Chalcones: Chemistry & Bioactivity - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/32781/8/08_chapter 1.pdf · This introductory chapter reviews the recent advances in the synthesis,

Chapter1

This introductory chapter reviews the recent advances in the synthesis, bioactivity and

application of chalcones as intermediate in organic synthesis.

Chalcones:Chemistry&Bioactivity

Chalcones: Chemistry & Bioactivity CHAPTER I

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1.1 Introduction

Throughout the ages mankind is dependent on nature, particularly on plants as

source of carbohydrates, proteins and fats for food and shelter. In addition, plants are

valuable source of a wide range of secondary metabolites, which are used as

pharmaceuticals, agrochemicals, flavours, fragrances, colours, bio pesticides and food

additives. With the presence of a wide variety of secondary metabolites, plants have

formed the basis of the traditional medicine systems that have been in existence for

-

phenolic compounds, including tannins and derived poly-phenols and their different

derivatives form one major group of phytochemicals.1 It has been found that in many

plants flavonoids protect them against their pathogenic bacteria and fungi.2 The

is the prime beneficiary of the dietary flavonoids knowing or unknowingly

utilizing them for prevention of diseases or cure. Their antioxidant properties,

cytostatic effects in tumorigenesis and ability to inhibit a broad spectrum of enzymes

have led researchers to regard these compounds as potential anticarcinogens and

cardio protective agents.3

The basic flavonoid structure is the flavan (1) nucleus, which consists of fifteen

carbon atoms arranged in three rings (C6-C3-C6), which are labelled A, B, and C

(Figure 1.1). The various classes of flavonoids differ in the level of oxidation and

pattern of substitution of the C ring, while individual compounds within a class differ

in the pattern of substitution of the A and B rings.4 Chalcones (1,3-diphenyl-2-propen-

1-one, 2) are the biogenetic precursor of flavonoids abundant in edible plants in

different chemical forms. Chalcone based compounds both natural and synthetic are


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very versatile as physiologically active compounds with a diverse array of biological

activities associated with them.

OA

B

C

1 O2

Figure 1.1 Structure of flavan and chalcone.

The therapeutic potential of the chalcone based compounds is supported by

their ease of preparation, potential of oral administration, safety and profound natural

abundance. The last decade witnessed the devotion of tremendous effort around the

world to elucidate the mechanisms of these chalconoids for their unparallel array of

biological activities. Consequently, a number of synthetic methods have also been

developed for the synthesis of this very important class of molecules including the

structural modification of the core chalcone moiety. Chemically, chalcones (2) are

unsaturated carbonyl system. Variation of the core chalcone moiety is mainly based on

used as traditional medicine for different ailments have been reported to contain a

substantial amount of these chalconoids.


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In addition to their numerous biological activities, chalcones find a pronounced

application in synthetic organic chemistry. Application of chalcones in the synthesis of

many heterocycles5 and as intermediate in the synthesis of many pharmaceuticals6 has

been well -hydroxychalcone is the main

synthon in the synthesis of different flavonoids (Scheme 1.1). Having such a varied

pharmacological activity and synthetic utility, chalcones have attracted chemists to

develop a large number of synthetic methodologies for their synthesis around the

world.

O

O

O

O

O

O

O

O

O

O

O

O

O

OHOH

Flavone Flavonone

Flavonol

Flavononol

Isoflavone Isoflavonone

OH

Scheme 1.1 Conversion -hydroxychalcone to different flavonoids.


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1.2 Biological activities of chalcones

A number of naturally occurring chalcones as well as their derivatives have

been isolated from various sources and identified with different biological activities. A

perusal of the existing literature reflects a number of activities associated with

different chalcones, some representative examples are given in this section.

1.2.1 Anticancer activity

Among the currently identified antitumor agents, chalcones represent an

important class of molecules. Deregulation of apoptosis or programmed cell death, in

multicellular organisms is a major contributor to the survival of tumour cells. The

process of apoptosis can be divided into two parts, sensors and effectors. The sensors

(extrinsic pathway) are responsible for monitoring the extracellular and intracellular

environment for conditions that influence whether a cell should live or die. These

signals regulate the second class of components (intrinsic pathway or mitochondrial

apoptosis pathway), which function to induce apoptotic death. Chalcones have been

found to act through the intrinsic as well as extrinsic apoptosis pathway to prevent

tumour progression.7 Traditions from different geographical regions of the world and

different time periods have documented the extensive use of liquorice (

) for the cure of different human ailments including as an anti-ulcer agent.8

Modern studies have identified different chalcones and flavonoids as the active

ingredients for their activity. Chalcones like isoliquiretigenin (3), licochalcone A (4)

and licochalcone E (5) have been isolated from liquorice and reported to be effective

against a series of human cancer cell lines.9


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O

OHHO OH

Isoliquiretigenin (3)

O

HO MeO

OH

Licochalcone A (4)

O

HO

OMe

OH

Licochalcone E (5)

O

OMeMeO

Flavokawain A (6)

OH

OMe

Xiaolin et al.10 isolated Flavokawain A (6) from Kava ( )

extract, which was found to be a suppressor of bladder tumour growth. In addition to

these natural chalcones, a number of chalcones have been synthesised and reported to

show anticancer activities.

1.2.2 Anti-inflammatory activity

Inflammation is characterized by activated immune cells in which there is a

vicious cycle of tissue destruction and repair due to either irremovable injurious

stimuli or a dysfunction in any component of the normal inflammatory response.11 The

vicitis,

gastritis, and hepatitis, for example, reflect inflammation of the bronchus, colon,

cervix, stomach, and liver, respectively. Many diseases are preceded by inflammation


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and it is already proven that inflammation is a major risk factor for type 2 diabetes,

atherosclerosis, cancer, and other chronic diseases.12 Several naturally occurring

chalcones have been reported to show anti-inflammatory properties. The inhibition of

prostaglandin E2 (PGE2) and nitric oxide (NO) production has been proposed as a

potential therapy for different inflammatory disorders.13

4-Hydroxycorodoin (7), which is reported to occur in

is found to possess anti-inflammatory effect through reduced activation

of the nuclear factor- B (NF- B) p65 and activator protein-1 (AP-1) pathways.14

O

O OH OH

4-Hydroxycorodoin (7)

O

MeO OMe

Flavokawain B (8)

OH

O

HO

OH

OHOH

OH

OH

Urundeuvine A (9)

O

HO

O

HO

OH

OHOH

HOOH

OH

Urundeuvine C (10)

H

H

O

A potent anti-inflammatory compound flavokawain B (8) was isolated from

, it significantly inhibited production of NO, and PGE2 in


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lipopolysaccharide (LPS) -induced RAW 264.7 cells.15 Two dimeric chalcones 9 and

10 were isolated from the stem bark of and were identified

with potent anti-inflammatory activity.16

1.2.3 Antioxidant activity

Free radicals are being formed during normal cellular metabolism and they are

known to contribute to healthy functions in human health and development when they

are not excessive. A mechanism for balancing the formation of free radicals and their

detoxification is essential for normal cellular function. When such a balance is

disrupted as a result of excessive generation of damaging species or low levels of

antioxidants, a cell enters into a state of oxidative stress and is damaged. If the damage

persists, the cell will enter a state of genetic instability that can lead to chronic diseases

including cancer.17

Many chalcones have been isolated from natural sources with impressive

antioxidant properties. Karanjapin (11) was isolated from the root bark of

and found to possess significant antioxidant activity.18 Paratocarpin B (12),

isolated from 19 and butein (13) isolated from was

also identified with antioxidant activity.20

OOH

MeO O

O

OMe

HO

karanjapin (11)

O

O

OH

OH

paratocarpin B (12)


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Xanthohumol (14) a prenyl chalcone present in hops and beer21 and 15, a

prenylated chalcone--glycoside22 isolated from displays

antioxidant activity.

O

OHHO OH

OH

butein (13)

HO

O

OH

OMe

Xanthohumol (14)

OH

O

O OH

15

OH

OHO

HO OH

OH

1.2.4 Antimicrobial activity

The increasing incidence of infection caused by the rapid development of

bacterial resistance to most of the known antibiotics is a serious health problem.23 The

increasing number of multi drug resistant microbes stimulates research efforts for

finding effective nature derived therapeutics.

Salem et al.24 reported the isolation and leishmanicidal activity of chalcones 16

and 17 from methanolic extract of . Prenylated

dihydrochalcones 18 and 19 were isolated from with antimalarial


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activity.25 Panduratin A (20) and hydroxypanduratin A (21) were isolated from

and reported to posses anti HIV26 and anti dangue27 activity.

Isobavachalcone (22) isolated from by ElSohly et al.28 was

identified with activities against AIDS-related opportunistic fungal pathogens

and .

O

CH3OMeHO

H3COH

R

16 R=H17 R=OH

HO OH

OH O

OH

18

HO OH

OH O

OH

19

O HH

OHRO

OH

20 R=CH321 R= H

O

HO OH OH

Isobavachalcone (22)


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1.2.5 Miscellaneous activities

In addition to the above-mentioned ones, there are many other activities

associated with chalconoid compounds. Hydroxy safflor yellow A (23),29 isobutrin

(24)30 and silymarin (25)31 are some hepatoprotective chalconoids/flavonoids isolated

OO

OHOH

OH

O

OHO

OHHO

HOHO

HO

HO

Hydroxysafflor yellow A (23)

OH

OH

OOH

OH

OO

OHHO

Isobutrin (24)

O

O

OH

OH

OHHO

OH

HO

O

O

O

OH

HO

OOH

OHO

OH

Silymarin (25)

O

H3CO OH OH

4-Hydroxyderricin (26)

O

HO OH

Xanthoangelol (27)

OH


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from natural sources. Enoki et al.32 identified 4-hydroxyderricin (26) and

xanthoangelol (27) from that showed strong insulin like activities in

controlling diabetes mellitus. 4-Hydroxyderricin (26) is reported to possess

antihypertensive activities also in rats.33

1.3 Synthesis of Chalcones

In 1880-81 L. Claisen34 and J. G. Schmidt35 published the reports of their

individual research of base catalyzed condensation between an aldehyde and a ketone,

which appear to be the first published report of chalcone preparation. The succeeding

century witnessed an ever-increasing interest of chemists and biologists towards the

synthesis as well as bioactivity studies of these chalconoids resulting numerous

research publications published and patents filed in different countries. Different

variations of Claisen-Schmidt condensation (CSC) using different catalysts or reaction

conditions have been developed. Amidst these numerous methodologies the classical

aqueous base catalysed version of CSC still stands as the most popular method of

chalcone synthesis.36

1.3.1 CSC via Enolate formation

In aldol condensation an enol or an enolate ion reacts with a carbonyl

- -hydroxyketone, followed by a

dehydration to give a conjugated enone. Basically, the CSC is a crossed aldol

-hydrogen and an aldehyde with no

-hydrogen. The base catalysed CSC proceeds via the formation of an enolate of the


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ketone which attacks the aldehydic carbon to form the adduct (A). Finally, elimination

of a water molecule gives the product chalcone (Scheme 1.2). Different inorganic and

organic bases have been employed for catalysing CSC under homogeneous and

heterogeneous reaction conditions. Among them hydroxides of alkali and alkaline

earth metals like NaOH, KOH, Ba(OH)2, LiOH, etc. are prominent.

O O

OH-

H

O

+

O

H

OH

O

-H2O

A

OH-

Scheme 1.2 Mechanism of base catalysed Claisen-Schmidt condensation.

1.3.1.1 NaOH

NaOH is one of the most used bases for the synthesis of chalcones. In these

methods equimolar amounts of the ketone and the aldehyde in ethanol is stirred with 2

to 3 equivalents of the base either in aqueous or non-aqueous conditions. For a

representative example, Cabrera et al.37 synthesized a number of substituted chalcones

employing NaOH (3.0 equiv) as catalyst in anhydrous ethanol (Scheme 1.3). After

completion, the reaction mixture is neutralised with dil. HCl and most of the products

were recrystallised from methanol.


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In their studies for the development of relatively small molecules as

antimicrobial agents, Sivakumar et al.38 synthesised a series of chalcones with

different substituents on the aryl rings using NaOH in methanol at room temperature in

3 h of reaction time with more than 80% product yields.

OO O

+i) aq.NaOH, EtOH, rt, overnightR' R R' R1'

2'3'

4'

5'6' 6

5

43

21ii) 10% HCl

R' = H R = H, 4-Cl, 2-Br, 4-Br, 4-OCH3, 4-SCH3, 4-NHCOCH3

R' = 2'-OH R = 4-NO2, 2-NO2, 4-Cl, 4-Br, etc.

Scheme 1.3 Synthesis of chalcones using NaOH.

1.3.1.2 KOH

KOH is another Gr. I base widely used as catalyst in CSC to synthesize

chalcones. Different reports are there39 for the synthesis of substituted chalcones using

aq. KOH as catalyst (Scheme 1.4).

OO O

+i) 50% KOH, EtOH,12 hR' R R' R1'

2'3'

4'

5'6' 6

5

43

21ii) 2M HCl, pH = 3-4

R' = H R = H = H = 4-OMe = H = 3,4-O-CH2-O- = H = 3,4,5-OMe = 3-OMe, 4-OH = 3,4,5-OMe, etc.

Scheme 1.4 Synthesis of chalcones using KOH.


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In addition to chalcones, this method was used to prepare some heterocyclic

chalcone analogues40 (Scheme 1.5).

N

O

N

O O

+i) 50% KOH, EtOH,12 hii) 2M HCl, pH = 3-4

78%

OO

+i) 50% KOH, EtOH,12 hii) 2M HCl, pH = 3-4

78%

NH

H

ONH

MeO MeO

Scheme 1.5 Synthesis of heterocyclic chalcone analogues.

1.3.1.3 LiOH.H2O

LiOH.H2O was found to be a highly efficient dual activation catalyst for

Claisen-Schmidt condensation of various aryl methyl ketones with aryl/heteroaryl

aldehydes providing an easy synthesis of 1,3-diaryl-2-propen-1-ones under mild

conditions. Quantitative yields of substituted chalcones were obtained when equimolar

mixture of the ketone and aldehyde was stirred in ethanol at room temperature in

presence of 10 mol% LiOH.H2O in 1-240 min41 (Scheme 1.6). The reactions were

found to be chemoselective with carbonyl substrates bearing halogen atom and nitro

group without any competitive aromatic nucleophilic substitution. The resultant

chalcones did not undergo Michael addition with the ketone enolate.


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Ar1COCH3 + Ar2CHO Ar1

O

Ar2i) LiOH.H2O, 1-240 minii) 2% HCl

Ar2 = Ph = 4-OMePh = 4-NMe2Ph = 4-ClPh, etc.

Ar1 = Ph = Ph = Ph = Ph (34 examples).

Scheme 1.6 LiOH.H2O catalysed CSC.

Other bases like Ba(OH)2.8H2O,42 Mg-Al-OtBu hydrotalcite43 was also utilized

for the synthesis of chalcones under homogeneous conditions. Quantitative yields can

be obtained using these methods in substrates where the aromatic ring contains no

hydroxyl group except in the ortho position. With the presence of hydroxyl group on

the phenyl ring, the electrophilicity of the benzaldehyde carbonyl carbon reduces due

to the delocalization of the phenoxide anion formed. This results in decreased product

formation44 (Scheme 1.7).

HO

H

O

-O

H

O

O

H

O-BHB-

Scheme 1.7 Delocalisation of the phenoxide anion formed in presence of base.


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However hydroxy groups present in the ortho position are not available for

phenoxide formation owing to intramolecular hydrogen bonding with the carbonyl

oxygen (Scheme 1.8).

R

O

R = H, CH3

OH

R

OH

O

Scheme 1.8 Formation of intramolecular hydrogen bond.

On the other hand the basic salts of hydroxy substituted aromatic carbonyls

precipitate out in the highly alkaline environment.37,39(b) Thus it becomes necessary to

use protecting groups in the preparation of hydroxychalcones under basic

conditions.39(b) The hydroxyl groups are protected by converting it to their THP,40

MOM45 or benzyl ether37 which are stable in basic medium. With hydroxy protected

aromatic carbonyls, Ba(OH)2.8H2O is the catalyst of choice and anhydrous alcohols

are used as solvent in general, to keep the protecting groups intact.

In addition to these inorganic bases there are also reports of using organic

bases for the synthesis of chalcones. Trivedi et al46 used piperidine as catalyst in

CHCl3 at 80 °C for the synthesis of a series of novel coumarinyl chalcone derivatives

for their studies of antiviral activity (Scheme 1.9).


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OR4

R3

R2

R1 OH

O

O

H

O

OR4

R3

R2

R1 OH

O

O

RR

R = H = 4-OH = 4-OCH3 = 4-OC6H5 = 2-NO2 = 3-NO2 = 4-N(CH3), 4-OH = 4-O(CH3), 4-OH = 3,4-di-OCH3

R1 = CH3, R2 = H, R3 = H, R4 = CH(CH3)2R1 = H, R2 = Cl, R3 = CH3, R4 = H

+ piperidine, CHCl380 °C

Scheme 1.9 Synthesis of coumarinyl chalcones.

1.3.2 Heterogeneous & Ecofriendly methods

One of the major drawbacks of these alkali base catalysed methods for

chalcone synthesis is that 2.5 to 3.0 equivalents of catalyst, as well as same equivalents

of mineral acid for its neutralisation is required in the work up of these methods. Like

other homogeneously catalysed methods of organic syntheses47 these are also

criticised for their highly detrimental environmental impact as a large volume of

aqueous waste is generated in the catalyst quench and product separation stage.

Responding to this environmental cry, methods are developed for the synthesis of

chalcones using these alkali bases under environmentally benign reaction conditions.

Rateb et al. reported the synthesis of chalcones under solvent free conditions in

quantitative yields by grinding the methyl ketones and aldehydes with solid NaOH

(1.4 equiv) in 5-10 minutes of reaction time.48 The solid catalyst was removed by


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simple cold aqueous washing and the products were purified by recrystallisation

(Scheme 1.10).

NaOH, Grinding3 -15 min

RCOCH3 R'CHO+ RCOCH=CHR'

R = 2-furyl R' = 2-furyl = 2-thienyl = C6H5 = 4-CH3C6H4 = 4-FC6H4 = 4-ClC6H4

R = 2-naphthyl R' = C6H5 = 4-CH3C6H4 = 4-FC6H4

= 4-CH3C6H4 = 4-ClC6H4 = 2-thienyl

Scheme 1.10 Synthesis of chalcones using NaOH under solvent free condition.

Sarda et al. used NaOH (20 mol%) over neutral Al2O3 at 60 °C to synthesise ten

different chalcones under solvent free condition.49

Solid K2CO3 (10 mol%) in PEG-400 was used to synthesise chalcones. The

reaction mixture was stirred at 90-120 °C for 1.5-2.5 h and the product was

recrystallised after removal of the catalyst by cold aqueous washing (Scheme 1.11).

O

H

O O

RR

R = H, 4-CH3, 4-OCH3, 4-Cl, 4-NO2

+K2CO3, PEG-400

90-120 °C, 1.5-2.5 h

Scheme 1.11 Synthesis of chalcones using K2CO3, PEG-400.


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It was found that longer reaction times were needed in the reactions for the products

with high melting points. Higher yields could be obtained in the condensation of

ketones and aldehydes with electron-withdrawing groups in the aromatic ring, such as

-Cl, -Br, and -NO2, than with electron-donating groups, such as -CH3 and -OCH3.50

Two basic activated carbons Na- and Cs-Norit were used to catalyze the CSC

under sonochemical irradiation by C. J. Duran-Valle and his co-workers.51 A new type

of catalyst were prepared by grafting amino groups on sodium and cesium exchanged

X zeolite.52 This new catalyst was successfully applied for the synthesis of chalcones

in solvent free conditions under ultrasonic irradiation.

Solhy et al. synthesised a reusable hydroxyapatite [Ca10(PO4)6(OH)2] and used

with water as co-catalyst for the synthesis of fifteen substituted chalcones53 (Scheme

1.12). They studied the impact of water on the catalyst reactivity and high activation of

the same was observed in its presence. To investigate the origin of this activation,

different organic solvents of similar or higher microwave absorbance as/to water were

also tested, and it was confirmed that water is acting as co catalyst when combined

with hydroxyapatite, making the process highly efficient.

O

H

O O

RR+Hydroxyapetite

H2O, MWR' R'

R' = H R = H = 4-Cl = 3-NO2 = 4-OMe = 4-OH

R' = 4-NO2 R = H = 4-Cl = 3-NO2 = 4-OMe = 4-OH

R' = OMe R = H = 4-Cl = 3-NO2 = 4-OMe = 4-OH

Scheme 1.12 Synthesis of chalcones using reusable hydroxyapetite.


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1.3.3 CSC via Enol mode

The acid catalysed version of CSC proceeds through the formation of an enol.

The enol attacks the protonated aldehyde to give the addition product. This is followed

by elimination of a water molecule to give the product chalcone (Scheme 1.13). The

advantage of the CSC via enol mode over the enolate mode is that, it can be directly

applied for the synthesis of hydroxychalcones without prior protection of the hydroxy

group.43

O

H+

OH OH+

+

O

H+

O

H

OH O

-H2O

Scheme 1.13 Mechanism of CSC via enol mode.

CSC via enol mode is advantageous for the preparation of chalcones with base

sensitive groups. Though different mineral acids were used to catalyze this reaction,44

a perusal of the recent literature showed a sharp decline in their use. It is because of

the requirement of harsh reaction conditions,49 formations of unwanted side products36

and associated waste disposal problem54 in realizing most of these methods.

Sipos et al55 used HCl gas saturated in absolute ethanol for the condensation of 4-

hydroxy benzaldehyde with different substituted acetophenones (Scheme 1.14).


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O

H

O O

+ HCl, rtabs. EtOH

R' R'

R' = 3-NO2 = 2-OH, 4-NO2 = 3-OH, 4-NO2 = 3-OH, 6-NO2

OH OH

Scheme 1.14 Claisen-Schmidt condensation using HCl in absolute ethanol.

Eun-Jin et al. used catalytic amount of H2SO4 in methanol for the synthesis of a

variety of substituted chalcones. The method was extended for the synthesis of some

sulfonamide--chalcones and sulfonate--chalcones for their biological studies56

(Scheme 1.15).

O

H

O O

+R1 R1R2 R2H2SO4MeOH

R1 = H R2 = H = OH = OH = NH2 = OH

O

HN OH

SO

OR

R = H, CH3, F, NH2

O

O OHSO

OR

R = H, CH3, F, NH2

Scheme 1.15 Synthesis of substituted chalcones using H2SO4.


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In situ generated HCl was used for carrying out this reaction by Petrov et al. by

using SOCl2/EtOH system. Four hydroxy substituted chalcones were also prepared in

addition to other substituted chalcones44 (Scheme 1.16).

O

H

O O

RR+ abs. EtOH, rtR' R'

R' = H R = H = 2-OMe = 3-OMe = 4-OMe = 3-OH = 4-OH = 3-Cl = 4-Cl

SOCl2

R' = 4-OCH3 R = H = 4-OMe = 4-ClR' = 4-Cl R = H = 4-OMe = 4-OH = 4-ClR' = 4-OH R = H

Scheme 1.16 SOCl2/EtOH catalysed synthesis of chalcones.

A novel solid sulfonic acid, bamboo char sulfonic acid was applied to catalyse

the Claisen-Schmidt condensation of substituted benzaldehydes with acetophenones

under solvent-free condition to synthesize chalcones. The solid acid catalyst was

prepared from bamboo sawdust via sulphuric acid charring and sulfonation. Moderate

to good yields of chalcones were obtained in 24 h reaction time.57

Lewis acids provide environmentally benign alternative routes for many

hitherto mineral acid catalysed organic transformations.58 Various Lewis acids have

been successfully applied for the synthesis of chalcones also.

Kumar et al.59 used ZrCl4 both in solvent free and in solvent (dry DCM)

reaction conditions to catalyze the CSC (Scheme 1.17). In this fast and clean reaction,


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substituted chalcones were synthesised in moderate to good yields (70-93%) using 20

mol% of the catalyst. No solvent was used when one or both the substrates are liquid

and anhydrous CH2Cl2 was used when both the substrates are solid. Use of 60-80

mol% of ZrCl4 resulted in the formation of 1,4-conjugate addition product in addition

to the chalcone.

R1 = Ph R2 = Ph = Ph = 4-OMePh = 4-OMePh = Ph = 4-OMePh = 4-OMePh = 2,6-ClPh = Ph = 2-C4H3O = 4-OMePh = 2-NO2Ph = Ph

R1 R2

O O+ neat/ dry DCM, rt

ZrCl4 (20 mol%)

O

R1 R2H

R1 = 3-NO2Ph R2 = 2-OHPh = 4-NO2Ph = Ph = Ph = 4-OHPh = 4-OMePh = 4-OHPh = Naphthyl = Ph = Naphthyl = 4-OMePh = Ph = 4-OC2H4NC4H8Ph

Scheme 1.17 Synthesis of chalcones using ZrCl4.

Narender et al. used BF3-Et2O for the synthesis of chalcones in dry dioxane in

a very short reaction time with very good product yield.36 They applied this method for

the synthesis of chalcones with a varied substituents (Scheme 1.18).

R' = CH3 R = 3,4-OMePh = Ph = Ph = 4-OHPh = 4-OHPh = 4-OAcPh = 4-OHPh = 4-AcNHPh = 4-OMePh = 3-OHPh = 2-NO2Ph

R' R R'

O

RO O

+BF3-Et2O,

dry Dioxane, rtH

R' = 4-NO2Ph R = 4-OMePh = 2,4-OMePh = 2-NO2Ph = 4-OHPh = 3,4-OMePh = 2,4-ClPh = 3,4-OMePh = 2,4-OMePh = 3,4-FPh = 3-OHPh = 4-OMePh

Scheme 1.18. Chalcone synthesis using BF3-Et2O.


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In addition to its applicability in synthesising hydroxychalcones, another

feature of this method is that it can be applied for substrates with base sensitive groups

like esters and amides (Figure 1.2).

O

O

O

OH

O

HN

O

OMe

O

OHO

O

OMeOC16H33

OMe

Figure 1.2 Synthesised chalcones with base sensitive substrates using BF3-Et2O.

K. V. Sashidhara and his co-workers used readily available, mild and

inexpensive Lewis acid molecular iodine in dry dioxane for the synthesis of

substituted chalcones60 (Scheme 1.19).

OO O

+ I2 (5 mol%)R' R R' R1'2'

3'4'

5'6' 6

5

43

2140°C, (15-20 min)

Dioxane

R' = H R = 4-OEt = 4-Me = 4-OEt = 4-OMe = 4-OEt = 4-Cl = 4-OEt = H = 2-OMe

R' = 4-Me R = 2-OMe = 4-OMe = 2-OMe = 4-Cl = 2-OMe = 4-Me = 3-OEt, 4-OH = 4-OMe = 3-OEt, 4-OH = 4-Cl = 3-OEt, 4-OH

Scheme 1.19 Molecular iodine catalysed CSC.


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Wang et al.61 used molecular iodine for catalyzing the CSC between different

ketones and aldehydes under solvent free and grinding conditions. In this very simple

reaction, chalcones were synthesised in 83-95% yield in 5-10 minutes of reaction time

(Scheme 1.20).

R' = H R = 4-CH3 = H = 3-NO2 = H = 4-N(CH3)2 = H = 2-OH = 4-CH3 = H

OO O

+ I2 (10 mol%)R' R R' R1'2'

3'4'

5'6' 6

5

43

21Grinding, rt

5-10 min

R' = 4-NO2 R = H = 2,4-OMe = 3-NO2 = 4-Br = 4-OH = 3-OMe = 2-NO2 = 2,4-OH = 4-N(CH3)2

Scheme 1.20 I2 catalysed synthesis of chalcones by grinding.

In a recent report, Siddiqui et al.62 synthesized a series of chromonyl chalcones

employing Zn-(L-proline)2 as a recyclable Lewis acid catalyst in water. The catalyst

was reused for five consecutive cycles without any loss of activity (Scheme 1.21).

O

O OR

Q

O+

H2O, Zn(L-proline)2reflux, 15-30 min

O

OR

Q

O

N

N

HO

HO

OQ = etc., R = H, CH3, Cl

Scheme 1.21 Synthesis of chromonyl chalcones using Zn-(L-proline)2.


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1.3.4 Ionic liquids in catalyzing CSC

In recent years, ionic liquids have been emerged as a powerful alternative to

conventional organic solvents due to their particular properties, such as undetectable

vapour pressure, wide liquid range, as well as ease of recovery and reuse, making them

a greener alternative to volatile organic solvents.63 Different research groups have

investigated the applicability of these ionic liquids in the synthesis of chalcones.

Dong et al.64 used some sulfonic acid functionalised task specific ionic liquids

(TSIL) for catalysing the CSC to synthesise chalcones. Seven TSILs were studied and

found to effectively catalyse the CSC (Scheme 1.22).

R1 R2

O O+

TSIL

O

R1 R2H140°C

R1 = Ph R2 = Ph R1 = Ph R2 = 3-ClPh = Ph = 4-OMePh = 4-OMePh = Ph = Ph = 3-OMePh = 4-OMePh = 4-OMePh = Ph = 2-OMePh = 4-OMePh = 4-ClPh = Ph = 4-ClPh = 4-NO2Ph = 4-OMePh

TSILs: [TMPSA][HSO4]

[TEPSA][HSO4],

[TBPSA][HSO4], etc.

Scheme 1.22 Sufonic acid functionalised TSIL catalysed synthesis of chalcones.

Shen et al.54 reported an efficient and environmentally friendly solvent-free

method for the synthesis of chalcone using Brønsted acidic ionic liquids as dual

catalyst and solvent. Ionic liquids like [(HSO3)BBIM]BF4 catalysed the reaction most

efficiently at 140 °C and the catalyst was reused for three cycles without any

appreciable loss of activity.


|27

Four readily available and economic TSILs viz. [TEBSA][HSO4], [TEBSA][NO3],

[TEBSA][CF3COO] and [TEBSA][pTSO] have been used as recyclable catalysts for

the CSC of benzaldehydes and acetophenones to synthesize chalcones by Qian et al.65

A clean and efficient method for the synthesis of chalcones using reusable

phosphonium ionic liquid catalyst [PhosILCl] was developed by Pawar et al.

Chalcones were synthesised in high yields using this ecofriendly method in 2.5 to 3.5

h reaction time.66

1.3.5 Miscellaneous Methods of Chalcone synthesis

Apart from Claisen-Schmidt condensation, some other routes were also

developed for the synthesis of chalcones. In particular Suzuki reaction using phenyl

boronic acids, Julia-Kocienski olefination and Wittig reaction were studied for the

synthesis of chalcones.

1.3.5.1 Via Suzuki reaction

Palladium-catalyzed Suzuki cross coupling of haloarenes with arylboronic acid is

among the most powerful C-C bond-formation reactions available to synthetic organic

chemists.67 Like in many other organic syntheses, palladium catalysed cross coupling

reactions find their application in chalcone synthesis also. Eddarir et al.68 developed a

method for the synthesis of chalcones based on the Suzuki reaction either between

cinnamoyl chlorides and phenylboronic acids or between benzoyl chlorides and

phenylvinylboronic acids (Scheme 1.23). The reaction is not affected by substituents

located either on the acyl chloride or on the boronic acid.


|28

Cl

OR''R'

R

BOH

HO+

Cs2CO3, toluene

O

R

R'R''

R R' R''

H H HH CF3 HH H CF3H NO2 HOMe H HOMe OMe H

(PPh3)4Pd

Scheme 1.23 Chalcone synthesis via Suzuki reaction.

Mohammad et al.69 developed a method for direct cross-coupling reaction of

benzoyl chlorides and potassium styryltrifluoroborates to the corresp -

unsaturated aromatic ketones in the presence of PdCl2(dtbpf) catalyst under microwave

irradiation. This method was used for the synthesis of chalcones with a variety of

substituents (Scheme 1.24).

O

R1 R2BF3K

Cl

O

R1 R2PdCl2(dtbpf)

K2CO3, 1,4-DioxaneMW, 140°C, 30 min

+

8 examples.

Scheme 1.24 Pd (II) catalysed cross-coupling reaction in the synthesis of chalcones.


|29

1.3.5.2 Julia-Kocienski olefination

Kumar et al. developed 2-(Benzo[]thiazol-2-ylsulfonyl)-1-phenylethanones as

a new reagent for the synthesis of chalcones via Julia-Kocienski olefination with

aldehydes in presence of a base in good to excellent yields70 (Scheme 1.25).

OS

O O

S

N+ R1CHO

DBU

Ph

O

R1

THF, 13-21h

S

NSH

OBr

i) K2CO3, acetone, 30 min, rtii) mCPBA, DCM, rt, 1.5h

R1 = Ph = 4-OMePh = 4-OCH2CH2ClPh = 4-FPh = 4-ClPh, etc.

Scheme 1.25 Julia-Kocienski olefination in the synthesis of chalcones.

1.3.5.3 Chalcone synthesis by Fries Rearrangement

Jeon et al.71 prepared chalcones using aryl cinnamates by Fries rearrangements

catalysed by TiCl4 in moderate to good yields (Scheme 1.26).

O

OTiCl4

130°C

O OH

R1 = H, 3-Me, 4-Me, 3-OMe, 4-OMe, 3-OH, 2-Me, 2-OMe

37-70%

R1

R1

Scheme 1.26 TiCl4 mediated chalcone synthesis via Fries rearrangement.


|30

1.3.5.4 Via Wittig reaction

The Wittig reaction is a powerful method for the regio- and stereo controlled

construction of carbon-carbon double bonds. Wittig reaction was also used for

synthesising chalcones.72,73 In these methods reaction of a stable ylide with aldehydes

is used for synthesising the desired chalcones (Scheme 1.27).73

CHO

COR2Ph3P COR2

water

R1 = H R2 = Ph = 4-NO2 = Ph, etc.

R1 R1

Scheme 1.27 Synthesis of chalcones using stable ylides.

1.4 Chalcones in organic synthesis

Chalcones find many applications in organic synthesis as intermediates.

Flavanones are important naturally occurring pharmacological compounds and are

valuable precursors for the synthesis of flavanoids. Preparation of flavanones (29) has

been carried out by intramolecular cyclis -hydroxychalcone (28) under

various conditions using acids, bases, thermolysis, electrolysis and photolysis.74

Different catalysts like acetic acid,37 piperidine,74 CH3COONa,75 H3PO4,76 PEG-40077

have been employed for this conversion (Scheme 1.28).


|31

O

OH

O

O

2928

Scheme 1.28 Conversion of 2 -hydroxychalcone to flavonone.

Flavones (30 -hydroxychalcones are refluxed in DMSO in

presence of I237 and it can be further transformed to flavonol (31) by treatment with

HOF.CH3CN78 (Scheme 1.29).

O

OH

O

OI2, DMSO

reflux

O

OHOF.CH3CN

1 minOH

30 3128

Scheme 1.29 Synthesis of flavones and flavonol from 2 -hydroxychalcone.

2,3-Dihydroflavanols (32) can be obtained from chalcones using NaOH-

H2O2,74 or diethylamine-H2O279 (Scheme 1.30).

O

OH

O

O

OH

28 32

Scheme 1.30 Synthesis of 2,3-dihydroflavanol.


|32

-Hydroxychalcones can be converted to their corresponding isoflavone (33)

and isoflavonone (34) by the action of thallium nitrate trihydrate followed by

-double bond80 (Scheme 1.31).

(i) Tl(NO3).3H2O, DCM:MeOH(ii) 1N HCl, MeOH, reflux

O

O

O

O

10% Pd-C, HCO2NH4acetone-methanol

OH

O 33

33

28

34

Scheme 1.31 Synthesis of isoflavone and isoflavonones.

1.5 Conclusion

With the presence of numerous secondary metabolites, plants have been a

source of medicinal products from time immemorial and many useful drugs were

developed from these plant sources. It is clear that plants will continue to be a major

source of new drug leads. Effective drug development will depend on

multidisciplinary collaboration embracing natural product lead discovery and

optimization through the application of total and diversity oriented synthesis.

Chalcone, the synthetic precursor of many plant derived secondary metabolites, is a


|33

privileged structure with varied biological and synthetic utilities. With the replacement

of homogeneously catalysed classical yield oriented methods of their synthesis with

environmentally benign methods and with advanced techniques of biological studies,

chalcone based research is gaining momentum. The impressive number of publications

coming out from different laboratories around the world in the preceding years clearly

indicates the possibility of the development of chalcone based drugs for various

human ailments coming to the market in the near future.

References

1. Rao, S. R.; Ravishankar, G. A. 2002, , 101-152.

2. Cowan, M. M. . 1999, , 564-582.

3. Skibola, C. F.; Smith, M. T. 2000, , 375-383.

4. Pietta, P. G. . 2000, , 1035-1042.

5. Powers, D. G.; Casebier, D. S.; Fokas, D.; Ryan, W. J.; Troth, J. R.; Coffen, D.

L. 1998, , 4085-4096.

6. Perozo-Rondon, E.; Martín-Aranda, R. M.; Casal, B.; Duran-Valle, C. J.; Lau,

W. N.; Zhang, X. F.; Yeung, K. L. 2006,, 183-187.

7. Liu, X.; Kim, C. N.; Yang, J.; Jemmerson, R.; Wang, X. 1996, , 147-

157.

8. Fiore, C.; Eisenhut, M.; Ragazzi, E.; Zanchin, G.; Decio, A.

. 2005, , 317-324.

9. a) Takahashi, T.; Takasuka, N.; ligo, M.; Baba, M.; Nishino, H.; Tsuda, H.;

Okuyama, T. . 2004, , 448-453; b) Xiao, X-Y.; Hao, M.; Yang,


|34

X-Y.; Ba, Q.; Li, M.; Ni, S-J.; Wang, L-S.; Du, X. . 2011, , 69-

75; c) Yoon, G.; Jung, Y. D.; Cheon, S. H. . 2005, , 694-

695.

10. Zi, X.; Simoneau, A. R. . 2005, , 3479-3486.

11. Westbrook, A. M.; Szakmary, A.; Schiest, R. H. . 2010, , 40-59.

12. Yadav, V. R.; Prasad, S.; Sung, B.; Agrawal, B. B. . 2011, ,

295-309.

13. Nowakowska, Z. . 2007, , 125-137.

14. Feldman, M.; Tanabe, S.; Epifano, F.; Genovese, S.; Curini, M.; Grenier, D.

. 2011, , 26-31.

15. Lin, C-T.; Kumar, K. J. S.; Tseng, Y-H.; Wang, Z-J.; Pan, M-Y.; Xiao, J-H.;

Chien, S-C.; Wang, S-Y. . 2009, , 6060-6065.

16. Viana, G. S. B.; Bandeira, M. A. M.; Matos, F. J. A. 2003, ,

189-195.

17. a) Spallolz, J. E. . 1994, , 45-64; b) Ugir, H. S.;

Bhattacharya, S. . 2007, , 1149-1154.

18. Ghosh, A.; Mandal, S.; Banerji, A.; Kar, M.; Banerji, J. .

2009, , 209-210.

19. Chin, Y-W.; Jung, H-A.; Liu, Y.; Su, B-N.; Castoro, J. A.; Keller, W. J.;

Pereira, M. A.; Kinghorn, A. D. . 2007, , 4691-4697.

20. Lee, E. H.; Song, D-G.; Lee, J. Y.; Pan, C-H.; Um, B. H.; Jung, S. H.

. 2008, , 1626-1630.

21. Miranda, C. L.; Stevens, J. F.; Ivanov, V.; McCall, M.; Frezi, B.; Deinzer, M.


|35

L.; Buhler, D. R. 2000, 3876-3884.

22. Cioffi, G.; Escobar, L. M.; Braca, A.; Tommasi, N. D. . 2003, ,

1061-1064.

23. Saleh, M.; Abbott, S.; Perron, V.; Lauzon, C.; Penney, C.; Zacharie, B.

. 2010, , 945-949.

24. Salem, M. M.; Werbovetz, K. A. . 2005, , 108-111.

25. Carroll, A. R.; Fechner, G. A.; Smith, J.; Guymer, G. P.; Quinn, R. J.

. 2008, , 1479-1480.

26. Cheenpracha, S.; Karalai, C.; Ponglimanont, C.; Subhdhirasakul, S.;

Tewtrakul, S. . 2006, , 1710-1714.

27. Kiat, T. S.; Pippen, R.; Yosof, R.; Ibrahim, H.; Khalid, N.; Rahman, N. A.

. 2006, , 3337-3340.

28. ElSohly, H. N.; Joshi, A. S.; Nimrod, A. C.; Walker, L. A.; Clark, A. M.

. 2001, , 87-89.

29. Zhang, Y.; Guo, J.; Dong, H.; Zhao, X.; Zhou, L.; Li, X.; Liu, J.; Niu, Y.

. 2011, , 438-444.

30. Gupta, S. R.; Ravindranath, B.; Seshadri, T. R. 1970, , 2231-

2235.

31. Dixit, N.; Baboota, S.; Kohli, K.; Ahmad, S.; Ali, J. . 2007,

, 172-179.

32. Enoki, T.; Ohnogi, H.; Nagamine, K.; Kudo, Y.; Sugiyama, K.; Tanabe, M.;

Kobayashi, E.; Sagawa, H.; Kato, I. . 2007, , 6013-

6017.


|36

33. Ogawa, H.; Ohno, M.; Baba, K. . 2005, , 19-

23.

34. Claisen, L.; Claparede, A. . 1881, , 349.

35. Schmidt, J. G. . 1880, , 2342.

36. Narender, T.; Reddy, K. P. . 2007, , 3177-3180.

37. Cabrera, M.; Simoens, M.; Falchi, G.; Lavaggi, M. L.; Piro, O. E.; Castellano,

E. E.; Vidal, A.; Azqueta, A.; Monge, A.; de Cerain, A. L.; Sagrera, G.;

Seoane, G.; Cerecettoa, H.; Gonzaleza, M. . 2007, ,

3356-3367.

38. Sivakumar, P. M.; Seenivasan, S. P.; Kumar, V.; Doble, M.

. 2007, , 1695-1700.

39. a) Lv, P-S.; Sun, J.; Luo, Y.; Yang, Y.; Zhu, H-L. .

2010, , 4657-4660; b) Chimenti, F.; Bizzarri, B.; Manna, F.; Bolasco, A.;

Secci, D.; Chimenti, P.; Granese, A.; Rivanera, D.; Lilli, D.; Scaltrito, M. M.;

Brenciagila, M. I. . 2005, , 603-607; c) Boumendjel,

A.; Boccard, J.; Carrupt, P-A.; Nicolle, E.; Blanc, M.; Geze, A.; Choisnard, L.;

Wouessidjewe, D.; Matera, L.; Dumontet, C. . 2008, , 2307-

2310; d) Bhat, B. A.; Dhar, K. L.; Puri, S. C.; Saxena, A. K.; Shanmugavel,

M.; Qazi, G. N. 2005, , 3177-3180.

40. Montes-Avila, J.; Diaz-Camacho, S. P.; Siacairos-Felix, J.; Delgado-Vargas,

F.; Rivero, I. A. . 2009, , 6780-6785.

41. Bhagat, S.; Sharma, R.; Sawant, D. M.; Sharma, L.; Chakraborti, A. K.

2006, , 20-24.


|37

42. Manna, F.; Chimenti, F.; Fioravanti, R.; Bolasco, A.; Secci, D.; Chimenti, P.;

Ferlini, C.; Scambia, G. . 2005, , 4632-4635.

43. Kantam, M. L.; Prakash, B. V.; Reddy, C. V. . 2005, , 1971-

1978.

44. Petrov, O.; Ivanova, Y.; Gernova, M. . 2008, , 315-316.

45. Khupse, R. S.; Erhardt, P. W. . 2007, , 1507-1509.

46. Trivedi, J. C.; Bariwal, J. B.; Upadhyay, K. D.; Naliapara, Y. T.; Joshi, S. K.;

Pannecouque, C. C.; Clercq, E. D.; Shah, A. K. . 2007, ,

8472-8474.

47. Clark, J. H. . 2002, , 791-797.

48. Rateb, N. M.; Zohdi, H. F. . 2009, , 2789-2794.

49. Sarda, S. R.; Jadhav, W. N.; Bhusare, S. R.; Wasmatkar, S. K.; Dake, S. A.;

Pawar, R. P. . 2009, , 265-269.

50. Cao, Y-Q.; Dai, Z.; Zhang, R.; Chen, B-H. . 2005, , 1045-

1049.

51. Duran-Valle, C. J.; Fonseca, I. M.; Calvino-Casilda, V.; Picallo, M.; Lopez-

Peinado, A. J.; Martin-Aranda, R. M. 2005, , 500-506.

52. Perozo-Rondon, E.; Martín-Aranda, R. M.; Casal, B.; Duran-Valle, C. J.; Lau,

W. N.; Zhang, X. F.; Yeung, K. L. 2006,, 183-187.

53. Solhy, A.; Tahir, R.; Sebti, S.; Skouta, R.; Bousmina, M.; Zahouily, M.;

Larzek, M. 2010, , 189-193.

54. Shen, J.; Wang, H.; Liu, H.; Sun, Y.; Liu, Z. 2008,

, 24-28 and references cited therein.


|38

55. Sipos, G. Y.; Sirokmán, F. 1964, , 489.

56. Kim, E-J.; Ryu, H. W.; Curtis-Long, M. J.; Han, J.; Kim, J. Y.; Cho, J. K.;

Kang, D.; Park, K. H. . 2010, , 4237-4239.

57. Xu, Q.; Yang, Z.; Yin, D.; Zhang, F. . 2008, , 1579-1582.

58. Corma, A.; Gercía, A. . 2003, , 4307-4366.

59. Kumar, A.; Atanksha. 2007, , 212-216.

60. Sashidhara, K. V.; Rosaiah, J. N.; Kumar, A. . 2009, , 2288-

2296.

61. Wang, H.; Zeng, J. . 2009, , 1209-1212.

62. Siddiqui, Z. N.; Musthafa, T. N. M. . 2011, , 4008-4013.

63. Hallett, J. P.; Welton, T. . 2011, , 3508-3576; Dong, F.; Jian, C.;

Zhenghao, F.; Kai, G.; Zuliang, L. . 2008, , 1924-1927.

64. Dong, F.; Jian, C.; Zhenghao, F.; Kai, G.; Zuliang, L. . 2008, ,

1924-1927.

65. Qian, H.; Liu, D. . 2011, , 1146-1149.

66. Sarda, S. R.; Jadhav, W. N.; Tekale, S. U.; Jadhav, G. V.; Patil, B. R.; Gajanan

S. Suryawanshi, G. S.; Pawar, R. P. . 2009, , 481-484.

67. Chang, C-P.; Huang, Y-L.; Hong, F-E. 2005, , 3835-3839.

68. Eddarir, S.; Cotelle, N.; Bakkoura, Y.; Rolandoa, C. . 2003,

, 5359-5363.

69. Al-Masum, M.; Ng, E.; Wai, M. C. . 2011, , 1008-1010.

70. Kumar, A.; Sharma, S.; Tripathi, V. D.; Srivastava, S. 2010, ,

9445-9449.


|39

71. Jeon, J-H.; Yang, D-K.; Jun, J-G. 2011, , 65-70.

72. Xu, C.; Chen, G.; Huang, X. . 1995, , 559-561.

73. Dambacher, J.; Zhao, W.; El-Batta, A.; Anness, R.; Jiang, C.; Bergdahl, M.

. 2005, , 4473-4477.

74. Tanka, K.; Sugino, T. . 2001,, 133-134.

75. Chimenti, F.; Fioravanti, R.; Bolasco, A.; Chimenti, P.; Secci, D.; Rossi, F.;

L. . 2010, , 1273-1279.

76. Chen, D-U.; Kuo, P-Y.; Yang, D-Y. . 2005, , 2665-

2668.

77. Kumar, D.; Patel, G.; Mishra, B. G.; Varma, R. S. . 2008, ,

6974-6976.

78. Golan, E.; Hagooly, A.; Rozen, S. . 2004, , 3397-3399.

79. Saxena, S.; Makrandi, J. K.; Grover, S. K. 1985, 110-111.

80. Khupse, R. S.; Erhardt, P. W. . 2008, , 275-277.

Documents

Chalcones: Chemistry & Bioactivity - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/32781/8/08_chapter 1.pdf · This introductory chapter reviews the recent advances in the synthesis,