Chapter Chapter Chapter Chapter 4444

Applications of Ionic Liquids Applications of Ionic Liquids Applications of Ionic Liquids Applications of Ionic Liquids as Catalystas Catalystas Catalystas Catalyst

Chapter 4

123

Application of ionic liquids as catalysts has enabled the researchers to explore not only

the physical but also the chemical interactions of either their bulky cations or anions with

the reactants under study. Following the literature on ionic liquids as catalysts (Section

1.8.2), attempts were made towards the development of a metal containing allyl

functionalized morpholinium based ionic liquid for the purpose of catalyzing two well-

known organic transformations - Biginelli reaction and Knoevenagel condensation. It has

been proposed that when the allyl functionalized morpholinium based ionic liquid

‘[amm]Br’ is taken together with the metal salt Pd(OCOCH3)2, it is the complex

‘[amm]2[PdBr2(OCOCH3)2]’ (Figure 4.1), produced in the reaction mixture that is the

actual catalytic species that participates in the reaction.

O

N

2

PdBr2(OCOCH3)2

Figure 4.1: Catalytic complex [amm]2[PdBr2(OCOCH3)2]

4.1 INTRODUCTION

4.1.1 Morpholinium ionic liquids – Ionic liquids based on morpholinium cation.

N-alkyl-N-methyl-morpholinium salts are increasingly under attention because of their

moderate or low toxicity (EC50 between 0.15 mM and 14.13 mM), short synthesis time,

simple purification steps, good product reproducibility and economical synthetic

pathways.1,2 As reported by Lee et al.,

2 in comparison to salts of imidazole and pyrrolidine,

the ones based on morpholinium ions require cheap morpholinium cation sources as

compared to organic cations such as 1-vinyl-2-pyrrolidinone, 1-methylpyrrolidine and 1-

methyl imidazole. These thermally and electrochemically stable ILs have been expected to

be potential candidates as electrolytes in batteries and other electronic devices.3,4

They have

Chapter 4

124

also been used in the size controlled synthesis of crystalline palladium nanoparticles using

[bmmor]BF4 (N-butyl-N-methyl-morpholinium tetrafluoroborate) as a stabilizer.5

Morpholinium based ionic liquids are increasingly being used in the field of catalysis

leading towards the development of new catalysts. Ionic liquid [morH]HSO4

(morpholinium bisulfate) was found to be an effective catalyst for the condensation reaction

of indoles with carbonyl compound to yield bis(indolyl)methanes at room temperature.6

The methodology has several merits such as mild reaction condition, inexpensive catalyst,

stability at room temperature and it was also found that this catalyst could also be recovered

quantitatively and reused without much loss of catalytic activity.

List et al. have reported a highly efficient method for the aldol condensation of

acetone with aromatic aldehydes, using morpholinium trifluoroacetate as the catalyst.7

The easily availability of the catalyst together with high selectivity and functional

group tolerance makes this a valuable procedure.

4.1.2 N-allyl-functionalised ionic liquids

Functionalised ionic liquids exhibit a range of physical and chemical properties that

are well suited to specific applications (Catalytic applications: Section 1.8.2.2). As an

example, ILs bearing the O,O-diphenylphosphonyl functionality have been evaluated

as mechanical lubricants8 and ILs with fluorous chains can act as surfactants.

9

Applications also include the use of acid-functionalised ionic liquids in the

acetalisation of aldehydes 10,11

and urea- and thiourea functionalized ILs in the

extraction of metal ions from aqueous solutions.12,13

Thiol-functionalized ILs have

been shown to stabilize gold and platinum nanoparticles.14,15

Similarly, nitrile-

functionalised ILs can stabilize palladium nanoparticles, which also exhibit catalytic

activity in many C-C coupling reactions.16,17

Amongst the allyl-functionalised ILs, N-allyl-imidazolium salts have been reported as

early as 1971.18

At the time of discovery, the liquid nature of these compounds and

hygroscopicity was not appreciated. However, the low melting temperature and the

deliquescent nature has been attributed to high flexibility of the allyl group and intra-

hydrogen bonding between H-atoms of the imidazole ring and the counter anion.

As yet, no extensive study on catalytic properties of ILs bearing alkene functionality has

been reported, although it has been shown that 1-allyl-3-methylimidazolium chloride can

Chapter 4

125

be used as a solvent for cellulose acetylation.19 Ohno et al have synthesized a series of

allyl-imidazolium halides and investigated their conductivities, viscosities and thermal

properties, indicating that the introduction of an allyl group onto the N-position of the

imidazole ring can effectively suppress their crystallization.20

These alkene functionalized ILs have also been considered as useful synthons for the

synthesis of many other low melting molten salts or functionalized ILs. Addition

reactions to side chains of these allyl functionalized compounds can represent an

important synthetic route to a wide range of novel and potential ILs.21

Besides this

allyl-functionalized imidazole and pyrrolidine based ionic liquids, have also been

used as electrolytes for capacitors and dry sensitized solar cells respectively.22,23

4.1.3 Metal containing ionic liquids and their applications

Ionic liquids and ionic liquid crystals (ILCs) of imidazolium salts composed of

various transition and main group metals have been reviewed extensively by Vasam et

al.24

ILCs are liquid crystalline, ionic compounds with melting point less than 100°C.

The presence of metal ions provides numerous additional properties such as color,

geometry and magnetism, which are distinguishable compared to simple ILCs.25-30

Metal-containing ILCs are also potentially very useful as an ordered media/potential

solvents, catalysts, catalyst precursors and reagents for organic transformations

and provide eco-friendly protocols. They have also been found to play key roles in

material science. Many of these IL systems are air and moisture stable and are

considered as alternatives for air and moisture sensitive chloroaluminate-based ILs.

Based on their melting point this study has been divided into three classes:

A Metal containing ionic liquids, ILs

B Metal containing ionic liquid crystals, ILCs

C IL supported metal catalysts – IL tagged to the ligand of a metal complex

(Section 1.8.2.3)

In this study only A and B have been considered

A Metal containing ionic liquids, ILs: The prolific works of Seddon, Welton,

DuPont and their coworkers from the period of 1990’s gave a special significance to

the ILs and their derivatives composed of transition-metals and main group metals.31

Chapter 4

126

Synthesis of two isomorphous imidazolium salts [emim]2MCl4, where M=Co or Ni

(Figure 4.2 (a-b)) with melting point 90°C–100°C, were prepared directly by mixing

the corresponding metal chloride with [emim]Cl under dry nitrogen atmosphere.31,32

Crystal structure studies of these ILs revealed that extended hydrogen bonding

networks could be present between the MCl4-2

and the ring hydrogens.

Figure 4.2: [emim]2MCl4 (a) M= Co, (b) M= Ni 31

Amongst the palladium containing ILs, DuPont’s group has reported the synthesis and

catalytic action of [bmim]2PdCl4 (Figure 4.3) in the hydrodimerization of 1,3-

butadiene in [bmim]BF4 medium.32

IR spectral data and crystal structure of this metal

containing IL also showed the presence of strong hydrogen bonding between the

chloride and imidazolium hydrogens. It has been found that during the catalytic

process, the compound [bmim]2PdCl4 in [bmim]BF4 underwent dealkylation and

produced the catalyst precursor trans-[PdCl2(mim)2]2 (Figure 4.4).

N

N

2Bu

PdCl4-2

N

N Pd

Cl

Cl

N

N Pd

Cl

Cl

N

N

Figure 4.3: [bmim]2PdCl4 32 Figure 4.4: trans-[PdCl2(mim)2]2

32

Chapter 4

127

Later, Seddon’s group also used the [bmim]2PdCl4 (Figure 4.3) as a catalyst for Heck

reaction conducted in a three-phase [bmim]PF6/hexane/water system.33

In this case

generation of metal-NHC (NHC= N-heterocyclic carbenes) in the catalytic cycle was

anticipated. Soon, Ortwerth et al.34

characterized the structure of another palladium

based IL, [emim]2PdCl4, which was prepared by the reaction of Pd(acac)2 with an

acidic [emim]Cl– AlCl3 system.

Shreev and co-workers35

on the other hand, focused the formation of ionic liquid-

coordinated compound (Figure 4.5 (b)) with the dissolution of PdCl2 in an ionic

liquid of mono-quaternary bis-2,2-bimidazole (Figure 4.5 (a)) for a Pd(II) catalyzed

Heck reaction. This IL-coordinated Pd(II) complex (Figure 4.5 (b)) performed well

for at least 10 times without significant loss in its activity.

Figure 4.5: (a) Ionic liquid of mono-quaternary bis-2,2-bimidazole (b) Coordinated

Ionic liquid formed by dissolution of PdCl2 with (a)35

Dyson and co-workers16

also prepared an ionic liquid-coordinated Pd(II) complex

[Pd(N≡CC3mim)2-Cl2]BF4, Figure 4.6, (N≡CC3mim = 1-butylnitrile-2,3-dimethyl-

imidazolium) by using a nitrile functionalized ionic liquid. This complex (Figure 4.6)

was employed as a solvent and recyclable catalyst during the hydrogenation of 1,3-

cyclohexadiene.

Figure 4.6: Ionic liquid-coordinated Pd(II) complex [Pd(N≡CC3mim)2-Cl2]BF4 16

Chapter 4

128

B Metal containing ionic liquid crystals

The pioneering work has been done by Bruce’s and Seddon’s groups, who reported

the synthesis of liquid crystalline [Cn-mim]2MCl4, where M= Co, Ni or Pd (Figure

4.7 (a-c)) and Cn = alkyl chain of CnH2n +1, n = 12–18.36,37 The thermal stability of

these compounds was found to be directly proportional to with the length of the alkyl

chain attached to the imidazolium cation. The crystal and liquid polymorphism for

compounds of [Cn-mim]2PdCl4 (Figure 4.7 (c)) was also investigated by these groups

and was also found to be a function of alkyl chain length (n = 12, 14, 16, 18).25

While

the compounds of n = 10 and 12 were found non mesogenic, the compounds with n=

14, 16, 18 showed liquid crystalline behavior. The melting point values for these

compounds were higher than the counter parts with inorganic anions like Cl-, BF4

- and

PF6-, but comparable with [CoCl4]

-2 or [NiCl4]

-2. Moreover, it was suggested that the

use of these ordered liquid-crystal as a solvent could certainly influence the selectivity

in catalytic reactions.

N

N

CnH2n+1 2

MCl4

n= 10,12, 14, 16, 18

Figure 4.7: [Cn-mim]2MCl4 (a) M= Co, (b) M= Ni (c) M= Pd 36,37

Metal containing ILCs composed of N,N´-dialkylimidazolium salts of Pd(II) and

Cu(II) i.e. [(Cn)2-im]2MCl4, (Figure 4.8 (a,b)) where n = 8, 10, 12, 14, 16 , and 18 for

M = Pd(II) (Figure 4.8 (a)) and n = 10, 12, 14, 16, and 18 for M = Cu(II) (Figure 4.8

(b)) were prepared and structurally characterized by Lin’s group.27

The crystal

structures of [(C12)2-im]2[PdCl4 ] and [(C12)2-im]2[CuCl4]. H2O were found to be the

first example of metal containing ILCs based on [(Cn)2-im] salts.

N

N

CnH2n+1

CnH2n+12

MCl4

Figure 4.8: [(Cn)2-im]2[MCl4] (a) M= Pd and (b) M= Cu

27

Chapter 4

129

In this study; a palladium dicarbene complex trans-[((Cn)2-imY)2PdCl2] (Figure 4.9 (a))

and carbine-imidazolecomplex trans-[((Cn)2-imY)(Cn-im)PdCl2] (Figure 4.9 (b)) were

identified as the thermal decomposition products of Pd-IL complex Figure 4.8 (a).

Figure 4.9: (a) trans-[((Cn)2-imY)2PdCl2] (b) trans-[((Cn)2-imY)(Cn-im) PdCl2]; (n=16) 27

4.1.4 Metal containing allyl-functionalised ionic liquids

Dyson et al. have described the synthesis and characterization of metal containing allyl

functionalized imidazolium ionic liquid; [amim]PdBr2Cl2 (amim= 1-allyl-3-methyl-

imidazolium) (Figure 4.10 (a)). The complex [amim]PdBr2Cl2 underwent de-alkylation

in presence of AIBN and afforded the complex shown in (Figure 4.10 (b)). These

researchers also discussed some nascent reactions that they could undergo, indicating that

these compounds could be a source to a variety of other functionalized ionic liquids. 21

allyl bromide PdCl2

AIBN

R= Me/ Allyl

Figure 4.10: (a) Synthesis of metal containing allyl functionalized imidazolium ionic

liquid; [amim]PdBr2Cl2 (amim= 1-allyl-3-methyl-imidazolium) (b)

polymerization of [amim]PdBr2Cl2 in presence of AIBN21

Chapter 4

130

4.1.5 Work Objective

Convinced by the easy synthetic procedure for morpholine based ionic liquids and catalytic

applications of metal containing ionic liquids, an allyl-functionalized morpholine based

ionic liquid, [amm]Br (N-allyl-N-methylmorpholinium bromide) has been treated with a

metal salt (palladium acetate) so as to afford ‘[amm]Br-Pd(OCOCH3)2’ system. UV-

spectrophotometric studies indicated the formation of metal containing ionic liquid complex

‘[amm]2PdBr2(OCOCH3)2’ (Figure 4.1). Catalytic performance of this ionic liquid- metal

salt system: ‘[amm]Br-Pd(OCOCH3)2’ has been investigated through series of Biginelli

condensation and Knoevenagel condensation in Sections 4A and Section 4B respectively.

4.2 SYNTHESIS OF CATALYTIC SYSTEM: [amm]Br-Pd(OCOCH3)2

The catalytic system: [amm]Br-Pd(OCOCH3)2 was synthesized from [amm]Br and

Pd(OCOCH3)2 (Scheme 4.1, Figure 4.11). The precursor, allyl functionalized ionic liquid:

N-methyl-N-(prop-2-enyl) morpholinium bromide or N-allyl-N-methyl morpholinium

bromide, [amm]Br was synthesized from N-methyl morpholine as per simple and efficient

method proposed by Feng et al.38 [amm]Br was then characterized by

1H and

13C NMR

studies. This was found to be a stable hydrophilic ionic liquid. In the next step an equimolar

mixture of [amm]Br was reacted with palladium acetate in a suitable solvent. To a solution

of [amm]Br (1mole) in ethanol (5.0ml) palladium acetate (1mole) was added. The mixture

that turned dark red (Figure 4.12), was stirred for not more than 36 hours and the catalytic

complex was isolated by evaporation of the solvent under reduced pressure.

O

N

O

NBr

Br-Pd(OCOCH3)2

O

N

2

[PdBr2(OCOCH3)2]

2

N-methylmorpholine [amm]Br (N-allyl-N-methylmorpholiniumbromide)

[amm]Br- Pd(OCOCH3)2

Scheme 4.1: Synthesis of catalytic system [amm]Br-Pd(OCOCH3)2

Chapter 4

131

[amm]BF4

Pd(OCOCH3)2in

ethanol

Ionic liquid-metal salt catalytic

system; [amm]Br-Pd(OCOCH3)2

Figure 4.11: Schematic representation for synthesis of ionic liquid- metal salt catalytic

system ‘[amm]Br- Pd(OCOCH3)2’

Figure 4.12: Visual changes during synthesis of catalytic system [amm]Br- Pd(OCOCH3)2

4.3 UV-VISIBLE SPECTRUM FOR [amm]Br-Pd(OCOCH3)2 SYSTEM

Evidence for the complexation between the hydrophilic ionic liquid [amm]Br and the

metal salt palladium acetate was laid forward by UV-Visible spectrophotometry

studies. A solution of palladium acetate absorbed at 400 nm of UV-Visible spectrum.

When palladium acetate was stirred with hydrophilic allyl-functionalized

morpholinium ionic liquid; [amm]Br (N-allyl-N-methylmorpholinium bromide), its

absorbance shifted to a lower wavelength with a decrease in intensity. This implies a

Chapter 4

132

hypsochromic shift and was indicative of a complex formation (Figure 4.13).

Wavelength shift from 399nm in palladium acetate to 327nm in the complex obtained

could be attributed to the formation of complex [amm]2[PdBr2(OCOCH3)2].

Figure 4.13: UV-Vis absorbance spectrum of (b) catalytic system [amm]Br-

Pd(OCOCH3)2 w.r.t (a) palladium acetate

4.4 CONCLUSION

Morpholinium based ionic liquid require easy synthetic steps compared to those

containing an imidazole nucleus. Allyl-functionalized morpholinium based ionic

liquid could be easily synthesized with less moisture sensitivity compared to

imidazolium based ionic liquid such as [bmim]BF4. Complexation of the hydrophilic

ionic liquid [amm]Br with a metal salt further reduced its moisture sensitivity and

increased the stability. The metal salt-ionic liquid conjugate system ([amm]Br-

Pd(OCOCH3)2), as prepared by the method, was further employed for the synthesis of

Biginelli derivatives and Knoevenagel adducts.

[amm]Br- Pd(OCOCH3)2

Pd(OCOCH3)2

Chapter 4

133

SECTION 4A

Application of Novel hydrophilic ionic liquid-metal salt system;

‘[amm]Br- Pd(OCOCH3)2’ towards catalytic synthesis of series

of Biginelli derivatives under solventless conditions.

A novel hydrophilic palladium containing morpholine based ionic liquid (derived from

N-allyl-N-methylmorpholinium bromide with an easy synthetic procedure) has been used

to catalyze the synthesis of wide series of Biginelli derivatives (Scheme 4A.1); 3,4-

dihydropyrimidin-2(1H)-ones or -thinoes and 3,4,5,6,7,8-hexahydroquinazolin-2(1H)-

ones or thiones in a one pot three component reaction. Urea/thiourea, an aromatic

aldehyde and a β-ketoester/enolisable ketone (substituted acetophenone/cyclohexanone)

couple in the presence of [amm]Br- Pd(OCOCH3)2 system at room temperature under

solventless conditions to afford the heterocyclic derivatives in good yields.

Scheme 4A.1: Synthesis of 3,4-dihydropyrimidin-2(1H)-ones or -thinoes and 3,4,5,6,7,8-

hexahydroquinazolin-2(1H)-ones or thiones using [amm]Br-

Pd(OCOCH3)2]

3,4-dihydropyrimidin-2(1H)-ones or -thinoes

3,4,5,6,7,8-hexahydroquinazolin-2(1H)-ones or thiones

CHO

R

H2N NH2

X

HN NH

X

R

HN NH

R

O

+Pd(OAc)2 - [amm]Br

Pd(O

Ac) 2 - [

amm]B

r

Pd(OAc)2 - [amm]Br

O

O

R'

R

HN NH

X

O OEtR

OEtO

O

Chapter 4

134

4A.1 INTRODUCTION

4A.1.1 ‘3,4-dihydropyrimidin-2-ones’ and conventional methods of synthesis

In 1893 Italian chemist Pietro Biginelli (at University of Florence) reported this

reaction for the first time which is taken as the birth of this reaction. It is popularly

named after him i.e. Biginelli Reaction. Classically, the reaction was reported as acid-

catalyzed condensation of ethyl acetoacetate, benzaldehyde and urea in ethanol which

upon refluxing followed by cooling gives a solid crystalline product 3,4-

dihydropyrimidin-2(1H)-one. Thus this was apparently a three component reaction

(Scheme 4A.2) and the acid used was hydrochloric acid.39

Scheme 4A.2: Conventional acid catalyzed Biginelli reaction39

The scope of this reaction was gradually extended by the variation of all the three

building blocks, allowing access to a large number of multifunctionalized

dihydropyrimidines (DHPMs) of medicinal use.40-48

Dihydropyrimidines show a

diverse range of biological activities. They are known to possess activities such as

antibacterial and antiviral (nitractin), antitumor, analgesic and anti-inflammatory,49

antiplatelet aggregation and antihypertensive activity. Thus, development of

methodologies for efficient lead structure identification and for pharmacophore

variation of dihydropyrimidine motif has always attracted the attention of

pharmaceutical industry.50,51

Catalysts employed till date can be broadly categorized into five variants-Bronsted

acids, Lewis acids, ionic liquids, biocatalysts and organocatalysts. In addition, few

rate enhancement processes have also been adopted like sonication, microwave

irradiation and certain other miscellaneous processes.

Chapter 4

135

The reaction conditions traditionally employed involve strong Bronsted and Lewis

acids, such as LiClO4, LaCl3.7H2O, InCl3, Bi(OTf)3, BiCl3, Mn(OAc)3, Cu(OTf)2,

FeCl3.6H2O, ZrCl4 or SnCl2.2H2O.52

Among the Si-MCM-41 or montomorillonite K

10 clay supported ZnCl2, AlCl3, GaCl3, InCl3 and FeCl3 catalysts, FeCl3/Si-MCM-41

has shown best results for microwave assisted synthesis of dihydropyrimidinones.53

Formic acid has been used under solventless conditions for microwave irradiated

synthesis of these compounds54

while Cu(OTf)2 has also been used at 100°C in the

presence of ethanol.55

There have also been previous reports on the use of solid-phase

protocols which allow higher degree of throughput and automation.56

An earlier

method to synthesize dihydropyrimidinones in ionic liquid, as reported by Sain et al.,

involved heating and this was the possible reason why the catalyst could not be

recycled.57

Additionally, the yields obtained with some of the aldehydes were low.

Similarly, Azhar et al. have synthesized dihydropyrimidinones using Cu(BF4)2. xH2O

as a catalyst, but as in the previous case, the catalyst had recyclability issues.58

ILs are considered as the green solvent of the present century which obey the twelve

principles of the green chemistry and are used extensively as catalysts or solvent or both

in the organic synthesis.59-61

In this decade, the use of ILs in Biginelli reaction have

attracted much attention either to enhance rate of reaction or to make a synthetic protocol

greener. In the synthesis of DHPMs a variety of ILs viz. task-specific,62,63

polymer-

supported,64 chiral ionic liquid

65 have been used. Few amongst these are: [bmim]FeCl4,

66

[Hmim]HSO4,67 [C4mim]HSO4,

68 [bmim]BF4 immobilized Cu(acac)2,

69 [bmim]Sac,

70-72

[bmim]PF6,73

[bmim]BF4,74

[bmim]Cl×2AlCl3,75

n-butyl-pyridinium tetrafluoroborate,76

tri-(2-hydroxyethyl) ammonium acetate,77 etc. It is worthwhile to note that all the ionic

liquids used have been based upon the imidazolium nuclei.

4A.1.2 Work objective

An ionic liquid-metal salt system-‘[amm]Br-Pd(OCOCH3)2’ expected to form a metal

containing ionic liquid complex-‘[amm]2PdBr2(OCOCH3)2’ (Figure 4.1) was used as

a catalyst for the synthesis of a series of biologically active heterocyclic compounds

Chapter 4

136

‘3,4-dihydropyrimidin-2-ones’ and ‘3,4,5,6,7,8-hexahydroquinazolin-2(1H)-ones’

at room temperature under atmospheric pressure. The advantage of using this system

for Biginelli reaction over other ILs was the ease in the synthetic procedure for

morpholine based molten salts over imidazole based or pyridine based molten salts.

Metal salt- ionic liquid system could be easily recycled for further turns without

significant loss in its activity. It was envisaged that the use of a metal containing

olefin functionalized ionic liquid complex for catalytic purposes could open new

avenues for research in the field of ionic liquid catalysis. The purpose of choosing a

palladium salt over other metal salts can be attributed to the high catalytic efficiency

and low melting temperature of its complexes over certain other commonly used

metal salt complexes.

4A.2 GENERAL PROCEDURE FOR [amm]Br-Pd(OCOCH3)2 CATALYZED

SYNTHESIS OF BIGINELLI DERIVATIVES UNDER SOLVENTLESS

CONDITIONS.

In a mixture containing active methylene compound/ketonic compound (2mmole) (as

per Scheme 4A.4, Scheme 4A.5 and Scheme 4A.6), aromatic aldehyde (2mmole),

urea or thiourea (3mmole), 10-15 mole% of liquid ‘palladium acetate-ionic liquid’

complex system (synthesized as per procedure given in Section 4.2) was added and

was allowed to stir at room temperature till the reaction reached completion (as

indicated by TLC). 5 ml of cold water was added to the reaction mixture and stirred.

The solid material obtained was filtered and the washings were retained. The product

was further washed with cold water and recrystallized from ethyl acetate/n-hexane or

ethanol to afford the pure product. The aqueous washings were evaporated in vacuum

to afford the liquid catalytic system which could be recycled at least five turns with no

loss in its activity.

Chapter 4

137

4A.3 RESULTS AND DISCUSSION

The study was started by reacting 2mmole of benzaldehyde with 2mmole of

ethylacetoacetate and 3mmole of urea at room temperature in the presence of a catalytic

amount of ionic liquid, [amm]Br (N-allyl-N-methylmorpholinium bromide) (Scheme

4A.3). Even in presence of this allyl functionalized morpholinium ionic liquid, TLC

indicated the product formation but the yield of the product was rather low. Upon

complexation of [amm]Br with other metal salts, the complexes were formed, but were

not stable in air and moisture. However, with palladium acetate a red colored complex

was formed (Figure 4.11 and Figure 4.12) that was not only stable in air and moisture

but gave a high percentage yield. Thereby, upon functionalization of the ionic liquid with

a transition metal salt its catalytic efficiency increased many folds.

Based on these preliminary investigations, three series of compounds were formed by

varying the active methylene compound/ketonic compound in the conventional

Biginelli reaction. The first series involved urea/thiourea, aromatic aldehyde and an

active methylene compound (ethylacetoacetate) (Scheme 4A.4, Table 4A.1). In this

3,4-dihydropyrimidin-2(1H)-ones were formed as the product with ethoxycarbonyl

substituent at 5th position of the parent nucleus. The mechanism is presumed to

involve the condensation of the aldehyde with the urea molecule followed by the

nucleophilic addition of the 1,3-dicarbonyl compound (ethylacetoacetate). As shown

in Figure 4A.1, the mechanistic steps could be facilitated by the catalytic complex

‘[amm]2PdBr2(OCOCH3)2’ formed by the complexation reaction between [amm]Br

and Pd(OCOCH3)2, thereby increasing the rate of the reaction.

CHO

+

OEt

O O

+

H2N NH2

O HN NH

O

O OEt

[amm]Br

r.t.

Scheme 4A.3: Synthesis of 5-ethoxycarbonyl-4-phenyl-6-methyl-3,4-dihydropyrimidin-

2(1H)-onea

aReaction condition: 1mmole of benzaldehyde, 1mmole of ethylacetoacetate and 2mmole of urea

reacted at room temperature in the presence of a catalytic amount of ionic liquid [amm]Br

Chapter 4

138

Figure 4A.1: Mechanism proposed for the of the formation of 3,4-dihydropyrimidin-2-

ones in presence of catalytic system, [amm]Br- Pd(OCOCH3)2]a

aReaction condition: Condensation of an aromatic aldehyde (benzaldehyde) with urea and ethylacetoacetate

The second series involved urea, aromatic aldehyde and acetophenone derivatives

(Scheme 4A.5, Table 4A.2) yielding 3,4-dihydropyrimidin-2(1H)-ones (phenyl

substituent at the 5th position) as products and third involved the use of cyclohexanone

as the ketonic compound so as to afford 3,4,5,6,7,8-hexahydroquinazolin-2(1H)-ones

(Scheme 4A.6, Table 4A.3).

Synthesis of 3,4-dihydropyrimidin-2(1H)-ones (Scheme 4A.4) with ethoxycarbonyl

substituent at 5th position of the pyrimidine-one nucleus was a bit faster as compared

to the synthesis of 3,4-dihydropyrimidin-2(1H)-ones with phenyl derivative at 5th

position (Scheme 4A.5). This could be attributed to the greater nucleophilicity of the

carbanion formed in case of ethylacetoacetate as compared to that of the carbanion

formed from the acetophenone derivatives.

H2N

O

NH2

H O

N

[amm]2[PdBr2(OCOCH3)2]

N

H

O

NH2

O O

OC2H5

Pd

[amm]2[PdBr2(OCOCH3)2]

HN NH2

O

O

-H2O

-H2O

O OC2H5

NHHN

O

O OC2H5

Chapter 4

139

CHO

+

OEt

O O

+

H2N NH2

XHN NH

X

O OEt

R

R

[amm]Br- Pd(OCOCH3)2]

Scheme 4A.4: Synthesis of 5-ethoxycarbonyl-3,4-dihydropyrimidin-2(1H)-ones a

aReaction condition: Condensation of 2mmole of aromatic aldehyde, 2mmole of ethylacetoacetate and

3mmole of urea/thiourea in presence of 10 mole% of catalytic system [amm]Br- Pd(OCOCH3)2 at room

temperature.

CHO

O

H2N NH2

XHN NH

RR

X

[amm]Br-Pd(OCOCH3)2]

R'

R'

Scheme 4A.5: Synthesis of 5-phenyl substituted-3,4-dihydropyrimidin-2(1H)-ones a

aReaction condition: Condensation of 2mmole of aromatic aldehyde, 2mmole of acetophenone

derivative and 3mmole of urea/thiourea in presence of 15 mole% of catalytic system [amm]Br-

Pd(OCOCH3)2 at room temperature.

CHO O

H2N

X

NH2

HN NH

X

[amm]Br-Pd(OCOCH3)2]

R R

Scheme 4A.6: Synthesis of 3,4,5,6,7,8-hexahydroquinazolin-2(1H)-onesa

aReaction condition: Condensation of 2mmole of aromatic aldehyde, 2mmole of cyclohexanone and 3mmole

of urea/thiourea in presence of 12 mole% of catalytic system [amm]Br-Pd(OCOCH3)2 at room temperature.

Chapter 4

140

4A.3.1 Catalyst concentration

Concentration of catalyst required for conversion of 1mmole of benzaldehyde, 1mmole

ethylacetoacetate and 1.5mmole of urea to 5-ethoxycarbonyl-4-phenyl-6-methyl-3,4-

dihydropyrimidin-2(1H)-one was 10mole% (Table 4A.1, Entry 4A.2.1). However, for

converting 1mmole of benzaldehyde, 1mmole of acetophenone and 1.5mmole of urea to

the corresponding product 4-phenyl-3,4-dihydropyrimidin-2(1H)-one a little higher

concentration of the catalyst was needed i.e. 15mole% (Table 4A.2, Entry 4A.2.1). This

could be attributed to reduced acidic character of the methyl proton in acetophenone as

compared to that in the active methylene group in ethylacetoacetate. Synthesis of

3,4,5,6,7,8-hexahydroquinazolin-2(1H)-ones required 12 mole% of the catalyst

(Table 4A.3, Entry 4A.3.1).

Table 4A.1: [amm]Br-Pd(OCOCH3)2 catalyzed synthesis of ethoxy carbonyl

substituted 3,4-dihydropyrimidin-2(1H)-onesa

S. No. X R Productb Yield (%) Time (min)

4A.1 O

H

HN NH

O

O OEt

98 12

4A.2 O 4-Cl- HN NH

O

O OEtCl

95 14

4A.3 O 4-(OCH3)- HN NH

O

O OEtMeO

98 12

4A.4 O 4-(NO2)- HN NH

O

O OEtO2N

92 15

Chapter 4

141

S. No. X R Productb Yield (%) Time (min)

4A.5 O 2-(OCH3)-

4(OCH3)

HN NH

O

O OEt

OMe

MeO

96 18

4A.6 O 3-(OCH3)-4(OH) HN NH

O

O OEtHO

H3CO

90 20

4A.7 O 4-(CH3)- HN NH

O

O OEtH3C

84 15

4A.8 O 4-(OH)- HN NH

O

O OEtHO

88 20

4A.9 S H HN NH

S

O OEt

87 10

4A.10 S 4-(OCH3)- HN NH

S

O OEtMeO

90 12

4A.11 S 4-Cl- HN NH

S

O OEtCl

84 15

aReaction condition: Condensation of 2mmole of aromatic aldehyde, 2mmole of ethylacetoacetate

and 3mmole of urea/thiourea in presence of 10 mole% of catalytic system [amm]Br-Pd(OCOCH3)2 at

room temperature. b Isolated pure crystallized product, characterization using

1H-NMR,

13C-NMR and

mass spectrum studies

Chapter 4

142

Table 4A.2: [amm]Br-Pd(OCOCH3)2 catalyzed synthesis of phenyl substituted

3,4-dihydropyrimidin-2(1H)-onesa

Entry X R R´ Productb Yield (%) Time(min)

4A.2.1. O H H

HN NH

O

86 10

4A.2.2. O 4-Cl H

HN NH

O

Cl

90 12

4A.2.3. O 4-(OCH3) H

HN NH

O

H3CO

97 10

4A.2.4. O 4-(NO2) H

HN NH

O

O2N

87 14

4A.2.5. O 2-(OCH3)-

4(OCH3) H

HN NH

O

H3CO

OCH3

98 15

4A.2.6. O 3-(OCH3)-

4(OH) H

HN NH

O

HO

H3CO

96 08

Chapter 4

143

Entry X R R´ Productb Yield (%) Time(min)

4A.2.7. O 4-(CH3)- H

HN NH

O

H3C

90 14

4A.2.8. O 4-(OH)- H

HN NH

O

HO

95 12

4A.2.9. S H H

HN NH

S

98 14

4A.2.10. S 4-(OCH3) H

HN NH

S

H3CO

94 10

4A.2.11. S 4-Cl H

HN NH

S

Cl

86 15

4A.2.12 O H 4-OCH3

HN NH

O

och3

92 18

4A.2.13 O 4-OCH3 4-OCH3

HN NH

O

och3

H3CO

94 18

aReaction condition: Condensation of 2mmole of aromatic aldehyde, 2mmole of acetophenone

derivative and 3mmole of urea/thiourea in presence of 15 mole% of catalytic system [amm]Br-

Pd(OCOCH3)2 at room temperature. bIsolated pure crystallized product, characterization using

1H-

NMR, 13

C-NMR and mass spectrum studies

Chapter 4

144

Table 4A.3: [amm]Br-Pd(OCOCH3)2 catalyzed synthesis of 3,4,5,6,7,8-

hexahydroquinazolin-2(1H)-onesa

Entry X R Productb Yield (%) Time (min)

4A.3.1. O H

HN NH

O

95 10

4A.3.2. O 4-Cl

HN NH

O

Cl

88 15

4A.3.3. O 4-(OCH3)

HN NH

O

H3CO

98 08

4A.3.4. O 4-(NO2)

HN NH

O

O2N

85 14

4A.3.5. O 2-(OCH3)-

4(OCH3)

HN NH

O

H3CO

OCH3

95 09

4A.3.6. O 3-( OCH3)-4-

(OH)

HN NH

O

HO

H3CO

98 12

Chapter 4

145

Entry X R Productb Yield (%) Time (min)

4A.3.7. O 4-(CH3)-

HN NH

O

H3C

92 14

4A.3.8. O 4-(OH)-

HN NH

O

HO

95 12

4A.3.9. S H

HN NH

S

H

94 16

4A.3.10. S 4-(OCH3)

HN NH

S

H3CO

97 12

4A.3.11. S 4-Cl

HN NH

S

Cl

89 15

aReaction condition: Condensation of 2mmole of aromatic aldehyde, 2mmole of

cyclohexanone and 3mmole of urea/thiourea in presence of 12 mole% of catalytic system

[amm]Br-Pd(OCOCH3)2 at room temperature. bIsolated pure crystallized product, characterization

using 1H-NMR,

13C-NMR and mass spectrum studies

4A.3.2 Catalyst recyclability

The catalytic complex [amm]Br-Pd(OCOCH3)2 could be recycled by separating it from

the aqueous residue of the reaction mixture by simply evaporating the solvent in

vacuum. It could be re-used over five subsequent turns in each of the reaction

schemes so as to yield 3,4-dihydropyrimidin-2(1H)-ones and 3,4,5,6,7,8-

hexahydroquinazolin-2(1H)-ones in high yields. The data for recyclability of catalyst

Chapter 4

146

for the model reaction (1mmole of benzaldehyde, 1mmole of ethylacetoacetate and

1.5mmole urea reacted in presence of 10mole% [amm]Br-Pd(OCOCH3)2) has been

plotted as a bar graph in Figure 4A.2. It was observed that with each subsequent

cycle, the catalytic activity of palladium containing ionic liquid decreased negligibly

(as observed by a decrease in the yields of the product).

Figure 4A.2: Recyclability of catalytic system [amm]Br-Pd(OCOCH3)2 for the

formation of 3,4-dihydropyrimidin-2(1H)-onesa

aReaction conditions: 1mmole of benzaldehyde, 1mmole of ethylacetoacetate and 1.5mmole urea

stirred in presence of 10mole% [amm]Br-Pd(OCOCH3)2

4A.4 CONCLUSION

A hydrophilic palladium containing ionic liquid has been developed, which is

catalytically active towards the synthesis of three series of Biginelli derivatives that

can serve as precursors to the synthesis of numerous pharmacologically active

compounds. All the compounds isolated were in their crude form which could be

recrystallized to give pure crystalline compounds with sharp and distinct melting

points. The catalyst could not only be recovered but also re-used over a number of

turns and this demonstrated the catalytic property of the complex. Due to the presence

of the catalytic transition metal element palladium, the complex [amm]Br-

Pd(OCOCH3)2 can be explored for other organic transformations as well.

Chapter 4

147

SECTION 4B

Application of novel hydrophilic ionic liquid-metal salt system

‘[amm]Br-Pd(OCOCH3)2’ towards catalytic synthesis of

Knoevenagel adducts under solventless conditions.

A useful reaction for the synthesis of substituted olefins has been carried out using a

novel catalytic system ‘[amm]Br-Pd(OCOCH3)2’. The reaction commences under

neutral conditions (without the addition of base) under solventless conditions. The

metal salt- ionic liquid system catalyses the condensation between aromatic aldehydes

and active methylene compounds (ethylcyanoacetate, malononitrile and malonic acid)

efficiently giving excellent product yields. The catalytic metal containing ionic liquid

complex system could be recycled and re-used up to five subsequent turns without the

need for additional reagent.

CHO

+

EWG

EWG

[amm]Br-Pd(OCOCH3)2

H

EWG

EWG

r.t

EWG= CN, COOEt, COOH

Scheme 4B.1 Knoevenagel condensation catalyzed by [amm]Br-Pd(OCOCH3)2

Chapter 4

148

4B.1 INTRODUCTION

4B.1.1Knoevenagel condensation and conventional methods of synthesis

The Knoevenagel condensation is a useful carbon-carbon bond formation reaction78

possessing variety of applications in the synthesis of fine chemicals,79 hetero-Diels-Alder

reactions80 and in the synthesis of carbocyclic as well as heterocyclic compounds.

81 The

reaction has been extensively utilized in the preparation of coumarin derivatives,82

cosmetics,83 perfumes

84 and pharmaceutical chemicals.

85 The conventional Knoevenagel

condensation between a carbonyl compound and an active methylene compound has

been carried out using bases such as ethylenediamine,86 piperidine

87 or corresponding

ammonium salts,88 amino acids,

89 dimethylaminopyridine

90 and potassium fluoride

mixture.91 These electrophilic alkenes have also been synthesized under heterogeneous

conditions92

using inorganic salts such as Al2O3,93

zeolite94

and calcite.95 Ionic liquids

95

have also played a vital role as a reaction media for this condensation. However,

some of these processes require harsh conditions and hence certain milder methods need

to be developed for obtaining these condensation products under conditions which can be

tolerated by sensitive functional groups (from both synthetic and environmental point of

view). The synthetic challenge is thus, to carry out this reaction in a neutral medium thus

avoiding the use of bases.

Room temperature ionic liquids (which have very low vapor pressure and are

thermally stable) have been recognized as a possible environmentally benign

alternative to volatile solvents in the chemical industry. Several classical organic

processes have been successfully performed in ionic liquids (using them as solvents or

catalysts).96-98

The application of task-specific ionic liquids with specific functional

groups, which can be used as both as reagent and medium, but can also catalyze

special reactions can further enhance the versatility of the ionic liquids.99-104

Typically, ionic liquids cited in literature that have been employed for the

Knoevenagel condensation, have an acidic counter anion such as nitrate in n-

butylpyridinium nitrate105

and ethylammoniumnitrate.106

Although a task specific

ionic liquid [NH3+CH2CH2OH][CH3COO

-] with weak basic character has been used

for condensation of aldehydes with certain active methylene compounds, but this

Chapter 4

149

ionic liquid also required acetic acid for its synthesis and in some cases the reaction

required to be carried out at an elevated temperature.107

In another case, the common

room temperature ionic liquid [bmim]PF6 has been used, but required the presence of

an additional catalyst sodium methoxide for the synthesis of 3-substituded coumarin

derivatives via Knoevenagel condensation.108

4B.1.2 Work Objective

In order to circumvent the problems encountered in all the methods which have been

used till date for catalyzing the well-known Knoevenagel condensation, catalytically

active, metal containing, hydrophilic and neutral ionic liquid-metal salt complex

[amm]Br-Pd(OCOCH3)2 could be used as a major breakthrough. As already discussed

before, the complex system was not only catalytically active but also stable over

reaction completion and could be recycled over subsequent turns.

4B.2 TYPICAL PROCEDURE FOR THE SYNTHESIS OF KNOEVENAGEL

ADDUCTS USING [amm]Br-Pd(OCOCH3)2 UNDER SOLVENTLESS

CONDITIONS

To a mixture of aldehyde (5.0 mmol) and active methylene compound (6.0 mmol),

10mole% of metal salt- ionic liquid complex system (as prepared in Section 4.2) was

added. The resulting reaction mixture was stirred at room temperature for a specified

period (Table 4B.1). The progress of the reaction was monitored by thin layer

chromatography (TLC). Upon complete conversion (as indicated by TLC) the

reaction mixture was diluted by adding ethyl acetate (50 ml) and washed with water

thrice followed by a brine wash. The organic layer was dried over anhydrous sodium

sulphate (Na2SO4) followed by evaporation of the solvent using a rotary evaporator

under reduced pressure so as to give the desired product, which after recrystallisation

afforded the pure Knoevenagel products (Table 4B.1). The complete spectral analysis

and compositional data revealed the formation of Knoevenagel products with

excellent purity.

Chapter 4

150

Subsequently, the first aqueous washing of the reaction mixture containing ethyl

acetate was retained and this was evaporated under reduced pressure to retain the

original catalytically active ionic liquid complex.

4B.3 RESULTS AND DISCUSSIONS

In order to investigate the versatility of the reaction, various aromatic aldehydes were

reacted with active methylene compounds viz. malononitrile, malonic acid and

ethylcyanoacetate (Scheme 4B.1). As expected, the yield of the products and the time

required for condensing 5mmole of an aldehyde with 6 mmole of an active methylene

compound was dependent upon the acidic character of the methylene protons in the

active methylene compound (Table 4B.1). In general, substituent at the ortho-position

of the aromatic aldehydes (Table 4B.1: Entries 4B.1.1, 4B.1.3 and 4B.1.5) seemed

to decrease the rate of the reaction together with the overall yield and this may be

because of steric constraints offered to the incoming nucleophile. Ketones showed no

reactivity at all under similar conditions (Table 4B.1: Entry 4B.18).

4B.3.1 Catalyst concentration

Concentration of a catalyst is one of the major parameters in optimizing the yield of

the product. It has been observed in this case that increase in the concentration of the

catalyst beyond 10mole% did not affect the yield further. Hence, this was selected to

be the optimum concentration (Figure 4B.1). This data has been plotted for the model

reaction under study (Table 4B.1, Entry 4B.1).

Chapter 4

151

Figure 4B.1: Catalyst concentration optimization for Knoevenagel condensationa

aReaction conditions: 5mmole of benzaldehyde reacted with 6mmole of ethylcyanoacetate in presence

of catalyst [amm]Br-Pd(OCOCH3)2

4B.3.2 Catalyst recyclability

Applicability of hydrophilic ionic liquid-metal salt catalytic system [amm]Br-

Pd(OCOCH3)2 as a recyclable catalyst was tested by carrying out repeated runs of the

reaction (Table 4B.1, Entry 4B.1) using the same batch of the catalyst (Figure 4B.2). The

data shows a gradual decrease in catalytic activity with increasing number of cycles. This

may be because of possibility of wear and tear in case of ionic liquids (as compared to

conventional catalysts) is low because of their distinct physiochemical properties.

Figure 4B.2: Catalyst recyclability study for Knoevenagel condensationa.

aReaction Condition: 5mmole of benzaldehyde reacted with 6mmole of ethylcyanoacetate in presence

of 10mole% of catalyst [amm]Br-Pd(OCOCH3)2

Chapter 4

152

Table 4B.1: [amm]Br-Pd(OCOCH3)2catalyzed Knoevenagel condensationa

Entry Aldehyde Active methylene

compound Product

Time

(h)

Yield

(%)

4B.1.1 CHO

C

O

ON

C2H5OOC

C N

0.30 98

4B.1.2 CHO

HO OH

O O

HOOC

COOH

0.58 97

4B.1.3 CHO

NN C

C N

N

0.33 98

4B.1.4 CHOCl

HO OH

O O

HOOC

COOH

Cl

0.50 92

4B.1.5 CHOCl

C

O

ON

C2H5OOC

C N

Cl

0.75 95

4B.1.6 CHOCl

NN C

C N

N

Cl

0.25 97

4B.1.7 CHOCl

O

O

O

O

Cl

1.00 81

4B.1.8 CHOMeO

HO OH

O O

HOOC

COOH

H3CO

1.16 92

4B.1.9 CHOMeO

C

O

ON

C2H5OOC

C N

H3CO

1.41 97

4B.1.10 CHOMeO

NN C

C N

N

H3CO

0.83 94

4B.1.11 CHO

OH

NN

C

C N

N

OH

0.41 85

Chapter 4

153

Entry Aldehyde Active methylene

compound Product

Time

(h)

Yield

(%)

4B.1.12 CHOHO

C

O

ON

C2H5OOC

C N

HO

0.75 89

4B.1.13 CHO

NO2

C

O

ON

C2H5OOC

C N

NO2

0.83 91

4B.1.14 CHOC2H5

C

O

ON

C2H5OOC

C N

C2H5

1.33 72

4B.1.15 CHO

OCH3H3CO

C

O

ON

C2H5OOC

C N

OCH3H3CO

1.25 80

4B.1.16 CHO

H3CO

HO

C

O

ON

C2H5OOC

C N

HO

HO

0.41 83

4B.1.17 CH3CHO C

O

ON

H3C

N

O

OC2H5

4.16 5

4B.1.18 CH3CCH3

O

C

O

ON

N

O

OC2H5

12.0 -

aReaction Condition: 5mmole of carbonyl compound reacted with 6mmole of active methylene

compound in presence of 10mole% of catalyst [amm]Br-Pd(OCOCH3)2

4B.4 CONCLUSION

Metal containing room temperature ionic liquid complex system- [amm]Br-

Pd(OCOCH3)2 has been proved efficient for the well-known Knoevenagel reaction.

The ionic liquid under study is neutral, leaving no toxic residues into the atmosphere

and has an easy synthesis method and a work up procedure. Moreover, it does not

even require the presence of an additional acidic or alkaline promoter to the reaction.

The study opens avenues for exploring other such metal containing ionic liquids or

complexes with enhanced and task specific catalytic activity.

Chapter 4

154

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