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SUMMARY

CHAPTER-I

NAFION®NR50 CATALYZED A3-COUPLING FOR THE SYNTHESIS OF

PROPARGYLAMINES VIA C-H ACTIVATION

Propargylamines are major skeletons and synthetically versatile key intermediate for

the preparation of many nitrogen-containing biologically active compounds.

Propargylamines were synthesized by one-pot three components A3-coupling of

aldehydes, alkynes and amines. Although several methods have been reported for A3-

coupling, but most of them have serious drawbacks, such as harsh reaction conditions,

use of toxic solvents, non-recyclability of reagent and use of hazardous radiations like

ultrasonic. To overcome all the drawbacks and our continuous efforts towards the

development of new synthetic methods and the role of recyclable solid acid catalyst in

organic transformations, we report herein an efficient recyclable A3- coupling reaction

(via C–H activation) catalyzed by Nafion®NR50. A mixture of aldehydes, secondary

amines and phenylacetylene in CH3CN were stirred at 70-80 oC under a nitrogen

atmosphere in the presence of Nafion®NR50. The formation of propargylamines was

confirmed by spectral analysis.

CHAPTER-II

A NOVEL AND HIGHLY EFFICIENT METHOD FOR THE SYNTHESIS OF

DITHIOCARBAMATES AND ITS EVALUATION AS ANTICANCER AND

ANTIBACTERIAL AGENTS CATALYZED BY CAN IN PEG-H2O SYSTEM

Organic dithiocarbamates (DTCs) have received considerable attention due to their

interesting chemistry and wide utility. They have widely been used in

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pharmaceuticals and agrochemicals as intermediates for the protection of amino

groups and recently in the synthesis of ionic liquids. In rubber industry,

dithiocarbamates have been used as vulcanization accelerators and antioxidants

because they have strong metal binding capacity. There are limited preparative

methods have been developed for the synthesis of dithiocarbamates. However, these

synthetic approaches suffer from the drawbacks such as low availability of starting

materials, harsh reaction conditions, high temperature, unsatisfactory yields and

expensive catalyst that may be harmful to be environment or sophisticated

techniques. The discovery of new green and more efficient synthetic protocols for

preparation of industrial and biologically active organo-sulfur compounds via C-S

bond formation have attracted a great deal of attention. In this context, PEG could

be used as green and recyclable reaction medium for selective reactions. A number

of reviews have also explained PEG chemistry and its application in biotechnology

and medicine. To address the concerns raised by volatile organic medium,

polyethylene glycol as an efficient reaction medium for CAN-catalyzed C-S bond

formation. Ceric ammonium nitrate (CAN) act as a water-compatible Lewis acid in

aqueous medium.

Given the proven utility of dithiocarbamates and the versatility of ceric

ammonium nitrate (CAN) and PEG-H2O system, these compounds were synthesized

using CAN as catalyst in PEG-H2O system. All the compounds showed excellent

antibacterial and anticancer activities. The structures of the synthesized

dithiocarbamates were confirmed by spectral analysis.

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CHAPTER-III

PART A: POLYETHYLENE GLYCOL: A RECYCLABLE SOLVENT

SYSTEM FOR THE SYNTHESIS OF BENZIMIDAZOLE

DERIVATIVES USING CAN AS CATALYST

Benzimidazole is a group of substances have found practical applications in organic

synthesis and a significant structural element in medicinal chemistry owing to its

diverse biological activities. Benzimidazoles are also being developed as DNA minor

groove binding agents with antitumor activity. These act as ligand to transition-metal

for modeling biological systems.

Benzimidazoles have been synthesized by a number of method and using a variety

of starting material. Although these methods suffer with many drawbacks such as long

reaction time, usage of expensive and corrosive reagent, high temperature with lesser yield

products. Hence the development of a synthetic protocol that is nature friendly and simple

remains an ever challenging objective. The versatility of CAN and the green nature of PEG

encouraged us to couple them together and study their utility for the synthesis of title

compounds. Reaction of equimolar amounts of o-phenylenediamine and aldehydes in the

presence of CAN as catalyst and PEG as reaction media yielded benzimidazoles in

excellent yields. All the known compounds were characterized by comparing their physical

property (MPs) and appearance of a broad singlet δ 9.67-13.09 due to NH in 1H NMR.

PART B: POTASSIUM CARBONATE (K2CO3) CATALYZED SYNTHESIS

OF THIOHYDANTOINS IN POLYETHYLENE GLYCOL AS AN

EFFICIENT AND REUSABLE SOLVENT MEDIUM

The substituted thiohydantoins based scaffolds have found attention in medicinal and

agriculture chemistry because they display a fascinating array of biological properties.

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353

The classical method for the synthesis of thiohydantoin is the reaction of isothiocyanate

with N-substituted α-amino acids or their esters. Numerous versions for the synthesis of

thiohydantoin derivatives have been developed in the past including solid phase synthesis,

microwave assisted synthesis, multicomponent reaction and fluorous synthesis. These

methods suffer mainly from the drawbacks such as lack of versatility, use of expensive

and corrosive reagents and solvents, long reaction times and tediuous workup procedures.

On the basis of complexing properties of PEG with K2CO3, we chose K2CO3

as catalyst in the synthesis of thiohydantoin. The various reported reactions of K2CO3

not only show its essentiality for particular reaction but also depict its other

characteristics like solubility in water, mild character, ecofriendly, non-toxic reaction,

low cost and easy availability. Thus K2CO3 provides mild basic condition for the

synthesis of thiohydantoins by easy separation with water.

Reaction between equimolar amounts of monosubstituted thiourea and

chloroacetylchloride with PEG as solvent and K2CO3 as catalyst yielded

thiohydantoin derivatives in excellent yields. The structure of all the products was

unambiguously established on the basis of their spectral analysis (IR, 1H NMR, 13C

NMR and mass spectral data).

CHAPTER IV

PART A: CERIUM CHLORIDE (CeCl3.7H2O) AS AN HIGHLY EFFICIENT

CATALYST FOR ONE-POT THREE-COMPONENT MANNICH

REACTION

Mannich reaction is one of the most important C-C bonds forming reaction. Basically,

Mannich reaction is the synthesis of β-amino carbonyl compounds and as such is one of

the most important reaction in organic synthesis. The gaining impetus of the Mannich

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reaction has been fuelled by the ubiquitous nature of nitrogen containing compounds in

drugs and natural products. The Mannich reaction is usually catalyzed by organic or

mineral acids. However, the classical Mannich reaction is plagued by a number of serious

disadvantages with limited applications. Therefore, numerous modern versions of

Mannich reaction have been developed to overcome the negative aspect of this classical

method. These early three-component reactions were hampered due to a number of

serious limitations such as long reaction times, harsh reaction conditions, toxicity and

difficulty in product isolation. Cerium(III) chloride heptahydrate (CeCl3.7H2O), which

has attracted considerable attention because of its diverse application as a promoter in

organic synthesis. In addition, many advantages such as excellent solubility in water,

inexpensiveness, eco-friendly nature, uncomplicated handling, high reactivity, fast

conversions and convenient work up procedures make CeCl3.7H2O a potent catalyst in

organic synthesis. In this work, we have found CeCl3.7H2O as an efficient catalyst for the

synthesis of β-amino carbonyl compounds at room temperature through a one-pot three-

component reaction of aromatic aldehydes, ketones and aromatic amines in methanol. It

is also noteworthy to mention that our environmentally benign reaction does not generate

any toxic waste products. The formation of the product was confirmed by appearance of a

doublet at δ 3.41 due to -CH2 in 1H NMR, 13C NMR, IR and mass spectra also support

the formation of the product.

PART B: A NOVEL METHOD FOR THE SYNTHESIS OF

TETRAHYDROBENZO[a]-XANTHEN-11-ONE DERIVATIVES

USING CERIUM(III) CHLORIDE Xanthene and its derivatives are known as an important class of heterocyclic

compounds, widely used as lecodyes, PH-sensitive fluorescent materials for

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visualization of biomolecules and are utilized in laser technologies due to their

photochemical and photophysical properties. They possess diverse biological and

therapeutic properties such as anti-inflammatory, antiviral and antibacterial activities.

These compounds are being utilized as antagonists for paralyzing action of

zoxazolamine and in photodynamic therapy. Among the molecules of this class,

benzoxanthen is a prominent structural motif found in various natural products and

synthetic compounds with important biological activities. Several methods have been

reported for the synthesis of tetrahydrobenzo[a]-xanthen-11-one and

benzo[f]chromen-3-one derivatives. These procedures have limitations of long

reaction time, harsh reaction conditions and often required expensive catalysts. The

eco-friendly nature of cerium(III) chloride as catalyst in the synthesis of organic

compounds, encouraged us to study their utility for the synthesis of

tetrahydobenzo[a]-xanthen-11-one derivatives via one-pot three-component reaction

of aldehydes, β-naphthol and cyclic 1, 3-dicarbonyl compounds in methanol at 50 ºC.

The structure of the compounds was confirmed by the appearance of singlet at δ 4.72

due to C-H in 1H NMR.

CHAPTER V

GOLD(III) CHLORIDE (HAuCl4.3H2O) IN PEG: A NEW CATALYTIC

SYSTEM FOR THE SYNTHESIS OF FUNCTIONALIZED

SPIROCHROMENES

The heterocyclic spirooxindole ring is a core structure presenting in a number of

pharmaceuticals and natural products including cytostatic alkaloids such as

tryptostatins, spirotryprostatins A, B and cyclotryprostatins. Among the oxygen-

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356

containing heterocycles fused with spirooxindole ring system, functionally substituted

4H-chromenes have received considerable attention due to the wide-ranging

biological properties such as anticoagulant, diuretic, anticancer and antianaphylactic

activities. Both naturally occurring and synthetic ensures that the synthesis of 5,6,7,8-

tetrahydro-4H-chromene derivatives bearing nitrile functionality remains a topic of

current interest. There are several methods have been reported for the synthesis of

spirooxindoles with fused chromenes in which conventional synthesis involves the

one-pot three-component condensation of isatin with cyclic 1,3-diketones and

malononitrile.

Recently, gold catalyzed reactions are an emerging area of interest in

transition-metal catalysis with tremendous potential for important synthetic

methods. Cationic gold(I) and gold(III) salts are soft carbophilic Lewis acids, have

shown extraordinary capability of activating C-C double and triple bond for an

inter or intra molecular nucleophilic attack to form a new C-C and C-N bond

formation reactions. On the other hand, the homogeneous mixture of PEG and

gold(III) chloride (HAuCl4.3H2O) as reaction components suggested that this is a

novel and highly efficient catalytic system for the synthesis of spirooxindole

derivatives.

We investigated an efficient and green protocol for one-pot three-component

reaction of isatins or acenaphthoquinone with active methylene compounds and cyclic

1,3-diketones catalyzed by gold(III) chloride (HAuCl4.3H2O) for the synthesis of

functionalized spirochromenes in polyethylene glycol (PEG) as green solvent medium

at 70 °C. The structure of the compounds was confirmed by the appearance of broad

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357

singlet at δ 7.42 due to -NH2 in 1H NMR, 13C NMR, IR and mass spectra also support

the formation of the product.

CHAPTER VI

DODECYLPHOSPHONIC ACID (DPA): A HIGHLY EFFICIENT CATALYST

FOR THE SYNTHESIS OF 2H-INDAZOLO[2,1-b]PHTHALAZINE-TRIONES

UNDER SOLVENT-FREE CONDITIONS

Among a large number of N-containing heterocyclic compounds i.e. phthalazine

moieties as ‘fusion site’ have received of great interest due to some pharmacological

and clinical applications. Moreover, phthalazine derivatives have 2-bridgehead

nitrogen atom in fused ring system, possess antimicrobial, anticonulsant, cytotoxic,

antifungal, anticancer and antiinflammatory activities. Despite their great importance,

several methods have been reported for the synthesis of phthalazine derivatives. These

methods have several disadvantages such as the use of toxic and explosive reagents,

harsh reaction conditions, and non recyclable catalyst. Dodecyphosphonic acid (DPA)

is a mild, recyclable and non-corrosive organic acid, acts as an efficient solid

surfactant type Bronsted acid catalyst. In this context, we decided to explore the

environmentally benign method for the synthesis of 2H-indazolo[2,1-b]phthalazine-

trione derivatives via one-pot three-component condensation of aromatic aldehydes,

1,3-dicarbonyl compounds and phthalhydrazide using dodecylphosphonic acid (DPA)

as recyclable catalyst under solvent free condition. The structure of synthesized

compounds was confirmed by spectral analysis.

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