Metal‐Catalyzed Routes to Dibenzodiazepines (DBDAs) and Structural Analogues: Recent Advances

Abstract

It is common knowledge that the use of transition metals as catalysts has greatly revolutionized various coupling procedures to access heterocyclic compounds of significant industrial interest. Dibenzodiazepines (DBDAs) are a particularly important group of heterocyclic compounds, with considerable pharmaceutical applications. In this review, we look at some of the catalytic methods that have been developed during the last 10 years for the synthesis of these targets. Palladium catalysts have been frequently used for these transformations, and particularly for the Buchwald–Hartwig reaction which has been a key reaction in a number of synthetic pathways. Copper has also been frequently used, including some other metals like iron and molybdenum, but to a lesser extent. In most cases, the examples chosen are for the synthesis of DBDAs with interesting medicinal properties and will be of interest to medicinal chemists. It should also be mentioned that due to the structural characteristics of these compounds the potential for diversification – principally for functional group incorporation – is immense. Emerging and facilitating technologies have also been employed for the synthesis of these molecules and are reviewed here.

Unsymmetrically-Substituted 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-dione Scaffold—A Useful Tool for Bioactive Molecules Design

“…2-benzoyl-5,12-dihydrodibenzo[b,f] [ 1 , 4 ] diazocine-6,11-dione ( 3c ), crystallized from ethyl acetate, yield 55%, beige crystals, m.p. 156.0–157.0 °C, R.f.…”

“…Its further development is largely dependent on the availability of new synthetic methods and approaches leading to heterocyclic derivatives [ 1 ]. Tricyclic heterocyclic scaffolds, possessing two non-polar phenyl rings separated by a seven-membered heterocycle, and their structural analogues, are challenging synthetic targets for organic chemists [ 2 , 3 , 4 , 5 ]. The development of a wide range of novel synthetic methods has led to the synthesis of a broad variety of derivatives with significant biological activity, where the tricyclic antipsychotic drugs focused the most attention [ 6 ].…”

“…While searching for novel tricyclic heterocyclic derivatives of medicinal importance [7][8][9], we turned our attention to 5,12-dihydrodibenzo[b,f ] [1,4]diazocine-6,11-dione 3 as a potential privileged scaffold for design and development of novel bioactive compounds. A brief literature survey revealed, that such compounds could be obtained from a condensation reaction of benzene-1,2-diamine and diethyl phthalate [13], benzene-1,2-diamine, and benzocyclobutene-l,2-dione [14,15] or Beckmann rearrangement of appropriate tricyclic dibenzoazepine oximes [16,17].…”

“…A brief literature survey revealed, that such compounds could be obtained from a condensation reaction of benzene-1,2-diamine and diethyl phthalate [13], benzene-1,2-diamine, and benzocyclobutene-l,2-dione [14,15] or Beckmann rearrangement of appropriate tricyclic dibenzoazepine oximes [16,17]. The parent compound 3 (R 1 = R 2 = R 3 = R 4 = H) could also be synthesized from benzene-1,2-diamine and 1,2-phenylenebis ((1H-benzo[d] [1,2,3]triazol-1-yl)methanone) obtained from phthaloyl dichloride and 1H-benzo [d] [1,2,3]triazole [18], while condensation of 5,6-diaminouracil with phtalic anhydride resulted in the formation of fused pyrimido [4,5-b] [1,4]diazocine ring [19].…”

“…

f ][1,4] diazocine-6,11-diones were synthesized in the new protocol. The desired modifications of the dibenzodiazocine scaffold were introduced at the stages of proper selection of building blocks as well as post-cyclization modifications with alkylation or acylation agents, expanding the structural diversity and possible applications of synthesized molecules.

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