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13 pages, 1146 KiB

Open AccessArticle

2-Bromopyridines as Versatile Synthons for Heteroarylated 2-Pyridones via Ru(II)-Mediated Domino C–O/C–N/C–C Bond Formation Reactions

by Miha Drev, Helena Brodnik, Uroš Grošelj, Franc Perdih, Jurij Svete, Bogdan Štefane and Franc Požgan

Molecules 2024, 29(18), 4418; https://doi.org/10.3390/molecules29184418 - 17 Sep 2024

Viewed by 329

Abstract

A novel methodology for the synthesis of 2-pyridones bearing a 2-pyridyl group on nitrogen and carbon atoms, starting from 2-bromopyridines, was developed employing a simple Ru(II)–KOPiv–Na₂CO₃ catalytic system. Unsubstituted 2-bromopyridine was successfully converted to the penta-heteroarylated 2-pyridone product using this [...] Read more.

A novel methodology for the synthesis of 2-pyridones bearing a 2-pyridyl group on nitrogen and carbon atoms, starting from 2-bromopyridines, was developed employing a simple Ru(II)–KOPiv–Na₂CO₃ catalytic system. Unsubstituted 2-bromopyridine was successfully converted to the penta-heteroarylated 2-pyridone product using this method. Preliminary mechanistic studies revealed a possible synthetic pathway leading to the multi-heteroarylated 2-pyridone products, involving consecutive oxygen incorporation, a Buchwald–Hartwig-type reaction, and C–H bond activation. Full article

(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)

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17 pages, 3152 KiB

Open AccessArticle

Synthesis of Benzofuran Derivatives via a DMAP-Mediated Tandem Cyclization Reaction Involving ortho-Hydroxy α-Aminosulfones

by Rong-Rong Zhu, Xi-Qiang Hou and Da-Ming Du

Molecules 2024, 29(16), 3725; https://doi.org/10.3390/molecules29163725 - 6 Aug 2024

Viewed by 563

Abstract

An efficient cascade cyclization strategy was developed to synthesize aminobenzofuran spiroindanone and spirobarbituric acid derivatives utilizing 2-bromo-1,3-indandione, 5-bromo-1,3-dimethylbarbituric acid, and ortho-hydroxy α-aminosulfones as substrates. Under the optimized reaction conditions, the corresponding products were obtained with high efficiency, exceeding 95% and 85% yields [...] Read more.

An efficient cascade cyclization strategy was developed to synthesize aminobenzofuran spiroindanone and spirobarbituric acid derivatives utilizing 2-bromo-1,3-indandione, 5-bromo-1,3-dimethylbarbituric acid, and ortho-hydroxy α-aminosulfones as substrates. Under the optimized reaction conditions, the corresponding products were obtained with high efficiency, exceeding 95% and 85% yields for the respective derivatives. This protocol demonstrates exceptional substrate versatility and robust scalability up to the Gram scale, establishing a stable platform for the synthesis of 3-aminobenzofuran derivative. The successful synthesis paves the way for further biological evaluations with potential implications in scientific research. Full article

(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)

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18 pages, 2492 KiB

Open AccessArticle

Product Selectivity Control in the Brønsted Acid-Mediated Reactions with 2-Alkynylanilines

by Valerio Morlacci, Massimiliano Aschi, Marco Chiarini, Caterina Momoli, Laura Palombi and Antonio Arcadi

Molecules 2024, 29(15), 3693; https://doi.org/10.3390/molecules29153693 - 4 Aug 2024

Viewed by 609

Abstract

Brønsted acid-catalysed/mediated reactions of the 2-alkynylanilines are reported. While metal-catalysed reactions of these valuable building blocks have led to the establishment of robust protocols for the selective, diverse-oriented syntheses of significant heterocyclic derivatives, we here demonstrate the practical advantages of an alternative methodology [...] Read more.

Brønsted acid-catalysed/mediated reactions of the 2-alkynylanilines are reported. While metal-catalysed reactions of these valuable building blocks have led to the establishment of robust protocols for the selective, diverse-oriented syntheses of significant heterocyclic derivatives, we here demonstrate the practical advantages of an alternative methodology under metal-free conditions. Our investigation into the key factors influencing the product selectivity in Brønsted acid-catalysed/mediated reactions of 2-alkynylanilines reveals that different reaction pathways can be directed towards the formation of diverse valuable products by simply choosing appropriate reaction conditions. The origins of chemo- and regioselectivity switching have been explored through Density Functional Theory (DFT) calculations. Full article

(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)

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12 pages, 1476 KiB

Open AccessArticle

Synthesis of Substituted 1,2-Dihydroisoquinolines by Palladium-Catalyzed Cascade Cyclization–Coupling of Trisubstituted Allenamides with Arylboronic Acids

by Masahiro Yoshida, Ryunosuke Imaji and Shinya Shiomi

Molecules 2024, 29(12), 2917; https://doi.org/10.3390/molecules29122917 - 19 Jun 2024

Viewed by 662

Abstract

1,2-Dihydroisoquinolines are important compounds due to their biological and medicinal activities, and numerous approaches to their synthesis have been reported. Recently, we reported a facile synthesis of trisubstituted allenamides via N-acetylation followed by DBU-promoted isomerization, where various substituted allenamides were conveniently synthesized [...] Read more.

1,2-Dihydroisoquinolines are important compounds due to their biological and medicinal activities, and numerous approaches to their synthesis have been reported. Recently, we reported a facile synthesis of trisubstituted allenamides via N-acetylation followed by DBU-promoted isomerization, where various substituted allenamides were conveniently synthesized from readily available propargylamines with high efficiency. In light of this research background, we focused on the utility of this methodology for the synthesis of substituted 1,2-dihydroisoquinolines. In this study, a palladium-catalyzed cascade cyclization–coupling of trisubstituted allenamides containing a bromoaryl moiety with arylboronic acids is described. When N-acetyl diphenyl-substituted trisubstituted allenamide and phenylboronic acid were treated with 10 mol% of Pd(OAc)₂, 20 mol% of P(o-tolyl)₃, and 5 equivalents of NaOH in dioxane/H₂O (4/1) at 80 °C, the reaction proceeded to afford a substituted 1,2-dihydroisoquinoline. The reaction proceeded via intramolecular cyclization, followed by transmetallation with the arylboronic acid of the resulting allylpalladium intermediate. A variety of highly substituted 1,2-dihydroisoquinolines were concisely obtained using this methodology because the allenamides, as reaction substrates, were prepared from readily available propargylamines in one step. Full article

(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)

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17 pages, 2498 KiB

Open AccessArticle

Using Quinolin-4-Ones as Convenient Common Precursors for a Metal-Free Total Synthesis of Both Dubamine and Graveoline Alkaloids and Diverse Structural Analogues

by Rodrigo Abonia, Lorena Cabrera, Diana Arteaga, Daniel Insuasty, Jairo Quiroga, Paola Cuervo and Henry Insuasty

Molecules 2024, 29(9), 1959; https://doi.org/10.3390/molecules29091959 - 25 Apr 2024

Cited by 1 | Viewed by 914

Abstract

The Rutaceae family is one of the most studied plant families due to the large number of alkaloids isolated from them with outstanding biological properties, among them the quinoline-based alkaloids Graveoline 1 and Dubamine 2. The most common methods for the synthesis [...] Read more.

The Rutaceae family is one of the most studied plant families due to the large number of alkaloids isolated from them with outstanding biological properties, among them the quinoline-based alkaloids Graveoline 1 and Dubamine 2. The most common methods for the synthesis of alkaloids 1 and 2 and their derivatives involves cycloaddition reactions or metal-catalyzed coupling processes but with some limitations in scope and functionalization of the quinoline moiety. As a continuation of our current studies on the synthesis and chemical transformation of 2-aminochalcones, we are reporting here an efficient metal-free approach for the total synthesis of alkaloids 1 and 2 along with their analogues with structural diversity, through a two-step sequence involving intramolecular cyclization, oxidation/aromatization, N-methylation and oxidative C-C bond processes, starting from dihydroquinolin-4-ones as common precursors for the construction of the structures of both classes of alkaloids. Full article

(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)

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15 pages, 3371 KiB

Open AccessArticle

Electrochemical Radical Tandem Difluoroethylation/Cyclization of Unsaturated Amides to Access MeCF₂-Featured Indolo/Benzoimidazo [2,1-a]Isoquinolin-6(5H)-ones

by Yunfei Tian, Dongyu Guo, Luping Zheng, Shaolu Yang, Ningning Zhang, Weijun Fu and Zejiang Li

Molecules 2024, 29(5), 973; https://doi.org/10.3390/molecules29050973 - 22 Feb 2024

Viewed by 768

Abstract

A metal-free electrochemical oxidative difluoroethylation of 2-arylbenzimidazoles was accomplished, which provided an efficient strategy for the synthesis of MeCF₂-containing benzo[4,5]imidazo[2,1-a]-isoquinolin-6(5H)-ones. In addition, the method also enabled the efficient construction of various difluoroethylated indolo[2,1-a]isoquinolin-6(5H)-ones. [...] Read more.

A metal-free electrochemical oxidative difluoroethylation of 2-arylbenzimidazoles was accomplished, which provided an efficient strategy for the synthesis of MeCF₂-containing benzo[4,5]imidazo[2,1-a]-isoquinolin-6(5H)-ones. In addition, the method also enabled the efficient construction of various difluoroethylated indolo[2,1-a]isoquinolin-6(5H)-ones. Notably, this electrochemical synthesis protocol proceeded well under mild conditions without metal catalysts or exogenous additives/oxidants added. Full article

(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)

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19 pages, 26194 KiB

Open AccessArticle

Reactivity and Stability of (Hetero)Benzylic Alkenes via the Wittig Olefination Reaction

by Ajmir Khan, Mohammed G. Sarwar and Sher Ali

Molecules 2024, 29(2), 501; https://doi.org/10.3390/molecules29020501 - 19 Jan 2024

Cited by 2 | Viewed by 1210

Abstract

Wittig olefination at hetero-benzylic positions for electron-deficient and electron-rich heterocycles has been studied. The electronic effects of some commonly used protective groups associated with the N-heterocycles were also investigated for alkenes obtained in the context of the widely employed Wittig olefination reaction. [...] Read more.

Wittig olefination at hetero-benzylic positions for electron-deficient and electron-rich heterocycles has been studied. The electronic effects of some commonly used protective groups associated with the N-heterocycles were also investigated for alkenes obtained in the context of the widely employed Wittig olefination reaction. It was observed that hetero-benzylic positions of the pyridine, thiophene and furan derivatives were stable after Wittig olefination. Similarly, electron-withdrawing groups (EWGs) attached to N-heterocycles (indole and pyrrole derivatives) directly enhanced the stability of the benzylic position during and after Wittig olefination, resulting in the formation of stable alkenes. Conversely, electron-donating group (EDG)-associated N-heterocycles boosted the reactivity of benzylic alkene, leading to lower yields or decomposition of the olefination products. Full article

(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)

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15 pages, 3362 KiB

Open AccessArticle

(3+2)-Cycloadditions of Levoglucosenone (LGO) with Fluorinated Nitrile Imines Derived from Trifluoroacetonitrile: An Experimental and Computational Study

by Grzegorz Mlostoń, Katarzyna Urbaniak, Marcin Palusiak, Zbigniew J. Witczak and Ernst-Ulrich Würthwein

Molecules 2023, 28(21), 7348; https://doi.org/10.3390/molecules28217348 - 30 Oct 2023

Cited by 1 | Viewed by 1195

Abstract

The in situ-generated N-aryl nitrile imines derived from trifluoroacetonitrile smoothly undergo (3+2)-cycloadditions onto the enone fragment of the levoglucosenone molecule, yielding the corresponding, five-membered cycloadducts. In contrast to the ‘classic’ C(Ph),N(Ph) nitrile imine, reactions with fluorinated C(CF₃ [...] Read more.

The in situ-generated N-aryl nitrile imines derived from trifluoroacetonitrile smoothly undergo (3+2)-cycloadditions onto the enone fragment of the levoglucosenone molecule, yielding the corresponding, five-membered cycloadducts. In contrast to the ‘classic’ C(Ph),N(Ph) nitrile imine, reactions with fluorinated C(CF₃),N(Ar) analogues lead to stable pyrazolines in a chemo- and stereoselective manner. Based on the result of X-ray single crystal diffraction analysis, their structures were established as exo-cycloadducts with the location of the N-Ar terminus of the 1,3-dipole at the α-position of the enone moiety. The DFT computation demonstrated that the observed reaction pathway results from the strong dominance of kinetic control over thermodynamic control. Full article

(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)

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24 pages, 3811 KiB

Open AccessArticle

Novel Strigolactone Mimics That Modulate Photosynthesis and Biomass Accumulation in Chlorella sorokiniana

by Daria Gabriela Popa, Florentina Georgescu, Florea Dumitrascu, Sergiu Shova, Diana Constantinescu-Aruxandei, Constantin Draghici, Lucian Vladulescu and Florin Oancea

Molecules 2023, 28(20), 7059; https://doi.org/10.3390/molecules28207059 - 12 Oct 2023

Cited by 2 | Viewed by 1310

Abstract

In terrestrial plants, strigolactones act as multifunctional endo- and exo-signals. On microalgae, the strigolactones determine akin effects: induce symbiosis formation with fungi and bacteria and enhance photosynthesis efficiency and accumulation of biomass. This work aims to synthesize and identify strigolactone mimics that promote [...] Read more.

In terrestrial plants, strigolactones act as multifunctional endo- and exo-signals. On microalgae, the strigolactones determine akin effects: induce symbiosis formation with fungi and bacteria and enhance photosynthesis efficiency and accumulation of biomass. This work aims to synthesize and identify strigolactone mimics that promote photosynthesis and biomass accumulation in microalgae with biotechnological potential. Novel strigolactone mimics easily accessible in significant amounts were prepared and fully characterized. The first two novel compounds contain 3,5-disubstituted aryloxy moieties connected to the bioactive furan-2-one ring. In the second group of compounds, a benzothiazole ring is connected directly through the cyclic nitrogen atom to the bioactive furan-2-one ring. The novel strigolactone mimics were tested on Chlorella sorokiniana NIVA-CHL 176. All tested strigolactones increased the accumulation of chlorophyll b in microalgae biomass. The SL-F3 mimic, 3-(4-methyl-5-oxo-2,5-dihydrofuran-2-yl)-3H-benzothiazol-2-one (7), proved the most efficient. This compound, applied at a concentration of 10⁻⁷ M, determined a significant biomass accumulation, higher by more than 15% compared to untreated control, and improved the quantum yield efficiency of photosystem II. SL-F2 mimic, 5-(3,5-dibromophenoxy)-3-methyl-5H-furan-2-one (4), applied at a concentration of 10⁻⁹ M, improved protein production and slightly stimulated biomass accumulation. Potential utilization of the new strigolactone mimics as microalgae biostimulants is discussed. Full article

(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)

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11 pages, 1512 KiB

Open AccessArticle

Synthesis of 4-(Phenylchalcogenyl)tetrazolo[1,5-a]quinolines by Bicyclization of 2-Azidobenzaldehydes with Phenylchalcogenylacetonitrile

by Loana I. Monzon, Nicole C. M. Rocha, Gabriela T. Quadros, Pâmela P. P. Nunes, Roberta Cargnelutti, Raquel G. Jacob, Eder J. Lenardão, Gelson Perin and Daniela Hartwig

Molecules 2023, 28(13), 5036; https://doi.org/10.3390/molecules28135036 - 27 Jun 2023

Cited by 1 | Viewed by 1247

Abstract

A general methodology to access valuable 4-(phenylchalcogenyl)tetrazolo[1,5-a]quinolines was developed by the reaction of 2-azidobenzaldehyde with phenylchalcogenylacetonitriles (sulfur and selenium) in the presence of potassium carbonate (20 mol%) as a catalyst. The reactions were conducted using a mixture of dimethylsulfoxide and water [...] Read more.

A general methodology to access valuable 4-(phenylchalcogenyl)tetrazolo[1,5-a]quinolines was developed by the reaction of 2-azidobenzaldehyde with phenylchalcogenylacetonitriles (sulfur and selenium) in the presence of potassium carbonate (20 mol%) as a catalyst. The reactions were conducted using a mixture of dimethylsulfoxide and water (7:3) as solvent at 80 °C for 4 h. This new methodology presents a good functional group tolerance to electron-deficient and electron-rich substituents, affording a total of twelve different 4-(phenylchalcogenyl)tetrazolo[1,5-a]quinolines selectively in moderate to excellent yields. The structure of the synthesized 4-(phenylselanyl)tetrazolo[1,5-a]quinoline was confirmed by X-ray analysis. Full article

(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)

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Review

Jump to: Research

42 pages, 11760 KiB

Open AccessReview

Synthesis of Nitrogen-Containing Heterocyclic Scaffolds through Sequential Reactions of Aminoalkynes with Carbonyls

by Antonio Arcadi, Valerio Morlacci and Laura Palombi

Molecules 2023, 28(12), 4725; https://doi.org/10.3390/molecules28124725 - 12 Jun 2023

Cited by 4 | Viewed by 1711

Abstract

Sequential reactions of aminoalkynes represent a powerful tool to easily assembly biologically important polyfunctionalized nitrogen heterocyclic scaffolds. Metal catalysis often plays a key role in terms of selectivity, efficiency, atom economy, and green chemistry of these sequential approaches. This review examines the existing [...] Read more.

Sequential reactions of aminoalkynes represent a powerful tool to easily assembly biologically important polyfunctionalized nitrogen heterocyclic scaffolds. Metal catalysis often plays a key role in terms of selectivity, efficiency, atom economy, and green chemistry of these sequential approaches. This review examines the existing literature on the applications of reactions of aminoalkynes with carbonyls, which are emerging for their synthetic potential. Aspects concerning the features of the starting reagents, the catalytic systems, alternative reaction conditions, pathways and possible intermediates are provided. Full article

(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)

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