Chromones reduction

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... 

Grignard reaction, 3, 711 Chromone-2-carboxylic acid, 7-phenyl-ethyl ester reduction, 3, 704... 

The acylation of dienamines has not been extensively investigated. The dienamine (127) prepared by Birch reduction of N,N-dimethyl-p-toluidine has been shown to react with diketene (90) to give the chromone (128), showing that attack occurs at the /9-carbon of the dienamine system. 

Method B involves the preparation of precursor of 2-alkyl-l-benzo-pyrylium salts, as shown in Scheme ll.50 2-Alkylbenzopyrylium salts have been prepared by condensation of salicylaldehyde with appropriate ketone in acetic acid or by alkylation or reduction of coumarin or chromone derivatives. Reaction of 2-alkylbenzopyrylium salts with salicylaldehyde gives directly a spirodibenzopyran or 2-vinynologue benzopyrylium salt 17 which then can be converted into the spirodibenzopyran by piperidine or pyridine. 

The stereochemistry of 338 and 339 in each case results from initial conjugate addition of MeO" at position 2 of the chromone ring. Ensuing attack of the formed enolate 342 upon PhI(OMe)2 occurs in an anti manner because of steric interaction. Sequential addition of MeO to the carbonyl group of 343 gives 344, and intramolecular reductive elimination of C6H5I then occurs with inversion of configuration, 344 345. The reaction is... 

Modification of the substitution pattern on the same chromone gives a compound with smooth muscle relaxant activity, flavoxate (184). The synthesis of this flavone ester is initiated with methylation of the hydroxypropiophenone 177 to 178 followed by reduction of the nitro group to yield aniline 179. 

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. 

A structurally unusual 3-blocker that uses a second molecule of itself as the substituent on nitrogen is included here in spite of the ubiquity of this class of compounds. Exhaustive hydrogenation of the chromone (13-1) leads to a reduction of both the double bond and the carbonyl group, as in the case of (11-2). The car-boxyhc acid is then reduced to an aldehyde (13-2) by means of diisobutylaluminum hydride. Reaction of that intermediate with the ylide from trimethylsulfonium iodide gives the oxirane (13-3) via the addition-displacement process discussed earlier (see Chapters 3 and 8). Treatment of an excess of that epoxide with benzylamine leads to the addition of two equivalents of that compound with each basic nitrogen (13-4). The product is then debenzylated by catalytic reduction over palladium to afford nebivolol (13-5) [16]. The presence of four chiral centers in the product predicts the existence of 16 chiral pairs. 

Metal hydrides usually reduce the carbonyl to alcohol but LAH converts xanthone into a dixanthyl ether (454) or xanthene (453) according to the conditions. The latter product is also obtained by the Wolff-Kishner-Huang-Minlon reduction. Metal-liquid ammonia opens the pyran-4-one ring of chromones and flavones to form dihydrochalcones and other compounds (79JOC1494). 

Replacement of halogens attached to a pyran-4-one ring has only recently been studied. The lability of a 2-chloro atom in the chromone ring has been known since 1960. It is readily displaced by nucleophiles and reductively displaced by hydrogen (Scheme 32) <60CR(250)2819, 75AP385, 77H(6)1581>. 

Generally, nucleophilic attack of chromones opens the pyranone ring. However, the reduction of flavone by LAH yields 4//-flavene (2-phenylchrom-2-ene) (62CI(L)1793). 

Enamines also react with diketene to form chromones (60JCS26). One drawback to this method is the use of 2,3-dihydro-Ar,Ar-dimethyl-p-toluidine, prepared by Birch reduction of the aromatic amine, and the consequent need to aromatize the reduced chromone which is the initial product. 

Table 8 Formation of Chroman-4-ones by Reduction of Chromones...

Dehydrorotenone 1 can be readily transformed into rotenone 2 by reduction of the chromone to the chromanol followed by Oppenauer oxidation. Two elegant syntheses of dehydrorotenone 1 used DCC as a key reagent as follows (i) treatment of derrisic acid 3 with DCC/EtjN followed by reaction of the intermediate thus obtained with sodium propanoate in ethanol gave 1. (ii) Condensation of tubaic acid 4 with the pyrrolidine enamine derived from 5 in the presence of DCC also gave 1. 

The photo-cycloaddition of ethylene to 3-alkoxy chromones such as 315 has been applied to the synthesis of marine sesquiterpene filiformin and congeners (Scheme 43) <1996JOC4391>. Tandem [2+2] 7i-photo-cycloaddi-tion and y-hydrogen abstraction provided tetracyclic intermediate 316 which was converted to terpene 317 by subsequent oxetane ring reduction and acid-catalyzed rearrangement. 

Chromones, flavones, and isoflavones of general types 396 and 398 have been reported to undergo reduction with nickel borohydride in dry methanol at ambient temperatures to give the corresponding 277-l-benzopyran-4-ols in good yields. In all cases studied, the products obtained were found to be the air-stereoisomers, for example, 397 and 399 (Scheme 64) <2002JCM201>. 

The reduction of substituted chromones 402 with 9-borabicyclo[3.3.1]nonane (9-BBN) proceeds in a regioselective fashion to give 2/7-chromenes 403 (Scheme 66). Other boranes resulted in reduction to give chromanones <2001BCJ967>. 

The total reduction of the enone system present in chromone to the corresponding chroman is effected by hydrogenation and is a key step during the synthesis of 2-(aminomethyl)chromans (2-AMCs) for evaluation of their affinity for the dopamine (DA) D2 receptor <1997JME4235>. Luche reduction of a chroman-4-one is used during the synthesis of antagonists of leukotrine D4 <1998BML1791>. 

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