Synthesis and structural analysis of 1,4′-pyrazolo[3,4-e][1,4]thiazepin-7′(6H)ones: An example of conformational chirality in seven-membered heterocycles

• The N -alkylation of the spirothiazepinone ring gave rise to conformational chirality in the final products. • NMR and chromatography analysis showed the presence of a preferred conformer supporting the conformational chirality. • Computational calculation suggested a potential dynamic chirality depending on the aggregation state. • The intermolecular interactions in solution reinforced the chiral properties of the N -alkylated derivatives favoring one enantiomorphic conformation over the other. A series of five new N-alkylspiro[1,4]thiazepin-2-ones was obtained in good yields using a two-step synthesis strategy involving the preparation of the spirothiazepinone core, followed by the N-alkylation using alkyl halides in alkaline conditions. The latter N-alkylation reaction gave rise to conformational chirality, evidenced in NMR spectra, polarimetry, chiral HPLC, and X-ray diffraction analysis. X-ray studies revealed the presence of enantiomorphic boat-type conformers in centrosymmetric unit cells interacting by van der Waals forces, in contrast to a predominant conformer in solution supported by the chiral properties of the N-alkylated derivatives. The present work makes an important contribution to the study of the structural properties of 1,4-thiazepinone systems and the phenomenon of conformational chirality in seven-membered N-heterocycles.