4-Hydroxycoumarine

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). 

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). 

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. 

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. 

In this work, we have studied the reaction of 4-hydroxycoumarin (67) and 3-(dimethylamino-methylene)chromane-2,4-dione (68) with aromatic binu-cleophilic compounds (Scheme 19). 

Hydroxycoumarin (67) was found to react with o-phenylenediamine on refluxing in toluene to give product 69 (Scheme 20). According to the elemental analysis, IR and NMR spectroscopy data, the structure of 4-(2-... 

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). 

We also investigated reaction of 4-hydroxycoumarin with an excess of Ar,Ar-dimethylformamide dimethyl acetal (DMFDMA) which afforded the corresponding 3-(dimethylaminomethylene)-chromane-2,4-dione derivative 72. The structure was again confirmed by IR, NMR, and MS analyses. 

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 transformation using 4-hydroxycoumarin (2-781) as the 1,3-dicar-bonyl compound the cycloadduct 2-794 was obtained also in good yield. In order to demonstrate the general applicability of this process, a small library using substituted pyruvate was prepared without optimizing the reaction conditions for the single transformations. a-Ketonitrile can also be used, though with a much lower yield. 

Gerasov AO, Shandura MP, Kovtun YP (2008) Series of polymethine dyes derived from 2, 2-difluoro-l, 3, 2-(2H)-dioxaborine of 3-acetyl-7-diethylamino-4-hydroxycoumarin. Dyes Pigm 77 598-607... 

Kirkiacharian S, Thuy DT, Sicsic S, Bakhchinian R, Kurkjian R, Tonnaire T (2002) Structure-activity relationships of some 3-substituted-4-hydroxycoumarins as HIV-1 protease inhibitors II. Farmaco 57 703-708... 

The pyranocoumarin 105 can be prepared via a three-component Diels-Alder reaction between 4-hydroxycoumarin, ethyl vinyl ether and an a-dicarbonyl compound. Similarly to the above, upon treatment of 105 with sulfuric acid in THF, hydrolysis and rearrangement occur to give the furofurochromenone 106. The hemiacetal functionality in 106 may then be oxidized with pyridinium chlorochromate (PCC) to give the lactone 107 <2001EJ03711> (Scheme 28). 

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