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.

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.
2

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.

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.

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.

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.
6

(a) oxyiminium salt

(b) hydrazonium salt

(c) sulphonyl iminium salt7

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), UltraViolet (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
8

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 Phase Anion (X-) KBr SnCl61670 KBr SbCl61691 KBr NO31698 Mull 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.

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.

10

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) Phase Anion (X-)

1664 mull Cl-

1681 CH2Cl2 Cl-

When double bonds are in conjugation with the iminium salt, there is no appreciable change in the position of absorption.
11

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 15N labelling, 1 H NMR and 13C NMR spectroscopy. However, our focus will be on the 1H NMR and 13C NMR of an iminium salt.
1

H 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).

12

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.

H 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.
13

13

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

13

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

14

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.

15

(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.

16

 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.
17

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.

18

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.

19

(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

20

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.

21

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.

22

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.

23

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.

24

Alo and Adesogan28 reported the instantaneous reaction of N-(arylsulphonyl) pyrrolidine2-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.

25

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.

26

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 Noxide 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.

27

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 formation of the iminium salt (103).
13

C spectra respectively indicated the

28

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 250C for 3 hours.

Martin36 also used imine (108) which was transformed into the iminium ion (109) by the action of trifluoroacetic acid at -400C.

29

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.

30

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.

31

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.

32

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)
33

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-Hydroxy6-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.

34

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.

35

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).

36

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.

37

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 arteriosclerotics. (145), an intermediate of novel anti-

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.
38

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.

39

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.

40

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, Nsmoothly 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.

41

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

42

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.

43

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-trisubstituted1,2,3,4-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.

44

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.

45

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.

46

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.

47

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).

48

Kobayoshi and co-workers64 also reported the facile synthesis of 9-Dialkylamino-9Hpyrrolo[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.

49

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 phydroxybenzoic 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.

50

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.

51

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.

52

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.

53

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 construction 77 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.

54

The method will involve the reaction between benzene sulphonyl chloride (234) and LProline (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.

55

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.

56

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.

57

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.

500

1.98

0.83 1.88

1.04

1.98

0.83 1.88

1.04

1.00

0.88

1.05

1.05

3.00

8.0 ppm (t1)

7.0

6.0

5.0

4.0

3.0

2.0

1.05

7.839

7.569 7.586

7.498 7.514 7.531

6.886 7.250
7.50 ppm (t1) 7.00

IA16 - 1 203, CDCl3, zg30, D

4.246 4.267 4.272

100 50 0

3.672

3.482 3.495

3.229 3.249 3.269

2.055 2.067

1.999 2.021

1.960

1.927

1.724
400 300 200 100 0 1.0

58

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.

59

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.

60

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-(2nitrobenzenesulphonyl)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

61

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.

62

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 2amino-substituted pyrrolidine did not take place under this condition. As a result, IR analysis of the compound was not carried out.
63

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.

64

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-12911cm-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 120oC 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.

65

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.

66

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.

67

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.

68

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.

69

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.

70

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.

71

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

72

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

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. 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.

74

REFERENCES 1. Paukstelis, J. V. In Enamines Cook, A. G., Ed.; Marcel Dekker: New York. N.Y., 1969; 2. Adams, R. and Mahan, J. E. Basicity Studies of Tertiary Vinyl Amines, J. Am. Chem. Soc., 1942, 64, 2588-93 3. Bhme, H. and Viehe, H. G. Iminium Salt in Organic Chemistry, Eds.; Wiley: New York, 1976, Part 1, 108-149 & Part 2, 655-732. 4. Katritzky, J.; Meth-Cohn, O.; Rees, C. V.; Attenden, G. Comprehensive Organic Functional Group Transformation: Synthesis: Carbon With One Heteroatom Attached By a Multiple Bond , Vol. 3 , 1995, 5. Blaha K.; Cervinka, O. Advanced Heterocyclic Chemistry, 1966; Vol. 6, 147 6. Leonard, N. J. and Paukstelis, J. V. Direct Synthesis of Ternary Iminium Salt by Combination of Aldehydes and Ketones With Secondary Amine Salts, J. Org. Chem., 1963, 28(11), 3021-4 7. Familoni, O. B. Synthetic Approaches To Some Sulphur-Containing Heterocycles Ph.D (chem.) Thesis, University of Lagos, Lagos (1990). 8. Optiz, G.; Hellman, H. and; Schubert, H. W., Enamine, I: Simple Enamine and its Spectra, Ann. Chem., 1959, 623(1), 117 9. Witkop, B. and Patrick, J. B., Sodium Borohydride Reduction of Quaternary Schiff Bases and Alkaloids, J. Am. Chem. Soc., 1953, 75(18), 4474

75

10. Dorschein, W.; Tienfenthaler, H.; Goth, H.; Cerutti, P.; and Schmid, H., Photo Reactions of Iminium Salt with methanol and Formamide, Helv. Chimica Acta, 1967, 50, 1759 11. Allenstein, E.; and Schmidt, P., The Infra-red Spectra of The Hydrogen Halide Addition Compounds of Acetonitrile, Spectrochim Acta, 1964, 20, 1451 12. Abraham, R. J. and Loftus, P., Proton and Carbon-13 NMR Spectroscopy, Heyden & Sons Ltd, pp IX 13. Olah, G. A., Carbocations and Electrophilic Reactions, Angew Chem., Int. Ed. Engl., 1973, 12(3), 173 14. Gal, J.; Phillips, B. A.; and Smith, R., The Mass Spectra of Imidoyl Halides and Bromoiminium Bromides, Can. J. Chem., 1973, 51(1), 132 15. Speckamp, W. N.; and Hiemstra, H., Intramolecular Reactions of N-Acyliminium Intermediates, Tetrahedron, 1985, 41(20), 4367 16. Hiemstra, H.; and Speckamp, W. N., In Comprehensive Organic Synthesis, Trost, B. M.; Flemming, I.; Heathcock, C. H.; Eds; Pergamon: Oxford, 1991, 2, 1047 17. Bose, A. K.; Spiegelman, G.; and Manhas, M. S., Studies on Lactams. Part XVI. Stereochemistry of -Lactams Formation, Tetrahedron Lett., 1971, 12(34), 3167 18. Nortey, S. O.; McComsey, D. F.; and Maryanoff, B. E., Stereochemical Observations in the Synthesis of Novel 1,4,5,9b-Tetrahydro-5-phenyl-2H-azeto[2,1-a] isoquinolin-2-one Derivatives, Heterocycles, 1993, 35, 1075

76

19. Marson, C. M.; Grabowska, V.; Fallah, A.; Walsgrove, T.; Eggleston, D. S.; and Baures, P. W., Stereoselective Syntheses of Substituted 5,6-Dihydro-2(1H)pyridinones in Polyphosphate Media, J. Org. Chem., 1994, 59, 291 20. Nossin, P. M. M.; and Speckamp, W. N., Stereochemical Control By Remote Substituents In -Acyliminium Oleifin Cyclisation, Tetrahedron Lett., 1980, 21(20), 1991 21. Bhme, H.; and Hartke, K., ber N--Halogenalkyl-carbonsureamide, VII Die Umsetzung Schiffscher Basen mit Carbonsurehalogeniden, Chem. Ber., 1963, 96(2), 600 22. Belleau, D., Synthesis in the Field of the Erythrina Alkaloids: Part I. The Synthesis of Hexahydroapoerysotrine, Can. J. Chem., 1957, 35(7), 651 23. David, M.; Dhimane, H.; Vanucci Bacque, C.; and Lhommet, G., Stereocontrolled Addition of -Type Nucleophiles to a Bicyclic N-Acyliminium Ion. New Access to trans-2,6-Disubstituted Piperidine Substructures., Chem. Inform, 1998, 29(23), 12930 24. Yi-Yin, Ku; Grieme, T.; Yu-Ming, Pu; Bhatia, A. V.; King, S. A., A Simple OnePot Procedure For The Iminium Salt Formation: An Efficient Route To Arylethylamines, Tetrahedron Lett., 2005, 46(9), 1471-4 25. Orazi, O. O.; Corral, R. A.; and Bravo, R., Intramolecular SulphonylAmidomethylation. Part 1: Cyclization of Benzylsulphonamides, J. Het. Chem., 1986, 23(6), 1701-8

77

26. Tarik, M. I.; Siddiqui, H. L.; Hussain, I. and Afzal, S., A Facile Synthesis Of Commercially Important Methylene-Bis-Thiocyanate, J. Chem Soc. Pakistan, 2008, 30(3), 472-5 27. Saidi, M.; Azzizi, N. and Naimi-Jamal, M. R., Lithium Perchlorate Assisted OnePot Three-Component Aminoalkylation of Electron-rich Aromatic Compounds, Tetrahedron Lett., 2001, 42, 8111-3 28. Adesogan, E. K.; and Alo, B. I., Synthesis of Dihydrothidiazine-1,1-dioxide, J. Chem. Soc. Comm. 1979, 673 29. Alo, B. I.; and Familoni, O. B., N-(arylsulphonyl)tetrahydropyridinium Salts: Intermediates For Multi-ring Heterocycles, Part 1. Synthesis of Hexahydropyrido [1,2-b][1,2,4] benzothiadiazine dioxides, J. Chem. Soc., Perkin Trans. 1, 1990, 18358 30. Polonovski, M.; and Polonovski, M., Amine Oxides of Alkaloids I., Bull Soc. Chim. Fr., 1926, 39, 11147-67 31. Leonard, N. J.; Hay, A. S. et al, Unsaturated Amines III. Introduction of ,Unsaturation By Means of Mercuric Acetate, J. Am. Chem. Soc., 1955, 77, 439 32. Hata, S.; Koyama, H. and Shimizu, M., Synthesis Of ,-Disubstituted -Amino Esters: Nucleophilic Addition To Iminium Salts Generated From Amino Ketene Silyl Acetals J. Org. Chem., 2011, 76(23), 9670-7 33. Makoto Shimizu Unexpected and Intriguing Reactivity of -Imino Esters and

Iminium Salts, Pure Appl. Chem., 2006, 78, 10, 1867-76

78

34. Chun, L. M. and Hang, C. T. Formation and Reaction of Organoindium, Organozinc and Organomagnesium Reagents with Imines and Carbonyl Compounds, 2008, Pao Yue-Kong Library, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong 35. Osato, H.; Osaki, M.; Oyama, T.; Takagi, Y.; Hida, T.; Nishi, K., and Kabaki, M. Pilot Plant Preparation of Tert-Butyl-4-(2-Hydroxyethyl)-4-(Pyrrolidin-1-yl)-

piperidine-1-Carboxylate via a Safe, Scalable Reformatsky-Type Reaction, Org. Process & Research Dev., 2011, 15(6), 1433-7 36. Stephen F. Martin, Recent Applications of Imines as Key Intermediates in The Synthesis of Alkaloids and Novel Nitrogen Heterocycles, IUPAC, Pure & Appl. Chem., 2009, 81, 195-204 37. Ferroud, C.; Rool, P.; Santamaria, J. A Chemical Study of The Oxidation of Tertiary Amines and Alkaloids Through Monoelectronic Transfer, Tetrahedron Lett., 1998, 39(51), 9423-9426 38. Grierson, D. Modified Polonowski Reaction, Org. Reactions; 1990, 39, 85 39. Dean, R. T.; Padgett, H.; and Rapoport*, H. A High Regiospecific Preparation Of Iminium Salt J. Am. Chem. Soc., 1976, 98, 7448-9 40. Gupton, J. T.; Clough, S. C.; Miller, R.; Norwood, B.; Hickenboth, C.; Chertudi, I. B.; Cutro, S.; Pietrich, S.; Hicks, F.; Wilkinson, D.; and Sikorski, J., The application of vinylogous iminium salt derivatives to the regiocontrolled preparation of heterocyclic appended pyrazoles, Tetrahedron, 2002, 58(27), 5467-74 41. Schlegel, J.; and Maas, G. Propyne Iminium Salts By N-Alkylation Of Alkynyl Imines, J. Syn. Org. Chem., 1999, 1, 100
79

42. Li - Xin Dai; Ying Rui Lin; Xue-Long Hou; and Yong Gui Zhou Stereoselective Reactions With Imines, Pure Appl. Chem., 1999, 71, 6, 1033-40 43. Le Gall*, E; Pignon, A.; and Martens, T. A Practical Route To Tertiary DiarylmethylAmides or Carbamates From Imines, Organozinc Reagents and Acylchlorides or Chloroformates, Beilsten Journal of Org. Chem., 2011, 7, 997-1002 44. Ofial, A. R.; and Mayr, H., A Novel Penta-Annulation Reaction of Iminium Ions, Liebigs Ann., 1997, 1997(2), 333 45. Taylor, A. M.; and Schreiber, S. L. Enantioselective Addition of Terminal Alkynes to Isolated Isoquinoline Iminiums, Org. Letters, 2006, 8(1), 143-6 46. Atmani, A.; Combret, J. C.; Malhiac, C.; Mulengi, J. K. ,- Unsaturated -amino phosphonates: Synthesis & Reactivity, Tetrahedron Lett., 2000, 41, 6045-8 47. Levin, V.; Dilman, A.; Belyakov, P.; Korlyukov, A.; Struchkova, M.; Tartakovsky, V. Interaction of Silyl Triflates with Enamines: Iminium Ion Formation vs Silylation, Tetrahedron Lett., 2005, 46(21), 3729-32 48. Enders, D.; and Shilvock, J. P. Some Recent Applications of -Amino Nitrile Chemistry, Chem. Soc. Rev., 2000, 29, 359-73 49. Schneider, C.; and Brner, C. Novel and Stereocontrolled Synthesis of Enantiopure and Polyalkyl Substituted Piperidines, Synlett, 1998, 652-4 50. Fenster, E.; Smith, B. T.; Gracias,V.; Milligan, G. L.; and Aube, J. Nucleophilic Addition To Iminium Ethers In The Preparation of Functionalized N-Alkyl Heterocycles, J. Org. Chem., 2008, 73, 201-5

80

51. Aitken, R. A.; Ali, K.; de Elena, N.; and Lightfoot, P. Synthesis and Structure of Highly Polarised Double Bond Compounds Derived From S-Proline Tetrahedron Lett., 2000, 41, 7965-8 52. Saidi, M. R.; and Azzizi, N. A Novel and Efficient For The Synthesis of Aminonitrile By The Reaction of Aminals with Trimethylsilyl Cyanide Catalysed by Iodine, J. Iranian Chem. Soc., 2004, 1(2), 136-140 53. Jarrahpour, A.; and Zarei, M. Efficient One-Pot Synthesis of 2-Azetidinones from Acetic Acid Derivatives and Imines Using Methoxymethylene-N,N-Dimethyliminium Salt, Tetrahedron, 2010, 66, Issues 27-28, 5017-23 54. Katritzky, A.; and Arend, M. A Convenient and Highly Regioselective One-Pot Synthesis of Quinolines by Addition of a Vilsmeier-Type Reagent to N-Arylamines, J. Het. Chem.,1998, 33, 9989-91 55. Levin, V.; Kozlov, M. A.; Song, Y. H.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A. Nucleophilic Fluoroalkylation Of Iminium Salts Tetrahedron Lett.,, 2008, 49(19), 3108-11 56. Alo, B. I.; Adegoke, E. A.; Ligali-Ali, M.; and Adesogan, E. K., Synthesis of 1,2,4Benzothiadiazines via Readily Generated Iminium Ions, Trans. 1, 1986, 805-7 57. Hancock, M. T.; and Pinhas, A. R. Conversion of an Aziridine to a 1,2-Diamine, Tetrahedron Lett., 2003, 44, 7125-8 58. Zheng, L. Y.; and Xu Bai, Grignard Additions To Quinoxalinium Salt, Chinese Chem. Lett., 2006, 17(2), 165-8 J. Chem. Soc., Perkin

81

59. Brook, C.; and Jahangir, M. A. Activation of Imines to Nucleophilic Attack by Grignard Reagents, Syn. Comm., 1988, 18(9), 893-8 60. Shimizu, M.; Kusunoki, T.; Yoshida, M.; Kondo, K.; and Mizota, I. Efficient Mannich Reaction using Iminium Salts Generated from Glycine Derivatives, Chem. Lett., 2011, 40(4), 351 61. Page, P. C. B.; Farah, M. M.; Buckley, B. R.; and Blacker, A. J. New Chiral Binaphthalene-Derived Iminium Salt Organocatalysts for Asymmetric Epoxidation of Alkenes, J. Org. Chem., 2007, 72(12), 4424-4430 62. Azizi, N.; and Saidi, M. R., A New Protocol For The BaylisHillman Reaction: The Reaction of Iminium Salts Prepared in situ With Methyl Acrylate, Tetrahedron Lett., 2002, 43(24), 4305-8 63. Tom N. J., and Ruel E. M., An Efficient Synthesis of Substituted Quinolines, Synthesis, 2001, 1351 64. Kobayoshi, K.; Takanohashi, A.; Hashimoto, K.; Morikawa, O.; Konishi, H. A Facile Synthesis of 9-Dialkylamino-9H-pyrrolo [1,2-a] Indoles via Iminium Salts, Terahedron, 2006, 62(13), 3158-61 65. Moghaddam, F. M.; Mirjafaray, Z.; Saeidian, H.; Taheri, S.; and Soltanzadeh, B. Synthesis of 8-membered Hydroquinolines Related to Alkaloid Skeletons via Addition of 4-Hydroxycoumarin to Quinolinium Salts, Tetrahedron, 2010, 66(21), 3678-81 66. De Kimpe, N.; Boelens, M.; and Contreras, J. Rearrangement of 5-(Bromomethyl)1-pyrrolinium Salts into Functionalized Piperidines, Tetrahedron Lett., 1996, 37(18), 3171-4
82

67. Rousselet, G.; Capdevielle, P.; and Maumy, M., Copper-induced synthesis of iminiums: Trimethylamine oxidation or amine N-oxide conversion, Tetrahedron Lett., 1995, 36(28), 4999 68. Chen, J.; and Cunico, R. F. -(Dimethylamino)amides From a Carbamoyl Silane and Iminium Salts, Tetrahedron Lett., 2002, 43, 8595-7 69. Winter, A.; and Risch*, N. Cross Mannich Reaction of Aldehydes; Efficient Synthesis of Substituted Pyridines, J. Syn. Org. Chem., 2003, 17, 2667 70. Ellwood, A. R.; and Porter, M. J., Selective Conversion of Alcohols into Alkyl Iodides Using a Thioiminium Salt, J. Org. Chem., 2009, 74(20), 7982-5 71. Leonard, N. J.; and Musker, W. K., Unsaturated Amines Part XVI. An Oxidative Cyclisation Route To Oxazolidines and Tetrahydro-1,3-oxazines, J. Am. Chem. Soc., 1960, 82, 5148 72. Amato, J. S.; Chung, J. Y. L.; Cvetovich, R. J.; Gong, X.; McLaughlin, M.; and Reamer, R. A., Synthesis of 1-tert-Butyl-4-chloropiperidine: Generation of an Ntert-Butyl Group by the Reaction of a Dimethyliminium Salt with Methylmagnesium Chloride, J. Org. Chem., 2005, 70(5), 19301933 73. Shen, H.C.; Wang, J.; Cole, K. P.; McLaughlin, M. J.; Morgan, C. D.; Douglas, C. J.; Hsung, R. P.; Coverdale, H. A.; Gerasyuto, A. I.; Hahn, J. M.; Liu, J.; Sklenicka, H. M.; Wei, L.; Zehnder, L. R.; and Zificsak, C. A., A Formal [3 + 3] Cycloaddition Reaction. Improved Reactivity Using ,-Unsaturated Iminium Salts and Evidence for Reversibility of 6-Electron Electrocyclic Ring Closure of 1-Oxatrienes, J. Org. Chem., 2003, 68(5), 17291735

83

74. (a) Braekman, J. C.; Daloze, D. In Studies in Natural Products Chemistry Atta-urRahman, Ed.; Elsevier: Amsterdam, 1990; Vol. 6, p 421. (b) Tufariello, J. J. Alkaloids from Nitrones Acc. Chem. Res. 1979, 12(11), 396. (c) Pichon, M.; Figadere, B. Synthesis of 2,5-Disubstituted Pyrrolidines Tetrahedron: Asymmetry 1996, 7, 927. 75. (a) Elbein, A.; Molyneux, R. I. In Alkaloids, Chemical and Biological Perspectives Pelletier, S. W., Ed.; John Wiley: New York, 1990; Vol. 5, p 1-54. (b) Attygalle, A. B.; Morgan, E. D. Chemicals from the Glands of Ants Chem. Soc.Rev. 1984, 13, 245. (c) Schmeltz, I.; Hoffmann, Nitrogen Containing Compounds in Tobacco and Tobacco Smoke D. Chem. Rev., 1977, 77, 295. 76. (a) Elliott, R. L.; Kopecka, H.; Lin, N.-H.; He, Y.; Garvey, D. S. A Short, Efficient Synthesis of the Novel Cholinergic Channel Activator, ABT 418, from L-Proline Synthesis, 1995, 772. (b) Lin, N.-H.; Carrera, G. M., Jr.; Anderson, D.J.; Synthesis and Evaluation of Nicotine Analogs as Neuronal Nicotinic Acetylcholine Receptor Ligands J. Med. Chem., 1994, 37(21), 3542. 77. Jones,T. H.; Franko, J. B.; Blum, M. S.; Fales, H. M. Unsymmetrical 2,5Dialkylpyrrolidines via Reductive Amination of 1,4-Diketones Tetrahedron Lett., 1980, 21, 789. 78. Machinaga, N.; Kibayashi, C., Enantioselective Total Synthesis of (+)- and (-)Pyrrolidine 197B, A New Class of Alkaloid from the Dendrobatid Poison Frog J. Org. Chem., 1991, 56, 1386. 79. Elseviers Encyclopedia of Organic Chemistry, Radt, F., Ed., 1955, Series III, Vol. 12B, pp 4841-5686, Elsevier Publishing Co., London.

84

80. Poddubnaya, N. A.; and Maksimov, V. I., J. Gen. Chem. USSR, 1959, 29, 3448

85