Applications of multicomponent reactions for the synthesis of diverse heterocyclic scaffolds

A four-component coupling process involving sequential reactions of aldehydes, primary amines, acid chlorides, and nucleophiles has been developed to prepare multifunctional substrates that may be employed in subsequent ring-forming reactions to generate a diverse array of functionalized heterocyclic scaffolds. This new approach to diversity-oriented synthesis was then applied to the first total synthesis of the isopavine alkaloid (+/-)-roelactamine.     

Tetrahydrofuran-based amino acids as library scaffolds

A furanose sugar amino acid (SAA) has been utilized as a library scaffold for the first time. Two furanose SAA scaffolds were examined to illustrate their potential for derivatization. The resulting 99-member library contained three orthogonal points of diversification that allowed easy access to ethers and carbamates from a hydroxyl moiety, a range of ureas from an azide (via an amine), and a range of amides from a methyl ester. The novel amide formation (by displacement of the methoxide from the methyl ester moiety) was achieved in good yield and purity with high structural confidence. Full characterization of several library intermediates (including a crystal structure) was obtained. The library was submitted for antibacterial screening.     

Extensively stereodiversified scaffolds for use in diversity-oriented library synthesis

The syntheses of stereodiverse libraries of 12 and 19 are reported, where each asterisk represents an independently varied stereocenter. These scaffolds provide additional templates for investigations of geometric diversity in library syntheses. Libraries of these N-Fmoc-amino acids were further functionalized by incorporation into a peptide sequence, demonstrating the utility of 12 and 19 as building blocks for diversity oriented synthesis.     

Deep eutectic solvent-mediated expedient multicomponent synthesis of oxazine scaffolds

A simple, efficient, and eco-friendly protocol for the synthesis of 1,3-oxazine derivatives, viz. 7-aryl-7,8-dihydro-6H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-e][1,3]oxazines and 3-aryl-3,4-dihydro-2H- naphtho[2,3-e][1,3]oxazine-5,10-diones, involving one-pot multicomponent condensation reaction of various amines and formaldehyde with sesamol/2-hydroxy-1,4-naphthoquinone, respectively, catalyzed by a choline chloride–oxalic acid deep eutectic solvent has been developed. The method offers several advantages, including mild reaction conditions, simple operating procedure, recyclable and biodegradable catalyst, short reaction times, and excellent yields of the target products.

     

Enol esters: versatile substrates for Mannich-type multicomponent reactions

The interaction of cyclic enol esters with diversely substituted anilines and ethyl glyoxalate yields, under Sc(OTf)3 catalysis, disubstituted N-aryl lactams in a multicomponent reaction. The protocol allows access to the trans stereoisomers after an epimerization of the initial mixture in which the cis isomers predominate. Vinyl acetate yields quinoline derivatives, whereas isopropenyl acetate leads to the corresponding Mannich adducts.     

Glycoconjugate libraries accessed by multicomponent reactions

Glycobiology opens a wide field for new therapeutic approaches. However, the complexity and unavailability of various carbohydrate test compounds has excluded this class of natural products from modern screening systems. Alternatively, glycomimetics are considered to be more drug-like candidates for development. By means of multicomponent condensations (MCCs) utilizing suitable carbohydrate synthons, rapid and effective access to glycoconjugate libraries can be obtained. The flexibility of MCCs allows the assembly of diverse carbohydrate containing libraries. It may be assumed that MCCs containing carbohydrate moieties will play an important role in glycomimetic chemistry and biology.     

Recent developments in asymmetric multicomponent reactions

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.     

Discovery of a multi-bond forming, four-step tandem process: construction of drug-like polycyclic scaffolds

A one-pot tandem process involving an Overman rearrangement, ring closing enyne metathesis and a hydrogen bonding directed Diels-Alder reaction has been developed for the efficient diastereoselective synthesis of functionalised amino substituted tetralin and indene ring systems.     

Direct access to heterocyclic scaffolds by new multicomponent Ugi-Smiles couplings

New heterocyclic scaffolds can be easily prepared by the coupling of heteroaromatic phenols (pyridines, pyrimidines) with carbonyl compounds, amines, and isocyanides. This transformation related to the Ugi reaction probably involves a Smiles rearrangement. The scope of this methodology is further extended by the successful use of heterocyclic thiols to form highly functionalized thioamides.     

Catalytic multicomponent reactions for the synthesis of N-aryl trisubstituted pyrroles

Dirhodium(II) salts efficiently catalyze the three-component assembly reaction of an imine, diazoacetonitrile (DAN), and an activated alkynyl coupling partner to form substituted 1,2-diarylpyrroles in moderate to good yields. The transition-metal-catalyzed decomposition of the diazo compound in the presence of the imine presumably generates a transient azomethine ylide that undergoes cycloaddition with dipolarophiles in a highly convergent manner.     

Organocatalytic enantioselective multicomponent reactions (OEMCRs)

The achieved level of expertise in organocatalytic processes has allowed synthetic chemists to apply this useful synthetic strategy to enantioselective multicomponent reactions. Although, this new methodology is still in its infancy, the reported results show the possibilities and versatility of this type of reaction, with an extraordinary level of atom efficiency being reached. All examples, from classical Mannich, Biginelli, Michael, and Diels–Alder reactions to new amination–reduction and Tietze reactions, allow the synthesis of complex chiral molecules with several stereogenic elements created in just one process. In fact, the organocatalyst acts in this type of process as a clear enzyme mimic, but with an ample substrate scope.     

Innovative macromolecular syntheses via isocyanide multicomponent reactions

Isocyanide multicomponent reactions assemble more than two reaction components by exploiting the reactivity of the isocyanide carbon atom toward addition of electrophiles and nucleophiles. Reactions such as the Passerini three‐component and Ugi four‐component coupling reactions have a long and successful history in organic synthesis, which has only recently been explored in polymer chemistry. In a short time, this class of multicomponent reactions has been established as a viable method for the synthesis of linear polymers as well as more complex architectures such as miktoarm star polymers and dendrimers. This highlight discusses the recent accomplishments made with regard to innovative syntheses of polymers and dendrimers via the Passerini and Ugi reactions. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 3985–3991     

Recent advances in the iron-catalysed multicomponent reactions

Iron-catalysed reactions are widely used in organic synthesis owing to its benefits over other metals. Among the important organic reactions, multicomponent reactions play a significant role due to its greener aspects like high atom economy, minimal amount of by-product, economic feasibility etc. For the past few years, iron-catalysed multicomponent reactions have attracted the attention of several chemists which lead to the invention of some fine chemistry. The majority of iron-catalysed multicomponent reactions results in the synthesis of heterocyclic compounds having biologically active natural products, pharmaceutical etc. These developments in the iron-catalysed multicomponent reactions are the focus of this review. This is the first review in this topic which covers the literature up to 2020, and it encompasses the different methods for the synthesis of acyclic, carbocyclic and heterocyclic compounds.     

Double- and triple-cobalt catalysis in multicomponent reactions

The combination of different types of cobalt-catalyzed transformations in one-pot procedures is described. One of the key building blocks, a boron-functionalized isoprene derivative (boroprene), led to the realization of four-component reaction sequences comprising the cobalt-catalyzed Diels-Alder and a 1,4-hydrovinylation reaction. Eventually, a reaction sequence including a cobalt-catalyzed Diels-Alder reaction, a cobalt-catalyzed 1,4-hydrovinylation, an allylboration, and a cobalt-catalyzed Alder-ene reaction led to a five-component one-pot reaction sequence in which five carbon-carbon bonds were formed in excellent regio- and diastereoselectivity to generate complex products in good overall yields.     

A convergent synthesis of enantiopure bicyclic scaffolds through multicomponent Ugi reaction

An efficient and convergent Ugi synthesis of enantiomerically pure N-acyl-2,5-disubstituted pyrrolidines was coupled with an appropriate secondary transformation to give two series of bicyclic derivatives, namely hexahydro pyrrolo-oxazocinediones and -diazepinediones.     

The multicomponent reactions and their libraries for natural and preparative chemistry

It was recently recognized that three different types of multi-component reactions (MCRs) exist. In preparative chemistry, the MCRs of type II form their products particularly efficiently. These reactions correspond to equilibria of educts and intermediate products, whose final products are formed practically irreversibly. In recent years, the four component reaction of the isocyanides (U-4CR) of type II and their unions with various reactions and MCRs have become an important industrial process for preparing products and their libraries. It has been demonstrated that all conceivable collections of U-4CR educts can be converted into the corresponding products. In the usual chemical reactions, only the substituents of the products can be varied, whereas the U-4CR and related reactions can also produce skeletally different types of products with diverse substituents. The preparative advantages of forming products by the one-pot MCRs and the great variety of the possible products are illustrated in this review.     

Effective strategy for polymer synthesis: multicomponent reactions and click polymerization

The rational selection of organic reactions in polymer synthesis is an important research content of polymer science. In recent years, multicomponent reaction as an efficient and green synthesis method has attracted the wide attention of researchers, injecting new and powerful vitality into the field of polymer synthesis. In the study of multicomponent reaction, researchers found the intersection of multicomponent reaction and click chemistry and put forward the concept of Multicomponent Click Reaction (MCR-Click), which is a kind of Multicomponent Reaction with high activity, atomic economy, and some green chemical properties. The application of MCR in polymer chemistry is reviewed in this paper. It is expected that this reaction will arouse the attention of polymer chemists and play a new role in polymer science.