Microwave-assisted one-pot synthesis of bioactive UGI-4CR using fluorite as benign and heterogeneous catalyst

Article abstract of DOI:10.1080/00397911.2013.781184

Fluorite has been used as an activating heterogeneous catalyst for a rapid and facile one-pot synthesis of biologically active Ugi four-component reaction (Ugi-4CR) under microwave irradiation in good to moderate yields with short reaction times. The catalyst is environmentally benign, commercially available, and reusable several times with no reduction in its efficiency. The resulting Ugi derivatives 5(a-h) were characterized on the basis of ¹H and ¹³C NMR, infrared, elemental analysis, and mass spectral data. The synthesized moieties were screened for their potential antibacterial activities in vitro against a few microorganisms: Staphylococcus aureus (Gram positive) Bacillus subtilis (Gram positive) Escherichia coli (Gram negative) and Proteus vulgaris (Gram negative). The screening data show that compounds 5a, 5c, 5e, and 5h are highly active against the strains. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.781184

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Microwave-Assisted One-Pot Synthesis
of Bioactive UGI-4CR Using Fluorite as
Benign and Heterogeneous Catalyst
Ipsita Mohanram a , Jyotsna Meshram a , Ambareen Shaikh a
Bhavna Kandpal a
&
a Department of Chemistry , Rashtrasant Tukadoji Maharaj Nagpur
University , Nagpur , Maharashtra , India
Published online: 05 Sep 2013.
To cite this article: Ipsita Mohanram , Jyotsna Meshram , Ambareen Shaikh & Bhavna Kandpal
(2013) Microwave-Assisted One-Pot Synthesis of Bioactive UGI-4CR Using Fluorite as Benign
and Heterogeneous Catalyst, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:24, 3322-3328
To link to this article: http://dx.doi.org/10.1080/00397911.2013.781184
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Synthetic Communications1, 43: 3322–3328, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.781184
MICROWAVE-ASSISTED ONE-POT SYNTHESIS OF
BIOACTIVE UGI-4CR USING FLUORITE AS BENIGN
AND HETEROGENEOUS CATALYST
Ipsita Mohanram, Jyotsna Meshram, Ambareen Shaikh, and
Bhavna Kandpal
Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur
University, Nagpur, Maharashtra, India
GRAPHICAL ABSTRACT
Abstract Fluorite has been used as an activating heterogeneous catalyst for a rapid and
facile one-pot synthesis of biologically active Ugi four-component reaction (Ugi-4CR)
under microwave irradiation in good to moderate yields with short reaction times. The cata-
lyst is environmentally benign, commercially available, and reusable several times with no
reduction in its efficiency. The resulting Ugi derivatives 5(a–h) were characterized on
the basis of 1H and 13C NMR, infrared, elemental analysis, and mass spectral data. The
synthesized moieties were screened for their potential antibacterial activities in vitro against
a few microorganisms: Staphylococcus aureus (Gram positive), Bacillus subtilis (Gram
positive), Escherichia coli (Gram negative), and Proteus vulgaris (Gram negative). The
screening data show that compounds 5a, 5c, 5e, and 5h are highly active against the strains.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Received January 2, 2013.
Address correspondence to Ipsita Mohanram, Department of Chemisty, Rashtrasant Tukadoji
Maharaj Nagpur University, Nagpur, Maharashtra, India. E-mail: ipsita.mohanram@gmail.com
3322

SYNTHESIS OF BIOACTIVE UGI-4CR
3323
Keywords Biological activity; fluorite; green synthesis; heterogeneous catalysis;
microwave irradiation; Ugi-4CR
INTRODUCTION
The utility of microwave (MW) energy in synthetic organic chemistry has been
increasingly recognized in recent years.[1] Microwave-assisted solid-phase heterogeneous
reactions are environmentally benign methodologies that have greater selectivity,
enhanced reaction rates, cleaner products, and manipulative simplicity.[2] Microwave-
mediated multicomponent reactions constitute an especially attractive synthetic strategy
for rapid and efficient library generation because products are formed in a single step
and diversity can be achieved simply by varying the reacting components.[3]
Among many kinds of multicomponent condensations, the Ugi reaction[4] is
highly convergent for the rapid generation of organic druglike molecule libraries
and many different types of biologically active targets.[5] The Ugi-4CR in which an
amine, an aldehyde or ketone, a carboxylic acid, and an isocyanide combine to yield
a-N-acylaminoamide[6] is particularly attractive because of the wide range of pro-
ducts obtainable through variation of the starting materials. The quinoline nucleus
is present in several natural compounds and pharmacologically active substances dis-
playing a broad range of biological activity. Quinolines and their derivatives
have been found to possess anti-inflammatory,[7] antimalarial,[8] antimicrobial,[9]
anticonvulsant,[10] antineoplastic,[11] vasorelaxing,[12] and antiproliferative[13] activi-
ties. Ugi four-component derivatives have also been found to have various applica-
tions (viz., anesthetics, antibiotics, natural product isolation, HIV protease inhibitor
crixivan,[14–16] etc.). Therefore, it is of significance to develop novel preparations for
Ugi-4CR having a quinoline nucleus.
Classically, the Ugi reaction was performed at room temperature or under reflux
in methanol with reaction times up to 12–24 h or more using several catalysts.[17–20]
However, most of these methods employ long reaction times with moderate yields.
Recently, a new, simple, and elegant synthesis of Ugi-4CR has been described using
ionic liquids and water.[21,22] Moreover, fluorite has also been used as a mild and effi-
cient promoter for various organic reactions.[23,24] Fluorite[25,26] (also called fluorspar)
is a naturally occurring halide mineral composed of calcium fluoride (CaF2). Fluorite
is the primary source of fluorine and its compounds. It has a hardness of 4 on Mohs’s
scale and a melting point of 1360 ꢀC. However, this rock mineral is an intrinsically
acidic substance, but it cannot be used in solution chemistry bacause of its insolubility
in organic solvents and water. In view of the remarkable importance from pharma-
cological, industrial, and synthetic points of view, herein we report that fluorite acts
as a heterogeneous mild acid catalyst for the one-pot synthesis of biologically active
Ugi-4CR under a microwave method within the framework of green chemistry proto-
col. Fluorite is environment benign, reusable, and commercially available.
RESULTS AND DISCUSSION
In the present study, we report the condensation of 2-chloroquinoline-3-
carbaldehyde, substituted aniline, ethylisocyanoacetate, and an aromatic carboxylic
acid via a microwave method in the presence of fluorite as a catalyst (Scheme 1). The

3324
I. MOHANRAM ET AL.
reaction initiates with the formation of imine from amine and aldehyde with loss of 1
equivalent of water. Proton exchange with carboxylic acid activates the iminium ion
for nucleophilic addition of the isonitrile with its terminal carbon atom to nitrilium
ion. A second nucleophilic addition takes place at this intermediate with the car-
boxylic acid anion. The final step is a Mumm rearrangement with transfer of the acyl
group from oxygen to nitrogen. All steps in the reaction are reversible except the
Mumm rearrangement, which drives the whole reaction sequence. Although we have
synthesized Ugi-4CR derivatives with 2-chloroquinoline-3-carbaldehyde, substituted
aniline, ethylisocyanoacetate, and an aromatic carboxylic acid, these sequences of
reaction can also be performed with various aliphatic as well as aromatic aldehydes.
A majority of the variations can also be made at the carboxylic acid and primary
amine center, whereas only a few combinations of educts do not react. Ugi-4CR can
also proceed using various isonitriles.[27]
Fluorite acts as a mild acid in the dehydration reaction and increases the reac-
tion rate without affecting the yield of desired products. The results of model reac-
tion (Scheme 1) pertaining to yield and reaction times are summarized in Table 1. It
is significant from Table 1 that the catalytic amount of fluorite accomplishes the
reaction successfully and the use of microwave energy further enhances the yield
of the product with reduction in time. Consistent yields of 70–95% were obtained
in 2–10 min of microwave irradiation in a green chemistry protocol.
The integral part of this study is to synthesize Ugi-4CR using fluorite as a cata-
lyst; we therefore study the activity of fluorite by comparing three reactions in the
presence of catalyst and same reactions in the absence of catalyst. The reactions were
Scheme 1. Synthesis of Ugi-4CR derivatives using fluorite under MW irradiation. (Figure is provided in
color online.)

SYNTHESIS OF BIOACTIVE UGI-4CR
3325
Table 1. Time and % yield of Ugi-4CR derivatives using fluorite (2% wt)
under MW irradiation
Compounds
Time (min)
% Yielda
M.P (ꢀC)
5a
5b
5c
5d
5e
5f
3
6.5
2
92
89
95
88
91
90
89
90
178–180
168–172
158–160
173–175
142–145
160–162
153–155
164–166
7.5
4.5
2.5
10
5
5g
5h
aIsolated yields after recrystallization.
performed via microwave using 3-nitrobenzaldehyde, aniline, methylisocyanoace-
tate, and a sequence of primary, secondary, and tertiary aliphatic carboxylic acid
in similar reaction conditions. The results are tabulated in Table 2. Consistent
decrease in yields and increase in reaction time were observed in the presence as well
as in the absence of the catalyst for primary, secondary, and tertiary aliphatic acids
respectively. Although fluorite is an excellent catalyst, moderate yields have been
obtained. This is possibly due to aliphatic carboxylic acids.[28] In the case of aliphatic
acids, electron-donating alkyl groups are present, which do not allow carboxylic acid
to donate its proton easily and ultimately lead to the decrease in the formation of
the carboxylate ion. In aromatic acids, benzene ring is an electron-withdrawing com-
pound and the carboxylic acid easily donates its proton and forms carboxylate ion,
which is a good nucleophile.
To check the efficiency of the catalyst, we have synthesized compound 5c in
three consecutive reactions using various amounts of catalyst as 2% and 2.5% weight
with respect to all reactants. Fluorite was crushed into pieces 1–2 mm in size before
use, frequently washed with distilled water and acetone, and dried. Efficient recycl-
ability was observed in three consecutive reactions and the desired product was
obtained in the stipulated time period. No change in the yields and purity of the
desired product was observed (Table 3). It is noteworthy that the catalyst was easily
isolated after the completion of reaction and reused several times. All synthesized
1
compounds were evaluated by H NMR, 13C NMR, infrared, elemental analysis,
and mass spectral data.
Table 2. Comparative study of Ugi-4CR with and without fluorite catalyst
(2% wt) under MW irradiation
Catalyst
No catalyst
Entry Carboxylic acids Time (min) %Yielda Time (min) %Yielda
1
2
3
Acetic
Isobutyric
Pivalic
14
18
25
70
66
58
30
45
62
53
40
120
aIsolated yields after recrystallization.

3326
I. MOHANRAM ET AL.
Table 3. Recycling experiments of catalytic activity of fluorite using
compound 5c
Catalyst (wt %) Cycle Time (min) %Yielda Recovery (wt %)
2
1
2
3
1
2
3
2
2
2
2
2
2
95
93
94
90
92
95
97
97
98
96
98
97
2.5
aIsolated yields after recrystallization.
ANTIBACTERIAL ACTIVITY
The synthesized compounds 5(a–h) were screened for antibacterial activities
against S. aureus, B. subtilis, E. coli, and P. vulgaris using the well diffusion method.
Each test compound (5 mg) was dissolved in ethanol (5 ml, 1000 mg=ml), which was
used as sample solution. Sample size for all the compounds was fixed at 0.1 ml.
Ampicillin and streptomycin were used as standard drugs, and ethanol was used
as negative control. The cultures of the bacterial strains were inoculated in 10 ml
nutrient broth and incubated at 37 ꢀC for 24 h. The Petri dishes and nutrient agar
medium were sterilized by autoclaving. To this sterilized nutrient medium 1 ml of
one-day-old bacterial culture was added and spread over the Petri plate. The wells
impregnated with 1000 mg=ml of newly synthesized compounds were introduced
aseptically in the nutrient agar plate. All the nutrient agar plates were incubated
at 37 ꢀC for 24 h, after which the plates were observed for clear zone of inhibition.
The screening results from Table 4 indicate that the compounds 5a, 5c, 5e, and 5h
showed excellent antibacterial activities, whereas 5b, 5d, 5f, and 5g show moderate
to negligible activity against the used strains.
Table 4. Antibacterial activity of Ugi-4CR derivatives 5 (a–h)
Gram-positive bacteria
Gram-negative bacteria
E. coli P. vulgaris
Compound
S. aureus
B. subtilis
5a
5b
þþþ
þþ
þþþ
þ
þþþ
þþ
þþ
—
5c
5d
þþþ
þ
þþþ
þ
þþ
þþ
þ
þþ
5e
þþþ
þþ
þþ
—
þþþ
þþþ
þ
þþþ
þ
5f
5g
þþ
þ
þþ
þþþ
þþ
þþþ
5h
Ampicillin
Streptomycin
þþþ
þþþ
þþþ
þþ
þþ
þþþ
þþþ
þþþ
þþþ
Key to symbols: Inactive ¼ —(inhibition zone < 5 mm); Slightly active ¼ þ(inhibition zone 5–10 mm);
Moderately active ¼ þþ (inhibition zone 10–15 mm); Highly active ¼ þþþ (inhibition zone > 15 mm).

SYNTHESIS OF BIOACTIVE UGI-4CR
3327
EXPERIMENTAL
All reagents and solvents are of analytical grade and were used directly. All
melting points were determined by the open-tube capillaries method and are uncor-
rected. The microwave (MW) reactions were carried out in a CEM 908010, bench
mate model, 300-W laboratory MW reactor. IR spectra (tmax in cmꢁ1) were recorded
1
on Schimadzu-IR Prestige 21 spectrophotometer using the KBr technique. H and
13C NMR spectra were recorded on a Bruker-Avance (400-MHz) spectrophotometer
using dimethylsulfoxide (DMSO-d6) solvent and tetramethylsilane (TMS) as an
internal standard. Mass spectra were recorded on a Waters Micromass Q-T micro-
spectrometer. The elemental analysis (C, H, and N) of compounds was performed on
a Carlo Erba-1108 elemental analyzer. Antibacterial screening was carried out at the
Department of Biotechnology, Sindhu Mahavidyalaya, Nagpur, India.
A mixture of 2-chloroquinoline-3-carbaldehyde (0.01 mol), substituted aniline
(0.01 mol), ethylisocyanoacetate (0.01 mol), and aromatic carboxylic acid (0.01 mol)
was dissolved in 5 ml of 95% ethanol and the catalyst, fluorite (2% weight with
respect to all reactants), was taken in a conical flask capped with a funnel and irra-
diated under microwave at 120 W (Scheme 1). The completion of the reaction was
monitored by thin-layer chromatography (0.5 mm thick) using silica gel-G–coated
Al plates (Merck) by using a mixture of ethyl acetate and hexane as mobile phase,
and spots were visualized by exposing the dry plates in iodine vapors. After com-
pletion, the reaction mixture was allowed to attain room temperature. The crude
product and catalyst was collected by filtration. The crude product was purified
by recrystallization from hot ethanol.
CONCLUSION
In conclusion, this study shows that fluorite is an excellent heterogeneous mild
acid catalyst for one-pot microwave-mediated synthesis of biologically active Ugi-
4CR, thereby reducing reaction time with good to excellent yields in a green chemical
pathway. Furthermore, utility, no toxicity, reusability, low cost, and ease of isolation
after completion of reaction are the remarkable features of the catalyst.
ACKNOWLEDGMENTS
We are thankful to Rajiv Gandhi National Fellowship (Grant No. RGNF-SC-
UTT-2299) University Grants Commission, New Delhi, for financial support. The
authors thank the head, Department of Chemistry, Rashtrasant Tukadoji Maharaj
Nagpur University, Nagpur, for providing laboratory facilities and the director,
SAIF, Chandigarh, for providing necessary spectral data.
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