3- -7-hydroxycoumarin

Further transformation included additional hydroxylation steps leading to 2,6-dihydroxyquinoline and a trihydroxyquinoline (probably 2,5,6-trihydroxyquinoline). Shukla [322], working with Pseudomonas sp. identified an alternate pathway, involving additional metabolites, besides the 2-hydroxyquinoline and 8-hydroxycoumarin. These were 2,8-dihydroxyquinoline and 2,3-dihydroxyphenylpropionic acid. Quinoline-adapted cells were also able to transform 2-hydroxyquinoline and 8-hydroxycoumarin without a lag phase, providing additional support for their intermediate role as intermediates in the metabolism of quinoline. 

Schwarz et al. in agreement with Shukla observed the formation of 2-Oxo-l, 2-dihydroquinoline, 8-hydroxy-2-oxo-l, 2-dihydroquinoline, 8-hydroxycoumarin, and 2,3-dihydroxy-phenylpropionic acid were found as intermediates of quinoline transformation by P. fluorescens 3 and P. putida 86 [325], They compared that metabolic pathway with the one obtained for Rhodococcus strain B1 (Fig. 22). This bacterium was unable to yield denitrogenated metabolites (i.e., 2-oxo-l, 2-dihydroquinoline, 6-hydroxy-2-oxo-l, 2-dihydroquinoline, and 5-hydroxy-6-(3-carboxy-3-oxopropenyl)-lH-2-pyridone). 

Figure 23 sketches these four pathways, namely the 5,6-dihydroxy-2(lH)quinolinone pathway, the 7,8-dihy-droxy-2(lH)quinolinone pathway, the anthranilate pathway, and the 8-hydroxycoumarin pathway. 

Quinaldine (2-methyl-quinoline) (2) 2-methyl-4(lH)-quinolinone (3) 3 -hydroxy-2-methyl-4( 1 H)quinolinone (4) N-acetylanthranilic acid (5) Anthranilic acid (6) Catechol (1) Quinoline (2) 2(lH)quinolinone (3) 8-hydroxy-2(lH)quinolinone (4) 8-hydroxycoumarin (5) 2, 3-dihydroxyphenylpropionic acid... 

Acetaldehyde Formaldehyde o-Hydroxyphenylacetic acid 6- Hydroxy coumarin 7- Hydroxycoumarin T same retention 8- Hydroxycoumarin J times for the column used propane phase... 

A family of 8-hydroxycoumarin antibiotics formed by Bacilluspumilus BN-103. A. A exhibits good activity against Gram-positive bacteria as well as Salmonella wdShigella species. Also anti-inflammatory and protective effects against stress-induced stomach ulcers were observed in a rat model. The acute LDsq amounts to 132 mg/kg (mouse p.o.). A. are used as acaricides. 

A simplified procedure is possible by using polyphosphoric acid as the condensing agent. Add 160 g. of polyphosphoric acid to a solution of 11 g. of resorcinol in 13 g. of ethyl acetoacetate. Stir the mixture and heat at 75-80° for 20 minutes, and then pour into ice-water. Collect the pale yellow solid by suction filtration, wash with a little cold water, and dry at 60°. The yield of crude 4-methyl-7-hydroxycoumarin, m.p. 178-181°, is 17 g. Recrystalbsation from dilute ethanol yields the pure, colourless compound, m.p. 185°. 

The antagonisms that exist between unsaturated fatty acids, and carotene and vitamin E are compHcated and largely undefined. Linoleic acid acts as an antivitamin to i7/-a-tocopherol [59-02-9, 1406-18-9, 10191-41-0] (vitamin E) by reducing availabiHty through direct intestinal destmction. Various Hpoxidases destroy carotenes and vitamin A (73). Dicoumarol [66-76-2] (3,3 -methylenebis(4-hydroxycoumarin)) is a tme antimetaboHte of vitamin K [12001 -79-5] but seems to occur only in clover and related materials that are used primarily as animal feeds (74). 

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). 

Hydroxycoumarin [1076-38-6] can be synthesized by cyclization of acetyl methyl salicylate. It is a coumatin metaboHte occurring in spoiled hay. Derivatives of 4-hydroxycoumarin such as dicoumarol [66-76-2] warfarin [81-81-2] cyclocoumarol [518-20-7] ethylbis—coumaracetate [548-00-5] and bis-4-hydroxycoumarin [25892-93-7] are synthetic blood anticoagulants (see Blood, coagulants and anticoagulants). 

Hydroxycoumarin [93-35-6] known as umbeUiferone, occurs naturally in gum resins of umbeUiferae and is an important coumatin metaboHte. It is readily manufactured from resorcinol and maleic or fumaric acid. UmbeUiferone and fymethylumbelliferone are used as fluorescent brighteners. 

Dicoumarol [66-76-2] (5) was isolated from spoiled sweet clover hay. It is prepared synthetically by reaction of 4-hydroxycoumarin with formaldehyde (85). It is used in anticoagulant therapy often associated with heparin. 

Warfarin [81-81-2] (6) is prepared by the Michael condensation of benzyHdene acetone with 4-hydroxycoumarin (86). It is used as a rodenticide (see Poisons, commercial) and in anticoagulant therapy. 

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). 

Hydroxycoumarin [1076-38-6] M 162.1, m 206 , pK st 9.0. Crystd from water and dried in a vacuum desiccator over Sicapent. 

The ultraviolet spectra provide further evidence for the predominance of the hydroxycoumarin structure. The spectra of 4-hydroxycoumarin (20, R = H) and 20 (R = Me) are very similar, indicating that the former exists in the hydroxy form, and this formulation is supported by more recent ultraviolet spectral data." Later, the ultraviolet spectra of 26 (R = H) and 26 (R = Me) were reported to differ, this difference being considered to indicate that 4-hydroxycoumarins exist in a keto form in ethanoP however, this... 

Reaction of 2-chloromethyl-4//-pyrido[l,2-u]pyrimidine-4-one 162 with various nitronate anions (4 equiv) under phase-transfer conditions with BU4NOH in H2O and CH2CI2 under photo-stimulation gave 2-ethylenic derivatives 164 (01H(55)535). These alkenes 164 were formed by single electron transfer C-alkylation and base-promoted HNO2 elimination from 163. When the ethylenic derivative 164 (R = R ) was unsymmetrical, only the E isomer was isolated. Compound 162 was treated with S-nucleophiles (sodium salt of benzyl mercaptan and benzenesulfinic acid) and the lithium salt of 4-hydroxycoumarin to give compounds 165-167, respectively. 

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,... 

Therapeutic Function Anticoagulant, Vitamin K antagonist Chemical Name 3-(Q -acetonyl-p-nitrobenzyl)-4-hydroxycoumarin Common Name Nicoumalone Structural Formula ... 

Chemical Name 4-hydroxy-3-(Tphenylpropyl)-2H-Tbenzopyran-2-one Common Name 3-(Tphenylpropyl)-4-hydroxycoumarin... 

The 3-carbethoxy-3 (1 -phenylpropyl)-4-oxo-dihydrocoumarin may be hydrolyzed and decar-boxylated as follows. The crude product is heated to 85°C for /a hour with 100 parts by volume of 5% aqueous sodium hydroxide, while agitating or stirring. To remove traces of undissolved oil, the cooled solution is treated with 1 part by weight of charcoal, whereupon it is filtrated and acidified to Congo reaction with dilute sulfuric acid. The 3-(1 -phenylpropyl)-4-hydroxycoumarin formed is separated off and recrystallized in 80% ethanol, whereupon it melts at 178°-179°C according to U.S. Patent 2,701,804. 

Chemical Name 3-(a-acetonylbenzyl)-4-hydroxycoumarin sodium salt Common Name —... 

Benzene-1,2-diamines react with 4-hydroxycoumarin to give products 25. It has been established that the reaction proceeds by way of4-substitutedcoumarins 24. Selected examples are given.276... 

A solution of 4-hydroxycoumarin (1.62 g. 10 mmol) and a benzene-1,2-diamine (10 mmol) in xylene (50 mL) was refluxed for 3 h. The solution was cooled and the precipitated product was collected, washed with Et20 or hexane and recrystallized (MeCN or dioxane). 

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>. 

Fergusson, D. (1994). The effects of 4-hydroxycoumarin Anticoagulant Rodenticides on Birds and the Development of Techniques for Non-destructively Monitoring Their Ecological Effects, Ph.D. Thesis, University of Reading, UK. 

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