1,3-Dimethylbarbituric Acid

Argintaru, O. Andreea

doi:10.1002/047084289x.rn01256

Cited by 5 publications

(10 citation statements)

References 56 publications

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“…Taken together, these results correlate with decreasing polarization of the CC bond, as reflected in the significant difference in acidity from DMBA and Meldrum’s acid on one side and malononitrile on the other (p K a = 4.68, p K a = 4.83, and p K a = 11.8, respectively) …”

Section: Resultsmentioning

confidence: 60%

Dynamic Covalent Metathesis in the C═C/C═N Exchange between Knoevenagel Compounds and Imines

Flídrová

Lehn

2018

J. Am. Chem. Soc.

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Fast and reversible dynamic covalent C═C/C═N exchange takes place without catalyst in nonpolar solvents between barbiturate-derived Knoevenagel (Kn) compounds and imines. A detailed study of the reaction indicates that it proceeds by an associative organo-metathesis mechanism involving the formation of a four-membered ring azetidine intermediate by addition of the imine C═N group to the C═C bond of the Kn compound. This intermediate could be generated cleanly and stabilized at low temperature by condensation of the o,p-dinitrophenyl Kn derivative with the cyclic imine 1-azacyclohexene. It was characterized by extensive NMR and mass spectrometric studies. The process described represents a genuine dynamic covalent organo-metathesis through a four-membered ring adduct as intermediate. It paves the way for the exploration of a wide set of dynamic systems involving (strongly) polarized C═C bonds and various imines, extending also into covalent dynamic polymers and polymolecular assemblies.

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Section: Resultsmentioning

confidence: 60%

Dynamic Covalent Metathesis in the C═C/C═N Exchange between Knoevenagel Compounds and Imines

Flídrová

Lehn

2018

J. Am. Chem. Soc.

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“…Latent cyclic C-nucleophiles such as 1,3-dimethylbarbituric acid (1,3-DMB), dimedone and Meldrum's acid, to name just the three most popular ones, are versatile reagents useful for many transformations in organic synthesis. [1,2,3] For example, they are often involved as nucleophilic partners in multicomponent condensation reactions, especially for the synthesis of diverse heterocyclic scaffolds. [1,2,4] Indeed, owing both to the facile deprotonation of their activated methylene and other positive attributes (e. g., wide variety of biological activities for barbituric acid and its derivatives, ambivalent electrophilic and nucleophilic reactivity modes for Meldrum's acid, …), they are therefore regarded as superior alternatives to malonate esters.…”

Section: Introductionmentioning

confidence: 99%

“…[1,2,3] For example, they are often involved as nucleophilic partners in multicomponent condensation reactions, especially for the synthesis of diverse heterocyclic scaffolds. [1,2,4] Indeed, owing both to the facile deprotonation of their activated methylene and other positive attributes (e. g., wide variety of biological activities for barbituric acid and its derivatives, ambivalent electrophilic and nucleophilic reactivity modes for Meldrum's acid, …), they are therefore regarded as superior alternatives to malonate esters. Their wide popularity goes beyond applications in synthetic chemistry.…”

Section: Introductionmentioning

confidence: 99%

“…[9] Furthermore, in vitro assays conducted with glutathione (GSH) have clearly shown the protective effect of biological thiols against non-enzymatic hydrolysis of these xanthene-based "covalent-assembly" fluorescent probes, produced by a reversible Michael addition process. [9b] Interestingly, recent achievements in the chemistry of functionalized latent cyclic C-nucleophiles (e. g., barbituric acid, piperidine-2,4-dione and Meldrum's acid derivatives) usable as versatile "clickable" platforms, [10] may lead to consider additional roles for these malonate esters substitutes in the context of such enzyme-activated fluorogenic probes: (1) to permit the release of a second molecule of interest (e. g., drug or second fluorescent reporter), concomitant with in situ formation of fluorophore; (2) to achieve facile (bio)conjugation to a further (bio)molecule aimed at enhancing water solubility, cell permeability and/or targeting ability for specific tissues or cell organelles (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

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Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme‐Responsive “Covalent‐Assembly” Fluorescent Probes with Tailor‐Made Properties**

Renault

Capello

Yao

et al. 2023

Chemistry An Asian Journal

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Latent cyclic carbon‐centered nucleophiles (latent C‐nucleophiles) are recently proving their value in the field of reaction‐based fluorescent probes, far beyond their primary utility in organic synthesis. They are typically used to introduce a Michael acceptor moiety acting as a recognition/reaction site for analyte to be detected or as a kinetic promoter of fluorogenic cascade reactions triggered by a reactive species. C‐nucleophiles bearing a further reactive handle offer an additional opportunity for tuning the physicochemical/targeting properties or providing drug‐releasing capabilities to these probes, through the covalent attachment of ad hoc chemical moiety. In order to implement such strategy to fluorogenic/chromogenic enzyme substrates based on the “covalent‐assembly” principle, we have explored the potential of some functionalized derivatives of barbituric acid, piperidine‐2,4‐dione and Meldrum's acid. Our investigations based on the rational design and analytical validations of enzyme‐responsive caged precursors of fluorescent pyronin dyes and 7‐(diethylamino)coumarin‐3‐carboxylic acid, led to identify a versatile candidate suitable for this late‐stage structural optimization approach. This Meldrum's acid derivative enables to either enhance water solubility or achieve the reversible conjugation of a targeting ligand, while promoting in situ formation of fluorophore upon enzymatic activation. This study opens the way to novel multifunctional fluorescence imaging probes and optically modulated small conjugate‐based theranostics.

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“…[9] Furthermore, in vitro assays conducted with glutathione (GSH) have clearly shown the protective effect of biological thiols against non-enzymatic hydrolysis of these xanthene-based "covalentassembly" fluorescent probes, produced by a reversible Michael addition process. [9b] Interestingly, recent achievements in the chemistry of functionalized latent cyclic C-nucleophiles (e.g., barbituric acid, piperidine-2,4-dione and Meldrum's acid derivatives) usable as versatile "clickable" platforms [10] , may lead to consider additional roles for these malonate esters substitutes in the context of such enzyme-activated fluorogenic probes: (1) to permit the release of a second molecule of interest (e.g., drug or second fluorescent reporter), concomitant with in situ formation of fluorophore; (2) to achieve facile (bio)conjugation to a further (bio)molecule aimed at enhancing water solubility, cell permeability and/or targeting ability for specific tissues or cell organelles (Figure 2). In order to demonstrate the feasibility of this original "structural tuning" method, we have assessed several cyclic C-nucleophiles, some of them being reported in the literature recently, in the construction of novel pyronin precursors responsive to PGA.…”

Section: Introductionmentioning

confidence: 99%

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme-Responsive "Covalent-Assembly" Fluorescent Probes with Tailor-Made Properties

Renault

Capello

Yao

et al. 2023

Preprint

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Latent cyclic carbon-centered nucleophiles (latent C-nucleophiles) are recently proving their value in the field of reaction-based fluorescent probes, far beyond their primary utility in organic synthesis. They are typically used to introduce a Michael acceptor moiety acting as a recognition/reaction site for analyte to be detected or as a kinetic promoter of fluorogenic cascade reactions triggered by a reactive species. C-nucleophiles bearing a further reactive handle offer an additional opportunity for tuning the physicochemical/targeting properties or providing drug-releasing capabilities to these probes, through the covalent attachment of ad hoc chemical moiety. In order to implement such strategy to fluorogenic/chromogenic enzyme substrates based on the "covalent-assembly" principle, we have explored the potential of some functionalized derivatives of barbituric acid, piperidine-2,4-dione and Meldrum's acid. Our investigations based on the rational design and analytical validations of enzyme-responsive caged precursors of fluorescent pyronin dyes and 7-(diethylamino)coumarin-3-carboxylic acid, led to identify a versatile candidate suitable for this late-stage structural optimization approach with a minor impact on stability and activation kinetics of probe. This Meldrum's acid derivative, synthesized from levulinic acid, enables to either enhance water solubility or achieve the reversible conjugation of a targeting ligand, while promoting in situ formation of fluorophore upon enzymatic activation. This study opens the way to novel multifunctional fluorescence imaging probes and optically modulated small conjugate-based theranostics drawing on the promising "covalent-assembly" strategy.

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1,3-Dimethylbarbituric Acid

Cited by 5 publications

References 56 publications

Dynamic Covalent Metathesis in the C═C/C═N Exchange between Knoevenagel Compounds and Imines

Dynamic Covalent Metathesis in the C═C/C═N Exchange between Knoevenagel Compounds and Imines

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme‐Responsive “Covalent‐Assembly” Fluorescent Probes with Tailor‐Made Properties**

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme-Responsive "Covalent-Assembly" Fluorescent Probes with Tailor-Made Properties

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