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22 pages, 10199 KiB

Open AccessArticle

Novel Benzimidazole-Endowed Chalcones as α-Glucosidase and α-Amylase Inhibitors: An Insight into Structural and Computational Studies

by Prashasthi V. Rai, Ramith Ramu, P. Akhileshwari, Sudharshan Prabhu, Nupura Manish Prabhune, P. V. Deepthi, P. T. Anjana, D. Ganavi, A. M. Vijesh, Khang Wen Goh, Mohammad Z. Ahmed and Vasantha Kumar

Molecules 2024, 29(23), 5599; https://doi.org/10.3390/molecules29235599 - 27 Nov 2024

Cited by 2 | Viewed by 1719

Abstract

In search of novel antidiabetic agents, we synthesized a new series of chalcones with benzimidazole scaffolds by an efficient ‘one-pot’ nitro reductive cyclization method and evaluated their α-glucosidase and α-amylase inhibition studies. The ‘one-pot’ nitro reductive cyclization method offered a simple route for [...] Read more.

In search of novel antidiabetic agents, we synthesized a new series of chalcones with benzimidazole scaffolds by an efficient ‘one-pot’ nitro reductive cyclization method and evaluated their α-glucosidase and α-amylase inhibition studies. The ‘one-pot’ nitro reductive cyclization method offered a simple route for the preparation of benzimidazoles with excellent yield and higher purity compared to the other conventional acid- or base-catalyzed cyclization methods. ¹H, ¹³C NMR, IR, and mass spectrum data were used to characterize the compounds. Single-crystal XRD data confirmed the 3D structure of compound 7c, which was crystalized in the P

\bar{1}

space group of the triclinic crystal system. Hirshfeld surface analysis validates the presence of O-H..O, O-H…N, and C-H…O intermolecular hydrogen bonds. From the DFT calculations, the energy gap between the frontier molecular orbitals in 7c was found to be 3.791 eV. From the series, compound 7l emerged as a potent antidiabetic agent with IC₅₀ = 22.45 ± 0.36 µg/mL and 20.47 ± 0.60 µg/mL against α-glucosidase and α-amylase enzymes, respectively. The in silico molecular docking studies revealed that compound 7l has strong binding interactions with α-glucosidase and α-amylase proteins. Molecular dynamics studies also revealed the stability of compound 7l with α-glucosidase and α-amylase proteins. Full article

(This article belongs to the Section Medicinal Chemistry)

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10 pages, 2854 KiB

Open AccessPerspective

Phenyl Formate as a CO Surrogate for the Reductive Cyclization of Organic Nitro Compounds to Yield Different N-Heterocycles: No Need for Autoclaves and Pressurized Carbon Monoxide

by Fabio Ragaini, Francesco Ferretti and Manar Ahmed Fouad

Catalysts 2023, 13(2), 224; https://doi.org/10.3390/catal13020224 - 18 Jan 2023

Cited by 4 | Viewed by 2372

Abstract

The reductive cyclization of different organic nitro compounds by carbon monoxide, catalyzed by transition metal complexes, is a very efficient and clean strategy for the synthesis of many N-heterocycles. However, its use requires the use of autoclaves and pressurized CO lines. In [...] Read more.

The reductive cyclization of different organic nitro compounds by carbon monoxide, catalyzed by transition metal complexes, is a very efficient and clean strategy for the synthesis of many N-heterocycles. However, its use requires the use of autoclaves and pressurized CO lines. In this perspective, the authors will present the results obtained in their laboratories on the use of phenyl formate as a convenient CO surrogate, able to liberate carbon monoxide under the reaction conditions and allowing the use of a cheap glass pressure tube as a reaction vessel. In most cases, yields were better than those previously reported by the use of pressurized CO, proving that the use of CO surrogates can be a viable alternative to the gaseous reagent. Full article

(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members (EBMs) of Catalysts)

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7 pages, 1211 KiB

Open AccessProceeding Paper

Use of Phenyl Formate as a CO Surrogate for the Reductive Cyclization of Organic Nitro Compounds to Yield Different N-Heterocycles: Avoiding the Use of Autoclaves and Pressurized Gases

by Fabio Ragaini, Francesco Ferretti and Manar Ahmed Fouad

Chem. Proc. 2022, 12(1), 85; https://doi.org/10.3390/ecsoc-26-13711 - 18 Nov 2022

Viewed by 1577

Abstract

The reductive cyclization of different organic nitro compounds by carbon monoxide, catalyzed by transition metal complexes, is a very efficient and clean strategy for the synthesis of many N-heterocycles. However, it requires the use of autoclaves and pressurized CO lines. In this [...] Read more.

The reductive cyclization of different organic nitro compounds by carbon monoxide, catalyzed by transition metal complexes, is a very efficient and clean strategy for the synthesis of many N-heterocycles. However, it requires the use of autoclaves and pressurized CO lines. In this paper, the authors will present the results obtained in their laboratories on the use of phenyl formate as a convenient CO surrogate, able to liberate carbon monoxide under reaction conditions and allowing for the use of a cheap glass pressure tube as a reaction vessel. In most cases, yields were better than those previously reported using pressurized CO, proving that the use of CO surrogates can be a viable alternative to the gaseous reagent. Full article

(This article belongs to the Proceedings of The 26th International Electronic Conference on Synthetic Organic Chemistry)

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13 pages, 2355 KiB

Open AccessArticle

Decoration of A-Ring of a Lupane-Type Triterpenoid with Different Oxygen and Nitrogen Heterocycles

by Joana L. C. Sousa, Hélio M. T. Albuquerque, Armando J. D. Silvestre and Artur M. S. Silva

Molecules 2022, 27(15), 4904; https://doi.org/10.3390/molecules27154904 - 31 Jul 2022

Cited by 1 | Viewed by 2172

Abstract

Betulinic acid (BA) was used as starting building block to create a library of novel BA-derived compounds containing O- and N-heterocycles. Firstly, BA was converted into methyl betulonate (BoOMe), which was used as intermediate in the developed methodologies. 1,2-Oxazine-fused BoOMe compounds [...] Read more.

Betulinic acid (BA) was used as starting building block to create a library of novel BA-derived compounds containing O- and N-heterocycles. Firstly, BA was converted into methyl betulonate (BoOMe), which was used as intermediate in the developed methodologies. 1,2-Oxazine-fused BoOMe compounds were obtained in 12–25% global yields through a Michael addition of nitromethane to methyl (E)-2-benzylidenebetulonate derivatives, followed by nitro group reduction and intramolecular cyclization. Remarkably, the triterpene acts as a diastereoselective inducer in the conjugate addition of nitromethane, originating only one diastereomer out of four possible ones. Furthermore, other oxygen and nitrogen-containing heterocycles were installed at the A-ring of BoOMe, affording 2-amino-3-cyano-4H-pyran-fused BoOMe, diarylpyridine-fused BoOMe and 1,2,3-triazole–BoOMe compounds, using simple and straightforward synthetic methodologies. Finally, BA was revealed to be a versatile starting material, allowing the creation of a molecular diversification of compounds containing a triterpenic scaffold and O- and N-heterocycles. Full article

(This article belongs to the Special Issue Steroidal and Triterpenoid Compounds: Natural Sources, Bioactivities and Applications)

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15 pages, 9503 KiB

Open AccessFeature PaperArticle

Synthesis of Indoles by Palladium-Catalyzed Reductive Cyclization of β-Nitrostyrenes with Phenyl Formate as a CO Surrogate

by Francesco Ferretti, Manar Ahmed Fouad and Fabio Ragaini

Catalysts 2022, 12(1), 106; https://doi.org/10.3390/catal12010106 - 17 Jan 2022

Cited by 8 | Viewed by 3688

Abstract

The reductive cyclization of suitably substituted organic nitro compounds by carbon monoxide is a very appealing technique for the synthesis of heterocycles because of its atom efficiency and easiness of separation of the only stoichiometric byproduct CO₂, but the need for [...] Read more.

The reductive cyclization of suitably substituted organic nitro compounds by carbon monoxide is a very appealing technique for the synthesis of heterocycles because of its atom efficiency and easiness of separation of the only stoichiometric byproduct CO₂, but the need for pressurized CO has hampered its diffusion. We have recently reported on the synthesis of indoles by reductive cyclization of o-nitrostyrenes using phenyl formate as a CO surrogate, using a palladium/1,10-phenanthroline complex as catalyst. However, depending on the desired substituents on the structure, the use of β-nitrostyrenes as alternative reagents may be advantageous. We report here the results of our study on the possibility to use phenyl formate as a CO surrogate in the synthesis of indoles by reductive cyclization of β-nitrostyrenes, using PdCl₂(CH₃CN)₂ + phenanthroline as the catalyst. It turned out that good results can be obtained when the starting nitrostyrene bears an aryl substituent in the alpha position. However, when no such substituent is present, only fair yield of indole can be obtained because the base required to decompose the formate also catalyzes an oligo-polymerization of the starting styrene. The reaction can be performed in a single glass pressure tube, a cheap and easily available piece of equipment. Full article

(This article belongs to the Special Issue 10th Anniversary of Catalysts: Molecular Catalysis)

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21 pages, 4412 KiB

Open AccessArticle

An Efficient Approach to 2-CF₃-Indoles Based on ortho-Nitrobenzaldehydes

by Vasiliy M. Muzalevskiy, Zoia A. Sizova, Vladimir T. Abaev and Valentine G. Nenajdenko

Molecules 2021, 26(23), 7365; https://doi.org/10.3390/molecules26237365 - 4 Dec 2021

Cited by 7 | Viewed by 2873

Abstract

The catalytic olefination reaction of 2-nitrobenzaldehydes with CF₃CCl₃ afforded stereoselectively trifluoromethylated ortho-nitrostyrenes in up to 88% yield. The reaction of these alkenes with pyrrolidine permits preparation of α-CF₃-β-(2-nitroaryl) enamines. Subsequent one pot reduction of nitro-group by Fe-AcOH-H [...] Read more.

The catalytic olefination reaction of 2-nitrobenzaldehydes with CF₃CCl₃ afforded stereoselectively trifluoromethylated ortho-nitrostyrenes in up to 88% yield. The reaction of these alkenes with pyrrolidine permits preparation of α-CF₃-β-(2-nitroaryl) enamines. Subsequent one pot reduction of nitro-group by Fe-AcOH-H₂O system initiated intramolecular cyclization to afford 2-CF₃-indoles. Target products can be prepared in up to 85% yields. Broad synthetic scope of the reaction was shown as well as some followed up transformations of 2- CF₃-indole. Full article

(This article belongs to the Special Issue Advances in Organic Synthesis: A Theme Issue in Honor of Professor Mieczysław Mąkosza)

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15 pages, 1511 KiB

Open AccessArticle

An Efficient Synthesis of 2-CF₃-3-Benzylindoles

by Vasiliy M. Muzalevskiy, Zoia A. Sizova and Valentine G. Nenajdenko

Molecules 2021, 26(16), 5084; https://doi.org/10.3390/molecules26165084 - 22 Aug 2021

Cited by 6 | Viewed by 3090

Abstract

The reaction of α-CF₃-β-(2-nitroaryl) enamines with benzaldehydes afforded effectively α,β-diaryl-CF₃-enones having nitro group. Subsequent reduction of nitro group by NH₄HCO₂-Pd/C system initiated intramolecular cyclization to give 2-CF₃-3-benzylindoles. Target products can be prepared in [...] Read more.

The reaction of α-CF₃-β-(2-nitroaryl) enamines with benzaldehydes afforded effectively α,β-diaryl-CF₃-enones having nitro group. Subsequent reduction of nitro group by NH₄HCO₂-Pd/C system initiated intramolecular cyclization to give 2-CF₃-3-benzylindoles. Target products can be prepared in up to quantitative yields. Broad synthetic scope of the reaction was shown. Probable mechanism of indole formation is proposed. Full article

(This article belongs to the Special Issue The Chemistry of Nitrocompounds)

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19 pages, 10622 KiB

Open AccessArticle

One-Pot Synthesis of Novel Multisubstituted 1-Alkoxyindoles

by Ye Eun Kim, Hyunsung Cho, Yoo Jin Lim, Chorong Kim and Sang Hyup Lee

Molecules 2021, 26(5), 1466; https://doi.org/10.3390/molecules26051466 - 8 Mar 2021

Cited by 4 | Viewed by 2794

Abstract

Studies on a one-pot synthesis of novel multisubstituted 1-alkoxyindoles 1 and their mechanistic investigations are presented. The synthesis of 1 was successfully achieved through consecutive four step reactions from substrates 2. The substrates 2, prepared through a two-step synthetic sequence, underwent [...] Read more.

Studies on a one-pot synthesis of novel multisubstituted 1-alkoxyindoles 1 and their mechanistic investigations are presented. The synthesis of 1 was successfully achieved through consecutive four step reactions from substrates 2. The substrates 2, prepared through a two-step synthetic sequence, underwent three consecutive reactions of nitro reduction, intramolecular condensation, and nucleophilic 1,5-addition to provide the intermediates, 1-hydroxyindoles 8, which then were alkylated in situ with alkyl halide to afford the novel target products 1. We optimized the reaction conditions for 1 focusing on the alkylation step, along with the consideration of formation of intermediates 8. The optimized condition was SnCl₂·2H₂O (3.3 eq) and alcohols (R¹OH, 2.0 eq) for 1–2 h at 40 °C and then, base (10 eq) and alkyl halides (R²Y, 2.0 eq) for 1–4 h at 25–50 °C. Notably, all four step reactions were performed in one-pot to give 1 in good to modest yields. Furthermore, the mechanistic aspects were also discussed regarding the reaction pathways and the formation of side products. The significance lies in development of efficient one-pot reactions and in generation of new 1-alkoxyindoles. Full article

(This article belongs to the Special Issue Indole and Its Bioisosteric Replacements in Medicinal Chemistry)

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7 pages, 1459 KiB

Open AccessShort Note

Ethyl 1-Butyl-2-(2-hydroxy-4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate

by Reshma Sathyanarayana and Boja Poojary

Molbank 2021, 2021(1), M1192; https://doi.org/10.3390/M1192 - 24 Feb 2021

Viewed by 3459

Abstract

Ethyl 4-(butylamino)-3-nitrobenzoate upon “one-pot” nitro-reductive cyclization using sodium dithionite and substituted aldehyde in dimethyl sulphoxide affords ethyl 1-butyl-2-(2-hydroxy-4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate in an 87% yield. The structural characterization was determined by Fourier-transfer infrared spectroscopy (FT-IR), Proton nuclear magnetic resonance (¹H-NMR), [...] Read more.

Ethyl 4-(butylamino)-3-nitrobenzoate upon “one-pot” nitro-reductive cyclization using sodium dithionite and substituted aldehyde in dimethyl sulphoxide affords ethyl 1-butyl-2-(2-hydroxy-4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate in an 87% yield. The structural characterization was determined by Fourier-transfer infrared spectroscopy (FT-IR), Proton nuclear magnetic resonance (¹H-NMR), Carbon-13 nuclear magnetic resonance (¹³C-NMR), mass spectrometry, Ultraviolet-visible(UV-Vis), photoluminescence (PL), thin-film solid emission spectra, cyclic voltammetry (CV) and thermogravimetric (TGA) analysis. Molecular electrostatic potential (MEP) was studied to determine the reactive sites of the molecule. Full article

(This article belongs to the Collection Heterocycle Reactions)

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10 pages, 1423 KiB

Open AccessCommunication

Two Annulated Azaheterocyclic Cores Readily Available from a Single Tetrahydroisoquinolonic Castagnoli–Cushman Precursor

by Elizaveta Karchuganova, Olga Bakulina, Dmitry Dar’in and Mikhail Krasavin

Molecules 2020, 25(9), 2049; https://doi.org/10.3390/molecules25092049 - 28 Apr 2020

Cited by 3 | Viewed by 3189

Abstract

A novel approach to indolo[3,2-c]isoquinoline and dibenzo[c,h][1,6]naphthyridine tetracyclic systems was discovered based on switchable reduction of 2-methoxy-3-(2-nitrophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid prepared via Castagnoli–Cushman reaction. Reduction with ammonium formate resulted in the expected selective transformation of the nitro group (thus [...] Read more.

A novel approach to indolo[3,2-c]isoquinoline and dibenzo[c,h][1,6]naphthyridine tetracyclic systems was discovered based on switchable reduction of 2-methoxy-3-(2-nitrophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid prepared via Castagnoli–Cushman reaction. Reduction with ammonium formate resulted in the expected selective transformation of the nitro group (thus providing access to substituted dibenzo[c,h][1,6]naphthyridine via cyclization and dehydrogenation). However, attempted reduction with sodium sulfide initiated a previously unknown reaction cascade including double reduction, cyclization, and decarboxylation, leading to formation of indolo[3,2-c]isoquinoline polyheterocycle in one synthetic step. Full article

(This article belongs to the Collection Heterocyclic Compounds)

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5 pages, 511 KiB

Open AccessShort Note

2-(3,4-Dimethoxyphenyl)-N-(4-methoxyphenyl)-1-propyl-1H-benzo[d]imidazole-5-carboxamide

by Prakash Bhaskar, Vasantha Kumar, Suresha Kumara Tholappanavara Hanumanthappa and Sowmya Haliwana Banakara Vijaykumar

Molbank 2019, 2019(3), M1079; https://doi.org/10.3390/M1079 - 9 Sep 2019

Cited by 1 | Viewed by 2745

Abstract

2-(3,4-Dimethoxyphenyl)-N-(4-methoxyphenyl)-1-propyl-1H-benzo[d]imidazole-5-carboxamide was synthesized by the ‘one-pot’ reductive cyclization of N-(4-methoxyphenyl)-3-nitro-4-(propylamino)benzamide with 3,4-dimethoxybenzaldehyde, using sodium dithionite as a reductive cyclizing agent using DMSO as a solvent. The structure of newly synthesized compound was elucidated based on IR, ¹H-NMR, ¹³C-NMR, and LC-MS data. Full article

(This article belongs to the Special Issue Molecules from Radical Reactions)

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7 pages, 52 KiB

Open AccessArticle

Synthesis of New Potentially Bioactive Bicyclic 2-Pyridones

by Maxime D. Crozet, Pascal George, Michel P. Crozet and Patrice Vanelle

Molecules 2005, 10(10), 1318-1324; https://doi.org/10.3390/10101318 - 31 Oct 2005

Cited by 13 | Viewed by 9118

Abstract

Three convenient methods of reduction of the nitro group of 5-nitroimidazoles and 5-nitrothiazole that bear a diethylmethylene malonate group in an ortho-like position with respect to the nitro group and cyclization of the resulting amino derivatives are reported. These reactions afforded the target [...] Read more.

Three convenient methods of reduction of the nitro group of 5-nitroimidazoles and 5-nitrothiazole that bear a diethylmethylene malonate group in an ortho-like position with respect to the nitro group and cyclization of the resulting amino derivatives are reported. These reactions afforded the target bicyclic 2-pyridones in good to excellent yields. Full article

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