Synthesis of 1,4-benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones by addition of Grignard reagents to derivatives of o-aminobenzonitrile

Abstract

Addition of organometallics to N-(alpha-haloacyl)-o-aminobenzonitrile resulted in the formation of 2,5-disubstituted 1,4-benzodiazepin-3-ones, whereas N-(beta-haloacyl)-o-aminobenzonitrile gave 2,6-disubstituted 1,5-benzodiazocin-4-ones under similar conditions. Initial cylization of N-(beta-haloacyl)-o-aminobenzonitrile to obtain the corresponding lactam (e.g.alpha,alpha-dimethyl-N-(2-cyanophenyl)-beta-lactam) increased the yield of 1,5-benzodiazocin-4-ones significantly. Somewhat surprisingly, addition of lithium reagents to N-(beta-haloacyl)-o-aminobenzonitrile gave 4,4-disubstituted quinazolines via Grob fragmentation.

Chemical Biology: What is Its Role in Drug Discovery?

“…Phosphaoseltamivir conjugates were synthesised and used to study influenza neuraminidases (Carbain et al, 2009). Since the 1,4-benzodiazepine moiety is present in well-known drugs such as Valium and Xanax, a study on the synthesis of novel 1,4-benzodiazepin-3-ones was carried out (Pettersson & Bergman, 2009). Novel Milnacipran derivatives were synthesised as potential anti-depressants (Vervisch et al, 2009).…”

Regioselective Synthesis of 2‐Acylquinazolines and 3H‐1,4‐Benzodiazepin‐3‐ones by a Ugi 4CC/Staudinger/aza‐Wittig Sequence

“…Recently, some 3 H ‐1,4‐benzodiazepin‐3‐ones were found to show biological activities, such as high AT 2 receptor affinity and GPIIb/IIIa antagonistical activity . A few synthetic methods have also appeared during the last decade, usually involving nucleophilic aromatic substitution , cycloaddition of some N ‐alkenoyl aryl azides , and addition of Grignard reagents to o ‐aminobenzonitriles .…”