Synthesis of Small and Medium-Sized Ring Fused Quinazolinones

Abstract

Quinazolinones are natural alkaloids that play a crucial role in exhibiting a wide range of biological and pharmacological activities. Among them, ring-fused quinazolinones are commonly found in various natural alkaloids and synthetic molecules, showcasing a diverse array of bioactivities. In this study, we focused on synthesizing tricyclic quinazolinones. Medium and small-sized ring fused quinazolinones were achieved via direct cyclization of quinazolinone intermediates having tert-butyl ethylcarbamate and H as nitrogen substituents, respectively. Firstly, we focused on cyclic amine and urea moieties to fuse with quinazolinone skeletons to obtain novel 11-membered ring fused quinazolinones. Key intermediates were prepared through a copper-catalyzed domino reaction. We successfully incorporated an alkyl side chain with a functionalized amine moiety. The construction of the 11-membered ring urea moiety involved direct cyclization using 1,1'- carbonyldiimidazole (CDI) of a diamino quinazolinone intermediate, which was generated through a series of steps including reductive amination and Bocdeprotection. Secondly, we explored the synthesis of deoxyvasicinone derivatives, which are smaller-sized ring fused quinazolinones. The cyclization process for forming the smaller-sized ring was carried out under both basic and acidic conditions, resulting in the formation of two deoxyvasicinone analogues. Under basic conditions, 1-acetyl-2,3-dihydro pyrrolo[2,1-b]quinazolin-9(1H)-one analogues were synthesized via direct cyclization in the presence of I2. Under acidic conditions, we synthesized 1- acetylpyrrolo[2,1-b]quinazolin-9(3H)-one analogues through a two-step process involving α,α-dichlorination followed by intramolecular C–N bond cyclization, with para-toluene sulfonic acid (PTSA) serving as a catalyst. The developed synthetic strategies provide valuable insights into the preparation and modification of quinazolinone derivatives.