One-Pot Synthesis of Diverse Collections of Benzoxazepine and Indolopyrazine Fused to Heterocyclic Systems

Vunnam Srinivasulu, Ihsan Shehadeh, Monther A. Khanfar, Omar G. Malik, Hamadeh Tarazi, Imad A. Abu-Yousef, Anusha Sebastian, Nabil Baniowda, Matthew John O'Connor, Taleb H. Al-Tel

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Abstract

The development of efficient and modular synthetic methods for the synthesis of diverse collection of privileged substructures needed for a drug design and discovery campaign is highly desirable. Benzoxazepine and indolopyrazine ring systems form the core structures of distinct members of biologically significant molecules. Several members of these families have gained attention due to their broad biological activities, which depend on the type of ring-fusion and peripheral substitution patterns. Despite the potential applications of these privileged substructures in drug discovery, efficient, atom-economic, and modular strategies for their access are underdeveloped. Herein, a one-step build/couple/pair strategy that uniquely allows access to diversely functionalized benzoxazepine and indolopyrazine scaffolds is described. The methodology features a one-pot combination of condensation, Mannich, oxidation, and aza-Michael addition reactions, employing a variety of functionalized anilines and aldehydes suitably poised with Micheal acceptor. Scandium triflate (Sc(OTf) 3 ) in acetonitrile (ACN) was found to promote the construction of benzoxazepines scaffolds, while sodium metabisulfite (Na 2 S 2 O 5 ) in aqueous EtOH rapidly enhanced the cascade reaction that led to diverse collections of indolopyrazine frameworks. These protocols represent modular, efficient, and atom-economic access of constrained benzoxazepine and indolopyrazine systems with more than 10 points of diversity and large substrate tolerance.

Original languageEnglish (US)
Pages (from-to)934-948
Number of pages15
JournalJournal of Organic Chemistry
Volume84
Issue number2
DOIs
StatePublished - Jan 18 2019

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ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Srinivasulu, V., Shehadeh, I., Khanfar, M. A., Malik, O. G., Tarazi, H., Abu-Yousef, I. A., Sebastian, A., Baniowda, N., O'Connor, M. J., & Al-Tel, T. H. (2019). One-Pot Synthesis of Diverse Collections of Benzoxazepine and Indolopyrazine Fused to Heterocyclic Systems. Journal of Organic Chemistry, 84(2), 934-948. https://doi.org/10.1021/acs.joc.8b02878