Densely functionalized 2-alkylaminoquinazolinones can be transformed into a variety of heterocycles. As part of our exploration of a regiospecific quinazolinone rearrangement, we recently described a telescoped, dual rearrangement strategy affording highly diversified, N-substituted (E)-amidoarylamidines. Further examination of the nature of the appended amine component of the quinazolinone revealed that the resulting product amidines could spontaneously cyclize to form tetrahydro-1H-pyrrolopyrazino[2,1-b]quinazolin-11(5H)-ones. Development of this tandem quinazolinone rearrangement-intramolecular ring-closure of ortho-amido-NH-(Z)-benzamidines afforded diastereomerically-enriched tetrahydro-1H-pyrrolopyrazino[2,1-b]quinazolin-11(5H)-ones. This highly efficient, four-step, seven-transformation method was used to generate 20 examples in up to 86% yield and with up to 89:11 dr. The protocol showed a wide tolerance for various electronic and steric substitutions and required only a single, final purification. Mechanistic considerations are bolstered by the isolation and characterization of an ortho-amido-NH-(Z)-benzamidine reaction intermediate. This work showcases our novel method for quinazolinone synthesis, broadening access to this understudied privileged structural class and related natural product frameworks.

Diastereoselective multicomponent synthesis of tetrahydro-1H-pyrrolopyrazino[2,1-b]quinazolin-11(5H)-ones via sequential quinazolinone rearrangement & intramolecular ring closure of (Z)-benzamidines

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.