Coumarin chloromethylation

Benzo[b]furan-2-carboxylic acids bromination, 4, 602 chloromethylation, 4, 602 from coumarins, 3, 686 IR spectra, 4, 590 methyl ester... 

Irreversible inhibition is probably due to the alkylation of a histidine residue.43 Chymotrypsin is selectively inactivated with no or poor inhibition of human leukocyte elastase (HLE) with a major difference the inactivation of HLE is transient.42,43 The calculated intrinsic reactivity of the coumarin derivatives, using a model of a nucleophilic reaction between the ligand and the methanol-water pair, indicates that the inhibitor potency cannot be explained solely by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack 43 Studies on pyridyl esters of 6-(chloromethyl)-2-oxo-2//-1 -benzopyran-3-carboxylic acid (5 and 6, Fig. 11.5) and related structures having various substituents at the 6-position (7, Fig. 11.5) revealed that compounds 5 and 6 are powerful inhibitors of human leukocyte elastase and a-chymotrypsin thrombin is inhibited in some cases whereas trypsin is not inhibited.21... 

Several aryl esters of 6-chloromethyl-2-oxo-2//-l -benzopyran-3-carboxylic acid act as human Lon protease inhibitors (alternate substrate inhibitors)46 without having any effect on the 20S proteasome. Proteasomes are the major agents of protein turnover and the breakdown of oxidized proteins in the cytosol and nucleus of eukaryotic cells,47 whereas Lon protease seems to play a major role in the elimination of oxidatively modified proteins in the mitochondrial matrix. The coumarin derivatives are potentially useful tools for investigating the various biological roles of Lon protease without interfering with the proteasome inhibition. 

Nicolle, J.-P. Hamon, J.-F. Wakselman, M. Lactones phenoliques halomethylees, inhibiteurs bifonctionnels de proteases IV. Preparation de derives chloromethyles de la dihydro-3,4-benzyl-3-coumarine et de la tetrahydro-2,3,4,5-benzoxepinone-2. Bull. Soc. Chim. Fr. 1977, 83-88. 

Mor, A. Maillard, J. Favreau, C. Reboud-Ravaux, M. Reaction of thrombin and proteinases of the fibrinolytic system with a mechanism-based inhibitor, 3,4-dihydro-3-benzyl-6-chloromethyl-coumarin. Biochim. Biophys. Acta 1990, 1038, 158-163. 

Recently, chloromethylated benzocoumarin 11c, hydroxylmethylated benzocou-marin 12, and chloromethylated coumarin 13 were used in the efficient preparation of several fluorescent ester conjugates of /V-benzyloxycarbonyl-neurotransmitter amino acids, such as p-alanine, tyrosine, 3,4-dihydroxyphenylalanine (DOPA), glutamic acid, and y-aminobutyric acid (GABA) [39, 40],... 

Chloromethylation of pyran-2-ones, such as 5,6-dimethylpyran-2-one (260), and coumarins proceeds at C-3. The related Mannich reaction on 4-hydroxycoumarin yields the 3-aminomethyl derivative (53JA1883) while 3-hydroxycoumarin (261) is aminomethy-lated at C-4 (69JMC531). 

C-Substitution of coumarins and chromones has been observed in both rings in strongly acidic media, in which presumably it is a hydroxy-benzopyrylium cation that is attacked, substimtion takes place at C-6, for example nitration. This can be contrasted with the dimethylaminomethylation of chromone, iodin-ation of flavones or the chloromethylation of coumarin where hetero-ring substitution takes place, presumably via the non-protonated (non-complexed) heterocycle (CAUTION CH2O/HCI also produces some CICH2OCH2CI, a carcinogen). 

Coumarin and some of its methoxy-derivatives undergo acetoxymethylation, usually at C-3, in yields of up to 87% when heated with manganese(iii) acetate in a solvent such as acetic acid-acetic anhydride. Varying amounts of the 3-(diacetoxymethyl)-derivatives were also isolated in some experiments, and in the reaction with 7,8-dimethoxycoumarin the benzene ring was sufficiently reactive to allow the formation of 3,6-di(acetoxymethyl)-7,8-dimethoxy-coumarin. Ring-contraction of 4-(chloromethyl)coumarin in aqueous alkali proceeded in 92% yield to give benzofuran-3-acetic acid. " ... 

Chloromethyl)oxirane 24 Chlorophyll 556 Chloroquine 406 Chlorpromazin 446 Chroman 341,344 2H-Chromene 318 4H-Chromene 335 2H-Chromenone see coumarine 4H-Chromenone see chromone Chromone 336,340... 

---