Isocyanide-based multicomponent reactions for the synthesis of benzopyran derivatives with biological scaffolds.

Benzopyrans (BZPs) are among the most privileged and influential small O-heterocycles that form the core of many natural compounds, commercial drugs, biological compositions, agrochemicals, and functional materials. BZPs are divided into six general categories including coumarins, chromans, 2H-chromenes, 4H-chromenes, chromones, and 4-chromanones, each of which is abundant in many plants and foods. These oxygenated heterocyclic compounds are fascinating motifs and have extensive applications in biology and materials science. Hence, numerous efforts have been made to develop innovative approaches for their extraction and synthesis. However, most of them are step-by-step or multi-step strategies that suffer from waste material generation and a tedious extraction process. Isocyanide-based multicomponent reactions (I-MCRs) offer a highly efficient method for overcoming these problems. The I-MCR is a simple and environmentally friendly one-pot domino procedure that does not require intermediate isolation or workup and is generally more efficient in material usage. This review covers all research articles related to I-MCRs for synthesizing BZP derivatives from the beginning to the middle of the year 2023. This strategy will be useful for organic and pharmaceutical chemists to design new drugs and optimize the synthesis steps of biological compounds and commercial drugs with benzopyran cores.

Using Triazolobenzodiazepine as the Cyclic Imine in Various Types of Joullié-Ugi Reactions.

The triazolobenzodiazepine as a cyclic imine was employed in a variety of Joullié-Ugi reactions, and three new families of unique triazolobenzodiazepine connected to carboxamide and tetrazole products were synthesized via a three-component reaction of the cyclic imine and isocyanides with each species of a carboxylic acid/water/TMSN3 under mild conditions in high yields. Furthermore, triazolobenzodiazepine imine was used in an interesting strategy based on the modified Ugi reaction (pseudo-Joullié-Ugi reaction) of cyclic imines with an isocyanide and acetylenedicarboxylates under catalyst-free conditions for the synthesis of triazolobenzodiazepine-fused pyrroles. Mechanistic investigation reveals that triazolobenzodiazepine-fused pyrroles have been generated via a surprising route. Significantly, the use of triazolobenzodiazepine in the Joullié-Ugi, azido-Joullié-Ugi, and pseudo-Joullié-Ugi reactions of a broad scope of biological scaffolds occurred under mild, simple conditions without any catalyst.

The new synthesis of pyrrole-fused dibenzo[b,f][1,4]oxazepine/thiazepines by the pseudo-Joullié-Ugi reaction via an unexpected route with high chemoselectivity.

A novel and unexpected route for synthesizing pyrrole-fused dibenzoxazepines/thiazepines has been designed based on a modified Ugi reaction of cyclic imines with isocyanides and acetylenedicarboxylates under catalyst-free conditions. Mechanism investigation indicates that this process is carried out through the production of zwitterion species (Huisgen's 1,4-dipole), which is a key intermediate in the chemoselectivity of products. This Huisgen's 1,4-dipole is trapped in situ with isocyanides and a variety of pyrrole-fused dibenzoxazepines/thiazepines are synthesized in a simple one-pot operation with high yields and chemoselectivity. This strategy opens a new route in Ugi reactions (pseudo-Joullié-Ugi reaction) for the synthesis of pyrrole-fused heterocycles as special pharmaceutical scaffolds.

Isocyanide-based consecutive Bargellini/Ugi reactions: an efficient method for the synthesis of pseudo-peptides containing three amide bonds.

Isocyanide-based consecutive Bargellini/Ugi multicomponent reactions as a combinatorial strategy have been developed for the synthesis of new class of pseudo-peptides. Via Bargellini reaction 3-carboxamido-isobutyric acids are prepared using acetone, chloroform, sodium hydroxide, and isocyanides. Then, using Ugi multicomponent reaction strategy, pseudo-peptides containing three amide bonds are synthesized using the Bargellini reaction product, aldehydes, amines, and isocyanides. This is an efficient and eco-friendly approach for easy access to wide variety of structurally diverse, drug-like pseudo-peptides from cheap and readily available precursors in high yields.

Chemoselective synthesis of fully substituted pyrroles via a one-pot four-component isocyanide-based reaction.

Small-ring heterocycles comprising pyrrole and pyrazole are well known for their rich biological properties. In this article, an efficient green sonochemical approach was designed for the synthesis of novel, fully substituted pyrroles connected to pyrazole scaffolds via a one-pot, four-component isocyanide-based sequential reaction. This reaction was carried out using various 5-amino-pyrazoles, aldehydes, dialkyl acetylenedicarboxylates and isocyanides for the synthesis of fully functionalized pyrroles with high chemoselectivity in the presence of a catalytic amount of PTSA·H2O, in good to excellent yields under ultrasound irradiation. This waste-free (-H2O) reaction exhibited a high atom economy and step economy via creating four new bonds, including two C-N and two C-C bonds, and the formation of two five-member heterocycles which are connected in a single operation. The mechanism of this four-component domino process involved sequential imination-dipolar cyclization-[1,5]-H shift reactions. The synthesized compounds possess interesting fluorescence features, and the bioactive scaffolds might attract great interest in the fields of clinical diagnostics and biomedical research in the future.

Multicomponent reactions as a potent tool for the synthesis of benzodiazepines.

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.

The status of isocyanide-based multi-component reactions in Iran (2010-2018).

Isocyanides as key intermediates and magic reactants have been widely applied in organic reactions for direct access to a broad spectrum of remarkable organic compounds. Although the history of these magical compounds dates back more than 100 years, it still has been drawing widespread attention of chemists who confirmed their versatility and effectiveness. Because of their wide spectrum of pharmacological, industrial and synthetic applications, many reactions with the utilization of isocyanides are reported in the literature. In this context, Iranian scientist played a significant role in the growth of isocyanides chemistry. The present review article covers literature from the period starting from 2010 onward and encompasses new synthetic routes and organic transformation involving isocyanides by Iranian researchers. During this period, a diverse range of isocyanide-based multi-component reactions (I-MCRs) has been reported such as a new modification of Ugi, post-Ugi, Passerini and Groebke-Blackburn-Bienayme condensation reactions, isocyanide-based [1 + 4] cycloaddition reactions, isocyanide-acetylene-based MCRs, isocyanide and Meldrum's acid-based MCRs, several unexpected reactions besides green mediums and novel catalytic systems for the synthesis of diverse kinds of pharmaceutically and industrially remarkable heterocyclic and linear organic compounds. This review also emphasizes the neoteric applications of I-MCR for the synthesis of valuable peptide and pseudopeptide scaffolds, enzyme immobilization and functionalization of materials with tailorable properties that can play important roles in the plethora of applications.

5-Amino-pyrazoles: potent reagents in organic and medicinal synthesis.

5-Amino-pyrazoles have proven to be a class of fascinating and privileged organic tools for the construction of diverse heterocyclic or fused heterocyclic scaffolds. This review presents comprehensively the applications of 5-amino-pyrazoles as versatile synthetic building blocks in the synthesis of remarkable organic molecules with an emphasis on versatile functionalities. Following a brief introduction of synthesis methods, planning strategies to construct organic compounds, particularly diverse heterocyclic scaffolds, such as poly-substituted heterocyclic compounds and fused heterocyclic compounds via 5-amino-pyrazoles, have been summarized. Fused heterocycles are classified as bicyclic, tricyclic, tetracyclic, and spiro-fused pyrazole derivatives. These outstanding compounds synthesized via wide variety of approaches include conventional reactions, one-pot multi-component reactions, cyclocondensation, cascade/tandem protocols, and coupling reactions. 5-Amino-pyrazoles represent a class of promising functional reagents, similar to the biologically active compounds, highlighted with diverse applications especially in the field of pharmaceutics and medicinal chemistry. Notably, this critical review covers the articles published from 1981 to 2018.

Copper phthalocyanine-conjugated pectin via the Ugi four-component reaction: An efficient catalyst for CO2 fixation.

Due to the cost-effectivity and biodegradability advantages of pectin, this type of polysaccharide attracted the attention of many researchers for catalyst construction. Accordingly, pectin was used as a green support in this study to construct an efficient heterogeneous catalytic system based on the conjugation of metal phthalocyanines. To end this, pectin was first oxidized with periodate oxidant agent to effectively immobilize a tetra-amino copper phthalocyanine (Cu-PcTA) through a green, simple, and an efficient one-pot Ugi four-component reaction (Ugi-4CR). Then, the catalytic activity of the copper phthalocyanine-conjugated pectin was investigated in the CO2 fixation reaction to cyclic carbonates. Optimum catalytic conditions were as follows: 30 mg of prepared catalyst, 3 bar CO2 pressure, 90 °C, 2 h, and TBAB as a co-catalyst. Pectin can successfully improve the catalytical properties of the Cu-PcTA over the CO2 fixation reaction.

Isocyanide-Based Multicomponent Reactions in Water: Advanced Green Tools for the Synthesis of Heterocyclic Compounds.

Reaction rate acceleration using green methods is an intriguing area of research for chemists. In this regard, water as a "green solvent" plays a crucial role in the acceleration of some organic transformations and reveals exclusive selectivity and reactivity in comparison with conventional organic solvents. In particular, multicomponent reactions (MCRs) as sustainable tools lead to the rapid generation of small-molecule libraries in water and aqueous media due to the prominent role of the hydrophobic effect. MCRs, as diversity-oriented synthesis (DOS) methods, have great efficiency with simple operations, atom, pot, and step economy synthesis, and mechanistic beauty. Among diverse classes of MCRs, isocyanide-based multicomponent reactions (I-MCRs), as sustainable and versatile reactions, have gained considerable attention in the synthesis of diverse heterocycle rings, especially in drug design because of the peculiar nature of isocyanide as a particular active reactant. I-MCRs that are performed in water are mild, environmentally friendly, and easily controlled, and have a reduced number of workup, purification, and extraction steps, which fit well with the advantages of "green" chemistry. Performing these powerful organic transformations in water and aqueous media is accompanied by acceleration owing to negative activation volumes, which originate from connecting several reactants together to generate a single product. It should be noted that the combination of MCR strategy and aqueous phase reaction is of growing interest for the development of sustainable synthetic techniques in organic conversions. However, an exclusive account focusing on the recent progress in eco-friendly I-MCRs for the construction of heterocycles in water and aqueous media is particularly lacking. This review highlights the progress of various kinds of I-MCRs in water and aqueous media as benign methods for the efficient construction of vital heterocyclic scaffolds, with a critical discussion of the subject in the period 2000-2021. We hope that this themed collection will be of interest and beneficial for organic and pharmaceutical chemists and will inspire more reaction development in this fascinating field.

Cyclic Imines in Ugi and Ugi-Type Reactions.

Ugi four-component reactions (U-4CRs) are widely recognized as being highly efficient for the synthesis of pseudopeptides. However, the products of these reactions are not so interesting as drug candidates because they are not conformationally restricted enough for a potent interaction with biological targets. One possible way to overcome this problem is to replace amine and oxo components in the U-4CRs with cyclic imines in so-called Joullié-Ugi three-component reactions (JU-3CRs). This approach provides a robust single-step route to peptide moieties connected to N-heterocyclic motifs that are found as core skeletons in many natural products and pharmaceutical compounds. JU-3CRs also provide much better diastereoselectivity than their four-component analogues. We survey here the redesign of many synthetic routes for the efficient preparation of a wide variety of three-, five-, six-, and seven-membered heterocyclic compounds connected to the peptide backbone. Additionally, in the Ugi reactions based on the cyclic imines, α-acidic isocyanides, or azides can be replaced with normal isocyanides or acids, respectively, leading to the synthesis of N-heterocycles attached to oxazoles or tetrazoles, which are of great pharmaceutical significance. This Review includes all research articles related to Ugi reactions based on the cyclic imines to the year 2020 and will be useful to chemists in designing novel synthetic routes for the synthesis of individual and combinatorial libraries of natural products and drug-like compounds.

Green one-pot synthesis of multicomponent-crosslinked carboxymethyl cellulose as a safe carrier for the gentamicin oral delivery.

Multicomponent reactions (MCRs) as a green strategy was used to crosslink carboxymethylcellulose (CMC) via the construction of bioactive carboxamide skeletons for the gentamicin (GM) oral delivery. The prepared multicomponent-crosslinked (MCC) CMC hydrogels (CMC-MCC) were fully characterized using various methods. To explain the productivity of the prepared system, GM delivery tests performed in the simulated gastrointestinal tract (GIT) conditions. CMC-MCC could efficiently protect the loaded-GM against the acidic environment of the stomach and enhance the sustainability of drug dosing with controlling the releases in the GIT circumstances. The antibacterial performance showed that the GM-loaded CMC-MCC has notable activity against S. aureus and E. coli bacteria. Besides, the cytotoxicity study indicated that CMC-MCC toward healthy normal human umbilical vein endothelial cells (HUVEC) has a cytocompatibility nature.