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Ultrasonics Sonochemistry 15 (2008) 571–577

Ultrasound-assisted reaction of2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide with potassium

salt of curcumin under PTC conditions

Kattera S. Parvathy, Pullabhatla Srinivas *

Department of Plantation Products, Spices and Flavour Technology, Central Food Technological Research Institute, Mysore 570 020, India

Received 28 July 2007; received in revised form 25 August 2007; accepted 18 September 2007Available online 5 November 2007

Abstract

Reaction of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide with potassium salt of curcumin [bis-1,7-(3 0-methoxy-4 0-hydroxy)phe-nyl-5-hydroxy-1,4,6-heptatrien-3-one] under either thermal or high pressure conditions affect the labile substrate, curcumin, thus result-ing in drastic reduction in the yields of the glucosides. This drawback could be effectively overcome by carrying out the biphasic reactionin the presence of a phase transfer catalyst under the effect of ultrasound. The reaction under the sonochemical conditions was faster andresulted in the increased yield of the glucoside products. The reaction was investigated in detail with a view to optimizing the yield of theglucosides. The detailed study clearly indicated the important role of the nature and quantity of the phase transfer catalyst employed inthe reaction. Also, the selectivity with respect to the formation of mono- or di-b-glucosides under both mono- and biphasic reaction con-ditions was clearly discernable. The study establishes a simple synthetic protocol for the glucoside derivatives of curcumin in high yieldsand selectivity using ultrasonic waves.� 2007 Elsevier B.V. All rights reserved.

Keywords: Ultrasound; Phase transfer catalyst; Curcumin; Mono- and di-b-glucosides; Selectivity

1. Introduction

Phase transfer catalysis (PTC) technique is extremelyuseful for carrying out reactions between substances ofpreferential solubility in different solvent phases. For exam-ple, one of the reactants can be an organic compound dis-solved in an organic medium and the other one a salt of analcohol or phenol soluble in the aqueous phase. The cata-lyst does play a very critical role in these biphasic reactions.Its choice and the careful monitoring of the reaction condi-tions are essential features that govern the course of thereaction and determine the yields of the products. Thereare several advantages of the phase transfer catalysis sys-

1350-4177/$ - see front matter � 2007 Elsevier B.V. All rights reserved.

doi:10.1016/j.ultsonch.2007.09.007

* Corresponding author. Tel.: +91 821 2512352; fax: +91 821 2517233.E-mail addresses: psrinivas@cftri.res.in, pullabhatla_s@yahoo.co.uk

(P. Srinivas).

tems over single-phase systems, such as an increased reac-tion rate, lower reaction temperature, avoiding the needfor expensive anhydrous or aprotic solvents and the useof water along with an organic solvent as the reaction med-ium. Catalysts extensively employed in PTC reactionsinclude quaternary ammonium or phosphate salts or crownethers/cryptates. Quaternary ammonium salts with theirinherent capability to dissolve in both aqueous and organicliquids are the catalysts of choice for most phase transferapplications. The efficiency of phase transfer catalysis isinfluenced by the bulkiness of the groups attached to thephase transfer catalyst. However, certain reactions studiedin two-phase system under PTC conditions being slowwould require acceleration and such reactions are usuallycarried out at higher temperatures. In case of heat-labilesubstrates this impediment could be overcome by use ofultrasound. Ultrasound accelerated chemical reactions, infact, are well known and documented in literature [1]. It

572 K.S. Parvathy, P. Srinivas / Ultrasonics Sonochemistry 15 (2008) 571–577

is demonstrated as an alternative energy source for organicreactions normally accomplished by employing higher tem-peratures. Improved yields and increased selectivity arereported when ultrasound is employed in homogeneousas well as heterogeneous reactions [2]. Effect of ultrasoundon PTC reactions has been reported [3–6]. Ultrasound as atechnique of synthesis is extensively used in synthesis oforganometallics, in enzyme catalyzed reactions and manyother synthetic reactions involving reaction mixtures hav-ing more heterogeneity in their solubility.

In our studies on curcumin – a natural yellow colorantof turmeric, which is a spice used primarily as a food col-orant and also to flavor several foods – study of the synthe-sis of its glucoside derivative was investigated. Curcumin, isa nutraceutical compound used worldwide for medicinal aswell as food purposes [7,8]. It has attracted special atten-tion due to its potent pharmacological activities such asto protect cells from b-amyloid insult in Alzheimer’s dis-ease [9] and cancer preventive properties [10]. Biologicalactivities of curcumin chelated to metal ions as well as anti-oxidant effects of curcumin are also documented in litera-ture [11,12]. However, curcumin is insoluble in water atacidic and neutral pH. Though it is soluble under alkalineconditions, the color of the chromophore changes to deepred and it also undergoes degradation. Its low solubilityin aqueous systems is a disadvantage as it renders its usein water based food products difficult. The alkyl and arylportion of the molecule makes it lipophilic and hence, sol-uble only in fats and organic media. In order to make itwater soluble, it is envisaged that attachment of a polargroup or molecule would enhance the hydrophilicity ofthe molecule. This can be achieved, for example, by makingsuitable sugar derivatives. Basically, the reaction of Koe-nigs–Knorr synthesis of glycosides tried under classicalcondition involves formation of glycosyl halides followedby the glycosyl transfer in the presence of heavy metal salts[13] to get the glycoside. Known methods of preparation ofcurcumin sugar derivatives employ the reaction of a-D-tet-raacetohaloglucose with curcumin under biphasic condi-tions in the presence of a phase transfer catalyst at highertemperatures but give very low yields [14,15]. Condensa-tion reaction of arylaldehyde with acetyl acetone–B2O3

complex also gives curcumin glycoside boron complex[16]. Attempts are also made to synthesize curcumin gluco-side by enzymatic means using amyloglucosidase [17] andCatharanthus roseus cell cultures by supplying curcuminexogenously [18]. Lower yields, higher temperatures andlonger reaction times are the drawbacks of chemical andenzymatic synthetic methods reported.

In the present work, reaction of 2,3,4,6-tetra–O-acetyl-a-D-glucopyranosyl bromide with potassium salt of curcu-min under biphasic conditions using phase transfer cata-lysts was studied under the influence of ultrasound forthe synthesis of curcumin glucoside, as a new approachto Koenigs–Knorr reaction. The results of synthesis of cur-cumin glucoside under both mono- and biphasic conditionswill be discussed.

2. Method

2.1. Apparatus and materials

All the solvents and reagents employed in the synthesiswere of analytical reagent grade. Column chromatographyof the compounds was carried out using silica gel (100–200mesh size). 1H NMR spectra for the compounds wererecorded on a Bruker Avance 500 MHz spectrometer usingdeuterated solvents, CDCl3 and DMSO-d6. Coupling con-stants (J values) are given in Hz. Mass spectral analyses ofthe synthetic compounds were carried out using MS(Waters Q-Tof Ultima) in the ES positive mode. Ultra-sound device used for the reaction was Vibracell with ahigh intensity tapered probe of tip diameter �6.5 mm fromSonics and Materials Inc., Newtown, USA. For the reac-tions, the ultrasound reactor was set at 25% amplitudeand pulse cycle of 25 s (on) and 5 s (off) with frequencyof 40 KHz and an output power of 750 W. Thin-layerchromatographic (TLC) analysis was performed on silcagel 60 F254 (Merck KgaA, 64271 Darmstadt, Germany)coated on alumina sheet and 3% methanol in chloroformwas used as the developing solvent. Isolation of the prod-ucts was by column chromatography on silica gel (100–200mesh) with chloroform as the eluent. High performanceliquid chromatography of these samples was carried outon reverse phase C-18 column with methanol: water(70:30) containing trifluroacetic acid (0.1%) as the mobilephase at flow rate of 1 ml/ min and monochromatic detec-tion at 423 nm.

2.2. Preparation of 2,3,4,6-tetra-O-acetyl-a-D-

glucopyranosyl bromide [19]

To acetic anhydride (145 g, 1.42 mol) cooled to 4 �C,perchloric acid (1 ml) was added drop-wise maintainingthe temperature below 4 �C. Glucose (35 g, 0.194 mol)was then added slowly maintaining the temperaturebetween 30 and 40 �C. After cooling the reaction mixtureto 20 �C, red phosphorus (10.25 g) was added followedby drop-wise addition of bromine (20 ml) maintaining thetemperature below 20 �C. Water (12 ml) was then addedover a period of 1 h maintaining temperature below20 �C. The reaction mixture was stirred for 2 h, and thendiluting with dichloromethane (100 ml), filtered throughglass wool. The organic layer was washed with cold satu-rated solution of sodium bicarbonate followed by chilledwater. The organic phase was filtered through activated sil-ica gel and the solvent distilled under reduced pressure. Theproduct was crystallized from diethyl ether–hexane (1:2)mixture and stored in an airtight amber colored glass bottleat 4 �C in a refrigerator. [65 g, 81%, m.p. 87 �C, NMR(CDCl3): 2.04 (s, 3H); 2.06 (s, 3H); 2.10 (s, 3H); 2.11 (s,3H); 4.13(dd, 1H, J = 1.5 Hz and J = 12.5 Hz); 4.29–4.35(m, 2H); 4.85(1H, dd, J = 4 Hz and J = 10 Hz); 5.17 (t,1H, J = 9.5 Hz); 5.56 (t, 1H, J = 9.5 Hz); 6.62 (d, 1H,J = 4 Hz).

K.S. Parvathy, P. Srinivas / Ultrasonics Sonochemistry 15 (2008) 571–577 573

2.3. General procedure for the preparation of curcumin

glucoside tetraacetate (CGTA)

2.3.1. Biphasic reaction conditions

To a solution of curcumin (1, Scheme 1, 1 g, 2.7 mmol)in chloroform (40 ml), aqueous KOH (0.6 g, 10.8 mmol in20 ml water) was added followed by the addition of a solu-tion of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide(2.2 g, 5.35 mmol) in chloroform (40 ml). To the reactionmixture an aqueous solution of benzyltributylammoniumchloride (0.5 g, 1.6 mmol in 20 ml water) was added. Themixture was sonicated until the completion of the reaction(4 h), which was indicated, by phase separation and analy-sis by TLC. The organic layer was washed with water,dried over anhydrous sodium sulfate and distilled underreduced pressure. The crude sample was loaded onto silicagel (100–200 mesh) column and eluted out with CHCl3.Pure fractions were pooled and evaporated to afford curcu-min mono and di-b-glucoside tetraacetates in 78% yield (2and 3).

Compound Structure number

R

Curcumin 1 OH

Curcumin mono- -glucoside

tetraacetate 2

OH

Curcumin di- -glucoside tetra-

acetate

3

Curcumin mono- -glucoside 4 OH

Curcumin di- -glucoside 5

R

O

MeO

H

OHOH

AcAcO

β

β

β

β

Scheme 1. Curcumin and it

2.3.2. Monophasic reaction conditions

Potassium salt of curcumin (1.1 g, 2.7 mmol) was takenalong with benzyl tributylammonium chloride (0.5 g,1.6 mmol) and 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosylbromide (2.2 g, 5.35 mmol) in DMSO (30 ml) and was son-icated until the completion of the reaction (20 h). Then, sol-vent in the reaction mixture was evaporated under reducedpressure. The residue was dissolved in chloroform and theorganic layer washed with water, dried over anhydroussodium sulfate and distilled under vacuum. The crude sam-ple loaded onto silica gel (100–200 mesh) column andeluted out with distilled CHCl3. Pure fractions were pooledand evaporated to afford curcumin mono-b-glucoside tet-raacetate in 50% yield (2).

2.4. General procedure for the preparation of curcumin

glucoside (CG)

To a solution of curcumin di-b-glucoside tetraacetate (3,1 g) in dry methanol (10 ml), sodium methoxide, prepared

R'

OH

O

OAc

HH

H

H

HAcOAcO

OAc

O

R'

OMe

OH

O

OH

HH

H

H

OH

O

O

OH

HH

H

H

HOH

OH

OH

O

O

OAc

HH

H

H

HO

OAc

O

O

OAc

HH

H

H

HAcOAcO

OAc

O

O

OH

HH

H

H

HOH

OH

OH

O

s glucoside derivatives.

Table 1The effect of phase transfer catalyst on the yields of products ofultrasound-assisted reaction of potassium salt curcumin with a-2,3,4,6-tetra-O-acetyl-1-bromoglucose

Entry Catalysta Time (h) Yield (%) X:Yb

1 Benzyltributylammonium chloride 4 78 0.4:12 Cetyltributylammonium bromide 4 50 1:03 Tetrabutylammonium bromide No reaction

a Potassium salt of curcumin to catalyst ratio: 1:0.59.b X and Y-compounds 2 and 3 (Scheme 1).

Q+PhO

-+ KX

)))))AQUEOUS PHASE

ORGANIC PHASE

Q+X

- + PhO

-K

+

Q+X

- + PhOR Q

+PhO

-+ RX

Q - Quaternary ammonium salt (Phase transfer catalyst)

PhOH - Curcumin

RX - 2, 3, 4, 6-Tetra–O-acetyl-α–D-glucopyranosyl bromide

Scheme 2. Mechanism of the reaction of potassium salt of curcumin witha-2,3,4,6-tetra-O-acetyl-1-bromoglucose under the combined effect ofultrasound and PTC.

574 K.S. Parvathy, P. Srinivas / Ultrasonics Sonochemistry 15 (2008) 571–577

by dissolving sodium (60 mg) in dry methanol (8 ml), wasadded and the mixture was stirred. The deacetylation reac-tion was monitored on TLC. At the end of the reaction(0.5 h), the solution was neutralized by the addition offreshly regenerated Dowex (IR-120) H+ resin. The resinwas filtered and the solvent distilled under reduced pressureto afford pure curcumin di-b-glucoside in 95% yield (5).

3. Results and discussion

Reaction of a solution of curcumin in chloroform withaqueous KOH led to facile formation of potassium saltof curcumin indicated by the decolorization of the organiclayer with concomitant transfer of the pigment to the aque-ous phase. A solution of 2,3,4,6-tetra-O-acetyl-a-D-gluco-pyranosyl bromide in chloroform was added, whichconstituted a biphasic system with the glycosyl halide inthe organic phase and the potassium salt of the phenolicsubstrate, curcumin, in the aqueous phase. Aqueous solu-tion of benzyltributylammonium chloride was then addedand the contents were stirred which resulted in the forma-tion of a homogeneous mixture. The reaction mixture wasrefluxed for 12 h under stirring until the aqueous andorganic phases got separated and the aqueous layer becamecolorless. The organic layer after work up and chromato-graphic separation afforded mixture of mono- and digluco-side tetracetates of curcumin in an isolated yield of 15%.The reaction was also carried out under pressure of10 bar and with stirring in a pressure vessel for 4 h andthe reaction product purified by chromatography to affordcurcumin glucoside tetracetates in 10% yield. The resultsindicated that the reactions employing higher temperaturesand pressures led to formation of intractable products,apparently due to the labile nature of curcumin, which isprone to degradation under high pH and temperatures.This affected the overall yield of the targeted glucosides.The use of ultrasound as an alternative source for provid-ing the activation energy for this reaction was thus envis-aged. Also, in our earlier work on reaction of SN1-activehalides with zinc thiocyanate [2], we showed that ultra-sound accelerated the nucleophilic substitution reactionand afforded superior selectivity with respect to preponder-ant formation of alkyl thiocyanates with the ambident thio-cyanate nucleophile. The reaction of potassium salt ofcurcumin with 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosylbromide, accordingly, when carried out under sonochemi-cal conditions afforded enhanced yield of the glucosides(>65%), This interesting finding prompted us to furtherprobe the reaction in detail to explore the possibility ofoptimizing the yield and selectivity of the formation ofglucosides.

The reaction was carried out with three different phasetransfer catalysts, tetra-substituted ammonium halides.The reaction with benzyltributylammonium chloride affor-ded the higher yield of the glucosides in a reaction time of4 h (Table 1, entry 1). In this reaction, the selectivity is alsoreflected in the preponderant formation of the diglucoside.

Cetyltributylammonium bromide facilitated the comple-tion of the reaction in 4 h but the yield of the productwas less (Table 1, entry 2). Interestingly, here the formationof the mono-b-glucoside was observed. However, tetrabu-tylammonium bromide did not catalyze the reaction. Theresults clearly indicate the vital role in the catalysis playedby the nature of the alkyl or aryl nature of the substituentson the ternary ammonium salt. The critical requirement ofan aryl moiety in the phase transfer catalyst can also berelated to the structural features of curcumin.

In heterogeneous reactions containing two immiscibleliquid phases, the limited mass transfer of the reactantsbetween the phases due to their solubility characteristicsis the cause for slow reaction rates. While, phase transfercatalyst (PTC) causes homogenization of the two phases,ultrasound is known to effect cavitation and facilitate themixing of two phases, thereby, providing high interfacialarea with the formation of fine emulsion and enhancinginterfacial contact between the reactants [6]. In the presentstudy, the reaction sequence is envisaged as presented inScheme 2. Reaction of potassium salt of curcumin (PhO�

K+) with the trialkylarylammonium halide (Q+ X�, PTC)in the aqueous phase results in the formation of the trialky-larylammonium salt of curcumin (Q+ PhO�). The later onmigration to organic phase, reacts with the halosugar (RX)to afford curcumin glucoside (PhOR). The trialkylarylam-monium halide is regenerated and the reaction, which isaccelerated by ultrasound, proceeds further along theabove pathway. In fact, the reaction at ambient tempera-ture without ultrasonic irradiation showed negligible prod-uct formation even after 48 h. Therefore, it is nowdemonstrated that Koenigs–Knorr type reaction of2,3,4,6-tetra-O-acetyl-a-D-1-bromoglucose with curcumin

Table 2The effect of amount of catalyst on product yields of ultrasound-assistedreaction of potassium salt of curcumin (2.7 mmol) with a-2,3,4,6-tetra-O-acetyl-1-bromoglucose (5.35 mmol)

Entry Catalyst (mmol) Time (h) Yield (%) X:Y

1 0.8 No reaction2 1.6 4 78 0.4:13 3.2 4 50 1:0.854 3.8 12 43 0.3:1

Table 3Ultrasound-assisted reaction reaction of curcumin (2.7 mmol) with a-2,3,4,6-tetra-O-acetyl-1-bromoglucose (5.35 mmol) in presence of benzyl-tributylammonium chloride (1.6 mmol) and KOH in chloroform (80 ml)and water (40 ml)

Entry KOH(mmol)

Reaction time(h)

Product(X:Y)

Isolated yield(%)

1 5.4 10 No reaction2 10.8 4 0.4:1 783 16.2 10 0.76:1 74.94 21.6 12 0.3:1 72.3

Table 4Ultrasound-assisted reaction reaction of potassium salt of curcumin(2.7 mmol) with a-2,3,4,6-tetra-O-acetyl-1-bromoglucose (5.35 mmol) andbenzyltributylammonium chloride (1.6 mmol) in organic solvents (30 ml)

Entry Solvent Reaction time(h)

Product(X:Y)

Isolated yield(%)

1 Ethanol 2 1:0 21.72 DMSO 20 1:0.3 50.63 Methanol 2 1:0 36.2

K.S. Parvathy, P. Srinivas / Ultrasonics Sonochemistry 15 (2008) 571–577 575

is facilitated by combined effect of ultrasound and PTCwhich promote proper mixing along with better mass trans-fer of reactants between the two phases.

Completion of the reaction in these experiments wasindicated by separation of the layers and the discolorationof the aqueous phase and confirmed by analysis of theproduct by TLC. The product was easily isolable fromthe reaction mixture by separation of the organic phase,its treatment with water, drying followed by distillationto afford crude product. TLC of the product showed twospots with RF values of 0.75 and 0.60 respectively. HPLCof the products showed retention time of 15.37 and 22.92.MS analysis of the product [ESI-MS] exhibited two molec-ular mass ions at 721.34 [M+Na]+ and m/z 1051.48[M+Na]+ corresponding to mono- and diglucoside tetrac-etates of curcumin. The compounds were separated by col-umn chromatography of the product on silica gel withchloroform for elution. They were characterized as the tet-racetates of mono- and di-b-glucosides of curcumin by the1H NMR spectral data (2 and 3, Table 5). The signals at3.90, 6.88, 7.00 and 7.07 correspond to the methoxyl andaromatic protons of the curcumin moiety. While signalscorresponding to the olefinic protons appear as doubletsat 6.49 and 7.60 with J value of 16 Hz, the enolic protonappears at 5.75. The four singlets at 2.02–2.13 character-ized the glucoside moiety, which corresponded to the acetylgroups. Protons on carbons 1–6 in the glucose portion ofthe molecule appeared at characteristic positions in the4.25–6.66 ranges. The integrals for the signals of methoxylto acetyl groups in 1:2 and 1:4 ratio and the number of C1–C6 protons of the glucose moieties characterized 2 and 3 asthe mono and the di-b-glucoside tetraacetate derivatives ofcurcumin respectively. The nucleophilic substitution takesplace by inversion of the configuration at the anomericposition of the sugar moiety resulting in the formation b-glucoside as shown in the reaction in Scheme 3.

Experiments were also carried out to determine the opti-mum quantity of the catalyst in the reaction of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide with potassiumsalt of curcumin. When benzyltributylammonium chloridewas employed in 0.8 mmol, the reaction did not occur(Table 2, entry 1). Only when used in 1.6 mmol, the reac-

O

BrOAc

HH

H

H

HAcOAcO

OAc

+ PhO- K+

PTC, CHCl3/H2O2

Potassium salt of curcumin

-Tetra–O-Acetyl- –D-Glucopyranosyl bromide

)))))

α α

Scheme 3. Ultrasound-assisted reaction of potassium salt of curcumin w

tion did progress smoothly and in 4 h, afforded the gluco-side tetracetates in more than 75% yield. Higherquantities of the catalyst neither facilitated the reactionnor improved the selectivity of the reaction. These findingssuggest the amount of catalyst also is an important aspectof the reaction conditions.

Interestingly, the amount of the base, potassiumhydroxide, employed for the formation of the salt of curcu-min played a critical role in the reaction. Surprisingly,when the base was employed in 5 mmol (entry 1, Table

O

HOAc

HH

H

H

OAcOAcO

OAc

+ KBr

, 25oC

2

Ph

Curcumin-di-glucoside tetraacetate

)

β-

ith a-2,3,4,6-tetra-O-acetyl-1-bromoglucose under PTC conditions.

Table 51H NMR spectral data for the glucoside derivatives of curcumin

Compound 1H NMR signals from aromatic nucleusand substituents on the aromatic moietyof aglycone

1H NMR signals fromhepta-1,4,6-trien-5-ol-3-one moiety of aglycone

1H NMR signals from glucoside moiety

Curucmin (1) 3.90 (s, 6H, OCH3), 6.88 (d, 2H, J = 8Hz), 7.00(s, 2H), 7.07 (d, 2H, J = 8.5 Hz)

6.42 (d, 2H, J = 16 Hz),7.54 (d, 2H, J = 16 Hz),5.75 (s, 1H)

–

Curcumin mono-b-glucosidetetraacetate(2)

3.95 (s, 6H, OCH3), 6.94 (d, 2H,J = 8.5 Hz), 7.06 (d, 2H, J = 1.5 Hz), 7.13(dd, 2H, J = 1.5 and 8.25 Hz)

6.49 (d, 2H, J = 16 Hz),7.60 (d, 2H, J = 16 Hz),5.81 (s, 1H)

2.02 (s, 3H, COCH3), 2.03 (s, H, OCH3), 2.07 (s, 3H,COCH3), 2.11 (s, 3H, COCH3), 4.17(dd, 1H, J = 2.5 Hz),4.3 (dd, 1H, J = 5.5 Hz), 4.45 (d, 1H, J = 8 Hz), 5.01,(t,1H, J = 8 Hz), 5.18 (t, 1H, J = 9.5 Hz), 5.23 (t, 1H,J = 9.5 Hz), 5.97(m, 1H)

Curcumin di-b-glucosidetetraacetate(3)

3.97 (s, 6H, OCH3), 6.95 (d, 2H,J = 8 Hz), 7.07 (d, 2H, J = 2 Hz), 7.14(dd, 2H, J = 2 and 8 Hz)

6.50 (d, 2H, J = 16 Hz),7.61 (d, 2H, J = 16 Hz),5.82 (s, 1H)

2.09 (s, 6H, COCH3), 2.124 (s, 6H, COCH3), 2.128 (s, 6H,COCH3), 2.13 (s, 6H, COCH3), 4.25 (dd, 2H, J = 3 Hz and7 Hz), 4.40 (dd, 2H, J = 3 Hz and 6 Hz), 4.45 (dd, 2H,J = 7 Hz and 12 Hz), 5.25 (dd, 2H, J = 4.5 Hz and 5 Hz),5.58 (d, 2H, J = 4 Hz), 5.92 (br, s, 2H), 6.66 (s, 2H)

Curcumin mono-b-glucoside(4)

3.77 (s, 6H, OCH3), 7.05 (d, 2H,J = 8.5 Hz), 7.18 (d, 2H, J = 8 Hz), 7.32(s, 2H)

6.81(d, 2H, J = 16 Hz),7.52 (d, 2H, J = 16 Hz),6.04 (s, 1H)

3.6 (m, 1H), 4.31 (br, s, 1H), 4.5 (t, 1H, J = 5.5 Hz), 4.93 (d,1H, J = 7 Hz), 4.98 (d, 1H, J = 5 Hz), 5.06 (br, s, 1H), 5.25(d, 1H, J = 4 Hz), 3.1–3.4 (m, 4H)

Curcumin di-b-glucoside (5)

3.77 (s, 6H, OCH3), 7.05 (d, 2H,J = 8.5 Hz), 7.18 (d, 2H, J = 8 Hz), 7.32(s, 2H)

6.81(d, 2H, J = 16 Hz),7.52 (d, 2H, J = 16 Hz),6.04 (s, 1H)

3.6 (m, 3H), 4.31 (br, s, 1H), 4.5 (t, 2H, J = 5.5Hz), 4.93 (d,2H, J = 7 Hz), 4.98 (d, 2H, J = 5 Hz), 5.06 (br, s, 2H), 5.25(d, 2H, J = 4 Hz)., 3.1–3.4 (m, 8H)

576 K.S. Parvathy, P. Srinivas / Ultrasonics Sonochemistry 15 (2008) 571–577

3), the reaction did not occur. Use of base in more than15 mmol (entry 3, Table 3) led to obtaining good yieldsof the glucosides but the selectivity shifted more towardsthe formation of the mono-glucoside. Further increase ofbase to 21 mmol (entry 4, Table 3) slowed the reactionand also decreased the yield. Optimum yield and selectivitytowards preponderant formation of the di-b-glucoside wasobtained when the base was used in 10 mmol (entry 2,Table 3), wherein the reaction was completed in 4 h.

The reaction was also investigated under mono-phasicconditions with the aryltrialkyl ammonium salt of curcu-min produced in situ from the potassium salt of curcuminand the phase transfer catalyst. The reaction was studied inalcoholic solvents and DMSO. Among these, the reactionin DMSO afforded the mono-b-glucoside in 20 h in 50%yield (Table 4, entry 2). Interestingly, the reactions yieldedthe monoglucoside selectively.

Tetraacetates of mono- and di-b-glucosides of curcumincould be conveniently deacetylated using sodium methox-ide in dry methanol at room temperature. HPLC analysisshowed two peaks of retention time 7.5 and 11.86. TheMS analysis of the products [ESI-MS] exhibited two molec-ular mass ions at 553.28 [M+Na]+ and m/z 715.35[M+Na]+, which were further characterized as mono-and di-b-glucosides of curcumin by NMR spectral data(4 and 5, Table 5).

4. Conclusions

Ultrasound brought about acceleration and increase inyields of the curcumin glucosides in the Koenigs–Knorr typereaction of 2,3,4,6-tetra-O-acetyl-a-D-1-bromoglucose withthe potassium salt of curcumin [bis-1,7-(3 0-methoxy-4 0-hydroxy)phenyl-5-hydroxy-1,4,6-heptatrien-3-one] underthe biphasic reaction conditions in the presence of benzyltri-

butylammonium chloride as a phase transfer catalyst. Thereaction was carried out conveniently at ambient tempera-ture overcoming the drawbacks of the earlier methods,employing heat in presence of a base, which led to decompo-sition of the labile curcumin substrate and concomitantlower yields. The importance of the role of the nature andquantity of the phase transfer catalyst in the reaction hasbeen established in this study. The reaction was stereo-selec-tive leading to the preponderant formation of either mono-or di-b-glucoside tetracetates of curcumin under controlledconditions in mono- and biphasic reactions respectively.This work establishes a simple synthetic methodology forthe glucoside derivatives of curcumin in high yields andselectivity using ultrasonic waves.

Acknowledgements

Authors thank Council of Scientific & Industrial Re-search, New Delhi, India for the scholarship to KSP andDepartment of Biotechnology, New Delhi, India. Theauthors are grateful to Dr. V. Prakash, Director, CFTRI,for his support and constant encouragement for the work.Help from Mr. J.R. Manjunatha, Mr. Padmere MukundLakshman and Mrs. G. Sulochanamma in the NMR, MSand HPLC studies of the compounds is gratefullyacknowledged.

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