Base-Mediated [3 + 4]-Cycloaddition of Anthranils with Azaoxyallyl Cations: A New Approach to Multisubstituted Benzodiazepines

Abstract

A new [3 + 4] cycloaddition of azaoxyallyl cations and anthranils has been achieved for rapid access to multisubstituted benzodiazepine derivatives. A variety of anthranils and α-halo hydroxamates were both effective substrates with simple operations under transition-metal-free conditions. The intriguing features of this method include its mild nature of the reaction conditions, high efficiency, broad substrate scope, and wide functional group compatibility.N itrogen heterocycles are widespread structural motifs in bioactive natural products, therapeutic agents, agrochemicals, and material molecules with significant activities. 1 In particular, benzodiazepines, a member of the family of privileged scaffold, occupy a significant place in pharmaceutical ingredients. 2 As representative examples shown in Figure 1, SB-214857 (lotrafiban), a potent glycoprotein IIb/IIIa receptor antagonist, displays antithrombotic activity. 3 Diazepam, commercially known as Valium, is used to treat anxiety. 2a Abbemycin, isolated from Streptomyces sp. AB-999F-52, is an antibiotic. 4 TRAIL (tumor necrosis factor-related apoptosisinducing ligand)-resistance could be overcome by use of fuligocandin B. 5 Circumdatin D and E are two quinazolinobenzodiazepine alkaloids isolated from the fungus Aspergillus ochraceus. 6 Given the rich biological profiles of the sevenmembered nitrogen heterocycles in organic synthesis and medical chemistry, the development of a novel method to access benzodiazepine and related scaffolds remains highly desirable.[3 + 4]-Cycloaddition reaction is an efficient strategy to assemble seven-membered rings. 7 In recent years, azaoxyallyl

Mechanistic Investigations for the Formation of Active Hexafluoroisopropyl Benzoates Involving Aza‐Oxyallyl Cation and Anthranils

“…2, Scheme 1). [28b,30b] However, in light of an interesting transformation recently reported by Zhao et al [30a] . with 3‐substituted anthranils under similar reaction conditions leading to direct access of norbornane type benzodiazepines via 3+4 cycloannulation (eq.…”

Recent Advances in Transition-Metal-Free (4+3)-Annulations

“…For example, the reaction of 2.1a with -halohydroxamates 2.1b, a precursor to aza-oxyallyl cations 2.1c, generates intriguing bicyclic compounds such as 2.1d (Scheme 2.1). 8 In this scenario, K 2 CO 3 triggers an HBr elimination from 2.1b, giving rise to the reactive intermediate 2.1c. This work is just a recent example among many, exploiting a similar strategy, using inorganic bases to promote the (4+3)-annulations.…”

Anthranils: versatile building blocks in the construction of C–N bonds and N-heterocycles

“…Recently, a base-promoted [4 + 3] cycloaddition of azaoxyallyl cations and anthranils has been developed for rapid access to multisubstituted benzodiazepines (Scheme 28). 35 A variety of anthranils and α-halo hydroxamates 75 participated in this reaction very well under transition metal-free conditions. The in situ-generated azaoxyallyl cation was considered to be a key intermediate for this transformation.…”