4- substituted coumarin routes

Several older syntheses are based on o-hydroxyacetophenones but these routes generally offer little or no advantage over other methods. The Reformatsky reaction has been used to prepare 3- and 3,4-substituted coumarins (44JIC109) and the Kostanecki-Robinson reaction may yield coumarins instead of or as well as the chromone (see Section 2.24.3.4.1 for further discussion). 

Umbelliferone is the pivotal metabolite in the pathways to substituted coumarins and furano- or pyranocoumarins. Its 7-0-methylation to herniarin (Fig. 4.3) or 0-prenylation and C-alkylation reactions are often observed in coumarin-producing higher plants where the prenylation at C-6 or C-8 mark the entry to the routes branching linear from angular furano- and pyranocoumarins (Fig. 4.5). In Ruta graveolens and Ammi rmjus, the prenylation reactions are catalysed by particulate enzymes (Hamerski et at, 1990), and... 

Most of the common classes of coumarin systems have been synthesized although routes to furanocoumarins in high yield continue to be of interest. Most synthetic effort in the past decade has centered on isopentenyl substituted coumarins, due largely to Murray and his students. In common with many other groups of natural products, emphasis in coumarin chemistry has shifted away from purely chemical matters of isolation, structure and synthesis to areas of... 

Although various methods were reported for the synthesis of 4-substituted coumarin, inconvenient reaction conditions were utilized in most of the previously reported reactions [109]. As mentioned before, route A in Scheme 3.7 is the most widely used in the synthesis of the title compound. For example, Yang described the preparation of 4-substituted coumarin using palladium-catalyzed cross-coupling reaction of 4-tosylcoumarins [110a] and nickel-catalyzed... 

Even though the route A could provide a variety of 4-substituted coumarins, a drawback to this procedure is that some of the organometallic reagents are not readily available. Therefore, in spite of the present methodologies, there is still a need to explore a versatile synthetic methodology for the construction of a chemical library of 4-substituted coumarin derivatives. We considered the alternative route to the synthesis of 4-substituted coumarins, depicted by route B in Scheme 3.7. We assumed that this route could provide a versatile vray of introducing a variety of different substituents at the 4-position of coumarin. The direct preparation and application of 4-coumarinylzinc bromide represents a novel and versatile approach to many new substituted coumarins [113]. 

In conclusion, a novel synthetic route for the preparation of 4-substituted cou-marin derivatives has been demonstrated. It has been accomplished by utilizing a simple coupling reaction of a readily available 4-coumarinylzinc bromide (I), which was prepared via the direct insertion of active zinc to 4-bromocoumarin. The subsequent coupling reactions with a variety of different electrophiles have been carried out under mild conditions, providing a new class of 4-substituted coumarins. 

R. Girotti, A. Marrochi, L. Minufi, O. Piermatti, F. Pizzo, L. Vaccaro, Diels-Alder reactions of 3-substituted coumarins in water and imder high-pressure condition. An uncatalyzed route to tetrahydro-6H-benzo[c]chromen-6-ones, J. Org. Chem. 71 (2006) 70-74. 

The vigorous conditions which are necessary serve to detract from the value of the Perkin synthesis, leading to the production of tarry material which adversely affects the yield of coumarin. Difficulties encountered in the synthesis of substituted o-hydroxybenzaldehydes also limit the application of this route. The obvious advantages of the method are that there are no doubts about the orientation of the product and that, unlike the Pechmann reaction, formation of the isomeric chromones is not possible. 

The second route to this key intermediate (49) also oecured along two paths, both emanating from the readily available dihydroxy-4-methylcoumarin (53). Ben-zylation115) of the dihydrie phenol (53) afforded a mixture of the desired 5-ben-zyloxy-7-hydroxy substituted (54), and the dibenzylated derivative (55). Methyla-tion of the monoprotected coumarin (54), then gave the desired (49). 

Coupling of 4-tosyloxypyran-2-ones with organozinc reagents or with electron-rich alkenes are useful routes to 4-substituted derivatives <05CL796, 05OL5585>. Both 4-hydroxypyran-2-ones and the related coumarins yield coumestans on reaction with catechols in the presence of O2 and catalysed by lacasse enzymes <05SL3126>. 

The Pd-catalysed reaction of phenols with propynoic acids offers an atom-economic and green route to coumarins. Although the reaction with propynoic acid itself is not regioselective, 3-phenylpropynoic acid gives a single product from w-substituted phenols <04S1466>. The synthesis of coumarins both from alkynes, CO and iodophenols and by the reaction of phenols with propiolic esters is facilitated by Co/Rh nanoparticles <04SL2541>. 

Among polyheterocyclic systems, coumarins are synthesized by many routes, including the Pechmann reaction [51], which involves condensation of phenols with yS-ketoesters. This reaction, which has been the most widely applied method, has recently been studied under the action of MW irradiation by several authors [52], including the GS-MW process for 4-substituted 7-aminocoumarins [53]. Synthesis of methyl 7-aminocoumarin-4-carboxylates (51 and 52) by the Pechmann reaction involves heating a mixture of m-aminophenol and dimethyl oxalate at 130 °C (Scheme 9.17). Under such conditions, however, the yield of the reaction is variable, usually low (36%). Use of graphite as a support led to the expected lactone in slightly better yield (44%). 

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. ... 

S. Cacchi, G. Fabrizi, L. Moro, P. Pace, Stereo- and regioselective palladium-catalyzed hydroarylation and hydrovinylation of functionalised alkynes a route to substituted Z-2-cinnamyl esters, 3-chromen-2-ols, and coumarins, S)fnlett (1997) 1367-1370. 

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