Hydroxycoumarins synthesis

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). 

Laufer MC, Hausmann H, Holderich WF (2003) Synthesis of 7-hydroxycoumarins by Pechmann reaction using Nation resin/silica nanocomposites as catalysts. J Catal 218 315-320... 

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],... 

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. 

Interestingly enough, a closely related protocol was successfully proposed for the synthesis of spirooxindoles-containing tetrahydrochromene skeletons when aromatic aldehydes were switched for isatin derivatives. This high-yielded reaction was performed with dimedone, 4-hydroxycoumarin, or barbituric acids in water using triethylbenzylammonium chloride (TEBA) as catalyst (Scheme 36) [125]. A Knoevenagel condensation occurred first between isatin and malonitrile derivative, followed by Michael addition of 1,3-dicarbonyl substrates and cyclization to the cyano moiety. 

Research Focus Synthesis of poly(hydroxymaleimide-co-hydroxystyrene) compolymer containing pendant 7-hydroxycoumarin and aliphatic or perfluoaliphatic... 

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... 

The bis(hydroxycoumarin) derivative dicoumarol (45), which was first identified as the causative agent of sweet clover disease in cattle, is used as an anticoagulant in the treatment of thrombosis. Similar compounds with other linking groups have been used, and warfarin (46), which was first introduced as a rodenticide, is also of value. The hydroxycoumarins interfere with the function of vitamin K in the synthesis of prothrombin and other blood... 

A very simple synthesis of coumestrol (228) has been described by Kappe and coworkers (Scheme 46) (74ZN(B)292). It is based upon dehydrogenation of 4-hydroxy-3-phenyl-coumarins to coumestans (720PP233). A number of 2 -hydroxy 3-phenylcoumarins were oxidized with lead tetraacetate to the corresponding coumestans 3-(l-acetoxy-4-methoxy-2-oxo-3,5-cyclohexadienyl)coumarins were obtained as by-products (76BCJ1955). Coumes-tan itself (226) has been obtained by photolysis of the phenol ether (232), which is in turn available from 4-hydroxycoumarin (229) and (diacetoxyiodo)benzene (Scheme 47) (78CB3857) via an iodonium ylide (231). 

Propenonitrile can also function as the three-carbon unit, as in the synthesis of 3,4-dihydro-7-hydroxycoumarin (74IJC564). 

Addition to six-membered oxygen heterocycles is also common. The photocycloaddition of 5,7-dimethoxycoumarin to tetramethylethylene has been described,269 and 4-hydroxycoumarin (326) undergoes facile addition to cyclohexene on direct irradiation to give the cyclobutane (327)270 analogous additions to a variety of other alkenes have been reported, and the cycloaddition of 4-methoxycoumarin to 2-methylpropene has been employed in a synthesis of l,2-dihydrocyclobuta[c]coumarin.271 Photoaddition of the 1,2-bisenol lactone (328) to tran.s-stilbene yields propellane (329),272 and [ 2 + 2] cycloaddition is observed along with other competing photoreactions on irradiation of chromone in the presence of alkenes.273... 

In plants coumarins and hydroxycoumarins are believed to be synthesized from /ram-cinnamic acid (3.29) and /ram-/ -coumaric acid (3.30), respectively, but the exact mechanism for its synthesis is still unknown. One possible biosynthetic route toward coumarin is via o-hydroxylation of 3.29 to give coumaric acid (3.94), followed by glycosylation to result in /ram-coumaric acid-2-O-glucosidc (3.95) (Figure 3-14). 

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). 

This synthesis involves Michael cycloaddition reaction of the readily available 4-hydroxycoumarine 1 with a cyanocrotonitrile 2 in ethanolic piperidine to afforded 2-amino-3-cyano-4-methyl-4H, 5H-pyrano-benzopyran-5-one (3). Treatment of 3 with acetic anhydride for 0.5 h and/or 3 h under reflux afforded N-acetyl and [l]benzopyrano[3/,4/ 5,6]pyrano(2,3-d) pyrimidine-6,8-dione derivatives (4) and (5a), respectively. Also, interaction of 3 with benzoyl chloride or formic acid gave the corresponding pyrimidine derivatives (5b,c) while its treatment with formamide afforded the aminopyrimi-dine derivative (6). 

Oral anticoagulants. Structurally related to vitamin K, 4-hydroxycoumarins act as false vitamin K and prevent regeneration of reduced (active) vitamin K from vitamin K epoxide, hence the synthesis of vitamin K-dependent clotting factors... 

Coumarins are an important family of fragrance chemicals with herbaceous, haylike odors. The conventional methods for coumarin synthesis require drastic conditions. For example, 4-methyl-7-hydroxycoumarin 39 (Eq. 15.4.1) is prepared via the Pechmann reaction by stirring a mixture of resorcinol 37 and ethyl acetoacetate 38 in H2SO4 for 12-14 h (63). 

The value of 4-hydroxycoumarin in synthesis has been discussed <07THC(11)283> and its use in the synthesis of 3,4-disubstituted coumarins has been reported <07JOC7279>. The 3-arylation of 4-hydroxycoumarins, achieved using aryllead triacetates, sets up a substrate for a cascade of reactions which leads to the [2]benzopyrano[4,3-c][l]benzopyran system <07JOC3293> and the EDDA-catalysed reaction of 4-hydroxycoumarin with a,[3-unsaturated arylaldehydes produces pyrano[3,2-c]benzopyran-5-ones <07T10025>. Propargylation and... 

A short and simple synthesis of chromeno[3,4-h][4,7]phenanthrolines 119 has been investigated by Tu and co-workers [167] using a three-component reaction of an aromatic aldehyde, 6-aminoquinoline and 4-hydroxycoumarine in water, under microwave irradiation without any catalyst. This method has the advantage of short reaction time, high yields, low cost and being environment-friendly (Scheme 92). 

In the fused benzofuran series, the same method, applied to bromoacyl-o-hydroxycoumarins ° and bromoacyl-o-hydroxyxan-thones allows the synthesis of the corresponding oxo-dihydrofuro derivatives. The nitrogenated analogs of compounds 237 (2,3-dihydro-3-oxofuro[2,3-6] and -furo[3,2-c] pyridines) have also been obtained. ... 

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