1

Chapter-1

Introduction

1.1. Organofluorine Chemistry:

Organofluorine chemistry describes the chemistry of

organofluorine compounds, organic compounds that contain the

carbon-fluorine bond. Organofluorine compounds find diverse

applications ranging from oil and water-repellents to pharmaceuticals,

refrigerants and reagents in catalysis. Fluorine chemistry is a large

field. It is represented by its own section of the American Chemical

Society and several specialized journals. Methods for the synthesis of

fluorine-containing molecules of potential biological significance have

expanded in their scope and effectiveness since the early 1960's and

fluorinated analogs of virtually any molecule are now available.1-6

The chemistry of organofluorine molecules is unique because of

the properties of fluorine. The fluorine atom has a van der Waals

radius of 1.47 Å, a size more comparable to that of oxygen (1.52 Å)

than to that of the other halogens (chlorine=1.8 Å, bromine= 1.95 Å,

iodine= 2.15 Å). Fluorine was once thought to be similar in size to

hydrogen (1.2 Å), but it is now considered isosterically similar to a

hydroxyl group.7 Compared to other halogens, fluorine is extremely

electronegative having an electronegativity of 4.0 as compared to an

electronegativity of 3.0 for chlorine and 2.8 for bromine.8 This high

electronegativity confers a strong polarity to the carbon-fluorine bond.

2

The carbon-fluorine bond also has one of the largest bond

energies in nature. For monofluorinated alkanes, the carbon-fluorine

bond is 25 kcal/mol stronger than that of the carbon-chlorine

bond.9,10 The strength of the carbon-fluorine bond contributes to the

stability of fluorinated molecules. In fact, many fluorinated

agrochemicals capable of enzyme inhibition are fluorine stabilized

analogues of the natural enzyme substrate. A dramatic illustration of

the strength and stability of the C-F bond is monofluoroacetate, which

can withstand boiling with 100% sulfuric acid without any

defluorination.11For many man-made fluorinated organics, such as

the perfluorinated organics, stability is also probably related to the

fact that their molecular structure is unlike anything currently known

in nature.

Fluorine is the most abundant halogen in the earth’s crust and

ranks 13th in abundance among all elements.12This may explain

instances of natural organofluorine production. The best known of

these natural organofluorine compounds is monofluoroacetate (MFA).

MFA is produced by plants in the genus Dichapetalum as well as

Palicoureamarcgravii, Acacia georginae, Gastrolobiumgrandiflorum,

and Oxylobium species.13 The West African plant

Dichapetalumtoxicarium also produces ω-fluorooleic acid,

ω-fluoropalmitic acid, and possibly ω-fluorocaprate and

ω-fluoromyristate.14 Certain fungi also produce fluorinated organics;

Streptomyces Clavus and Streptomyces Cattleya produce the fluorine-

containing antibiotic nucleocidin and 4-fluorothreonine,

3

respectively.13-15StreptomycesCattleya is also capable of producing

monofluoroacetate.15 Finally, production of CFC-11, CFC-12, CFC-

113, HCFC-21, HCFC-22, tetrafluoroethylene and

chlorotrifluoroethylene has been reported in volcanic gases and drill

wells.16,17

It is important to note that all of the known biologically

produced fluorinated organics contain only one fluorine atom. This

contrast with many man-made fluorinated organics, which often

contain many fluorine substituents and may even, be fully fluorinated.

Because of their many useful properties, the number of man-made

fluorinated organics has dramatically increased over the past few

years. The organofluorine molecules actually do exhibit significant

biological effects, as inhibitors of enzymes, cell-cell communication,

membrane transport, and processes for energy.18-24The biomedical

applications of organofluorine compounds range from

pharmaceuticals to medical diagnosis.25 Reiss and Krafft26 discuss

potential uses of fluorocarbons, fluorinated surfactants and

fluorinated colloidal systems in biomedical applications. Examples of

fluorinated materials with impressive biological activity include 1

(diflucan, fluconazole), once heavily advertised in popular magazines

as a one-dose treatment for vaginal yeast infections; compounds 2

and 3, which are antibacterials that have been developed in response

to the increasing resistance of bacterial infections to currently used

drugs; Lefenuron 4, a growth regulator used to control fleas on

4

household pets; and pyrrole 5, which finds application as an

insecticide.

Insertion of fluorine into a potential drug or agricultural

chemical can produce an incredible range of biological effects, from

complete metabolic inertness to very highly enhanced specificity for

binding at a particular receptor site. These or related compounds have

been used in aerosol propellants, catalysts, surfactants, refrigerants,

plastics, anesthetics, pesticides, plant growth regulators, medicines,

adhesives, fire retardants, and even blood substitutes.27-36

Advantages do fluorine to bioactive molecule:

� As the second smallest substituent, fluorine closely mimics

hydrogen with respect to steric requirements at enzyme receptor

sites. It is also effective replacement isosteric oxygen, as in the

OH group. The trifluoromethyl group, however, is not only

substantially larger than methyl, but occupies more space than

isopropyl;

� The presence of fluorine often leads to increased lipid solubility,

thereby enhancing rates of absorption and transport of drugs

in vivo. While fluoro is only slightly more lipophilic than

hydrogen, trifluoromethyl is much more lipophilic than methyl

or chloro, which are frequently replaced by CF3. This factor is

often the most significant in improving pharmacological activity;

� The high electronegativity of fluorine alters electronic effect and,

thereby, chemical reactivity and physical properties;

5

� Fluorine imparts increased oxidative and thermal stability

because the C-F bond is much stronger than C-H bond.

However, improved stability may have the downside, as in the

‘lethal synthesis’ associated with fluoroacetate;

� In special cases such as 5-FU (5-Fluoro uracil), the specific

location of ‘deceptor’ fluorine instead of hydrogen blocks an

essential biochemical reaction and leads to its tumor inhibitory-

behavior.

1.2. Green Chemistry (GC):

The conventional synthesis of organic compounds generally

involves a large number of synthetic operations, including extraction

and purification processes in each individual step. This leads to not

only synthetic inefficiency but also generates large amounts of waste.

Green chemistry37 as the name indicates is a technology imbedded,

environmental friendly and cost effective utilization of resources that

minimize or even eliminate the production of harmful by-products in

the design and manufacturing of the product. Presence of such

unwanted by-products not only lowers the yield of the desired product

but may also interface with the utilization of the product. Presence of

these by-products even after the purification process limits its use.

Under these prospective green chemistry aims to eliminate the

production of these unwanted products and hence widens the usage

of products.

6

Green Chemistry which is the latest and one of the most

researched topics now days has been in demand since 1990’s.

Majority of research in green chemistry aims to reduce the energy

consumption required for the production of desired product whether it

may be any drug, dyes and other chemical compounds. It aims to

reduce or even eliminates the production of any harmful bi-products

and maximizing the desired product without compromising with the

environment.

1.2.1. The twelve principles of Green Chemistry:

1. Prevention: It is better to prevent waste than to treat or

clean up waste after it has been created.

2. Atom Economy: Synthetic methods should be designed to

maximize the incorporation of all materials used in the process into

the final product.

3. Less Hazardous Chemical Syntheses: Wherever practicable,

synthetic methods should be designed to use and generate substances

that possess little or no toxicity to human health and the

environment.

4. Designing Safer Chemicals: Chemical products should be

designed to effect their desired function while minimizing their

toxicity.

7

5. Safer Solvents and Auxiliaries: The use of auxiliary

substances (e.g., solvents, separation agents, etc.,) should be made

unnecessary wherever possible and innocuous when used.

6. Design for Energy Efficiency: Energy requirements of

chemical processes should be recognized for their environmental and

economic impacts and should be minimized. If possible, synthetic

methods should be conducted at ambient temperature and pressure.

7. Use of Renewable Feedstocks: A raw material or feedstock

should be renewable rather than depleting whenever technically and

economically practicable.

8. Reduce Derivatives: Unnecessary derivatization (use of

blocking groups, protection/ deprotection, temporary modification of

physical/chemical processes) should be minimized or avoided if

possible, because such steps require additional reagents and can

generate waste.

9. Catalysis: Catalytic reagents (as selective as possible) are

superior to stoichiometric reagents.

10. Design for Degradation: Chemical products should be

designed so that at the end of their function they break down into

innocuous degradation products and do not persist in the

environment.

11. Real-time analysis for Pollution Prevention: Analytical

methodologies need to be further developed to allow for real-time, in-

8

process monitoring and control prior to the formation of hazardous

substances.

12. Inherently Safer Chemistry for Accident Prevention:

Substances and the form of a substance used in a chemical process

should be chosen to minimize the potential for chemical accidents,

including releases, explosions, and fires.

Green Chemistry (GC) has become a powerful tool in organic

chemistry in the last decade and especially in recent years.38 Now a

days, there are several method s are developed to synthesis organic

compounds in greener ways. Among this, the microwave assisted

reaction, solvent less neat reaction, grinding reaction, green solvents

reactions and green catalyst reaction are important.

1.2.2. Microwave Assisted Organic Reactions (MAOS):

Chemistry under extreme or non-classical conditions is

currently a dynamically developing issue in applied research and

industry. Alternatives to conventional synthetic or waste treatment

procedures might increase production efficiency or save the

environment by reducing the use or generation of hazardous

substances in chemical production.Traditionally, organic synthesis at

elevated temperature is carried out by conductive heating with an

external heat source (electric plate heater, oil bath or heating mantle).

This is a comparatively slow and inefficient method for transferring

energy to the reaction since it depends on convection currents and the

thermal conductivity of the various materials that must be penetrated,

9

resulting in the temperature of the reaction vessel being higher than

that of the reaction mixture. In addition, a temperature gradient can

develop within the sample and local overheating can lead to product,

substrate or reagent decomposition.

In contrast, microwave irradiation Microwave (MW) energy is a

non-classical energy source produces efficient internal heating by

direct coupling of microwave energy with the solvent, reagents or

catalysts presented in the reaction mixture. In typical microwave

ovens, the magnetrons (microwave generators) produce a microwave

wavelength of 12.25 cm, which corresponds to a frequency of

2.45 GHz. Microwave irradiation triggers heating by two main

mechanisms: dipolar polarization and ionic conduction.39-41Since first

reports of the use of MW heating to accelerate organic chemical

transformations,42,43 numerous articles have been published on the

subject of microwave-assisted synthesis and related topics-microwave

chemistry has certainly became an important field of modern organic

chemistry. In early days, microwave heating was often used as an

optional protocol when a particular reaction has failed to proceed

under other conditions or requires exceedingly long reaction time or

high temperature. Dedicated microwave chemistries have now made it

obvious that many types of chemical transformations that require

heating can be carried out successfully under microwave conditions.

Microwave technology has also been applied in various formats

ranging from the traditional solution-phase synthesis to solid-phase

and solvent free reactions.

10

The obvious advantage of MW heating at atmospheric pressure

is that the danger of explosions due to increased pressure is

eliminated and that the equipment required is much less expensive.

Early reactions have been performed in opened vessels, such as

Erlenmeyer flasks, in domestic MW ovens, in solvent-free conditions.44

Non-uniform heating and difficulties with mixing and temperature

measurement are technical constraints that limited the scale of

microwave chemistry with dry media. An alternative employed polar,

high boiling solvents with opened vessels in unmodified domestic

microwave ovens. In these ovens, despite of the power level that

commonly fluctuates, there were other problems with safety. Heating

organic solvents with opened vessels can lead to violent explosions.To

avoid hazards due to the flammability of solvents, the conventional

chemical reflux system could be used if the water condenser is outside

the microwave cavity. Mingos et al.45 has described this kind of

domestic oven modification for atmospheric pressure operating

conditions.

The first safe commercial equipment for MW heating at

atmospheric temperature was produced by Prolabo French Company

and now the support is made by CEM. It is important to note that,

CEM products can operate at atmospheric conditions using opened

vessels and standard glassware or at elevated pressure and

temperature using sealed vessels. In situ temperature and pressure

control, infrared temperature control, variable speed stirring and

infinitely variable control of microwave power input are available and

11

make to stop the device when the reaction become out of control.

Because of good safety, these equipments, which are computerized,

can be easily used in laboratory research as well as in up-scaling

manufactures.

S.R.K. Pingali et al.46 have reported an efficient synthetic

procedure for the preparation of a diverse library of 1,3-benzodioxoles

was developed by applying controlled microwave heating in

comparison with currently available conventional heating. Reactions

were completed in less than 3 h. The isolation of product is simple,

the isolated yields are good to excellent, and this method is applicable

to large scale production.

S.R.Devineni et al.47 reported the CeCl3.7H2O supported on

silica (CeCl3.7H2O-SiO2) is used as a heterogeneous, efficient and

recyclable catalyst for a three component one-pot reaction of an

amine, aldehydes and diethyl phosphite to synthesize

a diaminophosphonate derivatives under microwave irradiation

exploiting neat reaction conditions.

A three-component Mannich reaction of different ketones with

aromatic aldehydes and different amines in microwave irradiation

under solvent free condition afforded corresponding β-amino carbonyl

compounds in excellent yields was developed by U. Sankappa Rai

et al.48 This method proved as a novel and improved modification of

the reported three-component Mannich reaction in terms of milder

12

reaction conditions, reaction times, clean reaction profiles, very small

quantity of catalyst and simple workup procedure.

B.M.Sahoo et al.49reported a rapid, improved, and ecofriendly

synthesis of thiopyrimidines is carried out via one-pot

multicomponent reaction of ethyl cyanoacetate, substituted

benzaldehydes, and thiourea in presence of ethanolic K2CO3 using

microwave irradiation heating method. Excellent yields, shorter

reaction time, and easy workup are the major advantageous features

of this green protocol.

Under microwave irradiation K.P. Srivastava et al.50 reported a

rapid, efficient, clean and environmentally benign exclusive method of

synthesis of symmetrical phthaloicbisamine dithiocarbamicanhydrides

has been developed using reaction of sym-phthaloyl dichloride with

amine dithiocarbamic anhydride effectively in an aqueous medium

with excellent yields.

A novel methodology for facile production of α-cyanochalcones

under microwave irradiation isdescribed by S.J. Deshpande et al.51

Utilizing a Knoevenagel condensation between benzoylacetonitriles

and aromatic aldehydes, substituted chalcones are generated via a

15 min, one-pot synthesis.

P.S. Vargas et al.52 reported microwave-assisted synthesis of a

series of 1-aryl-4-dimethylaminomethylene pyrrolidine-2,3,5-triones

from the cyclocondenation reaction of ethyl 5,5,5-trichloro-3-

dimethylamino methylene-2,4-dioxopentanoate with aniline. This

13

process is an efficient alternative to the conventional thermal heating

and furnishes the products in a short reaction time, under mild

conditions.

S. Majumder et al.53 has developed an efficient method for the

synthesis of fused dihydroindeno[1,2-b]furans (13). One-pot three-

component reaction of 1,3-indanedione, aromatic aldehyde and

pyridiniumylide in the presence of triethylamine under microwave-

irradiation in solvent-free conditions afforded dihydroindeno[1,2-

b]furans in a diastereoselective manner in excellent yields.

A convenient, environmentally friendly and novel synthesis of

quinoxalines using silica gel as the catalyst was described by

V. Jeeha et al.54 The choice of microwave conditions has been shown

to have a substantial impact on the reaction outcome with closed-

vessel microwave irradiation resulting in the formation of quinoxalines

in high yields and short reaction times.

A one-pot, microwave-assisted protocol has been developed by

D. Rocchi et al.55 for the synthesis of 5,6-dihydroquinazolinones (15)

that incorporate structural fragments from chalcones,

acetylacetoacetate, ammonium formate and formamide. This process

generates two rings, two carbon–carbon and three carbon-nitrogen

bonds and does not require the use of chromatographic purification.

The dihydroquinazolinones were efficiently aromatized without the

need for metal-based oxidants by a microwave-assisted halogenation-

14

elimination sequence in the presence of N-bromosuccinimide, again in

the absence of chromatographic purification.

A. Mahindra et al.56 reported an efficient and facile, solvent-free

peptide synthesis (Scheme-10) assisted by microwave irradiation,

using DIC/HONB as the coupling reagent combination was reported.

Key features of this original protocol are solvent-free synthesis, very

short reaction time and scalability without affecting yield and purity.

The versatility of the method was successfully demonstrated by

synthesizing several biologically active peptides in high purity, yield

and without racemization.

B.L. Li et al.57 has reported ionic liquid as catalysts for one-pot

Fischer indole synthesis (Scheme-11) under microwave irradiation

and in a water medium. Various types of indoles were prepared using

single-carbonyl ketones/aldehydesor cyclohexandiones with

aryhydrazine hydrochlorides in water under microwave irradiation.

A modular, multicomponent synthesis of 1,2,3,4-tetrasubstituted

pyrroles promoted by the inexpensive CeCl3.7H2O, was reported by

C.C. Silveira et al.58 The reaction was carried out under microwave

irradiation, affording good yields of products in short time.

1.2.3. Grindstone Chemistry:

Grindstone Chemistry is a branch of green chemistry for

solvent-free chemical reactions which can be probably conducted in

high yield by just grinding solid/solid, solid/liquid, or even

liquid/liquid together. Grindstone chemistry-a greatly evolved version

15

of Toda’s method of grinding solids together for solvent free chemical

reactions, and also called ball-milling chemistry or mechano-

chemistry- is of interest in synthesizing heterocycles because it takes

place under mild conditions, in the absence of a solvent, and under

eco-friendly conditions. The grindstone chemistry was first introduced

by Toda et al.59 In grinding technique the reaction proceeds through

generation of local heat by grinding of substrate and reagent by mortar

and pestle. Reactions are initiated by grinding, with the transfer of very

small amount of energy through friction. A variety of organic

transformations has been reported in grind stone chemistry for several

well-known reactions such as, Biginelli reaction,60 one-pot synthesis of

spiro-indolinetriones,61 Aldol condensation,62,63 Claisen-Schmidt

reaction,64 Reformatskyreactions,65 Dieckmann condensations,66

Knoevenagel condensations,67,68 Reductions,69 and etc.,70,71

D. Sharma et al.72 reported coumarins by modified Pechmann

condensation using grinding technique under solvent-free condition at

room temperature. The Pechmann condensation for the synthesis of

coumarins involving grinding of different phenols and β-ketoesters in

the presence of p-toluenesulfonic acid at room temperature under

solvent-free conditions has been described (Scheme-13). A faster

reaction and higher yields compared to the conventional methods are

the advantages of present protocol.

An environmentally benign Knoevenagel condensation of various

aromatic aldehydes with 4-thiazolidinones in the presence of

16

anhydrous ammonium acetate can be achieved by grinding at room

temperature in the absence of solvents was reported by

N.H. Metwally et al.73(Scheme-14).

Q. Ding et al.74 have synthesized 2,4-disubstituted thiazoles by

a one-pot reaction of aldehydes and α-bromoketones with

thiosemicarbazide by grinding under catalyst and solvent-free

conditions (Scheme-15). This method has notable advantages in

terms of simple workup, neat conditions, high yield, reasonably rapid

reaction rate, and environmental friendliness.

S.B.Guo et al.75 have reported D,L-proline catalyzed one-pot

synthesis of pyrans and pyrano[2,3-c]pyrazole derivatives by a

grinding method under solvent-free conditions. The condensation of

aromatic aldehydes, malononitrile, and dimedone or 3-methyl-1-

phenyl-2-pyrazolin-5-one gave 2-Amino-3-cycano-4-aryl-7,7-

dimethyl-5,6,7,8-tetrahydrobenzo[b]pyrans (22) or 6-amino-5-cyano-

4-aryl-1,4-dihydropyrano[2,3-c]pyrazoles (23).

A series of quinoxaline derivatives (24) were efficiently

synthesized in excellent yields by the reaction of 1,2-diamines and

1,2-diketones with grinding catalyzed by p-toluenesulfonic acid under

solvent-free conditions at room temperature was reported by Da-Qing

Shiet et al.76 Compared with the classical synthetic method, this new

method has the advantages of convenient manipulation and

environmental friendliness.

17

The synthesis of azines (25) of aromatic aldehydes and ketones

in good yields was reported by J. Safari and S.G. Ravandi.77 This

reaction was carried out under solvent-free conditions and in the

absence of catalyst to afford good yields of the relevant azines. The

reaction is also environmentally friendly without the inconvenience of

undesired by-products and has advantages over the previously

reported methods.

K. Jakhar and J.K. Makrandi78 have reported an eco-friendly

oxidative bromination of alkanones by an aqueous grinding technique.

The α-bromoalkanones have been synthesized by reacting alkanones

with ammonium bromide and ammonium per sulfate in high yields

using an aqueous grinding technique (Scheme-19).

A short and efficient synthetic route, for alkylation and acylation

of aromatic compounds in the absence of solvent is developed by

M. Ghiaci and J. Asghari.79 According to the reaction system and

conditions used different alkyl and acyl arenes are obtained in

moderate to good yields.

A very simple and highly efficient eco-friendly procedure for

Baker-Venkataraman rearrangement (Scheme-20) has now been

developed by Dinesh Sharma et al.80 which involves the grinding of 2-

aryloxyacetophenones/2-cinnamoyloxyacetophenones with pulverized

potassium hydroxide in a mortar by a pestle and avoids the use of

organic solvents at any stage of the reaction.

18

A rapid, improved, and environmentally benign synthesis of 4,4´-

aryl or alkyl methylene-bis(1H-pyrazol-5-ols)(28) has been accomplished

by tandem Knoevenagel-Michael reaction81 of 1-aryl-3-alkyl-1H-pyrazol-

5-ol with various aldehydes catalyzed by ammonium acetate.

Citric acid promoted synthesis of 2,3-dihydroquinazolin-4(1H)-

ones with good to excellent yields is achieved by tandem reaction of

anthranilamides(or anthranilhydrazides) with aldehydes was reported

by Q.S. Ding et al.82 (Scheme-22) under grinding at room temperature

and solvent-free conditions. This method has notable advantages in

terms of simple workup, short reaction time, cost-effective, and

environmentally benign.

Parvin Kumar et al.83 have been reportedan efficient,

environmentally benign, one‐pot and simple synthesis of

2‐aryl/heteroarylbenzothiazoles by the reaction of 2‐aminothiophenol

and aryl/heteroaryl aldehydes mediated by hypervalent iodine (III)

reagents under solvent‐free condition at room temperature is

demonstrated. All the reactions were carried out by grinding the

reactants (2‐aminothiophenol and aryl/heteroaryl aldehydes) with

hypervalent iodine (III) reagents in a mortar with pestle (Scheme-23).

Phenyliodinebistrifluoroacetate act as an efficient oxidizing reagent in

comparison to iodobenzenediacetate in term of reaction time but

yields are comparative. The advantages of this protocol are the

one‐step procedure, mild reaction conditions, high yields of the

products, and no side reactions.

19

A grinding-induced catalyst and solvent-free domino

multicomponent reaction84 (Scheme-24) for the synthesis of 1,4-

dihydropyridines has been developed using aldehydes, amines, DEAD

(diethyl acetylenedicarboxylate), and malononitrile/ethyl cyanoacetate.

Koichi Sato et al.85 have reported an efficient and convenient

approach to the synthesis of azulene derivatives bearing a carboxamide

unit based on solvent-free Passerini reaction, using grinding is described

(Scheme-25). This method provides several advantages such as high

efficiency, operational simplicity, and mild conditions.

The conversion of carbonyl compounds (aliphatic, heterocyclic,

and aromatic) into the corresponding oximes86 (up to quantitative

yields) was achieved by simply grinding the reactants without using

any solvent in the presence of Bi2O3 (Scheme-26). The methodology

has the advantages of being rapid, cheap, eco-friendly, easy to handle,

requiring shorter reaction time, and quite general covering all types of

aldehydes and ketones. Interestingly, the reaction never preceded

further neither to provide amide via Beckmann rearrangement nor

nitriles via dehydration. Reusability of Bi2O3 was also checked.

Entities such as chloro, nitro, and hydroxyl were found to be inert to

the reaction condition.

1.2.4. Multicoponent reactions (MCRs):

Multicomponent reactions (MCRs) are special types of

synthetically useful organic reactions in which three or more different

starting materials react to a final product in the one-pot

20

procedure.Such reactions are atom-efficient processes by

incorporating the essential parts of the starting materials into the final

product. MCRs are dynamic tools in the modern drug discovery

process and allow the fast, automated, and high-throughput

generation of organic compounds87. In the past years the

pharmaceutical industry has focused more and more on diversity-

oriented and biased combinatorial libraries.88-90 Furthermore, the

discovery of novel MCRs can be considered as an interesting topic for

academic research that also satisfies a practical interest of applied

science.91-93

Based on reaction mechanisms, MCRs are divided into three

subclasses, as follows.

Type I:

In type I MCRs, the starting materials, intermediates and

products are in equilibrium with each other. The yield of the final

product depends on the thermodynamics and the product is often

isolated as a mixture with intermediates and starting materials.

Type II:

Type II MCRs are sequences of reversible reactions that are

terminated by an irreversible reaction step, which drives the reaction

to completion. This last step often involves a highly exothermic

21

reaction like an aromatization, a ring closure or the oxidation of the

Carbon.

Type III:

Although they are not uncommon in biochemical pathways in

living cells, type III MCRs, in which all reaction steps are irreversible,

are very rare in preparative chemistry.

The first MCR was reported by Strecker in 1850 thereafter

several MCRs are reported and still going on. Up to date, many well-

known MCRs, such as Biginelli Reaction, Bucherer-Bergs Reaction,

Gewald Reaction, HantzschDihydropyridine (Pyridine) Synthesis,

Mannich Reaction, Passerini Reaction, Ugi Reaction and etc., have

been described.

Khangvan Pham et al.94 developed a one-pot procedure for the

synthesis of isoindolin-1-imine derivatives (Scheme-27) by a simple

three component condensation of 2-cyanobenzaldhyde, ammonium

acetate, and 4-hyroxycoumarin derivatives or 1,3-dicarbonyl

compounds or 4-hydroxyquinolin-2(1H)-one in ethanol under reflux

for 20-60 min with excellent yields. The advantages of this procedure

are operational simplicity, excellent yields, and short reactive time,

without catalyst, easy workup, and green environmental impact.

A simple and efficient method was developed by

M. Lashkari et al.95 for one-pot, five-component synthesis of highly

22

functionalized piperidines (Scheme-28) from reactions of β-keto

esters, aromatic aldehydes, and various amines catalyzed in acetic

acid medium. The reaction proceeded smoothly to generate the

corresponding product in good yield.

A faster and efficient synthesis of polysubstituted pyrroles has

been achieved via a four-component reaction from β-ketoesters,

benzylamines, aromatic aldehydes and nitro methane in the presence

of Amberlyst-15 under ultrasound. A variety of pyrrole derivatives

(Scheme-29) were synthesized by this simple and straightforward

methodology in good yields was reported by P.R.K.Murthi et al.96

An efficient one pot synthesis of a series of pluripotent (E)-1-(3-

methyl-5-aryl-7-styryl-5H-thiazolo[3,2-a]pyrimidin-6-yl)-3-arylprop-2-

en-1-ones97 (39) was reported. It involves reaction of 5-acetyl-6-

methyl-4-aryldihydropyrimidine-2-thiones, propargyl bromide and

aromatic aldehydes in presence of ethanolic KOH. The newly

synthesized compounds were evaluated for antimalarial activity and

HIV-RT inhibitors.

An efficient and greener protocol for the synthesis of 12-aryl-

8,9,10,12-tetrahydrobenzo[a]xanthen-11-one (40) using

tetradecyltrimethylammonium bromide (TTAB) at room temperature in

water was described by P.V. Shinde et al.98

Annulated benzothiazoloquinazolines99 (41) have been

synthesized by a diversity oriented simple and convenient synthesis

involving one-pot three-component reaction of substituted

23

2-aminobenzothiazoles with α-tetralone and aromatic/heteroaromatic

aldehydes in ethanol in the presence of catalytic amount of TEA.

A series of novel tetrazolo[1,5-a]thiopyrano[3,4-d]pyrimidine

derivatives100 (42) were synthesized by reaction of aryl aldehyde, 2H-

thiopyran-3,5(4H,6H)-dione, and 5-aminotetrazole under solvent-free

conditions (Scheme-33). The features of this procedure are mild

reaction conditions, high yields, and operational simplicity.

A new one-pot four component procedure for synthesis of

densely functionalized pyrroles using commercially available

ninhydrin with phosphorane intermediates produced in the reaction

between triphenylphosphine, ammonium thiocyanate (or ammonium

acetate) and various dialkylacetylenedicarboxylates (Scheme-34) was

developed by Javad Azizian et al.101

A one pot, three component synthesis of tetrazoles (44) via

thiourea has been accomplished in water was reported by

M. Sathishkumar et al.102 Water enhances the solubility of a higher

number of components in the three component protocol thus

promoting the reaction. The synthesis involves a chemoselective

exocyclic reaction, regioselective electrocyclisation and a preferred

conformational orientation of the tetrazole side chain which is

rationalized based on the relative magnitude of Garbisch angle

strain/allylic strains anticipated during the course of the reaction.

An efficient one-pot condensation of beta-naphthol, aldehyde

and active methylene substrate is achieved using catalytic amount of

24

phosphomolybdic acid (Scheme-36). This MCR resulted in the

synthesis of several napthopyran derivatives103 in good yields.

A series of novel 2-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-

phenylthiazoles104 (46) have been prepared by a three-component

cyclo-condensation of various chalcones, thiosemicarbazide and

phenacyl bromide. The easy work-up of the products, rapid reaction,

and mild conditions are notable features of this protocol. The reaction

was efficiently catalyzed in one-pot by a few drops of HCl in EtOH

under reflux conditions providing the title compounds in moderate to

high yields.

Borono-Mannichreaction105 (Scheme-38) was performed in

solvent-free conditions under microwave irradiation with short

reaction time. Full conversion of the starting materials towards the

expected product was achieved, starting from stoichiometric quantities

of reactants, avoiding column chromatography. No purification step

other than an aqueous washing was required.

A straightforward three-component reaction of preformed

aromatic or in situ generated benzylic organozinc reagents with

amines and ethyl glyoxylate allows the synthesis of a range of α-amino

esters106 (48) in very good yields. The procedure, which is

characterized by its simplicity, allows the concise synthesis of esters

bearing a phenylglycine or a phenylalanine scaffold

An easy and efficient one-pot, three-component reaction of

aldehydes, hydroxylamine, and [bmim]N3 enables the synthesis of

25

5-substituted 1H-tetrazole derivatives was reported by

M.M. Heravi et al.107

An efficient base-catalyzed [3+3] oxidative aromatization108 of

α,β-unsaturated carbonyl compounds with dimethyl glutaconate

under mild, metal-free conditions affords substituted benzenes in high

to excellent yields with oxygen as oxidant and water as sole by-

product (Scheme-41). In situ generation of the α,β-unsaturated

carbonyl compounds from aldehydes and ketones enables a more

convenient tandem [3+2+1] aerobic oxidative aromatization reaction.

1.3.1. 1,5-dione:

1,5-Diketones are one of the important synthetic intermediates

and desirable starting material for preparing numerous

heterocycles109-111 and poly functional compounds.112-115 The

cyclization of 1,5-diketones to yielding heterocycles, makes them

convenient method for the synthesis of various heterocyclic

compounds. The reaction between 1,5-diketones and hydrogen

sulphide gives thiopyrans,116 whereas with ammonia and its derivative

gives pyridine, dihydropyridine, diazapine and pipridine117 as

product. The heterocyclization of 1,5-diketones under acids forms

pyrans, pyrylium salts and di or tetra hydropyrans.118The

1,5-diketones also have the ability to remove the heavy metals from

aqueous solution with high efficacy.119

W. Liu et al.120 describes a fast, mild, convenient and simple

method for preparing 1,5-diketones by Michael reaction under

26

solvent-free condition (Scheme-42). Fourteen new 1,5-diketone

compounds containing ferrocenyl were synthesized and reported.

An efficient and environmentally friendly Michael addition

(Scheme-43) of 2-[(2-oxo-2-phenylethyl)sulfanyl]-1-phenyl-1-

ethanones (diphenacyl sulfides) to substituted chalcones using

microwave irradiation under solvent-free conditions, affording

differently substituted 1,3,5-triarylpentan-1,5-diones was reported by

N. Paul et al.121

The Claisen-Schmidt reaction between 1,1´-diacetylferrocene

and ferrocene carboxaldehyde under microwave irradiation has been

investigated by S. Pedotti and A. Pattii122 in different conditions. The

selective synthesis of 1,5-dioxo-3-ferrocenyl[5]ferrocenophane (53) has

been achieved and a simple protocol for its purification was

established.

M. Ceylan and H. Gezegen123 have investigated eight different

chalcone-1,5-diketone derivatives (Scheme-45) were prepared by the

reaction of chalcone derivatives with cyclohexanone under the solvent-

free phase transfer catalyst condition with moderate to high yields.

The mechanistic pathway of the reaction can be explained by the

Michael-type addition of cyclohexanone to chalcone derivatives.

A tandem cross-coupling reaction124 of aryl methyl ketones with

aromatic aldehydes has been accomplished employing barium

isopropoxide as a catalyst, in which barium enolates are generated

and then three consecutive reactions (aldol reaction/β-

27

elimination/conjugate addition) occur (Scheme-46). This one-pot

procedure is a convenient method to obtain symmetrical 1,5-diketones

in good yields.

A sequential condensation of α-cyano esters, aldehydes, and

ketones with catalytic amount of pyrrolidine/acetic acid at room

temperature has been developed byGang Liu andYingcai Wang.125 This

method offers a chemoselective, one-pot cascade access to δ-ketoα-

cyano esters (Scheme-47) with moderate to good yields under mild

condition.

Mao Wu-Taoa et al.126 has been synthesized5-bis(4-

methoxyphenyl)-3-(4-methyl-1,2,3-thiadiazol-5-yl)-pentane-1,5-dione

(57) by the reaction of 4-methyl-1,2,3-thiadiazole-5-carbaldehyde with

4΄-methoxyacetophenone, and its structure wascharacterized by IR,

NMR, HR-MS, elemental analysis and single-crystal X-ray diffraction.

Shun-Jun Ji et al.127 reported Michael reactions of deoxybenzoin

or dibenzyl ketone with ferrocenyl substituted chalcones catalyzed by

sodium hydroxide under ultrasound irradiation can afford the

corresponding Michael adducts with excellent yields. It presents a

convenient, efficient and simple method for the preparation of

ferrocenyl substituted 1,5-diketone compounds in the presence of

ultrasound irradiation.

A new three-component reaction of α-thiocyanato ketones under

microwave irradiation for the stereoselective synthesis of

E-3-aroylidene-2-oxindole derivatives has been described by

28

Xue Wang et al.128 The domino reaction simultaneously installs C-S

and C-C bonds through continuous [3+2] cyclo addition/ring opening

of in situ generated 1,3-oxathiolanes/SN2-type reaction sequence

(Scheme-50).

1.3.2. Chalcone:

The α,β-unsaturated ketones 1,3-diarylprop-2-en-1-ones called

as chalcones. The chalcones are synthesized by Claisen-Schmidt

condensation of an arylaldehyde with aryl methyl ketone. The reason

that organic chemists are interested to synthesize chalcone is simple.

Chalcone and its derivatives, among the large families of plant

constituents, have displayed a broad spectrum of pharmacological

activities. Changes in their structure have offered a high degree of

diversity that has proven useful for the development of new medicinal

agents having improved potency and lesser toxicity. Chalcone are

important starting materials for the syntheses of different classes of

heterocyclic compounds such as flavonoids,129 isoflavonoids,130

pyrazole,131 pyrimidine,132,133 and etc.,134,135

A. Gomez-Rivera et al.136 synthesized three nitro substituted

chalcones (60) and to evaluate their anti-inflammatory activity in the

model of carrageenan induced edema in rats. The nitro chalcone were

prepared by Aldol condensation using of mechanical agitation and

environmentally friendly solvents and the three structures were

evaluated on biological activity and they showed anti-inflammatory

protective effect by both oral and intraperitoneal administration.

29

Twenty-five novel pyranochalconederivatives137 (61) were

synthesized and evaluated for their in vitro and in vivo antiproliferative

activities. This study demonstrated that pyranochalcone derivatives

could have beneficial antitumor activity as a novel microtubule

stabilizing agent.

A new potentially useful nonlinear optical organic material,

1-(5-chlorothiophen-2-yl)-3-(2,3-dimethoxyphenyl)prop-2-en-1-one(62)

has been synthesized138 and grown as a high-quality single crystal by

the slow evaporation technique. The compounds exhibit good optical

limiting at 532 nm. The best optical limiting behavior of this molecule

is due to the substituted strong electron donor.

S.A. Khan et al.139 have been synthesized Chalcone derivatives,

by the reaction of 3-acetyl-2,5-dimethylthiophene with corresponding

active aldehyde in ethanolic NaOH in microwave oven (Scheme-53).

The anti-bacterial activity of these compounds were first tested in vitro

by the disk diffusion assay against two gram-positive and two gram-

negative bacteria, and then the minimum inhibitory concentration was

determined with the reference of standard drug Chloramphenicol.

K. Parikh and D. Joshi140 have synthesized some benzimidazole-

clubbed chalcone derivatives and were tested for their antibacterial

and antifungal activities and were reported in form of minimum

inhibitory concentration values.

Two methods for the synthesis of indole-based chalcone

derivatives, namely (E)-1-(2-chloro-1-(4-chlorobenzyl)-1H-indol-3-yl)-3-

30

aryl(hetaryl)prop-2-en-1-ones141 are described, involving the

ultrasound-assisted or solvent-free Claisen-Schmidt condensation

reaction of 3-acetyl-2-chloro-1-(4-chlorobenzyl)indole and various

aromatic aldehydes.

A series of coumarin-chalcone hybrids have been synthesized by

K.V. Sashidhara et al.142 and evaluated for their in vitro cytotoxicity

against a panel of four human cancer cell lines and normal

fibroblasts.

Chalcone derivatives on estradiol framework have been

synthesized by H.O.Saxena et al.143 Some of the derivatives showed

potent anticancer activity against some human cancer cell lines.

Active anticancer derivatives were also evaluated for osmotic

hemolysis using the erythrocyte as a model system. It was observed

that chalcone derivatives showing cytotoxicity against cancer cell lines

did not affect the fragility of erythrocytes and hence may be

considered as non-toxic to normal cells.

Synthesis of various Chalcones of (E)-1-(3,5-

bis(trifluoromethyl)phenyl)-3-(substituted)phenylprop-2-en-1-one (70)

from 3,5-bis(trifluoromethyl)acetophenone and substituted

benzaldehydes in presence of KOH. The synthesized compounds were

screened for antimicrobial activity.144

A series of novel 2,4,5-trimethoxy chalcones derivatives145 (71)

of biological interest were prepared by Claisen-Schmidt Condensation

31

reaction and were evaluated for antioxidant and antimicrobial

activities against some selected pathogenic bacteria and fungi.

Alexander Ciupa et al.146 have inspired by biologically active

natural products, a hybrid analogue that combines the

N-Methylurocanic side chain of the sarcodictyin family of compounds

with the chalcone moiety (72-75) has been proposed, synthesised and

examined for antiproliferative activity in three cancer cell lines and

one normal primary cell line.

The validity of the chalcone scaffold for the design of inhibitors

of monoamine oxidase has previously been illustrated. In a systematic

attempt to investigate the effect of heterocyclic substitution on the

monoamine oxidase inhibitory properties of this versatile scaffold, a

series of furanochalcones (76-79) were synthesized and tested

asinhibitors of monoamine oxidase.147

A group of novel N-4-piperazinyl-ciprofloxacin-chalcone (80)

hybrids was prepared by M. Abdel-Aziz et al.148 One-dose anticancer

test results indicated that compounds exhibited the highest ability to

inhibit the proliferation of different cancer cell lines.

A new series of imidazo[2,1-b]pyridine/pyrimidine chalcone

derivatives149 (Scheme-58) were synthesized and evaluated for their

anticancer activity. These chalcone derivatives showed promising

activity against cancer. One of the representative compound of this

series could be considered as the potential lead for its development as

a new anticancer agent.

32

1.3.3. Dihyropyrimidones (DHPMs):

In 1893, the synthesis of functionalized 3,4-dihydropyrimidin-

2(1H)-ones (DHPMs) via three-component condensation reaction of an

aromatic aldehyde, urea and ethyl acetoacetate was reported for the

first time by Pietro Biginelli. In the past two decades, such Biginelli-

type dihydropyrimidones have received a considerable amount of

attention due to the interesting pharmacological properties associated

with this heterocyclic scaffold. Various modifications have been

applied to Biginelli reaction to get better yield and to synthesize

biologically active analogs. Different catalysts have been reported to

increase the yield of the reaction. Microwave synthesis strategies have

also been applied to shorten the reaction time. Solid phase synthesis

and combinatorial chemistry has made possible to generate library of

DHPM analogs. Therefore, Biginelli reaction for the synthesis of

dihydropyrimidinones has received renewed interest and several

improved procedures have been reported such as H2SO4,150 HCl,151

Lewis acids such as BF3.OEt2,152 zeolites,153 and metal trifles,154 a

variety of other conditions such as ultrasonic,155 microwave-

assisted,156 and low melting acidic157 methods and ionic liquids158 also

have been reported in literatures.

Hassan Kefayati et al.159 reported a bronsted acidic ionic liquid,

1-methylimidazolium hydrogen sulfate, in the presence of catalytic

amount of chlorotrimethylsilane has been used as an efficient and

reusable catalyst for the one-pot synthesis of 3,4-dihydropyrimidin-

33

2(1H)-ones and hydroquinazoline-2,5-diones under thermal and

solvent-free conditions (Scheme-59). High yields of the products were

obtained in a few minutes by using this new catalysis system.

A series of conformationally flexible and restricted dimers of

monastrol as well as related dihydropyrimidones have been

synthesized by employing one-pot Biginelli multicomponent reaction

(Scheme-60&61). These dimers have been evaluated for cytotoxic

potency against selected human cancer cell lines and some of the

compounds have exhibited more cytotoxic potency than the parent

monastrol. Further, the DNA binding ability by thermal denaturation

studies and antimicrobial activities of these compounds are also

discussed by A. Kamal et al.160

A Series of hitherto unreported piperidone grafted

pyridopyrimidines synthesized by A. Basiri et al.161 through ionic

liquid mediated multi-component reaction (Scheme-62). These

compounds were evaluated for their inhibitory activities against AChE

and BChE enzymes. Molecular modeling, performed for the most

active compounds using three dimensional crystal structures of

TcAChE and hBChE, disclosed binding template of these inhibitors

into the active site of their respective enzymes.

J.S. Ghomi et al.162 describes the synthesis of pyrimidine-2-

thione derivatives under conventional and ultrasonic irradiation by

the reaction of chalcones and thiourea (Scheme-63). The effects of

ultrasound on organic reactions are attributed to cavitations, a

34

physical process that create, enlarge, and implode gaseous and

vaporous cavities in an irradiated liquid.

An efficient synthesis of novel 4-(2-phenyl-1,2,3-triazol-4-yl)-

3,4-dihydropyrimidin-2(1H)-(thio)ones (87) from 1,3-dicarbonyl

compounds, 2-phenyl-1,2,3-triazole-4-carbaldehyde and urea or

thiourea under ultrasound irradiation and using samarium

perchlorate as catalyst was described by C.J. Liu et al.163

M. Dutta et al.164 have synthesized compounds containing fused

3,4-dihydropyrimidin-2(1H)-one or 3,4-dihydropyrimidine-2(1H)-

thione moieties three-component reactions of a steroidal or

nonsteroidal ketone, an alkyl or aryl aldehyde, and urea or thiourea in

the presence of sodium ethoxide (Scheme-65). The products were

isolated in good yields after short reaction times under mild

conditions.

A rapid and efficient one-pot method for the synthesis of 4,6-

diarylpyrimidin-2(1H)-ones (89) and related heterocycleswere

described. The condensation of acetophenone derivatives, aldehydes

and urea in the presence of sulfamic acid was employed to synthesize

a variety of pyrimidinonesin moderate to excellent yields. The scope

and limitations of this method are described by M.M. Heravi et al.165

B.R.P. Kumar et al.166 reported a library consisting of some

novel Hantzsch dihydropyridines (90) and Biginelli

dihydropyrimidines of biological interest as well as their synthesis and

analysis. The synthesized compounds were screened for their in vitro

35

antibacterial activity against bacteria and furthermore, compounds

were subjected to in vitro cytotoxicity against Vero cells.

The three component condensation of an aldehyde, Substituted

urea and 3-oxobutanamide in presence of catalytic amount of AlCl3 is

disclosed for the synthesis of pyrimidine under solvent free microwave

irradiation conditions (Scheme-68). High yields are achieved even 1g

scale, while reaction times are considerably shortened compare to

conventional method. The antimicrobial activities of the pyrimidines167

are compared with those of known chosen standard drugs.

N. Chauhan et al.68 synthesized various (N-(2-chloro-4-

(trifluoromethyl) phenyl)-4-(substitutedphenyl)-1,2,3,4-tetrahydro-6-

methyl-2-oxopyrimidine-5-carboxamide (92) from N-(2-chloro-4-

(trifluoromethyl) phenyl)-3-oxobutanamide, Substituted

benzaldehydes and urea in presence of Con.HCl. The structures of the

synthesized compounds were confirmed on the basis of spectral and

elemental analysis. The synthesized compounds were screened for

antimicrobial activity.

1.3.4. Cyanopyridones:

The pyridine skeleton is of great importance to chemists as well

as to biologists as it is found in a large variety of naturally occurring

compounds and also in clinically useful molecules having diverse

biological activities.In association with this, Pyridone and their

derivatives play an essential role in several biological processes and

have considerable chemical and pharmacological importance.169-171

36

The 3-cyanopyridin-2-one nucleus is the structural basis of the alkaloid

ricinine (93), the first known alkaloid containing a cyano-group.

Milrinone (94) is a 3-cyano-2-oxopyridine derivative that has been

introduced to the clinic for the treatment of congestive heart failure.

Beheshtia et al., developed new selective and environmental

friendly methodologies for the preparation of fine chemicals, they

performed the synthesis of 4-alkyl(aryl)-6-aryl-3-cyano-2(1H)-

pyridinones and their 2-imino isosteres172,173 through one-pot multi-

component reaction of 3,4-dimethoxyacetophenone, malonitrile or

ethyl cyanoacetate, an aldehyde and ammonium acetate in the

presence of K2CO3.

The one-pot reaction of 2-cyanoaceto hydrazide with aldehyde

and an activated nitrile in ethanol containing a catalytic amount of

piperidine yielded pyridine-2-one derivative.174-176

Condensation of ethyl cyanoacetate with α,β-unsaturated

ketones in presence of excess ammonium acetate afforded

3-cyanopyridin-2-ones.177,178 Also, a green chemistry approach

describing reaction of α,β-unsaturated ketones with ethyl

cyanoacetate using samarium iodide as catalyst has been reported.179

Alnajjar et al.180 reported the conversions of 2-cyano-5-

(dimethylamino)-5-phenylpenta-2,4-dienamides into nicotinic acid

derivatives by boiling in EtOH/HCl. But, When 2-cyano-5-

(dimethylamino)-5-phenylpenta-2,4-dienamides are heated under

reflux in acetic acid, nicotinic nitrile derivatives are obtained.

37

The condensation of an enone or enal with cyanoacetamide

derivatives and t-BuOK furnishes either 3-cyano-2-pyridones or 3-

unsubstituted-2-pyridones, depending on whether the reaction is

carried out in the presence or in the absence of O2 (Scheme-73). In

the first case, in situ oxidation of Michael-type intermediates takes

place; in the second case, a "decyanidative aromatization" of such

intermediates occurs.181,182

The condensation of ketone with dimethylformamide

dimethylacetal afforded vinylogous amide, which in turn reacted with

cyanoacetamide under basic conditions to generate the 5,6-diaryl-3-

cyano-2-pyridones.183

5-Substituted-4-methyl-3-cyano-6-hydroxy-2-pyridones (102)

were synthesized from cyanoacetamide and the corresponding alkyl

ethyl acetoacetate in methanol in the presence of potassium hydroxide

at 60ºC. Cyclization of cyanoacetamide with an alkyl ethyl

acetoacetate belongs to a 3-2 type of condensation where the pyridine

nucleus is formed.184

Melikyan et al. have reported synthesis of novel N-substituted-

3-cyanopyridin-2-ones185 from ylidenecyanoacetic acid ethyl esters

intwosteps (Scheme-76).

Martin and coworkers reinvestigated the cyclocondensation of

2-cyanoacetohydrazide with (4-methoxybenzylidene)malononitrile.

They have found that prolonged heating lead only to the formation of

1,6-diamino-4-(4-methoxyphenyl)-3,5-dicyano-2-pyridone186 (104).

38

5-Aryl-3-cyano-2-pyridones (105) have been prepared by the

cyclization of cyanoacetamide condensated with 2-aryl-3-

dimethylamino-2-propenals. The 2-arylvinamidinium salts were

condensed with cyanoacetamide in refluxing methanol that contained

sodium methoxide to give the desired 5-aryl-3-cyano-2-pyridones.187

The vinamidinium salts were prepared by the standard Vilsmeier-

Haack reaction from the appropriate aryl acetic acid.

1.4. Nuclear Magnetic Resonance Spectroscopy:

Nuclear Magnetic Resonance (NMR) spectroscopy is one of the

most powerful techniques for structural determination of organic and

inorganic compounds. Only magnetically active nuclei (i.e., those

possessing a non-zero nuclear spin) can be observed using this

technique, but since among them are included isotopes of H and C (as

well as isotopes of N, P, F...), and since all organic molecules and most

inorganics are composed mainly of carbon and hydrogen. NMR

spectroscopy has become an essential tool for both organic and

inorganic chemists.

1.4.1. 2D-NMR techniques

1.4.1.1 HOMOCOR (Homonuclear Correlation Spectroscopy)

This two dimensional technique reveals correlations between

coupled protons. Cross peaks are obtained for all protons that have

measurable coupling. Diagonal peaks are due to chemical shift

equivalent protons and they do not provide useful information.

39

1.4.1.2. HSQC (Heteronuclear single Quantum Correlation)

This two dimensional NMR technique correlates13C nuclei with

directly attached protons. The resolution is very high since the

experiment is proton detected 1H-13C correlation. Only one bond

couplings (1JC,H) are detected and other two bond and three bond

carbon-hydrogen couplings are eliminated.

1.4.1.3. HMBC (HeteronuclearMutiple Bond Correlation)

This is also two dimensional proton detected 1H-13C are sacrificed

and two and three bond carbon-hydrogen couplings are detected.

1.4.1.4. NOESY (Nuclear Overhauser Exchange Spectroscopy)

When two protons are very close to each other in space,

radiation of one proton increases the intensity of the signal due to noe

other proton, whether the two protons are coupled are not. In this two

dimensional NMR technique, the cross peaks reveals the spatial

proximity if the protons.

1.5. Biological activity literature survey:

1.5.1. Chalcone:

Chalcones are potential biocides, some naturally occurring

antibiotics and aminochalcones probably own their biological activity

to the presence of α,β- unsaturated carbonyl group.

i. Antimicrobial Activity188,189

ii. Antileishmanial Activity190,191

iii. Anticancer Activity192,194

40

iv. Antioxidant Activity195,196

v. Antimalarial Activity197-199

vi. Analgesic Activity200

vii. Anti-inflammatory Activity201-203

viii. Antidiabatic204

ix. Anti-Tuberculosis205

x. Antifungal206,207

xi. Anticonvulsant208

1.5.2. Dihydropyrimidone:

Dihydropyrimidones (DHPMs) synthesis plays vital role in

medicinal chemistry because of its pharmacological properties. The

literature survey on the biologically active dihydropyrimidones has

been carried out and reported.

i. Calcium channel blocker209-212

ii. Antifilarial agent213

iii. Anti-HIV agents214,215

iv. Anti-malarial216,217

v. Anti-inflammatory218

vi. Anti-tubercular activity219-221

vii. Antioxidant Activity222,223

viii. Anti-tumor224,225

1.5.3. Cyanopyridones:

2-Pyridones represent a unique class of pharmacophore, which

are observed in various therapeutic agents226,227 in medicinal

41

treatment. These heterocycles attracted attention because of their

applications as bioactive compounds. Also, 2-pyridones were used as

ligands for the late 3d-metals.228

i. Antibacterial activity229

ii. Antifungal activity230

iii. Sedative231

iv. Antibiotics232

v. Anti-HIV233,234

1.6. Molecular Docking

Molecular docking is used to predict the structure of the

intermolecular complex formed between two molecules.The small

molecule called Ligand usually interacts with protein’s binding sites.

Binding sites are areas of protein known to be active in forming of

compounds. There are several possible mutual conformations in

which binding may occur. These are commonly called binding modes.

The role of in silico chemistry is emerging in drug design and

discovery. In an effort to find lead compounds atlower cost and greater

speed, computational chemistry methods have focused on developing

fast and highly efficient molecular docking methods for virtual

screening.235,236 In recent years, progress has been made in developing

docking algorithms that predict ligand binding to proteinsand by now

several docking programs are available such as AutoDock,237,238

GOLD, 239,240 Glide, 241,242 and FlexX.243

42

1.7. The scope of the present investigation:

Multi component reactions (MCRs) continue to attract synthetic

organic chemist due to several merits. Significantly complex organic

molecules can be synthesized from relatively simpler starting

materials in a single step. This makes them more economical and

green as compared with conventional multistep synthesis. MCRs have

been successfully used to synthesize different classes of compounds

or scaffolds. The delta-diketones(1,5-diones) plays a significant role as

synthetic intermediates and desirable precursor for the synthesis of

many heterocycles. We have synthesized two series of delta-

diketones, (i) 1-cyclopropyl-2-(2-flurophenyl)-3,5-diphenylpentane-1,5-

diones (106-119) under solvent-free grindstone method and

(ii)1,2,3,5-tetraarylpentane-1,5-diones (157-168) by simple one-pot.

The chalcones have attracted considerable attention as they are

endowed with wide range of pharmacological activities. Hence, we

planned to synthesize a α,β-unsaturated system, which comprises

both fluorine and hydroxyl group together to give a compact

structure of bioactive (E)-3-[4-(Difluoromethoxy)-3-hydroxyphenyl]-1-

phenylprop-2-en-1-ones (120-130).

Synthesis of bioactive compounds in the field of organic

chemistry received significant attention resulting in substantial

advances both in the synthetic and medicinal aspects. Heterocyclic

compounds are synthetically challenging ones as models for a number

of physiologically active natural products. It is well known that a

number of hetereocyclic compounds containing nitrogen; sulfur and

oxygen possess different pharmacophoric properties. We considered it

worthwhile to synthesize a system that unites both nitrogen and

sulphur or oxygen atoms to furnish new series of biolabile4,5,6-

triphenyl-3,4-dihydropyrimidin-2(1H)-thiones / ones (131-137).

43

Promising diverse pharmacological activities are shown by various

organofluorine compounds. They are reported to exert a number of

important physiological activities. Hence, we report the synthesis of

trifluoromethyl containing two new series of 6-phenyl-4-(4-

(trifluoromethyl)phenyl)-3,4-dihydropyrimidine-2(1H)-thiones (138-145).

As there is a need for “clean technology revolution” there has

been considerable interest in the Microwave Assisted Organic

Syntheses (MAOS) protocol for rapid synthesis of a variety of organic

compounds. Based on the above technology, we synthesized a novel

series of dihydropyrimidones(131-145).

Pyridone play vital role in several biological processes and have

considerable chemical and pharmacological importance, hence we

planned to synthesis novel 2-oxo-6-phenyl-4-(4-(trifluoromethyl)phenyl)-

1,2-dihydropyridine-3-carbonitriles (146-156).

The structures of all the newly synthesized novel structurally

diverse heterocyclic compounds are discussed with the help of m.p.’s,

FT-IR, LC-MS, one-dimensional NMR (1H,13C), D2O exchanged 1H

NMR, two-dimensional 1H-13C HSQC and HMBC spectra.

It was envisaged that the new series of compounds synthesized

by this study are expected to endow with wide spectrum of biological

properties. Hence, the possible in vitro antibacterial potency of the

newly synthesized compounds are also explored and discussed.

The molecular docking is a vital tool in structural molecular

biology and computer-assisted drug design. The goal of ligand –protein

docking is to predict the predominant binding modes of a ligand with

a protein. The molecular docking was carried out on some synthesized

ligands with selected protein.

Fig.1. Microwave field in a domestic microwave oven, showing the

typical uneven pattern of hot spots (shown here in purple) and cold

spots.

Fig.2. The Single-Mode Resonator design generates an even heating

pattern in a lab-scale sized reaction vessel, leading to a high degree of

synthesis reproducibility.

Fig.3. Grinding with mortar and pestle

Fe Ar

O

Ph

Ph

O

Fe Ph

O Ar O

Ph

NaOH, EtOH

))) 600C

Scheme-49 58