Synthesis, Selected Transformations, and Biological Activity of Alkoxy Analogues of Lepidilines A and C

Abstract

Condensation of diacetyl monooxime with formaldimines derived from alkoxyamines in glacial acetic acid at room temperature leads to corresponding 2-unsubstituted imidazole N-oxides bearing an alkoxy substituent at the N(1) atom of the imidazole ring. Subsequent O-benzylation afforded, depending on the type of alkylating agent, either symmetric or nonsymmetric alkoxyimidazolium salts considered as structural analogues of naturally occurring imidazole alkaloids, lepidilines A and C. Some of the obtained salts were tested as precursors of nucleophilic heterocyclic carbenes (NHCs), which in situ reacted with elemental sulfur to give the corresponding N-alkoxyimidazole-2-thiones. The cytotoxic activity of selected 4,5-dimethylimidazolium salts bearing either two benzyloxy or benzyloxy and 1-adamantyloxy groups at N(1) and N(3) atoms was evaluated against HL-60 and MCF-7 cell lines using the MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay. Notably, in two cases of alkoxyimidazolium salts, no effect of the counterion exchange (Br− → PF6−) on the biological activity was observed.

Synthesis and Cytotoxic Activity of Lepidilines A–D: Comparison with Some 4,5-Diphenyl Analogues and Related Imidazole-2-thiones

“…In our recent publication, 2-unsubstituted imidazole N -oxides such as 2 were used as key building blocks for the preparation of a series of benzyloxy analogues of lepidiline A. 7 In the presented study, deoxygenation of N -oxides 2 was required to get the desired 1,4,5-tri- and 1,2,4,5-tetrasubstituted imidazoles. In an initial experiment, the known 1-benzyl-4,5-dimethylimidazole N -oxide ( 2a ) 8 was treated with freshly prepared Raney-nickel, in EtOH, and the obtained 1-benzyl-4,5-dimethylimidazole ( 5a ) was N -alkylated with benzyl chloride under microwave (MW) irradiation.…”

“… 12 In a recent report, this method was successfully applied for the conversion of numerous benzyloxy-functionalized imidazolium salts into the corresponding imidazole-2-thiones. 7 Thus, lepidilines A and C seem to be attractive substrates for further functionalization via the respective intermediate carbenes (NHCs). In a typical experiment, imidazolium chloride 1a was treated with Et 3 N and S 8 in dry pyridine solution at room temperature ( Scheme 5 , Method A).…”

The Fluoride Anion-Catalyzed Sulfurization of Thioketones with Elemental Sulfur Leading to Sulfur-Rich Heterocycles: First Sulfurization of Thiochalcones

“…In the present work, fluoride anion was shown to act as an alternative, nucleophilic catalyst and can replace smelly and unstable sodium (or potassium) thiophenolate in the activation of elemental sulfur in reactions with thiiranes. The presented research should be considered as a new contribution to our continuous studies on exploration of elemental sulfur and small-ring, congested S-heterocycles (thiaziridiens, thiiranes) in sulfurization reactions of diverse organic compounds, including stable thioketones [10,22,24,30] but also transient nucleophilic heterocyclic carbenes (NHC) [40,41].…”

Expedient synthesis of NOxy-Heterocyclic Carbenes (NOHC) ligands and metal complexes using mechanochemistry

“…Efficient methods for their preparation have been reported in recent decades, [32][33][34][35] but so far, the number of applications is rather limited. One can cite their usage as ionic liquids (in the form of corresponding imidazolium salt), [36][37][38][39][40][41][42] for biological applications, [43] as ligands for complexation of metals, [44][45][46][47][48] as additives in reactions [ 49 , 50 ] or as unique building blocks for the preparation of some co-crystals [ 51 , 52 ]. In our continuing studies on the preparation of this class of imidazole derivatives and owing to the success of the mechanochemical strategy for the preparation of NHCs, we decided to explore the mechanosynthesis of NOHCs and corresponding metal complexes, using a vibratory ball mill (vbm) ( Scheme 1 ).…”