Chapter-1

Introduction

1.1. Introduction

Heterocyclic compounds are cyclic compounds in which one (or) more of the ring carbons are

replaced by another atom. The non-carbon atoms in such rings are referred to as “heteroatoms”.

Heterocycles form, by far, the largest of the classical divisions of organic chemistry. Moreover, they are

of immense importance not only biologically and industrially but also to the functioning of any

developed human society as well. The majority of pharmaceutical products that mimic natural products

with biological activity are heterocycles. Therefore, researchers are on a continuous pursuit to design

and produce better pharmaceuticals, pesticides, insecticides, rodenticides, and weedicides by following

natural models. Heterocycles play a major part in biochemical processes and are also side groups of the

most typical and essential constituents of living cells. Other important practical applications of these

compounds can also be citied, for instance, their use as additives and modifiers in a wide variety of

industries including cosmetics, reprography, information storage, plastics, solvents, antioxidants, and

vulcanization accelerators. Finally, as an applied science, heterocyclic chemistry is an inexhaustible

resource of novel compounds. A vast number of combinations of carbon, hydrogen, and heteroatoms

can be designed, providing compounds with the most diverse physical, chemical, and biological

properties.1,2 Among the approximately 20 million chemical compounds identified by the end of the

second millennium, more than two-thirds are fully or partially aromatic, and approximately one-half are

heteroaromatic.

Heterocyclic compounds, especially nitrogen heterocycles, are most important class of compounds in

the pharmaceutical and agrochemical industries, in which heterocycles comprising around 60% are

covered as a drug substances. 5-membered N-heterocycles such as pyrroles, indoles, and carbazoles are

important structural motifs and are present in an extensive number of biologically active compounds.3

The 5-membered N-heterocycles are of exceptional interest in the pharmaceutical industry, as they

appear in the core structure of several drugs. Six membered heterocycles such as substituted pyridines

exhibit a broad range of biological activity. They are used to modulate hypertension, anginapectoris, act

as Ca2+ channel blockers and are anti-diabetic, heptaprotective and show anti-tumor properties.4 The

fused quinoline moiety is also present in an extensive number of naturally occurring and biologically

active photochemical properties.5 In addition, pyridine derivatives are also used as organic bases and

organocatalysts in organic synthesis.

6-Membered aromatic rings containing two nitrogen atoms, such as phthalazinones,

quinazolinones, pyrimidines and pyrimidinones, possess a broad spectrum of biological activities and are

therefore of interest as target compounds in pharmaceutical and medicinal chemistry.6 6-Membered

rings containing three nitrogen atoms, like 1,3,5-triazines are used as a templates in supramolecular

chemistry and dendrimer synthesis, due to their unlike C3 symmetric core structure.7 7-and higher

membered nitrogen containing compounds, e.g. benzodiazepines, show interesting anticancer

properties and inhibit HIV-1 reverse transcriptase.8

Due to the immense biological activities of nitrogen containing heterocyclic compounds, we

have became interested in the synthesis of various polyhydroquinoline, N-substituted pyrroles,

pyrrole[1,2-α]quinoxalines, quinoxalines, bisindoles, and functionalization of indoles and 7-azaindoles. In

addition to the above nitrogen containing compounds we have also focused on acylation of protic

nucleophilies such as alcohols, sugars, phenols, amines and thiols. The following few sections covers the

review of the N-heterocyclic compounds we have undertaken as a core are of research.

1.1.1. Dihydropyridines:

Heterocycles containing the dihydropyridine ring are important targets in synthetic and

medicinal chemistry as they are the key moiety in numerous biologically active compounds.9 Some of

them, such as Amlodipine 1, Felodipine 2, Isradipine 3, Lacidipine 4, Nifedipine 5, (Figure 1.1) are

prominent drugs in the treatment of cardiovascular diseases and hypertension as effective calcium

channel blockers.10 1,4-dihydropyridines are also good precursors for the synthesis of corresponding

substituted pyridine derivatives11 and are useful as reducing agents for imines in the presence of a

catalytic amount of Lewis acid.12

Figure 1.1. Pharmacologically active compounds containing the dihydropyridine motif.

1.1.2. 3,4-Dihydropyridine-2 (1H)-one:

Owing to their remarkable pharmacological properties such as calcium channel blockers,

antitumor and anti-inflammatory activities, dihyropyrimidinones and their derivatives have increasingly

attracted the attention of chemists.13 Nitractin 6 was first reported in the 1960’s as an agent against the

trachoma group of viruses.14 Monastrol 7 is known as a specific inhibitor for mitotic kinesis Eg5 and is

considered as lead compound to develop new anticancer drugs.15 Also, (R)-SQ32926 8 has been

identified as a potent orally active antihypertensive agent.16 Furthermore, some marine natural products

containing the dihydropyrimidine-5-carboxylate core have been isolated which exhibited interesting

biological activities.17

Figure 1.2. Pharmacologically active compounds containing the 3,4-Dihydropyridine-2 (1H)-one motif.

1.1.3. Pyrroles:

The chemistry of pyrrole and its derivatives has been enjoying a relative renaissance of interest

due to the growing abundance of pyrrolic components in a various natural products, pharmaceuticals,

and new materials. Pyrrole is the major constituent of naturally occurring tetra pyrroles, such as Hem,

Chlorophyll, Vitamin B12 and various cytochrome enzymes. Moreover, the blockbuster Atorvastatin

calcium 9 (Lipitor@) is a pentasubstituted pyrrole and is the most prescribed drug for cholesterol

lowering.18 N-substituted pyrrole compounds N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole 10

and N-(4-carboxy-4-chloro)phenyl pyrrole 11 are novel human immunodeficiency virus type-1 entry

inhibitors.19

Figure 1.3. Pharmacologically active compounds containing the pyrrole motif.

1.1.4. Quinoxalines:

Figure 1.4. Pharmacologically active compounds containing the quinoxaline motif.

Quinoxaline 12 is also known as benzopyrazine. It is a heterocyclic compound containing

benzene ring and pyrazine ring. Quinoxaline and its derivatives are important nitrogen containing

heterocycles20 that possess a broad spectrum of physiological and biological activities and can act as a

anti-cancer21 and anti-HIV22 agents, glucagon receptor antagonists23 and angiotensin receptor

antagonists.24 They have also been used as a template for the synthesis of GABA benzodiazepines

receptor agonists or antagonists25 and for other therapeutic applications.26 Besides these

pharmaceutical applications, this class of compounds has also been used as building blocks for the

synthesis of organic semiconductors, dyes, useful rigid subunits in macrocyclic receptors, and chemically

controllable switches.27 Due to the similarity between some antitubercular drugs and quinoxaline, as

well as the presence of the quinoxaline moiety in some broad spectrum antibiotics, it was hoped that

quinoxaline analogs would exhibit antitubercular activity. Some of quinoxaline analogs, such as 2,3-

bis(2-pyridyl)-quinoxaline 13 (DPQ) complexed with transition metals are of current interest in view of

its binding to DNA. This may suggest that conjugation of biologically active peptides with quinoxaline

analogs can head to new therapeutic agents possessing interesting anticancer properties.28

1.1.5. Indoles:

Figure 1.5. Pharmacologically active compounds containing the indole motif.

Indoles and their derivatives possess various biological properties like antibacterial, cytotoxic,

antioxidative and insecticidal activities. Bis(indolyl)alkanes has received considerable attention because

of occurrence in bioactive metabolites of terrestrial and marine origin.29 3,3’-Diindolyl methane 14 (DIM)

is a major digestive product of indol-3-methanol, a potential anticancer component of cruciferous

vegetables.30 3,3’-Diindolyl methane is potent activator of the immune system in vivo.31 Recent biological

studies show that 3,3’-diindolyl methane 14 worked as HIV-1 integrase inhibitor.32 Vibrindole A 15

exhibits antibacterial activity33 and its metabolites of the marine bacterium Vibrio parahaemocyticas.

Compound 16 has growth inhibitory activity on prostate cancer cells.34 Compound 17 reported to act as

non steroidal aromatage inhibitor against breast cancer.35

The indole moiety is present in a number of drugs currently on the market. Many of them

belong to triptans, which are used mainly in the treatment of migraine headaches. These are agonists of

migraine associated 5HT1B and 5HT1D serotonin receptors. Sumatriptan 18. (Imitrex) was developed by

Glaxo for the treatment of migraines. Relative to the second generation triptans, Sumatriptan has lower

oral bioavailability and a shorter half-life. Frovatriptan 19 (Frova) was developed by Vernalis for the

treatment of menstruation associated headaches. Frovatriptan’s affinity for migraine specific serotonin

receptors 5HT1B is believed to be the highest among al triptans.36 In addition, Frovatriptan binds to

5HT1D and 5HT7 receptor subtypes.37 Zolmitriptan 20 marketed by AstraZeneca is used to treat acute

migraine attacks and cluster headaches. GlaxoSmithKline’s Naratriptan 21 (Amerge) is also used in the

treatment of migraines and some of its effects include dizziness, tiredness, tingling of the hands and

feet’s and dry mouth. All available triptans are well tolerated and effective.38

Figure 1.6. Pharmacologically active compounds containing the indole motif

Various approaches adopted to synthesize this important class utilizing different green catalysis,

homogeneous and heterogeneous catalysis like Iron, Palladium and resins.

1.1.6. Introduction to green catalysis:

Our on-going research on N-heterocyclic compounds we became interested to apply greener,

environmentally sound synthetic protocols and reaction conditions for the synthesis of above nitrogen

containing heterocyclic compounds. Catalyst is becoming a

strategic field of science because it represents a new way to meet the challenges for scientists have

included the discovery and the development of new synthetic pathways using alternative reaction

conditions and solvents for improved selectivity and the design of less toxic and inherently safer

chemicals. Significant progress has been made in the improvement of sustainability39 and the role of

catalysis as a key technology to achieve the objectives of sustainable chemistry has been considered.40

The area of catalysis is sometimes referred to as a “foundational pillar” of green chemistry.41 Catalytic

reactions often reduce energy requirements and decrease separations because of increased selectivity,

they may permit the use of renewable feed stocks of less toxic reagents (or) minimize the quantities of

reagents needed. New catalytic organic transformations they have offered several possibilities for a

relevant improvement in the eco-compatibility of fine chemical production, allowing a drastic decrease

in the E-factor.

Current research activities on new green catalytic systems that provide resource-saving

synthetic transformations through transition metal catalyzed reactions.42 Recently, the discovery of

those recyclable catalysts are growing interest in investigation of the chemical and catalytic properties.

Recyclable catalysts, because of their unique properties, have now become a well-established best

choice for many chemical transformations with preeminence established now in both heterogeneous

and homogeneous processes.

1.1.7. Homogeneous and heterogeneous catalysts:

Catalyst can be broadly divided into two branches, homogeneous and heterogeneous. In a

homogeneous catalytic system, the active catalyst sites and the reactants are in the same phase, this

system allows for easier interactions between the components, which in turn results in better activity.

Homogeneous catalysts have several other advantages, such as high turnover numbers and high

selectivity. Although these catalysts are widely used in a variety of industries, it is often difficult to

isolate and separate the final product after the reaction completion. Even when it is possible to separate

the catalyst from the reaction mixture, trace amount of catalyst are likely to remain in the final product.

It is essential to remove the catalyst because metal contamination is highly regulated, especially in the

drug and pharmaceutical industry. One efficient way to overcome the problem of isolation and

separation with a homogeneous catalyst is the heterogenization of active catalytic molecules, thus

creating a heterogeneous catalytic system.43 Heterogenization is commonly achieved by entrapment or

grafting of the active molecules on surface (or) inside the process of a solid support, such as silica, or

alumina. However, the active sites in heterogeneous catalyst are not as accessible as in a homogeneous

catalyst, and thus the activity of the catalyst is usually reduced.

1.1.8. Importance of solvent:

In addition to the catalyst, solvents are also play a vital role in the reactions. Today, in the fine

chemical (or) pharmaceutical industries, solvents are used in larger quantities relative to the product.

Therefore, solvents are considered as the major cause of the environmental damage attributed to an

industrial process. The idea of “green solvent” expresses the aim to minimize the environmental impact

resulting from the use of solvent in the chemical process. Therefore, the term green solvent should be

associated with low toxicity, low vapor pressure, and good biodegradability or non-environmentally

damaging. Currently, water, supercritical fluids (SCFs), florous solvents and solvents from renewable

sources are considered green solvents. Obviously, water is the most desirable solvent because it is

abundant, inexpensive, and safe. Water is one of the most fascinating liquids on the Earth and quite

often exerts a remarkable influence over the chemical transformations performed in this media. Over

the last decade, as bystander to an explosion of research activity on the use of water, a substantial

contribution was in fact made by the endeavors of green chemistry.44 Therefore it is the aim for us to

synthesis of heterocycles using water as a solvent because they represent one of the most important

classes of organic molecules present in most life forms on Earth. Reaction in solvent-free conditions has

been also an excellent way to minimize the waste. Furthermore, the use of solvent free conditions has

several advantages like reduce the use of high amount of volatile organic solvents, reducing pollution

and some cases desired products attained easily.

1.1.9. Iron as a catalyst:

Consequently, we need a catalyst system that not only shows high activity and selectivity but

also possesses the ease of catalyst separation and recovery. Therefore, we want to use iron as a catalyst

for the synthesis of nitrogen containing heterocyclic compounds. Iron is one of the most important

metals in nature, which is closely related to the life of the human being.45 In nature, iron is the most

abundant transition metal and plays a very important role in the human body as a “king of metal”, which

showed its magical catalytic ability to facilitate many bioactivities.46 The application of iron in human

history can be traced back to ancient times. Initiated from the mining of the ferrolite, the study of iron is

also one of the oldest fields in chemistry. Iron is also one of the metals which have been early and

successfully used in constructing organic compounds. Since then, the development of iron chemistry in

organic synthesis has never been due to its advances and significance. The studies in this field have been

well reviewed in different aspects in past several decades. To date, many scientists have made

significant contributions in this filed, and various iron catalyzed organic transformations have been

revealed,47 including nucleophilic additions, substitutions, protections, deprotections, reductions,

oxidations, hydrogenations, cycloadditions, iosmerizations, rearrangements, and as well as

polymerizations etc.

1.1.10. Palladium as a catalyst:

Along with iron, we explored Palladium catalyzed reactions. The palladium catalyzed

transformations have seen a fascinating development in recent years. The importance of palladium in

synthesis is evident from the huge number of name reactions in connection with this in the formation of

C–C, C–N, C–O and even C–S bonds in the mildness of most of these processes, tolerating many

functional groups. Palladium catalyzed C–N, C–C, and C–O bond forming reactions, between indole and

7-azaindole and amides, amines, amino acids and phenols have recently being gained popularity among

the scientific community for different discovery drug development programs. Particularly, various 7-

azaindoles(1H-pyrrole[2,3-b]pyridine,48 including 4-substituted compounds49 have also been find

applications in various therapeutic areas. Despite their utility in various drug development programs,

methods for the synthesis and functionalization of indoles and 7-azaindoles scaffolds remain limited.

Amino substituted 7-azaindoles appear in a variety of biologically active molecules 22, 23, 24 and 2550

(Figure 1.7). They are very challenging and lengthy to prepare via the traditional methods.

Figure 1.7. Pharmacologically active compounds containing the amino-azaindole motif.