Ensembles of rings with a coumarin unit 1. Synthesis of 3-(2-R-thiazol-4-yl)-and 3-(4-R-thiazol-2-yl)coumarins

We have synthesized 3-(2-R-thiazol-4-yl)coumarins (R=H, CH₃, CH₂CN, Ar) by condensation of 3-(-bromoacetyl)coumarins with thioamides. We obtained 3-(4-R-thiazol-2-yl)coumarins (R=H, Ar) by several methods. By reaction of 2-cyanomethyl-4-phenylthiazole with 2-hydroxybenzaldehydes, we synthesized 2-imino-3-(4-phenylthiazol-2-yl)coumarins, which were converted to the corresponding coumarins by acid hydrolysis. For 3-(2-R-thiazol-4-yl)coumarins (R=CH₂CN), we carried out reactions with aromatic aldehydes. We propose alternative methods for synthesis of 2-[2-aryl(hetaryl)-1-cyanoethenyl]-4-(coumarin-3-yl)thiazoles.Ukrainian Pharmaceutical Academy, Kharkov 310002. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1345–1355, October, 1997.     

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.     

Sequential Pd(II)-Pd(0) catalysis for the rapid synthesis of coumarins

Electrophilic palladium-catalyzed cycloisomerization of brominated aryl propiolates produces brominated coumarins. The brominated coumarins can be diversified by reduction of the Pd(II) catalyst to Pd(0) followed by Suzuki, Sonogashira, Heck, or Hartwig-Buchwald coupling. Thus, a single loading of precatalyst can be used to conduct sequential reactions, allowing the synthesis of functionalized coumarins. Extension of this methodology toward the synthesis of coumarin libraries is discussed.     

A practical strategy for the characterization of coumarins in Radix Glehniae by liquid chromatography coupled with triple quadrupole-linear ion trap mass spectrometry

The aim of the present study was to develop a practical method for the characterization of coumarins in Radix Glehniae by liquid chromatography–mass spectrometry (LC–MS). First, 10 coumarin standards (including two pairs of isomers) were studied, and mass spectrometry fragmentation patterns and elution time rules for the coumarins were found. Then, an extract of Radix Glehniae was analyzed by the combination of two scan modes, i.e., multiple ion monitoring-information-dependent acquisition-enhanced product ion mode (MIM-IDA-EPI) and precursor scan information-dependent acquisition-enhanced product ion mode (PREC-IDA-EPI) on a hybrid triple quadrupole-linear ion trap mass spectrometer. A total of 41 coumarins were identified on the basis of their mass spectrometry fragmentation patterns. This is the first time that these two scan modes have been combined to characterize chemical constituents in traditional Chinese medicine. This new method allowed the identification of coumarins in Radix Glehniae in trace amounts. The methodology proposed in this study could be valuable for the structural characterization of coumarins from complex natural and synthetic sources.     

Interaction of coumarin derivatives with human serum albumin: investigation by fluorescence spectroscopic technique and modeling studies

Interactions of several 7-aminocoumarins with human serum albumin (HSA) were studied by using fluorescence spectroscopic technique and modeling studies. There is a large change in fluorescence spectral parameters like intensity, emission maxima and anisotropy for all aminocoumarins. There were two binding sites for cou-1, 311 and a single binding site for other coumarins. The binding constant(s) are large for all coumarins reflective of a strong binding. These spectral studies show that structural variants at the third, fourth and seventh position affects binding. The probable location of these coumarins in domain II has been predicted based on modeling. The effect of structural modification on the efficiency of binding was obtained for various other coumarins, using modeling.     

Medicinal foodstuffs. XX. Vasorelaxant active constituents from the roots of Angelica furcijuga Kitagawa: structures of hyuganins A, B, C, and D

From the methanolic extract with vasorelaxant activity obtained from Angelica furcijuga Kitagawa, four new khellactone-type coumarins, hyuganins A, B, C, and D, were isolated together with twelve known coumarins, two known acetylenic compounds, and a known lignan. The structures of hyuganins A, B, C, and D were determined on the basis of chemical and physicochemical evidence. Nine principal coumarins (hyuganin A, anomalin, pteryxin, isopteryxin, isoepoxypteryxin, praerosides II and IV, apiosylskimmin, (R)-peucedanol 7-O-beta-D-glucopyranoside), two acetylenic compounds [(-)-falcarinol and falcarindioll, and related compounds were examined for inhibitory activities on high concentration of K+ (High K+)- and dl-norepinephrine (NE)-induced contractions. The results indicate that the 3'- and 4'-acyl groups of khellactone-type coumarins are essential for the inhibitory activity on the contractions by High K+. Hyuganin A and anomalin showed inhibitory effects on High K+-induced contraction, but not on NE-induced contraction. Other active coumarins (pteryxin, isopteryxin, isoepoxypteryxin) and an acetylenic compound (falcarindiol) non-selectively inhibited both contractions by High K+ and NE.     

Total synthesis of naturally occurring 5,6,7- and 5,7,8-trioxygenated coumarins

The synthesis of five naturally occurring polyoxygenated coumarins is described. It concerns two 5,6,7-trioxygenated coumarins, i.e., 6-hydroxy-5,7-dimethoxycoumarin (fraxinol) 1 and 5,6,7-trimethoxycoumarin 2, and three 5,7,8-trioxygenated coumarins, i.e., 8-hydroxy-5,7-dimethoxycoumarin (leptodactylone) 3, 5,7,8-trimethoxycoumarin 4 and 8-(3-methyl-2-butenyloxy)-5,7-dimethoxycoumarin (artanin) 5. Key feature of the synthetic pathway is the synthesis of suitable tetraoxygenated benzaldehydes, which are then converted to the corresponding coumarins via a Wittig reaction.     

A study of the analytical behaviour of selected synthetic and naturally occurring coumarins using liquid chromatography, ion trap mass spectrometry, gas chromatography and polarography and the construction of an appropriate database for coumarin characterisation

The aim of this paper is to provide analytical chemical information on a range of naturally occurring and synthetic coumarins. This analytical chemical information on liquid chromatography-electrospray ionisation-mass spectrometry (HPLC-ESI-MS), ion trap mass spectrometry (ESI-MSⁿ), gas chromatography-flame ionisation detection (GLC-FID) and polarographic behaviour is then incorporated into a database which is of use in identifying unknown coumarins isolated from natural sources. This paper is also concerned with understanding the effect of functional groups in coumarins on their analytical chemical behaviour using the above techniques.     

Constituents from Clausena excavata

Three new coumarins containing a C(10) terpenoid side chain, clauslactones R - T (1 - 3), together with 14 known coumarins (4 - 17) and 11 known carbazole alkaloids (18 - 28), were isolated from the leaves and stems of Clausena excavata. Their structures were established by detailed spectroscopic analyses. Furthermore, the stereochemistry of 1 was confirmed by single-crystal X-ray diffraction analysis, which was the first example among coumarins with a C(10) terpenoid side chain. Additionally, compounds 22 and 27 were found to show moderate topoisomerase II inhibitory effects at 50 microM.     

The Synthesis of a Series of Phosphoryl Coumarins

Different hydroxy substituted coumarins were successfully phosphorylated with diisopropylphophite （DIPPH） by the Atherton-Todd reaction in 76-89% yields. Moreover, the reaction activities of different hydroxys of the coumarins in the Atherton-Todd reaction were studied.     

The characterisation of coumarins from selected structural classes by electrospray ionisation quadrupole time-of-flight tandem mass spectrometry

Electrospray ionisation quadrupole time-of-flight tandem mass spectrometry (ESI-QTOF-MS/MS) has been used for characterisation of a selection of naturally occurring and synthetic coumarins from different structural classes. The product ions, suggested in earlier studies by electrospray ionisation ion trap mass spectrometry (ESI-MS(n)), are unequivocally established for the representative coumarins by virtue of accurate mass measurement. Synthetic coumarins that are unsubstituted in the heterocyclic ring give rise to a major product ion by loss of CO(2), whereas those substituted in the heterocyclic ring generally undergo alternative fragmentation releasing neutral species such as ketene or methyl ketene. Naturally occurring coumarins, unsubstituted in the heterocyclic ring and substituted in the benzene ring with chains or rings of hydrocarbons and oxygen, principally fragment at the side chain releasing unsaturated hydrocarbons. The ESI-QTOF-MS/MS behaviour of some naturally occurring and synthetic quinolines which are structurally similar or fragment similarly are included where appropriate.     

Studies of coumarins from the Chinese drug Qianhu, XXVII: structure of a new simple coumarin glycoside from Bai-Hua Qianhu, Peucedanum praeruptorum

A new simple coumarin glycoside, named praeroside VI (1), along with six known coumarins, were isolated from an aqueous extract of Bai-Hua Qianhu, the root of Peucedanum praeruptorum DUNN. (Umbelliferae). Spectroscopic analysis and chemical studies were carried out to investigate the structure of the new coumarin, which was concluded to be 1. Additionally, two simple glycosidic coumarins and four simple nonglycosidic coumarins were identified as apiosylskimmin (2), hymexelsin (3), umbelliferone (4), scopoletin (5), isofraxidin (6) and 8-carboxy-7-hydroxy coumarin (7), respectively. This is the first reported identification of compound 7 as a constituent of plant materials.     

Simultaneous determination of urinary metabolites of methoxypsoralens in human and Umbelliferae medicines by high-performance liquid chromatography

A high-performance liquid chromatography method has been developed for the determination of coumarins and furocoumarins (psoralens). Nine coumarins and furocoumarins are separated simultaneously on a Hypersil C(8) (25 cm x 4.6-mm i.d.) column with a gradient of methanol and acetonitrile aqueous solution as mobile phase at 1.0 mL/min with two-channel UV-vis absorbance detection. The limits of detection are 0.366, 0.219, 0.317, 0.440, 0.536, 0.300, 0.531, 0.531, 0.237, and 0.280 ng/mL for coumarin, 7-hydroxycoumarin, 7-methoxycoumarin, citropten (5,7-dimethoxycoumarin), 7-ethoxy-4-methylcoumarin, psoralen, xanthotoxin (8-methoxypsoralen), bergapten (5-methoxypsoralen), isopimpinellin (5,8-dimethoxypsoralen), and imperatorin (9-isopenteneoxypsoralen), respectively. Human urine is analyzed 1-6 days after ingestion of the oral Chinese medicines. This lead to the conclusion that the concentration of coumarins and furocoumarins is higher than that of the control urine. The coumarins and furocoumarins are detected at 312 and 249 nm, respectively.     

Structure of polymeric coumarins. I. Determination of the double bonds in copolymers and the initial coumarins by ozonization

The paper gives the results obtained in a study of the structure of coumarin derivatives by the following metheds: ozonization of the double bonds in the monomeric and polymeric coumarins, and also in mixtures of polyvinylpyrrolidone with monomeric coumarins, and the treatment of the monomeric coumarins under the conditions of radical copolymerization but without the participation of N-vinylpyrrolidone.     

Qualitative and quantitative determination of the major coumarins in Zushima by high performance liquid chromatography with diode array detector and mass spectrometry

A method, high-performance liquid chromatography coupled with diode array and electrospray tandem mass spectrometry (HPLC-DAD-ESI-MS), was developed to qualitatively identify and quantitatively determine the 10 major active coumarins of Zushima. The analysis was performed by using a ZORBAX SB-C18 analytical column (250 mm x 4.6 mm ID, 5 microm) at gradient elution of 0.5% aqueous formic acid and acetonitrile with diode array detection (325 nm). The method was validated for linearity, precision, accuracy, limit of detection and quantification. The proposed method was successfully applied for the qualitative and quantitative analysis of 10 coumarins in five different species of Zushima which had great variation on the contents of investigated coumarins.     

Tungstate sulfuric acid catalyzed one-pot synthesis of a new class of aroylamido coumarins under solvent-free conditions

A one-pot synthesis of novel aroylamido coumarins from the reaction of 4-hydroxycoumarin with aryl glyoxals and benzamides in the presence of a catalytic amount of tungstate sulfuric acid (TSA) is described. The method is operationally simple and provides access to a variety of aroylamido coumarins in good yields.     

7-Dialkylamino-3-[1,5-diaryl(3-pyrazolinyl)]coumarins: two-photon absorption in solution and in polymer film

Cross section of the two-photon absorption in 7-dialkylamino-3-(3-pyrazolinyl)coumarins in acetone and polymethylmethacrylate films has been found to be dependent on the substrate and medium nature. 7-Dialkylamino-3-[1,5-diaryl(3-pyrazolinyl)]coumarins are shown to be effective in the photosensitive media with excitation at 1060 nm for optical recording of information.     

Sulfated zirconia, a mild alternative to mineral acids in the synthesis of hydroxycoumarins

Sulfated zirconia (1%) was employed as Pechmann’s catalyst without solvent or in some cases using a small amount of ethanol to obtain coumarins in moderate to good yields. With this procedure, no significant acidic waste was obtained and an environmental friendly alternative to obtain coumarins is provided.     

Chemical constituents of Micromelum minutum. Isolation and structural elucidation of new coumarins

The chemical constituents of an acetone extract of the stems of Micromelum minutum Wight et Arn (Rutaceae), collected at Nakorn-Rachasima province in Thailand, were studied. Six new coumarins, named micromarin-A (1), -B (2), -C (3), -F (4), -G (5), and -H (6), were isolated along with six known coumarins, and their structures were elucidated by chemical and spectroscopic methods.     

Synthesis of Dihydrobenzo[h]coumarins and Their 4‐Methyl Analogs

Dihydrobenzo[h]coumarins (5a–7a) and their 4‐methyl analogs (5b–7b) were synthesized from 1‐naphthol via two different synthetic routes. One pathway is the direct condensation of 5,8‐dihydro‐1‐naphthol (9) with malic acid or ethyl acetoacetate, affording 7,10‐dihydrobenzo[h]coumarins 7a and 7b, respectively. The other is through the oxidation of 7,8,9,10‐tetrahydrobenzo[h] coumarins (15a–b), followed by the reduction of the carbonyl group and dehydration of hydroxyl group, giving 7,8-dihydrobenzo[h]coumarins (5a, b) and 9,10-dihydrobenzo[h]coumarins (6a, b). The regio selectivities for the oxidation reactions of 15a, b were rationalized on the basis of quantum chemical calculations and further confirmed by the X‐ray crystallographic analysis of the derivatives of oxidation products.