Coumarin ring opening

Coumarin ring opening—Benzilic acid rearrangement s. 17, 278... 

Refaetive coumarin ring opening Hydrophenanthrene ring s. 13, 95, 862 c... 

Compound 24a was also obtained in 17% yield by heating of 4-hydroxy-3-nitrocoumarin 27 [12] with hydrazine hydrate in ethanol. A similar reaction of 27 with methylhydraine in boiling ethanol did not afford 24b because of the decomposition of the starting coumarin. However, when 27 was treated with methylhydrazine at room temperature for 24 h without solvent, the ring-opened methylhydrazine adduct 28 (36% yield) and 1,2-dihydro-5-(2-hydroxyphenyl)-l-methyl-4-nitro-3H-pyrazol-3-one 26 (ll%yield) were... 

In the above cases, the photoreactivity of indole, coumarin, pyridine, and so forth, does not compete effectively with PFR, which becomes the major reaction. However, in the case of the chromene depicted in Scheme 28, the electrocyclic ring opening prevails over PFR. By contrast, the analogous chromane undergoes clearly acyl migration [86]. 

Suggest mechanisms for the ring opening of (a) coumarin to 2-hydroxycinnamic acid [3-(2-hydroxyphenyl)propenoic acid] by treatment with aqueous sodium hydroxide, and (b) a mechanism whereby 2-methylchromone is ring opened under the same conditions to 2-(3-oxobutanoyl)phenol (2-HOC HjCOCH,COMe). 

Finally, the intramolecular ring opening of unsaturated 5(4//)-oxazolones derived from 2-hydroxybenzaldehyde is noteworthy. Here, the condensation of hippuric acid and 2-hydroxybenzaldehyde under classical conditions gives a 3-(acylamino)coumarin 602 directly without isolation of an intermediate oxazo-... 

Several reports for the synthesis of coumarins have used lactone formation to erect the tricyclic core (Equation 44) < 1995T3197,1999SC929>. Other approaches to similar coumarins include the ring opening of an epoxide (Equation 45) <2002TA1799>. 

Marked inter-species differences have been observed in the metabolism and toxicity of coumarin. The metabolism of coumarin involves two primary pathways, 7-hydroxylation and ring-opening to ort/zo-hydrox5 henylacetaldehyde. Coumarin is hepatotoxic in rat, mouse and dog, species in which ring-opening predominates. In contrast, humans and baboons, in which 7-hydroxylation is most evident, rarely show... 

Coumarin is rapidly and extensively absorbed after topical or oral administration to human subjects. It undergoes very extensive metabolism along two major pathways, 7-hydroxylation and ring-opening to ort/ro-hydroxyphenylacetaldehyde. There are numerous minor metabolites, many of which are secondary products from the primary metabolites. The relative extent of these two major pathways is highly variable between species. Ring-opening predominates in rodents, while 7-hydroxylation is particularly evident in htrmans. 

Although pyridones are usually resistant to alkali, pyrone rings are often easily opened. Pyran-2-ones are reversibly ring-opened by aqueous alkali to acid anions (222). Hydroxide ions convert coumarins (223) reversibly into salts of coumarinic acids (224) which can be converted into the trans isomers (225), and chromones (226) into 3-dicarbonyl compounds (227). 

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. 

Several kinds of nucleophiles react with pyran-2-ones and coumarins some of these reactions involve ring opening and, occasionally, recyclization into another ring. A nucleophile (Nu) which cleaves the ring attacks to break one of the bonds of the ring oxygen atom as shown in Scheme 13. 

Many methods have been described for the reduction of coumarins (B-77MI22301) but undesired byproducts are frequently formed. A thorough study of the catalytic reduction of several coumarins has recently shown that careful choice of conditions can lead to high yields of either the 3,4-dihydrocoumarin (306) or the ring opened product (305) which can be cyclized efficiently (Scheme 18) (80JHC1597). 

The acid-catalyzed cyclization of 3-(2-hydroxyphenyl)propan-l-ones leads to chrom-2-enes. This reaction accounts for the formation of 2,4-diphenylchrom-2-ene from the reaction of phenylmagnesium bromide on coumarin. The organometallic reagent ring-opens the coumarin to the ketone which cyclizes to the chromene on boiling with acetic acid (Scheme 26) (63T839). In a similar manner, various benzocoumarins afford propanones which cyclize readily in acetic acid to the naphthopyran (70JCS(C)1758). 

The reaction of phenols with the spiro /3-lactone (397), obtained from the reaction of diketene with ethyl diazoacetate, leads to coumarins (79JCS(Pl)525). Initial ring opening of the spiro compound to the diketo ester followed by regioselective intramolecular acylation would seem to be a possible mechanism (Scheme 129). 

Similarly, it proved possible to calculate (10) the values of the equilibrium constants for the ring opening of coumarins in alkaline media from data (11) on the decrease of coumarin waves in alkaline media (7) ... 

The 2,3-dihydrobenzo[l,2-7 5,4-3 ]difuran 705 can undergo a cycloaddition reaction with tetrazine 706 followed by furan ring opening and lactonizaton to afford the pyridazino-fused coumarin 707 (Scheme 174) <2005T4805>. Similarly, benzo[l,2-3 5,4-7 ]difurans 708 react with tetrazine 706 to form the pyridazino-fused coumarins 709 and 710 (Equation 283) <2005T4805>. 

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]. 

A new class of thiazole-fused diazepinones 79 was prepared by treatment of 2-arylamino-4-coumarinyl-5-formyl thiazoles 78 with hydrazine hydrate in refluxing ethanol to yield the rearranged products via ring-opening by attack of the intermediate hydrazone on the lactone of the coumarin <07SC99>. 

Ammonia and amines do not convert coumarins into 2-quinolones, nor chromones into 4-quinolones, but isocoumarins do produce isoquinolones. Ring-opened products from chromones and secondary amines can be obtained where the nucleophile has attacked at C-2. 

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