Chromone ring

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. 

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... 

The amine is then used to introduce a nitrile by diazotization followed by treatment of the diazonium salt with cuprous cyanide (180) the methyl ether is then cleaved by means of aluminum chloride. Treatment of the phenolic ketone 181 with benzoyl chloride and sodium benzoate serves to build up the chromone ring (182). The nitrile is next hydrolyzed to the acid with sulfuric acid. Esterification of the carboxyl as—its acid chloride—with N-(2-hydroxyethyl)piperi-... 

A The Mannich reaction proceeds through the intervention of the N,A dimethylmethyleniininium cation [Me N =CHJ, This is insufficiently electrophilic to react with the benzene ring under the mild reaction conditions. Similarly, were the electrophile to react with the carbonyl oxygen atom of the heterocycle, this reaction would be reversible, as an aminomethyl ether is relatively unstable in acidic media. Thus, it seems plausible that the chromone utilizes enol or enolate character to trap the electrophile at C-3, followed by deprotonation of the adduct to reform the chromone ring system ( heme 5.9). 

In the bischromone (169), which is valuable in the treatment of asthma, the two chromone moieties are inclined at about 53° to each other. Furthermore, the carboxyl groups lie in the plane of the chromone rings, whilst the central hydroxyl group is directed away from the chromone ring planes (7UPS1458,74MI22204). 

One of the rare nucleophilic displacements on the chromone ring is the formation of 2-amino-3-chlorochromone (518) or its tautomer by the action of ammonia on the nitrile (517) at low temperature (74JCS(P1)2570). 

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>. 

The best a,yaj, selectivity in this series was obtained with the introduction of a tert-butyl group at position 2 of the chromone ring (compound 6). 

Flavonol glycosides (flavinoids) such as rutin, hesperidin, and querectin, which contain the chromone ring system, were found to have AR-inhibiting activity. Querectin was the most potent. 

The pyrano[3,2-c]xanthen-7-one exhibits the two absorption bands associated with a heteroatom at a peri position of the benzopyran nucleus. Pyrano[2,3-a]xanthen-12-one 44, in which the fusion of the chromone ring is reversed, shows an intense single band blue-shifted some 14 nm relative to 2,2-diphenyl-2//-naphtho[l,2-6]pyran [Xmax 403, 482 nm (PhMe)]. Both isomers are readily degraded <01HCA117>. It is noteworthy that 44 could not be... 

An aryl piperidiol (44) was formed and formation of an (X-hydroxyacetophenone (45) enabled the formation of the chromone ring by... 

Cromolyn sodium is a bischromone that contains the fundamental benzopyrene moiety of khellin (Fig. 44.32). The two chromone rings are necessary for activity and must be coplanar, with a linking chain of no longer than six carbons. If one changes the linking chain to positions 8 and 8 ... 

As an initial step to the introduction of a carbonyl group at the 3-position of the chromone ring, we started with the synthesis of 3-formyl derivatives on which only a few reports (7., had been published. The 4-oxo-4H-l-... 

Only in a few cases, the nucleophiles preferred to add on the unsaturated side chain appended to chromone ring in 27 and thus providing isoflavaone-based ring systems (cascades II, VII-IX). 

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