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11 pages, 2707 KiB

Open AccessArticle

Approach to Pyrido[2,1-b][1,3]benzothiazol-1-ones via In Situ Generation of Acyl(1,3-benzothiazol-2-yl)ketenes by Thermolysis of Pyrrolo[2,1-c][1,4]benzothiazine-1,2,4-triones

by Ekaterina A. Lystsova, Alexander S. Novikov, Maksim V. Dmitriev, Andrey N. Maslivets and Ekaterina E. Khramtsova

Molecules 2023, 28(14), 5495; https://doi.org/10.3390/molecules28145495 - 18 Jul 2023

Cited by 2 | Viewed by 990

Abstract

Acyl(imidoyl)ketenes are highly reactive heterocumulenes that enable diversity-oriented synthesis of various drug-like heterocycles. Such ketenes, bearing heterocyclic substituents, afford angularly fused pyridin-2(1H)-ones in their [4+2]-cyclodimerization reactions. We have utilized this property for the development of a new synthetic approach to pharmaceutically [...] Read more.

Acyl(imidoyl)ketenes are highly reactive heterocumulenes that enable diversity-oriented synthesis of various drug-like heterocycles. Such ketenes, bearing heterocyclic substituents, afford angularly fused pyridin-2(1H)-ones in their [4+2]-cyclodimerization reactions. We have utilized this property for the development of a new synthetic approach to pharmaceutically interesting pyrido[2,1-b][1,3]benzothiazol-1-ones via the [4+2]-cyclodimerization of acyl(1,3-benzothiazol-2-yl)ketenes generated in situ. The thermal behaviors of 3-aroylpyrrolo[2,1-c][1,4]benzothiazine-1,2,4-triones and 3-benzoylpyrrolo[2,1-b][1,3]benzothiazole-1,2-dione (two new types of [e]-fused 1H-pyrrole-2,3-diones reported by us recently) have been studied by thermal analysis and HPLC to elucidate their capability to be a source of acyl(1,3-benzothiazol-2-yl)ketenes. As a result, we have found that only 3-aroylpyrrolo[2,1-c][1,4]benzothiazine-1,2,4-triones are suitable for this. The experimental results are supplemented with computational studies that demonstrate that thermolysis of 3-aroylpyrrolo[2,1-c][1,4]benzothiazine-1,2,4-triones proceeds through an unprecedented cascade of two thermal decarbonylations. Based on these studies, we discovered a novel mode of thermal transformation of [e]-fused 1H-pyrrole-2,3-diones and developed a new pot, atom, and step economic synthetic approach to pyrido[2,1-b][1,3]benzothiazol-1-ones. The synthesized drug-like pyrido[2,1-b][1,3]benzothiazol-1-ones are of interest to pharmaceutics, since their close analogs show significant antiviral activity. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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15 pages, 2939 KiB

Open AccessArticle

Formal [3 + 2] Cycloaddition of α-Imino Esters with Azo Compounds: Facile Construction of Pentasubstituted 1,2,4-Triazoline Skeletons

by Yasushi Yoshida, Hidetoshi Ida, Takashi Mino and Masami Sakamoto

Molecules 2023, 28(11), 4339; https://doi.org/10.3390/molecules28114339 - 25 May 2023

Cited by 1 | Viewed by 927

Abstract

1,2,4-Triazole and 1,2,4-triazoline are important components of bioactive molecules and catalysts employed in organic synthesis. Therefore, the efficient synthesis of these components has received significant research attention. However, studies on their structural diversity remain lacking. Previously, we developed chiral phase-transfer-catalyzed asymmetric reactions of [...] Read more.

1,2,4-Triazole and 1,2,4-triazoline are important components of bioactive molecules and catalysts employed in organic synthesis. Therefore, the efficient synthesis of these components has received significant research attention. However, studies on their structural diversity remain lacking. Previously, we developed chiral phase-transfer-catalyzed asymmetric reactions of α-imino carbonyl compounds with α,β-unsaturated carbonyl compounds and haloalkanes. In this study, we demonstrate the formal [3 + 2] cycloaddition reaction of α-imino esters with azo compounds under Brønsted base catalysis, resulting in the corresponding 1,2,4-triazolines in high yields. The results revealed that a wide range of substrates and reactants can be applied, irrespective of their steric and electronic characteristics. The present reaction made the general preparation of 3-aryl pentasubstituted 1,2,4-triazolines possible for the first time. Furthermore, a mechanistic study suggested that the reaction proceeds without isomerization into the aldimine form. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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16 pages, 3029 KiB

Open AccessArticle

Triethylamine-Promoted Oxidative Cyclodimerization of 2H-Azirine-2-carboxylates to Pyrimidine-4,6-dicarboxylates: Experimental and DFT Study

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

Molecules 2023, 28(11), 4315; https://doi.org/10.3390/molecules28114315 - 24 May 2023

Cited by 2 | Viewed by 1256

Abstract

An unprecedented oxidative cyclodimerization reaction of 2H-azirine-2-carboxylates to pyrimidine-4,6-dicarboxylates under heating with triethylamine in air is described. In this reaction, one azirine molecule undergoes formal cleavage across the C-C bond and another across the C=N bond. According to the experimental study [...] Read more.

An unprecedented oxidative cyclodimerization reaction of 2H-azirine-2-carboxylates to pyrimidine-4,6-dicarboxylates under heating with triethylamine in air is described. In this reaction, one azirine molecule undergoes formal cleavage across the C-C bond and another across the C=N bond. According to the experimental study and DFT calculations, the key steps of the reaction mechanism include nucleophilic addition of N,N-diethylhydroxylamine to an azirine to form an (aminooxy)aziridine, generation of an azomethine ylide, and its 1,3-dipolar cycloaddition to the second azirine molecule. The crucial condition for the synthesis of pyrimidines is generation of N,N-diethylhydroxylamine in the reaction mixture in a very low concentration, which is ensured by the slow oxidation of triethylamine with air oxygen. Addition of a radical initiator accelerated the reaction and resulted in higher yields of the pyrimidines. Under these conditions, the scope of the pyrimidine formation was elucidated, and a series of pyrimidines was synthesized. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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9 pages, 2790 KiB

Open AccessCommunication

Chiral Indolizinium Salts Derived from 2-Pyridinecarbaldehyde—First Diastereoselective Syntheses of (−)-1-epi-lentiginosine

by Hisami Rodriguez-Matsui, David M. Aparicio, María L. Orea, Jorge R. Juárez, Victor Gómez-Calvario, Dino Gnecco, Alan Carrasco-Carballo and Joel L. Terán

Molecules 2023, 28(9), 3719; https://doi.org/10.3390/molecules28093719 - 25 Apr 2023

Viewed by 1200

Abstract

The first diastereoselective synthesis of (−)-1-epi-lentiginosine from a common chiral trans-epoxyamide derived from 2-pyridincarbaldehyde is reported. This methodology involves a sequential oxirane ring opening and intramolecular 5-exo-tet cyclization of tosylate trans-epoxyalcohol to afford a diastereomeric mixture [...] Read more.

The first diastereoselective synthesis of (−)-1-epi-lentiginosine from a common chiral trans-epoxyamide derived from 2-pyridincarbaldehyde is reported. This methodology involves a sequential oxirane ring opening and intramolecular 5-exo-tet cyclization of tosylate trans-epoxyalcohol to afford a diastereomeric mixture of indolizinium salts in a one-pot fashion, followed by regio- and diastereospecific pyridinium ring reduction. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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12 pages, 1997 KiB

Open AccessArticle

Ruthenium-Catalyzed Oxidative Synthesis of N-(2-triazine)indoles by C-H Activation

by Ming Zeng, Jiaqi Chen, Fengye Li, Haojie Li, Lan Zhao, Dengzhao Jiang, Jun Dai and Wenbo Liu

Molecules 2023, 28(9), 3676; https://doi.org/10.3390/molecules28093676 - 24 Apr 2023

Viewed by 1083

Abstract

1,3,5 triazines, especially indole functionalized triazine derivatives, exhibit excellent activities, such as anti-tumor, antibacterial, and anti-inflammatory activities. Traditional methods for the synthesis of N-(2-triazine) indoles suffer from unstable materials and tedious operations. Transition-metal-catalyzed C-C/C-N coupling provides a powerful protocol for the synthesis of [...] Read more.

1,3,5 triazines, especially indole functionalized triazine derivatives, exhibit excellent activities, such as anti-tumor, antibacterial, and anti-inflammatory activities. Traditional methods for the synthesis of N-(2-triazine) indoles suffer from unstable materials and tedious operations. Transition-metal-catalyzed C-C/C-N coupling provides a powerful protocol for the synthesis of indoles by the C-H activation strategy. Here, we report the efficient ruthenium-catalyzed oxidative synthesis of N-(2-triazine) indoles by C-H activation from alkynes and various substituted triazine derivatives in a moderate to good yield, and all of the N-(2-triazine) indoles were characterized by ¹H NMR, ¹³C NMR, and HRMS. This protocol can apply to the gram-scale synthesis of the N-(2-triazine) indole in a moderate yield. Moreover, the reaction is proposed to be performed via a six-membered ruthenacycle (II) intermediate, which suggests that the triazine ring could offer chelation assistance for the formation of N-(2-triazine) indoles. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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15 pages, 2690 KiB

Open AccessArticle

DABCO-Catalyzed Mono-/Diallylation of N-Unsubstituted Isatin N,N′-Cyclic Azomethine Imine 1,3-Dipoles with Morita-Baylis-Hillman Carbonates

by Qiumi Wang, Sicheng Li, Guosheng Yang, Xinyu Zou, Xi Yin, Juhua Feng, Huabao Chen, Chunping Yang, Li Zhang, Cuifen Lu and Guizhou Yue

Molecules 2023, 28(7), 3002; https://doi.org/10.3390/molecules28073002 - 28 Mar 2023

Viewed by 1349

Abstract

Allylation of N-unsubstituted isatin N,N′-cyclic azomethine imines with Morita-Baylis-Hillman carbonates in the presence of 1–10 mol% DABCO in DCM at room temperature, rapidly gave N-allylated and N, β-diallylated isatin N,N′-cyclic azomethine imine 1,3-dipoles [...] Read more.

Allylation of N-unsubstituted isatin N,N′-cyclic azomethine imines with Morita-Baylis-Hillman carbonates in the presence of 1–10 mol% DABCO in DCM at room temperature, rapidly gave N-allylated and N, β-diallylated isatin N,N′-cyclic azomethine imine 1,3-dipoles in moderate to high yields. The reaction features mild reaction conditions, easily practical operation, and short reaction times in most cases. Furthermore, the alkylated products were transformed into novel bicyclic spiropyrrolidine oxoindole derivatives through the [3+2] or [3+3]-cycloaddition with maleimides or Knoevenagel adducts. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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16 pages, 14082 KiB

Open AccessArticle

Tetranuclear Copper(I) and Silver(I) Pyrazolate Adducts with 1,1′-Dimethyl-2,2’-bibenzimidazole: Influence of Structure on Photophysics

by Gleb B. Yakovlev, Aleksei A. Titov, Alexander F. Smol’yakov, Andrey Yu. Chernyadyev, Oleg A. Filippov and Elena S. Shubina

Molecules 2023, 28(3), 1189; https://doi.org/10.3390/molecules28031189 - 25 Jan 2023

Cited by 3 | Viewed by 1380

Abstract

A reaction of a cyclic trinuclear copper(I) or silver(I) pyrazolate complex ([MPz]₃, M = Cu, Ag) with 1,1′-dimethyl-2,2’-bibenzimidazole (L) leads to the formation of tetranuclear adducts decorated by one or two molecules of a diimine ligand, depending on the [...] Read more.

A reaction of a cyclic trinuclear copper(I) or silver(I) pyrazolate complex ([MPz]₃, M = Cu, Ag) with 1,1′-dimethyl-2,2’-bibenzimidazole (L) leads to the formation of tetranuclear adducts decorated by one or two molecules of a diimine ligand, depending on the amount of the ligand added (0.75 or 1.5 equivalents). The coordination of two L molecules stabilizes the formation of a practically idealized tetrahedral four-metal core in the case of a copper-containing complex and a distorted tetrahedron in the case of a Ag analog. In contrast, complexes containing one molecule of diimine possess two types of metals, two- and three-coordinated, forming the significantly distorted central M₄ cores. The diimine ligands are twisted in these complexes with dihedral angles of ca. 50–60°. A TD-DFT analysis demonstrated the preference of a triplet state for the twisted 1,1′-dimethyl-2,2’-bibenzimidazole and a singlet state for the planar geometry. All obtained complexes demonstrated, in a solution, the blue fluorescence of the ligand-centered (LC) nature typical for free diimine. In contrast, a temperature decrease to 77 K stabilized the structure close to that observed in the solid state and activated the triplet states, leading to green phosphorescence at ca. 500 nm. The silver-containing complex Ag₄Pz₄L exhibited dual emission from both the singlet and triplet states, even at room temperature. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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25 pages, 8634 KiB

Open AccessArticle

K₂CO₃-Promoted Formal [3+3]-Cycloaddition of N-Unsubstituted Isatin N,N′-Cyclic Azomethine Imine 1,3-Dipoles with Knoevenagel Adducts

by Guosheng Yang, Sicheng Li, Qiumi Wang, Huabao Chen, Chunping Yang, Zhongqiong Yin, Xu Song, Li Zhang, Cuifen Lu and Guizhou Yue

Molecules 2023, 28(3), 1034; https://doi.org/10.3390/molecules28031034 - 19 Jan 2023

Cited by 1 | Viewed by 1358

Abstract

The synthesis of dicyclic spiropyridazine oxoindole derivatives by using [3+3]-cycloaddition of N-unsubstituted isatin N,N′-cyclic azomethine imine 1,3-dipoles was reported. The products bearing two consecutive stereocenters, including spiroquaternary stereocenters in one ring structure, can be effectively obtained in moderate to [...] Read more.

The synthesis of dicyclic spiropyridazine oxoindole derivatives by using [3+3]-cycloaddition of N-unsubstituted isatin N,N′-cyclic azomethine imine 1,3-dipoles was reported. The products bearing two consecutive stereocenters, including spiroquaternary stereocenters in one ring structure, can be effectively obtained in moderate to excellent yields (20–93%) and low to moderate diastereoselectivities (1:9–10:1 dr). The synthesized compounds (>35 examples) were characterized by single-crystal XRD, FTIR, NMR, and mass spectral analysis. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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15 pages, 1967 KiB

Open AccessArticle

Directed Lithiation of Protected 4-Chloropyrrolopyrimidine: Addition to Aldehydes and Ketones Aided by Bis(2-dimethylaminoethyl)ether

by Frithjof Bjørnstad, Eirik Sundby and Bård Helge Hoff

Molecules 2023, 28(3), 932; https://doi.org/10.3390/molecules28030932 - 17 Jan 2023

Cited by 1 | Viewed by 1389

Abstract

Pyrrolopyrimidines are important scaffolds for the preparation of bioactive molecules. Therefore, developing efficient and flexible ways for selective functionalization of the pyrrolopyrimidine skeleton is of interest. We have investigated lithiation-addition at C-6 of protected 4-chloro-7H-pyrrolo [2,3-d]pyrimidine as a route [...] Read more.

Pyrrolopyrimidines are important scaffolds for the preparation of bioactive molecules. Therefore, developing efficient and flexible ways for selective functionalization of the pyrrolopyrimidine skeleton is of interest. We have investigated lithiation-addition at C-6 of protected 4-chloro-7H-pyrrolo [2,3-d]pyrimidine as a route to new building blocks for medicinal chemistry. It was found that bis(2-dimethylaminoethyl) ether as an additive increased the yield in the additional reaction with benzaldehyde. Deuterium oxide quench experiments showed that this additive offered both a higher degree of lithiation and increased stability of the lithiated intermediate. The substrate scope of the protocol was investigated with 16 aldehydes and ketones, revealing the method to be excellently suited for reaction with aldehydes, cyclohexanone derivatives and 2,2,2-trifluoroacetophenone, while being less efficient for acetophenones. Yields in the range of 46–93% were obtained. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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14 pages, 2513 KiB

Open AccessArticle

Natural Product-Oriented Photo-Induced Denitrogenative Annulations of 1-Alkenylbenzotriazoles

by Zhiguo Wang, Yi Chen, Zhen Dong and Yefeng Tang

Molecules 2023, 28(1), 363; https://doi.org/10.3390/molecules28010363 - 02 Jan 2023

Cited by 1 | Viewed by 1612

Abstract

The photo-induced denitrogenative annulations of a variety of 1-alkenylbenzotriazoles were investigated. By judiciously manipulating the structural variations of 1-alkenylbenzotriazoles, two characteristic polycyclic skeletons associated with monoterpene indole alkaloids were constructed through a diverted and controllable manner. The present work not only enriches the [...] Read more.

The photo-induced denitrogenative annulations of a variety of 1-alkenylbenzotriazoles were investigated. By judiciously manipulating the structural variations of 1-alkenylbenzotriazoles, two characteristic polycyclic skeletons associated with monoterpene indole alkaloids were constructed through a diverted and controllable manner. The present work not only enriches the photochemistry of 1-alkenylbenzotriazoles, but also offers a unified approach to access skeletally diverse indole alkaloid scaffolds. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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18 pages, 7344 KiB

Open AccessArticle

5-Chloroisoxazoles: A Versatile Starting Material for the Preparation of Amides, Anhydrides, Esters, and Thioesters of 2H-Azirine-2-carboxylic Acids

by Anastasiya V. Agafonova, Mikhail S. Novikov and Alexander F. Khlebnikov

Molecules 2023, 28(1), 275; https://doi.org/10.3390/molecules28010275 - 29 Dec 2022

Cited by 1 | Viewed by 1010

Abstract

Amides, anhydrides, esters, and thioesters of 2H-azirine-2-carboxylic acids were prepared by a rapid procedure at room temperature involving FeCl₂-catalyzed isomerization of 5-chloroisoxazoles to 2H-azirine-2-carbonyl chlorides, followed by reaction with N-, O-, or S-nucleophiles mediated by an ortho [...] Read more.

Amides, anhydrides, esters, and thioesters of 2H-azirine-2-carboxylic acids were prepared by a rapid procedure at room temperature involving FeCl₂-catalyzed isomerization of 5-chloroisoxazoles to 2H-azirine-2-carbonyl chlorides, followed by reaction with N-, O-, or S-nucleophiles mediated by an ortho-substituted pyridine. With readily available chloroisoxazoles and a nucleophile, 2-picoline can be used as an inexpensive base. When a high yield of the acylation product is important, the reagent 2-(trimethylsilyl)pyridine/ethyl chloroformate is more suitable for the acylation with 2H-azirine-2-carbonyl chlorides. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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12 pages, 1891 KiB

Open AccessArticle

N,N′-Di-Boc-2H-Isoindole-2-carboxamidine—First Guanidine-Substituted Isoindole

by Petar Štrbac, Anamarija Briš and Davor Margetić

Molecules 2022, 27(24), 8954; https://doi.org/10.3390/molecules27248954 - 15 Dec 2022

Viewed by 1386

Abstract

Synthesis of N,N′-Di-Boc-2H-isoindole-2-carboxamidine, the first representative of isoindoles containing guanidine functionality, was carried out. The cycloaddition reactivity of this new Diels–Alder heterodiene was studied and the title compound was employed as a cycloaddition delivery reagent for guanidine functionality. Higher reactivity was found [...] Read more.

Synthesis of N,N′-Di-Boc-2H-isoindole-2-carboxamidine, the first representative of isoindoles containing guanidine functionality, was carried out. The cycloaddition reactivity of this new Diels–Alder heterodiene was studied and the title compound was employed as a cycloaddition delivery reagent for guanidine functionality. Higher reactivity was found in comparison with the corresponding pyrrole derivative. Substitution with fluorine or guanidine functionality does not change the reactivities of isoindoles, and these findings are in good accord with computational results. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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28 pages, 4550 KiB

Open AccessArticle

Design, Synthesis and Assay of Novel Methylxanthine–Alkynylmethylamine Derivatives as Acetylcholinesterase Inhibitors

by Danila V. Reshetnikov, Igor D. Ivanov, Dmitry S. Baev, Tatyana V. Rybalova, Evgenii S. Mozhaitsev, Sergey S. Patrushev, Valentin A. Vavilin, Tatyana G. Tolstikova and Elvira E. Shults

Molecules 2022, 27(24), 8787; https://doi.org/10.3390/molecules27248787 - 11 Dec 2022

Cited by 3 | Viewed by 1547

Abstract

Xanthine derivatives have been a great area of interest for the development of potent bioactive agents. Thirty-eight methylxanthine derivatives as acetylcholinesterase inhibitors (AChE) were designed and synthesized. Suzuki–Miyaura cross-coupling reactions of 8-chlorocaffeine with aryl(hetaryl)boronic acids, the CuAAC reaction of 8-ethynylcaffeine with several azides, [...] Read more.

Xanthine derivatives have been a great area of interest for the development of potent bioactive agents. Thirty-eight methylxanthine derivatives as acetylcholinesterase inhibitors (AChE) were designed and synthesized. Suzuki–Miyaura cross-coupling reactions of 8-chlorocaffeine with aryl(hetaryl)boronic acids, the CuAAC reaction of 8-ethynylcaffeine with several azides, and the copper(I) catalyzed one-pot three-component reaction (A³-coupling) of 8-ethynylcaffeine, 1-(prop-2-ynyl)-, or 7-(prop-2-ynyl)-dimethylxanthines with formaldehyde and secondary amines were the main approaches for the synthesis of substituted methylxanthine derivatives (yield 53–96%). The bioactivity of all new compounds was evaluated by Ellman’s method, and the results showed that most of the synthesized compounds displayed good and moderate acetylcholinesterase (AChE) inhibitory activities in vitro. The structure-activity relationships were also discussed. The data revealed that compounds 53, 59, 65, 66, and 69 exhibited the most potent inhibitory activity against AChE with IC₅₀ of 0.25, 0.552, 0.089, 0.746, and 0.121 μM, respectively. The binding conformation and simultaneous interaction modes were further clarified by molecular docking studies. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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15 pages, 4108 KiB

Open AccessArticle

A Green Approach to 2-Substituted Benzo- and Naphthothiazoles via N-bromosuccinimide/Bromide-Mediated C(aryl)-S Bond Formation

by Ainka T. Brown and Nadale K. Downer-Riley

Molecules 2022, 27(22), 7876; https://doi.org/10.3390/molecules27227876 - 15 Nov 2022

Cited by 1 | Viewed by 1554

Abstract

2-Substituted benzo- and naphthothiazoles have been conveniently prepared from the intramolecular cyclization of phenylthioureas and activated thiobenzanilides or the coupling of isothiocyanates with amines under mild conditions using N-bromosuccinimide/tetrabutylammonium bromide in 1,2-dimethoxyethane (DME) under ambient conditions. The reactions produce moderate to excellent [...] Read more.

2-Substituted benzo- and naphthothiazoles have been conveniently prepared from the intramolecular cyclization of phenylthioureas and activated thiobenzanilides or the coupling of isothiocyanates with amines under mild conditions using N-bromosuccinimide/tetrabutylammonium bromide in 1,2-dimethoxyethane (DME) under ambient conditions. The reactions produce moderate to excellent yields with good functional group tolerance and avoid the use of harsh thermal conditions, corrosive reagents, halogenated solvents, toxic metal salts, and expensive metal catalysts, and are amenable to preparations on a gram-scale. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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13 pages, 2049 KiB

Open AccessArticle

SNH Amidation of 5-Nitroisoquinoline: Access to Nitro- and Nitroso Derivatives of Amides and Ureas on the Basis of Isoquinoline

by Elena K. Avakyan, Anastasia A. Borovleva, Diana Yu. Pobedinskaya, Oleg P. Demidov, Artem P. Ermolenko, Alexander N. Larin and Ivan V. Borovlev

Molecules 2022, 27(22), 7862; https://doi.org/10.3390/molecules27227862 - 14 Nov 2022

Viewed by 1244

Abstract

For the first time, amides and ureas based on both 5-nitroisoquinoline and 5-nitrosoisoquinoline were obtained by direct nucleophilic substitution of hydrogen in the 5-nitroisoquinoline molecule. In the case of urea and monosubstituted ureas, only 5-nitrosoisoquinoline-6-amine is formed under anhydrous conditions. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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20 pages, 5487 KiB

Open AccessArticle

Synthesis, Self-Assembly in Crystalline Phase and Anti-Tumor Activity of 2-(2-/4-Hydroxybenzylidene)thiazolo[3,2-a]pyrimidines

by Artem S. Agarkov, Anna A. Nefedova, Elina R. Gabitova, Alexander S. Ovsyannikov, Syumbelya K. Amerhanova, Anna P. Lyubina, Alexandra D. Voloshina, Pavel V. Dorovatovskii, Igor A. Litvinov, Svetlana E. Solovieva and Igor S. Antipin

Molecules 2022, 27(22), 7747; https://doi.org/10.3390/molecules27227747 - 10 Nov 2022

Cited by 2 | Viewed by 1151

Abstract

A series of new thiazolo[3,2-a]pyrimidines different by aryl substituents in 2 and 5 positions are synthesized and characterized in solution as well as in the crystalline phase using ¹H and ¹³C NMR-, IR-spectroscopies, mass-spectrometry methods, and single crystal X-ray [...] Read more.

A series of new thiazolo[3,2-a]pyrimidines different by aryl substituents in 2 and 5 positions are synthesized and characterized in solution as well as in the crystalline phase using ¹H and ¹³C NMR-, IR-spectroscopies, mass-spectrometry methods, and single crystal X-ray diffraction (SCXRD). The SCXRD study revealed the role of intermolecular H-bonding in the formation of supramolecular architectures (racemic monomers, centrosymmetric racematic dimers, or homochiral 1D chains) of obtained thiazolo[3,2-a]pyrimidines derivatives depending on solvents (aprotic DMSO or protic EtOH) used upon the crystallization process. Moreover, the in vitro study of cytotoxicity toward different tumor cells showed their high or moderate efficiency with moderate cytotoxicity against normal liver cells which allows to consider the obtained thiazolo[3,2-a]pyrimidine derivatives as promising candidates for application as antitumor agents. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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13 pages, 1641 KiB

Open AccessArticle

Simultaneous Enantiodivergent Synthesis of Diverse Lactones and Lactams via Sequential One-Pot Enzymatic Kinetic Resolution–Ring-Closing Metathesis Reactions

by Anna Brodzka, Dominik Koszelewski and Ryszard Ostaszewski

Molecules 2022, 27(22), 7696; https://doi.org/10.3390/molecules27227696 - 09 Nov 2022

Viewed by 1092

Abstract

One of the goals of diversity-oriented synthesis is to achieve the structural diversity of obtained compounds. As most biologically active compounds are chiral, it is important to develop enantioselective methods of their synthesis. The application of kinetic resolution in DOS is problematic because [...] Read more.

One of the goals of diversity-oriented synthesis is to achieve the structural diversity of obtained compounds. As most biologically active compounds are chiral, it is important to develop enantioselective methods of their synthesis. The application of kinetic resolution in DOS is problematic because of low efficiency (max. 50% yield) and many purification steps. The further derivatization of kinetic resolution products in DOS leads to the formation of a narrow library of compounds of the same stereochemistry. To overcome these limitations, we present a new concept in which the kinetic resolution is combined, the subsequent reaction of which in a one-pot protocol leads to the simultaneous formation of two skeletally and enantiomerically diverse platform molecules for DOS. Their further derivatization can gain access to a double-sized library of products in respect to a classical approach. The validity of our concept was evidenced in enzymatic kinetic resolution followed by a ring-closing metathesis cascade. From racemic carboxylic acid ester, a simultaneous formation of enantiopure lactones and lactams was achieved. These compounds are important building blocks in organic and medicinal chemistry and until now were synthesized in separate procedures. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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15 pages, 2345 KiB

Open AccessArticle

Unusual Formation of 1,2,4-Oxadiazine Core in Reaction of Amidoximes with Maleic or Fumaric Esters

by Sofia I. Presnukhina, Marina V. Tarasenko, Kirill K. Geyl, Svetlana O. Baykova, Sergey V. Baykov, Anton A. Shetnev and Vadim P. Boyarskiy

Molecules 2022, 27(21), 7508; https://doi.org/10.3390/molecules27217508 - 03 Nov 2022

Cited by 2 | Viewed by 1322

Abstract

We have developed a simple and convenient method for the synthesis of 3-aryl- and 3-hetaryl-1,2,4-oxadiazin-5-ones bearing an easily functionalizable (methoxycarbonyl)methyl group at position 6 via the reaction of aryl or hetaryl amidoximes with maleates or fumarates. The conditions for this reaction were optimized. [...] Read more.

We have developed a simple and convenient method for the synthesis of 3-aryl- and 3-hetaryl-1,2,4-oxadiazin-5-ones bearing an easily functionalizable (methoxycarbonyl)methyl group at position 6 via the reaction of aryl or hetaryl amidoximes with maleates or fumarates. The conditions for this reaction were optimized. Different products can be synthesized selectively in good yields depending on the base used and the ratio of reactants: substituted (1,2,4-oxadiazin-6-yl)acetic acids, corresponding methyl esters, or hybrid 3-(aryl)-6-((3-(aryl)-1,2,4-oxadiazol-5-yl)methyl)-4H-1,2,4-oxadiazin-5(6H)-ones. The reaction is tolerant to substituents’ electronic and steric effects in amidoximes. As a result, a series of 2-(5-oxo-3-(p-tolyl)-5,6-dihydro-4H-1,2,4-oxadiazin-6-yl)acetic acids, their methyl esters, and 1,2,4-oxadiazoles based on them were prepared and characterized by HRMS, ¹H, and ¹³C NMR spectroscopy. The structures of three of them were elucidated with X-ray diffraction. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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20 pages, 2448 KiB

Open AccessArticle

In Vitro Anticancer Screening, Molecular Docking and Antimicrobial Studies of Triazole-Based Nickel(II) Metal Complexes

by Sachin A. Deodware, Umesh B. Barache, Pratibha C. Dhale, Kundalkesha D. Gaikwad, Chandan Shivamallu, Panchsheela A. Ubale, Ali A. Shati, Mohammad Y. Alfaifi, Serag Eldin I. Elbehairi, Raghu Ram Achar, Ekaterina Silina, Victor Stupin, Juan Frau, Norma Flores-Holguín, Shashikant H. Gaikwad, Shiva Prasad Kollur and Daniel Glossman-Mitnik

Molecules 2022, 27(19), 6548; https://doi.org/10.3390/molecules27196548 - 03 Oct 2022

Cited by 1 | Viewed by 1851

Abstract

Herein we describe the synthesis of a series of nickel(II) complexes (C1–C3) with Schiff bases (HL1–HL3) derived from 4-amino-5-mercapto-3-methyl-1,2,4-triazole and ortho/meta/para-nitrobenzaldehyde having composition [Ni(L)₂(H₂O)₂]. The obtained ligands and their complexes were characterized using physico-chemical techniques viz., elemental [...] Read more.

Herein we describe the synthesis of a series of nickel(II) complexes (C1–C3) with Schiff bases (HL1–HL3) derived from 4-amino-5-mercapto-3-methyl-1,2,4-triazole and ortho/meta/para-nitrobenzaldehyde having composition [Ni(L)₂(H₂O)₂]. The obtained ligands and their complexes were characterized using physico-chemical techniques viz., elemental analysis, magnetic moment study, spectral (electronic, FT-IR, 1H-NMR) and thermal analysis. The elemental analysis and spectral analysis revealed that Schiff bases behave as monoanionic bidentate ligands towards the Ni(II) ion. Whereas, the magnetic moment study suggested the octahedral geometry of all the Ni(II) complexes. The thermal behavior of the complexes has been studied by thermogravimetric analysis and agrees well with the composition of complexes. Further, the biological activities such as antimicrobial and antifungal studies of the Schiff bases and Ni(II) complexes have been screened against bacterial species (Staphylococcus aureus and Pseudomonas aeruginosa) and fungal species (Aspergillus niger and Candida albicans) activity by MIC method, the results of which revealed that metal complexes exhibited significant antimicrobial activities than their respective ligands against the tested microbial species. Furthermore, the molecular docking technique was employed to investigate the active sites of the selected protein, which indeed helped us to screen the potential anticancer agents among the synthesized ligand and complexes. Further, these compounds have been screened for their in vitro anticancer activity using OVCAR-3 cell line. The results revealed that the complexes are more active than the ligands. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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14 pages, 1521 KiB

Open AccessArticle

Antiprotozoal Activity of Azabicyclo-Nonanes Linked to Tetrazole or Sulfonamide Cores

by Johanna Dolensky, Clemens Hinteregger, Andreas Leitner, Werner Seebacher, Robert Saf, Ferdinand Belaj, Pascal Mäser, Marcel Kaiser and Robert Weis

Molecules 2022, 27(19), 6217; https://doi.org/10.3390/molecules27196217 - 21 Sep 2022

Cited by 4 | Viewed by 1034

Abstract

N-(Aminoalkyl)azabicyclo[3.2.2]nonanes possess antiplasmodial and antitrypanosomal activity. A series with terminal tetrazole or sulfonamido partial structure was prepared. The structures of all new compounds were confirmed by NMR and IR spectroscopy and by mass spectral data. A single crystal structure analysis enabled the [...] Read more.

N-(Aminoalkyl)azabicyclo[3.2.2]nonanes possess antiplasmodial and antitrypanosomal activity. A series with terminal tetrazole or sulfonamido partial structure was prepared. The structures of all new compounds were confirmed by NMR and IR spectroscopy and by mass spectral data. A single crystal structure analysis enabled the distinction between isomers. The antiprotozoal activities were examined in vitro against strains of Plasmodium falciparum and Trypanosoma brucei rhodesiense (STIB 900). The most active sulfonamide and tetrazole derivates showed activities in the submicromolar range. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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14 pages, 1611 KiB

Open AccessArticle

Cycloaddition of 4-Acyl-1H-pyrrole-2,3-diones Fused at [e]-Side and Cyanamides: Divergent Approach to 4H-1,3-Oxazines

by Ekaterina E. Khramtsova, Aleksandr D. Krainov, Maksim V. Dmitriev and Andrey N. Maslivets

Molecules 2022, 27(16), 5257; https://doi.org/10.3390/molecules27165257 - 17 Aug 2022

Viewed by 1463

Abstract

4-Acyl-1H-pyrrole-2,3-diones fused at [e]-side with a heterocyclic moiety are suitable platforms for the development of a hetero-Diels–Alder-reaction-based, diversity-oriented approaches to series of skeletally diverse heterocycles. These platforms are known to react as oxa-dienes with dienophiles to form angular 6/6/5/6-tetracyclic [...] Read more.

4-Acyl-1H-pyrrole-2,3-diones fused at [e]-side with a heterocyclic moiety are suitable platforms for the development of a hetero-Diels–Alder-reaction-based, diversity-oriented approaches to series of skeletally diverse heterocycles. These platforms are known to react as oxa-dienes with dienophiles to form angular 6/6/5/6-tetracyclic alkaloid-like heterocycles and are also prone to decarbonylation at high temperatures resulting in generation of acyl(imidoyl)ketenes, bidentate aza- and oxa-dienes, which can react with dienophiles to form skeletally diverse products (angular tricyclic products or heterocyclic ensembles). Based on these features, we have developed an approach to two series of skeletally diverse 4H-1,3-oxazines (tetracyclic alkaloid-like 4H-1,3-oxazines and 5-heteryl-4H-1,3-oxazines) via a hetero-Diels–Alder reaction of 4-acyl-1H-pyrrole-2,3-diones fused at [e]-side with cyanamides. The products of these transformations are of interest for drug discovery, since compounds bearing 4H-1,3-oxazine moiety are extensively studied for inhibitory activities against anticancer targets. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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14 pages, 3944 KiB

Open AccessArticle

Synthesis of Functionalized Azepines via Cu(I)-Catalyzed Tandem Amination/Cyclization Reaction of Fluorinated Allenynes

by Anna N. Philippova, Daria V. Vorobyeva, Pavel S. Gribanov, Ivan A. Godovikov and Sergey N. Osipov

Molecules 2022, 27(16), 5195; https://doi.org/10.3390/molecules27165195 - 15 Aug 2022

Cited by 4 | Viewed by 1605

Abstract

An efficient method for the selective preparation of trifluoromethyl-substituted azepin-2-carboxylates and their phosphorous analogues has been developed via Cu(I)-catalyzed tandem amination/cyclization reaction of functionalized allenynes with primary and secondary amines. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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17 pages, 3375 KiB

Open AccessArticle

First Example of Fluorinated Phenanthroline Diamides: Synthesis, Structural Study, and Complexation with Lanthanoids

by Nane A. Avagyan, Pavel S. Lemport, Konstantin A. Lysenko, Alexey O. Gudovannyy, Vitaly A. Roznyatovsky, Valentine S. Petrov, Mikhail F. Vokuev, Yuri A. Ustynyuk and Valentine G. Nenajdenko

Molecules 2022, 27(15), 4705; https://doi.org/10.3390/molecules27154705 - 23 Jul 2022

Cited by 9 | Viewed by 1655

Abstract

An efficient approach to the synthesis of diamides of 4,7-difluoro-1,10-phenanthroline-2,9-dicarboxylic acid was elaborated. Direct nucleophilic substitution with 4,7-dichloro-1,10-phenanthroline precursors opened access to difluoro derivatives in high yield. As a result, four new fluorinated ligands were prepared in up to 88% yield. Their structure [...] Read more.

An efficient approach to the synthesis of diamides of 4,7-difluoro-1,10-phenanthroline-2,9-dicarboxylic acid was elaborated. Direct nucleophilic substitution with 4,7-dichloro-1,10-phenanthroline precursors opened access to difluoro derivatives in high yield. As a result, four new fluorinated ligands were prepared in up to 88% yield. Their structure was proved by a combination of spectral methods and X-ray data. A set of lanthanoid complexes was prepared to demonstrate the utility of new ligands. The structure of the complexes was studied in solid state (IR-spectroscopy, X-ray diffraction) and in solution (NMR-spectroscopy). Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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22 pages, 6332 KiB

Open AccessArticle

4,5-Bis(arylethynyl)-1,2,3-triazoles—A New Class of Fluorescent Labels: Synthesis and Applications

by Anastasia I. Govdi, Polina V. Tokareva, Andrey M. Rumyantsev, Maxim S. Panov, Johannes Stellmacher, Ulrike Alexiev, Natalia A. Danilkina and Irina A. Balova

Molecules 2022, 27(10), 3191; https://doi.org/10.3390/molecules27103191 - 17 May 2022

Cited by 7 | Viewed by 1777

Abstract

Cu-catalyzed 1,3-dipolar cycloaddition of ethyl 2-azidoacetate to iodobuta-1,3-diynes and subsequent Sonogashira cross-coupling were used to synthesize a large series of new triazole-based push–pull chromophores: 4,5-bis(arylethynyl)-1H-1,2,3-triazoles. The study of their optical properties revealed that all molecules have fluorescence properties, the Stokes shift [...] Read more.

Cu-catalyzed 1,3-dipolar cycloaddition of ethyl 2-azidoacetate to iodobuta-1,3-diynes and subsequent Sonogashira cross-coupling were used to synthesize a large series of new triazole-based push–pull chromophores: 4,5-bis(arylethynyl)-1H-1,2,3-triazoles. The study of their optical properties revealed that all molecules have fluorescence properties, the Stokes shift values of which exceed 150 nm. The fluorescent properties of triazoles are easily adjustable depending on the nature of the substituents attached to aryl rings of the arylethynyl moieties at the C4 and C5 atoms of the triazole core. The possibility of 4,5-bis(arylethynyl)-1,2,3-triazoles’ application for labeling was demonstrated using proteins and the HEK293 cell line. The results of an MTT test on two distinct cell lines, HEK293 and HeLa, revealed the low cytotoxicity of 4,5-bis(arylethynyl)triazoles, which makes them promising fluorescent tags for labeling and tracking biomolecules. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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Review

Jump to: Research

47 pages, 18460 KiB

Open AccessReview

Preparation and Synthetic Applications of Five-to-Seven-Membered Cyclic α-Diazo Monocarbonyl Compounds

by Daniil Zhukovsky, Dmitry Dar’in, Olga Bakulina and Mikhail Krasavin

Molecules 2022, 27(6), 2030; https://doi.org/10.3390/molecules27062030 - 21 Mar 2022

Cited by 2 | Viewed by 2592

Abstract

The reactivity of cyclic α-diazo monocarbonyl compounds differs from that of their acyclic counterparts. In this review, we summarize the current literature available on the synthesis and synthetic applications of three major classes of cyclic α-diazo monocarbonyl compounds: α-diazo ketones, α-diazo lactones and [...] Read more.

The reactivity of cyclic α-diazo monocarbonyl compounds differs from that of their acyclic counterparts. In this review, we summarize the current literature available on the synthesis and synthetic applications of three major classes of cyclic α-diazo monocarbonyl compounds: α-diazo ketones, α-diazo lactones and α-diazo lactams. Full article

(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)

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