Reactions of 3-Formylchromone with Active Methylene and Methyl Compounds and Some Subsequent Reactions of the Resulting Condensation Products.

This review presents a survey of the condensations of 3-formylchromone with various active methylene and methyl compounds, e.g. malonic or barbituric acid derivatives, five-membered heterocycles, etc. The utilisation of the condensation products for the synthesis of different heterocyclic systems, which is based on the ability of the γ-pyrone ring to be opened by the nucleophilic attack is also reviewed. Finally, the applications of microwave irradiation as an unconventional method of reaction activation in the synthesis of condensation products is described and the biological activity of some chromone derivatives is noted.


Introduction
From a synthetic viewpoint, 3-formylchromone (1, Figure 1) occupies an important position in the synthesis of various heterocyclic systems. Due to the availability of three electron deficient sites: carbon C-2, the aldehyde carbon and the C-4 carbon of the carbonyl group, 3-formylchromone is able to serve as a heterodiene as well as a dienophile or a Michael acceptor and fused heterocycles can be prepared directly by reaction of 1 with bifunctional nucleophiles.
Since a facile synthesis of 1 by the Vilsmeier-Haack reaction was first published [1], the interest on the chemistry of chromones and their pharmacological utilisation hasn't decreased. Several reviews dealing with the synthesis, properties and reactions of 1 were published [2,3], however, condensations of 1 with active methylene and methyl compounds didn't appear to generate great interest in the earlier research.
This review presents the synthetic capability and the exploitation of the abovementioned types of condensation, achieved using the microwave irradiation method of synthesis as a new and very convenient rate enhancing method [4 -7]. Several types of subsequent reactions of the condensation products illustrate the ability of chromone derivatives to serve as excellent precursors for the synthesis of a wide variety of heterocyclic systems.
When the mixture of 1, 2,4-pentanedione and the catalytic amount of hydrochloric acid is treated in acetic acid at room temperature and then heated at 70-80ºC for 2 hrs, only products 7a and 7b, respectively, were isolated in 40-45% yields [17], which demosntrates 1,2 -addition of 2,4-pentanedione to protonated 1. On the other hand, the mechanism of base-catalysed condensation of 1 consists on the initial attack of the nucleophile at the C-2 of pyrone ring, followed by ring opening and recyclisation to 11 with subsequent elimination of water to give 7 (Scheme 2, path b) [2,16]. of diethyl 5-(2-hydroxybenzoyl)-2-methylisophtalate 16 [16] (Scheme 3).Thus, 15a (R = CH 3 ) on treatment with excess ethyl acetoacetate in the presence of piperidine in ethanol gives 16, which can be also formed in 80 % yield by one-step reaction of 1 with excess ethyl acetoacetate in piperidineethanol medium (Scheme 3, path a). The proposed mechanism involves initial condensation of 1 with ethyl acetoacetate followed by Michael addition of the second molecule of ethyl acetoacetate and subsequent rearrangement (Scheme 3, path b).

Condensations of 1 with 5-nitrofuryltrichloromethylsulphone
Product 17 [18] was formed, when 1 was treated with 5-nitrofuryltrichlormethylsulphone in glacial acetic acid in the presence of ammonium acetate and piperidine at 50-80 °C. Further 17 gave with diazomethane the cyclopropanes 18 instead of the expected pyrazoline derivatives.

path b
These results can be explained by non-finished stepwise mechanism (Scheme 4). Nucleophilic attack of diazomethane on the polarised C=C double bond of trisubstituted ethylenes produces carbanion, which undergoes a cyclopropane forming S N i reaction with the simultaneous elimination of N 2 .

Condensations of 1 with 1,3-indandione and the other five-membered fused heterocycles
1,3-Indandione was used as a component for condensations with 1 under various reaction conditions. Products 23 were synthesized in 61-92% yields either by 20 min of reflux in glacial acetic acid in the presence of piperidine [23] or by 4-6 min of the microwave irradiation in acetic anhydride without any catalyst [21]. Nearly identical yields (61%) were obtained when these reactions were performed in ethanol in the absence of a catalyst at room temperature [24].
Heating of 33a in ethanolic or methanolic solution of sodium carbonate lead to 37-78% yields of pyrroles 34 (Scheme 7). Analogously it is possible to obtain products 33b from 1 and N-acetylglycine [39]. Both of the products 33a and 33b can be transformed to 36 by treatment with amines. In an alternate method, compounds 36 could also be obtained by condensations of 1 with 1,2-disubstituted imidazolin-5(4H)-ones, which were prepared from N-acylglycine and the corresponding amine.
Substituted benzoylpropionic acids cyclized readily with 1 to 35 [26]. Classical heating in acetic anhydride in the presence of potassium acetate gave 78% of products 35, while the irradiation in microwave oven in the same medium needed only 1-4 min to prepare 35 in 62-84% yields.
3-Formylchromones were condensed with substituted 4-coumarinylacetic acids in acetic anhydride in the presence of potassium carbonate as the catalyst either by heating at 80-90 °C for 3 hrs or by 4-10 min of irradiation in microwave oven. The expected products 38 were not obtained directly and the reaction led to arising of 2-hydroxy derivatives 37, which were transformed to 2-ethoxy derivatives 40 by reflux in ethanol. Compounds 38 were formed only by reflux of 37 or 40 in acetic acid. Derivatives 37, 38 and 40 were able to change into each other as it is indicated in scheme 8. It was proved that only chromone parts of molecules of 37, 38 and 40 reacted with primary amines or formamide. After nucleophilic attack the pyrone ring was opened to cause the rearrangement of chromone system into pyridine derivatives 41 and 42, respectively [28].
On the other hand, Shingare and co-workers [29] described the condensations of substituted 3formylchromones with 6,8-dimethylcoumarin-4-acetic acid. Even if the reactions were carried out in pyridine, after 6 hrs of reflux the opening of the pyrone ring was not observed. Condensation products 38 were obtained in 46-69 % yields.
Their subsequent alcoholysis with various alcohols at 60-100 °C in the presence of ptoluenesulfonic acid gives ethers 43 and 44 (R 2 = CH 3 , C 2 H 5 , CH 2 -CH=CH 2 ) in about 80% yields. It was also found, that all prepared compounds 43 and 44 underwent a rearrangement by heating with acetic acid at 60-80 °C to afford products 45 and 46 in about 75 % yields [30] (Scheme 10).

Condensations of 1 with barbituric acid derivatives
3-Formylchromone was easily condensed with several pyrimidine derivatives [20,31]. Product 47 was obtained in 94 % yield after 10 min of reflux of 1 and barbituric acid in pyridine [20] (Scheme 10). Two types of condensation products were synthesized by treatment of 1 with 1,3-dimethyl-4iminouracil depending on the reaction conditions [31].
When the reaction took place in water, a Knoevenagel type product 48 was produced in 39 % yield. On the other hand using of the ethanol-water medium (1:1) in the presence of a catalytic amount pyridine led to product 49 in 28% yield. Substituted barbituric or thiobarbituric acids reacted with 1 in acetone under triethylaminepyridine catalysis to afford products 50 in 13-21 % yields, while an acetic acid-acetic anhydride medium has been identified as suitable for preparing pyrimidopyranopyrimidines 51, which were obtained in 12-64 % yieds [31].

Reactions with 2-thioxothiazolidin-4-one
Condensations of various aldehydes, including 1 with acylated 3-aminorhodanines were also published [33]. The acylation of 3-amino group of rhodanine was taken place by the reflux of 3aminorhodanine with acylhalogenides in tetrahydrofurane. Subsequent condensation of 3aminoacetylrhodanine with 1 in ethanol gave product 56.
The addition of ketene-S,S-acetal to compound 63a was carried out by in situ reaction of ethyl cyanoacetate and carbon disulfide under similar phase-transfer catalysis conditions. Product 70 was obtained after 30 min heating in 77 % yield. Thiapyridone 71 was prepared in 73 % yield by reaction of cyanothioacetamide with 63a at sodium ethanolate-ethanol.
Finally, thiourea and guanidine hydrochloride served as suitable precursors of pyrimidine derivatives. The pyrimidinethione 74 was furnished in 85 % yield by treatment of 63a with thiourea in potassium hydroxide -ethanol medium, while using guanidine hydrochloride at the similar conditions led to arising of aminopyrimidine 75 in 79 % yield (Scheme 13).

Condensations of 1 with phenylacetic acids, aryl-or heteroarylsubstituted acetonitriles and sixmembered fused heterocycles
The condensation of 1 with phenylacetic acid [40] in acetic anhydride in the presence of piperidine as a catalyst furnished the products 76 in 47 -68 % yields. The spectral data showed the presence acetyl instead of the carboxy group, which could be explained by decarboxylation followed by acetylation in situ (Scheme 14). 1-Naphtylacetonitrile condenses with 1 to give only moderate yields (30-38 %) of products 77 after 17-20 hrs of heating at 150 °C. Under the influence of microwave irradiation the yields of 77 were increased only marginally (39-46 %), but the reaction times were shortened to 10 min [26].
2-Methyl-3-acetylchromone contains two active methyl groups, which can react by aldol condensation. Products 93 were obtained by the reaction of 1 with substituted 2-methyl-3-acetylchromones in acetic anhydride-potassium acetate medium by the classical method, which required the heating at 120-130 °C for 2-3 hrs as well as by 40 sec-2 min irradiation in the microwave oven (Scheme 15). In both cases the reaction occurred only at the 2-methyl group [51].

Condensations of 1 with 2-methylbenzothiazole and 2-methylbenzimidazole derivatives
An effective method for synthesis of benzothiazolium salts 94 consists on the preparing of 3-alkyl or 3-aryl-2-methylbenzothiazolium halides and their subsequent condensations with 1 [52]. 2-Methyl-benzothiazolium salts were synthesized either by 2-20 hr of heating of 2-methylbenzothiazole with alkyl or arylhalides in acetonitrile or nitromethane or by 10-30 min of the irradiation of reaction mixture in microwave oven (Scheme 16, path a). In the following step 2-methylbenzothiazolium salts were treated with 6-substituted 1 in acetonitrile to give 29-85% of 94 after 3-35 min of the microwave irradiation or 0.5-8 hrs of heating. The opposite sequence of reaction steps was used at the synthesis of 94c, as well as the products 96 (Scheme 16, path b). Condensations of 1 with 2-methylbenzothiazole or 2-methylbenzimidazole carried out in dimethylsulfoxide-boric acid medium at 120 °C to give compounds 96 in 50 -68 % yields. Decreasing of the reaction temperature to 60°C lead to products 97a, 97b, which were prepared in 81, 85 % yields (Scheme 16). Most of products 94 showed antialgal activity towards Chlorella vulgaris [53]. Products 95 were prepared by the treatment of 94 with ethanol, dimethylamine or 2,3-dimethylbenzothiazolium methylmetasulphate in acetonitrile in the presence of triethylamine [54].

Conclusions
Knoevenagel condensations of 3-formylchromone with active methylene and methyl compounds, described in this review, represent not only a convenient synthetic route leading to many biologically active compounds, but combined with the cleavage of the pyrone ring by the attack of nucleophiles and subsequent rearrangement, they are widely utilised in the synthesis of new heterocyclic systems. The microvawe irradiation method of reaction activation was in many cases successfully used for increasing the yields, as well as to achieve a considerable shorterning of reaction times.