Divergent 2‐Chloroquinazolin‐4(3H)‐one Rearrangement: Twisted‐Cyclic Guanidine Formation or Ring‐Fused N‐Acylguanidines via a Domino Process

Abstract

A highly efficient 2‐chloroquinazolin‐4(3H)‐one rearrangement was developed that predictably generates either twisted‐cyclic or ring‐fused guanidines in a single operation, depending on the presence of a primary versus secondary amine in the accompanying diamine reagent. Exclusive formation of twisted‐cyclic guanidines results from pairing 2‐chloroquinazolinones with secondary diamines. Use of primary amine‐containing diamines permits a domino quinazolinone rearrangement/intramolecular cyclization, gated through (E)‐twisted‐cyclic guanidines, to afford ring‐fused N‐acylguanidines. This scalable, structurally tolerant transformation generated 55 guanidines and delivered twisted‐cyclic guanidines with robust plasma stability and an abbreviated total synthesis of an antitumor ring‐fused guanidine (4 steps, 55 % yield).

Design and synthesis of novel quinazolinone-based derivatives as EGFR inhibitors with antitumor activity

“…Nineteen new quinazolin-4(3 H )-one derivatives 3a–g and 6a–l were synthesised according to Scheme 1 . The key starting compounds 3-phenyl-2-thioxo-2,3-dihydroquinazolin-4( 1H )-one ( 1a ) and 3–(4-chlorophenyl)-2-thioxo-2,3-dihydroquinazolin-4( 1H )-one ( 1b ) were obtained in good yields by reacting anthranilic acid with the appropriate aryl isothiocyanate in refluxing ethanol in presence of triethylamine as catalyst 30 , 31 . Compounds 1a,b were then treated with hydrazine hydrate 99% as reported to yield 2-hydrazinyl-3-phenylquinazolin-4( 3H )-one ( 2a ) and 3–(4-chlorophenyl)-2-hydrazinylquinazolin-4( 3H )-one ( 2b ) 31 .…”

“…The original NMR spectra of the investigated compounds are provided as supporting information. Compounds 1a,b 30 , 31 , 2a,b 31 , 4a,b 32 , 33 and 5a,b 32 , 33 were prepared as reported.…”

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).…”

“…We studied the rearrangement using a 2-dichloromethylquinazolinone because the 2,2-dichloroacetyl chloride required for the quinazolinone assembly was more economical than 2fluoro-2-chloroacetyl chloride, the same products were expected, and chloride as a leaving group was likely more favorable than the loss of fluoride, possibly improving the yield. Furthermore, we also knew from the benzamidines' optimizations that incorporating an amido-N-3-fluoro-4-methoxyphenyl group (i.e., amide-PMP group in 6) typically provided analogs with a better overall profile, and reaction optimization could then be more easily monitored by 19 F NMR. Taking these considerations into account, reaction optimization with 2-(dichloromethyl)-3-(3-fluoro-4-methoxyphenyl)-6-nitroquinolin-4(3H)-one was undertaken (Table S1 in the Supporting Information).…”