Aryl coumarins derivatives

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. 

Using Pd-mediated cross-coupling reactions, such as Suzuki, Heck, and Sonoga-shira- Hagihara reaction, researchers efficiently constructed a library of 151 coumarin derivatives from eight 3-bromocoumarins cross-coupled with ten aryl/heteroaryl boronic acids, ten alkenes, and ten alkynes (Fig. 4). 

Synthesis of the benzopyran ring has also been performed by microwave-assisted copper-catalysed cross coupling of an aryl iodide with terminal alkynes, in the presence of copper(I) iodide/triphenylphosphine (Scheme 3.35)56. An alternative approach involving microwave heating of mixtures of salicylaldehyde and various derivatives of ethyl acetate in the presence of piperidine has enabled rapid Knoevenagel synthesis of coumarin derivatives (Scheme 3.35)57. 

Recently, a new method for synthesizing coumarin derivatives has exploited the properties of aryl-cerium reagents, as illustrated in Scheme 19/ Interestingly, the bulky arylcerium reagent (13) adds to the easily enolizable r-butyl acetoacetate in satisfactory yield. 

Coumarin Derivatives Coumarins are known as an interesting class of laser dyes. Various structures are able to behave as type II photoinitiators (they work in their first excited singlet state) or to sensitize the photolysis of peresters or bis-aryl imidazoles [210] (see below). 

Synthesis and photochromism of aryl(heteroaryl)- and diheteroaryle-thenes Coumarin derivatives 13HC219. 

Starting from scaffold 178 linked to Rink amide resin, two libraries of psolaren analogs (181 and 182) were prepared from a common o-dianilino intermediate 180. The benzoimidazole ring of psolaren analogs 181 was formed upon treatment of 180 with aryl isothiocyanates in the presence of Die, whereas for analogs 182 cyclization was carried out with l,T-thiocarbonyldiimidazole (TCD) followed by S-alkylation with alkyl hahdes in the presence of Af,Af-diisopropylethylamine. The unique spectral properties of these coumarin derivatives indicated that they may be useful in photochemotherapy. 

This procedure facilitated the modihcation and purification of coumarin derivatives, but it was restricted to one-dimensional chemical diversity. Lam and coworkers overcame this limitation and improved the overall synthetic efficiency using 7-fluoro-4-methyl-6-nitrocoumarin-3-carboxylic acid as a scaffold with three potential derivatization points (Figure 14.5). After loading the carboxyhc acid onto a Rink amide resin, the aryl fluoride underwent aromatic nucleophihc substitution and the nitro group was reduced to render an additional heterocycfic ring that could incorporate further diversity. This versatile synthetic route yielded a wide spectrum of coumarin dyes, such as imidazocoumarins, lactam coumarins, and thioimidazocoumarins. ... 

Recently, the synthetic utility of dimethyl formamide (DMF) as the nucleophilic trigger in aryne MCRs was developed independently by the Miyabe and Yoshida groups. The three-component coupling reaction between aryne, DMF, and an active methylene compound such as acetyl acetone, dibenzoyl methane, cyclohexane 1,3-dione, etc. resulted in the formation of either 2H-chromenes 105 or coumarin derivatives 106 [75,76]. The insertion of fhe carbonyl group of DMF to the aryne generates the o-quinone methide intermediate 104. Subsequent reaction of 104 with cyclic or acyclic 1,3-diketones as the third component resulted in the formation of 2H-chromenes 105. Intriguingly, furnished coumarin derivatives 106 were formed when 3-ketoester or a-(hetero)aryl esters were used as the third component (Scheme 53). 

While the hydroarylation of ethyl propiolates affords dx-cinnamates, aryl propiolates undergo intramolecular hydroarylation to give coumarin derivatives (Scheme 18.25) [23]. For example, the reaction of 4 -tcrt-butylphenyl phenylpropiolate in the... 

The arylation of alkenes by treatment with a diazonium chloride (or bromide) solution and cupric chloride (or bromide) is called the Meerwein arylation reaction, after its discoverer (Meerwein et al., 1939). Originally, it was discovered using a,P-unsaturated carbonyl compounds, namely coumarin (Scheme 10-43) and cinnamic derivatives (Schemes 10-44 and 10-45). As Scheme 10-45 shows, the Meerwein reac-... 

The arylation of alkenes was discovered by Meerwein146 in 1939 using ,/)-unsaturated carbonyl compounds, namely coumarin and cinnamic derivatives. Diazotizations for Meerwein reactions are made in aqueous HC1. The substitution proper may be combined with addition of HC1 to the double bond. As catalyst, CuCl2 is used. Various observations (see elsewhere7k) demonstrate that in typical Meerwein systems, part of Cu11 is reduced to Cu1. 

Hydroxycoumarins can be converted into 4-arylcoumarins via the Pd-catalysed coupling of 4-stannylcoumarins with aryl iodides (95SC2883), whilst the three component reaction of 4-hydroxy-coumarins, triethyl orthoformate and hydrazines yields A-derivatives of 3-methylenechroman-2,4-diones (95M579). 

Tolmetin Sodium, USP. Tolmetin sodium. I-methyl-5-(p-toluoyl)pyrrule-2-acetate dihydrate sodium. McN-25.<9 (Tolectin). is an arylacetic acid derivative with a pyrrole a- the aryl group. This drug is absorbed rapidly, with a lela-tivcly short plasma half-life (I hour). It is recommended for use in the management of acute and chronic RA. It shm- similar, but le.ss frequent, adverse effects with aspirin. Il doe-not potentiate coumarin-like drugs nor alter the Mood levels of sulfonylureas or insulin. Like other drugs in this class, it inhibits prostaglandin synthetase and lowers PCE blood levels. 

The reaction mechanisms have been explored in the coumarin, ketocoumarin, or titanocene derivative/bis-aryl imidazole Cl-HABPmercaptobenzoxazole system [240]. For example (10.67), when the sensitizer is the coumarin Cl, an electron transfer occurs and the formed Cl-HABI radical anion leads to a lophyl radical that undergoes a hydrogen transfer with the thiol SH (the lophyl radical anion reacts with the thiol radical cation). The Cl/SH interaction can also participate in the initiation process. The role of new thiols and disulfides has been recently studied [241]. 

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