Microwave-assisted synthesis of hydroxamic acid incorporated quinazolin-4[3H]-one derivatives

• Published in: Sustainable chemistry and pharmacy 2022-10, Vol.29, p.100772, Article 100772
• Main Authors: Mikra, Chrysoula, Melissari, Zoi, Kokotou, Maroula G., Gritzapis, Panagiotis, Fylaktakidou, Konstantina C.
• Format: Article
• Language: English
• Subjects: 3-Hydroxy-quinazolin-4[3H]-one; Hydroxamic acids; Microwave irradiation; Privileged structures
• ISSN: 2352-5541; 2352-5541
• DOI: 10.1016/j.scp.2022.100772

A series of 3-hydroxy, 3-ethoxy and 3-benzyloxy-2-methylquinazolin-4[3H]-one derivatives were synthesized in one-pot four-component or in a two-step protocol under microwave irradiation. More specifically, anthranilic acids in combination with triethyl-orthoacetate, the corresponding hydroxylamine hydrochloride derivative (NH2OR·HCl, R = H, Et, Bn) and pyridine in AcOH were irradiated in a microwave reactor at 130–160 °C for 0.5–2 h to give the desired 2-methyl quinazolin-4[3H]-one derivatives in moderate to excellent yields. Isolation of the benzoxazinone intermediates via the reaction of the corresponding anthranilic acids with Ac2O and sequential reaction with NH2OR·HCl in AcOH in the presence of Na2CO3 provided an alternative second formation pathway. The scope and the limitations of the procedures are discussed for anthranilic acids in relation to each hydroxylamine derivative, evaluating data obtained from all attempted reactions and HRMS/MS analyses. The two protocols investigate the formation of molecules that consist of a quinazolinone “privileged” structure fragment accompanied by hydroxamic acid as an additional pharmacophore incorporated within the same molecule, in a rigid, compact form. Both pharmacophores may be highly functionalized and serve as useful intermediates in organic, medicinal and material chemistry, giving the profile of a “synthon” to such molecules. The green character of the reaction is qualified due to: a) the use of acetic acid as the green solvent to replace toxic pyridine; b) the quantity of pyridine, which at the one-pot protocol is in molar equivalency to the amine hydrochloride; c) the short reaction time; d) the relatively high yields. [Display omitted] •One-pot MWI assisted four component green synthesis of 3-OH-2-Me-quinazolinones.•One-pot or two-step MWI assisted green synthesis of 3-OEt-2-Me-quinazolinones.•Efficient two-step MWI assisted green synthesis of 3-OBn-2-Me-quinazolinones.•Synthesis of hydroxamic acid incorporated quinazolinones derivatives.