Poster Presentation Royal Australian Chemical Institute National Congress 2026

The synthesis of 5H-pyrimido[5,4-b]indole and 5H-pyridazino[4,5-b]indole (#214)

Dane Tregeagle 1 , Michael Kassiou 2
  1. The University of New South Wales Canberra, Campbell, ACT, Australia
  2. The University of Sydney, Sydney, NSW, Australia

Carboline based alkaloids have been known to have a diverse range of biological activities with the ability to act as anti-tumour, anti-fungal, anti-inflammatory and neuroprotective agents.1,2 The synthesis of α, β, γ and δ carbolines are concise and well explored with the respective carbolines being accessible via the Cadogan cyclisation.3 However, the synthesis of the related 5H-pyrimido[5,4-b]indole and 5H-pyridazino[4,5-b]indole is under-reported and underdeveloped.4  With the Cadogan cyclisation being unsuitable for these two structures, a 4 and 5 linear step synthesis was devised where the relevant pyrimidine or pyridazine ring was constructed via the lactam, aromatised and subsequently de-halogenated to afford the target species. The target compounds were subsequently functionalised at the nitrogen to yield the respective amides, demonstrating the utility of the described tricycles as intermediates within synthetic organic chemistry.  Whilst the synthesis of 5H-pyridazino[4,5-b]indole and 5H-pyrimido[5,4-b]indole have been spuriously reported, this represents the first time these tricyclics have been synthesised and fully characterised via their chlorinated precursors with cheap and readily available materials.5

 

  1. (1) Szabó, T.; Volk, B.; Milen, M. Recent Advances in the Synthesis of β-Carboline Alkaloids. Molecules 2021, 26 (3), 663. https://doi.org/10.3390/molecules26030663.
  2. (2) Li, D.; Yang, R.; Wu, J.; Zhong, B.; Li, Y. Comprehensive Review of α-Carboline Alkaloids: Natural Products, Updated Synthesis, and Biological Activities. Front. Chem. 2022, 10. https://doi.org/10.3389/fchem.2022.988327.
  3. (3) Kaur, M.; Kumar, R. A Minireview on the Scope of Cadogan Cyclization Reactions Leading to Diverse Azaheterocycles. Asian J. Org. Chem. 2022, 11 (6), e202200092. https://doi.org/10.1002/ajoc.202200092.
  4. (4) Daly, K.; Nomak, R.; Snyder, J. K. A Facile Preparation of Pyrrolo[3,4-b]Indoles. Tetrahedron Lett. 1997, 38 (50), 8611–8614. https://doi.org/10.1016/S0040-4039(97)10312-4.
  5. (5) Monge, A.; Palop, J. A.; Goñi, T.; Martinez-Crespo, F.; Recalde, I.; Fernandez-Alvarez, E. Synthesis of 4-Hydrazino-5H-Pyrimido[5,4-b]Indole and Related Compounds. J. Heterocycl. Chem. 1986, 23 (3), 647–649. https://doi.org/10.1002/jhet.5570230302.