Synthesis, Characterization and Biological Screening of ...shodhganga.inflibnet.ac.in/bitstream/10603/62136/7/07_chapter 01.pdf · Synthesis, Characterization and Biological Screening

Synthesis, Characterization and Biological Screening of Some Heterocyclic Compounds

PRATAPSINHA B. GOREPATIL 1

INTRODUCTION

Therapeutic/ Biological Importance of Heterocycles:

Heterocyclic compounds hold a special place among the pharmaceutically

significant natural products and synthetic compounds. Syntheses of various heterocycles

have been research objective for over a century. The chemistry of heterocyclic

compounds and their synthetic routes form the platform of medicinal, chemical and

pharmaceutical research. The remarkable ability of heterocyclic nuclei to serve both as

biomimetic and reactive pharmacophores made them key elements of numerous drugs.

Heterocyclic compounds are an integral part of organic synthesis. Nearly more than

half of the known organic compounds contain at least one heterocyclic ring. Many

heterocyclic compounds occur naturally and are actively involved in biological processes,

like nucleic acid bases, which are derivatives of the pyrimidine and purine rings systems,

as being crucial to the mechanism of replication. Many dyestuffs and pigments such as

indigo (1.1), strychnine (1.2), hemoglobin (1.3) and chlorophyll (1.4) are also having

heterocyclic moiety.1 Vitamins, penicillin and some amino acids like histidine,

tryptophan, proline are also having heterocyclic compounds.



Among the various heterocycles oxygen, nitrogen and sulfur bearing heterocycles

are immense importance to researchers as they include highly stable aromatic compounds

exhibiting wide range of biological activities such as medicine,2 agriculture,

3 veterinary

products and also as sensitizers, developers, antioxidants, copolymers, etc. During the

past decades, compounds bearing heterocyclic nuclei have received much attention due to

their chemotherapeutic value in the development of novel antimicrobials.4-5

Most of the

heterocyclic compounds with oxygen, nitrogen and sulfur as heteroatoms from the classes

like benzimidazole, benzothiazole, benzoxazole, quinoline have displayed wide range of

bioactivities. These heterocycles have been studied extensively because of their ready

accessibility; diverse chemical reactivity’s and wide range of biological activities.



In heterocyclic compounds fused heterocycles attract attention of researchers

because of its importance as building units in pharmaceuticals. Examples include

allopurinol (1.5) as a gout therapeutic,6 sildenafil (1.6) as Viagra, tubers din (1.7) as an

anticancer agent, abacavir (1.8) as an anti HIV agent, acyclovir (1.9) as an antiviral agent

for the treatment of Herpes.

Benzofused heteroaromatic compounds, in particular benzofused azoles, are

important building blocks in biologically and therapeutically active compounds, natural

products, and functional materials.7 In benzofused azoles- Benzo-1, 3-diazoles like

benzimidazole, benzoxazole and benzothiazole have attracted much interest in diverse

areas of chemistry.8

These heterocycles have shown different pharmacological activities.

The studies of structure–activity relationship interestingly reveal that change of the

structure of substituent groups commonly results the change of its bioactivity9-13

such as

antibacterial, antiulcer (1.10), antihypertensive, antivirals, antifungals, anticancer (1.11),



and antihistamines (1.12).14–19

These compounds are also used as ligands for asymmetric

transformations,20

exhibit nonlinear optical21

and luminescent22

/fluorescent.23

There are large numbers of synthetic benzo-1, 3-diazole compounds with

additional important applications and many are valuable intermediates in synthesis which

increases the great interest in both fields, theoretical and classical organic synthesis.

Recent Synthetic Protocols:

Following is a brief review on alternative safer and coast effective synthetic protocols.

“Classical organic synthesis seems to be inefficient and is now under pressure because

of increasing environmental awareness. How can it be improved?”

Organic chemistry is a vibrant and growing scientific discipline that touches a

vast number of scientific areas. It’s started as the chemistry of life, when that was thought

to be different from the chemistry in the laboratory. A reasonable way to define organic

chemistry is the study of the relationship between the structure and properties of carbon

compounds. The function of organic synthesis is to provide this study with access to

these compounds in a pure form, either by extraction from natural resources or via

synthesis, hence, “Synthesis is the heart of Chemistry”.

Organic synthesis is one of the foundation stone of the natural sciences. Synthetic

organic chemistry provides efficient routes and novel methods to synthesize molecules.

The development of excellent synthetic reactions leads to the creation of new organic



compounds, often opening up completely new areas of chemistry. Organic synthesis has

provided valuable materials in the form of medicines, food products, cosmetics, dyes,

paints, agrochemicals, biomolecules and high-tech substances like polymers. Chemists

have used their knowledge and skill to prepare a large number of new materials, which

are far better and more useful than the natural products such as high-tech polymers,

designer drugs, genetic materials and new energy sources.

Finally, organic synthesis is also undertaken with the goal of developing the most

economic route for the industrial synthesis of a product for which there is a definite need.

Nowadays, the green chemistry revolution is providing an enormous number of

challenges to those who practice chemistry in industry, education and research. With

these challenges however, there are an equal number of opportunities to discover and

apply new chemistry and to enhance the much-tarnished image of chemistry.24

In this

context would like to introduce the new image of chemistry, the challenge for today’s

organic chemists is not only synthesis of organic molecules but also to develop an

innovative, cleaner and greener process.

Green chemistry, also called sustainable chemistry, is a philosophy of chemical

research and engineering that encourages the design of products and processes that

minimize the use and generation of hazardous substances. Whereas environmental

chemistry is the chemistry of the natural environment, and of pollutant chemicals in

nature, green chemistry seeks to reduce and prevent pollution at its source. The focus is

on minimizing the hazard and maximizing the efficiency of any chemical choice. It is

distinct from environmental chemistry which focuses on chemical phenomena in the

environment. Examples of applied green chemistry are supercritical water oxidation, on

water reactions, and solvent free reactions. In 2005 Ryoji Noyori identified three key

developments in green chemistry: use of supercritical carbon dioxide as green solvent,

aqueous hydrogen peroxide for clean oxidations and the use of hydrogen in asymmetric

synthesis.25

The challenge for chemists and others is to develop new processes that allow to

achieve environmental benefits that are now required, in terms of safe chemistry. This



requires a new approach which sets out to reduce the materials and energy intensity of

chemical processes and products, minimize or eliminate the dispersion of harmful

chemical in the environment, maximize the use of renewable resources and extend the

durability and recyclability of the products. Some of the challenges for chemists include

the discovery and development of new synthetic pathways using alternative feed stocks

or more selective chemistry, identifying alternative reaction conditions and the

preservation of resources and the avoidance of toxic reagents as well as toxic solvents26

for improved selectivity and energy minimization and designing less toxic and inherently

safer chemicals. In chemical synthesis, the ideal will be a combination of a number of

environmental, health and safety, and economic targets (Fig. 1.1).

That’s why organic chemists are focusing on one-pot procedures. Indeed,

effective organic synthesis is predicated on site-isolation, the physical separation of

reagents or catalysts from each other. Synthetic organic chemists typically achieve site-

isolation by using separate flasks or reactors. The main problem, related to this kind of

“multi-pots” processes is amenable to the waste of solvents, because each step requires an

extraction, so, formation of an aqueous layer that must be treated at all. Beyond solvent,

high yielding reactions often produce salts and other impurities that must be removed to

avoid deleterious effects on the downstream transformations. Serial reactions and

purifications require massive amounts of solvents and materials.

Figure 1.1

ATOM EFFICIENT

SIMPLE METHOD

MAXIMUM YIELD

AVAILABLE MATERIALS

ENVIRONMENTALLY

ACCEPTABLE

NO WASTE REAGENTS

ONE STEP

SAFE

IDEAL

SYNTHESIS



Improving efficiency is one of the main pursuits of modern organic synthesis

research.27-28

This is further reinforced by the increasing concerns of environmental

protection and sustainability in past decades. To date the design, development, and

utilization of efficient environmentally benign synthetic process has become a

conscientious choice of synthetic chemists.29-30

One attractive strategy is to design and

develop a novel one-pot multistep synthesis that helps simplify reaction handling and

product purification, improve synthetic efficiency, and reduce solvent consumption and

disposal. This will ultimately help reduce consumption of natural resources, minimize the

potential, harmful impact of various chemicals on environment, and increase

sustainability.31

In contrast, modern synthesis management must seek procedures that

allow the formation of several bonds, whether C−C, C−O or C−N in one process. This

new approach is called “One-Pot” philosophy; it can be defined as, a strategy to improve

the efficiency of a chemical reaction whereby a reactant is subjected to successive

chemical transformation in just one reactor.

Multicomponent reactions (MCRs) have already created a stir among the organic

community and emerged as a powerful tool for the construction of novel and complex

molecular structures due to their advantages over conventional multistep synthesis;32

the

major advantages of MCRs include lower costs, shorter reaction times, high atom

economy, energy saving, and avoidance of time consuming expensive purification

processes.33

It is the fact that MCRs are generally much more environment friendly, and

offer instantaneous access to large compound libraries with diverse functionalities, with

the avoidance of protection and deprotection steps, for possible combinatorial surveying

of structural variations.34

Considering the need of incorporation of the green tools and to develop

convenient an efficient synthetic protocols for organic transformation that time catalyst

play an important role. Catalysis is broadly divided into homogenous and heterogeneous

catalysis. Homogenous catalytic reaction is one in which the reactant and catalyst are in

the same phase and if the reactants and catalyst are in different phase, it is heterogeneous

catalysis. However, many of these homogeneous catalytic processes suffered from a



serious limitation, namely, the separation and recovery of the catalyst. Recently the use of

heterogeneous catalysts35-47

has received considerable importance in organic synthesis

because of ease of handling, enhanced reaction rates, greater selectivity, and simple

workup. Furthermore, the exploitation of heterogeneous catalysts permits the easy

separation and reuse of the catalysts. This methodology constitutes a powerful tool in

chemistry, allowing extremely complex chemical transformations to take place in a one

pot, cleaner, and more efficient process. Transition metal catalysis is one of the

research areas with the richest history and chemistry. A wide range of transition metal-

catalyzed reactions, including hydrogenation, cross-couplings, metathesis, and various

addition and oxidation reactions, are utilized on industrial scales to manufacture valuable

products such as polymers, pesticides and human pharmaceuticals.48-55

The importance of catalysis to the pharmaceutical industry has steadily increased

over the past two decades. This was due to several interrelated factors: the increasing

regulatory requirements, for example, policies on single enantiomer drugs56

and

environmental protection, the pressure to reduce drug development cost and time; the lost

revenue for even a modestly successful drug can easily reach millions of dollars per day,

and the continued discovery of new practical catalysts from both academia and industry.

The interplay of all these factors resulted in the current rapid uptake of catalysis in

pharmaceutical research, development and production.57

In view of the above biological and pharmaceutical significance of the

heterocyclic compounds chemists developed newer convenient and rapid synthetic routes

for these value added heterocycles. It is reviewed that the classical cyclocondensation

reported for obtaining therapeutically active heterocycles bearing S/O and N heteroatoms

are time consuming, low yielding, requiring toxic solvents and catalysts and to

accomplish these cyclocondensations the catalysts employed are non-recyclable and work

up procedures of the isolations of the products are found to be more tedious.

Since last two decades efforts are also found to be directed to employ some of the

green tools to accelerate and to make synthetic routes environmentally benign for getting

bioactive heterocycles.



Keeping this object in mind the synthetic work for obtaining known and new

bioactive heterocycles and their precursors have been carried. While constructing the

molecules, successful attempts have been made to provide modified convenient and cost

effective synthetic routes for obtaining the required precursors and the desired products

with high yields.

Hence the present work entitled “Synthesis, characterization and biological

screening of some heterocyclic compounds” was undertaken and the details of the

synthetic work (carried using simple, efficient methods and also environmentally benign

green protocols like aqueous reaction media or nontoxic solvents, one pot synthesis and

reusable heterogeneous catalyst), characterizations of the intermediates and desired

products have been presented in the forthcoming four chapters of this thesis.



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