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17 pages, 4225 KiB

Open AccessArticle

Comparative Nitrene-Transfer Chemistry to Olefins Mediated by First-Row Transition Metal Catalysts Supported by a Pyridinophane Macrocycle with N4 Ligation

by Himanshu Bhatia, Lillian P. Adams, Ingrid Cordsiemon, Suraj Kumar Sahoo, Amitava Choudhury, Thomas R. Cundari and Pericles Stavropoulos

Molecules 2025, 30(15), 3097; https://doi.org/10.3390/molecules30153097 - 24 Jul 2025

Viewed by 410

Abstract

A 12-membered pyridinophane scaffold containing two pyridine and two tertiary amine residues is examined as a prototype ligand (^tBuN4) for supporting nitrene transfer to olefins. The known [(^tBuN4)M^II(MeCN)₂]²⁺ (M = Mn, Fe, Co, and [...] Read more.

A 12-membered pyridinophane scaffold containing two pyridine and two tertiary amine residues is examined as a prototype ligand (^tBuN4) for supporting nitrene transfer to olefins. The known [(^tBuN4)M^II(MeCN)₂]²⁺ (M = Mn, Fe, Co, and Ni) and [(^tBuN4)Cu^I(MeCN)]⁺ cations are synthesized with the hexafluorophosphate counteranion. The aziridination of para-substituted styrenes with PhI=NTs (Ts = tosyl) in various solvents proved to be high yielding for the Cu(I) and Cu(II) reagents, in contrast to the modest efficacy of all other metals. For α-substituted styrenes, aziridination is accompanied by products of aziridine ring opening, especially in chlorinated solvents. Bulkier β-substituted styrenes reduce product yields, largely for the Cu(II) reagent. Aromatic olefins are more reactive than aliphatic congeners by a significant margin. Mechanistic studies (Hammett plots, KIE, and stereochemical scrambling) suggest that both copper reagents operate via sequential formation of two N–C bonds during the aziridination of styrene, but with differential mechanistic parameters, pointing towards two distinct catalytic manifolds. Computational studies indicate that the putative copper nitrenes derived from Cu(I) and Cu(II) are each associated with closely spaced dual spin states, featuring high spin densities on the nitrene N atom. The computed electrophilicity of the Cu(I)-derived nitrene reflects the faster operation of the Cu(I) manifold. Full article

(This article belongs to the Special Issue Synthetic Studies Aimed at Heterocyclic Organic Compounds, 2nd Edition)

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11 pages, 4115 KiB

Open AccessArticle

Porous Composite Polymers Composed of Polyethyleneimine and Cyclodextrins: Synthesis and Application as Adsorbents for an Organic Compound

by Naofumi Naga, Yuma Miyazaki and Tamaki Nakano

Separations 2025, 12(4), 94; https://doi.org/10.3390/separations12040094 - 10 Apr 2025

Cited by 1 | Viewed by 434

Abstract

Polyethyleneimine-based porous composites have been prepared by ring-opening polymerization of 2,2-bishydroxymethylbutanol-tris[3-(1-aziridinyl)propionate] (3AZ), a tri-aziridine compound, in water, in the presence of cyclodextrins (CDs), i.e., α-CD, γ-CD, methyl-β-cyclodextrin (Me-β-CD), monoacetyl-β-cyclodextrin (Ac-β-CD), and hydroxypropyl-β-cyclodextrin (HP-β-CD). The corresponding 3AZ-CD porous polymer composites were successfully obtained in [...] Read more.

Polyethyleneimine-based porous composites have been prepared by ring-opening polymerization of 2,2-bishydroxymethylbutanol-tris[3-(1-aziridinyl)propionate] (3AZ), a tri-aziridine compound, in water, in the presence of cyclodextrins (CDs), i.e., α-CD, γ-CD, methyl-β-cyclodextrin (Me-β-CD), monoacetyl-β-cyclodextrin (Ac-β-CD), and hydroxypropyl-β-cyclodextrin (HP-β-CD). The corresponding 3AZ-CD porous polymer composites were successfully obtained in most cases under a wide range of CD concentrations, 5–20 wt%, and reaction temperatures, 20–60 °C. The reaction system in the presence of Ac-β-CD preferentially yielded gels. The polymer composites were composed of connected particles with sizes of the order of 10⁻⁹ m. The particle sizes decreased with an increase in the CD concentration. Young’s moduli of the 3AZ-CD porous polymer composites tended to increase with an increase in bulk density. The 3AZ-CD porous polymer composites with Me-β-CD and HP-β-CD effectively adsorbed phenolphthalein in the solution. The adsorption value increased with increasing the CD content and rose to more than 600 mg/g of porous polymer composite. Full article

(This article belongs to the Special Issue Application of Advanced Materials and Technologies in the Separation and Adsorption)

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24 pages, 7062 KiB

Open AccessReview

Recent Advances in Transition Metal-Catalyzed Ring-Opening Reaction of Aziridine

by Partha Sarathi Bera, Yafia Kousin Mirza, Tarunika Sachdeva and Milan Bera

Compounds 2024, 4(4), 626-649; https://doi.org/10.3390/compounds4040038 - 11 Oct 2024

Cited by 2 | Viewed by 3112

Abstract

The smallest strained, saturated N-heterocycles, such as aziridine, can be a valuable building block in synthetic organic chemistry. Ring-opening reactions with various nucleophiles could be the most important strategy to synthesize various value-added molecular entities. Therefore, regioselective ring-opening reactions of aziridines with various [...] Read more.

The smallest strained, saturated N-heterocycles, such as aziridine, can be a valuable building block in synthetic organic chemistry. Ring-opening reactions with various nucleophiles could be the most important strategy to synthesize various value-added molecular entities. Therefore, regioselective ring-opening reactions of aziridines with various heteroatomic nucleophiles and carbon nucleophiles establish a useful synthetic methodology to synthesize biologically relevant β-functionalized alkylamines. The regio-selective ring-opening of aziridines is highly dependent on the substrate combination, and stereochemical control is challenging for Lewis acid-promoted reactions. Therefore, the development of a robust, catalytic ring-opening process that assists in the accurate prediction of regioselectivity and stereochemistry is highly desirable. Consequently, a large number of publications detailing distinct methods for aziridine ring-opening reactions can be found in the literature. In this review, we discuss several transition metal catalyzed cross-coupling reaction protocols for the ring opening of substituted aziridines with various carbon nucleophiles. Full article

(This article belongs to the Special Issue (Bio)molecules from Natural Extracts: An Infinite World of Opportunities)

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28 pages, 8079 KiB

Open AccessReview

D-Hexopyranosides with Vicinal Nitrogen-Containing Functionalities

by Jana Pospíšilová, Daniel Toman, Tomáš Ručil and Petr Cankař

Molecules 2024, 29(15), 3465; https://doi.org/10.3390/molecules29153465 - 24 Jul 2024

Viewed by 935

Abstract

Various substituted D-hexopypyranosides units with nitrogen-containing functionalities are present in many important natural compounds and pharmaceutical substances. Since their complex structural diversity contributes to a broad spectrum of biological functions and activities, these derivatives are frequently studied. This review covers syntheses of D-hexopyranosides [...] Read more.

Various substituted D-hexopypyranosides units with nitrogen-containing functionalities are present in many important natural compounds and pharmaceutical substances. Since their complex structural diversity contributes to a broad spectrum of biological functions and activities, these derivatives are frequently studied. This review covers syntheses of D-hexopyranosides with vicinal nitrogen-containing functionalities since the 1960s, when the first articles emerged. The syntheses are arranged according to the positions of substitutions, to form a relative configuration of vicinal functionalities, and synthetic methodologies. Full article

(This article belongs to the Special Issue Advances of Heterocyclic Chemistry with Antibacterial and Antifungal Activity)

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31 pages, 5091 KiB

Open AccessArticle

Access to 2-Fluorinated Aziridine-2-phosphonates from α,α-Halofluorinated β-Iminophosphonates—Spectroscopic and Theoretical Studies

by Mateusz Klarek, Tomasz Siodła, Tahar Ayad, David Virieux and Magdalena Rapp

Molecules 2023, 28(14), 5579; https://doi.org/10.3390/molecules28145579 - 22 Jul 2023

Cited by 2 | Viewed by 1862

Abstract

The efficient one-pot halofluorination of a β-enaminophosphonate/β-iminophosphonate tautomeric mixture resulting in α,α-halofluorinated β-iminophosphonates is reported. Subsequent imine reduction gave the corresponding β-aminophosphonates as a racemic mixture or with high diastereoselectivity. The proposed protocol is the [...] Read more.

The efficient one-pot halofluorination of a β-enaminophosphonate/β-iminophosphonate tautomeric mixture resulting in α,α-halofluorinated β-iminophosphonates is reported. Subsequent imine reduction gave the corresponding β-aminophosphonates as a racemic mixture or with high diastereoselectivity. The proposed protocol is the first example of a synthesis of N-inactivated aziridines substituted by a fluorine and phosphonate moiety on the same carbon atom. Based on spectroscopic and theoretical studies, we determined the cis/trans geometry of the resulting fluorinated aziridine-2-phosphonate. Our procedure, involving the reduction of cis/trans-fluoroaziridine mixture 24, allows us to isolate chiral trans-aziridines 24 as well as cis-aziridines 27 that do not contain a fluorine atom. We also investigated the influence of the fluorine atom on the reactivity of aziridine through an acid-catalyzed regioselective ring-opening reaction. The results of DFT calculations, at the PCM/ωB97x-D/def2-TZVPD level of theory, are in good agreement with the experiments. The transition states of the S_N2 intramolecular cyclization of vicinal haloamines have been modeled. Full article

(This article belongs to the Special Issue Advances in Modern Fluorine Chemistry)

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18 pages, 2713 KiB

Open AccessArticle

Synthesis of Enantiomerically Enriched Protected 2-Amino-, 2,3-Diamino- and 2-Amino-3-Hydroxypropylphosphonates

by Aleksandra Trocha, Dorota G. Piotrowska and Iwona E. Głowacka

Molecules 2023, 28(3), 1466; https://doi.org/10.3390/molecules28031466 - 2 Feb 2023

Viewed by 2120

Abstract

Simple and efficient strategies for the syntheses of enantiomerically enriched functionalized diethyl 2-amino-, 2,3-diamino- and 2-amino-3-hydroxypropylphosphonates have been developed starting from, respectively, N-protected (aziridin-2-yl)methylphosphonates, employing a regioselective aziridine ring-opening reaction with corresponding nucleophiles. Diethyl (R)- and (S)-2-(N [...] Read more.

Simple and efficient strategies for the syntheses of enantiomerically enriched functionalized diethyl 2-amino-, 2,3-diamino- and 2-amino-3-hydroxypropylphosphonates have been developed starting from, respectively, N-protected (aziridin-2-yl)methylphosphonates, employing a regioselective aziridine ring-opening reaction with corresponding nucleophiles. Diethyl (R)- and (S)-2-(N-Boc-amino)propylphosphonates were obtained via direct regiospecific hydrogenolysis of the respective enantiomer of (R)- and (S)-N-Boc-(aziridin-2-yl)methylphosphonates. N-Boc-protected (R)- and (S)-2,3-diaminopropylphosphonates were synthesized from (R)- and (S)-N-Bn-(aziridin-2-yl)methylphosphonates via a regiospecific ring-opening reaction with neat trimethylsilyl azide and subsequent reduction of (R)- and (S)-2-(N-Boc-amino)-3-azidopropylphosphonates using triphenylphosphine. On the other hand, treatment of the corresponding (R)- and (S)-N-Bn-(aziridin-2-yl)methylphosphonates with glacial acetic acid led regiospecifically to the formation of (R)- and (S)-2-(N-Bn-amino)-3-acetoxypropylphosphonates. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 2nd Edition)

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1 pages, 188 KiB

Open AccessAbstract

Pd-Catalyzed Cycloaddition of Bicyclic Aziridine with Isocyanates

by Mariana Crespo Monteiro, Carlos A. M. Afonso and Filipa Siopa

Med. Sci. Forum 2022, 14(1), 97; https://doi.org/10.3390/ECMC2022-13424 - 1 Nov 2022

Viewed by 915

Abstract

Nitrogen-containing heterocycles can have several applications in the pharmaceutical industry since they contain a wide spectrum of biological activities. Imidazolidinones have shown activity against leukemia, lung cancer, and metabolic disorders. These cyclic urea frameworks can be obtained through transition-metal-catalyzed intermolecular cycloaddition using an [...] Read more.

Nitrogen-containing heterocycles can have several applications in the pharmaceutical industry since they contain a wide spectrum of biological activities. Imidazolidinones have shown activity against leukemia, lung cancer, and metabolic disorders. These cyclic urea frameworks can be obtained through transition-metal-catalyzed intermolecular cycloaddition using an aziridine moiety as the starting material. These reactions often provide effective one-step procedures that result in heterocyclic derivatives that are challenging to access through conventional approaches. We have previously described the photoreaction of butyl pyridinium salt with the corresponding bicyclic aziridine in continuous flow. Additionally, we reported that the palladium-catalyzed ring opening of bicyclic aziridines with active methylenes exhibited a new S_N2’ selectivity. In this study, the reaction between bicyclic aziridines and several isocyanates, in the presence of Pd(0)-catalyst is presented. The reactions proceed through ring opening of the aziridine moiety, with the formation of the π-allylpalladium complex, followed by cyclization via nucleophilic addition of nitrogen to the isocyanate, affording regioselectively imidazolidinones. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

22 pages, 10864 KiB

Open AccessFeature PaperArticle

Ionic Liquids-Assisted Ring Opening of Three-Membered Heterocycles with Thio- and Seleno-Silanes

by Damiano Tanini, Tommaso Pecchi, Nikolai V. Ignat’ev and Antonella Capperucci

Catalysts 2022, 12(10), 1259; https://doi.org/10.3390/catal12101259 - 17 Oct 2022

Cited by 2 | Viewed by 2199

Abstract

Ring opening reactions of strained heterocycles (epoxides, aziridines, thiiranes) by silyl chalcogenides, such as thiosilanes and selenosilanes, can be efficiently performed in a variety of ionic liquids, which can behave as reaction media and in some cases also as catalysts. This protocol enables [...] Read more.

Ring opening reactions of strained heterocycles (epoxides, aziridines, thiiranes) by silyl chalcogenides, such as thiosilanes and selenosilanes, can be efficiently performed in a variety of ionic liquids, which can behave as reaction media and in some cases also as catalysts. This protocol enables an alternative access to β-functionalized sulfides and selenides under mild conditions. Full article

(This article belongs to the Special Issue Synthesis and Catalytic Applications of S-, Se- and Te-Containing Compounds: Recent Advances in Organic Synthesis)

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13 pages, 1506 KiB

Open AccessArticle

Atom Economical Multi-Substituted Pyrrole Synthesis from Aziridine

by Lingamurthy Macha, Ranjith Jala, Sang-Yun Na and Hyun-Joon Ha

Molecules 2022, 27(20), 6869; https://doi.org/10.3390/molecules27206869 - 13 Oct 2022

Viewed by 3360

Abstract

Multi-substituted pyrroles are synthesized from regiospecific aziridine ring-opening and subsequent intramolecular cyclization with a carbonyl group at the γ-position in the presence of Lewis acid or protic acid. This method is highly atom economical where all the atoms of the reactants are [...] Read more.

Multi-substituted pyrroles are synthesized from regiospecific aziridine ring-opening and subsequent intramolecular cyclization with a carbonyl group at the γ-position in the presence of Lewis acid or protic acid. This method is highly atom economical where all the atoms of the reactants are incorporated into the final product with the removal of water. This new protocol is applied to the synthesis of various pyrroles, including natural products. Full article

(This article belongs to the Special Issue Recent Developments in the Synthesis and Functionalization of Nitrogen Heterocycles)

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8 pages, 1382 KiB

Open AccessArticle

The Anionic Polymerization of a tert-Butyl-Carboxylate-Activated Aziridine

by Chandan Giri, Jen-Yu Chang, Pierre Canisius Mbarushimana and Paul A. Rupar

Polymers 2022, 14(16), 3253; https://doi.org/10.3390/polym14163253 - 10 Aug 2022

Cited by 5 | Viewed by 3456

Abstract

N-Sulfonyl-activated aziridines are known to undergo anionic-ring-opening polymerizations (AROP) to form polysulfonyllaziridines. However, the post-polymerization deprotection of the sulfonyl groups from polysulfonyllaziridines remains challenging. In this report, the polymerization of tert-butyl aziridine-1-carboxylate (BocAz) is reported. BocAz has an electron-withdrawing [...] Read more.

N-Sulfonyl-activated aziridines are known to undergo anionic-ring-opening polymerizations (AROP) to form polysulfonyllaziridines. However, the post-polymerization deprotection of the sulfonyl groups from polysulfonyllaziridines remains challenging. In this report, the polymerization of tert-butyl aziridine-1-carboxylate (BocAz) is reported. BocAz has an electron-withdrawing tert-butyloxycarbonyl (BOC) group on the aziridine nitrogen. The BOC group activates the aziridine for AROP and allows the synthesis of low-molecular-weight poly(BocAz) chains. A ¹³C NMR spectroscopic analysis of poly(BocAz) suggested that the polymer is linear. The attainable molecular weight of poly(BocAz) is limited by the poor solubility of poly(BocAz) in AROP-compatible solvents. The deprotection of poly(BocAz) using trifluoroacetic acid (TFA) cleanly produces linear polyethyleneimine. Overall, these results suggest that carbonyl groups, such as BOC, can play a larger role in the in the activation of aziridines in anionic polymerization and in the synthesis of polyimines. Full article

(This article belongs to the Special Issue Multiphase Systems with Polymeric Matrices: Polymer Blends and Composites)

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14 pages, 4346 KiB

Open AccessArticle

Aziridine Ring Opening as Regio- and Stereoselective Access to C-Glycosyl-Aminoethyl Sulfide Derivatives

by Aleksandra Tracz, Martyna Malinowska, Stanisław Leśniak and Anna Zawisza

Molecules 2022, 27(6), 1764; https://doi.org/10.3390/molecules27061764 - 8 Mar 2022

Cited by 4 | Viewed by 3641

Abstract

A short synthetic route to stereoselective access to C-glycosyl-aminoethyl sulfide derivatives has been developed through the reaction of tributhyltin derivatives of glycals with aziridinecarboaldehyde and the regioselective ring opening of a chiral aziridine with thiophenol. The absolute configurations of the resulting diastereoisomers [...] Read more.

A short synthetic route to stereoselective access to C-glycosyl-aminoethyl sulfide derivatives has been developed through the reaction of tributhyltin derivatives of glycals with aziridinecarboaldehyde and the regioselective ring opening of a chiral aziridine with thiophenol. The absolute configurations of the resulting diastereoisomers were determined by 1H NMR spectroscopy. Full article

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15 pages, 5858 KiB

Open AccessArticle

Copper-Catalyzed Ring-Opening Reactions of Alkyl Aziridines with B₂pin₂: Experimental and Computational Studies

by Lucilla Favero, Andrea Menichetti, Cosimo Boldrini, Lucrezia Margherita Comparini, Valeria Di Bussolo, Sebastiano Di Pietro and Mauro Pineschi

Molecules 2021, 26(23), 7399; https://doi.org/10.3390/molecules26237399 - 6 Dec 2021

Cited by 2 | Viewed by 3850

Abstract

The possibility to form new C–B bonds with aziridines using diboron derivatives continues to be a particularly challenging field in view of the direct preparation of functionalized β-aminoboronates, which are important compounds in drug discovery, being a bioisostere of β-aminoacids. We now report [...] Read more.

The possibility to form new C–B bonds with aziridines using diboron derivatives continues to be a particularly challenging field in view of the direct preparation of functionalized β-aminoboronates, which are important compounds in drug discovery, being a bioisostere of β-aminoacids. We now report experimental and computational data that allows the individuation of the structural requisites and of reaction conditions necessary to open alkyl aziridines using bis(pinacolate)diboron (B₂pin₂) in a regioselective nucleophilic addition reaction under copper catalysis. Full article

(This article belongs to the Special Issue Synthesis and Application of Organoboron Derivatives)

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9 pages, 1912 KiB

Open AccessArticle

Microwave Heating Promotes the S-Alkylation of Aziridine Catalyzed by Molecular Sieves: A Post-Synthetic Approach to Lanthionine-Containing Peptides

by Valentina Verdoliva, Giuseppe Digilio, Michele Saviano and Stefania De Luca

Molecules 2021, 26(20), 6135; https://doi.org/10.3390/molecules26206135 - 11 Oct 2021

Cited by 1 | Viewed by 2621

Abstract

Aziridine derivatives involved in nucleophilic ring-opening reactions have attracted great interest, since they allow the preparation of biologically active molecules. A chemoselective and mild procedure to convert a peptide cysteine residue into lanthionine via S-alkylation on aziridine substrates is presented in this paper. [...] Read more.

Aziridine derivatives involved in nucleophilic ring-opening reactions have attracted great interest, since they allow the preparation of biologically active molecules. A chemoselective and mild procedure to convert a peptide cysteine residue into lanthionine via S-alkylation on aziridine substrates is presented in this paper. The procedure relies on a post-synthetic protocol promoted by molecular sieves to prepare lanthionine-containing peptides and is assisted by microwave irradiation. In addition, it represents a valuable alternative to the stepwise approach, in which the lanthionine precursor is incorporated into peptides as a building block. Full article

(This article belongs to the Special Issue New Developments and Emerging Trends in Microwave Technology for Chemical Synthesis)

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17 pages, 4553 KiB

Open AccessReview

Synthetic Applications of Aziridinium Ions

by Jala Ranjith and Hyun-Joon Ha

Molecules 2021, 26(6), 1774; https://doi.org/10.3390/molecules26061774 - 22 Mar 2021

Cited by 21 | Viewed by 5370

Abstract

Nonactivated aziridine with an electron-donating group at the ring nitrogen should be activated to an aziridinium ion prior to being converted to cyclic and acyclic nitrogen-containing molecules. This review describes ways to generate aziridinium ions and their utilization for synthetic purposes. Specifically, the [...] Read more.

Nonactivated aziridine with an electron-donating group at the ring nitrogen should be activated to an aziridinium ion prior to being converted to cyclic and acyclic nitrogen-containing molecules. This review describes ways to generate aziridinium ions and their utilization for synthetic purposes. Specifically, the intra- and intermolecular formation of aziridinium ions with proper electrophiles are classified, and their regio- and stereoselective transformations with nucleophiles are described on the basis of recent developments. Full article

(This article belongs to the Special Issue Aziridine Chemistry)

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13 pages, 1836 KiB

Open AccessArticle

Alkylative Aziridine Ring-Opening Reactions

by Jieun Choi, Taehwan Yu and Hyun-Joon Ha

Molecules 2021, 26(6), 1703; https://doi.org/10.3390/molecules26061703 - 18 Mar 2021

Cited by 5 | Viewed by 5104

Abstract

In this study, the highly strained three-membered aziridine ring was successfully activated as the aziridinium ion by alkylation of the ring nitrogen with a methyl, ethyl or allyl group, which was followed by ring opening with external nucleophiles such as acetate and azide. [...] Read more.

In this study, the highly strained three-membered aziridine ring was successfully activated as the aziridinium ion by alkylation of the ring nitrogen with a methyl, ethyl or allyl group, which was followed by ring opening with external nucleophiles such as acetate and azide. Such alkylative aziridine ring opening provides an easy route for the synthesis of various N-alkylated amine-containing molecules with concomitant introduction of an external nucleophile at either its α- or β-position. Full article

(This article belongs to the Special Issue Aziridine Chemistry)

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