3-substituted coumarin

The Knoevenagel reaction between o-hydroxyaryl aldehydes and ketones and substituted acetonitriles affords high yields of 3-substituted coumarins in aqueous alkaline media <96H(43)1257>, whilst 4-hydroxycoumarins have been elaborated to pyrano [3,2-c]benzopyran-5-ones by reaction with aromatic aldehydes and malononitiile <96P148>. The imine (10) resulting from the complex reaction of o-hydroxyacetophenone with malononitrile undergoes a 1,5-tautomeric shift in solution <96JCS(P1)1067>. 

Brufola G, Fringuelli F, Piermatti O, Pizzo F (1996) Simple and efficient one-pot preparation of 3-substituted coumarins in water. Heterocycles 43 1257-1266... 

One-pot conversions of 2-hydroxy(acylbenzenes) with anhydrides or acid chlorides to produce coumarins [52-54] and flavones [54-58] under mild liquiddiquid or solidtliquid two-phase conditions via a Baker-Venkataraman type reaction (Scheme 6.19) are catalysed by quaternary ammonium salts. 3-Substituted coumarins are produced from salicylaldehyde and malonodinitrile, or substituted acetonitriles, in high yield (>85%) in a one-pot catalysed sequential aldol-type reaction and cycliza-tion in the absence of an added organic solvent [59]. When 2 -hydroxychalcones are reduced under catalytic two-phase conditions with sodium borohydride, 2,4-cis-flavan-4-ols are produced [60] (see Section 11.3). 

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. 

Keywords aromatic hydroxyaldehyde, ethyl malonate, methyl malonate, Knoe-venagel reaction, microwave irradiation, 3-substituted coumarin... 

The hyperbaric 4 + 2-cycloaddition of 1,2,4-trioxegenated 1,3-dienes with dieno-philes, A-phenylmaleimide, and methyl and phenyl acrylates produced the expected endo-cycloadducts with excellent stereo- and regio-control.113 The high-pressure (g) Diels-Alder reactions of 3-substituted coumarins with methylbuta-1,3-dienes in water formed tetrahydro-6H-benzo[c]chromen-6-ones in high yields (85-95%).114... 

A variety of 3-substituted coumarins react with an excess of dimethylsulfoxonium methylide, presumably forming the 3,4-fused cyclopropane derivative which rearranges to the cyclopenta[ >] benzofuran (95TL5603). 

The use of coumarin in Diels-Alder reactions is, by comparison to pyran-2-ones, still largely unexplored. This is likely due to the low reactivity of the double bond at positions 3 and 4. Diels-Alder reactions with 3-substituted coumarins are rare, despite the potential to synthesize tetrahydro-6//-benzo[c]chromen-6-ones, important precursors to functionalized biphenyls and several natural products. Electron-withdrawing substitution at C-3 does not serve to efficiently activate the dienophilic system thus, it has been found that high temperatures and pressures are necessary to effect the reaction (e.g., Equation 25) <2006JOC70>. 

Esterification of salicylaldehydes with acetic acid derivatives forms 2-formylphenyl acetate intermediates, which cyclize in high yield to afford 3-substituted coumarins (Scheme 168) <2004SC3129>. 

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

Fig. 5.10 3-Substituted coumarin derivatives 26 with high fluorescence quantum yields identified by screening of substance libraries.

The direct irradiation of the parent coumarin in the presence of alkenes results only in an inefficient photodimerization and [2 + 2]-photocycloaddition. Lewis acid coordination appears to increase the singlet state lifetime, and leads to improved yields in the stereospecific [2 + 2]-photocycloaddition [95]. Alternatively, triplet sensitization can be employed to facilitate a [2 + 2]-photocycloaddition. Yields of intramolecular [2 + 2]-photocycloadditions remain, however, even with electron-rich alkenes in the medium range at best. The preference for HT addition and for formation of the exo-product is in line with mechanistic considerations discussed earlier for other triplet [2 + 2]-photocycloadditions [96, 97]. Substituted coumarins were found to react more efficiently than the parent compound, even under conditions of direct irradiation. 3-Substituted coumarins, for example, 3-methoxy-carbonylcoumarin [98], are most useful and have been exploited extensively. The reaction of 3-ethoxycarbonylcoumarin (100) with 3-methyl-l-butene yielded cleanly the cyclobutane 101 (Scheme 6.36) with a pronounced preference for the exo-product (d.r. = 91/9). Product 101 underwent a ring-opening/ring-closure sequence upon treatment with dimethylsulfoxonium methylide to generate a tetrahydrodibenzofur-an, which was further converted into the natural product ( )-linderol A (102) [99]. 

Substituted coumarins react with butadienes in water at 150 °C and in CH2CI2 under pressure to give the cycloadducts, tetrahydrodibenzo[6,r/]pyranones, the precise structure of which is dependent on the diene used (Scheme 31) <06JOC70>. 

Cycloadditions between 3-substituted coumarins 5 and dienes 6 allow various novel coumarin derivatives to be prepared regioselectively in high yields (Scheme 7.2). 

The moisture- and air-stable ionic liquids, l-butyl-3-methylimidazolium tetra-lluoroborate [bmim]BF and l-butyl-3-methylimidazolium hexafluorophosphate [bmim]PFg, were used as green recyclable alternatives to volatile organic solvents for the ethylenediaimnonium diacetate-catalyzed Knoevenagel condensation between aldehydes or ketones with active methylene compounds. As described by Su et al. [57], the ionic hquids containing a catalyst were recycled several times without decrease in yields and reaction rates. In the case of 2-hydroxybenzaldehyde, the reactions led to the formation of 3-substituted coumarin derivatives in high yields of up to 95% (Scheme 17.11). When ethyl cyanoacetate was used, 2-imino-27f-l-benzopyran-3-carboxyhc acid ethyl ester was formed. 

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. ... 

Reagent 1 has been used to provide rapid access to a variety of 3-substituted coumarins (29 and 30) in good yield. 

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. 

Rhodium-catalyzed-carbonylation of o-alkynyl phenols has resulted in the formation of 3-substituted coumarins and 3-substituted benzofuran-2-ones, under the water-gas shift reaction conditions (Takashi et al. 1998). Rhg(CO)ig was employed as the catalyst in the carbonylation. The reaction has been shown to involve oxidative addition and insertion of carbon monoxide followed by reductive elimination. Coumarins were obtained in low yield (20%-40%) (Scheme 10.4). 

In a similar way, use of substituted acetonitriles in the above procedure (Scheme 38) give the corresponding 3-substituted coumarins in 66-98% yields (Scheme 39). 

The 3 + 2-cycloaddition reaction of azomethine ylides with c-deficient alkenes produced polysubstituted l- and D-unnatural prolines. Also, phosphoramidite-(7u(OTf)2 complexes catalyse the 1,3-dipolar cycloaddition reactions of azomethine ylides with nitroalkenes to yield exo-tetrasubstituted proline esters." The 1,3-dipolar cycloaddition of non-stabilized azomethine ylides, from iV-alkyl-a-amino acids and aldehydes, with 3-substituted coumarins provides l-benzopyrano[3,4-c]pyrrolidines in good yields and high regio- and stereo-selectivity." The organocatalytic 1,3-dipolar cycloaddition of azomethine ylides, derived from azlactones, with methyleneindolinones produced spirooxindoles with high yields (up to 95%) and high diastereo- (93 7 dr) and enantioselectivity (98% ee). ... 

Cyclocondensation of alkynoates with donor-substituted phenols mediated by Pd(0) or Co/Rh nanoparticles leads to 3-substituted coumarins, for example, 21 [38] ... 

Table 7.2 Synthesis of 3-substituted coumarins in aqueous and ethanolic media...

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. 

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