One-pot, regiospecific assembly of (E)-benzamidines from δ- and γ-amino acids via an intramolecular aminoquinazolinone rearrangement

Abstract

The efficient generation of novel, N-linked benzamidines resulting from a regiospecific rearrangement of quinazolinones is described. This methodology study explored reaction parameters including the effect of changing solvent and temperature, as well as varying electronic substituents on the structural core. The transformation was extensively optimized in terms of reaction conditions and scope, resulting in a protocol that consistently affords diversely functionalized amidines in high yield. The process permits regional structural derivatization that was previously inaccessible, and the multistep process was also reduced to a telescoped, five-step sequence that efficiently affords pharmacologically unique (E)-benzamidoamidines from N-BOC protected γ- and δ-amino acids.

Efficacy of a brain-penetrant antiviral in lethal Venezuelan and eastern equine encephalitis mouse models

“…Synthesis of benzamidine-based, New World alphavirus inhibitors ( 24 ) such as BDGR-4 (compound 1; Table 1) depends on a regiospecific chemical rearrangement ( 39 , 40 ) of quinazolinone intermediates (fig. S1).…”

Telescoped synthesis of C3-functionalized (E)-arylamidines using Ugi–Mumm and regiospecific quinazolinone rearrangements

“…10 Further, we had reported previously a differentiated telescoped method by which simplified quinazolinones were converted to benzamidines. 8 Nonetheless, it was uncertain if the new process was amenable to being streamlined in this way, as excess reagents in the Ugi reaction and the new process as a whole introduced by-products that would be carried throughout and may interfere with the efficiency of progressive reactions.…”

“…13 C NMR (101 MHz, CDCl 3 ) δ 163. 8,160.6,153.0,135.7,134.2,126.8,123.3,119.2,105.0,61.9,47.2,45.3,42.3,41.4,37.2,23.1,23.0,11.5,3.9,3.6. HRMS (ESI): Calculated for C 20 H 27 N 5 O (M++H): 354.22884; Found: 354.22999.…”

“…This unique scaffold originated from a regiospecific rearrangement of chloroalkylquinazolinone 1a treated with 1,2-bis(methylamino)ethane to exclusively yield (E)-amidobenzamidine 3a (Scheme 1). We subsequently reported a one-pot method 8 by which extended N-Boc-protected amino acids were converted to quinazolinones 1b that could be efficiently transformed into more diverse amidines 3b. Both methods relied on generation of quinazolinone intermediates 1a-b from standard acylation of anthranilic acids, followed by amidation/cyclization.…”

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

“…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. , …”