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Special Issue "Recent Developments in the Synthesis and Functionalization of Nitrogen Heterocycles"

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

Deadline for manuscript submissions: 31 January 2023 | Viewed by 13228

Special Issue Editors

Dr. Alexey M. Starosotnikov
E-Mail Website
Guest Editor
N.D. Zelinsky Institute of Organic Chemistry RAS, Leninsky Prosp. 47, 119991 Moscow, Russia
Interests: nitro compounds; heterocyclic chemistry; cycloadditions; pyridines; azoles; synthetic methods; biologically active compounds
Dr. Maxim A. Bastrakov
E-Mail Website
Guest Editor
N.D. Zelinsky Institute of Organic Chemistry RAS, Leninsky Prosp. 47, 119991 Moscow, Russia
Interests: organic synthesis; heterocyclic compounds; nitro compounds; nitrogen heterocycles; biologically active compounds; dearomatization; cycloaddition reactions
Dr. Igor L. Dalinger
E-Mail Website
Guest Editor
N.D. Zelinsky Institute of Organic Chemistry RAS, Leninsky Prosp. 47, 119991 Moscow, Russia
Interests: nitrogen heterocycles; heterocyclic chemistry; organic chemistry

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

Manuscript Submission Information

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Keywords

  • nitrogen heterocycles
  • synthetic methods
  • azoles
  • azines
  • functionalization of N-heterocycles

Published Papers (26 papers)

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Research

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Article
Synthesis of Functionalized Isoquinolone Derivatives via Rh(III)-Catalyzed [4+2]-Annulation of Benzamides with Internal Acetylene-Containing α-CF3-α-Amino Carboxylates
Molecules 2022, 27(23), 8488; https://doi.org/10.3390/molecules27238488 (registering DOI) - 02 Dec 2022
Viewed by 131
Abstract
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
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Article
Synthesis of 1,5-Substituted Pyrrolidin-2-ones from Donor–Acceptor Cyclopropanes and Anilines/Benzylamines
Molecules 2022, 27(23), 8468; https://doi.org/10.3390/molecules27238468 (registering DOI) - 02 Dec 2022
Viewed by 160
Abstract
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
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Article
Regioselective Synthesis and Molecular Docking Studies of 1,5-Disubstituted 1,2,3-Triazole Derivatives of Pyrimidine Nucleobases
Molecules 2022, 27(23), 8467; https://doi.org/10.3390/molecules27238467 (registering DOI) - 02 Dec 2022
Viewed by 161
Abstract
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
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Article
Energetic [1,2,5]oxadiazolo [2,3-a]pyrimidin-8-ium Perchlorates: Synthesis and Characterization
Molecules 2022, 27(23), 8443; https://doi.org/10.3390/molecules27238443 (registering DOI) - 02 Dec 2022
Viewed by 172
Abstract
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
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Article
First Synthesis of 3-Glycopyranosyl-1,2,4-Triazines and Some Cycloadditions Thereof
Molecules 2022, 27(22), 7801; https://doi.org/10.3390/molecules27227801 - 12 Nov 2022
Viewed by 345
Abstract
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
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Article
Mechanochemical Approach towards Multi-Functionalized 1,2,3-Triazoles and Anti-Seizure Drug Rufinamide Analogs Using Copper Beads
Molecules 2022, 27(22), 7784; https://doi.org/10.3390/molecules27227784 - 11 Nov 2022
Viewed by 316
Abstract
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
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Article
Electrochemically Induced Synthesis of Imidazoles from Vinyl Azides and Benzyl Amines
Molecules 2022, 27(22), 7721; https://doi.org/10.3390/molecules27227721 - 09 Nov 2022
Viewed by 308
Abstract
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
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Article
Synthesis, Characterization and DFT Study of a New Family of High-Energy Compounds Based on s-Triazine, Carborane and Tetrazoles
Molecules 2022, 27(21), 7484; https://doi.org/10.3390/molecules27217484 - 02 Nov 2022
Viewed by 435
Abstract
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
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Article
Substitutional Diversity-Oriented Synthesis and In Vitro Anticancer Activity of Framework-Integrated Estradiol-Benzisoxazole Chimeras
Molecules 2022, 27(21), 7456; https://doi.org/10.3390/molecules27217456 - 02 Nov 2022
Viewed by 572
Abstract
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
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Article
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 SNAr and Cross-Coupling Reactions
Molecules 2022, 27(21), 7372; https://doi.org/10.3390/molecules27217372 - 30 Oct 2022
Viewed by 534
Abstract
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
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Article
Multifunctional Derivatives of Spiropyrrolidine Tethered Indeno-Quinoxaline Heterocyclic Hybrids as Potent Antimicrobial, Antioxidant and Antidiabetic Agents: Design, Synthesis, In Vitro and In Silico Approaches
Molecules 2022, 27(21), 7248; https://doi.org/10.3390/molecules27217248 - 25 Oct 2022
Viewed by 453
Abstract
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
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Article
MnO2-Mediated Oxidative Cyclization of “Formal” Schiff’s Bases: Easy Access to Diverse Naphthofuro-Annulated Triazines
Molecules 2022, 27(20), 7105; https://doi.org/10.3390/molecules27207105 - 21 Oct 2022
Viewed by 407
Abstract
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
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Article
Reactions of Trifluorotriacetic Acid Lactone and Hexafluorodehydroacetic Acid with Amines: Synthesis of Trifluoromethylated 4-Pyridones and Aminoenones
Molecules 2022, 27(20), 7098; https://doi.org/10.3390/molecules27207098 - 20 Oct 2022
Viewed by 422
Abstract
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
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Article
Domino Aza-Michael-SNAr-Heteroaromatization Route to C5-Substituted 1-Alkyl-1H-Indole-3-Carboxylic Esters
Molecules 2022, 27(20), 6998; https://doi.org/10.3390/molecules27206998 - 18 Oct 2022
Viewed by 418
Abstract
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 SNAr 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 SNAr 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 SNAr 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
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Article
Atom Economical Multi-Substituted Pyrrole Synthesis from Aziridine
Molecules 2022, 27(20), 6869; https://doi.org/10.3390/molecules27206869 - 13 Oct 2022
Viewed by 422
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
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Article
Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas Reaction
Molecules 2022, 27(18), 6071; https://doi.org/10.3390/molecules27186071 - 17 Sep 2022
Viewed by 510
Abstract
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
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Article
An Alliance of Polynitrogen Heterocycles: Novel Energetic Tetrazinedioxide-Hydroxytetrazole-Based Materials
Molecules 2022, 27(18), 5891; https://doi.org/10.3390/molecules27185891 - 11 Sep 2022
Viewed by 867
Abstract
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
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Article
Aziridination Reactivity of a Manganese(II) Complex with a Bulky Chelating Bis(Alkoxide) Ligand
Molecules 2022, 27(18), 5751; https://doi.org/10.3390/molecules27185751 - 06 Sep 2022
Viewed by 637
Abstract
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
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Article
Nucleophilic Functionalization of 2-R-3-Nitropyridines as a Versatile Approach to Novel Fluorescent Molecules
Molecules 2022, 27(17), 5692; https://doi.org/10.3390/molecules27175692 - 03 Sep 2022
Viewed by 485
Abstract
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
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Article
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
Molecules 2022, 27(17), 5681; https://doi.org/10.3390/molecules27175681 - 02 Sep 2022
Viewed by 653
Abstract
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
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Article
Synthesis of a Pyrrolo[1,2-a]quinazoline-1,5-dione Derivative by Mechanochemical Double Cyclocondensation Cascade
Molecules 2022, 27(17), 5671; https://doi.org/10.3390/molecules27175671 - 02 Sep 2022
Viewed by 429
Abstract
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
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Article
[1,5]-Hydride Shift Triggered N-Dealkylative Cyclization into 2-Oxo-1,2,3,4-tetrahydroquinoline-3-carboxylates via Boronate Complexes
Molecules 2022, 27(16), 5270; https://doi.org/10.3390/molecules27165270 - 18 Aug 2022
Viewed by 516
Abstract
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
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Article
CK2 Inhibition and Antitumor Activity of 4,7-Dihydro-6-nitroazolo[1,5-a]pyrimidines
Molecules 2022, 27(16), 5239; https://doi.org/10.3390/molecules27165239 - 17 Aug 2022
Viewed by 752
Abstract
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
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Review

Jump to: Research

Review
Folic Acid Antimetabolites (Antifolates): A Brief Review on Synthetic Strategies and Application Opportunities
Molecules 2022, 27(19), 6229; https://doi.org/10.3390/molecules27196229 - 22 Sep 2022
Viewed by 566
Abstract
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
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Review
Heterocyclic Compounds as Dipeptidyl Peptidase-IV Inhibitors with Special Emphasis on Oxadiazoles as Potent Anti-Diabetic Agents
Molecules 2022, 27(18), 6001; https://doi.org/10.3390/molecules27186001 - 15 Sep 2022
Viewed by 756
Abstract
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
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Review
Recent Strategies in Transition-Metal-Catalyzed Sequential C–H Activation/Annulation for One-Step Construction of Functionalized Indazole Derivatives
Molecules 2022, 27(15), 4942; https://doi.org/10.3390/molecules27154942 - 03 Aug 2022
Cited by 1 | Viewed by 651
Abstract
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
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

1.

Title: Reactions of trifluorotriacetic acid lactone and hexafluorodehydroacetic acid with amines: synthesis of trifluoromethylated 4-pyridones and aminoenones

Author: Vyacheslav Y. Sosnovskikh
Abstract: 
Dehydroacetic acid and triacetic acid lactone were shown to be versatile substrates for 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 cyclisation took place forming the corresponding benzodiazepine and pyrazole. The obtained 2,6-bis(trifluoromethyl)-4-pyridones were able to react with active methylene compounds giving fluorinated merocyanine dyes.

2.

Title: Atom economical multi-substituted pyrrole synthesis from aziridine
Authors: Lingamurthy Macha, Ranjith Jala, Sang-Yun Na and Hyun-Joon Ha*
Affiliation: Department of Chemistry, Hankuk University of Foreign Studies, Yongin 17035, Korea
Affiliation: Multi-substituted pyrroles were synthesized from regiospecific aziridine ring opening, and subsequently intramolecular cyclization with a carbonyl group at g-position in the presence of Lewis acid. This method is highly economical in that all reactants are incorporated into the final product with water removal with the removal of water. In addition, we observed that this reaction's oxidation state depended on the function group of the starting substrates. This new protocol was applied to the synthesis of various pyrroles including natural products.

3.

Title: Substitutional diversity-oriented synthesis and in vitro anticancer activity of framework-integrated estradiol-benzisoxazole chimeras
Authors: Ferenc Kovács 1, Dóra Izabella Adamecz 2, Ferenc István Nagy 2, Mónika Kiricsi 2 and Éva Frank 1, *
Affiliation: 
1 Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
2 Department of Biochemistry and Molecular Biology, Doctoral School of Biology, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary

* Correspondence: [email protected]; Tel.: +36-62-544-275
Abstract:

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 formally combined to novel molecules by structural integration of their aromatic rings. Simple estrogen starting materials, such as estrone, estradiol and estradiol-3-methyl ether were used for the multistep transformations. Some of the heterocyclic derivatives were prepared from the estrane precursor by a formylation/Friedel-Crafts acylation – oximation – cyclization sequence, while 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, PC-3, DU 125) 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 the 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 anti-cancer activity compared to the 17-acetylated counterparts. The present study concludes that novel estradiol-benzisoxazole chimeras exert remarkable cancer cell-specific antiproliferative activity and trigger apoptosis in cancer cells.

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