Substituted coumarins

Apium graveolens infected (512) with Sclerotinia sclerotio-rum 

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

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Chemical properties of deposited monolayers have been studied in various ways. The degree of ionization of a substituted coumarin film deposited on quartz was determined as a function of the pH of a solution in contact with the film, from which comparison with Gouy-Chapman theory (see Section V-2) could be made [151]. Several studies have been made of the UV-induced polymerization of monolayers (as well as of multilayers) of diacetylene amphiphiles (see Refs. 168, 169). Excitation energy transfer has been observed in a mixed monolayer of donor and acceptor molecules in stearic acid [170]. Electrical properties have been of interest, particularly the possibility that a suitably asymmetric film might be a unidirectional conductor, that is, a rectifier (see Refs. 171, 172). Optical properties of interest include the ability to make planar optical waveguides of thick LB films [173, 174]. 

For the preparation of 4-substituted coumarins, a phenol may be condensed with ethyl acetoacetate under the influence of sulphuric acid. Thus resorcinol (II) readily undergoes this condensation (which is represented diagrammatically above) to give 7-hydroxy-4-methyl-coumarin (III). Note that the coumarins, like all 2 pyrones, are systematically lactones. 

A change in the pK of the molecule by elimination of the acidic enol function and inclusion of basic nitrogen leads to a marked change in biologic activity. That agent, chromonar (13) shows activity as a coronary vasodilator. Alkylation of ethyl acetoacetate with 2-chlorotriethylamine affords the substituted ketoester (10). Condensation with resorcinol in the presence of sulfuric acid affords directly the substituted coumarin (11). 

The rate acceleration imposed by 0-cyclodextrin was explained in terms of a microsolvent effect 6> The inclusion of the substrate within the hydrophobic cavity of cyclodextrin simulates the changes in solvation which accompany the transfer of the substrate from water to an organic solvent. Uekama et al.109) have analyzed the substituent effect on the alkaline hydrolysis of 7-substituted coumarins (4) in the... 

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>. 

Asymmetric syntheses of warfarin <96TL8321> and the axially chiral bicoumarin, isokotanin A <96TL3015> have been reported. The former is based on a Rh-catalysed asymmetric hydrogenation of a 3-(a,P-unsaturated ketone) substituted coumarin, whilst the key steps of the latter are an asymmetric Ullmann coupling and a selective demethylation. The stereochemistry of the fused dihydrocoumarin resulting from Li/NHs reduction of... 

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... 

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],... 

Omitted from Table 4 are Hershfield and Schmir s data (Tables B.l, 10-13 and B.2, 28-31) for the lactonization of substituted coumarinic acids. The EMk/EMeq ratios calculated from their data (given in Tables B.l and B.2) fall in the range 1-4 x 10-4, and thus differ sharply from the ratios in Table 4. This is a consequence of the surprisingly high equilibrium constants for lactonization. These were calculated (Hershfield and Schmir, 1973a,b) from rate constants for the hydroxide-catalysed lactonization (which is apparent as a pH-independent reaction for very reactive systems). Though the procedure used appears to be valid, these equilibrium constants differ substantially from those measured for the acid-catalysed reactions, although no direct comparison is possible for any one compound. 

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). 

An asymmetric induction can be performed during the cathodic reduction of various substituted coumarins in the presence of chiral alkaloids. A mixture of dimers and dihydrocoumarins is obtained in various yields according to the nature of the alkaloids (31-89% of dimer and 5-67% of dihydrocoumarin with unsubstituted coumarin) [273]. 

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. 

Spectral data for substituted coumarins and chromones are widely spread in the literature, and references should be sought from the review literature. 

Although most substituted coumarins give rise to signals which agree with those calculated by the normal additivity of substituent chemical shifts, deviations from the predicted values are observed for C-6 and C-7 and for the carbon atoms of the substituents in 6,7-dimethylcoumarin (8IT2021). These ortho proximity effects have been noted in aromatic... 

The UV spectra of many coumarins have been studied in different solvents with a view to correlating the effects of the nature and position of substituents (74MI22201). The spectral parameters do indeed show a dependence on these properties and several general rules have been proposed to enable the spectral features of a substituted coumarin to be predicted. Not unexpectedly, such predictions are not exact and a study of some disubstituted derivatives of coumarin has shown that the rules are not always obeyed (78T1221). The compounds which do not adhere to the rules possess a 4-methoxy group and the spectra are characterized by two double absorption bands in the ranges 267-296 and 303-322 nm. This behaviour has been attributed to the additional cross-conjugation provided by the methoxy substituent. 

Mass spectra of some methyl-substituted coumarins have been reported (710MS(5)249). The fragmentation of 4-methyIcoumarin proceeds with expulsion of carbon monoxide giving the 3-methylbenzofuran radical cation. Subsequent loss of a hydrogen radical occurs producing the highly abundant benzopyrylium species at m/e 131. A peak at m/e 131 is also of prominence in the spectrum of 6-methylcoumarin. 

Both direct and heavy-atom methods have been used to determine structures of substituted coumarins. Examples include 4-hydroxycoumarin and its 3-bromo derivative (65AX927, 66AX646) and the 7,8- and 6,7-dihydroxycoumarins, daphnetin and esculetin, respectively <76AX(B)946, 77AX(B)283). In the last compounds, hydrogen bonds link the molecules in the crystal. The stacking distances are comparable to those for other substituted coumarins <75AX(B)1287). A study of the structure of 7-hydroxy-4-methylcoumarin contains... 

Similarly, a substituted coumarin is converted into a benzofuran-2-carboxylic acid (291), a reaction which is useful in the determination of structure (73JCS(Pl)278l). 

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. 

Several older syntheses are based on o-hydroxyacetophenones but these routes generally offer little or no advantage over other methods. The Reformatsky reaction has been used to prepare 3- and 3,4-substituted coumarins (44JIC109) and the Kostanecki-Robinson reaction may yield coumarins instead of or as well as the chromone (see Section 2.24.3.4.1 for further discussion). 

Hydroxyacetophenone reacts with DMF under Vilsmeier conditions to yield chromone-3-carbaldehyde (72LA(765)8). The reaction appears to be generally applicable, various substituents being acceptable in the aromatic ring (74T3553). Furthermore, acetylhydroxy-naphthalenes yield the corresponding benzochromones, and the pyranochromone (452) is formed from the appropriately substituted coumarin. 

Substituted coumarins undergo 1,4-addition with Grignard reagents other than methyl-magnesium halides in THF to give 4,4-disubstituted 3,4-dihydrocoumarins (74JCS(P1)569). 

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). 

In the case of the parent acetylaminosalicylaldehyde, it was stated85 that, under similar conditions, no 3-phenyl-7-aminocoumarin was obtained. Furthermore, this reaction has also been carried out with a number of heterocyclic acetic acids of general formula 205, resulting in the formation of the various 3-heterocyclic-7-amino-substituted coumarins (206). 

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

The important points that emerge from the studies on the five chlorocoumarins in the solid state are the following, (a) All chloro substituted coumarins (7-chloro, 6-chloro, 4-chloro, 4-methyl 7-chloro and 4-methyl 6-chloro coumarins) undergo dimerization in the solid state. While four of these give syn head-head dimer as the photoproduct, 4-chlorocoumarin gives a mixture of anti-head-tail and syn head-tail in poor yields ( 25%). (b) Two of them namely 4-... 

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... 

A1 Polycyclic aromatic hydrocarbons (PAHs), substituted coumarins, debrisoquine... 

It appears reasonable to assume from the dramatic changes in the supramolecular assembly of fluorine-substituted coumarin, 4-styrylcoumarin, and 1,4-diphenyl-butadiene that significant contributions to the lattice energy arise... 

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