Coumarins electrophilic substitution

Coumarin, 6-ethoxycarbonyl-4,5,7-trihydroxy-synthesis, 3, 805-806 Coumarin, 3-hydroxy-Mannich reaction, 3, 680 mass spectra, 3, 609 Coumarin, 4-hydroxy-alkylation, 3, 692 azo dyes from, I, 331 electrophilic substitution, 2, 30 IR spectra, 3, 596 Mannich reaction, 3, 680 mass spectra, 2, 23 3, 609 molecular structure, 3, 622 reactions... 

Whereas benzopyrylium salts are resistant to electrophilic substitution, even in the benzene moiety, the benzopyrones [coumarins (81), isocoumar-ins (82), and chromones (83)] are readily halogenated in either ring, with... 

Electrophilic aromatic substitution of other benzo-fused v-deficient systems generally follows predictable pathways. Thus, benzopyrylium salts are in general resistant to electrophilic substitution even in the benzo-fused ring. Chromones behave somewhat similarly, although substitution can be effected under forcing conditions. Coumarins, on the other hand, undergo nitration readily in the 6-position while bromination results in substitution at the 3-position as a consequence of addition-elimination. 

The chemical reactivity of coumarin to a large extent resembles that of pyran-2-one. Electrophilic substitution occurs preferentially in the carbocyclic ring at C-6. Substitution at C-3 can also occur when more vigorous conditions are employed. Coumarin is readily attacked by nucleophiles, giving rise to a variety of ring-opened products. 

An electrophilic substitution of potential synthetic value but one which is rarely utilized is the introduction of a mono- or di-acetoxymethyl group by the action of manganese(III) acetate on a coumarin. This ring system is more amenable than many to this reagent and a variety of products may be obtained by altering the ratio of reactants (Scheme 12) (79BCJ2386). 

Pd-catalyzed reaction of o-iodophenol (26) with alkynes offers a good synthetic method of functionalized benzofurans 27. The silyl group in the benzofuran 27, obtained from tri-isopropylsilylalkyne, can be used for electrophilic substitution or desilylation to yield 28 [11]. In the reaction of 26 under CO atmosphere (1 atm), the insertion of 4-octyne occurs in preference to the insertion of CO to generate the alkenylpalladium 29, to which CO insertion occurs to afford the acylpalladium 30. Finally, intramolecular reaction of 30 yields the coumarin 31. The chromone 32 is not obtained [12]. 

Application of zeolites, clays, and resins as surrogates for mineral acids and metal chlorides in the field of aromatic electrophilic substitution (Lionel et al. 1993) provided an impetus for their application in the synthesis of coumarins. 

Other less oxophilic electrophiles give C-6 substituted coumarins, but it is unclear whether the substrate for such reactions is the free coumarin or a cation formed by protonation or bonded by a Lewis acid at the carbonyl oxygen. Some typical reactions are shown in Scheme 5.3. 

The Pechmann reaction is thought to proceed through electrophilic aromatic substitution of the phenol. The resulting /3-hydroxy ester then cyclizes and dehydrates to the coumarin, although of course dehydration may occur earlier in the sequence (Scheme 113). Indeed, the observation that 2-hydroxycinnamic acids readily yield coumarins in sulfuric acid (32JCS1681) renders these compounds or their esters plausible intermediates in the reaction. 

Coumarins are readily accessed via the Pechmann condensation of phenols and 1,3-dicarbonyl compounds, which proceeds via electrophilic aromatic substitution of the phenol followed by dehydration and lactonization <1984CHEC, 1996CHEC-II>. In this manner, the amino acid bearing coumarins 676 are formed by a Pechmann condensation of phenols and 2-amino-6-ethoxy-4,6-dioxohexanoic acid 677 (Scheme 161) <2004AGE3432>. The popularity of this approach results from the wide range of readily available substrates (phenols and 1,3-dicarbonyl compounds). However, a major drawback is that electron withdrawing groups on the phenolic component dramatically reduces the yield of a Pechmann reaction. 

The substitution pattern of TfOH-mediated electrophilic aminomethylation of psoralens (furo-coumarins) by V-(hydroxymethyl)phthalimide has been elucidated <85JHC73>. Multiple phthal-imidoylated adducts were obtained when a B-ring hydroxy or methoxy activating group was present, and these resisted simple cleavage with NH2NH2. However, this two-step procedure to aminomethyl group introduction worked well when the psoralens contained only methyl substituents. 

An additional and mosh useful feature of lithiation of a methoxymethyl ether of a phenol is that yields of lithiation are very high (90% or more). This is due to better complexation of R—Li with —OCHjOCHj group which then confers better basicity to the complexed BuLi. The ortho carbon substitution is then achieved in excellent yield and further reaction with appropriate electrophiles give ortho hydroxyaromatic aldehydes which are starting compounds for coumarins. 

No simple examples are known of electrophilic or radical substitution of either heterocyclic or homocyclic rings of benzopyrylium salts flavylium and l-phenyl-2-benzopyrylium salts nitrate in the substituent benzene ring. Having said this, the cyclisation of coumarin-4-propanoic acid may represent Friedel-Crafts type intramolecular attack on the carbonyl-O-protonated form i.e. on a 2-hydroxy-1-... 

Chromone-3-carbonitrile reacted with various hydrazines and reactive methylene compounds to form benzopyrano[4,3-c]pyrazoles or 4-(2-hydroxybenzoyl)-1-phenylpyrazoles and benzopyrano[2,3-6]pyridines. Preferential electrophilic attack at C-5 of 6-substituted chromones (and coumarins) has been demonstrated again by a Fischer indolization of ethyl 6-hydrazinochromone-2-carboxylate (173) to give (174) in good yield. 

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