Application of the intramolecular Diels-Alder vinylarene (IMDAV) reaction for the synthesis of benzo-, carbocyclo-, thienothiopheneisoindolecarboxylic acids and its limitations.

Thienylallylamines, readily accessible from the corresponding thienyl aldehydes, react with maleic and trifluoromethylmaleic anhydrides leading to the formation of acids with a thieno[2,3- f ]isoindole core. The reaction sequence involves two successive steps: acylation of the nitrogen atom of the initial allylamine and the intramolecular Diels-Alder vinylarene (IMDAV) reaction. The scope and limitations of the proposed method were thoroughly investigated. It has been revealed with the aid of X-ray analysis and DFT calculations that the key step, the IMDAV reaction, proceeds through an exo -transition state, giving rise to the exclusive formation of a single diastereomer of the target heterocycle. The obtained functionally substituted thieno[2,3- f ]isoindole carboxylic acids are potentially useful substrates for further transformations and bioscreening. The antimicrobial evaluation of the obtained compounds revealed that 1-oxo-2-(3-(trifluoromethyl)phenyl)hexahydrobenzo[4,5]thieno[2,3- f ]isoindole-10-carboxylic acid is the most active sample in the synthesized library. It exhibits antibacterial activity against sensitive strains of Gram-positive bacteria, including S. aureus , Enterococcus faecium , Bacillus cereus , and Micrococcus luteus , as well as the Gram-negative bacteria E. coli and Pseudomonas fluorescens , with MIC values ranging from 4 to 64 μg mL ^-1 . 9-Oxo-8-phenyloctahydronaphtho[2,1- d ]thieno[2,3- f ]isoindole-10-carboxylic acid showed antifungal activity against yeast culture C. albicans with a MIC value of 32 μM.