A sustainable approach towards the three-component synthesis of unsubstituted 1H-imidazoles in the water at ambient conditions

Article abstract of DOI:10.1080/10286020.2020.1760852

A green protocol for the synthesis of unsubstituted imidazoles has been demonstrated herein. The reaction is realized using commercially available lipase enzyme, porcine pancreas lipase (PPL) in water. The reaction conditions are selective and mild which helped to tolerate a wide variety of functional groups to give the desired products in good chemical yields. (Figure presented.).

Full text of DOI:10.1080/10286020.2020.1760852

Journal of Asian Natural Products Research
ISSN: 1028-6020 (Print) 1477-2213 (Online) Journal homepage: https://www.tandfonline.com/loi/ganp20
A sustainable approach towards the three-
component synthesis of unsubstituted
1H-imidazoles in the water at ambient conditions
Suraj S. Kapale, Hemchandra K. Chaudhari, Suraj N. Mali, Balaram S. Takale
Hitesh Pawar
&
To cite this article: Suraj S. Kapale, Hemchandra K. Chaudhari, Suraj N. Mali, Balaram S.
Takale & Hitesh Pawar (2020): A sustainable approach towards the three-component synthesis of
unsubstituted 1H-imidazoles in the water at ambient conditions, Journal of Asian Natural Products
Research
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JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
https://doi.org/10.1080/10286020.2020.1760852
A sustainable approach towards the three-component
synthesis of unsubstituted 1H-imidazoles in the water at
ambient conditions
a
a
a
Suraj S. Kapale , Hemchandra K. Chaudhari
, Suraj N. Mali , Balaram S.
b
c
Takale and Hitesh Pawar
a
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal
b
Parekh Marg, Matunga (E), Mumbai 400019, India; Department of Chemistry and Biochemistry,
University of California, Santa Barbara, CA 93106, USA; Centre of Biosciences, Institute of Chemical
c
Technology, Matunga (E), Mumbai 400019, India
ABSTRACT
ARTICLE HISTORY
A green protocol for the synthesis of unsubstituted imidazoles
has been demonstrated herein. The reaction is realized using
commercially available lipase enzyme, porcine pancreas lipase
Received 15 January 2020
Accepted 22 April 2020
KEYWORDS
Imidazole; aldehyde;
ammonium acetate; lipase
(
PPL) in water. The reaction conditions are selective and mild
which helped to tolerate a wide variety of functional groups to
give the desired products in good chemical yields.
1. Introduction
Enzyme catalysis is advancing very rapidly where directed evolution [1], enzyme
immobilization [2], cascade, and asymmetric reactions have attracted tremendous
attention [3]. In this regard, the 2018 Nobel prize besotted to enzyme catalysis should
not be a surprize considering the growth and potential of this field [4]. The advanced
study or mutation of genes there by directed evolution of enzyme by Arnold group
from Caltech has taken the application of the enzyme in organic synthesis to the next
level, and there is now no limit on how the enzyme can manipulate organic transfor-
mations those were hard to achieve through traditional ways.
CONTACT Hemchandra K. Chaudhari
hk.chaudhari@ictmumbai.edu.in
Department of Pharmaceutical Sciences
and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga (E), Mumbai 400019, India
Supplemental data for this article is available online at https://doi.org/10.1080/10286020.2020.1760852.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
S. S. KAPALE ET AL.
Figure 1. Important drugs bearing mono-or disubstituted imidazole.
While there is a lot to be done in engineering enzymes [5], the naturally occurring
enzymes are cheap and very easy to access due to their commercial availability to be dir-
ectly used in manufacturing organic compounds. In other words, if the chemistry is
done using commercially available ligands, then it can be explored quickly by commun-
ities who have little or no access to engineering enzymes. For example, lipase which in
the human body helps to break fats to fatty acid and glycerol is easily available and
hence, also widely studied in a series of organic transformations [6–8] Also, enzyme
.
catalysis mostly follows twelve principles of green chemistry [9], which shall not be over-
looked by looking at the current scenario of pollution created through wastes from
chemical factories. Keeping these points in mind and our interest in developing new
technologies for synthesis of medicinally important heterocycles [10], to demonstrate
that easily available lipase enzyme can be used for three-component condensation, lead-
ing to the formation of imidazoles which are considered to be highly important blocks
of medicinal products [11,12]. Some mono- and disubstituted imidazole containing drugs
examples are mentioned in Figure 1. Nevertheless, such moieties could be prepared in
good chemical yields using organic or inorganic reagents including metal catalysts
[13,14]. These protocols are although efficient; never clean enough to get the desired
product in purest form. Pertaining to regulation from pharmaceutical bodies, only no or
few ppm of toxic metal impurities were accepted in newly developed drugs [15].
2. Results and discussion
Considering now nature does chemistry using enzymes, attempts were made to per-
form this condensation of the reaction in water as a reaction solvent. As expected,
reaction took place in water to give 80% yield of the desired product. Across examin-
ation of howg organic solvents work for this reaction, the solvents which are generally
preferred for enzyme catalysis but not greener were screened. As presented in Table
1
, dimethylsulfoxide (DMSO), ethanol, methanol, acetic acid, and dimethyl forma-
mide (DMF) were tested. Out of these, ethanol gave comparable results to that of
water. Other unusual solvents for such chemistry lead to decreased chemical yield.
Also reducing the catalyst loading to half resulted in lower yield.
The best conditions were then applied on different substrates to see the generality
of the reaction (Scheme 1). The variation in aldehydes shows that both electron-
donating and electron withdrawing groups were tolerated by the reaction conditions to

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
a
Table 1. Solvent optimization study for the synthesis of imidazoles.
b
Entry
Solvent
t (h)
Yields (%)
c
1
2
3
4
5
6
7
8
9
Water
1
1
2
4
4
4
4
4
4
4
70 (55)
Ethanol
Methanol
DMSO
DMF
Acetic acid
THF
Chloroform
40
60
50
55
70
50
40
50
50
CH Cl
2 2
1
a
0
Acetonitrile
b
Reaction conditions: Glyoxal (1mmol), Benzaldenyde (1mmol), Ammonium acetate (2mmol) and Isolated yields.
c
ꢀ
Reaction was carried out using (50mg) of lipase catalyst in the water at 45 C for 1 hr are shown in Scheme 1.
Scheme 1. General procedures for the synthesis of unsubstituted imidazoles.
give moderate to good chemical yields (entries 3a & 3 b vs 3e & 3f in Figure 2. Halo
substitution on benzaldehyde has no problem in the reactivity (3c). Polar and strong
coordinating functional groups such as NH (entry 3d), -COOH (entry 3f) were also
2
found to give good chemical yields. Hetetro aryl aldehydes such as pyridine thiophene
gave a moderate yield of the desired products (entries 3 g & 3 h). This protocol was
then extended to the synthesis of tri-substituted imidazoles. From entries 3i-3m, it is
clear that reaction could be performed on all types of aldehydes. However, this reaction
was unable to give the desired products when either 1-Phenylpropane-1, 2-dione (3n) or
aliphatic aldehyde were used as one of the reaction components, which is in complete
harmony with enzyme catalysis where substrate specifications are highly important.
In a similar way, when glyoxal was treated with ammonium acetate and different
substituted benzaldehydes, 2-aryl substituted imidazole could be easily prepared
(Figure 2). Again, various functional groups are tolerated here.
In summary, it has been shown that monosubstituted imidazoles which are an
integral part of pharmaceuticals could be synthesized using commercially available
enzymes in water. The reaction is much greener compared to the ones reported in
the literature. This protocol is also applied for the synthesis of trisubstituted imida-
zoles. Further, the reaction could be applied to a wide variety of substrates.
3. Experimental
3.1. General experimental procedures
Melting points of all the compounds were recorded by the Analab Thermo Cal melt-
1
ing point apparatus in the open capillary tube and are uncorrected from H NMR

4
S. S. KAPALE ET AL.
Figure 2. Substrate scope for the synthesis of 2-Arylimidazole.
spectra were recorded on MR400 Agilent Technology NMR spectrometer using tetra-
methylsilane (TMS) as an internal standard the spectral data were obtained from the
ICT, Mumbai, India and DMSO-D /CDCl as a solvent. Chemicals and solvents used
6
3
were of LR grade and purchased from SD fine, Aldrich, Avra Synthesis and
Spectrochem, Mumabi, India Ltd, used without purification. The purity determination
of the starting materials and reaction monitoring was accomplished by thin-layer
chromatography (TLC) on Merck silica gel G F254 plates were purchased from Viresh
Chemicals Mumbai, India Ltd.
3
.2. General procedures for the synthesis of unsubstituted imidazoles
A mixture of glyoxal (0.058 g), benzaldehyde (0.106 g), ammonium acetate (0.154 g),
and lipase (0.05 g) were taken in a 50-ml, two-necked, round-bottomed flask. The
ꢀ
reaction mixture was stirred for 1-4 h at 45 C. in 10 ml water. After completion of
the reaction as indicated by thin-layer chromatography (TLC; ethyl acetate/n-hexane,
2
:1), the reaction mixture was filtered and washed with water (3 Â 10 ml), and the
solid residue was crystallized from ethyl acetate to give pure product 3a as white

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5
solid. All other products were prepared following this procedure and were identified
1
by their melting point, H NMR comparing to the literature.
In similar way, tri-substituted imidazoles are synthesized from benzil (0.004 g),
benzaldehydes (0.009 g), ammonium acetate (0.026 g), lipase (0.05 g) in 10 ml water,
were taken in a 50 ml two-necked round bottomed flask. The reaction mixture was
ꢀ
stirred for 4 hrs at 50 C.
Acknowledgements
The spectral data were obtained from the Institute of Chemical Technology, Mumbai.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
SSK and HKC are thankful to TEQIP III CoE-PI, India for financial support.
ORCID
Hemchandra K. Chaudhari
http://orcid.org/0000-0001-6866-9147
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