Chalcones

Chalcones (1.24) and dihydrochalocones (1.25) have a linear C3-chain connecting the two rings. The C3-chain of chalcones contains a double bond, whereas the C3-chain of dihydrochalcones is saturated. 

Chalcones, such as butein (1.26), are yellow pigments in flowers. An example of a dihydrochalcone is phloridzin (phloretin-2 -0-D-glucoside) (1.27), a compound found in apple leaves, and which has been reported to have anti-tumor activity (Nelson and Falk, 1993). 

Licochalcone (50) is a natural product that is isolated from the roots of Chinese liquorice and is reported to have antileishmanial activity [49]. A series of chromene-substituted chalcones related to licochalcone have been reported to have antileishmanial activity [50]. Compound 51 was reported to have an IC50 of 1.2 pM against Leishmania major promastigotes versus meglumine antimoniate (IC50 =30 pM). Various compounds related to 51 have potent antileishmanial activity (IC50 3 pM) with potency similar to 51, but they did not show cytotoxicity. 

The reaction of chalcone 231 with chlorosulfonic acid was studied under different conditions treatment with the reagent (three equivalents) at 0 °C (5 hours) or at 50 °C (3 hours) gave no reaction, while at 100 °C, the product was benzoic acid. However, reaction with excess chlorosulfonic acid (six equivalents) at room temperature for 1 or 3 weeks gave the 4-sulfonyl chloride 232 in yields of 27 or 75% respectively. (Equation 73). 

In chalcone 231, sulfonation is facilitated by the activating influence of the a, -alkenic double bond which causes an overall donation of electrons into the aromatic ring. 4-Methoxychalcone 233 reacted with chlorosulfonic acid (five equivalents) for 1 week to give the 3-sulfonyl chloride (234, 63%) (Equation 74). 

The increased yield in the chlorosulfonation of 3-methoxychalcone (63%) as compared with chalcone (27%), under comparable conditions, is a reflection of the activating effect of the methoxy group which also directs the orientation of sulfonation into the 3-position. 

The relative ease of sulfonation of 235 in comparison with chalcone 231 is due to the greater reactivity of the naphthalene nucleus towards electrophilic substitution and the orientation of sulfonation occurs in the predicted 4-position of the naphthalene ring in view of the electron-donating character of the alkenic double bond. 2-, 3-, and 4-Methoxy, 3,4-dimethoxy- and 4-phenyl-chalcone, together with the 2-thienyl and cinnamylidene analogues reacted with chlorosulfonic acid (six equivalents or three equivalents in thionyl chloride) at room temperature to give the corresponding sulfonyl chlorides. The orientation of sulfonation was discussed in terms of stereoelectronic factors and was confirmed by NMR spectral analysis. 

In 3-methoxychalcone, both the 4- and 6-positions are activated towards sulfonation by the combined effects of the alkenic double bond and the methoxy group, consequently reaction can occur in either position. 3-Methoxychalcone with chlorosulfonic acid (six equivalents) for 3 hours gave the 6-sulfonyl chloride (60%), while treatment with chlorosulfonic acid (six equivalents) in excess thionyl chloride afforded the 4,6-disulfonyl chloride (88%).  

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Pyridyl)hydrazine (Aldrich), 4-acetylpyridine (Acros), N,N,N -trimethylethylenediamine (Aldrich), methylrhenium trioxide (Aldrich), InQj (Aldrich), Cu(N0j)2-3H20 (Merck), Ni(N03)2-6Il20 (Merck), Yb(OTf)3(Fluka), Sc(OTf)3 (Fluka), 2-(aminomethyl)pyridine (Acros), benzylideneacetone (Aldrich), and chalcone (Aldrich) were of the highest purity available. Borane dimethyl sulfide (2M solution in THE) was obtained from Aldrich. Methyl vinyl ketone was distilled prior to use. Cyclopentadiene was prepared from its dimer immediately before use. (R)-l-acetyl-5-isopropoxy-3-pyrrolin-2-one (4.15) has been kindly provided by Prof H. Hiemstra (University of Amsterdam). 

The aromatic shifts that are induced by 5.1c, 5.If and S.lg on the H-NMR spectrum of SDS, CTAB and Zn(DS)2 have been determined. Zn(DS)2 is used as a model system for Cu(DS)2, which is paramagnetic. The cjkcs and counterion binding for Cu(DS)2 and Zn(DS)2 are similar and it has been demonstrated in Chapter 2 that Zn(II) ions are also capable of coordinating to 5.1, albeit somewhat less efficiently than copper ions. Figure 5.7 shows the results of the shift measurements. For comparison purposes also the data for chalcone (5.4) have been added. This compound has almost no tendency to coordinate to transition-metal ions in aqueous solutions. From Figure 5.7 a number of conclusions can be drawn. (1) The shifts induced by 5.1c on the NMR signals of SDS and CTAB... 

Some trivial names are retained acetone (2-propanone), biacetyl (2,3-butanedione), propiophen-one (CgHj—CO—CH2CH3), chalcone (C(,H5—CH=CH—CO—CgH5), and deoxybenzoin (C<,H5—CH3—CO—C H ). 

Photolysis in general produced oxazoles and a variety of other products including aminochalcones, nitriles, aldehydes and chalcone oximes. A number of photolytic intermediates have been postulated, represented by (151), (152), (153) and (154) (77CL1195, 75T1373, 73HCA2588, 73TL2283). 

The reaction of 3,5-diphenyl-2-isoxazoline with lithium diisopropylamide produced with 2 equivalents of base a chalcone oxime, while in the presence of 1 equivalent and an alkyl iodide, ring alkylation occurred at the 4-position of the nucleus (Scheme 48) (80LA80, 78TL3129). 

Treatment of 2-isoxazolines with acid usually leads to ring rupture and formation of chalcone products 62HC(l7)l), although 5-methyl-3-phenyl-2-isoxazoline forms a quaternary salt with dimethyl sulfate in the presence of perchloric acid (Scheme 51) (73BSF1390). 

Reaction of quaternized isoxazolin-5-ones with phenylmagnesium bromide produced a chalcone and dibenzoylethane. Those 5-ones with a 4,4-disubstituent undergo addition of the Grignard reagent to give a 5-ol (Scheme 63) (73BSF3079). 

A 1 1 adduct from diphenylsulfilimine and a benzoylacetylene underwent an intramolecular cyclization reaction to give an isoxazole in good yield (equation 40). Similarly, the 1 1 adduct from iodoazide and chalcone gave 3,5-diphenylisoxazole (equation 41). These two approaches to regiospecific isoxazole synthesis are of little practical significance. Additional examples of the (OCCCN) reaction are given in equations (42) and (43). 

Ceroplastol synthesis, 1, 428 Cetyl alcohol synthesis, 1, 478 Chaetoglobasins structures, 4, 376 Chalcone, o -azido-2 -oxy-synthesis, 3, 823 Chalcone, 2-hydroxy-reduction, 3, 751 Chalcone, 2 -hydroxy-mass spectra, 3, 618 Chalcone dibromides flavone synthesis from, 3, 823 Chalcones polymers, 1, 304 Chanoclavine synthesis, 6, 423 Charge density waves in stacks of ions, 1, 351-352 Chartreusin... 

Benzalacetophenone (Chalcone) [94-41 -7] M 208.3, m 56-58", b 208"/25mm, pK -5.73 (aq H2SO4). Crystd from EtOH wanned to 50° (about 5mL/g), iso-octane, or toluene/pet ether, or recrystd from MeOH, and then twice from hexane. SKIN IRRITANT. 

Chalcones yield orange-red to brown-colored zones [4] as do 4-aminoazobenzene derivatives, but their colors begin to change after 10 min and slowly fade [5]. Penicillic acid is visible as a greyish-black zone [18]. 

An obvious outcome of the Hantzsch synthesis is the symmetrical nature of the dihydropyridines produced. A double protection strategy has been developed to address this issue. The protected chalcone 103 was reacted with an orthogonally protected ketoester to generate dihydropyridine 104. Selective deprotection of the ester at C3 could be accomplished and the resultant acid coupled with the appropriate amine. Iteration of this sequence with the C5 ester substituent ultimately gave rise to the unsymmetrical 1,4-dihydropyridine 105. 

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). 

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. 

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. 

As will be discussed in the next section, 1,5-pentanediones are obtained by Michael addition of acetophenones to chalcones. The addition and cyclization may be merged in one step (see Section II,C,2,g). When acetophenone was condensed with chalcone (74) in the presence of or of HC104, jS-phenylpropio-... 

Boron trifluoride etherate, is also a good catalyst for this hydride transfer to chalcone. Unlike triphenylmethyl perchlorate, however, chalcone is able to enter Michael additions with the 1,5-diketone followed by eliminations leading to unexpected products, e.g., 3-benzyl-2,4,6-triphenylpyrylium from 2-carbethoxy-l,3,5-tri-phenylpentane-l,5-dione and chalcone the benzyl group originates from chalcone, the elimination product being ethyl benzoylacetate. ... 

More serious limitations and precautions apply to compounds in which not all three R, R, and R" groups are aromatic. Autocondensation of benzylideneacetone (111) yields an unstable chloroferrate which may be 113 or 115, according to whether a Michael addition to 112 or a crotonic condensation to 114 is first involved. Since compound 113 could readily be prepared from 2,6-dimethyl-4-phenylpyrylium and benzaldehyde, the structure of the reaction product should be easily soluble. Another equivocal product is formed from two moles of benzylideneacetone, but a definite structure (116) results from chalcone and benzylideneacetone. ... 

Anindeno[1.2-6]pyrylium (123) has been reported to result from the autocondensation of chalcone (FeCls-f Ac20). ... 

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