Recent developments in solvent-free multicomponent reactions: a perfect synergy for eco-compatible organic synthesis

Review: more than 400 refs.

This chapter illustrates how much asymmetric organometallic catalysis has contributed to the development of enantioselective domino and multicomponent reactions. It updates the major progress in the field of enantioselective one-, two-, and multicomponent domino reactions promoted by chiral metal catalysts. It is divided into two parts, which deal with one- and two-component domino reactions, and multicomponent reactions, respectively. The first part is subdivided into 12 sections, dealing successively with domino reactions initiated by the Michael reaction, domino reactions initiated by an aldol reaction, domino reductive aldol reactions, domino reactions initiated by a [2+2+2] cycloaddition, domino reactions initiated by an allylic alkylation, domino Passerini-type reactions, domino carbonyl ylide-formation—1,3-dipolar cycloaddition reactions, domino reactions initiated by the Heck reaction, domino reactions initiated by the Wacker reaction, domino reactions based on cyclisations, domino radical reactions, and finally miscellaneous domino reactions. The second part of the chapter, which concerns the multicomponent reactions, is subdivided into 10 sections, dealing with multicomponent reactions initiated by the Michael reaction, multicomponent reactions based on the Mannich reaction, multicomponent reactions initiated by a pericyclic reaction, multicomponent reactions based on the Passerini reaction, multicomponent reactions initiated by the Friedel—Crafts reaction, multicomponent reactions of alkynes, aldehydes and amines, multicomponent reactions of 1,3-dienes, aldehydes and reducing agents, multicomponent reductive amination reactions of ketones, multicomponent Kabachnik—Fields reactions, and finally miscellaneous multicomponent reactions. This chapter demonstrates the economic interest in combinations of asymmetric metal catalytic processes, with the concept of domino and multicomponent reactions. These allow attainment of high molecular complexity with often high stereocontrol through simple operational one-pot procedures, and advantages of savings in solvent, time, energy, and costs. The wide variety of these fascinating domino reactions reflects that of the metals employed to induce them. Indeed, an increasing number of different metals such as magnesium, scandium, titanium, ruthenium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver, gold, zinc and aluminium, as well as tin, have been found to be effective catalysts.

Multicomponent reactions have become increasingly popular as tools for the rapid generation of small-molecule libraries. However, to ensure sufficient molecular diversity and complexity, there is a continuous need for novel reactions. Although serendipity has always played an important role in the discovery of novel (multicomponent) reactions, rational design strategies have become much more important over the past decade. In this Review, we present an overview of general strategies that allow the design of novel multicomponent reactions. The challenges and opportunities for the future will be discussed.

Transition metal-catalyzed C-H bond functionalization has numerous applications in organic synthesis as a powerful type of bond transformation. In particular, the combination of C-H functionalization with other types of chemical transformations in the manner of multicomponent reactions is an even more beneficial tool in the synthesis of small organic molecules because such reactions provide a platform for the rapid generation of high molecular diversity and complexity by making use of the advantages of both latent C-H bond transformation and the multicomponent reaction. Herein, we provide a review highlighting the research advances in the multicomponent reactions built upon transition metal-catalyzed C-H bond functionalization. The content spans from the reactions featuring the functionalization of C(sp3)-H, C(sp2)-H and C(sp)-H bonds over the last decade.

Multicomponent reactions (MCRs) are one-pot processes in which at least three reactants are combined to assemble a novel target product by intrinsic molecular diversity, optimal atom economy, and high efficiency. The development and design of new MCRs that yield valuable chemical products represent a major focus in organic chemistry. Meldrum's acid is a distinctive β-keto ester that is crucial in organic synthesis, especially in MCRs. The C5 position of this molecule demonstrates significant reactivity towards electrophilic substitution, whereas the carbonyl centers at C4 and C6 are notably vulnerable to nucleophilic attack. Its dual characteristics as both a nucleophile and electrophile, along with its tendency for enolization and decarboxylation, render it an essential synthon for the effective assembly of various heterocyclic scaffolds and acyclic organic compounds. In parallel, isocyanides have attracted significant attention as a versatile building block in MCRs because of their unique ambident reactivity. The combination of Meldrum's acid with isocyanide has opened a powerful avenue in diversity-oriented synthesis, leading to the discovery of unexpected products such as succinimide, carboxamide, imino-furopyranones, cyclopenta[b] pyridines, benzodiazepines, benzooxazepines, amidodiesters, functionalized triamides, and enamides. In continuation of our earlier review on Meldrum's acid and isocyanide-based MCRs, this minireview covers an in-depth discussion of this field, especially focusing on the most recent results from 2015 to 2025.

Multicomponent reactions (MCRs) receive increasing attention because they address both diversity and complexity in organic synthesis. Thus, in principle diverse sets of relatively complex structures can be generated from simple starting materials in a single reaction step. The ever increasing need for optically pure compounds for pharmaceutical and agricultural applications as well as for catalysis promotes the development of asymmetric multicomponent reactions. In recent years, asymmetric multicomponent reactions have been applied to the total synthesis of various enantiopure natural products and commercial drugs, reducing the number of required reaction steps significantly. Although many developments in diastereoselective MCRs have been reported, the field of catalytic enantioselective MCRs has just started to blossom. This critical review describes developments in both diastereoselective and catalytic enantioselective multicomponent reactions since 2004. Significantly broadened scopes, new techniques, more environmentally benign methods and entirely novel MCRs reflect the increasingly inventive paths that synthetic chemist follow in this field. Until recently, enantioselective transition metal-catalyzed MCRs represented the majority of catalytic enantioselective MCRs. However, metal contamination is highly undesirable for drug synthesis. The emergence of organocatalysis greatly influences the quest for new asymmetric MCRs.

By generating structural complexity in a single step from three or more reactants, multicomponent reactions (MCRs) make it possible to synthesize target compounds with greater efficiency and atom economy. The history of such reactions can be traced to the mid-19th century when Strecker first produced alpha-aminonitriles from the condensation of aldehydes with ammonia and hydrogen cyanide. Recently, academic chemists have renewed their interest in MCRs. In part, the pharmaceutical industry has fueled this resurgence because of the growing need to assemble libraries of structurally complex substances for evaluation as lead compounds in drug discovery and development programs. The application of MCRs to that increasingly important objective remains limited by the relatively small number of such reactions that can be broadly applied to prepare biologically relevant or natural-product-like molecular frameworks. We were interested in applying logic-based approaches, such as our single reactant replacement (SRR) approach, as a way both to improve known MCRs and to design new multiple-component routes to bioactive structures. This Account provides several examples that illustrate the use of SRR with known MCRs as starting points for synthetic innovation in this area. As part of our working hypothesis, we initially explored strategies for engineering improvements into known MCRs, either by increasing the dimensionality--that is, changing an n-component to an (n + 1)-component reaction--or broadening the scope of useful input structures, or both. By exhaustively applying retrosynthetic analysis to the cognate MCR to identify and exploit alternative entry points into the overall reaction manifold, we have devised several such re-engineered MCRs. Serendipitous findings have also augmented the yield of useful developments from our logic-inspired approach. In some cases, we have identified surprising links between different compound families that provide useful new entry points for chemical library synthesis. In other cases, the same re-engineering logic made it possible (sometimes in unexpected ways) to transform certain nonelementary two-component reactions into higher order MCRs. While logic may also inspire the search for new MCRs, the design process requires added chemical creativity, which cannot be reduced to a simple formula. The long-term goal of our research is to expand the useful repertoire of such reactions, which are important as complexity-generating tools in both combinatorial and diversity-oriented synthesis.

Since Strecker's discovery of multicomponent reactions (MCRs) in 1850, the strategy of applying an MCR approach has been in use for over a century. Due to their ability to quickly develop molecular diversity and structural complexity of interest, MCRs are considered an efficient approach in organic synthesis. Although MCRs such as the Ugi, Passerini, Biginelli, and Hantzsch reactions are widely studied, this review emphasizes the significance of selective MCRs to elegantly produce organic compounds of potential use in medicinal chemistry and industrial and material science applications, as well as the use of the MCR approach to sustainable methods. During synthesis, MCRs provide advantages such as atom economy, recyclable catalysts, moderate conditions, preventing waste, and avoiding solvent use. MCRs also reduce the number of sequential multiple reactions to one step.

Multicomponent Reactions in Polymer Science.

Tetrahydropyridines (THPs) are important nitrogen-based ring compounds found in many natural and synthetic molecules with wide biological importance. Their simple structure and chemical flexibility make them valuable in drug design and organic synthesis. Among different synthetic methods, multicomponent reactions (MCRs) have become a fast, efficient, and eco-friendly approach for preparing a large variety of THP derivatives in a single step. This review focuses on recent developments in the synthesis of tetrahydropyridines using MCRs with different nitrogen sources such as amines, enamines, imines, ammonia, ammonium acetate, etc. It also highlights green and sustainable methods like solvent-free, microwave-assisted, photoinduced, and catalyst-free reactions. Overall, this review explains how multicomponent reactions provide an easy, economical, and environmentally friendly route for building diverse tetrahydropyridine structures useful in chemical and medicinal research.

Review: 284 refs.

Background: The use of solid bases as heterogeneous catalysts allows the replacement of conventional bases in Organic Chemistry, being of outmost importance. Lamellar double hydroxides or hydrotalcites are materials having excellent basic properties and high surface areas. As their surface properties have been used as bifunctional catalysts allowing the incorporation of metals and depending on the calcination temperature, these materials may exhibit Lewis or Brönsted basic sites. Additionally, they are widely used in various organic synthesis reactions. Objective: This contribution has been aimed to provide a compilation of the application of hydrotalcites as basic materials in organic synthesis, with a particular emphasis on multicomponent reactions. Conclusion: Hydrotalcites act as heterogeneous catalysts that conduct highly efficient processes in short reaction times and with the advantage of their easy recovery and reuse without significant loss of their catalytic activity. In addition, due to the modification of their structural and chemical properties, they are catalysts with multiple applications in organic synthesis such as Michael addition reactions, dehydrogenation reactions of alcohols, Knoevenagel condensations, reduction reactions, oxidations, epoxidations, multicomponent reactions, among others. Multicomponent reactions are of major interest since they allow obtaining compounds that have high biological activity and are generated through processes in a single step by combining three or more starting reagents under solvent-free conditions.

Creating sequential one-pot combinations of multi-component reactions (MCRs) and multi-catalysis cascade (MCC) reactions is a challenging task that has already emerged as a new technology in synthetic organic chemistry. Through one-pot sequential combination of MCRs/MCC reactions, the chemical products (fine chemicals, agrochemicals and pharmaceuticals) that add value to our lives can be produced with less waste and greater economic benefits. Within this Emerging Area, we describe our recent developments and designs for sequential one-pot MCRs/MCC reactions to facilitate their realization as biomimetics in organic chemistry.

The synthesis of quinoline derivatives through multicomponent reactions (MCRs) has emerged as an efficient and versatile strategy in organic synthesis. MCRs offer the advantage of constructing complex molecular architectures in a single step, utilising multiple starting materials in a convergent manner. This review provides an overview of recent advancements in the field of quinoline synthesis via MCRs. Various MCRs, such as the Povarov reaction, the Gewald reaction, and the Ugi reaction have been successfully employed for the synthesis of diverse quinoline scaffolds. These methodologies not only showcase high atom economy but also allow the incorporation of structural diversity into the final products. The versatility of MCRs enables the introduction of functional groups and substitution patterns tailored to specific applications. This review highlights the significance of quinoline derivatives in medicinal chemistry, materials science, and other interdisciplinary areas. The continuous innovation and development of novel MCR-based approaches for quinoline synthesis hold great promise for the rapid and efficient generation of valuable compounds with a wide range of biological and physicochemical properties.

Preface. Personal Foreword. 1. Introduction: Microwave Synthesis in Perspective. 1.1 Microwave Synthesis and Medicinal Chemistry. 1.2 Microwave: Assisted Organic Synthesis (MAOS) - A Brief History. 1.3 Scope and Organization of the Book. 2. Microwave Theory. 2.1 Microwave Radiation. 2.2 Microwave Dielectric Heating. 2.3 Dielectric Properties. 2.4 Microwave Versus Conventional Thermal Heating. 2.5 Microwave Effects. 2.5.1 Thermal Effects (Kinetics). 2.5.2 Specific Microwave Effects. 2.5.3 Non-Thermal (Athermal) Microwave Effects. 3. Equipment Review. 3.1 Introduction. 3.2 Domestic Microwave Ovens. 3.3 Dedicated Microwave Reactors for Organic Synthesis. 3.4 Multimode Instruments. 3.4.1 Milestone s.r.1. 3.4.2 CEM Corporation. 3.4.3 Biotage AB. 3.4.4 Anton Paar GmbH. 3.5 Single-Model Instruments. 3.5.1 Biotage AB. 3.5.2 CEM Corporation. 3.6 Discussion. 4. Microwave Processing Techniques. 4.1 Solvent-Free Reactions. 4.2 Phase-Transfer Catalysis. 4.3 Reactions Using Solvents. 4.3.1 Open-versus Closed-Vessel Conditions. 4.3.2 Pre-Pressurized Reaction Vessels. 4.3.3 Non-Classical Solvents. 4.4 Parallel Processing. 4.5 Scale-Up in Batch and Continuous-Flow. 5. Starting with Microwave Chemistry. 5.1 Why Use Microwave Reactors? 5.2 Translating Conventionally Heated Methods. 5.2.1 Open and Closed Vessels? 5.2.2 Choice of Solvent. 5.2.3 Temperature and Time. 5.2.4 Microwave Instrument Software. 5.3 Reaction Optimization and Library Generation - A Case Study. 5.3.1 Choice of Solvent. 5.3.2 Catalyst Selection. 5.3.3 Time and Temperature. 5.3.4 Reinvestigation by a Design of Experiments Approach. 5.3.5 Optimization for Troublesome Building Block Combinations. 5.3.6 Automated Sequential Library Production. 5.4 Limitations and Safety Aspects. 6. Literature Survey Part A: General Organic Synthesis. 6.1 Transition Metal-Catalyzed Carbon-Carbon Bond Formations. 6.1.1 Heck Reactions. 6.1.2 Suzuki Reactions. 6.1.3 Sonogashira Reactions. 6.1.4 Stille Reactions. 6.1.5 Negishi, Kumada, and Related Reactions. 6.1.6 Carbonylation Reactions. 6.1.7 Asymmetric Allylic Alkyations. 6.1.8 Miscellaneous Carbon-Carbon Bond-Forming Reactions. 6.2 Transition Metal-Catalyzed Carbon-Heteroatom Bond Formations. 6.2.1 Buchwald-Hartwig Reactions. 6.2.2 Ullmann Condensation Reactions. 6.2.3 Miscellaneous Carbon-Heteroatom Bond-Forming Reactions. 6.3 Other Transition Metal-Mediated Processes. 6.3.1 Ring Closing Metathesis. 6.3.2 Pauson-Khand Reactions. 6.3.3 Carbon-Hydrogen Bond Activation. 6.3.4 Miscellaneous Reactions. 6.4 Rearrangement Reactions. 6.4.1 Claisen Rearrangements. 6.4.2 Domino/Tandem Claisen Rearrangements. 6.4.3 Squaric Acid-Vinylketene Rearrangements. 6.4.4 Vinylcyclobutane-Cyclohexene Rearrangements. 6.4.5 Miscellaneous Rearrangements. 6.5 Diels-Alder Cycloaddition Reactions. 6.6 Oxidations. 6.7 Catalytic Transfer Hydrogenations. 6.8 Mitsunobu Reactions. 6.9 Glycosylation Reactions and Related Carbohydrate-Based Transformations. 6.10 Multicomponent Reactions. 6.11 Alkylation Reactions. 6.12 Nucleophilic Aromatic Substitutions. 6.13 Ring-Opening Reactions. 6.13.1 Cyclopropane Ring-Opening. 6.13.2 Aziridine Ring-Openings. 6.13.3 Epoxide Ring-Opening. 6.14 Addition and Elimination Reactions. 6.14.1 Michael Additions. 6.14.2 Addition to Alkenes. 6.14.3 Addition to Alkenes. 6.14.4 Addition to Nitriles. 6.15 Substitution Reactions. 6.16 Enamine and Imine Formations. 6.17 Reductive Aminations. 6.18 Ester and Amide Formation. 6.19 Decarboxylation Reactions. 6.20 Free Radical Reactions. 6.21 Protection/Deprotection Chemistry. 6.22 Preparation of Isotopically Labeled Compounds. 6.23 Miscellaneous Transformations. 6.24 Heterocycle Synthesis. 6.24.1 Three-Membered Heterocycles with One Heteroaton. 6.24.2 Four-Membered Heterocycles with One Heteroatom. 6.24.3 Five-Membered Heterocycles with One Heteroatom. 6.24.4 Five-Membered Heterocycles with Two Heteroatom. 6.24.5 Five-Membered Heterocycles with Three Heteroatom. 6.24.6 Five-Membered Heterocycles with Four Heteroatom. 6.24.7 Six-Membered Heterocycles with One Heteroatom. 6.24.8 Six-Membered Heterocycles with Two Heteroatom. 6.24.9 Six-Membered Heterocycles with Three Heteroatom. 6.24.10 Larger Heterocyclic and Polycyclic Ring Systems. 7. Literature Survey Part B: Combinatorial Chemistry and High-Throughput Organic Synthesis. 7.1 Solid-Phase Organic Synthesis. 7.1.1 Combinatorial Chemistry and Solid-Phase Organic Synthesis. 7.1.2 Microwave Chemistry and Solid-Phase Organic Synthesis. 7.1.3 Peptide Synthesis and Related Examples. 7.1.4 Resin Functionalization. 7.1.5 Transition Metal Catalysis. 7.1.6 Substitution Reactions. 7.1.7 Multicomponent Chemistry. 7.1.8 Microwave-Assisted Condensation Reactions. 7.1.9 Rearrangements. 7.1.10 Cleavage Reactions. 7.1.11 Miscellaneous. 7.2 Soluble Polymer-Supported Synthesis. 7.3 Fluorous Phase Organic Synthesis. 7.4 Grafted Ionic Liquid-Phase-Supported Synthesis. 7.5 Polymer-Supported Reagents. 7.6 Polymer-Supported Catalysts. 7.6.1 Catalysts on Polymeric Supports. 7.6.2 Silica-Grafted Catalysts. 7.6.3 Catalysts Immobilized on Glass. 7.6.4 Catalysts Immobilized on Carbon. 7.6.5 Miscellaneous. 7.7 Polymer-Supported Scavengers. 8. Outlook and Conclusions. Index.