Environmentally benign synthesis, molecular properties prediction and anti-inflammatory activity of novel isoxazolo[5,4-d]isoxazol-3-yl-aryl-methanones via vinylogous Henry nitroaldol adducts as synthons

Article abstract of DOI:10.1016/j.bmcl.2015.01.041

Synthesis of novel 6-methylisoxazolo[5,4-d]isoxazol-3-yl-aryl-methanones 5 has been achieved via nitro-nitrite rearrangement by utilizing vinylogous nitroaldol adducts as synthons under mild conditions. Furthermore, the new series of compounds 5a-i were a

Full text of DOI:10.1016/j.bmcl.2015.01.041

Accepted Manuscript
Environmentally benign synthesis, molecular properties prediction and anti-in-
flammatory activity of novel isoxazolo[5,4-d]isoxazol-3-yl-aryl-methanones
via vinylogous Henry nitroaldol adducts as synthons
E. Rajanarendar, S. Rama Krishna, D. Nagaraju, K. Govardhan Reddy, B.
Kishore, Y.N. Reddy
PII:
S0960-894X(15)00053-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.01.041
BMCL 22381
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
29 October 2014
19 January 2015
20 January 2015
Please cite this article as: Rajanarendar, E., Rama Krishna, S., Nagaraju, D., Govardhan Reddy, K., Kishore, B.,
Reddy, Y.N., Environmentally benign synthesis, molecular properties prediction and anti-inflammatory activity of
novel isoxazolo[5,4-d]isoxazol-3-yl-aryl-methanones via vinylogous Henry nitroaldol adducts as synthons,
Bioorganic & Medicinal Chemistry Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.2015.01.041
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Environmentally benign synthesis, molecular properties prediction and anti-
inflammatory activity of novel isoxazolo[5,4-d]isoxazol-3-yl-aryl-methanones
via vinylogous Henry nitroaldol adducts as synthons
E. Rajanarendar*a , S. Rama Krishna a , D. Nagaraju a, K. Govardhan Reddy a , B. Kishore a ,
Y. N. Reddyb
aDepartment of Chemistry, Kakatiya University, Warangal, 506 009 AP, India
bDepartment of Pharmacology and toxicology, Kakatiya University, Warangal, 506 009AP, India
______________________________________________________________________________
H3C
O
H3C
NO2
CH3
N
N
N
O
Ar
O
O
1
5

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Environmentally benign synthesis, molecular properties prediction and anti-
inflammatory activity of novel isoxazolo[5,4-d]isoxazol-3-yl-aryl-methanones via
vinylogous Henry nitroaldol adducts as synthons
E. Rajanarendar*a , S. Rama Krishna a , D. Nagaraju a, K. Govardhan Reddy a , B. Kishore a , Y. N. Reddyb
aDepartment of Chemistry, Kakatiya University, Warangal, 506 009 AP, India
bDepartment of Pharmacology and toxicology, Kakatiya University, Warangal, 506 009AP, India
A B S T R A C T
Synthesis of novel 6-methylisoxazolo[5,4-d]isoxazol-3-yl-aryl-methanones 5 has been achieved via nitro-nitrite rearrangement by utilizing vinylogous
nitroaldol adducts as synthons under mild conditions. Furthermore, the new series of compounds 5a-i were assessed for molecular properties prediction, drug-
likeness by Molinspiration (Molinspiration, 2008) & MolSoft (MolSoft, 2007) softwares, lipophilicity and solubility parameters using ALOGPS 2.1 program.
The new series of compounds 5a-i were screened for their anti-inflammatory activity.
Keywords: 6-Methylisoxazolo[5,4-d]isoxazol-3-yl-aryl-methanones; Molecular properties prediction; Drug-likeness; Anti-inflammatory activity
In today’s era of drug development, shaped by high
throughput screening and combinatorial chemistry, fast
bioavailability screening of virtual libraries consisting of
hundreds of thousands even millions of molecules is required. In
recent years, several new parameters have been introduced for
absorption prediction, including molecular size and shape
descriptors, hydrogen-bonding capabilities, and surface
properties1-6. High oral bioavailability is often an important
consideration for the development of bioactive molecules as
therapeutic agents. Thus, an important goal for drug research is to
gain sufficient understanding of the molecular properties that
limit oral bioavailability to facilitate the design of viable new
drug candidates.
The isoxazoles possessing aryl and carboxamide moieties were
also shown to have potent in vivo antithrombiotic efficacy15.
Based on the significance of pharmacological profile of
isoxazole derivatives, and as a sequel to our work on the
synthesis of biologically important isoxazolyl heterocycles16-19
we, herein, describe the green route for synthesis of novel 6-
methylisoxazolo[5,4-d]isoxazol-3-yl-aryl-methanones
5
via
vinylogous nitroaldol adducts as synthons. The new compounds
5 were subjected to molecular properties prediction and drug
likeness by Molinspiration (2008) and MolSoft (2007) softwares.
Further lipophilicity and solubility parameters were assessed by
ALOGPS 2.1 program and investigated for their anti-
inflammatory activity.
The Henry reaction is one of the most important versatile and
fundamental base–catalyzed carbon-carbon bond7 forming
reaction for the preparation of β-nitroalcohol adducts in synthetic
organic chemistry. β-Nitroalcohol adducts are useful
intermediates for building of natural products, such as
nitroalkenes, 2-nitroketones, β-aminoalcohols, carboxylic acids,
azides, α-hydroxy ketones, aldehydes and sulfides8,9.
The synthsis of title compound’s 5a-i was accomplished by
synthetic sequence shown in Scheme 1. The reaction was first
explored with two test experiments by grinding together 3,5-
dimethy-4-nitroisoxazole 1 (3 mmol) and freshly distilled
benzaldehyde 2 (1 mmol) with 5 mol% and 10 mol% of
imidazole as mild Lewis base catalyst respectively. The reaction
furnished vinylogous nitroaldol adducts 3. The best overall yield
(98%) was obtained with 10 mol% of imidazole catalyst and the
reaction is found to be more effective in terms of short reaction
time 5 min20.
A major discovery in the search of novel anti-inflammatory
agents without deleterious side effects exhibited by the
conventional NSAIDs came from the identification of two
different isoforms of the cyclooxygenase (COX) enzymes known
as COX-1 and COX-2. COX-1 is a constitutive isoform that is
involved in normal cellular functions whereas COX-2 is an
inducible isoform that is expressed only after inflammatory
To investigate the scope of imidazole catalyzed synthesis of 2-
(3-methyl-4-nitro-5-isoxazolyl)-1-aryl-1-ethanols 3, several
aromatic aldehydes were examined in this reaction. In all the
cases, the products were obtained in excellent yields. The great
advantages of the present procedure using imidazole in Henry
reaction are the mild condition, high yields, short reaction times,
simple experimental set-up and workup without any undesired
by-products. Besides this, it is equally efficient and is compatible
with different functional groups (electron releasing and electron
stimulus10,11
. Isoxazoles bearing sulfone and carboxamide
moieties demonstrated to have significant pharmacological
applications. For example, cyclooxygenase-2 (COX-2) selective
inhibitors, Celecoxib12, Rofecoxib13 and Valdecoxib14 are
currently prescribed for the treatment of arthritis and
inflammatory diseases. These COX-2 inhibitors exhibited anti-
inflammatory activity with reduced gastrointestinal side effects.

withdrawing groups) and the approach proved to be of general
application.
methanones 5 a-i for the prediction of lipophilicity, solubility and
Lipinski “Rule of Five”.
Lipophilicity: The ALOGPS method is part of the ALOGPS 2.1
program24 was used to predict lipophilicity25 and aqueous
solubility26,27 of the compounds. The lipophilicity calculations
within this program are based on the associative neural
networking approach and the efficient partition algorithm. The
LogKow (Kow-WIN) program28 estimates the log octanol/water
partition coefficient (logP) of organic chemicals and drugs by an
atom/fragment contribution method developed at Syracuse
Research Corporation29. The XLOGP2 is an atom-additive
method applying corrections30,31. Computed partition coefficients
for the studied compounds by XLOGP2 method varied between
2.67–3.57 and 1.79–2.86 by KoWWIN method (Table 1). The
LogKoW (KoW-WIN) method is best supported for the most of
the compounds on the basis of lipophilicity (≤5) to consider an
oral drug/lead.
With the finding of Henry reaction resulting in vinylogous
nitroaldol adducts 3, we utilized these synthons 3 as building
blocks for the synthesis of novel 6-methylisoxazolo[5,4-
d]isoxazol-3-yl-aryl-methanones 5 via nitro-nitrite rearrangement.
O
OH
I
O
O
N
O
H3C
NO2
H3C
Ar-CHO
NO2
CH3
H3C
2
O
H
N
N
N
EtOAc
O
N
NH
O
O
0
25 min, 80
C
Ar
Ar
Grinding
O
HO
4
3
1
Et3N
DMF
O
N
O
H3C
H3C
ONO
O
H3C
NO2
N
N
N
O
O
O
Ar
Ar
Table 1
Ar
O
O
A
Calculated partition coefficients and solubilities of 6-
methylisoxazolo[5,4-d]isoxazol-3-yl-aryl-methanones (5a-i)
B
3, 4 & 5
-----------
a) Ar = C6H5
3, 4 & 5
-----------
Compd.
5a
ALOGPS
KoW-WIN
1.97
XLOGP2
2.78
f) Ar = 4-NMe2lC6H4
g) Ar = 2-BrC6H4
h) Ar = 4-ClC6H5
i) Ar = 4-BrC6H4
b) Ar = 2-NO2C6H5
c) Ar = 2-OHC6H5
d) Ar = 4-OMeC6H4
e) Ar = 2-ClC6H4
H3C
O
N
-3.16(16.00 mg/l)
-3.63(64.40 mg/l)
-2.90(31.00 mg/l)
-3.25(14.00 mg/l)
-3.51(80.35 mg/l)
-3.23(16.00 mg/l)
-3.41(12.00 mg/l)
-3.50(82.77 mg/l)
-3.40(12.00 mg/l)
N
O
Ar
5b
1.79
2.67
O
5
5c
2.27
2.80
5d
2.05
2.69
Scheme 1. Synthesis of 6-methylisoxazolo[5,4-d]isoxazol-3-yl-
aryl-methanones 5a-i.
5e
2.61
3.40
5f
2.15
2.98
5g
2.86
3.57
The 2-(3-methyl-4-nitro-5-isoxazolyl)-1-phenyl-1-ethanone 4 a
(1 mmol) was stirred at 90 C for 2 h with catalytic amount of
Et3N in DMF. The anionic intermediate A generated in situ by
interaction
o
5h
2.61
3.40
5i
2.86
3.57
of
2-(3-methyl-4-nitro-5-isoxazolyl)-1-phenyl-1-
ethanone 4 a with Et3N undergoes nitro-nitrite rearrangement to
yield corresponding nitrite like intermediate B, which in turn
undergoes cyclization to yield the title compound viz., 6-
methylisoxazolo[5,4-d]isoxazol-3-yl-aryl-methanone 5 a in good
yield22. The reaction is extended to differently substituted
ethanones 4 b-i , and in each case the product was obtained 5 b-i
in good yield.
Solubility: Drug solubility is an important factor that affects the
movement of a drug from the site of administration in to the
blood. It is known that insufficient solubility of drug can lead to
poor absorption32. Investigation of the rate-limiting steps of
human oral absorption of 238 drugs32 showed that the absorption
of a drug is usually very low if the calculated solubility is
<0.0001 mg/l. According to that, the investigated compounds 5a-
i were found to fulfill the requirements of solubility (ALOGPS)
and could be considered as a drug candidate for oral absorption.
Absorption, polar surface area, and “Rule of five” properties:
High oral bioavailability is an important factor for the
development of bioactive molecules as therapeutic agents. Good
intestinal absorption, reduced molecular flexibility (measured by
the number of rotatable bonds), low polar surface area or total
hydrogen bond count (sum of donors and acceptors), are
important predictors of good oral bioavailability4,33. Molecular
properties such as membrane permeability and bioavailability is
always associated with some basic molecular descriptors such as
logP (partition coefficient), molecular weight (MW), or hydrogen
bond acceptors and donors counts in a molecule32. Lipinski6 used
these molecular properties in formulating his “Rule of Five”. The
rule states that most molecules with good membrane permeability
have logP ≤5, molecular weight ≤500, number of hydrogen bond
acceptors ≤10, and number of hydrogen bond donors≤5. This rule
is widely used as a filter for drug-like properties. Table 2
contains calculated percentage of absorption (%ABS), molecular
polar surface area (PSA) and Lipinski parameters of the
The structures of all newly synthesized compounds (3, 4, and
5) are herein reported were confirmed by analytical and spectral
data (IR, 1H NMR, 13C NMR and MS).
In Silico study of Drug likeness and molecular
properties:Analysis of the structures of orally administered
drugs, and of drug candidates, as pioneered by Lipinski, has so
far been the primary guide to correlating physical properties with
successful drug development23,24. This analysis has been very
useful and has led to a set of rules relating to the importance of
lipophilicity (octanol-water partition), molecular weight (MW),
and the number of hydrogen bond donors and acceptors.
Nonetheless, there are limitations on it as it relates to oral
bioavailability. These include the lack of quantitative assessment
of oral bioavailability in the data analyzed, a need to assume that
all orally administered drugs are intended to be absorbed, the
assumption that oral bioavailability is generally high for orally
administered drugs. Good bioavailability can be achieved with an
appropriate balance between solubility and partitioning
properties. Thus in order to achieve good oral drugs we have
subjected a series of 6-methylisoxazolo[5,4-d] isoxazol-3-yl-aryl-

investigated compounds of the series (5a-i). Magnitude of
absorption is expressed by the percentage of absorption.
Absorption percent was calculated29 using the expression: %ABS
= 109 - 0.345 PSA. Polar surface area (PSA) was determined by
the fragment-based method of Ertl and coworkers34,35. A poor
permeation or absorption is more likely when there are more than
5H bond donors, 10 H-bond acceptors. Hydrogen-bonding
capacity has been also identified as an important parameter for
describing drug permeability33. The series (5a-i) under
investigation has most of the compounds possessing less number
of hydrogen bond donors (≤5) but do possess considerable
number of acceptors (≤10) as shown in Table 3. Number of
rotatable bonds is important for conformational changes of
molecules under study and ultimately for the binding of receptors
or channels. It is revealed that for passing oral bioavailability
criteria, number of rotatable bonds should be ≤104. The
compounds in this series (5a-i) in general possess high number of
rotatable bonds (2-3) and therefore, exhibit conformational
flexibility. Molecular polar surface area (PSA) is a very useful
parameter for the prediction of drug transport properties. PSA is
a sum of surfaces of polar atoms (usually oxygen, nitrogen and
attached hydrogen) in a molecule. PSA and volume is inversely
proportional to %ABS. Compound 5e, 5g, 5h, and 5i have
maximum absorption (88.79%) as their corresponding polar
surface area and volume are least among the series.
Table 3
Drug-likeness of 6-methylisoxazolo[5,4-d]isoxazol-3-yl-aryl-
methanones (5a-i)
Compd. GPCRL
ICM
0.04
KI
NRL
-0.17
-0.16
0.05
PI
EI
5a
5b
5c
5d
5e
5f
-0.18
-0.24
-0.10
-0.12
-0.17
-0.02
-0.32
-0.12
-0.26
-0.18
-0.20
-0.06
-0.10
-0.12
0.03
-0.44
-0.45
-0.32
-0.36
-0.52
-0.27
-0.57
-0.42
-0.52
-0.04
-0.16
0.04
-0.05
-0.06
-0.05
0.01
-0.05
-0.12
0.03
-0.05
-0.12
-0.00
-0.12
-0.06
-0.11
0.01
5g
5h
5i
-0.04
0.04
-0.26
-0.14
-0.18
-0.23
-0.12
-0.25
-0.06
GPCRL: GPCR Ligand; ICM: Ion Channel Modulator; KI:
Kinase Inhibitor; NRL: Nuclear Receptor Ligand; PI: Protease
Inhibitor; EI: Enzyme Inhibitor.
Anti-inflammatory analysis: Anti-inflammatory activity was
determined by carrageenan induced paw edema method36. Wistar
rats of either sex weighing 150-200 g were divided into 6 groups
(n=6) and they were fasted 18 h before the experiment with water
ad libitum. Group-I received 1% sodium CMC (negative control),
Group-II received ibuprofen at a dose of 100 mg/kg (positive
control) and Group-III to VI were given the compounds 5a-i (100
mg/kg). All the compounds 5a-i were given in oral route. After
30 minutes, 0.1 mL of 1% carrageenan suspension in normal
saline was injected into the subplantar region of the left hind paw
of each rat to induce edema. The edema volumes of the injected
paw measured with the help of plethysmograph at the interval of
0, 1, 2, 4 and 6 h. The difference between the paw volumes of
treated animals were compared with that of the control group and
the mean edema volume was calculated. Percentage inhibition
was calculated as per the formula, %inhibition= [Vo-Vt)/Vo] x
100, where Vo = volume of the paw control at time t, Vt =
volume of the paw of drug treated at time t.
Table 2
Physico-Chemical properties calculations of 6-methyl isoxazole
[5,4-d]isoxazol-3-yl-aryl-methanones (5a-i)
Com %A Volu PS NRO HB HB log Form
pd.
BS
me
A
TB
A
D
P,
ula
weig
ht
(A3)
(A
2)
Cal
cd.
5a
5b
5c
5d
5e
5f
88.7 211.
62
77.0 236.
73
77.0 222.
72
85.8 243.
47
88.7 226.
87
87.7 261.
13
88.7 232.
56
88.7 228.
82
88.7 233.
48
58.
29
2
3
2
3
2
3
2
2
2
5
7
6
6
5
5
5
5
5
0
0
1
0
0
0
0
0
0
2.75
228
8
92.
74
2.62
2.58
2.80
3.35
3.01
3.30
3.43
3.64
273
244
258
262
271
306
262
306
1
75.
83
1
In vitro cylcooxygenase inhibition studies: The compounds, 5a-i
were tested for their ability to inhibit in vitro COX-1 and COX-2
using a colorimetric COX (ovine) inhibitor screening kit (Catalog
No. 760 112, Cayman Chemicals Inc., Ann Arbor, MI,USA)
using the previously established method37.
66.
98
9
58.
59
9
The anti-inflammatory activity of the title compounds, 5a-i
were evaluated by carrageenan-induced paw edema method in
rats36 at a dose of 100 mg/kg body weight using ibuprofen as a
reference drug. Results were expressed as a mean ± S.E. The
anti-inflammatory properties were recorded at successive
intervals of 0, 1, 2, 4 and 6 h and compared with that of standard
ibuprofen. The anti-inflammatory activity data (Table 4)
indicated that all the compounds 5a-i exhibited significant
activity by decreasing the paw volume that was produced by
carrageenan. Among all the compounds 5 a-i tested, it is
interesting to note that the compounds 5e, 5g, 5h and 5i showed
better anti-inflammatory activity. This may be due to the
presence of chloro and bromo substitutions on the benzene ring,
besides the presence of isoxazolo [5,4-d]isoxazole frame work.
The presence of electron donating methyl and methoxy groups on
benzene ring (5c and 5d) did not influence the activity much.
61.
55
7
5g
5h
5i
58.
59
9
58.
59
9
58.
59
9

Table 4
Table 5
Anti-inflammatory activity of 6-methylisoxazolo[5,4-d]isoxazol-
3-yl-aryl-methanones # (5a-i)
In vitro cylcooxygenase inhibition studies of 6-methylisoxazolo
[5,4-d]isoxazol-3-yl-aryl-methanones # (5a-i)
Paw volume (mL of Hg)b
%inhibitiona,b
Groupa
0h
0.36±0. 0.80±0. 0.86±0.0 0.82±0.0 0.63±0.0
01 03
8ns 6** 3**
0.37±0. 0.75±0. 0.83±0.0 0.81±0.0 0.63±0.0
03 05
5ns 3** 1**
0.34±0. 0.82±0. 0.93±0.0 0.80±0.0 0.61±0.0
03 01
4ns 2** 3**
0.31±0. 0.78±0. 0.70±0.0 0.83±0.0 0.62±0.0
04
3** 5**
0.22±0. 0.51±0. 0.68±0.0 0.51±0.0 0.50±0.0
08 06
1**
0.35±0. 0.78±0. 0.83±0.0 0.63±0.0 0.55±0.0
02 08
3ns 3* 3**
0.22±0. 0.50±0. 0.68±0.0 0.65±0.0 0.51±0.0
03 02
4* 2**
0.21±0. 0.53±0. 0.65±0.0 0.67±0.0 0.41±0.0
01 04
2ns 3** 3***
0.23±0. 0.52±0. 0.69±0.0 0.54±0.0 0.32±0.0
04 01
3** 1***
Contro 0.36±0. 0.90±0. 1.07±0.0 1.2±0.05 0.96±0.0
05
Ibupro 0.30±0. 0.66±0. 0.70±0.0 0.60±0.0 0.40±0.0
fen
03* 5*** 5*** 5***
1h
2h
4h
6h
Compound
COX-1(10 μM)
29.6
COX-2 (10 μM)
30.1
5a
5b
5c
5d
5e
5f
5g
5h
5i
5a
27.4
36.9
40.1
17.8
35.6
18.3
16.4
19.3
28.3
40.0
51.6
86.1
44.2
80.3
79.3
72.7
5b
5c
5d
5e
5f
Celecoxib
2.8
100
1
3
aValues are acquired using in vitro ovine COX-1/COX-2 assay
kit (Catalog No. 760 112, Cayman Chemicals Inc., Ann Arbor,
MI).
3
2
bExperiments were carried out in duplicate and have less than
10% error.
cTest compounds and Celecoxib were administered orally at the
dose of 10 mg/kg.
5g
5h
5i
In conclusion, we have demonstrated a convenient,
facile, efficient and environmentally benign protocol for the
synthesis of novel 6-methylisoxazolo[5,4-d]isoxazol-3-yl-aryl-
methanones via. vinylogous nitroaldol adducts as synthons The
newly synthesized compounds 5 a-i were evaluated for their
anti- inflammatory activity. Compounds 5 e, 5 g, 5 h and 5 i
exhibited significant activity as that of standard drug. This
happen to be the first report to study the molecular properties
prediction and drug-likeness on isoxazole compounds . These
studies indicated that most of the compounds behave as an oral
absorption drugs.
3
5
l
3
8
3
Acknowledgments
5
aDose levels: test compound (100 mg/kg b.wt) Ibuprofen (100
mg/kg b.wt)
The authors are thankful to Head, Department of Chemistry,
Kakatiya University,Warangal, India for providing necessary
facilities and to the Director, Indian Institute of Chemical
Technology (IICT), Hyderabad, India for providing spectral data.
bValues are expressed as mean ± S.E.
Statistically significant compound to respective control value
*P<0.05, **P<0.01, ***P<0.001
nsNonsignificant, compared to control.
#n=6, number of animals used in each group
The preliminary in vitro cyclo oxygenase inhibition studies of 6-
methylisoxazolo[5,4-d] isoxazol-3-yl-arylmethanones 5 a-i have
evidenced that 5e, 5g, 5h and 5i are more selective and active
than compounds 5a, 5b, 5c, 5d, and 5f. To study the activity,
different substitutents are introduced on the benzene ring. Results
indicated that compounds 5e, 5g, 5h and 5i having chloro and
bromo substitutents on benzene ring showed better activity and
they are selective towards cyclooxygenase-2 enzyme. Other
compounds showed good anti-inflammatory activity but they are
less selective cox-2 inhibitors, when compared with standard
drug Celecoxib. The possible improvement of selective COX-2
inhibitory activity of this basic isoxazolo[5,4-d] isoxazole moiety
through modulation of ring substituents and/or additional
functionalization warrants further investigations [Table 5]
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49.
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3.
4.
5.
6.
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ethanols 3 (1 mmol) and o-iodoxybenzoic acid (IBX) (1
o
mmol) in EtOAc (10 mL) was refluxed at 80 C for 4 h.
After completion of the reaction (monitored by TLC), the
reaction mixture was cooled to room temperature and
filtered. The separated solid was washed with water and
recrystallized from ethanol.
General procedure for the synthesis of 6-
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i)
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General procedure for the environmentally benign
synthesis of 2-(3-methyl-4-nitro-5-isoxazolyl)-1-aryl-1-
ethanols (3a-l)
37.
A mixture of 3,5-dimethyl-4-nitroisoxazole 1 (3 mmol),
aromatic aldehyde 2 (1 mmol), and 10 mol% of Imidazole
was gently ground by hand using a motar and pestle of an
appropriate size. The progress of the reaction was
monitored by TLC. (Analytical TLC was performed on
Merck precoated 60 F254 silica gel plates. Visualization
was done by exposure to iodine vapour). The reaction

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E-Mail address: rajanarendareligeti@gmail.com (E. Rajanarendar).