Substituted 3,4-dihydrocoumarins

Rezayan, P. Azerang, S. Sardari, A. Sarvary, Chem. Biol. Drug Des. 2012, 80,929-936. Synthesis and biological evaluation of coumarin derivatives as inhibitors of mycobacterium bovis (BCG), (c) A. Shaabani, A. Sarvary, E. Soleimani, A. H. Rezayan, M. Heidary, Mo/. Divers. 2008,12,197-202. A novel method for the synthesis of snbstitnted 3,4-dihydro-coumarin derivatives via isocyanide-based three-component reaction, (d) A. Shaabani, E. Soleimani, A. H. Rezayan, A. Sarvary, H. R. Khavasi, Org. Lett. 2008, 10, 2581-2584. Novel isocyanide-based four-component reaction a facile synthesis of fuUy substituted 3,4-dihydrocoumarin derivatives. 

Keywords 2-Hydroxybenzaldehydes, Meldrum s acid, isocyanides, aromatic/aliphatic alcohols, dichloromethane, room temperature, one-pot multicomponent reaction, Ugi reaction, substituted 3,4-dihydrocoumarins... 

To a magnetically stirred solution of 2-hydroxybenzaldehyde (1, 1 mmol) and Meldrum s acid (2, 1 mmol) in ethanol or methanol (5 mL) (and alcohol 4 other than ethanol or methanol in dichloromethane) was added isocyanide (3,1 mmol) and the reaction mixture was stirred at room temperature for stipulated period (5-8 h in ethanol or methanol and 24-36 h in dichloromethane). After completion of the reaction, as indicated by TLC (ethyl acetate/n-hexane, 2 1), the precipitate (in case of dichloromethane medium, the solvent was removed under vacuum to have the crude mass) was washed with ethanol or diethyl ether to afford substituted 3,4-dihydrocoumarin 5 as white powder in good to excellent yield (70-96%). Each of the products was characterized by analytical as well as detailed spectral studies including IR, NMR, NMR, and mass. 

Shaabani, A., Soleimani, E., Rezayan, A. H., Sarvary, A., and Khavasi, H. R. (2008). Novel Isocyanide-based four-component reaction A facile synthesis of fully substituted 3,4-dihydrocoumarin derivatives. Org. Lett., 10, 2581-2584. 

Bromomethyl-3,4-dibromo-3,4-dihydrocoumarin 1 (Fig. 11.4) and its chloro-methylated analogue 2b rapidly and progressively inactivate a-chymotrypsin and also the activities of a series of trypsin-like proteases. A benzyl substituent characteristic of good substrates of a-chymotrypsin was introduced at the 3-position to make inhibition more selective. This substituted dihydrocoumarin 3 irreversibly inhibited a-chymotrypsin and other proteases. These functionalized six-membered aromatic lactones, and their five- and seven-membered counterparts, 3//-benzofuran-2-ones 2a26 and 4,5-dihydro-3//-benzo[b]oxepin-2-ones 2c,27 were the first efficient suicide inhibitors of serine proteases. Their postulated mechanism of action is shown in Scheme 11.2. 

A Yb(OTf)3-catalyzed reaction between 5-alkylidene Meldrum s acid derivatives 1068 and phenols provides a route to 4-substituted dihydrocoumarins (Equation 418) <2006JOC409>. 

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... 

After the nucleophilic attack by the hydroxyl function of the active serine on the carbonyl group of the lactone, the formation of the acyl-enzyme unmasks a reactive hydroxybenzyl derivative and then the corresponding QM. The cyclic structure of the inhibitor prevents the QM from rapidly diffusing out of the active center. Substitution of a second nucleophile leads to an irreversible inhibition. The second nucleophile was shown to be a histidine residue in a-chymotrypsin28 and in urokinase.39 Thus, the action of a functionalized dihydrocoumarin results in the cross-linking of two of the most important residues of the protease catalytic triad. 

An aza-analogue of the functionalized dihydrocoumarin 2b, the 3-benzyl-3,4-dihydro-1 //-quinolin-2-one 8b, and its five-membered analogue, a substituted indolin-2-one 8a, were synthesized (Fig. 11.6). 

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]. 

Phenols are also suitable nucleophiles for 5-alkylidene-l,3-dioxane-4,6-diones, when activated by Yb(OTf)3. Depending on the substitution pattern at C-1, several useful coumarins, dihydrocoumarins, 4-chromanones, and chromones were obtained (Scheme 21) <2006JOC409>. 

TL5803>. Libraries of 2-substituted phenylpropyl amides and amines have been obtained from dihydrocoumarins <99TL1241>. 

During a study of dihydrocoumarins (68JOC1202) it was observed that 4-(2-bromoethyl)-3,4-dihydrocoumarin (291) was converted into a 4-substituted chroman on reaction with an amine. Ring opening occurs through nucleophilic attack at C-2 and this is followed by an intramolecular nucleophilic substitution. In a similar manner, chroman-4-ylacetic acid results on reaction with potassium hydroxide in methanol. 

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). 

The reaction of substituted ketene acetals with alkenyl Fischer Cr carbene complexes provides a convenient one-pot approach to 4-aryl-3,4-dihydrocoumarins (Scheme 33)... 

Both Siegel et al. (122) and Lawrence et al. (123) have described automated systems for the purification of small arrays of amines and amides. A 48-member array of P-amino alcohols prepared from epoxides and amines was purified using SPE by Shuker et al. (124). Blackburn et al. (125) have described the purification of a 60-member 3-aminoimidazo[l,2-fl]pyridine array obtained from a multiple-component condensation, and Bussolari et al. (126) purified a small array of phenylpropyl amines obtained from dihydrocoumarins and amines. A few applications where ion-exchange resins have been substituted with other solid phases have also recently appeared. For example, the purification of several carbohydrate arrays tagged as hydrophobic O-laurates using Ci8 silica producing up to 10-30 mg of >90% pure individuals was described by Nilsson et al. (127), and Curran et al. purified fluorous-... 

The other example of a rhodium migration was discovered when 3-substituted-3-(2-hydroxyphenyl)cyclobutanones were subjected to rhodium-catalyzed conditions (Scheme 17) [76], The reaction generates dihydrocoumarin derivatives in high... 

In the synthesis of coumarins by the von Pechmann reaction, a spiro-compound (251) was simultaneously formed from 4-chloro-2-methylphenol (and from 2,3,5-trimethylphenol). A possible mechanism for this reaction involves the formation of the lactone (252), which reacts with another molecule of the phenol. The condensation of the dicyano-ester (253) [obtained from malononitrile and ethyl cyanoacetate] with substituted o-hydroxybenzaldehydes yields substituted coumarinimines, e.g. (254).A series of 4,6,7-substituted coumarins have been prepared and assessed for their suitability in fluorescence labelling of polymers. Esters of the type PhCH CRCOaAr react with AICI3 to give coumarins, which are probably formed via dihydrocoumarins (255) by dearylation. ... 

Dihydrocoumarins can be obtained by heating phenols with p-substituted cinnamic esters without recourse to acidic catalysis <97SYN931>. 

Chromanols are prepared in good yields by cyclization of hydroquinone, resorcinol, and catechol with phytyl chloride in the presence of cation-exchange resin complexes of metal ions. ° The reaction of dihydrocoumarins with readily available 0 ,Grignard reagents has led to chromans which are spiro-substituted at the 2-position (125). The initially formed O-hydroxyphenylethyl cycloalkanols (124) were converted to chromans in high yield by simple acid treatment. ... 

Asymmetric synthesis of 3,4-dihydrocoumarin 41 was achieved by rhodium(I) catalyzed intramolecular reaction of phenol-substituted cydobutanone 42 (Scheme 3.21) [33]. When the reaction of 3,3-disubstituted cyclobutanones was performed in the presence of electron-deficient alkenes, the arylrhodium species generated via 1,4-rhodium shift underwent addition to the alkenes, providing 5-alkylated dihydrocoumarins (Scheme 3.22). 

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