Download PDF
Synthesis
DOI: 10.1055/a-2784-2600
Paper
Published as part of the Special Issue dedicated to Prof. Franziska Schoenebeck, recipient of the 2025 Dr. Margaret Faul Women in Chemistry Award

Selective Reductions of Complex Pyridines via NTf-Pyridinium Salts

Authors


Supported by: National Institutes of Health S10OD036347
This work was supported by funds from the National Institutes of Health (NIH) under award numbers R01GM124094, R35GM156435, and S10OD036347.
Further Information
   Permissions and Reprints All articles of this category


Graphical Abstract

Abstract

Piperidines are widely found in biologically active compounds, and accessing these N-heterocycles from pyridines is a commonly used strategy. However, this approach is challenging when pyridines are embedded in complex structures, such as those found in pharmaceutical compounds. Here, we present a sequential approach to piperidines that commences with a hydride addition to NTf-activated pyridinium salts. In this method, we combined tris(pentafluorophenyl)borane as a catalyst with a silane reducing agent to achieve 4-selective mono-reduction, and then combined it with metal-catalyzed reductions to obtain tetrahydropiperidine and piperidine derivatives. The process operates on a broad range of pyridines with various functional groups and substitution patterns, as well as on pyridine-containing drugs.

Keywords

Pyridines - Piperidines - Reduction - NTf-pyridinium salts - Dihydropyridines - Tetrahydropyridines - Late-stage functionalization

Supplementary Material



Publication History

Received: 07 December 2025

Accepted after revision: 08 January 2026

Accepted Manuscript online:
19 January 2026

Article published online:
11 February 2026

© 2026. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

  • References

  • 1 Frolov NA, Vereshchagin AN. Int J Mol Sci 2023; 24: 2937
    Search in Google Scholar
  • 2 Marshall CM, Federice JG, Bell CN, Cox PB, Njardarson JT. J Med Chem 2024; 67: 11622
    Search in Google Scholar
  • 3 Vitaku E, Smith DT, Njardarson JT. J Med Chem 2014; 57: 10257
    Search in Google Scholar
  • 4 Goel P, Alam O, Naim MJ, Nawaz F, Iqbal M, Alam MI. Eur J Med Chem 2018; 157: 480
    Search in Google Scholar
  • 5 Liu GQ, Opatz T. Adv Heterocycl Chem 2018; 125: 107
    Search in Google Scholar
  • 6 Källström S, Leino R. Bioorg Med Chem 2008; 16: 601
    Search in Google Scholar
  • 7 Weintraub PM, Sabol JS, Kane JA, Borcherding DR. Tetrahedron 2003; 59: 2953
    Search in Google Scholar
  • 8 Lyons TW, Leibler INM, He CQ, Gadamsetty S, Estrada GJ, Doyle AG. J Org Chem 2024; 89: 1438
    Search in Google Scholar
  • 9 Williams S, Qi LM, Cox RJ, Kumar P, Xiao JL. Org Biomol Chem 2024; 22: 1010
    Search in Google Scholar
  • 10 Despois A, Cramer N. ChemRxiv. Cambridge: Cambridge Open Engage; 2025.
    Search in Google Scholar
  • 11 Comparini LM, Pineschi M. Molecules 2023; 28
  • 12 Glorius F. Org Biomol Chem 2005; 3: 4171
    Search in Google Scholar
  • 13 Zhang FH, Sasmal HS, Rana D, Glorius F. J Am Chem Soc 2024; 146: 18682
    Search in Google Scholar
  • 14 Dolewski RD, Hilton MC, McNally A. Synlett 2018; 29: 8
    Search in Google Scholar
  • 15 Fan XT, Zheng JH, Li ZH, Wang HD. J Am Chem Soc 2015; 137: 4916
    Search in Google Scholar
  • 16 Kaithal A, Chatterjee B, Gunanathan C. Org Lett 2016; 18: 3402
    Search in Google Scholar
  • 17 Ji PF, Feng XY, Veroneau SS, Song Y, Lin WB. J Am Chem Soc 2017; 139: 15600
    Search in Google Scholar
  • 18 Tamang SR, Singh A, Unruh DK, Findlater M. ACS Catal 2018; 8: 6186
    Search in Google Scholar
  • 19 Königs CDF, Klare HFT, Oestreich M. Angew Chem Int Ed 2013; 52: 10076
    Search in Google Scholar
  • 20 Gutsulyak DV, van der Est A, Nikonov GI. Angew Chem Int Ed 2011; 50: 1384
    Search in Google Scholar
  • 21 Oshima K, Ohmura T, Suginome M. J Am Chem Soc 2011; 133: 7324
    Search in Google Scholar
  • 22 Shu M, Park S. Chem Commun 2025; 61: 15674
    Search in Google Scholar
  • 23 Heusler A, Fliege J, Wagener T, Glorius F. Angew Chem Int Ed 2021; 60: 13793
    Search in Google Scholar
  • 24 Huang X, Shi Q, Lai G, Angew WHL. Angew Chem Int Ed. 2025
    Search in Google Scholar
  • 25 Hackel T, McGrath NA. Molecules 2019; 24
  • 26 Geier SJ, Chase PA, Stephan DW. Chem Commun 2010; 46: 4884
    Search in Google Scholar
  • 27 Gandhamsetty N, Park S, Chang S. J Am Chem Soc 2015; 137: 15176
    Search in Google Scholar
  • 28 Oestreich M, Hermeke J, Mohr J. Chem Soc Rev 2015; 44: 2202
    Search in Google Scholar
  • 29 Liu DH, Pflüger PM, Outlaw A. et al. J Am Chem Soc 2024; 146: 11866
    Search in Google Scholar
  • 30 Glorius F, Spielkamp N, Holle S, Goddard R, Lehmann CW. Angew Chem Int Ed 2004; 43: 2850
    Search in Google Scholar