Dihydropyrazinoquinazolinones via S_N2 Sulfamidate Ring-Opening and a Sequential Quinazolinone–Amidine Rearrangement Strategy (SQuAReS)

Abstract

A synthesis of dihydropyrazino-[2,1-b]-quinazolinones is described using a 2-alkylaminoquinazolinone-mediated ring opening of a-/chiral sulfamidates, followed by a tandem quinazolinone–amidine rearrangement termed SQuAReS. This approach takes advantage of sulfamidates whose regioselective ring opening, after hydrolysis, appends an optimally distanced nucleophilic amine to a quinazolinone such that subsequent domino rearrangements are favored, integrating unique substitution patterns on a privileged core. This three-step protocol integrated five telescoped transformations and generated 20 pyrazinoquinazolinones in up to 74% yield with high enantiomeric fidelity and diastereoselectivity.

Mannich‐Type Condensation and Domino Quinazolinone‐Amidine Rearrangement Affords Ring‐Fused Mackinazolinones with Anti‐Amoebic Activity

“…[11] To explore chemical space on quinazolin-4-ones in our medicinal chemistry programs, we envisioned that a Mannich-type reaction between a tethered, N-protected 2-alkylamine 7 and Nprotected aminal 8 a would generate cyclized Mannich products 9. Subsequent N-deprotection would enable a Sequential Quinazolinone-Amidine Rearrangement Strategy (SQuAReS) [12] to afford pyrrolidine-and piperidine-fused, sp 3 -enriched, quinazolin-4-ones 10 (Scheme 1, panel C). Notably, this approach would append an oblique extension on the mackinazolinone skeleton with the benefit of imbedding heteroatoms to balance physiochemical properties and provide synthetic handles for scaffold optimization.…”