4- -3,4-dihydrocoumarin

Propionic acid, 2-bromo-3-(3-indolyl)-methyl ester rearrangement, 4, 279 Propionic acid, 3-(3,4-dimethyoxyphenyl)-dihydrocoumarin synthesis from, 3, 848 Propionic acid, indolyl-synthesis, 4, 232 Propionic acid, 3-(l-indolyl)-sodium salt pyrolysis, 4, 202 Propionic acid, 3-(3-indolyl)-intramolecular acylation, 4, 220, 221 Propionic acid, 3-phenoxy-chroman-4-one synthesis from, 3, 855 Propionic acid, 3-(3-phenylisoxazoI-5-yl)-bromination, 6, 25... 

The 3-carbethoxy-3 (1 -phenylpropyl)-4-oxo-dihydrocoumarin may be hydrolyzed and decar-boxylated as follows. The crude product is heated to 85°C for /a hour with 100 parts by volume of 5% aqueous sodium hydroxide, while agitating or stirring. To remove traces of undissolved oil, the cooled solution is treated with 1 part by weight of charcoal, whereupon it is filtrated and acidified to Congo reaction with dilute sulfuric acid. The 3-(1 -phenylpropyl)-4-hydroxycoumarin formed is separated off and recrystallized in 80% ethanol, whereupon it melts at 178°-179°C according to U.S. Patent 2,701,804. 

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... 

Kataoka M, K Honda, S Shimizu (2000) 3,4-Dihydrocoumarin hydrolase with haloperoxidase activity from Acinetobacter calcoaceticus. Eur J Biochem 267 3-10. 

By modification of method A, Jones has transformed 2,4-bis-OBoc-benzy-aldehyde 5 into the 3-carbomethoxy dihydrocoumarin 43 in 68% yield (Fig. 4.23).lla The reaction proceeds by the addition of phenyl Grignard followed by addition of a preformed mixture of methyl malonate and sodium hydride and warming to room temperature. This particular example obviates the need for prior initiation by an organolithium reagent. 

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. 

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. 

SCHEME 11.2 Postulated mechanism of inactivation of a serine protease by a functionalized dihydrocoumarin such as molecule 3 (i i = benzyl).28... 

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). 

Unfunctionalized acidic dihydrocoumarin 17 Functionalized acidic dihydrocoumarin 18... 

A new series of unfunctionalized (17) and functionalized (18) 3,4-dihydrocoumarins (Fig. 11.11) was synthesized. These new benzopyranones differ from the previous neutral dihydrocoumarins, which are suicide substrates of proteinases (Section 11.4, in that they have a carboxy substituent on their aromatic ring and a side chain phenylacetamido group at the 3-position of the heterocycle instead of a benzyl one in compound 3. 

Bechet, J.-J. Dupaix, A. Blagoeva, I. Inactivation of a-chymotrypsin by new bifunctional reagents halomethylated derivatives of dihydrocoumarins. Biochimie 1977, 59, 231-239. 

Dihydrocoumarin produces the following product upon photolysis ... 

Coumarins are formed by the intramolecular hydroarylation of an activated alkyne. The basic starting materials for this fast, efficient and general Pd-catalysed reaction are phenols and alkynoic acids (Scheme 42), An intermolecular version in which electron-rich phenols react with 4-methoxycinnamic acid leads to high yields of 3,4-dihydrocoumarins... 

Michael addition of di- and tri-hydric phenols to /V-cinnamoylimidazoles followed by a lactonisation offers a route to 4-aryI-3,4-dihydrocoumarins and their [/]-benzologues <00S123>. The lactonisation of the naphthoquinone derivative 66 is sensitive to the acidic cyclising medium and it is possible to obtain the thermodynamically less stable o-quinone derivative exclusively (Scheme 44) <00TL3007>. Some related quinones have been obtained from 1-benzylisoquinolines via an arylnaphthoquinone <00T6O23>. 

A similar intramolecular alkylation of arene-ene substrates is catalyzed by RuGl3/AgOTf, providing good to excellent yields of cyclization products (chromanes, tetralins, terpenoids, and dihydrocoumarins).25 This method is applied to the synthesis of tricyclic terpenoids, which are formed in nearly quantitative yields with high stereoselectivities (trans cis various between 99 1 and 99 2), as shown in Equation (24). 

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]. 

Reduction of coumarin in aqueous methanol, pH 5-6, in the presence of alkaloids yields an increased amount of dihydrocoumarin. Tliis is also the case for reduction of 4-methylcoumarin and now the 4-methyldihydrocoumarin isolated is optically active [137]. Tlie enantiomeric excess and yield of diliydrocompound both depend on the alkaloid used (Table 3.9) and Low concentrations of alkaloid are effective in achieving asynunetric induction. Concentrations of codeine above 4 mM do not further influence either the yield of dihydrocompound or the degree of induction. 

Formation of the dihydrocoumarin by reduction of 4-methylcoumarin in the presence of alkaloids in aqueous methanol pH 5-6, mercury cathode potential -1.8 V vs. see. Ref [137],... 

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