Quinazolin-4(3H)-ones and 5,6-Dihydropyrimidin-4(3H)-ones from β-Aminoamides and Orthoesters

Abstract

Quinazolin-4(3H)-ones have been prepared in one step from 2-aminobenzamides and orthoesters in the presence of acetic acid. Simple 2-aminobenzamides were easily converted to the heterocycles by refluxing in absolute ethanol with 1.5 equivalents of the orthoester and 2 equivalents of acetic acid for 12–24 h. Ring-substituted and hindered 2-aminobenzamides as well as cases incorporating an additional basic nitrogen required pressure tube conditions with 3 equivalents each of the orthoester and acetic acid in ethanol at 110 °C for 12–72 h. The reaction was tolerant towards functionality on the benzamide and a range of structures was accessible. Workup involved removal of the solvent under vacuum and either recrystallization from ethanol or trituration with ether-pentane. Several 5,6-dihydropyrimidin-4(3H)-ones were also prepared from 3-amino-2,2-dimethylpropionamide. All products were characterized by melting point, FT-IR, 1H-NMR, 13C-NMR, and HRMS.

Chemical Space Exploration around Thieno[3,2-d]pyrimidin-4(3H)-one Scaffold Led to a Novel Class of Highly Active Clostridium difficile Inhibitors

“…Intermediate 2-methyl-4 H -pyrido­[2,3- d ]­[1,3]­oxazin-4-one 18 (162 mg, 1.0 mmol) was used as the starting material to synthesize target compound 3 according to method A as a white solid (78 mg, 48% yield), mp 275–278 °C [lit. mp 261–263 °C] …”

Orthoesters: Multiple Role Players in Organic Synthesis

“…In general, Aridoss's reaction times were short and the yields were high, ranging from 87 to 90%. Likewise, Gavin et al . described preparation of the mono and disubstituted quinazolinones in EtOH from the reactions of 1.0 equiv.…”

Orthoesters in heterocycle synthesis

“…The Bunce group has published an improved procedure for the preparation of quinazolin-4(3H)-ones. 62 This method examined cyclizations of 2-aminobenzamide (115) with a series of orthoesters promoted by AcOH. Best results were observed when the reaction was performed in EtOH with AcOH (2-3 equiv) at 110 o C in a sealed tube.…”

“…This account also described an extension of this process to the preparation of 5,6-dihydropyrimidin-4(3H)-ones, but the yields were modest for all examples except when R was Ph. 62 El-Gaby et al utilized orthoesters in a novel approach to pyrimidothienopyridazines. 63 Synthesis of the cyclization substrate 5-amino-3-methyl-4-styryl-6-carbamoylthienyl[2,3-c]pyridazine (120) was achieved in five steps (57%) from 5,6-dimethyl-3-oxo-2,3-dihydropyridazine-4-carbonitrile.…”