Benzodiazepines (BZDs), a diverse class of benzofused seven-membered N-heterocycles, display essential pharmacological properties and play vital roles in some biochemical processes. They have mainly been prescribed as potential therapeutic agents, which interestingly represent various biological activities such as anticancer, anxiolytic, antipsychotic, anticonvulsant, antituberculosis, muscle relaxant, and antimicrobial activities. The extensive biological activities of BZDs in various fields have encouraged medicinal chemists to discover and design novel BZD-based scaffolds as potential therapeutic candidates with the favorite biological activity through an efficient protocol. Although certainly valuable and important, conventional synthetic routes to these bicyclic benzene compounds contain methodologies often requiring multistep procedures, which suffer from waste materials generation and lack of sustainability. By contrast, multicomponent reactions (MCRs) have recently advanced as a green synthetic strategy for synthesizing BZDs with the desired scope. In this regard, MCRs, especially Ugi and Ugi-type reactions, efficiently and conveniently supply various complex synthons, which can easily be converted to the BZDs via suitable post-transformations. Also, MCRs, especially Mannich-type reactions, provide speedy and economic approaches for the one-pot and one-step synthesis of BZDs. As a result, various functionalized-BZDs have been achieved by developing mild, efficient, and high-yielding MCR protocols. This review covers all aspects of the synthesis of BZDs with a particular focus on the MCRs as well as the mechanism chemistry of synthetic protocols. The present manuscript opens a new avenue for organic, medicinal, and industrial chemists to design safe, environmentally benign, and economical methods for the synthesis of new and known BZDs.

Multicomponent reactions as a potent tool for the synthesis of benzodiazepines

A blue light-promoted reaction between aryldiazoacetates and different nucleophiles has been developed in the presence of THF (and other cyclic ethers) as solvent, allowing the incorporation of these three elements...

A Visible Light-Mediated Three-Component Strategy Based on the Ring-Opening of Cyclic Ethers with Aryldiazoacetates and Nucleophiles

Multicomponent reactions 9i.e., those that engage three or more starting materials to form a product that contains significant fragments of all of them), have been widely employed in the construction of compound libraries, especially in the context of diversity-oriented synthesis. While relatively less exploited, their use in target-oriented synthesis offers significant advantages in terms of synthetic efficiency. This review provides a critical summary of the use of multicomponent reactions for the preparation of active pharmaceutical principles.

/pdf/multicomponent-reactions-for-the-synthesis-of-active-2r2v40xw.pdf

Multicomponent Reactions for the Synthesis of Active Pharmaceutical Ingredients

Stereoselective cyclohexadienylamine synthesis through rhodium-catalysed [2+2+2] cyclotrimerization

Click-based conjugated microporous polymers as efficient heterogeneous photocatalysts for organic transformations

The Ugi Three-Component Reaction; a Valuable Tool in Modern Organic Synthesis

Fluorene and fluorenone are privileged structures with extensive utility in both materials science and drug discovery Here, we describe syntheses of those moieties through isocyanide-based multicomponent reactions (IMCRs) and the incorporation of the products in diverse and complex derivatives that can be further utilized We performed six different IMCRs, based on the dual functionality of 9-isocyano-9H-fluorene, and we describe 23 unprecedented adducts

Fluorene-Based Multicomponent Reactions

Local anesthetics occupy a prime position in clinical medicine as they temporarily relieve the pain by blocking voltage‐gated sodium channels. However, limited structural diversity, problems with the efficiency of syntheses and increasing toxicity, mean that alternative scaffolds with improved chemical syntheses are urgently needed. Here, we demonstrate a multicomponent reaction (MCR)‐based approach both towards the synthesis of commercial local anesthetics and towards novel derivatives as potential anesthesia candidates via scaffold hopping. The reactions are efficient and scalable, and several single‐crystal structures have been obtained. In addition, our methodology has been applied to the synthesis of the antianginal drug ranolazine, via an Ugi three‐component reaction. Representative derivatives from our libraries were evaluated as neuronal activity inhibitors using local field potential recordings (LFPs) in mouse hippocampal brain slices and showed very promising results. This study highlights new opportunities in drug discovery targeting local anesthetics.

Maria Thomaidi

Papers

The Ugi Three-Component Reaction; a Valuable Tool in Modern Organic Synthesis

Fluorene-Based Multicomponent Reactions

Local Anesthetics via Multicomponent Reactions