Chalcone: a Versatile Molecule Chetana B

ISSN:0975-1459 Chetana B Patil et al /J. Pharm. Sci. & Res. Vol.1(3), 2009, 11-22.

Chalcone: A Versatile Molecule Chetana B. Patil*, S. K. Mahajan, Suvarna A. Katti Department of Pharmaceutical Chemistry, M. G. V’s Pharmacy College, Panchavati, Nashik-422003, Maharashtra, India.

______

ABSTRACT: Chalcones are 1,3-diphenyl-2-propene-1-one, in which two aromatic rings are linked by a three carbon α,β-unsaturated carbonyl system.These are abundant in edible plants and are considered to be precursors of flavonoids and isoflavonoids. The aim of this review to give summary of methods for synthesis of chalcones, its chemical modifications to flavonoids, flavanone, pyrazoles, oxazoles, pyrimidines. This article also highlights antioxidant potential of chalcone, mechanism of antioxidant activity of chalcones and structure activity relationship of chalcone derivatives for antioxidant ability and different methods to evaluate antioxidant activity of chalcone, antiinflammatory, cytotoxic and antihyperglycemic activity of chalcones is also discussed in this review article.

KEYWORDS: Antioxidant, chalcone, Claisen-schimdt reaction, MOM (methoxymethyl)-protected benzaldehyde ______

INTRODUCTION [1] Chalcones are synthesized by Chalcones are 1,3-diphenyl-2-propene- claisen-schmidt condensation of 1-one, in which two aromatic rings aldehyde and ketone by base are linked by a three carbon α, β- catalyzed or acid catalyzed followed unsaturated carbonyl system as, by dehydration to yield chalcones.

O 6 2' 1 3 1' 5 3' A. Base catalyzed reaction [2][3][4] 1 2 A B The main method for the 4 2 6' 4' synthesis of chalcones is the classical 3 5' Claisen-Schmidt condensation in the Chalcone presence of aqueous alkaline bases.

These are abundant in edible plants and are considered to be precursors Procedure [2] of flavonoids and isoflavonoids. Place a solution of 22g of sodium Chalcones possess conjugated hydroxide in 200ml of water and double bonds and a completely 100g (122.5ml) of rectified spirit in a delocalized Π-electron system on both 500ml bolt-head flask provided with benzene rings. Molecules possessing a mechanical Stirrer. Immerse the such system have flask in a bath of crushed ice, pour relatively low redox potentials and in 52g (0.43mol) of freshly distilled have a greater probability of acetophenone, start the stirrer and undergoing electron transfer reactions. then add 46g (44ml, 0.43mol) of 1. Methods for synthesis of chalcones: pure benzaldehyde. ______*For Correspondence Email: [email protected] 11

Chetana B Patil et al /J. Pharm. Sci. & Res. Vol.1(3), 2009, 11-22.

Mechanism[2]

Ar H H2C Ar' Ar Ar' + NaOH

O O O O Ketone Aldehyde + H

H H

Ar Ar' Ar Ar' -H2O

OH O O Chalcone

Keep the temperature of the mixture to litmus and then with 20ml of ice- at about 250C (the limits are 15- cold rectified spirit. The crude 300C) and stir vigorously until the chalcone after drying in the air 0 mixture is so thick that stirring is no weighs 88g and melts at 50-54 C. longer effective (2-3 hr). Remove the Recrystallized from rectified spirit 0 stirrer and leave the reaction mixture warmed to 50 C (about 5ml per g). in an ice chest or refrigerator The yield of pure overnight. Filter the product with benzylideneacetophenone (a pale 0 suction on a buchner funnel or a yellow solid) mp 56-57 C, is 77g (85%).This substance should be sintered glass funnel, wash with cold water until the washings are neutral handled with great care since it acts as a skin irritant.

Chetana B Patil et al /J. Pharm. Sci. & Res. Vol.1(3), 2009, 11-22.

B. Acid catalyzed reaction: Mechanism[5]

O OH OH

CH 3 + H CH3 CH3

Acetophenone

CH 2 + H

O OH OH

H + H H H

Benzaldehyde

H OH OH O H OH

CH2 + H

O H + H

O H O H H H H

OH OH2 H H

- H3O

Chalcone

Chetana B Patil et al /J. Pharm. Sci. & Res. Vol.1(3), 2009, 11-22.

Procedure [6] It is necessary to use protective group for the preparation of the To a stirred mixture of acetophenone hydroxy chalcones under basic (0.01mol) and benzaldehyde conditions. By using SOCl2 as a (0.01mol) in absolute ethanol (5ml), convenient alternative to the gaseous add thionyl chloride (0.05ml) HCl in the aldol condensation. dropwise and continue stirring for two hour at room temperature. Allow C. Methods for sy nthesis o f to stand reaction mixture for 12hr. chalcones having hydroxy Precipitate the reaction mixture by substituted aldehyde precursors[7] addition of water. Filter the product, The chalcone derivatives are prepare wash with cold ethanol. The yield of through base-catalyzed claisen-schimdt pure benzylideneacetophenone (a pale condensation of MOM-protected yellow solid) mp 56-570C, is 77.0g benzaldehydes with para- substituted (85%). acetophenones followed by acid catalyzed hydrolysis. In the reactions, the MOM- protected benzaldehydes In the presence of SOCl2/EtOH as a are used instead of non-protected catalyst various substituted chalcones dihydroxylated ones, because the are synthesized by aldol condensation. procedure with the free The HCl is generate in situ by the dihydroxylated benzaldehydes required reaction of SOCl2 with absolute long reaction time (more than one ethanol. day) and relatively high temperature (above 600C) which resulted in poor The aldol reaction is perform also yields with unknown degraded under acidic medium, using HCl, products. BF3, B2O3, p-toluene sulfonic acid, etc. The most common method The MOM group is proven to be the applies ethanol saturated with HCl. best choice. The MOM-protected The yields are low and vary between benzaldehydes which are readily 10% - 40%. According to the prepared by treating the corresponding literature data the presence of benzaldehydes with MOMCl in basic hydroxyl substituents in the aromatic condition (K2CO3/acetone), are aldehyde hinders the basic catalyze successfully converted to the chalcone aldol reaction. The reason behind that derivatives with diverse substitution is the fact that the basic catalysts patterns of two hydroxyl groups on decrease the activity of the aldehyde benzaldehyde origin ring B. Now the component because of delocalization hydroxyl protected chalcones are of the anion, which is illustrated deprotect in situ by acid hydrolysis below, to provide the desired final chalcone derivatives in good yields (>70%) with some exception.

O B O O HO O O H BH H H Anion delocalization of the aldehydic component 14

Chetana B Patil et al /J. Pharm. Sci. & Res. Vol.1(3), 2009, 11-22.

The relatively low yields for some 5 with 1N aqueous NaOH solution. products containing para- hydroxyl Extract the aqueous solution with acetophenone are consider probably EtoAc (20 ml x 3). Wash the organic due to the phenoxide ion formation layer with water (20 ml x 2) and brine from the acetophenone in the presence (20ml), dry over anhydrous MgSO4 of strong and excess amount of base. and evaporate to give a crude solid. The double bond geometry of all Purify resulting product by column chalcones is determine as E form the chromatography, elute with hexane- characteristic coupling constants ethyl acetate co-solvent to afford a between α and β protons. solid.

I. Hydroxy benzaldehydes protect ed D. Microwave assisted synthesis[8] by MOM[7] The Claisen–Schmidt condensation Cool the solution of hydroxy stays the most common method in benzaldehyde (21.17 mmol) and homogeneous phase or in interfacial K2CO3 (217.20 mmol) in acetone solid-liquid conditions using barium (100ml) to 00C under Argon hydroxide catalyst (C-200). atmosphere and add Unfortunately 2’-hydroxychalcones methoxymethylchloride (MOM-Cl, always cyclized to flavanones. One 93.65 mmol) dropwise. Stir the synthetic pathway to avoid this resulting mixture at room temperature undesirable reaction is using for 6-10 hr. Dilute the reaction protective group or the Friedel–Crafts mixture with water (100ml) and reaction of phenols with acyl halides. extract with ethyl acetate (50ml x 3). This method request long reaction Wash organic layer with water and time and anhydrous conditions which brine, dry over anhydrous MgSO4 limits the scope of its application. and evaporate to dryness to yield Convenient reaction procedure for the crude MOM- protected benzaldehyde. synthesis of 2’-hydroxychalcones with Purify by silica gel column very good yields without formation of chromatography to give analytically by-products. By applying successful pure compounds (90-99%). microwave irradiation for the preparation of target molecules . The II. General syntheti c procedure for reaction took place in well closed the preparation o f pressure tube for 2 min with high dihydroxychalcones[7] yields. It is noteworthy to mention that To a solution of MOM-protected to carry out the reaction in an open benzaldehydes (0.9 mmol) and vessel failed. A mixture of two acetophenone (10mmol) in ethanol products (3 and 4) and starting (10ml), add 5% aqueous NaOH compounds was obtained in this case. (1.1mmol, 0.5ml). Stir the reaction Obviously, the well closed tube mixture at room temperature for 1-2 affords to reach temperatures much hr. Moniter the reaction, add 10% higher than boiling point of ethanol. HCl (1ml) and continue stirring for The measured temperature in the 30 min at 600C to deprotect the reaction tube immediately after the MOM groups. Dilute the mixture irradiation was 1320C. with water (20 ml) and adjust pH to

Chetana B Patil et al /J. Pharm. Sci. & Res. Vol.1(3), 2009, 11-22.

R2 CHO O O O R3 2 R R1 CH3 1 R R2 KOH/EtOH uW or 2 O OH 1320C OH 1 4 R 3 R3 3

2. Chemical modifications of dry with MgSO4 anhydrous. chalcones: Evaporate the solvent in vaccuo.

I. Flavonoids[9] Purify the residue by chromatographic Flavonoids or bioflavonoids are a column (SiO2, petroleum ubiquitous group of polyphenolic ethermethylene dichloride (0-30%). substances which are present in most plants. Flavonoids have been shown [II] S ynthesis of 3, 5-d iphenyl-4, 5- to have antibacterial, anti- dihydro-1, 2-oxazole[11] inflammatory, antiallergic, Dissolve anhydrous sodium acetate antimutagenic, antiviral, antineoplastic, (0.02 mol) in hot acetic acid. Add anti-thrombotic and vasodilatory hydroxylamine hydrochloride (0.01 activity. The potent antioxidant mol) in absolute alcohol (10ml) to activity of flavonoids their ability to the solution of chalcone in ethanol. scavenge hydroxyl radicals, Transfer the solution of sodium superoxide anions and lipid peroxy acetate in acetic acid to this reaction radicals may be the most important mixture and reflux for 10 hr. Pour function of flavonoids. the reaction mixture into ice cold The structural components common to water, Filter the product and these molecules include two benzene recrystallize with ethanol. rings on either side of a 3-carbon ring. Multiple combinations of [III] Synthesis of 1, 3, 5 -triphenyl-4, hydroxyl groups, sugars, oxygen, and 5- dihydro-1H-pyrazole[11] methyl groups attached to these To a mixture of chalcone and phenyl structures create the various classes hydrazine (0.01 mol) in absolute of flavonoids; flavonols, flavanones, alcohol, add catalytic amount of flavones, flavan-3-ols (catechins), pyridine and reflux reaction mixture anthocynins and isoflavones. for 5-8 hr. Cool the reaction mixture, Pour slowly into crushed ice with General procedure for the synthesis stirring. Filter the solid product. Dry of flavanone[10] and recrystallize with ethanol. Reflux a solution of the 2’- hydroxychalcone (1 equiv) in AcOH 3. Pharmacological profile: glacial (25.0 ml/mmol of 2’- I Antioxidants[9] hydroxychalcone) for 72 hr. Pour the Free radicals, including the .- mixture into water. Extract with superoxide radical (O2 ), hydroxyl EtOAC (3x25.0ml). Wash the organic radical (.OH), hydrogen peroxide layer with brine until neutrality and (H2O2), and lipid peroxide radicals

Chetana B Patil et al /J. Pharm. Sci. & Res. Vol.1(3), 2009, 11-22. have been implicated in a number groups of chalcones. The ortho (i.e. of disease processes, including catechol structure) and para- asthma, cancer, cardiovascular dihydroxylated benzene ring system disease, cataracts, diabetes, are generally known to delocalize gastrointestinal inflammatory electrons. As the phenoxy radicals diseases, liver disease, macular occurring at the ortho- (i.e. catechol degeneration, periodontal disease and structure) or para-dihydroxylated other inflammatory processes. These benzene ring system are much more radical oxygen species (ROS) are readily converted to a fairly stable produced as a normal consequence of semiquinone radicals while, meta biochemical processes in the body dihydroxylated benzene ring system is and as a result of increased exposure comparatively less efficient to to environmental and/or dietary delocalize electrons as the phenoxy xenobiotics. radicals occurring at the meta dihydroxylated ring system is Antioxidants are the agents, which converted to quinone structure which can inhibit or delay the oxidation of is not much stable. an oxidisable substrate in a chain reaction. O O OH R RH R Chalcones belongs to the largest class OH O H O of plant secondary metabolites. Which, in many cases, serve in plant ortho-semiquinone ortho-quinone defense mechanisms to counteract ortho-substituted reactive oxygen species (ROS) in O OH O order to survive and prevent R RH molecular damage and damage by microorganisms, insects, and O OH O herbivores. They are known to H R possess antioxidant character at para-substituted para-semiquinone para-quinone various extents. The antioxidant OH activity of natural compounds like R RH O chalconoids is related to a number of No further reaction different mechanisms such as free OH radical scavenging, hydrogen donation OH singlet oxygen quenching, metal ion meta-substituted chelation and acting as a substrate for free radicals such as superoxide and Proposed ra tionale for stro ng hydroxide. activity of ortho- and para dihydroxylated c halcones vs meta- Mechanism o f antioxidant activity dihydroxylated ones. of chalcones[7] When the chalcone molecules react Structure Activity Relationship[7] with the radicals, they are readily It is proven as, the chalcone converted to the phenoxy radicals due compounds with the ortho- (i.e. 2’, to the high reactivity of hydroxyl 3’- and 3’,4’-) and para- (i.e. .2,5’-)

Chetana B Patil et al /J. Pharm. Sci. & Res. Vol.1(3), 2009, 11-22. substitution patterns show an excellent peroxynitrite, a potent oxidizing antioxidant activities (80-90% of molecule that contributes to tissue control at the concentration of 50µM) injury during inflammatory responses. which are comparable to those of Nitric oxide is generated from L- ascorbic acid and α-tocopherol as arginine by nitric oxide synthase positive reference materials. (NOS).

On the contrary, the compounds with Compounds that inhibit excess meta- (i.e. 2’,4’-, 3’,5’-) substitution production of NO by macrophages pattern demonstrate very dramatic might be of benefit for the prevention decrease in activities which are and treatment of autoimmune around 25% of the control even at diseases, septic shock and different the concentration of 200µM (IC50 > inflammatory pathologies. 200µM). Chalcones with substituents that Thus, it indicate that the substitution increase the electronic density of the patterns of two hydroxyl groups on B-ring, such as methoxy, butoxy or ring B are very important structural dimethylamine groups, did not show factors for their radical scavenging significant activity in the inhibition of activity enhancement. the nitrite production.

The para substituted group exhibited Trimethoxy chalcone derivatives with better free radical scavenging activities fluoro substitution at C4’ are better than ortho substituted system. inhibitors of nitrite production. Trifluoromethyl group at C2’ in The variation of the substituents at dimethoxy chalcones as well as para position of ring A makes no trimethoxy chalcones possess very distinctive differences in activities. potent inhibition of nitrite This observation indicates that the accumulation. electronic effects of para- subsistent of the phenyl ring-A does not affect Trifluoromethyl group at C3’ or C4’ the radical scavenging activity and in dimethoxy chalcone as well as therefore are unlikely to contribute to trimethoxy chalcone possess less variation of antioxidant activities. activity than when it is at C2’.

II Antiinflammatory[12] III Cytotoxic activity[13] Activated macrophages play a key Mannich bases of phenolic role in inflammatory responses and azobenzenes demonstrated cytotoxic release a variety of mediators, activity, and various mannich bases including nitric oxide (NO). NO is a analogs of chalcones exhibited potent potent vasodilator that facilitates cytotoxicity against murine P338 and leukocyte migration and formation of L1210 leukemia cells as well as edema, as well as leukocyte activity several human tumor cell lines. and cytokine production. Mannich bases of heterocyclic NO can also react with chalcones are evaluated for cytotoxic superoxide anion to form activity against four human cancer

Chetana B Patil et al /J. Pharm. Sci. & Res. Vol.1(3), 2009, 11-22. cell lines (PC-3, MCF-7, KB and glucose lowering activity. Compounds KB-VIN). Mannich base of chalcone vicinally deoxygenated as dimethoxy with morpholine substitution at C3 or and methylenedioxy substitution C5 and pyridyl or phenyl at C2 showed the best antihyperglycemic substitution are found to possess good activity when compared to the cytotoxic activity. corresponding monomethoxy compounds. Compounds containing IV Hypoglycemic activity[14] propanolamine chain at para position Non-insulin dependent diabetes showed significant activity as mellitus (NIDDM, type-II diabetes) is compared to meta and ortho a chronic metabolic disease substituted compounds. characterized by insulin resistance, hyperglycemia and hyperinsulinaemia. V Antihepatotoxic activity[15] The disease is often associated with Silymarin isolated from seeds of obesity, dyslipidemia and hypertension silybum marianum commonly known leading to cardiovascular risks. as Milk Thistle has been used as a potent Antihepatotoxic agent against a β3-adrenergic receptors (β3-AR) are variety of toxicants. It is a mixture found on the cell surface of both of three isomers namely, silybin (1), white adipose (WAT) and brown silydianin (2) and silychristin (3). adipose tissue (BAT) where their Silybin is the most active component stimulation promotes lipolysis and containing 1,4-dioxane ring system, thermogenesis respectively. BAT also whereas other isomers do not possess plays an important role in the 1,4-dioxane ring, and thus do not maintenance of glucose homeostasis; display significant activity. hence β3-AR agonists are useful for treating diabetes as well as obesity. Chalcone derivatives possessing 1,4- The aryloxypropanolamines were first dioxane ring system exhibiting described as β3-AR agonists. antihepatotoxic activity. The potent compounds possess 2-hydroxy methyl Chalcones with proper substitution group at position 2 of the dioxane have recently been isolated from ring of chalcone derivatives, which Broussonetia papyrifera known to has also indicated that the presence selectively inhibit enzymes like of hydroxy methyl group at position protein tyrosine phosphatase 1B 2 in dioxane ring possesses a (PTP1B) and aldose reductase. Their significant role in exhibiting the antioxidant property attracted to antihepatotoxic activity. This is in explore hybrid structures as accordance with the view that silybin antihyperglycemic agents, because too possess the same group at the oxidative stress also plays an same position. important role in diabetic patients leading to vascular complications. The substitution in the aromatic ring of chalcones have no significant role 3, 4-Dimethoxy compound displayed in exhibiting antihepatotoxic activity. significant antihyperglycemic effect. Mono methoxy series showed blood

Chetana B Patil et al /J. Pharm. Sci. & Res. Vol.1(3), 2009, 11-22.

VI Antimicrobial activity[16] to be the least active. Compound , Compounds with electron releasing containing triazole and chloro groups such as methoxy and hydroxyl substituents, was found to be the showed better antibacterial activity most potent antiplasmodial derivative than the others not having such evaluated, suggesting that small groups. Compounds having lipophilic groups containing single or pharmacophores such as chloro, multiple nitrogen can enhance dichloro and fluoro groups have antimalarial activity in vitro. exhibited more antifungal activity on all the three fungi than the others. In vitro antiplasmodial results of 4- Chalcone derivatives with these chloro, 4-methoxy and 3,4,5- substituents showing greater trimethoxy series suggested that small antimicrobial activity. or medium sized but highly lipophilic groups containing multiple nitrogen or VII Antimalerial activity[17][18][19] amine in acetophenone moiety impart Antimalarial property of some antiplasmodial potential. Such chalcone derivatives is derived from compounds may provide additional their ability to inhibit the parasitic hydrogen bonding with histidine enzyme, cysteine protease. The residue present at the active site of enzyme catabolizes globin into small the enzyme, cysteine protease. This is peptides within the acidic food the first report in which chalcones vacuole of the intra-erythrocytic containing small highly polar, malaria parasite. Without cysteine lipophilic cyclic amines are showing protease action osmotic swelling antimalarial potential. occurs, food vacuolar functions are impaired, and parasite death ensues. VIII Antileishmanial activity[20] Malaria blood stage cysteine protease Conventional structure activity as the most likely target enzyme of relationships show that antileishmanial chalcones. The chalcones are activity is favoured by chalcones with conjugates of α, ß-unsaturated ketones more hydrophilic character, with the that assume linear or near planar most active members found among structure. This structure is stable in 40-hydroxychalcones. The good acidic food vacuolar environment antileishmanial activities of the where malarial cysteine protease acts, naphthalenyl and pyridinyl derivatives and structural conformation may fit suggest that considerable tolerance for well into the long cleft of the active the size of ring A exists. site of the enzyme. IX Tyrosinase inhibitors[21] [22] The chloro-series compounds showed Tyrosinase (monophenol marked antiplasmodial activity. monooxygenase, E: C: 1.14. 18.1), also Compound , a triazole substituted known as polyphenol oxidase), is a chalcone was found to be the most copper-containing enzyme widely effective against the parasites, and distributed in nature. It catalyzes two pyrrole and benzotriazole showed reactions involving molecular oxygen comparable activities. The morpholine in the melanin biosynthesis pathway: substituents in chloroseries was found the hydroxylation of monophenols to

Chetana B Patil et al /J. Pharm. Sci. & Res. Vol.1(3), 2009, 11-22. o-phenols (monophenolase activity), [7] Beom-Tae Kim, Kwang-Joong O, Jae-Chul and the oxidation of the o-phenols to Chun, and Ki-Jun Hwang, Bull. Korean Chem.Soc. 2008, Vol. 29, No. 6 o-quinones (diphenolase activity). [8] Edmont V. Stoyanov,a,* Yves Champavier,b These quinones are highly reactive Alain Simonc and Jean-Philippe Baslyc, and tend to polymerize spontaneously Bioorganic & Medicinal Chemistry Letters 12 to form brown pigments of high (2002) 2685–2687 molecular weight (melanins), which [9] Alan L. Miller, ND, Alternative Medicine Review, volume 1, Number 2, 1996, 103-111 determine the color of mammalian [10] Mauricio Cabrera, Macarena Simoens, skin and hair. Quinones can also Gabriela Falchi, M. Laura Lavaggi, Oscar E. react with amino acids and proteins Piro, Eduardo E. Castellano, Anabel Vidal, and thus enhance the development of Amaia Azqueta, Antonio Monge, Adela brown color. The inhibitory activity Lopez de Cerain, Gabriel Sagrera, Gustavo Seoane, Hugo Cerecetto and Mercedes of a series of chalcones was set Gonzalez, Bioorganic & Medicinal Chemistry against their structure and their 15 (2007) 3356-3367 antioxidant potency (which can [11] Archita Bapna, Swati Ojha & G. L. contribute to prevent pigmentation Talesara, Indian Journal of Chemistry, resulting from nonenzymatic vol.47B, July 2008, pp.1096-1107 [12] Javier Rojas, Miguel Paya´ ,Jose´ N. oxidation). The position of the Dominguez and M. Luisa Ferra´ ndiz, hydroxyl groups attached to the A Bioorganic & Medicinal Chemistry Letters 12 and B aromatic rings is of major (2002) 1951–1954 importance, while hydroxylation on [13] M. Vijaya Bhaskar Reddy , Chung-Ren Su , ring B contributes markedly more to Wen-Fei Chiou , Yi-Nan Liu , Rosemary Yin- Hwa Chen ,Kenneth F. Bastow , Kuo-Hsiung inhibition than when it is on ring A. Lee , Tian-Shung Wua, Reddy, M. V. B. et al., Butein, an effective tyrosinase Bioorg. Med. Chem. (2008), inhibitor, was also able to delay doi:10.1016/j.bmc.2008.06.018 linoleic acid auto-oxidation, as shown [14] M. Satyanarayana, Priti Tiwari, by conjugated diene (CD) formation. Brajendra K. Tripathi, A. K. Srivastava And Ram Pratap, Bioorganic & Medicinal The OH in position 4 (ring B) was Chemistry 12 (2004) 883–889 the major factor affecting potency. [15] SHAH ALAM KHAN*, BAHAR AHMED AND TANVEER ALAM, Pak. J. References: Pharm. Sci., 2006, Vol.19(4), 290-294 [1] Abdur RAHMAN, Rumana QURESHI, [16] Y. RAJENDRA PRASAD, P. RAVI Mehvish KIRAN, Farzana Latif ANSARI, Turk KUMAR and B. RAMESH, Int. J. Chem. Sci.: J Chem., 31 (2007) , 25 – 34. 5(2), 2007, 542-548 [2] Vogel’s Textbook of practical organic [17] Nidhi Mishra , Preeti Arora , Brajesh chemistry, fifth edition, by Funiss B. S., Kumar , Lokesh C. Mishra , Amit Hannford A. J., Smith P. W. G., Tatchell A. Bhattacharya , Satish K. Awasthi , Virendra K. R., (2004), 1032-1035. Bhasin , European Journal of Medicinal [3] Advanced Organic Chemistry, Reactions, Chemistry 43 (2008) 1530e1535 Mechanisms, and Structure, Fourth edition, [18] Alain Valla , Benoist Valla , Dominique by Jerry March, A Wiley-Interscience Cartier , Régis Le Guillou , Roger Labia, Publication 939-943 Loic Florent , Sébastien Charneau , Joseph [4] Morrison and Boyd, Organic Chemistry, Schrevel , Pierre Potier European Journal of sixth edition, 2004, 971-990, 997-820. Medicinal Chemistry 41 (2006) 142–146 [5] Mukherji S. M., Singh S. P., Kapoor R. [19] Mao Sheng CHENG, Rong Shi LI, P., Organic Chemistry, vol.II, International George KENYON Chinese Chemical Letters (P) Limited, Publishers, 2003, 586-587. Vol. 11, No. 10, pp. 851−854, 2000 [6] Ognyan Petrov , Yordanka Ivanova, Mariana [20] Mei Liu, Prapon Wilairat, Simon L. Croft, Gerova, Catalysis Communications 9 (2008) Bioorganic & Medicinal Chemistry 11 (2003) 315–316 2729–2738 21

Chetana B Patil et al /J. Pharm. Sci. & Res. Vol.1(3), 2009, 11-22.

[21] Ohad Nerya , Ramadan Musa , Soliman [22] Nishida Jun, Gao Hong and Kawabata Khatib , Snait Tamir , Jacob Vaya, Jun, Bioorganic & Medicinal Chemistry Phytochemistry 65 (2004) 1389–1395 15 (2007) 2396-2402