Activated fly ash catalyzing the synthesis of novel potent 4-thiazolidinones of 4-amino antipyrine anils using CEM discover microwave methodology and their virtual screening

Article abstract of DOI:10.1080/10426507.2013.769977

Fly ash, an industrial waste, has been used as an efficient and cost-effective activating catalyst for the synthesis of new potent thiazolidinones (4a-n), starting from imine (3a-n) and thioacetic acid. The reactions were performed under CEM Discover micr

Full text of DOI:10.1080/10426507.2013.769977

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Activated Fly Ash Catalyzing
the Synthesis of Novel Potent 4-
Thiazolidinones of 4-Amino Antipyrine
Anils Using CEM Discover Microwave
Methodology and Their Virtual Screening
Manoj Dilip Shanti a b , Kaveri Shanti b & Jyotsana Meshram b
a Rajiv Gandhi College of Engineering & Research , Nagpur , 440033 ,
India
b Department of Chemistry , Rashtrasant Tukadoji Maharaj Nagpur
University , Nagpur , -440033 , India
Published online: 06 Sep 2013.
To cite this article: Manoj Dilip Shanti , Kaveri Shanti & Jyotsana Meshram (2013) Activated Fly Ash
Catalyzing the Synthesis of Novel Potent 4-Thiazolidinones of 4-Amino Antipyrine Anils Using CEM
Discover Microwave Methodology and Their Virtual Screening, Phosphorus, Sulfur, and Silicon and the
Related Elements, 188:10, 1351-1360, DOI: 10.1080/10426507.2013.769977
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Phosphorus, Sulfur, and Silicon, 188:1351–1360, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.769977
ACTIVATED FLY ASH CATALYZING THE SYNTHESIS OF
NOVEL POTENT 4-THIAZOLIDINONES OF 4-AMINO
ANTIPYRINE ANILS USING CEM DISCOVER MICROWAVE
METHODOLOGY AND THEIR VIRTUAL SCREENING
Manoj Dilip Shanti,1,2 Kaveri Shanti,2 and Jyotsana Meshram2
1Rajiv Gandhi College of Engineering & Research, Nagpur 440033, India
2Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur University,
Nagpur-440033, India
GRAPHICAL ABSTRACT
Abstract Fly ash, an industrial waste, has been used as an efficient and cost-effective activating
catalyst for the synthesis of new potent thiazolidinones (4a–n), starting from imine (3a–n) and
thioacetic acid. The reactions were performed under CEM Discover microwave irradiation in
solvent-free conditions. This reaction is scalable to a multigram scale and the methodology has
resulted in an efficient synthesis. Herein, a benign, environment friendly, efficient, and extremely
fast procedure for the synthesis of thiazolidinones have been demonstrated. The produced
thiazolidinone molecules were characterized on the basis of elemental analysis, infrared (IR),
mass spectral, and 1H NMR spectral data. The synthesized moieties were screened virtually
and discussed for their possible biological activity.
Supplementary materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental
files: Additional text and tables.
Keywords Activated fly ash; thiazolidinones; solvent-free; virtual screening; biological activity
Received 4 June 2012; accepted 19 January 2013.
The authors are thankful to the reviewers for their valuable suggestions.
Address correspondence to Manoj Dilip Shanti, Department of Chemistry, Rashtrasant Tukadoji Maharaj
Nagpur University, Nagpur India-440033. E-mail: mnjshanti@yahoo.co.in
1351

1352
M. D. SHANTI ET AL.
INTRODUCTION
The green chemistry principles include the development of safer chemicals, safer
solvents, solvent-free synthetic methods, “atom economy,” and inherent safer reaction
conditions for accident prevention. Traditionally, thiazolidinones are heterocyclic com-
pounds well known for their broad spectrum of biological activities such as antibacterial,
antifungal, antitubercular, anthelmintic, anti-inflammatory, anti-thyroid, local anesthetic,
COX-1 inhibitive, antiproliferative, antihistaminic, anti-HIV activities and for monoamine
oxidase inhibition.1–6 In recent years, several new methods for the preparation of thiazo-
lidinone derivatives and reactions have been reported in the literature, using conventional
homogeneous acid catalysts such as H2SO4, HF, AlCl3, FeCl3 etc.7 Previously, Wang8 and
Desai and co-workers reported the facile microwave-enhanced synthesis of thiazolidinones
using ZnCl2 in dimethylformamide (DMF).9 However, these reactions suffered from a few
shortcomings, such as lengthy reaction times (2–8 h), the use of high-boiling-point solvents
[DMF, THF (tetrahydrofuran), dioxane], low yields (50–60%), and the use of reactants with
high toxicity, which bound their use for the synthesis of complex molecules. A combina-
tion of the mineral-supported and microwave irradiation has been used to carry out a wide
range of reactions under solvent-free conditions.10 Synthesis of organic compounds under
solvent-free conditions, especially adopted to microwave irradiation, leads to increased
safety and environmental facets.11
For this purpose, heterogeneous catalysis plays an elementary role, chiefly due to
its economic and environmental advantages (i.e. minimum execution time, low corrosion,
waste minimization, recycling of the catalyst, easy transport, and clearance of catalysts).12
Of course, the combination of heterogeneous catalysis with solvent-free conditions under
microwave irradiation represents a suitable way toward the so-called model synthesis.13
Microwave irradiation facilitates the polarization of the molecule under irradiation, causing
a rapid reaction to occur, which increases the yield and the so-called atom economy. The
discussed drawbacks were eliminated when the reactions were carried out in the presence of
zeolite as an activator under microwave irradiation, which has already been reported.14 Thus,
owing to our interest to use something less costly in comparison with zeolites, we attempted
to use activated fly ash as an inexpensive activator for the synthesis of 4-thiazolidinones 4
(a–n) by the reaction of imine 3 (a–n) with thioglycolic acid under microwave irradiation
to catalyze reactions that have industrial, pharmacological, and therapeutic importance..
Making use of waste and finding something valuable out of it almost makes the synthesis
a cost-reductive process. The high synthetic utility and pharmacological importance of
thiazolidinone family have prompted us to realize a virtual pharmacological study of
the antibacterial activity of the compounds 4 (a–n) (Scheme 1). Herein, we performed
an investigation of compounds 4 (a–n) because they represent an attractive model for a
theoretical and experimental study of the pharmacophore and their medical applications
because of the large variability and combination in their substituents. The main interesting
tasks of this work are: (i) developing a robust synthetic protocol for the heterocycles,
(ii) interpreting the calculated/predicted results for designing of new compounds, (iii)
performing pharmacophore modeling based on structures to support the lead optimization
process, and (iv) finding the right molecule for the right target.
RESULTS AND DISCUSSION
The emerging interest for the use of solid inorganic acids in organic synthesis
in comparison with liquid acids is advantageous due to the simplicity in handling and

SYNTHESIS OF THIAZOLIDINONES USING ACTIVATED FLY ASH
1353
Scheme 1 Schematic representation of fly ash-catalyzed microwave production of 4-thiazolidinones.
environmental protection.15,16 The use of fly ash also reveals some features such as reduc-
tion in the thermal degradation, better selectivity, and easy work-up after reaction. The
results when compared with known classical laboratory methods show a tremendous de-
cline in the reaction time, from hours to minutes. The idea behind the methodology to use
fly ash as an activator arose due to the silica contents of the fly ash and its surface adsorption
properties.
Fly ash was collected from BILT Paper Mills, Ashti, Maharashtra, India. The particle
size and its composition were recorded accordingly from an analysis by the company. It can
adsorb all kinds of molecules smaller than its size.17 The specific gravity and specific surface
area of fly ash were 1.81 and 131 m2/g, respectively. The chemical compositions of fly ash
used for catalysis are reported in Table 1. The chemical compositions vary depending upon
the type of coal used. It is rather inconsistent to get fly ash with same amount of ingredients
all the time. We just checked for the content of silica and alumina in the provided fly ash.
The high silica content yields high chemical resistance. It is stable above 500–600◦C.
It can absorb various small molecules such as water, hydrochloric acid, ammonia, methanol,
and hydrogen sulfide. It has several advantages, including being environmentally friendly,
nontoxic, inexpensive, recoverable, and reusable. Therefore, we decided to explore its

1354
M. D. SHANTI ET AL.
Table 1 Composition of fly ash used in the present study
Variation depending upon
type of coal used
Constituents
Fly ash (%)
SiO2
68.23
2.50
15.53
4.12
70.5 9.6
7.5 4.3
22.8 5.4
4.9 2.9
1.3 0.7
Fe2O3
Al2O3
CaO
MgO
0.78
suitability in the heterocyclization reaction. Our synthetic approach is very simple and clear.
First, Schiff’s bases, 1, 2-dihydro-2, 3-dimethyl-4-(4-oxo-2-substituted phenylthiazolidin-
3-yl)-1-phenylpyrazol-5-one, were prepared from the reaction of 4-amino-1,2-dihydro-2,3-
dimethyl-1-phenylpyrazol-5-one and different aromatic aldehydes using a reported method
by the MORE technique.18,19. Finally, imines on heterocyclization with mercaptoacetic acid
using activated fly ash under microwave irradiation afforded 4-thiazolidinones, as shown
in Scheme 1.
Initially, we investigated the microwave-assisted synthesis of 4-(2-hydroxybenzylid-
eneamino)-1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one (imine) by taking salicyalde-
hyde and 4-amino antipyrine in a 1:1 molar ratio and irradiated the reaction mixture at
different temperatures 100, 120, 140, 160◦C for a time period ranging from 10 to 40 sec
(tabulated in Table 2). The progress of the reaction was monitored by thin-layer chro-
matography (TLC) using the ethyl acetate:petroleum ether (EtOAc:Pet. ether) (2:8) eluting
system, and the completion of the reaction was observed when the reaction mixture was
irradiated at 140◦C for 20 sec, giving the highest yield.
The resultant imine was then heterocyclized with mercaptoacetic acid in 1:1 propor-
tion with a varying amount of activated fly ash (0.25, 0.5, and 0.75 g) for a period of 5–10 min
at different temperatures 160, 170, 180◦C. The progress of the reaction was monitered by
TLC using the EtOAc:Pet. ether (3:7) eluting system. Best results were obtained with 0.50 g
of activated fly ash, irradiation time of 8 min, at 170◦C. An optimization chart with fixed
amounts of activated fly ash, time, and yield are given in Table 3. This method is very easy
and can be used for synthesis of different thiazolidinones 4 (a–n), depending on different
substituted groups. Structural features of the synthesized azomethine and thiazolidinone
1
were obtained from FTIR, elemental analysis, H NMR, 13C NMR(thiazolidinone), and
mass spectral studies and they confirmed their structures.
In the infrared (IR) spectra of the 4-amino-1, 2-dihydro-2, 3-dimethyl-1-
phenylpyrazol-5-one, the characteristic absorptions around 1620 cm−1 and 1750 cm−1 are
Table 2 Optimization of microwave-mediated synthesis of imines
Reaction monitoring by TLC
[EtOAc: Pet.Ether (2:8)]
Entry
Temperature (◦C)
Time (sec)
% Yield
1
2
3
4
100
120
140
160
10
10
10
10
20
20
20
20
30
30
30
30
40
40
40
40
RNC
RNC
RNC
RNC
RNC
RNC
RC
RNC
RNC
—
RC
RC
—
92
92
95
95
RC
—
—
RNC, reaction not completed; RC, reaction completed

SYNTHESIS OF THIAZOLIDINONES USING ACTIVATED FLY ASH
1355
Table 3 Optimization chart for activated fly ash-catalyzed solvent-free synthesis of 4-thiazolidinones under
microwave radiation.
,
General representation of compounds 4(a–n)
Compound
R
Activated fly ash (g) Temperature (◦C) Time (min) Isolated yield (%)
4a
4b
0.50
0.50
170
170
08
10
90
93
4c
0.50
170
07
95
4d
4e
0.50
0.50
170
170
09
08
95
90
4f
0.50
170
08
89
4g
4h
4i
0.50
0.50
0.50
0.50
0.50
170
170
170
170
170
09
10
10
15
09
92
85
84
85
90
4j
4k
4l
0.50
0.50
0.50
170
170
170
10
07
09
85
91
90
4m
4n

1356
M. D. SHANTI ET AL.
assigned to (–C N) azomethine linkages and (–C O) carbonyl functionality, respectively,
to be present in the imines. The stretching frequencies for –C N were absent in the IR
spectrum, which confirms the cyclization at the hetero atom.
Method for Activation of Fly Ash
The fly ash collected was first sieved in a 100 mesh sieve to remove any coarser and
foreign particles and then was mechanically ground in a ball mill to a fine powder. The
particle size distribution was found to be between 30 and 80 μm. Finely ground fly ash
was kept at a temperature of about 900–1000◦C in a muffle furnace for 1 h for activation
and was used for investigation. The carbon, sulfur, and other impurities were removed by
thermal activation and the resultant fly ash is called activated fly ash. The activated fly
ash was then checked for its activity and found to be one of the most efficient microwave
absorbers with a very high specificity to microwave heating. This work was conducted in
a commercial microwave appartaus (CEM Discover focused MW synthesis system) in a
10-mL crimp-sealed, thick-walled glass tube.
Virtual Screenings and Molecular Properties Calculations
Molinspiration Clculations23–31. CLogP is the octanol/water partition coefficient
that is calculated by the methodology developed by Molinspiration as a sum of fragment-
based contributions and correction factors (Tables S1 and S2). Molecular polar surface
area (MPSA) is calculated based on the methodology published by Ertl et al. as a sum of
fragment contributions. O- and N-centered polar fragments are considered. PSA has been
shown to be a very good descriptor characterizing drug absorption (including intestinal
absorption), bioavailability, Caco-2 permeability, and blood–brain barrier penetration, as it
is the surface sum of overall polar atoms (usually oxygen and nitrogen), including attached
hydrogens also. Prediction results of the molecular properties [TPSA, G-protein coupled
receptor (GPCR) ligands, and ion channel modulators (ICMs)] of compounds 4 (a–n) are
presented in Table S2.
It is clear from the tabular data that the compounds 4f and 4g have good PSA values
comparable with ampicillin and streptomycin. It is predicted that the negative charges
of the oxygen and nitrogen atoms of the thiazolidinone group and the partial π-positive
charges of sulfur and supplementary arm 2-OH contribute more positively in favor of the
antibacterial activity. It has been hypothesized that the difference in charges between two
heteroatoms of the same pharmacophore site may facilitate the inhibition of bacteria, more
than that of viruses. It has been further found that the activity increases with the increase
in the negative charge of one heteroatom of the common pharmacophore fragment of the
compounds. Expert system for calculation of the drug likeness score toward GPCR ligands,
ICMs, kinase inhibitors, nuclear receptor ligands, and protease inhibitors based on the
Molinspiration technology has been tested—the results of which are tabulated in Table S2
and compounds such as 4e, 4f, 4g, 4i, and 4j are in good agreement with the reference
drugs used.
Osiris Calculations20–28. Structure-based design is now fairly routine, but many
potential drugs fail to reach the clinic because of ADME-Tox (absorption, distribution,
metabolism, excretion, and toxicity) liabilities. The Osiris calculations are tabulated in
Table S3. Toxicity risks (mutagenicity, tumorigenicity, irritation, reproduction) and physic-
ochemical properties (mi log P, solubility, drug likeness, and drug score) of compounds 4a

SYNTHESIS OF THIAZOLIDINONES USING ACTIVATED FLY ASH
1357
and 4b are calculated by the methodology developed by Osiris. The toxicity risk predictor
locates fragments within a molecule that indicate a potential toxicity risk. Toxicity risk
alerts are an indication that the drawn structure may be harmful concerning the risk cate-
gory specified. The data evaluated in Table S3 indicate that all structures are supposed to
be mutagenic, tumorigenic, non-irritating, with no reproductive effects when run through
the mutagenicity assessment system, shown with red and green spheres, comparable with
standard drugs used. All the compounds 4a–n have log P values under the acceptable
criteria.
Our estimated log S value is a unit stripped logarithm (base 10) of a compound’s
solubility measured in mol/liter. There are more than 80% of the drugs on the market
that have a (estimated) log S value greater than –4. And, to our surprise, we found all
the synthesized compounds having a value greater than –4. Further, Table S3 shows drug
likeness of compounds 4a and 4j that is in the comparable zone with that of standard drugs
used for comparison and even greater than them except for the ortho- and the para-nitro
derivatives, i.e., 4f and 4j. We have calculated the overall drug score for compounds 4a
and 4j and compared it with that of standard drugs (ampicillin and streptomycin) used,
as shown in Table S2. The drug score combines drug likeness, mi log P, log S, molecular
weight, and toxicity risks in one handy value that may be used to judge the compound’s
overall potential to qualify as a drug. This value is calculated by multiplying contributions
of the individual properties with Equation (1):
DS = ꢀ(1/2 + 1/2Si)ꢀti
(1)
where, S = 1/1+eap+b, DS is the drug score, Si is the contributions calculated directly from
mi log P, log S, molecular weight, and drug likeness (pi) via the second equation, which
describes a spline curve. Parameters a and b are (1, –5), (1, 5), (0.012, –6), and (1, 0) for mi
log P, log S, molecular weight, and drug likeness, respectively. ti is the contributions taken
from the four toxicity risk types. The ti values are 1.0, 0.8, and 0.6 for no risk, medium risk
and high risk, respectively. The reported compounds 4a–j showed moderate to good drug
score as compared with standard drugs used, except 4f and 4j.
CONCLUSION
In conclusion, we have developed an activated fly ash-catalyzed, simple, solvent-free,
cost-effective, and environmentally benign technique for the synthesis of 4-thiazolidinones.
This reaction is scalable to multi-gram scale. These compounds have been synthesized in
high yield by using fly ash and avoiding the use of any solvent under microwave irradiation.
Making use of a waste and carrying out a useful reaction out of it are really inspirational
for future research. The astonishing reduction in the rate of reaction invariably made the
process efficient from a future perspective to other such acid-catalyzed reactions. Apart
from this, the virtual screening results are in good agreement with the standard drugs used
for comparison. So, it is worth synthesizing the drug moieties on such a green scale.
EXPERIMENTAL SECTION
General
All reagents, solvents, and the catalyst are of analytical grade from a commercial
source and used directly. All the melting points were determined in a SONAR scientific

1358
M. D. SHANTI ET AL.
melting point apparatus and are uncorrected. The purity of compounds was checked rou-
tinely by thin-layer chromatography (TLC) (0.5 mm thickness) using silica gel-G coated
Al-plates (Merck) and the spots were visualized by exposing the dry plates to iodine vapors.
IR spectra (υmax in cm−1) were recorded on a Bruker ALPHA FTIR spectrometer, 1H NMR
spectra on a Bruker WM 400-MHz NMR instrument using CDCl3 and dimethyl sulfoxide
(DMSO)-d6 as solvents and tetramethylsilane (TMS) as internal reference (chemical shifts
in δ, ppm), and mass spectra on a Jeol JMS D-300 spectrometer operating at 75 eV. The
elemental analysis (C, H, N, and S) of compounds was performed on a Carlo Erba-1108
elemental analyzer. The results were found to be in good agreement with the calculated
values. The microwave-assisted reactions are carried out in a “CEM DISCOVER” manu-
factured by CEM Technologies Corporation.29 In this unit, microwaves are generated by a
magnetron at a frequency of 2450 MHz, having an output energy range of 100–500 W.
Microwave-Mediated General Synthesis of 4-(2-Hydroxybenzylidenea-
mino)-1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one 3(a). 4-(2-hydroxybenz-
ylideneamino)-1, 2-dihydro-2, 3-dimethyl-1-phenylpyrazol-5-one was obtained by the
condensation of 4-amino-1, 2-dihydro-2, 3-dimethyl-1-phenylpyrazol-5-one and salicy-
laldehyde. This work was conducted in a commercial microwave apparatus (CEM Discover
focused microwave synthesis system) in a typical solvent-free approach. A mixture of 4-
amino antipyrine(1) (2.46 mmol, 1.5 g) and salicylaldehyde (4.92 mmol, 3.0 g) without any
solvent was taken in a 10-mL crimp-sealed, thick-walled glass tube and irradiated at 140◦C
(400 W) for 20 sec. After completion of the reaction, the resultant mixture was allowed to
cool down to room temperature. After cooling, the resultant solid was crushed, washed with
cold ethanol, filtered, and dried under vacuum to give the crude product. The crude product
was recrystallized from methanol.30,31 The same method was followed for the production of
other imines (3b–n). The spectral characterization is given in the Supplemental Materials.
Microwave-Mediated Activated Fly Ash-Catalyzed General Synthesis
of 1, 2-Dihydro-4-(2-(2-hydroxyphenyl)-4-oxothiazolidin-3-yl)-2, 3-dimethyl-
1-phenylpyrazol-5-one 4(a):. A mixture of 4-(2-hydroxybenzylideneamino)-1, 2-
dihydro-2, 3-dimethyl-1-phenylpyrazol-5-one (3a) (3.23 mmole, 1.0 g), SHCH2COOH
(thioacetic acid) (3.23 mmole, 0.30 g), and activated fly ash (0.50 g) was taken in a 10-mL
crimp-sealed, thick-walled glass tube and irradiated at 170◦C (400 W) in a commercial
microwave apparatus (CEM Discover focused microwave synthesis system) in a typical
solvent-free approach for 8 min. The reaction was monitored by TLC. After completion
of the reaction, the pasty solid obtained was allowed to cool. To that, ethanol (15 mL)
was added and stirred for 5 min, up to the dissolution of the pasty solid. The fly ash was
filtered out of the mother liquor for the other reaction. The mother liquor was poured onto
crushed ice and the pH of the solution was set to 10 using 10% NaHCO3 solution. The
reaction mass was then stirred, filtered, and washed with cold water. The crude product
was recrystallized from methanol. The same process was used for the production of other
thiazolidinones 4(b–n).
White-yellow solid; yield: 90%. mp 139–141◦C. IR (cm−1, KBr): 1295 ( C O),
3250 ( OH); 1H NMR (ppm, DMSO-d6): 1.88 (s, 3H, CH3), 2.52 (s, 3H, N CH3), 3.43
(s, 2H, −CH2-thiazolidinone),5.91 (s,1H, N CH), 6.50–7.45 (m, 9H, aryl), 12.10 (s, H,
OH). 13C NMR (100 MHz) [δ (ppm), CDCl3]: 171.47 (C O), 170.84 (C O), 150.12
(C OH), 136.64 (C), 105.32 (C), 50.52 (CH), 36.26 (N CH3), 33.12 (CH2), 16.26 (CH3),
129.33, 126.77, 123.22, 122.98, 120.50, 117.32, 115.90, 115.70, 111.10 (Caromatic); MS
(m/z) 404 (M + 23). Anal. Calc. for: C20H19N3O3S, C, 62.97; H, 5.02; N, 11.02; O, 12.58;
S, 8.41%. Found: C, 62.80; H, 5.78; N, 10.80%.

SYNTHESIS OF THIAZOLIDINONES USING ACTIVATED FLY ASH
1359
Supplementary Data
Complete spectral characterization data and Tables S1–S3 are provided in the Sup-
plemental Materials.
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