Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Kinetic resolution of planar chiral metallocenes using Rh-catalysed enantioselective C–H arylation

Nature Synthesis volume 2, pages 49–57 (2023)Cite this article

Subjects

Abstract

Planar chiral metallocenes have found application in the fields of asymmetric catalysis, medicinal chemistry and materials science. Asymmetric C–H functionalisation provides an efficient synthetic route to substituted chiral metallocenes. However, these methods are often limited by the metallocene substitution patterns they can access. Here, we report a Rh-catalysed asymmetric C–H arylation of 1,2-disubstituted and 1,3-disubstituted pyridyl ferrocenes. Pre-installation of substituents at either the 2- or 3-position of the pyridyl ferrocenes enables this kinetic resolution process to provide access to enantio-enriched 1,2-disubstituted and 1,3-disubstituted metallocenes, and their corresponding C–H arylated products, in excellent enantioselectivity, with selectivity factor values up to 618. This process is able to tolerate a broad range of pre-installed functional groups, such as alkyl, alkenyl, aryl, silyl, thio and fluoro, as well as substitution on the 1′-cyclopentadienyl ring. The utility of the process has been shown through synthesis and examination of chiral ferrocene ligands.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The methods for synthesizing planar chiral metallocenes.
Fig. 2: Reaction scale-up, product synthetic utility and reaction monitoring.

Similar content being viewed by others

Data availability

All data relating to the experimental procedures, optimisation studies and characterisation of the new compounds are included in the Supplementary Information. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2119566 (7ca). Copies of the CCDC data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  1. Lippert, B. Bioorganometallics. Biomolecules, Labeling, Medicine (Wiley-VCH, 2006).

  2. Štěpnička, P. Ferrocenes (Wiley, 2008).

  3. Dai, L.-X. & Hou, X.-L. Chiral Ferrocenes in Asymmetric Catalysis (Wiley-VCH, 2010).

  4. Togni, A. Planar‐chiral ferrocenes: synthetic methods and applications. Angew. Chem. Int. Ed. Engl. 35, 1475–1477 (1996).

    Article  CAS  Google Scholar 

  5. Fu, G. C. Applications of planar-chiral heterocycles as ligands in asymmetric catalysis. Acc. Chem. Res. 39, 853–860 (2006).

    Article  CAS  Google Scholar 

  6. Battelle, L. F. et al. Absolute configuration of a 1,2-disubstituted ferrocene derivative with planar and central elements of chirality and the mechanism of the stereoselective metalations of optically active α-ferrocenyl tertiary amines. J. Am. Chem. Soc. 95, 482–486 (1973).

    Article  CAS  Google Scholar 

  7. Nomura, H. & Richards, C. J. Allylic imidate rearrangements catalyzed by planar chiral palladacycles. Chem. Asian J. 5, 1726–1740 (2010).

    Article  CAS  Google Scholar 

  8. Tsukazaki, M. et al. Direct and highly enantioselective synthesis of ferrocenes with planar chirality by (−)-sparteine-mediated lithiation. J. Am. Chem. Soc. 118, 685–686 (1996).

    Article  CAS  Google Scholar 

  9. Dendele, N. et al. Synthesis of a [2.2]paracyclophane based planar chiral palladacycle by a highly selective kinetic resolution/C–H activation reaction. Chem. Commun. 48, 1991–1993 (2012).

    Article  CAS  Google Scholar 

  10. Saint-Denis, T. G. et al. Enantioselective C(sp3)-H bond activation by chiral transition metal catalysts. Science 359, eaao4798 (2018).

    Article  Google Scholar 

  11. Newton, C. G., Wang, S.-G., Oliveira, C. C. & Cramer, N. Catalytic enantioselective transformations involving C-H bond cleavage by transition-metal complexes. Chem. Rev. 117, 8908–8976 (2017).

    Article  CAS  Google Scholar 

  12. Liu, C.-X. et al. Synthesis of atropisomers by transition-metal-catalyzed asymmetric C–H functionalization reactions. J. Am. Chem. Soc. 143, 14025–14040 (2021).

    Article  CAS  Google Scholar 

  13. Arae, S. & Ogasawara, M. Catalytic asymmetric synthesis of planar-chiral transition-metal complexes. Tetrahedron Lett. 56, 1751–1761 (2015).

    Article  CAS  Google Scholar 

  14. Gao, D.-W., Gu, Q., Zheng, C. & You, S.-L. Synthesis of planar chiral ferrocenes via transition-metal-catalyzed direct C–H bond functionalization. Acc. Chem. Res. 50, 351–365 (2017).

    Article  CAS  Google Scholar 

  15. Liu, C.-X., Gu, Q. & You, S.-L. Asymmetric C–H bond functionalization of ferrocenes: new opportunities and challenges. Trends Chem. 2, 737–749 (2020).

    Article  CAS  Google Scholar 

  16. Gao, D.-W. et al. Enantioselective synthesis of planar chiral ferrocenes via palladium-catalyzed direct coupling with arylboronic acids. J. Am. Chem. Soc. 135, 86–89 (2013).

    Article  CAS  Google Scholar 

  17. Liu, L. et al. Asymmetric synthesis of planar chiral ferrocenes by enantioselective intramolecular C-H arylation of N-(2-haloaryl)ferrocenecarboxamides. Org. Lett. 16, 5336–5338 (2014).

    Article  CAS  Google Scholar 

  18. Deng, R. et al. Palladium-catalyzed intramolecular asymmetric C–H functionalization/cyclization reaction of metallocenes: an efficient approach toward the synthesis of planar chiral metallocene compounds. J. Am. Chem. Soc. 136, 4472–4475 (2014).

    Article  CAS  Google Scholar 

  19. Schmiel, D. & Butenschön, H. Directed iron-catalyzed ortho-alkylation and arylation: toward the stereoselective catalytic synthesis of 1,2-disubstituted planar-chiral ferrocene derivatives. Organometallics 36, 4979–4989 (2017).

    Article  CAS  Google Scholar 

  20. Xu, J. et al. Palladium-catalyzed enantioselective C(sp2)–H arylation of ferrocenyl ketones enabled by a chiral transient directing group. Chem. Commun. 54, 689–692 (2018).

    Article  CAS  Google Scholar 

  21. Luo, S., Xiong, Z., Lu, Y. & Zhu, Q. Enantioselective synthesis of planar chiral pyridoferrocenes via palladium-catalyzed imidoylative cyclization reactions. Org. Lett. 20, 1837–1840 (2018).

    Article  CAS  Google Scholar 

  22. Xu, B.-B., Ye, J., Yuan, Y. & Duan, W.-L. Palladium-catalyzed asymmetric C–H arylation for the synthesis of planar chiral benzothiophene-fused ferrocenes. ACS Catal. 8, 11735–11740 (2018).

    Article  CAS  Google Scholar 

  23. Liu, C.-X. et al. Rhodium-catalyzed pyridine-assisted C–H arylation for the synthesis of planar chiral ferrocenes. CCS Chem. 2, 642–651 (2020).

    Article  CAS  Google Scholar 

  24. Liu, C.-X. et al. Pd-catalyzed asymmetric oxidative C-H/C-H cross-coupling reaction between dialkylaminomethylferrocenes and indolizines. Chem Catal. 2, 102–113 (2022).

    Article  Google Scholar 

  25. Pi, C. et al. Redox of ferrocene controlled asymmetric dehydrogenative Heck reaction via palladium-catalyzed dual C–H bond activation. Chem. Sci. 4, 2675–2679 (2013).

    Article  CAS  Google Scholar 

  26. Gair, J. J. et al. Di-palladium complexes are active catalysts for mono-N-protected amino acid-accelerated enantioselective C–H functionalization. ACS Catal. 9, 11386–11397 (2019).

    Article  CAS  Google Scholar 

  27. Chen, H., Wang, Y.-X., Luan, Y.-X. & Ye, M. Enantioselective twofold C−H annulation of formamides and alkynes without built-in chelating groups. Angew. Chem. Int. Ed. Engl. 59, 9428–9432 (2020).

    Article  CAS  Google Scholar 

  28. Jia, L. et al. Synthesis of planar chiral ferrocenes via a Pd(0)-catalyzed syn-carbopalladation/asymmetric C–H alkenylation process. Chem. Commun. 56, 1737–1740 (2020).

    Article  CAS  Google Scholar 

  29. Lou, S. et al. Enantioselective C–H alkenylation of ferrocenes with alkynes by half-sandwich scandium catalyst. J. Am. Chem. Soc. 143, 2470–2476 (2021).

    Article  CAS  Google Scholar 

  30. Zhang, P.-C. et al. Simultaneous construction of axial and planar chirality by gold/TY-Phos-catalyzed asymmetric hydroarylation. Nat. Commun. 12, 4609 (2021).

    Article  CAS  Google Scholar 

  31. Shibata, T. & Shizuno, T. Iridium-catalyzed enantioselective C-H alkylation of ferrocenes with alkenes using chiral diene ligands. Angew. Chem. Int. Ed. Engl. 53, 5410–5413 (2014).

    Article  CAS  Google Scholar 

  32. Liu, L. et al. Achiral CpXIr(III)/chiral carboxylic acid catalyzed enantioselective C–H amidation of ferrocenes under mild conditions. ACS Catal. 10, 7117–7122 (2020).

    Article  CAS  Google Scholar 

  33. Zhang, Q.-W. et al. Rhodium-catalyzed enantioselective intramolecular C-H silylation for the syntheses of planar-chiral metallocene siloles. Angew. Chem. Int. Ed. Engl. 54, 6918–6921 (2015).

    Article  CAS  Google Scholar 

  34. Zhao, W.-T. et al. Rhodium-catalyzed 2-arylphenol-derived six-membered silacyclization: straightforward access toward dibenzooxasilines and silicon-containing planar chiral metallocenes. ACS Catal. 8, 7997–8005 (2018).

    Article  CAS  Google Scholar 

  35. Mu, D. et al. Streamlined construction of silicon-stereogenic silanes by tandem enantioselective C–H silylation/alkene hydrosilylation. J. Am. Chem. Soc. 142, 13459–13468 (2020).

    Article  CAS  Google Scholar 

  36. Chuard, T. et al. Planar chirality: a fascinating symmetry breaking which leads to ferroelectricity in ferrocenyl liquid crystals. Chem. Commun. 2109–2110 (2000).

  37. Steurer, M., Tiedl, K., Wang, Y. & Weissensteiner, W. Stereoselective synthesis of chiral, non-racemic 1,2,3-tri- and 1,3-disubstituted ferrocene derivatives. Chem. Commun. 4929–4931 (2005).

  38. Keith, J. M., Larrow, J. F. & Jacobsen, E. N. Practical considerations in kinetic resolution reactions. Adv. Synth. Catal. 343, 5–26 (2001).

    Article  CAS  Google Scholar 

  39. Ogasawara, M. et al. Kinetic resolution of planar-chiral ferrocenylphosphine derivatives by molybdenum-catalyzed asymmetric ring-closing metathesis and their application in asymmetric catalysis. ACS Catal. 6, 1308–1315 (2016).

    Article  CAS  Google Scholar 

  40. Chu, L., Xiao, K.-J. & Yu, J.-Q. Room-temperature enantioselective C–H iodination via kinetic resolution. Science 346, 451–455 (2014).

    Article  CAS  Google Scholar 

  41. Gao, D.-W., Gu, Q. & You, S.-L. Pd(II)-catalyzed intermolecular direct C−H bond iodination: an efficient approach toward the synthesis of axially chiral compounds via kinetic resolution. ACS Catal. 4, 2741–2745 (2014).

    Article  CAS  Google Scholar 

  42. Yao, Q.-J., Zhang, S., Zhan, B.-B. & Shi, B.-F. Atroposelective synthesis of axially chiral biaryls by palladium-catalyzed asymmetric C-H olefination enabled by a transient chiral auxiliary. Angew. Chem. Int. Ed. Engl. 56, 6617–6621 (2017).

    Article  CAS  Google Scholar 

  43. Brauns, M. & Cramer, N. Efficient kinetic resolution of sulfur-stereogenic sulfoximines by exploiting CpXRhIII-catalyzed C-H functionalization. Angew. Chem. Int. Ed. Engl. 58, 8902–8906 (2019).

    Article  CAS  Google Scholar 

  44. González, J. M., Cendón, B., Mascareñas, J. L. & Gulías, M. Kinetic resolution of allyltriflamides through a Pd-catalyzed C–H functionalization with allenes: asymmetric assembly of tetrahydropyridines. J. Am. Chem. Soc. 143, 3747–3752 (2021).

    Article  Google Scholar 

  45. Hua, Y. et al. Kinetic resolution of tertiary benzyl alcohols via palladium/chiral norbornene cooperative catalysis. Angew. Chem. Int. Ed. Engl. 60, 12824–12828 (2021).

    Article  CAS  Google Scholar 

  46. Gressies, S. et al. Ligand‐enabled enantioselective Csp3–H activation of tetrahydroquinolines and saturated aza‐heterocycles by RhI. Angew. Chem. Int. Ed. Engl. 57, 9950–9954 (2018).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the National Key R&D Program of China (2021YFA1500100), NSFC (21821002, 91856201, 22071260) and Science and Technology Commission of Shanghai Municipality (19590750400, 21520780100). S.-L.Y. acknowledges support from the Tencent Foundation through the Xplorer Prize.

Author information

Authors and Affiliations

  1. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Chen-Xu Liu, Fangnuo Zhao, Zuolijun Feng, Quannan Wang, Qing Gu & Shu-Li You

Authors
  1. Chen-Xu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fangnuo Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zuolijun Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Quannan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qing Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shu-Li You
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.-L.Y. conceived the work and designed the experiments. C.-X.L. conducted the experiments. C.-X.L., F.Z., Z.F. and Q.W. synthesised and characterised the substrates. C.-X.L., Q.G. and S.-L.Y. wrote the manuscript.

Corresponding author

Correspondence to Shu-Li You.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks Zhong Jin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Discussion.

Supplementary Data 1

Crystallographic data for 7ca; CCDC reference 2119566.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, CX., Zhao, F., Feng, Z. et al. Kinetic resolution of planar chiral metallocenes using Rh-catalysed enantioselective C–H arylation. Nat. Synth 2, 49–57 (2023). https://doi.org/10.1038/s44160-022-00177-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s44160-022-00177-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing