Coumarin-3-carboxylic acid esters

MeO, R = Me, R = H) have been prepared in moderate yields by oxidation of the benzopyrano[3,2-c]coumarins (32) to the chromones (33) whose lactone group was then simultaneously hydrolysed and methylated [121], The methyl ester (31, R = Me) of the flavone-3-carboxylic acids was obtained when sufficient dimethyl sulphate was present. By a similar sequence of reactions, a 5,6-benzo-homologue of the 3-carboxylic acid ester was prepared. 

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

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

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

Coumarin-3-carboxylic acid, 6-nitro-ethyl ester reduction, 3, 691 Coumarinic acid synthesis, 3, 685 Coumarinoisocoumarin synthesis, 3, 834 Coumarins acetoxylation, 3, 680 acylation, 3, 689 annelated... 

Irreversible inhibition is probably due to the alkylation of a histidine residue.43 Chymotrypsin is selectively inactivated with no or poor inhibition of human leukocyte elastase (HLE) with a major difference the inactivation of HLE is transient.42,43 The calculated intrinsic reactivity of the coumarin derivatives, using a model of a nucleophilic reaction between the ligand and the methanol-water pair, indicates that the inhibitor potency cannot be explained solely by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack 43 Studies on pyridyl esters of 6-(chloromethyl)-2-oxo-2//-1 -benzopyran-3-carboxylic acid (5 and 6, Fig. 11.5) and related structures having various substituents at the 6-position (7, Fig. 11.5) revealed that compounds 5 and 6 are powerful inhibitors of human leukocyte elastase and a-chymotrypsin thrombin is inhibited in some cases whereas trypsin is not inhibited.21... 

Several aryl esters of 6-chloromethyl-2-oxo-2//-l -benzopyran-3-carboxylic acid act as human Lon protease inhibitors (alternate substrate inhibitors)46 without having any effect on the 20S proteasome. Proteasomes are the major agents of protein turnover and the breakdown of oxidized proteins in the cytosol and nucleus of eukaryotic cells,47 whereas Lon protease seems to play a major role in the elimination of oxidatively modified proteins in the mitochondrial matrix. The coumarin derivatives are potentially useful tools for investigating the various biological roles of Lon protease without interfering with the proteasome inhibition. 

Coumarin. The coumarin moiety is found in a number of important drugs. This is a bicyclic heterocycle containing two six-membered rings and two oxygens, one endo-cyclic, one exocyclic. Since the coumarin contains an intramolecular lactone ester, it undergoes hydrolysis to yield a carboxylic acid and a phenol. 

The susceptibility of the indole ring towards electrophilic attack has also been exploited by Merour in the annulation of a coumarin unit to the indole ring. The heating of the o-bromophenyl ester of indole-2-carboxylic acid in the presence of a palladium-triphenylphosphine catalyst led to the formation of the tetracyclic product in 66% yield (4.32.)40... 

Salicylaldehydes and some o-hydroxyaryl ketones react with Meldrum s acid to give coumarin-3-carboxylic acids <03TL1755>. 3-Cyanocoumarins, and thus the 3-carboxylic acids, are available in high yield from a Knoevenagel reaction between salicylaldehydes and malononitrile in water <0382331>. 3-Chlorocoumarins result from the cathodic reduction of trichloroacetyl esters of o-hydroxyacetophenones <03T9161>. 

We have been particularly enamored with the development of experiments involving carbon-carbon bond formation, especially as part of tandem reactions occurring in a single container (see the Diels-Alder reaction. Figure 1). One such reaction is the synthesis of simple esters of coumarin-3-carboxylic acids via a Knoevenagel condensation between malonic esters and various a-hydroxybenzaldehydes, followed by intramolecular nucleophilic acyl substitution. This conversion, catalyzed by piperidine, has been carried out under a variety of conditions, for example, at room temperature without solvent... 

Fairly high yields of coumarins are obtainable by irradiation for 4-6 h of methoxycinnamic acids in acetonitrile-water saturated with oxygen and containing naphthalene-1,4-dinitrile. Further routes to the flavone ring system continue to appear. Flavone-3-carboxylic acids are ao ssible from fi-phenoxybenzylidenemalonic acids and either sulphuric acid or trifluoroacetic acid-trifluoroacetic anhydride. Attempts to cyclize the malonic esters were less... 

The same effect has been reported for the coumarins hydroxylated at C- 7 and/or C- 8 positions [260]. Namely, the 3-carboxylic acids and ester derivatives (55b,c) were less active than their 3-unsubstituted congeners umbelliferone and daphnetin (55a,d) against phytopathogenic fungi. Acetylation of the hydroxyl groups generally increased the activity, probably due to the increase in lipophilic characteristics of these compounds. 

Condensation of 4,6-dimethoxy-2-hydroxyacetophenone with diethyl carbonate and an alkoxide ion has now been shown to give the coumarin-3-carboxylic ester (245), and not 4-hydroxy-5,7-dimethoxycoumarin (246), as originally reported. Heating the ester with aqueous alkali resulted in hydrolysis and decarboxylation to (246). The well-established acid cyclization of salicyl-aldehyde with ethyl cyanoacetate to give coumarin-3-carboxylic acids has been studied in alkaline media and found to give the ester (247 X = O) and the imino-ester (247 X = NH). When the proportion of the cyano-ester was increased, high yields of the latter were obtained. "... 

---