Coumarine 4-hydroxycoumarin

Many plants produce coumarins coumarin itself is found in sweet clover and contributes to the smell of new-mown hay. However, if sweet clover is allowed to ferment, oxidative processes initiated by the microorganisms lead to the formation of 4-hydroxycoumarin rather than coumarin. 4-Hydroxycoumarin then reacts with formaldehyde, also produced via the microbial degradative reactions, and provides dicoumarol. 

Several important natural compounds have an alkyl chain at the C-3 position of 4-hydroxycoumarins. In a synthesis of 3-geranyl-coumarin, 4-hydroxycoumarin was reacted with an aldehyde to generate intermediate 194, which was trapped with thiophenol to produce 195. Reduction of 195 under hydrogenation conditions in the presence of Raney-Ni catalyst afforded alkylated 4-hydroxycoumarin 196 <19970PP223> (Equation 18). 

Melilotus officinalis Lamk. Flavonoids, resin, tannins, coumarins, hydroxycoumarin, hydrocoumarin.99107 Reduce the risk of phlebitis and thrombosis, sedative, antispasmodic. 

Coum rinic Acid Compounds. These synthetic phyUoquinone derivatives and congeners have been employed as anticoagulants since the isolation of 3,3 -methylenebis(4-hydroxy-2H-l-benzopyran-2-one) [66-76-2] (bis-4-hydroxycoumarin or dicoumarol) (1) from spoiled sweet clover in 1939. The ingestion of the latter was responsible for widespread and extensive death of bovine animals at that time. The parent compound for the synthesis of many congeners is 4-hydrocoumarin, which is synthesized from methyl salicylate by acetylation and internal cyclization. The basic stmctures of these compounds are shown in Figure 2, and their properties Hsted in Table 6 (see Coumarin). 

Oxidation. Coumarin is not readily oxidized by chromic acid but, by action of the Fenton s reagent, it is converted into 7-hydroxycoumarin (umbeUiferone) [93-35-6] (28). 

The literature had reported the preparation of a coumarin hydroxylamine by the reaction of 4-hydroxycoumarin with hydroxylamine. A reinvestigation of the reaction showed the product to be l,2-benzisoxazole-3-acetic acid (Scheme 172) (69JHC279). 

The distributions of phenolic isomers in hydroxylations in the animal body arc often similar to those obtained by Fenton s reagent. For example, the hydroxylation of coumarin by the rabbit gives the six hydroxycoumarins in amounts decreasing in the order 3- >7->6- >8- >4- /—5-, whereas Fenton s reagent gives mainly the 3-, 5-, and 7-derivatives with traces of the 6- and 8-derivatives. It may, however, be misleading to draw conclusions about the nature of... 

Further work in this area showed that only one of the cou-marin rings was needed for biologic activity. Condensation of the hydroxyacetophenone, 4, with diethyl carbonate affords 4-hydroxycoumarin (2). The reaction may involve the 3-ketoester (5) cyclization of this would afford 2. Alternately, the reagent may first give the 0-acyl derivative cyclization as above will give the same product. Michael condensation of the coumarin with benzalacetone (6) affords the anticoagulant warfarin (named after its place of origin Wisconsin Alumni Research Foundation,... 

The Knoevenagel reaction between o-hydroxyaryl aldehydes and ketones and substituted acetonitriles affords high yields of 3-substituted coumarins in aqueous alkaline media <96H(43)1257>, whilst 4-hydroxycoumarins have been elaborated to pyrano [3,2-c]benzopyran-5-ones by reaction with aromatic aldehydes and malononitiile <96P148>. The imine (10) resulting from the complex reaction of o-hydroxyacetophenone with malononitrile undergoes a 1,5-tautomeric shift in solution <96JCS(P1)1067>. 

An improved route to fluorinated 4-hydroxycoumarins has been reported, based on a facile decarboxylation-deacetylation of their 3-(3-oxopropanoic acid) derivatives <96TL15S1>. The reaction of methyl salicylates with triphenylphosphoranylidene ketene, Ph3P=C=C=0, affords 4-methoxycoumarins <96JCS(P1)2799> and the formation of coumarin 3-phosphonates from salicylaldehydes and phosphonoacetates, Et02CCH2P(0)(0R)2, has been investigated <96T12597>. 

In a similar manner, 4-hydroxycoumarin reacts with equimolar amounts of 4-aminothiophenol and 4-aminophenol to give the corresponding coumarin derivatives 71a,b (Scheme 21). 

Hydroxycoumarins and 4-hydroxyquinolinones have also been applied as 1,3-dicarbonyl compounds. Using these compounds, Raghunathan and coworkers prepared pyrano[3,2-c]coumarins [387] and pyranoquinolinones [388] under traditional conditions, while the group of Yadav synthesized similar pyrano[3,2-c]coumarins employing ionic liquids as solvents [389]. 

In a similar manner, reaction of enol ether 2-787, hydroxycoumarin (2-781), and a-diketone 2-786 led to the cycloadduct 2-788 in 79% yield using Yb(OTf)3 as catalyst (Scheme 2.174). 2-788 could be transformed into the natural product preethulia coumarin (2-789). 

Another example of fluorescence intensity modulation in cou-marins is the 3-azido substitution that quenches the fluorescence completely. These compounds are used as starting material for the synthesis of fluorescent triazolocoumarins by click chemistry [31], Interestingly, the fluorescence of some coumarins depends strongly on the solvent. This is the case for 7-alkoxycoumarins that have been used as probes for microenvironments [32], 7-hydroxycoumarin that is pH sensitive, and 7-NR2 substituted coumarins such as coumarin 120 whose quantum yield is reduced in nonpolar solvents due to a change in the 3D structure [33],... 

Coumarin itself has a poor quantum yield, but appropriate substitution leads to fluorescent compounds emitting in the blue-green region (400-550 nm). Substitution in position 4 by a methyl group leads to umbelliferone. 7-Hydroxycoumarins are very sensitive to pH. For example, 4-methyl-7-hydroxycoumarin (4-methyl-umbelliferone) can be used as a fluorescent pH probe (see Chapter 10). 

A derivative of coumarin that has been extensively used for intracellular pH measurement is 4-methylumbelliferone (4-methyl-7-hydroxycoumarin) because of its pKa value of 7.8, the relatively large variation in its fluorescence intensity versus pH, and its low toxicity. Excitation ratio measurements at 365 and 334 nm with observation at 450 nm permit a six- to ten-fold increase over the pH range from 6 to 8. 

The adipoylated film was washed several times with anhydrous toluene and dioxane, followed by reaction with 7-hydroxycoumarin in dioxane containing sodium hydride for 2 hrs at room temperature. After coupling the coumarin, the film was extracted with methanol in a Soxhlet apparatus, rinsed with water, and dried under vacuum... 

The film reacted with adipoyl chloride followed by coupling with 7-hydroxycoumarin was subjected to methanolysis at 1 N HC1 and 60°C. The regenerated coumarin was assayed at pH 10 by fluorescence spectroscopy at an excitation wavelength of 329 nm and an emission wavelength of 455 nm. A Hitachi MPF-4 Fluorescence Spectrophotometer was used for all fluorescence measurements. 

After extraction, the urethanated films were subjected to alkaline hydrolysis of urethanes to liberate the corresponding amines, while the adipoylated films were hydrolyzed after having reacted with 7-hydroxycoumarin. Amounts of the released amines and coumarin were determined by fluorescence spectroscopy as described in the Experimental section. Since aniline as well as butylamine has no appreciable fluorescence by themselves, their fluorescence assay was made after reacting with o-phthalaldehyde in the presence of mercaptoethanol. In Figure 3, where relative fluorescence intensities are plotted as a function of concentrations of amines and hydroxycoumarin, one can see that the fluorescence intensities vary linearly with their concentration to permit us the quantitative determination of extremely small amounts of amines and hydroxycoumarin. 

The orally effective anticoagulant drugs are fat-soluble derivatives of 4-hydroxycoumarin or indan-l,3-dione, and they resemble vitamin K. Warfarin is the oral anticoagulant of choice. The indandione anticoagulants have greater toxicity than the coumarin drugs. 

In xanthenes, even if all one-photon allowed transitions are also two-photon allowed, the shape of the bands and their relative intensities are very different in the IPA and 2PA spectra [76,78]. This is not the case for other laser dyes and chromophores, for which the two spectra are almost identical (if represented as a function of the total transition energy), showing peaks in the same position and with very similar band shapes. Some example of chromophores in this category are coumarin 307 [78], coumarin 102 [80], 7-hydroxycoumarin [81], lucifer yellow [78], and cascade blue [78]. 

Warfarin is a coumarin derivative, namely, 3-(a-acetonylbenzyl)-4-hydroxycoumarin, known to be an antagonist of vitamin K, 2-methyl-3-phyty 1-1,4-naphthoquinone. Some reports (for a review, see Ref. 359)... 

Hadidi et al. (1997) gave members of a family 2 mg coumarin orally and collected their urine for 8 h. One subject excreted < 0.03% of the dose as 7-hydroxy coumarin and 50% as ort/io-hydroxyphenylacetic acid, but three others excreted mainly 7-hydroxy-coumarin (> 41% of dose) and 4-10% as ort/io-hydroxyphenylacetic acid. Oscarson et al. (1998) refer to two individuals (among a population of two hundred) who were totally deficient in 7-hydroxycoumarin excretion after an oral dose of 5 mg coumarin. 

Shilling et al. (1969) reported that after an oral dose of 200 mg coumarin per subject, while 7-hydroxycoumarin accounted for 79% of the excreted dose (range, 68-92%), a further 4% of the dose (range, 1-6%) was present in the first 24-h urine as ort/io-hydroxyphenylacetic acid. 

Unlike in humans, the major metabolic pathway of coumarin in rats is the 3,4-epoxidation pathway. After a 100-mg/kg bw oral dose of [3- C]coumarin, urinary 3-hydroxycoumarin, 7-hydroxycoumarin, ort/zo-hydroxyphenyllactic acid and ortho-hydroxyphenylacetic acid accounted for 1.8, 0.4, 0.8 and 20% of the dose, respectively. Various metabolites including ort/zo-hydroxyphenylacetic acid were detected in the faeces (Kaighen Williams, 1961). Other studies in vivo have confirmed that rats are poor 7-hydroxylators of coumarin, with urinary 7-hydroxycoumarin accounting for < 1% of the dose (van Sumere Teuchy, 1971 Lake et al, 1989a). 

Because of the relative ease of measurement of 7-hydroxycoumarin, many studies have examined this pathway of coumarin metabolism after oral administration. Overall, several species including rats, most mouse strains, Syrian hamsters, guinea-pigs, dogs, marmosets and squirrel monkeys are poor 7-hydroxylators, excreting <5% of the administered dose as urinary 7-hydroxycoumarin (Cohen, 1979 Lake, 1999). 

Certain mouse strains, such as DBA/2 and 129/Rr strains, excrete up to 26% of an intra-peritoneally administered dose of coumarin as 7-hydroxycoumarin (Lush Andrews, 1978). Species such as rabbits, cats and pigs have been reported to excrete 12-19% of the dose as urinary 7-hydroxycoumarin (Kaighen Williams, 1961 Gangolli et ah, 1974 Lake, 1999). In contrast, baboons, like humans, are extensive 7-hydroxylators of coumarin, excreting 60-66% of a dose of coumarin as urinary 7-hydroxycoumarin (Gangolli eta/., 1974 Waller Chasseaud, 1981). 

Apart from glucuronic acid and sulfate conjugation of hydroxycoumarins, other phase II pathways of coumarin metabolism have been identified. For example, ortho-coumaric acid may be conjugated with glycine (Lake, 1999), and a coumarin mercapturic acid conjugate has also been reported (Huwer et al., 1991). Coumarin may also be metabolized by the gastrointestinal microflora to 3,4-dihydrocoumarin and ort/io-hydroxyphenylpropionic acid under anaerobic conditions (Scheline, 1968). 

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