Diastereoselective, Multicomponent Synthesis of Pyrrolopyrazinoquinazolinones via a Tandem Quinazolinone Rearrangement/Intramolecular Ring Closure of Tautomeric (Z)-Benzamidines

Abstract

An expedient route to enantiopure, diastereomeric pyrrolopyrazinoquinazolinones was developed following the discovery of a domino quinazolinone rearrangement−intramolecular cyclization of N−H benzamidines. A Ugi−Mumm−Staudinger sequence employing an optically pure proline derivative gave quinazolinones that, upon N-Boc deprotection, rearranged to tautomeric Z-benzamidines. Subsequent spontaneous cyclization afforded 15 diastereomeric pyrazinoquinazolinone pairs in up to 83% overall yield and 89:11 d.r which were separated easily via routine chromatographic purificationthe only one required in the entire process.

Recent advances in the synthesis of 2,3-fused quinazolinones

“…In 2021, a simple method to access diastereomeric pyrrolopyrazinoquinazolinones was developed via a domino quinazolinone rearrangement and intramolecular cyclization of the N–H bond of benzamidines by Golden and co-workers (Scheme 59). 57 Firstly, quinazolinone 114 was constructed using the four-component Ugi–Mumm–Staudinger sequence, and then N -Boc deprotection of quinazolinone 114 converted it to the tautomeric Z -benzamidine 115 . Subsequently, spontaneous cyclization afforded the diastereomeric pyrazinoquinazolinones 116 .…”

Piperazinobenzodiazepinones: New Encephalitic Alphavirus Inhibitors via Ring Expansion of 2-Dichloromethylquinazolinones

“… 16 − 18 Consequently, we discovered several quinazolinone-based transformations leading to differentiated, bioactive heterocyclic frameworks. 19 , 20 …”

“…16−18 Consequently, we discovered several quinazolinone-based transformations leading to differentiated, bioactive heterocyclic frameworks. 19,20 For instance, 2-chloroquinazolinones, when treated with 1,2dimethylethanediamine, undergo a similar rearrangement to generate benzylguanidines 2 with improved plasma stability compared to the benzamidine series 1. 19 Herein, we describe the discovery of piperazine-fused benzodiazepinones 4 that result from the ring expansion of 2-dichloromethylquinazolinones 3 when treated with N,N′-dialkylethane-1,2-diamines (Scheme 1, panel b).…”

“…Following the discovery of a novel 2-chloromethylquinazolinone rearrangement that afforded potent, antialphaviral benzamidines 1 (Scheme , panel a), we have continued to explore this chemistry to elucidate the benzamidine pharmacophore and build structure–activity and structure–property relationships (SAR and SPR, respectively). − Consequently, we discovered several quinazolinone-based transformations leading to differentiated, bioactive heterocyclic frameworks. , …”

Dihydropyrazinoquinazolinones via SN2 Sulfamidate Ring-Opening and a Sequential Quinazolinone–Amidine Rearrangement Strategy (SQuAReS)

“…Recently, we reported a route to diastereomeric pyrrolopyrazino­quinazolinones (Figure a) . In that work, a Ugi–Mumm/aza-Wittig protocol generated densely functionalized quinazolinones that underwent a tandem quinazolinone rearrangement/intramolecular amidine ring closure.…”