1 Chapter-1

CHAPTER-I

Introduction and Literature survey

2 Chapter-1

1.1 Introduction

Literature survey revealed that the history of heterocyclic chemistry began in

the 1800's, in step with the development of organic chemistry 1-5. After World War II,

there was an enormous expansion research has took place in the field of heterocycles.

Among one half of over six million compounds recorded in Chemical Abstracts are

heterocyclic. Heterocyclic chemistry is among the most complex and challenging branch

of organic chemistry and heterocyclic compounds constitute the largest and most unique

family of organic compounds. Many broader aspects of heterocyclic chemistry are

recognized as disciplines of general significance that impinge on almost all aspects of

modern organic chemistry, medicinal chemistry and biochemistry. Heterocyclic

compounds offer a high degree of structural diversity and have proven to be broadly and

economically useful as therapeutic agents.

Heterocyclic compounds are organic compounds containing at least one atom

of carbon and at least one element other than carbon, such as sulfur, oxygen or nitrogen

within a ring structure 6. Since in heterocycles non-carbons usually are considered to

replace carbon atoms, they are called heteroatoms e.g. different from carbon and

hydrogen. A ring with only heteroatoms is called homocyclic compound and heterocycles

are the counterparts of homocyclic compounds. Thus incorporation of oxygen, nitrogen,

sulfur or an atom of a related element into an organic ring structure in place of a carbon

atom gives rise to a heterocyclic compound. These structures may comprise either simple

aromatic rings or non-aromatic rings. The heterocyclic compounds usually possess a

3 Chapter-1

stable ring structure which does not readily hydrolyzed or depolymerized. Those

containing one heteroatom are in general, stable. Those with two heteroatoms are more

likely to occur as reactive intermediates.

Heterocyclic compounds played a vital role in biological processes and are

wide spread as natural products. They are widely found in nature particularly in nucleic

acids, plant alkaloids, anthocyanins and flavones as well as in haem and chlorophyll.

Additionally some vitamins, proteins, hormones contain aromatic heterocyclic system.

Synthetically produced heterocycles designed by organic chemists are used for instance

as agrochemicals and pharmaceuticals and play an important role in human life.

Heterocycles have enormous potential as the most promising molecules as lead structures

for the design of new drugs 7-10.

In short, heterocyclic chemistry is the branch of chemistry dealing with

synthesis, properties and applications of heterocycles

This thesis emphasizes the application of new heteroaryl and aryl bis-imines,

zeolites and proline as green catalyst for the preparation of well known drug intermediate

and generation of small library molecules of potential pharmacological interest based on

thiazole. In detailed the protocol mentions a) a new and efficient method for the

preparation of novel aryl and heteroaryl bis-imines, biological activity and its application

in increasing the enantioselectivity of racemic secondary alcohol in presence of lipase a

key intermediate in well known drug called rivastigmine. b) A novel approach for

construction of thiazole ring and the proline mediated Sonogashira coupling for

generation of libraries of small molecules of potential pharmacological interest based on

4 Chapter-1

4-alkynyl substituted thiazole. Moreover the biological activity of bisimines and thiazole

moiety has been explored. In addition, the reactions conditions are mild and mention the

use of environmentally friendly catalysts and compatible to each other to enable

sequential reactions. Industrial applications of these catalysts have steadily increased.

1.2: Literature Review

1.2.1: Achiral Bis-Imines

Schiff base was first reported by Hugo Schiff in 1864.11 Schiff bases can be

prepared by condensing carbonyl compounds and amines in different conditions and in

different solvents with the elimination of water molecules. The presence of a dehydrating

agent normally favors the formation of Schiff bases. Though the Schiff bases are stable

solids, care should be taken in the purification steps as it undergoes degradation.

Chromatographic purification of Schiff bases on silica gel is not recommended as they

undergo hydrolysis. The common structural feature of these compounds is the

azomethine group with a general formula RHC=N-R’, where R and R’ are alkyl, aryl,

cyclo alkyl or heterocyclic groups which may be variously substituted. Presence of a lone

pair of electrons in an sp2 hybridized orbital of nitrogen atom of the azomethine group is

of considerable chemical importance and impart excellent chelating ability especially

when used in combination with one or more donor atoms close to the azomethine group.

Examples of a few compounds are given in Figure- 1. This chelating ability of the Schiff

bases combined with the ease of preparation and flexibility in varying the chemical

environment about the C=N group makes it an interesting ligands in coordination

chemistry.

5 Chapter-1

In addition to these, Schiff base macrocycles have been prepared by well known

self condensation reaction of appropriate formyl- or keto- and primary amine precursors

and find wide applications in macrocyclic and supramolecular chemistry. Schiff bases

easily form stable complexes with most transition metal ions and stabilize them in

various oxidation states.

Fig 1.1: Some examples of Schiff bases

When aldehyde is a salicylaldehyde derivative and amine is a diamine derivative, the

condensation produces interesting N2O2 Schiff base compounds. The so called salen

6 Chapter-1

ligands are very much like porphyrins and, unlike the latter, can be easily prepared.

Although the term salen was originally used only to describe the tetradentate Schiff bases

derived from salicylaldehyde and ethylenediamine, the term salen-type is now used in the

literature to describe the class of (O, N, N, O) tetradentate bis Schiff ligands. Stereogenic

centers or other elements of chirality (planes, axes) can be introduced in the synthetic

design of Schiff bases (Figure 1.2).

Fig 1.2: N2O2 Schiff base compounds

7 Chapter-1

Stereo chemical investigation carried out with the aid of molecular model showed that

Schiff base form a charge transfer complex between N atom and oxygen atoms of the

Schiff bases with the aid of metals like Cu, Zn and Co. Transition metal complexes of

such ligands are important enzyme models. The rapid development of these ligands

resulted in an enhance research activity in the field of coordination chemistry leading to

very interesting conclusions.

1.2.2: Achiral bis-imines as synthetic tools for active pharma ingredients:

Schiff base complexes play a central role in various homogeneous catalytic

reactions and the activity of these complexes varies with the type of ligands,

Coordination sites and metal ions. Literature reports reveal that a large number of Schiff

base metal complexes exhibit catalytic activities. Chiral Schiff base complexes are more

selective in various reactions such as oxidation, hydroxylation, aldol condensation and

epoxidation. A discussion on the catalytic activity of Schiff base metal complexes in

various reactions are outlined in this section.

Chirality in drug synthesis receives special attention due to the implications of

different biological activities exhibited by the enantiomers of chiral molecules. A survey

done in 2006 for the syntheses of 128 drug candidate molecules under development in the

Process Chemistry R&D departments of GlaxoSmithKline, AstraZeneca and Pfizer

revealed that 69 drug molecules contained at least one asymmetric center. Only two

chiral drug molecules out of 69 were developed as racemates. In the case of racemic

drugs available already on the market, the switch to single-isomer drugs offers the

possibility to extend the patent lifetime. Racemic drugs may still be approved if the

8 Chapter-1

choice of a racemate versus a single-enantiomer formulation is justified. The advantage

of a single stereoisomer drug is a superior therapy which could be accomplished by

reduction in dose, reduced variability in metabolism and response and improved

tolerability.

As already stated achiral bis-imines is regarded as an attractive tool for

pharmaceutical sector in the synthesis of new drug molecules. The complexity of small

APIs is increasing continuously regarding the number of different functional groups and

number of asymmetric centers. The properties of achiral bis-imines such as regio- and

stereoselectivity are useful to develop synthetic routes under mild conditions and with

reduced number of steps when protection/deprotection steps are avoided. Academic

research has already proved that many intermediates for drug synthesis may be accessed

by achiral bis-imines mediated in presence of chiral actualizer with high selectivity. The

challenge is to transfer the knowledge from the laboratory bench to the production plant

and to integrate it into the overall chemical synthesis of a drug molecule.

Excellent reviews are available for applications of bisimines for the synthesis

of pharmaceutical intermediates. The examples which follow below are selected to

illustrate the potential of the achiral bisimines towards the preparation of drug

intermediate. The achiral bisimines step is shown in the boxes.

Case 1 – (S)-Miconazole

As a synthetic application of the procedure, we have achieved the

enantioselective synthesis of (S)-miconazole (Scheme 1.1), a potent antifungal agent. (S)-

1-(2,4- Di chlorophenyl)-2-nitroethanol, obtained from the Henry reaction of nitro

9 Chapter-1

methane and was reduced in a yield of 82% to the corresponding hydroxylamine by

treatment with zinc/HCl. This transformation was not successful with other procedures,

such as catalytic hydrogenation, because they caused hydrogenolysis of the C- Cl bond.

The imidazole ring was synthesized from glyoxal, formal. The imidazole ring was

synthesized from glyoxal, formaldehyde, and ammonium acetate, to give in a yield of

70%.Finally alkylation of the hydroxyl group with 2,4-dichloro-1-(chloromethyl)benzene

afforded (S)-miconazole in a yield of 76% with an ee value of 98%, without loss of

optical purity in any of the synthetic sequence.

Scheme-1.1

RCHO + CH3NO2

N N

Cu(OAc)2.H2ODIPEA,EtOH-40 to -650 C

RNO2

OH

(S)

Henry reaction catalyzed by Cu and iminopyridine ligand

The protocol mentions a highly enantioselective Henry reaction with aldehydes that uses

a new aminopyridine ligand based on our previous design for iminopyridine ligands.

High enantioselectivity have also been achieved with other C2-symmetric N, N-ligands,

such as bisimines19 and bispyridines with metal catalyst.

Case 2 – cis-Bis-b-lactams

Although b-lactam derivatives are well known for their antibiotic activities,

recently they have also been used as a synthon for the synthesis of various natural and

unnatural products. Ojima has shown the utility of bis-b-lactams for the synthesis of

10 Chapter-1

peptides. The synthesis of bis-b-lactams, in general, has been reported by step-wise

construction of achiral bisimines as shown in Scheme 1.2

Scheme-1.2

Synthesis of bis-b-lactams

The protocol mentions new approach for the synthesis of bis-b-lactams in single step

derived from bis-amine

1.2.3: 4 - Substituted Thiazole:

Molecules that possess sulfur atoms are important in living organisms. One such

important class of heterocyclic compound that contains one sulfur atom is known as

thiazole. Five membered aromatic rings occupy a position of particular significance in the

enormous field of heterocyclic chemistry. Thiazole is one of the important members of

this family and thus merits a comprehensive study. Thiazole derivatives were first

reported by Hantzsch and Weber in 1887, although benzothiazoles had been described in

1879. The importance of thiazole ring system was enhanced in the 1930’s, when

Williams and Cline showed that thiamin (vitamin B1) contained a thiazole ring and one of

the major sulfa drugs, sulfathiazole was produced. The class of heterocyclic compounds

known as thiazole is found in many natural and synthetic products with a wide range of

pharmacological activities with different biological activities that represent a very

important field in drug discovery. The depiction of various applications of thiazoles is

described in figure -1.3

11 Chapter-1

Fig 1.3: Various applications of thiazoles

Literature survey reveals that the 4-substitutedalkynylthiazole has received considerable

attention as they are endowed with variety of biological activities and wide range of

therapeutic activities. There are few literatures available on these derivatives.

Literature survey reveals that the 4-substituted akynyl-thiazole has received

considerable attention as they are endowed with variety of biological activities and wide

range of therapeutic activities. There are few literatures regarding derivatives of thiazole

are termed as under.

Rossen. et al., have reported thiazole as carbonyl biostere. A novel class of

highly potent and selective 5HT3 receptor antagonists.18

Oya Bozdag Dundar et al., has synthesis zed novel class 2, 4-disubstituted

thiazoles antimicrobial activity 19.

12 Chapter-1

Mislins et al., have reported synthesis of new thiazole analogues of pyochelin a

siderophore of p-argenosa and Borkholderia cepacia. A new conversion of

thiazolin ti thiazole.20

Ryabinin. et al., have reported synthesis and evaluation of oligi-1,3 thiazole

carboxamide derivatives as HIV-1 reverse transcriptase.21

S

N

HN

O S

N

HN

O

NH2

NH

H2NO

Subbagh HI. et al., reported anti-tumor activity, after synthesis and anti-tumor

activity of ethyl 2-substituted aminothiazole-4-carboxylate analogs22.

13 Chapter-1

Pattan. et al., reported anti-inflammatory activity, after synthesis,

characterization and anti-inflammatory activity of some 2-amino thiazole

derivatives23.

Subbagh HI. et al., has synthesis zed novel class 2,4-disubstituted thiazoles

antimicrobial activity 24.

Literature survey reveals that the 4-substitutedalkynylthiazole has received considerable

attention as they are endowed with variety of biological activities and wide range of

therapeutic activities. There are few literatures available on these derivatives.

14 Chapter-1

1.3 Concepts and Applications of green chemistry catalysts:

Green chemistry is an approach to the design, manufacture and use of chemical

products to intentionally reduce or eliminate chemical hazards.25, the goal of green

chemistry is to create better, safer chemicals while choosing the safest, most efficient

ways to synthesize them and to reduce wastes.

In 1991 Paul Anastas coined the term and defined the field of ‘‘Green

Chemistry’’. The same year the first ‘‘Green Chemistry’’ program, the ‘‘Alternative

Synthetic Pathways’’ research program, was launched. From a theoretical viewpoint, like

‘‘atom economy’’ proposed by Trost and the ‘‘E factor’’ introduced by Sheldon, gave

impetus to the creation of a new way of thinking about chemistry and to the development

of a green metric able to provide quantitative support to compare the ‘‘greenness’’ of

alternative products and processes26.

From a functional point of view, several earnest attempts made to promote

green chemistry activities got under way. In 1995 the Presidential Green Chemistry

Challenge Award, put forth by Anastas to the White House, was approved. Since then,

every year the Presidential Green Chemistry Challenge Awards highlight achievement in

research, development and industrial implementation of technologies that prevents

pollution at source while contributing to the competitiveness of the innovators. In

1997Anastas co-founded the Green Chemistry Institute, which worked closely with

industries and universities on environmental issues, and expanded its international

network to consortia in many different nations. Other initiatives in the green chemistry

field rapidly spread throughout the world, e.g. in Italy, Canada, UK, Australia and Japan

15 Chapter-1

and above all Green Chemistry journal was launched in 1999 by the Royal Society of

Chemistry.

Green chemists also take a life cycle approach to reduce the potential risks

throughout the production process. A green chemistry approach is one of “continual

improvement, discovery, and innovation” that will bring us ever closer to processes and

products that are safe within natural ecosystems. Finally a product should safely degrade

as a biological nutrient or it should be safely recycled

1.3.1: Catalysis

Catalysis is the engine that drives the development of chemistry. Everybody can

easily recognize that top achievements in applied chemistry are focused on industrial

applications of catalysis, rational design, serendipitous discovery or combinatorial

identification of new ligands, catalysts, new solid supports (organic, inorganic,

amorphous or mesoporous silica phases, metal organic frameworks, etc).

An ideal catalyst should approach 100% selectivity while reaching high levels of

productivity. Selectivity refers first of all to

(i) Chemoselectivity, which means the catalyst, must be able to select preferred

reactants from complex mixtures.

(ii) Regioselectivity, which means selection of preferred sites of the reacting

substrate.

(iii) Stereoselectivity, which means preferred formation of a single stereoisomer.

Catalysis is traditionally divided into heterogeneous and homogeneous catalysis. In this

case costly and time-consuming unit operations, such as crystallization, chromatography

or distillation, are necessary to both purify the product and to recover and eventually

16 Chapter-1

NH

CO2H

L-proline (organocatalyst)

reuse the catalyst. The heterogenized catalyst is, however, often less effective than their

homogeneous counterparts.

Thus there exists a need to develop new, innovative approaches toward the design

of recoverable and reusable asymmetric catalysts with the aim of combining the

advantages of heterogeneous and homogeneous catalysis.

1.3.2: Different type of green chemistry catalysts

1

Fe

Cl

ClCl

Iron(III) chloride

2

3 4

Jacobson catalyst

5 6

Fig1.4: Examples of Green chemistry catalyst.

H BF

FFhomogeneous acid catalysts

17 Chapter-1

1.3.3: Life -cycle assessment

Green chemists also take a life cycle approach to reduce the potential risks

throughout the production process. They work to assure that a product will pose minimal

threats to human health or the environment during production, use, and at the end of its

useful life when it will be recycled, or disposed of. A green chemistry approach is one of

“continual improvement, discovery, and innovation” that will bring us ever closer to

processes and products that are safe within natural ecosystems. Ultimately a product

should safely degrade as a biological nutrient or it should be safely recycled

Fig 1.5: Life cycle approach of green chemistry process

Green chemistry reduces all along the life cycle of chemical production and also gives

economic benefit, thereby reduces societal pressure and government legislation.

1.4: Recent Literature of green chemistry catalysts

1.4.1 Iron chloride as catalyst

Organometallic catalysts have a tremendous importance in the field of modern

organic synthesis. Many processes only take place when metal complexes offer new

reaction pathways. The organic ligands complexed to the metal allow tuning the

18 Chapter-1

reactivity of the metal and are responsible for the chemo- and stereoselective outcome of

the catalyzed reaction. Among the large variety of transition metals which were used as

catalysts iron plays a special role. In contrast to toxic metals (i.e. Cr, Os, Co.), iron is a

physiologically and environmentally friendly metal. The few toxic iron compounds can

easily be oxidized or hydrolysed to harmless iron salts. And the large aboundance of iron

in earth’s crust (4.5 %, second most after aluminium) renders it a very cheap metal source

compared to those which were mainly used for catalytic processes (i.e. Pt,28 Pd,29

Ru30…). Its low costs offer the possibility to engage iron in stoichiometric manner.

Despite these obvious advantages only few iron complexes are used for synthetic

applications.

Iron is the most abundant metals on the earth, although the coordination

chemistry of iron has been widely developed in the past decades, it is really surprising

that until lately iron was underrepresented as homogeneous catalysis compared to the

other transition metals. However the last few years have seen a rise of the use of iron as a

catalyst and very efficient processes that are now able to compete with other metal

catalyzed ones have emerged in the carbon-carbon bond formation. Iron salts have

recently attracted considerable attention as inexpensive and environment friendly agents

in a wide range of selective processes in organic synthesis. Iron (III) chloride for its

acidic properties the hexahydrate and anhydrous salts were useful for the reactions like

hydrolysis,31,32 acetal formation,33-34 reductive etherification,35 acylation,36

hydrosilylation, oxidation and carbon nitrogen bond formation.37

19 Chapter-1

Recent Applications of Iron (III) Chloride

Aldol reaction

The aldol reaction can be extended in vinylogous terms, 38 when conjugated

silyldienol ether is used as the nucleophile. Such species are usually prepared from

unsaturated ketones or esters, in some cases by means of an iron-catalyzed process. In an

early report,39 Kharasch and Tawny observed that the reaction of the unsaturated ketone

1 isophorone with methylmagnesium bromide in the presence of a catalytic (20 mol %)

amount of FeCl3 led to a selective deprotonation of the starting material. Trapping of

the intermediate magnesium enolate with trimethylsilyl chloride gave conjugated

tri- methylsilyl enolether 2, which was then used as nucleophile in the reaction with

aldehydes and ortho- formates, which is mentioned in scheme 1.3

Scheme- 1.3

Further example of an iron-catalyzed addition of a nucleophile to a carbonyl compound

was recently described by Loh and co-workers.40 They identified that in ionic liquids

iron trichloride hexahydrated acts as very effective catalyst for the double addition of

indole 3 to aldehydes 4 yielding bis(indolyl)methanes41 5 in high yields, which is

mentioned in scheme 1.4.

20 Chapter-1

Scheme- 1.4

Michael reactions

Recently, modified Michael reactions have been used for the synthesis of

highly substituted pyridines, employing unsaturated oximes 6 as acceptors in the presence

of ethyl acetoacetate.42 Even under iron catalysis it was necessary to work at very high

temperature to obtain the product 7, as mentioned in scheme 1.5

Scheme-1.5

The mechanism of the pyridine ring formation is not yet clear, but a realistic

assumption can be formulated as follows: after the conjugate addition of ethyl

acetoacetate to the enone oxime, cyclization occurs, which is accompanied by

elimination of a water molecule. The loss of a second molecule of water allows the

system to become aromatic.

The use of donors with a nucleophilic nitrogen atom (aza-Michael reactions) has

also been investigated, and it has been shown that iron (III) chloride is capable of

catalyzing the addition of various secondary amines to unsaturated ketones and esters.43

21 Chapter-1

Aza Michael reactions

A very similar attempt was recently applied in the conjugate addition of amines to

R-acetamidoacrylic acid, allowing the preparation of a number of dialkyl- amino-R-

alanine derivatives.44 It is observed that in this case FeCl3 acts as a Lewis acid,

coordinating the acetamido group 8 of and consequently enhancing its reactivity as

Michael accepter, 9 mentioned in scheme 1.6

Scheme – 1.6

The aza-Michael reaction has also been attempted under iron catalysis employing

carbamates as nucleophiles. Strikingly, among the various metal salts investigated, only

FeCl3 and FeCl3.6H2O proved to be active in the conjugate addition of ethyl carbamate to

chalcone10, the latter being more effective to give product 13. In this case, the authors

found that the addition of a stoichiometric quantity of Me3SiCl, which is also a useful

additive in the conjugate addition of organ copper reagents, 45 was necessary for the

reaction to successfully proceed, mentioned in scheme 1.7

Scheme – 1.7

22 Chapter-1

Nazarov cyclization

The Nazarov cyclization46 is a effective method to generate cyclopentene

derivatives starting from di- vinyl ketones. This reaction is normally catalyzed by means

of stoichiometric quantities of Lewis acids, and only isolated reports about the use of

catalytic quantities of the latter are known.47 Denmark and co-workers employed

anhydrous FeCl3 to achieve the cyclization of ketone 14 possessing a vinylsilane48 the

advantages of this version in comparison to the classic one are that all side reactions are

suppressed and only a single regioiso mer of the final product 15 is formed, mentioned in

scheme 1.8

Scheme – 1.8

Ring Opening Reactions

The opening of epoxides catalyzed by Lewis acid has been widely studied. Iran

poor et al. have demonstrated that iron(III) chloride is efficient for this purpose49

Advantageously, the reaction can be performed using FeCl3.6H2O sup- ported on silica,

which is easier to handle giving equivalent or superior results.50 This iron-supported

catalyst is then superior to other Lewis acids (BF3‚Et2O, SnCl4, and FeCl3) that are

unable to promote oxirane-opening by bromides and chloride ions.51 Starting from

various types of ep- oxides(16), the reaction proceeds with the usual regio- and

stereoselectivity, and the opening products(17 & 18) are obtained with good to high

yield (54-95%) as mentioned in scheme 1.9.

23 Chapter-1

Scheme – 1.9

Whereas the precise role of the iron catalysts in the catalyzing of the opening of

oxiranes is not well defined, some experiments have shown that radical species were

formed during the course of the reaction.52 When the alcoholysis of epoxides is

performed in the presence of acrylamide, polyacrylamide formation and a considerable

decrease of the reaction rate were observed. It is therefore not surprising that prior

attempt to perform asymmetric versions of the reaction afforded products with very low

ee.53

1.4.2 Achiral bis imines as ligands

The chelating ability of the Schiff bases combined with the ease of preparation

and flexibility in varying the chemical environment about the C=N group makes it an

chemically interesting ligands in coordination chemistry.

In addition to these, Schiff base macrocycles have been prepared by well known

self condensation reaction of appropriate formyl- or keto- and primary amine precursors

and find wide applications in macrocyclic and supramolecular chemistry. Schiff bases

easily form stable complexes with most transition metal ions and stabilize them in

various oxidation states.

24 Chapter-1

In addition to these, Schiff base macrocycles (Figure 3) have been prepared by

well known self condensation reaction of appropriate formyl- or keto- and primary amine

precursors and find wide applications in macrocyclic and supramolecular chemistry 55-56.

Schiff bases easily form stable complexes with most transition metal ions and stabilize

them in various oxidation states.

NNH H

OH HON

N

HH

R R

N N

OHHO

OHHON

N

Macrocycle-2

Macrocycle-1

Fig 1.6: Macrocyclic Schiff base compounds

Medicinal chemistry

Many Schiff bases are known to be medicinally important and used to design

medicinal compounds 35-38. It was seen that the biological activity of Schiff bases either

increase or decrease upon chelation with metal ions 57-59.Cobalt(II), nickel(II) and

copper(II) complexes of Schiff bases derived from3-substituted-4-amino-5-mercapto-

1,2,4-triazole and 8-formyl-7-hydroxy-4- methylcoumarin show potent antibacterial

activity against Escherichia coli, Staphylococcus aureus, Streptococcus pyogenes,

25 Chapter-1

Pseudomonas aeruginosa and Salmonella typhi and antifungal activities against

Aspergillus niger, Aspergillus flavus and Cladosporium 60.Ru(II)–PPh3/AsPh3 complexes,

containing hydrazone oxime ligands, show considerable activity against selected bacterial

species and are capable of binding to Herring sperm DNA in mixed modes 61.

The Cr(III), Fe(III) and Co(III) complexes formed form tetradentate

(ONNO) Schiff base ligands, 1,4-bis[3-(2-hydroxy-1-naphthaldimine)propyl]piperazine

and 1,8-bis[3-(2-hydroxy-1-naphthaldimine)-pmenthane, show medium antimicrobial

activity 62 compared to standard antibiotics63. The antibacterial activity of the tridentate

Schiff base, formed by condensation of 2-amino-3-carboxyethyl-4, 5-dimethylthiophene

with salicylaldehyde, was found to increase on chelation with transition metal ions 64 Co

(II), Ni (II), Cu (II) and Zn(II) complexes of the Schiff base derived from vanillin and

DL-α-aminobutyricacid were also found to exhibit higher antibacterial activity compared

to the free Schiff bases 65.

Several mono and binuclear transition metal complexes of the Schiff base

derived from phenylaminoacetohydrazide and dibenzoylmethane are more potent

bactericides and fungicides than the ligand 48. Sharma and Piwnica-Worms reported

Schiff base complexes that target hemozoin aggregation like the antimalarial drug,

chloroquine 66-68.

Epoxidation reactions

McGarrigle and Gilheany have given a detailed discussion on the achiral and

asymmetric epoxidation of alkenes catalyzed by chromium and manganese-salen

complexes 69. They mainly focused on the mechanism, catalytic cycle, intermediates, and

mode of selectivity. Among these Mn-(salen)-type complexes, Jacobsen’s complex, has

26 Chapter-1

been demonstrated to be very effective for the enantioselective epoxidation of

unfunctionalised olefins 70, 71. However, the second-generation Mn-(salen) catalysts

introduced by Katsuki and co-workers have surpassed Jacobsen’s catalyst in terms of

selectivity and activity, but they are not as synthetically accessible, and this has limited

their application72-74

19 20 The manganese Schiff base chelate, 19, synthesized by Zhao et al. exhibit

moderate asymmetric induction (31–74% ee) in the epoxidation of dihydronaphthalene

with higher turnover number75. Fernandez et al. epoxidised various unfunctionalised

olefins with very high yield and poor asymmetric induction in presence of the manganese

Schiff base complex, 20 76,77. Kureshy et al. have reported the catalytic activity of the

nickel(II) Schiff base complexes of N,N’- bis(2 hydroxyphenyl)ethylenediimine, in the

epoxidation of olefins such as cyclohexene, 1- hexene, cis- and trans stilbenes, indene

with sodium hypochloride 78.

In addition to the homogeneous catalytic reaction, supported transition metal

Schiff base complexes also find wide application in catalysis. Among these polymer

supported and zeolite encapsulated Schiff base complexes are the most widely used in

heterogeneous catalysis.

27 Chapter-1

1.4.3 Enzymes as catalyst

The development and use of newer synthetic methods for the stereoselective

synthesis of chiral molecules has increased enormously in the recent years especially in

chemical and pharma industry.79 Biocatalysis being an environmentally friendly process

have attracted particular attention for this purpose. Indeed, the uses of enzymes such as

lipases, Oxidoreductases, transaminases, lyases, or oxygenases in combination with

chemical catalysts have already been explored for the industrial production of many

chiral organic molecules or intermediates.80-84 For example high enantioselectivity was

observed in lipase-mediated preparation of alcohols and amines.85-87 Nevertheless, these

biocatalysts work under mild reaction condition (e.g. room temperature, atmospheric

pressure, etc.), and their immobilized forms being stable in organic solvents, allowed an

easy separation of products and potential re-cycling of enzyme thereby enhancing

economic viability.88,89The synthesis of organic compounds with exact stereochemistry at

the asymmetric center represents a real challenge for modern chemistry. If there is more

than one asymmetric center in a molecule the complexity of the task increases

considerably. Three main routes towards enantiopure compounds are available: making

use of chiral pool, resolution (separation) of racemates and asymmetric synthesis.

Chiral pool refers to the use of asymmetric centers naturally occurring in

enantiopure molecules like carbohydrates, a-amino acids, terpenes, hydroxy acids and

alkaloids. Resolution of racemates may be achieved by diastereomer crystallization, by

chemical as well as by enzymatic kinetic methods or by chromatographic procedures.

Asymmetric synthesis converts achiral molecules to stereoisomerism by using chiral

chemical catalysts or biocatalysts.

28 Chapter-1

Table-1.1 Classification of Enzymes

S.No Enzyme Class

Reaction Type

01 Oxidoreductases Oxidation/Reduction of C-H, C-C, C=C bonds

02 Transferases Transfer of groups: aldehydic, ketonic, acyl, sugar, phosphoryl or methyl

03 Hydrolases Hydrolysis/Formation of esters, amides, lactones, lactams, epoxides, nitriles, anhydrides, glycosides

04 Lyases Addition/elimination of small molecules on C=C,C=N, C=O bonds

05 Isomerases Isomerizations such as racemizations, epimerization

06 Ligases Formation/Cleavage of C-O, C-S, C-N, C-C bonds with concomitant triphosphate cleavage.

On the other hand, the thermodynamic equilibrium is not necessarily reached

without special arrangements due to product inhibition. The rate acceleration of enzyme-

mediated processes in aqueous environments compared with non-enzymatic reactions is

by a factor of 108-1010. Metabolic pathways and cell growth require highly diverse

reactions such as the formation and breaking of carbon-carbon bonds, peptide and ester

bonds, saturation/desaturation of carbon-carbon bonds, and oxidation, for instance, by

oxygen. As a consequence, enzymes evolve as highly specialized catalysts for different

types of chemical reactions. The enzymes are classified in six different classes by the

Enzyme Commission from the International Union of Biochemistry and Molecular

Biology according to the type of a chemical reaction they catalyze (Table 1.1). Lipases,

the enzymes used in this thesis, belong to the class 3 of hydrolases, and they catalyze the

hydrolysis of triglycerides in Nature. In early 1980´s the scope of biocatalysis was

expanded for new applications in synthetic chemistry by the observation that enzymes are

active in organic solvents containing little or no water.90, 91

29 Chapter-1

From a mechanistic point of view, lipases, esterases, and proteases (when

acting on esters) follow a similar mechanism.92 In general; a nucleophilic group from the

active site of the enzyme attacks the carbonyl group of the ester. The nucleophilic group

of lipases, esterases, and some proteases is the hydroxyl group of a serine.93 For some

proteases; it can also be either a carboxylic group of an aspartic acid or a thiol

functionality of a cysteine.94

The active site of many lipases is formed by residues of a serine, a histidine, and

an aspartate (the so-called “catalytic triad”). The first X-ray structures of lipases reported

in 199095,96 contributed significantly to the mechanistic understanding of these enzymes.

The active site is usually covered by a lid, or flap, but in the presence of the substrate or

an organic solvent, this flap moves away, and in this way, the active site becomes

accessible to the substrate. 96

The mechanism for the esterification, and in the reverse way for the hydrolysis,

can be characterized as bi-bi ping-pong.97 The special hydrogen-bonding rearrangement

of the three amino acids increases the nucleophilicity of the serine residue, enabling

attack at the carbonyl group of the acyl donor, to form the “acyl-enzyme intermediate”.

Subsequently, the substrate alcohol will attack the acyl-enzyme to give the product. From

an enantio discrimination point of view, almost all of the known lipases follow the

Kazlauskas’ rule.98 This simple empirical model is based on the fact that the substituents

at the sterocenter (one large and one medium) are placed in two different pockets

according to their size.99

30 Chapter-1

Fig 1.7: Reaction Mechanism of CALB. In recent years, the combination of X-ray crystallographic and molecular modeling

studies has led to an understanding of the chiral recognition of secondary alcohols at the

molecular level by studying the TS-2 as the key step in the enantiodiscrimination. As an

example, in Figure 5, we can see the productive docking TS-2 for (R)-2-pentanol in the

active site of Candida antarctica lipase B (CALB).

Fig 1.8: Productive docking for (R)-2-pentanol in the active site of CALB.

31 Chapter-1

In accordance with the empiric Kazlauskas’ rule, the methyl substituent is located in the

medium-sized pocket (in green) pointing down and the large propyl substituent is

pointing up. Thus, only the R-substrate with the medium-sized substituent pointing down

and the large group pointing up has a productive docking and therefore can be acetylated.

Achiral Acyl Donors in Kinetic Resolution The full potential of lipase catalysis exploited only when the thermodynamic

equilibrium is shifted to the product side. The acyl donor may influence the equilibrium

position and the rate of acylation/deacylation. Three main groups of achiral acyl donors

are used for kinetic resolution: reversible, quasi-irreversible and irreversible.

Table 1.2. Achiral acyl donors

Reversibe Acyl Donors

Quasi irreversible acyl donors Irreversible acyl donors

Screening of the acyl donors in the optimization of kinetic resolution in this thesis

included mainly 2,2,2-trifluoroethyl esters, enol esters (vinyl and isopropenyl esters) and

cyclic anhydrides. In the case of 2,2,2-trihaloethyl esters as quasi-irreversible acyl donors

an alcohol with low nucleophilicity is liberated (CF3CH2OH or CCl3CH2OH) from the

acyl donor which is accordingly expected to be unreactive as a nucleophile. Reduced

32 Chapter-1

nucleophilicity is obtained by introducing electron-withdrawing groups in the alkyl part

of the acyl donor. Cyanomethyl esters have been seldom used in enzymatic reactions

possibly because the hydrogen cyanide is formed in the reaction mixture. Oximes have

been used as acylating agents mainly for regioselective protection of sugars and

nucleosides, but the work-up of the reaction encountered difficulties in removing the

remaining oxime. Enol esters commonly used as irreversible acyl donors68 are vinyl

esters (R´=H), isopropenyl esters (R´=CH3) and ethoxy vinyl esters (R´=OEt). The

leaving group of the irreversible acyl donors is an enol that immediately tautomerises to

the keto form (CH3CHO, CH3COCH3, EtOAc), respectively and, accordingly, no

nucleophile is available for backward reaction. However, acetaldehyde released in the

case of vinyl esters may cause enzyme deactivation by participation to a Millard type

reaction with the lysine residues of the enzyme.

The applications of anhydrides as acyl donors in enzyme-mediated

transesterification of alcohols are not numerous. Possible reasons are the high acylation

power of anhydrides which may acylate the enzyme or may lead to chemical background

acylation of alcohol racemates. Moreover, the acid product in the reaction medium may

change the pH of the enzymatic microenvironment. Promising applications were found

for cyclic anhydrides such as succinic anhydride. When succinic anhydride is used as an

acyl donor for the kinetic resolution of alcohols, unreacted alcohol may be separated from

the product monoester by aqueous-organic extraction. This procedure is attractive

especially for large-scale applications where column chromatography, often used for the

purification of resolution mixtures in laboratories, is not suitable.

33 Chapter-1

Recent applications of enzyme

The majority of applications of lipases in catalytic asymmetric synthesis has

involved kinetic resolution of racemates. The drawback with kinetic resolution is that a

maximum of 50% of the starting material can be used to give product. One way to

circumvent this problem is to employ meso substrates (“the meso trick”) or prochiral

substrates. With the use of these substrates, all of the starting material can be utilized.

Now, because most of the substrates used for enzyme catalyzed reactions do not have the

symmetry element of a mirror plane (i.e., meso and prochiral compounds) but are chiral

racemic compounds, kinetic resolution is still the major application of enzymes. Another

approach is nonmetallic racemization methods. However, this approach is mainly limited

to substrates that possess a stereogenic center with an acidic proton. Thus, the most

common approach is to combine the enzyme with a base-catalyzed racemization via enol

formation.

DKR of Alcohols

The combination of the enzymatic kinetic resolution with metal-catalyzed

racemizations via hydrogen transfer for preparing enantiomerically pure alcohols was

introduced by Williams and Blackvall.100,101 Ba¨ckvall and co-workers developed an

efficient system based on the use of p chlorophenyl acetate 2 as the acyl donor and the

robust ruthenium catalyst 1 for the racemization.

The acyl donor is compatible with the ruthenium racemizations catalyst 1, and the

latter does not need the addition of an external base or the addition of the corresponding

ketone for the racemization. Thus, an efficient DKR of secondary alcohols 21 was

34 Chapter-1

obtained by combining immobilized CALB transesterification using para-chorlo phenyl

acetate as acyl donor to give product 22 and ruthenium-catalyzed racemizations as

mentioned in Scheme 1.10a.

Scheme-1.10

21 22

Recently, Ba¨ckvall and co-workers have developed a new protocol in which p-

chlorophenyl acetate 2 has been replaced by commercially available isopropenyl acetate.

This has provided similar results, but the use of an appropriate hydrogen source is needed

to prevent a drop in yield due to ketone formation as mentioned in Scheme 1.10b.

DKR of Diols

The combination of ruthenium and enzyme catalysis was also applied to the DKR

of secondary symmetrical diols 23 (as meso/dl mixtures). The DKRs were carried out

using ruthenium catalyst 1 (4 mol %), immobilized CALB (60 mg/mmol substrate) as the

biocatalyst, and p-chlorophenyl acetate 2 (3 equiv) as the acyl donor in toluene at 70 °C

give product , as mentioned in Scheme 1.11.

35 Chapter-1

Scheme – 1.11

23 24

Hydroxy Nitriles

Ba¨ckvall and co-workers have applied the combination of enzyme and metal

catalysts for the deracemization of alpha-hydroxyl nitriles.101,102 Chiral alpha hydroxy

nitriles are direct precursors of ç-amino alcohols and alpha -hydroxyl acid derivatives,

which are versatile building blocks in both asymmetric synthesis and medicinal chemistry

as mentioned in Scheme 1.12.103

Scheme- 1.12

Protected Hydroxy Aldehydes

Kim and co-workers have studied the possibility to perform DKR on protected

hydroxy aldehydes 25.104 For this purpose, 2-hydroxypropanal and 3-hydroxybutanal

were protected with 1,2-benzenedimethanol. For both substrates, good yields and high

enantioselectivity were obtained 26 when the ruthenium catalyst 1 was combined with a

lipase as mentioned in Scheme 1.13.

36 Chapter-1

Scheme – 1.13

25 26

DKR of Amines

The chemo enzymatic DKR can also be used for the preparation of

enantiomerically enriched amines, Reetz and co-workers demonstrated the first example

of chemo enzymatic DKR for the preparation of enantiopure amines.105 Thus, the

combination of immobilized CALB as biocatalysts and palladium on carbon as

racemization catalysts was used for the synthesis of (R)-N-(1-phenylethyl) acetamido (27)

from 1-phenylethylamine (28) in moderate yield (64%) and enantiomerically pure form.

The racemization step, which proceeds via an amine-imine equilibrium promoted by

palladium (0), is very slow resulting in long reaction times (8 days).The formation of the

latter products is best explained by reductive amination of the imine intermediate formed

followed by elimination of ammonia as mentioned in scheme 1.14.106

Scheme – 1.14

27 28

Kim and co-workers have recently improved the efficiency of the combined Pd/CALB

DKR process by using ketoximes as starting materials under hydrogen atmosphere.107

37 Chapter-1

Scheme -1.15

The above applications are the recent development of the combination of an enzymatic

kinetic resolution and a metal-catalyzed racemization leading to a DKR process as

mentioned in scheme 1.15.

Enzyme catalysis (for the resolution of a racemate) and metal catalysis (for the

racemization of the slow reacting enantiomer) is a powerful combination for obtaining

successful DKR processes. The high efficiency of these processes makes them attractive

alternatives to existing methods in asymmetric catalysis for obtaining highly

functionalized chiral alcohols and amines in enantiomerically pure form.

1.4.4 Zeolites as catalyst

Zeolites exist in nature and have been known for almost 250 years as

aluminosilicate minerals. Most common examples of zeolites are clinoptilolite, faujasite,

offretite, ferrierite, and chabazite.108 The term “Friedel-Crafts (FC) chemistry” has been

used to cover an ever-increasing number of reactions related to the first aluminium

chloride reaction discovered by Friedel and Crafts in 1877. Incidentally they observed

that, an alkylhalogenide or acylhalogenide reacted with benzene in the presence of

anhydrous AlCl3 forming alkyl- or acyl-substituted aromatic, products. Delighted by this

38 Chapter-1

continued working on this subject and found out that all class of Lewis acids could

catalyze this and also many other related reactions such as dealkylation, polymerization,

and isomerization.

As a result of their work, it became generally accepted that a reaction

combining two or more organic molecules through the formation of carbon to carbon

bonds under the influence of anhydrous AlCl3 or related catalysts, is a Friedel-Crafts

reaction. Later on, Bronsted acids and Lewis-Bronsted acid associations were found to

also catalyze these reactions, extending the original scope of the Friedel-Crafts reaction

to any substitution, isomerisation, elimination, cracking, polymerisation or addition

reaction taking place under the effect of Lewis or Bronsted acids. The principal

relationship between these different reactions is their electrophilic reaction mechanism.

There seems to be no fundamental reason to limit the scope of Friedel-Crafts reactions to

the formation of C-C bonds. The formation of many other bonds such as C-N, C-O,

C-S and C-X is in harmony with the general Friedel-Crafts mechanistic principle.

Nevertheless, since the Friedel and Crafts were exclusively limited to the substitution of

aromatic substrates, it is proper to use the name Friedel-Crafts for those reactions

involving the formation of a new carbon-carbon bond by electrophilic substitution on an

aromatic ring in the presence of Lewis or Bronsted acid as catalyst. The group is named

as acyl group. Acylation reaction is a reaction whereby an acyl group is introduced into a

compound. In this context, the Friedel-Crafts acylation reaction is the reaction whereby

an acyl group is effectively introduced into an aromatic ring.

In Friedel-Crafts acylation reactions, either acyl chlorides or carboxylic acid

anhydrides are used as acylating reagents. The product of the reaction is an aryl ketone.

39 Chapter-1

In the following sections Friedel-Crafts acylation reactions and their mechanisms are

explained according to the type of catalyst used.

FRIEDEL-CRAFTS ACYLATION REACTIONS WITH HOMOGENEOUS

LEWIS-ACID CATALYSTS

If the aromatic compound to be acylated is not highly reactive, it is a necessity to

add at least one equivalent of a Lewis acid catalyst to the reaction mixture. In the case of

Lewis acid catalysts such as AlCl3, the first step in Friedel-Crafts acylation reaction

appears to be the formation of an electrophilic acylium ion from an acyl halide in the

following way.

R Cl

O

+ AlCl3: R Cl

O+

: AlHCl3

R Cl

O+

: AlCl3R

O

:

R O+

+ AlCl4

O

R + AlCl4

O

R+ HCl + AlCl3

General Reaction mechanism of Freidal-Crafts with Homogeneous-Acid Catalysts

As it is clear from the mechanism, the Lewis acid catalyst cannot be regenerated

and formation of corrosive waste product such as HCl occurs as a result of the hydrolysis

of intermediate complex.

40 Chapter-1

FRIEDEL-CRAFTS ACYLATION REACTIONS OVER

HETEROGENEOUS ZEOLITE CATALYSTS

In heterogeneous zeolite-catalysed Friedel-Crafts acylation reaction, a

mechanism similar to Lewis acid catalysed reaction is assumed to apply, in which the

adduct is formed by the interaction of the surface acid sites with an acylating agent. The

plausible mechanism is given below.

R Cl

O

+: R Cl

OH+

+

:O

R+

H+-Zeol- Zeol

+ R Cl

OH+

+

: Zeol

O

R+ HXZeol-

O

RZeol- H+-Zeol-

General Reaction mechanism of Freidal-Crafts with Heterogeneous-Acid Catalysts

FRIEDEL-CRAFTS ACYLATION OF Bis-Trimethysilyacetylene

In homogeneous catalytic systems, the acylation of bis-Trimethysilyacetylene

results in a mixture of mono and di BTSA(bis-Trimethysilyacetylene),apart from that

unreacted starting material with side products has been observed Since the homogeneous

catalyst provides free catalytic sites and acyl halide being more reactive group resulted in

unreacted starting material with side products. On the other hand, in heterogeneous

catalytic systems, most of catalytic sites are fixed on external surfaces and inner pores.

41 Chapter-1

Therefore, the selectivity of the products will be changed in accordance with the

restriction imposed on the sites.

In heterogeneous catalytic systems, diffusion characteristics of reactant and

product molecules must also be taken into account while trying to figure out the selective

acylation. Bharathi et al., investigated the diffusion characteristics of acetylated 2-MN

inside the large pore zeolites. Moreover, he studied the chemical interaction between the

zeolite guest-host molecules using energy minimization calculations by carrying out the

diffusion of these molecules along the a direction in the 12-membered channels of

mordenite, L, and β zeolites. For zeolite, the diffusivity value is always between 0 and 1,

and values closer to 1 indicate higher diffusivity. Both of these results imply that the pore

dimensions, shape of the pores and their correspondence to the size and shape of the

molecules determine the diffusion characteristics of molecules.

Today most of these and many other zeolites are of great interest in many

fields. Out of these fields, catalysis is the most essential application of zeolites in terms of

financial market size, but not in terms of tons of production per year (Weitkamp et. al,

1999). Zeolites exhibit unusually high activity for various acid catalyzed reactions.

The properties that make zeolites proper for heterogeneous catalytic

applications are given in literature as follows: Zeolites have porous crystal structures

made up of channels and cages that allow a large surface area thus a large number of

catalytic sites. Fine-tuning and tailoring of the pore size of a given zeolites can be

achieved by various post synthesis modification techniques like pore size engineering has

been proposed.’ pore size engineering' has been coined

42 Chapter-1

They have exchangeable cations allowing the introduction of cations with

various catalytic properties. If these cationic sites are exchanged to H+, they can have a

high number of strong acid sites .Since they are solid, they can easily be removed from

products and therefore they are environmentally benign. No waste or disposal problems is

observed with zeolites ( Espeel et al., 1999).Their molecular sieve action can be used to

control which molecules have access to and which molecules can depart from the active

sites which is defined as shape-selectivity.109

But unfortunately from the catalytic perspective, naturally occurring forms of zeolites are

of limited value, because

1. They almost always contain undesired impurity phases,

2. Their chemical composition changes from one deposit to another and even from one

stratum to another in the same deposit,

3. Nature has not optimized their properties for catalytic applications”

It is possible with the establishment of a relationship between the acid properties of the

zeolites catalysts and the outcome of the reaction that a drug molecule or one of its

intermediates will be synthesized over a zeolite-based catalyst in the near future.110

Chemical Structure and reactivity Zeolites are hydrated aluminosilicates that are built from an infinitely extending

three-dimensional network of SiO4 and [AlO4]-1 tetrahedral. These tetrahedral join

together in through shared oxygen atoms with various regular arrangements, to form

hundreds of different three-dimensional crystal frameworks. Since the trivalent aluminum

is bonded to four oxygen anions, each AlO4 tetrahedron in the framework bears a net

43 Chapter-1

negative charge which is balanced by a cation, generally from the group IA or IIA. The

chemical composition of zeolites may be represented by the empirical formula: 111

Where A is a cation with the charge m, (x + y) is the number of tetrahedral per

crystallographic unit cell and x/y is the so-called framework silicon / aluminum ratio

SiO4 and AlO4 building blocks of zeolites.

Fig 1.9: Schematic presentation of the channel system of Beta Zeolite

Molecular sieving is the selective adsorption of molecules, whose dimensions are below a

certain critical size, into the intracrystalline void system of a molecular sieve.112,113 The

use of kinetic diameter of a molecule is very popular for comparison with zeolites pore

dimensions, but also the shape of the molecule in relation to the shape of the pore

openings.114 In zeolites, most of the active sites are located in the well-defined and

molecularly sized pores and cages. Throughout a reaction, the transforming molecules are

continuously exposed to steric limitations imposed by the zeolite structure, possibly

changing the course of the reaction and finally resulting in product distributions showing

deviations from those obtained in the homogeneous phase.115

44 Chapter-1

In this context, molecular shape selectivity can be described as the

restrictions imposed on guest molecules by size and shape of the zeolites pores. There are

three types of molecular shape selectivity observed associated with zeolites

a) Reactant selectivity implies that those molecules with high diffusivity will react

preferentially and selectively, while molecules excluded from the zeolite interior

will only react on the external surface of the zeolite

b) Product selectivity implies that products with high diffusivity will be

preferentially desorbed, while the bulkier molecules will be converted and

equilibrated to smaller molecules which will diffuse, or eventually react to form

larger species which will block the pores

c) Transition state selectivity takes place when certain reactions are prevented as the

transition state necessary for them to proceed is not reached because of the space

restrictions.

Modification of the shape selective properties of zeolites is possible with different

approaches for catalytic purposes. Most of these approaches not only change the shape

selective but also the acid properties of zeolites.103113

APPLICATIONS ZEOLITES

There are three traditional fields of application for zeolites: separation,

purification, drying and environment treatment process; petroleum refining,

petrochemical, coal and fine chemical industries; ionexchange, detergent industry,

radioactive waste storage, and treatment of liquid waste.104-114

45 Chapter-1

Zeolites has been widely used in many applications due to their unique

properties (thermal stability, acidity, hydrophobicity/hydrophilicity of surfaces, ion-

exchange capacity, low density and large void volume, uniform molecular sized channels,

adsorption for gas and vapor and catalytic properties). These materials have been widely

used as commercial adsorbents for drying and purification of gases and for bulk

separation of, for example, normal-/iso-paraffins, isomers of xylenes and olefins, and O2

from air, as catalysts for petroleum refining and petrochemistry, and as ion

exchangers105115summarized in table-3

Table 1.3. Applications of Zeolites

Process catalyst Products

Catalytic cracking Re-Y, US-Y ZSM-5 Gasoline, fuels Hydro cracking Y, Mordenite + Mo, W, Ni Kerosene, diesel,

Benzene Alkylation of aromatics

ZSM-5, Mordenite p-xylene, ethyl-benzene

Hydroisomerization Mordenite + Pt, Pd i-pentane, i-hexane

Xylene isomerization ZSM-5 p-xylene

Catalytic dewaxing Mordenite, ZSM-5 + Ni, noble metals

Improvement of cold flow properties

Transalkylation Mordenite Xylenes, cumene

In the last years there has been an increase in the usage of zeolites in different

compositions to delete and bury different radio-contaminations. The presence of

radionuclides in wastes is a major environmental concern.116Recent paper published

researched the interaction of synthetic zeolites with Cs+ and Ur6+ and sowed that zeolites

are very effective adsorbents for radio- contaminant removal. 117Zeolites will continue to

46 Chapter-1

be used in the separation and purification technology through the chemical process

industry. Future trends involve environmental and biopharmaceutical application.118

1.4.6 Proline as catalyst

Organocatalysis is the acceleration of chemical reactions with a

substoichiometric amount of an organic compound which does not contain a metal atom.

119 Despite the very recent introduction of this type of catalysis to synthetic chemistry,

organocatalytic reactions look back on a venerable history. Evidence has been found that

this type of catalysis played a determinant role in the formation of prebiotic key building

blocks, such as sugars, and thus allowed the introduction and spread of homochirality in

living organisms.120According to this hypothesis, enantiomerically enriched amino acids,

such as l-alanine and l-isovaline, which may be present with up to 15%ee in

carbonaceous meteorites, catalyze the dimerization of glycal and an aldoltype reaction

between glycal and formaldehyde to afford sugar derivatives with significant

enantiomeric excess.

Although organic molecules have also been used since the beginnings of

chemistry as catalysts, their application in enantioselective catalysis has only emerged as

a major concept in organic chemistry in the last few years.121,122 A s a result of both

determined scientific interest, such as usually accompanies emerging fields, and the

recognition of the huge potential of this new area, Organocatalysis has received

considerable attention.

The pinpointing of “privileged” catalyst classes showing general superiority for

many reaction types is undoubtedly one of the most intriguing aspects and may have a

considerable impact on the development of new catalytic systems.123 Some organic and

47 Chapter-1

organ metallic molecules have the extraordinary capacity to mediate efficiently a variety

of mechanistically distinct reactions.

When a catalyst, such as l-proline, performs well in one reaction, it can be

expected to mediate all similar reactions under optimized reaction conditions. However,

less closely related reactions may also be promoted by catalysts of the same class. Our

understanding of the mechanistic details of individual reaction pathways is improving.

Organocatalytic reactions proceed either by a much “tighter” or a much “looser”

transition state than those mediated by chiral metal complexes. The former class of

Organocatalysis includes compounds that act as covalently bonded reagents. The latter

class induces a high level of enantioselectivity mainly through such interactions as

hydrogen bonding or ion pairing. The enormous potential of hydrogen bonding as an

activating interaction has been recognized only recently. The scope of organocatalytic

reactions has been expanded considerably. Typical transition-metal-mediated coupling

reactions, such as Suzuki, 124 Sonogashira, 125 Ullmann, 126 and Heck-type coupling

reactions, 127 as well as the Tsuji–Trost reaction,128 can now be performed under metal-

free conditions.

The development of catalysts with a higher molecular weight and increased

complexity often leads to a sharp improvement not only in the selectivity of the catalyst,

but also in its kinetic profile. In an increasing number of asymmetric reactions these

catalysts can meet the high standards of modern synthetic methods. Whereas many metal

centers are good Lewis acids, organic catalysts tend to react as heteroatom-centered

(mainly N (O)-, P (O)-, and S (O)-centered) Lewis bases. However, novel, previously

unexplored catalyst classes are emerging. For example, asymmetric catalysis by Bronsted

48 Chapter-1

acids is a recent addition to the field of organic catalysis. Moreover, the design and use of

synergic systems and bifunctional catalysts, which have two distinct functionalities (e.g. a

Lewis base and a Bronsted acid) within the same molecule, is becoming more and more

common.129 Organocatalytic methods have great practical potential in devising

multicomponent and tandem sequences. In the future all these reactions will also find use

outside the academic environment for the synthesis of complex molecular structures.

Most organocatalysts used currently are bifunctional, commonly with a

Bronsted acid and a Lewis base center. These compounds activate both the donor and the

acceptor, thus resulting in a considerable acceleration of the reaction rate. The vast

majority of organocatalytic reactions are amine based reactions. In this asymmetric

aminocatalysis amino acids, peptides, alkaloids, and synthetic nitrogen-containing

molecules are used as chiral catalysts. Most of these reactions proceed by the generalized

enamine cycle or as charge accelerated reactions through the formation of iminium

intermediates. These two types of activation are often complementary and can therefore

sometimes be used as alternatives in the same transformation.

The donor molecule can be activated through the formation of an enamine,

which leads to an increase in the electron density at the reactive center or centers; the

acceptor molecule can be activated through the formation of an onium salt, which leads

to a decrease in the electron density at the reactive center. Until now the most successful

catalyst for enamine-type reactions has undoubtedly been l-proline. Although the natural l

form is usually used, both enantiomers of proline are available,120129 which is an

advantage over enzymatic methods. It is remarkable the variety of reactions that may be

mediated with this simple amino acid, whose simplicity contrasts with the complex

49 Chapter-1

machinery of the natural enzymes (class I aldolases) capable of performing similar

transformations

What are the main features that make proline such a good catalyst? Proline is the

only natural amino acid with secondary amine functionality and thus has a higher pKa

value and enhanced nucleophilicity relative to other amino acids.

Fig 1.10: L-Proline mediated Enamine catalytic cycle

Proline can therefore react as a nucleophile with carbonyl groups or Michael acceptors to

form iminium ions or enamines. As the carboxylic acid functionality of the amino acid

acts as a Bronsted acid in these reactions, proline can be regarded as a bifunctional

catalyst. The high, often exceptional enantioselectivity of proline mediated reactions can

be rationalized by the capacity of this molecule to promote the formation of highly

organized transition states with extensive hydrogen-bonding networks. In all proline-

mediated reactions the proton transfer from the amine or the carboxylic acid group of

proline to the forming alkoxide or imide is essential for charge stabilization and C_C

bond formation in the transition state. Although most, if not all, partial steps in amine-

50 Chapter-1

catalyzed reactions are equilibrium reactions, enhanced nucleophilicity of the catalyst can

lead to a number of equilibrated reactions with electrophiles present in the medium,

resulting in a low turnover number. This drawback can be remedied by using a higher

catalyst loading if the catalyst is inexpensive. Proline is not the only organic molecule

able to promote enamine reactions, and not all enamine reactions can be mediated by l-

proline. Furthermore, synthetic shortcomings persist; for example, in the dimerization or

oligomerization of a-unbranched aldehydes it is difficult to avoid competing reactions.

Reactions with acetaldehyde or acetophenone generally lead to low yields and low

selectivity. Although proline continues to play a central role in aminocatalysis, its

supremacy is being challanged by new synthetic analogues and by more-complex

oligopeptides. Chiral imidazolidinone catalysts also offer better rates and selectivity in a

number of reactions.

NO

O

Cu(I)H

Activates Nuceophile

Activates Electrophile

Fig 1.11: Copper-based bifunctional catalyst system.

On the basis of the mechanistic consideration of copper-catalyzed coupling reactions, we

expected that possible bifunctional catalyst system generated in situ could attach both the

electrophilic and nucleophilic substrates, could lead to double activation and would be an

efficient catalyst for the alkynylation reaction.

51 Chapter-1

Recent Applications of Proline

Although organic molecules have also been used since the beginnings of

chemistry as catalysts, their application in enantioselective catalysis has only emerged as

a major concept in organic chemistry in the last few years. As a result of both determined

scientific interest, such as usually accompanies emerging fields, and the recognition of

the huge potential of this new area, organocatalysis has received considerable attention.

When a catalyst, such as l-proline, performs well in one reaction, it can be expected to

mediate all similar reactions under optimized reaction conditions. This thesis emphasizes

much on proline as one among eco friendly catalyst.

Aldol condensation

Remarkably, in this synthesis the racemic keto aldehyde 29 could be used in an

aldol reaction in the presence of d-proline (2) as the catalyst. All of the asymmetric

centers of the erythronolide backbone were derived directly or indirectly from this rather

poor reaction, which gave the product 30 with only 36%ee. However, enantiomerically

pure 27 could be obtained by simple recrystallization, which made the process eminently

practical as in Scheme 1.16

Scheme- 1.16

52 Chapter-1

Morita–Baylis–Hillman reaction

Although cinchona alkaloids continue to play a major role as catalysts in the

asymmetric Morita–Baylis–Hillman reaction, peptide-based catalysts are emerging as

alternatives. One exciting advance is the use of a nucleophilic catalyst cinchona alkaloid

or peptide in combination with a suitable acid as a cocatalyst, such as proline or a proline

containing oligopeptides, in a Morita–Baylis–Hillman reaction with methyl vinyl

ketone.130, 131 Although the cocatalyst accelerates the reaction and improves the

enantioselectivity, the influence of the configuration of the additive is minimal.

Noncovalent interactions between the nucleophilic catalyst and the cocatalyst were

evoked to explain the synergistic effect.

Objective of the thesis

Synthesis of compounds to explore the potential biologically active agents still

draws continued interest: molecular manipulation, combinations of biologically active

moieties into one molecule and synthesis of totally newer moieties have been the methods

of research. There is an increased interest in the use of environmentally benign reagents

and conditions particularly to solvent-free procedures. Thus, avoiding organic solvents

during the reactions in organic synthesis leads to clean, efficient and economical

technology: safety is largely increased, working is considerably simplified, cost is

reduced, increased amounts of reactants can be used, etc. Also, reactivities and

sometimes selectivities are enhanced.

The experimental work of this thesis have been application of green chemistry

catalyst towards the preparation of enantiopure drug intermediate and its application in

the well known drug called Rivastigmine in addition to prepare potential

53 Chapter-1

pharmacological interest of thiazole derivatives. The aim was to introduce the

enantiopurity into the intermediates or potential intermediates in the synthetic pathways

of drugs by achiral bisimines mediated lipase-catalyzed kinetic resolution and

construction of thiazole ring mediated by zeolite and an improved process for

preparation of 4-Alkynyl substituted thiazoles. Apart from that the biological activities of

bisimines and thiazole analogues has been explored.

a) Alcohols rac-(RS-4) were studied as intermediates for the synthesis of

Rivastigmine. The purpose was to prepare enantiopure stereoisomers of rac-(RS-

4) using Achiral Bis-Imines mediated in presence of lipase (Chiral Actualizer) -

catalyzed kinetic resolution. Lipase catalysis was used to obtain the both

enantiomers of the racemates. The work is described in paper I.

b) Heterocyclic 4-Alkynyl substituted thiazoles were studied as potential

pharmacological interest. Whereas the protocol mentions the construction of

thiazole moiety by zeolites and its application for the preparation of 4-Alkynyl

substituted thiazoles from proline mediated Sonogashira coupling for the

generation of library molecules. The work is described in papers II