2-Substituted chromones

In the present study, we describe the effects produced by 3-formyl-chromones substituted at the 6-position. We evaluated their cytotoxicity against human tumor cell fines and normal cells, and also investigated the structurally related coumarine (2H- l-benzopyran-2-one) derivatives [24]. 

Among the nucleophilic zwitterions, Huisgen s zwitterions (50) reacted with both 27-ketoesters and 27-aldehydes to provide chromone-substituted pyrrole ring-system 55 as the major product. Only in some cases of 27-aldehydes, 63 a novel ring system was obtained as minor products. Zwitterion 47, that is, methyl isocyanoacetate displayed unbiased reactivity toward 27-ketoesters/aldehydes and yielded benzopyrones supporting substituted finan ring in high yields (54, Schemes 27.3 and 27.4). 

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

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... 

It is known that tropylium may be prepared from tropylidene via hydride abstraction by PhgC or MegC carbonium ions therefore, it is very likely that here too the dehydrogenation is a hydride transfer from the 1,5-dione to an acceptor. A similar dehydrogenation of chromanones to chromones, with triphenylmethyl perchlorate was reported. A study of the electrooxidation of 1,5-diones on a rotating platinum electrode showed that 1,5-diaryl-substituted diones afford pyrylium salts in these conditions and that the half-wave potentials correlate with yields in chemical dehydrogenations. 

Khellin is a natural product closely related to the psoralens in which a chromone ring has been substituted for the cou-marin. The plant material has been used since ancient times as a folk remedy modern pharmacologic work has confirmed the bronchio-dilating and antispasmodic activity of khellin. The synthesis outlined below, it should be noted, is selected from a half-dozen or so reported within the last quarter century. 

Whereas benzopyrylium salts are resistant to electrophilic substitution, even in the benzene moiety, the benzopyrones [coumarins (81), isocoumar-ins (82), and chromones (83)] are readily halogenated in either ring, with... 

A one-pot process to form 1,3,4-substituted pyrazoles 25 by Suzuki coupling of arylboronic acids to chromone 24, followed by condensation with hydrazine has been reported <06JCO286>. The synthesis of 3 or 5-o-hydroxyphenol-4-benzylpyrazoles has been accomplished by treatment of 3-benzylchromones, 3-benzylflavones and their 4-thiochromone analogs with hydrazine hydrate in hot pyridine <06EJO2825>. 

An interesting annelation reaction of allene-derived 13-dipoles with 3-(IV-aryliminomethyl)chromones 38 affords, in fair yields, after [4 +3] cycloaddition and a subsequent cascade of rearrangements, derivatives of the novel iV-aryl-2,3-dihydro-4-ethoxycarbonylchromano[2,3-h]azepin-6-one system 39 (for example, R = Me, R1 = Cl) (Scheme 9). In the initial cycloaddition, the substituted chromone acts as an azadiene moiety <00OL2023>... 

Synthesis of 3-substituted chromone derivatives for their antibacterial studies. 

Chromones (14) and flavones (phenylchromones, 15) are pyranones when they have a hydroxyl group substituted in such a position that they can act as bidentate 0,0-donors then they and their complexes are relevant to the present review. Fig. 3 shows formulae for chromone, flavone, and the polyhydroxyflavones (16-20) which appear in this review. 

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. 

Syntheses of 2- and 3-substituted chromones normally start from 2-hydroxyphenyl ketones. In the first of two examples, a route to flavone is shown in Scheme 5,10 using 2-hydroxyacetophenone (2-hydrox-yphenylethanone) and benzoyl chloride as starting materials. Initially, the phenolic group of the acetophenone is O-acylated by benzoyl chloride, using pyridine as a base (a Schotten-Baumann-type reaction). 

A similar route to 3-substituted chromones and isoflavone (R = Ph) Scheme 5.10 relies upon a Claisen-Hke condensation between the enolate of a 2-hydroxyphenyl ketone and ethyl formate (methanoate) (Scheme 5.11). 

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>. 

Electrophilic aromatic substitution of other benzo-fused v-deficient systems generally follows predictable pathways. Thus, benzopyrylium salts are in general resistant to electrophilic substitution even in the benzo-fused ring. Chromones behave somewhat similarly, although substitution can be effected under forcing conditions. Coumarins, on the other hand, undergo nitration readily in the 6-position while bromination results in substitution at the 3-position as a consequence of addition-elimination. 

The dibenzopyranone ring system may be viewed as a chromone with an additional fused benzene ring and thus generally related to the antiasthmatic mediator release inhibitor cromolyn (see Chapter 11). Two dibenzopyranones have in fact been investigated for this indication in the clinic. Friedel-Crafts cyclization of the substituted cresyloxybenzoic acid (2-1) in sulfuric acid leads to the dibenzopyranone (2-2). The methyl group is then oxidized to a carboxylic acid by means of chromic acid. The acid is then converted to its sodium salt, xanoxate sodium (2-3) [2]. 

Using the Scheme shown below, a series of substituted chromones was prepared. Yields ranged from 13 - 67%... 

Spectral data for substituted coumarins and chromones are widely spread in the literature, and references should be sought from the review literature. 

Several older syntheses are based on o-hydroxyacetophenones but these routes generally offer little or no advantage over other methods. The Reformatsky reaction has been used to prepare 3- and 3,4-substituted coumarins (44JIC109) and the Kostanecki-Robinson reaction may yield coumarins instead of or as well as the chromone (see Section 2.24.3.4.1 for further discussion). 

The vigorous conditions which are necessary serve to detract from the value of the Perkin synthesis, leading to the production of tarry material which adversely affects the yield of coumarin. Difficulties encountered in the synthesis of substituted o-hydroxybenzaldehydes also limit the application of this route. The obvious advantages of the method are that there are no doubts about the orientation of the product and that, unlike the Pechmann reaction, formation of the isomeric chromones is not possible. 

Not unexpectedly, a substituent on the acetyl group of the 2-hydroxyacetophenone has an effect on the condensation, though successful preparations of 3-substituted chromones have been achieved. A neat alternative approach to such chromones involves alkylation of the intermediate diketone and subsequent cyclization (34JCS1311). 

Where the substitution pattern of the acetophenone is such that the formation of isomeric chromones can be envisaged, the reaction does not appear to show any regioselectivity (Scheme 157) <71JCS(C)1324>. 

The presence of a substituent on the original methyl group of the hydroxyacetophenone prevents formation of the labile 3-acylchromone but otherwise has little effect provided the substituent is not solvolyzed. A number of 3-substituted chromones have been obtained in this manner (55JOC38). 

Hydroxyacetophenone reacts with DMF under Vilsmeier conditions to yield chromone-3-carbaldehyde (72LA(765)8). The reaction appears to be generally applicable, various substituents being acceptable in the aromatic ring (74T3553). Furthermore, acetylhydroxy-naphthalenes yield the corresponding benzochromones, and the pyranochromone (452) is formed from the appropriately substituted coumarin. 

In the presence of boron trifluoride and methanesulfonyl chloride, polyhydric acetophenones react with DMF to give 3-substituted chromones. It is postulated that ring for-mylation is prevented through deactivation by complex formation between the substrate and boron trifluoride (76CC78). 

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