Coumarin System Research Articles

Ethyl 2-[(2-oxo-2H-chromen-6-yl)oxy]acetate

Ethyl 2-[(2-oxo-2H-chromen-6-yl)oxy]acetate, C13H12O5, a member of the pharmacologically important class of coumarins, crystallizes in the monoclinic C2/c space group in the form of sheets, within which molecules are related by inversion centers and 21 axes. Multiple C—H...O weak hydrogen-bonding interactions reinforce this pattern. The planes of these sheets are oriented in the approximate direction of the ac face diagonal. Intersheet interactions are a combination of coumarin system π–π stacking and additional C—H...O weak hydrogen bonds between ethyl acetoxy groups.

Ce3+ and Fe2+ co-enhanced ratiometric fluorescence probe utilizing copper nanoclusters and coumarin for sensitive assay of hydrogen peroxide and glucose

A novel ratiometric fluorescent probe was constructed for sensitive assay of hydrogen peroxide (H2O2) and glucose, which utilized the synergistically enhanced effects of Ce3+ and Fe2+ on copper nanoclusters (CuNCs) and coumarin. In the CuNCs-Ce3+/Fe2+-coumarin system, Ce3+ triggered the aggregation-induced emission phenomenon of CuNCs, and Fe2+ catalyzed the Fenton reaction to efficiently yield hydroxyl radical (•OH). In the presence of H2O2, the 625-nm red fluorescence of CuNCs was sharply quenched owing to the oxidation of CuNCs to Cu(II) by •OH, but the 460-nm blue fluorescence of 7-hydroxycoumarin from the oxidation of coumarin by •OH dramatically increased. Based on the reversible changes in two fluorescence signals, a satisfactorily ratiometric probe was constructed for H2O2 assay with a detection limit (LOD) of 0.6 μM accompanied by a visual color variation from red to blue. For glucose assay, this ratiometric probe gave a linear range of 3.2–160 μM and LOD of 0.96 μM owing to the oxidization of glucose to yield H2O2 in the presence of glucose oxidase and O2. Overall, the newly developed ratiometric probe shows a great prospect in real applications for visual assay of H2O2 and glucose by our naked eyes.

Synthesis of a Coumarin-Based Analogue of Schweinfurthin F.

The natural schweinfurthins are stilbenes with significant antiproliferative activity and an uncertain mechanism of action. To obtain a fluorescent analogue with minimal deviation from the natural structure, a coumarin ring system was annulated to the D-ring, creating a new analogue of schweinfurthin F. This stilbene was prepared through a convergent synthesis, with a Horner–Wadsworth–Emmons condensation employed to form the central stilbene olefin. After preparation of a tricyclic phosphonate via a recent and more efficient modification of the classic Arbuzov reaction, condensation was attempted with an appropriately substituted bicyclic aldehyde but the coumarin system did not survive the reaction conditions. When olefin formation preceded generation of the coumarin, the stilbene formation proceeded smoothly and ultimately allowed access to the targeted coumarin-based schweinfurthin analogue. This analogue displayed the desired fluorescence properties along with significant biological activity in the National Cancer Institute’s 60-cell line bioassay, and the pattern of this biological activity mirrored that of the natural product schweinfurthin F. This approach gives facile access to new fluorescent analogues of the natural schweinfurthins and should be applicable to other natural stilbenes as well.

A New Highly Selective Colorimetric and Fluorometric Coumarin-based Chemosensor for Hg2.

A novel colorimetric and fluorometric method based on coumarin as signalling unit wasdeveloped for Hg2+ recognition and quantification. Initially, the alkyne functionality wasincorporated into a coumarin system and the resulting molecule showed higher specificity andsensitivity for Hg2+ over other cations in both absorption and emission sensing assays. TheHg2+ recognition was detected as visible colour change from colourless to yellow and asfluorescence quenching. The colour change was assigned to the increased intramolecularcharge transfer (ICT) in the signalling unit upon Hg2+ binding whereas a decline in thefluorescence intensity was ascribed to the heavy atom effect from Hg2+. In order to generate amaterial with high sensing performance level, alkyne-functionalized molecule was hosted intoa polymeric material. The resulting functionalized polymer showed higher sensitivity andselectivity for Hg2+ over its corresponding coumarin molecule. The investigation of thepossible binding modes for Hg2+ suggested both alkyne and triazole functionalities as potentialbinding sites for Hg2+. The limit of detection (LOD) and limit of quantification (LOQ) of theproposed method were evaluated and values less than a recommended maximum level of Hg2+contaminant in drinking water (2.00 μg/L) were obtained (LOD = 0.44 μg/L and LOQ = 1.33μg/L). The real-life application of the method was investigated using natural water samples containing Hg2+ levels equivalent to the maximum tolerable concentration of Hg2+ in drinkingwater. The outcomes suggested that the method could be used in the sensing and determination of Hg2+ level of contaminant in the environment.

Understanding the Role of Aromaticity and Conformational Changes in Bond Dissociation Processes of Photo-Protecting Groups.

Photoremovable protecting groups (PPGs) provide spatial and temporal control over the release of various chemicals. Using surface hopping studies with multireference electronic structure methods we have unravelled the nuclear and the electronic events at play. Furthermore, the electronic changes along the reaction path were probed using excited state aromaticity quantifiers and orbital analysis. We find that upon irradiation with light of appropriate wavelength on the substituted coumarin system a π-π* electronic excitation occurs which is followed by an electron loss from the aromatic ring on gaining proper alignment between the π* and the C-LG (LG = leaving group) σ*. This alignment is brought about by a critical dihedral angle change in the molecule, which subsequently triggers C-LG bond cleavage. The sequence of events is indicative of an intramolecular electron catalyzed process which is established through investigations of changes in aromaticity of the phenyl ring which acts as an electron reservoir.

Synthesis, Spectrometric Characterization (ESI-MS, NMR, IRTF), X-Ray Study and Quantum Chemical Calculations of 2-oxo-2H-chromen-7-yl Benzoate

The paper presents a combined experimental and computational study of 7-substituted coumarin derivative, the 2-oxo-2H-chromen-7-yl benzoate (I). The compound was prepared in the laboratory by linking the coumarin system (7-hydroxycoumarin) to benzoyl chloride and crystallized in the monoclinic space group P2 1 with = 3.86010(10), = 27.7876(9), = 5.7453(2) A, = = 90, =91.063(3)° and = 2. The compound has been characterized structurally by spectroscopy and by single-crystal X-Ray diffraction. In the latter, the structure of (I) was solved by direct methods and refined to a final R value of 0.038 for 2260 independent reflections. Its structure is stabilized by intramolecular C-H•••O and intermolecular C-H•••O hydrogen bonds that extended as infinite 1D chain along [001]. Stabilization is also ensured by oxygen-π stacking interaction between the aromatic ring and oxygen of the benzoate moiety. The analysis of intermolecular interactions through the mapping of d norm and shape-index revel that the most significant contributions to the Hirshfeld surface 36.2 and 27.9% are from H•••H and O•••H contacts, respectively. Besides, the molecular geometry of (I) was also optimized using density functional theory (DFT/RB3LYP), the basic ab initio model i.e the restricted Hartree-Fock (RHF) methods with the 6-311 ++ G(d, p) basis set in ground state and frequency calculations with RB3LYP method using 6-31G(d,p) basis set. The theoretical data resulting from these quantum chemical calculations are generally in good agreement with the observed structure. The only significant observed difference is in the torsion angles between the coumarin ring system and the benzoate ring, where the observed CO -CC value (59.6 (4)°) is slightly lower than the DFT/RB3LYP calculated value (54.32°) and the frequency calculations (41.23°) value and larger than that of the RHF computed value (110.63°). The non-linear optical effects (NLO), molecular electrostatic potential (MEP), frontier molecular orbitals (FMO), and the Mulliken charge distribution were also investigated theoretically. The theoretical HOMO-LUMO energy gap values originating from these calculations are 4.465 eV (DFT/RB3LYP/6-311++G(d,p)) and 4.434 eV (FREQ/ RB3LYP/6-31G(d,p)).

Crystal Structure of 3-[1-(4-Methylphenyl)-9,10-dihydro-4-azaphenanthren-3-yl]benzo[f]coumarin

The crystal structure of the title compound is determined by single crystal X-ray structure analysis. The structure was solved by direct method and refined to a final R-value of 0.0469 for 2826 observed reflections. The benzocoumarin ring system is planar. The central ring of 4-azaphenantrene moiety has a half chair conformation, phenyl substituent forms dihedral angle of 56.46° with the mean plane of 4-azaphenantrene system. The coumarin system is rotated relative to the latter by 15.48(2)°. This orientation is stabilized by two weak intramolecular C–H···N hydrogen bonds.

Structural, spectroscopic and first-principles studies of new aminocoumarin derivatives.

The new aminocoumarin derivatives 3-[1-(3-hydroxyanilino)ethylidene]-3H-chromene-2,4-dione, (1), 3-[1-(4-hydroxyanilino)ethylidene]-3H-chromene-2,4-dione, (2), and 3-[1-(2-hydroxyanilino)ethylidene]-3H-chromene-2,4-dione, (3), all C17H13NO4, were synthesized by reacting an equimolar amount of 3-acetyl-4-hydroxycoumarin and the corresponding aminophenol in absolute ethanol. Structural and spectroscopic analysis of these phases revealed that derivatives (1) and (2) are isomers of previously reported (3) [Brahmia et al. (2013). Acta Cryst. E69, o1296]. The crystal structures of meta derivative (1) and para derivative (2) were ab initio determined from powder X-ray diffraction data using the direct-space approach. Both (1) and (2) adopt the orthorhombic space group P212121. These isomers show hydrogen bonds and rich π-π stacking, together with π...H interactions, which are built by conjugated systems of coumarin and phenol rings. In the crystalline lattice, the packing of (1) and (3) are mainly stabilized through O-H...O hydrogen bonding between neighbouring coumarin molecules, while hydrogen bonds between coumarin and water molecules build the stable crystal structure of derivative (2). A big similarity in the skeletons of the IR spectra of these isomers was noticed. Derivative (2) exhibits two weak bands which were not present in the spectra of the other two derivatives, at 2370 and 2948 cm-1, which can be assigned to the O-H vibrations of the solvent (H2O) trapped in the structure of (2). These aminocoumarin derivatives display absorption maxima in the visible region, attributed to π-π delocalization involving the whole electronic system of the compounds with a considerable charge-transfer character originating from the aminophenyl ring and pointing towards the coumarin system which is characterized by a high electron-accepting character. Additionally, the isolated molecular ground-state geometries were optimized at the PBE0/TZP level and the electronic properties, molecular electrostatic potential and Hirshfeld charges were determined.

Vinylogous Annulation Cascade Toward Stereoselective Synthesis of Highly Functionalized Indanone Derivatives

AbstractA base promoted vinylogous annulation cascade of alkylidene malononitriles with cyclopentene‐1,3‐diones with a subsequent reduction sequence has been devised to furnish densely functionalized 3‐hydroxyindanone scaffolds in high yields with excellent diastereoselectivity. Unlike preceding approaches that account for the formation of the pentanoid ring, this strategy features construction of the aromatic ring. The protocol is scalable, displays very broad substrates scope including late‐stage functionalization of bioactive estrone, applicable to activated coumarin system, and is suitable to access an indenoquinoline derivative.magnified image

Aryl alkynoates in the radical synthesis of coumarins

Radical reactions occupy a significant place in synthetic organic chemistry and significantly complement and expand modern approaches to the synthesis of substituted coumarins. This minireview summarizes various synthetic approaches to the construction of the coumarin system, based on radical cascade reactions starting with aryl alkynoates. The methods considered for constructing the coumarin system include cyclization reactions with the formation of two C–C bonds, as well as one C–C bond and C–P, C–S, C–Se, C–Hal bonds.

Recent Progress in the Synthesis of 4-Arylcoumarins

Current approaches to the synthesis of 4-arylcoumarins (neoflavones) are reviewed. This is an important group of O-containing natural flavonoids that are widely used not only to prepare natural and synthetic neoflavone analogs but also to design compound libraries based on 4-arylcoumarins for biological activity studies. The use of new transition-metal catalysts and unconventional activation methods for cyclization of the coumarin system, arylation of activated coumarins, and direct arylation of unactivated coumarins are discussed.

Dye Tool Box for a Fluorescence Enhancement Immunoassay.

Immunochemical analytical methods are very successful in clinical diagnostics and are nowadays also emerging in the control of food as well as monitoring of environmental issues. Among the different immunoassays, luminescence based formats are characterized by their outstanding sensitivity making this format especially attractive for future applications. The need for multiparameter detection capabilities calls for a tool box of dye labels in order to transduce the biochemical reaction into an optically detectable signal. Here, in a multiparameter approach each analyte may be detected by a different dye with a unique emission color (covering the blue to red spectral range) or a unique luminescence decay kinetics. In the case of a competitive immunoassay format for each of the different dye labels an individual antibody would be needed. In the present paper a slightly modified approach is presented using a 7-aminocoumarin unit as the basic antigen against which highly specific antibodies were generated. Leaving the epitope region in the dyes unchanged but introducing a side group in positon 3 of the coumarin system allowed us to tune the optical properties of the coumarin dyes without the necessity of new antibody generation. Upon modification of the parent coumarin unit the full spectral range from blue to deep red was accessed. In the manuscript the photophysical characterization of the coumarin derivatives and their corresponding immunocomplexes with two highly specific antibodies is presented. The coumarin dyes and their immunocomplexes were characterized by steady-state and time-resolved absorption as well as emission spectroscopy. Moreover, fluorescence depolarization measurements were carried out to complement the data stressing the different binding modes of the two antibodies. The binding modes were evaluated using the photophysics of 7-aminocoumarins and how it was affected in the respective immunocomplexes, namely, the formation of the intramolecular charge transfer (ICT) as well as the twisted intramolecular charge transfer (TICT). In contrast to other antibody-dye pairs reported a distinct fluorescence enhancement upon formation of the antibody-dye complex up to a factor of 50 was found. Because of the easy emission color tuning by tailoring the coumarin substitution for the antigen binding in nonrelevant position 3 of the parent molecule, a dye tool box is on hand which can be used in the construction of competitive multiparameter fluorescence enhancement immunoassays (FenIA).

Synthesis, spectroscopic characterization, X-ray study and in vitro cytotoxicity of 5-hydroxycoumarin derivatives and their copper complexes

We have synthesized a series of bromo derivatives of 5-hydroxycoumarin and two new Cu(II) complexes with 6-acetyl-8-bromo-5-hydroxy-4,7-dimethylcoumarin (L2) and 6-acetyl-3,8-dibromo-5-hydroxy-4,7-dimethylcoumarin (L3) ligands, designed as potential active compounds against human cancer cell lines. The elemental analysis, mass spectroscopy, NMR and infrared spectroscopy have been used for basic characterization of analyzed compounds. The X-ray crystal structure analysis for one representative organic compound, 3,6,8-tribromo-5-hydroxy-4,7-dimethylcoumarin (c) has been performed. It has shown that coumarin system is nearly planar and the Br⋯Br interaction is a very characteristic feature of the molecular association for organic ligands. The complexes, Cu(L2)2·3H2O and Cu(L3)(ClO4)·2.5H2O, have been found as four-coordinated and contain copper in the +2 oxidation state according to X-ray absorption spectroscopy. All the compounds have been screened in vitro for their cytotoxic activity against mouse fibroblast and human prostate cancer cells. The coordination products of brominated ligands have shown to be more active than the free ligands and demonstrate significant in-vitro cytotoxicity against human prostate cancer cells (DU145).

A Redox-Driven Fluorescence “Off–On” Molecular Switch Based on a 1,1′-Unsymmetrically Substituted Ferrocenyl Coumarin System: Mimicking Combinational Logic Operation

A unique electrochemical- and fluorescence-active molecular switch based on a 1,1′-unsymmetrically substituted ferrocenyl coumarin system has been developed. Upon chemical oxidation of the ferrocene moiety with Fe(ClO4)3, the present system displays high fluorescence output through an inhibited photoinduced electron transfer (PET) process and also exhibits slight diminution of emission intensity upon the addition of Hg2+. The feasibility of the PET process was further verified by the Weller equation and DFT studies, which indicate that oxidation of ferrocene units in 5 depletes electron population from the HOMO of central ferrocene, and thus the PET process is forbidden and re-emergence of fluorescence is observed. Theoretical studies further revealed that charge transfer in the excited state from coumarin-centered orbitals (LUMO+1) to mercury-centered empty orbitals (LUMO) may be attributed to fluorescence quenching upon addition of Hg2+ ion. The unprecedented combination of Fe3+ ion, Hg2+ ion, and sodiu...

ChemInform Abstract: A C‐3‐Selective Direct Alkylation of Coumarins by Using a Microwave‐Assisted Xanthate‐Based Radical Reaction.

A xanthate-based oxidative radical process for the direct alkylation of the coumarin ring system is presented. In the reaction, a vinylic and unactivated C–H bond of the coumarin system is replaced by an α-acyl functionality under neutral conditions. This reaction has a high reaction site selectivity, which can realize alkylation at the C-3 position.

A C‐3‐Selective Direct Alkylation of Coumarins by Using a Microwave‐Assisted Xanthate‐Based Radical Reaction

AbstractA xanthate‐based oxidative radical process for the direct alkylation of the coumarin ring system is presented. In the reaction, a vinylic and unactivated C–H bond of the coumarin system is replaced by an α‐acyl functionality under neutral conditions. This reaction has a high reaction site selectivity, which can realize alkylation at the C‐3 position.

Theoretical and experimental local reactivity parameters of 3-substituted coumarin derivatives.

Local reactivity descriptors, such as atomic charges, atomic electrostatic potential and atomic Fukui indices were computed for a series of 3-substituted coumarin (2-oxo-2H-1-benzopyran) derivatives, using density functional theory (DFT) and Möller-Plesset methods (MP2). The variation of those properties as a function of the substituents was compared with the variation of the measured XPS binding energies. The atomic electrostatic potentials and XPS binding energies serves as indicators of the electrophilicity of a given center within a molecule, while the atomic Fukui indices describe its degree of electronic localization, known as atomic softness. The correlation between those theoretical and experimental properties allowed us to follow the effect of electron withdrawing substituents on the electrophilicity of a given atomic center. The Fukui indices provided additional information about the softening/hardening of the center of interest due to presence of different substituents to the coumarin system. On the basis of these analysis, the 1,2-addition would be favored for 3-acetyl, 3-phosphono, and 7-diethylamino substituents, while 3-carboxyl, 3-ethoxycarbonyl, and 3-nitro substituent would favor 1,4-addition. The substituted coumarins would preferably react with soft nucleophiles at position 2 and with hard nucleophiles at position 4.

A convenient approach to the design and synthesis of indolo[3,2-c]coumarins via the microwave-assisted Cadogan reaction

3-(4,5-Dimethoxy-2-nitrophenyl)coumarins bearing various substituents on the benzene ring of the coumarin system have been prepared from salicylaldehydes and 2-(4,5-dimethoxy-2-nitrophenyl)acetonitrile by means of the Perkin condensation. Further cyclization of these 3-aryl coumarins through the microwave-assisted Cadogan reaction afforded the corresponding indolo[3,2-c]coumarins in good to excellent yields.

Synthesis of benzopyranopyrrolidines via 1,3-dipolar cycloaddition of nonstabilized azomethine ylides with 3-substituted coumarins

A three-component reaction of 3-substituted coumarins with N-alkyl-α-amino acids and aldehydes gave 1-benzopyrano[3,4-c]pyrrolidines as a result of a 1,3-dipolar cycloaddition of an intermediate nonstabilized azomethine ylide at the double bond of the coumarin system in moderate to good yields. In most cases, high regio- and stereo-selectivity of the [3+2] cycloaddition was observed.

Structural characterization of derivatives of 4-methylcoumarin – Theoretical and experimental studies

The quantum chemical conformational analysis was performed for 4-methylcoumarin derivatives substituted with the hydroxy, acetyl and/or alkoxy groups. Their crystal structures were determined by a single crystal X-ray crystallography. The structural data in the solid were compared with the results of the quantum chemical analysis in the gas phase. The results indicated that the coumarin system is nearly planar and several conformers differing in the orientation of the methoxy and acetyl groups are observed. The stereochemistry of the lowest energy rotamers in the gas phase is retained in solid state; intermolecular forces are to weak for inducing conformational changes. In the crystals of studied 4-methylcoumarin derivatives the π⋯π stacking of benzopyran systems is a very characteristic and persistent feature of the molecular association. The extend of the π⋯π overlapping depends on substituents.