Since 1995 the new chemistry of multicomponent reactions and their libraries,including their heterocyclic chemistry

A growing number of products, including many heterocycles, can be prepared by the one‐pot MultiComponent Reactions (MCRs) just by mixing three or more educts, and in many cases practically quantitative yields of pure products can be obtained. The 3CR by α‐aminoalkylations of nucleophiles began in the middle of the last century, and the syntheses of heterocycles by MCRs of three and four components were introduced by Hantzsch in the 1880s. The MCRs of the isocyanides with four and more educts began in 1959, and their compound libraries were mentioned since 1961. However, only since 1995 the often automated one‐pot chemistry of the MCR of the isocyanides is used extensively. If a chemical compound can be prepared by a sequence of two component reactions or a suitable MCR, the latter is always a superior procedure. The U‐4CR can be combined with other chemical reactions and MCRs as one‐pot reactions of n > 4 components, and such unions even have a much greater variety of structurally and stereochemically different products. The educts and products of Ugi‐type MCRs are more variable than those of all previous chemical reactions and other MCRs. Due to the progress in screening and automation processes in the last few years, many new compounds have been formed and investigated more rapidly than ever before. The search for new desirable products can be accomplished more than 10,000 times faster than by the older conventional methods. The now popular chemistry of the MCRs of the isocyanides fills the since long empty part of organic chemistry.     

Molecular libraries in liquid phase via UGI-MCR

Standard chemistry prescribes the conversion of one or two compounds into their products. In contrast, Eintopf (one-pot) multicomponent reactions (MCRs) involve at least three different compounds. One-pot MCRs are a useful tool in combinatorial chemistry: From a mixture of educts a large number of products can be simultaneously formed in liquid phase, called a soluble molecular library. The member compounds of such libraries are investigated simultaneously for desired properties, e.g. antibiotic activity. The main constraint is, that the underlying chemistry must not produce unknown side reactions and must lead to a broad spectrum of stable products with high yields. Isocyanide multicomponent chemistry allows the generation of soluble libraries of very different sizes, which are easy to screen for biological or pharmaceutical efficacy using the algorithms presented. Products can easily be enumerated and the kinetics of the isocyanide chemistry is simple to investigate. Combinatorial chemistry is capable of generating and optimizing leads faster and with fewer resources than by conventional means. Combinatorial chemistry based on isocyanide chemistry is by far the most important and most impressive technique in use today to reducing time and costs associated with lead generation and optimization during the drug discovery process. The simplicity of the reaction conditions involved means that the generation and screening of libraries can be automated.     

Lewis acid-catalyzed formation of Ugi four-component reaction product from Passerini three-component reaction system without an added amine

In the presence of a Lewis acid the phenol-Passerini three-component reaction (phenol-P-3CR) system is found to deliver a product of the phenol-Ugi four-component reaction (phenol-U-4CR). It is the first demonstration of an isocyanide as an amine equivalent in isocyanide-based multicomponent reactions (IMCRs). In general, by using Ti(O-i-Pr)₄ in MeOH both phenol-U-4CR and U-4CR products are synthesized from an aromatic aldehyde, a phenolic or carboxylic acid, and an isocyanide. Moreover, by using MeCN as the solvent, the phenol-P-3CR products can be obtained in good yields without contamination of the phenol-U-4CR products.     

Multicomponent Reactions with Isocyanides

Multicomponent reactions (MCRs) are fundamentally different from two-component reactions in several aspects. Among the MCRs, those with isocyanides have developed into popular organic-chemical reactions in the pharmaceutical industry for the preparation of compound libraries of low-molecular druglike compounds. With a small set of starting materials, very large libraries can be built up within a short time, which can then be used for research on medicinal substances. Due to the intensive research of the last few years, many new backbone types have become accessible. MCRs are also increasingly being employed in the total synthesis of natural products. MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures. However, this requires that the chemist learns the "language" of MCRs, something that this review wishes to stimulate.     

Diastereoselective multicomponent synthesis of dihydropyridones with an isocyanide functionality

[Structure: see text] In a search for new multicomponent strategies leading to valuable small heterocycles, a new highly diastereoselective four-component reaction (4CR) was found in which a phosphonate, nitriles, aldehydes, and isocyanoacetates combine to afford functionalized 3-isocyano-3,4-dihydro-2-pyridones. In this strategy, initially a 1-azadiene is generated, which is trapped in the same pot by an isocyanoacetate as the fourth component. Multicomponent reactions (MCRs) that lead to heterocycles containing isocyano substituents are unprecedented and offer many possibilities for further differentiation.     

Sequential one-pot combination of multi-component and multi-catalysis cascade reactions: an emerging technology in organic synthesis

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.     

Separation of the reaction products of cyanazine and terbuthylazine nitrosation by thin-layer chromatography

N-Nitroso-triazine herbicide species were synthesized as reference standards and their reaction products were separated by TLC. The method was established for analytical as well as for preparative amounts to achieve a sufficient separation between the educts, the byproducts and the N-nitrosated moieties. Separation of the reaction mixture was performed by two-dimensional TLC, using different mobile phases for each dimension. In the second dimension two developments were executed using the same solvent mixture. To examine the quality of performance, the separation zones were scrapped off, extracted and analyzed in the HPLC-diode array detection (DAD) mode in comparison with standards of the educts and the products of their N-nitrosation. This method minimizes the contact with the resulting N-nitroso compounds. At present nothing is known about the toxicological relevance or risk assessment on human health of N-nitrosocyanazine or N-nitrosoterbuthylazine species. Therefore the practical handling of these putative mutagenic and carcinogenic substances should be seen under the aspect of precaution and prevention of contamination.     

Separation of the reaction products of cyanazine and terbuthylazine nitrosation by thin-layer chromatography

N-Nitroso-triazine herbicide species were synthesized as reference standards and their reaction products were separated by TLC. The method was established for analytical as well as for preparative amounts to achieve a sufficient separation between the educts, the byproducts and the N-nitrosated moieties. Separation of the reaction mixture was performed by two-dimensional TLC, using different mobile phases for each dimension. In the second dimension two developments were executed using the same solvent mixture. To examine the quality of performance, the separation zones were scrapped off, extracted and analyzed in the HPLC-diode array detection (DAD) mode in comparison with standards of the educts and the products of their N-nitrosation. This method minimizes the contact with the resulting N-nitroso compounds. At present nothing is known about the toxicological relevance or risk assessment on human health of N-nitrosocyanazine or N-nitrosoterbuthylazine species. Therefore the practical handling of these putative mutagenic and carcinogenic substances should be seen under the aspect of precaution and prevention of contamination. Received: 25 August 1997 / Revised: 13 October 1997 / Accepted: 21 October 1997     

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.     

Chemoselective Condensation of β-Naphthol,Dimethyl Malonate,and Aromatic Aldehydes Promoted by Niobium Pentachloride

A multicomponent reaction of β-naphthol, dimethyl malonate, and aromatic aldehydes in the presence of NbCl₅ as promoter is described. Under similar conditions, aromatic aldehydes with different substituents exhibited different behaviors than β-naphthol and dimethyl malonate. In these MCRs, 4-aryl-3,4-dihydrobenzo[f]coumarins are obtained as the major products (41–93%) and 14-aryl-14H-dibenzo[a,j]xanthenes as the minor products (1–38%).     

Multicomponent reactions and combinatorial chemistry

Multi-component reactions (MCRs) constitute a methodology to shorter syntheses of natural products or complex molecules for drug discovery. Due to the large number of accessible compounds, this type of chemistry has become very popular between scientists who are working in the area of combinatorial chemistry. Over the last decade combinatorial chemistry has evolved from the synthesis of great quantity of simple compounds to the parallel synthesis of complex molecules with a widely varied structure. MCRs are ideally suited for this trend, being free of limitations of a traditional multistep synthesis. The close connection and interference of multicomponent reactions and combinatorial chemistry are discussed in this review.     

Formation of CC Bonds by Addition of Free Radicals to Alkenes

There are many reactions in which CC bonds are formed by addition of free radicals to alkenes. Information about the mechanism is important for the synthesis of specific target molecules. The rate of addition of alkyl radicals to alkenes is controlled by steric and polar effects. The stabilities of the educts and products are of only limited importance, since the transition states for these exothermic reactions occur very early on the reaction coordinate. Variations in reactivity and selectivity can be described using frontier orbital theory: for nucleophilic radicals the dominant interactions are those between SOMO's and LUMO's, and for electrophilic radicals those between SOMO's and HOMO's. The large differences in the steric effects of α - and β- substituents of alkenes can be explained by postulating an unsymmetrical transition state— the radical approaches one of the C atoms preferentially. Regioand stereoselectivities can be predicted and are determined, in general, by steric effects.     

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.     

Efficient Synthesis for a Wide Variety of Patellamide Derivatives and Phosphatase Activity of Copper-Patellamide Complexes

Copper complexes of patellamides have shown catalytic activity in a variety of reactions but their biological function remains unknown. There are significant differences between the natural macrocycles and synthetic analogues in the various catalytic activities. It therefore is essential to be able to perform in vivo and ex vivo reference measurements with the natural patellamide macrocycles, very similar derivatives and a large range of synthetic analogues. The preparative method described allows for a highly adaptable synthetic process producing building blocks for a large range of patellamide derivatives: apart from natural compounds, a new synthetic patellamide was prepared that does not have any substituents at any of the four heterocycles. Together with the variation of substituents at the aliphatic backbone, this allowed to elucidate the catalytic activity for phosphoester hydrolysis as a function of the structure and dynamics of the dicopper(II)-patellamide complexes, both by experiment and DFT-based mechanistic studies.     

Recent Developments on Five-Component Reactions

Multicomponent reactions (MCRs) have inherent advantages in pot, atom, and step economy (PASE). This important green synthetic approach has gained increasing attention due to high efficiency, minimal waste, saving resources, and straightforward procedures. Presented in this review article are the recent development on 5-compoment reactions (5CRs) of the following six types: (I) five different molecules A + B + C + D + E; pseudo-5CRs including (II) 2A + B + C + D, (III) 2A + 2B + C, (IV) 3A + B + C, (V) 3A + 2B, and (VI) 4A + B. 5CRs with more than five-reaction centers are also included.     

Photochemical Rearrangements and Fragmentations of Benzene Derivatives and Annelated Arenes

In this article the numerous intramolecular reactions of electronically excited benezene derivatives, which in many instances are only mentioned in original papers, are systematically analyzed and arranged according to reaction types. All known reaction types can be classified, and subdivided into reactions of the benzene ring (ionization, ring opening, ring alteration), reactions with participation of side chains (α-, β-, γ-cleavage, homolysis, heterolysis), reactions of substituents with side chains (cyclization, dealkylation, cleavage of protective groups), and reactions of side chains with the aromatic ring (substitution, addition, dearomatization, cyclization). The selectivity of the energetically feasible competing reactions is primarily determined by geometric factors. Applications of the empirical effects are numerous and varied in preparative organic chemistry. Many of the reactions under discussion are already utilized industrially (e.g. in photochromism, UV stabilization, photography, information storage, printing, coating and polymer technology, and pharmacy).     

Direct and dye-sensitized aqueous photo-oxidation of 3-indoleacetic acid, methyl-3-indoleacetate and 1-methyl-3-indoleacetic acid 1-methyl-3-indoleacetic acid II: Quantum yields and mechamism

Mechanisms accounting for the types and yields of the products obtained in direct and dye-sensitized photo-oxidation of the compounds 3-indoleacetic acid (1a), methyl-3-indoleacetate (1b) and 1-methyl-3-indoleacetic acid (1c) in aqueous buffer (pH 5 or pH 8) containing 10% methanol are discussed. In the direct irradiation at pH 5 of acid 1a and its methyl ester 1b, the first detectable products are the corresponding 3-indolemethanols 6a and 6b, their methyl ethers 7a and 7b, and the dimeric compounds 14a and 14b, in aerobic and anaerobic conditions. The same primary products are detected in dye-sensitized photo-oxidation at pH 5. These results support the primary formation of radicals I and II, and of the peroxy forms III and IV, from which thermal reactions can explain all the products found. In both direct and dye-sensitized photo-oxidation at pH 8, only products from the oxidative cleavage of the indolic 2,3-double bond are observed. In dye-sensitized reactions, the products found are in accordance with the existence of competing type I (through radicals) and type II (through singlet oxygen) photosensitized oxygenation processes, their relative proportions depending on the pH of the medium. In direct irradiation, the same intermediates seem to be formed. Quantum yield values of 1a disappearance also depend on the experimental conditions, the highest value found being 28.5% for the direct irradiation at pH 5.     

Copper-Catalyzed Borylative Couplings with C−N Electrophiles

Copper-catalyzed borylative multicomponent reactions (MCRs) involving olefins and C−N electrophiles are a powerful tool to rapidly build up molecular complexity. The products from these reactions contain multiple functionalities, such as amino, cyano and boronate groups, that are ubiquitous in medicinal and process chemistry programs. Copper-catalyzed MCRs are particularly attractive because they use a relatively abundant and non-toxic catalyst to selectively deliver high-value products from simple feedstocks such as olefins. In this Minireview, we explore this rapidly emerging field and survey the borylative union of allenes, dienes, styrenes and other olefins, with imines, nitriles and related C−N electrophiles.     

微结构的纳米设计膜反应器中的催化

For thermodynamically and kinetically controlled catalytic reactions,the influence of a membrane is discussed. For reactions operating near to the thermodynamic equilibrium,the conversion can be increased if one/all of the products is/are selectively removed in an extractor type membrane reactor. Examples are esterifications,dehydrogenations,and water dissociation using water,hydrogen,and oxygen selective membranes,respectively. For kinetically controlled reactions,i.e. reactions with a very negative free enthalpy,mainly the selectivity can be increased via the control of the partial pressure of the educts by dosing effects using distributor/contactor membrane reactors. Examples are partial oxidations and hydrogenations. In detail,the application of an oxygen transporting perovskite hollow fiber membrane with a nano-designed grain boundary structure in the hydrogen production by thermal water splitting and in the partial oxidation of hydrocarbons as case studies for thermodynamically and kinetically controlled reactions is discussed.