7-Substituted 4-methyl coumarins

The synthesis of 7-substituted 4-methyl coumarins was described using nanocrystaUine sulfated-zirconia catalyst with excellent catalytic activity under solvent-free conditions by B. Tyagi et al. The results were revealed that m-amino phenol is more reactive than w-hydroxy phenol (07JMCCF247). 

Tyagi, B. Mishra, M. K. Jasra, R. V. Synthesis of 7-substituted 4-methyl coumarins by Pechmaim... 

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. 

In general, the a SCS are similar to those of corresponding 1- and 2-substituted naphthalenes (20, 49, 70-72). There are only a few exceptions. For example, the a-methyl effect in 7-methyl-coumarin is considerably larger than for all other isomers (11.2 vs. 8.3-9.7 ppm) (20). Despite the similarity of the a-hydroxy effects in 4-hydroxycoumarin and 1-naphthol (22.4 and 23.4 ppm, respectively), the corresponding methoxy effects are quite different (22.6 and 27.6 ppm, respectively). In 6-cyano- and 7-nitrocoumarin the a SCS are smaller by ca. 3 ppm than in 2 cyano- and 2-nitro-naphthalene. Again, there is no satisfactory explanation. 

The rate of photobleaching of the dye 7-amino-4-methyl-coumarin (6 X 10 M) in 10% ethanolic aqueous solutions is decreased by 20-30% in the presence of 10 M p- and y-CD. In the case of the trifluoromethyl-substituted analog, the photobleaching was accelerated in y-CD and unchanged in P-CD. Both the geometry and the stoichiometry of the inclusion complexes are expected to be key factors [349]. 

N,iV-Disulfonyl ynamides react with salicylaldehydes through a keteni-mine intermediate in the presence of triethylamine giving access to 3-substituted iminosulfonylcoumarins (140BC3986). Biscoumarins fused at the pyrone ring arise from the indium(III) trifluoromethanesulfonate-catalyzed reaction of methyl coumarin-3-carboxylate with phenols, in good yields (14JOC8723). A library of 3,3 -biscoumarin-based protein kinase inhibitors is achieved from the condensation of 2 -hydroxyacetophenones... 

Esculetin, umbeUiferone (7-hydroxycoumarin) and 7-hydroxy-4-methyl coumarin are strong xanthine oxidase inhibitors (Chang and Chiang 1995). The structure of 7-hydroxy coumarin plays a very important role in xanthine oxidase inhibition, the 6-hydroxy group present in the molecule of 7-hydroxy coumarin, e.g. esculetin enhanced the activity, whereas substitution by the 6-methoxy group, e.g. scopoletin (formula [47]), reduced the inhibitory effect. (Chang and Chiang 1995). 

Sinhamahapatra et al. (2011) reported that the microwave-assisted synthesis is the most appropriate method for synthesis of coumarins as it provides improved yield in very less time. Mesoporous zirconium phosphate (m-ZrP) is used as a solid acid catalyst for the synthesis of coumarins via Pechmann condensation reaction. Among the substituted phenols, m-amino phenol is more reactive and 100% yield was obtained in very short time at low temperature due to the presence of ring activating amine group in meta position. The m-ZrP is also active towards phenols for the synthesis of 4-methyl coumarin, where only 57% yield was obtained in conventional heating method. 

Claisen rearrangement of 4-methyl-7-[4-(substituted-but-2-ynyloxy]-coumarins under the microwave irradiation was reported by Valizadeh and Shockravi (2006). A good yield of 4 -substituted methyl-4,5 -dimethylangelicins was obtained in short reaction times. 

As improvements over P-methylumbeUiferone (55—57), 4-methyl-7-amino-coumarin [26093-31-2] (12a) and 7-dimethylamino-4-methylcoumarin [87-014] (12b) (58—61) were proposed. These compounds are used for brightening wool and nylon either in soap powders or detergents, or as salts under acid dyeing conditions. They are obtained by the Pechmaim synthesis from appropriately substituted phenols and P-ketocarboxyflc acid esters or nitriles in the presence of Lewis acid catalysts (see Coumarin). 

Coumarin itself has a poor quantum yield, but appropriate substitution leads to fluorescent compounds emitting in the blue-green region (400-550 nm). Substitution in position 4 by a methyl group leads to umbelliferone. 7-Hydroxycoumarins are very sensitive to pH. For example, 4-methyl-7-hydroxycoumarin (4-methyl-umbelliferone) can be used as a fluorescent pH probe (see Chapter 10). 

Of the many substituted and functionalized alkenes that have been combined with diazo dipoles to give A -pyrazolines or products derived from them (i.e., A -pyrazolines, pyrazoles, cyclopropanes), only a selection will be mentioned. These include ot-alkylidene-cycloalkanones (62), -flavanones, -thioflavanones, -chroma-nones, and thiochromanones (63,64) a-arylidene-indanones and -indolones (65) diarylideneacetones (66) l-benzopyran-2(77)-ones (coumarins) (67,68) 4-nitro-1,2-oxazoles (69) 2-alkylidene-2-cyanoacetates (70) dimethyl 2,3-dicyanofuma-rate (71) tetracyanoethylene (72) tetraethyl ethylenetetracarboxylate (72) 1,4-quinones (35,73-75) 2-X-l,l,l-trifluoro-2-propene [X = Br, (76), SPh, SOPh, S02Ph (77)] nitroalkenes (78) including sugar nitroalkenes (79) 1-diethoxyphos-phoryl-1-alkenyl-sulfoxides (80) methyl 2-(acetylamino)cinnamate and -acrylate... 

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. 

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). 

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... 

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]. 

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. 

Formylation of 5,7-dihydroxy -( -propyl)-coumarin (1) provided on 8-formy-lated product (26). Treatment of the compound 26 with 3-chloro-3-methyl-l-butyne to introduce regioselectively the chromene 27 because the phenolic hydroxyl group at the C position was less accessible for formylated substitution because of a presumed hydrogen-bonding interaction. To construct the enantiomerically pure rra i-2,3-dimethyl chroman-4-ol system, Deshpande et al." ° used organoborone... 

Monosubstituted Analogs Xie et al. synthesized a series of monosub-stituted derivatives at the coumarin 3,4, 5, and 6 positions. The data in Table 9-2 show that mono-methyl substitution at the 3, 4, or 5 position (51, 53, and 59) greatly increased potency in comparison with 2. 3- and 4-Methoxy DCK analogs (52 and 54) showed slightly less potency whereas 5-methoxy DCK (60) retained activity. However, although methylation or methoxylation at the 3, 4, and 5 positions did not affect the antiviral activity of DCK analogs, these same substitutions at... 

Umbelliferone is the pivotal metabolite in the pathways to substituted coumarins and furano- or pyranocoumarins. Its 7-0-methylation to herniarin (Fig. 4.3) or 0-prenylation and C-alkylation reactions are often observed in coumarin-producing higher plants where the prenylation at C-6 or C-8 mark the entry to the routes branching linear from angular furano- and pyranocoumarins (Fig. 4.5). In Ruta graveolens and Ammi rmjus, the prenylation reactions are catalysed by particulate enzymes (Hamerski et at, 1990), and... 

Cinnamic acids can be created from the methylation of coumarins. Methoxy substituted coumarins produce lower yields than do non-substituted and hydroxy substituted coumarins. 

---