Cycloaddition Reaction in Organic Synthesis

A special issue of Organics (ISSN 2673-401X).

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 27881

Special Issue Editors

Institute of Organic Chemistry & Technology, Cracow University of Technology, Warszawska 24, 31-155 Krakow, Poland
Interests: cycloaddition reactions; nitrocompounds; cycloaddition; heterocycles; reaction mechanisms; organic reactivity; DFT calculations
Special Issues, Collections and Topics in MDPI journals
Department of Chemistry, Perm State University, ul. Bukireva 15, Perm 614990, Russia
Interests: cycloaddition; polycarbonyl compounds; 1H-pyrrole-2,3-diones; molecular docking, biological activity

Special Issue Information

Dear Colleagues,

Cycloaddition reactions are the most universal protocol for the preparation of a wide range of carbo- and heterocyclic molecular systems. In this way, it is possible to synthesize three-, four-, five- six- (etc.) membered cyclic molecules, including almost any combination of heteroatoms. Most of these types of processes proceed with high yields and selectivity. Additionally, cycloaddition reactions are realized with full atomic-economy. Therefore, this class of organic processes is valuable from the point of view of green chemistry.

The latest discoveries shed new insight on the mechanisms of cycloaddition processes, as well as factors which stimulate chemo-, regio-, and stereoselectivity. So, this issue should attract great attention from organic chemists. This Special Issue is especially dedicated to the presentation of new, important discoveries in the mentioned field. In particular, we invite short laboratory notes including rare cases of the reaction course, full papers with comprehensive studies, kinetic considerations about substituent and/or solvent effects as well as activation parameters, preparation of analogs of natural products, mechanistic experimental and/or theoretical studies, prediction of the reactivity and selectivity on the basis of modern organic theories, biological activity of the products obtained via cycloaddition reactions. Review articles by experts in the field will also be welcome.

Prof. Dr. Radomir Jasinski
Prof. Dr. Luis R. Domingo
Dr. Ekaterina Stepanova
Guest Editors

Manuscript Submission Information

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Keywords

  • Cycloaddition
  • Heterocycles
  • Reaction mechanisms
  • Chemo-, regio-, and stereoselectivity
  • Quantumchemical computational study
  • Molecular electron density theory
  • Biological activity of the compounds prepared via cycloaddition reactions

Published Papers (6 papers)

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Research

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15 pages, 4881 KiB  
Article
The Role of the Catalyst on the Reactivity and Mechanism in the Diels–Alder Cycloaddition Step of the Povarov Reaction for the Synthesis of a Biological Active Quinoline Derivative: Experimental and Theoretical Investigations
Organics 2021, 2(1), 57-71; https://doi.org/10.3390/org2010006 - 18 Mar 2021
Cited by 8 | Viewed by 3671
Abstract
An experimental and theoretical study of the reactivity and mechanism of the non-catalyzed and catalyzed Povarov reaction for the preparation of a 4-ethoxy-2,3,4,4a-tetrahydro-2-phenylquinoline as a biological active quinoline derivative has been performed. The optimization of experimental conditions indicate that the use of a [...] Read more.
An experimental and theoretical study of the reactivity and mechanism of the non-catalyzed and catalyzed Povarov reaction for the preparation of a 4-ethoxy-2,3,4,4a-tetrahydro-2-phenylquinoline as a biological active quinoline derivative has been performed. The optimization of experimental conditions indicate that the use of a catalyst, namely Lewis acid with an electron-releasing group, creates the best experimental conditions for this kind of reaction. The chemical structure was characterized by the usual spectroscopic methods. The prepared quinoline derivative has been also tested in vitro for antibacterial activity, which displays moderate inhibitory activity against both Escherichia coli and Staphylococcus aureus. The antioxidant activity was investigated in vitro by evaluating their reaction with 1,1-diphenyl-2-picrylhydrazyl DPPH radical, which reveals high reactivity. The computational study was performed on the Diels–Alder step of the Povarov reaction using a B3LYP/6-31G(d,p) level of theory. The conceptual DFT reactivity indices explain well the reactivity and the meta regioselectivity experimentally observed. Both catalysts enhance the reactivity of the imine, favoring the formation of the meta regioisomers with a low activation energy, and they change the mechanism to highly synchronous for the Lewis acid and to stepwise for the Brønsted acid. The reaction of imine with allyl alcohol does not give any product, which requires high activation energy. Full article
(This article belongs to the Special Issue Cycloaddition Reaction in Organic Synthesis)
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12 pages, 1372 KiB  
Article
Theoretical Insight into the Reversal of Chemoselectivity in Diels-Alder Reactions of α,β-Unsaturated Aldehydes and Ketones Catalyzed by Brønsted and Lewis Acids
Organics 2021, 2(1), 38-49; https://doi.org/10.3390/org2010004 - 05 Mar 2021
Cited by 2 | Viewed by 2952
Abstract
Experimentally, a reversal of chemoselectivity has been observed in catalyzed Diels–Alder reactions of α,β-unsaturated aldehydes (e.g., (2E)-but-2-enal) and ketones (e.g., 2-hexen-4-one) with cyclopentadiene. Indeed, using the triflimidic Brønsted acid Tf2NH as catalyst, the reaction gave a Diels–Alder adduct derived from [...] Read more.
Experimentally, a reversal of chemoselectivity has been observed in catalyzed Diels–Alder reactions of α,β-unsaturated aldehydes (e.g., (2E)-but-2-enal) and ketones (e.g., 2-hexen-4-one) with cyclopentadiene. Indeed, using the triflimidic Brønsted acid Tf2NH as catalyst, the reaction gave a Diels–Alder adduct derived from α,β-unsaturated ketone as a major product. On the other hand, the use of tris(pentafluorophenyl)borane B(C6F5)3 bulky Lewis acid as catalyst gave mainly the cycloadduct of α,β-unsaturated aldehyde as a major product. Our aim in the present work is to put in evidence the role of the catalyst in the reversal of the chemoselectivity of the catalyzed Diels–Alder reactions of (2E)-but-2-enal and 2-Hexen-4-one with cyclopentadiene. The calculations were performed at the ωB97XD/6-311G(d,p) level of theory and the solvent effects of dichloromethane were taken into account using the PCM solvation model. The obtained results are in good agreement with experimental outcomes. Full article
(This article belongs to the Special Issue Cycloaddition Reaction in Organic Synthesis)
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12 pages, 5289 KiB  
Article
Application of β-Phosphorylated Nitroethenes in [3+2] Cycloaddition Reactions Involving Benzonitrile N-Oxide in the Light of a DFT Computational Study
Organics 2021, 2(1), 26-37; https://doi.org/10.3390/org2010003 - 16 Feb 2021
Cited by 13 | Viewed by 6590
Abstract
The regiochemistry of [3+2] cycloaddition (32CA) processes between benzonitrile N-oxide 1 and β-phosphorylated analogues of nitroethenes 2a–c has been studied using the Density Functional Theory (DFT) at the M062X/6-31+G(d) theory level. The obtained results of reactivity indices show that benzonitrile N-oxide 1 can [...] Read more.
The regiochemistry of [3+2] cycloaddition (32CA) processes between benzonitrile N-oxide 1 and β-phosphorylated analogues of nitroethenes 2a–c has been studied using the Density Functional Theory (DFT) at the M062X/6-31+G(d) theory level. The obtained results of reactivity indices show that benzonitrile N-oxide 1 can be classified both as a moderate electrophile and moderate nucleophile, while β-phosphorylated analogues of nitroethenes 2a–c can be classified as strong electrophiles and marginal nucleophiles. Moreover, the analysis of CDFT shows that for [3+2] cycloadditions with the participation of β-phosphorylatednitroethene 2a and β-phosphorylated α-cyanonitroethene 2b, the more favored reaction path forms 4-nitro-substituted Δ2-isoxazolines 3a–b, while for a reaction with β-phosphorylated β-cyanonitroethene 2c, the more favored path forms 5-nitro-substituted Δ2-isoxazoline 4c. This is due to the presence of a cyano group in the alkene. The CDFT study correlates well with the analysis of the kinetic description of the considered reaction channels. Moreover, DFT calculations have proven the clearly polar nature of all analyzed [3+2] cycloaddition reactions according to the polar one-step mechanism. Full article
(This article belongs to the Special Issue Cycloaddition Reaction in Organic Synthesis)
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16 pages, 8701 KiB  
Article
Mpro-SARS-CoV-2 Inhibitors and Various Chemical Reactivity of 1-Bromo- and 1-Chloro-4-vinylbenzene in [3 + 2] Cycloaddition Reactions
Organics 2021, 2(1), 1-16; https://doi.org/10.3390/org2010001 - 04 Jan 2021
Cited by 15 | Viewed by 3660
Abstract
The regioselectvity and the mechanism of the (32CA) cycloadditions reactions of 1-bromo-4-vinylbenzene 1 and 1-chloro-4-vinylbenzene 2 with benzonitrile oxide 3 were investigated under the molecular electron density theory (MEDT) at the B3LYP/6-311++G(d,p) computational level. Evaluation of the ELF reveals that these zwitterionic type [...] Read more.
The regioselectvity and the mechanism of the (32CA) cycloadditions reactions of 1-bromo-4-vinylbenzene 1 and 1-chloro-4-vinylbenzene 2 with benzonitrile oxide 3 were investigated under the molecular electron density theory (MEDT) at the B3LYP/6-311++G(d,p) computational level. Evaluation of the ELF reveals that these zwitterionic type (zw-type) 32CA reactions take place in a two-stage one-step mechanism. This MEDT study shows that the meta isoxazolines are kinetically and thermodynamically favored over the ortho ones, these 32CA reactions being completely regioselective, in agreement with experimental outcomes. In addition, the efficiency of isoxazolines against SARS-CoV-2 have been also investigated. According to the docking analysis, the present study concludes that 5-(p-bromophenyl)-3-phenyl-2-isoxazoline (B-m) shows better interactions for the inhibition of SARS-CoV-2 in comparison to chloroquine. Full article
(This article belongs to the Special Issue Cycloaddition Reaction in Organic Synthesis)
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13 pages, 5374 KiB  
Article
Participation of Phosphorylated Analogues of Nitroethene in Diels–Alder Reactions with Anthracene: A Molecular Electron Density Theory Study and Mechanistic Aspect
Organics 2020, 1(1), 36-48; https://doi.org/10.3390/org1010004 - 23 Nov 2020
Cited by 13 | Viewed by 3414
Abstract
The structure and the contribution of the bis(2-chloroethyl) 2-nitro 1a and 2-bromo-2-nitroethenylphosphonates 1b with anthracene 2 in the Diels–Alder (DA) reactions have been studied within the Molecular Electron Density Theory (MEDT) at the B3LYP functional together with 6-31G(d), 6-31+G(d) and 6-31+G(d,p) basic sets. [...] Read more.
The structure and the contribution of the bis(2-chloroethyl) 2-nitro 1a and 2-bromo-2-nitroethenylphosphonates 1b with anthracene 2 in the Diels–Alder (DA) reactions have been studied within the Molecular Electron Density Theory (MEDT) at the B3LYP functional together with 6-31G(d), 6-31+G(d) and 6-31+G(d,p) basic sets. Analysis of the Conceptual Density Functional Theory (CDFT) reactivity indices indicates that 1a and 1b can be classified as a strong electrophile and marginal nucleophile, while 2 is classified as a strong electrophile and strong nucleophile. The studied DA reactions take place through a one-step mechanism. A Bonding Evolution Theory (BET) of the one path associated with the DA reaction of 1a with 2 indicates that it is associated with non-concerted two-stage one-step mechanism. BET analysis shows that the first C2-C3 single bond is formed in Phase VI, while the second C1-C6 single bond is formed in the Phase VIII. The formation of both single bonds occurs through the merging of two C2 and C3, C1 and C6 pseudoradical centers, respectively. Full article
(This article belongs to the Special Issue Cycloaddition Reaction in Organic Synthesis)
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Review

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21 pages, 2778 KiB  
Review
On the Question of Zwitterionic Intermediates in the [3+2] Cycloaddition Reactions: A Critical Review
Organics 2020, 1(1), 49-69; https://doi.org/10.3390/org1010005 - 26 Nov 2020
Cited by 41 | Viewed by 4955
Abstract
New discoveries require a fundamental revision of the view on the mechanism of the 32CAreaction (according to the older nomenclature defined as 1,3-dipolar cycloaddition reactions). The view of the one-step, “concerted” mechanism of such processes developed in the 20-century is very popular today, [...] Read more.
New discoveries require a fundamental revision of the view on the mechanism of the 32CAreaction (according to the older nomenclature defined as 1,3-dipolar cycloaddition reactions). The view of the one-step, “concerted” mechanism of such processes developed in the 20-century is very popular today, both in academic literature and among organic chemists who do not specialize in such transformations. Meanwhile, more and more reports bring examples of reactions that clearly cannot be treated as processes without intermediates. However, these examples are documented very differently. In addition to comprehensive studies using many complementary research techniques, there are also reports in which the presence of intermediates in the cycloaddition environment is postulated on the basis of very unreliable premises. This review is an attempt at a critical analysis and systematization of data in the presented area. Full article
(This article belongs to the Special Issue Cycloaddition Reaction in Organic Synthesis)
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