The Synthetic Access to Fused 6,7,8,9-Tetrahydro- 5H-pyridoazepines: Evaluation of Ring-Closure Strategies

Authors

  • Bohdan Yu. Solod Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Enamine Ltd, Ukraine
  • Mykhailo V. Vovk Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Ukraine https://orcid.org/0000-0003-3101-9911

DOI:

https://doi.org/10.24959/ophcj.26.354129

Keywords:

pyridoazepane, fused heterocycles, ring-closure reactions, synthetic accessibility, organic synthesis

Abstract

The synthetic accessibility of fused pyridoazepane frameworks was investigated through a series of strategies designed to construct differently fused azepane systems. Several precursor designs enabling alternative ring-closure topologies were explored. A “lactam” pathway proved synthetically inaccessible under various conditions due to chemoselectivity issues and competing intermolecular processes. In contrast, an efficient route to the 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine framework was achieved via an intramolecular cyclization strategy, in which the amine functionality was introduced prior to ring assembly. The developed route proceeds under practical laboratory conditions using inexpensive reagents and was demonstrated on a gram scale. These findings provide insight into the structural factors governing ring-closure efficiency in pyridoazepine systems and establish a practical entry to a previously underexplored fused heterocyclic scaffold.

Supporting Agency

  • The authors received no specific funding for this work.

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References

  1. Amin, A.; Qadir, T.; Sharma, P. K.; Jeelani, I.; Abe, H. A Review on The Medicinal And Industrial Applications of N-Containing Heterocycles. Open Med. Chem. J. 2022, 16. https://doi.org/10.2174/18741045-v16-e2209010.
    |
  2. Marshall, C. M.; Federice, J. G.; Bell, C. N.; Cox, P. B.; Njardarson, J. T. An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013–2023). J. Med. Chem. 2024, 67 (14), 11622-11655. https://doi.org/10.1021/acs.jmedchem.4c01122.
    | |
  3. Li, H.; Chen, T.; Wu, B.; Jin, X.; Liu, J.; Bao, M. Recent Advances in the Synthesis of Nitrogen-Containing Heterocycles Based on Hydrazine-Directed C−H Bond Activation/Annulation Reactions. Eur. J. Org. Chem. 2025, 28 (9), e202401233. https://doi.org/10.1002/ejoc.202401233.
    |
  4. Mallappa; Chahar, M.; Choudhary, N.; Yadav, K. K.; Qasim, M. T.; Zairov, R.; Patel, A.; Yadav, V. K.; Jangir, M. Recent advances in the synthesis of nitrogen-containing heterocyclic compounds via multicomponent reaction and their emerging biological applications: a review. J. Iran. Chem. Soc. 2025, 22 (1), 1-33. https://doi.org/10.1007/s13738-024-03142-3.
    |
  5. Sivaraj, N.; Sakthivel, K.; Kikushima, K.; Kostić, M. D.; Dohi, T.; Singh, F. V. Recent advances in non-conventional synthesis of N-heterocyclic compounds: emerging strategies and biological perspectives. RSC Adv. 2025, 15 (42), 35509-35531. https://doi.org/10.1039/D5RA06028A.
    | |
  6. Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57 (24), 10257-10274. https://doi.org/10.1021/jm501100b.
    | |
  7. Ward, M.; O'Boyle, N. M. Analysis of the structural diversity of heterocycles amongst European medicines agency approved pharmaceuticals (2014–2023). RSC Med. Chem. 2025, 16 (10), 4540-4570. https://doi.org/10.1039/D5MD00403A.
    | |
  8. Shearer, J.; Castro, J. L.; Lawson, A. D. G.; MacCoss, M.; Taylor, R. D. Rings in Clinical Trials and Drugs: Present and Future. J. Med. Chem. 2022, 65 (13), 8699-8712. https://doi.org/10.1021/acs.jmedchem.2c00473.
    | |
  9. Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. Rings in Drugs. J. Med. Chem. 2014, 57 (14), 5845-5859. https://doi.org/10.1021/jm4017625.
    | |
  10. Bemis, G. W.; Murcko, M. A. The Properties of Known Drugs. 1. Molecular Frameworks. J. Med. Chem. 1996, 39 (15), 2887-2893. https://doi.org/10.1021/jm9602928.
    | |
  11. Hu, Y.; Stumpfe, D.; Bajorath, J. Recent Advances in Scaffold Hopping. J. Med. Chem. 2017, 60 (4), 1238-1246. https://doi.org/10.1021/acs.jmedchem.6b01437.
    | |
  12. Mityuk, A. P.; Kiriakov, O. M.; Tiutiunnyk, V. V.; Lebed, P. S.; Grabchuk, G. P.; Rusanov, E. B.; Volochnyuk, D. M.; Ryabukhin, S. V. Trifluoromethyl Vinamidinium Salt as a Promising Precursor for Fused β-Trifluoromethyl Pyridines. J. Org. Chem. 2023, 88 (5), 2961-2972. https://doi.org/10.1021/acs.joc.2c02684.
    | |
  13. Kaliberda, O. V.; Leha, D. O.; Peredrii, V. S.; Levchenko, K.; Zarudnitskii, E. V.; Ryabukhin, S. V.; Volochnyuk, D. M. Scalable Synthesis of 6-Functionalized 1,4-Oxazepanes. Org. Process Res. Dev. 2026, 30 (4), 916-927. https://doi.org/10.1021/acs.oprd.5c00494.
  14. Subota, A. I.; Artamonov, O. S.; Gorlova, A.; Volochnyuk, D. M.; Grygorenko, O. O. Approach to 5-substituted 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines. Tetrahedron Lett. 2017, 58 (20), 1989-1991. https://doi.org/10.1016/j.tetlet.2017.04.030
    |
  15. De, S.; Kumar S K, A.; Shah, S. K.; Kazi, S.; Sarkar, N.; Banerjee, S.; Dey, S. Pyridine: the scaffolds with significant clinical diversity. RSC Adv. 2022, 12 (24), 15385-15406. https://doi.org/10.1039/D2RA01571D.
    | |
  16. Zha, G.-F.; Rakesh, K. P.; Manukumar, H. M.; Shantharam, C. S.; Long, S. Pharmaceutical significance of azepane based motifs for drug discovery: A critical review. Eur. J. Med. Chem. 2019, 162, 465-494. https://doi.org/10.1016/j.ejmech.2018.11.031
    | |
  17. Casadei, M. A.; Galli, C.; Mandolini, L. Ring-closure reactions. 22. Kinetics of cyclization of diethyl (.omega.-bromoalkyl)malonates in the range of 4- to 21-membered rings. Role of ring strain. J. Am. Chem. Soc. 1984, 106 (4), 1051-1056. https://doi.org/10.1021/ja00316a039.
    |
  18. Lowe, D. The Rings Less Traveled. https://www.science.org/content/blog-post/rings-less-traveled (accessed Oct 11, 2025).
  19. Mallo-Abreu, A.; Prieto-Díaz, R.; Jespers, W.; Azuaje, J.; Majellaro, M.; Velando, C.; García-Mera, X.; Caamaño, O.; Brea, J.; Loza, M. I.; Gutiérrez-de-Terán, H.; Sotelo, E. Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A2B Adenosine Receptor Antagonists. J. Med. Chem. 2020, 63 (14), 7721-7739. https://doi.org/10.1021/acs.jmedchem.0c00564.
    | |
  20. Neel, L.; Ma, H.; Reda, A.; Li, M.; Flammia, R.; Woodard, S.; Gillespie, J. C.; Selley, D. E.; Dewey, W. L.; Pagare, P. P.; Zhang, Y. Investigating the Landscape of C6-Azaindole Side Chain on the Epoxymorphinan Skeleton via the Nitrogen Walk Concept: A Strategy to Enhance Drug-Like Properties. J. Med. Chem. 2026, 69 (3), 2330-2348. https://doi.org/10.1021/acs.jmedchem.5c02175.
    | |
  21. Chen, H.; Liang, B. (Shanghai Zhimeng Biopharma Inc.). P-phenylenediamine derivative as potassium channel regulator and preparation method and medical application thereof. US Patent 12157726B2, 21.07.2022.
  22. Henrich, M.; Abel, U.; Muller, S.; Kubas, H.; Meyer, U.; Hechenberger, M.; Kauss, V.; Zemribo, R. (Merz Pharma GmbH and Co KGaA). Metabotropic glutamate receptor modulators. WO Patent 2012/052451A1, 26.04.2012.
  23. Dukat, M.; Fiedler, W.; Dumas, D.; Damaj, I.; Martin, B. R.; Rosecrans, J. A.; James, J. R.; Glennon, R. A. Pyrrolidine-modified and 6-substituted analogs of nicotine: A structure—affinity investigation. Eur. J. Med. Chem. 1996, 31 (11), 875-888. https://doi.org/10.1016/S0223-5234(97)89850-9.
    |
  24. Cheng, Y.-X.; Dukat, M.; Dowd, M.; Fiedler, W.; Martin, B.; Damaj, M. I.; Glennon, R. A. Synthesis and binding of 6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine and related ring-opened analogs at central nicotinic receptors. Eur. J. Med. Chem. 1999, 34 (2), 177-190. https://doi.org/10.1016/S0223-5234(99)80051-8.
    |
  25. Nishikawa-Shimono, R.; Kuwabara, M.; Fujisaki, S.; Matsuda, D.; Endo, M.; Kamitani, M.; Futamura, A.; Nomura, Y.; Yamaguchi-Sasaki, T.; Yabuuchi, T.; Yamaguchi, C.; Tanaka-Yamamoto, N.; Satake, S.; Abe-Sato, K.; Funayama, K.; Sakata, M.; Takahashi, S.; Hirano, K.; Fukunaga, T.; Uozumi, Y.; Kato, S.; Tamura, Y.; Nakamori, T.; Mima, M.; Mishima-Tsumagari, C.; Nozawa, D.; Imai, Y.; Asami, T. Discovery of novel indole derivatives as potent and selective inhibitors of proMMP-9 activation. Bioorg. Med. Chem. Lett. 2024, 97, 129541. https://doi.org/10.1016/j.bmcl.2023.129541.
    | |
  26. Zawodny, W.; Montgomery, S. L.; Marshall, J. R.; Finnigan, J. D.; Turner, N. J.; Clayden, J. Chemoenzymatic Synthesis of Substituted Azepanes by Sequential Biocatalytic Reduction and Organolithium-Mediated Rearrangement. J. Am. Chem. Soc. 2018, 140 (51), 17872-17877. https://doi.org/10.1021/jacs.8b11891.
    | |
  27. Srinivasan, A. K.; Rajashekar, K.; Shyamapada, B.; Syam Kumar, U. K. Facile and Simple Synthesis of N-Alkyl and N-Aryl 2-Benzazepines by Nucleophilic Heteroannulation. Synth. Commun. 2014, 44 (21), 3112-3121. https://doi.org/10.1080/00397911.2014.928327.
    |
  28. Meyers, A. I.; Hutchings, R. H. The asymmetric synthesis of 1-alkyl-2,3,4,5-tetrahydro-benzazepines and benzo[β]-1-azabicyclo[5,3,1]decanes. Tetrahedron 1993, 49 (9), 1807-1820. https://doi.org/10.1016/S0040-4020(01)80537-8.
    |

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Published

2026-05-01

How to Cite

(1)
Solod, B. Y.; Vovk, M. V. The Synthetic Access to Fused 6,7,8,9-Tetrahydro- 5H-Pyridoazepines: Evaluation of Ring-Closure Strategies. J. Org. Pharm. Chem. 2026, 24, 29-37.

Issue

Vol. 24 No. 1 (2026)

Section

Original Researches

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