Coumarins methylation

Methyl-5,7-dihydroxycoumarin. See 5,7-Dihydroxy-4-methyl coumarin Methyl Di-lcinol. See Methoxydiglycol Methyl dimethylacetate. See Methyl isobutyrate Methyl trans-2,3-dimethylacrylate. See Methyl tiglate... 

Fermentation of Streptomyces niveus in the presence of Me-[ C]-L-methionine yielded novobiocin with an incorporation of 10 per cent of the added isotope °°. The radioactivity was distributed between the 0-methyl and gem-dimethyl groups of the sugar noviose (66 per cent) and the C-methyl group of the coumarin fragment (123,35 per cent) and thus indicated that the coumarin methyl group was formed by a process of C-methylation. The timing of this step is, however, not known. Enzyme systems have been isolated from Streptomyces niveus which are capable of rapid amide bond formation between the isoprenyl 4-hydroxybenzoic acid (125) and the coumarin (123) to give novobiocic acid. The reaction requires ATP and presumably involves some form of activation of the p-hydroxybenzoyl carboxyl function. 

For the preparation of 4-substituted coumarins, a phenol may be condensed with ethyl acetoacetate under the influence of sulphuric acid. Thus resorcinol (II) readily undergoes this condensation (which is represented diagrammatically above) to give 7-hydroxy-4-methyl-coumarin (III). Note that the coumarins, like all 2 pyrones, are systematically lactones. 

Chapter V. Quinaldine (V,2) 2-methyl-, 2 5-dimethyl- and 2-acetyl-thiophene (V,8-V,10) 2 5-dimethyl and 2 4-dimethyl-dicarbethoxy-p3nrole (V,12-V,13) 2-amino- and 2 4 dimethyl-thiazole (V,15-V,16) 3 5-dimethyl-pyrazole (V,17) 4-ethylp3rridine (from pyridine) (V,19) n-amyl-pyridines from picolines) (V,28) picolinic, nicotinic and isonicotinic acid (V,21-V,22) (ethyl nicotinate and p-cyanop3n idine (V,23-V,24) uramil (V,25) 4-methyl-(coumarin (V,28) 2-hyi-oxylepidine (V,29). 

As improvements over P-methylumbeUiferone (55—57), 4-methyl-7-amino-coumarin [26093-31-2] (12a) and 7-dimethylamino-4-methylcoumarin [87-014] (12b) (58—61) were proposed. These compounds are used for brightening wool and nylon either in soap powders or detergents, or as salts under acid dyeing conditions. They are obtained by the Pechmaim synthesis from appropriately substituted phenols and P-ketocarboxyflc acid esters or nitriles in the presence of Lewis acid catalysts (see Coumarin). 

In detergent perfumes, the stabiUty of vanillin is not always certain. It depends on the association made with other raw materials, eg, with patchouli, frankincense, cloves, most of the animal notes, and such chemicals as amyl saUcylate, methyl ionones, heflotropin, gamma undecalactone, linalool, methyl anthrarulate, benzyl acetate, phenyl ethyl alcohol, cedar wood derivatives, oak mosses, coumarin, benzoin. Pern balsam, and cistus derivatives. In some cases, these mixtures can cause discoloration effects. 

For more specific analysis, chromatographic methods have been developed. Using reverse-phase columns and uv detection, hplc methods have been appHed to the analysis of nicotinic acid and nicotinamide in biological fluids such as blood and urine and in foods such as coffee and meat. Derivatization techniques have also been employed to improve sensitivity (55). For example, the reaction of nicotinic amide with DCCI (AT-dicyclohexyl-0-methoxycoumarin-4-yl)methyl isourea to yield the fluorescent coumarin ester has been reported (56). After separation on a reversed-phase column, detection limits of 10 pmol for nicotinic acid have been reported (57). 

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). 

Methylation. Methylating agents such as methyl sulfate and methyl iodide react with coumarin in the presence of sodium hydride to give methyl 2-methoxycinnamate [15854-58-7] (29). 

Benzo[b]furan-2-carboxylic acids bromination, 4, 602 chloromethylation, 4, 602 from coumarins, 3, 686 IR spectra, 4, 590 methyl ester... 

Coumarin, 7-amino-7-(diethylamino)-, I, 333 Coumarin, 7-amino-4-methyl-fluorescence spectra, 3, 601 Coumarin, 7-amino-3-phenyl-brightening agents, I, 339 Coumarin, 4-aryl-occurrence, 3, 677 synthesis, 3, 810 Coumarin, 3-arylazo-4-hydroxy-structure, 3, 643 Coumarin, 3-bromo-reactions... 

Coumarin, 4-methyl-7-methoxy-mass spectra, 3, 608 Coumarin, 4-methylsulfonylmethyl-synthesis, 3, 805 Coumarin, nitro-reduction, 3, 691 Coumarin, 3-nitro methylation, 3, 682 Coumarin, 3-phenoxy-synthesis, 3, 807... 

Coumarin brightening agents, 1, 339-340 Coumarin-4-carboxylic acid methyl ester synthesis, 3, 806 synthesis, 3, 809... 

Coumarin-3-carboxylic acid, 4-methyl-ethyl ester... 

Over the years the literature is filled with examples where the initial characterization was incorrect. One example is illustrated below. In 1940, Sethna and Shah presumed that they synthesized coumarins 42 and 43 from a reaction between P-orcacetophenone (44) and its 4-0-methyl ether 45 under standard Kostanecki-Robinson conditions, respectively. Three decades later Bose and Shah synthesized coumarin 43 via another route and concluded that the initial assignment made by Sethna and Shah was incorrect. After the Bose and Shah findings were published, Ahluwalia and Kumar concluded that the Sethna and Shah products were actually chromones 46 and 47 based on proton NMR data and chemical derivatization. Despite these shortcomings, the Kostanecki-Robinson reaction remains an effective method for formation of both coumarins and chromones. 

Anisic aldehyde, CgHgOj, is a methyl ether of para-oxy-benzaldehyde, which is found to a small extent in the oils of fennel and aniseed. It is manufactured on an extensive scale artificially, and is the basis of all the perfumes of the hawthorn or May blossom type. It is known commercially as aubepine . A certain amount of anisic aldehyde is obtained as a by-product in the manufacture of coumarin, but the greater- part of it is obtained by very careful oxidation of anethol, the characteristic constituent of aniseed oil, which has the constitution—... 

It is the methyl ether of a, phloroglucinol derivative, related to coumarin. Its constitution is as follows —... 

Chemical Name 8-(2-Hvdroxv-3-t-butylaminopropoxv)-5-methyl coumarin hydrochloride Common Name —... 

A mixture of 3 gof 8-(2-hydroxy-3-chloropropoxy)-5-methyl coumarin,4.3 g of t-butylamine and 60 ml of ethenol Is heated et 100°C in a sealed tube for 15 hours. The reaction mixture is concentrated under reduced pressure to dryness. The residue Is recrystallized from a mixture of ethanoi and ether to give 2.1 g of the desired product melting at 226° to 228 C (with decomposition). 

Al Preparation of 7-Hydroxy-4,8-Dimethy/coumarin Chilled ethyl acetoacetate (157 ml, 1.20 mols) followed by 2-methyl-resorcinol (130 g, 1.04 mols) was dissolved in well-stirred concentrated sulfuric acid (600 ml) at such a rate as to keep the temperature below 10°C (ice bath). The stirred solution was allowed to warm gradually and after 3 hours was added to water (ca 8 liters) with mechanical stirring. The product was collected, washed twice with water, and dried at 70° to 80°C until the first sign of darkening. Yield 191.3 g (95.4%). Recrystallization from aqueous ethanol gave 7-hydroxy-4,8-dimethylcoumarin as colorless needles, MP 260.5° to 261°C. In dilute sodium hydroxide, the compound gives a yellow solution which exhibits blue fluorescence. 

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