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Recent Developments in the Synthesis and Functionalization of Nitrogen Heterocycles

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

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 88992

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Special Issue Editors

Dr. Alexey M. Starosotnikov

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N.D. Zelinsky Institute of Organic Chemistry RAS, Leninsky Prosp. 47, 119991 Moscow, Russia
Interests: nitro compounds; heterocyclic chemistry; cycloadditions; pyridines; azoles; synthetic methods; bologically active compounds
Special Issues, Collections and Topics in MDPI journals

Dr. Maxim A. Bastrakov

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N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian
Interests: organic snthesis; heterocyclic compounds; nitro compounds; nitrogen heterocycles; biologically active compounds; dearomatization; cycloaddition reactions
Special Issues, Collections and Topics in MDPI journals

Dr. Igor L. Dalinger

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Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian
Interests: nitrogen heterocycles; heterocyclic chemistry; organic chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nitrogen heterocycles constitute a broad class of organic compounds. Many of their representatives have applications in pharmaceuticals, high-energy substances, dyes, non-linear optical materials and many others. The impetuous development of the pharmaceutical industry and material science stimulates the search for new synthetic approaches and new methods for the functionalization of N-heterocycles; these are some of the key objectives of modern organic chemistry. As a result of such research, in addition to achieving these objectives, new and sometimes unexpected applications of N-heterocycles may arise.

In this Special Issue, original research papers and high-quality reviews on the chemistry of N-heterocycles are welcome. This Special Issue will focus on research advances in the synthesis, reactivity, and applications of aromatic and saturated nitrogen heterocyclic compounds.

Dr. Alexey M. Starosotnikov
Dr. Maxim A. Bastrakov
Dr. Igor L. Dalinger
Guest Editors

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Keywords

nitrogen heterocycles
synthetic methods
azoles
azines
functionalization of N-heterocycles

Published Papers (43 papers)

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17 pages, 1311 KiB

Open AccessArticle

Rapid Assembly of Pyrrole-Ligated 1,3,4-Oxadiazoles and Excellent Antibacterial Activity of Iodophenol Substituents

by Hyein Kim, Lina Gu, Huisu Yeo, Umji Choi, Chang-Ro Lee, Haiyang Yu and Sangho Koo

Molecules 2023, 28(8), 3638; https://doi.org/10.3390/molecules28083638 - 21 Apr 2023

Viewed by 1480

Pyrrole-ligated 1,3,4-oxadiazole is a very important pharmacophore which exhibits broad therapeutic effects such as anti-tuberculosis, anti-epileptic, anti-HIV, anti-cancer, anti-inflammatory, antioxidant, and antibacterial activities. A one-pot Maillard reaction between D-Ribose and an L-amino methyl ester in DMSO with oxalic acid at 2.5 atm and [...] Read more.

Pyrrole-ligated 1,3,4-oxadiazole is a very important pharmacophore which exhibits broad therapeutic effects such as anti-tuberculosis, anti-epileptic, anti-HIV, anti-cancer, anti-inflammatory, antioxidant, and antibacterial activities. A one-pot Maillard reaction between D-Ribose and an L-amino methyl ester in DMSO with oxalic acid at 2.5 atm and 80 °C expeditiously produced pyrrole-2-carbaldehyde platform chemicals in reasonable yields, which were utilized for the synthesis of pyrrole-ligated 1,3,4-oxadiazoles. Benzohydrazide reacted with the formyl group of the pyrrole platforms to provide the corresponding imine intermediates, which underwent I₂-mediated oxidative cyclization to the pyrrole-ligated 1,3,4-oxadiazole skeleton. The structure and activity relationship (SAR) of the target compounds with varying alkyl or aryl substituents of the amino acids and electron-withdrawing or electron-donating substituents on the phenyl ring of benzohydrazide were evaluated for antibacterial activity against Escherichia coli, Staphylococcus aureus, and Acinetobacter baumannii as representative Gram(–) and Gram(+) bacteria. Branched alkyl groups from the amino acid showed better antibacterial activities. Absolutely superior activities were observed for 5f-1 with an iodophenol substituent against A. baumannii (MIC < 2 μg/mL), a bacterial pathogen that displays a high resistance to commonly used antibiotics. Full article

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

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13 pages, 2023 KiB

Open AccessArticle

Simple Synthetic Approach to N-(Pyridin-2-yl)imidates from Nitrostyrenes and 2-Aminopyridines via the N-(Pyridin-2-yl)iminonitriles as Intermediates

by Andriani G. Chaidali and Ioannis N. Lykakis

Molecules 2023, 28(8), 3321; https://doi.org/10.3390/molecules28083321 - 09 Apr 2023

Cited by 1 | Viewed by 1853

A facile, green, synthetic protocol of several substituted N-(pyridin-2-yl)imidates from nitrostyrenes and 2-aminopyridines via the corresponding N-(pyridin-2-yl)iminonitriles as intermediates is reported. The reaction process involved the in situ formation of the corresponding α-iminontriles under heterogeneous Lewis acid catalysis in the presence [...] Read more.

A facile, green, synthetic protocol of several substituted N-(pyridin-2-yl)imidates from nitrostyrenes and 2-aminopyridines via the corresponding N-(pyridin-2-yl)iminonitriles as intermediates is reported. The reaction process involved the in situ formation of the corresponding α-iminontriles under heterogeneous Lewis acid catalysis in the presence of Al₂O₃. Subsequently, α-iminonitriles were selectively transformed into the desired N-(pyridin-2-yl)imidates under ambient conditions and in the presence of Cs₂CO₃ in alcoholic media. Under these conditions, 1,2- and 1,3-propanediols also led to the corresponding mono-substituted imidates at room temperature. The present synthetic protocol was also developed on one mmol scale, providing access to this important scaffold. A preliminary synthetic application of the present N-(pyridin-2-yl)imidates was carried out for their facile conversion into the N-heterocycles 2-(4-chlorophenyl)-4,5-dihydro-1H-imidazole and 2-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine in the presence of the corresponding ethylenediamine and 1,3-diaminopropane. Full article

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

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10 pages, 1803 KiB

Open AccessCommunication

Bathochromic Shift of Fluorescence Peak in Dipyrrolo[1,2-a:2′,1′-c]quinoxaline by Introducing Each of Electron-Donating and Electron-Withdrawing Substituent

by Shoji Matsumoto, Makoto Takamori and Motohiro Akazome

Molecules 2023, 28(7), 2896; https://doi.org/10.3390/molecules28072896 - 23 Mar 2023

Cited by 5 | Viewed by 1711

Development of organic fluorophore is an important theme. Especially, the fluorophores with longer fluorescence peaks are useful to biological probes. One of the methods to change the fluorescence peak is the introduction of substituents. However, opposing characteristics of the substituents lead to different [...] Read more.

Development of organic fluorophore is an important theme. Especially, the fluorophores with longer fluorescence peaks are useful to biological probes. One of the methods to change the fluorescence peak is the introduction of substituents. However, opposing characteristics of the substituents lead to different changes in the fluorescence peaks. Furthermore, the introduction of the substituent also affects their electric properties. Thus, if the materials were developed with the substituent effect on the optical and electric properties separately, it will be useful to design the functional materials related to both optical and electric properties. Herein, we investigated the substituent effect of dipyrrolo[1,2-a:2′,1′-c]quinoxalines on fluorescence properties. We synthesized the compounds bearing electron-donating or electron-withdrawing substituents at the benzene ring on dipyrrolo[1,2-a:2′,1′-c]quinoxaline, which would have more direct influence on the optical properties. By introducing each substituent at the 6 position of dipyrrolo[1,2-a:2′,1′-c]quinoxaline, the bathochromic shift was observed in the fluorescence spectra. In the case of fluorine substituent, the change of the fluorescence peak reached was about 19 nm. Using a TDDFT calculation, we explained the reason for such a substituent effect that large on the increment of LUMO energy or decrement of HOMO energy occurred by introducing electron-withdrawing or electron-donating substituents at the 6 position, respectively. The substituent effect on the change of orbital energies is typical although the different characteristics of substituents resulted in the similar tendency about the change of fluorescence peak. Furthermore, with the introduction of phenyl substituents at the 3 and 10 positions, we achieved 40–50 nm longer fluorescence peaks compared with that of the original dipyrrolo[1,2-a:2′,1′-c]quinoxaline. Full article

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

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18 pages, 3532 KiB

Open AccessArticle

Mechanochemistry Frees Thiourea Dioxide (TDO) from the ‘Veils’ of Solvent, Exposing All Its Reactivity

by Francesco Basoccu, Federico Cuccu, Pietro Caboni, Lidia De Luca and Andrea Porcheddu

Molecules 2023, 28(5), 2239; https://doi.org/10.3390/molecules28052239 - 28 Feb 2023

Cited by 3 | Viewed by 1991

The synthesis of nitrogen-based heterocycles has always been considered essential in developing pharmaceuticals in medicine and agriculture. This explains why various synthetic approaches have been proposed in recent decades. However performing as methods, they often imply harsh conditions or the employment of toxic [...] Read more.

The synthesis of nitrogen-based heterocycles has always been considered essential in developing pharmaceuticals in medicine and agriculture. This explains why various synthetic approaches have been proposed in recent decades. However performing as methods, they often imply harsh conditions or the employment of toxic solvents and dangerous reagents. Mechanochemistry is undoubtedly one of the most promising technologies currently used for reducing any possible environmental impact, addressing the worldwide interest in counteracting environmental pollution. Following this line, we propose a new mechanochemical protocol for synthesizing various heterocyclic classes by exploiting thiourea dioxide (TDO)’s reducing proprieties and electrophilic nature. Simultaneously exploiting the low cost of a component of the textile industry such as TDO and all the advantages brought by a green technique such as mechanochemistry, we plot a route towards a more sustainable and eco-friendly methodology for preparing heterocyclic moieties. Full article

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

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15 pages, 1832 KiB

Open AccessArticle

Total Synthesis of Hemerocallisamine I Paved by Gram-Scale Synthesis of (2S,4S)-4-Hydroxyglutamic Acid Lactone

by Lucia Pinčeková, Eva Jančiová, Dušan Berkeš, Róbert Gyepes, Andrej Kolarovič and Oľga Caletková

Molecules 2023, 28(5), 2177; https://doi.org/10.3390/molecules28052177 - 26 Feb 2023

Viewed by 1313

Total synthesis of the 2-formylpyrrole alkaloid hemerocallisamine I is presented, both in racemic and enantiopure form. Our synthetic strategy involves (2S,4S)-4-hydroxyglutamic acid lactone as the key intermediate. Starting from an achiral substrate, the target stereogenic centers were introduced by [...] Read more.

Total synthesis of the 2-formylpyrrole alkaloid hemerocallisamine I is presented, both in racemic and enantiopure form. Our synthetic strategy involves (2S,4S)-4-hydroxyglutamic acid lactone as the key intermediate. Starting from an achiral substrate, the target stereogenic centers were introduced by means of crystallization-induced diastereomer transformation (CIDT) in a highly stereoselective fashion. A Maillard-type condensation was crucial to constructing the desired pyrrolic scaffold. Full article

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

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23 pages, 3305 KiB

Open AccessArticle

Multicomponent Domino Cyclization of Ethyl Trifluoropyruvate with Methyl Ketones and Amino Alcohols as A New Way to γ-Lactam Annulated Oxazacycles

by Marina V. Goryaeva, Olesya A. Fefelova, Yanina V. Burgart, Marina A. Ezhikova, Mikhail I. Kodess, Pavel A. Slepukhin, Vasily S. Gaviko and Victor I. Saloutin

Molecules 2023, 28(4), 1983; https://doi.org/10.3390/molecules28041983 - 20 Feb 2023

Viewed by 1322

A new route to bicyclic γ-lactams was found, which was proposed as a three-component cyclization of ethyl trifluoropyruvate with methyl ketones and 1,2-, 1,3-amino alcohols. As a result, a series of trifluoromethyl-substituted tetrahydropyrrolo [2,1-b]oxazol-5-ones and tetrahydropyrrolo[2,1-b][1,3]oxazine-6-ones was synthesized, in [...] Read more.

A new route to bicyclic γ-lactams was found, which was proposed as a three-component cyclization of ethyl trifluoropyruvate with methyl ketones and 1,2-, 1,3-amino alcohols. As a result, a series of trifluoromethyl-substituted tetrahydropyrrolo [2,1-b]oxazol-5-ones and tetrahydropyrrolo[2,1-b][1,3]oxazine-6-ones was synthesized, in which the substituent at the nodal carbon atom was varied. The introduction of a twofold excess of ethyl trifluoropyruvate in reactions with amino alcohols and acetone made it possible to obtain the same bicycles, but functionalized with a hydroxyester fragment, which are formed due to four-component interactions of the reagents. Transformations with 2-butanone and aminoethanol lead predominantly to similar bicycles, while an analogous reaction with aminopropanol gives N-hydroxypropyl-2,3-dihydropyrrol-5-one. Almost all bicycles are formed as two diastereomers, the structure of which was determined using ¹H, ¹⁹F, ¹³C NMR spectroscopy, including two-dimensional experiments and XRD analysis. A domino mechanism for the formation of tetrahydropyrrolo[2,1-b]oxazacycles was proposed, which was confirmed by their stepwise synthesis through the preliminary preparation of the aldol and bis-aldol from ethyl trifluoropyruvate and methyl ketones. Full article

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

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17 pages, 4024 KiB

Open AccessArticle

3-Aryl-5-aminobiphenyl Substituted [1,2,4]triazolo[4,3-c]quinazolines: Synthesis and Photophysical Properties

by Alexandra E. Kopotilova, Tatyana N. Moshkina, Emiliya V. Nosova, Galina N. Lipunova, Ekaterina S. Starnovskaya, Dmitry S. Kopchuk, Grigory A. Kim, Vasiliy S. Gaviko, Pavel A. Slepukhin and Valery N. Charushin

Molecules 2023, 28(4), 1937; https://doi.org/10.3390/molecules28041937 - 17 Feb 2023

Viewed by 1350

Amino-[1,1′]-biphenyl-containing 3-aryl-[1,2,4]triazolo[4,3-c]quinazoline derivatives with fluorescent properties have been designed and synthesized. The type of annelation of the triazole ring to the pyrimidine one has been unambiguously confirmed by means of an X-ray diffraction (XRD) method; the molecules are non-planar, and the [...] Read more.

Amino-[1,1′]-biphenyl-containing 3-aryl-[1,2,4]triazolo[4,3-c]quinazoline derivatives with fluorescent properties have been designed and synthesized. The type of annelation of the triazole ring to the pyrimidine one has been unambiguously confirmed by means of an X-ray diffraction (XRD) method; the molecules are non-planar, and the aryl substituents form the pincer-like conformation. The UV/Vis and photoluminescent properties of target compounds were investigated in two solvents of different polarities and in a solid state. The samples emit a broad range of wavelengths and display fluorescent quantum yields of up to 94% in toluene solutions. 5-(4’-Diphenylamino-[1,1′]-biphenyl-4-yl)-3-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-c]quinazoline exhibits the strongest emission in toluene and a solid state. Additionally, the solvatochromic properties were studied for the substituted [1,2,4]triazolo[4,3-c]quinazolines. Moreover, the changes in absorption and emission spectra have been demonstrated upon the addition of water to MeCN solutions, which confirms aggregate formation, and some samples were found to exhibit aggregation-induced emission enhancement. Further, the ability of triazoloquinazolines to detect trifluoroacetic acid has been analyzed; the presence of TFA induces changes in both absorption and emission spectra, and acidochromic behavvior was observed for some triazoloquinazoline compounds. Finally, electronic-structure calculations with the use of quantum-chemistry methods were performed for synthesized compounds. Full article

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

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20 pages, 6709 KiB

Open AccessArticle

ESIPT-Capable 4-(2-Hydroxyphenyl)-2-(Pyridin-2-yl)-1H-Imidazoles with Single and Double Proton Transfer: Synthesis, Selective Reduction of the Imidazolic OH Group and Luminescence

by Nikita A. Shekhovtsov, Elena B. Nikolaenkova, Alexey A. Ryadun, Denis G. Samsonenko, Alexsei Ya. Tikhonov and Mark B. Bushuev

Molecules 2023, 28(4), 1793; https://doi.org/10.3390/molecules28041793 - 14 Feb 2023

Cited by 6 | Viewed by 1888

1H-Imidazole derivatives establish one of the iconic classes of ESIPT-capable compounds (ESIPT = excited state intramolecular proton transfer). This work presents the synthesis of 1-hydroxy-4-(2-hydroxyphenyl)-5-methyl-2-(pyridin-2-yl)-1H-imidazole (L^OH,OH) as the first example of ESIPT-capable imidazole derivatives wherein the [...] Read more.

1H-Imidazole derivatives establish one of the iconic classes of ESIPT-capable compounds (ESIPT = excited state intramolecular proton transfer). This work presents the synthesis of 1-hydroxy-4-(2-hydroxyphenyl)-5-methyl-2-(pyridin-2-yl)-1H-imidazole (L^OH,OH) as the first example of ESIPT-capable imidazole derivatives wherein the imidazole moiety simultaneously acts as a proton acceptor and a proton donor. The reaction of L^OH,OH with chloroacetone leads to the selective reduction of the imidazolic OH group (whereas the phenolic OH group remains unaffected) and to the isolation of 4-(2-hydroxyphenyl)-5-methyl-2-(pyridin-2-yl)-1H-imidazole (L^H,OH), a monohydroxy congener of L^OH,OH. Both L^OH,OH and L^H,OH demonstrate luminescence in the solid state. The number of OH···N proton transfer sites in these compounds (one for L^H,OH and two for L^OH,OH) strongly affects the luminescence mechanism and color of the emission: L^H,OH emits in the light green region, whereas L^OH,OH luminesces in the orange region. According to joint experimental and theoretical studies, the main emission pathway of both compounds is associated with T₁ → S₀ phosphorescence and not related to ESIPT. At the same time, L^OH,OH also exhibits S₁ → S₀ fluorescence associated with ESIPT with one proton transferred from the hydroxyimidazole moiety to the pyridine moiety, which is not possible for L^H,OH due to the absence of the hydroxy group in the imidazole moiety. Full article

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

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17 pages, 1630 KiB

Open AccessArticle

Heterogeneous Photocatalysis as a Potent Tool for Organic Synthesis: Cross-Dehydrogenative C–C Coupling of N-Heterocycles with Ethers Employing TiO₂/N-Hydroxyphthalimide System under Visible Light

by Elena R. Lopat’eva, Igor B. Krylov, Oleg O. Segida, Valentina M. Merkulova, Alexey I. Ilovaisky and Alexander O. Terent’ev

Molecules 2023, 28(3), 934; https://doi.org/10.3390/molecules28030934 - 17 Jan 2023

Cited by 4 | Viewed by 1961

Despite the obvious advantages of heterogeneous photocatalysts (availability, stability, recyclability, the ease of separation from products and safety) their application in organic synthesis faces serious challenges: generally low efficiency and selectivity compared to homogeneous photocatalytic systems. The development of strategies for improving the [...] Read more.

Despite the obvious advantages of heterogeneous photocatalysts (availability, stability, recyclability, the ease of separation from products and safety) their application in organic synthesis faces serious challenges: generally low efficiency and selectivity compared to homogeneous photocatalytic systems. The development of strategies for improving the catalytic properties of semiconductor materials is the key to their introduction into organic synthesis. In the present work, a hybrid photocatalytic system involving both heterogeneous catalyst (TiO₂) and homogeneous organocatalyst (N-hydroxyphthalimide, NHPI) was proposed for the cross-dehydrogenative C–C coupling of electron-deficient N-heterocycles with ethers employing t-BuOOH as the terminal oxidant. It should be noted that each of the catalysts is completely ineffective when used separately under visible light in this transformation. The occurrence of visible light absorption upon the interaction of NHPI with the TiO₂ surface and the generation of reactive phthalimide-N-oxyl (PINO) radicals upon irradiation with visible light are considered to be the main factors determining the high catalytic efficiency. The proposed method is suitable for the coupling of π-deficient pyridine, quinoline, pyrazine, and quinoxaline heteroarenes with various non-activated ethers. Full article

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

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15 pages, 4217 KiB

Open AccessArticle

Alkyl 4-Aryl-6-amino-7- phenyl-3-(phenylimino)-4,7-dihydro- 3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxylates: Synthesis and Agrochemical Studies

by Victor V. Dotsenko, Anna E. Sinotsko, Vladimir D. Strelkov, Ekaterina A. Varzieva, Alena A. Russkikh, Arina G. Levchenko, Azamat Z. Temerdashev, Nicolai A. Aksenov and Inna V. Aksenova

Molecules 2023, 28(2), 609; https://doi.org/10.3390/molecules28020609 - 06 Jan 2023

Cited by 5 | Viewed by 1515

The reaction between dithiomalondianilide (N,N’-diphenyldithiomalondiamide) and alkyl 3-aryl-2-cyanoacrylates in the presence of morpholine in the air atmosphere leads to the formation of alkyl 6-amino-4-aryl-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]- pyridine-5-carboxylates in 37–72% yields. The same compounds were prepared in 23–65% yields by ternary condensation of aromatic aldehydes, ethyl(methyl) [...] Read more.

The reaction between dithiomalondianilide (N,N’-diphenyldithiomalondiamide) and alkyl 3-aryl-2-cyanoacrylates in the presence of morpholine in the air atmosphere leads to the formation of alkyl 6-amino-4-aryl-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]- pyridine-5-carboxylates in 37–72% yields. The same compounds were prepared in 23–65% yields by ternary condensation of aromatic aldehydes, ethyl(methyl) cyanoacetate and dithiomalondianilide. The reaction mechanism is discussed. The structure of ethyl 6-amino-4-(4-methoxyphenyl)-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxylate was confirmed by X-ray crystallography. Two of the prepared compounds showed a moderate growth-stimulating effect on sunflower seedlings. Three of the new compounds were recognized as strong herbicide safeners with respect to herbicide 2,4-D in the laboratory and field experiments on sunflower. Full article

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

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22 pages, 3321 KiB

Open AccessArticle

Synthesis of Functionalized Isoquinolone Derivatives via Rh(III)-Catalyzed [4+2]-Annulation of Benzamides with Internal Acetylene-Containing α-CF₃-α-Amino Carboxylates

by Daria V. Vorobyeva, Dmitry A. Petropavlovskikh, Ivan A. Godovikov, Fedor M. Dolgushin and Sergey N. Osipov

Molecules 2022, 27(23), 8488; https://doi.org/10.3390/molecules27238488 - 02 Dec 2022

Cited by 4 | Viewed by 1263

A convenient pathway to a new series of α-CF₃-substituted α-amino acid derivatives bearing pharmacophore isoquinolone core in their backbone has been developed. The method is based on [4+2]-annulation of N-(pivaloyloxy) aryl amides with orthogonally protected internal acetylene-containing α-amino carboxylates under [...] Read more.

A convenient pathway to a new series of α-CF₃-substituted α-amino acid derivatives bearing pharmacophore isoquinolone core in their backbone has been developed. The method is based on [4+2]-annulation of N-(pivaloyloxy) aryl amides with orthogonally protected internal acetylene-containing α-amino carboxylates under Rh(III)-catalysis. The target annulation products can be easily transformed into valuable isoquinoline derivatives via a successive aromatization/cross-coupling operation. Full article

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

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21 pages, 2017 KiB

Open AccessArticle

Synthesis of 1,5-Substituted Pyrrolidin-2-ones from Donor–Acceptor Cyclopropanes and Anilines/Benzylamines

by Maksim A. Boichenko, Andrey Yu. Plodukhin, Vitaly V. Shorokhov, Danyla S. Lebedev, Anastasya V. Filippova, Sergey S. Zhokhov, Elena A. Tarasenko, Victor B. Rybakov, Igor V. Trushkov and Olga A. Ivanova

Molecules 2022, 27(23), 8468; https://doi.org/10.3390/molecules27238468 - 02 Dec 2022

Cited by 4 | Viewed by 1938

We developed a straightforward synthetic route to pharmacologically important 1,5-substituted pyrrolidin-2-ones from donor–acceptor cyclopropanes bearing an ester group as one of the acceptor substituents. This method includes a Lewis acid-catalyzed opening of the donor–acceptor cyclopropane with primary amines (anilines, benzylamines, etc.) to γ-amino [...] Read more.

We developed a straightforward synthetic route to pharmacologically important 1,5-substituted pyrrolidin-2-ones from donor–acceptor cyclopropanes bearing an ester group as one of the acceptor substituents. This method includes a Lewis acid-catalyzed opening of the donor–acceptor cyclopropane with primary amines (anilines, benzylamines, etc.) to γ-amino esters, followed by in situ lactamization and dealkoxycarbonylation. The reaction has a broad scope of applicability; a variety of substituted anilines, benzylamines, and other primary amines as well as a wide range of donor–acceptor cyclopropanes bearing (hetero)aromatic or alkenyl donor groups and various acceptor substituents can be involved in this transformation. In this process, donor–acceptor cyclopropanes react as 1,4-C,C-dielectrophiles, and amines react as 1,1-dinucleophiles. The resulting di- and trisubstituted pyrrolidin-2-ones can be also used in subsequent chemistry to obtain various nitrogen-containing polycyclic compounds of interest to medicinal chemistry and pharmacology, such as benz[g]indolizidine derivatives. Full article

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

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13 pages, 1785 KiB

Open AccessArticle

Regioselective Synthesis and Molecular Docking Studies of 1,5-Disubstituted 1,2,3-Triazole Derivatives of Pyrimidine Nucleobases

by Vincenzo Algieri, Paola Costanzo, Matteo Antonio Tallarida, Fabrizio Olivito, Antonio Jiritano, Giulia Fiorani, Francesca Peccati, Gonzalo Jiménez-Osés, Loredana Maiuolo and Antonio De Nino

Molecules 2022, 27(23), 8467; https://doi.org/10.3390/molecules27238467 - 02 Dec 2022

Cited by 2 | Viewed by 1843

1,2,3-triazoles are versatile building blocks with growing interest in medicinal chemistry. For this reason, organic chemistry focuses on the development of new synthetic pathways to obtain 1,2,3-triazole derivatives, especially with pyridine moieties. In this work, a novel series of 1,5-disubstituted-1,2,3-triazoles functionalized with pyrimidine [...] Read more.

1,2,3-triazoles are versatile building blocks with growing interest in medicinal chemistry. For this reason, organic chemistry focuses on the development of new synthetic pathways to obtain 1,2,3-triazole derivatives, especially with pyridine moieties. In this work, a novel series of 1,5-disubstituted-1,2,3-triazoles functionalized with pyrimidine nucleobases were prepared via 1,3-dipolar cycloaddition reaction in a regioselective manner for the first time. The N1-propargyl nucleobases, used as an alkyne intermediate, were obtained in high yields (87–92%) with a new two-step procedure that selectively led to the monoalkylated compounds. Then, FeCl₃ was employed as an efficient Lewis acid catalyst for 1,3-dipolar cycloaddition between different aryl and benzyl azides and the N1-propargyl nucleobases previously synthesized. This new protocol allows the synthesis of a series of new 1,2,3-triazole derivatives with good to excellent yields (82–92%). The ADME (Absorption, Distribution, Metabolism, and Excretion) analysis showed good pharmacokinetic properties and no violations of Lipinsky’s rules, suggesting an appropriate drug likeness for these new compounds. Molecular docking simulations, conducted on different targets, revealed that two of these new hybrids could be potential ligands for viral and bacterial protein receptors such as human norovirus capsid protein, SARS-CoV-2 NSP13 helicase, and metallo-β-lactamase. Full article

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

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19 pages, 3242 KiB

Open AccessArticle

Energetic [1,2,5]oxadiazolo [2,3-a]pyrimidin-8-ium Perchlorates: Synthesis and Characterization

by Kirill V. Strizhenko, Anastasia D. Smirnova, Sergei A. Filatov, Valery P. Sinditskii, Adam I. Stash, Kyrill Yu. Suponitsky, Konstantin A. Monogarov, Vitaly G. Kiselev and Aleksei B. Sheremetev

Molecules 2022, 27(23), 8443; https://doi.org/10.3390/molecules27238443 - 02 Dec 2022

Cited by 1 | Viewed by 1648

A convenient method to access the above perchlorates has been developed, based on the cyclocondensation of 3-aminofurazans with 1,3-diketones in the presence of HClO₄. All compounds were fully characterized by multinuclear NMR spectroscopy and X-ray crystal structure determinations. Initial safety testing [...] Read more.

A convenient method to access the above perchlorates has been developed, based on the cyclocondensation of 3-aminofurazans with 1,3-diketones in the presence of HClO₄. All compounds were fully characterized by multinuclear NMR spectroscopy and X-ray crystal structure determinations. Initial safety testing (impact and friction sensitivity) and thermal stability measurements (DSC/DTA) were also carried out. Energetic performance was calculated by using the PILEM code based on calculated enthalpies of formation and experimental densities at r.t. These salts exhibit excellent burn rates and combustion behavior and are promising ingredients for energetic materials. Full article

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

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16 pages, 4389 KiB

Open AccessArticle

First Synthesis of 3-Glycopyranosyl-1,2,4-Triazines and Some Cycloadditions Thereof

by Éva Bokor, Attila Ferenczi, Mahir Hashimov, Éva Juhász-Tóth, Zsófia Götz, Alshimaa Ibrahim Zaki and László Somsák

Molecules 2022, 27(22), 7801; https://doi.org/10.3390/molecules27227801 - 12 Nov 2022

Cited by 1 | Viewed by 1080

C-glycopyranosyl derivatives of six-membered heterocycles are scarcely represented in the chemical literature and the title 3-glycopyranosyl-1,2,4-triazines are completely unknown. In this paper, the first synthesis of this compound class is accomplished by the cyclocondensation of C-glycosyl formamidrazones and 1,2-dicarbonyl derivatives. In [...] Read more.

C-glycopyranosyl derivatives of six-membered heterocycles are scarcely represented in the chemical literature and the title 3-glycopyranosyl-1,2,4-triazines are completely unknown. In this paper, the first synthesis of this compound class is accomplished by the cyclocondensation of C-glycosyl formamidrazones and 1,2-dicarbonyl derivatives. In addition, the synthesis of C-glycopyranosyl 1,2,4-triazin-5(4H)-ones was also carried out by the transformation of the above formamidrazones with α-keto-carboxylic esters. Inverse electron demand Diels–Alder reactions of 3-glycopyranosyl-1,2,4-triazines with a bicyclononyne derivative yielded the corresponding annulated 2-glycopyranosyl pyridines. Full article

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

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12 pages, 2712 KiB

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Mechanochemical Approach towards Multi-Functionalized 1,2,3-Triazoles and Anti-Seizure Drug Rufinamide Analogs Using Copper Beads

by Dhananjay Bhattacherjee, Igor S. Kovalev, Dmitry S. Kopchuk, Matiur Rahman, Sougata Santra, Grigory V. Zyryanov, Pralay Das, Rituraj Purohit, Vladimir L. Rusinov and Oleg N. Chupakhin

Molecules 2022, 27(22), 7784; https://doi.org/10.3390/molecules27227784 - 11 Nov 2022

Cited by 5 | Viewed by 1416

Highly regiospecific, copper-salt-free and neat conditions have been demonstrated for the 1,3-dipolar azide-alkyne cycloaddition (AAC) reactions under mechanochemical conditions. A group of structurally challenging alkynes and heterocyclic derivatives was efficiently implemented to achieve highly functionalized 1,4-disubstituted-1,2,3-triazoles in good to excellent yield by using [...] Read more.

Highly regiospecific, copper-salt-free and neat conditions have been demonstrated for the 1,3-dipolar azide-alkyne cycloaddition (AAC) reactions under mechanochemical conditions. A group of structurally challenging alkynes and heterocyclic derivatives was efficiently implemented to achieve highly functionalized 1,4-disubstituted-1,2,3-triazoles in good to excellent yield by using the Cu beads without generation of unwanted byproducts. Furthermore, the high-speed ball milling (HSBM) strategy has also been extended to the synthesis of the commercially available pharmaceutical agent, Rufinamide, an antiepileptic drug (AED) and its analogues. The same strategy was also applied for the synthesis of the Cl-derivative of Rufinamide. Analysis of the single crystal XRD data of the triazole was also performed for the final structural confirmation. The Cu beads are easily recoverable from the reaction mixture and used for the further reactions without any special treatment. Full article

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

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15 pages, 1773 KiB

Open AccessFeature PaperArticle

Electrochemically Induced Synthesis of Imidazoles from Vinyl Azides and Benzyl Amines

by Vera A. Vil’, Sergei S. Grishin and Alexander O. Terent’ev

Molecules 2022, 27(22), 7721; https://doi.org/10.3390/molecules27227721 - 09 Nov 2022

Cited by 1 | Viewed by 1738

An electrochemically induced synthesis of imidazoles from vinyl azides and benzyl amines was developed. A wide range of imidazoles were obtained, with yields of 30 to 64%. The discovered transformation is a multistep process whose main steps include the generation of electrophilic iodine [...] Read more.

An electrochemically induced synthesis of imidazoles from vinyl azides and benzyl amines was developed. A wide range of imidazoles were obtained, with yields of 30 to 64%. The discovered transformation is a multistep process whose main steps include the generation of electrophilic iodine species, 2H-azirine formation from the vinyl azide, followed by its reactions with benzyl amine and with imine generated from benzyl amine. The cyclization and aromatization of the obtained intermediate lead to the target imidazole. The synthesis proceeds under constant current conditions in an undivided cell. Despite possible cathodic reduction of various unsaturated intermediates with C=N bonds, the efficient electrochemically induced synthesis of imidazoles was carried out. Full article

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

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22 pages, 3741 KiB

Open AccessArticle

Synthesis, Characterization and DFT Study of a New Family of High-Energy Compounds Based on s-Triazine, Carborane and Tetrazoles

by Anton V. Makarenkov, Sergey S. Kiselev, Elena G. Kononova, Fedor M. Dolgushin, Alexander S. Peregudov, Yurii A. Borisov and Valentina A. Ol’shevskaya

Molecules 2022, 27(21), 7484; https://doi.org/10.3390/molecules27217484 - 02 Nov 2022

Cited by 3 | Viewed by 1853

An efficient one-pot synthesis of carborane-containing high-energy compounds was developed via the exploration of carbon–halogen bond functionalization strategies in commercially available 2,4,6-trichloro-1,3,5-triazine. The synthetic pathway first included the substitution of two chlorine atoms in s-triazine with 5-R-tetrazoles (R = H, Me, Et) [...] Read more.

An efficient one-pot synthesis of carborane-containing high-energy compounds was developed via the exploration of carbon–halogen bond functionalization strategies in commercially available 2,4,6-trichloro-1,3,5-triazine. The synthetic pathway first included the substitution of two chlorine atoms in s-triazine with 5-R-tetrazoles (R = H, Me, Et) units to form disubstituted tetrazolyl 1,3,5-triazines followed by the sequential substitution of the remaining chlorine atom in 1,3,5-triazine with carborane N- or S-nucleophiles. All new compounds were characterized by IR- and NMR spectroscopy. The structure of four new compounds was confirmed by single crystal X-ray diffraction analysis. The density functional theory method (DFT B3LYP/6-311 + G*) was used to study the geometrical structures, enthalpies of formation (EOFs), energetic properties and highest occupied and lowest unoccupied molecular orbital (HOMO and LUMO) energies and the detonation properties of synthesized compounds. The DFT calculation revealed compounds processing the maximum value of the detonation velocity or the maximum value of the detonation pressure. Theoretical terahertz frequencies for potential high-energy density materials (HEDMs) were computed, which allow the opportunity for the remote detection of these compounds. Full article

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

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26 pages, 1550 KiB

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Substitutional Diversity-Oriented Synthesis and In Vitro Anticancer Activity of Framework-Integrated Estradiol-Benzisoxazole Chimeras

by Ferenc Kovács, Dóra Izabella Adamecz, Ferenc István Nagy, Benedek Papp, Mónika Kiricsi and Éva Frank

Molecules 2022, 27(21), 7456; https://doi.org/10.3390/molecules27217456 - 02 Nov 2022

Cited by 2 | Viewed by 1663

Hybridization of steroids and other pharmacophores often modifies the bioactivity of the parent compounds, improving selectivity and side effect profile. In this study, estradiol and 3′-(un)substituted benzisoxazole moieties were combined into novel molecules by structural integration of their aromatic rings. Simple estrogen starting [...] Read more.

Hybridization of steroids and other pharmacophores often modifies the bioactivity of the parent compounds, improving selectivity and side effect profile. In this study, estradiol and 3′-(un)substituted benzisoxazole moieties were combined into novel molecules by structural integration of their aromatic rings. Simple estrogen starting materials, such as estrone, estradiol and estradiol-3-methylether were used for the multistep transformations. Some of the heterocyclic derivatives were prepared from the estrane precursor by a formylation or Friedel–Crafts acylation—oximation—cyclization sequence, whereas others were obtained by a functional group interconversion strategy. The antiproliferative activities of the synthesized compounds were assessed on various human cervical, breast and prostate cancer cell lines (HeLa, MCF-7, PC3, DU-145) and non-cancerous MRC-5 fibroblast cells. Based on the primary cytotoxicity screens, the most effective cancer-selective compounds were selected, their IC₅₀ values were determined and their apoptosis-inducing potential was evaluated by quantitative real-time PCR. Pharmacological studies revealed a strong structure–function relationship, where derivatives with a hydroxyl group on C-17 exhibited stronger anticancer activity compared to the 17-acetylated counterparts. The present study concludes that novel estradiol-benzisoxazole hybrids exert remarkable cancer cell-specific antiproliferative activity and trigger apoptosis in cancer cells. Full article

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

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21 pages, 3556 KiB

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Efficient Synthesis of 4,8-Dibromo Derivative of Strong Electron-Deficient Benzo[1,2-d:4,5-d’]bis([1,2,3]thiadiazole) and Its S_NAr and Cross-Coupling Reactions

by Timofey N. Chmovzh, Daria A. Alekhina, Timofey A. Kudryashev and Oleg A. Rakitin

Molecules 2022, 27(21), 7372; https://doi.org/10.3390/molecules27217372 - 30 Oct 2022

Cited by 4 | Viewed by 2021

An efficient synthesis of hydrolytically and thermally stable 4,8-dibromobenzo[1,2-d:4,5-d’]bis([1,2,3]thiadiazole) by the bromination of its parent heterocycle is reported. The structure of 4,8-dibromobenzo[1,2-d:4,5-d’]bis([1,2,3]thiadiazole) was confirmed by X-ray analysis. The conditions for the selective aromatic nucleophilic substitution [...] Read more.

An efficient synthesis of hydrolytically and thermally stable 4,8-dibromobenzo[1,2-d:4,5-d’]bis([1,2,3]thiadiazole) by the bromination of its parent heterocycle is reported. The structure of 4,8-dibromobenzo[1,2-d:4,5-d’]bis([1,2,3]thiadiazole) was confirmed by X-ray analysis. The conditions for the selective aromatic nucleophilic substitution of one bromine atom in this heterocyclic system by nitrogen nucleophiles are found, whereas thiols formed the bis-derivatives only. Suzuki–Miyaura cross-coupling reactions were found to be an effective method for the selective formation of various mono- and di(het)arylated derivatives of strong electron-deficient benzo[1,2-d:4,5-d’]bis([1,2,3]thiadiazole), and Stille coupling can be employed for the preparation of bis-arylated heterocycles, which can be considered as useful building blocks for the synthesis of DSSCs and OLEDs components. Full article

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

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25 pages, 4089 KiB

Open AccessArticle

Multifunctional Derivatives of Spiropyrrolidine Tethered Indeno-Quinoxaline Heterocyclic Hybrids as Potent Antimicrobial, Antioxidant and Antidiabetic Agents: Design, Synthesis, In Vitro and In Silico Approaches

by Nouha Bouali, Manel Ben Hammouda, Iqrar Ahmad, Siwar Ghannay, Amira Thouri, Amal Dbeibia, Harun Patel, Walid Sabri Hamadou, Karim Hosni, Mejdi Snoussi, Mohd Adnan, Md Imtaiyaz Hassan, Emira Noumi, Kaïss Aouadi and Adel Kadri

Molecules 2022, 27(21), 7248; https://doi.org/10.3390/molecules27217248 - 25 Oct 2022

Cited by 6 | Viewed by 1899

To combat emerging antimicrobial-resistant microbes, there is an urgent need to develop new antimicrobials with better therapeutic profiles. For this, a series of 13 new spiropyrrolidine derivatives were designed, synthesized, characterized and evaluated for their in vitro antimicrobial, antioxidant and antidiabetic potential. Antimicrobial [...] Read more.

To combat emerging antimicrobial-resistant microbes, there is an urgent need to develop new antimicrobials with better therapeutic profiles. For this, a series of 13 new spiropyrrolidine derivatives were designed, synthesized, characterized and evaluated for their in vitro antimicrobial, antioxidant and antidiabetic potential. Antimicrobial results revealed that the designed compounds displayed good activity against clinical isolated strains, with 5d being the most potent (MIC 3.95 mM against Staphylococcus aureus ATCC 25923) compared to tetracycline (MIC 576.01 mM). The antioxidant activity was assessed by trapping DPPH, ABTS and FRAP assays. The results suggest remarkable antioxidant potential of all synthesized compounds, particularly 5c, exhibiting the strongest activity with IC₅₀ of 3.26 ± 0.32 mM (DPPH), 7.03 ± 0.07 mM (ABTS) and 3.69 ± 0.72 mM (FRAP). Tested for their α-amylase inhibitory effect, the examined analogues display a variable degree of α-amylase activity with IC₅₀ ranging between 0.55 ± 0.38 mM and 2.19 ± 0.23 mM compared to acarbose (IC₅₀ 1.19 ± 0.02 mM), with the most active compounds being 5d, followed by 5c and 5j, affording IC₅₀ of 0.55 ± 0.38 mM, 0.92 ± 0.10 mM, and 0.95 ± 0.14 mM, respectively. Preliminary structure–activity relationships revealed the importance of such substituents in enhancing the activity. Furthermore, the ADME screening test was applied to optimize the physicochemical properties and determine their drug-like characteristics. Binding interactions and stability between ligands and active residues of the investigated enzymes were confirmed through molecular docking and dynamic simulation study. These findings provided guidance for further developing leading new spiropyrrolidine scaffolds with improved dual antimicrobial and antidiabetic activities. Full article

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

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22 pages, 4411 KiB

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MnO₂-Mediated Oxidative Cyclization of “Formal” Schiff’s Bases: Easy Access to Diverse Naphthofuro-Annulated Triazines

by Ramil F. Fatykhov, Igor A. Khalymbadzha, Ainur D. Sharapov, Anastasia P. Potapova, Nataliya N. Mochulskaya, Anton N. Tsmokalyuk, Alexandra V. Ivoilova, Polina N. Mozharovskaia, Sougata Santra and Oleg N. Chupakhin

Molecules 2022, 27(20), 7105; https://doi.org/10.3390/molecules27207105 - 21 Oct 2022

Cited by 6 | Viewed by 2096

A different type of MnO₂-induced oxidative cyclization of dihydrotriazines has been developed. These dihydrotriazines are considered as a “formal” Schiff’s base. This method provided easy access to naphthofuro-fused triazine via the C-C/C-O oxidative coupling reaction. The reaction sequence comprised the nucleophilic [...] Read more.

A different type of MnO₂-induced oxidative cyclization of dihydrotriazines has been developed. These dihydrotriazines are considered as a “formal” Schiff’s base. This method provided easy access to naphthofuro-fused triazine via the C-C/C-O oxidative coupling reaction. The reaction sequence comprised the nucleophilic addition of 2-naphthol or phenol to 1,2,4-triazine, followed by oxidative cyclization. The scope and limitations of this novel coupling reaction have been investigated. Further application of the synthesized compound has been demonstrated by synthesizing carbazole-substituted benzofuro-fused triazines. The scalability of the reaction was demonstrated at a 40 mmol load. The mechanistic study strongly suggests that this reaction proceeds through the formation of an O-coordinated manganese complex. Full article

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

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17 pages, 2620 KiB

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Reactions of Trifluorotriacetic Acid Lactone and Hexafluorodehydroacetic Acid with Amines: Synthesis of Trifluoromethylated 4-Pyridones and Aminoenones

by Vladislav V. Fedin, Sergey A. Usachev, Dmitrii L. Obydennov and Vyacheslav Y. Sosnovskikh

Molecules 2022, 27(20), 7098; https://doi.org/10.3390/molecules27207098 - 20 Oct 2022

Cited by 3 | Viewed by 1511

Dehydroacetic acid and triacetic acid lactone are known to be versatile substrates for the synthesis of a variety of azaheterocycles. However, their fluorinated analogs were poorly described in the literature. In the present work, we have investigated reactions of trifluorotriacetic acid lactone and [...] Read more.

Dehydroacetic acid and triacetic acid lactone are known to be versatile substrates for the synthesis of a variety of azaheterocycles. However, their fluorinated analogs were poorly described in the literature. In the present work, we have investigated reactions of trifluorotriacetic acid lactone and hexafluorodehydroacetic acid with primary amines, phenylenediamine, and phenylhydrazine. While hexafluorodehydroacetic acid reacted the same way as non-fluorinated analog giving 2,6-bis(trifluoromethyl)-4-pyridones, trifluorotriacetic acid lactone had different regioselectivity of nucleophilic attack compared to the parent structure, and corresponding 3-amino-6,6,6-trifluoro-5-oxohex-3-eneamides were formed as the products. In the case of binucleophiles, further cyclization took place, forming corresponding benzodiazepine and pyrazoles. The obtained 2,6-bis(trifluoromethyl)-4-pyridones were able to react with active methylene compounds giving fluorinated merocyanine dyes. Full article

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

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16 pages, 809 KiB

Open AccessArticle

Domino Aza-Michael-S_NAr-Heteroaromatization Route to C5-Substituted 1-Alkyl-1H-Indole-3-Carboxylic Esters

by Ebenezer Ametsetor, Spencer Farthing and Richard A. Bunce

Molecules 2022, 27(20), 6998; https://doi.org/10.3390/molecules27206998 - 18 Oct 2022

Cited by 1 | Viewed by 1669

A new synthesis of C5-substituted 1-alkyl-1H-indole-3-carboxylic esters is reported. A series of methyl 2-arylacrylate aza-Michael acceptors were prepared with aromatic substitution to activate them towards S_NAr reaction. Subsequent reaction with a series of primary amines generated the title compounds. [...] Read more.

A new synthesis of C5-substituted 1-alkyl-1H-indole-3-carboxylic esters is reported. A series of methyl 2-arylacrylate aza-Michael acceptors were prepared with aromatic substitution to activate them towards S_NAr reaction. Subsequent reaction with a series of primary amines generated the title compounds. Initially, the sequence was expected to produce indoline products, but oxidative heteroaromatization intervened to generate the indoles. The reaction proceeded under anhydrous conditions in DMF at 23–90 °C using equimolar quantities of the acrylate and the amine with 2 equiv. of K₂CO₃ to give 61–92% of the indole products. The reaction involves an aza-Michael addition, followed by S_NAr ring closure and heteroaromatization. Since the reactions were run under nitrogen, the final oxidation to the indole likely results from reaction with dissolved oxygen in the DMF. Substrates incorporating a 2-arylacrylonitrile proved too reactive to prepare using our protocol. The synthesis of the reaction substrates, their relative reactivities, and mechanistic details of the conversion are discussed. Full article

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

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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 1908

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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20 pages, 1578 KiB

Open AccessArticle

Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas Reaction

by Natalia A. Danilkina, Ekaterina A. Khmelevskaya, Anna G. Lyapunova, Alexander S. D’yachenko, Alexander S. Bunev, Rovshan E. Gasanov, Maxim A. Gureev and Irina A. Balova

Molecules 2022, 27(18), 6071; https://doi.org/10.3390/molecules27186071 - 17 Sep 2022

Cited by 2 | Viewed by 1621

The scope and limitations of the Nicholas-type cyclization for the synthesis of 10-membered benzothiophene-fused heterocyclic enediynes with different functionalities were investigated. Although the Nicholas cyclization through oxygen could be carried out in the presence of an ester group, the final oxaenediyne was unstable [...] Read more.

The scope and limitations of the Nicholas-type cyclization for the synthesis of 10-membered benzothiophene-fused heterocyclic enediynes with different functionalities were investigated. Although the Nicholas cyclization through oxygen could be carried out in the presence of an ester group, the final oxaenediyne was unstable under storage. Among the N-type Nicholas reactions, cyclization via an arenesulfonamide functional group followed by mild Co-deprotection was found to be the most promising, yielding 10-membered azaendiynes in high overall yields. By contrast, the Nicholas cyclization through the acylated nitrogen atom did not give the desired 10-membered cycle. It resulted in the formation of a pyrroline ring, whereas cyclization via an alkylated amino group resulted in a poor yield of the target 10-membered enediyne. The acylated 4-aminobenzenesulfonamide nucleophilic group was found to be the most convenient for the synthesis of functionalized 10-membered enediynes bearing a clickable function, such as a terminal triple bond. All the synthesized cyclic enediynes exhibited moderate activity against lung carcinoma NCI-H460 cells and had a minimal effect on lung epithelial-like WI-26 VA4 cells and are therefore promising compounds in the search for novel antitumor agents that can be converted into conjugates with tumor-targeting ligands. Full article

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

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14 pages, 3240 KiB

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An Alliance of Polynitrogen Heterocycles: Novel Energetic Tetrazinedioxide-Hydroxytetrazole-Based Materials

by Dmitry M. Bystrov, Alla N. Pivkina and Leonid L. Fershtat

Molecules 2022, 27(18), 5891; https://doi.org/10.3390/molecules27185891 - 11 Sep 2022

Cited by 5 | Viewed by 2431

Energetic materials constitute one of the most important subtypes of functional materials used for various applications. A promising approach for the construction of novel thermally stable high-energy materials is based on an assembly of polynitrogen biheterocyclic scaffolds. Herein, we report on the design [...] Read more.

Energetic materials constitute one of the most important subtypes of functional materials used for various applications. A promising approach for the construction of novel thermally stable high-energy materials is based on an assembly of polynitrogen biheterocyclic scaffolds. Herein, we report on the design and synthesis of a new series of high-nitrogen energetic salts comprising the C-C linked 6-aminotetrazinedioxide and hydroxytetrazole frameworks. Synthesized materials were thoroughly characterized by IR and multinuclear NMR spectroscopy, elemental analysis, single-crystal X-ray diffraction and differential scanning calorimetry. As a result of a vast amount of the formed intra- and intermolecular hydrogen bonds, prepared ammonium and amino-1,2,4-triazolium salts are thermally stable and have good densities of 1.75–1.78 g·cm⁻³. All synthesized compounds show high detonation performance, reaching that of benchmark RDX. At the same time, as compared to RDX, investigated salts are less friction sensitive due to the formed net of hydrogen bonds. Overall, reported functional materials represent a novel perspective subclass of secondary explosives and unveil further opportunities for an assembly of biheterocyclic next-generation energetic materials. Full article

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

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14 pages, 1501 KiB

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Aziridination Reactivity of a Manganese(II) Complex with a Bulky Chelating Bis(Alkoxide) Ligand

by Sudheer S. Kurup, Natalie M. Woodland, Richard L. Lord and Stanislav Groysman

Molecules 2022, 27(18), 5751; https://doi.org/10.3390/molecules27185751 - 06 Sep 2022

Cited by 1 | Viewed by 1890

Treatment of Mn(N(SiMe₃)₂)₂(THF)₂ with bulky chelating bis(alkoxide) ligand [1,1′:4′,1′′-terphenyl]-2,2′′-diylbis(diphenylmethanol) (H₂[O-terphenyl-O]^Ph) formed a seesaw manganese(II) complex Mn[O-terphenyl-O]^Ph(THF)₂, characterized by structural, spectroscopic, magnetic, and analytical methods. The reactivity of Mn[O-terphenyl-O] [...] Read more.

Treatment of Mn(N(SiMe₃)₂)₂(THF)₂ with bulky chelating bis(alkoxide) ligand [1,1′:4′,1′′-terphenyl]-2,2′′-diylbis(diphenylmethanol) (H₂[O-terphenyl-O]^Ph) formed a seesaw manganese(II) complex Mn[O-terphenyl-O]^Ph(THF)₂, characterized by structural, spectroscopic, magnetic, and analytical methods. The reactivity of Mn[O-terphenyl-O]^Ph(THF)₂ with various nitrene precursors was investigated. No reaction was observed between Mn[O-terphenyl-O]^Ph(THF)₂ and aryl azides. In contrast, the treatment of Mn[O-terphenyl-O]^Ph(THF)₂ with iminoiodinane PhINTs (Ts = p-toluenesulfonyl) was consistent with the formation of a metal-nitrene complex. In the presence of styrene, the reaction led to the formation of aziridine. Combining varying ratios of styrene and PhINTs in different solvents with 10 mol% of Mn[O-terphenyl-O]^Ph(THF)₂ at room temperature produced 2-phenylaziridine in up to a 79% yield. Exploration of the reactivity of Mn[O-terphenyl-O]^Ph(THF)₂ with various olefins revealed (1) moderate aziridination yields for p-substituted styrenes, irrespective of the electronic nature of the substituent; (2) moderate yield for 1,1′-disubstituted α-methylstyrene; (3) no aziridination for aliphatic α-olefins; (4) complex product mixtures for the β-substituted styrenes. DFT calculations suggest that iminoiodinane is oxidatively added upon binding to Mn, and the resulting formal imido intermediate has a high-spin Mn(III) center antiferromagnetically coupled to an imidyl radical. This imidyl radical reacts with styrene to form a sextet intermediate that readily reductively eliminates the formation of a sextet Mn(II) aziridine complex. Full article

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

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15 pages, 5556 KiB

Open AccessArticle

Nucleophilic Functionalization of 2-R-3-Nitropyridines as a Versatile Approach to Novel Fluorescent Molecules

by Vladislav V. Nikol’skiy, Mikhail E. Minyaev, Maxim A. Bastrakov and Alexey M. Starosotnikov

Molecules 2022, 27(17), 5692; https://doi.org/10.3390/molecules27175692 - 03 Sep 2022

Cited by 1 | Viewed by 1386

A number of new 2-methyl- and 2-arylvinyl-3-nitropyridines were synthesized and their reactions with thiols were studied. It was found that 3-NO₂ tends to be selectively substituted under the action of sulfur nucleophiles in the presence of another nucleofuge in position 5. Correlations [...] Read more.

A number of new 2-methyl- and 2-arylvinyl-3-nitropyridines were synthesized and their reactions with thiols were studied. It was found that 3-NO₂ tends to be selectively substituted under the action of sulfur nucleophiles in the presence of another nucleofuge in position 5. Correlations between the substitution pattern and regioselectivity as well as photophysical properties were established. Some synthesized compounds possessed a large Stokes shift. Full article

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

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17 pages, 2685 KiB

Open AccessArticle

Copper(II)-Catalyzed (3+2) Cycloaddition of 2H-Azirines to Six-Membered Cyclic Enols as a Route to Pyrrolo[3,2-c]quinolone, Chromeno[3,4-b]pyrrole, and Naphtho[1,8-ef]indole Scaffolds

by Pavel A. Sakharov, Nikolai V. Rostovskii, Alexander F. Khlebnikov and Mikhail S. Novikov

Molecules 2022, 27(17), 5681; https://doi.org/10.3390/molecules27175681 - 02 Sep 2022

Cited by 6 | Viewed by 1823

A method for the [2+3] pyrroline annulation to the six-membered non-aromatic enols using 3-aryl-2H-azirines as annulation agents is developed in the current study. The reaction proceeds as a formal (3+2) cycloaddition via the N1-C2 azirine bond cleavage and is catalyzed by [...] Read more.

A method for the [2+3] pyrroline annulation to the six-membered non-aromatic enols using 3-aryl-2H-azirines as annulation agents is developed in the current study. The reaction proceeds as a formal (3+2) cycloaddition via the N1-C2 azirine bond cleavage and is catalyzed by both Cu(II) and Cu(I) compounds. The new annulation method can be applied to prepare pyrrolo[3,2-c]quinoline, chromeno[3,4-b]pyrrole, and naphtho[1,8-ef]indole derivatives in good to excellent yields from enols of the quinolin-2-one, 2H-chromen-2-one, and 1H-phenalen-1-one series. Full article

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

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13 pages, 3692 KiB

Open AccessArticle

Synthesis of a Pyrrolo[1,2-a]quinazoline-1,5-dione Derivative by Mechanochemical Double Cyclocondensation Cascade

by Vanessza Judit Kolcsár and György Szőllősi

Molecules 2022, 27(17), 5671; https://doi.org/10.3390/molecules27175671 - 02 Sep 2022

Cited by 1 | Viewed by 1409

N-heterocyclic compounds, such as quinazolinone derivatives, have significant biological activities. Nowadays, as the demand for environmentally benign, sustainable processes increases, the application of compounds from renewable sources, easily separable heterogeneous catalysts and efficient, alternative activation methods is of great importance. In this [...] Read more.

N-heterocyclic compounds, such as quinazolinone derivatives, have significant biological activities. Nowadays, as the demand for environmentally benign, sustainable processes increases, the application of compounds from renewable sources, easily separable heterogeneous catalysts and efficient, alternative activation methods is of great importance. In this study, we have developed a convenient, green procedure for the preparation of 3a-methyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazoline-1,5-dione through a double cyclocondensation cascade using anthranilamide and ethyl levulinate. Screening of various heterogeneous Brønsted acid catalysts showed that Amberlyst^® 15 is a convenient choice. By applying mechanochemical activation in the preparation of this N-heterotricyclic compound for the first time, it was possible to shorten the necessary time to three hours compared to the 24 h needed under conventional conditions to obtain a high yield of the target product. Full article

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

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9 pages, 752 KiB

Open AccessArticle

[1,5]-Hydride Shift Triggered N-Dealkylative Cyclization into 2-Oxo-1,2,3,4-tetrahydroquinoline-3-carboxylates via Boronate Complexes

by Elvira R. Zaitseva, Dmitrii S. Ivanov, Alexander Yu. Smirnov, Andrey A. Mikhaylov, Nadezhda S. Baleeva and Mikhail S. Baranov

Molecules 2022, 27(16), 5270; https://doi.org/10.3390/molecules27165270 - 18 Aug 2022

Viewed by 1452

A new simple one-pot two-step protocol for the synthesis of 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate from 2-(2-(benzylamino)benzylidene)malonate under the action of BF3·Et2O was developed. It was shown that the reaction proceeds through the formation of a stable iminium intermediate containing a difluoroboryl bridge in the dicarbonyl fragment [...] Read more.

A new simple one-pot two-step protocol for the synthesis of 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate from 2-(2-(benzylamino)benzylidene)malonate under the action of BF3·Et2O was developed. It was shown that the reaction proceeds through the formation of a stable iminium intermediate containing a difluoroboryl bridge in the dicarbonyl fragment of the molecule. Full article

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

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14 pages, 1425 KiB

Open AccessArticle

CK2 Inhibition and Antitumor Activity of 4,7-Dihydro-6-nitroazolo[1,5-a]pyrimidines

by Daniil N. Lyapustin, Svetlana K. Kotovskaya, Ilya I. Butorin, Evgeny N. Ulomsky, Vladimir L. Rusinov, Denis A. Babkov, Alexander A. Pokhlebin, Alexander A. Spasov, Vsevolod V. Melekhin, Maria D. Tokhtueva, Anna V. Shcheglova and Oleg G. Makeev

Molecules 2022, 27(16), 5239; https://doi.org/10.3390/molecules27165239 - 17 Aug 2022

Cited by 2 | Viewed by 1705

Today, cancer is one of the most widespread and dangerous human diseases with a high mortality rate. Nevertheless, the search and application of new low-toxic and effective drugs, combined with the timely diagnosis of diseases, makes it possible to cure most types of [...] Read more.

Today, cancer is one of the most widespread and dangerous human diseases with a high mortality rate. Nevertheless, the search and application of new low-toxic and effective drugs, combined with the timely diagnosis of diseases, makes it possible to cure most types of tumors at an early stage. In this work, the range of new polysubstituted 4,7-dihydro-6-nitroazolo[1,5-a]pyrimidines was extended. The structure of all the obtained compounds was confirmed by the data of ¹H, ¹³C NMR spectroscopy, IR spectroscopy, and elemental analysis. These compounds were evaluated against human recombinant CK2 using the ADP-GloTM assay. In addition, the IC₅₀ parameters were calculated based on the results of the MTT test against glioblastoma (A-172), embryonic rhabdomyosarcoma (Rd), osteosarcoma (Hos), and human embryonic kidney (Hek-293) cells. Compounds 5f, 5h, and 5k showed a CK2 inhibitory activity close to the reference molecule (staurosporine). The most potential compound in the MTT test was 5m with an IC₅₀ from 13 to 27 µM. Thus, our results demonstrate that 4,7-dihydro-6-nitroazolo[1,5-a]pyrimidines are promising for further investigation of their antitumor properties. Full article

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

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Review

Jump to: Research

42 pages, 5338 KiB

Open AccessReview

Photodynamic Therapy: From the Basics to the Current Progress of N-Heterocyclic-Bearing Dyes as Effective Photosensitizers

by Eurico Lima and Lucinda V. Reis

Molecules 2023, 28(13), 5092; https://doi.org/10.3390/molecules28135092 - 29 Jun 2023

Cited by 12 | Viewed by 2870

Photodynamic therapy, an alternative that has gained weight and popularity compared to current conventional therapies in the treatment of cancer, is a minimally invasive therapeutic strategy that generally results from the simultaneous action of three factors: a molecule with high sensitivity to light, [...] Read more.

Photodynamic therapy, an alternative that has gained weight and popularity compared to current conventional therapies in the treatment of cancer, is a minimally invasive therapeutic strategy that generally results from the simultaneous action of three factors: a molecule with high sensitivity to light, the photosensitizer, molecular oxygen in the triplet state, and light energy. There is much to be said about each of these three elements; however, the efficacy of the photosensitizer is the most determining factor for the success of this therapeutic modality. Porphyrins, chlorins, phthalocyanines, boron-dipyrromethenes, and cyanines are some of the N-heterocycle-bearing dyes’ classes with high biological promise. In this review, a concise approach is taken to these and other families of potential photosensitizers and the molecular modifications that have recently appeared in the literature within the scope of their photodynamic application, as well as how these compounds and their formulations may eventually overcome the deficiencies of the molecules currently clinically used and revolutionize the therapies to eradicate or delay the growth of tumor cells. Full article

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

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46 pages, 16773 KiB

Open AccessReview

1,3-Butadiynamides the Ethynylogous Ynamides: Synthesis, Properties and Applications in Heterocyclic Chemistry

by Illia Lenko, Carole Alayrac, Igor Bożek and Bernhard Witulski

Molecules 2023, 28(11), 4564; https://doi.org/10.3390/molecules28114564 - 05 Jun 2023

Viewed by 1896

1,3-butadiynamides—the ethynylogous variants of ynamides—receive considerable attention as precursors of complex molecular scaffolds for organic and heterocyclic chemistry. The synthetic potential of these C4-building blocks reveals itself in sophisticated transition-metal catalyzed annulation reactions and in metal-free or silver-mediated HDDA (Hexa-dehydro-Diels–Alder) cycloadditions. 1,3-Butadiynamides also [...] Read more.

1,3-butadiynamides—the ethynylogous variants of ynamides—receive considerable attention as precursors of complex molecular scaffolds for organic and heterocyclic chemistry. The synthetic potential of these C4-building blocks reveals itself in sophisticated transition-metal catalyzed annulation reactions and in metal-free or silver-mediated HDDA (Hexa-dehydro-Diels–Alder) cycloadditions. 1,3-Butadiynamides also gain significance as optoelectronic materials and in less explored views on their unique helical twisted frontier molecular orbitals (Hel-FMOs). The present account summarizes different methodologies for the synthesis of 1,3-butadiynamides followed by the description of their molecular structure and electronic properties. Finally, the surprisingly rich chemistry of 1,3-butadiynamides as versatile C4-building blocks in heterocyclic chemistry is reviewed by compiling their exciting reactivity, specificity and opportunities for organic synthesis. Besides chemical transformations and use in synthesis, a focus is set on the mechanistic understanding of the chemistry of 1,3-butadiynamides—suggesting that 1,3-butadiynamides are not just simple alkynes. These ethynylogous variants of ynamides have their own molecular character and chemical reactivity and reflect a new class of remarkably useful compounds. Full article

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

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36 pages, 11109 KiB

Open AccessReview

Green Synthesis of Aromatic Nitrogen-Containing Heterocycles by Catalytic and Non-Traditional Activation Methods

by R. Bernadett Vlocskó, Guoshu Xie and Béla Török

Molecules 2023, 28(10), 4153; https://doi.org/10.3390/molecules28104153 - 17 May 2023

Cited by 3 | Viewed by 2100

Recent advances in the environmentally benign synthesis of aromatic N-heterocycles are reviewed, focusing primarily on the application of catalytic methods and non-traditional activation. This account features two main parts: the preparation of single ring N-heterocycles, and their condensed analogs. Both groups include compounds [...] Read more.

Recent advances in the environmentally benign synthesis of aromatic N-heterocycles are reviewed, focusing primarily on the application of catalytic methods and non-traditional activation. This account features two main parts: the preparation of single ring N-heterocycles, and their condensed analogs. Both groups include compounds with one, two and more N-atoms. Due to the large number of protocols, this account focuses on providing representative examples to feature the available methods. Full article

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

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26 pages, 11583 KiB

Open AccessReview

A Brief Review on the Synthesis of the N-CF₃ Motif in Heterocycles

by Zizhen Lei, Wenxu Chang, Hong Guo, Jiyao Feng and Zhenhua Zhang

Molecules 2023, 28(7), 3012; https://doi.org/10.3390/molecules28073012 - 28 Mar 2023

Cited by 8 | Viewed by 3548

The trifluoromethyl group is widely recognized for its significant role in the fields of medicinal chemistry and material science due to its unique electronic and steric properties that can alter various physiochemical properties of the parent molecule, such as lipophilicity, acidity, and hydrogen [...] Read more.

The trifluoromethyl group is widely recognized for its significant role in the fields of medicinal chemistry and material science due to its unique electronic and steric properties that can alter various physiochemical properties of the parent molecule, such as lipophilicity, acidity, and hydrogen bonding capabilities. Compared to the well-established C-trifluoromethylation, N-trifluoromethylation has received lesser attention. Considering the extensive contribution of nitrogen to drug molecules, it is predicted that constructing N-trifluoromethyl (N-CF₃) motifs will be of great significance in pharmaceutical and agrochemical industries. This review is mainly concerned with the synthesis of heterocycles containing this motif. In three-membered heterocycles containing the N-CF₃ motif, the existing literature mostly demonstrated the synthetic strategy, as it does for four- and larger-membered heterocycles. Certain structures, such as oxaziridines, could serve as an oxidant or building blocks in organic synthesis. In five-membered heterocycles, it has been reported that N-CF₃ azoles showed a higher lipophilicity and a latent increased metabolic stability and Caco-2-permeability compared with their N-CH₃ counterparts, illustrating the potential of the N-CF₃ motif. Various N-CF₃ analogues of drugs or bioactive molecules, such as sildenafil analogue, have been obtained. In general, the N-CF₃ motif is developing and has great potential in bioactive molecules or materials. Give the recent development in this motif, it is foreseeable that its synthesis methods and applications will become more and more extensive. In this paper, we present an overview of the synthesis of N-CF₃ heterocycles, categorized on the basis of the number of rings (three-, four-, five-, six- and larger-membered heterocycles), and focus on the five-membered heterocycles containing the N-CF₃ group. Full article

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

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31 pages, 9232 KiB

Open AccessReview

Synthesis of Phosphorus(V)-Substituted Six-Membered N-Heterocycles: Recent Progress and Challenges

by Yulia Volkova and Igor Zavarzin

Molecules 2023, 28(6), 2472; https://doi.org/10.3390/molecules28062472 - 08 Mar 2023

Cited by 2 | Viewed by 2601

Heterocycles functionalized with pentavalent phosphorus are of great importance since they include a great variety of biologically active compounds and pharmaceuticals, advanced materials, and valuable reactive intermediates for organic synthesis. Significant progress in synthesis of P(O)R₂-substituted six-membered heterocycles has been made [...] Read more.

Heterocycles functionalized with pentavalent phosphorus are of great importance since they include a great variety of biologically active compounds and pharmaceuticals, advanced materials, and valuable reactive intermediates for organic synthesis. Significant progress in synthesis of P(O)R₂-substituted six-membered heterocycles has been made in the past decade. This review covers the synthetic strategies towards aromatic monocyclic six-membered N-heterocycles, such as pyridines, pyridazines, pyrimidines, and pyrazines bearing phosphonates and phosphine oxides, which were reported from 2012 to 2022. Full article

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

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27 pages, 9338 KiB

Open AccessReview

Imidazole: Synthesis, Functionalization and Physicochemical Properties of a Privileged Structure in Medicinal Chemistry

by Heber Victor Tolomeu and Carlos Alberto Manssour Fraga

Molecules 2023, 28(2), 838; https://doi.org/10.3390/molecules28020838 - 13 Jan 2023

Cited by 34 | Viewed by 7464

Imidazole was first synthesized by Heinrich Debus in 1858 and was obtained by the reaction of glyoxal and formaldehyde in ammonia, initially called glyoxaline. The current literature provides much information about the synthesis, functionalization, physicochemical characteristics and biological role of imidazole. Imidazole is [...] Read more.

Imidazole was first synthesized by Heinrich Debus in 1858 and was obtained by the reaction of glyoxal and formaldehyde in ammonia, initially called glyoxaline. The current literature provides much information about the synthesis, functionalization, physicochemical characteristics and biological role of imidazole. Imidazole is a structure that, despite being small, has a unique chemical complexity. It is a nucleus that is very practical and versatile in its construction/functionalization and can be considered a rich source of chemical diversity. Imidazole acts in extremely important processes for the maintenance of living organisms, such as catalysis in enzymatic processes. Imidazole-based compounds with antibacterial, anti-inflammatory, antidiabetic, antiparasitic, antituberculosis, antifungal, antioxidant, antitumor, antimalarial, anticancer, antidepressant and many others make up the therapeutic arsenal and new bioactive compounds proposed in the most diverse works. The interest and importance of imidazole-containing analogs in the field of medicinal chemistry is remarkable, and the understanding from the development of the first blockbuster drug cimetidine explores all the chemical and biological concepts of imidazole in the context of research and development of new drugs. Full article

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

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81 pages, 27765 KiB

Open AccessReview

Azomethine Ylides—Versatile Synthons for Pyrrolidinyl-Heterocyclic Compounds

by Siva S. Panda, Marian N. Aziz, Jacek Stawinski and Adel S. Girgis

Molecules 2023, 28(2), 668; https://doi.org/10.3390/molecules28020668 - 09 Jan 2023

Cited by 12 | Viewed by 1937

Azomethine ylides are nitrogen-based three-atom components commonly used in [3+2]-cycloaddition reactions with various unsaturated 2π-electron components. These reactions are highly regio- and stereoselective and have attracted the attention of organic chemists with respect to the construction of diverse heterocycles potentially bearing four new [...] Read more.

Azomethine ylides are nitrogen-based three-atom components commonly used in [3+2]-cycloaddition reactions with various unsaturated 2π-electron components. These reactions are highly regio- and stereoselective and have attracted the attention of organic chemists with respect to the construction of diverse heterocycles potentially bearing four new contiguous stereogenic centers. This review article complies the most important [3+2]-cycloaddition reactions of azomethine ylides with various olefinic, unsaturated 2π-electron components (acyclic, alicyclic, heterocyclic, and exocyclic ones) reported over the past two decades. Full article

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

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23 pages, 5683 KiB

Open AccessReview

Folic Acid Antimetabolites (Antifolates): A Brief Review on Synthetic Strategies and Application Opportunities

by Igor S. Kovalev, Grigory V. Zyryanov, Sougata Santra, Adinath Majee, Mikhail V. Varaksin and Valery N. Charushin

Molecules 2022, 27(19), 6229; https://doi.org/10.3390/molecules27196229 - 22 Sep 2022

Cited by 9 | Viewed by 3464

Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common methods and approaches are presented for the synthesis of therapeutically significant antimetabolites of folic acid, which are Methotrexate [...] Read more.

Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common methods and approaches are presented for the synthesis of therapeutically significant antimetabolites of folic acid, which are Methotrexate (MTX), Raltitrexed (Tomudex, ZD1694), Pralatrexate, Pemetrexed, TNP-351, and Lometrexol. In addition, the applications or uses of these folic acid antimetabolites are also discussed. Full article

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

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17 pages, 4585 KiB

Open AccessReview

Heterocyclic Compounds as Dipeptidyl Peptidase-IV Inhibitors with Special Emphasis on Oxadiazoles as Potent Anti-Diabetic Agents

by Badrud Duza Mohammad, Mirza Shahed Baig, Neeraj Bhandari, Falak A. Siddiqui, Sharuk L. Khan, Zubair Ahmad, Farhat S. Khan, Priti Tagde and Philippe Jeandet

Molecules 2022, 27(18), 6001; https://doi.org/10.3390/molecules27186001 - 15 Sep 2022

Cited by 12 | Viewed by 2664

Dipeptidyl peptidase-IV (DPP-IV) inhibitors, often known as gliptins, have been used to treat type 2 diabetes mellitus (T2DM). They may be combined with other medications as an additional treatment or used alone as a monotherapy. In addition to insulin, sulfonylureas, thiazolidinediones, and metformin, [...] Read more.

Dipeptidyl peptidase-IV (DPP-IV) inhibitors, often known as gliptins, have been used to treat type 2 diabetes mellitus (T2DM). They may be combined with other medications as an additional treatment or used alone as a monotherapy. In addition to insulin, sulfonylureas, thiazolidinediones, and metformin, these molecules appear as possible therapeutic options. Oxadiazole rings have been employed in numerous different ways during drug development efforts. It has been shown that including them in the pharmacophore increases the amount of ligand that may be bound. The exceptional hydrogen bond acceptor properties of oxadiazoles and the distinct hydrocarbon bonding potential of their regioisomers have been established. Beside their anti-diabetic effects, oxadiazoles display a wide range of pharmacological properties. In this study, we made the assumption that molecules containing oxadiazole rings may afford a different approach to the treatment of diabetes, not only for controlling glycemic levels but also for preventing atherosclerosis progression and other complications associated with diabetes. It was observed that oxadiazole fusion with benzothiazole, 5-(2,5,2-trifluoroethoxy) phenyl, β-homophenylalanine, 2-methyl-2-{5-(4-chlorophenyl), diamine-bridged bis-coumarinyl, 5-aryl-2-(6′-nitrobenzofuran-2′-yl), nitrobenzofuran, and/or oxindole leads to potential anti-diabetic activity. Full article

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

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41 pages, 9476 KiB

Open AccessReview

Recent Strategies in Transition-Metal-Catalyzed Sequential C–H Activation/Annulation for One-Step Construction of Functionalized Indazole Derivatives

by Pezhman Shiri, Atefeh Roosta, Wim Dehaen and Ali Mohammad Amani

Molecules 2022, 27(15), 4942; https://doi.org/10.3390/molecules27154942 - 03 Aug 2022

Cited by 7 | Viewed by 2002

Designing new synthetic strategies for indazoles is a prominent topic in contemporary research. The transition-metal-catalyzed C–H activation/annulation sequence has arisen as a favorable tool to construct functionalized indazole derivatives with improved tolerance in medicinal applications, functional flexibility, and structural complexity. In the current [...] Read more.

Designing new synthetic strategies for indazoles is a prominent topic in contemporary research. The transition-metal-catalyzed C–H activation/annulation sequence has arisen as a favorable tool to construct functionalized indazole derivatives with improved tolerance in medicinal applications, functional flexibility, and structural complexity. In the current review article, we aim to outline and summarize the most common synthetic protocols to use in the synthesis of target indazoles via a transition-metal-catalyzed C–H activation/annulation sequence for the one-step synthesis of functionalized indazole derivatives. We categorized the text according to the metal salts used in the reactions. Some metal salts were used as catalysts, and others may have been used as oxidants and/or for the activation of precatalysts. The roles of some metal salts in the corresponding reaction mechanisms have not been identified. It can be expected that the current synopsis will provide accessible practical guidance to colleagues interested in the subject. Full article

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

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