Rapid Access to Polyfunctionalized 3,4‐Dihydroquinazolinones through a Sequential N‐Acyliminium Ion Mannich Reaction Cascade

Abstract

A microwave‐promoted one‐pot, three‐component sequential cyclization‐Mannich reaction of unactivated ketones, o‐formyl carbamates and primary amines has been developed. Cyclic N‐acyliminium ions are generated in situ from the carbamate and amine starting materials. This metal‐free cascade protocol provides rapid access to structurally diverse 3,4‐dihydroquinazolinones in good to excellent yields with high regioselectivity for the terminal methyl group, in the case of unsymmetrical methyl alkyl ketones. Key features of the developed protocol include its operational simplicity, ease of product purification, and wide functional group tolerance.

A Simple Metal-Free Cyclization for the Synthesis of 4-Methylene-3-Substituted Quinazolinone and Quinazolinthione Derivatives: Experiment and Theory

“…For example, 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 and primary amines to form polyfunctionalized 3,4-dihydroquinazolinones. Fukamachi et al (2010) described a selective construction of 3,4-dihydroquinazoline-2-thiones by reacting 3-(2-isothiocyanatophenyl)propanoic derivatives with primary amines.…”

Facile preparation of 3-substituted 2-quinazolinones via electrogenerated base

“…Zhu et al 9 described an efficient synthesis of 4-alkyl-2(1H)-quinazolinones by cyclization of 1-(2-alkynyl-phenyl)ureas catalyzed by TfOH. More recently Odell et al 10 published a rapid access to polyfunctionalized 3,4-dihydroquinazolinones through a sequential N-acyliminium ion Mannich reaction cascade.…”

Enolizable Carbonyls and N,O‐Acetals: A Rational Approach for Room‐Temperature Lewis Superacid‐Catalyzed Direct α‐Amidoalkylation of Ketones and Aldehydes

“…We believe that this study improves the chemical applicability of the venerable N ‐acyliminium ions, and also provides a better understanding of their catalytic reactivity with weak nucleophiles. The potential of the fascinating and easily available Sn(NTf 2 ) 4 Lewis superacid catalyst is also broadened, and we hope that the specific and general information gained from this study will be useful to the scientific community …”