Substituted-7-Oxygenated Coumarins

Formula M.p. [ x]l Solvent Plant Source(s) Leading References 

C19H20O5 non-cryst. 78—80 -130 -44 CHCI3 CHCI3 Seseli libanotis Agasyllis latifolia (371) (445, 581) 

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After the separation of furanocoumarin, spectroscopic methods can be used to identify and quantify these phenolic compounds. Coumarin shows absorption bands at 274 and 311 nm, which have been attributed to the benzene and pyrone rings, respectively. Methyl substitution at C-5, C-7, or C-8 leads to a bathochromic shift of the 274 nm maximum but leaves the 311 nm maximum practically unchanged [68]. 7-Oxygenated coumarins show strong absorption bands at about 217 and 315-330 run with weak peaks or shoulders at 240-250 nm. Linear furanocoumarins show four zones of absorption at 205-225, 240-255, 260-270, and 298-316 nm. Angular furanocoumarins can readily be distinguished from linear forms since the maxima at 242-245 and 260-270 are absent [69]. 

The Michael addition of nucleophiles to coumarins catalyzed by solid bases provides an interesting approach to the synthesis of 4-substituted 3,4-dihydrocumarins, because with the conventional Michael catalysts the alkaline hydrolysis of the 8-lactone predominates (Scheme 44). Results were obtained when the Michael addition of diethyl malonate to coumarin was catalyzed by the activated Ba(OH)2 292). An unusual 1,2-addition-elimination process at the C = 0 bond was observed. The mechanism of this reaction was explained on the basis of the microcrystalline structure of the catalyst. It was suggested that the rigid coumarin molecule interacts with the Ba ions through the lone-pair electrons of both oxygen atoms of the... 

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. 

In some instances, especially with the oxygen and sulfur heterocycles, the overall reaction leading to a substituted product does not involve an SEAr mechanism but proceeds by an addition followed by elimination sequence, as outlined for the bromination of coumarin in equation (4). The choice of experimental conditions can affect the outcome of the reaction, as illustrated in the formation of (114) and (115) in Section 3.2.1.4.7. 

Since the phosphate anion is resonance stabilised, nucleophilic substitution of the bromine atom of the coumarin derivative can occur by either of the two free oxygen atoms. Thus two diastereomers will be produced, which may be distinguished between merely by considering the configuration at the phosphorus atom. In a publication it was shown that using the tetrabutyl-ammonium salt of cyclic AMP (cAMP) in acetonitrile the diastereoisomeric ratio was 85 15 in favour of the compound with an S-configured phosphorus atom [10]. 

Coumarin (11.46), iscoumarin (11.47), and chromone (11.48) should each be more reactive than the corresponding pyrone, and consideration of conjugative effects indicates substitution to be preferred at the 3-position of 11.46 and 11.48, and at the 4-position of 11.49. Isocoumarin (11.47), in which the oxygen lone pair is less readily delocalized into the benzenoid ring, should be more reactive than the other two isomers. Substituents in these molecules will have very marked directional effects because of significant bond fixation. 

Tables 3 and 4 contain results from a study of a series of coumarins and fiirocoumarins in, 1,2-dibromoethane, which found that the lactone carbonyl signal consistently appeared near 350 ppm more variability was seen for the single bonded oxygen, especially for the furocoumarins, typically appearing at 220 ppm [85]. Synthetic 3-aryl coumarins also exhibit 6(C=0) and 5(-0-) values near those mentioned above [86]. Recently, a study of a series of 7-substituted-4-methylcoumarins, with a wide range in electronic character of the substituents, demonstrated that the carbonyl signal is quite sensitive to substituent effects and that the NMR chemical shift is reasonably well correlated with the carbonyl oxygen AMI estimated electron density [87].

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-... 

In general, a practical synthesis of a coumarin has an oxygen substituted aromatic ring as the starting compound, in which a carbon substituent is introduced at the ortho position. An aromatic lithiation reaction is valuable for this. 

The basic skeleton of isoprenoids may be modified by the introduction of a wide variety of chemical groups, by isomerization, shift of double bonds, methyl groups, etc. Hence a bewildering number of chemical structures arises. In addition compounds derived from other biogenic pathways may contain isoprene residues. For instance the K vitamins (D 8.1), ubiquinones (D 8.3), chlorophylls (D 10.1), plastoquinones, and tocopherylquinones (D 22.4) have isoprenoid side chains with up to ten isoprene units. Polyketides (D 3.3), alkaloids (D 8.4.2), and coumarins (D 22.2.2) may be substituted by dimethylallyl groups. The terpene residues are attached to nucleophilic sites, such as active methylene groups and phenolic oxygen atoms. 

Isopentenyl and geranyl groups substituted either on carbon or oxygen are widespread substituents in coumarins. However, when occurring in the 3-position such terpene groups are frequently found rearranged. Grundon and... 

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