FABAD J. Pharm. Sci., 36, 223-242, 2011 SCIENTIFIC REVIEW Chemical and Structural Properties of Chalcones I Begüm EVRANOS AKSÖZ*°, Rahmiye ERTAN** Chemical and Structural Properties of Chalcones I Şalkon I’in Kimyasal ve Yapısal Özellikleri Chalcones belong to the flavonoid family and display several Şalkonlar flavonoid sınıfında yer alan ve önemli biyolojik pharmacological activities which are very important. They etkiler gösteren bileşiklerdir. Pek çok sentez reaksiyonunda can be used as an initial compound for synthesis of a lot of başlangıç bileşiği olarak kullanılabilmektedirler. Bu compounds. Therefore, many researchers have synthesized yüzden çok sayıda araştırıcı bu bileşikleri sentezleyerek these compounds and evaluated their biological activities. In bu bileşiklerin biyolojik etkilerini incelemektedir. Bu this review, we aimed to provide a comprehensive presentation derleme ile araştırıcılara şalkon türevlerinin kimyasal of chemical and structural properties of chalcone derivatives, reaksiyonlarını ve yapısal özelliklerini bir arada topluca to the researchers. sunmayı amaçladık. Key Words: Review, chalcones, reactions, synthesize, con- Anahtar Kelimeler: Derleme, şalkonlar, reaksiyonlar, sen- formational structure tez, konformasyonel yapı Received: 10.03.2012 Revised: 26.11.2012 Accepted: 03.04.2013 * *Medicines and Medical Devices Agency, Analyses and Control Laboratories, 06100 Sıhhiye, Ankara-Turkey ** Ankara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Tandogan, Ankara-Turkey ° Corresponding Author E-mail: [email protected] 223 Aksöz, Ertan 1. INTRODUCTION molecules binds to A and B ring instead of C ring of Chalcones (1,3-diaryl-2-propen-1-ones) are flavo- flavonoids (Figure 1). Chalcones turn to flavanones noids found in fruits and vegetables, that attracted with a stereospecific reaction catalyzed by chalcone attention because of their pharmacological activities isomerase enzyme in plants. Close biogenetic and such as antiinflammatory (1-7), antibacterial (8-12), structural relation between chalcones and flavanones antifungal (13-17), antiviral (18-22), antioxidant (23-32), is the reason for these compounds usually found antineoplastic (33-41). Most of aromatic rings of nat- together in natural products. This is the cause of ural chalcones are found as hydroxylated. Chalcones, the identification of chalcone, dihydrochalcone and dihydrochalcones and aurones are composed of pig- aurones together with flavanone and dihydroflavonol ments whose colour changes from yellow to orange generally. Chalcones are called as minor flavonoids. in some Coreopsis and Asteraceae taxa species. These But using name of minor flavonoids for chalcones compounds are found not only in flowers but also doesn’t seem appropriate because of increasing of in lots of different tissues of the plants. Free radical new species of flavonoids (42). scavenging properties of phenol groups of chalcones increased the interest in consumption of plants that As flavonoid term, mostly plant pigments are included chalcones (18). expressed which includes benzo-g-pirone and flavone (Figure 1). Essential compounds of flavonoids Chalcones are included dimer, oligomer, Diels-Alder include a phenyl group at 2nd position of benzo- adducts and different conjugates. At the same time g-piron (chromone) ring system. Flavonoids differ because of being precursors of all of other flavonoid according to size, saturation and the substituents of groups, chalcones are very important biosynthetic g-pyrone ring which is called C ring (43). compounds. Essential property that separates chalcones and dihydrochalcones from the other The ethylenic bond between C2 and C3 of C ring flavonoids is that an open chain with three carbon of flavones provides conjugation between A and B ring. In this way the ring structure of flavones 6' 5' 8 6' 5' O 2' 3' 8 8 2 6' 5' 8 O 2 O 7 O 7 7 B 4' 9 2 B 4' A C 7 B OH A C A C 6 B 4' + 6 A 6 2' 3' 3 2' 3' 6 6' ' 5 10 3 5 3 5 3' 5 OH O 2' 5 4 O O Flavone Isoflavone Anthocyanidine Flavonol 6' HO OH 4' 4 OH HO 7 O 2 OH HO OH ' ' 6 B 4 OH 4 A 2 ' ' 6 B A 4 A 2 C 2' B ' 6 2 5 4 ' OH O 6 2 OH O OH O Chalcone Flavanone Dihydrochalcone 6' 5' ' OH 8 HO 6 3 HO 6 OH ' O O OH 3' 7 O 2 B 4 4' A C CH B OH A C 2 ' 4 A C ' 3' B OH 6 2 4 4 5 4 OH O OH O OH O Aurone Auronol Flavanonol Figure 1. Some flavonoid species 224 FABAD J. Pharm. Sci., 36, 223-242, 2011 becomes stronger than other flavonoids. Although 2. CHEMICAL REACTIONS OF CHALCONES anthocyanidines differ from other flavonoids by 2.1. Oxidation of chalcones losing carbonyl group in C ring, their biological 2.1.1. Algar-Flynn oxidation of chalcones characteristics are similar to other flavonoids. While the reaction of acetaminochalcones with Chalcone derivatives are ring-chain isomers of selenium dioxide gives 6-acetaminoflavones, the flavanone derivatives. Aurone derivatives situates reaction of acetaminochalcones with alkaline in flavonoids by having benzofuranone structure hydrogen peroxide give 6-acetaminoflavonols as the (42,44,45). result of Algar-Flynn oxidation (47). Additionally I2/ DMSO can be used as oxidation reagent to synthesize Chalcone containing plants, such as Glycyrrhiza, flavones. (48,49) (Scheme 1). Flavanone derivatives Angelica, Ruscus and Piper species have been used as are composed by refluxing 2’-hydroxy chalcones medicine in Asia, Africa and South America. Several with glacial acetic acid (49) (Scheme 2). pure chalcones were approved for clinical use. One of the chalcones came on the market is metochalcone 2.1.2. Epoxidation of chalcones (1-(2,4-Dimethoxyphenyl)-3-(4-methoxyphenyl) The epoxidation of ethylenic groups of natural -2-propen-1-one), the others are a choleretic drug compounds such as chromone, chalcone and and an antiulcer drug (sofalcone), (2- [5- [(3-methyl- isoflavone with hydrogen peroxide occurs very fastly 2-buten-1-yl) oxy] -2- [3- [4- [(3-methyl-2-buten-1-yl) and with high yield in 1-butyl-3-methyl imidazolium oxy] phenyl] -1-oxo-2-propen-1-yl] phenoxy] acetic tetrafluoroborate ([bmim] BF4) (3) (Scheme 3). acid) (46). H2O2 O alkali Ar OH R OH Ar O SeO 2 O o R 160-170 C Ar O R I2 / DMSO O Ar: C6H5, p-C6H4OCH3, 3,4-C6H3 (CH2O2), m-C6H4OH R:CH3CONH, H Scheme 1. Oxidation of chalcones R3 OH R3 O AcOH / R2 R2 R1 O O R1 Scheme 2. Oxidation reactions of chalcones R2 H2O2/NaOH R2 R1 R1 [bmim]BF4 O O O Scheme 3. Epoxidation of chalcones 225 Aksöz, Ertan Br (CH )n Br S (CH )n Br SH 2 2 TEA/DMF O O piperidine, 4-methylpiperidine TEA/DMF morpholine, piperazine S (CH2)n N X O Scheme 4. S-Alkylation reaction of mercapto chalcones 2.2. Substitution reactions of chalcones enantioselectivity. Absolute configuration of Michael 2.2.1. S-Alkylation reactions addition substances is determined with chemical S-Alkylation is obtained with the reaction of (E)-4- methods and X-ray christallography (50). Mercaptochalcones and dibromoalkanes in N,N- Dimethyl formamide in the presence of triethylamine 1- (1-Alkyl-benzimidazole-2-yl) -4-nitro-3-aryl-butan- (TEA) at room temperature (7) (Scheme 4). 1-one is synthesized by addition of nitromethane to the b-carbon atom of benzimidazole chalcone in the 2.2.2. O-Alkylation reactions presence of K2CO3 and tetrabutilamonium bromür O-Alkylation occurs with the heating reaction of (TBAB) (Scheme 7). However, if the reaction occurs (E)-4-hydroxy chalcones and dibromoalkanes in under strong basic conditions, a lot of product will be dry acetone in the presence of anhydrous potasium composed such as dehidrating reactions products. carbonate (7) (Scheme 5). However this synthesis reaction can be made with a simple, effective and fast method in the presence 2.3. Addition reactions of chalcones of K2CO3 and TBAB with no solvent in pestle (51). 2.3.1. Michael addition reaction of chalcones When the same reaction was carried out in the Michael addition is usually made under strong absence of TBAB, the addition of nitromethane is basic conditions. Substituted chalcones give not succeeded. enantioselective Michael addition reaction with 2-nitropropane by using Chiral Azacrown Ether Microwave is used for the addition of compounds (CAE) as catalyst (Scheme 6). It has been seen that having active methylene to the chalcones in the phosphine oxido alkyl compound is formed with presence of potasium carbonate and water (Scheme %87 yield. The substituent which is on chalcone 8). In this method organic solvent is not used and is effective in determining of reaction’s yield and pure product is synthesized with high yield (52). O (CH )n Br OH Br (CH2)n Br 2 K2CO3 /Anhydrous acetone O O piperidine, 4-methylpiperidine TEA/DMF morpholine, piperazine O (CH2)n N X O Scheme 5. O-Alkylation reaction of hydroxy chalcones with dibromoalkanes 226 FABAD J. Pharm. Sci., 36, 223-242, 2011 CH3 CH3 O O NO2 H3C + CAE * H C NO2 H3C NaOtBu Toluene CAE: NaOtBu: sodium tert-butoxide OMe O O O N R O O O O R = H,-CH2CH2OCH3,–(CH2) 4P (O) Ph2 Scheme 6. Reaction of chalcones with 2-nitropropane CH3 NO2 / K2CO3/ Physical Grinding X R R NO2 N O H N O CH2 CH3NO2 / K2CO3 C C C C CH2 CH N H Ethanol/5-6 Hour N Ethanol / 250C CH3 NO2 / K2CO3 / TBAB/ Physical Grinding/ 5 Minute Scheme 7. Reaction of chalcones with nitromethane The addition of cyclic thiourea compounds to the 2.3.2 Bromination of chalcones chalcones and following cyclodehidrating reaction Bromination of chalcones can be made with pure (Michael addition) give rise to formation of imidazo starting substance, special reagents and microwave [2,3-b] 1,3-thiazine ring (53) (Scheme 9).