In Melting Points We Trust: A Review on the Misguiding Characterization of Multicomponent Reactions Adducts and Intermediates

We discuss herein the problems associated with using melting points to characterize multicomponent reactions’ (MCRs) products and intermediates. Although surprising, it is not rare to find articles in which these MCRs final adducts (or their intermediates) are characterized solely by comparing melting points with those available from other reports. A brief survey among specialized articles highlights serious and obvious problems with this practice since, for instance, cases are found in which as many as 25 quite contrasting melting points have been attributed to the very same MCR adduct. Indeed, it seems logical to assume that the inherent non-confirmatory nature of melting points could be vastly misleading as a protocol for structural confirmation, but still many publications (also in the Q1 and Q2 quartiles) insist on using it. This procedure contradicts best practices in organic synthesis, and articles fraught with limitations and misleading conclusions have been published in the MCRs field. The drawbacks inherent to this practice are indeed serious and have misguided MCRs advances. We therefore suggest some precautions aimed at avoiding future confusions.     

An Environmentally Benign Catalytic Method for Versatile Synthesis of 1,4-Dihydropyridines via Multicomponent Reactions

The synthesis of diverse 1,4‐dihydropyridines have been achieved via the multicomponent reactions of aldehydes, enaminones and amines. The reactions have been smoothly performed in water to provide all products with moderate to excellent yields by using lactic acid as a green catalyst.     

Fe‐Catalyzed Multicomponent Reactions: The Regioselective Alkoxy Allylation of Activated Olefins and its Application in Sequential Fe Catalysis

We present herein a versatile and broadly applicable Fe‐catalyzed regioselective alkoxy allylation of activated double bonds. Substituted allylic carbonates are converted into the corresponding σ‐enyl Fe complexes by reaction with Bu₄N[Fe(CO)₃(NO)] (TBAFe) at 30 °C. The liberated alkoxide adds to an activated double bond with the generation of a C‐nucleophile, which is trapped by the σ‐enyl Fe complex in a regioselective manner. Alternatively, the alkoxide acts as a base in deprotonating an external pronucleophile, which undergoes Michael addition. The method is characterized by a broad functional group tolerance, mild reaction conditions, low catalyst loadings, and high regioselectivities in favor of the ipso‐substitution product.     

Asymmetric Multicomponent Reactions Based on Trapping of Active Intermediates

Metal carbenes derived from transition metal‐catalyzed decomposition of diazo compounds react with nucleophiles with heteroatoms, such as alcohols and amines, to generate highly active oxonium/ammonium ylides intermediates. These intermediates can be trapped by appropriate electrophiles to provide three‐component products. Based on this novel trapping process, we have developed novel multicomponent reactions (MCRs) of diazo compounds, alcohols/anilines, and electrophiles. The nucleophiles were also extended to electron‐rich heterocycles (indoles and pyrroles)/arenes, in which the resulting zwitterionic intermediates were also trapped by electrophiles. By employing efficient catalysis strategy, the reactions were realized with excellent stereocontrol and wide substrate scope. In this personal account, we introduce our breakthroughs in the development of novel asymmetric MCRs via trapping of the active ylides and zwitterionic intermediates with a number of electrophiles, such as imines, aldehyde, and Michael acceptors, under asymmetric catalysis. Transition metal/chiral Lewis acid catalysis, transition metal/Brønsted acid catalysis, and chiral transition‐metal catalysis, enable excellent stereocontrolled outcomes. The methodologies not only provide experimental evidence to support the existence of protic onium ylides intermediates/zwitterionic intermediates and the stepwise pathways of carbene‐induced O?H, N?H and C?H insertions, but also offer a novel approach for the efficient construction of chiral polyfunctional molecules.     

Construction of Cyclobutanes by Multicomponent Cascade Reactions in Homogeneous Solution through Visible-Light Catalysis

[2+2] Photocycloaddition of two olefins is a general method to assemble the core scaffold, cyclobutane, found in numerous bioactive molecules. A new approach to synthesize cyclobutanes through multicomponent cascade reactions by merging aldol reaction and Witting reaction with visible-light-induced [2+2] cycloaddition is reported. An array of cyclobutanes with high selectivity has been achieved from commercially available aldehydes, ketones (or phosphorus ylide), and olefins with visible-light irradiation of a catalytic amount of (fac-tris(2-phenylpyridinato-C₂,N)iridium) ([Ir(ppy)₃]) at room temperature. Control experiments and spectroscopic studies revealed that the triplet–triplet energy transfer from the excited [Ir(ppy)₃]* to enones, generated in situ from aldehyde and ketone or aldehyde and phosphorus ylide, is responsible for these simple and efficient muticomponent transformations.     

通过不对称多组分反应高效构建手性磺酰胺类化合物

手性磺酰胺类化合物在新型药物方面研究中占据越来越重要的地位.我们成功地实现了磺酰胺、芳基重氮乙酸酯以及亚胺的不对称三组分反应.此反应给出了高达85%产率,以及优异的非对映选择性（d.r.>20：1）和对映选择性（最高可达99%ee）,为高效构建具有两个手性碳的光学纯磺酰胺类化合物提供了一种快速合成方法.我们将反应放大到了克级规模,并对三组分产物进一步衍生得到一种具有三个手性中心的光学纯含亚砜亚胺骨架的五元环化合物.反应的选择性通过过渡金属与手性磷酸协同催化控制.     

Multicomponent Reactions for the Synthesis of Heterocycles

Multicomponent domino reactions (MDRs) serve as a rapid and efficient tool for the synthesis of versatile heterocycles, particularly those containing structural diversity and complexity, by a one‐pot operation. These reactions can dramatically reduce the generation of chemical wastes, costs of starting materials, and the use of energy and manpower. Moreover, the reaction period can be substantially shortened. This Review covers recent advances on multicomponent domino reactions for the construction of five‐, six‐, and seven‐membered heterocyclic skeletons and their multicyclic derivatives.     

Diastereoselective Synthesis of Cyclopenta[c]furans by a Catalytic Multicomponent Reaction

A diastereoselective three‐component reaction between alkynyl enones, aldehydes and secondary amines is reported. With the aid of a benign indium catalyst, a range of highly substituted cyclopenta[c]furan derivatives can be obtained in a single‐step procedure. The formation of the stereodefined heterocyclic motifs takes place via in situ generation of enamines followed by two sequential cyclization steps.     

Multicomponent Synthesis of Purines and Pyrimidines: From the Origin of Life to New Sustainable Approaches for Drug-Discovery Applications

It is widely accepted that purines and pyrimidines, the building blocks that gave origin to life on our planet, were created through multicomponent reactions (MCRs) on early abiotic Earth. These heterocyclic scaffolds gradually evolved into a wide range of biologically relevant molecules regulating many different physiological processes and thus becoming widely exploited as templates for the development of new drugs. Accordingly, over the years, the synthetic community has dedicated many efforts in the attempt to hypothesize and replicate the original abiotic synthesis of purines and pyrimidines, thus developing a number of multicomponent synthesis to access these scaffolds. The following evolution of synthetic chemistry towards green approaches for the production of new molecules and the recent interest in pharmaceutical sustainability underlines the importance of multicomponent synthesis of new heterocycles. This review article provides an overview of the most important multicomponent approaches for the synthesis of purine and pyrimidine derivatives for potential pharmacological applications.     

Applications of Multicomponent Reactions to the Synthesis of Diverse Heterocyclic Scaffolds

The sequencing of multicomponent reactions (MCRs) and subsequent cyclization reactions is a powerful stratagem for the rapid synthesis of diverse heterocyclic scaffolds. The optimal MCR is sufficiently flexible that it can be employed to generate adducts bearing a variety of functional groups that may then be selectively paired to enable different cyclization manifolds, thereby leading to a diverse collection of products. The growing interest in diversity‐oriented synthesis has led to increased attention to this paradigm for library synthesis, which has inspired many advances in the design and implementation of MCRs for the construction of diverse heterocyclic scaffolds.     

Expansion of the Concept of Nonlinear Effects in Catalytic Reactions Beyond Asymmetric Catalysis

The observation and investigation of nonlinear effects in catalytic reactions provides valuable mechanistic insight. However, the applicability of this method was, until now, limited to molecules possessing chirality and therefore to asymmetric synthesis. The concept of nonlinear effects is expanded to catalytic reactions beyond asymmetric catalysis by using derivatives instead of enantiomers and by considering rates instead of enantiomeric excess. Additionally, its systematic application to investigate the mechanism of catalytic reactions is presented. By exceeding the limitation to asymmetric reactions, the study of nonlinear effects can become a general tool to elucidate reaction mechanisms.     

Multicomponent Reactions,Union of MCRs and Beyond

Multicomponent reactions (MCRs), which are located between one‐ and two‐component and polymerization reactions, provide a number of valuable conceptual and synthetic advantages over stepwise sequential approaches towards complex and valuable molecules. To address current limitations in the number of MCRs and the resulting scaffolds, the concept of union of MCRs was introduced two decades ago by Dömling and Ugi and is rapidly advancing, as is apparent by several recently published works. MCR technology is now widely recognized for its impact on drug discovery projects and is strongly endorsed by industry in addition to academia. Clearly, novel scaffolds accessible in few steps including MCRs will further enhance the field of applications. Additionally, broad expansion of MCR applications in fields such as imaging, materials science, medical devices, agriculture, or futuristic applications in stem cell therapy and theragnostics or solar energy and superconductivity are predicted.     

Multicomponent Reactions Based on SO2 Surrogates: Recent Advances

Compounds containing sulfonyl-derived functional groups have received intensive attention owing to their widespread applications in life science, pharmaceuticals and materials science. To access this type of compounds, the multi-component sulfonylation reactions relying on sulfur dioxide (SO₂) insertion strategy have emerged as novel and attractive approaches in the past decade. The utilization of SO₂ surrogates for SO₂ insertion in the multicomponent reactions (MCRs) have improved reaction flexibility and step economy. Moreover, some advances have been achieved in the challenging but practical asymmetric MCRs for the construction of high value-added chiral sulfones. This review aims to summarize the progress made in the MCRs involving SO₂ surrogates from 2019 to 2022, and point out the potentials and challenges in this field.     

Catalytic Enantioselective Isocyanide-Based Reactions: Beyond Passerini and Ugi Multicomponent Reactions

The development of catalytic enantioselective isocyanide-based reactions is currently of great interest because the resulting products are valuable in organic synthesis, pharmacological chemistry, and materials science. This review assembles and comprehensively summarizes the recent achievements in this rapidly growing area according to the reaction types. Special attention is paid to the advantages, limitations, possible mechanisms, and synthetic applications of each reaction. In addition, a personal outlook on the opportunities for further exploration is given at the end.     

One-Pot Multicomponent Reactions for the Efficient Synthesis of Highly Functionalized Dihydropyridines

Abstract

An efficient, atom-economic, one-pot protocol has been developed for the synthesis of highly functionalized dihydropyridines via four-component reactions of aromatic aldehydes, arylamines, malononitrile, and dimethylacetylenedicarboxylate in the presence of sodium hydroxide in ethanol. This domino reaction proceeded smoothly in good to excellent yields and offered several advantages, including short reaction time, simple experimental procedure, and applicability to a broad range of substrates.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Catalysis of Cascade and Multicomponent Reactions of Carbonyl Compounds and CH Acids by Electricity

This review is concerned with modern trends in the use of electrochemically induced chain reactions in cascade and multicomponent electroorganic synthesis. The review summarizes the data on the use of electrochemically induced chain reactions in cascade and multicomponent organic synthesis, which were published mainly in the last decade.     

Multicomponent Reactions Involving Diazo Reagents: A 5-Year Update

This review summarizes recent developments in multicomponent reactions of diazo compounds. The role of diazo reagent and the type of interaction between components was analyzed to structure the discussion. In contrast to previous reviews on related topics mostly focused on metal catalyzed transformations, a substantial amount of organocatalytic or catalyst-free methodologies is covered in this work.