Direct Access to Quinone-Fused 5-Substituted-1,4-Benzodiazepine Scaffolds from Azidoquinones with/without [1,2]-Azide-Nitrogen Migration: Mechanistic Insights

Abstract

Seven-membered nitrogen heterocycles have a strong influence in drug discovery due to their inherent 3D character, which allows the ability to explore a vast conformational space with a biological target. Notably, the privileged 1,4-benzodiazepine scaffold is dominant in treating the central nervous system due to its binding affinity with the GABAA receptor. Herein, we report a protocol for the transformation of azidoquinones to p-quinone fused 5-substituted-1,4-benzodiazepines (p-QBZDs) from InCl3-catalyzed intermolecular tandem cycloannulation of azidoquinones with amines and aldehydes. Detailed mechanistic studies reveal that the EDA complex between azidoquinones and InCl3 is crucial in determining the reaction pathway. In the absence of EDA complex formation, the reaction proceeds via the intermediacy of 2,3-bridged-2H-azirine followed by regiospecific addition of an amine to CN/ring opening/cyclization to deliver p-QBZD with 1,2-azide-nitrogen migration. In the case of EDA complex formation, the reaction proceeds through regioselective aza-Michael addition/nitrene insertion with aldehyde and subsequent cyclization to deliver p-QBZD and p-quinone fused imidazole as a secondary product without 1,2-azide-nitrogen migration. This protocol provides straightforward access to redox-active quinone embedded 5-substituted-1,4-benzodiazepines from azidoquinones with diverse substrate scopes that would find potential applications in medicinal chemistry and drug discovery.

2H‐Azirines: Recent Progress in Synthesis and Applications

“…Very recently, Kamaraj et al [28] discovered a InCl 3 -catalyzed intermolecular tandem cycloannulation of azidoquinones with amines and aldehydes, furnishing p-quinone fused 5-substituted-1,4-benzodiazepines (p-QBZDs) (Scheme 14). The reaction proceeded via the intermediacy of 2,3-bridged-2H-azirine followed by regiospecific addition of an amine to C=N/ring opening/cyclization to deliver p-QBZD with 1,2-azide-nitrogen migration.…”

Annulations involving p-benzoquinones: stereoselective synthesis of fused, spiro and bridged molecules

“…In 2023, Krishnan and Kamaraj devised a three-component reaction of quinone azides 82 , aromatic amines 83 and aldehydes 84 for the construction of quinone-fused benzodiazepines 85 . 88 The main feature of this reaction includes 1,2-azide-nitrogen migration, as illustrated in the mechanism (Scheme 25). The InCl 3 -catalyzed tandem intermolecular cyclo-annulation reaction proceeds via the formation of bridged aziridine B (through the extrusion of N 2 from A ).…”

High-yielding regioselective synthesis of p-quinone fused 5-substituted-1,4-benzodiazepine scaffolds via Pictet–Spengler type cycloannulation

“…12 Hence, a new class of BZDs with a broad spectrum of bioactivities with minimal adverse effects is highly desirable and is evidenced in the last two decades by the continuous flow of publications/patents, ∼43 990 hits, and ∼5186 results for clinical trials in “PubMed.” While attempting the total synthesis of Calothrixin A/B, we have encountered a serendipitous transformation of azido- p -quinones to p -quinone fused 5-substituted-1,4-benzodiazepines ( p -QBZDs) from InCl 3 -catalyzed intermolecular tandem cycloannulation of azido- p -quinones with amines and aldehydes. 13 Also, we have demonstrated that the electron-donor–acceptor (EDA) complex formation between azido- p -quinones and InCl 3 is crucial in determining the reaction pathway. In the absence of EDA complex formation, the reaction proceeds via the intermediacy of 2,3-bridged-2 H -azirine followed by regiospecific addition of an amine to CN/ring opening/cyclization to deliver p -QBZD with 1,2-azide-nitrogen migration.…”

“…Though this straightforward transformation of azido- p -quinones to structurally diversified p -quinone fused 5-substituted-1,4-benzodiazepine scaffolds compatible with various azido- p -quinones, it has certain undesired limitations like substrate-dependent yield, multiple reaction pathways and unavoidable secondary reactions (Scheme 1B). 13 To date, there are only two reports on the analogous p -quinone fused 1,4-benzodiazepines with limited substrate scope, regioselectivity issues and difficulties in accessing the required intermediates (Scheme 1C). In 2007, Reiner et al reported 14 the synthesis of N -aryl-5-aryl/alkyl substituted-1,4-naphthoquino-benzodiazepines from symmetrically/unsymmetrically substituted 2,3-bis(anilino)-1,4-naphthoquinone with aromatic/aliphatic aldehydes.…”

“…Gratifyingly, while examining the mechanistic studies on InCl 3 -mediated transformation of azido- p -quinones to p -QBZD, we have realized that the 2-amino-3-arylamino-1,4-quinone serves as a critical intermediate in determining the yield of p -QBZD. 13 Hence, to overcome the limitations mentioned above, we propose an alternative route for synthesizing the key intermediate 2-amino-3-arylamino-1,4-quinone from p -quinones. Herein, we report a versatile and robust protocol to access p -quinone fused 5-substituted-1,4-benzodiazepine scaffolds in high yield through Lewis/ Brønsted acid mediated reaction of 2-amino-3-arylamino-1,4-quinone via Pictet–Spengler type cycloannulation under mild reaction condition (Scheme 1D).…”