ISSN: 2320-5407 Int. J. Adv. Res.

12(10), 199-216

Journal Homepage: -www.journalijar.com

Article DOI:10.21474/IJAR01/19633
DOI URL: http://dx.doi.org/10.21474/IJAR01/19633

RESEARCH ARTICLE
DIVERSE SYNTHETIC APPROACHES TO CRAFT IMIDAZOLES - A REVIEW

Sodah Karun and Dr. Khilnani Veena

K. J. Somaiya College of Science and Commerce, Vidyavihar, Mumbai - 400077.
……………………………………………………………………………………………………....
Manuscript Info Abstract
……………………. ………………………………………………………………
Manuscript History Imidazoles are five membered heterocyclic ring compounds containing
Received: 10 August 2024 two nitrogen atoms as a part of a five membered ring. Imidazole is a
Final Accepted: 14 September 2024 pharmacologically important molecule mainly used as antihypertensive,
Published: October 2024 antiplasmodial, antifungal and anticancer agents etc. It can be
Key words: -
synthesized by using a variety of starting materials by different
Imidazoles, Classical, Green, Syntheses synthesis such as – Debus Radziszewski, Van Leusen, Wallach
synthesis to name a few. By altering the starting materials different
derivatives of imidazole can be synthesized and show a wide range of
pharmacological activites. Hence organic chemists are continuously
striving to synthesize novel imidazole derivatives that could show
better pharmacological effects. This review article focuses on different
types of synthesis available to chemists for this versatile molecule.

Copyright, IJAR, 2024. All rights reserved.

……………………………………………………………………………………………………....
Introduction: -
Planar, amphoteric, heterocyclic ring with two nitrogen atoms in 1, 3 –position in a five membered ring is called
imidazole. Imidazole has a pKa of 14.5, which makes it somewhat more acidic than alcohols but less acidic than
phenols, carboxylic acids, and other substances. The conjugate acid has a pKa of roughly 7, which makes it more
basic than pyridine as a base [1]. The pharmacological actions exhibited by derivatives of imidazoles have attracted
the interest of synthetic chemists in the synthesis of new drugs with a range of medicinal applications. It has been
observed that compounds of imidazole exhibit anti-tumor, anti-inflammatory, antiviral, anti-ulcer, antibacterial and
antifungal properties [2]. According to a different study, a compound with the imidazole ring showed the strongest
anti-proliferative action against four different cancer cell types, including MCF-7, H1299, HeLa, and B16-F10. Its
average IC50 value was 7.219 µM. It is necessary to look into a new justification for anticancer medications in order
to find tailored treatments with less systemic adverse effects. Imidazole has the ability to overcome the unresolved
drawbacks of clinical medications that are now in the market and might be used as a chemical framework for
innovative anticancer treatments that have multiple potential modes of action, according to certain reported studies
[3]. These five-membered N-heterocycles have several uses due to their straightforward synthesis techniques and
ring functionalization. Consequently, efficient and economical methods for selective production have drawn a lot of
attention in imidazole chemistry. Therefore, a straightforward and effective method for preparing the imidazole
moiety is required [4].

Classical strategies:
Imidazole can be synthesized in the laboratory using a variety of techniques, such as Wallach, Debus-Radziszewski,
Van Leusen, and others. With these techniques, several substituted imidazoles can be prepared by simply altering
the functional groups that are present in the reactants.

Corresponding Author: -Dr. Khilnani Veena 199

Address: -K. J. Somaiya College of Science and Commerce, Vidyavihar, Mumbai -
400077.
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Nidhi Rani etal (2023) [5] mentioned that Heinrich Debus created imidazole for the first time in 1858. But as early
as the 1840s, other imidazole derivatives were found, which were made by combining formaldehyde and glyoxal
[R1 = R2 = H] with ammonia. Linjie Kong etal (2010) [6] prepared 2, 4, 5 – trisubstituted imidazoles by reacting 1, 2
– diketones with an aldehyde in presence of excess ammonium acetate at 180° C for 2 mins in a microreactor under
pressure.

R1 O O R1
180°C / 2 mins
N
+ R2 H
+ NH4OAc microreactor / pressure R2
R1 O NH
R1
Figure - 1

A. Mazut et al, (2015) [7] have shown that interactions between glyoxal and more neutral inorganic ammonium salts
such as ammonium sulphate in water at room temperature can generate imidazole, imidazole-2-carboxaldehyde and
2,2-bis-1H-imidazole.

Bao Hu et al. (2011) [8] used 2-azido acrylates and nitrones, a highly effective and practical technique for the
synthesis of 1,2,4,5-tetrasubstituted imidazoles has been established, this reaction was carried out under moderate
conditions.

O -
O
O Ph OEt
+
OEt N Ph
+ N
Ph
Ph H N
Ph N3 Ph
Figure - 2

Ankit Siwach et al. (2012) [9] utilized benzil, ammonium acetate, and substituted benzaldehyde, by Radziszewski
synthesis techniques to create imidazoles, and the antibacterial characteristics of the resulting compounds were
determined.

O
O N
+ 2 NH3 + + 3 H2O
O H N

Figure - 3

Ahmad K et al. (2013) [10] carried out the above reaction by using ammonium acetate in place of ammonia in
presence of potassium permanagnate and copper sulphate as catalyst and refluxing in ethanol. Leyla Poorali et al.
(2013) [11] also achieved high yields and quick reaction times in the synthesis of tri and tetrasubstituted imidazoles
by using benzil, aliphatic or aromatic amines, ammonium acetate, and a catalytic quantity of antimony chloride (or
stannous chloride dihydrate) in a solvent-free environment. Using them as efficient and reusable catalysts, new and
quick access to the synthesis of unique polysubstituted imidazoles is possible.

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O
SbCl3 / SnCl2. 2H2O
+ R1-CHO + CH3COONH4
Solvent free, Δ
N

O R1
NH

O N
SbCl3 / SnCl2. 2H2O R1
+ R1-CHO + R2-NH2 + CH3COONH4
Solvent free, Δ
N
O
R2

Figure - 4
Ma B.B et al. (2015) [12] also carried out Debus-Radziszewski synthesis by the combination of di – tertbutyl
tetraone and aromatic aldehyde.
Xunan Zheng et al. (2020) [13], Van Leusen et al. (1977) [14] mentioned the use of aldimines to prepare substituted
imidazoles using the Van Leusen technique by reaction with tosyl methyl isocyanide or even sulfonyl methyl
isocyanides respectively.

R2 R2
N N
+ Tos
K2CO3
NC CH3OH, Δ
R1 H
R1 N
Figure - 5
Benincori, T et al. (1993) [15] carried out Wallach synthesis by heating N, N-dimethyl oxamide with phosphorus
oxychloride in phosphorus pentachloride giving an intermediate (a), which was then further reduced with HI to
generate N-methyl imidazole. This process yields 2-chloro-N-methyl imidazole.

O NH Cl
O N
CH3
PCl5 N CH3
+ Cl P Cl Δ H3C N
Reduction
CH3 Cl
N
O NH Cl Cl
a
CH3
Figure - 6
Ritesh Kumar et al. (2020) [16] suggested that in order to prepare imidazole; ethylene diamine and alkyl nitriles can
be first reacted in presence of sulphur to produce imidazoline (b), which can then be further dehydrogenated with
barium manganate to produce modified imidazole.

NH2 N N
R Sulphur BaMnO4
+ R R

N N
NH2 N

H H
b

Figure - 7

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Deepak Chaudhury et al. (2015) [17] included Markwald's imidazole synthesis by using potassium thiocyanide and
α-aminoketone to produce an intermediate (c) that could then be further oxidized to produce modified imidazole.

R O R H R
N NH
[O]
+ KSCN
R SH R
R NH2 N N
H
c

Figure - 8

Suma Sanikommu (2020) et al. [18] suggested a reaction between the α-halo ketone and amidine to obtain
imidazoles. But this method worked well for the synthesis of 2, 4- or 2,5-biphenyl imidazoles.

O HN
+ -H2O
N

Br H2N -HBr
N

Figure - 9 H

Nirjhar Saha et al. (2023) [19] reported a metal – free synthesis in which alpha diketones reactwith guanidine in the
presence of methanol to produce an intermediate (d) which was further reduced with hydrogen gas in presence of
palladium catalyst and methanol for eight hours to yield substituted amino imidazole.

O NH2 R2 N R2 NH
CH3OH H2/Pd, CH3OH
R2 NH2 NH2
R1 + R.T, 30 mins R.T, 8 hours
HO N N
HN NH2 R1
O R1 d

Figure 10

Ammonia can also be used to react with a mixture of tartaric acid dinitrate and modified formaldehyde to form
substituted imidazole. In addition, imidazole itself can be produced by heating the dicarboxylic acid produced with
quinolone in the presence of copper to yield 2-alkyl imidazole-4, 5-dicarboxylic acid (e), which is then further
reacted with aniline to yield 4-substituted benzamide [20].
COOH COOH
NH2
HOOC
O 2N OH O
+ 2 NH3 + R-CHO NH
+
O2 N OH O
HOOC
N R
COOH COOH

Figure - 11 e

HOOC
NH
O
R
N
HN
C6 H5

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Dipanshu Panday et al. (2020) [21] reported that substituted imidazoles can be made by reacting an imidate with a α-
aminoacetal or α-aminoaldehyde to generate an imidine (f) that eventually cyclizes by forming a single bond.

H5 C2 O NH2 R OHC N
NH
+ NH R
H5 C2 O R1
OHC R1 NH R NH
R1
f
Figure - 12

E. V. Aleksandrova et al. (2011) [22] suggested lithiating 1-methylimidazole first, then treating the intermediate 2-
lithio derivative (g) with a halogenating reagent (e.g. per chloryl fluoride, trichloro acetyl chloride, carbon
tetrachloride, hexachloroethane). This is the conventional method for producing 2-halo-1-methylimidazoles (yields
55–80%).

N N N
BuLi Halogenating agent
THF, -78°C Li X
N N N
CH3 CH3 CH3
g

Figure - 13

Prashant Tripathi et al. (2023) [23] reported a two-step reaction method to generate novel imidazole derivatives.
First, aryl ethanones reacted with selenium dioxide in dioxane to give phenyl glyoxal (h), and then aromatic
aldehyde was used to cyclize the compound in the presence of acetic acid and ammonium acetate. They also
investigated how the produced chemicals affected bacteria.

O O
H
CH3 SeO2 NH4OAc, C6H5 - CHO N
Dioxan, reflux Glacial CH3COOH, reflux C6 H5
O
NH
h

Figure - 14

A. Bhatnagar et al. (2011) [24] suggested that benzimidazole is found in Vitamin B12 and may be made in a variety
of ways that are more significant than imidazole. Specifically, benzimidazole is created when 1, 2-diaminobenzene
is heated in an acidic medium and condensed with a carboxylic acid.
NH2 O N
100°C
+ R
- 2H2O
R

NH2 N
HO
H

Figure - 15
Ian de Toledo et al. [25] reported a method of stepwise oxidation followed by condensation using p-tolualdehyde
and acetophenone as exemplar carbonyl substrate. Following considerable optimization, it was found that
acetophenone may be catalyzed with 10 mol% aqueous HBr in dimethyl sulphoxide at 85°C to produce equivalent
glyoxal (i). After adding a methanol: dimethyl sulphoxide (6:4) solution along with synthesized glyoxal to a mixture
of p-tolualdehyde and ammonium acetate in methanol, the necessary imidazole was extracted in a 69% yield.

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O O H
H
CH3 N
Aq HBr ( 10 mole%) H3C CH3
DMSO, 85°C NH4OAc, DMSO/CH3OH
O
18 hours RT, 18 hours NH
i

Figure - 16

Louis G et al. (2021) [26] carried out efficiency and modularity of metalated isocyanide (j) condensation with
nitrogenous π-electrophiles set it apart. An isocyanide can be deprotonated to produce an isocyanide-stabilized
anion, which during condensation with a nitrile or imidate yields a transitory imine that easily cyclizes to produce
imidazole.

Br
_ M +
+ R1 N
N – RM + R2 N R3
R1 C N –
R1 C N N
R2
R2 R3
j

Figure 17

Green strategies:
These techniques are essentially a greener way to synthesize the same moieties through the use of environmentally
safe processes that have negligible or no impact on the environment. Imidazole synthesis has been carried out by
using water, Deep Eutectic Solvent (DES) or Tertiary Butyl Hydro Peroxide (TBHP) as solvents which are
environmentally benign [27].

1) Using Organocatalysts:
Recently small organic molecules have been used to catalyze organic reactions and this has greatly minimized the
use of metal-based catalysts, and the reactions can be carried out even in the presence of water [28]. Also, carbon
dioxide molecules have been used as a one carbon source for synthesis because it is readily available, cheap and
non-toxic [29].

Doug E. Frantz et al. (2004) [30] used thiazolium-catalyzed addition of an aldehyde to an acyl imine producesα-
ketoamide in situ, which is then subjected to closing of ring to yield substituted imidazoles in the one-pot synthesis.
The Stetter reagent (k), thiazolium salt, acts as anorganocatalyst in this process.

+
N
H3C –
Tol I R3 NH R2
N
O OH R3
O O S O k R1NH2
CH3 R2
+ (C2H5)3N, solvent
O AcOH
R4 H R3 R2 R4 O N
NH 40°-60°C R4
R1

Figure - 18

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S. Samai et al. (2009) [31] synthesized trisubstituted imidazole derivatives organocatalytically, 1, 2-dicarbonyl
compound was reacted with aryl halide, and ammonium acetate at 60°C in presence of 15% L-proline. For
tetrasubstituted imidazoles an additional molecule of primary amine was used under similar conditions.

H5 C6 O
H5 C6
15 mol% L - Proline N
+ R-CHO + CH3COONH4
CH3OH, 60°C R
H5 C6 O H5 C6 NH

H5 C6 O
H5 C6
15 mol% L - Proline N
+ R1-CHO + CH3COONH4 + R2-NH2
CH3OH, 60°C R1
H5 C6 O H5 C6 N
R2
Figure - 19

Jayant Sonar et al. (2019) [32] synthesized 2, 4, 5-trisubstituted imidazoles at 160 °C utilizing biodegradable lactic
acid, an aromatic aldehyde, benzil, and ammonium acetate. Lactic acid is a green solvent that is safe for the
environment and is used in this straightforward process. Additionally, lactic acid is a promoter and is easily
produced by the fermentation of carbohydrates.

Ph O
Ph
Lactic acid N
+ Ar-CHO + CH3COONH4
160°C
Ar
Ph O Ph NH

Figure - 20

2) Using Nanoparticles:
Mariyam Hajjami et al. (2015) [33] developed a second green method in which 2,4,5-trisubstituted imidazole was
produced by reacting benzil with a substituted aldehyde in the presence of nano-aluminum nitride catalyst in a
solvent-free system at 130ºC and a few drops of water.

O N
O nano AlN R
+ water (few drops)
N
R H solvent free, 130°C
O H

Figure - 21

Sundaram Singh et al. (2019) [34] used zirconium oxide nanoparticles in a one-pot multicomponent process
involving isatin derivatives, ammonium acetate, and substituted benzaldehydes to create imidazole derivatives.

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R5

O R3 R4 N R4
R1 O H R1
ZrO2 NPS (15 mol%) R3
O + H3C + R5
NH
Δ / 110°C
N ONH4 O N
2
R R2
Figure - 22

Myo Thwin et al. (2019) [35] used cuaimine and Fe3O4 (magnetite) magnetic nanoparticles, four component reaction
was carried out between benzil, benzaldehyde, aniline, and ammonium acetate under varying time and temperature
conditions, solvent types, and solvent-free conditions to create substituted imidazoles.

Ph
O H N
O O NH2
Cuaimine / Fe3O4 MNP's Ph
N
+ + + CH COONH
3 4
Solvent free, 80°C
Ph Ph

Figure - 23

Liela K. Ahmadi et al. (2022) [36] carried out synthesis of Cr2O3 (chromium oxide) nanoparticles from zingiber
extract followed by using as a green catalyst for the microwave-assisted synthesis of imidazole from benzil,
aromatic aldehyde, and ammonium acetate.
O O

O N
Green Cr2O3 nano catalyst
+ H 5C 6 H
+ CH3COONH4
M.W, H2O
C6 H5
N
H
Figure - 24

Also S.M. Bagwan et al. (a) (2022), S.M. Bagwan et al. (b) (2022) [37, 38] and Srinivasa Gupta et al. (2019) [39]
used 15 mol % silver nanoparticles or 15 mol % copper oxide nanoparticles and magnetic nano cobalt ferrite
(CoFe2O4) respectively as catalyst for the same reaction while refluxing in presence of ethanol.

Najmeh Zahedi et al. (2018) [40] carried out the above reaction with 9, 10-phenanthraquinone instead of benzil, then
the reaction was catalyzed by reusable perovskite-type oxide (nanoparticles) to form phenanthro-imidazole
derivative. Esmail Korani (2018) [41] and Aravind Gajenji et al. (2022) [42] carried out solvent free imidazole
synthesis by magnetic core–shell nanoparticles containing I3-as a novel catalyst or by ultrasound assisted synthesis
using NiO nanoparticles.

Heber. V. Tolomeu et al. (2023) [43] in a multicomponent synthesis, obtained numerous tetrasubstituted imidazole
derivatives using different aldehydes, benzil, ammonium acetate, and prop-2-ynylamine in the presence of nano
copper nanoferrite (CuFe2O4) as a catalyst in 50 % ethanol under reflux for around 50 minutes.

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–
Ar
O NH2
N CH
CH3COONH4 N
+ Ar-CHO + Δ, CuFe2O4 NPs (10 % mol}
Reflux, 50 mins
O CH

Figure - 25

Nguyen T. Chung et al. (2023) [44) reacted o-phenylene diamine with aromatic aldehyde, nanocrystalline
magnesium oxide, iodine at normal temperature and acetonitrile as a solvent.

NH2 N
Nanocrystalline MgO, I2
+ Ar-CHO
CH3CN, R.T Ar
NH2 NH
Figure - 26

Najmedin Azizi (2023) [45] used simple carbon nitride catalyst encased FeCeOx nanoparticle production for very
efficient and reusable substituted imidazole synthesis.

O O NH2
N
H O FeCeOx.@g-C3N4
+ + H3C + Ethanol, 60°C N R1
O R1 ONH4

Figure - 27

Hieu etal. (2023) [46] reported four-component synthesis of imidazole using benzil/benzoin, aldehydes, primary
amines, and ammonium acetate at room temperature and without the use of a solvent, employing 2,6-
dimethylpyridinium trinitromethanide {[2,6-DMPyH]C(NO2)3} as a catalyst, results in the construction of
tetrasubstituted imidazole derivatives.

3) Using self-catalytic reaction:

Kiran Pradhan et al. (2016) [47] carried out a self-catalytic reaction by solvent-free multi-component synthesis. This
was performed by grinding the reactants and then heating them at 150°C and 160°C.

Ph
O O N
O Grind
+ R1 NH2 + + CH COONH
3 4 Heat, 150°C - 160°C R2
R2 H Ph N
Ph Ph
Figure - 28 R1

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4) Using Schiff’s base intermediate:

Pankaj Saxena et al. (2021) [48] carried out green imidazole synthesis using Schiff's base intermediate.
Sulphanilamide and substituted aryl halide were reacted to produce Schiff’s base. Isatin derivative was then
acetylated and reacted with Schiff's base in the presence of ammonium acetate using silica gel as solid support to
yield imidazole derivative. The synthesized imidazoles exhibited anticancer activity against Hep-2 cell as well as
antihelmintic activity.

O
O O R

H2N S NH2 + O + CH3COCl

O H N
H

Pyridine

H
NH2 R O

O S N
O
O
Schiff's base N

O
CH3COONH4 H3C
R
N

N N

H3C
O

O
S
O Figure - 29
NH2

5) Using Zeolite catalyst:

Sudarshan S. Dipake rt al. (2022) [49] synthesized 1, 2, 4, 5 - tetrasubstituted imidazole by reacting ammonium
acetate, substituted aniline, substituted aryl halide, and benzil in a solvent-free environment. This was done by using
a zeolite, ZSM – 11 as a green catalyst.
O H
O NH2
N R1
ZSM - 11 (48 hours)
+ + + CH3COONH4
Solvent free
O N

R1 R2

Figure - 30
R2

6) Using fruit juice catalyst:

Sushil Gulati et al. (2022) [50] used fruit juices as catalysts to synthesize bioactive imidazoles. As a catalyst Citrus
limon, Vitis vinifera and Cocos nucifera were added to benzil, aromatic aldehyde and ammonium acetate.

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O
O N
Citrus limon / Vitis vinifera / Cocos nucifera
H
+ + NH4OAc
mild reaction conditions
N
O H

Figure - 31

7) Using solid acid catalyst:

Ghodsi M. Ziarani et al. (2015) [51] produced 1, 2, 4, 5-tetra-substituted imidazoles by condensing the four
components of a 1, 2-diketone - benzil, a substituted aromatic aldehyde, ammonium acetate, and primary amine
using sulphonic acid functionalized silica (SiO2-Pr-SO3H) as a highly active heterogeneous solid acid catalyst in
solvent-free conditions at a temperature of 140º C.

O O NH2
N
H O
SiO2 - Pr - SO3H
+ + H3C + solvent free, 140°C N
R1
O R1 ONH4

Figure - 32

8) Using Fly ash:

P. Ezhilmathi et al. (2019) [52] condensed benzil, 2-amino ethyl pyrrolidine, benzaldehyde, and ammonium acetate
in ethanol at 80 º C in the presence of fly ash supported Bi2O3–ZnO catalyst.

H2N
H O N
O CH3
Flyash Bi2O3 - ZnO
+ + N
+ O
Δ / Ethanol N
ONH4 Stirring - 9 hrs.
O

N
Figure - 33

9) Using microwaves:
Modern synthetic organic chemistry got a boost due to the advent of microwave assisted organic synthesis, since the
reactions could be carried out in one step using metal free conditions, in short duration of time and with high yields
[53].
Na Zhao et al. (2005) [54] synthesized benzimidazoles from o - phenylene diamine, carboxylic acid, or acetoacetic
ester in solvent free conditions with the aid of microwaves.

NH2 O
N
+ solvent free
R1
MW
NH2 R1 R2 NH

R1- CH3 or C6H5

Figure - 34
R2- CH2COOEt or OH

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Javad Safari et al. (2010) [55] synthesized 2, 4, 5 trisubsituted imidazole with an effective catalyst like
(NH4)6Mo7O24⋅4H2O in a single pot and three component condensation of benzil, aryl aldehyde, and ammonium
acetate in solvent-free conditions using microwave irradiation.

NH2 O
N
+ solvent free
R1
MW
NH2 R1 R2 NH

R1- CH3 or C6H5

Figure - 35
R2- CH2COOEt or OH

Neha Gupta (2017) [56] reported that aldehydes, benzil, and ammonium acetate can be microwaved in the presence
of ethanol to create 2,4,5-trisubstituted imidazoles in excellent yields. This process makes use of a Schiff's base
complex nickel catalyst (Ni-C). Haitham D. Hanoon (2019) [57] used 8-hydroxy-7-iodoquinoline-5-sulfonic acid
(HISA) as a catalyst in this reaction

S.V. Nalageet al. (2010) [58] used a green method involving the condensation of benzil, vanillin and ammonium
acetate in the presence of polyethylene glycol. Substituted imidazoles were prepared using microwave synthesis.
Polyethylene glycol is inexpensive, non-toxic, reusable and easily accessible.

H O

O
N
Poly ethylene glycol
+ + CH3COONH4
MW, 5 - 8 mins
OH
O N
OCH3
H OCH3
OH
Figure - 36

Arvind B. Tapase et al. (2022) [59] obtained 1,2,4,5 – tetrasubstituted imidazole by subjecting benzil, aromatic
aldehyde, primary amine, ammonium acetate in presence of sulphamic acid as catalyst. E. Gelens et al. (2006) [60]
carried out the same reaction with chloroform or acetic acid as solvent under microwaves.

M. Bouchakour et al. (2021) [61] synthesized novel disubstituted imidazole by treatment of 1, 2 – dione with
ammonium acetate and aldehyde using MW in presence of acetic acid at 180° C for 5 mins.
R

O O NH
N
R - CHO
NH4OAc (excess)
H3C O AcOH H3C O
(CH 2) 7 (CH2)7 CH3 MW 5 mins (CH 2) 7 (CH2)7 CH3
O O
Figure - 37

Pilar M. Fresneda et al. (2001) [62] utilized a regioselective synthesis method that combines the cyclization of the
resultant ketoamides (l) by ammonium acetate under microwave irradiation after the reaction of azidoacetyl indoles
with carboxylic acids in the presence of tertiary phosphines to obtain 2,4-disubstituted imidazoles in two steps.

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O N3 O N
NH R1
R1
R1COOH CH3COONH4 / DMF NH
(CH3)3P O MW
N N N
H H l
H
Figure - 38

Poonam Gupta et al. (2015) [63] reported that in the presence of acid chloride, 1,2-di(furan2-yl)-2-oxoethyl
carboxylates react to generate an intermediate (m) that is then converted to trisubstituted imidazoles by reacting with
ammonium acetate under microwave irradiation.

O O CH3COONH4 N
O RCOCl O O
O MW, 130°C R
solvent free
OH O R N

m H
O N O O
Figure 39

10) Making use of chalcones - a natural product:

Chettiyan T F. Salfeena et al. (2018) [64] studied the relationship between structure and activity indicating that
modified chalcones have improved activity. Additionally, the presence of enone functionality makes it a better
precursor for a variety of chemical processes generating imidazoles.

R1
O
N
Cu(OTf)2, I2
R
1
R
2
+ R3 NH2 Toluene, 70°C R2
N

Figure - 40
R3
11) Catalyst free synthesis:
N. Naresh Kumar Reddy et al. (2017) [65] employed catalyst-free synthesis. Vinyl azides and amidines are
oxidatively cyclized by [3+2] cycloaddition with 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) under mild
conditions, utilizing acetonitrile as a solvent, to produce 2,4-disubstituted imidazoles.

NH
NH R2 N3
DBU
.HCl
+ CH3CN, Δ R1
R1 NH2 CH2 N R2
Figure - 41

12) Without Using Any Solid Surface, Catalyst, or Solvent:

Swati Samanta et al. (2013) [66] made 2,4,5-trisubsituted imidazoles by heating 1, 2-diketone, aromatic aldehyde,
and ammonium acetate in a 1:1:3 moleratio for three to six hours at 130°C.

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Ph O
Ph
N
Δ, 130°C
+ Ar-CHO + CH3COONH4
3 - 6 hours
Ph NH Ar
Ph O Figure - 42
13) Using ultrasound:
Sushant R. Khedkar et al. [67] reported a one-pot three-component reaction using an innovative and environmentally
friendly NiFe2O4-geo-polymer nano-catalyst to synthesize imidazole derivatives, with the aid of ultrasonic
irradiation. The nano-NiFe2O4 supported on geo-polymer proved to be an excellent recyclable catalyst.

O
))))) 80°C
N
+ R-CHO + 2 NH4OAc
NiFe2O4 NPs
R

O geopolymer N
Figure - 43 H

Xian-Long Yu etal. (2023) [68] reported thatthis reaction was also carried out by ultrasound-assisted protocol giving
high yields of imidazoles, up to 97% by using Fe 3O4 magnetic nano particles (MNPs) as catalyst. Faezeh
Shafaeiaetal (2019) [69] reported that these magnetic nanoparticles are reusable provided they are used in solvent
free conditions at 50°C
Debasree Saha et al. (2024) [70] reported the synthesis of corresponding imidazole derivatives by ultrasonic
irradiation of 1,2-diketones (benzil/anisil) and aromatic aldehyde in the presence of ammonium acetate and the
HMS-SA (Hexagonal Mesoporous Silica – Solid Acid) catalyst.
Ph O Ph O
Ph
HMS SA catalyst N
or
+ Ar-CHO + CH3COONH4
Ethanol, US
25 - 45 mins Ar
Ph O Ph OH Ph N
Figure - 44
H
Alicia R. Arellano etal. (2016) [71] reported that aromatic aldehydes and ethylene diamine were reacted with ultra-
sound using NBS as an oxidant and water as a solvent, yielding good to outstanding results in 12–18 minutes. After
being assessed as Mono Amine Oxidase (MAO) inhibitors, the resultant imidazolines showed good selectivity and
activity in the micro molar (µM) range.

NH2 N
NBS –
Ar
+ Ar-CHO + CH3COONH4 US, 12 - 18 mins
N
NH2 Figure - 45
H

D. S. Zinad et al. (2020) [72] showed that the stability and formation rate of synthesized compounds can be further
investigated by theoretical calculations, such as DFT and thermodynamic studies.

Conclusions: -

We have covered the most up-to-date, easy, and eco-friendly techniques for making imidazoles. When synthesizing
imidazoles, research chemists might choose from a variety of conventional or environmentally benign methods.
Thus, chemists could attempt to prepare molecules based on the above methods by changing some of the
pharmacophores to obtain compounds having profound therapeutic effects and minimum toxicity.

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