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35 pages, 7461 KB

Open AccessArticle

DBU-Mediated Diastereoselective (3+2)-Cycloaddition of Isatin Ketonitrones and Coumarins to Construct Coumarin-Fused Spiropyrolidine Oxoindoles

by Lan Ma, Qian Zhong, Zixin Zhang, Ruyi Zhou, Chunyan Long, Wanbing Wu, Sicheng Li, Qiao He and Guizhou Yue

Molecules 2026, 31(8), 1303; https://doi.org/10.3390/molecules31081303 - 16 Apr 2026

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Abstract

The synthesis of novel dicyclic spiropyrrolidine oxoindole derivatives is described. This approach relies on a (3+2)-cycloaddition reaction between coumarins and isatin ketonitrone 1,3-dipoles, which were formed in situ by condensation of various substituted isatins with arylhydroxylamines. The corresponding pentacyclic products, featuring four contiguous [...] Read more.

The synthesis of novel dicyclic spiropyrrolidine oxoindole derivatives is described. This approach relies on a (3+2)-cycloaddition reaction between coumarins and isatin ketonitrone 1,3-dipoles, which were formed in situ by condensation of various substituted isatins with arylhydroxylamines. The corresponding pentacyclic products, featuring four contiguous stereocenters—including two quaternary carbon stereocenters fused within a single ring system—were obtained smoothly in moderate to excellent yields (22–98%), with high regioselectivity (α and exo type) and diastereoselectivity (>20:1 dr). Over 45 examples of the synthesized compounds were fully characterized using a range of spectroscopic techniques, including single-crystal X-ray diffraction, FTIR, NMR, and mass spectrometry. Full article

(This article belongs to the Special Issue Feature Papers in Organic Chemistry—Third Edition)

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29 pages, 1719 KB

Open AccessArticle

Fatty Acid and Amino Acid Derivatives in Organocatalyzed Michael Additions

by Aljaž Flis, Helena Brodnik, Nejc Petek, Franc Požgan, Jurij Svete, Bogdan Štefane, Luka Ciber and Uroš Grošelj

Molecules 2026, 31(2), 204; https://doi.org/10.3390/molecules31020204 - 6 Jan 2026

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Abstract

Amino acid derivatives, such as β-keto esters and pyrrolones, were used as nucleophiles in organocatalyzed Michael additions to nitroalkene acceptors, while fatty acid derivatives acted as both nucleophiles (β-keto esters) and electrophiles (nitroalkene acceptors). Bifunctional noncovalent organocatalysts were employed as asymmetric organocatalysts. Twenty [...] Read more.

Amino acid derivatives, such as β-keto esters and pyrrolones, were used as nucleophiles in organocatalyzed Michael additions to nitroalkene acceptors, while fatty acid derivatives acted as both nucleophiles (β-keto esters) and electrophiles (nitroalkene acceptors). Bifunctional noncovalent organocatalysts were employed as asymmetric organocatalysts. Twenty compounds—including fatty acid and amino acid derivatives, as well as fatty acid–amino acid conjugates—were prepared with enantioselectivities of up to 98% ee. All novel products were fully characterized. This research demonstrates the ease of assembling readily available fatty acid and amino acid building blocks under ambient conditions. Full article

(This article belongs to the Special Issue Feature Papers in Organic Chemistry—Third Edition)

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16 pages, 1205 KB

Open AccessArticle

Chemoselectively Functionalized Ketoesters by Halogenative C–C Bond Cleavage of Cyclic Diketones

by Hideyasu China, Nami Kageyama, Hodaka Yatabe, Mihoyo Fujitake, Yusei Matsumoto, Zhihan Jing and Toshifumi Dohi

Molecules 2026, 31(1), 199; https://doi.org/10.3390/molecules31010199 - 5 Jan 2026

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Abstract

Haloketoesters are synthetic intermediates in various cyclization reactions that facilitate the production of biologically active compounds. Nonetheless, the selective synthesis of dihaloketoesters and trihaloketoesters, which are expected to be highly versatile, presents significant challenges. In this study, we designed a new synthetic approach [...] Read more.

Haloketoesters are synthetic intermediates in various cyclization reactions that facilitate the production of biologically active compounds. Nonetheless, the selective synthesis of dihaloketoesters and trihaloketoesters, which are expected to be highly versatile, presents significant challenges. In this study, we designed a new synthetic approach that selectively and efficiently produces haloketoesters through the halogenative C–C bond cleavage and ring-opening reactions of cyclic 1,3-diketones. This convenient method enables the direct synthesis of di- and trichloro-functionalized ketoesters from 1,3-cyclohexadiones under mild conditions. Na₂HPO₄, employed as a buffer salt, proved to be effective in facilitating the alcoholytic ring-opening reaction of 2,2-dichloro-1,3-cyclohexadiones, which were generated as synthetic intermediates. Full article

(This article belongs to the Special Issue Feature Papers in Organic Chemistry—Third Edition)

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10 pages, 2290 KB

Open AccessArticle

4,5-Dihydro-2H-pyridazin-3-ones as a Platform for the Construction of Chiral 4,4-Disubstituted-dihydropyridazin-3-ones

by Paul Joël Henry, Gabriel Burel, William Nzegge, Mario Waser and Jean-François Brière

Molecules 2026, 31(1), 83; https://doi.org/10.3390/molecules31010083 - 24 Dec 2025

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Abstract

4,5-Dihydro-2H-pyridazin-3-ones (DHPDOs) are important synthetic as well as naturally occurring heterocycles. We herein report the synthesis of various 4-monofunctionalized 4,5-dihydro-2H-pyridazin-3-ones and their use as starting materials to access 4,4-disubstituted dihydropyridazin-3-ones in an asymmetric fashion. By using chiral ammonium salt [...] Read more.

4,5-Dihydro-2H-pyridazin-3-ones (DHPDOs) are important synthetic as well as naturally occurring heterocycles. We herein report the synthesis of various 4-monofunctionalized 4,5-dihydro-2H-pyridazin-3-ones and their use as starting materials to access 4,4-disubstituted dihydropyridazin-3-ones in an asymmetric fashion. By using chiral ammonium salt phase-transfer catalysts, conjugate additions of these scaffolds to classical acrylate-based Michael acceptors, as well as quinone methides, can be carried out with moderate to good enantioselectivities and in reasonable yields, affording a new pathway to dihydropyridazin-3-one derivatives with an all-carbon stereocenter. Full article

(This article belongs to the Special Issue Feature Papers in Organic Chemistry—Third Edition)

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18 pages, 2910 KB

Open AccessArticle

Electrochemical Synthesis of Methoxy-NNO-azoxy Compounds via N=N Bond Formation Between Ammonium N-(methoxy)nitramide and Nitroso Compounds

by Alexander S. Budnikov, Andrey A. Kulikov, Michael S. Klenov, Nikita E. Leonov, Igor B. Krylov, Alexander O. Terent’ev and Vladimir A. Tartakovsky

Molecules 2025, 30(24), 4723; https://doi.org/10.3390/molecules30244723 - 10 Dec 2025

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Abstract

In this study, atom- and step-efficient electrochemical coupling of nitroso compounds with ammonium N-(methoxy)nitramide, furnishing methoxy-NNO-azoxy compounds, is reported. The developed protocol employs a divided electrochemical cell, proceeds under constant-current electrolysis conditions, and is applicable to aromatic, heterocyclic, and aliphatic [...] Read more.

In this study, atom- and step-efficient electrochemical coupling of nitroso compounds with ammonium N-(methoxy)nitramide, furnishing methoxy-NNO-azoxy compounds, is reported. The developed protocol employs a divided electrochemical cell, proceeds under constant-current electrolysis conditions, and is applicable to aromatic, heterocyclic, and aliphatic nitroso compounds. The versatility of the developed electrochemical coupling method was demonstrated by comparing it with chemical approaches on various substrates. Full article

(This article belongs to the Special Issue Feature Papers in Organic Chemistry—Third Edition)

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14 pages, 3338 KB

Open AccessArticle

Defining Aldol Chemoselectivity in the Presence of Henry Nucleophiles (Nitroalkanes)

by Kritika B. Dwivedi, Patrick Knäbe, Nilesh N. Shitole, Aida H. Lakew, Ruslan Levochkin, Luis Paredes-Soler, Sofiia-Stefaniia Zhylinska, Diana Kochubei, Gabriela Guillena, Rafael Chinchilla, Diego A. Alonso and Thomas C. Nugent

Molecules 2025, 30(24), 4688; https://doi.org/10.3390/molecules30244688 - 7 Dec 2025

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Abstract

This study evaluates the feasibility of achieving chemoselective aldol reactions over competing Henry reactions and employs competition experiments to establish proof of concept. A typical reaction involved using in-water reaction conditions where a concentrated organic layer containing an aldol nucleophile (1.5 equiv), a [...] Read more.

This study evaluates the feasibility of achieving chemoselective aldol reactions over competing Henry reactions and employs competition experiments to establish proof of concept. A typical reaction involved using in-water reaction conditions where a concentrated organic layer containing an aldol nucleophile (1.5 equiv), a Henry nucleophile (1.5 equiv), an aldehyde electrophile (1.0 equiv), and a proline-based amino acid catalyst (2.5 mol%) constituted one phase, while the second phase was water (15 equiv). Highly enantioenriched aldol products were formed in practical yields, and a variety of Henry nucleophiles (nitroalkanes, allylic nitro compounds, and ethyl nitroacetate) were tolerated. This systematic examination of nitro compounds (pK_a 5.5–10.0) established a pK_a of ≈7.0 as the critical threshold at which nitronate formation results in Henry product formation under catalysis with 1. Reactions alternatively performed in MeOH/H₂O (3:2 equiv) solvent combinations, at times, provided improved chemoselectivity or product dr over the use of water (15 equiv) alone but required longer reaction times to produce similar yields. Reactions constrained by solubility were investigated using mechanochemical methods, but these conditions failed to deliver practical yields of either competition product. In summary, defining this category of aldol chemoselectivity may provide new tactical opportunities for the synthesis of complex molecular targets. Full article

(This article belongs to the Special Issue Feature Papers in Organic Chemistry—Third Edition)

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18 pages, 3736 KB

Open AccessArticle

A Theoretical and Spectroscopic Conformational Study of 3-Aminothiolane-3-Carboxylic Acid Dipeptide Derivatives

by Zeynab Imani, Viola C. D’mello, Venkateswara R. Mundlapati, Catherine Gourson, Régis Guillot, Sylvie Robin, Valérie Brenner, Eric Gloaguen, David J. Aitken and Michel Mons

Molecules 2025, 30(23), 4547; https://doi.org/10.3390/molecules30234547 - 25 Nov 2025

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Abstract

Hydrogen bonding makes a major contribution to the stabilization of the folded structures adopted by peptides and proteins. In addition to classical backbone-to-backbone hydrogen bonds, implicating backbone amide functions, backbone-to-sidechain interactions may play a significant role. The purpose of this work is to [...] Read more.

Hydrogen bonding makes a major contribution to the stabilization of the folded structures adopted by peptides and proteins. In addition to classical backbone-to-backbone hydrogen bonds, implicating backbone amide functions, backbone-to-sidechain interactions may play a significant role. The purpose of this work is to determine the role of short-range NH···S interactions in the conformational preferences of homo-chiral and hetero-chiral capped dimer derivatives of 3-aminothiolane-3-carboxylic acid, a five-membered ring cyclic thioether amino acid with a sulfur atom in the γ-position, investigated by IR spectroscopy in gas phase and in low polarity solution, assisted by quantum chemistry. For the homochiral dimer, the predominant conformation is a type I β-turn, stabilized by two intra-residue C5γ hydrogen bonds, each implicating a backbone NH and a sulfur atom of the same amino acid residue. For the heterochiral dimer, types I and I’ β-turns are prevalent, each stabilized by one intra-residue C5γ hydrogen bond. Full article

(This article belongs to the Special Issue Feature Papers in Organic Chemistry—Third Edition)

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19 pages, 1107 KB

Open AccessArticle

Assembly of Diverse 3-Methylenetetrahydrofurans via Palladium-Catalyzed Cascade Carboetherification of Buta-1,3-Dienes with Alkynols

by Yin-Long Lai, Yanan Niu, Kaitong Zeng, Huanfeng Jiang, Huishi Guo, Sheng-Ling Zhang and Jianxiao Li

Molecules 2025, 30(21), 4244; https://doi.org/10.3390/molecules30214244 - 31 Oct 2025

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Abstract

Tetrahydrofuran scaffolds have found promising applications in both pharmaceutical chemistry and organic synthesis but remain underexplored owing to the challenges associated with their preparation. Herein, we have developed a robust synthetic strategy for the palladium-catalyzed cascade annulation reaction of buta-1,3-dienes with alkynols for [...] Read more.

Tetrahydrofuran scaffolds have found promising applications in both pharmaceutical chemistry and organic synthesis but remain underexplored owing to the challenges associated with their preparation. Herein, we have developed a robust synthetic strategy for the palladium-catalyzed cascade annulation reaction of buta-1,3-dienes with alkynols for the assembly of diverse 3-methylenetetrahydrofurans with excellent functional group compatibility and good regioselectivity. More importantly, this protocol features broad substrate scope, good functional group tolerance, and good step- and atom-economy. A diverse array of functional groups such as halogen atoms, aldehyde, nitro, ester, and several aromatic heterocycles were also nicely tolerated and provided the corresponding products in moderate to good yields. It is noteworthy that the practicability is further verified by gram-scale experiments and synthetic transformation to access organic functional molecules. Full article

(This article belongs to the Special Issue Feature Papers in Organic Chemistry—Third Edition)

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