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

Abstract

A series of tetracyclic imidazole derivatives 9a-9v and 10a-10h are prepared by multistep route starting from the known tricyclic diketones 2a-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-7j. In the last steps, aldehyde group is reduced, then alkylated to the two sets of isomeric x-dimethylaminoalkyl derivatives 9a-9v. N-deprotection of 9i-9v led to the compounds 10a-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 antiinflammatory activity.

Conformational properties and chiral separation of dibenzo[b,f]thieno[3,4-d]-fused oxepines and thiepines

“…Imidazo analogues 11 and 12 ( Fig. 1) had inversion barriers of 67.8 and 48.1 kJ/mol, respectively, too low to provoke any interest in separating enantiomers [19,20]. Compounds in this study contain one or more methylene groups in the ''side-arm'' at the C(2) position.…”

“…1), as continuation of our work on related tetracyclic systems, derivatives of imidazole [19]. Imidazo analogues 11 and 12 ( Fig.…”

Dibenzo[b,f]oxepin‐10(11H)‐one and dibenzo[b,f]thiepin‐10(11H)‐one as useful synthons in the synthesis of various dibenzo[e,h]azulenes

“…The use of substituted aldehyde and/or amine enables synthesis of 1,2‐substituted 1,3‐diaza‐dibenzo[ e,h ]azulenes. Moreover, compounds 13 themselves can be exploited as a useful framework for further modifications into numerous derivatives [16, 43].…”

“…However, when nonsymmetrically substituted imidazole derivatives 13c , 13d were used as the starting compounds, N (1)‐alkylation afforded structural isomers 15c , 15d and 16c , 16d (Scheme 11) [16].…”

“…Broad biological activity prompted the use of dibenzo[ b,f ]oxepines and dibenzo[ b,f ]thiepines as key building blocks in synthesis of various polycyclic compounds [10–12]. Recently, synthesis and biological activity of several novel heterocyclic dibenzo[ e,h ]azulene scaffolds have been reported [13–16]. Following literature findings that several different heterocycles can be synthesized from a single substrate [17, 18], an extensive survey of the synthesis of various heterocyclic dibenzo[ e,h ]azulenes resulted in efficient and all‐purpose strategy for the synthesis of dibenzoxepino[5,6]‐ and dibenzothiepino[5,6]‐fused five‐membered heterocycles originating from the common precursors, dibenzo[ b,f ]oxepine‐10(11 H )‐one and its sulfur analogue.…”