Synthesis 3,4-dimethoxybenzyl-2,4-dihydroxyphenyl ketone from Eugenol

Sabirin Matsjeh 1*, Mudasir1, Eti Nurwening Shoiikhah2, Andi Hairii Alimuddin3, Department of chemistry, Mathematics and Natural Sciences Faculty, Gadjah Mada

University2 Department of Pharmacologi, FK UGM

3 Department of chemistry, Mathematics ana Natural Sciences Faculty, TanjungpuraUniversity

* Tel/fax : +628164222849, e-mail: matsjeh@ugm.ac.id

ABSTRACT

The synthesis of 3,4-dimethoxybenzyl-2.4-dihydroxyphenyl ketone from eugenolhave been done by several steps. The first step, methyiation of eugenol to methyleugenol.Then

, oxydation of methyleugenol with KMn04 to 3,4-dimethoxy-phenyl acetic acid. Theacylation of 3,4-dimethoxy-phenyl acetic acid with resorcinol in BF3 etherate as a catalystand solvent to furnish compound 3,4-dimethoxybenzyl-2.4-dihvdroxvphenvl ketpne. Asfurther, the ketone compound was usea as precursor for isoflavone synthesis

Keywords: isoflavone, eugenol and acylation

INTRODUCTION

Isoflavone are subclass of flavonoids

which are found in fruits, nuts, soybeans,and soybased products [1], Isoflavoneshave demonstrated a variety of importantbiological .

activities, includingÿ

antioxidant], antibacterial [3],osteoporosis [4] a osf anticancer activities[5], Tfie biological activities of thesecompound that related to those beneficialeffects in human health had become the

interest topic in isoflavones researchincluding synthetic method.

Many synthetic methods have beendeveloped for the synthesis of isoflavones.The two most popular synthetic pathwaysto isoflavones are the deoxybenzoin (2-hydroxyphenyl benzyl ketone) and thechalcone routes. The Starting material forsynthesis isoflavone via deoxybenzoinroute is used phenylacetic acid andsubtituted phenols.

This research relates to synthesis of3

,4-dimethoxybenzyl -2,

4-dihydroxyphenylketone from eugenol as intermediatedeoxybenzoin compound for isoflavone

synthesis. The cyclization of thisintermediate deoxybenzoin to thecorresponding isoflavone was carried byreaction with boron trifluoride etherateand m&hanesulphonylchloride in DMF[6,7].

Eugenol was choosen as a rawmaterial, related to its structure whichhave ailyl group attached in pnenyi. Theoxidation of allyl group will obtainedsubstituted phenylacetic acid.

EXPERIMENTAL SECTION

Materials

Eugenol, DMS, resorcinol, ether,acetone, Na2S04, NaHC03, KMN04,acetic acid, water, sodium bisulit,

chloroform, TLC preparative, BF3.Et20,sodium acetate.

Instrumentation

FT-IR Spectrometer (ShimadzuFTIR-820 PC), GC-MS Spectrometer(Shimadzu QP 5000) and H-NMRSpectrometer (Jeol JNM-MY 60).

XIX International Chemistry Seminar: Palm Oil and Sustainable Chemistry,

Yogvakarta, 20 May, 2009

Procedure

Synthesis of methyleugenolEugenol (41 g, 0.25 mol) was

placed in a 2 L beaker glass, added withstirring 120 mL NaOH solution (12 g in 120mL aquades, 0.3 mol). After 20 min fromthe last addition, the mixture transferredinto separator funnel and allowed to stoodover night. The anorganic layer wasextracted with 3 x 25 mL petroleum ether.Then transfered into a 1 L three-necked

RB flask fitted with a reflux condensor, adropping funnel and thermometer. 19,2gram (0.15 mol) dimetilsulfat (DMS) addedrv\r+inn_iAiioa irsr 1 ÿ h at rnnm tamnnroti iroJ-MJI t«V/t I - lt#l « ,t/ M *_*t tUUIII

The mixture was heated under reflux for 3

h at 110-120 °C, cooled and then 60 mLaquades was added. The solution wereextracted with 3x 25 mL petroleum etherand then washed with NaOH 10%. The

organic layer contain methyleugenol waswashed with aquades until neutral anddried with sodium sulfat anhydrous for onenight. The product filtered and evaporatedwith reduced pressure.Synthesis of 3,4-dimethoxyphenylacetic acid

Solid KMr04 (5,23 g ; 0,05 mol) wasadded portionwise over 6 h to an ice-coldsolution of the methyleugenol (1,18 g ;0

,0067 mol) in a mixture of acetic acid (17mL), acetone (30 mL), and aquades (15mL). The mixture was stirred at roomtemperature for another 1 h and pouredinto water. The aqueous solution was thendecolorated with sodium bisulit

, extractedwith chloroform

, and evaporated. Thecrude products were purified by TLCpreparative (eluting with CHCI3).Synthesis of 3,4-dimethoxybenzyl-2,4-dihydroxyphenyl ketone

Resorcinol (0.003 mol, 0,33 g) wasadded to a mixture containing 3,4-Himothnwnhi=»n\/lar!i=>tir! ariH (C\ 003 mnlWh . iMM {#> ; iwwwuw

0,5 g) and BF3.Et20 (4.5 mL). The reaction

mixture was refluxed for 1.5 h and cooled,

and 60 mL of water was added; the

aqueous layer was extracted with ethylether (3 x 50 mL). The combined etherlayers were washed with saturatedaqueous sodium acetate (30 mL) andsaturated NaHC03 (15 mL), respectively.The layers were separated, and the ether

layer was dried with anhydrous Na2SC>4.Removal of ether by evaporation gave76 % of a yellow solid of 3,

4-

dimethoxybenzyl-2,4-dihydroxyphenylketone.

RESULTS AND DISCUSSION

Synthesis of methyleugenolMethyleugenol can be prepared by

aikylation of eugenol with dimethylsulphate as aikylation agent. Theproduet was yellow oil fo yield 89.78%.The chromatogram of gaschromatography of methyleugenolchrtuuoH that tho rw iritioc r\f rvr/vli ir*t ya/ocv."! IW "W HfVtl >!!V ItlWW VI {rfi WWWWl KMtf

93,61%.

Synthesis of 3,4-dimethoxyphenylacetic acid

3,4-dimethoxyphenylacetic acid as

starting material for synhesis ketoncompund was derived frommethyleugenol by the oxydation ofmethyleugenol with KMn04. In thisoxydation, the proauci was obtained21% 3,4-dimethoxyphenylacetic acid aswhite crystal with m.p.= 97-98

°C. The

spectrometry analysis with IR, GC-MSand 1

H NMR spectrophotometer of thisproduct was suitable with chemdrawestimation of the chemical shift of 3,4-

dimethoxy-phenyl acetic acid.Infrared spectra of this product

shows that this product is phenylaceticacid compound. This* is confirmed by thepresence of broad O-H hydroxyl stretchabsorption at 3448.72 cm

", which is

supported with the presence of sharppeak C=0 strecth at 1712.79 cm

"1.

Tahlo A rhamiral oh iff nf rvvurloHnn ruwli ir»ft auru r tin t/i wnj uouui i f-rt wuuuc

of methyleugenol_

Group of Proton 5 (ppm) IntegrationA 7

.15 3

B 4.25 6

C 3.

87 2

OH 11.0 1

Integration3

6

2

1

From table 1, there are three typesof magnetic environtment of the protons.Chemical shift (5) at 7.15 ppm was thethree aromatic proton which are statedequal at one chemical shift. Caracteristicranges of aromatic hydrogen is

appeared at ranges 6.5-8.5 ppm.Chemical shift (5) of proton from, methoxygroup are indicated at 4.25 ppm, chemicalshift at 11.0 is proton of hydroxy group andchemical shift at 3.87 ppm correlated toproton of methylen.

Based on the spectra data of massspectrometer, the molecular mass of thisprodut is 196. This corresponds to themolecular mass of 3,4-

dimethoxyphenylacetic acid.

Synthesis of 3,4-dimethoxybenzyl-2,4-di hydroxy phenyl ketone

3,4-dimethoxybenzy! -2,

4-dihydroxyphenyl ketone (deoxybenzoin) obtainedby Friedel-C rafts reaction of 3,4-dimethoxvphenylacetic acid and resorcinolusing boron trifluoride etherate as bothcatalyst and solvent. The correspondingdeoxybenzoin was isolated as a solid withm.p. 171-172 °C. The spectrometryanalysis with IR, GC-MS and 1H NMR

spectrophotometer of this product wasidentic with chemdraw estimation of the

chemical shift of 3,4-dimethoxybenzyl -2,4-dihydroxyphenyl ketone.

Infrared spectra of this productshowed that this product was 3,4-dimethoxybenzyl-2,4-dihydroxyphenylketone compound. This proved by thedisappearance of broad O-H hydroxylstretch absorption at 3448.72 cm

1

indicating acylation process between 3,4-dimethoxyphenylacetic acid and resorcinolhave been done.

Table 2 Chemicai shift of acyiation product Of3

,4-3

,4-dimethoxyphenylacetic acid and

resorcinol

Group of Proton 5 (ppm) IntegrationA 6

.9 3

B 6.

45 2

C 4.2 2

D 3.85 6

H-Aromatic 7.8 1

As shown in table 2, there are five

types of magnetic environtment of theprotons. Chemical shift (5) appear at twomagnetic field correspond to the sixaromatic protons in ring A and B.Chemical shift (5) at 6.9 ppm indicatedthree proton of A, at 6.45 ppm indicated

two proton of B and one aromatic protonfrom ring A at 7.8 ppm. Chemical shift(5) of methoxy group indicated by 3.85ppm, than chemical shift at 4.2 ppmcorrelated to proton of methylen.

Based on the spectra data of massspectrometer, the molecular mass of thisprodut is 288. This is likely to be themolecular mass of 3,4-dimethoxybenzyi-2

,4-dihydroxyphenyl ketone.

CONCLUSION

The methylation of eugenol wasresulted methyleugeno! 89 78%.Oxydation of methyleugenol wasresulted 3,4-dimethoxyphenytacetic acid21% and acylation of 3,

4-

dimethoxyphenylacetic acid was resulted3

,4-dimethoxybenzyl-2,

4-

dihydroxyphenyl ketone 76%.

ACKNOWLEDGEMENTS

The Ministry of Research andTechnotegp-ftSBublic of Indonesia forfunded this riset < jREFEREtJCES

1. Liggins, J., Bluck, L.J., Runswick, S.,

Atkinson, C., Coward, W.A.,

Bingham, S.A., 2000. Daidzein andgenistein content of fruits and nuts. J.Nutr. Biochem.HI, 326-331.

2. Kampkottera, A., Chovoloua, Y.,

Kulawika, A., Rohrdanzc, E.,

Weberb, N., Prokschb, P. and

Watjena, W.,2008, Isoflavonedaidzein possesses no antioxidantactivities in cell-free assays butinduces the antioxidant enzymecatalase, Nutrition Research28,620-628.

3. Rukachaisirikul T, Innok P, Aroonrerk

N, Boonamnuaylap W, Limrangsun

S, Boonyon C, Woonjina U and

Suksamrarn A, 2007, AntibacterialPterocarpans from Erythrinasubumrans, Journal ofEtnopharmacology, 110(1), 171-175.

4. Alekel, D.L., Alyson, St.G., Charles,

TP., Kathy, B.H., Jeanne, W.S.,

Thoshiya, T., 2000. Isoflavone-rich SoyProtein isolate attenuate Bone Loss in

The Thumbar Spine ofPerimenopausal Women, Am. J.Clin.Nut., 72, 844-852.

5.

Choi, E.J. and Kim, G-H, 2008,

Daidzein causes cell cycle arrest at theG1 and G2/M phases in human breastcancer MCF-7 and MDA-MB-453

cells, Phytomedicine , 15, 683-690.6

. Chang YC, Nair MG, Santell RC andHelferich WG, 1994, MicrowaveMediated Synthesis ofAnticarcinogenic Isoflavone fromSoybeans, J.Agric. Food Chem., 42,1869-1871.

7. Singh H and Pratap R, 2007,

Corrigendum to "A convenient one-potsynthesis of 7-hydroxy-isoflavonesfrom resorcinol with substituted

phenylacetic acids, Tetrahedron Lett.48(22), 3929.