Chromones effect

Over the years the literature is filled with examples where the initial characterization was incorrect. One example is illustrated below. In 1940, Sethna and Shah presumed that they synthesized coumarins 42 and 43 from a reaction between P-orcacetophenone (44) and its 4-0-methyl ether 45 under standard Kostanecki-Robinson conditions, respectively. Three decades later Bose and Shah synthesized coumarin 43 via another route and concluded that the initial assignment made by Sethna and Shah was incorrect. After the Bose and Shah findings were published, Ahluwalia and Kumar concluded that the Sethna and Shah products were actually chromones 46 and 47 based on proton NMR data and chemical derivatization. Despite these shortcomings, the Kostanecki-Robinson reaction remains an effective method for formation of both coumarins and chromones. 

In the course of synthesizing DNA-gyrase inhibitors Hogberg, Mitscher, and coworkers determined that an effective means of constructing the core of their inhibitors was via a K-R reaction. Under mild conditions, keto ethylester 52 was acylated using acetic formic anhydride in the presence of sodium formate to deliver chromone 53 in 75% yield. 

Perhaps one of the most effective agents currently available for the treatment of the bronchial spasms attendant to asthma is a synthetic agent that incorporates the chromone moiety. 

Chromones are also Michael acceptors, and Scheme 18 shows how 3-bromochromone reacts with 1,3-diketones in basic media. The reaction is fairly general and the yields can be as high as 90%, moreover, phenolic furans are not common and the approach provides an effective way of protecting the phenolic hydroxy group during furan ring formation.100... 

Method A The 2-hydroxyacetophenone (3 mmol) and acyl chloride (3.6 mmol) in PhH (20 ml) are stirred at 80°C with aqueous K,CO, (I0%, 20 ml) and TBA-HS04 (0.5 g, 1.5 mmol) for 2-3 h until the ester is completely formed. The PhH phase is separated, washed with H.O (3 x 20 ml) and dried by azeotropic distillation. Ring closure is effected by the addition of TosOH (1.55 g, 9 mmol) in PhH (20 ml) and azeotropic distillation. The organic solution is washed with aqueous NaHCO, (10%, 50 ml) and evaporated to yield the chromone. 

A carbonyl group can also be effective in the cyclization step following the rearrangement. Thus, para-methoxyphenyl 3-oxobutanoate (244) is rearranged to the p-diketone 245, which is, in turn, cyclized to chromone 246 in high yield (Scheme 64) [184]. 

Chloroquinolines are reactive groupings due to electron-deficient carbon to which the halogen is attached. This carbon is electron-deficient due to the combined electron-withdrawing effects of the chlorine substituent and the quinoline nitrogen. The electrophilic carbon is thus able to react readily with nucleophiles present in the body. The impact of this grouping on a molecule is illustrated by 6-chloro-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate (Figure 8.28). In contrast to many related compounds (chromone-carboxylates) lacking the chloroquinoline, 6-chloro-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate is excreted as a... 

I, 2-alkyl shift provides a convenient route for the synthesis of chromones 335 (Eq. 46), tetrahydroxanthones (336, n = 1) and higher homologs (336, n = 2) (Eq. 47). Both heat and ultrasonic conditions work well to effect this alkyl shift (94SC2637). 

There are few cases in which free /3-aldehydo esters have been condensed successfully with ureas. Commonly, alkoxymethylene esters are used. The initial reaction leads to an acyclic intermediate that may require a separate treatment to induce ring closure. The reaction of a /3-keto ester with urea may be a two-step process in which case acid catalysis can be used in the formation of an acyclic intermediate, with ring closure effected by strong alkali. When the ester component is a lactone or chromone, the product contains a hydroxyalkyl <2000JME3837> or 2-hydroxyphenyl substituent <2004S942>, as shown by the synthesis of the 5-(2-hydroxyethyl)-4-pyrimidinone 657 and the 6-(2-hydroxyphenyl)-pyrimidine 659. 

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 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. 

While treatment in HBr + AcOH by the Tarbell method424 leads directly from allylphenols 168 to compounds 169, other methods involve the formation of the brominated derivative obtained by adding HBr (in the presence of diphenylamine) to the allylphenol.432 Ring closure is effected by sodium ethoxide. Thus, the ll//-furo[3,2-a]xanthone derivative (177) can be obtained either directly from the allyl derivative (175) or via the bromo derivative (176).432 433 Similarly, 179 has been obtained from the chromone 178.434... 

A methyl group is commonly encountered at C-2 in chromones. Its effect is to shift the signal from H-3 upheld (67IJC93). 

Conversion of an aldehyde into a carboxyl group is effected with chromium trioxide-sulfuric acid in moderate yield. This is a synthetically valuable conversion because of the availability of chromone-3-carboxaldehydes (477). Photooxidation of the aldehyde (477 R = H, Me, Cl, OMe or OAc) in the presence of NBS gives high yields of 3-carboxylic acids (80SC889). 

The synthesis of chromones by the Kostanecki-Robinson method frequently yields a 3-acetylchromone. This acetyl group forms a 1,3-diketone with the pyran carbonyl group and is therefore labile in an alkaline medium. Treatment with aqueous carbonate or other base removes such groups but has no effect on other acyl substituents, for example the 6-acetyl of 3,6-diacetyl-2-methylnaphtho[l,2- ]pyran-4-one (516). 

A number of natural flavonoids, coumarins and chromones have a prenyl (3-methylbut-2-enyl) side chain which is capable of cyclization on to an oxygen atom to form a pyran ring (77HC(31)633). Prenylation is effected by reaction with either 3-methylbut-2-enyl (prenyl) bromide or 2-methylbut-3-en-2-ol in the presence of a base or a Lewis acid. When this reaction is applied to flavonoids, the prenyl group has a choice of two benzene rings and... 

The directing effect of a substituent in a chroman is sometimes different from that in chromone for example, bromination of the 7-methoxy compounds yields the 8-bromo-chromone not the 6-bromochroman, and nitration of 8-hydroxychromone gives mainly the... 

Hydroxyacetophenone requires an additional carbon atom, which will become C-2 of the heterocyclic product, before cyclization to the chromone can be effected. Direct C-formylation is not easy and the following syntheses illustrate the various techniques used to introduce this fragment. 

A wide variety of chromones has been prepared by this method since its introduction (01CB2475), and the literature abounds with examples. A fully detailed preparation of 3-ethylchromone is available (5SOSC(3)387). The presence of substituents in the aromatic ring of the acetophenone has minimal effect on the course of the reaction both electronreleasing and electron-withdrawing substituents are compatible with the synthesis. 

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). 

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). 

The condensing agent used in earlier studies was phosphorus pentoxide and it was believed that this led predominantly to chromones. Sulfuric acid, on the other hand, was considered to effect cyclization to the coumarin. Later workers have used polyphosphoric acid or phosphoryl chloride, though in general this change only brought about improvements in the yield. 

Unlike coumarin, chromone (206) undergoes efficient unsensitized photoaddition to tetramethylethylene, cyclopentene, ketene dimethyl acetal, and but-2-yne.180 The major product of such an addition to tetramethylene is the cis-fused cyclobutane derivative (207) the formation of the two minor products (208 and 209) is easily rationalized. Added benzophenone has no visible effect on this cycloaddition, which is therefore believed to involve the attack of triplet chromone on the ground-state alkene. Photoaddition to furo-chromones has also been studied,179 and the photosensitized cyclo-... 

Numerous examples of stilbene-to-dihydrophenanthrene photocyclization incorporating oxygen and sulfur heterocycles have been reported. Oxidation to the phenanthrene is usually effected by added iodine or by oxygen. Thus, irradiation of 2,3-diphenylchromone (37) results in the formation of phenanthro[9,10 -2,3]chromone (38)29 analogous photocyclizations have... 

Triflic acid supported on titania has proved to be an effective catalyst to transform hydroxyphenyl-l,3-propanediones to chromone derivatives in high yield and with high selectivity690 [Eq. (5.246)]. 

Treatment of the chroman-4-one 1 with benzyl chloride in DMF at 100°C gave the corresponding benzyl ether 2. When the reaction temperature was raised to 153°C, however, the products obtained were the chromone 3 and the flavone 4. It was subsequently shown that the same type of rearrangement could be effected simply by heating 1 with benzyl chloride in DMF containing potassium carbonate. 

Vaclavikova et al. [216] have investigated the effect of 13 flavonoid derivatives—aurones, chalcones, flavones, flavonols, chromones, and isoflavones—on 14 C-paclitaxel transport in two human breast cancer cell lines, the doxorubicin-resistant NCI/ADR-RES and sensitive MDA-MB-435. The compounds with known binding affinity toward the NBD of P-gp were selected. The four aurones studied most effectively inhibited P-gp-related transport in the resistant fine in comparison with other groups of flavonoids. The aurones also most effectively increased the intracellular accumulation of paclitaxel and decreased its efflux. The results obtained did not always correlate with the binding of flavonoid derivatives to P-gp, so this indicated that the binding was not the only factor influencing the transport of paclitaxel. The different aspects of inhibition of P-gp by polyphenols was recently reviewed by Kitagawa [212],... 

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