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. 1 They are strong bases, in fact are more basic than amines. They could be classified as α,β- 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 Mahan 2 in 1942. They showed that its structure was responsible for the strong basicity of tertiary cyclic saturated amines over primary and secondary amines. 1
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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 α,β-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.
1
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
Saturated Iminium Salt Aromatic Iminium Salt
Iminium Salt
Straight ChainIminium Salt
Cyclic Iminium Salt
Endocyclic Iminium Salt
Exocyclic Iminium Salt
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.
3
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.
4
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.
5
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
7
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
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 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.
9
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) 1664 1681
Phase mull CH2Cl2
Anion (X-) Cl- Cl-
11
When double bonds are in conjugation with the iminium salt, there is no appreciable
change in the position of absorption.
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.
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 δ13.513 whereas a
proton on an iminium carbon will normally show up in a region between δ7.5 and δ10.0. 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.
12
The proton on the carbon of an iminium function behaves like an aldehydic proton in NMR
since such proton absorbs between δ7.5-δ10.0 (aldehydic protons normally absorbs between
δ9.5-δ10.0 except when or if it contains a halogen substituent).
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.
13
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.
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 δ320.6 while the carbon of an iminium function shows up at a
position between δ130-δ180. 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 α-carbon of an iminium
salt. The N-substituted carbon atom absorbs between δ38.0-δ50.0.
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 π-bond systems (i.e double bonds or phenyl group) e.g.
14
Simple iminium salts like the compound below absorbs at a wavelength of 219nm in
hexane with an extinction coefficient “ε” between 5-5000
When the iminium salt is within a highly conjugated system, then the wavelength of
maximum absorption (λmax) will also show a bathochromic shift to a region between 242.5nm-
336.5nm.
When chromophores are available for conjugation, the λmax will increase (i.e a shift to
longer wavelength), Also the λmax 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 λmax.
1.6.4. Mass Spectra of an Iminium Salt3
15
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.
(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) β-Rearrangement
In this case, imines cannot be formed and so β-elimination occurs.
16
(c) Anion Rearrangement14
In this case, three possible rearrangements could occur
If the stabilizing anion is a good nucleophile, it may attack the α-carbon of the
iminium ion.
The anion could attack the SP3-carbon in the α-position leading to ring opening and
further rearrangement.
17
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.
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.
18
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.
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-α-chloroamides, rather than N-acyliminium salts.17,18
1.7.1. Sources of N-acyliminium Ions
19
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 α-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.
(c) N-Acylation of Imines21
20
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 π-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
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 π-nucleophiles to give trans adduct
(78) in 56-95% yields.
21
CHAPTER TWO
2.0. LITERATURE REVIEW
22
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 α-amino alcohols, α-amino ethers (e.g
oxazolidines), α-amino sulphides (e.g thiazolidines), and α-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 Familoni 29. 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 α-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.
Leonard’s 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 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.
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 α-tertiary amino acids.
Rapoport et al39 obtained iminium salts by briefly heating α-amino acids in phosphorus
oxychloride. N-β-phenylethylproline hydrochloride (116) was decarbonylated in this manner
31
and after adding the reaction mixture to water; the N-β-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 ϒ-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.
2.1.7. Use of Silver Compounds
36
Enders and Shilvock48 reported that α-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 Börner49 treated the cyanopiperidine (146) with silver triflate in acetonitrile
which gave rise to the iminium compound (147).
2.1.8. Other Methods
37
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 β-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
β-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 α-amino
phosphonate. With alkyl phosphites, the reaction afforded α-dialkylamino β,ϒ-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 β-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 α,α-Disubstituted α-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 β-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-workers 61 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.
Rapoport’s group39 in Berkeley reported the synthesis of some natural products like
tetrahydroberberine using iminium salts generated by heating α-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