Flavonol

The basic unit of the flavone-type dyes is 2-phenyIbenzopyrone (14) which unsubstituted is flavone [525-82-6], isoflavone [574-12-9] is (15) and flavonol [577-85-5] is (16). 

Flavone dyes having these stmctures are hydroxylated and methoxylated derivatives. The degree of hydroxylation varies from two in chrysin [480-40-0] (17) to six in gossypetin [489-35-0] (18). Those dyes containing not more than three hydroxyls are generally termed flavones whereas those containing up to and including six are flavonols. 

The flavone, isoflavone, and flavonol-type dyes owe their importance to the presence of an o-hydroxy carbonyl stmcture within the molecule. Positions 4 and 5 can chelate with different metallic salts to give colored, insoluble complexes. In other words, these dyes require a mordant in order to fix them onto the fiber. Perkin was able to predict the stmcture of unknown flavones by comparing the color of their complexes with the color of known complexes (70). For example, ferric chloride gives a green color with 5-hydroxyflavones and a brown one with 3-hydroxyflavones (71). 

Eosin Flavonoids Morin Flavonol, fisetin, robinetin Quercetin Rutin condensation products of urea, formaldehyde and methanol [126], pesticide derivatives [127] sweetening agents [128, 129] anion-active and nonionogenic surface-active agents [130] steroids, pesticides [29,132, 133] pesticides [134—137] vanadium in various oxidation states [138] uracil derivatives [139]... 

The Auwers flavone synthesis consists of treatment of dibromo-coumarones 1 with alcoholic alkali to give the flavonols 2. It can also be described as the three-step sequence of 3 — 6. 

There is no published mechanistic study on the Auwers flavone synthesis. The mechanism may involve the nucleophilic addition of oxonium 7, derived from 1, with hydroxide to give 8. Base-promoted ring opening of 8 could provide the putative intermediate 9, which then could undergo an intramolecular Michael addition to form 10. Expulsion of bromide ion from 10 would then give flavonol 2. 

Auwers and others soon discovered that the transformation 3 —> 6 did not consistently give flavonols such as 2. For example, alcoholic alkali treatment of dibromide 11 produced 2-benzoyl-benzofuran-3-one 12 instead of the corresponding flavonol. The same observation was made by Robert Robinson in a failed attempt to make datiscetin in 19257 It has reported that when there is a meta (to the coumarone ring oxygen) substituent such as methyl or methoxy, flavonol formation is hindered, whereas methyl, methoxy, and chlorine substituents at the ortho and para positions are conducive to flavonol formation. ... 

The conversion of 2 -hydroxychalcones to 2-aryl-3-hydroxy-4f/-lbenzopyran-4-ones (flavonols) by alkaline hydrogen peroxide oxidation is known as the Algar-Flynn-Oyamada (AFO) reaction or AFO oxidation. ... 

In 1934 the transformation of 2 -hydroxychalcones to flavonols in the presence of hydrogen peroxide and sodium hydroxide was reported simultaneously by Algar and Flynn in Ireland and Oyamada in Japan However, many reports following the original disclosures showed that the Algar-Flynn-Oyamada reaction could lead to several products including aurones 4, dihydroflavonols 5, 2-benzyl-2-hydroxydihydrobenzofuran-3-ones 6, and 2-arylbenzofuran-3-carboxylic acids... 

Despite the formation of several products, the AFO reaction has remained a popular method for the synthesis of flavonols. 

It is also hypothesized that formation of 2-benzyl-2-hydroxydihydrobenzofuran-3-ones 6 and 2-arylbenzofuran-3-carboxylic acids 7 are derived from an intramolecular attack of the phenoxide at the P-position. Despite the complex mechanism and multiple products, general trends have emerged through experimental results. If the chalcone lacks a 6 -methoxy group but has a hydroxyl group at the C2 or C4 positions, flavonols are favored. However, if the 6 -methoxy group is present and no hydroxyl substituent is present at C2 or C4 aurones and flavonols are formed. Others have also shown that pH and temperature influence the product distribution. 

The AFO reaction has seen very few variations since it was first reported in 1934. However, the most significant modification was reported in 1958 by Ozawa and further elaborated by Smith and others. Prior to this modification the intermediate chalcones were purified and then subjected to hydrogen peroxide in a basic medium. With the modification, the chalcone was generated in situ, from an aldehyde and a hydroxyacetophenone, and then allowed to react with aqueous hydrogen peroxide in the presence of sodium hydroxide to deliver the flavonol. Smith and coworkers conducted a limited study to examine the scope and limitations of this modification.Flavonols were delivered in 51-67% however, no flavonols were isolated with highly reactive aldehydes such as p-nitrobenzaldehyde and when 2-hydroxy-4-methoxyacetophenone was used. 

As described earlier one of the possible products from the AFO reaction is dihydroxyflavonols. Simpson and coworkers took advantage of this outcome in their synthesis of the flavonol rhamnocitrin (23). Chalcone 24 was subjected to the typical AFO conditions to deliver dihydroxyflavonol 25. The isolated product was further subjected to hydrogen peroxide to afford flavonol 25a in 30% yield. However, treatment of 25 with bismuth acetate, generated in situ from bismuth carbonate and acetic acid, gave 25a in 77% yield for a respectable 52% overall yield over two steps. 25a was then selectively demethylated with anilinium chloride to deliver rhamnocitrin (23). 

Hundreds of flavonols have been isolated and characterized many of them are biologically active. Hence a great synthetic interest has arisen. Some of the efforts have concentrated on the synthesis of naturally oecurring flavonols while others have focused on the synthesis of flavonol derivatives for structure activity relationships. ... 

In the example below, Bhardwaj and coworkers synthesized tetramethoxyflavone 36 this flavonol was believed to be the structure of a compound isolated from Artemisia annua Methyl ketone 37 and aldehyde 38 were smoothly condensed to afford chalcone 39 in 73% yield. 39 was then converted to 40 under slightly modified AFO conditions in low yield. Selective demethylation of 40 gave 36. However, spectral data and melting point data of 36 did not match up with the compound isolated from the plant. Hence, the original structure was misassigned and was not flavonol 36. 

Scriba and coworkers showed the utility of the AFO reaction by synthesizing a series of flavonols that exhibited anti-inflammatory activity. Two of the examnles are... 

In addition, Pfister and coworkers investigated 3-hydroxyflavone-6-carboxylic acids as histamine induced gastric secretion inhibitors. After condensing 3-acetyl-4-hydroxybenzoic acid (45) with a variety of aldehydes 46 to deliver the chalcones 47, these purified chalcones were then subjected to the standard AFO conditions to afford flavonols 48 in 51-80% yield. Subsequent alkylation of 48 with methyl iodide or isopropyl iodide followed by saponification of the corresponding esters gave the target compounds. 

Relative emission Intensity measurements were made at 475 nm for tin analysis, the emission maximum for the tln-flavonol complexes examined In this work. Emission spectra are uncorrected. 

Substrates other than free cells were also examined for luminescence activity in the presence of tin and flavonol. For example, glass slides covered with a well-developed but uncharacterized biofllm growth were exposed to 4.5 x 10 H n-butyltin trichloride in ethanol for 60 min. The slides were subsequently rinsed with ethanol and exposed to 1.4 x H... 

Tin Analysis. Figures 2, 3 and 4 Illustrate typical emission spectra obtained In the characterization of Sn /flavonol Interactions. As seen In Figure 2, the free ligand (5.0 x 10" M)... 

In ethanol In the absence of tin exhibits an emission maximum at 555 nm upon 366 nm excitation. Figures 3 and 4 show emission spectra of the Sn /flavonol complex on Irregularly shaped glass beads of 10-100 tm diameter, and of BuSn /flavonol accvmulated by Pseudomonas 244 cells respectively. The glass bead study serves as a model of tin adhesion to a small heterogeneous surface from which spectra can be directly obtained only by mlcrospectrofluorometrlc techniques. 

In vivo spectra of complexed tin on Pseudomonas 244 are essentially Identical to those of the glass bead model system, exhibiting an emission maxlmvm at 475 nm. A lower Intensity residual peak at 550 nm In Figure 4 Is due to uncomplexed flavonol, which was not completely removed from the cell membrane despite multiple washings. 

Figure 3. Emission spectrum of 10-100 fm surface sulfhydryl derlvatlzed glass beads following treatment with aqueous 1.0 x 10 M SnCl and ethanollc 5.0 x 10 M flavonol.

Figure 4. Emission spectrum of Pseudomonas 244 following treatment with aqueous 2.0 x 10" M n-butyltri-chlorotin and 50% ethanolic 1.0 x 10" M flavonol.

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