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Special Issue "Multicomponent Reaction"

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A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: closed (30 December 2012)

Special Issue Editor

Guest Editor
Dr. Irini Akritopoulou-Zanze

Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-3500, USA
Interests: drug discovery; de novo design and synthesis of biologically active scaffolds; focused compound libraries; multicomponent reactions

Special Issue Information

Dear Colleagues,

Multicomponent reactions (MCRs) are powerful transformations that incorporate portions of three or more reactants into new products in one pot procedures. They have been used extensively to form heterocyclic structures and they have been combined with subsequent transformations to yield complex structures, not easily accessible via classical synthetic reactions.
Efforts to discover new MCRs or further develop older ones, especially in combination with other transformations, contribute significantly to the advancement of organic synthesis by providing greater flexibility, novelty and efficiency. Applications of MCRs in drug discovery, material sciences, natural product synthesis and ligand and biological probe preparations further demonstrate the power of these reactions. Advances in cheminformatic tools allow for virtual MCR libraries to be first accessed in silico against a variety of different parameters before initiation of compound library synthesis.

This special issue of Molecules welcomes previously unpublished manuscripts covering all aspects of multicomponent reactions including their design, product assessment, methodology development and applications.

Dr. Irini Akritopoulou-Zanze
Guest Editor

Keywords

  • multicomponent reactions
  • isocyanide-based MCRS
  • heterocycle forming MCRS
  • library design
  • library synthesis
  • parallel synthesis
  • novel scaffolds
  • biologically active molecules
  • post MCR transformations
  • macromolecules

Published Papers (9 papers)

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Research

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Open AccessArticle One-Pot Ugi/Aza-Michael Synthesis of Highly Substituted 2,5-Diketopiperazines with Anti-Proliferative Properties
Molecules 2012, 17(12), 14685-14699; doi:10.3390/molecules171214685
Received: 21 November 2012 / Revised: 1 December 2012 / Accepted: 6 December 2012 / Published: 11 December 2012
Cited by 4 | PDF Full-text (333 KB) | Supplementary Files
Abstract
The well-known Ugi reaction of aldehydes with amines, carboxylic acids and isocyanides leads to the formation of acyclic α-acylaminocarboxamides. Replacement of the carboxylic acid derivatives with β-acyl substituted acrylic acids gives access to highly substituted 2,5-diketopiperazines in one single reaction-step without additives [...] Read more.
The well-known Ugi reaction of aldehydes with amines, carboxylic acids and isocyanides leads to the formation of acyclic α-acylaminocarboxamides. Replacement of the carboxylic acid derivatives with β-acyl substituted acrylic acids gives access to highly substituted 2,5-diketopiperazines in one single reaction-step without additives or complex reaction procedures. The obtained diketopiperazines show anti-proliferative effects on activated T cells and represent therefore potential candidates for targeting unwanted T cell-mediated immune responses. Full article
(This article belongs to the Special Issue Multicomponent Reaction)
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Open AccessCommunication Multicomponent Synthesis of 3,6-Dihydro-2H-1,3-thiazine-2-thiones
Molecules 2012, 17(2), 1675-1685; doi:10.3390/molecules17021675
Received: 5 January 2012 / Revised: 20 January 2012 / Accepted: 29 January 2012 / Published: 8 February 2012
Cited by 8 | PDF Full-text (259 KB) | Supplementary Files
Abstract
Non-fused 3,6-dihydro-2H-1,3-thiazine-2-thiones constitute a so far rather unexplored class of compounds, with the latest report dating back more than two decades. Thiazine-2-thiones contain an endocyclic dithiocarbamate group, which is often found in pesticides, in substrates for radical chemistry and in [...] Read more.
Non-fused 3,6-dihydro-2H-1,3-thiazine-2-thiones constitute a so far rather unexplored class of compounds, with the latest report dating back more than two decades. Thiazine-2-thiones contain an endocyclic dithiocarbamate group, which is often found in pesticides, in substrates for radical chemistry and in synthetic intermediates towards thioureas and amidines. We now report the multicomponent reaction (MCR) of in situ-generated 1-azadienes with carbon disulfide. With this reaction, a one-step protocol towards the potentially interesting 3,6-dihydro-2H-1,3-thiazine-2-thiones was established and a small library was synthesized. Full article
(This article belongs to the Special Issue Multicomponent Reaction)
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Open AccessArticle Prebiotic Activity of Polysaccharides Extracted from Gigantochloa Levis (Buluh beting) Shoots
Molecules 2012, 17(2), 1635-1651; doi:10.3390/molecules17021635
Received: 11 October 2011 / Revised: 28 December 2011 / Accepted: 13 January 2012 / Published: 7 February 2012
Cited by 9 | PDF Full-text (424 KB)
Abstract
Bamboo shoot crude polysaccharides (BSCP) extracted from the shoots of Gigantochloa levis gave about 3.27 ± 0.18% on dry basis and a very minute percentage of protein (0.02 ± 0.01%). The molecular weight of BSCP estimated by gel chromatography was found to [...] Read more.
Bamboo shoot crude polysaccharides (BSCP) extracted from the shoots of Gigantochloa levis gave about 3.27 ± 0.18% on dry basis and a very minute percentage of protein (0.02 ± 0.01%). The molecular weight of BSCP estimated by gel chromatography was found to be around 7.49 × 103 Da, while the molecular weights of purified fractions (F1 to F5) were around 1550.96, 1471.63, 1685.78, 1691.61 and 1551.67 Da, respectively. The FTIR spectrum of BSCP revealed the possibility that the extract contains β-glucan, which can be considered a valuable compound for the medical and food industries. These relate to the resistance of BSCP towards artificial human gastric juice which is more than 99%. Prebiotic activity tested using BSCP as a carbon source showed significant increase in the growth of B. animalis ATCC 1053, B. longum BB 536 and L. acidophilus ATCC 4356 as compared to the use of FOS. Survivality of S. choleraesuis JCM 6977 was found to be slower in both BSCP and FOS. Study conducted reflects a good sign for the BSCP to be exploited as a promising prebiotic. Full article
(This article belongs to the Special Issue Multicomponent Reaction)
Open AccessCommunication Consecutive Three-Component Synthesis of 3-(Hetero)Aryl-1H-pyrazoles with Propynal Diethylacetal as a Three-Carbon Building Block
Molecules 2011, 16(11), 9340-9356; doi:10.3390/molecules16119340
Received: 30 September 2011 / Revised: 19 October 2011 / Accepted: 21 October 2011 / Published: 7 November 2011
Cited by 5 | PDF Full-text (373 KB)
Abstract
A novel consecutive three-component synthesis of 3-(hetero)aryl-1H-pyrazoles via room temperature Sonogashira arylation of propynal diethylacetal used as a propargyl aldehyde synthetic equivalent has been disclosed. The final acetal cleavage-cyclocondensation with hydrazine hydrochloride at 80 °C rapidly furnishes the title compounds [...] Read more.
A novel consecutive three-component synthesis of 3-(hetero)aryl-1H-pyrazoles via room temperature Sonogashira arylation of propynal diethylacetal used as a propargyl aldehyde synthetic equivalent has been disclosed. The final acetal cleavage-cyclocondensation with hydrazine hydrochloride at 80 °C rapidly furnishes the title compounds in a one-pot fashion. Full article
(This article belongs to the Special Issue Multicomponent Reaction)
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Open AccessArticle Xanthate Based Radical Cascade Toward Multicomponent Formation of Pyrrolopyrimidines
Molecules 2011, 16(11), 9261-9273; doi:10.3390/molecules16119261
Received: 28 September 2011 / Revised: 23 October 2011 / Accepted: 28 October 2011 / Published: 4 November 2011
Cited by 5 | PDF Full-text (412 KB)
Abstract A short sequential synthesis of pyrrolidino- pyridines and pyrimidines illustrates the potential of combining Ugi-Smiles couplings with radical tin-free processes. Full article
(This article belongs to the Special Issue Multicomponent Reaction)
Open AccessArticle Small Molecule Library Synthesis Using Segmented Flow
Molecules 2011, 16(11), 9161-9177; doi:10.3390/molecules16119161
Received: 13 September 2011 / Revised: 18 October 2011 / Accepted: 21 October 2011 / Published: 2 November 2011
Cited by 13 | PDF Full-text (174 KB)
Abstract
Flow chemistry has gained considerable recognition as a simple, efficient, and safe technology for the synthesis of many types of organic and inorganic molecules ranging in scope from large complex natural products to silicon nanoparticles. In this paper we describe a method [...] Read more.
Flow chemistry has gained considerable recognition as a simple, efficient, and safe technology for the synthesis of many types of organic and inorganic molecules ranging in scope from large complex natural products to silicon nanoparticles. In this paper we describe a method that adapts flow chemistry to the synthesis of libraries of compounds using a fluorous immiscible solvent as a spacer between reactions. The methodology was validated in the synthesis of two small heterocycle containing libraries. The reactions were performed on a 0.2 mmol scale, enabling tens of milligrams of material to be generated in a single 200 mL reaction plug. The methodology allowed library synthesis in half the time of conventional microwave synthesis while maintaining similar yields. The ability to perform multiple, potentially unrelated reactions in a single run is ideal for making small quantities of many different compounds quickly and efficiently. Full article
(This article belongs to the Special Issue Multicomponent Reaction)
Open AccessArticle Studies on the Synthesis of DMAP Derivatives by Diastereoselective Ugi Reactions
Molecules 2011, 16(10), 8815-8832; doi:10.3390/molecules16108815
Received: 17 August 2011 / Revised: 11 October 2011 / Accepted: 12 October 2011 / Published: 20 October 2011
Cited by 9 | PDF Full-text (343 KB)
Abstract
Diastereoselective Ugi reactions of DMAP-based aldehydes with α-amino acids and tert-butyl isocyanide were examined. The reactions of 4-(dimethylamino)-2-pyridine-carboxaldehyde with various α-amino acids afforded 2-substituted DMAP derivatives with low diastereoselectivity. On the contrary, reactions with 4-(dimethylamino)-3-pyridine-carboxaldehyde delivered 3-substituted DMAP derivatives with moderate [...] Read more.
Diastereoselective Ugi reactions of DMAP-based aldehydes with α-amino acids and tert-butyl isocyanide were examined. The reactions of 4-(dimethylamino)-2-pyridine-carboxaldehyde with various α-amino acids afforded 2-substituted DMAP derivatives with low diastereoselectivity. On the contrary, reactions with 4-(dimethylamino)-3-pyridine-carboxaldehyde delivered 3-substituted DMAP derivatives with moderate to high diastereoselectivity. The combination of α-amino acid and DMAP-based aldehyde is thus important to achieve high diastereoselectivity. Kinetic resolution of a secondary alcohol using a chiral DMAP derivative obtained through these reactions was also examined. Full article
(This article belongs to the Special Issue Multicomponent Reaction)
Open AccessArticle Divergent Synthesis of Novel Five-Membered Heterocyclic Compounds by Base-Mediated Rearrangement of Acrylamides Derived from a Novel Isocyanide-Based Multicomponent Reaction
Molecules 2011, 16(10), 8775-8787; doi:10.3390/molecules16108775
Received: 21 September 2011 / Revised: 3 October 2011 / Accepted: 11 October 2011 / Published: 19 October 2011
Cited by 10 | PDF Full-text (237 KB)
Abstract
We have recently reported a novel multicomponent reaction between arylacetic acids and isocyanides, affording α-acyloxyacrylamides through an unusual mechanism. The products of this novel multicomponent reaction can rearrange to five membered heterocyclic compounds when exposed to an alkaline environment. Depending on the [...] Read more.
We have recently reported a novel multicomponent reaction between arylacetic acids and isocyanides, affording α-acyloxyacrylamides through an unusual mechanism. The products of this novel multicomponent reaction can rearrange to five membered heterocyclic compounds when exposed to an alkaline environment. Depending on the reaction conditions and on the substitution pattern on the substrates, various pyrrolidine derivatives can be selectively obtained. We now wish to report that libraries endowed with skeletal diversity, thus responding to the requirements of Diversity Oriented Synthesis (DOS), can be efficiently prepared in this manner, and phenotypic biological assays have shown interesting properties of some representative compounds. Full article
(This article belongs to the Special Issue Multicomponent Reaction)
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Review

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Open AccessReview Diversity Oriented Syntheses of Conventional Heterocycles by Smart Multi Component Reactions (MCRs) of the Last Decade
Molecules 2012, 17(1), 1074-1102; doi:10.3390/molecules17011074
Received: 9 December 2011 / Revised: 11 January 2012 / Accepted: 12 January 2012 / Published: 20 January 2012
Cited by 80 | PDF Full-text (964 KB)
Abstract
A collection of smart multicomponent reactions (MCRs) with continuative post condensation cyclizations (PCCs) is presented to construct conventional three- to seven-membered heterocyclic compounds in diversity oriented syntheses (DOS). These will provide a high degree of applying economical and ecological advantages as well [...] Read more.
A collection of smart multicomponent reactions (MCRs) with continuative post condensation cyclizations (PCCs) is presented to construct conventional three- to seven-membered heterocyclic compounds in diversity oriented syntheses (DOS). These will provide a high degree of applying economical and ecological advantages as well as of practicability. Water, ionic liquids, and solvent-less syntheses as well as use of various forms of energy as microwave and ultrasonic irradiation are examined and discussed. Full article
(This article belongs to the Special Issue Multicomponent Reaction)
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