4-Hydroxycoumarin compounds

The MIC of the acetates esculetin 2Ac (2a) and fraxetin 2Ac (4a ) were found to be equal to those of the parent compounds 2 and 4. Most probably, acetylation of the phenolic OH does not alter the antibacterial activity of the hydroxycoumarins. Compounds 4 and 4a are the most potent inhibitors of S. aureus among the tested Fraxinus ornus components. 

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°. 

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). 

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. 

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). 

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. 

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). 

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],... 

Also, (5-phenyl-l,3,4-oxadiazol-2-yl)-7-hydroxycoumarin is a tautomeric compound. In dilute solutions it is almost totally present in its protonated nitrogen tautomeric form. The deprotonation is a reversible process (Scheme 2). Quantum-mechanical calculations were carried out and correlated with experimental observations <2000SAA1773>. 

Reaction of 1,3-dicarbonyl compounds with vinyl sulfides gives the corresponding medium- and large-sized ring substituted furans 78 in moderate to good yields. In addition to cyclohexane-1,3-diones, 4-hydroxycoumarins and 4-hydroxyquinone can also be used as 1,3-dicarbonyl components . 

The enantioselective reduction of unsaturated alcohol derivatives has been applied to the synthesis of several biologically active compounds (Scheme 24.12). Warfarin (123, R=H) is an important anticoagulant that is normally prescribed as the racemate, despite the enantiomers having dissimilar pharmacological profiles. One of the earliest reported uses of DuPhos was in the development of a chiral switch for this bioactive molecule, facilitating the preparation of (R)- and (S)-warfarin [184]. Although attempted reduction of the parent hydroxycoumarin 122 (R=H) led to formation of an unreactive cyclic hemiketal, hydrogenation of the sodium salt proceeded smoothly with Rh-Et-DuPhos in 86-89% ee. 

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). 

Compounds 1 = 4-hydroxycoumarin 2 = umbelliferon 3 = 4-methyl-esculetin 4 = isopimpinellin 5 = esculin 6 = flavone 7 = a-naphtoflavone 8 = kaempferol 9 = quercetin 10 = isoquercitrin 11 = robinetin 12 = robinin 13 = myricetin 14 = luteolin 7-O-glucoside 15 = rutin 16 = hes-peretin 17 = hespiridin 18 = naringin 19 = pelargonin chloride 20 = polargonin chloride 21 = malvin chloride. 

Mechanistic aspects of the intermolecular cyclization reaction in the anodic oxidation of catechol in the presence of 4-hydroxycoumarin were discussed in Sect. 2.2. This reaction is a synthetically simple and versatile method for the preparation of formally [3 + 2] cycloadducts between a -diketo compound and catechol [44,45]. Anodic oxidation of catechol using controlled potential electrolysis (E = 0.9-1.1 V vs SCE) or constant current electrolysis (i = 5 mA/cm ) was performed in water solution containing sodium acetate (0.15 mol/1) in the presence of various nucleophiles such as 4-hydroxycoumarin,... 

Hydroxycoumarin can be considered as an enol tautomer of a 1,3-dicarbonyl compound conjugation with the aromatic ring favours the enol tautomer. This now exposes its potential as a nucleophile. Whilst we may begin to consider enolate anion chemistry, no strong base is required and we may formulate a mechanism in which the enol acts as the nucleophile, in a simple aldol reaction with formaldehyde. Dehydration follows and produces an unsaturated ketone, which then becomes the electrophile in a Michael reaction (see Section 10.10). The nucleophile is a second molecule of 4-hydroxycoumarin. 

The Knoevenagel reaction consists in the condensation of aldehydes or ketones with active methylene compounds usually performed in the presence of a weakly basic amine (Scheme 29) [116], It is well-known that aldehydes are much more reactive than ketones, and active methylene substrates employed are essentially those bearing two electron-withdrawing groups. Among them, 1,3-dicarbonyl derivatives are particularly common substrates, and substances such as malonates, acetoacetates, acyclic and cyclic 1,3-diketones, Meldrum s acid, barbituric acids, quinines, or 4-hydroxycoumarins are frequently involved. If Z and Z groups are different, the Knoevenagel adduct can be obtained as a mixture of isomers, but the reaction is thermodynamically controlled and the major product is usually the more stable one. 

Phenprocoumon Phenprocoumon, 3-(a-ethylbenzyl)-4-hydroxycoumarin (24.1.14), is synthesized by acylating sodium salts of diethyl ester (l-phenylpropyl)butyric acid with acetylsalicylic acid chloride, which forms the compound 24.1.12, which upon reaction with sodium ethoxide cyclizes to 3-(a-ethylbenzyl)-2-carboethoxy-4-hydroxycoumarin (24.1.13). Alkaline hydrolysis of this product and further decarboxylation gives phenprocoumon (24.1.14) [21-28]. 

Bom et al. (2000) demonstrated that ort/20-hydroxyphenylacetaldehyde (4 mmol/L) was much more cytotoxic than coumarin (4 mmol/L) to Chinese hamster ovary cells Kj, a cell line that does not contain cytochromes P450. When both of these compounds were investigated in metabolically active hepatocytes isolated from male Sprague-Dawley rats, ort/20-hydroxyphenylacetaldehyde (0.8 mmol/L) caused a greater cytotoxic response compared with coumarin (0.8 mmol/L). 3-Hydroxycoumarin (0.8 mmol/L), not a product of coumarin epoxidation, did not cause a change in cell viability or an increase in lactate dehydrogenase activity. 

Work on carbohydrates almost ceased in the laboratory after 1954, when Roseman, Huebner, Pankratz, and Link published studies on the metabolism of 4-hydroxycoumarin in an effort to learn something about the fate of Dicumarol in animals. They showed that the /3-D-glu-cosiduronic acid of this compound is secreted in the urine of dogs after it had been injected intravenously. The identity of the D-glucosi-duronic acid was confirmed by its chemical synthesis from 4-hydroxycoumarin and methyl tetra-O-acetyl-a-D-glucopyranosyluronate chloride. 

The hydrolysis of the Schiff base 63 is an acid-catalyzed reaction initiated by the protons liberated during the anodic oxidation. A successful synthesis could be achieved in an undivided cell. The starting compound 63 was oxidized at the anode, and the liberated protons were reduced at the cathode the solution did not become too acidic. This reaction was applied to the oxidation of 3-arylidenamino-4-hydroxycoumarin, which gave the expected 1,3-oxazole derivatives.78 The mechanism of the conversion 63 -> 64 involves... 

Quinolone (122), 2-pyridone (123), kojic acid (124) and 4-hydroxycoumarin (125) couple with diazonium salts (to form azo compounds, e.g. 126) and undergo Mannich reactions (e.g. with HCHO + HNMe2 to form -CH2NMe2 derivatives) at the positions indicated. Chromones undergo the Mannich reaction to give, for example, (127). 

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