The Synthesis of Diverse Annulated Pyridines with 6-Membered Functionalized Saturated Cycles for Medical Chemistry Research




organic synthesis, heterocyclic compounds, pyridines, building blocks, organofluorines, “magic methyl”, scaffold hopping


The article describes a set of pyridines annulated with functionalized 6-membered saturated rings, which are attractive building blocks for the synthesis of diversified compound libraries in medical chemistry. A certain array of compounds includes pyridines with condensed cyclohexane, piperidine and tetrahydropyran cycles containing keto-, amino-, carboxylic groups, as well as fluorinated fragments. The synthesis of the compounds using the procedure previously developed by us via CuCl2-catalyzed condensation of propargylamine with ketones was performed. The limits of application of this reaction were further expanded and determined in this work compared to our previous results. Condensed pyridines, which proved problematic or impossible to obtain by this method, were synthesized using other synthetic pathways. Thus, the study offers a number of new building blocks for use in drug discovery.

Supporting Agency

  • The authors received no specific funding for this work.


Download data is not yet available.


  1. Catalano, J. G.; Gudmundsson, K. S.; Svolto, A.; Boggs, S. D.; Miller, J. F.; Spaltenstein, A.; Thomson, M.; Wheelan, P.; Minick, D. J.; Phelps, D. P.; Jenkinson, S. Synthesis of a novel tricyclic 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system and CXCR4 antagonists with potent activity against HIV-1. Bioorg. Med. Chem. Lett. 2010, 20, 2186–2190.
  2. Ebetino, F. H.; Degenhardt, Ch. R; Jamieson, L. A; Burdsall, D. C. Recent Work on the Synthesis of Phosphonate-containing, Bone-active Heterocycles. Heterocycles 1990, 30, 855–862.
  3. Rogers, M. J.; Xiong, X.; Brown, R. J.; Watts, D. J.; Russell, R. G. G.; Bayless, A. V.; Ebetino, F. H. Structure-activity relationships of new heterocycle-containing bisphosphonates as inhibitors of bone resorption and as inhibitors of growth of Dictyostelium discoideum amoebae. Mol. Pharmacol. 1995, 47, 398–402.
  4. Paget, S. D.; Foleno, B. D.; Boggs, C. M.; Goldschmidt, R. M.; Hlasta, D. J.; Weidner-Wells, M. A.; Werblood, H. M.; Wira, E.; Bush, K.; Macielag, M. J. Synthesis and antibacterial activity of pyrroloaryl-substituted oxazolidinones. Bioorg. Med. Chem. Lett. 2003, 13, 4173–4177.
  5. Horne, D. B.; Biswas, K.; Brown, J.; Bartberger, M. D.; Clarine, J.; Davis, C. D.; Gore, V. K.; Harried, S.; Horner, M.; Kaller, M. R.; Lehto, S. G.; Liu, Q.; Ma, V. V.; Monenschein, H.; Nguyen, T. T.; Yuan, Ch. C.; Youngblood, B. D.; Zhang, M.; Zhong, W.; Allen, J. R.; Chen, J. J.; Gavva, N. R. Discovery of TRPM8 Antagonist (S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic Acid (AMG 333), a Clinical Candidate for the Treatment of Migraine. J. Med. Chem. 2018, 61, 8186–8201.
  6. Anderson, E. D.; Boger, D. L. Inverse Electron Demand Diels–Alder Reactions of 1,2,3-Triazines: Pronounced Substituent Effects on Reactivity and Cycloaddition Scope. J. Am. Chem. Soc. 2011, 133, 12285–12292.
  7. Mikami, Sh.; Toyota, M. Palladium Acetate-Catalyzed One-Pot Synthesis of Mono- and Disubstitued Pyridines. Heterocycles 2019, 99, 1315 – 1321.
  8. Xi, L.-Y.; Zhang, R.-Y.; Liang, S.; Chen, S.-Y.; Yu, X.-Q. Copper-catalyzed aerobic synthesis of 2-arylpyridines from acetophenones and 1,3-diaminopropane. Org. Lett. 2014, 16, 5269–5271.
  9. Abbiati, G.; Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. Sequential amination/annulation/aromatization reaction of carbonyl compounds and propargylamine: A new one-pot approach to functionalized pyridines. J. Org. Chem. 2003, 68, 6959–6966.
  10. Mondal, R.; Herbert, D. E. Synthesis of Pyridines, Quinolines, and Pyrimidines via Acceptorless Dehydrogenative Coupling Catalyzed by a Simple Bidentate P^N Ligand Supported Ru Complex. Organometallics 2020, 39, 1310–1317.
  11. Srimani, D.; Ben-David, Y.; Milstein, D. Direct synthesis of pyridines and quinolines by coupling of γ-amino-alcohols with secondary alcohols liberating H2 catalyzed by ruthenium pincer complexes. Chem. Commun. 2013, 49, 6632–6634.
  12. Michlik, S.; Kempe, R. Regioselectively functionalized pyridines from sustainable resources. Angew. Chem. Int. Ed. 2013, 52, 6326–6329.
  13. Pan, B.; Liu, B.; Yue, E.; Liu, Q.; Yang, X.; Wang, Z.; Sun, W. H. A ruthenium catalyst with unprecedented effectiveness for the coupling cyclization of γ-amino alcohols and secondary alcohols. ACS Catal. 2016, 6, 1247–1253.
  14. Sotnik, S. O.; Subota, A. I.; Kliuchynskyi, A. Y.; Yehorov, D. V.; Lytvynenko, A. S.; Rozhenko, A. B.; Kolotilov, S. V.; Ryabukhin, S. V.; Volochnyuk, D. M. Cu-Catalyzed Pyridine Synthesis via Oxidative Annulation of Cyclic Ketones with Propargylamine. J. Org. Chem. 2021, 86, 7315–7325.
  15. Pogrányi, B.; Mielke, T.; Díaz-Rodríguez, A.; Cartwright, J.; Unsworth, W. P.; Grogan, G. Preparative-Scale Biocatalytic Oxygenation of N-Heterocycles with a Lyophilized Peroxygenase Catalyst. Angew. Chem. Int. Ed. 2023, 62, e202214759.
  16. Ghera, E.; Ben David, Y.; Rapoport, H. Synthesis of functionalized quinoline derivatives by annulation of pyridines. J. Org. Chem. 1981, 46, 2059–2065.
  17. Zhu, Z.; Glinkerman, C. M.; Boger, D. L. Selective N1/N4 1,4-Cycloaddition of 1,2,4,5-Tetrazines Enabled by Solvent Hydrogen Bonding. J. Am. Chem. Soc. 2020, 142, 20778–20787.
  18. Boggs, Sh.; Elitzin, V. I.; Gudmundsson, K.; Martin, M. T.; Sharp, M. J. Kilogram-Scale Synthesis of the CXCR4 Antagonist GSK812397. Org. Process Res. Dev. 2009, 13, 781–785.
  19. Klar, H.; Zymalkowski, F. Eine Synthese des 1-Aza-des-N-berbins. Arch. Pharm. 1974, 307 (8), 577-584.
  20. Bridger, G.; Skerlj, R.; Kaller, A.; Harwig, C.; Bogucki, D.; Wilson, T. R.; Crawford, J.; McEachern, E. G.; Atsma, B.; Nan, S.; Zhou, Yu.; Schols, D. Chemokine receptor binding heterocyclic compounds. U. S. Patent US6750348B1, Jun 15, 2004.
  21. Zubar, V; Brzozowska, A.; Sklyaruk, Ja.; Rueping, M. Dehydrogenative and Redox-Neutral N-Heterocyclization of Aminoalcohols Catalyzed by Manganese Pincer Complexes. Organometallics 2022, 41, 1743–1747.
  22. Xiong, B.; Li, Ya; Lv, W.; Tan, Zh.; Jiang, H.; Zhang, M. Ruthenium-Catalyzed Straightforward Synthesis of 1,2,3,4-Tetrahydronaphthyridines via Selective Transfer Hydrogenation of Pyridyl Ring with Alcohols. Org. Lett. 2015, 17, 4054–4057.
  23. Zhang, J.; An, Zh.; Zhu, Ya.; Shu, X.; Song, H.; Jiang, Yi.; Wang, W.; Xiang, X.; Xu, L.; He, J. Ni0/Niδ+ Synergistic Catalysis on a Nanosized Ni Surface for Simultaneous Formation of C–C and C–N Bonds. ACS Catal. 2019, 9, 11438–11446.
  24. Balesstra, M.; Burke, J.; Chen, Zh.; Cogan, D.; Fader, L.; Guo, X.; McKibben, B.; Marshall, D. R.; Nemoto, P. A.; Yu. H. Aldosterone synthase inhibitors. U. S. Patent US2014323468A1, Oct 30, 2014.




How to Cite

Yehorov, D. V.; Subota, A. I. The Synthesis of Diverse Annulated Pyridines With 6-Membered Functionalized Saturated Cycles for Medical Chemistry Research. J. Org. Pharm. Chem. 2023, 21, 23-30.



Original Researches