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.     

Training the old dog new tricks: the applications of the Biginelli reaction in polymer chemistry

Recently, the Biginelli reaction, one of the most famous multicomponent reactions, has been introduced into the polymer chemistry to highly efficiently synthesize some interesting functional polymers. In this mini-review, several applications of the Biginelli reaction in polymer chemistry have been summarized, including polycondensation, post-polymerization modification, one-pot synthesis of well-defined polymer, etc. Meanwhile, the utilization of the Biginelli reaction in material science and chemical biology, and the future development of the Biginelli reaction in polymer chemistry have also been discussed.     

Sodium toluene-4-sulfonate as a reusable and ecofriendly catalyst for greener synthesis of 5-aminopyrazole-4-carbonitrile in aqueous medium

In these environmentally conscious days there is need to use eco-friendly greener technologies, such as solvent free, microwave, ultrasound and use of room temperature. Here report an efficient and green protocol for the synthesis of 5-aminopyrazole-4-carbonitrile from three component condensation of phenyl hydrazine, aldehyde, and malononitrile using NaPTS as catalyst in aqueous medium. Use of water has emerged as a versatile solvent for organic reaction; it is readily available, inexpensive, environmentally benign, neutral and natural solvent. Multicomponent reactions in water are of outstanding value in organic synthesis and green chemistry. The significant features of this article are short reaction time, provide excellent yield, removal of toxic solvent and use of water as green solvent.     

Catalytic diastereoselective petasis reactions

Multicomponent Petasis reactions: The first diastereoselective Petasis reaction catalyzed by chiral biphenols that enables the synthesis of syn and anti?β-amino alcohols in pure form has been developed. The reaction exploits a multicomponent approach that involves boronates, α-hydroxy aldehydes, and amines.     

One‐Pot Multicomponent Synthesis of β‐Amino Amides

Multicomponent reactions are excellent tools for rapid generation of small molecules with broad chemical diversity and molecular complexity. Herein, a novel one‐pot multicomponent synthesis of β‐amino amides from aldehydes, anilines, carboxylic acids and ynamides has been successfully developed. This process is practical and efficient to unravel synthetic utility and scalability. Moreover, an isotope labeling reaction was conducted to elucidate a plausible reaction mechanism.     

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.     

Synthesis of Pyranopyrazoles under Eco‐friendly Approach by Using Acid Catalysis

Multicomponent synthesis of pyranopyrazole derivatives by using montmorillonite K‐10 as a reusable green acid catalyst under eco‐friendly method in the presence of eco‐friendly solvent leads to novel protocol. Moreover, catalyst could be reused five times for the reaction without noticeable loss of activity. The scope of this path was to develop new synthetic molecules by using green catalysis for further screenings such as starting molecules for organic electronic materials and biological assays.     

Green synthesis of 3,4-dihydropyrimidinones using nano Fe3O4@meglumine sulfonic acid as a new efficient solid acid catalyst under microwave irradiation

Design, synthesis and characterization of nano Fe₃O₄@meglumine sulfonic acid as a new solid acid catalyst for the simple and green one pot multicomponent synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones was studied. New solid acid catalyst was prepared through a clean and simple protocol and characterized using FTIR, VSM, TGA, SEM, elemental analysis (CHN) and XRD techniques. Heterogenization of homogeneous catalyst as a green approach is a useful method for enhancing the efficiency of catalyst. Presented study was a new method for attachment of homogeneous highly soluble catalyst (meglumine sulfate) to the magnetite nanoparticle surfaces for preparing a heterogeneous and effective catalyst. Obtained heterogeneous and reusable solid acid catalyst has high performance in the synthesis of Biginelli compounds. The reaction was performed under microwave irradiation as a rapid and green condition. Easy work up as well as excellent yield (90–98%) of products in short reaction times (40–200 s) and reusable catalyst are the main advantages of presented procedure. Reaction products were characterized in details using physical and chemical techniques such as melting point, ¹H NMR, ¹³C NMR and FTIR.     

Merging the Isonitrile-Tetrazine (4+1) Cycloaddition and the Ugi Four-Component Reaction into a Single Multicomponent Process

Multicomponent reactions are of utmost importance at generating a unique, wide, and complex chemical space. Herein we describe a novel multicomponent approach based on the combination of the isonitrile-tetrazine (4+1) cycloaddition and the Ugi four-component reaction to generate pyrazole amide derivatives. The scope of the reaction as well as mechanistic insights governing the 4H-pyrazol-4-imine tautomerization are provided. This multicomponent process provides access to a new chemical space of pyrazole amide derivatives and offers a tool for peptide modification and stapling.     

Multicomponent and multicatalytic asymmetric synthesis of furo[2,3-b]pyrrole derivatives: further insights into the mode of action of chiral phosphoric acid catalysts

Multicomponent and multicatalytic reactions are those processes that try to imitate the way the enzymatic machinery transforms simple building blocks into complex products. The development of asymmetric versions of these reactions is a step forward in our dream of mirroring the exquisite selectivity of biological processes. In this context, the present work describes a new reaction for the asymmetric synthesis of furo[2,3-b]pyrrole derivatives from simple 3-butynamines, glyoxylic acid and anilines in the presence of a dual catalytic system, formed from a gold complex and a chiral phosphoric acid. Computations, aimed to understand the exceptional performance of 9-anthracenyl-substituted BINOL-derived phosphoric acid catalyst, suggest a fundamental role of non-covalent interactions being established between the catalyst and the reagents for the outcome of the multicomponent process. The linear geometry of the anthracenyl substituent along with the presence of an electron-withdrawing group in the aniline and an aromatic substituent in the 3-butynamine derivative seem to be key structural factors to explain the experimental results and, particularly, the high stereoselectivity.

Furo[2,3-b]pyrroles are selectively synthesized by a multicomponent reaction catalysed by a gold/chiral phosphoric acid system. The non-covalent interactions established between the acid and the reagents explain the exquisite stereoselectivity.     

Effect of hydroxypropylmethyl cellulose on the complexation of diclofenac with cyclodextrins

The effect of a hydrophilic polymer, hydroxypropylmethyl cellulose K4M, on the complexation of diclofenac sodium with b- and hydroxypropyl-b-cyclodextrins has been studied. Multicomponent systems were prepared with the drug, both cyclodextrin and the polymer. Phase solubility diagrams revealed the positive effect of the polymer on the complexation of the drug but this effect was found after autoclaving the solutions. Solid inclusion complexes were prepared by freeze-drying and characterized by thermal analysis (DSC) and X-ray diffractometry. In solid state, binary inclusion complexes enhance the dissolution behaviour of diclofenac but, from the b-cyclodextrin multicomponent complex, the polymer controls the release of the drug. In the case of hydroxy- propyl-b-cyclodextrin multicomponent system, the solubility of the drugs increases significantly compared with the binary complex. This revised version was published online in July 2006 with corrections to the Cover Date.     

生物催化在高分子合成中的应用

生物催化剂已被越来越多地用于高分子学中,产生了许多新的反应、工艺和商业用途.酶和全细胞工艺都引起了众多关注,生物催化剂的立体选择性是它们的主要优势之一,新的或改良的方法层出不穷.生物催化的进程主要集中在几个方面上:聚合反应、聚合物修饰反应、聚合物降解反应以及单体和低聚物的合成.在这篇文章中,我们总结了生物催化在高分子合成中的最新应用.     

Facile synthesis of chrysin-derivatives with promising activities as aromatase inhibitors

Flavones such as chrysin show structural similarities to androgens, the substrates of human aromatase, which converts androgens to estrogens. Aromatase is a key target in the treatment of hormone-dependent tumors, including breast cancer. Flavone-based aromatase inhibitors are of growing interest, and chrysin in particular provides a (natural) lead structure. This paper reports multicomponent synthesis as a means for facile modification of the chrysin core structure in order to add functional elements. A Mannich-type reaction was used to synthesize a range of mono- and disubstituted chrysin derivatives, some of which are more effective aromatase inhibitors than the benchmark compound, aminoglutethimide. Similarly, the reaction of chrysin with various isonitriles and acetylene dicarboxylates results in a new class of flavone derivatives, tricyclic pyrano-flavones which also inhibit human aromatase. Multicomponent reactions involving flavones therefore enable the synthesis of a variety of derivatives, some of which may be useful as anticancer agents.     

Synthesis of Heterocycles by Formal Cycloadditions of Isocyanides

Synthetic methodology for the synthesis of heterocycles is of continuous and high interest with applications in materials, catalysis, and medicines. Multicomponent reactions are suitable tools to efficiently generate chemically diverse sets of heterocycles with sufficient structural complexity. Especially isocyanides have proven to be particularly versatile building blocks in these one‐pot processes. Due to their electronic structure, isocyanides are able to act sequentially or simultaneously as a nucleophile and an electrophile. Traditionally, isocyanides are therefore frequently used in multicomponent chemistry. In the recent literature, numerous reactions have been reported that involve formal cycloadditions of isocyanides with conjugated heterodienes. This Focus Review aims at mapping this reactivity and at providing insight into the relationship between the various reported reaction partners and the observed reactivity modes.     

Acetic Acid-Mediated Synthesis of Kojic Acid Derivatives

Russian Journal of Organic Chemistry - A green acetic acid-mediated synthesis of kojic acid derivatives through a multicomponent reaction (MCR) has been developed. This new protocol is simple and...     

CuSO4 · 5H2O: A Novel,Green, Reusable,and Environmentally Friendly Catalyst for the One-Pot,Four-Component Synthesis of β-Acetamido Carbonyl Compounds

Multicomponent reactions for the synthesis of β-acetamido carbonyl compounds have been gained considerable attention in organic synthesis. In this articles, aromatic aldehydes have been employed in a one-pot reaction with enolizable ketones, acetonitrile, benzonitrile, and acetyl chloride in the presence of copper(II) sulfate petahydrate at ambient temperature to afford the corresponding β-acetamido ketones in very good yields. New compounds are reported. The use of readily available copper(II) sulfate petahydrate as a reusable and recyclable catalyst makes this process quite simple, convenient, and environmentally friendly.     

Green,One-Pot,Multicomponent Synthesis of Fused-Ring 2-Aminothiazoles

A facile, green, and efficient Fe(III) chloride, one-pot, multicomponent reaction (MCR) for synthesis of 2-aminothiazole-based compounds is reported. Considering the medicinal importance of fused ring 2-aminothiazoles, this process provides an easy route to the synthesis of this class of compound. Detailed mechanism of the reaction has been discussed.     

General non-catalytic approach to spiroacenaphthylene heterocycles: multicomponent assembling of acenaphthenequinone,cyclic CH-acids and malononitrile

The new type of non-catalytic cascade reaction was found: the direct multicomponent reaction of acenaphthenequinone, cyclic CH-acids, and malononitrile to form spiroacenaphthylene heterocycles. The direct heating in water acenaphthenequinone, cyclic CH-acids, and malononitrile at 80 °C results in the formation of spiroacenaphthylene heterocycles in 90–95% yields. Thus, a new simple and efficient green ‘one-pot’ method to synthesize substituted spiroacenaphthylene frameworks was found directly from simple starting compounds. The application of this convenient green multicomponent method is also beneficial from the viewpoint of diversity-oriented large-scale processes.     

Novel ionic liquid supported on Fe3O4 nanoparticles as an efficient catalyst for the synthesis of new chromenes

An efficient procedure for the synthesis of new chromenes by the multicomponent reaction of aldehydes, 4‐hydroxycoumarin and 2‐hydroxynaphthalene‐1,4‐dione in the presence of an ionic liquid supported on Fe₃O₄ nanoparticles is described. The ionic liquid supported on Fe₃O₄ nanoparticles as a magnetic catalyst gives products in high yields. Significant features of this method are: short reaction times, excellent yields, green method and use of an effective catalyst that can be recovered and reused many times without loss of its catalytic activity.     

Enzymatic Ugi Reaction with Amines and Cyclic Imines

The application of the Ugi reaction to the construction of new peptide scaffolds is an important goal of organic chemistry. To date, there are no examples of the Ugi reaction being performed with a cyclic imine and amine simultaneously. The application of 2‐substituted cyclic imines in an enzymatic three‐component Ugi‐type reaction provides an elegant and attractive synthesis of substituted pyrrolidine and piperidine derivatives in up to 60 % yield. Results on studies of the selection of an enzyme, amount of water, and solvent used in a novel three‐component Ugi reaction and the limitations thereof are reported herein. The presented methodology exploiting enzyme promiscuity in the multicomponent reaction fulfills the requirements associated with green chemistry. Several methods, such as isotope labeling and enzyme inhibition, were used to probe the possible mechanism of this complex synthesis. This research is the first example of an enzyme‐catalyzed Ugi‐type reaction with an imine, amine, and isocyanide.