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16 pages, 1439 KiB

Open AccessArticle

Straightforward Access to Polyfunctionalized δ-Lactams via Domino Aza–Michael/Thia–Michael/Aldol Sequence

by Axelle Genty, Ismail Alahyen, Marie-José Tranchant, Jérôme Lhoste, Vincent Dalla, Catherine Taillier and Sébastien Comesse

Molecules 2025, 30(10), 2154; https://doi.org/10.3390/molecules30102154 - 14 May 2025

Viewed by 365

Abstract

Domino reactions are powerful tools for the straightforward synthesis of complex molecules with a particular emphasis on functionalized azacycles. We report a contribution in this field, implemented via a new thia–Michael/aldol sequence between readily accessible N-alkoxyacrylamides and α,β-unsaturated carbonyls, for access to [...] Read more.

Domino reactions are powerful tools for the straightforward synthesis of complex molecules with a particular emphasis on functionalized azacycles. We report a contribution in this field, implemented via a new thia–Michael/aldol sequence between readily accessible N-alkoxyacrylamides and α,β-unsaturated carbonyls, for access to polysubstituted δ-lactams with acceptable-to-good yields and good selectivity. This method, initially developed in a two-component approach and characterized by the mildness of its reaction conditions, was shown to be compatible with various thiophenol derivatives and to employ a simple pre-thiasilylation step in a one-pot process. This further extension to the monotype aza–Michael/thia–Michael/aldol sequence establishes a proof-of-concept that acrylamides can react as both 1,3-bis-nucleophiles and 1,4-electrophiles in a single flask operation. Full article

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20 pages, 2905 KiB

Open AccessArticle

(E)-2-Benzylidenecyclanones: Part XX—Reaction of Cyclic Chalcone Analogs with Cellular Thiols: Unexpected Increased Reactivity of 4-Chromanone- Compared to 1-Tetralone Analogs in Thia-Michael Reactions

by Gábor Bognár, Fatemeh Kenari, Zoltán Pintér, Igor D. Borges, Ademir J. Camargo, Heibbe C. B. Oliveira, Flávio Olimpio Sanches-Neto, Valter H. Carvalho-Silva, Hamilton B. Napolitano and Pál Perjési

Molecules 2024, 29(23), 5493; https://doi.org/10.3390/molecules29235493 - 21 Nov 2024

Viewed by 1023

Abstract

In vitro relative cytotoxicity (IC₅₀ (IIb)/IC₅₀ (IIIb) of (E)-3-(4′-methylbenzylidene)-4-chromanone (IIIb) towards human Molt 4/C8 and CEM T-lymphocytes showed a >50-fold increase in comparison to those of the respective tetralone derivative (IIb). [...] Read more.

In vitro relative cytotoxicity (IC₅₀ (IIb)/IC₅₀ (IIIb) of (E)-3-(4′-methylbenzylidene)-4-chromanone (IIIb) towards human Molt 4/C8 and CEM T-lymphocytes showed a >50-fold increase in comparison to those of the respective tetralone derivative (IIb). On the other hand, such an increase was not observed in the analogous 4-OCH₃ (IIc and IIIc) derivatives. In order to study whether thiol reactivity—as a possible basis of the mechanism of action—correlates with the observed cytotoxicities, the kinetics of the non-enzyme catalyzed reactions with reduced glutathione (GSH) and N-acetylcysteine (NAC) of IIIb and IIIc were investigated. The reactivity of the compounds and the stereochemical outcome of the reactions were evaluated using high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Molecular modeling calculations were performed to rationalize the unexpectedly higher thiol reactivity of the chromanones (III) compared to the carbocyclic analog tetralones (II). The results indicate the possible role of spontaneous thiol reactivity of compounds III in their recorded biological effects. Full article

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13 pages, 2542 KiB

Open AccessArticle

Controllable Synthesis of Thioacetals/Thioketals and β-Sulfanyl Ketones Mediated by Methanesulfonic Anhydride and Sulfuric Acid Sulfuric Acid from Aldehyde/Acetone and Thiols

by Hexia Ye, Xinyao Zhao, Yajie Fu, Haibo Liu, Junchen Li and Xiaojing Bi

Molecules 2024, 29(20), 4785; https://doi.org/10.3390/molecules29204785 - 10 Oct 2024

Viewed by 1985

Abstract

A novel and controllable synthesis of thioacetals/thioketals and β-sulfanyl ketones mediated by the reaction of aldehyde/acetone with thiols has been developed. In this protocol, β-sulfanyl ketones can be generated without the prior preparation of α, β-unsaturated carbonyl compounds. A variety of thiols reacted [...] Read more.

A novel and controllable synthesis of thioacetals/thioketals and β-sulfanyl ketones mediated by the reaction of aldehyde/acetone with thiols has been developed. In this protocol, β-sulfanyl ketones can be generated without the prior preparation of α, β-unsaturated carbonyl compounds. A variety of thiols reacted with aldehyde/acetone and provided the corresponding thioacetals/thioketals and β-sulfanyl ketones in good to excellent yields, respectively. This protocol is operationally simple, mild, and atom-economical, providing controllable access to thioacetals/thioketals and thia-Michael addition products under mild conditions. Full article

(This article belongs to the Special Issue Organosulfur and Organoselenium Chemistry)

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20 pages, 2123 KiB

Open AccessArticle

Synthesis of α,ω-bis-Mercaptoacyl Poly(alkyl oxide)s and Development of Thioether Cross-Linked Liposome Scaffolds for Sustained Release of Drugs

by Spyridon Mourtas, Georgios Kourmoulakis, Stavros Kremezis, Pavlos Klepetsanis and Sophia G. Antimisiaris

Molecules 2024, 29(6), 1312; https://doi.org/10.3390/molecules29061312 - 15 Mar 2024

Viewed by 1747

Abstract

With the aim to develop novel scaffolds for the sustained release of drugs, we initially developed an easy approach for the synthesis of α,ω-homobifunctional mercaptoacyl poly(alkyl oxide)s. This was based on the esterification of the terminal hydroxyl groups of poly(alkyl oxide)s with suitably [...] Read more.

With the aim to develop novel scaffolds for the sustained release of drugs, we initially developed an easy approach for the synthesis of α,ω-homobifunctional mercaptoacyl poly(alkyl oxide)s. This was based on the esterification of the terminal hydroxyl groups of poly(alkyl oxide)s with suitably S-4-methoxytrityl (Mmt)-protected mercapto acids, followed by the removal of the acid labile S-Mmt group. This method allowed for the efficient synthesis of the title compounds in high yield and purity, which were further used in the development of a thioether cross-linked liposome scaffold, by thia–Michael reaction of the terminal thiol groups with pre-formed nano-sized liposomes bearing maleimide groups on their surface. The reaction process was followed by ¹H-NMR, using a Carr–Purcell–Meiboom–Gill (CPMG) relaxation dispersion NMR experiment (¹H-NMR CPMG), which allowed for real-time monitoring and optimization of the reaction process. The thioether cross-linked liposomal scaffold that was synthesized was proven to preserve the nano-sized characteristics of the initial liposomes and allowed for the sustained release of calcein (which was used as a hydrophilic dye and a hydrophilic drug model), providing evidence for the efficient synthesis of a novel drug release scaffold consisting of nanoliposome building blocks. Full article

(This article belongs to the Special Issue Molecular Approaches to Drug Discovery and Development)

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11 pages, 1656 KiB

Open AccessArticle

Thia-Michael Reaction under Heterogeneous Catalysis

by Giovanna Bosica, Roderick Abdilla and Alessio Petrellini

Organics 2023, 4(1), 86-96; https://doi.org/10.3390/org4010007 - 21 Feb 2023

Cited by 1 | Viewed by 3379

Abstract

Thia-Michael reactions between aliphatic and aromatic thiols and various Michael acceptors were performed under environmentally-friendly solvent-free conditions using Amberlyst^® A21 as a recyclable heterogeneous catalyst to efficiently obtain the corresponding adducts in high yields. Ethyl acrylate was the main acceptor used, although [...] Read more.

Thia-Michael reactions between aliphatic and aromatic thiols and various Michael acceptors were performed under environmentally-friendly solvent-free conditions using Amberlyst^® A21 as a recyclable heterogeneous catalyst to efficiently obtain the corresponding adducts in high yields. Ethyl acrylate was the main acceptor used, although others such as acrylamide, linear, and cyclic enones were also utilized successfully. Bifunctional Michael donor, 3-mercaptopropanoic acid, positively furnished the product, albeit in a lower yield and after leaving the reaction to take place for a longer time. The catalyst was easy and safe to handle and successfully recycled for five consecutive cycles. Full article

(This article belongs to the Collection Advanced Research Papers in Organics)

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16 pages, 2929 KiB

Open AccessReview

Thia-Michael Reaction: The Route to Promising Covalent Adaptable Networks

by Dimitri Berne, Vincent Ladmiral, Eric Leclerc and Sylvain Caillol

Polymers 2022, 14(20), 4457; https://doi.org/10.3390/polym14204457 - 21 Oct 2022

Cited by 29 | Viewed by 7070

Abstract

While the Michael addition has been employed for more than 130 years for the synthesis of a vast diversity of compounds, the reversibility of this reaction when heteronucleophiles are involved has been generally less considered. First applied to medicinal chemistry, the reversible character [...] Read more.

While the Michael addition has been employed for more than 130 years for the synthesis of a vast diversity of compounds, the reversibility of this reaction when heteronucleophiles are involved has been generally less considered. First applied to medicinal chemistry, the reversible character of the hetero-Michael reactions has recently been explored for the synthesis of Covalent Adaptable Networks (CANs), in particular the thia-Michael reaction and more recently the aza-Michael reaction. In these cross-linked networks, exchange reactions take place between two Michael adducts by successive dissociation and association steps. In order to understand and precisely control the exchange in these CANs, it is necessary to get an insight into the critical parameters influencing the Michael addition and the dissociation rates of Michael adducts by reconsidering previous studies on these matters. This review presents the progress in the understanding of the thia-Michael reaction over the years as well as the latest developments and plausible future directions to prepare CANs based on this reaction. The potential of aza-Michael reaction for CANs application is highlighted in a specific section with comparison with thia-Michael-based CANs. Full article

(This article belongs to the Section Polymer Chemistry)

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5 pages, 572 KiB

Open AccessCommunication

Synthesis of a New [3-(4-Chlorophenyl)-4-oxo-1,3-thiazolidin-5-ylidene]acetic Acid Derivative

by Jacek Szczepański, Helena Tuszewska and Nazar Trotsko

Molbank 2020, 2020(3), M1150; https://doi.org/10.3390/M1150 - 28 Jul 2020

Cited by 1 | Viewed by 3001

Abstract

The new methyl [3-(4-chlorophenyl)-2-{[(2,4-dichloro-1,3-thiazol-5-yl)methylidene]hydrazinylidene}-4-oxo-1,3-thiazolidin-5-ylidene]acetate was synthesized from 4-(4-chlorophenyl)-1-(2,4-dichloro-1,3-thiazol-5-yl)methylidene-3-thiosemicarbazide using dimethyl acetylenedicarboxylate as thia-Michael reaction acceptor. New compounds (3 and 4) were characterized by IR, ¹H and ¹³C NMR spectroscopy methods. Full article

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9 pages, 1498 KiB

Open AccessShort Note

2-{[(4-Hydroxy-3,5-dimethoxyphenyl)methylidene]hydrazinylidene}-4-oxo-1,3-thiazolidin-5-yl Acetic Acid

by Sangeetha Karanth, Badiadka Narayana, Sharath Chandra Kodandoor and Balladka Kunhanna Sarojini

Molbank 2018, 2018(3), M1009; https://doi.org/10.3390/M1009 - 29 Jul 2018

Cited by 1 | Viewed by 3127

Abstract

Thia-Michael addition of 2-[(4-hydroxy-3,5-dimethoxyphenyl)methylidene]hydrazine-1-carbothioamide (1) with maleic anhydride results in the formation of the title compound 2-{[(4-hydroxy-3,5-dimethoxyphenyl)methylidene]hydrazinylidene}-4-oxo-1,3-thiazolidin-5-yl acetic acid 2. The precursor 1 is synthesized by the reaction of 4-hydroxy-3,5-dimethoxybenzaldehyde and thiosemicarbazide in the presence of glacial acetic acid as [...] Read more.

Thia-Michael addition of 2-[(4-hydroxy-3,5-dimethoxyphenyl)methylidene]hydrazine-1-carbothioamide (1) with maleic anhydride results in the formation of the title compound 2-{[(4-hydroxy-3,5-dimethoxyphenyl)methylidene]hydrazinylidene}-4-oxo-1,3-thiazolidin-5-yl acetic acid 2. The precursor 1 is synthesized by the reaction of 4-hydroxy-3,5-dimethoxybenzaldehyde and thiosemicarbazide in the presence of glacial acetic acid as the catalyst. The structure of the title compound is determined by elemental analysis, FT-IR, ¹H-NMR, ¹³C-NMR and mass spectral data. In order to determine the molecular interactions with the bacterial enzyme, the title compound is further docked into the active site of the MurB protein of Staphylococcus aureus (PDB ID: 1HSK). The in vitro antibacterial and antifungal activity of the title compound is carried out in order to appraise its antimicrobial efficacy by determination of zone of inhibition and minimal inhibitory concentration. The compound is also evaluated for its antioxidant property by 2,2-diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging assay. Full article

(This article belongs to the Section Organic Synthesis and Biosynthesis)

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