Iodine mediated rearrangement of tetraarylpiperidin-4-ones: Synthesis, structure analysis and biological studies of 5-aryl-2-methoxy-2,4-diphenyl-1H-pyrrole-3-ones

Article abstract of DOI:10.1016/j.molstruc.2019.126980

An interesting iodine/methanol mediated rearrangement of tetraaylpiperidin-4-ones to 2-methoxy-2,4,5-triaryl-1H-pyrrole-3-ones is described. The structural features of the products are investigated by spectral data and single crystal X-ray analysis. The a

Full text of DOI:10.1016/j.molstruc.2019.126980

Journal of Molecular Structure 1199 (2020) 126980
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Iodine mediated rearrangement of tetraarylpiperidin-4-ones:
Synthesis, structure analysis and biological studies of 5-aryl-2-
methoxy-2,4-diphenyl-1H-pyrrole-3-ones
,
G. Vengatesh a, M. Sundaravadivelu a *, S. Muthusubramanian b
a Department of Chemistry, The Gandhigram Rural Institute (Deemed to Be University), Gandhigram, 624302, Tamil Nadu, India
b Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai, 625 021, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An interesting iodine/methanol mediated rearrangement of tetraaylpiperidin-4-ones to 2-methoxy-
2,4,5-triaryl-1H-pyrrole-3-ones is described. The structural features of the products are investigated by
spectral data and single crystal X-ray analysis. The antifungal, antibacterial and antioxidant character-
istics of the synthesized compounds have been studied.
Received 25 May 2019
Received in revised form
22 August 2019
Accepted 22 August 2019
Available online 26 August 2019
© 2019 Elsevier B.V. All rights reserved.
Keywords:
Iodine/MeOH
Ring contraction rearrangement
Pyrrole
2D NMR
X-ray-diffraction
Biological activity
1. Introduction
pyrrole is one of the most popular core units in many natural
products and more than hundred marketed drugs have pyrrole
In recent years, the molecular iodine finds immense applica-
tions in various organic reactions [1e3]. It is widely available, less
toxic, relatively inexpensive and stable towards air and moisture.
Iodine in methanol has been used as a successful reagent for the
transformation of cyclic compounds to aromatic compounds and
has been extensively used in the last decade [4e10]. Iodine medi-
ated reactions have resulted in the formation of new CeC, CeO,
CeN and NeS bonds [11e16]. Iodine and methanol play vital role in
the one-pot four-component domino reaction towards the syn-
thesis of substituted dihydro-2-oxypyrroles [17], in the one-pot
synthesis of flavanone and tetrahydro pyrimidine derivatives via
Mannich type reaction [18] and in the synthesis of 2,3-
disubstituted furopyridines via electrophilic cyclization of o-ace-
toxy and o-benzyloxyalkynylpyridines [19].
moiety in their skeleton. Pyrrole derivatives also act as building
blocks for various biologically active molecules and functional
materials [23]. Many alkaloids and amino acids contain the reduced
pyrrole ring [24]. Pyrrole derivatives exhibit anti-microbial [25],
anti-viral [26], antitumor [27], antitubulin [28], antimalarial [29]
and anticancer activities [30e32]. Examples of drug molecules
containing pyrrole cores are given in Fig. 1.
In an attempt to get tetrasubstituted symmetrical pyridine, the
dehydrogenation of tetraaryl piperidone was aimed at, wherein an
interesting rearrangement has occurred resulting in dihydropyrrole
derivative. The course of this reaction, the structure analysis and
the biological application of the pyrrole derivatives are described in
this article.
The nitrogen heterocyclic compounds have great importance
because of their profound application in material and biological
systems [20e22]. Among the nitrogen heterocyclic compounds,
2. Experimental
2.1. Materials and methods
The progress of the reactions was monitored by TLC and the
crude compounds have been purified by column chromatography
on silica gel 60e120 mesh (hexane: ethyl acetate). Melting points
* Corresponding author.
E-mail address: msundargri@gmail.com (M. Sundaravadivelu).
https://doi.org/10.1016/j.molstruc.2019.126980
0022-2860/© 2019 Elsevier B.V. All rights reserved.

2
G. Vengatesh et al. / Journal of Molecular Structure 1199 (2020) 126980
Fig. 1. Pyrrole cores containing drugs.
Scheme 1. Synthesis of 5-aryl-2-methoxy-2,4-diphenyl-1H-pyrrol-3-ones 3.
were determined by the open capillary method. FTꢀIR spectra were
recorded with a JASCO FT/IRꢀ4700 spectrometer using KBr pellets.
NMR spectra were recorded at 400 MHz with a Bruker AVANCE III
2.3. Typical experimental procedure for the synthesis of compounds
3a-3e
HD spectrometer. Chemical shifts are reported in
d
(ppm) scale
Reactants 1a-1e were prepared by modified Mannich conden-
sation by Nollar-Balaiah method. 3,5-diphenyl-2,6-diaryl piperi-
dine-4-one (1) (1 mmol) and iodine (2 mmol) were dissolved in
10 ml of methanol and the mixture was heated at 70 ꢁC for 5 h. The
reaction mixture was cooled and the solvent evaporated under
vacuum to obtain the yellow colour product 3. The crude product 3e
was recrystalized from methanol by solvent evaporation method.
relative to TMS as internal standard. The compound (2 mg) was
dissolved in 0.5 ml of DMSO/d6 and used to measure the 1H NMR
chemical shift. To record 13C NMR, DEPT-135, 1He1H COSY, NOESY,
HSQC, HMBC NMR spectra, 20 mg of the samples was used. Single
crystal structure data of compound 3e was collected by Bruker
Smart Apex II Diffractometer. Powder XRD data of compounds 3a-
3e were recorded by PANalytical X'pert3 powder X-ray
Diffractometer.
2.3.1. 2-Methoxy-2,4,5-triphenyl-1H-pyrrol-3-one (3a)
melting point (mp) 219 ꢁC. UV: 382 nm. FT-IR: 3266,
1670 cmꢀ1.1H-NMR (400 MHz, DMSO):
d
7.06 (2H, d, J ¼ 7.20 Hz),
7.11 (2H, t, J ¼ 7.20 Hz), 7.19 (2H, t, J ¼ 7.52 Hz), 7.35e7.42 (3H, m),
7.47e7.56 (5H, m), 7.60 (2H, d, J ¼ 8.04 Hz), 9.11 (1H, s). 13C-NMR
2.2. Antimicrobial studies
(100 MHz, DMSO): d 51.6, 91.8,107.6,126.1,126.2,128.4,128.8,128.8,
128.9, 129.2, 131.2, 132.1, 132.2, 137.6, 174.3, 196.9.
Compounds 3a-3e were screened for their in vitro antibacterial
and antifungal activities. They were screened against three Gram-
positive bacterial strains - Staphylococcus aureus, Bacillus cereus
and Enterococcus faecalis - and one Gram-negative bacterial species
- Klebsiella pneumoniae. The antifungal activity was assessed
against Candida albicans. Streptomycin (for bacterial activity) and
Nystatin (for fungal activity) were used as the references. The
antioxidant activity was studied by DPPH method.
2.3.2. 2-Methoxy-5-(4-methoxyphenyl)-2,4-diphenyl-1H-pyrrol-3-
one (3b)
mp 249 ꢁC. UV: 381 nm. FT-IR: 3258, 1662 cmꢀ1.1H-NMR
(400 MHz, DMSO):
d 3.33 (s, 3H), 3.82 (s, 3H), 7.05 (2H, d,
J ¼ 8.04 Hz), 7.09 (2H, d, J ¼ 7.32 Hz), 7.15 (1H, t, J ¼ 7.16 Hz), 7.23
(2H, t, J ¼ 7.68 Hz), 7.35e7.41 (3H, m), 7.51 (2H, d, J ¼ 6.96 Hz), 7.57

G. Vengatesh et al. / Journal of Molecular Structure 1199 (2020) 126980
3
Table 1
Yield and melting point of the synthesized compounds 3.
2.3.3. 5-(4-Chlorophenyl)-2-methoxy-2,4-diphenyl-1H-pyrrol-3-
one (3c)
mp 244 ꢁC. UV: 386 nm. FT-IR: 3263, 1665 cmꢀ1.1H-NMR
Entry Substrates (1)
1
Products (3)
Yield (%) mpo
C
(400 MHz, DMSO):
d
3.33 (s, 3H), 7.07 (2H, d, J ¼ 7.20 Hz), 7.14 (1H, t,
82
88
219
249
J ¼ 6.80 Hz), 7.22 (2H, t, J ¼ 6.80 Hz), 7.36e7.42 (3H, m), 7.52 (2H, d,
J ¼ 6.40 Hz), 7.59 (4H, s) 9.12 (1H, s). 13C-NMR (100 MHz, DMSO):
d
51.7, 91.8,107.9,126.2,126.3,128.5,128.8,128.9,129.2,129.3,129.9,
130.8, 131.9, 136.8, 137.3, 172.9, 196.9.
1a
3a
3b
3c
2
2.3.4. 2-Methoxy-2,4-diphenyl-5-(p-tolyl)-1H-pyrrol-3-one (3d)
mp 213 ꢁC. UV: 383 nm. FT-IR: 3256, 1668 cmꢀ1.1H-NMR
(400 MHz, DMSO):
d
2.37 (s, 3H), 3.33 (s, 3H), 7.07 (2H, d, J ¼ 6.80),
7.12 (1H, t, J ¼ 7.60 Hz), 7.21 (2H, t, J ¼ 7.20 Hz), 7.29 (2H, d,
J ¼ 8.00 Hz), 7.35e7.41 (3H, m), 7.48e7.525 (4H, m) 9.02 (1H, s). 13C-
1b
NMR (100 MHz, DMSO):
d 21.6, 51.6, 91.8, 107.3, 126.1, 126.2, 128.2,
3
80
83
76
244
213
233
128.3, 128.8, 128.9, 129.3, 129.8, 132.4, 137.7, 142.2, 174.2, 196.7.
2.3.5. 5-(4-Fluorophenyl)-2-methoxy-2,4-diphenyl-1H-pyrrol-3-
one (3e)
mp 233 ꢁC. UV: 383 nm. FT-IR: 3263, 1665 cmꢀ1.1H-NMR
1c
(400 MHz, DMSO):
d
3.34 (s, 3H), 7.07 (2H, d, J ¼ 7.20 Hz), 7.13 (1H, t,
4
J ¼ 7.32 Hz), 7.22 (2H, t, J ¼ 7.60 Hz), 7.34e7.42 (5H, m), 7.53 (2H, d,
J ¼ 7.60 Hz), 7.67 (2H, t, J ¼ 8.64 Hz) 9.10 (1H, s). 13C-NMR (100 MHz,
DMSO):
d 51.6, 91.8, 107.8, 116.3, 126.3, 127.5, 128.5, 128.8, 128.9,
129.3, 131.7, 132.1, 137.5, 164.2, 173.1, 196.8; m/z: calcd. for
23H18FNO2 359.132; found 359.118. anal. calcd. For C23H18FNO2: C,
1d
3d
3e
C
5
81.59, N, 8.63, H, 9.78. Found: C, 82.19, N, 8.98, H, 7.40.
3. Results and discussion
Iodine in methanol is found to be effective in the aromatization
of carbo and heterocyclic rings [7]. In an attempt to dehydrogenate
tetraaryl substituted piperidin-4-one to pyridine-4-ol (2), the
oxidative aromatization of 2,3,5,6-tetraarylpiperidin-4-one (1) was
aimed employing iodine and methanol. It was anticipated that the
presence of four aryl groups could drive the piperidone ring to
complete aromatization providing conjugation delocalizing the
1e
(2H, d, J ¼ 7.76 Hz) 8.94 (1H, s). 13C-NMR (100 MHz, DMSO):
d 51.6,
55.9, 91.8, 107.0, 114.6, 122.9, 126.1, 126.2, 128.4, 128.8, 129.4, 130.9,
132.7, 137.8, 162.3, 173.7, 196.4.
Table 2
1H NMR chemical shift value of compounds 3a-3e.
Compounds
Aliphatic
Aromatic ring A
Aromatic ring B
Aromatic ring C
NeH
OCH3
Others
Ortho
Meta
para
Ortho
Meta
para
7.42
Ortho
Meta
para
3a
3b
3c
3d
3e
9.11
8.94
9.12
9.02
9.10
3.34
3.33
3.33
3.33
3.34
e
7.06
7.09
7.07
7.07
7.07
7.19
7.23
7.22
7.31
7.24
7.11
7.13
7.15
7.12
7.13
7.47e7.53
7.51
7.52
7.50
7.53
7.60
7.57
7.59
7.52
7.37
7.05
4.56
e
3.82
e
7.35e7.41
7.36e7.42
7.38
e
2.37
e
7.41
7.42
7.21
7.36
e
7.40
7.64e7.67
e
Table 3
13C NMR chemical shift value of compound 3a-3e.
Compounds
C2
C3
C4
C5
CH3
3a
3b
3c
3d
3e
91.8
91.8
91.8
91.8
91.8
196.9
196.4
196.9
196.7
196.8
107.6
107.0
107.9
107.3
107.8
174.3
173.7
172.9
174.2
173.1
51.6
51.6
51.7
51.6
51.6
Compounds
Aromatic ring A
Aromatic ring B
Aromatic ring C
ipso
ortho
meta
para
ipso
ortho
meta
para
ipso
ortho
meta
para
3a
3b
3c
3d
3e
137.5
137.8
137.3
137.7
137.4
129.2
129.4
129.3
129.3
129.3
128.9
128.7
128.8
128.7
128.4
126.2
126.2
126.3
126.2
126.3
132.0
132.7
131.9
132.4
132.0
129.2
129.4
129.2
128.9
126.2
128.8
128.4
128.5
128.4
128.9
126.2
126.1
126.3
126.2
126.3
132.2
122.9
129.9
132.4
127.5
131.1
130.9
130.6
129.7
131.6
128.3
114.5
126.2
128.4
116.3
126.1
162.3
136.7
142.3
164.2

4
G. Vengatesh et al. / Journal of Molecular Structure 1199 (2020) 126980
reaction conditions to improve the yield or conditions. Tables 2 and
3 provide the NMR spectral features of compounds 3a-3e. The
unambiguous structural proof for 3 has been provided by the two-
dimensional NMR data and the single crystal X-ray analysis of one
of the compounds, 3e. Important NOESYand HMBC correlations are
shown in Fig. 2. Atom numbering of the compound 3 is given in
Fig. 3 for 1H and 13C NMR chemical shift identification. The features
of single crystal X-ray studies are described below.
3.1. Single crystal XRD studies
Fig. 2. Important NOESY and HMBC correlations.
3.1.1. Structural commentary
An ORTEP view of the compound 3e is shown in Fig. 4 and data
collection, structure refinement details are summarized in Table 4.
The crystal is orthorhombic with Aba2 space group with eight
molecules in the unit cell. The C12eC17 phenyl rings are almost
orthogonal to the central pyrrole ring, with dihedral angle 75.94ꢁ.
The phenyl and fluorophenyl rings are inclined to the central pyr-
role ring at angles of 45.88ꢁ for C18eC23 and 33.86ꢁ for C1eC6.
Probably due to the steric repulsion between the adjacent phenyl
and fluorophenyl rings, the dihedral angle is increased to 54.90ꢁ.
The central pyrrole ring containing phenyl, fluorophenyl rings and
methoxy group is not in the co-planar arrangement, the
N1eC10eC12eC13, N1eC10eO3eC11, C9eC8eC18eC23 and
N1eC7eC3eC4 torsion angles being ꢀ19.37, 64.57, ꢀ49.38
and ꢀ30.94, respectively.
Fig. 3. Atom numbering of compound 3.
pyridyl ring electrons, in spite of the probable nonplanarity. The
reaction was carried out with 200 mol percent of iodine in meth-
anol. The product obtained has been shown to be 2,4,5-triaryl-2-
methoxy-1H-pyrrol-3-one (3) (vide infra) instead of the expected
3,5-diphenyl-2,6-diaryl pyridin-4-ol (Scheme 1). Obviously, iodine
mediated ring contraction has occurred incorporating methoxy
group from the solvent, methanol. The reaction has been carried
out with differently substituted piperidones with very good yield
(Table 1). In fact, there was no need for any optimization of the
3.1.2. Supramolecular features
In the crystal, the molecules are linked by hydrogen bonding
(N1eH1/O2, C11eH11/F and C16eH16/F) and CeH …
ing (C17eH17 … Cg4 and C23eH23 … Cg2) interactions (Figs. 5 and
6). The shortest intermolecular hydrogen bond contact is
N1eH1/O2 (Table 1), which joins the molecules into an infinite
ribbon with graph-set motif C(9) along the b-axis direction (Fig. 5)
[33]. Two such adjacent hydrogen-bonded ribbons are connected to
each other via bifurcated C11eH11/F and C16eH16/F hydrogen
p stack-
Fig. 4. ORTEP view of the compound 3e.

G. Vengatesh et al. / Journal of Molecular Structure 1199 (2020) 126980
5
Table 4
Crystallographic data for and structure refinement parameters for compound 3e.
Crystal data
Chemical formula
C23H18FNO2
Mr
359.38
Crystal system, space group
Orthorhombic, Aba2
Temperature (K)
a, b, c (Å)
V (Å3)
296
19.6547 (9), 12.5104 (6), 15.1399 (6)
3722.7 (3)
8
Z
Radiation type
Mo Ka
0.09
m
(mmꢀ1
)
Crystal size (mm)
Data collection
0.35 ꢂ 0.30 ꢂ 0.20
Diffractometer
Bruker AXS Kappa Apex2 CMOS diffractometer
Absorption correction
Multi-scan SADABS (Bruer, 1999)
Tmin, Tmax
0.92, 0.96
16900, 4845, 3445
0.051
No. of measured, independent and observed [I > 2s(I)] reflections
Rint
(sin
Refinement
R[F2 > 2 (F2)], wR(F2), S
q
/l
)
max (Åꢀ1
)
0.683
s
0.059, 0.115, 1.14
No. of reflections
No. of parameters
No. of restraints
H-atom treatment
Drmax
Absolute structure
Absolute structure parameter
4845
247
1
H-atom parameters constrained
0.26, ꢀ0.19
, )
Drmin (e Åꢀ3
Refined as an inversion twin.
0.6 (15)
bonding and C17eH17 … Cg4 and C23eH23 … Cg2 stacking in-
teractions (Table 5, Fig. 5). Intramolecular stacking interactions are
observed between the acceptor pyrrole ring (N1/C7eC10) and
adjacent C11eH11B, C11eH11C and C13eH13 donor atoms (Fig. 6).
distances longer (distinct contact) than the van der Waals radii. In
Fig. 7, the interactions are characterized as the bright-red spots near
the nitrogen and oxygen, the diminutive-red sport near to Cg4
(C18eC23) phenyl ring. These indicate donor and acceptor roles in
the dominant NeH/O hydrogen bonding and CeH …
p stacking
interaction contacts. The overall two-dimensional fingerprint plot
and those delineated into H/H, C/H/H/C, F/H/H/F, H/O/
O/H, C/F/F/C contacts are illustrated in Fig. 8. The most
important interaction, H/H contributing 51.5% to the overall
crystal packing, is reflected as widely scattered points of high
density due to the large hydrogen content of the molecule. The
shorter hydrogen bonding interaction NeH/O is contributing 9.4%
to the overall crystal packing. The bifurcated CeH/F hydrogen
bonding interaction is contributing 9.5% to the overall crystal
3.1.3. Hirshfeld surface analysis
Hirshfeld surface analysis serves as a powerful tool for gaining
additional insight into intermolecular interactions of molecular
crystals. Hirshfeld surfaces and fingerprint plots were generated for
the title compound using Crystal Explorer [34,35]. On the Hirshfeld
surface mapped over dnorm in Fig. 7, the red colour indicates dis-
tance shorter (in close contact) than the van der Waals radii. The
white colour indicates contacts with distances equal to the sum of
van der Waals radii and the blue colour indicates contacts with
Fig. 5. A packing diagram of the compound 3e, showing a C(9) chain to the b axis formed via NeH/O hydrogen bond, bifurcated CeH/F and CeH …
p interactions.

6
G. Vengatesh et al. / Journal of Molecular Structure 1199 (2020) 126980
Fig. 6. Intramolecular and Intermolecular CeH …
p interactions.
Table 5
packing. The C/H/H/C interactions contribute 26.3% and weak
C/F/F/C intermolecular interactions contribute 1.2% to the overall
crystal packing.
Hydrogen-bond geometry (Å,o) Cg1, Cg2 and Cg4 are the centroids of the major and
minor components of the N1/C7eC10, C1eC6 and C18eC23 rings, respectively.
DꢀH … A
NeH1/O2i
DꢀH
H … A
D … A
DꢀH … A
0.86
0.96
0.93
0.95
0.95
0.93
0.93
0.93
2.19
2.87
2.66
2.99
2.66
2.81
2.83
2.98
2.910 (3)
3.166
3.187
2.879(5)
2.879(5)
3.007(4)
3.688(4)
3.864(4)
141
165
116
74
93
93
3.2. Power XRD analysis
C11eH11A … Fii
C16eH16 … Fiii
C11eH11B … Cg1iv
C11eH11C … Cg1iv
C13eH13 … Cg1iv
C17eH17 … Cg4v
C23eH23 … Cg2vi
It was tried to crystallize all the compounds, but compound 3e
alone provided crystals suitable for single crystal X-ray analysis.
The crystalline nature of the compounds 3a-3e was confirmed by
power XRD studies. The comparison of the powder XRD (PXRD)
pattern and single crystal XRD (SCXRD) pattern of the compound 3e
is shown in Fig. 9. The sharp pattern of PXRD clearly suggests the
154
159
Symmetry codes: (i) 3/2-x,1/2 þ y,z; (ii) ꢀ1/2 þ x,1-y,-1/2 þ z; (iii) x,1/2 þ y,1/2 þ z;
(iv) X,Y,Z; (v) 3/2-X,Y,-1/2 þ Z; (vi) 3/2-X,-1/2 þ Y,Z.
crystalline nature of compound 3e. In Fig. 9, large number of the 2
values are coinciding with PXRD and SCXRD results indicating a
similar pattern in both PXRD and SCXRD studies. The coinciding 2
q
q
values of both the experiments and the comparison of PXRD pat-
terns of compounds 3a-3e are given in the supporting information.
3.3. Mechanism
To provide a convincing mechanism for the conversion of
piperidone 1 to pyrrole-3-one 3 by the treatment of iodine in
methanol, a control experiment has been carried out (Scheme 2). It
has been shown that the presence of aryl groups at 3 and 5 posi-
tions of the piperidone is important for this reaction. Though
enough experimental proof is not there, a tentative mechanism for
the conversion of the piperidone 1 to pyrrole-3-one 3 by the
treatment of iodine in methanol can be visualized as shown in
Scheme 3.
Normally halogenation at alpha position through enol inter-
mediate is the course of reaction for any halogen treatment with
active methylene system. But here, before the iodide counter ion
attacks the alpha position, internal nucleophilic attack would have
taken place by nitrogen generating a three membered intermedi-
ate. The charged unstable three membered gets cleaved through
Fig. 7. The Hirshfeld surface mapped over dnorm, showing intermolecular interactions.

G. Vengatesh et al. / Journal of Molecular Structure 1199 (2020) 126980
7
Fig. 8. Two-dimensional fingerprint plots for the compound.
Scheme 2. Control experiment.
might have attacked the alpha carbon, which is electron deficient.
Another nucleophilic substitution could have occurred, now
methanol is the nucleophile and benzyl anion is the leaving group.
Benzyl anion is stable enough and that may be the driving force for
kicking it out. Subsequent dehydrogenation by iodine, which is
popular, might have led to the product 3. The presence of aryl at 3
and 5 positions are required to stabilize the cation B and for the
solvolysis reaction at the tertiary carbon of G.
3.4. Biological activity
As pointed out in the introduction, many dihydropyrrole de-
rivatives are found to be biologically active. Hence the antifungal,
antibacterial and antioxidant characteristics of the prepared pyr-
role derivatives 3 have been investigated and the results are pre-
sented here.
Fig. 9. Comparison of powder XRD and single crystal XRD patterns of compound 3e.
3.4.1. Antifungal activity
internal nucleophilic substitution, iodide being the nucleophile and
positively charged nitrogen being the leaving group. Now methanol
All the synthesized compounds were tested for their in vitro
antifungal activity against Candida albicans and the results are

8
G. Vengatesh et al. / Journal of Molecular Structure 1199 (2020) 126980
Scheme 3. Tentative mechanism.
Table 6
Antifungal activity of compounds 3ae3e.
Table 8
Zone of Inhibition (mm)
IC50 value for compounds 3a-3e.
Entry
Candida albicans
Entry
Compounds
IC50 Value (X 10ꢀ4) M
0.5 mg/mL
1.0 mg/mL
1.5 mg/mL
1
2
3
4
5
6
3a
3b
3c
3d
1.10
1.04
1.04
1.04
1.04
0.97
3a
3b
3c
3d
3e
Control
e
e
e
e
e
22
13
12
11
10
13
23
1
2
2
1
2
2
13
12
12
10
14
25
2
2
1
1
1
1
3e
Ascorbic acid
1
ControleNystatin; SolventeDMSO; (ꢀ) No activity; ( ) Standard deviation.
Table 7
Antibacterial activities of compounds 3ae3e.
Entry
Zone of Inhibition (mm)
Gram þ ve
Gram ꢀve
Klebsiella pneumoniae
Staphylococcus aureus
Bacillus cereus
Enterococcus faecalis
0.5 mg/mL 1.0 mg/mL 1.5 mg/mL 0.5 mg/mL 1.0 mg/mL 1.5 mg/mL 0.5 mg/mL 1.0 mg/mL 1.5 mg/mL 0.5 mg/mL 1.0 mg/mL 1.5 mg/mL
3a
3b
3c
3d
3e
e
e
e
e
e
e
e
e
e
e
e
e
14
10
11
12
12
14
15
1
1
2
1
2
1
15
12
15
13
16
17
1
1
2
1
2
2
e
e
e
e
e
21
e
e
10
12
10
12
10
13
2
1
1
2
1
1
12
14
12
15
12
15
1
2
2
2
1
1
14
16
14
16
14
16
1
1
1
2
2
2
e
e
e
e
10
e
1
11
e
2
e
e
e
e
14
14
1
1
14
15
1
1
11
23
1
2
12
24
1
1
Control 12
2
1
1
ControleStreptomycin; SolventeDMSO; (ꢀ) No activity; ( ) Standard deviation.

G. Vengatesh et al. / Journal of Molecular Structure 1199 (2020) 126980
9
Fig. 10. Kinetic study for DPPH Vs compound 3e: a) DPPH b) 3e.
presented in Table 6. At lower concentrations of the compounds
4. Conclusion
(3a-e; 0.5mg/mL), there was no activity but at higher concentra-
tions (1.0 and 1.5 mg/mL) moderate activity has been exhibited. The
F/Cl substituted compounds exhibit slightly more activity
compared to other compounds.
The ring contraction and rearrangement involving tetraar-
ylpiperidin-4-ones to 2-methoxy-2,4,5-triaryl-1H-pyrrole-3-ones
is reported. A tentative mechanism for the rearrangement is pro-
posed. The reaction conditions are mild and good yields are ob-
tained in the reaction. Synthesized compounds exhibit significant
antimicrobial, antifungal and antioxidant properties.
3.4.2. Antibacterial activity
The compounds 3ae3e were screened for their antibacterial
activities at three different concentrations of 0.5, 1.0 and 1.5 mg/mL
and the results are shown in Table 7. The data reveal that the Gram-
negative bacteria are more susceptible towards the tested com-
pounds than the Gram-positive ones. In Bacillus cereus pathogens,
compounds with electron withdrawing groups (3c and 3e) exhibit
slightly higher activity compared to compounds with electron
donating groups (3b and 3d). In Staphylococcus aureus and
Enterococcus faecalis, compounds 3c and 3e display good activity.
All the compounds exhibit good activity against Gram-negative
pathogen (Klebsiella pneumoniae). Compounds 3c and 3e display
higher activity than the other compounds.
Acknowledgment
The authors thank the UGC, New Delhi for Major Research
Project (grant No. 42e358/2013 (SR)) & UGC-Special Assistance
Program (SAP). The authors gratefully acknowledge DST- FIST NMR
facility of Department of Chemistry, Gandhigram Rural Institute
(Deemed to be University) for the NMR spectra. S. M acknowledges
CSIR, New Delhi for the award of Emeritus Scientist Scheme (Grant
No. 21(1030)/16/EMR-II).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.molstruc.2019.126980.
3.4.3. Antioxidant activity
The antioxidant behavior of the synthesized compounds has
been determined using the modified Brand-Williams method [36].
The radical scavenging activity against 1,1-diphenyl-2-
picrylhydrazyl (DPPH) is the most commonly used method for
ascertaining the antioxidant activity of a compound [37]. The
analyzing sample capable of donating electrons/hydrogen atoms
can turn the purple color of the solution to yellow [38]. The com-
pounds 3a-3e were evaluated for their free radical scavenging
phenomenon with ascorbic acid as the standard compound. Freshly
prepared DPPH solution (1 ml in ethanol) added to 5 mL of various
concentrations (2 ꢂ 10ꢀ4, 4 ꢂ 10ꢀ4, 6 ꢂ 10ꢀ4, 8 ꢂ 10ꢀ4, 10 ꢂ 10ꢀ4 M)
of test compounds. After 30 min incubation period at room tem-
perature, the absorbance was recorded at 517 nm. The IC50 values
were calculated for the tested compounds and ascorbic acid and are
summarized in Table 8 (see supplementary material for figures).
The effect of the radical scavenging is increased with the increasing
concentrations of the tested compounds. A lower IC50 value in-
dicates a good antioxidant activity. The kinetic study was per-
formed for the compound 3e to verify the quenching time for DPPH
radicals as shown in Fig. 10. As time increases, the intensity at
517 nm decreases indicating the quenching ability of the studied
compounds.
References
[1] L. Yang, X. Shi, B.-Q. Hu, Li-Xia Wang, Iodine-Catalyzed oxidative benzylic C-H
bond amination of azaarenes: practical synthesis of quinazolin-4(3H)-ones,
Asian J. Org. Chem.
201600041.
5 (2016) 494e498. https://doi.org/10.1002/ajoc.
[2] M. Jereb, D. Vrazic, M. Zupan, Iodine-catalyzed transformation of molecules
containing oxygen functional groups, Tetrahedron 67 (2011) 1355e1387.
https://doi.org/10.1016/j.tet.2010.11.086.
[3] P. Finkbeiner, B.J. Nachtsheim, Review iodine in modern oxidation catalysis,
Synthesis 45 (2013) 979e999. https://doi.org/10.1055/s-0032-1318330.
[4] S.K. Wang, M.T. Chen, D.Y. Zhao, X. You, Q.L. Luo, Iodine-Catalyzed oxidative
aromatization: a metal-free concise approach to meta-substituted phenols
from cyclohex-2-enones, Adv. Synth. Catal. 358 (2014) 2093e4099. https://
doi.org/10.1002/adsc.201600930.
[5] M.J. Mphahlele, F.K. Mogamisi, M. Tsanwani, S.M. Hlatshwayo, R.M. Mampa,
IodineeMethanol-promoted oxidation of 2-Aryl-1,2,3,4-tetrahydro-4-
quinolones to 2-Aryl-4-methoxyquinolines, J. Chem. Research (S) (1999)
706e707. https://doi.org/10.1039/A906306D.
[6] H.G. Bonacorso, J. Navarini, C.W. Wiethan, A.F. Junges, S. Cavinatto,
R. Andrighetto, M.A.P. Martins, N. Zanatta, Efficient entry to trifluoromethyl
substituted chromanes from oxidative aromatization of tetrahydro-2H-
chromen-5(6H)-ones using iodine/alcohol with conventional and microwave
methods, J. Fluorine Chem. 142 (2012) 90e95. https://doi.org/10.1016/j.
jfluchem.2012.06.024.
[7] J.S. Yadav, B.V. Subba Reddy, G. Sabitha, G.S. Kiran Kumar Reddy, Aromatiza-
tion of hantzsch 1,4-dihydropyridines with I2-MeOH, Synthesis 11 (2000)
1532e1534. https://doi.org/10.1055/s-2000-7613.

10
G. Vengatesh et al. / Journal of Molecular Structure 1199 (2020) 126980
[23] V. Cadierno, P. Crochet, Ruthenium-Catalyzed furan- and pyrrole-ring for-
[8] M.J. Mphahlele, F.A. Oyeyiola, SuzukieMiyaura cross-coupling of 2-aryl-6,8-
dibromo-1,2,3,4-tetrahydroquinolin-4-ones and subsequent dehydrogena-
tion and oxidative aromatization of the resulting 2,6,8-triaryl-1,2,3,4-
tetrahydroquinolin-4-ones, Tetrahedron 67 (2011) 6819e6825. https://doi.
org/10.1016/j.tet.2011.06.085.
mation, Curr. Org. Synth.
157017908786241590.
5 (2008) 343e364. https://doi.org/10.2174/
[24] A. Alizadeh, A. Rezvanian, L.-G. Zhu, One-pot synthesis of 4,5-dihydro-1H-
pyrrol-3-carboxamide derivatives via a four-component reaction, Tetrahe-
dron 64 (2008) 351e355. https://doi.org/10.1016/j.tet.2007.10.098.
[25] S.S. Basha, P. Ramachandra Reddy, A. Padmaja, V. Padmavathi, K.C. Mouli,
T. Vijaya, Synthesis and antimicrobial activity of 3-aroyl-4-heteroaryl pyrroles
and pyrazoles, Med. Chem. Res. 24 (2015) 954e964. https://doi.org/10.1007/
s00044-014-1169-8.
[26] X.Y. He, L. Lu, J. Qiu, P. Zou, F. Yu, X.K. Jiang, L. Li, S. Jiang, S. Liu, L. Xie, Small
molecule fusion inhibitors: design, synthesis and biological evaluation of (Z)-
3-(5- (3-benzyl-4-oxo-2-thioxothiazolidinylidene)methyl)-N-(3-carboxy-4-
hydroxy)phenyl-2,5- dimethylpyrroles and related derivatives targeting
HIV-1 gp41, Bioorg. Med. Chem. 21 (2013) 7539e7548. https://doi.org/10.
1016/j.bmc.2013.04.046.
[27] M. Wang, C. Ye, M. Liu, Z. Wu, L. Li, C. Wang, X. Liu, H. Guo, Synthesis and
antitumor activity of 5-(5-halogenated-2-oxo-1Hpyrrolo[2,3-b]pyridin-(3Z)-
ylidenemethyl)-2,4-dimethyl-1H-pyrrole3-carboxamides, Bioorg. Med. Chem.
Lett 25 (2015) 2782e2787. https://doi.org/10.1016/j.bmcl.2015.05.017.
[28] C. Da, N. Telang, P. Barelli, X. Jia, J.T. Gupton, S.L. Mooberry, G.E. Kellogg,
Pyrrole-Based antitubulin agents: two distinct binding modalities are pre-
dicted for C-2 analogues in the colchicine site, ACS Med. Chem. Lett. 3 (2012)
53e57. https://doi.org/10.1021/ml200217u.
[29] D.T. Mahajan, V.H. Masand, K.N. Patil, T.B. Hadda, V. Rastija, Integrating GUSAR
and QSAR analyses for antimalarial activity of synthetic prodiginines against
multi drug resistant strain, Med. Chem. Res. 22 (2013) 2284e2292. https://
doi.org/10.1007/s00044-012-0223-7.
[9] B. Zeynizadeh, K.A. Dilmaghani, A. Roozijoy, Aromatization of hantzsch ester
1,4-dihydropyridines with iodine under normal conditions and ultrasound
irradiation, J. Chin. Chem. Soc. 52 (2005) 1001e1004. https://doi.org/10.1002/
jccs.200500139.
[10] V. Domingo, C. Prieto, L. Silva, J.M.L. Rodilla, J. Quílez del Moral, A.F. Barrero,
Iodine, a mild reagent for the aromatization of terpenoids, J. Nat. Prod. 79
(2016) 831e837. https://doi.org/10.1021/acs.jnatprod.5b00914.
[11] R.A. Kumar, G. Saidulu, K.R. Prasad, G.S. Kumar, B. Sridhar, K.R. Reddy, Tran-
sition metal-free
a-C(sp3)H bond functionalization of amines by oxidative
cross dehydrogenative coupling reaction: simple and direct access to C-4-
Alkylated 3,4-dihydroquinazoline derivatives, Adv. Synth. Catal. 354 (2012)
2985e2991. https://doi.org/10.1002/adsc.201200679.
[12] W. Wei, C. Zhang, Y. Xu, X. Wan, Synthesis of tert-butyl peresters from al-
dehydes by Bu4NI-catalyzed metal-free oxidation and its combination with
the KharascheSosnovsky reaction, Chem. Commun. 47 (2011) 10827e10829.
https://doi.org/10.1039/C1CC14602E.
[13] J. Xie, H. Jiang, Y. Cheng, C. Zhu, Metal-free, organocatalytic cascade formation
of CeN and CeO bonds through dual sp3 CeH activation: oxidative synthesis
of oxazole derivatives, Chem. Commun. 48 (2012) 979e981. https://doi.org/
10.1039/C2CC15813B.
[14] T. Froehr, C.P. Sindlinger, U. Kloeckner, P. Finkbeiner, B.J. Nachtsheim, A metal-
free amination of benzoxazoles-the first example of an iodide-catalyzed
oxidative amination of heteroarenes, Org. Lett. 13 (2011) 3754e3757.
https://doi.org/10.1021/ol201439t.
[15] Z. Liu, J. Zhang, S. Chen, E. Shi, Y. Xu, X. Wan, Cross coupling of acyl and aminyl
radicals: direct synthesis of amides catalyzed by Bu4NI with TBHP as an
oxidant, Angew. Chem. Int. Ed. 51 (2012) 3231e3235. https://doi.org/10.1002/
anie.201108763.
[30] I.S. Williams, P. Joshi, L. Gatchie, M. Sharma, N.K. Satti, R.A. Vishwakarma,
B. Chaudhuri, S.B. Bharate, Synthesis and biological evaluation of pyrrole-
based chalcones as CYP1 enzyme inhibitors, for possible prevention of can-
cer and overcoming cisplatin resistance, Bioorg. Med. Chem. Lett 27 (2017)
3683e3687. https://doi.org/10.1016/j.bmcl.2017.07.010.
[16] A. Mariappan, K. Rajaguru, N. Merukan Chola, S. Muthusubramanian,
N. Bhuvanesh, Hypervalent iodine(III) mediated synthesis of 3-substituted 5-
Amino-1,2,4-thiadiazoles through intramolecular oxidative SeN bond for-
mation, J. Org. Chem. 81 (2016) 6573e6579. https://doi.org/10.1021/acs.joc.
6b01199.
[17] A.T. Khan, A. Ghosh, M.M. Khan, One-pot four-component domino reaction for
the synthesis of substituted dihydro-2-oxypyrrole catalyzed by molecular
iodine, Tetrahedron Lett. 53 (2012) 2622e2626. https://doi.org/10.1016/j.
tetlet.2012.03.046.
[18] V. Kavala, C. Lin, C.W. Kuo, H. Fang, C.F. Yao, Iodine catalyzed one-pot syn-
thesis of flavanone and tetrahydropyrimidine derivatives via Mannich type
reaction, Tetrahedron 68 (2012) 1321e1329. https://doi.org/10.1016/j.tet.
2011.11.022.
[31] J.S. Moreno, D. Agas, M.G. Sabbieti, M.D. Magno, A. Migliorini, M.A. Loreto,
Synthesis of novel pyrrolyl-indomethacin derivatives, Eur. J. Med. Chem. 57
(2012) 391e397. https://doi.org/10.1016/j.ejmech.2012.09.008.
[32] L. Dyson, A.D. Wright, K.A. Young, J.A. Sakoff, A. McCluskey, Synthesis and
anticancer activity of focused compound libraries from the natural product
lead, oroidin, Bioorg. Med. Chem. 22 (2014) 1690e1699. https://doi.org/10.
1016/j.bmc.2014.01.021.
[33] M.C. Etter, J.C. MacDonald, J. Bernstein, Graph-set analysis of hydrogen-bond
patterns in organic crystals, Acta Crystallogr. B46 (1990) 256e262. https://doi.
org/10.1107/S0108768189012929.
[34] F.L. Hirshfeld, Bonded-atom fragments for describing molecular charge den-
sities, Theor. Chim. Acta 44 (1977) 129e138. https://doi.org/10.1007/
BF00549096.
[19] A. Arcadi, S. Cacchi, S. Di Giuseppe, G. Fabrizi, F. Marinelli, Electrophilic
cyclization of o-acetoxyand o-benzyloxyalkynylpyridines: an easy entry into
2,3-disubstituted furopyridines, Org. Lett. 4 (2002) 2409e2412. https://doi.
org/10.1021/ol0261581.
[35] M.J. Turner, J.J. MacKinnon, S.K. Wolff, D.J. Grimwood, P.R. Spackman,
D. Jayatilaka, M.A. Spackman, Crystal Explorer, University of Western,
Australia, 2017.
[36] W. Brand-Williams, M.E. Cuvelier, C. Berset, Use of a free radical method to
evaluate antioxidant activity, Food Sci. Technol. Lett. 28 (1995) 25e30. https://
doi.org/10.1016/S0023-6438(95)80008-5.
[37] M. Burits, F. Bucar, Antioxidant activity of Nigella sativa essential oil, Phytother
Res. 14 (2000) 323e328. https://doi.org/10.1002/1099-1573(200008)14:5%
3c323::AID-PTR621%3e3.0.CO;2-Q.
[38] M.Z. Gul, F. Ahmad, A.K. Kondapi, I.A. Qureshi, I.A. Ghazi, Antioxidant and
antiproliferative activities of Abrus precatorius leaf extracts - an in vitro study,
BMC Complement Altern. Med. 13 (2013) 1e12. https://doi.org/10.1186/
1472-6882-13-53.
[20] G. Vengatesh, M. Sundaravadivelu, Quantum Chemical, Experimental, Theo-
retical Spectral (FT-IR and NMR) Studies and Molecular Docking Investigation
of 4,8,9,10-Tetraaryl-1,3-Diazaadamantan-6-Ones, Research on Chemical In-
termediates, 2019. https://doi.org/10.1007/s11164-019-03838-9.
[21] P. Goel, O. Alam, M.J. Naim, F. Nawaz, M. Iqbal, M.I. Alam, Eur. J. Med. Chem.
157 (2018) 480. https://doi.org/10.1016/j.ejmech.2018.08.017.
[22] Bartlomiej Sadowski, Khaled Hassanein, Barbara Ventura, Daniel T. Gryko,
Tetraphenylethylenepyrrolo[3,2-b]pyrrole hybrids as solid-state emitters: the
role of substitution pattern, Org. Lett. 20 (2018) 3183e3186. https://doi.org/
10.1021/acs.orglett.8b01011.