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https://doi.org/10.24271/garmian.84

http://garmian.edu.krd

Synthesis and Characterization of Some Hydroxylated Chalcones by using BF3.Et2O via Claisen-Schmidt Condensation Aso H. Hasan*a and Shajarahtunnur Jamil** * University of Garmian, College of Science, Department of Chemistry, Kurdistan- Iraq. ** Universiti Teknologi Malaysia, Faculty of Science, Department of Chemistry, UTM Skudai. a Corresponding author, E-mail: [email protected]

ABSTRACT The chalcones and their derivatives are important intermediates in organic synthesis. They serve as starting material for the synthesis of variety of heterocyclic compounds which are of physiological

importance.

In

this

study,

two

hydroxylated

chalcone

named

as

(2′,4′,4-

trihydroxychalcone and 4′,4-dihydroxychalcone) together with 2′,4′,4,6′-tetrahydroxy-3′prenylchalcone were synthesized by Claisen-Schmidt condensation of various hydroxyacetophenone

and

2,4,6-trihydroxy-3-C-prenylacetophenone

for

prenylated

chalcone

with

4-

hydroxybenzaldyhe using BF3.Et2O. The structures of all compounds were characterized using spectroscopic methods (NMR and IR). Keywords: hydroxylated chalcone, prenylchalcone, Claisen-Schmidt condensation, BF3.Et2O, H1 NMR and IR

1.

INTRODUCTION Chalcones are known as benzalacetophenone or benzylidene acetophenone. In chalcones,

two aromatic rings are linked by an aliphatic three carbon chain. Chalcone bears very well functional groups so that variety of novel heterocyclic with good pharmaceutical profile can be designed [1]. Chalcones are α, β-unsaturated ketone containing the reactive ketoethylenic group – CO-CH=CH-. They are coloured compounds due to the presence of the ketoethylenic group, which depend on the presence of other auxochromes [1]. Chalcones exist naturally such as prenylated chalcone, isobavachalcone (1), xanthohumol (2).

OH OH

HO HO

OH

OH O H3CO (1) 433

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The genus Artocarpus is one of the most important genera of the Moraceae, which is distributed throughout tropical and subtropical regions of the world and made up of approximately 50 species [2, 3]. In Malaysia, especially Peninsular Malaysia, Artocarpus is represented by 20 species and 23 species are known in Sabah and Sarawak [4, 5]. Some of the plants have been used for their edible fruits such as Artocarpus communis or altilis (locally known as “sukun”), A. heterophyllus (“nangka”) and A. integer (“chempedak”) and some of the species are used for light construction materials and furniture due to their strong and durable dark-coloured wood [5,6]. Phytochemical study on the leaves of Artocarpus lowii had yielded a prenylated dihydrochalcone, named as 2′,4′-dihydroxy-4-methoxy-3-prenyldihydrochalcone (3), together with two known compounds, 2′,4′,4-trihydroxy-3′-prenylchalcone (1) and 2′,4-dihydroxy-3′,4′-(2,2dimethylchromen) chalcone (4). All these compounds showed strong free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) [7]. OCH3 HO

OH O

OH O

OH O

(3)

(4)

The leaves of Artocarpus communis was reported to contain the three new geranyl chalcone derivatives identified as

isolespeol (5), 5'-geranyl-2',4',4-trihydroxychalcone (6) and

3,4,2',4'-tetrahydroxy-3'-geranyl dihydro chalcone (7), and two known compounds including lespeol (8) and xanthoangelol (9) have been isolated. All these compounds were evaluated against (SW 872, HT-29, COLO 205, Hep3B, PLC5, Huh7, and HepG2 cells) on human cancer cells. Compound (5) reported strongest inhibitory activity with an IC50 value of 3.8 µM against SW 872 human liposarcoma cells [8].

(5) 434

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HO

OH OH OH O

(7)

OH O

OH HO

OH O (8)

OH O (9)

Chalcones have been synthesized by a number of synthetic methods using various catalysts and reagents including BF3-Et2O. Narender and Reddy (2007) had synthesized variety of substituted chalcones by developing new method using BF3-Et2O. This method has been conducted for solvent free reactions and applicable for reactions concerning liquid reactants which are base sensitive functional groups such as esters and amides [9].

2.

EXPERIMENTAL

2.1

Chemicals and Instruments 2,4-Dihydroxyacetophenone and 2,4,6-trihydroxyacetophenone were purchased from

Sigma-Aldrich. BF3.Et2O was purchased from Molekula. Hexane, diethyl ether, ethyl acetate, chloroform, and acetone were used as the solvent for chromatographic method were reagent grade and purchased from commercial sources. Thin layer chromatography (TLC) was used precoated silica gel sheets (Merck Kiesel gel 60 F254) to monitor the reactions. Gravity column chromatography (CC) was carried out using normal phase Merck silica gel 60 (70-230 mesh). The spots were observed using UV lamp and vanilic sulphuric acid as a spraying agent. The 1H NMR spectra were recorded on a Burker Avance 400 MHz. The infrared (IR) spectra were recorded on Perkin Elmer 1650 FTIR spectrometer using KBr pellets as the disc for solid samples.

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2.2

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General Procedure for Synthesis of Hydroxychalcones BF3.Et2O (0.20 mL) was gradually added to a stirred solution of hydroxyacetophenones

(0.15 mmol) and 4-hydroxy benzaldehyde (18.3 mg, 0.15 mmol) in the presence of little amount of dioxane at room temperature. The reaction mixture was stirred for 2.5 hr. After that, the reaction mixture was filtered, washed with distilled water and extracted with Et2O (10 mL). The ethereal portion was dried over anhydrous Na2SO4. Then, the solvent was evaporated under reduced pressure to obtain dark orange solids, the crude product was purified by column chromatography using hexane: EtOAc as the solvent system. As shown in Scheme 1.

Scheme 1: The Formation of Hroxychalcones. 2.2.1 Synthesis of 2′,4′,4-Trihydroxychalcone (10) 2′,4′,4-trihydroxychalcone (47.8 mg, 9.38 %) was afforded as an orange solid with Rf = 0.30 in hexane: EtOAc (2:3); IR vmax cm-1: 3296 (OH), 1633 (C=O), 1563 (C=C olefinic), 1604 and 1454 (C=C aromatic), 1212 (C-O); 1H NMR (400 MHz, CD3COCD3) ppm: δ 13.65 (s, OH), 8.13 (1H, d, J=8.8 Hz, H-6′), 7.82 (2H, d, J= 14.0 Hz, H-α and H-β), 7.75 (2H, d, J= 8.8 Hz, H-2 and H-6), 6.94 (2H, d, J= 8.8 Hz, H-3 and H-5), 6.47 (1H, dd, J= 8.8 and 2.4 Hz, H-5′), 6.37 (1H, d, J = 2.0 Hz, H-3′). 2.2.2 Synthesis of 4′,4-Dihydroxychalcone (11) 4′,4-trihydroxychalcone (6 mg, 12.5%) was afforded as yellow solids with Rf = 0.30 in hexane:EtOAc (2:3); 1H NMR (400 MHz ,CD3Cl) ppm: δ= 6.87 (2H, d, J= 8.8 Hz, H-3 and H-5), 6.92 (2H, d, J= 8.8 Hz, H-3′ and H-5′), 7.40 (1H, d, J= 15.6 Hz, H-α), 7.76 (1H, d, J= 15.6 Hz, H-β), 7.54 (2H, d, J= 8.8 Hz, H-2 and H-6), 7.98 (2H, d, J= 8.8 Hz, H-2′ and H-6′). 2.2.3 Synthesis of 2′,4′,4,6′-Tetrahydroxy-3′-C-prenylchalcone (12) 2′,4′,4,6′-tetrahydroxy-3′-C-prenylchalcone (4 mg, 7.84%) was afforded as an orange solid with Rf = 0.25 in hexane: EtOAc (3:2); IR vmax cm-1: 3440 (OH), 2925 (CH3), 1637 (chelated C=O), 1260 (C-O); 1H NMR (400 MHz, CD3COCD3) ppm: δ 7.70 (1H, d, J= 16.0 Hz, H-β), 7.63 (2H,

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d, J= 8.8 Hz, H-2 and H-6), 7.53 (1H, s, H-5′), 7.10 (1H, d, J= 16.0 Hz, H-α), 6.92 (2H, d, J= 8.8 Hz, H-3 and H-5), 5.10 (1H, t, J= 7.2 Hz, H-2′′), 3.66 (1H, d, J= 7.2 Hz, H-1′′), 1.89 (1H, s, H4′′), 1.39 (1H, s, H-5′′).

3.

RESULTS AND DISCUSSION

3.1

Synthesis of 2′,4′,4-Trihydroxychalcone (10)

The IR spectrum of 2′,4′,4-trihydroxychalcone (10) showed stretching band for OH at 3296 cm1.

The absorption band for C=O was observed at 1633 cm-1. The stretching bands for C=C olefinic

and C=C aromatic were found at 1563 cm-1 and 1604 and 1454 cm-1 respectively. A band at 1212 cm-1 indicated the presence of C-O bond. The 1H NMR of 2′,4′,4-trihydroxychalcone (10) displayed the doublet signal centered at δ 7.82 with coupling constant of 14.0 Hz for H-α and H-β which integrated for two protons, characteristic of trans-olefinic protons of chalcone. An ABX spin system was present where two doublets observed at δ 6.37 (J =2.4 Hz) and 8.13 (J = 8.8 Hz) were attributable for H-3′ and H-6′ respectively while a doublet of doublet signal appeared at δ 6.47 (J= 8.8 and 2.4 Hz) was assigned to H-5′. The 1H NMR spectrum also exhibited the presence of signals at δ 6.94 (2H, J = 8.8 Hz, H-3 and H-5) and δ 7.75 (2H, J = 8.8 Hz, H-2 and H-6) for an A2B2 spin system of the aromatic B-ring. A downfield singlet at δ13.60 was assigned to the chelated hydroxyl at C-2. 3.2

Synthesis of 4′,4-Dihydroxychalcone (11)

The 1H NMR spectrum of 4′,4-dihydroxychalcone (11) displayed two doublets at δ 7.40 (1H, d, J=15.6 Hz) and δ 7.76 (1H, d, J=15.6 Hz) which were the characteristic signals due to the transolefinic protons, H-α and H-β. The spectrum also exhibited the presence of an A2B2 spin system signals centered at  6.87 (d, J = 8.8 Hz, H-3 and H-5) and  7.54 (d, J = 8.8 Hz, H-2 and H-6) which integrated for two protons each. These signals were assigned to the aromatic protons of Aring. While the presence of two doublets centered at δ 7.98 (2H, d, J = 8.8 Hz, H-2′ and H-6′) and 6.92 (2H, d, J = 8.8 Hz, H-3′ and H-5′). These signals were confirmed an A2B2 spin system for the aromatic protons of B-ring. 3.3

Synthesis of 2′,4′,4,6′-Tetrahydroxy-3′-C-prenylchalcone (12)

The IR spectrum of 2′,4′,4,6′-tetrahydroxy-3′-C-prenylchalcone showed a broad band at 3440 cm1

was assignable to OH group. The absorption band at 2925 cm-1 was due to sp3 C-H bond. The

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present of C=O was represented by a band at 1637 cm-1. The presence of C-O bond was indicated by the absorption band at 1260 cm-1. The 1H NMR spectrum of 2′,4′,4,6′-tetrahydroxy-3′-C-prenylchalcone (12) exhibited the two doublet signals at δ 7.70 (1H, d, J=16.0 Hz) and 7.10 (1H, d, J=16.0 Hz) corresponding for H-β and H-α respectively. These protons proved that desired chalcone (12) had been successfully synthesized. The presence of two doublet signals as A2B2 spin system was observed at δ 7.73 (2H, d, J=8.8 Hz) and δ 6.92 (2H, d, J=8.8 Hz). A singlet signal at δ 7.53 was assigned to H-5′. The two methyl groups were observed at δ1.89 (3H, s, H-4′′) and δ 1.39 (3H, s, H-5′′). A triplet at δ 5.10 (1H, J= 7.2 Hz) was attributable to the methylene proton, H-2′′ and a doublet resonated at δ 3.66 (2H, J =7.2 Hz) was assigned to the protons, H-1′′. 3.4

The General Mechanism for Synthesis of Chalcones by BF3.Et2O BF3 is catalyst act as the Lewis acid that has the partially positive charge centred on the

boron atom and the partially negative charge located on the three fluorines. On the other hand, the oxygen atom in acetyl group that has partially negative charge is localized in the region of oxygen’s nonbonding electron pair. When the expected reaction occurs between them, the nonbonding electron pair of oxygen attacks the boron atom of boron trifluoride, filling boron’s valence shell. The boron now carries a formal negative charge and the oxygen carries a formal positive charge [10]. Next step, this BF3 abstracted the proton from the α-carbon of acetyl group to produce an enolate ion. The nucleophilic enolate ion attacks to the electrophilic carbonyl group of the benzaldehyde to form the new carbon–carbon bond. Finally, an α and β –unsaturated ketone was formed. The reaction mechanism for the formation of chalcones by using BF3 is illustrated in Scheme 2.

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H2 C H

HO

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H2 C H

HO BF3

O

HO

HO

CH2

O BF3

CH2

O

O enolate form

H BF3

HO

CH2

+

O

OH

O

HO H

H

O

OH

O

OH

OH HO

HO

HO H O

O

BF3

Scheme 2: Possible Mechanism for the Formation of Chalcones by using BF3.Et2O.

4.

CONCLUSSION In this study, The Claisen-Schmidt condensation reaction between hydroxylated aceto-

phenone with hydroxybenzaldehyde had successfully afforded two chalcones and prenylated chalcone named as 2′,4′,4-trihydroxychalcone (107) , 4′,4-dihydroxychalcone (108) and prenylated chalcone namely 2′,4′,4,6′-tetrahydroxy-3′-C-prenylchalcone (109) in the presence of BF3.Et2O in dioxane with low yield of products. All structures of synthesized compounds were confirmed spectroscopically by 1H NMR and IR.

ACKNOWLEDGEMENTS We pay special thanks to Universiti Teknologi Malaysia, Department of Chemistry, Faculty of Science, UTM Skudai, and staffs of Science Faculty for their great cooperation and assistance throughout the lab process.

REFERENCES 1. Manmohan, S., Arindam, P. and Pratap, S. H. (2011). Synthesis and Characterization of Some Novel Chalcone Derivatives: An Intermediate for Various Heterocyclics Compounds. International journal of pharmaceutical innovations, 1(1), 1-7.

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2. Shamaun, S. S., Rahmani, M., Hashim, N. M., Ismail, H. B. M., Sukari, M. A., Lian, G. E. C. and Go, R. (2010). Prenylated flavones from Artocarpus altilis. Journal of natural medicines, 64(4), 478-481. 3. Jayasinghe, L., Balasooriya, B. A. I S., Padmini, W. C., Hara, N. and Fujimoto, Y. (2004). Geranyl chalcone derivatives with antifungal and radical scavenging properties from the leaves of Artocarpus nobilis. Phytochemistry, 65(9), 1287–1290. 4. Abegaz, B. M., Ngadjui, B.T., Dongo, E. and Tamboue, H. (1998). Prenylated Chalcones And Flavones From The Leaves of Dorstenia Kameruniana. Phytochemistry, 49(4), 1147-1150. 5. Kochummen, K. M. and Go, R. (2000). Moraceae. In Tree Flora Sabah and Sarawak; Ampang Press: Kuala Lumpur, Malaysia, 181–212. 6. Hakim, E. H., Achmad, S. A., Juliawaty, L. D., Makmur, L., Syah, Y. M., Aimi, N., Kitajima, M., Takayama, H. and Ghisalberti, E.L. (2006). Prenylated flavonoids and related compounds of the Indonesian Artocarpus (Moraceae), Journal of Natural Medicines, 60(3), 161–184. 7. Jamil, S., Sirat, H. M., Jantan, I., Aimi, N. and Kitajima, M. (2008). A New Prenylated Dihydrochalcone From The Leaves of Artocarpus Lowii. Journal of natural medicines, 62(3), 321-324. 8. Fang, S. C., Hsu, C. L., Yu, Y. S. and Yen, G. C. (2008). Cytotoxic effects of new geranyl chalcone derivatives isolated from the leaves of Artocarpus communis in SW 872 human liposarcoma cells. Journal of agricultural and food chemistry, 56(19), 8859-8868. 9. Narender, T. and Papi Reddy, K. (2007). A simple and highly efficient method for the synthesis of chalcones by using borontrifluoride-etherate. Tetrahedron letters, 48(18), 3177-3180. 10. Solomons, T., W., G. and Fryhl, C. (2009). Organic Chemistry. (10th Ed). Wiley: 103-104.

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