INVESTIGATION OF ELECTROPHILIC CYCLIZATION REACTIONS OF 2-ALKENYLTHIOIMIDAZOLES

Martyna Paulauskaitė1, Ieva Žutautė1

1 Faculty of Chemistry and Geosciences, Vilnius University, Lithuania

[email protected]

Compounds containing an imidazo[2,1-b][1,3]thiazine fragment exhibit a wide range of biological properties, including anti-tuberculosis [1], anti-inflammatory [2], antifungal [3], and amyloid aggregation inhibitory [4] activities. These compounds demonstrate excellent chemical stability and the ability to selectively bind to various biomolecules, making them highly attractive for synthetic and medicinal applications.

Typically, the imidazo[2,1-b][1,3]thiazine fragment formation involves nucleophilic substitution or condensation reactions, which often require multiple synthetic steps. A growing approach to synthesizing heterocyclic systems from alkynes is using nucleophilic cyclization reactions promoted by electrophiles [5]. This method allows for the efficient formation of imidazo[2,1-b][1,3]thiazine rings and ensures good selectivity and high yields. However, the electrophile-initiated cyclization of 2-alkenylthioimidazoles has been scarcely explored. The heterocycles produced by this reaction are expected to possess novel chemical properties and enhanced biological activity. In this study, 2-cinnamylthiobenzimidazole was chosen as a model compound to investigate the cyclization reaction outcome and optimize its conditions. After applying the best conditions, other 5-arylimidazo[2,1-b][1,3]thiazines were synthesized. Formed compounds obtain a readily cleavable group, which can be replaced by other nucleophiles or eliminated by treatment with a base yielding 5-aryl-5H-benzimidazo[2,1-b][1,3]thiazine.

Figure 1
Fig. 1. Synthesis of benzimidazo[2,1-b][1,3]thiazine frameworks


[1] J. X. Gong, et al., Synthesis, spectral characterization, and antituberculosis activity of thiazino[3,2-a]benzimidazole derivatives, Phosphorus Sulfur Silicon Relat. Elem. 2016, 191, 1036–1041.

[2] N. Slyvka, et al., Synthesis and anti-inflammatory activity of S-oxides of pyridinyloxy substituted imidazo[2,1-b][1,3]thiazines, Curr. Chem. Lett. 2023, 12 335–342.

[3] M. D. LaFleur, et al., Novel high-throughput screen against Candida albicans identifies antifungal potentiators and agents effective against biofilms, J. Antimicrob. Chemoth. 2011, 66, 820–826.

[4] I. Misiunaite, et al., Imidazo[2,1-b][1,3]thiazine Derivatives as Potential Modulators of Alpha-Synuclein Amyloid Aggregation, ACS Chem. Neurosci. 2024, 15, 4418-4430.

[5] B. Godoi, et al., Synthesis of Heterocycles via Electrophilic Cyclization of Alkynes Containing Heteroatom, Chem. Rev. 2011, 111, 2937-2980.