[1,5]-Hydride shift-cyclization versus C(sp2)-H functionalization in the knoevenagel-cyclization domino reactions of 1,4- And 1,5-Benzoxazepines

Dóra Szalóki Vargáné, László Tóth, Balázs Buglyó, Attila Kiss-Szikszai, Attila Mándi, Péter Mátyus, Sándor Antus, Yinghan Chen, Dehai Li, Lingxue Tao, Haiyan Zhang, Tibor Kurtán

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Abstract

Domino cyclization reactions of N-aryl-1,4- and 1,5-benzoxazepine derivatives involving [1,5]-hydride shift or C(sp2)-H functionalization were investigated. Neuroprotective and acetylcholinesterase activities of the products were studied. Domino Knoevenagel-[1,5]-hydride shift-cyclization reaction of N-aryl-1,4-benzoxazepine derivatives with 1,3-dicarbonyl reagents having active methylene group afforded the 1,2,8,9-tetrahydro-7bH-quinolino [1,2-d][1,4]benzoxazepine scaffold with different substitution pattern. The C(sp3)-H activation step of the tertiary amine moiety occurred with complete regioselectivity and the 6-endo cyclization took place in a complete diastereoselective manner. In two cases, the enantiomers of the chiral condensed new 1,4-benzoxazepine systems were separated by chiral HPLC, HPLC-ECD spectra were recorded, and absolute configurations were determined by time-dependent density functional theory- electronic circular dichroism (TDDFT-ECD) calculations. In contrast, the analogue reaction of the regioisomeric N-aryl-1,5-benzoxazepine derivative did not follow the above mechanism but instead the Knoevenagel intermediate reacted in an SEAr reaction [C(sp2)-H functionalization] resulting in a condensed acridane derivative. The AChE inhibitory assays of the new derivatives revealed that the acridane derivative had a 6.98 µM IC50 value.

Original languageEnglish
Article number1265
JournalMolecules
Volume25
Issue number6
DOIs
Publication statusPublished - Mar 2 2020

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Keywords

  • 1,4-benzoxazepine
  • 1,5-benzoxazepine
  • Acetylcholinesterase inhibitory activity
  • Domino Knoevenagel-[1,5]-hydride shift-cyclization
  • TDDFT-ECD calculation

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Vargáné, D. S., Tóth, L., Buglyó, B., Kiss-Szikszai, A., Mándi, A., Mátyus, P., Antus, S., Chen, Y., Li, D., Tao, L., Zhang, H., & Kurtán, T. (2020). [1,5]-Hydride shift-cyclization versus C(sp2)-H functionalization in the knoevenagel-cyclization domino reactions of 1,4- And 1,5-Benzoxazepines. Molecules, 25(6), [1265]. https://doi.org/10.3390/molecules25061265