ORIGINAL PAPER

Direct synthesis of 2,4,5-trisubstituted imidazoles from alcoholsand a-hydroxyketones by microwave

Arsalan Mirjafari

Received: 18 September 2012 / Accepted: 8 May 2013 / Published online: 23 May 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract This article reports a fast, simple and efficient

method to synthesize highly substituted imidazoles. Green

organic synthesis is needed to face current environmental

pollution. For instance the replacement of hazardous organic

compounds by safe alternatives is particularly relevant. Ionic

liquids are an environmentally friendly alternative to con-

ventional organic solvents due to their unique physico-

chemical properties. Substituted imidazoles have been

widely used to prepare pharmaceuticals. Many synthetic

approaches have been developed to produce substituted

imidazoles. However, despite considerable efforts only a few

green methods are reported for the synthesis of highly

substituted imidazoles. Here a straightforward and atom-

economic approach is reported to synthesize a series 2,4,5-

trisubstituted imidazoles directly from a-hydroxyketones

and alcohols employing 1-methyl-3-H-imidazolium nitrate

as a promoter and medium under microwave irradiation. The

protocol has several advantages such as high yields of

77–91 %, short reaction times of 6–8 min, easy purification

processes, and methodological simplicity due to the forma-

tion of carbon–carbon and carbon–heteroatom bonds in a

single step. The methodology has been further extended

towards the facile synthesis of Trifenagrel in good yield. This

method provides new opportunities for the rapid screening of

a wide range of compounds, either for the development of

new drugs or total synthesis of natural products.

Keywords Ionic liquids � 1-Methyl-3-H-imidazolium

nitrate � Trisubstituted imidazole � Microwave � Green

synthetic chemistry

Introduction

As environmental consciousness in chemical research and

industry increases, the challenges for sustainable environ-

ment calls for clean processes and technologies that reduce

or, preferably, eliminate waste generation and avoid the use

of toxic and/or hazardous reagents and solvents (Sheldon

2000). In the recent decade, applications of ionic liquids have

evaluated enormously due to unique potential of these low-

melting organic salts as environmentally compatible alter-

natives to conventional organic solvents; however, a com-

bination of unique physicochemical properties and a growing

interest in green/sustainable chemistry has led to an amazing

growth in the interest in ionic liquids for specialized tech-

nological applications (Wasserscheid and Welton 2008;

Ohno 2005; Mirjafari et al. 2012). Ionic liquids have emerged

as the most promising new reaction media because not only

can these materials dissolve many organic and inorganic

substrates, they also can serve as catalysts and more impor-

tantly, they can be readily recycled and are tunable to specific

chemical tasks, which could be very effective from the

environmental point of view (Cole et al. 2002; Davis 2004).

Regarding this issue, ionic liquids that manifest innately

Lewis-acidic character are well-precedented and have been

thoughtfully studied (Estager et al. 2010; Mirjafari et al.

2010). After the announcement of the first industrial process

involving an ionic liquid by BASF (BASIL process) in 2003,

the potential of ionic liquids for new chemical technologies is

beginning to be recognized (Plechkova and Seddon 2008).

Imidazoles and more specifically 2,4,5-triarylimidazoles

are commonly utilized ring systems within the pharma-

ceutical industry, as these heterocyles impart unique ther-

apeutic and pharmacological properties and also play

important role in the biochemical processes (Grimmett

1997). They have emerged as an integral part of many

A. Mirjafari (&)

Department of Chemistry and Mathematics, Florida Gulf Coast

University, Fort Myers, FL 33965, USA

e-mail: amirjafari@fgcu.edu

123

Environ Chem Lett (2014) 12:177–183

DOI 10.1007/s10311-013-0423-5

biological systems like histidine and histamine (Grimmett

1984) and an active backbone in exciting medications and

natural products e.g. Trifenagrel (Wolkenberg et al. 2004)

and Naamidine A (Fig. 1) (Aberle et al. 2006). Further-

more, these trisubstituted imidazoles are ideal scaffolds to

synthesize libraries of anti-bacterial (Khan et al. 2008),

anti-inflammatory and anti-allergic (Ucucu et al. 2001),

and anti-tumor (Sarshar et al. 2000) drugs-like compounds

and also to generate inhibitors of P38 mutagen-activated

protein kinase, as shown in Fig. 1 (Kim et al. 2008; Lindell

et al. 1996). There are several known multi-component

methods for the synthesis of 2,4,5-trisubstituted imidazoles

which have been reported by condensation of benzil (or

substituted benzil), aryl aldehyde and ammonium acetate

as an ammonia source, using a wide variety of catalysts

(Brackeen et al. 1994; Kidwai and Mothsra 2006; Das

Sharma et al. 2008) as well as different energy sources such

as microwave irradiation (Chauveau et al. 2010; Balalaie

et al. 2000) and ultrasounds (Khosropour 2008a). More-

over, these reactions are performed either in aqueous

solutions (Sparks and Combs 2004; Kokare et al. 2007;

Chauveau et al. 2010), in ionic liquids (Siddiqui et al.

2005; Xia and Lu 2007; Khosropour 2008b; Zang et al.

2010) or in solventless condition (Balalaie et al. 2000).

However, despite intensive studies, only few eco-friendly

methodologies exist for the construction of highly substi-

tuted imidazoles and most of the synthetic methods suffer

from one or more drawbacks such as harsh acidic condi-

tions, complex work-up processes, low atom-economy

(formation of large amount of wastes), use of metal-based

and expensive catalysts and moisture sensitive and hydro-

phobic ionic liquids.

During the course of our studies towards the development

of green synthetic routes for biologically active compounds

using the Brønsted acidic ionic liquid, 1-methyl-3-H-imi-

dazolium nitrate, as a simply made and hydrophilic ionic

liquid (Mirjafari et al. 2011), we report herein a novel, one-

pot, environmentally benign approach for direct microwave-

promoted synthesis of a variety of 2,4,5-trisubstituted imi-

dazoles 4a–r from a-hydroxyketones 1 and benzylic, het-

erocyclic alcohols 2 (without going through aldehydes), via

aerobic oxidation using 1-methyl-3-H-imidazolium nitrate

as a promoter and medium followed by in situ cyclocon-

densation with ammonium acetate 3 (Scheme 1). Although

few reports exist in the literature using a-hydroxyketones as

a starting material, to the best of our knowledge, this

transformation using alcohols instead of aldehydes has not

been previously addressed.

Experimental

Apparatus and analysis

The microwave system used in these experiments includes

the following items: Micro-SYNTH labstation, equipped

with a glass door, a dual magnetron system with pyramid

shaped diffuser, 1,000 W delivered power, exhaust system,

magnetic stirrer, ‘‘quality pressure’’ sensor for flammable

organic solvents, and ATC-FO fiber optic sensor TS3517

for automatic temperature control. 1H and 13C NMR were

recorded on a JEOL LA-400 spectrometer. All 1H NMR

spectra are reported in d units, parts per million (ppm)

downfield from tetramethylsilane as the internal standard

and coupling constants are indicated in Hertz (Hz).

Scheme 1 1-Methyl-3-H-imidazolium nitrate-promoted synthesis of

2,4,5-trisubstituted imidazoles under microwave irradiation

NH

N

N

NH

N

O NMe2

Trifenagrela

F

OH

SB202190C

N

NNH

NN

CH3

O

O

HO

OCH3

CH3

Naamidine Ab

N

N

N

F

RWJ67657d

OH

Fig. 1 Imidazole-based drug (Trifenagrel), natural product (Naami-

dine A) and p38 mitogen-activated protein kinase inhibitors

(SB202190 and RWJ67657). a Trifenagrel is potent 2,4,5-triarylim-

idazole arachidonate cyclooxygenase inhibitor that reduces platelet

aggregation in several animal species and human (Wolkenberg et al.

2004). b Naamidine A is one of the more prominent members of

biologically-active 2-aminoimidazole alkaloids which has been

isolated from sponges of the genus Leucetta (Aberle et al. 2006) c,d SB202190 and RWJ67657 are the members of p38 mitogen-

activated protein kinase inhibitors. Mitogen-activated protein kinases

(MAPKs) are a family of serine/threonine kinases that are part of the

signal transduction pathways, which connect inflammatory and

various other extracellular signals to intracellular responses e.g. gene

expression (Kim et al. 2008)

178 Environ Chem Lett (2014) 12:177–183

123

Typical procedure for the synthesis of 2,4,5-triphenyl-

1H-imidazole (4a)

A mixture of benzoin (0.21 g, 1.0 mmol), benzyl alcohol

(0.12 g, 1.2 mmol), and ammonium acetate (0.8 g,

10 mmol) in 1-methyl-3-H-imidazolium nitrate (3.75 g,

25.84 mmol) was stirred and irradiated for 6.5 min. Pres-

sure and temperature were monitored by dipping pressure

sensor and fiber optic in the reaction medium. After com-

pletion of the reaction (solid mass formation), the reaction

mixture was diluted with cold EtOH (10 mL) and the crude

product was isolated by filtration and recrystallized in hot

EtOH. The resulting product was rinsed with water and

n-hexane and then dried under the vacuum at 50 �C to

afford 4a (88 %) as a white solid. 4a: mp 276-278;

IR (KBr, cm-1) vmax: 3,453, 2,997, 2,464, 1,644, 1,218,

839, 719. 1H NMR (300 MHz, DMSO-d6) dH: 12.48 (s, br,

1H), 7.38–8.07 (m, 15H), 13C NMR (60 MHz, DMSO-d6)

dc: 138.5, 130.3, 128.3, 127.4, 122.0.

Results and discussion

Synthesis and role of 1-methyl-3-H-imidazolium nitrate

1-Methyl-3-H-imidazolium nitrate (Tm = 69.6 �C,

T5 %decomp. = 137 �C) was prepared through a simple and

100 % atom-efficient neutralization reaction of equimolar

of 1-methylimidazole and nitric acid (67 % w/w).

1-methyl-3-H-imidazolium nitrate is air-stable, hydro-

philic, and its physicochemical properties have been stud-

ied (Emel’yanenko et al. 2009). It has been used as a

solvent and promoter in the oxidative reactions and has

considerable potential as a reaction medium. The actual

oxidative role of ionic liquid is not clear. However,

according to published results, the mechanism can be

explained on the basis of potential oxidative ability of

1-methyl-3-H-imidazolium nitrate and atmospheric oxygen

mixture (Chiappe et al. 2006).

Optimization of reaction conditions

We sought to optimize the reaction condition for the for-

mation of 2,4,5-triphenyl-1H-imidazole 4a as model reac-

tion, by examining the effects of catalyst/ionic liquid,

temperature, time and microwave energy (Table 1). A

comprehensive study to examine the catalytic efficiency of

1-methyl-3-H-imidazolium nitrate was performed over

different catalyst/ionic liquid systems such as nitric acid

(Table 1, entry 2), Brønsted acidic ionic liquids (Table 1,

entries 3–5) and ionic liquids which were previously used

for this transformation (Table 1, entries 4–7) in the pres-

ence of air and under various reaction conditions. Poor

conversion to 4a was observed in the absence of catalyst

(Table 1, entry 1). The best yield of 4a was obtained by

carrying out the reaction with 1:1.2:10 equiv. of benzoin,

benzyl alcohol and ammonium acetate in 1-methyl-3-H-

imidazolium nitrate under microwave irradiation (95 �C,

80 W) for 6.5 min (Table 1, entry 9). Efficacy of micro-

wave heating was also ascertained by conducting the model

reaction using conventional heating and afforded inferior

yield (Table 1, entry 13). Based upon the previously

reported results, the microwave irradiation heating process

remarkably reduces the amount of energy needed to carry

out the reaction compared to the thermal conventional way,

which plays vital role from an environmental point of view

(Gronnow et al. 2005).

Table 1 Optimization of 4a synthesis conditions

Entry Catalyst/ionic

liquid

T (�C) Time

(min)

ESa Yield

(%)b

1 No catalyst 95 10 MW NRc

2 HNO3 95 10 MW NR

3 [Hmim][Cl]d 95 10 MW NR

4 [Hmim][HSO4]e 95 10 MW NR

5 [Hbim][BF4]f 95 10 MW NR

6 [emim][Ac]g 95 10 MW NR

7 [Hemim][BF4]h 95 10 MW NR

8 [Hmim][NO3]i 90 6.5 MW 81

9 [Hmim][NO3] 95 6.5 MW 88

10 [Hmim][NO3] 100 6.5 MW 88

11 [Hmim][NO3] 95 6 MW 83

12 [Hmim][NO3] 95 7 MW 88

13 [Hmim][NO3] 95 20 CH 12

Benzoin (1 mol), benzyl alcohol (1.2 mol), NH4OAc (10 mol),

1-methyl-3-H-imidazolium nitrate (3.75 g)a Energy source: microwave irradiation (80 W), conventional heatingb Isolated yieldc No progress in reaction was observedd 1-Methyl-3-H-imidazolium chloride as a Brønsted acidic ionic

liquide 1-Methyl-3-H-imidazolium hydrogen sulfate as a Brønsted acidic

ionic liquid (Khosropour 2008b)f 1-Methyl-3-H-imidazolium tetrafluoroborate as a Brønsted acidic

ionic liquid (Siddiqui et al. 2005)g 1-Ethyl-3-methylimidazolium acetate as a conventional ionic liquid

(Zang et al. 2010)h 1-Heptyl-3-methylimidazolium tetrafluoroborate as a conventional

ionic liquid (Xia and Lu 2007)i 1-Methyl-3-H-imidazolium nitrate as Brønsted acidic ionic liquid

Environ Chem Lett (2014) 12:177–183 179

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Table 2 Synthesis of 2,4,5-trisubstituted imidazoles from a-hydroxyketones, alcohols and, ammonium acetate using 1-methyl-3-H-imidazolium

nitrate

entry α-hydroxyketone alcohol product time (min) %yield

1b,c 4a 6.5 88

2b 4b 6.5 89

3b 4c 6 90

4c,d 4d 6 91

5b,c 4e 6.5 87

6b,c,e 4f 6.5 87

7e 4g 7 84

8e 4h 8 77

180 Environ Chem Lett (2014) 12:177–183

123

Table 2 continued

10b 4j 7 81

11b 4k 6.5 83

12b 4l 6.5 88

13b 4m 7 84

14b 4n 6.5 87

15b 4o 6.5 86

16b,c 4p 6.5 84

9d 4i 6.5 83

Environ Chem Lett (2014) 12:177–183 181

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Synthesis of 2,4,5-trisubstituted imidazoles

For the ultimate goal of applying this reaction in a diver-

sity-generating strategy, a wide range of substituted and

structurally diverse a-hydroxyketones, benzylic alcohols

bearing either electron-withdrawing or electron-donating

groups, were utilized to synthesize the corresponding 2,4,5-

trisubstituted imidazoles in good yields and in the short

reaction times (Table 2). Additionally, heterocyclic (4i, 4k,

4p, and 4q) and aliphatic (4r) substrates provided good

yields of the corresponding products as well as the steri-

cally hindered precursor (4h). The high yields and stable

transformations were performed without significant

amounts of undesirable side products. Despite some

reported methods, the proposed approach does not require

toxic and volatile organic solvents or metal-based catalysts.

Products isolation from reaction mixtures required just by

simple filtration. Imperatively, in this methodology the

imidazoles can be prepared using a-hydroxyketones and

alcohols as starting materials instead of 1,2-diketones and

aldehydes, respectively. It is worth to note that the 1,2-

diketones and aldehydes are generally prepared from the

oxidation reactions catalyzed by toxic oxidants and require

tedious experimental procedures (Sheldon 2000). There-

fore, the direct aerobic oxidation of starting materials in

our protocol constitutes a significant improvement in the

synthesis of trisubstituted imidazoles toward green chem-

istry. Another important aspect is that various functional-

ities, methoxy and nitrile, survived under the present

reaction conditions. Reaction conditions are mild enough

not to react with acid-sensitive moieties, such as ethers and

esters, which often undergo cleavage in strong acidic media

(4j, 4k and 4o). Based on the method described here,

Trifenagrel 4j was synthesized in 81 % in 7 min (Table 2,

entry 10). This new protocol for the synthesis of trisub-

stituted imidazoles accomplishes triple bottom line phi-

losophy of green chemistry and is an overriding addition to

the toolbox of medicinal chemists.

Conclusion

Overall, a three-component, single-step, green synthesis of

2,4,5-trisubstituted imidazoles via aerobic oxidation and cy-

clocondensation of a-hydroxyketones with various alcohols

and ammonium acetate using 1-methyl-3-H-imidazolium

nitrate as a promoter (or catalyst) and medium has been

described here. It has been demonstrated that the combination

of an ionic liquid and microwave energy is ideally suited for the

synthesis of a large library of 2,4,5-trisubstituted imidazoles.

Acknowledgments AM is grateful to the College of Art and Sci-

ences of Florida Gulf Coast University for financial support and also

would like to thank Professor James H. Davis Jr. and Dr. Richard A.

O’Brien at University of South Alabama for their valuable comments

and insights.

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Table 2 continued

17f 4q 7 82

18d 4r 7.5 79

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