4- Substituted coumarins, synthesis

Woods LL, Sapp J (1962) A new one-step synthesis of substituted coumarins. J Org Chem... 

Watson BT, Christiansen GE (1998) Solid phase synthesis of substituted coumarin-3-carbox-ylic acids via the knoevenagel condensation. Tetrahedron Lett 39 6087-6090... 

Atkins RL, Bliss DE (1978) Substituted coumarins and azacoumarins. Synthesis and fluorescent properties. J Org Chem 43 1975-1980... 

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],... 

A three-component coumarin synthesis involves the Pd-catalysed coupling of o-iodophenols with alkynes and subsequent insertion of carbon monoxide. With internal alkynes, pyridine is the crucial base for successful annulation the regioselectivity with unsymmetrically substituted alkynes is only moderate (Scheme 43) . 

Substituted coumarins arise from the use of 2-substituted 1,3-dicarbonyl compounds. The synthesis of a number of such keto esters has been described together with their conversion into the coumarin (65JOC4114). The use of hydrogen fluoride in place of sulfuric acid as condensing agent was found to be very advantageous. 

De la Hoz et al. have studied the microwave-assisted synthesis of substituted coumarins by the condensation of phenol, 1,3-dihydroxybenzene/l,3,5-trihydroxy-benzene and propynoic/propenoic acids55. The examples illustrate that the application of heterogeneous supported catalysts can eliminate the production of acidic waste streams, associated with conventional Lewis acid catalysts. This synthetic approach constitutes an interesting alternative to the Pechman reaction (Scheme 3.34). 

Fig. 5.8 Alkenes 19, (hetero)aryl boronates 20 and terminal alkynes 21 applied in the combinatorial synthesis of 3-substituted coumarins.

Kulkarni MV, Patil VD, Biradar VN,Nanjappa S (1981) Synthesis and biological properties of some 3-heterocyclic substituted coumarins. Arch Pharm (Weinheim) 34(5) 435... 

Deshpande, P. R Baker, D. C. A simple approach to the synthesis of the chiral substituted chroman ring of calophyllum coumarins. Synthesis, 1995, 630-632. 

Subhas Bose, D., Rudradas, A. P., Hari Babu, M. The indium(lll) chloride-catalyzed von Pechmann reaction a simple and effective procedure forthe synthesis of 4-substituted coumarins. Tetrahedron Lett. 2002, 43, 9195-9197. 

Coumarin belongs to type 13 mentioned in page 8. Two approaches to its synthesis are possible. One is according to type B and has an oxygen substituted aromatic ring (e.g. PhOH) as the starting compound. A carbon substituent such as —CHO could be introduced at the ortho position and the coumarin synthesis completed by standard methods In the other method which belongs to type A a carbon substituted aro-... 

As exemplified by equation (2), the Perkin condensation of o-hydroxybenzaldehydes is an important method for the synthesis of substituted coumarins. An interesting variation on this procedure has been reported recently. Heating a mixture of o-fluorobenzaldehyde, 2-thiopheneacetic acid, acetic anhydride and triethylamine affords directly the coumarin (20 equation 13) instead of the expected cinnamic acid (21). The reaction proceeds similarly with several arylacetic acids. The reaction presumably proceeds through the cinnamic acids (21). The observed product can conceivably arise by direct nucleophilic displacement involving the carboxylate or by an elimination/addition (benzyne) mechanism. The authors note that when 2-fluorobenzaldehyde is replaced by its 2-bromo analog in this reaction, the substituted cinnamic acid (22) is the major product and the corresponding coumarin (20) is obtained only in low yield. It is suggested that since it is known that fluoride is displaced more rapidly in nucleophilic aromatic substitution reactions, while bromo aromatic compounds form benzynes more rapidly, this result is consistent with a nucleophilic displacement mechanism. 

Coumarins. - There is interest in the synthesis of 3-substituted coumarins cyclization of substituted salicylaldehydes with cyanoacetamide, followed by treatment with phosphoryl chloride in DMF, has given coumarin-3-carbonitriles. High yields of 3-phenylcoumarins were obtained when ortho-hydroxy-aldehydes or -ketones were treated with phenylacetyl chloride-potassium carbonate.When cyclohexane-1,3-diones (187) were condensed with triethyl orthoformate and either urea and thiourea and the initial product (188) was allowed to condense with nitriles, the 3-carboxamide (189) was obtained in good yield.The antibacterial activity of some sulphones has prompted the synthesis of 3-arylsulphonyl-coumarins by oxidation of sulphides. ... 

In the synthesis of coumarins by the von Pechmann reaction, a spiro-compound (251) was simultaneously formed from 4-chloro-2-methylphenol (and from 2,3,5-trimethylphenol). A possible mechanism for this reaction involves the formation of the lactone (252), which reacts with another molecule of the phenol. The condensation of the dicyano-ester (253) [obtained from malononitrile and ethyl cyanoacetate] with substituted o-hydroxybenzaldehydes yields substituted coumarinimines, e.g. (254).A series of 4,6,7-substituted coumarins have been prepared and assessed for their suitability in fluorescence labelling of polymers. Esters of the type PhCH CRCOaAr react with AICI3 to give coumarins, which are probably formed via dihydrocoumarins (255) by dearylation. ... 

Inverse demand Diels-Alder reactions of tetrazines 1 to psoralenes 267 were reported to furnish tetracyclic pyridazine dicarboxylates 268, which were used as the key intermediates in the synthesis of nitrogenated isosteres of potent DNA inhibitors <2003T8171>. In some cases, cycloaddition was followed by opening of the furan ring to give pyridazinyl-substituted coumarins 271 (Scheme 66) <2000JHC907, 2003SL2225>. 

A dual catalyst system piperidine-iodine was used in the synthesis of 3-substituted coumarins through a one-pot three-component reaction of salicylaldehyde derivatives, P-keto esters, and l-(2-aminophenyl)pyrrole in DMF at room temperature (14T2048) and through a four-component reaction of salicylaldehyde derivatives, P-keto esters, ammonium acetate, and isatoic anhydride in DMF at 60°C (Scheme 55) (14SL1596). 

Conjugate addition products 322 and 323 have been subjected to hydro-genolysis in the presence of 10% Pd/C catalyst (Scheme 4.103). " 3-Substituted coumarins 324 were obtained in 50-66% yields from substrates 322 through fission of the benzyl ether and spontaneous cyclization via acyl substitution. Using compounds 323 as substrates, piperidinyl derivatives 325 were obtained in 45-61% yields, and the de-aminated derivatives 326 were also acquired in 9-21% yields. Such a synthetic method may enable the synthesis of multi-substituted coumarins (2//-l-benzopyran-2-ones), which are widely distributed in nature and many of which exhibit pharmacological activities. 

In continuation of previous studies on the development of various catalysts in the synthesis of organic compounds (Karami et al., 2012f,g,h), STA was used as a powerful and reusable catalyst for the new and solvent-free synthesis of 5,7-dihydroxy-4-substituted coumarin via the Pechmann condensation of phlo-roglucinol with P-ketoester (Scheme 3.32). 

Reddy et al. (2009) documented a novel protocol for a Pechmann reaction involving the synthesis of substituted coumarins from phenols and P-ketoesters catalyzed by sulfuric acid supported on the silica gel surface (Scheme 5.28). The method has several distinct advantages such as a clean reaction profile, operational simplicity, use of nontoxic catalysts, and higher yields in short reaction time and provides a valuable addition to the existing methods for the synthesis of coumarins. 

Benyaram, M. R., Boningari, T., Meghshyam, K. P. 2009. One-pot synthesis of substituted coumarins catalyzed by silica gel supported sulfuric acid under solvent-free conditions. Open Catal. J. 2 33-39. 

China Raju, B., Hari Babu, T., Madhusudana Rao, J. 2009. H3PWj204 catalysed efficient synthesis of 4-substituted coumarins. Indian J. Chem. 48B 120-123. 

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