Synthesis of 1,2,4,5-tetra substituted imidazole using ...shodhganga.inflibnet.ac.in/bitstream/10603/28272/10/10_chapter 5.pdf · silica gel as the catalyst for the synthesis under

131

CHAPTER-5

Synthesis of 1,2,4,5-tetra substituted imidazole using

secondary amine based ionic liquid and defective Keggin

type heteropoly acid. A comparative study of the efficiency

of the two catalysts

Introduction

The Chemistry of imidazole and its derivatives form an important topic in

medicinal as well as in synthetic organic chemistry. The imidazole nucleus forms an

important structure of some well-known components of human organism, i.e. the

amino acid histidine, Vit-B12, a component of DNA base structure and purines,

histamine and biotin (Figure 5.1). The well known microtubule stabilizing agents

Eleutherobin and Sarcodictyin1 are among the numerous other marine- and plant-

derived natural products2 which contain the imidazole ring. Highly substituted

imidazoles and benzimidazoles are structural scaffolds which are the building blocks

of many natural products having a wide spectrum of biological activities such as

anti-inflamatory,3 anti-allergic,4 analgesic,5 pesticides,6 fungicides and herbicides,7

sodium channel modulators,8 plant growth regulators,9 and glucagon receptor

antagonism10 and CB1 cannabinoid receptor antagonists.11 Lepidilines A and B,

which contain the imidazole moiety, show micromolar cytotoxicity against several

human cancer cell lines.12 They are the key intermediate for the synthesis of

Olmesartan medoxomil,13 an angiotensin II receptor antagonist used for the

treatment of high blood pressure. Other drug molecules which contain the

tetrasubstituted imidazole scaffold are Omeprazole,14 Losartan, Eprosartan,

Pimobendan and Trifenagrel.15 In recent years it is reported that the imidazole

structural core are active in other advanced areas of research such as fluorescence

labelling agents,16 biological imaging17 and chromophores for non-linear optic

systems.18 It is reported that many substituted imidazoles are also known inhibitors

of P38 MAP kinase,19 B-Raf kinase,20 transforming growth factor β1 (TGF- β1) type

132

1 activin receptor-like kinase (ALK5),21 cyclooxygenase-2(COX-2)22 and

biosynthesis of interleukin-1(IL-1)23 (one of the representative imidazole is shown in

Figure 5.2. Besides these, they are found to be applicable in conjugated and

functional polymers,24 in coordination complexes25 as important ligands in

metalloenzymes26 and as precursors of stable carbene ligands.27 Recent development

of green chemistry expands the role of imidazole, which is found to be an essential

cationic part of most of ILs.

Figure 5.1

Histamine Histidine Purine

Figure 5.2

This compound potently inhibited the

mitogenactivated protein kinase p38 (p38

IC50= 0.218µM) as well as the release of

the proinflammatory cytokines interleukin

-1β (IL-1β) and tumor necrosis factor α

(TNF α) from human whole blood after

stimulation with LPS.

The versatility of imidazole derivatives mentioned above has encouraged the

synthetic organic chemists to develop several synthetic routes to the highly

substituted imidazoles. There are many synthetic route to tetrasubstituted imidazoles

and among them the one pot multicomponent condensation strategy attains greater

NH

N

NH2

HO

O

NH

N

NH2 NH

NN

N

N

N

S

ON

F

N H

O

133

value as it obey the ‘economy of steps’ due to which the target molecules are often

obtained in a single step rather than the multiple step process which consequently

minimizes the tedious work-up procedures and the release of environmentally

hazardous wastes. In 1858, Debus reported the reaction between glyoxal and

ammonia, which is acknowledged as the pioneering method for the synthesis of

imidazoles28 and even today, research in imidazole chemistry continues unabated.

Some of the important methods are reviewed herein.

A novel synthetic approach to 2-substituted imidazole was done by D. J.

Hlasta via imidazolium ylides.29 Diisopropylethyl amine is the base used for the

reaction. It was observed that in the absence of the base, the yield of the desired

product was found to be low and the method synthetically less important. The

reaction is shown in Scheme 5.1.

Scheme 5.1

N

N

Bn

N

N

Bn

CON(i-Pr)2

N

N

Bn

OCON(i-Pr)2

R2

R1

ClCON(i-Pr)2

DIEA

R1R2CO

Tetrasubstituted imidazoles have been synthesized using different substrates and

different procedure which includes N-alkylation of trisubstituted imidazoles,30

cyclization of sulphonamides with mesoionic 1,3-oxazolium-5-olates,31

condensation of β-carbonyl-N acyl-N-alkylamines with ammonium acetate in HOAc

under reflux condition,32 conversion of N-(2-oxo)amides with ammonium

triflouroactate under neutral conditions33 and others. Another important route is

reported by B. Hu et al. for the synthesis of tetrasubstituted imidazole from 2-azido

134

acrylates and nitrones by novel Dominos reaction.34 The reaction is shown in

Scheme 5.2.

Scheme 5.2

R1 N3

R2N

O R4

R3 H

+N

NR4

R3

R2

R1MgSO4, DCE

660C, 48 hr

The aza-Wittig reactions of iminophosphoranes have received increased attention

considering their efficiency in the synthesis of nitrogen heterocyclic compounds.35

Y-B. Nie et al. had arrived at the target product by a sequential Aza-Wittig/

Michael/ Isomerisation reaction.36 At first, carbodiimides was obtained from aza-

Wittig reactions of iminophosphorane with arylisocyanates, then these

carbodiimides reacted with secondary amines in presence of a catalytic amount of

sodium alkoxide to give 1,2,4,5- tetrasubstituted imidazoles in good yields.

5.1.1. Synthesis by four component condensation

Recent development in the synthesis of tetrasubstituted imidazoles inspired

the scientist to perform the reaction by a one pot multicomponent condensation of

substrates namely 1,2 dicarbonyl compounds, aldehydes, amines and a source of

ammonia. The reactions were carried out under the influence of several catalysts.

S. Narayana Murthy et al. used DABCO (1,4-diazabicyclo[2.2.2]octane) as the basic

catalyst to get the target molecules from benzil, benzaldehyde derivatives, primary

amine and ammonium acetate.37 They have carried out the reactions in different

solvent such as methanol, ethanol, iso-propanol and tert-butanol and found that

tert-butanol is the most appropriate solvent in terms of high yield and lower reaction

time. The other catalysts which are used in the four component condensation are

135

silica bonded propylpiperazine N-sulfamic acid,38 BF3.SiO2,39 HClO4-SiO2,

40 InCl3-

3H2O,41 L-proline42 besides others. All the above mentioned reactions are carried

out under mild conditions and recovered yields were comparatively high. Further,

the use of inexpensive ecofriendly catalyst and reusability of some of the catalyst

makes these methods attractive. In all the reactions ammonium acetate was used as a

source of ammonia. These reactions are summarized in Scheme 5.3.

Scheme 5.3

R O

OR

R1 CHO R2 NH2 ++ NH4OAc+ BF3.SiO2, Solvent Free

SBPPSA, Solvent Free

InCl3-3H2O, MeOH

L-proline, MeOH

HClO4-SiO2, Solvent Free

N

N

R

R

R2

R1

In similar way, molecular iodine, a cheap and nontoxic catalyst also found to be

efficient in the synthesis of 1,2,4,5-tetrasubstituted imidazole from benzoin,

aromatic aldehyde, amine and ammonium acetate.43 The reaction is shown in

Scheme 5.4.

Scheme 5.4

Ph

O

OH

Ph

PhNH2 NH4OAc Ar-CHO+++I2

N

NPh

Ph

Ar

Ph

136

Recently, a new investigation for catalytic activity of different fluoroboric acids was

carried out by D. Kumar et al. for the synthesis of trisubstituted and tetrasubstituted

imidazoles from 1,2-diketone, aldehyde and ammonium salt and 1,2-diketone,

aldehyde, amine and ammonium acetate respectively.44 They have carried out

extensive analysis of the reaction using aqueous HBF4, solid supported HBF4, metal

tetrafluoroborates (inorganic salt), solid supported metal tetrafluoroborates, and

tetrafluoroborate based ILs as catalyst and concluded that HBF4-SiO2 is most

effective catalyst followed by LiBF4 and Zn(BF4)2 in comparison to the others.

Analysis for best nitrogen source was also examined by considering different

ammonium salts and results showed that ammonium acetate was found to be the best

and most suitable.

5.1.2. Microwave assisted synthesis of highly substituted imidazoles

It is well established that microwaves (MW) enhance reaction rates and

hence reduce the reaction time, increase selectivities and also the yields. Following

the observation of these advantages found by the use of MW technique, this

technique was used in a few reported publications for the synthesis of

tetrasubstituted imidazoles. S. Balalaie et al. successfully applied zeolite HY and

silica gel as the catalyst for the synthesis under MW irradiation with high yield.45 A

comparative study showed that yields with zeolite HY were lower than silica gel

because acidic sites on the surface of zeolite HY were weaker than that of silica gel

and hence excess zeolite HY was found to be necessary. One of the most interesting

applications of MW in the synthesis of highly substituted imidazole was reported by

S. E. Wolkenberg and co-workers. They used this method for the preparation of

imidazolium alkaloid lepidiline B6 and the platelet aggregation inhibitor trifenagrel

along with the synthesis of other related 2,4,5-trisubstituted imidazole.46 These

reactions are summerized in Scheme 5.5 and 5.6.

137

Scheme 5.5

Me O

OMe H Me

O

N

HN

Me

Me

Me

N

NMe

Me

Me

Ph

PhCl

NH4OAc, HOAc

180°C, MW, 5min

BnCl,CH3CN

MW, 5min+

Lepidiline B

Scheme 5.6

NH4OAc, HOAc

180°C, MW, 5min

Ph

Ph

O

O

OHC

O NMe2

N

HN

Ph

PhO NMe2

+

Trifenagrel

Different solid supports such as acidic, basic, neutral alumina, bentonite,

montmorillonite K10, montmorillonite KSF, silica gel and florisil was tested by A.

Ya et al. for the MW assisted synthesis of highly substituted imidazoles and found

acidic alumina to be most efficient in comparison to the others.47

5.1.3. Synthesis using ionic liquids and heteropoly acids as catalyst

Recently the concept of ILs received a great deal of attention in view of the

fact that almost all the ILs are environmental favourable compound and most of the

ILs are effective in all respects. The application of IL also examined in the synthesis

of highly substituted imidazoles. S. A. Siddiqui et al. applied imidazolium based ILs

138

in the synthesis of trisubstituted imidazoles.48 The other ILs which are used in the

synthesis of tetrasubstituted imidazoles are N-methyl-2-pyrrolidinium hydrogen

sulphate,49 1-Butyl-3-methylimidazolium bromide50 and a Bronsted acidic IL.51 In

addition to the ILs, the HPAs have also emerged as versatile catalysts for performing

a variety of organic synthesis starting from condensation reactions to oxidation and

reduction reactions. The application of the HPAs as a catalyst for the synthesis of

heterocyclic compounds is particularly important. The use of HPAs in organic

synthesis have been reviewed by Kozhevnikov.52 In particular the tetrasubstituted

imidazoles have been synthesized in a one pot procedure by Heravi et al.53 using the

Preyssler type HPA ( H14[NaP5W30O110]).

5.2. Materials and methods

From the review mentioned above it can be concluded that although a

variety of catalysts have been used for the synthesis of tetrasubstituted imidazoles,

giving good to excellent yields of the desired products, the nature of the catalysts

used and the experimental procedures involved are neither cost effective nor benign

to the environment. Additional drawbacks associated with these procedures are the

laborious and complex work-up and purification procedures involved, which results

in generation of a significant amounts of waste materials. Low selectivity,

occurrence of side reactions, and the necessity of strong acidic conditions leaves a

lot to be desired. Moreover high temperature and long reaction time make the

procedures unacceptable from the point of view of energy economy which is an

important tenet of green chemistry. The use of volatile organic solvents in some of

the synthetic methods makes the procedures cumbersome and hazardous.

It may be mentioned that the ILs are a group of non volatile solvents that can

be used as an alternative to the usual volatile organic compounds (solvents) in order

to reduce hazards due to exposure. The aim of this work is to examine whether the

simple acidic ILs could be used as catalyst for the synthesis of important

heterocycles such as the tetra substituted imidazoles. With this aim in view the

139

classical and cheap IL namely di-n-propylammonium hydrogensulphate was

prepared from easily available starting material and used for the synthesis of the

target molecule. Experiments have also been carried out to synthesize the target

tetrasubstituted imidazole using a particular HPA namely the defective Keggin type

HPA, H6PAlMo11O40 which was prepared by a novel green procedure from easily

available starting materials. The time required for the preparation of this HPA under

conventional heating (80°C) is 6 hours whereas, under MW irradiation it takes only

10 minutes. A comparison of the efficiency of the IL and the HPA on the synthesis

was examined. The synthesis using both the IL as well as the HPA as the catalyst

was promoted by MW.

Di-n-propylammonium hydrogensulphate, a quaternary ammonium IL was

prepared by simple addition of conc. sulphuric acid in di-n-propylamine. The detail

of preparation procedure is described in Chapter 2. Using this IL as catalyst the

target tetrasubstituted imidazoles were prepared from 1,2-diketone, aldehydes, alkyl

or arylamines and ammonium acetate or urea under the influence of MW. A major

improvement over other established procedures was the observation that urea could

be used as an alternative to ammonium acetate as a source of ammonia. In earlier

reports on the synthesis of 1,2,4.5-tetrasubstituted imidazoles, the use of urea as a

nitrogen source have not be explored. This study conclusively indicates that urea can

indeed be used as an alternative nitrogen source thus reducing the overall cost of the

conversion. In a typical procedure, a mixture of the 1,2 diketone, the aldehyde, the

alkyl/aryl amine, urea/ammonium acetate and the di-n-propylammonium hydrogen

sulphate IL was exposed to MW irradiation for short time to arrive at the target

1,2,4,5-tetrasubstituted imidazoles in almost pure form. Side products have been

found to be absent. The reaction is completed within 2-5 minutes and the recovered

yields are good to high. Isolation of the pure products involved only recrystallization

of the recovered crude in ethanol. The usual tedious work up procedure and other

chromatographic purification procedures were found unnecessary. It has also been

observed that the IL could be recovered and reused for further reaction without

appreciable depletion in activity. When the reaction mixture was extracted with

DCM the IL remained in the reaction vessel being insoluble in DCM. The same IL

140

could be reused for another run of the reaction with comparable efficiency. Another

important feature of the use of the di-n-propylammonium hydrogensulphate is the

observation that both the aromatic amines as well as the aliphatic amines gave good

yields of the product. The synthesis was studied using NaHSO4 instead of the di-n-

propylammonium hydrogensulphate. It was observed that NaHSO4 did catalyzed the

reaction but the observed yield was not more than 40%. The reaction was also

studied in the presence of a phase transfer catalyst, tetrapropylammonium bromide,

instead of the IL used it was observed that the reaction did not proceed at all. The

details of the study carried out are given in the experimental section of this chapter.

In an additional study, the defective Keggin type HPA was prepared and used for the

synthesis of the tetra substituted imidazole. A comparison of the reaction time and

the yield obtained, with both the IL as well as the HPA under consideration were

examined and the results indicate that both the di-n-propylammonium

hydrogensulphate and the defective Keggin type HPA are efficient catalysts for this

conversion.

Single crystal X-ray analysis of one of the new product namely 1-ethyl-2-(2',

6'-dichlorophenyl)-4, 5-di(4'-methylphenyl)-imidazole (1p) confirms the structure

(Figure 5.3). Crystals were obtained from ethanol in which case the results indicate

the presence of residual solvent in the crystal. Attempt to remove the solvent

destroyed crystallinity of the product and no worthwhile data could be obtained. All

products obtained were characterized by spectroscopic method such as IR, 1H-NMR, 13C NMR, Mass spectrometry and by comparing their melting points with those

reported in literature. 1H and 13C NMR spectra of two compounds are shown in

Figure 5.(4-7). The experimental results are summerized in Table 5.1 and the

reaction carried out is shown in Scheme 5.7. The crystallographic parameters are

summarized in Table 5.2.

141

Scheme 5.7

R O

R O

+ ++

Ar H

O

R1NH2 NH4OAc or NH2CONH2ILor HPAMW

N

N

R

R Ar

R1

(Yield= IL/83-92%, HPA/85-93%) 1(a-s)

R= Phenyl, p-tolyl

R1= C6H5-, C6H5CH2-, 4-NO2C6H4-, C2H5-, CH3-

IL= [n-Pr2NH2][HSO4]

Table 5.1: Solvent free MW induced one pot synthesis of 1, 2, 4, 5-tetrasubstituted

imidazole promoted by [n-Pr2NH2][HSO4] and defective keggin HPA using

ammonium acetate as nitrogen source.

Product R Ar R1 Reaction with

IL

Reaction with

HPA

Time

(min)

Yield

(%)a

Time

(min)

Yield

(%)a

1a Ph C6H5 C6H5CH2 2 85 10 89

1b Ph 4-CH3C6H4 C6H5CH2 2 87 10 92

1c Ph 2-CH3OC6H4 C6H5CH2 2 87 10 93

1d Ph 3,4-(OCH3)2C6H3 C6H5CH2 2 87 10 93

1e Ph 4-ClC6H4 C6H5CH2 2 85 13 90

1fb Ph 4-EtC6H4 C6H5CH2 2 87 10 92

1g Ph 3-BrC6H4 C6H5CH2 2 85 10 89

1h Ph 4-NO2C6H4 C6H5CH2 2 85 10 88

1ib Ph 2,5-(CH3)2C6H4 C6H5 2 84 10 90

1j Ph C6H5 C6H5 2 83 10 87

142

1kb Ph 4-ClC6H4 CH3 3 87 10 89

1lb Ph 4-EtC6H4 CH3 3 86 10 89

1mb Ph 2-CH3OC6H4 CH3CH2 3 90 10 92

1n Ph 4-ClC6H4 CH3CH2 3 90 10 92

1ob Ph 3,4-(OCH3)2C6H3 CH3CH2 3 90 10 92

1pb 4-CH3Ph 2,6-Cl2C6H3 CH3CH2 3 92 10 92

1qb Ph 4-ClC6H4 4-NO2C6H4 3 85 13 87

1rb Ph 3,4-(OCH3)2C6H3 4-NO2C6H4 3 85 13 88

1s Ph C6H5 4-NO2C6H4 3 83 13 85

a. Yields refers to the pure isolated products; b. New compound.

Table 5.2: Solvent free MW assisted one pot synthesis of 1, 2, 4, 5-tetrasubstituted

imidazole promoted by [n-Pr2NH2][HSO4] and HPA using urea as nitrogen source

Entry Product Reaction with IL Reaction with HPA

Time(min) Yield(%)a Time(min) Yield(%)

a

1 1a 2 86 10 89

2 1c 2 87 10 95

3 1d 2 86 10 95

4 1fb 2 87 10 90

5 1ib 2 85 10 90

6 1kb 3 90 10 90

7 1mb 3 90 10 90

8 1pb 3 92 10 93

9 1rb 3 85 13 86

a.Yields refers to the pure isolated products; b. New compound.

143

Table 5.3: Effect of catalyst on the solvent free one pot four component synthesis of

tetra substituted imidazole 1c with the usual reactants and urea

Entry Catalystb Time(min) Yield(%)

a

1 HPA 10 95

2 [n-Pr2NH2][HSO4] 2 87

3 NaHSO4 10 40

4 n-Pr4NBr 10 -

5 Catalyst free 10 -

a.Yields refers to the pure isolated product; b. 10 mol% amount of catalysts were

used.

Figure 5.3: ORTEP diagram of 1p

144

Table 5.4

Crystallographic parameter of compound 1p

empirical formula C25H22Cl2N2. C2H5OH

formula weight 467.43

crystal system Monoclinic

space group P 2(1)/n

T(K) 298

a/Å 11.7711(9)

b/Å 15.5380(12)

c/Å 13.9410(12)

α/deg 90.00

β/deg 95.289(5)

γ/deg 90.00

V / Å3 2538.9(4)

Dcalcd (g cm-3) 1.223

µ (mm-1) 0.271

Z 4

reflns collected 25872

unique reflns 7416

Observed reflns 3022

R1[I˃ 2σ(I)] 0.0837

wR2(all) 0.1546

goodness-of-fit 1.287

Diffractometer SMART Bruker Apex-II

145

Figure 5.4

9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)

1.011.000.731.064.610.77

7.6

4

7.5

9

7.5

7

7.3

4

7.3

2

7.2

7

7.2

3

7.2

2

7.1

9

7.1

3

6.9

1

6.8

9

5.1

0

3.8

9

3.6

9

1H NMR Spectrum of 1-Benzyl-2-(3', 4'-dimethoxyphenyl)-4,5-diphenylimidazole

Figure 5.5

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10Chemical Shift (ppm)

14

9.6

3

14

8.8

0

13

7.9

9

13

4.5

2

13

1.1

0

12

8.8

9

12

8.7

5

12

8.1

6

12

7.4

2

12

6.9

0

12

6.4

2

12

5.9

6

12

1.6

5

11

2.2

4

11

0.9

9

77

.53

77

.10

76

.68

55

.96

55

.69

48

.28

13C NMR NMR Spectrum of 1-Benzyl-2-(3', 4'-dimethoxyphenyl)-4, 5-

diphenylimidazole

N

N

O

O

N

N

O

O

146

Figure 5.6

10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)

0.990.701.000.321.360.273.05

7.5

7

7.5

4

7.5

2

7.4

7

7.2

7

7.2

1

7.1

8

7.1

6

7.1

1

7.0

9

3.8

5

3.8

0

3.7

8

3.7

5

3.7

3

0.9

3

0.9

0

0.8

8

1H NMR Spectrum of 1-Ethyl-2-(2'-methoxyphenyl)-4, 5-diphenylimidazole

Figure 5.7

200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)

157.5

3

144.6

9

134.7

6

132.6

6

131.7

7

130.9

2

130.8

1

128.9

3

128.4

0

127.8

8

126.7

1

125.9

1

120.8

8

110.8

5

77.4

1

76.9

9

76.5

7

55.4

7

39.4

7

15.8

5

13C NMR NMR Spectrum of 1-Ethyl-2-(2'-methoxyphenyl)-4, 5-diphenylimidazole

N

N

O

N

N

O

147

5.3. Conclusion

In conclusion, a one pot solvent free multicomponent reaction (MCR)

promoted by the synergic use of MW and simple IL on one hand and MW and the

HPA on the other, for the synthesis of the tetrasubstituted imidazole have been

carried out under simplified reaction conditions. The reaction conditions are simple

and product recovery easy. The study also indicated that the both the catalysts used

herein is much more efficient than those used earlier. The added advantage of both

the procedures is the reusability of the catalysts for further use.

5.4. Experimental section

Melting points were recorded in a VMP-D model Melting point apparatus

and are uncorrected. 1H-NMR and 13C-NMR spectra were recorded in a Bruker

Advance digital 300 MHz spectrometer in CDCl3. In both the recordings TMS was

used as the internal standard. IR spectra was recorded in a Perkin Elmer 1600 FT IR

spectrometer using KBr pallets. Mass spectra were recorded in a Waters Micromass

ZQ TM 400 mass spectrometer. Microwave irradiation was done in a MW reactor

procured from CatalystTM System. All reagents were purified by standard literature

procedure.

5.4.1. Preparation of di-n-propylammonium hydrogensulphate

The preparation and characterization is given in Chapter 2.

5.4.2. Preparation of defective Keggin heteropoly acid

H6PAlMo11O40

A stoichiometric mixture of H3PO4 85% (0.58 g., 0.01 mol), Al2O3.6H2O

(1.21 g., 0.005 mol) and MoO3 (14.4 g.,11 mol) was suspended in 150 mL of

distilled water in RBF and irradiated with MW for 10 minutes (560W). On cooling

148

the mixture to room temperature the unreacted MoO3 precipitated and recovered by

filtration. Reduced pressure removal of water and drying at 85°C for 24 hours gave

dark green crystals of composition H6PAlMo11O40 identical to that obtained earlier.52

The metal composition was established by powder X-ray diffraction studies. IR cm-1

1074, 98.2, 875, 765, 362 and 345.

5.4.3. General procedure for the synthesis of tetrasubstituted

imidazole with di-n-propylammonium hydrogen sulphate

A mixture of 1, 2 diketone (1 mmol), aldehydes (1 mmol), primary amines

(1 mmol), ammonium acetate (or urea) (1.5 mmol) and di-n-propylammonium

hydrogensulphate (10 mol %) was irradiated with MW (560 W) with stirring for 1-3

minute as mentioned in Table 4.1 and Table 4.2. On completion of the reaction

monitored by TLC using 20% ethyl acetate in petroleum ether (60-80°C), the

reaction mixture was extracted with DCM (5 mL x 3), washed with water, dried with

anhydrous Na2SO4 and solvent removed under reduced pressure. The crude

products were purified by recrystallization from ethanol.

5.4.4. General procedure for the synthesis of tetrasubstituted

imidazole using defective Keggin heteropoly acid H6PAlMo11O40

A mixture of 1,2-diketone (1 mmol), aldehydes (1 mmol), primary amines

(1 mmol), ammonium acetate (or urea) (1.5 mmol) and HPA (5 mol%) was

irradiated with MW (560 W) with stirring for 10-13 min. as mentioned in Table 5.1

and Table 5.2 On completion of the reaction determined by TLC, the reaction

mixture was extracted with DCM (5 mL x 3), washed with water, dried with

anhydrous Na2SO4. The combined extract was evaporated under reduced pressure to

obtain the crude product which was purified by recrystallization from ethanol. The

results are summarized in the Table 5.1 and Table 5.2.

149

5.4.5. Synthesis of compounds 1(k-p)

The synthesis was carried out as per the general procedure with 0.5 mL of

aliphatic amines (methyl amine and ethyl amine).

150

5.4.6. Spectral data of reported compounds

1-Benzyl-2,4,5-triphenylimidazole(1a)

Mp: 159-161°C (EtOH).

IR (KBr): ν 2890 (CH), 1590 (CN), 1480 cm-1.

1H NMR (300MHz, CDCl3): δH ppm 7.58-6.82 (m, 20H, Ar),

5.12 (s, 2H, CH2).

13C NMR (75MHz, CDCl3): δ ppm 148.08, 138.07, 137.56, 134.46, 131.08, 131.02,

130.94, 130.05, 129.08, 128.92, 128.81, 128.61, 128.59, 128.09, 127.36, 126.78,

126.37, 126.02, 48.28.

1-Benzyl-2-(4'-methylphenyl)-4,5-diphenylimidazole (1b)

Mp: 164-166 °C (EtOH).

IR (KBr): ν 2885 (CH), 1580 (CN), 1482 cm-1.


5.11 (s, 2H, CH2), 2.38 (s, 3H, CH3).


128.94, 128.75, 128.55, 128.06, 126.78, 125.99, 48.24, 21.36.

1-Benzyl-2-(2'-methoxyphenyl)-4,5-diphenylimidazole (1c)

Mp: 188-190°C (EtOH).

IR(KBr): ν 2823 (CH), 1593 (CN), 1460 (CC), 1250 cm-1

1H NMR (300 MHz, CDCl3): δH ppm 7.59- 6.82 (m, 19H,

N

N

N

N

N

N

O

151

Ar), 5.09 (s, 2H, CH2), 3.83 (s, 3H, OCH3).

13C NMR (75 MHz, CDCl3): δ ppm 160.04, 147.94, 137.61, 131.02, 130.37, 128.72,

128.53, 128.02, 127.27, 126.72, 126.25, 125.92, 123.29, 113.95, 55.27, 48.16.

HRMS (ESI): m/z= 416.1889 ([M]+).

1-Benzyl-2-(3',4'-dimethoxyphenyl)-4,5-diphenylimidazole (1d)

Mp: 163-165 °C (EtOH).

IR(KBr): ν 2835 (CH), 1600 (CN) cm-1.

1H NMR (300 MHz, CDCl3): δH ppm 7.64-6.89 (m, 18H,

Ar), 5.10 (s, 2H, CH2), 3.89 (s, 3H, OCH3), 3.69 (s, 3H,

OCH3).

13C NMR (75 MHz, CDCl3): δ ppm 149.63, 148.80, 137.99, 134.52, 131.10, 128.89,

128.75, 128.16, 127.42, 126.90, 126.42, 125.96, 121.65, 112.24, 110.99, 55.96,

55.69, 48.28.

1-Benzyl-2-(4'-chlorophenyl)-4,5-diphenylimidazole (1e)

Mp: 163-165 °C (EtOH).

IR (KBr): ν 2832 (CH), 1598 (CN) cm-1.


Ar), 5.09 (s, 2H, CH2).


129.11, 128.92, 128.79, 128.20, 126.85, 125.92, 48.34.

N

N

O

O

N

N

Cl

152

1-Benzyl-2-(4'-ethylphenyl)-4,5-diphenylimidazole (1f)

Mp: 138-140 °C (EtOH).

IR (KBr): ν 2958 (CH), 1597 (CN), 1492 (CC), 1446, 1388 cm-1

1H NMR (300 MHz, CDCl3): δH ppm 7.59-6.83 (m, 19H, Ar),

5.11 (s, 2H, CH2), 2.67 (q, 2H, J = 6 Hz, CH2), 1.24 (t, 3H, J =

6 Hz, CH3).


128.70, 128.51, 128.08, 128.02, 126.73, 126.26, 125.98, 48.22, 28.66, 15.41.

HRMS (ESI): m/z = 414.2098 ([M]+).

1-Benzyl-2-(3'-bromophenyl)-4,5-diphenylimidazole (1g)

Mp: 148-150 °C (EtOH).

IR (KBr): ν 2949 (CH), 1601(CN) cm-1.


Ar), 5.11 (s, 2H, CH2).


128.77, 128.69, 128.57, 128.11, 127.51, 127.22, 126.75, 126.51, 125.98, 125.90,

48.31.

1-Benzyl-2-(4'-nitrophenyl)-4,5-diphenylimidazole (1h)

Mp: 170-172 °C (EtOH).

IR (KBr): ν 2963 (CH), 1608 (CN) cm-1.


4.88 (s, 2H, CH2).

N

N

N

N

Br

N

N

NO2

153

13C NMR (CDCl3): δ ppm 148.92, 143.00, 136.57, 133.23, 131.10, 128.93, 128.79,

128.38, 128.05, 126.64, 126.48, 126.41, 124.65, 48.27.

2-(2', 5'-Dimethylphenyl)-1,4,5-triphenylimidazole (1i)

Mp: 173-175 °C (EtOH).

IR (KBr): ν 2942 (CH), 1598 (CN), 1492 (CC) cm-1.


ArH), 2.23 (s, 3H, CH3), 2.10 (s, 3H, CH3).


131.79, 130.94, 130.78, 130.40, 129.83, 129.73, 129.07, 128.46, 128.37, 128.05,

127.78, 127.71, 127.49, 127.41, 126.44, 20.73, 19.67.

HRMS (ESI): m/z = 400.1939 ([M]+).

1-methyl-2-(4'-chlororphenyl)-4,5-diphenylimidazole (1k)

Mp: 192-194 °C (EtOH).

IR(KBr): ν 2925 (CH), 1604 (CN), 1483 (CC), 735 (CCl) cm-1


ArH), 3.50 (s, 3H, NCH3).


130.84, 130.32, 129.38, 129.15, 129.05, 128.92, 128.77, 128.20, 127.01, 126.54,

33.29.

HRMS (ESI): m/z=344.1082 ([M]+).

N

N

N

NCl

154

1-methyl-2-(4'-ethylphenyl)-4, 5-diphenylimidazole (1l)

Mp: 127-130 °C (EtOH).

IR (KBr): ν 2920 (CH), 1597 (CN), 1480 (CC) cm-1.


ArH), 3.51 (s, 3H, NCH3), 2.73 (q, 2H, J = 6 Hz, CH2), 1.29

(t, 3H, J = 6 Hz, CH3).


127.97, 126.87, 33.06, 28.65, 15.40.

HRMS (ESI): m/z = 338.1786 ([M]+).

1-Ethyl-2-(2'-methoxyphenyl)-4,5-diphenylimidazole (1m)

Mp: 123-125°C (EtOH).

IR(KBr): ν 2924 (CH), 1600 (CN), 1462 (CC), 1260 (CO) cm-1

1H NMR (300 MHz, CDCl3): δH ppm 7.57-7.09 (14H, m,

ArH), 3.85 (3H, s, OCH3), 3.77 (2H, q, J = 6 Hz, CH2), 0.90

(3H, t, J = 6 Hz, CH3).


130.92, 130.81, 128.93, 128.68, 128.40, 127.88, 126.72, 125.91, 120.88, 120.66,

110.85, 55.47, 39.47, 15.85.

HRMS (ESI): m/z = 354.1736 ([M]+).

N

N

N

N

O

155

1-Ethyl-2(4'-chlorophenyl)-4,5-diphenylimidazole (1n)

Mp: 311-313 °C (EtOH).

IR (KBr): ν 2930 (CH), 1596 (CN) cm-1.

1H NMR (300MHz, CDCl3): δH ppm 7.68-7.16 (14H, m,

ArH), 3.94 (2H, q, J = 6 Hz, CH2), 1.03 (3H, t, J = 6 Hz,

CH3).


131.26, 130.98, 130.34, 129.89, 129.82, 129.66, 129.08, 129.01, 128.87, 128.76,

128.05, 126.70, 126.30, 39.65, 16.22.

1-Ethyl-2-(3',4'-dimethoxyphenyl)-4,5-diphenylimidazole (1o)

Mp: 173-175 °C (EtOH).

IR(KBr): ν 2928 (CH), 1608 (CN), 1482(CC), 1258 (CO) cm-1

1H NMR (300MHz, CDCl3): δH ppm 7.54-6.98 (13H, m, ArH),

3.96-3.90 (8H, m, 2OCH3 and CH2), 1.02 (3H, t, J = 6 Hz,

CH3).


129.21, 129.08, 128.66, 128.04, 126.77, 126.18, 124.11, 121.51, 112.72, 110.98,

56.04, 55.99, 39.65, 16.28.

HRMS (ESI): m/z = 384.1839 ([M]+).

N

NCl

N

N

O

O

156

1-Ethyl-2-(2', 6'-dichlorophenyl)-4, 5-di(4'-methylphenyl)imidazole (1p)

Mp: 135-137 °C (EtOH).

IR (KBr): ν 2924 (CH), 1605 (CN), 1450(CC), 738 (CCl) cm-1

1H NMR (300MHz, CDCl3): δH ppm 7.46-7.00 (11H, m,

ArH), 3.66 (2H, q, J = 6 Hz, NCH2), 2.45 (3H, s, CH3), 2.28

(3H, s, CH3), 1.00 (3H, t, J = 6 Hz, CH3).


130.86, 129.72, 128.65, 128.22, 128.08, 126.54, 39.32, 21.40, 21.10, 15.88.

HRMS (ESI): m/z = 420.1160 ([M]+).

1-(4'-nitrophenyl)-2-(4'-chlorophenyl)-4,5-diphenylimidazole (1q)

Mp: 122-124 °C (EtOH).

IR (KBr): ν 2928 (CH), 1590 (CN), 1489 (CC), 1351 (C-NO2),

739 (CCl) cm-1.

1H NMR (300MHz, CDCl3): δH ppm 8.05-7.03 (18H, m, ArH).


128.60, 127.77, 127.54, 126.47, 126.33, 113.31.

HRMS (ESI): m/z = 451.1089 ([M]+).

N

N

Cl

Cl

N

NCl

NO2

157

1-(4'-Nitrophenyl)-2-(3',4'-dimethoxyphenyl)-4,5-diphenylimidazole (1r)

Mp: 125-126 °C (EtOH).

IR (KBr): ν 2939 (CH), 1597 (CN), 1489 (CC), 1346 (C-

NO2), 1246 (CO) cm-1.


ArH), 7.59-7.56 (m, 2H, ArH), 7.30-7.12 (m, 12H, ArH),

6.70 (s, 1H, ArH), 3.86 (s, 3H, OCH3), 3.78 (s, 3H, OCH3).


128.56, 128.24, 127.40, 126.99, 124.36, 121.91, 112.28, 110.63, 55.83.

HRMS (ESI): m/z = 477.1689 ([M]+).

N

N

O2N

O

O

158

References

1. a) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza, A. M.; Carboni, J.;

Fairchild, C. R. J. Am. Chem. Soc. 1997, 119, 8744. b) D’Ambrosio, M.; Guerriero,

A.; Pietra, F. HelV. Chim. Acta 1987, 70, 2019. c) D’Ambrosio, M.; Guerriero, A.;

Pietra, R. HelV. Chim. Acta 1988, 71, 964.

2. Jin, Z.; Li, Z.; Huang, R. Nat. Prod. Rep. 2002, 19, 454.

3. a) Lombardino, J. G.; Wiseman, E. H. J. Med. Chem. 1974, 17, 1182. b)

Gallagher, F.; Fier-Thompson, S. M.; Garigipati, R. S.; Sorenson, M. E.; Smietana,

J. M.; Lee, D.; Bender, P. E.; Lee, J. C.; Laydon, J. T.; Griswold, D. E.; Chabot-

Fletcher, M. C.; Breton, J. J.; Adams, J. L. Bioorg. Med. Chem. Lett. 1995, 5, 1171.

4. Misono, M. Chem. Commun. 2001, 13, 1141.

5. Ucucu, U.; Karaburun, N. G.; Isikdag, I. Farmaco 2001, 56, 285.

6. Maier, T.; Schmierer, R.; Bauer, K.; Bieringer, H.; Buerstell, H.; Sachse, B. U.S.

Patent 4820335, 1989; Chem. Abstr. 1989, 111, 19494w.

7. Maier T, Schmierer R, Bauer K, Bieringer H, Buerstell H, Sachse B (1989) US

Patent, 4 820 335.

8. a) Liberatore, A.; Schulz, J.; Pommier, J.; Barthelemy, M.; Huchet, M.; Chabrier,

P.; Bigg, D. Bioorg. Med. Chem. Lett. 2004, 14, 3521. b) Cheung, D. W.; Daniel, E.

E. Nature 1980, 283, 485.

9. Schmierer R, Mildenberger H, Buerstell H (1987) German Patent 361:464

10. Chang, L. L.; Sidler, K. L.; Cascieri, M. A.; de Laszlo, S.; Koch, G.; Li, B.;

MacCoss, M.; Mantlo, N.; O’Keefe, S.; Pang, M.; Rolando, A.; Hagmann, W. K.

Bioorg. Med. Chem. Lett. 2001, 11, 2549.

11. Eyers, P. A.; Craxton, M.; Morrice, N.; Cohen, P.; Goedert, M. Chem. Biol.

1998, 5, 321.

159

12. Cui, B.; Zheng, B. L.; He, K.; Zheng, Q. Y. J. Nat. Prod. 2003, 66, 1101.

13. Norwood, D.; Branch, E.; Smith, B.; Honeywell, M. Drug Forecast 2002, 27,

611.

14. Lindberg, P.; Nordberg, P.; Alminger, T.; Brandstorm, A.; Wallmark, B. J. Med.

Chem. 1986, 29, 1327.

15. a) Koike, H.; Konse, T.; Sada, T.; Ikeda, T.; Hyogo, A.; Hinman, D.; Saito, H.;

Yanagisawa, H. Ann. Rep. Sankyo Res. Lab. 2004, 55, 1. b) Abrahams, S. L.; Hazen,

R. J.; Batson, A. G.; Phillips, A. P. J. Pharmacol. Exp. Ther.1989, 249, 359. c)

Leister, C.; Wang, Y.; Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6, 1453.

16. a) Zhu, H.-J.; Wang, J.-S.; Patrick, K. S.; Donovan, J. L.; DeVane, C. L.;

Markowitz, J. S. J.; Chromatogr, B. Anal. Technol. Biomed. Life Sci. 2007, 858, 91.

b) Kuroda, N.; Shimoda, R.; Wada, M.; Nakashima, K. Anal. Chim. Acta. 2000, 403,

131. c) Nakashima, K.; Yamasaki, H.; Kuroda, N.; Akiyama, S. Anal. Chim. Acta

1995, 303, 103.

17. Sun, Y.-F.; Huang, W.; Lu, C.-G.; Cui, Y.-P. Dyes Pigm. 2009, 81, 10.

18. Staehelin, M.; Burland, D. M.; Ebert, M.; Miller, R. D.; Smith, B. A.; Twieg, R.

J.; Volksen, W.; Walsh, C. A. Appl. Phys. Lett. 1992, 61, 1626.

19. a) Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. F.; Kumar, S.;

Green, D.; McNulty, D.; Blumenthal, M.; Heys, J. R.; Landvatter, S. W.; Strickler,

J. E.; McLaughlin, M. M.; Siemens, I. R.; Fisher, S. M.; Livi, J. P.; White, J. R.;

Adams, J. L.; Young, P. R. Nature 1994, 372, 739. b) Liverton, N. J.; Butcher, J.

W.; Claiborne, C. F.; Claremon, D. A.; Libby, B. E.; Nguyen, K. T.; Pitzenberger, S.

M.; Selnick, H. G.; Smith, G. R.; Tebben, A.; Vacca, J. P.; Varga, S. L.; Agrawal,

L.; Dancheck, K.; Forsyth, A. J.; Fletcher, D. S.; Frantz, B.; Hanlon, W. A.; Harper,

C. F.; Hofsess, S. J.; Kostura, M.; Lin, J.; Luell, S.; O’Neill, E. A.; Orevillo, C. J.;

Pang, M.; Parsons, J.; Rolando, A.; Sahly, Y.; Visco, D. M.; O’Keefe, S. J. J. Med.

Chem. 1999, 42, 2180.

160

20. Takle, A. K.; Brown, M. J. B.; Davies, S.; Dean, D. K.; Francis, G.; Gaiba, A.;

Hird, A. W.; King, F. D.; Lovell, P. J.; Naylor, A.; Reith, A. D.; Steadman, J. G.;

Wilson, D. M. Bioorg. Med. Chem. Lett. 2006, 16, 378.

21. Khanna, I. K.; Weier, R. M.; Yu, Y.; Xu, X. D.; Koszyk, F. J.; Collins, P. W.;

Koboldt, C. M.; Veenhuizen, A. W.; Perkins, W. E.; Casler, J. J.; Masferrer, J. L.;

Zhang, Y. Y.; Gregory, S. A.; Seibert, K.; Isakson, P. C. J. Med. Chem. 1997, 40,

1634.

22. Lange, J. H. M.; Van Stuivenberg, H. H.; Coolen, H. K. A. C.; Adolfs, T. J. P.;

McCreary, A. C.; Keizer, H. G.;Wals, H. C.; Veerman, W.; Borst, A. J. M.; de Loof,

W.; Verveer, P. C.; Kruse, C. G. J. Med. Chem. 2005, 48, 1823.

23. Gallagher, T. F.; Fier-Thompson, S. M.; Garigipati, R. S.; Sorenson, M. E.;

Smietana, J. M.; Lee, D.; Bender, P. E.; Lee, J. C.; Laydon, J. T.; Griswold, D. E.;

Chabot-Fletcher, M. C.; Breton, J. J.; Adams, J. L. Bioorg. Med. Chem. Lett. 1995,

5, 1171.

24. Yamamoto, T.; Uremura, T.; Tanimoto, A.; Sasaki, S. Macromolecules 2003, 36,

1047 and references therein.

25. Cotton, F. A.; Wilkinson, G.; Murillo, C. A.; Bochmann, M. “Advanced

Inorganic Chemistry”, Wiley: New York, 1999.

26. Holm, R. H.; Kennepohl, P.; Solomon, E. I. Chem. Rev. 1996, 96, 2239.

27. Herrmann, W. A. Angew. Chem. Int. Ed. 2002, 41, 1290.

28. Liebigs Debus, H. Ann. Chem. 1858, 107, 199.

29. Hlasta, D. J. Org. Lett. 2001, 3, 157.

30. Davidson, D.; Weiss, M.; Jelling, M. J. Org. Chem., 1937, 2, 319.

31. Consonni, R.; Dalla Croce, P.; Ferraccioli, R.; La Rosa, C. J. Chem. Res., Synop

1991, 7, 188.

161

32. a) Evans, D. A.; Lundy, K. M. J. Am. Chem. Soc. 1992, 114, 1495. b)

Schneiders, P.; Heinze, J.; Baumgartel, H. Chem. Ber. 1973, 106, 2415.

33. Claiborne, C. F.; Liverton, N. J.; Nguyen, K. T. Tetrahedron Lett. 1998, 39,

8939.

34. Hu, B.; Wang, Z.; Ai, N.; Zheng, J.; Liu, X.-H.; Shan, S.; Wang, Z. Org. Lett.

2011, 13, 6362.

35. a) Marsden, S. P.; McGonagle, A. E.; McKeever-Abbas, B. Org Lett. 2008, 10,

2589. b) Lertpibulpanya, D.; Marsden, S. P.; Rodriguez-Garcia, I.; Kilner, C. A.

Angew. Chem., Int. Ed. 2006, 45, 5000. c) Palacios, F.; Alonso, C.; Aparicio, D.;

Rubiales, G.; Santos, J. M. Tetrahedron 2007, 63, 523. d) Alajarin, M.; Bonillo, B.;

Ortin, M.-M.; Sanchez-Andrada, P.; Vidal, A.; Orenes, R.-A. Org. Biomol. Chem.

2010, 8, 4690. e) Devarie-Baez, N. O.; Xian, M. Org. Lett. 2010, 12, 752.

36. Nie, Y.-B.; Wang, L.; Ding, M.-W.; J. Org. Chem. 2012, 77, 696.

37. Narayana Murthy, S.; Madhav, B.; Nageswar, Y. V. D. Tetrahedron Lett. 2010,

51, 5252.

38. Niknam, K.; Deris, A.; Naeimi, F.; Majleci, F. Tetrahedron Lett. 2011, 52, 4642.

39. Sadeghi, B.; Mirjalili, B. B. F.; Hashemi, M. M. Tetrahedron Lett. 2008, 49,

2575.

40. Kantevari, S.; Vuppalapati, S. V. N.; Biradar, D. O.; Nagarapu, L. J. Mol. Catal.

A: Chem. 2007, 266, 109.

41. Sharma, S. D.; Hazarika, P.; Konwar, D. Tetrahedron Lett. 2008, 49, 2216.

42. Samai, S.; Nandi, G. C.; Singh, P.; Singh, M. S. Tetrahedron 2009, 65, 10155.

43. Kidwai, M.; Mothsra, P. Tetrahedron Lett. 2006, 47, 5029.

44. Kumar, D.; Kommi, D. N.; Bollineni, N.; Patel, A. R.; Chakraborti, A. K. Green

Chem. 2012, 14, 2038.

162

45. Balalaie, S.; Arabanian, A. Green Chem. 2000, 2, 274.

46. Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. H.; Wang, Y.; Zhao, Z.;

Lindsley, C. W. Org. Lett. 2004, 6, 1453.

47. Usyatinsky, A. Y.; Khmelnitsky, Y. L. Tetrahedron Lett. 2000, 41, 5031.

48. Siddiqui, S. A.; Narkhede, U. C.; Palimkar, S. S.; Daniel, T.; Lahoti, R. J.;

Srinivasan, K. V. Tetrahedron 2005, 61, 3539.

49. Shaterian, H. R.; Ranjbar, M. J. Mol. Liq. 2011, 160, 40.

50. Hasaninejad, A.; Zare, A.; Shekouhy, M.; Ameri Rad, J. J. Comb. Chem. 2010,

12, 844.

51. Davoodnia, A.; Heravi, M. M.; Safavi-Rad, Z.; Tavakoli-Hoseini, N. Synth.

Commun. 2010, 40, 2588.

52. Kozhevnikov, I. V. Chem.Rev. 1998, 98, 171.

53. Javid, A.; Heravi, M. M.; Bamoharram, F. F.; Nikpour, M. E-J. Chem. 2011, 8,

547.

Documents

Synthesis of 1,2,4,5-tetra substituted imidazole using ...shodhganga.inflibnet.ac.in/bitstream/10603/28272/10/10_chapter 5.pdf · silica gel as the catalyst for the synthesis under