Iodine catalyzed one-pot synthesis of highly substituted N-methyl pyrroles via [3 + 2] annulation and their in vitro evaluation as antibacterial agents

Article abstract of DOI:10.1039/c5ra11094g

A new class of highly substituted pyrroles have been synthesized via a simple, fast, and efficient method using environmentally friendly iodine catalyzed [3 + 2] annulation. N-Methyl-N-[(E)-1-(methylsulfanyl)-2-nitro-1-ethenyl]amine (NMSM) 1 and β-nitrostyrenes 3 underwent cycloaddition to afford the desired products 4 in excellent yields under solvent and metal free conditions. All the pyrrole derivatives were evaluated for their in vitro anti-bacterial activity. Among the synthesized pyrrole derivatives, 4b, 4c, 4e, 4g, 4i, 4j, 4l, 4m and 4n displayed good inhibitory properties against a panel of Gram positive and negative infectious pathogens.

Full text of DOI:10.1039/c5ra11094g

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DOI: 10.1039/C5RA11094G
Iodine catalyzed one-pot synthesis of highly substituted N-methyl
pyrrole via [3+2] annulation and their in vitro evaluation as
antibacterial agents
a
a
b
Biguvu Balachandra , Sivakumar Shanmugam, * Thillaichidambaram Muneeswaran , Muthiah
b
Ramakritinan
a
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai - 625 021, Tamil Nadu, India
b
Department of Marine and Coastal Studies, School of Energy, Environment and Natural
Resorurces, Madurai Kamaraj University, Madurai - 625 021, Tamil Nadu, India
*
Email: shivazzen@mkuniversity.org

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DOI: 10.1039/C5RA11094G
Cite this: DOI: 10.1039/c0xx00000x
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ARTICLE TYPE
Iodine catalyzed one-pot synthesis of highly substituted N-methyl
pyrrole via [3+2] annulation and their in vitro evaluation as antibacterial
agents
a
a
b
Biguvu Balachandra , Sivakumar Shanmugam *, Thillaichidambaram Muneeswaran , Muthiah
Ramakritinan
b
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Abstract: A new class of highly substituted pyrroles have been synthesized via simple, fast, and efficient,
method by environmental friendly iodine catalyzed via [3+2] annulation. NꢀmethylꢀNꢀ[(E)ꢀ1ꢀ
(methylsulfanyl)ꢀ2ꢀnitroꢀ1ꢀethenyl]amine (NMSM) 1 and βꢀnitro styrene 3 underwent cycloaddition to
afford desired product 4 in excellent yields under solvent and metal free conditions. All the pyrrole
derivatives were evaluated for their in vitro antiꢀbacterial activity. Among the synthesized pyrrole
derivatives, 4b, 4c, 4e, 4g, 4i, 4j, 4l, 4m and 4n displayed good inhibitory properties against a panel of
gram positive and negative infectious pathogens.
1
0
methodologies are focused on solvent and metal free synthesis of
1
5
Introduction
substituted pyrrole due to their lower energy consumption,
increased selectivity, minimized waste, hazards, toxicity and
cost. Recently, iodine catalyzed reactions have been
Over the decades, the design and synthesis of substituted
pyrroles are important building blocks in organic synthesis. This
key heterocyclic core is found in a large number of natural and
unnatural compounds, which has significant importance in
pharmacology and material science. Besides the natural products
and their analogues, unnatural pyrroles show attractive biological
activities, which are present in many of bioactive compounds like
HIV fusion inhibitors, antitubercular compounds,
nonꢀsteroidal antiꢀinflammatory compound tolmetin and
cholesterolꢀlowering agent atorvastatin, which is one of the top
14
5
5
6
0
5
0
considerable interest in various organic transformations due to its
low toxicity to environment, ready availability and inexpensive.
Therefore, it is worth contribute to the creation of
2
2
3
3
4
4
0
5
0
5
0
5
15
environmentally benign processes. In light of literature
1ꢀ15
precedent , it would be interested to develop an useful and
efficient approach to synthesis of Nꢀ and Sꢀmethyl substituted
1
a
1bꢀc
including
pyrrole derivatives, which have a major effect on partitioning into
16aꢀb
biological membranes
for example, methyl thioꢀethers and its
sulfoxides, sulfones are commonly occurring component in
1
dꢀe
selling drug worldwide (Figure 1).
derivatives show more biological activities like antioxidant,
The Substituted pyrrole
16cꢀd
biological active molecules.
The NꢀmethylꢀNꢀ[(E)ꢀ1ꢀ
2
3
(methylsulfanyl)ꢀ2ꢀnitroꢀ1ꢀethenyl]amine (NMSM) 1 is using in
the industrial scale for the manufacture of antiꢀulcer (Histamine
4
5
6
antiꢀinflammatory, antibacterial,
antifungal agents
and
7
antitumor etc. The Nꢀmethyl substituted heterocycles are
significant synthetic targets owing to their wide range of
applications as medicinal compounds and also they can modulate
physical and biological properties of the molecule. Methyl
17
18a
H2 receptor antagonists) bulk drugs ranitidine, nizatidine.
NMSM 1
18bꢀc
is a multiꢀfaceted building block in organic
synthesis.
homologation increases the inhibitory potency of HMGꢀCOA
R
8
aꢀd
inhibitors. The Sꢀmethyl substituted pyrrole derivatives and its
analogue are useful precursors for synthesizing H Receptor
Histamine Antagonists.
preparation of Nꢀ & Sꢀmethyl substituted heterocycles containing
structural scaffolds are in high demand.
2
8
eꢀg
As a result; methods for the
In general, the standard methods to synthesis of pyrrole are
9
10
Hantzsch, Knorr
&
PaalꢀKnorr
and multiꢀcomponent
transitionꢀmetalꢀcatalyzed
11
21
synthesis,
tandem reactions,
1
3
cyclization reactions etc. These methods put forward the
efficient construction of pyrroles with various substitution
pattern, atom economy and regioselectivity. Despite a number of
available synthetic strategies and advantages, the modern
6
5
Figure1. Pyrrole based biologically important compounds
The methyl sulfanyl group is an electron donor as well as good
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

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leaving group and it could be replaced with a variety of
at RT, however, there was not much improvement in the yield of
nucleophiles following the substitution nucleophilic vinyl (S V) 40 4a (Table 2, entries 2ꢀ6).
N
19
mechanism. In the current protocol, we reported highly
functionalized Nꢀmethyl substituted pyrrole derivatives 4 via oneꢀ
pot [3+2] cycloaddition of NMSM 1 and βꢀnitrostyrene 3 under
solvent free condition.
Table 2: Optimization reaction condition to the synthesis of 4a by manual
grinding method (Solvent free condition)
a
5
Results and Discussion
To commencement of our study, the model reaction of NMSM
1
benzaldehyde 2a and nitromethane was performed in the
b
Entry
Catalyst
Time (min)
Yield (%)
10
15
20
25
absence of catalyst in multiꢀcomponent fashion. Eventually, we
ended up with very less conversion of 4a in 5% yield (Table 1,
entry1). Then, reaction was carried out in the presence of solvents
like DMSO and DMF which was found to be counterproductive
under catalyst free at reflux conditions (Table 1, entry 2&3). To
further optimization of reaction condition the reaction was
employed in the presence of iodine catalyst in DMF solvent and
the results showed that compound obtained were in trace amounts
1
2
3
4
5
6
FeCl
AlCl
CuI
30
30
30
30
30
63
52
3
3
c
50
ZnCl
CuCl .2H O
2
53
c
2
2
49
Yb(OTf)3
Iodine
Acetic acid
30
30
30
65
70
65
(Table 1, entry 4).To improve the yield of 4a, different Lewis
7
8
acids such as FeCl , Yb (OTf) and CuI were used as catalysts to
3
3
afford 4a with 15ꢀ25% yield (Table 1, entries 6ꢀ9). However,
when molecular iodine was used as catalyst (10 mol %), the
target product 4a was obtained in 30% yield (Table 1 entry.5).
Unfortunately, there was no significant improvement in the
cycloaddition after increasing the temperature and amount of
catalyst.
a
Reaction conditions: 1 (1 mmol), 3a (1 mmol), Catalyst (10 mol %),
Isolated yields after column chromatography, starting material 1 was
b
c
45
recovered
Interestingly, the cycloaddition was obtained in 70% yield of 4a
in the presence of iodine catalyst (Table 2, entry 7). In acetic acid,
the conversion of 4a was obtained in moderate yield (Table 2,
Table 1: Optimization of the reaction conditions for three component
synthesis of 4a
50 entry 8).
a
Table 3: Optimization of the reaction conditions for two component
a
synthesis of 4a
b
Temp
Solvent
Yield
(%)
5
Entry
Catalyst
o
Time (h)
(
C)
b
c
Entry
Catalyst
Solvent
Temp
Time
(h)
6
5
48
9
8
8
8
Yield
(%)
1
2
3
4
5
6
7
8
9
ꢀ
90
9
12
12
12
9
(°C )
ꢀ
180
145
145
90
DMSO
Traces
Traces
Traces
c
1
2
3
4
5
6
7
8
9
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
65
90
RT
Reflux
Reflux
Reflux
Reflux
Reflux
50
55
55
55
55
32
25
10
c
ꢀ
DMF
c
MeOH
Iodine
Iodine
DMF
H
2
O
54
59
60
60
62
67
60
61
65
55
b
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
30
MeOH
EtOH
EtOH
MeOH
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
c
FeCl
3
90
9
20
FeCl
FeCl
FeCl
3
b
Yb(OTf)
AcOH
CuI
3
90
9
25
3
8
c
3
30 min
30 min
30 min
30 min
30 min
95
9
15
1
0
AlCl
CuI
3
c
90
9
17
11
1
2
ZnCl
2
a
Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), Nitromethane (1ml)
Catalyst (10mol %). Isolated yields after column chromatography
Starting material 1 was recovered.
13
CuCl2.
2
b
30
2
H O
c
14
Yb(OTf)
AcOH
3
ꢀ
ꢀ
-
ꢀ
55
55
55
90
45
30 min
5 min
5 min
6
72
50
82
67
66
1
1
1
1
5
6
7
8
2
0a
In order to improve the yield of 4a, nitrostyrene was prepared
separately and subjected to cycloaddition with NMSM 1 by
manual grinding using mortar and pestle at room temperature.
Iodine
Iodine
Iodine
MeOH
Reflux
35
Initially, we tried catalytic amount of anhydrous FeCl with 1 and
3
a
Reaction conditions: 1 (1 mmol), 3a (1 mmol), Catalyst (10 mol %).
Isolated yields after column chromatography, starting material 1 was
recovered
3
1
a in a grinding method to afford 4a in 63% yield (Table 2, entry
). We repeated the cycloaddition by using metal catalyst such as
b
c
55
AlCl CuI, ZnCl CuCl .2H O and Yb(OTf) by grinding method
3,
2,
2
2
,
3
2
| Journal Name, [year], [vol], 00–00
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We then tried alternative method to study the tolerance of 3a
and 1 to afford 4a under optimized reaction conditions with
various solvents and catalysts. The cycloaddition was employed
Among them, [3+2] cycloaddition under solvent free conditions
at 55 °C was found to be the ideal method for the synthesis of
tetra substituted pyrrole 4a in good yield (Table 3, entry 16). The
with NMSM 1 and 3a at 65 °C for 6 h under catalyst and solvent 35 NMR spectral data supports the structure of 4a.
5
0
5
0
5
free condition (Table 3, entry 1). However the yield was reduced
to 25% on increasing the temperature from 65 °C to 90 °C (Table
Following the optimized reaction condition, we have
investigated the scope of NMSM 1 and βꢀnitrostyrene 3 via [3+2]
cycloaddition to afford 4a-n (Table 4). The starting material
containing electron–donating and withdrawing groups of βꢀ
3
6
, entry 2). The yield of 4a was considerably increased to (54ꢀ
2%) yield, when the solvents were varied from water to ethanol
under reflux condition (Table 3, entries 4ꢀ8). While other Lewis 40 nitrostyrene 3 with 1 were well tolerated under optimized
1
1
2
2
acids were used as catalyst under solvent free conditions, the
desire product 4a was obtained in moderate yields (Table 3,
entries 9ꢀ14). The compound 4a was obtained in 50% yield, when
catalytic amount of acetic acid was used (Table 3, entry 15).The
reaction conditions to afford 4a-n in moderate to good yields (65ꢀ
90%). Temperature plays significant effect in the reaction
because; the yield was improved to 65ꢀ90% at 55 °C (Table, 4).
In the aryl group of βꢀnitrostyrene 3 contains an electron donating
solvent effect had not much influence to improve the product 45 as well as an electronꢀwithdrawing groups present at ortho and
yield. Further to design an environmentally benign procedure, a
model cycloaddition was performed between 1 and 3a at 55 °C in
the presence of iodine as catalyst. Interestingly, the cycloaddition
product 4a was obtained in 82% yield under solvent free
meta positions, which shows little influence to afford 4c, 4f, 4h,
4j in low yield. Whereas, the para substituents 4a, 4g, 4i, and 4k
was obtained in high yield. An electron withdrawing group such
as –NO was well tolerated under optimized condition and gave a
2
conditions in 5 min (Table 3, entry 16). The yield of 4a was 50 moderate yield of 65% of the desired product 4m (Table 4). The
decreased to 67% when reaction was carried out at 90 °C (Table 3
entry17). Similarly, the yield of 4a was decreased to 66%, when
the cycloaddition was performed in MeOH at reflux condition for
halogens substituted phenyl group of βꢀnitrostyrene 3 leads to the
formation of pyrrole 4g and 4i in 83% yield. The naphthyl
substituted βꢀnitrostyrene works well for formation of pyrrole 4n
and gave the maximum yield 90% (Table 4).In conclusion all
6
h (Table 3 entry18) along with iodine catalyst. Overall iodine
catalyzed cycloaddition (Table 1, 2 & 3) was found to be better 55 types of βꢀnitrostyrenes could be successfully applied in this
method for the synthesis of 4a.
reaction providing to Nꢀmethylated pyrroles 4a-4n in good yield.
Interestingly, nitro and thioether linkage containing substituted
structural scaffolds are allowed to make further coupling
Table 4: Oneꢀpot twoꢀcomponent synthesis of 4a-n via [3+2]
a
cycloaddition
20bꢀf
reaction.
In our present report, the synthesis of tetra
6
6
7
0
5
0
substituted pyrrole 4 assumes to get more attention as important
an intermediates in organic, biological, as well as material
chemistry. All the synthesized compounds
4 were well
1
13
characterized by IR and NMR ( H, C, DEPTꢀ135) spectra. The
1
H NMR spectrum of 4a was explained by taking as an example.
1
The H NMR spectrum shows two doublet at δ 7.28 ppm (d, J =
9
.0 Hz, 2H), 6.91 ppm (d, J = 8.6 Hz, 2H) for para methoxy
substituted phenyl group and the aromatic proton of substituted
pyrrole (C 5, H) appears as a singlet at 6.67 ppm. The Nꢀmethyl,
Sꢀmethyl and methoxy protons appear as singlet at 3.83 ppm 2.49
ppm and 3.79 ppm respectively. The singlet at δ = 6.67 ppm (Cꢀ5
proton) is the diagnostic signal for 4a.
Scheme 1: Plausible reaction mechanism to formation of 4
a
3
0
Reaction conditions: 1 (1 mmol), 3 (1 mmol), Catalyst (10 mol %),
21
Isolated yields after column chromatography
On the basis of literature reports , plausible mechanism was
75
proposed for the iodine catalyzed cycloaddition of 1 and 3 to
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yield 4 (Scheme.1). Here, iodine acts as a mild Lewis acid, which
sterilized using 0.45µm syringe filter. Briefly overnight grown
increases the nucleophilicity of NMSM 1. In the first step, due to 35 cultures containing 108 CFU/mL were spread on the Muller
the polarized pushꢀpull alkene of NMSM 1 undergoes Michael
addition of 3 to form new CꢀC single bond to form B. Further,
lone pair of sulphur atom of methyl sulfanyl group shifted their
electrons towards nitrogen, which makes intramolecular
Hinton agar plates. The sterile paper discs (Himedia lab) were
impregnated with filter sterilized compounds approximately 20
µL per disc. The paper discs were placed on the agar plates and
incubated at 30 °C for 24 h. After 24 h of incubation, the zone of
5
nucleophilic attack of nitrogen through formation of new NꢀC 40 inhibition around the discs was observed and measured (Table 5).
bond to give C. Intermediate C undergoes elimination of H O to
give intermediate D which on further elimination of nitrosyl
hydride (HNO) leads to the formation of product 4.
The values presented in the table were the average of the two
independent tests.
The results of the initial antibacterial activity screening
revealed that, among the pyrrole derivatives the compounds 4b,
45 4c, 4e, 4g, 4i, 4j, 4l, 4m, 4n displayed activity against gramꢀ
positive bacteria and gramꢀnegative bacteria, inhibitory zone (6ꢀ
2
10
Biological data
Disc diffusion method
1
1mm) shown in Table 5. The compounds 4e and 4l showed good
Based on the biological literature survey, the synthesized
activity against almost all bacteria. Whereas the compound 4g
compounds (4a-n) were evaluated for their antiꢀbacterial activity
displayed good activity against gramꢀpositive bacteria (Table 5
15
against selected gram positive and negative bacteria, which were 50 entry 7). These results showed considerable interest to find
individually responsible for various infections and disorders by
minimum inhibitory concentration (MIC).
2
2
using standard disk diffusion assay described by Murray et al
995. The gram negative bacteria such as Salmonella typhi,
Minimum inhibitory concentration (MIC)
1
The compounds which showed sensitivity to the bacteria was
selected for the determination of MIC.
Table 5: Antibacterial activity screening for compounds 4a-4n
29
a
a
Ent
ry
Comp
ound
code
Gram Negative
Gram Positive
S. B.
aerugionsa pneumonia subtilis
55 Table 6: MIC Values (ꢁg /mL) against infectious Pathogens
S. typhi E. coli
P.
B.cereus
a
a
Ent
ry
Gram Negative
S. E. coli
typhi
Gram Positive
S. B.
aerugionsa pneumonia subtilis cereus
Compound
code
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
8
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
7
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
6
9
ꢀ
ꢀ
9
ꢀ
P.
B.
ꢀ
1
2
3
4
5
6
7
8
9
4b
4c
4e
4g
4i
ꢀ
ꢀ
5.0
5.5
6.7
5.3
ꢀ
5.0
ꢀ
9
ꢀ
ꢀ
ꢀ
ꢀ
5.5
6.7
26.6
ꢀ
ꢀ
ꢀ
ꢀ
33.8 6.7
6.7
6.7
ꢀ
7
ꢀ
9
ꢀ
9
ꢀ
8
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
28.2
6.5
5.3
5.8
ꢀ
ꢀ
ꢀ
4g
4h
4i
ꢀ
8
ꢀ
11
ꢀ
ꢀ
4j
ꢀ
ꢀ
26.4
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
4l
ꢀ
5.3
ꢀ
26.4
ꢀ
5.3
ꢀ
7
ꢀ
ꢀ
ꢀ
4m
4n
ꢀ
1
1
1
1
1
1
1
0
1
2
3
4
5
6
4j
4k
8
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
29.8
1.0
5.9
2.0
b
1
0
Std
2.0
5.0
2.0
3.0
4l
6
9
ꢀ
ꢀ
9
ꢀ
11
ꢀ
8
ꢀ
8
ꢀ
a
Values show considerable activity, ꢁg /mL required to confine the
4m
4n
ꢀ
b
bacterial growth, Streptomycin, ꢀ No inhibition
ꢀ
ꢀ
7
7
ꢀ
8
ꢀ
The overnight grown cultures were adjusted to OD of 0.1. Stock
solutions of synthesized compounds and standard were serially
diluted to achieve a concentration between 10mM to 0.001mM
and 1to10 µg/mL respectively. MIC values of the compounds
were determined by adopting the microꢀwell dilution method
Cont.l
ꢀ
ꢀ
ꢀ
ꢀ
b
Std
14
10
15
14
18
16
60
a
20
25
30
Value represents the activity of compounds against the bacteria (with
.01M solution), Zone of inhibition in diameter (mm). Streptomycin. ꢀ
b
0
30
No inhibition
(Zgoda and Porter, 2001).
Briefly, each well of the 96 well
2
3
plates were seeded with the serially diluted compounds and
Escherichia coli, Pseudomonas aeruginosa cause typhoid fever,
2
4
25
65 bacterial cultures and nutrient broth to a final volume of 200 µL
per well. The well containing cells and nutrient broth serve as
negative control. Similarly the well seeded with DMSO, cells and
nutrient broth serve as solvent control. The plates were sealed
tightly with sterile plate sealer and incubated for 24 h in an orbital
70 shaker at 90 rpm. Bacterial growth was measured by optical
density (OD) at 600 nm using 96 well plate readers (ELISA Plate
reader) and also by the visual appearance of turbidity. Further
confirmation was made by plating 10µL of the samples from the
clear wells on nutrient agar.
haemolytic uremic syndrome, and nosocomial infections,
respectively. The gram positive Streptococcus pneumoniae is
responsible for bronchitis, rhinitis, acute sinusitis, otitis media,
conjunctivitis, meningitis, bacteraemia, sepsis, osteomyelitis,
septic arthritis, endocarditis, peritonitis, pericarditis, cellulitis,
and brain abscess. Bacillus subtilis, a gram positive model
organism causes food poisoning. Bacillus cereus, causes food
borne illness, causing severe nausea, vomiting, and diarrhoea and
are responsible for “fried rice syndrome. The stock solutions of
the synthesized compounds were prepared in DMSO and filter
26
2
7
”28
4
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MIC Values are defined as the lowest concentration that
synthesized compounds have good antibacterial activity.
completely inhibited visible growth of microorganism. The
compound 4b displayed activity against Bacillus cereus, Bacillus
subtilis (Gramꢀpositive bacteria) due the presence of phenyl
substitution on the pyrrole ring (Table 6, entry 1). Moreover 3ꢀ
methoxy substituted aryl group of pyrrole 4c showed
Experimental Section
General Consideration
5
0
5
Melting points were determined in open capillary tubes and were
considerable activity against Streptococcus pneumoniae, Bacillus 45 uncorrected. IR spectra were taken on a Jasco FTꢀIR instrument
ꢀ
1
subtilis (Table 6, entry 2). Whereas 3,4,5ꢀtrimethoxy compound
e displayed activity against both the gramꢀpositive bacteria and
in KBr pellets and reported in cm . Mass spectra were performed
with Agilent mass spectrometer and recorded in positive &
negative mode with an ESI source. The H and C NMR spectra
of the new compounds were measured at 300 MHz and 75MHz in
4
1
13
1
gramꢀnegative bacteria (Table 6, entry 3). The halogens
substituted phenyl derivatives of 4 showed good antibacterial
activities. Among the halogens, 4ꢀflouro derivative (4g) was the 50 CDCl3 and DMSOꢀd6 with TMS as the internal standard.
most effective on Bacillus subtilis and has a considerable activity
against Streptococcus pneumoniae (Table 6, entry 4).Whereas 4i
(4ꢀchloro) and 4j (2ꢀbromo) showed moderate activities on gramꢀ
negative bacteria Salmonella typhi (Table 6, entry 5, 6).
Chemical shifts were expressed in ppm, coupling constant (J
values) were given in Hertz (Hz) and spin multiplicities were
indicated by the following symbols: s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), dd (doublet of doublets), td
(triplet of doublets). Elemental analyses were carried out with
Perkin Elmer 2400 Series II analyzer. Silica gelꢀG plates (Merck)
were used for TLC analysis with a mixture of petroleum ether
1
55
(60ꢀ80 °C) and ethyl acetate as eluent. All chemicals were
purchased and used without further purification. The starting
60
material βꢀnitrostyrene 3 was prepared according to the previous
literature methods. NitroketeneꢀN,Sꢀacetal (NMSM)
1
is
commercially available and was used without further purification.
General procedure for preparation of β-nitrostyrene (3)
Aldehyde (0.05), nitro methane (0.05), and MeOH (10ꢀ20 mL)
were added to a round –bottom flask and then stirred vigorously.
NaOH solution (10.5M, 10 mL) was added drop wise in ice bath;
a large amount of yellow solid precipitated, and stirring was
6
7
7
5
0
5
continued for 15 min. Distilled H O was added until the solution
2
became clear, then the solution was added drop wise to
concentrated HCl (30 mL), and a yellow solid precipitated. The
yellow solid was filtered and washed with H O, then evaporated
2
Figure2. Minimum Inhibitory concentration of selected compounds
in a vacuum drying oven. After recrystallization (EtOH), yellow
Interestingly 3ꢀhydroxy substituted aryl group of 4l showed
wide range of activity (Table 6, entry 7), but 4ꢀnitro substituted
aryl group of 4m weakly effective against Salmonella typhi
needleꢀlike crystals were obtained. 4ꢀOMeꢀβꢀnitrostyrene (3a)
2
0
1
Isolated yield (93%) Yellow solid; M.P. 86ꢀ88 °C; H NMR (300
MHz, CDCl3): δ, 7.98 (d, J = 13.6 Hz, 1H), 7.52 (m, 3H), 6.96
(Table 6, entry 8). The compound 4n with naphthyl substitution
13
(
d, J = 8.8 Hz, 2H), 3.87 (s, 3H); C NMR (75 MHz, CDCl3): δ,
displayed activity against Bacillus cereus, Bacillus subtilis (gramꢀ
positive bacteria) (Table 6, entry 9). Due to strong resistant of
pathogens towards the antiꢀbacterial agent, some of the pyrrole
derivatives did not show inhibitory properties against gram
negative and positive bacteria (Table 5 & 6). The obtained results
showed that different substitutions influence the activity of the Nꢀ
methyl substituted pyrrole compounds.
1
62.88, 138.97, 134.91, 131.11, 122.44, 114.84, and 55.45. Other
βꢀnitro styrene derivatives were prepared with similar procedure
and characterized by H, C NMR.
2
5
1
13
8
0
General procedure for synthesis of substituted pyrrole (4)
NMSM 1 (1.0mmol), βꢀnitro styrene 3 (1.0mmol) and molecular
iodine (10mol %) were charged in a 25 ml glass vial equipped
with stirring bar. The reaction mixture was heated on oil bath at
55 °C for 5ꢀ10 min (Monitored by TLC). After cooling down to
room temperature, the resulting mixture was extracted with ethyl
acetate (3×7ml), and then washed with water (2×10ml) followed
by brine solution (1×15ml).The organic phases were collected
and dried with anhydrous Na SO , filtered, and concentrated in
3
0
CONCLUSION
85
Hence we have developed a simple, fast, and efficient method to
the synthesis of tetra substituted pyrrole in the presence of
catalytic amount of iodine under metal & solvent free conditions.
In comparison with reported procedures, the present one affords
environmentally benign approach for synthesis of pyrrole
derivatives 4a-n. In this procedure new C-C and C-N bonds were
effectively constructed. The presence of nitro and sulphur groups
were opens to further construction of complex derivatives. The
synthesized compounds 4a-n was evaluated for their antiꢀ
bacterial activity against selected bacteria. Most of the
2
4
vacuum. The residue was purified by column chromatography on
silica gel (petroleum ether/EtOAc) to afford the corresponding
products 4.
3
5
90
Experimental procedure for three component one pot
synthesis of substituted pyrrole (Table 1)
4
0
Aldehyde (1.0 mmol), nitro methane (1ml), and molecular iodine
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

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RSC Advances
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DOI: 10.1039/C5RA11094G
1
(10mol %) were charged in a 25 ml glass vial equipped with
Yellow solid; m.p.118ꢀ120°C; yield: 0.174g (84%); H NMR
stirring bar. The reaction mixture allowed refluxing at 90 °C for
(300 MHz, CDCl ): δ, 6.93 – 6.85 (m, 3H), 6.70 (s, 1H), 3.90 (s,
3H), 3.88 (s, 3H), 3.80 (s, 3H), 2.50 (s, 3H); C NMR (75 MHz,
3
13
5
0ꢀ60min, after cooling down to room temperature, NMSM 1
(1.0mmol) was added by sequentially and continued to reflux for
CDCl ): δ, 148.63, 137.22, 126.10, 124.91, 122.23, 121.97,
3
5
9h(Monitored by TLC). The resulting mixture was extracted with 60 121.02, 112.53, 111.13, 110.89, 55.90, 55.86, 34.85, 19.42; IR
ꢀ
1
ethyl acetate (3×7ml), and then washed with water (2×10ml)
followed by brine solution (1×15ml).The organic phases were
collected and dried with anhydrous Na SO , filtered, and
(ATR KBr cell, cm ): 804, 1240, 1504, 3741, 3840; Anal. Calcd
for C H N O S: C, 54.53; H, 5.23; N, 9.08 Found: C, 54.50; H,
5.21; N, 9.05; LCꢀMS (ESI) calcd.m/z: 308, found 309 [(M+H)] .
14
16
2
4
+
2
4
concentrated in vacuum. The residue was purified by column
chromatography on silica gel (petroleum ether/EtOAc) to afford
the corresponding products 4a.
1
-methyl-2-(methylthio)-3-nitro-4-(3,4,5-trimethoxyphenyl)-
10
65
1H-pyrrole (4e)
1
Yellow solid; m.p.132ꢀ134°C; yield: 0.198g (87%); H NMR
Experimental procedure for one pot synthesis of substituted
pyrrole by manual grinding method (Table 2)
(300 MHz, CDCl ): δ, 6.73 (s, 1H), 6.57 (s, 2H), 3.88 (s, 3H),
3
13
3
.86 (s, 6H), 3.80 (s, 3H), 2.51 (s, 3H); C NMR (75 MHz,
NMSM 1 (1.0mmol), βꢀnitro styrene 3 (1.0mmol) and catalyst
CDCl ): δ, 152.85, 137.43, 137.04, 127.68, 126.42, 122.44,
3
15
(10mol %) were allowed to manual grinding for 30 min 70 122.06, 105.96, 60.77, 56.04, 34.93, 19.44; IR (ATR KBr cell,
ꢀ
1
(
Monitored by TLC) at RT by using Mortar and pestle. The
cm ): 698, 820, 1105, 1339, 1497, 3741, 3840; Anal. Calcd for
C H N O S: C, 53.24; H, 5.36; N, 8.28 Found: C, 53.22; H,
resulting mixture was extracted with ethyl acetate (3×7ml), and
then washed with water (2×10ml) followed by brine solution
1
5
18
2
5
+
5.34; N, 8.25; LCꢀMS (ESI) calcd.m/z: 338, found 339 [(M+H)] .
(
1×15ml).The organic phases were collected and dried with
4
-(2-fluorophenyl)-1-methyl-2-(methylthio)-3-nitro-1H-
20
anhydrous Na SO , filtered, and concentrated in vacuum. The
2
4
75
pyrrole (4f)
residue was purified by column chromatography on silica gel
petroleum ether/EtOAc) to afford the corresponding products 4a.
1
Yellow solid; m.p.218ꢀ220°C; yield: 0.138g (77%); H NMR
(
(300 MHz, CDCl ): δ, 7.38 – 7.24 (m, 2H), 7.20 – 7.04 (m, 2H),
3
4
-(4-methoxyphenyl)-1-methyl-2-(methylthio)-3-nitro-1H-
13
6
.76 (s, 1H), 3.81 (s, 3H), 2.51 (s, 3H); C NMR (75 MHz,
pyrrole (4a)
CDCl ): δ, 161.60, 158.32, 130.60, 129.37, 129.26, 126.49,
3
1
25
Yellow solid; m.p.128ꢀ130°C; yield: 0.153g (82%); H NMR 80 123.97, 122.98, 120.49, 120.29, 115.64, 115.34, 35.12, 19.48; IR
ꢀ
1
(300 MHz, CDCl ): δ, 7.28 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 8.6
(ATR KBr cell, cm ): 636, 767, 1329, 1480, 2348, 3728; Anal.
Calcd for C H FN O S: C, 54.12; H, 4.16; N, 10.52; Found: C,
3
13
Hz, 2H), 6.67 (s, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 2.49 (s, 3H);
C
12
11
2
2
NMR (75 MHz, CDCl ): δ, 158.88, 136.99, 129.74, 126.09,
54.11; H, 4.14; N, 10.51; LCꢀMS (ESI) calcd.m/z: 266, found
267 [(M+H)] .
3
+
1
24.47, 122.17, 121.76, 113.55, 55.14, 34.87, 19.38; IR (ATR
ꢀ
1
30
KBr cell, cm ): 791, 1327, 1495, 3741, 3840; Anal. Calcd for
C H N O S: C, 56.10; H, 5.07; N, 10.06 Found: C, 56.01; H,
85
4-(4-fluorophenyl)-1-methyl-2-(methylthio)-3-nitro-1H-
pyrrole (4g)
1
3
14
2
3
5
.03; N, 10.02; LCꢀMS (ESI) calcd.m/z: 278, found 279
1
+
Yellow solid; m.p.168ꢀ170°C; yield: 0.149g (83%); H NMR
[
(M+H)] .
(
300 MHz, CDCl ): δ, 7.32 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.7
3
1
-methyl-2-(methylthio)-3-nitro-4-phenyl-1H-pyrrole (4b)
13
Hz, 2H), 6.69 (s, 1H), 3.80 (s, 3H), 2.50 (s, 3H); C NMR (75
1
35
Yellow solid; m.p.129ꢀ131°C; yield: 0.120g (72%); H NMR 90 MHz, CDCl
3
): δ, 163.84, 160.58, 130.45, 130.34, 128.24, 126.70,
(
2
1
300 MHz, CDCl ): δ, 7.35 (s, 5H), 6.71 (s, 1H), 3.80 (s, 3H),
122.42, 121.27, 115.23, 114.94, 35.03, 19.42; IR (ATR KBr cell,
3
ꢀ
1
13
cm ): 793, 829, 1210, 1322, 1489, 3741, 3840 ; Anal. Calcd for
C H FN O S: C, 54.12; H, 4.16; N, 10.52 Found: C, 54.10; H,
.50 (s, 3H). C NMR (75 MHz, CDCl ): δ, 137.00, 132.06,
3
28.46, 128.06, 127.20, 126.30,122.32, 122.06, 34.88, 19.38; IR
12 11
2
2
ꢀ
1
4
.13; N, 10.50; LCꢀMS (ESI) calcd.m/z: 266, found 267
(
ATR KBr cell, cm ): 691, 756, 1322, 1479, 2348, 3728.Anal.
+
40
Calcd for C H N O S: C, 58.05; H, 4.87; N, 11.28 Found: C, 95 [(M+H)] .
12
12
2
2
5
2
8.03; H, 4.86; N, 11.26; LCꢀMS (ESI) calcd. m/z: 248, found
49 [(M+H)] .
4
-(3-chlorophenyl)-1-methyl-2-(methylthio)-3-nitro-1H-
+
pyrrole (4h)
4
-(3-methoxyphenyl)-1-methyl-2-(methylthio)-3-nitro-1H-
1
Yellow solid; m.p.96ꢀ98 °C; yield: 0.142g (75%); H NMR (300
pyrrole (4c)
MHz, CDCl ): δ, 7.33 (s, 1H), 7.27 (m, 3H), 6.72 (s, 1H), 3.80,
3
13
1
1
00 (s, 3H), 2.50 (s, 3H); C NMR (75 MHz, CDCl ): δ, 136.64,
45
Yellow solid; m.p.127ꢀ129 °C; yield: 0.150g (80%); H NMR
3
(
3
300 MHz, CDCl ): δ, 7.27 (s, 1H), 6.91 (m 3H), 6.72 (s, 1H),
.82 (s, 3H), 3.80 (s, 3H), 2.50 (s, 3H); C NMR (75 MHz,
133.98, 133.62, 129.21, 128.41, 127.11, 126.94, 126.79, 122.74,
120.47, 34.93, 19.26; IR (ATR KBr cell, cm ): 778, 1312, 1478,
3
1
3
ꢀ1
CDCl ): δ, 159.38, 137.30, 133.46, 129.11, 126.24, 122.41,
3741, 3840; Anal. Calcd for C12H11ClN O S: C, 50.97; H, 3.92;
2 2
3
N, 9.91 Found: C, 50.95; H, 3.91; N, 9.90; LCꢀMS (ESI)
05 calcd.m/z: 282, found 283 [(M+H)] .
1
21.96, 121.00, 114.25, 113.01, 55.18, 34.89, 19.46; IR (ATR
+
ꢀ
1
1
50
KBr cell, cm ): 688, 784, 1321, 1477, 2349, 2930; Anal. Calcd
for C H N O S: C, 56.10; H, 5.07; N, 10.06 Found: C, 56.01;
H, 5.03; N, 10.02; LCꢀMS (ESI) calcd.m/z: 278, found 279
13
14
2
3
4
-(4-chlorophenyl)-1-methyl-2-(methylthio)-3-nitro-1H-
pyrrole (4i)
+
[
(M+H)] .
1
Yellow solid; m.p.76ꢀ78°C; yield: 0.158g (83%); H NMR (300
4
-(3,4-dimethoxyphenyl)-1-methyl-2-(methylthio)-3-nitro-1H-
MHz, CDCl ): δ, 7.34 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 7.1 Hz,
3
55
pyrrole (4d)
13
1
10 2H), 6.70 (s, 1H), 3.80 (s, 3H), 2.50 (s, 3H); C NMR (75 MHz,
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

RSC Advances
Page 8 of 9
View Article Online
DOI: 10.1039/C5RA11094G
CDCl ): δ, 136.89, 133.25, 130.72, 129.95, 128.30, 126.94, 55 1324, 1481, 3741, 3840 Anal. Calcd for C H N O S: C, 64.41;
3
16 14
2
2
ꢀ
1
1
1
5
22.48, 121.02, 35.05, 19.42; IR (ATR KBr cell, cm ): 832,
320, 1487, 3741, 3840; Anal. Calcd for C H ClN O S: C,
H, 4.73; N, 9.39 Found: C, 64.40; H, 4.71; N, 9.37; LCꢀMS (ESI)
+
calcd.m/z: 298, found 299 [(M+H)] .
1
2
11
2
2
0.97; H, 3.92; N, 9.91 Found: C, 50.95; H, 3.91; N, 9.90; LCꢀ
+
5
MS (ESI) calcd.m/z: 282, found 283 [(M+H)] .
Acknowledgements
4
-(2-bromophenyl)-1-methyl-2-(methylthio)-3-nitro-1H-
SS thank DST and UGCꢀMRP, New Delhi, for financial
assistance. We thank DSTꢀIRHPA for funding towards high
resolution NMR spectrometer. BBC thanks the University Grants
Commission, New Delhi, for the award of Senior Research
Fellowship.
pyrrole (4j)
Yellow solid; m.p.188ꢀ190 °C ; yield: 0.170g (77%); H NMR
300 MHz, CDCl ): δ, 7.63 (d, J = 7.9 Hz, 1H), 7.39 – 7.13 (m,
6
0
1
(
3
1
3
1
0
3H), 6.68 (s, 1H), 3.82 (s, 3H), 2.52 (s, 3H); C NMR (75 MHz,
CDCl ): δ, 134.01, 132.46, 131.24, 129.08, 127.05 , 126.45,
1
7
*
3
ꢀ
1
24.60, 122.87, 121.15, 35.15, 19.34; IR (ATR KBr cell, cm ):
64, 1325, 1479, 2347, 3615, 3728; Anal. Calcd for
Notes and references
a
65
Department of Organic Chemistry, School of Chemistry, Madurai
C H BrN O S: C, 44.05; H, 3.39; N, 8.56 Found: C, 44.03; H,
1
2
11
2
2
Kamaraj University, Madurai – 625 021. *shivazzen@mkuniversity.org;
Tel: Office: + 91 452 245 8471 Ex. 371
+
1
5
3.36; N, 8.55; LCꢀMS (ESI) calcd.m/z: 327, found 328 [(M+H)] .
*ꢀ Two carbon signals have merged together]
b
Department of Marine and Coastal Studies, School of Energy,
[
Environment and Natural Resources, Madurai Kamaraj University,
4
-(4-bromophenyl)-1-methyl-2-(methylthio)-3-nitro-1H-
70 Madurai – 625 021.Tamil Nadu, India.
† Electronic Supplementary Information (ESI) available: All the H &
NMR and Mass spectrums of 4a-n are available. See DOI:
1
13
pyrrole (4k)
C
1
Yellow solid; m.p.102ꢀ104 °C; yield: 0.174g (79%); H NMR
(300 MHz, CDCl ): δ, 7.49 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5
Hz, 2H), 6.70 (s, 1H), 3.80 (s, 3H), 2.50 (s, 3H); C NMR (75
MHz, CDCl ): δ, 136.83, 131.23, 131.19, 130.25, 126.99, 122.45,
1
1
1
1
0.1039/b000000x/
2
0
(a) C. Teixeira, F. Barbault, J. Rebehmed, K. Liu, L. Xie, H. Lu, S.
Jiang, B. Fan and F. Maurel, Bioorg. Med. Chem., 2008, 16, 3039ꢀ
3
1
3
75
3
048; (b) M. Biava, G. C. Porretta, D. Deidda, R. Pompei, A. Tafic
3
and F. Manettic, Bioorg. Med. Chem., 2004, 12, 1453ꢀ1458; (c) M.
Protopopova, E. Bogatcheva, B. Nikonenko, S. Hundert, L. Einck
and C. A. Nacy, Med. Chem., 2007, 3, 301ꢀ316; (d) V. Este´vez, M.
Villacampa, and J. C. Mene´ndez, Chem. Soc. Rev., 2010, 39, 4402ꢀ
4421; (e) V. Este´vez, M. Villacampa and J. C. Mene´ndez, Chem.
Soc. Rev., 2014, 43, 4633ꢀ4657.
ꢀ
1
21.40, 121.00, 35.07, 19.42; IR (ATR KBr cell, cm ): 617, 781,
320, 1439, 3741,3839; Anal. Calcd for C H BrN O S: C,
1
2
11
2
2
2
5
44.05; H, 3.39; N, 8.56 Found: C, 44.02; H, 3.37; N, 8.54; LCꢀ
MS (ESI) calcd.m/z: 327, found 328 [(M+H)] .
80
+
3
-(1-methyl-5-(methylthio)-4-nitro-1H-pyrrol-3-yl) phenol (4l)
2
(a) J. A. H. Lainton, J. W. Huffman, B. R. Martin and D. R. Compton
Tetrahedron Lett., 1995, 36, 1401ꢀ1404; (b) C. Y. DeLeon and B.
Ganem, Tetrahedron, 1997, 53, 7731ꢀ7752; (c) R. Martín, M.
Rodríguez Rivero and S. L. Buchwald, Angew. Chem. Int. Ed., 2006,
1
Yellow solid; m.p.140ꢀ142°C; yield: 0.151g (85%); H NMR
8
9
9
5
0
5
(300 MHz, CDCl ): δ, 7.33 – 7.15 (m, 1H), 6.90 (d, J = 7.4 Hz,
3
4
5, 7079ꢀ7082; (d) H. S. P. Rao and S. Sivakumar, Beilstein. J. Org.
3
0
1H), 6.81 (d, J = 11.8 Hz, 1H), 6.70 (s, 1H), 5.01 (s, 1H), 3.79 (s,
1
3
Chem., 2007, 3, 31; (e) H. Fan, J. Peng, M. T. Hamann and J. F. Hu,
Chem. Rev., 2008, 108, 264ꢀ287; (f) J. Deblander, S. V. Aeken, J.
Jacobs, N. D. Kimpe and K. A. Tehrani, Eur. J. Org. Chem., 2009,
4882ꢀ4892; (g) S. Rakshit, F. W. Patureau and F. Glorius, J. Am.
Chem. Soc., 2010, 132, 9585ꢀ9587; (h) R. J. Billedeau, K. R. Klein,
D. Kaplan and Y. Lou, Org. Lett., 2013, 15, 1421ꢀ1423; (i) P.
Dhanalakshmi and S. Sivakumar, RSC Adv., 2014, 4, 29493ꢀ29501;
(j) M. Arun Divakar, V. Sudhamani, S. Sivakumar, T. Muneeswaran,
S. Tamilzhalagan, M. Ramakritinan and K. Ganesan, RSC Adv.,
3
1
1
3
H), 2.49 (s, 3H); C NMR (75 MHz, DMSO): δ, 157.38,
36.71, 133.46, 129.44, 125.70, 123.91, 120.59, 118.98, 115.17,
ꢀ
1
14.30, 35.11, 19.33; IR (ATR KBr cell, cm ): 774, 1306, 1472,
447, 3741, 3840; Anal. Calcd for C H N O S: C, 54.53; H,
1
2
12
2
3
3
5
4.58; N, 10.60 Found: C, 54.51; H, 4.56; N, 10.58; LCꢀMS (ESI)
calcd.m/z: 264, found 265 [(M+H)] .
+
1
-methyl-2-(methylthio)-3-nitro-4-(4-nitrophenyl)-1H-pyrrole
2
015, 5, 8362ꢀ8370.
(4m)
3
4
(a) A. S. Demir, I. M. Akhmedov and O. Sesenoglu, Tetrahedron,
2002, 58, 9793ꢀ9799; (b) D. Wang, X. Hu and G. Zhao, Int. J. Food
Sci. Technol., 2008, 43, 1880ꢀ1886.
1
Yellow solid; m.p.258ꢀ260°C; yield: 0.128g (65%); H NMR
(300 MHz, CDCl ): δ, 8.23 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 8.9
Hz, 2H), 6.82 (s, 1H), 3.84 (s, 3H), 2.53 (s, 3H); C NMR (75
MHz, CDCl ): δ, 146.83, 139.15, 136.85, 129.31, 128.23, 123.45,
1
1
1
00
4
0
3
1
3
(a) V. J. Demopoulos and E. J. Rekka, Pharm. Sci., 1995, 84, 79ꢀ82;
(b) J. M. Muchowski, Adv. Med. Chem., 1992, 1, 109ꢀ135; (c) B.
3
Khalili, P. Jajarmi, B. EftekhariꢀSis and M. M. Hashemi, J. Org.
Chem., 2008, 73, 2090ꢀ2095.
(a) R. W. Bürli, D. McMinn, J. A. Kaizerman, W. Hu, Y. Ge, Q.
Pack, V. Jiang, M. Gross, M. Garcia, R. Tanaka and H. E. Moser,
Bioorg. Med. Chem. Lett., 2004, 14, 1253ꢀ1257.
(a) H. M. Meshram, B. R. V. Prasad and D. Aravind Kumar,
Tetrahedron Lett., 2010, 51, 3477ꢀ3480; (b) M. Z. Wang, H. Xu, T.
W. Liu, Q. Feng, S. J. Yu, S. H. Wang and Z. M. Li, Eur. J. Med.
Chem., 2011, 46, 1463ꢀ1472; (c) A. K. Verma, S. K. Reddy Kotla, T.
Aggarwal, S. Kumar, H. Nimesh and R. K. Tiwari, J. Org. Chem.,
ꢀ
1
23.09, 120.09, 35.29, 19.44; IR (ATR KBr cell, cm ): 807,
321, 1493, 2348, 3729; Anal. Calcd for C H N O S: C, 49.14; 105
5
6
1
2
11
3
4
4
5
H, 3.78; N, 14.33; Found: C, 49.13; H, 3.76; N, 14.34; LCꢀMS
+
(ESI) calcd.m/z: 293, found 294 [(M+H)] .
1
-methyl-2-(methylthio)-4-(naphthalen-1-yl)-3-nitro-1H-
1
1
10
15
pyrrole (4n)
1
Orange solid; m.p.168ꢀ170°C; yield: 0.181g (90%); H NMR
(300 MHz, CDCl ): δ, 7.91 – 7.82 (m, 2H), 7.68 (d, J = 8.2 Hz,
2
013, 78, 5372ꢀ5384.
5
0
3
7
(a) E. GimenezꢀArnau, S. Missailidis and M. F. G. Stevens, Antiꢀ
Cancer Drug. Des., 1998, 13, 431ꢀ451; (b) P. Cozzi and N. Mongelli,
Curr. Pharm. Des., 1998, 4, 181ꢀ201; (c) Y. R. Torres, T. S. Bugni,
R. G. S. Berlinck, C. M. Ireland, A. Magalhaes, A. G. Ferreira, R. M.
Rocha, J. Org. Chem., 2002, 67, 5429ꢀ5432; (d) B. Das, N. Bhunia
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1
H), 7.52 – 7.34 (m, 4H), 6.74 (s, 1H), 3.86 (s, 3H), 2.56 (s, 3H);
13
CNMR (75 MHz, CDCl ): δ, 138.20, 133.35, 132.45, 130.58,
3
1
1
28.25, 128.15, 127.31, 126.28, 126.12, 125.71, 125.29, 125.07,
ꢀ
1
23.46, 120.24, 35.05, 19.31; IR (ATR KBr cell, cm ): 780,
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