Abstract
A new series of 3-substituted 4-methylene-quinazolinthiones and 4-methylene-quinazolinones were synthesized in moderate to excellent yield through a simple reaction of 2-aminoacetophenones with isocyanates or isothiocyanates. The reaction shows good tolerance of many important functional groups in the presence of air and water under metal-free conditions. Only water is produced as a coproduct, rendering this “green” methodology a highly versatile and eco-friendly alternative to the existing methods for the construction of the quinazolinone/quinazolinthione framework. We have interpreted the reaction mechanism by use of quantum chemical calculations on the basis of state-of-the-art computational methods SMD-B3LYP-D3(BJ)/BS1//B3LYP/BS1.
Highlights
Quinazolinones and their derivatives occur frequently in natural and synthetic pharmaceutical products
Heterocyclization of compound 3 may occur by three different mechanisms (Scheme 2)
Quinazolinthione 4a can result from the nucleophilic attack of N-3 of compound 3 on the carbonyl group of the ketone followed by removal of water
Summary
Quinazolinones and their derivatives occur frequently in natural and synthetic pharmaceutical products. Such compounds act as inhibitors of inducible and neuronal nitric oxide synthases (Camacho et al, 2016), possess anti-melanogenesis activity (Thanigaimalai et al, 2010), inhibit aldosterone synthase (CYP11B) and act as antagonists of platelet activating factor (Walser et al, 1991; Grombein et al, 2015). Many 3,4-dihydroquinazolin-2(1H)-one derivatives have been previously synthesized (Huang et al, 2008; Khan et al, 2014, 2015, 2016; Kshirsagar, 2015; Camacho et al, 2016; Maiden and Harrity, 2016; Awad et al, 2018; Zhang et al, 2018; Elkholy et al, 2019; Gatadi et al, 2019; Long et al, 2019; Wang et al, 2019). Wang et al (2009) reported the synthesis of 4-alkyl-2(1H)-quinazolinones via the cyclization of 1-(2-alkynyl-phenyl)ureas catalyzed by TfOH and Saunthwal et al (2015) described a green and catalyst-free straightforward tandem synthesis of functionalized tetrahydroquinazolines from 2-aminophenylacrylate. Sawant et al (2015) developed a microwave-promoted sequential cyclization-Mannich reaction of ketones, o-formyl carbamates
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