1

CHAPTER ONE

1.0. INTRODUCTION

1.1. IMINIUM SALTS

Iminium Salts are highly versatile synthetic intermediate groups since they present an

extremely electrophilic carbon for nucleophilic attack.1They are strong bases, in fact are more

basic than amines. They could be classified as ,-unsaturated tertiary amine salts which

depends on their quaternary nitrogen atom for action. The general structure of an Iminium

salt is given below.

The structure of iminium salt was first postulated (in the study of alkaloid chemistry) by

Adams and Mahan2 in 1942. They showed that its structure was responsible for the strong

basicity of tertiary cyclic saturated amines over primary and secondary amines.

Iminium salt can be represented by the resonance structures (2) and (3) below which are in

dynamic equilibrium.

2

NMR studies of Iminium salts has shown that the positive charge is more resident on the

nitrogen atom than on the carbon atom3

of the iminium function, therefore the equilibrium

lies more to the left which favours structure (2) above. The presence of a double bond in the

alpha-position to the nitrogen atom leads to a very reactive group which is quite different

from tan aliphatic unsaturated amine where the double bond is isolated from the nitrogen

atom by at least one more single bond. The aliphatic unsaturated amine will be oleifinic and

will therefore exhibit properties of amines and/or oleifins.

The milder methods of preparation and efficient modern strategies such as their role in

tandem reaction procedures (e.g Aza-Cope Mannich Cyclization) and counter nucleophile

reactions demonstrate their increasing value as synthetic tools4.

1.2. TYPES OF IMINIUM SALTS

Broadly speaking, Iminium salts can be classified either as a saturated or aromatic iminium

salt. The saturated iminium salt can be further grouped into the straight chain and cyclic

iminium salt. The cyclic iminium salt can itself be further divided into the exocyclic and

endocyclic iminium salt. It can be represented as shown in the tree below.

3

Fig 1.1

An example of a straight chain iminium salt is given below.

The exocyclic iminium salt has its double bond outside the ring e.g.

The endocyclic iminium salt has its double bond within the ring e.g.

4

The Aromatic Iminium Salts are aromatic rings that contain a quaternised nitrogen atom e.g.

1.3. STABILIZING ANIONS

Iminium salts are usually stabilized by different types of counter ions.3,5

These

includes inorganic anions such as halides (F-, Cl

-, Br

-), Nitrateion (NO3

-), Cyano ion (CN

-

), Perchlorate ion (ClO4-), Tetrafluoro borate (BF4

-),Tetrafluoro aluminate (AlCl4

-),

Phosphorodichloridate anion (OPOCl2-) Hexachloro Stibate(V) ion (SbCl6

-), Hexachloro

stannate(V) ion (SnCl6-),and Hexafluoro phosphate(V) ion (PF6

-).Organic anions include

Acetate ion (CH3COO-), Trifluoro acetates (CF3COO

-), Toluene sulphonyl ion,

Trifluoromethane sulphonates (CF3SO3-), Picrates etc. The aldiminium ion is stabilized

by the triflate anion as shown below.

5

Leonard and Paukstelis6 considered perchlorate to be the best anion in their

experimental work with iminium salts. They concluded that fluoroborate salt functions

less efficiently than the Perchlorate salt but can probably be handled with greater

assurance of safety.

1.4. HETERO IMINIUM SALTS3

These are iminium salts in which a heteroatom is attached to the carbon atom of the

iminium function. Examples of these heteroatoms include Nitrogen, Sulphur, Oxygen,

Chlorine etc.

Examples of Hetero iminium Salts include;

1.4.1. Vinyl Iminium Salt

In this case, a vinyl group is attached to the carbon atom of the iminium function. An

example is given below.

6

1.4.2. Keteniminium Salt

When a double bond exists between the iminium carbon and the carbon next to it, such

an iminium salt is referred to as a keteniminium salt e.g.

1.4.3. Chloroiminium Salt

When a chlorine atom is attached to the carbon of an iminium function, such a salt is

referred to as chloroiminium salts or Dichloroiminium salts as the case may be e.g.

1.5. OXYIMINIUM, HYDRAZONIUM AND SULPHONYL IMINIUM SALT

A heteroatom can also be attached to the nitrogen atom of an iminium function. When the

heteroatom is oxygen, it is called an oxyiminium salt, in the case of a nitrogen attachment, it

is referred to as hydrazonium salt while sulphur-containing iminium salt are referred to as

sulphonyl iminium salt . Examples are given below.

7

(a) oxyiminium salt

(b) hydrazonium salt

(c) sulphonyl iminium salt7

8

In general, any heteroatom attached to an iminium salt must be neutral, if the hetero atom

is charged, then the salt becomes a ylide e.g. Nitrones

Also, the sulphur atom in a sulphonyl iminum salt must necessarily be neutral.

1.6. SPECTROSCOPIC PROPERTIES OF IMINIUM SALTS

Spectroscopic methods like Infra-red (IR), Nuclear Magnetic Resonance (NMR), Ultra-

Violet (UV), and Mass Spectroscopy have been employed in the study of the properties of

iminium salts. These methods are used to determine the formation and characteristics of

these salts. They are also used at times to determine the pathway these salts follow in

their reactions.

1.6.1. Infra-Red Spectroscopy of Iminium Salt

The infra-red spectra of a typical iminium salt8,9

reveals that the Carbon-Nitrogen

double bond absorbs strongly around the region 1680-1660cm-1

depending on the

stabilizing anion, the substituent on the carbon atom, and the medium in which the salt is

being analysed. An example is N-Substituted Tetrahydropiperidinium salt (27) which

9

shows variation in the position of the absorption bands as the stabilizing anions and

spectra phase are varied.8,10

This is illustrated in the table below.

Table 1.1

1644 1670 1691 1698

Phase KBr KBr KBr Mull

Anion (X-) SnCl6

- SbCl6

- NO3

- ClO4

-

The substituents on the carbon also have an effect on the position of absorption with

mull as the spectra phase. As the substitution increases, there is a shift to lower frequency.

This is exemplified below.

10

The observed absorption is due to the Carbon-Nitrogen stretching vibration which is

typically at 1680cm-1

. This is higher than the aliphatic amine stretching band which normally

appears in the region around 1220-1020cm-1

.

It has been found that Tetrafluoroborate anion (BF4-) shifted the position of absorption of

the iminium salt to higher frequency (1700cm-1

), though the effect of the other anions are not

so pronounced. In the example given below, the frequency of the iminium salt containing

perchlorate ion is low compared to that containing the tetrafluoroborate ion.

Halogens are also known to shift the absorption band of the iminium ion to lower

frequencies (1650-1590cm-1

) whenever they are present either as an anion or as substituent

on the iminium carbon.

11

The shift to lower frequencies is due to the mass effect and the weakening of the double

bond by the electron donating effect of the halogens.11

When the phase is varied, there is a change in frequency. This is shown in the table below

for compound (40).

Wavelength (cm-1

) 1664 1681

Phase mull CH2Cl2

Anion (X-) Cl

- Cl

-

When double bonds are in conjugation with the iminium salt, there is no appreciable

change in the position of absorption.

12

1.6.2. Nuclear Magnetic Resonance Spectra of an Iminium Salt

NMR spectroscopy has become a very important developing tool for organic chemists in

the determination of the structure of organic compounds.12

The structure and chemistry of

iminium salts have been studied by 15

N labelling, 1 H NMR and 13C NMR spectroscopy.

However, our focus will be on the 1H NMR and 13C NMR of an iminium salt.

1H NMR

Iminium ion comprises of two functions; the carbonium ion and the quartenised nitrogen.

This is represented by the resonance structures below.

The 1H NMR spectra of an iminium ion was compared with the spectra expected for each

of these two functions to determine which of them predominates. A typical carbonium ion is

the isopropyl cation [(CH3)2CH+]. The proton attached directly to the carbocationic centre of

an isopropyl cation showed up as an exceedingly deshielded septet at 13.513 whereas a

proton on an iminium carbon will normally show up in a region between 7.5 and 10.0. This

is observed because there is less positive charge on an iminium carbon compared to that of a

carbonium ion. This is proof that the positive charge is more resident on the nitrogen atom

than on the carbon atom of the iminium function.

The proton on the carbon of an iminium function behaves like an aldehydic proton in NMR

since such proton absorbs between 7.5-10.0 (aldehydic protons normally absorbs between

9.5-10.0 except when or if it contains a halogen substituent).

13

The presence of halogen on the iminium carbon caused the absorption to be shifted

downfield e.g.

The absorption is further shifted downfield when the stabilizing anion is a halogen e.g.

Comparing the proton on the carbon of an imine function with that of an iminium salt, it

was found that the protonation of an imine to give an iminium salt will have a deshielding

effect on the iminium proton which as a consequence leads to a shift downfield. It has been

established that the proton of carbonium ion is more deshielded than that of iminium salt and

imine.

1H NMR spectra of an iminium salt has also been compared with that of an enamine, the

proton of an iminum salt absorbs at a higher frequency. This is so because; the shielding

effect on the proton of the enamine has been greatly reduced as soon as a positively charged

nitrogen atom is formed.

14

13C NMR

13C NMR is used to study the carbon atom of the iminium function (this cannot be done

with 1H NMR). It has been stated earlier that the carbon of an iminium function is less

positive compared to a carbonium ion. The positively charged carbon of an isopropyl cation

[(CH3)2CH+] absorbs at 320.6 while the carbon of an iminium function shows up at a

position between 130-180. This is in agreement with the 1H NMR data which shows that

the positive charge is more resident on the nitrogen atom than on the -carbon of an iminium

salt. The N-substituted carbon atom absorbs between 38.0-50.0.

1.6.3. Ultra-Violet Spectra of an Iminium Salt

A ultra-violet spectrum is only useful in characterizing and analysing an iminium salt when

it is in conjugation with a -bond systems (i.e double bonds or phenyl group) e.g.

Simple iminium salts like the compound below absorbs at a wavelength of 219nm in

hexane with an extinction coefficient between 5-5000

15

When the iminium salt is within a highly conjugated system, then the wavelength of

maximum absorption (max) will also show a bathochromic shift to a region between

242.5nm-336.5nm.

When chromophores are available for conjugation, the max will increase (i.e a shift to

longer wavelength), Also the max will increase when auxochromes are available for

conjugation since they contain non-bonding electrons e.g. OR, -SR, -NR2.

When iminium salts are derived from enamines, there is no significant change in the value

of max.

1.6.4. Mass Spectra of an Iminium Salt3

Mass spectroscopy is not really a useful method of analysing iminium salt due to the

following reasons.

The Analysis involving mass spectroscopy is usually obtained by volatilizing the

sample before electron impact ionization or other ionization technique is applied.

Iminium salt is made up of fragment ions that can be obtained in the mass spectra of

nitrogen-containing compounds.

In mass spectroscopy, samples are usually heated before ionization takes place. Iminium

salts are not stable when heated, so the mass spectra obtained can no longer be regarded as

that of an iminium salt. Other species may have been formed. This could happen via any of

the three ways illustrated below.

16

(a) Thermal Elimination

When the iminium salt is heated, the stabilizing anion and one of the substituent on the

nitrogen atom is eliminated, thus an imine is analysed rather than an iminium salt.

(b) -Rearrangement

In this case, imines cannot be formed and so -elimination occurs.

(c) Anion Rearrangement14

In this case, three possible rearrangements could occur

If the stabilizing anion is a good nucleophile, it may attack the -carbon of the

iminium ion.

17

The anion could attack the SP3-carbon in the -position leading to ring opening and

further rearrangement.

In the case of a BF4- anion, the thermal degradation of the anion provides fluoride ion

which could attack the iminium ion and cause rearrangement.

In general, the Infrared and NMR spectroscopy are the most useful and reliable method for

the detection, characterization and/or analysis of iminium salts.

18

1.7. N-ACYLIMINIUM SALTS

N-acyliminium salts are iminium species in which the nitrogen atom is acylated. Owing to

the electron-attracting properties of the carbonyl group on nitrogen, the iminium carbon

becomes more electron-deficient; this causes such N-acyliminum salt to be more reactive as

electrophiles than simple N-alkyliminium salts.

The structure of a simple N-acyliminium salt is given by (62) below.

N-acyliminium ions can be generated as discrete salts, paired with non-nucleophilic

anions15

, although this is a relatively rare undertaking restricted to physicochemical studies.

Whereas, iminium salts are frequently isolable, their N-acyliminium counterparts are far

more reactive and seldom if ever isolated15,16

. N-acyliminium intermediates are usually

generated in situ, often under acidic or lewis acidic conditions.

An N-acyliminium ion is most likely not generated stoichiometrically in the course of a

reaction, as it can exist in equilibrium with a covalent adduct as shown below.

19

The proportion of the ionic form and the covalent form may vary significantly depending

on the nature of the anion and on experimental conditions. For example, the adducts formed

from the treatment of benzaldimines with simple acid chlorides are substantially comprised of

aryl--chloroamides, rather than N-acyliminium salts.17,18

1.7.1. Sources of N-acyliminium Ions

N-acyliminium ions can be accessed through a variety of means; however, as mentioned

earlier, they are very reactive, so they are almost always generated in situ. Below is a brief

overview of some of the useful procedures of generating N-acyliminium ions.

(a) Reaction of Amides with Aldehydes & Ketones19

Secondary amides combine with aldehydes or ketones to provide -hydroxyalkyl

derivatives, which can form the corresponding N-acyliminium ions on treatment with an acid.

(b) Reduction of Cyclic Imides20

This involves the reduction of cyclic imides in the presence of an alcohol to afford the

corresponding hydroxy lactam and/or the alkoxy lactam which are useful precursors of cyclic

N-acyliminium species.

20

(c) N-Acylation of Imines21

Imines readily prepared by the condensation of an aldehyde or ketone with a primary

amine, undergo acylation with an acid chloride or acid anhydride to form an adduct which

can act as acyliminium species.

N-acyliminium ions are very reactive towards a wide variety of -nucleophiles including

alkenes, allenes, alkynes, aromatic and heteroaromatic systems. They have been used majorly

in cyclisation reactions. An example of a cyclisation reaction involving N-acyliminium ion is

the formation of the erythrinane skeleton below.22

21

David et al23

treated amino ether (76) with lewis acids leads to the generation of the

bicyclic N-acyliminium ion (77) which reacts in turn with -nucleophiles to give trans adduct

(78) in 56-95% yields.

22

CHAPTER TWO

2.0. LITERATURE REVIEW

2.1. GENERATION OF IMINIUM SALTS

The usefulness of iminium salts in the synthesis of organic and heterocyclic compounds

has led to the growing interest in them. The formation of the salt has therefore been attempted

in several ways depending on the direction of approach of the reaction.

Iminium salts can commonly be prepared from the reactions of a secondary amine with a

carbonyl component, from enamines and imines by reaction with electrophiles such as H+

or

other SP3-nitrogen containing derivatives, such as -amino alcohols, -amino ethers (e.g

oxazolidines), -amino sulphides (e.g thiazolidines), and -amino nitriles, are efficient

sources of iminium salts.4

Iminium salt can either be generated as intermediates or isolated compounds. Newer

methods of generating iminium salts are been developed continually. Some of the classical

and new methods will be discussed here.

2.1.1. Condensation of a Carbonyl Component with Secondary Amine

This is a general method of preparing iminium salt, it is applicable to a variety of starting

materials that are easy to obtain.

Yin Ku et al24

reported a simple one-pot procedure for the formation of iminium salt. The

iminium salt (80) was generated in situ from the amine salt (79) and paraformaldehyde in one

pot and in a polar and aprotic solvent such as NMP.

23

Orazi et al25

also reported the preparation of iminium salts from benzyl sulphonamide.

They coupled the sulphonamide with an aldehyde in an acidic medium. The benzyl

sulphonamide behaved like a secondary amine as shown below.

Tarik et al26

also prepared iminium salt by refluxing a mixture of paraformaldehyde and

piperidine hydrochloride in benzene for five hours at a pH 3.0. They obtained a crystalline

yellow product which showed a stretching vibration of C=N at 1660cm to confirm the

formation of the iminium salt below.

24

-

Saidi and co-workers27

reacted an aldehyde with (trimethylsilyl)dialkylamine in ether in

the presence of lithium perchlorate to give the iminium salt (90).

2.1.2. Decarbonylation of Acid Chlorides Using Trifluoromethane Sulphonate

This method involves the treatment of an acid chloride with recrystallized silver

trifluoromethane sulphonate to form the iminium salt via decarbonylation.

25

Alo and Adesogan28

reported the instantaneous reaction of N-(arylsulphonyl) pyrrolidine-

2-carboxylic acid chloride (91) with silver trifluoromethane sulphonate or silver

trifluoromethane sulphonic acid at room temperature to give the sulphonyl iminium salt (92).

The pathway proposed for the loss of carbon monoxide in the reaction is given below.

The method was extended to the naphthalene analogue to give the iminium salt (94) below.

26

The same method was also used on six-membered rings by Alo and Familoni29

. They

generated the iminium salt (96) from N-(2-nitrobenzene sulphonyl)-piperidine-2-carboxylic

acid chloride (95).

This method is however not suitable for substrates containing a halogen or strongly

electron withdrawing substituents. The halogen will instead react with silver trifluoromethane

sulphonate while strongly electron withdrawing substituents like NO2 gives no reaction.

27

2.1.3. Oxidation of Tertiary Amine

The oxidation of tertiary amines by a number of reagents has been quite established as an

important synthetic route to iminium salts. Most of this kind of reaction reaction goes through

a Polonovski-type reaction.

The Polonovskis30

reported the treatment of a tertiary amine with hydrogen peroxide

followed by acetic anhydride to effect a de-alkylation of the amine and isolate an aldehyde

and acetamide. This reaction involves the oxidation of the amine by the peroxide to the N-

oxide followed by abstraction of an -hydrogen by a base to give a ylide-type intermediate,

the iminium salt (97), which does not react further.

By various modifications of this reaction, iminium salts are now prepared by similar

oxidations of tertiary amines.

Leonards group31 prepared iminium salts by dehydrogenating the compound (98) below

with mercuric acetate to obtain the -5(10) dehydroquinolizinium salt characterized as its

perchlorate.

28

Hata and his co-workers32

obtained alkoxy carbonyl iminium salts (101) from the oxidation

of tetra-substituted amino ketene silyl acetals (100) which they employed in synthesizing

many other compounds.

Shimizu33

also prepared an alkoxycarbonyl iminium salt by the oxidation of amino ketene

silyl acetal with oxidizing agent such as 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone(DDQ).

New signals at 9.27ppm and 193.6ppm in the 1H and

13C spectra respectively indicated the

formation of the iminium salt (103).

29

Chun and Hang34

reported the oxidation of the imidazole compound with NBS in glyme at

room temperature for 45 minutes to obtain the imidazolinium bromide salt.

Osato and co-workers35

reported the generation of the iminium salt from the oxidation of

the enamine (106) with trifluoroacetic acid below 50C. The iminium salt was stable at 25

0C

for 3 hours.

Martin36

also used imine (108) which was transformed into the iminium ion (109) by the

action of trifluoroacetic acid at -400C.

30

Feroud et al37

did a chemical study of the oxidation of tertiary amines and alkaloids

through mono-electronic transfer in which a singlet oxygen efficiently and clearly oxidized

tertiary amines in organic media of low polarity to form an iminium salt.

Grierson38

reported the formation of iminium salts from 2,3,5,6-tetrahydropyridines in the

presence of m-CPBA and TFAA. This is a modified Polonowski reaction, however, there are

some occasional drawbacks, and for instance the acidic conditions may not be compatible

with all functional groups in the molecule.

2.1.4. POCl3 Derivatives Induced Decarbonylation

This involves the development of a high yield, single step, regiospecific method for

preparing iminium salts from -tertiary amino acids.

31

Rapoport et al39

obtained iminium salts by briefly heating -amino acids in phosphorus

oxychloride. N--phenylethylproline hydrochloride (116) was decarbonylated in this manner

and after adding the reaction mixture to water; the N--phenylethyl-1-pyrrolinium ion (117)

was precipitated as the crystalline perchlorate.

Similarly, N-methylpipecolic acid was converted to N-1-methyltetrahydropyridinium

perchlorate or tetraphenylborate salt both in 94% yield.

Gupton and co-workers40

reported the synthesis of vinylogous iminum salt derivatives

from a ketone as shown below.

32

2.1.5. Alkylation of Imines

Direct alkylation of imines is another versatile method of preparing iminum salt. A variety

of iminum salts has been obtained in this manner.

Schlegel and Maas41

reported the generation of open-chain propyne iminium salts by the

N-alkylation of alkynyl imines with methyl triflate or triethyloxonium tetrafluoroborate. The

method gives access to propyne iminium salts in which the carbon-carbon triple bond bears

an alkyl, SiMe3 or H-substituent.

33

Xin Dai et al42

alkylated an imine with Trimethylsilyl chloride to obtain the iminium salt

(127)

Le Gall and co-workers43

described the reaction between imine (128) with an electrophilic

compound that are known to easily form nitrogen activating groups (e.g. methane sulphonyl

chloride) to furnish analogous iminium salts.

Ofial and Mayr44

reported a method of synthesizing cyclic iminium salts from acyclic

iminium salts. They used the preformed iminium salt (130) with hexachloroantimonate (V)

34

anion as the counter ion to react with (1,1-dimethylallyl)trimethylsilane (131) in

dichloromethane to give pyrrolidinium salts (132) in good yields.

Taylor and Schreiber45

prepared the alkyliminium salt by exposing the adduct (7-Hydroxy-

6-methoxy-3,4-dihydroisoquinoline) to 2-Bromobenzylbromide in ether.

They also neutralized commercially available 3,4-Dihydro-6,7-dimethoxyisoquinoline

hydrochloride and alkylated it with methyl iodide to form the isoquinolinium compound

(136) below.

35

2.1.6. Iminium Salts from Enamine

Iminium salt can be obtained via the transformation of an enamine. This can be done with

various reagents.

Iminium salts were quantitatively prepared by A. Atmani et al46

using acid chloride (such

as acetyl chloride) with -aminoenamines or by the reaction of methyl iodide with the same

enamine.

The above reaction takes place under mild working conditions and the isolation and

purification of the salts just requires their filtration and washing with appropriate solvent.

Levin et al47

studied the interaction of silyl triflates (R3SiOTf) with enamines. However

when R= C6F5, the product obtained is an enamine.

36

2.1.7. Use of Silver Compounds

Enders and Shilvock48

reported that -amino nitrile acts as stable precursors to iminium

ions. The addition of silver tetrafluoroborate to compounds (142) and (144) generated the

iminium compounds (143) and (145) respectively.

Schneider and Brner49

treated the cyanopiperidine (146) with silver triflate in acetonitrile

which gave rise to the iminium compound (147).

37

2.1.8. Other Methods

Fenster et al50

reported the treatment of cyclohexanone with hydroxylethyl or

hydroxypropyl azide in the presence of boron trifluoride followed by crystallization of the

resulting iminium ether as its tetrafluoroborate salt.

Aitken et al51

obtained the chiral iminium salt from (S)-proline for the kinetic resolution of

secondary alcohols. The salt was readily prepared by treatment of (S)-prolinol with CS2 and

aqueous sodium hydroxide to give the thiazolidinethione followed by quaternisation with

methyl iodide.

Saidi and Azzizi52

reacted compound (154) with trimethylsilylcyanide in the presence of

iodine to generate the iminium salt (155). This reaction involves the loss of cyanide ion.

38

2.2. SYNTHETIC UTILITY OF IMINIUM SALTS

Iminium salts have served as versatile reactive synthetic intermediates by virtue of their

ability to yield new carbon-carbon bonds via nucleophilic attack at the highly electrophilic

masked carbon and have been used in many syntheses involving fused heterocyclic ring

systems.

Osato et al35

reported a safe and scalable process via a reformatsky type reaction of

iminium salt (144) followed by red-Al reduction giving tert-butyl-4-(2-hydroxyethyl)-4-

(pyrrolidin-1-yl)piperidine-1-carboxylate (145), an intermediate of novel anti-

arteriosclerotics.

A cheap, versatile and convenient method for the synthesis of -lactams was reported by

Jarrahppour and Zarei.53

They used methoxymethylene-N,N-dimethyliminium salt as an acid

activator. This method was used for the preparation of monocyclic, spirocyclic, and N-alkyl

-lactams. The products were obtained in good to excellent yields.

39

The advantages of the above method are the mild reaction conditions, low cost, avoiding

the use of chlorinating agents and easy purification of the products.

Atmani et al46

engaged the iminium salt (149) in situ in the synthesis of -amino

phosphonate. With alkyl phosphites, the reaction afforded -dialkylamino ,-ethylenic

phosphonates in good yields.

Martin36

reported the stereo-controlled synthesis of highly substituted pyridine (152) by

trapping the iminium salt (151) with either sodium cyanide or triethylsilane.

40

Gupton and co-workers40

employed vinylogous iminium salts as useful precursors for the

region-controlled synthesis of heterocyclic appended pyrazoles.

Saidi et al27

described a one-pot method for the aminoalkylation of electron-rich aromatic

compounds using -naphthol with iminium salts prepared in situ in ethereal lithium

perchlorate. It gave good yields of amino-alkylated aromatic and aliphatic compounds.

41

Katritzky and Arend54

reacted Benzotriazole iminium salt with an N-arylamine to get

quinoline. The advantage of this approach is that it gave high yields and the starting materials

are readily available.

Levin et al55

reported that the iminium salt generated by the coupling of aldehydes, N-

smoothly reacts with silanes of the general formula Me3SiRf to afford the corresponding

tertiary amines having a fluorinated substituent. The key step, involving the carbon-carbon

bond formation is promoted by NaOAc or KF in DMF as a solvent.

42

Alo and Adesogan28

used the iminium salt in the preparation of tricyclic thiazides, this has

potential pharmaceutical (diuretic and anti-hypertensive) activity. This is described in the

reaction below.

Substituted analogue of this compound was also synthesised in the same manner by Alo et

al.56

43

The N-(arylsulphonyl)-tetrahydropiperidinium salts prepared by Alo and Familoni29

was

used in the synthesis of hexahydropyrido 3[1,2-b][1,2,4]benzothiadiazine-5,5-dioxide.

Hancock and Pinhas57

reported the conversion of phenyl-substituted aziridine to a 1,2

diamine using lithium iodide and an iminium salt.

44

Zheng and Xu Bai58

reported the Grignard addition to a quinoxalinium salt in the synthesis

of Substituted-1,2,3,4-tetrahydroquinoxaline. When 1 equivalent 0f the Grignard reagent was

used, 1,2-disubstituted-1,2,3,4-tetrahydroquinoxaline was the principal product.

However, when 4 equivalents of the Grignard reagent was used, 1,2,3-trisubstituted-

1,2,3,4-tetrahydroquinoxaline was obtained. The outcome of the reaction depends on the

amount of Grignard reagent used and the reaction temperature.

Brook and Jahangir59

described the use of Trimethylsilyl triflate (TMSOTf) in facilitating

the addition of Grignard reagents to several aryl aldimines. The mechanism proposed

involved the formation of an iminium salt.

45

Hata et al32

synthesized ,-Disubstituted -amino ester derivatives by the nucleophilic

addition of Grignard reagents to the generated iminium salt (186). The products were

obtained in moderate to good yields, in which aryl and ethynyl substituents are readily

introduced.

Yin Ku et al24

described an efficient route to -arylethylamines via an iminium salt.

Benzylic organozinc compounds were reacted with the iminium salts (189) generated in situ

from the amine salts and paraformaldehyde in one pot and in a polar and aprotic solvent such

as NMP.

46

Shimizu et al60

used iminium salt generated from the oxidation of amino ketene silyl

acetals to react with another ketene silyl acetal to give aspartic acid derivatives in good

yields.

Iminium salt can also be used as a catalyst. This was done by Page and co-workers61

in the

assymetric epoxidation of alkenes. The binaphthalene-fused azepinium salts was used as

organocatalyst in the reaction giving rise to the epoxide 1-Phenyl-7-oxabicyclo[4,1,0]

heptane.

47

Azizi and Saidi62

synthesised the Baylis-Hilman adduct (200) by reacting the iminium salt

prepared in situ with methyl acrylate in the presence of a catalytic amount of a tertiary amine

at ambient temperature.

Rapoports group39 in Berkeley reported the synthesis of some natural products like

tetrahydroberberine using iminium salts generated by heating -tertiary amino acids with

POCl3 and then warming the resultant iminium salt in HCl.

48

Tom and Ruel63

reported the hydrolysis of the intermediate quinolone iminium salt (204)

with 1N HCl in THF at room temperature to form the 3-formylquinoline derivative (205).

49

Kobayoshi and co-workers64

also reported the facile synthesis of 9-Dialkylamino-9H-

pyrrolo[1,2-a]indoles via iminum salts generated from 2-(Pyrrolo-1-yl)benzaldehydes and

secondary amine hydrochlorides followed by intramolecular trapping of the resulting

iminium carbon by the 2-position of the pyrrole. They are generally obtained in good yields.

Moghaddam et al65

reported the synthesis of 8-membered hydroquinolines related to

alkaloid skeletons via the addition of 4-Hydroxycoumarin to quinolinium salts.

50

Kimpe66

also reported the rearrangement of 5-(Bromomethyl)-1-pyrrolinium salts into

functionalized piperidines. 5-(Bromomethyl)-1-pyrrolinium bromides (212) undergo

rearrangement with alkoxides in the corresponding alcohol to afford 2,5-dialkoxy piperidines

(213), which are easily converted into 3-alkoxy piperidines.

Rousselet et al67

described the reaction of an iminium ion with the methyl ester of p-

hydroxybenzoic acid to give the corresponding adduct.

Chen and Cunico68

described the reaction of a carbomoysilane with iminium salts derived

from aldehydes lacking -hydrogens to give -(Dimethylamino)amides.

51

Winter and Risch69

also described the cross-mannich reaction of aldehyde in the synthesis

of substituted pyridines.

Ellwood and Porter70

treated a range of primary and secondary alcohols with the iminum

salt (224) to obtain the corresponding alkyl iodides in excellent yield with straightforward

purification. Selective formation of a primary iodide in the presence of a secondary alcohol

can be achieved.

52

Leonard et al71

synthesized Tetrahydro-1,3-oxazine by oxidizing the 30 amino alcohol with

mercury acetate to generate the endocyclic iminium salt which then undergoes an

intramolecular cyclisation reaction. They showed that this reaction was general for 30-amino-

-alcohols as the N-piperidino alcohols were also cyclised in the same fashion.

Amato et al72

reported the synthesis of 1-tert-butyl-4-chloropiperidine. They generated an

N-tert-butyl group by the reaction of a dimethyliminium salt with methylmagnesium chloride.

This process involves two efficient routes. In the first route, the key thionyl chloride mediated

chlorination reaction features the use of tetrabutylammonium chloride as an additive that

effectively suppresses the formation of an elimination-derived side product. In the second

route, a novel alternative synthesis of 1-tert-butyl-4-chloropiperidine was developed in which

the tertiary butyl group on the nitrogen is efficiently generated through the addition of

methylmagnesium chloride to a dimethyliminium salt in 71% overall yield.

53

Shen et al73

gave a detailed account regarding a formal [3 + 3] cycloaddition method using

4-hydroxy-2-pyrones and 1,3-diketones. This formal cycloaddition reaction or annulation

reaction is synthetically useful for constructing 2H-pyranyl heterocycles. The usage of ,-

unsaturated iminium salts is significant in controlling competing reaction pathways to give

exclusively 2H-pyrans.

54

2.3. AIM OF RESEARCH

As stated earlier, iminium salts are useful versatile intermediates in heterocyclic ring

synthesis since they present an extremely electrophilic carbon for nucleophilic attack. Some

of the methods of preparing endocyclic iminium salts have been described in the early part of

this research thesis including that of Rapoport and his group39

who reported a high yield

regiospecific preparation of endocyclic iminium salts by briefly heating -tertiary amino

acids in phosphorous oxychloride.

In the present work, Rapoports method of generating iminium salt and the use of this salt

in the synthesis of 2-substituted pyrrolidines will be explored.

The idea of using Rapoports method of generating iminium salt is very attractive since the

position of the incoming nucleophile is known and the starting materials are widely available.

Pyrrolidine derivatives are attractive synthetic targets74

because numerous biological

compounds possess pyrrolidine rings as their framework,75

and some of them are

pharmaceutically important.76

Substituted pyrrrolidines have been synthesized by (i) pyrrolidine ring construction77

and (ii) substituent modification of a preformed ring. Ring syntheses of some optically active

pyrrolidines are multistep: Kibayoshi et al. made 2,5-disubstituted pyrrolidines in seven steps

starting with D-mannitol.78

However, our method is a shorter route to the desired product.

The scheme proposed for the synthesis of compound (212) is given below.

55

The method will involve the reaction between benzene sulphonyl chloride (234) and L-

Proline (235) in sodium hydroxide to give 1-(phenylsulphonyl)pyrrolidine-2-carboxylic acid

(236). The iminium ion (237) will then be generated adapting the Rapports method39 by

briefly heating compound (236) in phosphorous oxychloride. The iminium ion thus generated

can then be trapped with nucleophiles such as NH2, -CN, -OEt to afford the 2-substituted

compounds 238(a) 238(c) above.

56

CHAPTER THREE

3.0. RESULTS AND DISCUSSION

As stated earlier, this thesis was designed to utilize an endocyclic iminium salt in the

synthesis of 2-substituted pyrrolidines. The scheme designed begins with the synthesis of 1-

(phenylsulphonyl)pyrrolidine-2-carboxylic acid.

3.1. SYNTHESIS OF 1-(PHENYLSULPHONYL)PYRROLIDINE-2-CARBOXYLIC

ACID

The synthesis of the above compound was achieved readily under Schotten-Baumann

conditions.79

In the first step, benzene sulphonyl chloride reacts with the amino acid to form

the desired compound, together with a proton and a chloride ion which combines to form

HCl. Addition of sodium hydroxide was required to neutralize the acid generated in the

reaction. Moreover the acid produced will form a salt with unreacted amino acid and

diminish the yield. So the addition of base to neutralize the acid is a way of optimizing the

reaction conditions.

The mechanism of this reaction involves the nucleophilic attack of the lone pair of

electrons on the nitrogen atom of the amino acid on the sulphonyl group.

57

On acidification and subsequent extraction with chloroform, a light yellow oil was

obtained in 74-82% yield. The reaction was monitored by TLC using chloroform and hexane

(8:2) as the eluent and two spots corresponding to the starting compound and product were

seen to travel upwards as shown below. The Rf value of the synthesized compound was

calculated to be 0.72.

On the IR spectrum of this compound, a band in the region 3600-2480cm-1

was observed

which corresponds to the hydrogen bonded O-Hstr of carboxylic acids. The observed broad

band was as a result of the hydrogen bonded carboxylic acid dimer structure. There was also

an absorption at 1740cm-1

due to the carboxylic C=Ostr band, and also at positions 1335cm-1

and 1109cm-1

which conforms with the S=Ostr antisymmetric and symmetric vibrations

respectively.

The compound was also characterized by 1H NMR. The spectra showed multiplet signals

at 2.02 which corresponds to the four methylene protons labelled a below.

58

Other absorptions include a triplet at 3.25 which corresponds to the two methylene

protons labelled b, another triplet at 4.27 that corresponds to the single proton labelled

c. The aromatic ring gave a multiplet at 7.53 which fits the protons labelled e and a

doublet at 7.84 which fits the protons labelled d (since these protons will most feel the

deshielding effect of the sulphonyl group). The singlet at 10.4 due to the carboxylic proton

labelled f cannot be seen since it disappeared on deuteration.

ppm (t1)1.02.03.04.05.06.07.08.0

0

100

200

300

400

500

7.8

39

7.5

86

7.5

69

7.5

31

7.5

14

7.4

98

7.2

50

6.8

86

4.2

72

4.2

67

4.2

46

3.6

72

3.4

95

3.4

82

3.2

69

3.2

49

3.2

29

2.0

67

2.0

55

2.0

21

1.9

99

1.9

60

1.9

27

1.7

24

1.0

0

0.8

8

1.0

5

1.0

5

3.0

0

1.0

5

1.0

4

1.9

8

0.8

31.8

8

IA16 - 1 203, CDCl3, zg30, D

ppm (t1)7.007.50

0

50

100

1.0

4

1.9

8

0.8

31.8

8

IA16 - 1 203, CDCl3, zg30, D

59

3.2. SYNTHESIS OF THE 2-SUBSTITUTED COMPOUNDS

3.2.1. Formation of Iminium Salt.

Rapoports method39 was adopted in the generation of the sulphonyl iminium salt. Their

method was based on the frequently reported observation that acid chlorides of -tertiary

amino acids are unstable. These observations were first rationalized by Maksimov who

reported that activated acyl derivatives of a-tertiary amino acids were thermally

decarbonylated, yielding in part a secondary amine and an aldehyde after decomposition with

water.

In the present work, the generation of the iminium salt was attempted by heating 1-

(phenylsulphonyl)pyrrolidine-2-carboxylic acid formed earlier in phosphorous oxychloride at

105oC for 3 minutes. The mechanism of this reaction involves the loss of a carbonyl. The

manner in which the carbonyl could be lost is given below.

Phosphorus oxychloride is electrophilic at the phosphorus atom (as expected with three

chlorine atoms and an oxygen atom attached) and is attacked by the carboxylic acid to give

the unstable intermediate (240) with the formation of HCl.

60

Protonation of the unstable intermediate (by the HCl just produced) results in another

tetrahedral intermediate which can collapse to the acyl chloride. The acyl chloride itself is not

stable and thus undergoes decarbonylation to form the iminium salt as illustrated above. The

iminium salt thus formed can be quenched by a nucleophile as shown below.

Sulphonyl iminium salt of this type had been synthesized by Adesogan and Alo28

via the

decarbonylation of N-arylsulphonyl-tertiary--aminoacid chlorides using silver trifluoro

methane sulphonate.

61

The above method is a mild and efficient way of obtaining sulphonyl iminium salt but

silver trifluoromethane sulphonate is very expensive and so phosphorus oxychloride was

chosen as an alternative.

3.2.2. Synthesis of 1-(phenylsulphonyl)-2-aminopyrrolidine

Adesogan and Alo28

in 1979 had reported the amino addition to a N-(2-

nitrobenzenesulphonyl)prolinium salt. This is illustrated by the reaction below.

However, the iminium salt was generated using silver trifluoromethane sulphonate which as

mentioned in the last section is very expensive.

In the present work, the scheme proposed for this reaction involves the nucleophilic attack

of the lone pair of electrons on the nitrogen atom on the electrophilic carbon of the iminium

salt.

After the iminium salt was allowed to cool a bit, it was engaged in situ by the addition of

aqueous ammonia unto it; this led to the formation of a dark brown sticky compound which

made stirring very difficult. After stirring for three hours at room temperature, the compound

62

was extracted in chloroform. On evaporation, a dark brown oil which solidified on standing

was obtained at the bottom of the beaker in moderate yield (56%). The reaction was followed

by TLC using ethyl acetate and hexane (5:5) as the eluent, and two spots corresponding to the

standing compound and product were seen under UV lamp to have travelled upwards on the

TLC plates as shown below. The Rf value of the product was calculated to be 0.38.

Infrared analysis of the synthesized compound showed that absorption due to the O-Hstr of

the starting compound (carboxylic acid) had been replaced by another band in the region

3127cm-1

-3004cm-1

. This suggests the presence of an amino group but another band at

position 1762cm-1

indicates that the carbonyl stretching band was still present.

As such, it was assumed that the iminium salt might have not been completely formed

under the conditions applied. So the temperature at which the iminium salt was initially

formed was then increased to 110oC and the time to 4 minutes. Applying these conditions, the

iminium salt was generated followed by the addition of aqueous ammonia. This was allowed

to stir for 12 hours, after which it was extracted and dried with anhydrous magnesium

sulphate. Evaporation of the solvent left behind in the beaker a dark brown oil which turned

into a solid on standing. The yield obtained was 47%. TLC of the compound formed (below)

was carried out using ethyl acetate and hexane (5:5) as the eluent. The calculated Rf value

was 0.41.

63

Infra-red analysis of compound obtained still indicated a band at 1762cm-1

which

corresponds to the C=O stretching band. The temperature at which the iminium salt was

generated was further increased to 120oC and the time was left at 5 minutes. The iminium salt

formed under this condition was again saturated with aqueous ammonia. After the usual work

up, a dark brown oil which turned into a dark brown solid on standing was obtained (37%).

The reaction was monitored with TLC using a mixture of chloroform and hexane (4:6) as the

eluting solvent. This showed that the starting compound remained unchanged as the two spots

corresponding to that of the starting compound and the product were having same Rf value.

TLC of same product was done again using ethyl acetate and hexane, but the two spots

were still travelling at the same distance. It was thus concluded that the formation of 2-

amino-substituted pyrrolidine did not take place under this condition. As a result, IR analysis

of the compound was not carried out.

64

3.2.3. Synthesis of 1-(phenylsulphonyl)-2-cyanopyrrolidine

Martin36

had earlier reported a similar cyano-addition by trapping the iminium salt below

with sodium cyanide in dichloromethane. The cyano compound formed was obtained in good

yield.

The iminium salt was generated by the action of trifluoroacetic acid on an imine as

illustrated below.

In the present work, the scheme involves the nucleophilic attack of the cyanide ion on the

electrophilic carbon of the iminium salt as shown below to give 2-cyano-substituted

compound.

65

The reaction was carried out by first heating 1-(phenylsulphonyl)pyrrolidine-2-carboxylic

acid (239) in POCl3 at 110oC for 3 minutes to generate the iminium salt followed by the

addition of saturated sodium cyanide solution. This was allowed to stir for 12 hours after

which it was extracted, washed and then dried. The extraction of the compound formed was

quite difficult as the organic and aqueous layer were not well distinctive. Evaporation of the

solvent left behind a dark brown oil, albeit in poor yield (18%). The poor yield might be as a

result of the difficulty encountered during extraction. The reaction was monitored with TLC

using ethyl acetate and hexane (5:5) as the eluent. The Rf value was calculated to be 0.27.

On the infrared spectra of the compound, a band was observed in the region 3014cm-1

-

2911cm-1

, but the expected band around 2250cm-1

was not seen. Again, the reaction

conditions were altered, the temperature at which the iminium salt will be generated was

increased from 110oC to 120

oC and the time from 3minutes to 10 minutes. This time, a dark

brown oil was obtained in 24% yield. TLC of the reaction was carried out as shown below

using ethyl acetate and hexane (5:5). This showed that there was no reaction as the two spots

corresponding to the starting compound and the product were on the same level. As a result,

IR analysis of the compound was not done.

66

The temperature and time at which the iminium salt was generated was again altered. This

time, 1-(phenylsulphonyl)pyrrolidine-2-carboxylic acid was heated in POCl3 at 105oC for 4

minutes to give the iminium salt which was trapped by the addition of saturated sodium

cyanide solution. After the solvent has been evaporated, a dark brown oil was obtained in

poor yield (27%). TLC of the reaction was done (as shown below) using ethyl acetate and

hexane (5:5) as eluent. The calculated Rf value was 0.48.

On the IR spectra of the compound, the bands due to the hydroxy group of the carboxylic

acid and the carbonyl group had disappeared and the only observed band was around

2382cm-1

which is close to the literature value of a typical cyano group. In the absence of 1H

NMR, it was concluded that 2-cyano substituted pyrrolidine might have been formed.

67

3.2.4. Attempted Synthesis of 2-Ethoxy-1-(phenylsulphonyl)pyrrolidine

This involves the nucleophilic attack by the lone pair of electrons on the oxygen atom of

the ethoxide on the electrophilic carbon of the iminium salt. The scheme designed for this

reaction is illustrated below.

Sodium ethoxide was first prepared by dissolving 4g of sodium metal in 10mL of ethanol.

This was followed by the evolution of hydrogen gas. The sodium ethoxide thus obtained was

added to the iminium salt generated in situ and this was allowed to stir for 12 hours. The

product was then extracted, washed and dried. On evaporation, a dark brown solid was

obtained in poor yield (36%). The TLC of the newly formed compound was done using

chloroform and hexane (4:6) as the eluent. As shown below, a spot was observed on the TLC

plate which clearly indicates a change in the starting compound. The Rf value was calculated

to be 0.24.

68

The Infrared analysis of the compound was carried out and a band was observed around

3042cm-1

which fits that of an aromatic C-Hstr and another band at 1760cm-1

which suggests

that a carbonyl is still present in the compound.

The temperature and time at which the iminium salt was formed was again varied, this

time, the temperature was increased to 110oC and the time was maintained at 3 minutes. The

previously formed sodium ethoxide was then added to the generated iminium salt. This was

left to stir at room temperature for 8 hours. After the usual work up, a brown solid was

obtained at the bottom of the beaker in poor yield (31%). The TLC of the compound was

carried out using ethyl acetate and hexane (5:5) as eluent. On the TLC plate (below), the two

observed spots corresponding to the starting material and the product had the same Rf value

which clearly indicates that there was no reaction.

Other attempts to further increase the temperature and time led to the formation of a

charred compound and as such it was assumed the 2-ethoxy substituted pyrrolidine

compound cannot be formed under these conditions.

69

CHAPTER FOUR

4.0. CONCLUSION

Although the synthesis of 1-(phenylsulphonyl)-2-cyano pyrrolidine was successful, the

synthesis of 1-(phenylsulphonyl)-2-cyano pyrrolidine and 2-Ethoxy-1-(phenylsulphonyl)

pyrrolidine were not. There is still much more work to be done in this line of research

particularly the detection, isolation and characterization of the sulphonyl iminium salt. This

could help to shed more light into the feasibility of this reaction and form the basis of future

research.

70

CHAPTER FIVE

5.0. EXPERIMENTAL SECTION

5.1. General Experimental Procedures

Infrared spectra were recorded on a Perkin-Elmer One FT-IR spectrophotometer in nujol

mulls and CHCl3. NMR spectra were recorded on Bruker 400 MHz Avance spectrometer and

were referenced using solvent signals (dH: 7.25 ppm for CDCl3; dC: 77.0 ppm for CDCl3).

All organic extracts were dried over anhydrous magnesium sulphate. Analytical thin-layer

chromatography was performed on pre-coated silica on aluminium sheets with F-254

indicator.

5.2. Synthesis of 1-(PhenylSulphonyl)Pyrrolidine-2-Carboxylic acid

L-Proline (1.434g, 0.012mole) was dissolved in 20mL of 1m NaOH. To the resulting

solution, Benzene Sulphonyl Chloride (2.0g, 0.011mole) was added drop wise with constant

stirring.

The reaction mixture was left to stir at room temperature for 16 hours after which a light

yellow solution was formed. The mixture was ensured to be basic throughout the course of

the reaction.

71

The resulting solution was extracted with chloroform to remove any unreacted materials. It

was then acidified with 3M HCl solution until the solution became clear. The mixture was

extracted thrice with chloroform.

The organic layer was dried over anhydrous sodium sulphate and then filtered. The organic

extract was evaporated off to leave behind a yellow oil.

Yield (2.456g, 82%) as a yellow oil: Rf 0.72 (8:2, chloroform-hexane); IR 3400cm-1

(COOH),

1740cm-1

(C=O), 1336cm-1

(S=O); 1H NMR (400MHz, CDCl3) 7.53- 7.84 (m, 5H), 4.27 (t,

1H), 3.25 (t, 2H), 1.72- 2.07 (m, 4H)

5.3. Synthesis of 1-(PhenylSulphonyl)-2-Amino Pyrrolidine

To 1-(phenylsulphonyl)-pyrrolidine-2-carboxylic acid (0.5g, 0.002mole) was added

phosphorus oxychloride (1mL) in a 50ml round bottom flask corked with a CaCl2 guard tube.

The mixture was heated at a temperature maintained at 105OC for 5 minutes after which

the flask was allowed to cool. 10 mL of ammonia was then added to the mixture and then

corked again. The mixture was left to stir for further three hours at room temperature.

The resulting mixture was extracted with chloroform and the extract was washed thrice

with distilled water and then dried over anhydrous MgSO4. The organic extract was

evaporated to leave behind a brown oil which solidified on standing.

72

Yield (0.229g, 56%) as a dark brown oil: Rf 0.31 (8:2, chloroform-hexane); IR (CHCl3)

300cm-1

(NH2), 1762cm-1

(C=O)

5.3. Synthesis of 1-(PhenylSulphonyl)-2-Amino Pyrrolidine

To 1-(phenylsulphonyl)-pyrrolidine-2-carboxylic acid (0.5g, 0.002mole) was added

phosphorus oxychloride (1mL) in a 50ml round bottom flask corked with a CaCl2 guard tube.

The mixture was heated at a temperature maintained at 105OC for 5 minutes after which

the flask was allowed to cool. 10 mL of ammonia was then added to the mixture and then

corked again. The mixture was left to stir for further three hours at room temperature.

The resulting mixture was extracted with chloroform and the extract was washed thrice

with distilled water and then dried over anhydrous MgSO4. The organic extract was

evaporated to leave behind a brown oil which solidified on standing.

Yield (0.229g, 56%) as a dark brown oil: Rf 0.31 (8:2, chloroform-hexane); IR (CHCl3)

300cm-1

(NH2), 1762cm-1

(C=O)

5.4. Synthesis of 1-(PhenylSulphonyl)-2-Cyano Pyrrolidine

73

To 1-(phenylsulphonyl)-pyrrolidine-2-carboxylic acid (0.5g, 0.002mole) was added

phosphorous oxychloride (1mL) in a 50ml round bottom flask corked with a CaCl2 guard

tube.

The mixture was heated at a temperature maintained at 105OC for 5 minutes after which

the flask was allowed to cool. 10 mL of saturated sodium cyanide solution was then added to

the mixture and then corked again. The mixture was left to stir for further three hours at room

temperature.

The resulting mixture was extracted with chloroform and the organic extract was washed

thrice with distilled water and then dried over anhydrous MgSO4. The organic extract was

evaporated to leave behind a brown oil.

Yield (0.139g, 27%) as a dark brown oil: Rf 0.48 (5:5, ethyl acetate-hexane); IR (CHCl3)

3014cm-1

, 2382cm-1

(CN), 1347cm-1

(S=O)

5.5. Synthesis of 2-Ethoxy-1-(PhenylSulphonyl)Pyrrolidine

74

To 1-(phenylsulphonyl)-pyrrolidine-2-carboxylic acid (0.5g, 0.002mole) was added

phosphorous oxychloride (1mL) in a 50ml round bottom flask corked with a CaCl2 guard

tube.

The mixture was heated at a temperature maintained at 105OC for 5 minutes after which

the flask was allowed to cool. 4mL of sodium ethoxide in ethanol was then added to the

mixture and then corked again. The mixture was left to stir for further three hours at room

temperature.

The resulting mixture was extracted with chloroform and the extract was washed thrice

with distilled water and then dried over anhydrous MgSO4. The organic extract was

evaporated to leave behind a dark brown solid.

Yield (0.182g, 36%) as a dark brown solid: Rf 0.85 (4:6, chloroform-hexane); IR (CHCl3)

3040cm-1

, 1745cm-1

(C=O), 1307cm-1

(S=O)

5.6. Preparation of Saturated Sodium Cyanide Solution

A saturated solution of potassium cyanide was prepared by dissolving little quantity of

NaCN crystals at a time in 10mL of distilled water until the crystals can no longer dissolve.

5.7. Preparation of Sodium Ethoxide in Ethanol Solution

The sodium metal which was stored in paraffin oil was washed in hexane. 2g of sodium

metal was then dissolved in 10mL of ethanol solution. This reacted to form the required

sodium ethoxide in ethanol with the release of hydrogen gas.

75

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