Central European Journal of Chemistry

* E-mail: nbadiadka@yahoo.co.uk

Cent. Eur. J. Chem. • 8(1) • 2010 • 174–181DOI: 10.2478/s11532-009-0124-x

174

1 Department of Post-Graduate Studies and Research in Chemistry, Mangalore University, Mangalagangotri 574 199, INDIA

2 Department of Studies in Chemistry, University of Mysore, Mysore 570 006, INDIA

Synthesis and characterization of some chalcones and their cyclohexenone derivatives

Thekke V. Sreevidya1, Badiadka Narayana1*, Hemmige S. Yathirajan2

Research Article

Received 27 February 2009; Accepted 18 August 2009

Abstract: A series of chalcones and their derivatives have been synthesized. Chalcones, 1-(1,3-benzodioxol-5-yl)-3-(aryl)-prop-2-en-1-ones were prepared by the aldol condensation of 1-(1,3-benzodioxol-5-yl)ethanones and aryl aldehydes. Based-catalyzed condensation of 1-(1,3-benzodioxol-5-yl)-3-(aryl)prop-2-en-1-ones with ethyl acetoacetate yields corresponding ethyl 4-(1,3-benzodioxol-5-yl)-6-(aryl)-2-oxocyclohex-3-ene-1-carboxylates. Some of the synthesized chalcones were reported in the literature; the newly synthesized compounds were characterized by single crystal X-ray studies, IR, 1H-NMR and LCMS mass spectral analysis.

Keywords: Chalcones • Michael addition • Single crystal XRD • Cyclohexenones

© Versita Warsaw and Springer-Verlag Berlin Heidelberg.

1. IntroductionChalcones, one of the major classes of natural products with widespread occurrence in fruits, vegetables, spices, tea and soy-based foodstuff, have been recently the subject of extensive investigations due to their interesting pharmacological activities. Chemically they consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon α,β-unsaturated carbonyl system. It is a unique template molecule that is associated with several biological activities. The radical quenching properties of the phenolic groups present in many chalcones have raised interest in the use of the compounds or chalcone-rich plant extracts as either drugs or food preservatives [1]. Chalcones have been reported to possess many useful properties, including anti-inflammatory [2], antifungal [3-5], antioxidant [6], cytotoxic [7] and anticancer [8-11] activities. Certain chalcone derivatives are reported to inhibit the polymerization of tubulin to form microtubules and can be used as antimitotic agents [12-15]. Chalcone derivatives are also known to inhibit the destruction of myelin sheath in the central nervous system of multiple

sclerosis patients and are thus useful in controlling the progressive nature of the disease [16]. Apart from being biologically important compounds, chalcone derivatives show non-linear optical (NLO) properties with excellent blue light transmittance and good crystallizability. Not only photonics deals with the synergy between optics and electronics, it also provides the ties between optical materials, devices and systems. The inventions of lasers and nonlinear optical phenomena (NLO) have opened up many new areas of devices and systems, like frequency conversion and optical switching, that are of practical interest to mankind [17]. The NLO effect in the organic molecules originates from a strong donor-acceptor intermolecular interaction, a delocalized π-electron system, and is also due to the ability to crystallize in non-centrosymmetric manner. Organic NLO materials are attracting a great deal of interest as they have greater optical susceptibilities, and higher optical thresholds for laser power compared to inorganic materials, as well as inherent ultrafast response times [18]. It is widely accepted that the NLO response is greatly increased upon lengthening of the chain of the conjugated π-bridge and chalcone derivatives have

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was filtered off and washed with cold methanol. Recrystallization from methanol yielded the pure compounds with 62-89% yields.

Synthesis of chalcones can also be carried out using LiOH as a dual activation catalyst [25].

2.2. General procedure for the synthesis of ethyl 4-(1, 3-benzodioxol-5-yl)-2-oxo- 6-(aryl)cyclohex-3-ene-1-carboxylate (5a-i)Chalcones and ethyl acetoacetate in the 1:1 ratio were refluxed in 15 mL of ethanol for 2 h in the presence of 0.5 mL 10% KOH. The reaction mixture was kept overnight at room temperature. The precipitate was filtered off and recrystallized from ethanol to yield the required material, as an isomeric mixture, with 58-78% yield.

2.3. Spectral data2.3.1. Ethyl 4-(1,3-benzodioxol-5-yl)-6-(4-lorophenyl)-2-oxocyclohex-3-ene-1-carboxylate (5a)IR (KBr, cm-1): 1664 cm-1 (νc=o ketone), 1735 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.06 (t, 3H, CH3), 2.56-2.70 (m, 2H, -CH-CH-Ar), 3.23-3.41(m, 2H, CH2-CH-Ar), 4.07- 4.14 (q, 2H, -OCH2), 6.05 (s, 2H, -OCH2O), 6.32 (s,1H, =CH), 6.89 (m, 3H, ArH), 7.31 (m, 4H, ArH); LCMS: 399 (M+1), 400 (M+2).

2.3.2. Ethyl 4-(1,3-benzodioxol-5-y l ) -6-(3,4-dimethoxyphenyl)-2-oxocyclohex-3-ene-1-carboxylate (5b)IR (KBr, cm-1): 1656 cm-1 (νc=o ketone), 1735 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.14 (t, 3H, CH3), 2.82-3.12 (m, 2H, -CH-CH-Ar), 3.56-3.68 (m, 2H, CH2-CH-Ar), 3.79 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 4.10- 4.16 (q, 2H, -OCH2), 6.08 (s, 2H, -OCH2O), 6.42 (s,1H, =CH), 6.74(d, 1H, ArH), 6.82 (m, 2H, ArH), 7.12 (m, 3H, ArH); LCMS: 425 (M+1), 426 (M+2).

2.3.3. E thyl 4-(1,3-benzodioxol-5-y l ) -6-(3-bromophenyl)-2-oxocyclohex-3-ene-1-carboxylate (5c) IR (KBr, cm-1): 1663 cm-1 (νc=o ketone), 1733 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.10 (t, 3H, CH3), 2.86-3.10 (m, 2H, -CH-CH-Ar ), 3.71-3.82 (m, 2H, CH2-CH-Ar), 4.07- 4.14 (q, 2H, -OCH2), 6.04 (s, 2H, -OCH2O), 6.49 (d,1H, ArH), 6.86 (d, 1H, ArH), 7.05 (d, 1H, ArH), 7.12 (m,1H, ArH), 7.26 (m, 2H, ArH), 7.44 (m, 1H, ArH), 7.49 (s,1H, =CH); LCMS: 445 (M+1), 446 (M+2).

2.3.4. E thyl 4-(1,3-benzodioxol-5-y l ) -6-(2-methoxynaphthalen-6-yl)-2-oxocyclohex-3-ene-1-carboxylate (5d)

such a configuration, with two planar rings connected by a conjugated double bond and hence, show significant nonlinearity [19].

Many chalcones have been reported as having high antimalarial activity, probably as a result of Michael addition of nucleophilic species to the double bond of the enone [20,21]. Licochalcone A, isolated from Chinese liquorice roots, has been reported as highly effective in chloroquine resistant Plasmodium falciparum strains in a [3H] hypoxanthine uptake assay [22,23].

Michael addition reactions of chalcones and azachalcones with ethyl acetoacetate have been successfully performed in the presence of catalytic amount of K2CO3 and under high speed vibration milling conditions [24]. The reactions took place at ambient temperature, without any solvent, and were completed within a very short time. In most cases, conventional side reactions were avoided and thus high chemoselectivity and quantitative yields were achieved. The desired Michael adducts obtained consisted exclusively of two diastereomers, ‘anti’ and ‘syn’, which were determined and assigned by 1H-NMR spectroscopy. Herein, we discuss the synthesis and characterization of two series of organic compounds, viz., chalcones and their cyclohexenone derivatives. Some of the chalcones were already reported in literature [25-28]. The newly synthesized compounds were characterized by elemental, IR, 1H-NMR and LCMS mass spectral analysis; a few chalcones were characterized using single crystal XRD.

2. Experimental procedureMelting points were taken in open capillary tubes and are uncorrected. The purity of the compounds was confirmed by thin layer chromatography using Merck silica gel 60 F254 coated aluminium plates in petroleum ether/ethyl acetate medium. IR spectra were recorded on Shimadzu- FTIR Infrared spectrometer in KBr (νmax in cm-1). 1H NMR spectra were recorded in CDCl3 on a Bruker (300 MHz) spectrometer using TMS as internal standard and mass spectra were recorded in LC/MSD Trap XCT spectrometer.

2.1. General procedure for the synthesis of chalcones (3a-n) 3’,4’-Methylenedioxyacetophenone (0.01 mol) and substituted aryl aldehydes (0.01 mol) were dissolved in methanol (25 mL) and 5 mL of 10% KOH solution was slowly added to it under stirring at 15-20°C. Stirring continued for 2 h at the same temperature. Progress of the reaction was monitored by TLC. The precipitate

Synthesis and characterization of some chalcones and their cyclohexenone derivatives

176

IR (KBr, cm-1): 1658 cm-1 (νc=o ketone), 1737 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.06 (t, 3H, CH3), 2.82-3.11 (m, 2H, -CH-CH-Ar ), 3.75-3.80 (m, 2H, CH2-CH-Ar), 3.86(s, 3H, OCH3), 4.03- 4.10 (q, 2H, -OCH2), 6.08 (s, 2H, -OCH2O), 6.39 (s,1H, =CH), 6.82 (dd, 2H, ArH), 6.86 (d, 1H, ArH), 7.44 (m, 6H, ArH); LCMS: 445 (M+1), 446 (M+2).

2.3.5. Ethyl 4-(1,3-benzodioxol-5-yl)-6-(3-nitrophenyl)-2-oxocyclohex-3-ene-1- carboxylate (5e)IR (KBr, cm-1): 1660 cm-1 (νc=o ketone), 1733 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.12 (t, 3H, CH3), 2.92-3.15 (m, 2H, -CH-CH-Ar ), 3.73-3.81 (m, 2H, CH2-CH-Ar), 4.07- 4.16 (q, 2H, -OCH2), 6.08 (s, 2H, -OCH2O), 6.51 (s,1H, =CH), 6.86 (m, 3H, ArH),7.25 (m, 2H, ArH), 7.62 (m, 2H, ArH); LCMS: 406 (M+1), 407 (M+2).

2.3.6. Ethyl 4,6-bis(1,3-benzodioxol-5-yl)-2-oxocyclohex-3-ene-1-carboxylate (5f)IR (KBr, cm-1): 1658 cm-1 (νc=o ketone), 1729 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.05 (t, 3H, CH3), 2.82-3.07 (m, 2H, -CH-CH-Ar), 3.66-3.77 (m, 2H, CH2-CH-Ar), 4.03- 4.10 (q, 2H, -OCH2), 6.04 (s, 2H, -OCH2O), 5.97 (s, 2H, -OCH2O), 6.48 (d,1H, ArH), 6.79 (d, 1H, ArH), 6.83 (d,1H, ArH), 6.86 (s, 1H, =CH ), 7.05 (d, 1H, ArH), 7.09 (d, 1H, ArH), 7.12 (d, 1H, ArH); LCMS: 409 (M+1), 410 (M+2).

2.3.7. Ethyl 4-(1,3-benzodioxol-5-y l ) -6-(2-bromophenyl)-2-oxocyclohex-3-ene-1-carboxylate (5g)IR (KBr, cm-1): 1664 cm-1 (νc=o ketone), 1737 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.10 (t, 3H, CH3), 2.86-3.12 (m, 2H, -CH-CH-Ar ), 3.73-3.81 (m, 2H, CH2-CH-Ar), 4.07- 4.14 (q, 2H, -OCH2), 6.06 (s, 2H, -OCH2O), 6.49 (d, 1H, ArH), 6.79 (d, 1H, ArH), 7.08 (d, 1H, ArH), 7.16 (m, 1H, ArH), 7.41 (m, 3H, ArH), 7.48 (s,1H, =CH); LCMS: 445 (M+1), 446 (M+2).

2.3.8. Ethyl 4-(1,3-benzodioxol-5-yl)-2-oxo-6-phenylcyclohex-3-ene-1-carboxylate (5i)IR (KBr, cm-1): 1663 cm-1 (νc=o ketone), 1737 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.05 (t, 3H, CH3), 2.76-3.11(m, 2H, -CH-CH-Ar), 3.76-3.81(m, 2H, CH2-CH-Ar), 4.03- 4.10 (q, 2H, -OCH2), 6.04 (s, 2H, -OCH2O), 6.50 (d, 1H, ArH), 6.86 (d,1H, ArH), 7.12 (dd, 2H, ArH), 7.32 (m,5H, ArH), 7.37 (s,1H, =CH); LCMS: 365 (M+1), 366 (M+2).

3. Results and DiscussionChalcones were synthesized by a base-catalyzed Claisen–Schmidt condensation of 3’,4’-methylenedioxyacetophenone and substituted

aryl aldehydes. The reaction of chalcones with ethyl acetoacetate is known to lead to three structurally diverse types of compounds, depending on the experimental conditions. The catalyst plays a major role in directing the reaction towards different end products. A strong Lewis acid such as BF3.etherate generates pyrylium cations during the reaction of chalcones and acetoacetic esters, but basic catalyst would turn the intermediate Michael addition product into cyclohexenones through the intramolecular cyclocondensation of the methyl group, originating from acetoacetic acid ester, and the ketone function of the chalcone. Thus in the presence of a base, chalcones containing 1,3-benzodioxolyl (3a-n) react with ethyl acetoacetate (4) to produce cyclohexenones (5a-i) by means of an intermediate Michael adduct, as given in Scheme 1. 1-(1,3-Benzodioxol-5-yl)-3-(aryl)prop-2-en-1-ones (3a-n) were prepared by the reaction of 1-(1,3-benzodioxol-5-yl)ethanones (1) with aromatic aldehydes (2) in presence of KOH in ethanol as given in Scheme 1. The newly synthesized chalcones were characterized by elemental and X-ray analysis. Some of the synthesized chalcones were already reported in literature as being synthesized in the presence of LiOH in methanol. In both, the reported and proposed method, the yields were higher than 70%; it seemed that the presence of LiOH increased the rate of the reaction. A much shorter reaction time and lack of an extraction step are the advantages of our procedure over the one reported in literature [25].

Thus 1-(1,3-benzodioxol-5-yl)-3-(aryl)prop-2-en-1-ones formed on treatment with ethyl acetoacetate in presence of KOH in ethanol yield Michael addition product. The intermediate formed on cyclization gave ethyl 4-(1,3-benzodioxol-5-yl)-2-oxo-6-(aryl)cyclohex-3-ene-1-carboxylate. This cyclization proceeds through the intramolecular condensation of a methyl group and a carbonyl group. The cyclocondensation of ethyl acetoacetate with chalcones leads to the generation of two chirality centers in the structure of cyclohexenones and both, R and S, configurations of the chiral carbon atoms are expected a mixture of diastereomers will result. No attempt has been undertaken to separate the diastereomeric cyclohexenones and they have been characterized as a mixture. The newly synthesized compounds have been characterized by elemental, IR, 1H-NMR and mass spectral analysis. The spectral data are reported in the experimental section and elemental analysis data are given in Tables 1 and 2. The structures of some chalcones viz., (2E)-1-(1,3-benzodioxol-5-yl)-3-(4-chlorophenyl)prop-2-en-1-one (I), (2E)-1-(1,3-benzodioxol-5-yl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one ( I I ) and (2E)-1-(1,3-benzodioxol-5-yl)-3-(3-

T.V. Sreevidya, B. Narayana, H. S. Yathirajan

177177

Compound No. Ar

Yield* (%)

Melting Point

ºC

Molecular Formula

Nature of Products

Elemental Analysis, % Found (Calculated)

C H N

3aCl

68 162-166 C16H11ClO3

Cream powder

67.14(67.03)

3.60(3.87) -

3b H3CO

OCH3

70 132-134 C18H16O5

White powder

69.20(69.22)

5.00(5.16) -

3cH3CO

66 147-149 C17H14O4

White powder

72.20(72.33)

4.98(5.00) -

3dO

O82 161-163 C17H12O5

Cream crystals

68.78(68.92)

3.99(4.08) -

3e 62 122-124 C24H16O3

Yellow powder

81.89(81.80)

5.00(4.58) -

3f 78 139-141 C16H12O3

Cream crystals

76.04(76.18)

4.52(4.79) -

3g NCH3

CH3

75 92-94 C18H17NO3

Yellow powder

73.12(73.20)

5.68(5.80)

4.81(4.74)

3hNO2

56 131-133 C16H11NO5

Yellow crystals

64.61(64.65)

3.52(3.73)

4.68(4.71)

3i

NO2

62 144-146 C16H11NO5

Yellow crystals

64.56(64.65)

370(3.73)

4.66(4.71)

3j

OCH3

OH 74 101-103 C17H14O5

Off-whitepowder

68.38(68.45)

4.70(4.73) -

3k

Br

77 120-122 C16H11BrO3

Brownish powder

57.96(58.03)

3.42(3.35) -

3l

Br69 117-119 C16H11BrO3

Brownish powder

58.12(58.03)

3.47(3.35) -

3mH3CO

65 124-126 C21H16O4

Cream powder

75.68(75.89)

4.66(4.85) -

3n

F

78 118-120 C16H11FO3

Off -white powder

71.04(71.11)

4.16(4.10) -

Table 1. Characterization Data of 1-(1,3-Benzodioxol-5-yl)-3-(aryl)prop-2-en-1-ones

O

O

O

Ar

Synthesis and characterization of some chalcones and their cyclohexenone derivatives

178

O

O

Ar

COOC2H5

O

Compound No. Ar Yield*

(%)Melting Point ºC

Molecular Formula

Nature of Products

Elemental Analysis, % Found (Calculated)

C H N

5a

Cl

78 135-137 C22H19ClO5 Cream powder 66.12(66.25)

4.72(4.80) -

5b H3CO

OCH3

62 132-134 C24H24O7 Yellow powder 67.60(67.91)

5.62(5.70) -

5c

Br

80 126-128 C22H19BrO5 Cream powder 59.45(59.61)

4.90(4.32) -

5dH3CO

76 116-118 C27H24O6 Cream powder 73.00(72.96)

5.14(5.44) -

5e

NO2

64 151-153 C22H19NO7

Yellowpowder

64.17(64.54)

4.85(4.68)

3.91(3.42)

5fO

O85 170-172 C23H20O7

Off white powder

67.70(67.64)

5.00(4.94) -

5g

Br

77 121-123 C22H19BrO5 Cream powder 59.48(59.61)

4.55(4.32) -

5hN

CH3

CH3

65 86-88 C24H25NO5

Yellowish powder

70.52(70.74)

6.04(6.18)

3.40(3.44)

5i 79 155-157 C22H20O5

Off-white powder

72.23(72.51)

5.25(5.53) -

Table 2. Characterization Data of (Ethyl 4-(1,3-benzodioxol-5-yl)-2-oxo-6-(aryl)cyclohex-3-ene-1-carboxylate)

bromophenyl)prop-2-en-1-one (III) were confirmed by single crystal X-ray study [29,30] and are given in Figs. 1, 2 and 3. The compound, (2E)-1-(1,3-benzodioxol-5-yl)-3-(4-chlorophenyl)prop-2-en-1-one (I), crystallizes in the monoclinic P21/c space group with cell parameters, a=2.7231(15), b = 4.9239(4), c = 11.9995(7)Å, β= 99.953(6)˚. The compound, (2E)-1-(1,3-benzodioxol-5-yl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one (II), crystallizes in the triclinic crystal system, space group P1 with a = 8.2961(2) Å, b = 13.8829(6) Å, c = 14.6713(7)Å, α = 64.185(4), β = 83.560(3)˚, γ = 84.966(3)˚ and in

(2E)-1-(1,3-benzodioxol-5-yl)-3-(3-bromophenyl)prop-2-en-1-one (III), the molecule adopts an E configuration with respect to the C=C double bond of the propenone unit and crystallizes in monoclinic, P21/c, a = 14.237(3) Å, b = 8.1811 (17) Å, c=11.717(2) Å, β= 100.658(3)°. The 13 non-H atoms of the benzodioxol and propenone units in III are approximately coplanar and the bromobenzene ring plane forms a dihedral angle of 10.8(1)° to this plane. The structure is layered, with the molecules forming a herring-bone arrangement within each layer.

T.V. Sreevidya, B. Narayana, H. S. Yathirajan

179179

Figure 1. Ortep drawings (a) and molecular packing (b) for (2E)-1-(1,3-benzodioxol-5-yl)-3-(4- chlorophenyl)prop-2-en-1-one

Figure 2. Ortep drawings (c) and molecular packing (d) for (2E)-1-(1,3-benzodioxol-5-yl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one

Figure 3. Ortep drawings (e) and molecular packing (f) for (2E)-1-(1,3-benzodioxol-5-yl)-3-(3- bromophenyl)prop-2-en-1-one

(a) (b)

(c) (d)

(e) (f)

Synthesis and characterization of some chalcones and their cyclohexenone derivatives

180

Hydrogen bonding and crystal packing effects influence the twist angle between the mean planes of the 1,3-benzodioxol-5yl and benzene groups in both I and II, while π-π stacking interactions between the adjacent 5-membered dioxol rings and the 9-membered benzodioxol group, as well as the benzyl ring, stabilize the crystal packing. In I there is an intermolecular C–H·O hydrogen bond between the C15 and O1 atoms. The dihedral angle between the mean planes of the 1,3-benzodioxol-5-yl group and the benzene ring is 18.26°. In II the compound crystallizes with two independent molecules in the asymmetric unit. Intermolecular C–H-O hydrogen bond interactions occur in both molecules that help to stabilize the crystal packing in the unit cell. The dihedral angle between the mean planes of the 1,3-benzodioxol-5-yl group and the benzene ring in the two independent molecules in II is 7.8(9)° (A) and 37.9(7)° (B), respectively. The molecular packing in I and II is stabilized by hydrogen bonding and also by π-π stacking interactions.

O

O

CH3

O

+ H

O

Ar BaseEtOH

O

O

O

Ar

Base CH3

O

COOC2H5

O

O

O

Ar

COOC2H5

OCH3

O

O

Ar

COOC2H5

O

1 2 (3a-n)

4

(5a-i)

*

*

Scheme 1. Claisen–Schmidt condensation of 3’,4’-methylenedioxyacetophenone and substituted aryl aldehydes

4. ConclusionsSome chalcones, such as 1-(1,3-benzodioxol-5-yl)-3-(aryl)prop-2-en-1-ones, and their cyclized products with ethyl acetoacetate, such ethyl 4-(1,3-benzodioxol-5-yl)-2-oxo-6-(aryl)cyclohex-3-ene-1-carboxylate derivatives, were synthesized and characterized by spectral analysis.

Acknowledgements

One of the author (TVS) thanks Mangalore University for the use of the research facilities and DST & UGC, Govt. of India, for financial support through FIST & SAP programmes.

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