Chromones—

The final structures of the chromones galapagin (383), lobodirin (384), mollin (385) and roccellin (386) from lichens were established by NOE difference spectroscopy (59S). 

Numerous xanthones have been isolated from lichens structurally elucidated and synthesized by Elix and co-workers and other authors since 1984 these are summarized in Table 7. Formulae 387-464 are listed separately. 

Aotearone see 5,7-Dichloro-3-O-methylnorlichexanthone Arthothelin (2,4,5-Trichloro- 387 268-269 Lecanora broccha  

Asemone see 4,5,7-Trichloro-3-O-methylnorlichexanthone Capistratone see 2,5,7-Trichloro-3-O-methylnorlichexanthone 2-Chlorolichexanthone 388 222-223 Lecanora spec., Pertusaria cicatricosa 201) 

O-methylnorlichexanthone with DMS-K2CO3 and subsequent demethylation with BCI3 

Microwave irradiation effects the Cu-promoted cyclisation of l-(2-hydroxyaryl)-3-arylpropane-l,3-diones 05TL6315 and also the reaction between phloroglucinol and P-ketoesters under solvent-free conditions 05JOC2855 , both of which yield chromones. 

Both flavanones and 2 -hydroxychalcones are oxidised to flavones in the absence of solvent by In salts supported on silica gel 05TL253 and the former also by Mn(OAc)3 05SC2723 . Various 3-(perhaloacyl)chromones, which exist as a mixture with their covalent hydrates, have been obtained from 2-hydroxy-2-(perhaloalkyl)chroman-4-ones on heating with the formylating agent, diethoxymethyl acetate 05SL1164 . 

L-Proline is an efficient catalyst for the reaction between 2 -hydroxyacetophenones and aryl and heteroaryl carboxaldehydes which yields a mixture of chalcone and chroman-4-one cyclic ketones afford only the 2-spiro-linked chromanone 05TL6991 and a lipase-catalysed reaction introduces asymmetry in a multistep synthesis of 3-benzylchromanones 05H(65)761 . 

Metallic lanthanum effects the stereoselective reductive dimerisation of 3-iodoflavanones to 3,3 -biflavanones as exemplified by the first synthesis of cf/-chamaejasmine 05OL271 and a Pd-catalysed diastereoselective cyclisation features in a route to the marine metabolite (-)-15-oxopuupehenol 05OL1477 . 

There is thus obtained bishydroxycoumarin (3). Subsequent pharmacologic and clinical work revealed this compound to be an effective anticoagulant drug in humans. It is of note that none of the synthetic anticoagulants shows in vitro activity. Rather, these compounds owe their effect to inhibition of synthesis by the liver of one of the co-factors necessary for coagulation. 

Further work in this area showed that only one of the cou-marin rings was needed for biologic activity. Condensation of the hydroxyacetophenone, 4, with diethyl carbonate affords 4-hydroxycoumarin (2). The reaction may involve the 3-ketoester (5) cyclization of this would afford 2. Alternately, the reagent may first give the 0-acyl derivative cyclization as above will give the same product. Michael condensation of the coumarin with benzalacetone (6) affords the anticoagulant warfarin (named after its place of origin Wisconsin Alumni Research Foundation, 

WARF) (7). The same reaction with p-nitrobenzalacetone (8) affords acenocoumarole (9). It might be mentioned in passing that one of the largest uses of warfarin is in fact as a rat poison animals that ingest the drug in large amounts simply bleed to death. 

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 first step in the sequence may involve Friedel-Crafts-type condensation of resorcinol with the enolate of 10 to afford the unsaturated ester, 11. Alkylation of the free phenol on 12 by means of ethyl bromoacetate affords chromonar (13).  

The chromone cromolyn sodium (5-5) was at one time considered the forerunner of a novel class of antiallergic and antiasthmatic drugs that act at one of the earliest stages of the allergic reaction. Detailed experiments, acmally conducted after the dmg s clinical effectiveness had been confirmed, suggested that the compound inhibited the release of mediators of the allergic reaction from mast cells. The dmg is not very active when taken orally and is usually applied topically to the lung by insufflation as its sodium salt. Considerable efforts to uncover additional structurally related mediator release inhibitors have had only limited success. 

The preparation starts much as does that of (3-blockers, by reaction of the phenol (5-1) with epichlorohydrin with the important difference that the reaction is conducted with a controlled amount of the epoxide. The initially formed glycydil ether (5-2) thus reacts with a second phenoxide ion to afford the double ether of glycerol (5-3). This product is then condensed with diethyl oxalate in the presence of a base. The initially formed acylation product (5-4) then undergoes internal hydroxyl exchange to form a coumarone ring. The structure shown for the initial 

Nitration of hydroxypropiophenone (7-1) followed by conversion of the phenol to its methyl ether by means of methyl iodide provides the intermediate (7-2) the nitro group is then reduced to the corresponding amine (7-3) by catalytic reduction. The newly introduced amine is then replaced by a nitrile group by successive conversion to the diazonium salt by means of nitrous acid followed by treatment with cuprous cyanide (7-4). Reaction with aluminum chloride removes the methyl ether to afford the ortho acylphenol (7-5). This is converted to the chromone (7-6) as above by reaction with benzoyl chloride and sodium benzoate. The nitrile is next hydrolyzed to the carboxylic acid (7-7) by means of sulfuric acid. The acid is then converted to its acid chloride by means of thionyl chloride and that treated with 2-(A -piperidyl)ethanol (7-8). There is thus obtained flavoxate (7-9) [8], a muscle relaxant whose name reflects its flavone nucleus. 

Apoptosis, the mechanism that times the lifetime of individual cells, is dismpted in neoplasms and largely accounts for their immortality. The benzopyran alvocidib (9-7), originally known as flavoperidol, has shown promising activity as an agent that restores apoptosis. In the absence of a direct reference, the scheme shown here is based on that for the compound in which methyl replaces the pendant chlorophenyl 

The value of l-(o-hydroxyphenyl)-3-arylpropane-l,3-diones in the synthesis of O-heterocycles by the Baker-Venkataraman reaction with aroyl chlorides has been exemplified by their conversion into 3-acylflavones, flavones, flavanones and 

4-hydroxycoumarins 06TL1347 . Progress in the synthesis of dihydrochalcones and thence homoisoflavonoids has been reported 06T841 . 

A Pd-oxazoline complex efficiently converts 3-halochromones into isoflavones in a Miyaura-Suzuki reaction 06T3395 . A one-pot synthesis of 7-hydroxyisoflavones from resorcinol and substituted phenylacetic acids has been described 06TL8161  

The asymmetric intramolecular crossed benzoin reaction catalysed by a chiral triazolium salt has been used to synthesise 3-hydroxychroman-4-ones 34 in good to high yields and ee. The absolute configuration at the quaternary stereocentre C-3 has been shown to be S by X-ray analysis of the camphanyl ester 06SL2431 . Both enantiomers of 2-(2-phenylethyl)chroman-4-one, flindersiachromanone, have been obtained from racemic l-phenylhex-5-en-3-ol after resolution via lipase-catalysed acetylation 06H(68)483 . 

The asymmetric hydrogenation of chroman-4-ones has been achieved in quantitative yield and with up to 98% ee using a chiral Ru catalyst 06JA8724 . 

A number of these structures are widespread as illustrated by peucenin (Table 12.1, ref. 38). Nuclear prenylation of 5,7-dihydroxy-2-methylchromone by the unspecific procedure of prenyl bromide in methanolic sodium methoxide afforded peucenin, 5,7-dihydroxy-2-methyl-6-prenylchromone (15%), together with the 6,8-di-C-prenyl compound (21 %) and 5-hydroxy-7-prenyloxychromone (1 %). The cyclisation of peucenin by the standard procedure with formic acid gave isopeucenin. 

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The fragmentation pattern of isoxazoles on electron impact has been well studied. It has been used as an important tool for the structural assignment of isoxazoles obtained from the reaction of chromones with hydroxylamine 79MI41600, 77JOC1356). For example, the structures of the isoxazoles (387) and (388) were assigned on the basis of their fragmentation patterns. Ions at mje 121 (100%) and mje 93 (19.8%) were expected, and indeed observed, for the isoxazole (388), and an ion at mje 132 (39.5%>) was similarly predicted and observed for the isoxazole (387). 

The reaction of hydroxylamine with 2-substituted chromones (392) where R = Me, Ph (76MI41601) or CO2H (79MI41600) gave exclusively 5-(o-hydroxyphenyl)isoxazoles (393). 

Benzofurans, 4, 531-597, 657-712 chroman synthesis from, 3, 785 chromene synthesis from, 3, 753 chromone synthesis from, 3, 828 CNDO, 4, 536... 

H-l-Benzopyran-4-ones — see Chromones 4H-l-Benzopyran-4-ones, 2-phenyl — see Flavones Benzopyranopyrazoles synthesis, S, 317, 341 Benzopyrano[4,3-c]pytazol-4-one synthesis, 3, 712 Benzopyrano[4,3-6]pyridine synthesis, 3, 712 Benzopyrano[4,3-ii]pyrimidine synthesis, 3, 712 Benzopyrans nomenclature, 1, 23 pyrylium salt synthesis from, 3, 873 reactions... 

Benzopyrylium perchlorate, 3-ethyI-reduction, 3, 662 Benzopyrylium salts C NMR, 3, 590 chromene synthesis from, 3, 756 chromone synthesis from, 3, 829 electrophilic substitution, 2, 49 mass spectra, 3, 618 reactions... 

Benzoxepin-4-carbaldehyde, dihydro-from chromones, 3, 713 Benzoxepin-4(3H)-one from isochromanone, 3, 726 [l]Benzoxepino[3,4-d]selenazoles synthesis, 6, 345 Benzoxepins... 

Chromone, 2-alkylamino-5,8-dimethoxy-synthesis, 3, 717 Chromone, 2-amino-aromaticity, 3, 714 tautomerism, 3, 644... 

Chromone, 2-amino-3-chloro-synthesis, 3, 713 diacetate, 3, 714 Chromone, 3-aroyl-photochemistry, 3, 695 Chromone, 2-benzhydryl-3-benzoyl-photoenolization, 3, 695 Chromone, 3-benzoyl-2-benzyl-photoenolization, 3, 695 Chromone, 3-benzoyl-2-methyl-synthesis, 3, 823 Chromone, 2-benzyl-in photochromic processes, 1, 387 Chromone, 3-benzyl-photolysis, 3, 695 Chromone, 3-bromo-synthesis, 3, 828 Chromone, 3-bromoacetyl-ring opening, 3, 713 Chromone, 3-bromo-2-methyl-reactions... 

Chromone, 2,3-dichloro-7-methoxy-synthesis, 3, 825 Chromone, dihydromass spectra, 2, 23 Chromone, 3,5-dihydroxy-2-methyl-selective methylation, 3, 716 Chromone, 5,7-dihydroxy-2-methyl-prenylation, 3, 716 Chromone, 3,7-dimethoxy-2-methyl-reactions... 

Chromone, 5-hydroxy-2-methyl-biosynthesis, 3, 876 Chromone, 6-hydroxy-2-methyl-reactions... 

Chromone, 7-hydroxy-2-methyl-bromination, 3, 707 Chromone, 3-hydroxymethylene-synthesis, 3, 821... 

Chromone, 3-hydroxymethyl-8-methoxy-antiallergic activity, 3, 707 Chromone, 7-methoxy-chlorosulfonation, 3, 708 Chromone, 7-methoxy-2-methyl-chloromethylation, 3, 708 Chromone, 2-methyl-chloromethylation, 3, 697 halogenation, 3, 709 IR spectra, 3, 596 mass spectra, 3, 613 oxidation, 3, 709 reactions... 

Chromone, N-methyltetrazol-5-yl-antiallergic activity, 5, 836 Chromone, 3-nitro-reactions... 

Chromone, 3-(tetrazol-5-yl)-antiallergic activity, 5, 836 degradation, 5, 815 Chromone, 3,5,7-trimethoxy-2-methyl-photolysis, 3, 695... 

Chromone-2-carbaldehyde, 3-methyl-synthesis, 3, 709 Chromonecarbaldehydes Knoevenagel condensation, 3, 711 Chromone-3-carbaldehydes mass spectra, 3, 615 oxidation, 3, 709 reactions, 3, 712 Schiff bases, 3, 712 synthesis, 3, 821 Chromone-2-carbonyl chloride Grignard reaction, 3, 711 Chromonecarboxamide, N-tetrazolyl-antiallergic activity, 3, 707 Chromone-2-carboxylic acid, 3-chloro-ethyl ester... 

Chromone-2-carboxylic acid, 8-cyano-6-methyl-ethyl ester... 

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