angew. Chem. Int. Ed. 50, 3362–3374 (2011).

    CAS  Google Scholar 

  9. Davies, H. M. L. & Manning, J. R. Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion. Nature 451, 417–424 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Daugulis, O., Do, H.-Q. & Shabashov, D. Palladium- and copper-catalyzed arylation of carbon–hydrogen bonds. Acc. Chem. Res. 42, 1074–1086 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Davies, H. M. L., Du Bois, J. & Yu, J.-Q. C−H functionalization in organic synthesis. Chem. Soc. Rev. 40, 1855–1856 (2011).

    CAS  PubMed  Google Scholar 

  12. Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C–H functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Colby, D. A., Bergman, R. G. & Ellman, J. A. Rhodium-catalyzed C–C bond formation via heteroatom-directed C–H bond activation. Chem. Rev. 110, 624–655 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Yu, J.-Q. & Shi, Z.-J. C–H Activation (Topics in Current Chemistry 292, Springer, 2010).

    Google Scholar 

  15. Yamaguchi, J., Yamaguchi, A. D. & Itami, K. C–H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals. Angew. Chem. Int. Ed. 51, 8960–9009 (2012).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  17. Li, H., Li, B.-J. & Shi, Z.-J. Challenge and progress: palladium-catalyzed sp3 C–H activation. Catal. Sci. Technol. 1, 191–206 (2011).

    Google Scholar 

  18. Hartwig, J. F. Borylation and silylation of C–H bonds: a platform for diverse C–H bond functionalizations. Acc. Chem. Res. 45, 864–873 (2012).

    CAS  PubMed  Google Scholar 

  19. Robbins, D. W. & Hartwig, J. F. Sterically controlled alkylation of arenes through iridium-catalyzed C–H borylation. Angew. Chem. Int. Ed. 52, 933–937 (2013).

    CAS  Google Scholar 

  20. Larsen, M. A. & Hartwig, J. F. Iridium-catalyzed C−H borylation of heteroarenes: scope, regioselectivity, application to late-stage functionalization, and mechanism. J. Am. Chem. Soc. 136, 4287–4299 (2014).

    CAS  PubMed  Google Scholar 

  21. Cho, J.-Y., Tse, M. K., Holmes, D., Maleczka, R. E. & Smith, M. R. Remarkably selective iridium catalysts for the elaboration of aromatic C−H bonds. Science 295, 305–308 (2002).

    CAS  PubMed  Google Scholar 

  22. Ishiyama, T. et al. Mild iridium-catalyzed borylation of arenes. High turnover numbers, room temperature reactions, and isolation of a potential intermediate. J. Am. Chem. Soc. 124, 390–391 (2002).

    CAS  PubMed  Google Scholar 

  23. Ishiyama, T., Sato, K., Nishio, Y. & Miyaura, N. Direct synthesis of aryl halosilanes through iridium(I)-catalyzed aromatic C–H silylation by disilanes. Angew. Chem. Int. Ed. 42, 5346–5348 (2003).

    CAS  Google Scholar 

  24. Cheng, C. & Hartwig, J. F. Rhodium-catalyzed intermolecular C–H silylation of arenes with high steric regiocontrol. Science 343, 853–857 (2014). .

    CAS  PubMed  Google Scholar 

  25. Fier, P. S. & Hartwig, J. F. Selective C–H fluorination of pyridines and diazines inspired by a classic amination reaction. Science 342, 956–960 (2013).

    CAS  PubMed  Google Scholar 

  26. Mkhalid, I. A. I., Barnard, J. H., Marder, T. B., Murphy, J. M. & Hartwig, J. F. C–H activation for the construction of C–B bonds. Chem. Rev. 110, 890–931 (2010).

    CAS  PubMed  Google Scholar 

  27. Liskey, C. W. & Hartwig, J. F. Iridium-catalyzed borylation of secondary C–H bonds in cyclic ethers. J. Am. Chem. Soc. 134, 12422–12425 (2012).

    CAS  PubMed  Google Scholar 

  28. Li, Q., Liskey, C. W. & Hartwig, J. F. Regioselective borylation of the C–H bonds in alkylamines and alkyl ethers. Observation and origin of high reactivity of primary C–H bonds beta to nitrogen and oxygen. J. Am. Chem. Soc. 136, 8755–8765 (2014).

    CAS  PubMed  Google Scholar 

  29. Simmons, E. M. & Hartwig, J. F. Catalytic functionalization of unactivated primary C–H bonds directed by an alcohol. Nature 483, 70–73 (2012).

    CAS  PubMed  Google Scholar 

  30. Kawamorita, S., Murakami, R., Iwai, T. & Sawamura, M. Synthesis of primary and secondary alkylboronates through site-selective C(sp3)–H activation with silica-supported monophosphine–Ir catalysts. J. Am. Chem. Soc. 135, 2947–2950 (2013).

    CAS  PubMed  Google Scholar 

  31. Zhang, L.-S. et al. Direct borylation of primary C–H bonds in functionalized molecules by palladium catalysis. Angew. Chem. Int. Ed. 53, 3899–3903 (2014).

    CAS  Google Scholar 

  32. Jana, R., Pathak, T. P. & Sigman, M. S. Advances in transition metal (Pd, Ni, Fe)-catalyzed cross-coupling reactions using alkyl-organometallics as reaction partners. Chem. Rev. 111, 1417–1492 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Smith, M. B. & March, J. March’s Advanced Organic Chemistry (Wiley, 2001).

    Google Scholar 

  34. Liu, W. & Groves, J. T. Manganese porphyrins catalyze selective C–H bond halogenations. J. Am. Chem. Soc. 132, 12847–12849 (2010).

    CAS  PubMed  Google Scholar 

  35. Schmidt, V. A., Quinn, R. K., Brusoe, A. T. & Alexanian, E. J. Site-selective aliphatic C–H bromination using N-bromoamides and visible light. J. Am. Chem. Soc. 136, 14389–14392 (2014).

    CAS  PubMed  Google Scholar 

  36. Giri, R., Chen, X. & Yu, J.-Q. Palladium-catalyzed asymmetric iodination of unactivated C–H bonds under mild conditions. Angew. Chem. Int. Ed. 44, 2112–2115 (2005).

    CAS  Google Scholar 

  37. Giri, R. et al. Catalytic and stereoselective iodination of prochiral C–H bonds. Tetrahedron: Asymmetry 16, 3502–3505 (2005).

    CAS  Google Scholar 

  38. Wasa, M. & Yu, J.-Q. Synthesis of β-, γ-, and δ-lactams via Pd(II)-catalyzed C–H activation reactions. J. Am. Chem. Soc. 130, 14058–14059 (2008).

    CAS  PubMed  Google Scholar 

  39. Rit, R. K., Yadav, M. R., Ghosh, K., Shankar, M. & Sahoo, A. K. Sulfoximine assisted Pd(II)-catalyzed bromination and chlorination of primary β-C(sp3)–H bond. Org. Lett. 16, 5258–5261 (2014).

    CAS  PubMed  Google Scholar 

  40. Mo, F. & Dong, G. Alcohols or masked alcohols as directing groups for C–H bond functionalization. Chem. Lett. 43, 264–271 (2014).

    CAS  Google Scholar 

  41. Camasso, N. M., Pérez-Temprano, M. H. & Sanford, M. S. C(sp3)–O bond-forming reductive elimination from PdIV with diverse oxygen nucleophiles. J. Am. Chem. Soc. 136, 12771–12775 (2014).

    CAS  PubMed  Google Scholar 

  42. Powers, D. C. et al. Connecting binuclear Pd(III) and mononuclear Pd(IV) chemistry by Pd–Pd bond cleavage. J. Am. Chem. Soc. 134, 12002–12009 (2012).

    CAS  PubMed  Google Scholar 

  43. Ren, Z., Mo, F. & Dong, G. Catalytic functionalization of unactivated sp3 C–H bonds via exo-directing groups: synthesis of chemically differentiated 1,2-diols. J. Am. Chem. Soc. 134, 16991–16994 (2012).

    CAS  PubMed  Google Scholar 

  44. Desai, L. V., Hull, K. L. & Sanford, M. S. Palladium-catalyzed oxygenation of unactivated sp3 C–H bonds. J. Am. Chem. Soc. 126, 9542–9543 (2004).

    CAS  PubMed  Google Scholar 

  45. Choong, I. C. & Ellman, J. A. Synthesis of alkoxylamines by alkoxide amination with 3,3′-di-tert-butyloxaziridine. J. Org. Chem. 64, 6528–6529 (1999).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the Cancer Prevention Research Institute of Texas for a start-up fund (R1118), the Welch Foundation (F-1781), Frasch Foundation and an American Chemical Society Petroleum Research Fund for research grants. G.D. is a Searle Scholar. V. Lynch is acknowledged for X-ray crystallography. We thank W. Pan for preparing substrates and M. Young for proofreading the manuscript. We also thank Johnson Matthey for a generous donation of palladium salts.

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Authors and Affiliations

  1. Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, USA

    Yan Xu, Guobing Yan, Zhi Ren & Guangbin Dong

  2. Department of Chemistry, Lishui University, Lishui City, 323000, People's Republic of China

    Guobing Yan

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  1. Yan Xu
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Contributions

Y.X. and G.Y. contributed equally to this work. Y.X., G.Y. and G.D. conceived and designed the experiments. Y.X., G.Y. and Z.R. performed the experiments. Y.X., G.Y. and Z.R. analysed the data. Y.X. and G.D. co-wrote the manuscript.

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Correspondence to Guangbin Dong.

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The authors declare no competing financial interests.

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Crystallographic data for compound 3c. (CIF 437 kb)

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Crystallographic data for compound 6. (CIF 2020 kb)

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Xu, Y., Yan, G., Ren, Z. et al. Diverse sp3 C−H functionalization through alcohol β-sulfonyloxylation. Nature Chem 7, 829–834 (2015). https://doi.org/10.1038/nchem.2326

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