3.1. Von Kostanecki method
Stanislaus von Kostanecki’s method was established in 1898-1899 and is considered one of the earliest methods of synthesis for flavones. It uses
o-hydroxyacetophenone (or
o-acetoxyacetophenone)
(1) and benzaldehyde
(2) as precursors to form 2’-hydroxychalcone (or 2’-acetoxychalcone), through a Claisen-Schmidt condensation. In the next step, the obtained chalcone is converted to flavone
(3), through bromination followed by a dehydrobromination reaction in alkali alcoholic solution (
Scheme 1).
Table 4 between the two compounds would form and then, by cyclization, a flavanone
(5) is formed. This flavanone is next subjected to nuclear bromination with bromine in carbon disulfide, resulting a 3-bromoflavanone
(6a) [
44] and, ultimately, the brominated intermediate suffers a dehydrobromination reaction, thus resulting a flavone (
Scheme 2) [
45,
46].
However, according to von Kostanecki’s collaboration with Emilewicz and Tambor (also known as Emilewicz-von Kostanecki cyclization), the chalcone
(8) is formed and then brominated, forming a chalcone dibromide
(9). This brominated compound is cyclized through the elimination of one bromine atom, resulting a 2-bromoflavanone
(6b) and, finally, the flavone after eliminating the second atom (
Scheme 3) [
2,
46].
The proposed mechanism debuts with a Claisen-Schmidt condensation, resulting a chalcone. Further, the chalcone is subjected to bromation on the C=C bond, with formation of a chalcone dibromide. Next step is the dehydrohalogenation reaction, coupled with cyclization, resulting a 2-bromoflavanone intermediate and then the flavone (
Scheme 4) [
2].
The limitations of the von Kostanecki method are the possibility of nuclear bromination and the tendency to form 2-benzylidene-coumaran-3-ones
(10) (benzalcoumaranones or aurones [
47]) (
Scheme 5) instead of flavones, when trying to synthesize natural flavones either with 5,7-disubstitution pattern or with a 4’- or 5’-alkoxy substituent or containing phloroglucinol moiety. Von Kostanecki obtained better results when used methyl ether derivates [
48,
49,
50]. Hutchins and Wheeler observed that treating the chalcone dibromides with potassium cyanide in ethanolic solution or heating above the melting point will convert them back into flavones [
50]. The same reagent converts benzalcoumaranones back to flavones (
Scheme 5). The quantity of ethanolic potassium cyanide influences the reaction’s outcome. In the case of 2-
p-alkoxybenzylidenecoumaran-3-ones, refluxing with an excess of reagent will cause the ring expansion of the aurone and form 4’-alkoxyflavones, while treating the chalcone dibromide with an insufficient quantity of ethanolic potassium cyanide would produce 2-benzylidene-coumaran-3-one, instead of flavone [
51].
The possible mechanism of obtaining flavones from aurones using ethanolic potassium cyanide debuts with the nucleophilic attack by cyanide anion on the methine carbon, followed by hydrogen transfer and carbanion formation. The carbanion’s electrons migrate, recreating the double bond, and preparing the ring expansion. Conjugation and nucleophilic attack by the newly-formed oxygen anion lead to the expulsion of cyanide anion, a good nucleofuge, and ring closure (
Scheme 6) [
51].
However, it has been established that aurone formation may be avoided by providing milder conditions for the dehydrohalogenation reaction [
46]. Donnelly and Doran have observed that the quantity of flavone increases with the decrease of base concentration [
52]. von Auwers and Anschutz have shown that 4’-alkoxyflavones can be obtained by doing the cyclization reaction in cold alcohol, rather than hot alcohol which generates aurones [
46,
53].
Zemplén and Bognár made an improvement of the von Kostanecki method and demonstrated that nuclear bromination could be avoided by submitting acetates of hydroxyflavanones to bromination in absolute chloroform and in the presence of UV light. The obtained intermediate was a 3-bromoflavanone, which can be easily dehydrobrominated, thus resulting a flavone. This method is suitable for obtaining 3-hydroxyflavones [
44,
48].
Improvements in the direct dehydrogenation of chalcones and flavanones were made by using selenium dioxide as oxidative reagent [
48,
54].
A new method by von Kostanecki was established in 1904, in collaboration with Szabránski. This method is used for obtaining 3-hydroxyflavones from flavanones, via isonitrosoflavanones. The flavanone is nitrosated with pentylnitrite and hydrochloric acid. The isonitrosoflavanone is converted to 3-hydroxyflavone by adding diluted sulphuric acid and eliminating hydroxylamine (
Scheme 7) [
55].
3.4. Baker-Verkataraman method
This method was established after the individual work of Baker and Verkataraman in 1933. It is used to obtain flavones from
o-acyloxyacetophenones (
20). These precursors are first converted into
o-hydroxydibenzoylmethane (
21) derivatives, by heating in benzene or toluene with anhydrous potassium carbonate. Then, using cold concentrated sulfuric acid, the o-hydroxydibenzoylmethane derivatives (
21) are cyclized into flavones [
2,
69] (
Scheme 14).
Verkataraman first used this method to obtain
α-naphtoflavone from 2-acetyl-1-naphthyl benzoate, by heating with sodium benzoate and benzoic anhydride [
70,
71]. Mahal and Verkataraman obtained the diketone derivative by treatement with NaNH
2 in ether at room temperature. Further cyclisation to the corresponding
α-naphtoflavone was performed with concentrated sulfuric acid in ethanol, at reflux [
72].
According to the mechanism, this method debuts with an intramolecular Claisen condensation between acetophenone and an ester group grafted on the aromatic ring, in
orto (an
o-acyloxyacetophenone), which can also be interpreted as an acyl group transfer. This is followed by cyclocondensation in acidic conditions, via a 2-hydroxyflavanone intermediate (
Scheme 15) [
2,
73].
Baker found out that under the action of sodium salts of carboxylic acids, this method could yield 3-acylflavones. Instead of doing a cyclocondensation, the
o-hydroxybenzoylmethane can be acylated on the methylene carbon, resulting a triacylmethane derivative. Next, this derivate is cyclized to 2-hydroxy-3-acylflavanone and then dehydrated, resulting a 3-acylflavone
(22) (
Scheme 16) [
69].
However, the conventional method could not produce large yields of flavones [
73]. Cramer and Elschnig discovered that the best catalyst is sodium ethoxide [
74]. Ares et al. suggested using potassium tert-butoxide for the diketone intermediate synthesis, obtaining higher yields [
75]. Jain et al. used benzoyl chloride in benzene, under phase transfer-catalysis conditions, with
n-tetrabutylamonium hydrogen sulphate, obtaining
o-hydroxydibenzoylmethane. Further treatment with
p-toluenesulphonic acid yielded to flavones with good results [
76]. A modification to this method permits the synthesis of hydroxyflavones with phloroglucinol units, by heating the 2-hydroxyacetophenones with aqueous 5% potassium carbonate and followed by treatment with acetic acid [
77]. Song and Ahn proposed the usage of tetrabutylammonium fluoride as phase transfer catalyst for the condensation of dibenzoylmethanes, also obtaining good yields [
78]. Another useful reaction condition for cyclocondensation was discovered by Stanek and Stodulski and uses N-triflylphosphoramide, an organocatalyst, which is active in mild reaction conditions [
79]. By using microwave irradiation, Pinto et al. managed to obtain 3-aroyl-5-hydroxyflavones from 2,6-diaroyloxyacetophenones [
80]. Same results were obtained with shorter reaction time, by using ethyl ammonium nitrate, a recyclable ionic liquid, under microwave irradiation [
81].
By cyclisation of dibenzoylmethanes with CuBr
2, 3-bromoflavones are formed, which can be converted into 3-aminoflavones [
82]. Other reported catalysts useful for converting dibenzoylmethanes into flavones are: FeCl
3 in dichloromethane [
83]; CuCl
2 under microwave irradiation [
84]; Cobalt(bis(salicylideniminato-3-propyl)hydroxide, a six coordinate cobalt Schiff base complex [
85]; montmorillonite K 10 Clay, under microwave irradiation (clay-catalyzed synthesis) [
86]; amberlyst 15, a cation-exchange resin, under reflux in isopropyl alcohol [
87]; solid supported catalysts like mesoporous titania/tungstophosphoric acid composites TiO
2/ H
3PW
12O
40 at reflux [
88], trifluoromethanesulfonic acid in toluene at reflux [
89], Wells-Dawson heteropolyacid in toluene at reflux, or solvent free [
90], molybdophosphoric and molybdosilicic Keggin heteropolyacids in acetonitrile at reflux [
91], silica gel supported NaHSO
4 in toluene at reflux [
92].
3.5. Algar-Flynn-Oyamada method
This method represents the collaboration between Algar and Flynn and the individual work of Oyamada from 1934-1935. It can be used for obtaining 3-hydroxyflavones from 2-hydroxychalcones by means of hydrogen peroxide in aqueous sodium hydroxide solution and cooling [
93]. Algar and Flynn used this method with hot potassium hydroxide alcoholic solution, both with good yields (
Scheme 17) [
94].
The mechanism suffered many alterations along the time. At first, Algar and Flynn were not able to isolate the intermediates. They proposed the transitory formation of an ethylene peroxide in the first stage of oxidation [
94]. Oyamada considers the existence of a flavanone intermediate, with the flavanonol being formed by the electrophilic attack of hydrogen peroxide on position 3 of the flavanone anion [
93,
95]. Dean and Podimuang demonstrated that no epoxides were formed as intermediates for obtaining 3-hydroxyflavones. They argued that a
β-position attack by the hydroperoxide anion would be difficult for phenolic chalcones, due to the internal electronic inactivation (see mesomere structure) and due to the basic conditions that turn them into anions, creating electrostatic repulsion of the hydrogen peroxide (
Scheme 18) [
96].
Starting from
o-hydroxychalcones, by means of epoxides as intermediates, two cyclization products can theoretically be formed: aurones, if the attack takes place in the position, and respectively flavonols (
via flavanones), if the attack takes place in the position (
Scheme 19). When 6'-substituted-2'-hydroxychalcones were used as precursors, it was found that the cyclization takes place preferentially by attack, with the formation of aurones as majority reaction products. This is due to the fact that the substituent grafted in the 6’-position of the chalcone displaces the keto group from the plane of the aromatic ring. This causes a steric inhibition of resonance from the 2’-oxygen anion and determine activation the -carbon [
59].
Adams and Main argued that it is not excluded that epoxides are precursors and intermediates in the formation of flavonols, by -attack. They demonstrated that by treating an epoxide at various pHs in aqueous acetonitrile solution and room temperature, led to small amounts of the
β-cyclization product, a flavonol derivative [
97,
98].
Dean and Podimuang’s theory was also challenged by Serdiuk et al. They concluded that epoxides are indeed intermediates in this method, by analyzing the thermodynamic characteristics of the intermediate reactions and finding out that the reactions of chalcones in anionic form with the hydroperoxide anion are energetically favorable [
95]. However, Bhattacharyya and Hatua demonstrated through the density functional theory that epoxidation is unlikely because of the electrostatic interaction of the hydroperoxide anion with the conjugated double bond, although an epoxide intermediate could still be formed at high temperatures and converted into aurone, supporting Dean and Podimuang’s work [
99].
The major limitation of the Algar-Flynn-Oyamada method consists in the fact that it cannot be applied for the synthesis of 3-hydroxyflavones by cyclisation of the corresponding 6’-substituted
o-hydroxychalcones because in this case the cyclization takes place preferentially by attack [
100]. Also, besides 3-hydroxyflavones, aurones can be easily obtained through
α-cyclization and sometimes even 2-benzyl-2-hydroxydihydrobenzofuran-3-ones
(23) and 2-arylbenzofuran-3-carboxylic acids
(24) are formed [
98,
101] (
Scheme 19).
Scheme 19.
Algar-Flynn-Oyamada reaction products. Aurone formation happens in higher yields when a 6'-substituted chalcone is used.
Scheme 19.
Algar-Flynn-Oyamada reaction products. Aurone formation happens in higher yields when a 6'-substituted chalcone is used.
A couple of modifications for this method exist: Na
2CO
3 and H
2O
2 in methanol and water for obtaining 5’-substituted-3-hydroxyflavones [
102], phase transfer catalysis (tetrabutylammonium bromide, iodide or hydrogensulphate, benzyltriphenylphosphonium chloride, ethyltriphenylphosphonium iodide, propyltriphenylphosphonium iodide or bromide) [
103], direct synthesis, starting from acetophenone and aldehyde, without isolating the chalcone intermediate, known as one-pot synthesis [
38,
104,
105,
106,
107].
The oxidative cyclisation with H
2O
2/OH
- of
o-hydroxychalcones was successfully extended in our research group for the synthesis of new analogues of hydroxyflavones containing the 2-phenylthiazole moiety instead of the benzene ring B of the basic skeleton of natural flavones. In a first step, the thiazole
o-hydroxy-heterochalcones were obtained in 75 - 82% yields by the condensation of
o-hydroxyacetophenone with different 2-arylthiazol-4-yl carbaldehydes (
Scheme 20). Their epoxidation with hydrogen peroxide followed by oxidative cyclisation afforded the corresponding 2-arylthiazole hydroxyflavones in 65 - 71% yields [
108].
The cyclisation pathway of thiazole and thiazolo[3,2b][1,2,4]triazole hetero-chalcones with hydrogen peroxide in basic media (NaOH) was investigated by V. Zaharia et al. By treatment with hydrogen peroxide of
o-hydroxy-heterochalcones in basic media, the corresponding hydroxy-chromones were obtained (
Scheme 21a). The unhydroxylated heterochalcones afforded in the same reaction conditions the corresponding epoxy-ketones (
Scheme 21b)[
109].
3.6. Claisen-Schmidt method
This method was established in 1962 and consists of two steps. The first step is a Claisen-Schmidt condensation between an acetophenone and benzaldehyde derivates, in basic medium, resulting chalcones. Second step represents the oxidative cyclization of chalcones, which can be achieved with a large variety of conditions and catalysts [
2] (
Scheme 22).
The mechanism of condensation debuts with the formation of an anion of the acetophenone, under basic conditions. The base extracts a proton from the carbon in
α-position. This is followed by a nucleophilic attack of the anion on the carbonyl group of benzaldehyde, thus resulting the chalcone [
110] (
Scheme 23).
The cyclization can be realized by many methods, first starting with iodine in hot dimethylsulfoxide (I
2/DMSO, Δ). Patonay et al. observed that this method is suitable for a large variety of substituents, including electron-donating and electron-withdrawing, sensitive to oxidation and protecting groups. Thus, it can be considered a general method of cyclization for obtaining flavones from 2’-hydroxychalcones [
111]. The mechanism involves the formation of a iodonium cation by the interaction of I
2 with the
o-hydroxycalcone, followed by cyclisation by nucleophilic attack of the
o-hydroxy group. Further elimination of hydroiodic acid afford the corresponding flavones. The solvent DMSO is important in this reaction because it acts as a co-oxidant and regenerates iodine [
112] (
Scheme 24).
By using microwave irradiation, the time of reaction is greatly reduced to approximatively 3 minutes [
113]. However, this method is limited in the case of 2’-hydroxychalcones with a phloroglucinol oxygenation pattern, resulting complex mixtures. Hans and Grover extended the applicability of iodine as an oxidant agent, by using instead sodium periodate in hot dimethylsulfoxide (NaIO
4/DMSO, Δ), managing to smoothly convert phloroglucinol-derived chalcones into corresponding flavones [
114] (
Scheme 25).
In order to extend the general method of cyclisation of
o-hydroxychalcones with iodine in dimethyl sulfoxide, our research group investigated this method using as precursors a series of 2-arylthiazole
o-hydroxychalcones. A similar chemical behaviour was observed in this case, the corresponding 2-arylthiazole flavones being obtained with 32-55% yields (
Scheme 26) [
115].
Another method capable of cyclizing this chalcones was established by Litkei et al., who used iodosobenzene diacetate (phenyliodine(III) diacetate, PIDA), a hypervalent iodine reagent, which forms iodosylbenzene
in situ [
117] (
Scheme 27). The same reagent was used for obtaining prenylated flavones, which are abundant in nature, from prenylated 2’-hydroxychalcones [
118].
The usage of ionic liquids for this oxidative cyclization was described in the literature. Du et al. developed a new method assisted by Cu(I) iodide, mediated by the ionic liquid [bmim][NTf2] (1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide) at low temperature. The reaction mechanism has not been fully elucidated, but the results so far reveal that a flavanone is formed intermediately. Flavanone seems to be dehydrogenated to the corresponding flavone in the same reaction conditions [
119]. Lahyani and Trabelsi reported the oxidative cyclisation of
o-hydroxychalcones with iodine monochloride in dimethylsulfoxide (ICl-DMSO), under ultrasounds. The method presents the advantages of ultrasound processes such as mild conditions, high yields and eco-friendliness. The mechanism is similar with the one from oxidative cyclization with I
2-DMSO [
120] (
Scheme 28).
Heating 2’-hydroxychalcones with iodine in triethylene glycol is also a good and inexpensive method. While the mechanism is not fully understood, the authors proposed a pathway which involves the iodination of chalcone, resulting chalcone diiodides, similar with the chalcone dihalides from the von Kostanecki’s method. Cyclization is the result of dehydrohalogenation, resulting a 3-iodoflavanone, which yields flavone after the
β-elimination of a second hydroiodic acid molecule [
121]. The usage of iodine on silica gel (I
2-SiO
2) was reported by Babu et al. with favorable results and less harmful effects towards environment [
122]. Another solid supported catalyst, iodine on neutral alumina (I
2-Al
2O
3), was reported by Sarda et al., with short reaction time, simple conditions and very good yields [
123] (
Scheme 29).
An alternative to the toxicity and corrosiveness of iodine was proposed by Kulkarni et al., who used ammonium iodide, on exposure to air and solvent-free conditions, which generated
in situ iodine and cyclized 2’-hydroxychalcone in high yields [
124] (
Scheme 30).
Selenium dioxide is another catalyst used for cyclization. It can be combined with various solvents, like pentan-1-ol [
125], but with low yields [
114]; dioxane [
126]; isoamyl alcohol with prolonged heating, formation of side products and low yields [
127]. Dimethylsulfoxide was also used with good yields [
128], but in order to diminish the high toxicity of DMSO, Gupta et al. managed to use selenium dioxide and traces of solvent over silica gel, under microwave irradiation with very good results [
129]. Similar with I
2/DMSO, SeO
2/DMSO is also problematic for chalcones with phloroglucinol oxygenation pattern [
114]. However, selenium dioxide is volatile and hazardous. Lamba and Makrandi proposed using sodium selenite (Na
2SeO
3), which is less volatile and found out that it acts as a proper dehydrogenating agent in DMSO [
130] (
Scheme 31).
In our research group, the oxidative cyclisation of 2-arylthiazole
o-hydroxychalcones with selenium dioxide in
n-butanol was investigated. In this case, the corresponding flavones and hydroxyflavones were formed, in different molar ratios (Scheme 40) [
27].
Palladium was also experimented on as a catalyst. Kasahara et al. used lithium chloropalladite (Li
2PdCl
4) and palladium(II) acetate, (CH
3COO)
2Pd), for obtaining flavones. The reaction was described as a phenoxypalladation, followed by the elimination of palladium (II) hydride (HPdX). This method also yielded small amounts of flavanone [
131] (
Scheme 32).
Cyclodehydrogenation with DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone) was proposed by Imafuku et al. Their method uses dioxane as solvent and results in a mixture of flavones, flavanones and aurones, with low yields [
132]. Another agent that acts in a similar manner is nickel peroxide (NiO
2) in dioxane, yielding a similar mixture. However, flavanones can be dehydrogenated to flavones, under the action of NiO
2 in benzene as solvent [
133] (
Scheme 33).
Disulfides are also a good choice for cyclodehydrogenation. Hoshino et al. used four disulfides: dineopentyl disulfide, diisopentyl disulfide, dipentyl disulfide and diphenyl disulfide, the later giving the best yields. The disadvantages of this method include the very high temperatures (260-290 °C) and very low yields when electron-withdrawing groups (NO
2) were present [
134] (
Scheme 34).
Initially meant for obtaining quinolines from 2’-aminochalcones, using FeCl
3·6H
2O in methanol, Kumar and Perumal applied the same method on 2’-hydroxychalcones and obtained flavones with satisfactory results [
135]. Similarly, Liu et al. used cerium sulphate tetrahydrate (Ce(SO
4)·4H
2O) on silica gel to obtain flavones from 2’-hydroxychalcones at 100ºC, aza-flavones and aza-flavanones from 2’-aminochalcones [
136] (
Scheme 35).
In addition to all the reagents previously mentioned, sodium perborate tetrahydrate (SPB) was proposed by Ganguly et al. They observed that depending on the solvent, this method could yield different products: warm acetic acid and SPB in excess yielded to flavones, while warm aqueous acetonitrile yielded to flavanones. For flavones, SPB and acetic acid generated peracetoxyboron anion species
(26), which oxidated the chalcones [
137,
138] (
Scheme 36).
Other reagents include indium(III) halides (InCl
3 and InBr
3) on silica gel and solvent-free conditions, with higher yields when InBr
3 was used [
139] or sodium tellurite in dimethylsulfoxide and anhydrous conditions (Na
2TeO
3-DMSO) [
140]. The reaction mechanism was not completely elucidated. The supposed reported pathway for the oxidative cylisation with indium halides involves the formation of flavanone as intermediate, which is dehydrogenated in the same reaction conditions to the corresponding flavone [
139]. Oxalic acid in ethanol reflux used by Zambare et al. proved to be a very useful and cheap method, with excellent yields over 90% [
141] (
Scheme 37).
Photocyclization was another manner to perform this reaction. However, it yielded only flavanones and in low quantities [
142]. By adding a heterocyclic N-oxide, pyrimido[5,4-g]pteridine N-oxide, Maki et al. managed to obtain flavones but still in unsatisfactory yields and only in a mixture with flavanones. The photoreaction involves a single electron transfer (SET) process from chalcone to N-oxide. Initially, the N-oxide is in a oxygenated form, pyrimido[5,4-g]pteridin-2,4,6,8(1
H,3
H,7
H,9
H)-tetrone 5-oxide
(27), and as the mixture forms, it gets deoxygenated to pyrimido[5,4-g]pteridine
(28) [
143]. Electrochemistry found applications in this reaction too. Saničanin and Tabaković cyclized 2’-hydroxychalcones by generating electrochemically a cation radical of tris-(4-bromophenyl)amine, which acted as a homogenous electron-transfer reagent. This method creates a mixture of flavanones and flavones in moderate yields [
144] (
Scheme 38).
A different approach, by creating a totally non-hazardous medium was used by Tamuli et al. They used as catalyst a mixture of two agro-food wastes of
Musa sp. ‘Malbhog’ peel ash (MMPA) and
Musa champa Hort. ex Hook. F. peel ash (MCPA), which provided basic conditions for the cyclodehydrogenation, solvent-free and room temperature [
145] (
Scheme 39).
Scheme 38.
(
a) Oxidative cyclization using photo- and electrochemistry. (
b) Mechanism of single electron transfer process (adapted from Maki et al. [
143]).
Scheme 38.
(
a) Oxidative cyclization using photo- and electrochemistry. (
b) Mechanism of single electron transfer process (adapted from Maki et al. [
143]).
Scheme 39.
Oxidative cyclization using banana peel ash in open air and solvent-free conditions (adapted from Tamuli et al. [
145]).
Scheme 39.
Oxidative cyclization using banana peel ash in open air and solvent-free conditions (adapted from Tamuli et al. [
145]).
Among the reported methods for the cyclization of o-hydroxychalcones, in our research group we investigated the most promising ones, in order to obtain new flavonoid analogues containing the 2-arylthiazole moiety instead of the benzene ring B. Our aim was also to investigate the chemical behaviour of 2-arylthiazole o-hydroxychalcones in the cyclization reactions.
The oxidative cyclisation of the 2-arylthiazole
o-hydroxychalcones afforded various reaction products, depending on the oxidizing agent. Flavanones were obtained with 40 - 55% yields by cyclisation of the corresponding 2-arylthiazole
o-hydroxychalcones in acidic catalysis (H
2SO
4 conc. in ethanol) [
116]. The cyclisation of 2-arylthiazole
o-hydroxychalcones in the presence of sodium acetate, in methanol as solvent, afforded also the corresponding flavanones in good yields. With copper(II) acetate in dimethyl-sulfoxyde, resulted a mixture of aurone and the corresponding flavone in an approximate 1:1 molar ratio [
27]. Hydroxyflavones were obtained by cyclisation of the same substrates with hydrogen peroxide in alkaline catalysis [
27] and flavones were obtained when iodine in dimethylsulfoxide was used [
27,
116]. The cyclisation with selenium dioxide in
n-butanol led to a mixture of flavones and hydroxyflavones [
27]. The cyclisation with mercury(II) acetate in pyridine as solvent afforded the corresponding Z-aurones with 70-86% yields [
27]. The cyclisation products and the reactions conditions are summarized in
Scheme 40.
The cyclisation of
o-methoxylated chalcones bearing the 2-arylthiazole moiety was further studied in similar reaction conditions. It was found that the reaction occurred differently, depending on the oxidizing agent and the reaction conditions. By treatment with iodine in dimethyl sulfoxide, at reflux, the corresponding flavones were formed. This fact indicates that the demethylation of the methoxy group of chalcone occurred, which allowed the cyclization to the corresponding flavone [
146]. Instead, when hydrogen peroxide in NaOH was used as cyclization agent, the formation of the corresponding epoxides was observed, which can be explained by the fact that the methoxy group is resistant in these reaction conditions and therefore the cyclization to flavone cannot take place (
Scheme 41) [
146].