Chapter I

Introduction

INTRODUCTION

The concept of “catalysis” is acclaimed as a method of controlling the rate

and direction of a chemical reaction since it is introduced by Berzelius1 in 1835. It

coordinated a number of disparate observations on chemical transformations by

attributing them to a “catalytic force” and coined the term catalysis to refer to the

‘decomposition of bodies3 by this force. Now-a-days, “catalysts” are considered to

be indispensable components for the majority of chemical reactions. As enzymes,

they regulate an array of transformations within natural organisms from single

cells to man. Researchers employed catalysts as supports for our daily lives

starting with manufacture of fuels2, clothing3, plastic goods4, fertilizers5 and

medicines6. Hence, “catalysis” is well described as the cornerstone of all chemical

processes. Around 80% of all chemicals rely on catalysts of one kind or other

during their synthesis.

In general, catalysts are conveniently divided into two groups,

homogeneous and heterogeneous, according to whether or not the reactant and

products share the same phase as the catalyst. Homogeneous catalysis provides

mild and selective routes for the synthesis of valuable chemicals from simple

organic precursors. But the catalysts are more sensitive to air and moisture. In

addition, the catalysts are difficult to separate from the products. These problems

are avoided by employing heterogeneous catalysts, and hence these catalysts have

acquired more fascination among catalyst researchers. Although, numerous

catalysts are available to accelerate various reactions, chemists find inconvenience

to carry out immiscible substrate reaction. For example, the reaction between

1-chlorooctane with sodium cyanide7 could not proceed even after a long reaction

time owing to the existence of two different immiscible aqueous/organic phases.

Normally for any type of organic reaction, it is a necessary condition to

cause the perfect collision between the two reactants to get the desired product.

The immiscible substrate reaction8 are normally very slow (due to some practical

difficulties). This is particularly due to the sparingly soluble substrate in the

biphase media. There are variety of techniques available to circumvent this

problem via., increasing the agitation rate,9'11 using cosolvents12, such as alcohol

or methanol etc. Increasing the agitation rates in any chemical reaction involves

loss of mechanicl/electrical energies. Similarly using cosolvents also decrease the

rate of the reaction due to the hydrogen bonded with the substrates or catalyst. As

a remedial measure, researchers have used aprotic solvents, such as

dimethylsulfoxide, dimethyl formamide, hexamethylphosphoramide and

acetonitrile, to carry those immiscible substrate reactions. It is observed that the

use of cosolvents13 proceed the reaction without forming hydrogen bond and

ultimately increased the rate of the reaction. Unfortunately, this polar aprotic

solvent technique also has some disadvantages partially in industrial process; the

solvents are expensive and difficult to remove by-products, are often accompanied

by the generation of a desired product, requirement of high temperature,

anhydrous solvent and are definitely an environmental hazard in large scale

operations. In view of all these demerits, researchers/industrialist are not

interested to use aprotic solvents also.14"16

LI. PHASE TRANSFER CATALYSIS

Phase transfer catalysis came in to limelight in the mid-1960s17 and caught

attention of many researchers for carrying out a wide class of otherwise slow

heterogeneous reactions. Reactions of two substances located in different phases

are often inhibited because of the inability of the reactants to come together. For

example, the reaction between 1-chlorooctane with sodium cyanide could not

proceed even after allowing quite long time, hence for the first time Jerrouse used

phase transfer technique;18 these immiscible reactions are brought about by the

use of an agent which transfers one reactant across the interface into the other

phase so that the reaction can proceed. The phase transfer agent is, however, not

consumed during the course of the reaction but performs the transport duty

repeatedly. The component that is responsible for transfer of reactant from

aqueous to organic is called “Phase-transfer catalyst” and the whole process is

said to be “Phase-transfer catalysis” (PTC).

In performing a phase-transfer reaction; the choice of a suitable catalyst

plays a pivotal role. For any phase transfer catalyzed technique, the three factors

are paramount importance; the ability of the catalyst to transfer one reagent from

its phase into the phase of the second reagent; the reagent once transferred must be

available in a highly reactive form and the recycling ability of the catalyst.

1.1.1. EXAMPLES OF PHASE TRANSFER CATALYSTS

Based on the structure of the molecule, the phase transfer catalysts are

broadly classified as follows

1. Quaternary ammonium, phosphonium and arsonium ions.19'34

3

Where R is usually alkyl or benzyl and X refers to the different anions

in the catalyst.

35 36” * 372. Macrocyclic (Crown) ’ ’ and macrobicyclic ( Cryptate) ethers.

3. Open chain polyether38 and single chain poly ethers.3 9

4. N-alkylphosphoramides.40

5. Methylene bridged phosphorous and sulfur oxides.41

Phase transfer catalysts are generally active depending upon the central

onium atoms. Quaternary onium salts are stable up to 150 C in the absence of

alkali and less stable around 70-80°C in the presence of alkali. Now variety of

quaternary onium salts can be synthesized and are available commercially for

various immiscible substrate reactions. Lower quaternary onium salts are easily

recovered than with some higher salts due to its tendency to form stable emulsion.

Phosphonium salts are thermally more stable than ammonium salts up to 150-

170°C; where as ammonium salts loose their activity rather rapidly at temperature

greater than about 110 -120°C.

1.2. GENERAL MECHANISM FOR THE PHASE TRANSFER

CATALYZED REACTION

Liquid-Liquid PTC corresponds to a system made of two phases: an

organic phase containing a liquid reagent with (or without) an organic solvent

non-miscible in water and an aqueous phase containing in most cases a

nucleophilic reagent M+Y‘. Moreover a quaternary ammonium or phosphonium

catalyst is partitioned between the two phases.

4

5

1.2.1. CLASSIFICATION OF PHASE TRASFER CATALYSIS

Phase transfer catalysis can be classified into three different categories

based on the physical states of the two phases. They are liquid/liquid, liquid/solid,

and gas/solid PTC techniques.

1.2.1.1. Liquid-Liquid Phase transfer catalysis

Liquid-Liquid PTC (LL-PTC) composed of two phases; an organic phase

containing a liquid reagent (RX) immiscible with water and an aqueous phase

containing a nucleophilic reagent(Nu’) and the quaternary onium catalyst (Q+X").

Starks8,16 and Malcosaza42'44 reported two different mechanism with best

illustration viz., extraction and interfacial mechanism. When sodium cyanide was

mixed with octylchloride, no product was observed even after prolonged time,

eventhough the former one is soluble in water. But on the introduction of catalytic

amount of quaternary ammonium chloride, an exchange occurs in the aqueous

phase between Na+CN’ and B114N+C1-. The ion pair, BimN'CI", due to presence of

16 carbons of the quaternary ammonium ion, phase transfers into organic where

the reaction take place. According to the interfacial mechanism, a molecule of an

organic substrate say phenylacetonitrile(RH) in the organic phase located near the

interface is deprotonated by the hydroxide ion which is also available near the

interface but within the aqueous phase (step 1). An ion pair [Na+R‘] is thus formed

at the boundary and as such is insoluble in both the phases. The anchored [Na+R-]

remains at the interface until the catalyst cation draws the organic anion deep into

the bulk organic phase in the form of new ion pair [QR~|. The quaternary counter

ion X- is simultaneously liberated into the aqueous phase (step 2). Finally, [Q+R-]

reacts with alkyl halide substrate R Y to produce the product R-R (step 3) and the

[Q+Y-] thus formed may reenter a next catalytic cycle. The interfacial mechanism

is shown below;

6

If a complexant is added, the solid M+Y- is solubilized in the solvent and

reacts under mild conditions. In a specific example, potassium permanganate is

added to a solution of benzene containing an olefin. Under these conditions the

crystals of KMn04 stand at the bottom of the flask, the solvent is colourless and

no reaction occurs. If a small amount of 18 crown 6 is added, the solvent

immediately turns purple (the permanganate dissolves) and the olefin is smoothly

oxidized. The complexants first used were the crown ethers, prepared by

Pedersen35, which showed high complexing abilities of alkali and alkaline earth

cations with the following properties.

7

a. extraction of cations owing to the selective complexation, which

b. activation of the anion paired to the complexed cation; the anion is said

results in the separation of enantiomers and open new promises in asymmetric

induction.

Presently the majority of current syntheses are more likely to be carried

out with liquid-liquid transfer conditions, with quaternary ammonium and

phosphonium catalysts. Solid-liquid catalysis using complexants is still hampered

by the high price of catalysts like crown-ethers or cryptants. In some cases, when

water needs to be strictly avoided, reactions are conducted under solid-liquid

conditions, with a quaternary ammonium or phosphonium catalyst (not a

complexant). Moreover, in order to solve the problem of catalyst recovery a new

technique has been proposed.

1.2.1.3.Gas-liquid phase transfer catalysis

Another interesting variant of the two phase catalytic method with great

potential was reported and developed by Tund48'50 and co-workers. GL-PTC

provide a continuous-flow through the molten thermally stable PTCs such as

depends upon the size and the substitution of the macrocyclic ethers45.

to be “naked”46

The chiral host molecules designed by Cram et al47 have achieved splendid

phosphonium salt crown ether and polyethylene glycol supported on a solid

nucleophile without solvent. The GL-PTC technique is the analogy of gas-liquid

chromatography. This can be chemically linked with inorganic support. Number

of reactions had been carried out following GL-PTC technique, for instance, the

synthesis of ethers and thioethers51’52, interconversion of alkyl halides53’54,

esterification 55 and trans-esterification56 are very important reactions.

1.2.1.4. Gas-Solid Phase Transfer catalysis (GS-PTC)

Yet another classification of PTC technique is a report of Gas-Solid phase

transfer catalysis.57 It is indicated that by passing a gaseous alkyl halide over a

catalytic column composed of a salt, a solid support and a phase transfer catalyst,

a substitution product was obtained. The phase transfer catalyst was either free or

immobilised on a silica matrix and thus the synthesis of alkyl iodides and esters

were possible. 58

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1.3. ADVANTAGES OF PHASE TRANSFER CATALYSTS59

(i) Increase productivity

(a) Higher the chemical yield

(b) Reduced the cycle time

(c) Reduce or consolidate unit operations

(d) Increase reactor volume efficiency

(ii) Improve environmental performance

(a) Eliminate, reduce or replace solvent

(b) Reduce non-product output

(iii) Increase quality •

(a) Improve selectivity

(b) Reduce variability

(iv) Enhance safety

(a) Control exotherms

(b) Use less hazardous raw materials

(v) Reduce other manufacturing cost

(a) Eliminate workup unit operation

(b) Use alternate less expensive or easier to handle raw materials

1.4. TRIPHASE CATALYSIS

Although, the soluble phase-transfer catalysts are so efficient and much

familiar to carry out two-phase reactions particularly for synthesis of speciality

chemicals with higher quantum yield, their usage is limited due to various reasons.

The main challenge in designing liquid/liquid industrial PTC process has

been the separation of the catalyst from the product. The chemical equilibrium

separation of the process which are used in the purification of the product usually

consume energy to get a product of a highly purity. In order to overcome this

difficulty, Regen and his coworkers60'64 proposed a so called "triphase catalysis",

in which the catalyst is immobilized on a solid support (organic and inorganic

10

substances). From the industrial application point of view, this solid supported-

catalyst can be easily separated from the final products simply by mechanical

separation, such as centrifugation or filtration. In addition, either the plug flow

reactor (PFR) or the continuous stirred tank reactor (CSTR) can be used to carry

out the triphase catalytic reaction. Several reactions for hydrolysis and

displacement were investigated with success. In genera!, both the organic solid

polymer and inorganic solid silica65,66 and aluminium oxide67 can be used as the

support of the triphase catalyst. Plowever, the inorganic solid silica and aluminium

oxide fracture easily during the agitation. Solid polymers are commonly used as

the support of the triphase catalyst.

1.4.1. REACTION MECHANISM

As developed by Regen, the reaction of triphase catalysis is carried out in a

three-phase liquid (organic)-solid (catalyst)-liquid (aqueous) system. The reaction

process between two immiscible reactants by triphase catalysis in a porous solid

pellet may involve as follows (a) mass transfer of reactants from bulk solution to

the surface of the catalyst pellet; (b) diffusion of reactants to the interior of the

catalyst pellet through pores; (c) surface or intrinsic reaction, of reactants with the

active sites of the catalyst pellet; (d) diffusion of products outward to the exterior

of the catalyst pellet through pores, and; (e) mass transfer of product to the bulk

solution from the surface of the catalytic pellet.

Probably the first pre-mediated and successful use of a polymer-supported

phase transfer catalyst was that reported by Regen60'64 using polymer-bound

11

benzyltrialkyl ammonium salts, although the results of investigations by Brown,68

using similar species and Montanari, ' using supported phosphonium salts,

crown ethers and cryptands70 in addition, followed quickly afterwards. Regen has

suggested the term “Triphase catalysis,73’82 the cross linked polymer being

regarded as a distinct third phase. Although this description may not be

particularly accurate in the-light of emerging experimental results, it does provide

a useful qualitative picture and the expression is gaining continued popularly.

If a similar mechanism to the one proposed for unbound catalysts operates

in supported system, then it is necessary to imagine the phase boundary existing at

the catalytic sites as depicted below,

Organic phase

The process of transporting anions back and forth across the boundary can

then occur via local backbone and side chain motion of the catalyst support. This

model would predict the efficiency of the catalysis to be improved by increasing

the length and hence the flexibility of the linkage between the catalyst and the

polymeric backbone by introducing a ‘spacer arm’ and this seems to be so in

practice. Number of applications of polymer-supported PTC’s in organic reactions

have been reported.80'101 This technique has the advantage of homogeneous

catalysis owing to the selection of a catalyst having an appropriate molecular

structure and heterogeneous catalysis since the catalyst is easily filtered off and

recovered after the reaction. However, the rates were often less than most of

• S7 88analogous soluble phase transfer catalysis because of diffusional limitations.1 ’

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1.5. DIFFERENT TYPES OF MECHANISMS IN PHASE TRANSFER

CATALYSIS

Two major mechanisms have been proposed so far to explain the behavior

of most phase transfer catalyzed reactions initiated by the hydroxide ion,

(PTC/OH- systems) the Stark’s Extraction mechanism8 and the Makosza’s

interfacial mechanism.102

1.5.1. STARK’S EXTRACTION MECHANISM

This mechanism describes liquid-liquid PTC in which an ion-pair, formed

by extraction of anion Y' into the organic phase by the onium salt cation Q1,

undergoes a rapid displacement with RX. The new salt [Q+X‘] then returns to the

aqueous phase, where Q+ picks up a new Y‘ ion for the next cycle (Scheme 1).

1.5.2. INTERFACIAL MECHANISM

In the case of interfacial mechanism, the ‘quat’ frequently employed in

PTC/OH- reactions are tetrabutylammonium hydroxide and it does not exhibit a

measurable ability to extract the hydroxide ion. This would suggest that the

classical triethyl benzyl ammonium ion (TEBA) that is more hydrophilic would

extract the OH- to an even lesser extent. TEBA induces enhanced reactivity in

hundreds of PTC/OH- reactions, whereas nucleophilic substitutions proceed very

13

slowly. Since these nucleophilic substitutions have been characterized under

extraction mechanism, it was assumed that another mechanism must be involved

in PTC/OH" reactions. Maicosza102 thus proposed an alternative mechanism called

the “interfacial mechanism”.

Organic Phase

1.6. APPLICATIONS OF PHASE TRANSFER CATALYSIS

The applications of single-site phase transfer catalysts (SPTC) have been

well documented because of its high reaction rate, high selectivity, lower energy

requirements and moderate operating temperature. Owing to these positive

advantages, the soluble SPTC have been applied in several areas of chemistry viz.,

heterocyclic chemistry,103 macromolecular chemistry,104 industrial chemistry,105

dye chemistry105, and medicinal chemistry.106,107 The SPTC’s have been used

more specifically to the synthesis of various life saving dings or pharmaceutical

intermediates. It has also been used for general purpose reactions of varied

categories depending upon the strong base reactions such as alkylation (C-, N-,

0-, S-alkylation),108 chiral alkylations,109 oxidation,110 (permanganate,

hypochlorite/hypobromite, hydrogen peroxide, oxygen/air, persulfate, transition

metal co-catalysis (carbonylation, reduction and hydrogenation, coupling

reaction),110 condensation (Aldol,110 Michael,111 Witting,112,113 Darzens114),

elimination,108 addition,105 polymerization,105 dehydrohalogenation,105

nucleophilic aromatic substitution,108 nucleophilic aliphatic substitution108

reactions viz., esterification,108 various displacement reactions such as (cyanide,

halide, azide, sulfide, thiocyanate, sulfite, nitrite, hydroxide, carbonate, cyanate)108

and also for the preparation of organometalic compounds. The following

discussion describes some of the important/selective application of different

SPTC’s in various reactions exclusively in organic chemistry.

1.6.1. C-ALKYL ATIONS

C-alkylation is one of the most fundamental organic reactions for building

the carbon skeleton of organic compounds. The Carbon-hydrogen bond of typical

hydrocarbons does not easily lend itself to dissociation into a proton and a

carbanion. Either an extremely strong base is needed to deprotonate the C-H bond

of an inactivated hydrocarbon or the C-H bond must be activated by strong

electron withdrawing groups to stabilize the carbanion to be formed. It is known

that PTC technique is a simple and less expensive method for performing

alkylation reactions. Most of the alkylation studies reported in literature are

involved an organic phase in contact with 50% aq. NaOH solution and a

quaternary ammonium salt or a stoichiometric amount of a quaternary ammonium

ion-pair.115 Phenyl acetonitrile116 was the first compound reported to undergo

phase transfer C-alkylations in the presence of ethyl bromide, concentrated

aqueous sodium hydroxide/lmol-% TEBA, the reaction is mildly exothermic and

requires 3-5 hour at 28-35°C. Another interesting prospect arises when dihalides

are used to alkylate ketones. Apparently 4-membered ring formation is disfavored

to such an extent in the acenapthone case that 1,3-dibromopropane C-alkylates

and then O-alkylates after a second enolization.117 The product is the

tetracyclicenol ether as shown in the following scheme.

14

15

In general, alkyl bromides are better C-alkylating agents than chlorides

provided concentrated sodium hydroxide is used in considerable excess. Iodides

and to some extent bromides (with a lower excess of NaOH) have an adverse effect

on alkylation, because iodide is extracted into the organic phase is preference to the

phenyl acetonitrile anion. Recently, alkylations were carried out in the presence of

solid K2C03/dibenzo-18-crown-6 in benzene solution.123 The C-alkylation of P-

lceto esters is effected with 1-halopropane in the presence of N-Bu4Br and

NaOH.113

A convenient synthesis of a-mercapto alkanoic acids involves PTC

alkylation8 of dithiocarbamates and subsequent hydrolysis. Similarly, a-Substituted

phenyl acetaldehydes are C-alkylated in the presence of aqueous NaOH/NBu4I. It

has also been reported that free arylacetic acids can be a-alkyalted in a one-pot

solid/liquid (powdered KOH/CTI2CI2/TEBA)119 procedure as mentioned in the

following scheme.

Methyl 2-phenyl sulfmyl acetates can be converted into cinnamic esters by

a one-pot alkylation. The C-alkylation of chloromethane sulfonamides gives 55-

88% yield when a small amount of TIMPT is present in addition to

NBu4Br/50%NaOH.120 Aryl acetylenes was also synthesized from alkyl iodides in

16

the presence of powdered KOH/18-crown-6 in fair yields without catalyst

(NaOH/PTC) gave unpleasant mixtures of products on reaction with ethyl iodide or

benzyl and allyl halides respectively.m’123

The cyclopentadiene was alkylated with tert-butyl bromide, 5(3%NaOH and

Aliquat-336 as a PTC which gives 44% of yield.124’125

greatly improved by complexation of aiyl group with chromium tricarbonyl.

1.6.2. CARBENE REACTIONS

Phase transfer catalyst was little more than a curiosity in the late 1960's

when Makosza first published his two-phase method for the generation of

dichlorocarbene. Using a reservoir of 50% aqueous sodium hydroxide, a

cosolvent of chloroform with olefin, and a catalytic amount ol benzyltriethyl

ammonium chloride, Makosza was able to achieve high yields of

cyclopropanation products. Dichlorocyclopropanation had previously been a

difficult reaction to conduct and the ease and economy of the new method

attracted broad interest in the organic chemical community. Dichloiocarbene

could be generated in a two phase aqueous-organic system in which NaOH was

used as base and that first captured the attention of the organic chemical

121poisoning. In contrast, 1,3,3-triphenyl propane and phenyl acetylene

Des Abbayes et al. 131 reported the alkylation of aryl acetic esters and was

17

community. Apart from several methods reported in literature for generation of

dihalocarbenes,132-136 the phase transfer catalytic method in aqueous conditions

seemed more facile in view of its easy handling, cost effectiveness, high yields

and purity of products etc., Makosza133 reported the following

dichlorocycloproponation of cyclohexene.

They have also formulated the mechanism for the reaction leads to

formation of dichlorocyclopropanation product under phase transfer conditions.

Initially, reaction of CHCI3 with OH' gave the CCI3 ’ anion intermediate at the

aqueous-organic phase boundary, where it was transferred into the organic phase

by the quaternary cation and from where the dichlorcarbene is generated.

Dihalocarbenes are very useful compounds that can be reduced to

cyclopropane derivatives treated with sodium to give allenes and can be converted

to a number of other products. Literature reports of the generation and reaction of

dichlorocarbene [.CCI2] stress the importance of operating under strictly

anhydrous conditions because of the ready and rapid hydrolysis of

dichlorocarbene. Cinquini and Coworkers137 reported the reaction of styrene with

18

dichlorocarbene produced from the reaction of aqueous CHCI3 with NaOH in the

presence of phase transfer catalyst to yield l,l-dichloro-2-phenyl cyclopropane.

It should be noted that this reaction, sometimes called the Makosza

reaction was simultaneously discovered by Starks, and examples are reported in a

patent, which is contemporaneous with Makosza's paper.

In some cases, the dichlorocyclopropanation product is not isolated but

undergoes secondary reactions and rearrangement. For example, the

dichlorocarbene adducts of norbornene138 and 3-methylindole139 are examples. In

both cases, the intermediate adduct loses chloride by ionization and simultaneous

opening of the cyclopropane ring to an allylic carbonium ion leads to ring

expanded products as illustrated in eqns. (1) and (2).

In addition to dichlorocarbene, dibromo-,140-142 chlorofluoro-,143

bromofluoro-,144fluoroiodo-,145 chloroiodo-146 and diiodocarbenes146 have all been

generated under phase transfer catalytic conditions. Attempts to generate

difluorocarbene have been unsuccessful. Of these dihalocarbenes, only

dibromocarbene has been extensively studied. It has been found that good yields

of dibromocarbene from the relatively expensive bromoform can be obtained

when a small amount of alcohol (preferably n-butanol) is added to the reaction

mixture141 and the best catalyst for the reaction is not a quaternary salt, but

tributylamine.142

1.6.3. OTHER ORGANIC REACTIONS

There are several organic reactions reported in literature such as N-

allcylation,147 0-alkylation,14s S-alkylation,149 Aldol condensation,150 Witting

reactions,151 dehydrohalogenation,152 oxidation,153 reduction,154 etc., under PTC

conditions. All these products are more useful in pharmaceuticals, agricultural

chemicals and other purposes than the other products.

1.6.4. CONDENSATION REACTIONS

1.6.4.1. MICHAEL ADDITION

Michael reaction is important particularly for C-C bond formations, and

sterioselective variants have been extensively investigated in recent years.

Michael addition157 of diethylmalonate to esters of 2-(l-hydroxyalkyl) propionate

was studied and reported with a high stereoselectivity towards the syn-

diastereomer (4:1 to 20:1) using 18-Crown-6 as a catalyst and catalytic amount of

KF was used as the base in dimethyl sulfoxide or acetonitrile as solvent. Similarly,

multiple Michael addition was achieved155 to form mostly tetra-, penta- and hexa

ester’s and they were focused as potential lubricants. Two types of C-H bonds

were deprotonated. Methylene (pKa~9) was first deprotonated and added to the

double bond of methyl acrylate. The resulting methylene groups, alpha to the ester

(pKa~19-20) were then deprotonated and added to other methylacrylate

19

20

molecules. Michael addition of a deactivated methylene (sulfonic acid alpha to

ester) to acrylate esters was performed and selectively yielded mono-addition

products in 56-95% yield.157

methyl acrylate under PTC/high concentration of aqueous base (50%) condition.

1.6.4.2. Barzen’s condenzation

Makosza et al.116 first reported Darzens reactions in presence of PTC.

Chloroacetonitrile was allowed to react with the cyclohexanone in the presence of

NaOH (50%) and triethylbenzyl ammonium, chloride for about 30 min. at

15-20 °C and the product viz., glycidic nitrile was obtained «79%.

Reierson et al.158 reported the Michael addition of cyclopentadiene with

Toke et al.159 also reported chiral phase transfer catalysts in the Michael

addition of 2-nitropropane to chalcone reaction using asymmetric PTC.

Similarly, a-Chlorophenylacetonitrile was also condensed with

benzaldehyde in the presence of 50% NaOH, TEBAC 160 as a PTC using benzene.

21

Recently Balakrishnan et al.161 also reported the Darzen’s condensation

between the cyclohexanone with n-bromobutane under di-site phase transfer

catalyst.

1.7. CHIRAL PHASE TRANSFER CATALYSIS

It is well known that the application of achiral phase transfer catalyst has

been frequently applied in various fields of chemistry, particularly in the organic

synthesis.162,163 However, asymmetric synthesis reactions using chiral phase

transfer catalyst have not been extensively studied as compared to general

asymmetric synthesis reactions.163,164 The field of catalytic asymmetric synthesis

is providing synthetic chemists with a new and powerful tool for the potential

asymmetric synthesis of complex organic molecules. The most notable catalysts

165are transition metals to promote the reactions in the presence of a chiral ligands.

It is true that most of the popular catalytic synthesis are inorganic in nature; one

must not forgot the use of purely organic catalysts like (S)-proline166 simple

peptide and particularly the best popular choice of viz., “ cinchona alkaloids”.

Normally, the asymmetric organic chemists used to select their asymmetric

catalysts based on the factors like (i) the variety of reactions that the catalyst can

promote (ii) the availability of both enantiomeric catalyst at a reasonable cost (iii)

the foremost factor is the stability of that catalyst. The updated literature survey

reveals that the “cinchona alkaloids” are popular chiral source, since it meets all

these criteria and making them one of the most adoring asymmetric catalysts to

date. The constituents of cinchona alkaloids consist of two pseudo enantiomeric

pairs such as cinchonine and cinchonidine, quinine and quinidine. These

constituents are extracted from the Bark of the cinchona tree; at a native of

tropical region. Due to the presence of various functional groups and hence its

structure cinchona alkaloids, emerged as versatile chiral basic catalysts.167 The

earliest uses of cinchona alkaloids in asymmetric catalysts were demonstrated by

Pracejus in 1960’s to catalyze the symmetric alkaholysis of ketenesir’8 and

subsequently Morrison and Mosher169 and Wynberg167 have employed the same

for different prochiral synthesis. The asymmetric version of chiral phase transfer

catalyst (CPTC) derived from the cinchona alkaloids have been developed and

successfully employed to different types of useful organic reactions. 170a,b‘ 171'173

The first pioneering work for the development of cinchona alkaloids-type phase

transfer catalysts was introduced by O’Donnell et al.17/1-176 and showed that

benzylammonium salts derived from one of the versatile cinchona alkaloids viz.,

“Cinchonidine” and were used for the asymmetric alkylation of the glycinate

imines. The synthetic methodology has been developed for carbon-carbon bond

constructions by either anionic or cationic amino acid equivalents as well as the

process, which establish carbon-nitrogen176 and carbon oxygen bonds.

22

acids was introduced by O’ Donnell in 1989;177 used the liquid/liquid phase

transfer catalyzed asymmetric alkylation of N,N-diphenylmethylene glycine tert-

butyl ester (scheme 1) with the aid of N-benzyl cinchona alkaloid salts as phase

transfer catalysts and it is considered as a first generation catalyst (Fig la).

Figure 1. The different generations of chiral phase transfer catalysts derived

from cinchona alkaloids in different periods.

The second generations of CPCT’s (Fig.lb) derived from cinchona

alkaloids were subsequently developed and reported by the same 0 Donnell and

co-workers on 1994178 i.e the N-alkyl O-alkyl cinchona alkaloid salts. Then the

third generation of CPCTC’s was described independently by Lygo17'J and

Corey180 in 1997 in which 9-anthracenylmethylcinchonidinium bromide (Fig. 1 c)

was introduced as an effective unit making the nitrogen face, leading to

substantially improved enantiomeric excess (figure 1). Recently, Maaioka et

al.181 developed very efficient non-cinchona alkaloid catalysts, C2-symmetric

chiral quaternary ammonium salts prepared from (S)-binaphthol.

In connection with the development of Sharpless asymmetric

dihydroxylation, the discovery of ligands with two independent Cinchona alkaloid

units attached to heterocyclic spacers led to considerable increases in both the

enantioselectivity and the scope of the substrate. Recently, dimeric182 (Figure 2)

2a, 2b and trimeric183 2c quaternary cinchona catalysts derived from o~, m- or p-

xylene dibromide (2a), 9,10-dibromo anthracenyl (2b) and mesitylene tribromide

respectively have been employed as chiral PTC’s achieving good

enantioselectivities.

24

Figure 2. Various types of dimeric and trimeric CPTC’s

25

1.8. APPLICATIONS OF CMPTC’S FOR THE VARIOUS ASYMMETRIC

REACTIONS

1.8.1. Alkylation of Schiff bases : Synthesis of a-amino acids

Alkylation of glycine Schiff bases is a well known and straight forward

procedure for the synthesis of a-amino acids in the racemic or optically active

form. Depending on the reaction sequence used, either mono- or disubstituted-

amino acids are available.

Further studies on this process by O’Donnel and co-workers 176'177’184

showed that the active species involved in the reactions were not N-

benzylammonium salts of the alkaloid, but O-alkyl-N-benzylammonium salts such

as lb which are formed in situ from the alkaloid and alkylating agents. An O-ally 1

group was found to be preferred over an O-benzyl substituent. Enantioselectivities

of the alkylation reactions catalyzed by second generation catalysts were slightly

better compared to those of the first, generation catalysts.

Scheme 2. Mono alkylation of Schiff base under CPTC’s conditions

Mono alkylation of schiff base was a key step for seveial asymmetric

syntheses of unnatural amino acids; metal-binding 2-amino-o-(2,2 -

bipyridinyl)propanoic acid,185’186 pyridinoxoamino acid derivatives, ^ as well as

220 such as cyclopropane and epoxides. Aziridines are highly strained. Ring strain

renders aziridines susceptible to the ring-opening reactions that dominate their

chemistry as shown below, makes them useful synthetic intermediates that folly

deserve a prominent place in the arsenal of the organic chemist.

In view of the long history of aziridine chemistry, it is not surprising that

the literature on the subject is very extensive. For the interested reader requiring a

general introduction, several excellent discussions are available.221 The ability of

aziridines to undergo highly regio-and stereo selective ring-opening reactions

makes them very valuable in organic synthesis. This ability has not gone

unnoticed in nature, where a number of molecules possessing an aziridine ring

have been shown to exhibit potent biological activity, which is intimately

associated with the reactivity of the strained heterocycle.

Structure-activity relationships have identified the aziridine ring as being

essential for antitumour activity and a vast amount of work has been concentrated

on synthesizing derivatives of these natural products with increased potency.

There are several reports for the synthesis of Chiral aziridines (Figure 3) from

various substrates via, nitrenes, azirines, aminoalcohols, imines, etc.

27

Chiral aziridines are very important substances in asymmetric synthesis

since they have been shown to be useful chiral auxiliaries, chiral ligands for

transition metals and chiral substrates in the preparation of biologically active

species such as amino acids, beta-lactams and alkaloids.222 Although many

methodologies are available for chiral aziridines, only a very few are catalytic in

nature.221 An efficient catalytic synthesis of chiral N-tosylaziridines has been

developed by Jacobsen and Evans. Recently, Jacobsen"" has reported a

catalytic asymmetric method for N-arylaziridines with enantiomeric excesses up

to 67% but in poor yields.

Lobo et al.226 also reported a new catalytic enantioselective method for N-

arylaziridines based on the quaternary salts of Cinchona alkaloids as phase-

transfer catalysts. Further they also have previously reported that N-acyl-N-

arylhydroxylamines and O-acyl-N-arylhydroxylainines are efficient aziridinating

agents for electron deficient olefins. But they are obtaining aziridines in moderate

to good yields and enantiomeric excesses up to 62% (Scheme 4) under chiral

phase transfer catalyst conditions.

Scheme 4. Enantioselective aziridination of hydroxamic acids

Recently Jacobsen et al.223 have studied the synthesis of N-arylaziridines

using bisoxazolines Copper (I) complex and reported an enantiomeric excess up to

reported a new catalytic enantio selective method for the preparation of N-aryl

aziridines in the presence of quaternary salts of cinchona alkaloids as a soluble

phase transfer catalysts. They have also studied that the N-arylhydroxylamines

and O-acyl-N-arylhydroxylamines as an efficient aziridinating agents for electron

deficient olefins and reported different chiral aziridines using cinchona alkaloid

derived chiral phase transfer catalyst, but here the chemical yield is 80% with

yield up to only 38%.

In this context, we envisaged that good results could be obtained with this

type of cinchona derived ammonium salts if a builder group containing starting

materials were employed as a bridge between the alkaloid moieties, in analogy to

Lygo’s,179 Park,183 Jew182 and Corey's180 improvements relative to the monomeric

catalysts. In order to improve the catalytic efficiencies and ee’s, the catalysts were

examined by newly synthesized single, dimeric, trimeric and tetrameric catalysts

derived from inexpensive starting materials with cinchona alkaloids as a chiral

moieties. The catalytic efficiencies were studied by the syntheses of a-amino

acids and N-aryl aziridines.

67% with a modest chemical yield (< 50%). Joao Aires-de-sousa et al226 have also

1.9. THE ORIGIN OF MULTI-SITE PHASE TRANSFER CATALYST

Phase transfer catalysis has become, in recent years, a widely used, well

established synthetic technique, applied with advantage to multitude of organic

transformations. In addition to steadily increasing number of reports in the

primary literature,6 20 there are several reviews,221’222 comprehensive monographs

and an ACS audio course which describes the phase transfer process and which

provide extensive compilation of phase transfer agents and reaction type. While

the lists of applications and in many cases the synthetic results are impressive,

phase transfer catalysts (PTCs) suffer some of the same disadvantages as more

conventional homo- and heterogeneous catalysts, i.e., separation and recovery. A

catalyst which contains only one reactive site is known as single site phase

transfer catalyst viz., tetraethyl ammonium chloride (TEAC), tetraethyl

phosphonium chloride (TEPC), tetrabutyl phosphonium bromide (TBPB) etc. If

the PTC has more than one active site, they are called as "Multi site phase transfer

catalyst” (MPTC). The soluble single site phase transfer catalyst such as TEAC,

TEPC, TBPB, viz are immensively popular due to their availability and easy

reaction work up. Even though, the vast number of the single site catalysts are

available for research, the selection of catalyst mainly depends on the scale of

economy. The efficacy of the catalytic activity of these multisite PTCs towards

simple Sn2 reactions was reported. In general multisite PTCs offer the potential ot

providing greater PTC activity and to effect a particular synthetic transformation

under mild conditions.

Systematic survey of the literature reveals that the studies of Idoux et al227 as

a first report dealing with multisite-phase transfer catalysts containing only three

active site (phosphonium ion) type of soluble and insoluble polymei-bound catalyst.

Balakrishnan et al34,115,161 had also reported the soluble MPTC containing two and

three active site (triethyl ammonium ion) type of catalysts which are used tor the

30

Balakrishnan et al.115 and Wang et al.161,230 have also reported soluble ammonium

quaternary onium ions having two active sites and the efficiency of the di-site

PTC were also examined through simple S>j2 reactions and some weak

* * ion 183 ">30nucleophihc SnAr reactions, Recently, dimeric and trimeric chiral

quaternary ammonium catalysts were synthesized from o-, m- or p-xylene

dibromide, bis(bromomethyl)naphthalenes and mesitylene tribromide

respectively. These CPTC’s have been employed for C-alkylation of

N-(diphenylmethylene)glycine tert-butyl ester and have been found to be good in

terms of chemical yield and ee’s. In the recent past our research group also

developed multi active centres of achiral and chiral catalysts. Recently we

condition containing six-site catalysts.

There is no other report on the MPTC containing more than four active site

either in soluble or insoluble form. No doubt that the number of catalytic site can

decide the efficiency of reaction which in turn control the economy of the reaction

process. Taking in to consideration the above mentioned aspects, we have decided to

synthesise novel soluble, as well as, insoluble achiral and chiral multisite PTC

containing maximum possible active sites (two to thirty two sites) catalysts from

pinene, dichlorocarbene addition to (R)-limonene, Darzen’s condensation to

4-nonanolide with l,6-dibromohexan-2-one, Michael addition to cyclopentadiene

with methylmethacrylate and enantio selective synthesis of a-amino acids & N-aryl

aziridines respectively.

various alkylation reactions. Maurizio et al228 reported poly(ethylene glycol)

supported tetrakis quaternary ammonium catalyst and it is recyclable in nature.

Jew et al.182 had also developed multi-active chiral centre which contained three

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