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Huisgen 3+n Dipolar Cycloaddition Reactions: An Accessible and Useful Tool in Modern Organic and Heterocycle Synthesis

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 22586

Special Issue Editor

Special Issue Information

Dear Colleagues,

Organic compounds, especially heterocycle derivatives, have been reported as highly valuable materials in medicine and pharmacy, opto-electronics, agriculture, and numerous other fields. One of the most challenging issues in fine organic and heterocycle chemistry remains the synthesis of such systems. The Huisgen 3+n dipolar cycloaddition reactions of ylides to various dipolarophiles represents, in this respect, a useful and powerful approach which allow for the construction of new heterocycle derivatives that are otherwise very difficult or impossible to obtain. On the other hand, Huisgen 3+n dipolar cycloaddition has given rise to interesting practical and theoretical problems of stereochemistry, regiochemistry, chorochemistry, etc., which are still waiting to be resolved.

The aim of this Special Issue is to provide a platform to present the latest developments in the Huisgen 3+n dipolar cycloaddition reactions in fine organic and heterocycle synthesis, focused on the cycloaddition reactions of ylides to various dipolarophiles as well as to the applications of the obtained compounds in medicine and pharmacy, opto-electronics, and agriculture, to name but a few.

Prof. Dr. Ionel Mangalagiu
Guest Editor

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Keywords

  • Huisgen 3+n dipolar cycloadditions
  • organic and heterocycles compounds
  • ylides
  • dipolarophiles
  • stereochemistry
  • regiochemistry
  • chorochemistry
  • quantum mechanics approaches (HOMO and LUMO orbital, etc.)
  • applications (medicine and pharmacy, opto-electronics, agriculture, etc.)

Published Papers (10 papers)

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Editorial

Jump to: Research, Review

3 pages, 179 KiB  
Editorial
Huisgen 3 + n Dipolar Cycloaddition Reactions: An Accessible and Useful Tool in Modern Organic and Heterocycle Synthesis
by Ionel I. Mangalagiu
Molecules 2023, 28(15), 5692; https://doi.org/10.3390/molecules28155692 - 27 Jul 2023
Viewed by 575
Abstract
Heterocycle derivatives have been reported as invaluable compounds in agriculture […] Full article

Research

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10 pages, 2261 KiB  
Communication
On the Question of Zwitterionic Intermediates in the [3 + 2] Cycloaddition Reactions between C-arylnitrones and Perfluoro 2-Methylpent-2-ene
by Katarzyna Mitka, Katarzyna Fela, Aleksandra Olszewska and Radomir Jasiński
Molecules 2021, 26(23), 7147; https://doi.org/10.3390/molecules26237147 - 25 Nov 2021
Cited by 6 | Viewed by 1588
Abstract
The molecular mechanism of the [3 + 2] cycloaddition reaction between C-arylnitrones and perfluoro 2-methylpent-2-ene was explored on the basis of DFT calculations. It was found that despite the polar nature of the intermolecular interactions, as well as the presence of fluorine atoms [...] Read more.
The molecular mechanism of the [3 + 2] cycloaddition reaction between C-arylnitrones and perfluoro 2-methylpent-2-ene was explored on the basis of DFT calculations. It was found that despite the polar nature of the intermolecular interactions, as well as the presence of fluorine atoms near the reaction centers, all reactions considered cycloaddition proceed via a one-step mechanism. All attempts for the localization of zwitterionic intermediates on the reaction paths were not successful. Similar results were obtained regardless of the level of theory applied. Full article
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19 pages, 22882 KiB  
Article
The Participation of 3,3,3-Trichloro-1-nitroprop-1-ene in the [3 + 2] Cycloaddition Reaction with Selected Nitrile N-Oxides in the Light of the Experimental and MEDT Quantum Chemical Study
by Karolina Zawadzińska, Mar Ríos-Gutiérrez, Karolina Kula, Przemysław Woliński, Barbara Mirosław, Tomasz Krawczyk and Radomir Jasiński
Molecules 2021, 26(22), 6774; https://doi.org/10.3390/molecules26226774 - 09 Nov 2021
Cited by 26 | Viewed by 2159
Abstract
The regioselective zw-type [3 + 2] cycloaddition (32CA) reactions of a series of aryl-substituted nitrile N-oxides (NOs) with trichloronitropropene (TNP) have been both experimentally and theoretically studied within the Molecular Electron Density Theory (MEDT). Zwitterionic NOs behave as moderate nucleophiles while TNP [...] Read more.
The regioselective zw-type [3 + 2] cycloaddition (32CA) reactions of a series of aryl-substituted nitrile N-oxides (NOs) with trichloronitropropene (TNP) have been both experimentally and theoretically studied within the Molecular Electron Density Theory (MEDT). Zwitterionic NOs behave as moderate nucleophiles while TNP acts as a very strong electrophile in these polar 32CA reactions of forward electron density flux, which present moderate activation Gibbs free energies of 22.8–25.6 kcal·mol−1 and an exergonic character of 28.4 kcal·mol−1 that makes them irreversible and kinetically controlled. The most favorable reaction is that involving the most nucleophilic MeO-substituted NO. Despite Parr functions correctly predicting the experimental regioselectivity with the most favorable O-CCCl3 interaction, these reactions follow a two-stage one-step mechanism in which formation of the O-C(CCl3) bond takes place once the C-C(NO2) bond is already formed. The present MEDT concludes that the reactivity differences in the series of NOs come from their different nucleophilic activation and polar character of the reactions, rather than any mechanistic feature. Full article
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14 pages, 4725 KiB  
Article
Synthesis of 1-(2-Fluorophenyl)pyrazoles by 1,3-Dipolar Cycloaddition of the Corresponding Sydnones
by Denisa Dumitrescu, Sergiu Shova, Constantin Draghici, Marcel Mirel Popa and Florea Dumitrascu
Molecules 2021, 26(12), 3693; https://doi.org/10.3390/molecules26123693 - 17 Jun 2021
Cited by 2 | Viewed by 2023
Abstract
3-Arylsydnones bearing fluorine and bromine atoms on the benzene ring were synthesized from N-nitroso-2-fluorophenylglycines and characterized by NMR spectroscopy. These were employed further in synthesis of the corresponding 1-(2-fluorophenyl)pyrazoles by 1,3-dipolar cycloaddition reaction with dimethyl acetylenedicarboxylate (DMAD) as activated dipolarophile. The sydnones [...] Read more.
3-Arylsydnones bearing fluorine and bromine atoms on the benzene ring were synthesized from N-nitroso-2-fluorophenylglycines and characterized by NMR spectroscopy. These were employed further in synthesis of the corresponding 1-(2-fluorophenyl)pyrazoles by 1,3-dipolar cycloaddition reaction with dimethyl acetylenedicarboxylate (DMAD) as activated dipolarophile. The sydnones as reaction intermediates were characterized by single crystal X-ray diffraction analysis showing interesting features such as halogen bonding as an important interaction in modeling the crystal structure. Full article
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15 pages, 2303 KiB  
Article
New Members of the Cinchona Alkaloids Family: Assembly of the Triazole Heterocycle at the 6′ Position
by Catalin Vasile Maftei, Martin Heiko Franz, Christian Kleeberg and Ion Neda
Molecules 2021, 26(11), 3357; https://doi.org/10.3390/molecules26113357 - 02 Jun 2021
Cited by 2 | Viewed by 2156
Abstract
The substance class of the well-known Cinchona alkaloids is widened by 6′-Amino-cinchonine and 6′-Amino-cinchonidine, novel compounds which incorporate a primary amino function in the quinolinic ring system. These key intermediates open the field for a range of fruitful chemistry. Here is described a [...] Read more.
The substance class of the well-known Cinchona alkaloids is widened by 6′-Amino-cinchonine and 6′-Amino-cinchonidine, novel compounds which incorporate a primary amino function in the quinolinic ring system. These key intermediates open the field for a range of fruitful chemistry. Here is described a short and direct pathway for the synthesis of triazole containing derivatives of the above-mentioned substances using the [3 + 2] Huisgen cycloaddition. For this purpose, the amines were first converted into the corresponding azides. Based on this, non-substituted and silyl-protected triazoles were synthesized as examples. Furthermore, didehydrated derivatives of quincorine and quincoridine were used as addition partners, resulting in compounds that carry the quinuclidine ring of the cinchona alkaloids at both ends. Some of these compounds were examined radiographically to investigate the position of the quinuclidine ring to the triazole. The solid-state structures of compounds 10, 11 and 28 were determined by X-ray diffraction analyses. Full article
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18 pages, 3464 KiB  
Article
Triazolyl Conjugated (Oligo)Phenothiazines Building Blocks for Hybrid Materials—Synthesis and Electronic Properties
by Hilla Khelwati, Adam W. Franz, Zhou Zhou, Werner R. Thiel and Thomas J. J. Müller
Molecules 2021, 26(10), 2950; https://doi.org/10.3390/molecules26102950 - 15 May 2021
Cited by 4 | Viewed by 1855
Abstract
The Cu-catalyzed alkyne-azide 1,3-dipolar cycloaddition variant provides a highly efficient entry to conjugated triazolyl-substituted (oligo)phenothiazine organosilicon derivatives with luminescence and reversible redox characteristics. Furthermore, by in-situ co-condensation synthesis several representative mesoporous MCM-41 type silica hybrid materials with embedded (oligo)phenothiazines are prepared and characterized [...] Read more.
The Cu-catalyzed alkyne-azide 1,3-dipolar cycloaddition variant provides a highly efficient entry to conjugated triazolyl-substituted (oligo)phenothiazine organosilicon derivatives with luminescence and reversible redox characteristics. Furthermore, by in-situ co-condensation synthesis several representative mesoporous MCM-41 type silica hybrid materials with embedded (oligo)phenothiazines are prepared and characterized with respect to their structural and electronic properties. The hybrid materials also can be oxidized to covalently bound embedded radical cations, which are identified by their UV/Vis absorption signature and EPR signals. Full article
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19 pages, 16592 KiB  
Article
Synthesis and Biological Screening of New Cyano-Substituted Pyrrole Fused (Iso)Quinoline Derivatives
by Maria Cristina Al-Matarneh, Roxana-Maria Amărandi, Ionel I. Mangalagiu and Ramona Danac
Molecules 2021, 26(7), 2066; https://doi.org/10.3390/molecules26072066 - 03 Apr 2021
Cited by 23 | Viewed by 2801
Abstract
Several new cyano-substituted derivatives with pyrrolo[1,2-a]quinoline and pyrrolo[2,1-a]isoquinoline scaffolds were synthesized by the [3 + 2] cycloaddition of (iso)quinolinium ylides to fumaronitrile. The cycloimmonium ylides reacted in situ as 1,3-dipoles with fumaronitrile to selectively form distinct final compounds, depending [...] Read more.
Several new cyano-substituted derivatives with pyrrolo[1,2-a]quinoline and pyrrolo[2,1-a]isoquinoline scaffolds were synthesized by the [3 + 2] cycloaddition of (iso)quinolinium ylides to fumaronitrile. The cycloimmonium ylides reacted in situ as 1,3-dipoles with fumaronitrile to selectively form distinct final compounds, depending on the structure of the (iso)quinolinium salt. Eleven compounds were evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compound 9a showed a broad spectrum of antiproliferative activity against cancer cell lines representing leukemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast and prostate cancer. In vitro assays and molecular docking revealed tubulin interaction properties of compound 9a. Full article
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12 pages, 546 KiB  
Article
Huisgen [3 + 2] Dipolar Cycloadditions of Phthalazinium Ylides to Activated Symmetric and Non-Symmetric Alkynes
by Vasilichia Antoci, Costel Moldoveanu, Ramona Danac, Violeta Mangalagiu and Gheorghita Zbancioc
Molecules 2020, 25(19), 4416; https://doi.org/10.3390/molecules25194416 - 25 Sep 2020
Cited by 5 | Viewed by 1882
Abstract
We present herein a straightforward and efficient pathway for the synthesis of pyrrolophthalazine cycloadducts via Huisgen [3 + 2] dipolar cycloaddition reactions of phthalazinium ylides to methyl propiolate or dimethyl acetylenedicarboxylate (DMAD). A thoroughly comparative study concerning the efficiency of synthesis, conventional thermal [...] Read more.
We present herein a straightforward and efficient pathway for the synthesis of pyrrolophthalazine cycloadducts via Huisgen [3 + 2] dipolar cycloaddition reactions of phthalazinium ylides to methyl propiolate or dimethyl acetylenedicarboxylate (DMAD). A thoroughly comparative study concerning the efficiency of synthesis, conventional thermal heating (TH) versus microwave (MW) and ultrasound (US) irradiation, has been performed. The cycloaddition reactions of phthalazinium ylides to methyl propiolate occur regiospecific, with a single regioisomer being obtained. Under conventional TH, the cycloaddition reaction of phthalazinium ylides with DMAD occurs to a mixture of inseparable partial and fully aromatized pyrrolophthalazine cycloadducts, while MW or US irradiation are leading only to fully aromatized compounds, with the reactions becoming selective. A feasible mechanism for formation of fully aromatized compounds is presented. Besides selectivity, it has to be noticed that the reaction setup under MW or US irradiation offer a number of other certain advantages: higher yields, decreasing of the amount of used solvent comparative with TH, decreasing of the reaction time from hours to minutes and decreasing of the consumed energy; consequently, these reactions could be considered environmentally friendly. Full article
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Review

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16 pages, 9218 KiB  
Review
[3 + n] Cycloaddition Reactions: A Milestone Approach for Elaborating Pyridazine of Potential Interest in Medicinal Chemistry and Optoelectronics
by Dorina Amariucai-Mantu, Violeta Mangalagiu and Ionel I. Mangalagiu
Molecules 2021, 26(11), 3359; https://doi.org/10.3390/molecules26113359 - 02 Jun 2021
Cited by 7 | Viewed by 2786
Abstract
During the last few decades, pyridazine derivatives have emerged as privileged structures in heterocyclic chemistry, both because of their excellent chemistry and because of their potential applications in medicinal chemistry and optoelectronics. This review is focused on the recent advances in [3 + [...] Read more.
During the last few decades, pyridazine derivatives have emerged as privileged structures in heterocyclic chemistry, both because of their excellent chemistry and because of their potential applications in medicinal chemistry and optoelectronics. This review is focused on the recent advances in [3 + n] cycloaddition reactions in the pyridazine series as well as their medicinal chemistry and optoelectronic applications over the last ten years. The stereochemistry and regiochemistry of the cycloaddition reactions are discussed. Applications in optoelectronics (in particular, as fluorescent materials and sensors) and medicinal chemistry (in particular, antimicrobials and anticancer) are also reviewed. Full article
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34 pages, 9851 KiB  
Review
Indolizines and Their Hetero/Benzo Derivatives in Reactions of [8+2] Cycloaddition
by Eugene V. Babaev and Ivan A. Shadrin
Molecules 2021, 26(7), 2050; https://doi.org/10.3390/molecules26072050 - 03 Apr 2021
Cited by 6 | Viewed by 3365
Abstract
Peculiarities of [8+2] cycloaddition of acetylenes to indolizines are reviewed. Especially mentioned are indolizines with leaving groups at positions 3 and 5. Cycloaddition to aza- and benzo derivatives are reviewed, as well as 1,10-cyclizations and processes leading to cyclazines where indolizines are intermediates. [...] Read more.
Peculiarities of [8+2] cycloaddition of acetylenes to indolizines are reviewed. Especially mentioned are indolizines with leaving groups at positions 3 and 5. Cycloaddition to aza- and benzo derivatives are reviewed, as well as 1,10-cyclizations and processes leading to cyclazines where indolizines are intermediates. Mechanistic features (adducts and cycloadducts) and theoretical aspects (one- or two-steps mechanism) are reviewed. Full article
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Scheme 1

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