Novel tetracyclic imidazole derivatives: Synthesis, dynamic NMR study, and anti-inflammatory evaluation

• Published in: Journal of heterocyclic chemistry Vol. 47; no. 3; pp. 640 - 656
• Main Authors: Rupčić, Renata, Modrić, Marina, Hutinec, Antun, Čikoš, Ana, Stanić, Barbara, Mesić, Milan, Pešić, Dijana, Merćep, Mladen
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.05.2010; Wiley
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; AMIDE BOND DISTORTIONS; CONFORMATION ANALYSES; INHIBITORS; MEDIUM-SIZED HETEROCYCLES; BEHAVIOR
• ISSN: 0022-152X; 1943-5193
• DOI: 10.1002/jhet.376

A series of tetracyclic imidazole derivatives 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n, 9o, 9p, 9r, 9s, 9t, 9v and 10a, 10b, 10c, 10d, 10e, 10f, 10g, 10h are prepared by multistep route starting from the known tricyclic diketones 2a, 2b, 2c, 2d. Intermediary dibenzooxepin[4,5‐d]imidazoles (3a, 3c) and dibenzothiepin[4,5‐d]imidazoles (3b, 3d) are N‐protected to 4e, 4f and to the isomeric compounds 5a, 5b and 6a, 6b. The isomeric compounds 5 and 6 are separated. Compounds 4, 5, and 6 are formylated at C(2) to afford 7a, 7b, 7c, 7d, 7e, 7f, 7g, 7h, 7i, 7j. In the last steps, aldehyde group is reduced, then alkylated to the two sets of isomeric ω‐dimethylaminoalkyl derivatives 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n, 9o, 9p, 9r, 9s, 9t, 9v. N‐deprotection of 9i–9v led to the compounds 10a, 10b, 10c, 10d, 10e, 10f, 10g, 10h. Assignment of the syn/anti structure to 5a and 6a was supported by 1D selective ROESY NMR spectra, whereas conformational mobility for the selected representatives 8a and 8b is studied by dynamic NMR. Activation energies (energy barriers for interconversion) are determined to be ∼11.5 and 16.2 kcal/mol, respectively. A series of derivatives 9 and 10 were tested in vitro for their anti‐inflammatory activity. J. Heterocyclic Chem., (2010).