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Synthetic Communications: AnInternational Journal for RapidCommunication of SyntheticOrganic ChemistryPublication details, including instructions forauthors and subscription information:http://www.tandfonline.com/loi/lsyc20

Versatility of AlternativeReaction Media: Water-Mediated Domino and GreenChemical Synthesis ofPyrimido[1,2-a]benzimidazoleUnder NonconventionalConditionsAnshu Dandia a , Ruby Singh a , Anuj Kumar Jain a &Dharmendra Singh aa Department of Chemistry, University of Rajasthan,Jaipur, India

Version of record first published: 29 Sep 2008

To cite this article: Anshu Dandia, Ruby Singh, Anuj Kumar Jain & DharmendraSingh (2008): Versatility of Alternative Reaction Media: Water-Mediated Domino andGreen Chemical Synthesis of Pyrimido[1,2-a]benzimidazole Under NonconventionalConditions, Synthetic Communications: An International Journal for RapidCommunication of Synthetic Organic Chemistry, 38:20, 3543-3555

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Versatility of Alternative Reaction Media:Water-Mediated Domino and Green Chemical

Synthesis of Pyrimido[1,2-a]benzimidazoleUnder Nonconventional Conditions

Anshu Dandia, Ruby Singh, Anuj Kumar Jain, and

Dharmendra SinghDepartment of Chemistry, University of Rajasthan, Jaipur, India

Abstract: A convenient and clean water-mediated synthesis of a series of4-amino-2-aryl-1,2-dihydro pyrimido[1,2-a]benzimidazoles (4) is reported usingalternative nonconventional energy sources. The products are obtained in shortertimes with excellent yields (78–89%) from the multicomponent reaction of 2-aminobenzimidazole (1), malononitrile=ethylcyanoacetate (2a=b), and carbonylcompounds (3). The reaction is found to be general with respect to the cyclicand acyclic carbonyl compounds. The procedure does not involve the use ofany additional reagent=catalyst, produces no waste, and represents a greensynthetic protocol with high atom economy.

Keywords: Aqueous media, microwave irradiations, pyrimido[1, 2-a]benzimidazole

INTRODUCTION

Several benzimidazole(1,3-dideazapurine) derivatives are important aspharmaceuticals because they have been found to possess various biolo-gical activities.[1–5] The notable clinical examples[6] being the antihistami-nic astemizole, antiulcerative omeprazole, and fungicide rabenzazole.

Received February 20, 2008.Address correspondence to Anshu Dandia, Department of Chemistry,

University of Rajasthan, Jaipur 302004, India. E-mail: dranshudandia@yahoo.co.in

Synthetic Communications1, 38: 3543–3555, 2008

Copyright # Taylor & Francis Group, LLC

ISSN: 0039-7911 print=1532-2432 online

DOI: 10.1080/00397910802164732

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Pyrimido[1,2-a]benzimidazoles represent a pharmaceutically importantclass of compound because of their diverse range of biological activities.[7]

Synthetic chemists continue to explore new methods to carry out che-mical transformations. One of these new methods is to run the reactionsin aqueous media. Organic reactions in water, without the use of anyharmful organic solvent, are of great interest, because water is nontoxic,nonflammable, abundantly available, and inexpensive.[8] Thus, water asthe reaction medium is generally considered a cheap, safe, and environ-mentally benign alternative to synthetic solvent. Furthermore, becauseof the low solubility of common organic compounds in water, the useof water as solvent often makes the purification of product very easyby simple filtration or extraction.[9]

Microwave[10] and ultrasonic irradiation,[11] as nonconventionalenergy sources for activation of reactions, has now become a very popu-lar and useful technology in organic chemistry. Further, the utility of amulticomponent reaction in preparing libraries to screen for functionalmolecules is well appreciated.[12]

The combination of microwave irradiation, ultrasonic irradiation,and aqueous-mediated conditions using multicomponent reactions leadto enhanced reaction rates, higher yields of pure products, easier workup,and sometimes selective conversions. Consequently, this protocol shouldbe welcome in these environmentally conscious days.

Conventional syntheses of pyrimido[1,2-a]benzimidazole derivativeshave been extensively studied by various workers,[13] and they suffermany drawbacks, such as multistep synthesis, low yields, and strong acid-s=bases as catalysts with volatile organic solvents that are difficult torecover. Consequently, there is a need for milder conditions, increasedvariation of the substituents in the components, and better yields.

As a continuation of our research devoted to performing reactionsunder solvent-free conditions[14] and using water as reaction medium,[15]

herein we report a versatile, environmentally friendly, one-pot, multicom-ponent synthesis of a potentially biologically important scaffold, pyri-mido[1,2-a]benzimidazoles (4), using nonconventional energy sources(i.e., microwaves and ultrasound) by reacting 2-aminobenzimidazole withmalononitrile=ethylcynoacetate and various carbonyl compounds bydifferent synthetic pathways.

RESULTS AND DISCUSSION

A multicomponent condensation reaction of 1, 2, and 3 afforded theproduct 4. To find the best method, we studied the synthesis of 4b, 4e,and 4h with different parameters as shown in Table 1.

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The facile reaction occurs in neat condition in absence of any solventand catalyst under microwave irradiation but the product required furtherpurification and recrystallization with suitable solvents, giving compara-tively lower yield. Further, although a reaction in ethanol also occurssmoothly, it requires due precautions and modifications in microwaveoven for operational safety. However, reaction in aqueous medium savebetter results under both microwaves and ultrasonic waves, probablybecause of the beneficial hydrophobic effect=solvophobicity and hydrogenbonding in water described previously.[16] For microwave-irradiated reac-tions, the crystalline product was separated after the reaction by coolingyields were high. With no need of further purification and crystallization.

Further comparison reactions were also studied under conventionalconditions and in the absence of catalyst. No reaction occurred in ethanol,whereas in an aqueous medium, long reaction times with lower yield wereobserved.

To further improve the procedure, the reaction was also studied usingcetyl trimethyl ammonium bromide as phase-transfer catalyst (Table 1,entries ix and x), but no change in yield was observed. Although reactiontime was reduced slightly, it may be concluded that the aqueous medium isthe perfect method for the synthesis of pyrimido[1,2-a]benzimidazoles (4).

To demonstrate its generality, the method was then extended foraromatic aldehydes with electron-withdrawing or donating groups, aswell as a-tetralone.

EXPERIMENTAL

Melting points were determined on a Toshniwal apparatus. The purity ofcompounds was checked on thin layers of silica gel in various nonaqueoussolvent systems [e.g., benzene–ethylacetate (9:1), benzene–dichloromethane

Scheme 1.

Pyrimido[1,2-a]benzimidazole 3545

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Table 1. Comparative study for synthesis of 4b, 4e, and 4h

Time=yield (%)

Entry Reaction conditions Method 4b 4e 4h

i Ethanol (MCR)a D No reaction No reaction No reactionii Ethanolþ triethylamine (MCR) D 8 h=68 7 h=52 5 h=62iii Ethanol (MCR) MW 6 min=84 5 min=82 4 min=82iv Ethanol (MCR) Ultrasound 5 h=85 4 h=86 4 h=84V Water (MCR) D 9 h=75 8 h=70 7 h=68Vi Water (MCR) MW 8 min=88 10 min=82 6 min=89

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Vii Water (MCR) Ultrasound 6 h=88 6 h=78 5 h=84Viii Neat (MCR) MW 3.5 min=81 3 min=81 2.5 min=70ix Water=PTCb (MCR) MW 6 min=87 8 min=80 6 min=83x Water=PTCb (MCR) Ultrasound 4 h=86 3.5 h=80 2.5 h=82xi Alkene nitrilec (2þ 3)þ 1 (ethanol) MW 5þ 4emin=80 8þ 4 min=82 3þ 2 min=78xii Alkene nitrile (2þ 3)þ 1 (water) MW 4þ 4 min=78 5þ 3 min=80 4þ 3 min=76xiii Anild (1þ 3)þ 2a=b (ethanol) MW 4þ 5f min=82 6þ 5 min=83 2þ 3 min=84xiv Anil (1þ 3)þ 2a=b (water) MW 5þ 6 min=80 4þ 4 min=82 3þ 3.5 min=82

Note. Power¼ 600 W for water and 360 W for alcohol.aMulticomponent reactions carried out in one pot.bCetyl trimethyl ammonium bromide is used as phase-transfer catalyst for entries ix and x.cAlkene-nitrile synthesized in situ by malononitrile (2)þcarbonyl compound (3).dAnil synthesized in situ by 2-aminobenzimidazole (1)þcarbonyl compound (3).e5þ 4 indicates that first irradiation for 5 min gave intermediate alkene-nitrile (detected by TLC), which was synthesized in situ, and

then further irradiation for 4 min after adding 2-aminobenzimidazole.f4þ 5 indicates that first irradiation for 4 min gave intermediate anil (detected by TLC), which was synthesized in situ, and then

further irradiation for 5 min after adding malononitrile.

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(8:2)]. IR spectra (KBr) were recorded on a Magna FT IR–550 spectro-photometer, and 1H NMR and 13C NMR spectra were recorded on aBruker DRX-300 using CDCl3 at 300.15 and 75.47 respectively. TMSwas used as internal reference. Mass spectram of representative com-pounds were recorded on a Kratos 50 mass spectrometer at 70 eV. Themicrowave-assisted reactions were carried out in a multimode microwaveoven (Panasonic-NN-781JF) equipped with inverter technology (generat-ing fixed frequency throughout the required time) for realistic control ofthe microwave operating at 1000 W generating 2450 MHz frequency andthe ultrasonic bath (Bandelin Sonorex) operating at 230 V generating 33KHz output frequency.

General Procedure for the Reaction of 2-Aminobenzimidazole (1), ActiveMethylene Reagents (2), and Carbonyl Compounds (3)

Conventional Method

A solution of 2-aminobenzimidazole (1) (0.01 mol), active methylenereagent (2) (0.01 mol), and carbonyl compound (3) (0.011 mol) in ethanol(50 ml) was refluxed for 3 days. However, no reaction occurred after theintermediate stage. Drops of trietylamine (4–5) were added to reactionmixture, and there was an immediate colour change from light yellowto reddish yellow. The reaction was continued for 5 h (thin-layer chroma-tography, TLC, control). The reaction mixture was kept overnight atroom temperature, and the resulting precipitate was filtered, washed withethanol, dried, and recrystallized from ethanol.

Neat=MW

An equimolar (0.01 mol) neat mixture of 1, 2, and 3 in an open vessel wasmixed thoroughly with a rod. Heat evolved, and the color changed fromwhite to pale yellow. The mixture was then irradiated in the MW oven ata power output of 600 W for an appropriate time (monitored by TLC).The mixture took on a dark yellow to reddish color. After completion ofthe reaction, ethanol (10 ml, sufficient to dissolve melted solid) was addedbefore filtration. The filtrate was kept overnight in the refrigerator, and whiteshiny crystals formed, which were filtered and recrystallizsed from ethanol.

Ethanol=MW

An equimolar (0.01 mol) quantity of 1, 2, and 3 was placed in a beaker,and the minimum quantity of ethanol, sufficient to make slurry, was

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added. The mixture was placed in the MW oven and irradiated at poweroutput of 360 W for 4–5 min (TLC). The product started to separate outimmediately after cooling the reaction mixture to room temperature (orin some cases during the course of reaction). The crystalline solid thatseparated out was filtered and found to be pure on TLC with no needof further recrystallization.

Ultrasonic Bath

An equimolar (0.01 mol) quantity of 1, 2, and 3 was placed in a beaker, anddissolved in ethanol with 3–4 drops of triethylamine. The mixture wasplaced under ultrasonic waves using an ultrasonic bath (operating at230 V generating 33 KHz output frequencies) for 30–40 min (TLC) atroom temperature. The product started to separate out during the courseof the reaction. The crystalline solid that separated out was filtered andfound to be pure on TLC with no need of further recrystallization.

Water=MW

An equimolar (0.01 mol) quantity of 1, 2, and 3 was placed in a beaker,and the minimum quantity of water (10 ml) was added. The mixture wasplaced in the microwave oven and irradiated at power output of 600 Wfor 7–8 min (TLC). The product started to separate out immediately afterthe reaction mixture cooled to room temperature. The crystalline solidthat separated out was filtered and found to be pure on TLC with noneed of further recrystallization. All compounds 4a-k were similarlysynthesized comparatively in high yields and reduced times using waterunder microwaves.

Data

4-Amino-2-Phenyl-1,2-Dihydropyrimido[1,2-a]benzimidazole-3-carbonitrile (4a)

Yield: 2.52 g (88%); white crystal; Mp¼ 208–209 �C. IR (KBr) Vmax

3420–3215 (br, NH & NH2), 2202 (CN), 1610 cm�1 (C¼N). 1H NMR(DMSO) (d, ppm) 5.20 (s, 1H, CH), 6.80 (s, 2H, NH2), 7.03 (t, 1H,Ar-H), 7.12 (t, 1H, Ar-H), 7.23 (d, 1H, Ar-H), 7.63 (d, 1H, Ar-H),7.28–7.38 (m, 5H, Ar-H), 8.61 (s, 1H, NH). C17H13N5 (287.32): calc. C,71.06; H, 4.56; N, 24.37. Found:C, 71.30; H, 4.57; N, 24.45%.

Pyrimido[1,2-a]benzimidazole 3549

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4-Amino-2-(4-Methoxyphenyl)-1,2-Dihydropyrimido[1,2-a]benzimidazole-3-carbonitrile (4b)

Yield: 2.59 g (88%); white shiny crystal; Mp¼ 197–199 �C. IR (KBr) Vmax

3470–3240 (br, NH & NH2), 2180 (CN), 1620 cm�1 (C¼N). 1H NMR(DMSO) (d, ppm) 3.71 (s, 3H, CH3), 5.14 (s, 1H, CH), 6.79 (s, 2H,NH2), 7.02 (t, 1H, Ar-H), 7.11 (t, 1H, Ar-H), 7.22 (d, 1H, Ar-H), 7.63(d, 1H, Ar-H), 6.63–6.91 (m, 4H, Ar-H), 8.53 (s, 1H, NH). C18H15

N5O (317.34): calc. C, 68.13; H, 4.76; N, 22.07. Found: C, 68.34; H,4.77; N, 22.14%.

4-Amino-2-(3-Nitrophenyl)-1,2-Dihydropyrimido[1,2-a]benzimidazole-3-carbonitrile (4c)

Yield: 2.65 g (80%); pale yellow crystal; Mp¼ 242–243 �C. IR (KBr) Vmax

3460–3230 (br, NH & NH2), 2190 (CN), 1625 (C¼N), 1575 & 1380 cm�1

(NO2). 1H NMR (DMSO) (d, ppm) 5.25 (s, 1H, CH), 6.86 (s, 2H, NH2),7.01 (t, 1H, Ar-H), 7.11 (t, 1H, Ar-H), 7.23 (d, 1H, Ar-H), 7.23 (d, 1H,Ar-H), 7.30–7.42 (m, 4H, Ar-H), 8.71 (s, 1H, NH). C17H12

N6O2 (332.32): calc. C, 61.44; H, 3.64; N, 25.29. Found: C, 61.24; H,3.65; N, 25.36%.

4-Amino-2-Methyl-2-Phenyl-1,2-Dihydropyrimido[1,2-a]benzimidazole-3-carbonitrile (4d)

Yield: 2.16 g (79%); white crystal; Mp¼ 228–230 �C. IR (KBr) Vmax

3470–3240 (br, NH & NH2), 2180 (CN), 1620 cm�1 (C¼N) 1HNMR(DMSO) (d, ppm) 1.60 (s, 1H, CH3), 6.79 (s, 2H, NH2), 7.01 (t, 1H,Ar-H), 7.11 (t, 1H, Ar-H), 7.21 (d, 1H, Ar-H), 7.63 (d, 1H, Ar-H),7.16–7.40 (m, 5H, Ar-H), 8.61 (s, 1H, NH). C18H15N5 (301.35): calc. C,71.74; H, 5.02; N, 23.24. Found: C, 71.98; H, 5.03; N, 23.31%.

40-Amino-10H-spiro[cyclopentane-1,20-pyrimido[1,2-a]benzimidazole]-30-carbonitrile (4e)

Yield: 2.12 g (80%); white crystal; Mp¼ 170–172 �C. IR (KBr) Vmax 3470–3250 (br, NH & NH2), 2915–2885 (br, ali. CH), 2175 (CN), 1630 cm�1

(C¼N). 1H NMR (DMSO) (d, ppm) 1.43–1.48 (m, 4H, CH2), 1.53–1.80(m, 4H, CH2), 5.95 (s, 2H, NH2), 7.07 (t, 1H, Ar-H), 7.19 (t, 1H, Ar-H),7.36 (d, 1H, Ar-H), 7.60 (d, 1H, Ar-H), 8.50 (s, 1H, NH). C15H15N5

(265.31): calc. C, 67.90; H, 5.70; N, 26.40. Found: C, 67.67; H, 5.72; N,26.48%.

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40-Amino-3,4-dihydro-2H,10H-spiro[naphthalene-1,20-pyrimido[1,2-a]-benzimidazole]-30-carbonitrile (4f)

Yield: 2.35 g (78%); brown powder; Mp¼ 310–311�C. IR (KBr) Vmax

3480–3245 (br, NH & NH2), 2925–2865 (br, ali. CH), 2175 (CN),1605 cm�1 (C¼N). 1HNMR (DMSO) (d, ppm) 2.19 (m, 2H,CH2), 2.64(m, 2H, cH2), 3.02 (m, 2H, CH2), 6.46 (s, 2H, NH2) 7.12 (t, 1H,Ar-H), 7.27 (t, 1H, Ar-H), 7.60 (m, 3H, Ar-H), 7.93 (m, 3H, Ar-H),8.62 (s, 1H, NH). C20H17N5 (327.38): calc. C, 73.37; H, 5.23; N, 21.39.Found: C, 73.62; H, 5.25; N, 21.46%.

Ethyl-4-amino-2-phenyl-1,2-dihydropyrimido[1,2-a]benzimidazole-3-carboxylate (4 g)

Yield: 2.97 g (89%); white crystal; mp¼ 220–221�C. IR (KBr) Vmax 3465–3240 (br, NH & NH2), 1740 (C¼O), 1620 (C¼N), 1080 cm�1 (C-O).1H NMR (DMSO) (d, ppm) 1.45 (t, 3H, CH3, J¼ 6.1Hz), 4.39 (q, 2H,CH2, J¼ 6.1Hz), 5.25 (s, 1H, CH), 6.85 (s, 2H, NH2), 7.05 (t, 1H, Ar-H), 7.15 (t, 1H, Ar-H), 7.25 (d, 1H, Ar-H), 7.65 (d, 1H, Ar-H), 7.25–7.32(m, 5H, Ar-H), 8.65 (s, 1H, NH). C19H18N4O2 (334.37): calc. C, 68.25; H,5.43; N, 16.76. Found: C, 68.50; H, 5.41; N, 16.80%.

Ethyl-4-amino-2-(3-nitrophenyl)-1,2-dihydropyrimido[1,2-a]benzimidazole-3-carboxylate (4 h)

Yield: 3.37 g (89%); yellow needles; Mp¼ 246–247�C. IR (KBr) Vmax

3473–3242 (br, NH & NH2), 1745 (C¼O), 1622 (C¼N), 1575 & 1380(NO2), 1085 cm�1 (C-O). 1H NMR (DMSO) (d, ppm) 1.39 (t, 3H, CH3,J¼ 6.3Hz), 4.42 (q, 2H, CH2, J¼ 6.3 Hz), 5.27 (s, 1H, CH), 6.88 (s, 2H,NH2), 7.05 (t, 1H, Ar-H), 7.10 (t, 1H, Ar-H), 7.22 (d, 1H, Ar-H), 7.24(d, 1H, Ar-H), 7.35–7.41 (m, 4H, Ar-H), 8.70 (s, 1H, NH).C19H17N5O4 (379.37): calc. C, 60.15; H, 4.52; N, 18.46. Found: C,60.35; H, 4.54; N, 18.51%

Ethyl-40-amino-10H-spiro[cyclohexane-1,20-pyrimido[1,2-a]benzimidazole]-30-carboxylate (4i)

Yield: 2.60 g (80%); white crystal; mp¼ 247–249 �C. IR (KBr) Vmax 3480–3240 (br, NH & NH2), 2930–2880 (br, ali. CH), 1730 (C¼O), 1630(C¼N), 1120 cm�1 (C–O). 1H NMR (DMSO) (d, ppm) 1.25–1.31(m, 4H, CH2), 1.42 (t, 3H, CH3, J¼ 6.2 Hz),1.63–1.93 (m, 6H, CH2),

Pyrimido[1,2-a]benzimidazole 3551

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4.40 (q, 2H, CH2, J¼ 6.2 Hz), 5.87 (s, 2H, NH2), 7.06 (t, 1H, Ar-H), 7.14(t, 1H, Ar-H), 7.34 (d, 1H, Ar-H), 7.64 (d, 1H, Ar-H), 8.72 (s, 1H, NH).C18H22N4O2 (326.39): calc. C, 66.24; H, 6.79; N, 17.17. Found: C, 66.46;H, 6.77; N, 17.22%.

Ethyl-40-amino-10H-spiro[cyclopentane-1,20-pyrimido[1,2-a]-benzimidazole]-30-carboxylate (4j)

Yield: 2.34 g (85%); white crystal; Mp¼ 230–231�C. IR (KBr) Vmax 3470–3240 (br, NH & NH2), 2920–2880 (br, ali. CH), 1720 (C¼O), 1620(C¼N), 1110 cm�1 (C-O). 1H NMR (DMSO) (d, ppm) 1.34 (t, 3H,CH3, J¼ 6.4 Hz), 1.41–1.47 (m, 4H, CH2), 1.52–1.81 (m, 4H, CH2),4.37 (q, 2H, CH2, J¼ 6.4 Hz), 5.96 (s, 2H, NH2), 7.06 (t, 1H, Ar-H),7.18 (t, 1H, Ar-H), 7.38 (d, 1H, Ar-H), 7.62 (d, 1H, Ar-H), 8.51 (s, 1H,NH). C17H20N4O2 (312,37): calc. C, 65.37; H, 6.45; N, 17.94. Found:C, 65.15, H, 6.47; N, 17.99%.

Ethyl-40-amino-3,4-dihydro-2H,10H-spiro[naphthalene-1,20-pyrimido[1,2-a]benzimidazole]-30-carboxylate (4k)

Yield: 2.91 g (78%); brown powder; mp¼ 208–210 �C. IR (KBr) Vmax

3475–3245 (br, NH & NH2), 2925–2870 (br, ali. CH), 1735 (C¼O),1625 (C¼N), 1130 cm�1 (C–O). 1HNMR (DMSO) (d, ppm) 1.40 (t,3H, CH3, J¼ 6Hz), 2.17 (m, 2H, CH2), 2.66 (m, 2H, CH2), 3.04 (m,2H, CH2), 4.41 (q, 2H, CH2, J¼ 6 Hz), 6.48 (s, 2H, NH2), 7.14 (t, 1H,Ar-H), 7.28 (t, 1H, Ar-H), 7.62 (m, 3H, Ar-H), 7.95 (m, 3H, Ar-H),8.65 (s, 1H, NH). C22H22N4O2 (374.44): calc. C, 70.57; H, 5.92; N,14.96. Found: C, 70. 80; H, 5.94; N, 14.91%.

Presence and position of NH and NH2 protons were confirmed bydeuterium exchange.

CONCLUSION

We have described herein an efficient, cleaner, green methodologyfor watermediated synthesis of pyrimido[1,2-a]benzimidazoles. Theadvantages, such as (i) no requirement of additional reagent=catalyst,(ii) nonflammable and nontoxic reaction medium, (iii) high yields, (iv)virtually no waste generation, and (vi) ease of product isolation=purification, fulfill the philosophy of green chemistry and make the pre-sent methodology environmentally benign.

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ACKNOWLEDGMENTS

Financial assistance from the Council for Scientific and IndustrialResearch (01/2248/08/EMR-II) (9/149/398/2005/EMR-I), New Delhiare gratefully acknowledged. We are also thankful to the RegionalSophisticated Instrumentation Centre Chandigarh, and Central DrugResearch Institute, Lucknow, for the elemental and spectral analyses.

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