Synthesis of Indeno[1,2-b]indole-9,10-diones: Toward a One-Pot, Two-Step Reaction

Abstract

Indeno[1,2-b]indole was shown to be a key scaffold for the design of new bioactive molecules in oncology (e.g., inhibitors of protein kinase CK2 and inhibitors of the breast cancer resistance protein ABCG2). Depending on the synthetic route chosen, a large variety of specific functionalizations can be achieved. In order to develop new indeno[1,2-b]indole-9,10-diones as CK2 inhibitors, four functionalized indeno[1,2-b]indoles were synthesized using a two-step reaction described in the literature. Given that the reactions reported led to unexpected results, such as incomplete reaction progress, very low yields, and significant formation of by-products, we first optimized the quantities of reagents (AcOH and N,N,N′,N′-tetraethyl sulfurous diamide) and the types of solvents used in the synthetic steps. Then, based on these optimal reaction conditions, a one-pot, two-step reaction was developed to maximize yields and standardize the process, thereby making it more convenient and straightforward.

Keywords

Indeno[1,2-b]indole - Ninhydrin - 3-Aminocyclohex-2-en-1-one - vic-Dihydroxyindeno[1,2-b]indole - N,O-Hemiaminal - N,N,N′,N ′-Tetraethyl sulfurous diamide - Deoxygenation - One-pot reaction

Publication History

Received: 04 October 2025

Accepted after revision: 03 December 2025

Article published online:
30 January 2026

• References

• 1 Hundsdörfer C, Hemmerling H-J, Götz C. et al. Bioorg Med Chem 2012; 20: 2282
• 2 Jabor Gozzi G, Bouaziz Z, Winter E. et al. J Med Chem 2015; 58: 265
• 3 Rongved P, Kirsch G, Bouaziz Z, Jose J, Le Borgne M. Eur J Med Chem 2013; 69: 465
• 4 Haidar S, Marminon C, Aichele D. et al. Molecules 2020; 25: 97
• 5 Marminon C, Werner C, Gast A. et al. Biol Chem. 2025
• 6 Exploration and Exploitation of Secondary Sites of Protein Kinase CK2 – XPLOR_CK2. https://anr.fr/Project-ANR-22-CE92-0081 (accessed May 21, 2025).
• 7 Hemmerling H-J, Reiss G. Synthesis 2009; 2009: 985
• 8 Lobo G, Monasterios M, Rodrigues J. et al. Eur J Med Chem 2015; 96: 281
• 9 Marminon C, Nacereddine A, Bouaziz Z, Nebois P, Jose J, Le Borgne M. Tetrahedron Lett 2015; 56: 1840
• 10 Bouzina A, Berredjem M, Nocentini A. et al. Eur J Med Chem 2021; 209: 112875
• 11 Qinggang J, Hongbin L. CN102532016 2012
• 12 Richey Jr HG, Farkas Jr J. J Org Chem 1987; 52: 479
• 13 Mukaiyama T, Takei H, Shimizu H. Bull Chem Soc Jpn 1967; 40: 939
• 14 Gratz A, Gotz C, Jose J. Electrophoresis 2010; 31: 634
• 15 Supplementary X-ray crystallographic data: Cambridge Crystallographic Data Centre, University Chemical Lab, Lensfield Road, Cambridge, CB2 1EW, UK. Available online: https://www.ccdc.cam.ac.uk/ (accessed May 28, 2024).
• 16 Sheldrick GM. SADABS. Germany: University of Göttingen; 1996
• 17 Sheldrick GM. Acta Crystallogr Sect A 2008; 64: 112