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

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 (Na2S2O5) 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.