Flavanones aldehydes

An improved version of the Knoevenagel reaction between acetophenones and aldehydes allows direct access to trarcr-2,3-disubstituted chroman-4-ones, examples of which show high anti-estrogenic activity <00T1811>. Reduction of flavanones by NaBUi leads to the 2,4-cis-flavan-4-ols from which 4-methoxyflavans can readily be obtained detailed H and 13C NMR data are provided <00T6047>. 

One of the simplest natural flavonoids is the flavanone liquiritigenin, a material that contributes to the bright yellow colour of liquorice root. Liquiritigenin may be synthesized readily, as shown, by a two-stage process starting from the phenolic ketone and aldehyde. 

The condensation of 2-hydroxyacetophenone with benzaldehyde yielded exclusively 2 -hydroxy-chalcone, and the cyclization to flavanone was not observed. An investigation of the species adsorbed on the catalyst (289) suggested that CS condensation on the Ba(OH)2 surface occurs via a very rigid transition state, whereby the OH group of 2-hydroxyacetophenone is bonded to the catalyst surface and placed at great distance from the carbonyl carbon atom of the aldehyde, making the cyclization of 2 -hydroxy-chalcone to flavanone difficult. Deactivation of the catalyst was not observed in the presence of moderate amounts of organic acids, such as benzoic, acrylic, or trichloroacetic acid. 

The oxime 7, prepared from salicyl aldehyde, is converted with iV-chlorosuccinimide into the hydrox-amic acid chloride 8. From this, the nitrile oxide is obtained with KHCO3, which reacts regioselec-tively with styrene to give the 3,5-diaryl-4,5-dihydroisoxazole 9. Catalytic hydrogenation leads to the y -hydroxy ketone 10, which on acid-catalysed cyclodehydration gives the flavanone 11. 

The ability of L-Pro to promote the Knoevenagel reaction has been harnessed in domino reaction sequences for the preparation of important target products. Several bicyclic and polycyclic systems have been obtained by these means. As an example, coumarines were prepared by the one-pot condensation reaction of o-hydroxybenzaldehydes with active methylene compounds (Scheme 2.8). In a related procedure, flavanones were synthesised from aromatic (3-ketoesters and aldehydes (Scheme 2.8). The domino sequence comprises in this case, a proline-catalysed Knoevenagel condensation and an intramolecular Michael addition. 

L-Pro was chosen as catalyst for the effective synthesis of flavanones from 2-hydro qracetophenones and aryl aldehydes. The transformation presumably occurs by the aldol condensation between both carbonyl... 

Yao et al. [92] reported one-pot synthesis of flavanone 64 via Mannich type reaction catalyzed by molecular iodine. A simple workup and the high compatibihty of functional groups made this an attractive synthetic approach to access flavanone derivatives (Scheme 10.46). The three-component Mannich reaction of aldehyde, amine, and enolizable ketone to obtain the P-aminocaibottyl compounds has been known, bnt when the Mannich reaction of benzaldehyde, aniline, and 2-hydroxyacetophenone had been explored in the presence of iodine, no trace of p-aminocaiboi l compound is observed and flavanone was formed as the sole product in moderate yield. 

The oxidation of a ( )-flavanone with Tl(ni) nitrate, Pb tetracetate, phenyliodonium diacetate (PIDA), or [hydroxyl(tosyloxy)iodo]benzene in trimethyl orthofonnate affords the corresponding ( )-2,3-dihydrobenzo[h]furan derivative as a major product. The structures, including the relative stereochemistry, and a plausible mechanism of formation are reported. The preferred formation of a flavone from the ( )-flavanone by PIDA is explained by quantum-chemical calculations on the intermediate formed by the addition of this reagent to the enol ether derivative of the ( )-flavanone." Formation of mixed anhydrides by rapid oxidation of aldehydes, activated by pivalic acid, Bu OCl in presence of pyridine and MeCN is catalysed by TEMPO (2,2,6,6-tetramethylpiperidin-l-oxyl). The anhydrides can be converted in situ to esters, secondary, tertiary or Weinreb amides in high yield. Oxidation of the aldehyde to 2-propyl esters is also possible using only catalytic amounts of pivalic acid." ... 

The formation of heterocychc amines of the IQ type is effectively inhibited by antioxidants. The presence of phenohc compounds such as flavanones and flavan-3-ols significantly inhibits their formation. The mechanism of the inhibitory effect is partly based on the ehmination of Strecker aldehydes, precursors of IQ mutagens, by condensation with phenols. For example, phenylacetaldehyde, a decarboxylation product of phenylalanine and a precursor of PhIP, produces two adducts, ( )-8-(phenylethenyl)naringenin and ( )-6-(phenylethenyl)naringenin withnaringenin (Figure 12.2). 

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