The quinazolin-4-one framework is a well-recognized constituent of natural products and drugs that, depending on functionalization, demonstrates a wide breadth of pharmacology. Following the discovery and development of a Sequential Quinazolinone-Amidine Rearrangement Strategy (termed SQuAReS), we recognized that diverse quinazolinone products could be generated with the construction of judiciously substituted starting materials to be used therein. To expand the structural diversity of quinazolinone-containing architecture for medicinal chemistry efforts, a Mannich-type reaction was developed between a quinazolinone C2-alpha carbon (blue dot) as an enolizable ketone equivalent, an appended reactive nitrogen atom, and an N-Cbz protected amino aldehyde. After optimization, this reaction generated the Mannich-type intermediates B in up to 95% yield and in a 3:1 ratio which favored the transdiastereomer. The observed selectivity was reasoned to result from a slightly preferred formation of an (E)-Mannich-enamine intermediate over the (Z)-isomer. Subsequently, intermediates B were shuttled into SQuAReS to undergo, after N-Cbz deprotection, a tandem quinazolinone rearrangement/intramolecular amidine ring closure to afford more than 23 quinazolinones C in up to 90% yield. The optimization and efficiency of the sequence will be discussed as a function of chosen Mannich reaction conditions, quinazolinone core substitution, selection of aldehyde partner, and N-Cbz deprotection conditions. Ultimately, this three-step protocol pairs a Mannich-type carbon-carbon bond formation with the efficiency of tandem rearrangement/ring closure platform to afford unique, sp³-enriched quinazolinone frameworks that are being utilized in our medicinal chemistry programs.

Matthew Lish

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