RECYCLABLE ACIDIC BR0NSTED IONIC LIQUID CATALYZED SYNTHESIS OF QUINOXALINE

 

TEJESWARARAO D*^a

^a Indian Institute of Chemical Technolgy, Fine Chemical Laboratory, Tarnaka, Hyderabad, India.

e-mail: teja.iict@gmail.com

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ABSTRACT

The acidic ionic liquid, 1-(4-sulfonic acid) butyl-3-methylimidazolium hydrogen sulfate [MimC₄SO₃H]HSO₄ catalyzed two-component condensation reaction of phenacyl bromide and o-phenylenediamine to afford corresponding quinoxaline derivatives. The inexpensive and non-toxic ionic liquids can be reused severaltimes without any perceptible loss of their activities.

Keywords: Phenacyl bromide, Quinoxaline, Ionic liquids, Catalyst, Green chemistry.

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INTRODUCTION

Quinoxalines, as a core structural motif, are everywhere in natural and unnatural compounds. In 20^th century the biological applications of diversequinoxaline analogues has drawn the attention of many organic chemists.¹"⁴Quinoxaline and its derivatives play an important role in medicinal chemistry and new drug discovery.⁵ In addition to that these are having many applications indyes preparation, chemically controllable switches, efficient electroluminescentmaterials, dehydroannulenes, and inorganic semiconductors.⁶"¹¹ Quinoxalinering moiety comprise part of the chemical structures of various antibioticssuch as Echinomycin, Levomycin and Actinoleutin¹²¹³, that are known toinhibit growth of gram positive bacteria and are also active against varioustransplantable tumors.

In recent literature a number of methods have been reported for the synthesis of substituted quinoxalines: oxidation-trapping of a-hydroxy ketoneswith 1,2-diamines,¹⁴ 1,4-addition of 1,2-diamines to diazenylbutenes,¹⁵cyclization-oxidation of phenacyl bromides and o-phenylenediamines throughsolid-phase synthesis¹⁶ and oxidative coupling of epoxides with ene-1,2-diamines.¹⁷ 2,3-Disubstituted quinoxalines have also been prepared by Suzuki-Miyaura coupling reaction,¹⁸ condensation of o-phenylenediamines and1,2-dicarbonyl compounds in MeOH/AcOH under microwave irradiation¹⁹.Most of the methods that have been reported for the synthesis of quinoxalinesrequire elevated temperatures and complex catalysts. Hence, there is a needto develop a simple, eco-friendly method under mild conditions for the preparation of quinoxalines.

From last two decades ionic liquids have emerged as solvent and catalytic system in many organic transformations and preparation of inorganiccompounds²⁰²¹, because of it’s low vapour pressure, high viscosity, highconductivity, thermal and oxidative stability, and inflammability. In addition tothat ionic liquids act as ideal medium in some specific reactions which involvereactive ionic intermediates. Furthermore, due to the stabilisation of chargedreactive intermediates by ionic liquids, can promote high selectivity and rate of reaction and are finding broad applications in synthetic organic chemistry.

Herein we report the use of ionic liquid (Fig. 1) as recyclable solvent for the oxidative condensation of phenacyl bromide and o-phenylenediamine toproduce quinoxaline derivatives in excellent yield at 65^oC-75^oC (Scheme 1).

1-(4-sulfonic acid) butyl-3-methylimidazolium hydrogen sulfate ([MimC₄SO₃H]HSO₄)

Figure 1: Chemical structure of representative ionic liquid

Scheme 1

 

All the reactions proceeded smoothly in ionic liquid without any need of other catalyst. In these reactions ionic liquid plays a dual role as solventand catalyst. The reaction of 2-bromo-1-phenylethanone 1a with benzene-1,2-diamine 2a in 1-(4-sulfonic acid) butyl-3-methylimidazolium hydrogensulfate ([MimC₄SO₃H]HSO₄) at 65-75^oC over a period of 45min resultedin the formation of 2-phenylquinoxaline 3a in 95% yield. The product wasisolated by simple extraction with diethyl ether. The left over viscous ionicliquid was thoroughly washed with ether and recycled in subsequent reactions.Encouraged by the satisfactory results of our first attempts, we examined severalother phenacyl bromides. The scope and generality of this process is illustratedwith respect to various aryl diamines and phenacyl bromides, and the resultsare presented in Table 1. Better yields were obtained when phenacyl bromidehas electron donating substituents than electron withdrawing substituents, Inall the cases excellent yields were obtained. In similar manner 2-bromo-1-(6-chloropyridin-3-yl)ethanone condensed with various o-phenylenediaminederivatives to produce corresponding products (entries 12,13,14). 1-(4-sulfonicacid) butyl-3-methylimidazolium hydrogen sulfate [MimC₄SO₃H]HSO₄ and allphenacyl bromide derivatives were prepared according to reported procedures.²²This method is even effective with highly functionalized phenacyl bromides.For example, reaction of 2-bromo-1-(4-(3-fluoro-4-nitrophenoxy)phenyl)ethanone1i with o-phenylenediamine 2a under similar conditions to produce2-(4-(3-fluoro-4-nitrophenoxy)phenyl) quinoxaline 3o in good yield (Scheme2).

Scheme 2

^aReaction conditions: Phenacyl bromide (1.0 mmol), o-phenylene diamine (1.1 mmol), [MimC₄SO₃H]HSO₄ (5mol %). ^bIsolated yield.

It is very important to recycle ionic liquids in the context of economic feasibility. In view of the efficiency of the reaction in [MimC₄SO₃H]HSO₄,we examined its recyclability. After separating the organic phase from the worked up reaction mixture, the left over [MimC₄SO₃H]HSO₄ was reactivatedby drying under vacuum at 80-100^oC for 20 min., and was reused for the samereaction without any perceptible loss of catalytic activity. These results areshown in Figure 2. The yield was only slightly decreased after the third cycle,indicating that the catalyst possessed an excellent reusability under the samereaction conditions. Apart from yield and recyclability, this process involvedsimple work-up procedure for isolation of the desired final product.

Table 1: Synthesis of quinoxalines in-(4-sulfonic acid) butyl-3-methylimidazolium hydrogen sulfate³

Figure 2: Graphical representation of obtained yields over four cycles

a-Halocarbonyl compounds show better reactivity in the presence of ionic liquids thereby reducing the reaction times, and improving the yields. The rateenhancement in an ionic liquid is probably due to increased polarization of the-CH₂-Br bond in the polar ionic medium and also because of stabilization of the charged ionic intermediates by ionic liquid. In an ionic liquid , polarization of carbonyl compound is increased significantly compared to organic solvents.

The experimental procedure is very simple and convenient in addition to that, it does not require any aqueous work-up thereby avoiding the generationof toxic waste. Since the products were weakly soluble in the ionic liquid, theywere easily separated by simple extraction with ether. The rest of the viscousionic liquid was thoroughly washed with ether and recycled. The recoveredionic liquid was activated at 85^oC under reduced pressure and reused withoutany significant loss of activity. By using recovered ionic liquid in the secondrun afforded similar yield to that obtained in the first run. However, in the third and fourth run, the yields were gradually decreased. For example, the reaction of 2-bromo-1-(p-tolyl)ethanone 1d and benzene-1,2-diamine 2a in[MimC4SO3H]HSÜ4 to produce 2-/>-tolylquinoxaline 3h gave 95, 93, 92, and 90% yields respectively over four cycles (Figure 1). The products obtainedwere of the same purity as in the first run. The simple experimental and productisolation procedures combined with ease of recovery and reuse of this novelreaction media is expected to contribute to the development of green strategiesfor the synthesis of quinoxalines.

In summary, this paper describes a convenient and efficient method for the synthesis of quinoxalines via the oxidative cyclization of highly reactivephenacyl bromides and o-phenylenediamine using ionic liquids as promoters.The simple experimental and product isolation procedures combined withease of recovery and reuse of this reaction media is expected to contributeto the development of environmentally friendly processes for the synthesis of quinoxalines of biological and medicinal importance. The use of ionic liquidsas promoters for this transformation avoids the use of moisture sensitive and heavy metal Lewis acids.

EXPERIMENTAL

SYNTHESIS AND CHARACTERIZATION OF (1-(4-SULFONIC ACID) BUTYL-3-METHYLIMIDAZOLIUM HYDROGEN SULFATE

1-Methylimidazole (15.8 ml, 0.2mol) and 1,4-butane sultone (22 ml,0.2mol) were charged into a 100 ml round-bottom flask. Then, the mixture was stirred at 40^oC for 10h. The white solid zwitterion was washed repeatedlywith ether (80x5 ml) to remove non-ionic residues and dried in vacuum. Then,a stoichiometric amount of concentrated sulfuricacid (98%, 10.9 ml) wasadded by dropwise and the mixture stirred for 6 h at 80^oC to form the IL.*H NMR (400 MHz, D2O): 5 = 1.28-1.32 (m, 2H, -CH2), 1.56-1.60 (m, 2H,-CH2X2.48-2.52 (t, J = 7.7 Hz, 2H, -CH2), 3.45 (s, 3H, -CH3), 3.78-3.82 (t, J =7.1 Hz, 2H, -CH2), 7.00 (s, 1H, imidazole), 7.05 (s, 1H, imidazole), 8.27 (s, 1H,imidazole);¹³C NMR (100 MHz, D2O): 5 = 20.75, 27.90 (-CH2), 35.63 (-CH₃,imidazole), 48.75, 49.94 (-CH2), 121.90, 123.62 and 135.77 (-CH, imidazole).

General Procedure:

A mixture of phenacyl bromide (1 mmol) and o-phenylenediamine (1.2 mmol) in [MimC₄SO₃H]HSO₄ (3 mL) was heated at 70^oC for the appropriatetime (see Table 1). After completion of the reaction, as indicated by TLC, the reaction mixture was washed with diethylether (3x10mL). diluted with water(3 mlx10 ml). The combined ether extracts were concentrated in vacuo and the resulting product was directly charged onto a small silica gel column and elutedwith a mixture of ethyl acetate:n-hexane (0.5:9.5) to afford pure quinoxaline.The rest of the viscous ionic liquid was further washed with ether and recycledin subsequent runs. However, in the case of solids, the products were purifiedby recrystallization from appropriate solvents.

The spectral and analytical data of all compounds are given below.

(3a) 2-phenylquinoxaline:¹⁵ Milky white colour solid; mp 75-78^oC; *H NMR (300 MHz, CDCl₃) 5 (ppm) 7.61-7.40 (m, 3H, Ar-H), 7.82-7.66 (m, 2H,Ar-H), 8.16-8.06 (m, 2H, Ar-H), 8.25-8.17 (m, 2H, Ar-H), 9.31 (s, 1H, Ar-H);¹³C NMR (75 MHz, CDCl₃) 5 (ppm) 127.3, 129.0, 129.1, 129.5, 129.6, 130.1, 130.2, 136.7, 141.5, 142.2,143.3, 151.7; MS (ESI) m/z 207 (M+H)+; HRMS(ESI) Calcd for C^H^N (M+H)+ 207.0922, found 207.0929.

(3b) 6-methyl-2-phenylquinoxaline: White colour solid; mp 134-136^oC; *H NMR (300 MHz, CDCl₃) 5 (ppm) 2.62 (s, 3H, Ar-CH₃), 7.61-7.42 (m, 4H,Ar-H), 8.03-7.82 (m, 2H, Ar-H), 8.18 (m, 2H, Ar-H), 9.24 (d, J =7.3MHz, 1H,Ar-H); ¹³C NMR (75MHz, CDCl₃) 5 (ppm) 20.1, 127.2, 127.9, 128.4, 128.8,129.6, 136.9, 139.9, 140.3, 140.6, 140.9, 142.2, 150.8; MS (ESI) m/z 220(M+H)+; HRMS (ESI) Calcd for C^H^N (M+H)+ 220.1082, found 220.1085.

(3c) 6,7-dimethyl-2-phenylquinoxaline: Light yellow colour solid; mp 122-124^oC; *H NMR (300 MHz, CDCl₃) 5 (ppm) 2.51 (s, 6H, Ar-CH₃), 7.56-7.41 (m, 3H, Ar-H), 7.89-7.79 (m, 2H, Ar-H), 8.20-8.12 (m, 2H, Ar-H), 9.19 (s,1H, Ar-H); ¹³C NMR (CDCl₃, 75MHz) 5 (ppm) 20.3, 20.4, 127.3, 128.1, 128.6, 129.0, 129.8, 140.1, 140.8, 142.4; MS (ESI) m/z 234 (M+H)+; HRMS (ESI)Calcd for C₁₆H₁₄N₂ (M+H)+ 234.1220, found 234.1223.

(3d) 2-(3-nitrophenyl)quinoxaline: Light orange colour solid; mp 185-187^oC; ‘H NMR (300MHz, CDCl₃) 5 (ppm) 7.72-7.90 (m, 3H, Ar-H), 8.118.25 (m, 2H, Ar-H), 8.30 (td, 1H, .7(1,2) = 8.3, 7(1,3) =2.3, 7(1,3) =1.5, , Ar-H), 8.6(d, 1H, 7=8.3, Ar-H), 9.09-9.15(m, 1H, Ar-H), 9.41(s, 1H, Ar-H); ¹³C NMR(CDCl₃, 75MHz) 5 (ppm) 122.5, 124.7, 129.2, 129.8, 130.2, 130.5, 130.9, 133.1, 142.5; MS (ESI) m/z: 252 (M+H)+; HRMS (ESI) Calcd for C₁₄H₉N₃O₂(M+H)+ 252.1652 found 252.1657.

(3e) 3-(quinoxalin-2-yl) benzenamine: Yellow colour solid; mp 163-165^oC; ³H NMR (500 MHz, CDCl₃) 5 (ppm) 3.80 (bs, 2H, -NH2), 6.76 (dd, 1H, 7(1,2) =2.9, 7(1,3)=8.9, Ar-H), 7.20-7.33(m, 1H, Ar-H), 7.45-7.59 (m, 2H,Ar-H), 7.64-7.80(m, 2H, Ar-H), 8.09(s, 2H, J=10.9, Ar-H), 9.25 (s, 1H, Ar-H);¹³C NMR (CDCl₃, 75MHz) 5 (ppm) 113.8, 117.0, 117.8, 129.1, 129.4, 129.5, 130.1, 130.2, 137.8, 141.6, 142.2, 143.5, 147.3, 152.0; MS (ESI) m/z :222(M+H)+; HRMS (ESI) Calcd for C₁₆H₁₁N₃ (M+H)+ 222.1249, found 222.1258.

(3f) 6-methyl-2-p-tolylquinoxaline: Milky white colour solid; mp 146-147^oC; ³H NMR (300 MHz, CDCl₃) 5 (ppm) 2,45(s, 3H, Ar-CH₃), 2.61(s, 3H, Ar-CH₃), 7.31 (d, 7 =8.3, 3H, Ar-H), 7.59-7.47 (m, 1H, Ar-H), 8.02-7.79 (m,2H, Ar-H), 8.07 (d, 7 =8.3, 2H, Ar-H), 9.22 (d, 7 =7.5, 1H, Ar-H); ¹³C NMR(CDCl₃, 75MHz) 5 (ppm) 21.3, 128.7, 129.1, 129.2, 129.3, 129.4, 130.3, 142.7, 142.8, 150.9; MS (ESI) m/z 234 (M+H)+; HRMS (ESI) Calcd for C₁₆H₁₄N₂(M+H)+234.1230, found 234.1237.

(3g) 6,7-dimethyl-2-p-tolylquinoxaline: Light brown colour solid; mp 127-129^oC; ³H NMR (300 MHz, CDCl₃) 5 (ppm) 2,45 (s, 3H, Ar-CH3), 2.51(s, 6H, Ar-CH3), 7.30 (d, 7 = 8.0, 2H, Ar-H), 7.82 (d, 7 = 9.5, 2H, Ar-H), 8.05(d, 7 = 8.0, 2H, Ar-H), 9.17 (s, 1H, Ar-H); ¹³C NMR (75MHz, CDCl₃) 5 (ppm)21.3, 22.9, 128.5, 129.0, 129.1, 129.3, 139.9, 140.3, 141.3, 142.9, 151.9; MS(ESI) m/z 248 (M+H)+; HRMS (ESI) Calcd for C₁₆H₁₄N₂ (M+H)+ 248.1390,found 248.1398.

(3h) 2-p-tolylquinoxaline: Brown colour solid; mp 90-92^oC; ³H NMR ( 300 MHz, CDCl₃) 5 (ppm) 2.45 (s, 3H, Ar-CH₃), 7.37-7.29 (m, 2H, Ar-H),7.77-7.64 (m, 2H, Ar-H), 8.14-8.04 (m, 4H, Ar-H), 9.28 (s, 1H, Ar-H); ¹³CNMR (75 MHz,CDCl₃) 5 (ppm) 21.4, 127.4, 129.0, 129.2, 129.5, 129.8, 130.1, 133.9, 140.4, 141.4, 142.2, 143.2, 151.7; MS (ESI) m/z: 220 (M+H)+; HRMS(ESI) Calcd for C₁₅H₁₂N₂ (M+H)+ 220.1080, found 220.1083.

(3i) 2-(4-fluorophenyl) quinoxaline:¹⁶ Yellow colour solid; mp: 120-122^oC; ³H NMR (JCAMP, CDCl₃) 5 (ppm) 7.18-7.28 (m, 2H, Ar-H), 7.677.82 (m, 2H, Ar-H), 8.06-8.12 (td, 2H, Ar-H), 8.18-8.27 (m, 2H, Ar-H), 9.27 (s, 1H, Ar-H); ¹³C NMR (75 MHz, CDCl₃) 5 (ppm) 116.0, 116.3, 129.1, 129.4,129.5, 129.5, 130.3, 132.9, 142.8, 150.6, 165.8; MS (ESI) m/z 225 (M+H)+;HRMS (ESI) Calcd for C₁₄H₉FN₂ (M+H)+ 225.0924, found 225.0929.

(3j) 2-(4-nitro-phenyl)-quinoxaline: Yellow colour solid; mp 187-189^oC; ³H NMR (400 MHz, CDCl₃) 5 (ppm) 7.77-7.85 (m, 2H, Ar-H), 8.11-8.18 (m,2H, Ar-H), 8.40 (s, 4H, Ar-H), 9.36 (s, 1H, Ar-H); ¹³C NMR (75 MHz, CDCl₃)5 (ppm) 127.7, 128.4, 129.2, 130.1, 130.8, 131.4, 133.0,138.6, 142.8, 147.0,149.1; MS (ESI) m/z 252(M+H)+; HRMS (ESI) Calcd for C₁₄H₉N₃O₂ (M+H)+252.0756, found 252.0766.

(3k) 4-quinoxalin-2-yl-aniline: Black colour solid; mp 167-169^oC; ³H NMR (500MHz, CDCl₃) 5 (ppm) 6.76 (dd, 1H, 7=8.9,7= 3.0, Ar-H), 7.29 (t, 1H, 7 =7.9, Ar-H), 7.45-7.58 (m, 2H), 7.64-7.79 (m, 231, Ar-H), 8.09 (t, 2H, 7 = 10.8, Ar-H), 9.25 (s, 1H, Ar-H); ¹³C NMR (75MHz, CDCl₃) 5 (ppm)113.7, 116.9, 117.6, 129.0, 129.3, 129.4, 129.9, 130.1, 137.7, 141.4, 142.1,143.4, 147.2; MS (ESI) m/z 222 (M+H)⁺; HRMS (ESI) Calcd for C₁₆H₁₁N₃(M+H)+ 222.1392, found 242.1410.

(3l) 2-(6-chloropyridin-3-yl)quinoxaline: White solid; M.P; 135-137^oC; ³H NMR (300 MHz, CDCl₃): d 9.32 (s, 1H), 9.19 (d, 1H, 7 = 2.26 Hz), 8.49-8.53(dd, 1H, 7 = 2.2, 5.28 Hz), 8.16-8.10 (m, 2H), 7.85-7.76 (m, 2H), 7.51 (d, 1H,7 = 8.3 Hz); IR (KBr): 2978, 2853, 1624, 1580, 1476, 1364, 1208, 1104, 946cm'¹; EIMS: m/z: (M+H)+: 242.0.

(3m) 2-(6-chloropyridin-3-yl)-7-methylquinoxaline: White solid; M.P; 151-153^oC; ³HbNMR (300 MHz, CDCl₃+DMSO): d 9.33 (d, 2H, J= 5.12),9.21 (d, 2H, 7 = 2.92 Hz), 8.61-8.54 (dd, 2H, 7 = 2.9, 5.8 Hz), 8.04-7.95 (dd,2H, 7 = 2.9, 5.8 Hz), 7.92-7.86 (m, 2H), 7.68-7.58 (m, 2H), 7.53 (d, 2H, 7 = 8.7Hz), 2.65 (s, 6H); IR (KBr): 2920, 2853, 1872, 1630, 1580, 1436, 1322, 1210,1104, 1007, 870 cm’¹; EIMS: m/z: (M+H)+: 256.0.

(3n) 2-(6-chloropyridin-3-yl)-6,7-dimethylquinoxaline: Colourless solid; M.P; 170-172^oC; ¹H NMR (300 MHz, CDCl₃): d 9.22 (s, 1H), 9.18 (d, 1H,7 = 2.2 Hz), 8.49-8.53 (dd, 1H, 7 = 2.2, 6.0 Hz), d 7.88 (d, 2H, 7 = 3.7 Hz),7.51 (d, 1H, 7 = 8.3 Hz), 2.57 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): d 152.6, 148.2, 147.0, 141.4, 141.2, 140.9, 137.1, 131.6, 128.5, 128.1, 124.5, 116.2, 29.6, 20.3; IR (KBr): 2978, 2920, 2853, 1624, 1580, 1528, 1476, 1436, 1364,1322, 1208, 1104, 1052 cm-¹; ESIMS: m/z: (M+H)+: 270.0; HRMS calculatedfor C₁₅H₁₂ClN₃ 270.0798. Found. 270.0790.

(3o) Brown colour solid. mp 92-94^oC; ¹H NMR (300 MHz, CDCl₃) 5 (ppm) 6.65- 6.79 (m, 3H, Ar-H), 7.08-7.20 (m, 2H, Ar-H), 7.65-7.80 (m, 2H,Ar-H), 8.05-8.13 (m, 2H, Ar-H), 8.16- 8.25 (m, 2H, Ar-H), 9.27 (s, 1H, Ar-H); ¹³C NMR (300 MHz, CDCl₃) 5 (ppm) 96.1, 107.7, 108.0, 110.5, 110.8, 119.6, 120.9, 127.9, 128.0, 128.2, 129.2, 129.4, 129.5, 129.6, 129.7, 130.1, 130.2, 142.5, 156.7, 166.8; MS (ESI) m/z 362 (M+H)+; HRMS(ESI) Calcd forC₂₀H₁₂FN₃O₃(M+H)+ 362.0940, found: 362.0926.

ACKNOWLEDGEMENTS

Financial supports from Council of Scientific and Industrial Research and Indian Institute of Chemical Technology are gratefully acknowledged.

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