Efficient iodine catalyzed three components domino reaction for the synthesis of 1-((phenylthio)(phenyl)methyl)pyrrolidin-2-one derivatives possessing anticancer activities

Article abstract of DOI:10.1039/c2ob25530h

A simple and efficient three components domino reaction of γ-butyrolactam (2-pyrrolidinone), aromatic aldehyde and substituted thiophenol catalyzed by elemental iodine resulted in the formation of 1-((phenylthio)(phenyl)methyl)pyrrolidin-2-one derivatives. The stability of the synthesized analogues was evaluated in stimulated gastric fluid (SGF) and bovine serum albumin (BSA). In vitro anticancer activity was investigated in the low micromolar range and a few analogues were found to possess good activity. This current protocol provides several advantages like shorter reaction time, excellent yield and convenient work-up.

Full text of DOI:10.1039/c2ob25530h

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 5343
www.rsc.org/obc
COMMUNICATION
Efficient iodine catalyzed three components domino reaction for the synthesis
of 1-((phenylthio)(phenyl)methyl)pyrrolidin-2-one derivatives possessing
anticancer activities†
Gunasekar Ramachandran,a Natesan S. Karthikeyan,a,b Periyasamy Giridharanc and
Kulathu I. Sathiyanarayanan*a
Received 12th March 2012, Accepted 1st June 2012
DOI: 10.1039/c2ob25530h
the new multi-component domino reactions approach was
believed to possess some of the green chemistry principles and
thus they were accepted as green chemistry methods.7
A simple and efficient three components domino reaction of
γ-butyrolactam (2-pyrrolidinone), aromatic aldehyde and
substituted thiophenol catalyzed by elemental iodine resulted
in the formation of 1-((phenylthio)(phenyl)methyl)pyrroli-
din-2-one derivatives. The stability of the synthesized ana-
logues was evaluated in stimulated gastric fluid (SGF) and
bovine serum albumin (BSA). In vitro anticancer activity was
investigated in the low micromolar range and a few ana-
logues were found to possess good activity. This current pro-
tocol provides several advantages like shorter reaction time,
excellent yield and convenient work-up.
Elemental iodine is emerging as an effective Lewis acid cata-
lyst which has been revealed to be a powerful catalyst for several
organic transformations and enhances the utility in organic syn-
thesis.8 In several combinatorial syntheses, elemental iodine is
used as a catalyst and affords numerous advantages like lower
reaction time, low cost, excellent yield, convenient work-up and
use of simple precursors to synthesize complex molecules.9
For the first time we are presenting the synthesis of 1-((phenyl-
thio)(phenyl)methyl)pyrrolidin-2-one derivatives (4) via
a
domino reaction of γ-butyrolactam, aromatic aldehyde and sub-
stituted thiophenol using iodine as a catalyst and a few of the
analogues are found to have good anticancer activity.
In our initial study, we examined the optimized reaction con-
dition to evaluate the efficiency of catalyst for the reaction
among γ-butyrolactam, benzaldehyde and 4-bromothiophenol
under various conditions. In our model reaction several Lewis
acids such as ZnCl2, AlCl3, HgCl2 and CAN were screened and
we optimized the reaction condition.
It is well-known that 5-membered nitrogen-containing hetero-
cycles are of great biological and pharmacological interest.1 The
γ-butyrolactam ring is implanted in numerous biological com-
pounds as a subunit structure2 and in several reactions like asym-
metric synthesis enantiomerically pure pyrrolidones can also act
as chiral auxiliaries.3
In the past few years significant importance has been attached
to combinatorial synthesis and it has generated considerable
interest in the domino reaction,4 in which several reactions are
emerging as useful tools for the formation of carbon–carbon and
carbon–heteroatom bonds in synthetic chemistry to create fasci-
nating and novel drug like scaffolds.5
As shown in Table 1, when the reaction was performed
without catalyst and with other Lewis acids like ZnCl2, AlCl3,
HgCl2 and CAN the reaction did not proceed.
It was remarkable to note that molecular iodine played a sig-
nificant role in our domino reaction. Thus to investigate the
molar percentage of the catalyst required to produce excellent
yield, we carried out the reaction with 1 mol% and increased this
up to 25 mol% of catalyst. A high yield was observed when
using 15 mol% of iodine as the catalyst whereas the use of
increased quantities of catalyst did not further improve the yield
significantly, and we carried out all the reactions with 15 mol%.
The solvent effect was the next factor considered for better
yield. Thus experiments were carried out in various solvents such
as polar protic, aprotic and nonpolar solvents using 15 mol% of
iodine as the catalyst for all the reactions (Table 1, entry 12–21).
As shown in Table 1, we obtained better yields with polar
aprotic solvents such as acetonitrile, dichloromethane (DCM)
and tetrahydrofuran (THF) than with polar protic solvents like
ethanol, n-butanol and isopropyl alcohol (IPA) and nonpolar
In the search for unique therapeutic scaffolds, several research
groups have established the individuality of the domino reaction
as a powerful tool for the preparation of such molecules, which
is the most challenging objective in modern organic synthesis.6
Thus, in recent times in organic chemistry, the improvement of
aChemistry Division, School of Advanced Sciences, VIT University,
Vellore-632014, Tamilnadu, India. E-mail: sathiyakuna@hotmail.com;
Fax: +914162243092
bCentre for Plastic Information Systems (CPIS), Department of
Chemistry Education, Pusan National University, Busan-609735,
South Korea
cHigh Throughput Screening, Piramal Life Sciences Ltd, Mumbai 400
063, India
†Electronic supplementary information (ESI) available: Experimental
procedure, full compound characterization, 1H NMR, 13C NMR and
HPLC. See DOI: 10.1039/c2ob25530h
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5343–5346 | 5343

View Article Online
Table 1 Screening of catalyst and solvent effect on the domino
reaction of γ-butyrolactam, benzaldehyde and 4-bromothiophenola
Entry
Catalyst (mol%)
Solvent (mL)
Yieldb (%)
1
2
3
4
5
6
7
8
None
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
None
CH3CN
DCM
THF
Ethanol
n-Butanol
IPA
Hexane
Benzene
Pentane
—
—
—
—
—
89
89
89
85
79
54
—
63
89
65
51
16
12
11
25
28
ZnCl2 (25)
AlCl3 (25)
HgCl2 (25)
CAN (25)
Iodine (25)
Iodine (20)
Iodine (15)
Iodine (10)
Iodine (5)
Iodine (1)
Iodine (15)
Iodine (15)
Iodine (15)
Iodine (15)
Iodine (15)
Iodine (15)
Iodine (15)
Iodine (15)
Iodine (15)
Iodine (15)
Scheme 1 A possible mechanism for the formation of product (4).
9
10
11
12
13
14
15
16
17
18
19
20
21
Scheme 2 Reaction of γ-butyrolactam and benzaldehyde.
solvents like hexane, benzene and pentane. In the absence of
solvent no desired product was obtained and in the case of DCM
maximum yield was obtained. Hence, the optimal solvent for
these reaction transformations was DCM.
This is in consonance with our proposed mechanism, the pres-
ence of EDG in the benzene ring of benzaldehyde made the
oxygen form a bond with hydrogen from pyrrolidones very effec-
tively and helped the catalysis of the reaction with iodine in the
initial step. Both will be retarded by EDG in the benzene ring of
benzaldehydes. In the initial step, iodine attacks the carbonyl
oxygen of aldehyde and gives rise to the reaction, thereby carbo-
nyl carbon gets bonded with nitrogen of γ-butyrolactam to form
an N-acyliminium cation intermediate. Nucleophilic attack of thio-
phenol on the N-acyliminium cation yields the desired product (4).
A possible mechanism for this reaction is proposed in Scheme 1.
For the synthesis of product (4), two mechanisms are possible.
One possible mechanism is the formation of thiohemiacetal in
the first step and the second step is the attack of amide on thio-
hemiacetal to yield the desired product. Another possible mech-
anism is the generation of an N-acyliminium ion in the first step
followed by the attack of nucleophile (thiophenol) on the N-acy-
liminium ion leading to the formation of the desired product. In
order to elucidate the exact mechanism, we carried out two reac-
tions. One was the reaction between γ-butyrolactam and benzal-
dehyde, and the other was between thiophenol and benzaldehyde
under the same conditions with 15 mol% iodine in DCM. In the
former reaction we added thiophenol to the reaction mixture
after 30–40 min and got the product (4), if the reaction was
allowed to proceed without adding thiophenol it gives 1,1′-((2-
bromophenyl)methylene)bis(pyrrolidin-2-one) product (5).10a
This reaction scheme and its mechanism are represented in
Schemes 2 and 3 respectively.
a Reaction conditions: γ-butyrolactam (10 mmol), benzaldehyde
(10 mmol) and 4-bromothiophenol (10 mmol) at room temperature
(25 °C). b Isolated yield.
Table 2 Domino reaction of γ-butyrolactam, aromatic aldehyde and
substituted thiophenol using iodine as a catalyst leading to the formation
of product (4)
Entry
Benzaldehyde
Thiophenol
Product
Yielda (%)
1
2
3
4
5
6
7
8
Parent
2-Me
4-Me
2-OMe
4-OMe
4-Cl
2-F
2-OEt
4-Br
1-Naphth-
Terephth-
4-Benzyloxy
Parent
4-Cl
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-Br
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
58
62
69
45
71
78
89
65
80
83
80
75
89
95
89
92
9
10
11
12
13
14
15
16
In the latter one we added γ-butyrolactam to the reaction
mixture after 30–40 min but did not get the product (4). Instead
of getting product (4) we got (phenylmethylene)bis((4-methoxy
phenyl)sulfane) product (6).10b The reaction scheme and its
mechanism are represented in Schemes 4 and 5 respectively.
4-Br
4-Br
4-Br
2-Br
4-Br
a Isolated yield.
5344 | Org. Biomol. Chem., 2012, 10, 5343–5346
This journal is © The Royal Society of Chemistry 2012

View Article Online
Hence we have concluded that the mechanism for this reaction
would proceed through only an N-acyliminium intermediate.
Finally we corroborated the mechanism by recording LC-Ms for
the N-acyliminium intermediate formed during the reaction
between γ-butyrolactam and 2-fluorobenzaldehyde which
strongly confirms the presence of an N-acyliminium intermediate
as shown in Fig. 1.
diverse range of aromatic aldehydes and thiophenols to explore
the generality of the reaction in other systems as shown in
Table 3.
The structure of compound 4j was further confirmed by the
single crystal X-ray diffraction analysis as shown in Fig. 2.
We also investigated the scope and the limitation of this
domino reaction. We found that aldehydes possessing electron-
withdrawing groups (EWG) on the benzene ring gave the
product in excellent yield within a short reaction time, whereas
electron donating groups (EDG) in aldehydes gave a lower yield
and took a longer time. This is because EWG in aromatic
aldehydes allow the aldehyde group to react more rapidly with
We found out the optimal conditions for the three components
(1–3) domino reaction and carried out these reactions with a
Scheme 3 A possible mechanism for the formation of product (4 and 5).
Fig. 1 LC-Ms spectra of an N-acyliminium intermediate from com-
pound 4g.
Scheme 4 Reaction of γ-butyrolactam and benzaldehyde.
Fig. 2 The ORTEP diagram of compound 4j as obtained by X-ray
Scheme 5 A possible mechanism for the formation of product (6).
crystallography.
Table 3 In vitro anticancer studies for the synthesised analogue against different cancer cell lines
Concentration (IC50 in μM)a
ACHN
Renal
cancer
PANC1
Pancreatic
cancer
CALU-1
Lung
cancer
H460
Non-small cell
lung cancer
HCT116
Colon
cancer
MCF7
Breast
cancer
MCF10A
Normal breast
epithelium
Entry
Code
1
2
3
4
5
6
7
8
4b
4f
4g
4i
1.6 0.13
0.9 0.07
1.2 0.21
0.7 0.06
3.1 0.39
2.5 0.42
2.1 0.32
0.6 0.05
1.5 0.32
0.8 0.06
0.9 0.1
1.2 0.17
2.9 0.65
1.9 0.14
1.4 0.16
0.64 0.07
2.6 0.24
0.9 0.08
1.1 0.12
0.6 0.05
3.3 0.22
2.1 0.17
1.5 0.21
0.8 0.07
2.7 0.27
1.1 0.13
1.06 0.14
0.8 0.05
3.5 0.44
2.3 0.15
2.4 0.33
1.1 0.12
1.8 0.16
1.3 0.12
0.9 0.08
0.9 0.08
2.2 0.24
1.7 0.36
2.7 0.42
1.2 0.14
2.3 0.27
2.4 0.19
1.3 0.09
1.2 0.12
3.6 0.38
2.6 0.17
3.3 0.25
1.7 0.14
9.8 0.63
9.6 0.57
11.34 0.94
14.87 1.52
14.7 0.89
10.4 0.78
15.6 0.92
8.9 0.73
4j
4m
4n
4o
a The experiment was performed in triplicate for three repeats, and IC50 values were expressed as mean SEM.
This journal is © The Royal Society of Chemistry 2012 Org. Biomol. Chem., 2012, 10, 5343–5346 | 5345

View Article Online
the nitrogen atom of γ-butyrolactam to form an N-acyliminium
cation (intermediate) in a more stable system leading to a faster
reaction and giving a higher yield, while in aromatic aldehydes
containing EDG the formation of an N-acyliminium cation is
less stable leading to a slower reaction and lower yield.
substitution patterns, mild reaction conditions and a convenient
work-up.
Acknowledgements
We have evaluated in vitro anticancer activity for the syn-
thesized molecule at four different concentrations of 0.3 μM,
1 μM, 3 μM and 10 μM against a panel of five cancer cell lines.
The human tumor cell lines of renal cancer, pancreatic cancer,
lung cancer, colon cancer and normal breast epithelium of
MCF7 and MCF10A were used for evaluating anticancer activity
on the high throughput screening platform using Cell Counting
Kit (CCK8) cell proliferation and cytotoxicity assays.
The authors thank Dr Arun Balakrishnan, Vice President, Exter-
nal Liaison and Screening Piramal Life Sciences Limited,
Mumbai, for the anticancer screening.
Notes and references
1 (a) A. I. Meyers and L. Snyder, J. Org. Chem., 1993, 1, 36;
(b) C. M. Moody and D. W. Young, Tetrahedron Lett., 1994, 35, 7277;
(c) B. Rigo, D. Fasseur, N. Cherepy and Couturier, Tetrahedron Lett.,
1989, 30, 7057; (d) G. Poli, S. C. Baffoni, G. Giambastiani and
G. Renginato, Tetrahedron, 1998, 54, 10403.
A preliminary screening showed that some of the derivatives
exhibited moderate to strong anticancer activity on various
cancer cell lines which have been shown in the ESI.†
2 (a) A. H. Gouliaev and A. Senning, Brain Res. Rev., 1994, 19, 180;
(b) E. J. Cory and F. Zhang, Org. Lett., 2000, 2, 4257; (c) R. Aslanian,
G. Lee, R. V. Iyer, N. Shih, J. J. Piwinski, R. W. Draper and
A. T. McPhail, Tetrahedron: Asymmetry, 2000, 11, 3867; (d) A.
S. Paraskar and A. Sudalai, Tetrahedron, 2006, 62, 4907.
3 (a) J. K. Whitesell, Chem. Rev., 1989, 89, 1581; (b) E. Arvanitis,
M. Motevalli and P. B. Wyatt, Tetrahedron Lett., 1996, 37, 4277;
(c) D. Ma and J. Jiang, Tetrahedron: Asymmetry, 1998, 9, 575.
4 (a) A. Domling, Chem. Rev., 2006, 106, 17; (b) E. Ruijter, R. Scheffelaar
and R. V. A. Orru, Angew. Chem., Int. Ed., 2011, 50, 6234;
(c) L. F. Tietze, G. Brasche and K. Gericke, Domino Reactions in
Organic Synthesis, John Wiley-VCH, Weinheim, 2006, 542–565;
(d) B. Ganem, Acc. Chem. Res., 2009, 42, 463; (e) M. Li, Z. Zuo, L. Wen
and S. Wang, J. Comb. Chem., 2008, 10, 436; (f) N. K. Terrett, Combina-
torial Chemistry, Oxford University Press, New York, 1998;
(g) L. T. Tietza, Chem. Rev., 1996, 96, 115.
For those drug molecules that are active against cancer cells in
the preliminary screening, we studied their molecular stability in
stimulated gastric fluid11 and bovine serum albumin.12 SGF was
prepared according to the US Pharmacopeia (USP XII 1995).11a
BSA with high purity (>98%) was purchased from SRL Pvt. Ltd
which was made fatty acid free by using Norit12a and prepared
following the standard method.12b
The molecular stability was measured by UV-Visible spectra
(λ = 400–190 nm) for an interval of time in SGF and BSA as
shown in the ESI.† At different drug concentrations a linear cali-
bration curve was plotted under similar conditions from which
the sample concentrations were calculated.
The molecular stability was measured by the percentage of
concentration loss in comparison to the freshly prepared known
samples. Some of the drug molecules showed moderate to strong
stability towards SGF and BSA for 4–5 h. Detailed stability
studies of SGF and BSA for compounds 4b, 4f, 4g, 4i, 4j and
4m–o using UV-Visible spectra have been given in the ESI.†
We evaluated IC50 values of primary active compounds at 8
different concentrations (0.003 μM, 0.01 μM, 0.03 μM, 0.3 μM,
1 μM, 3 μM, 10 μM and 30 μM) to study the activity against
cancer cell lines at varied concentrations. The results revealed
that the compound 4i showed potent IC50 in the range of 0.6 μM
to 1.2 μM in cancer cells, while IC50 of normal breast epithelium
cells showed 14.87 μM for MCF10A and 1.2 μM for MCF7.
Hence, 4i was highly active towards proliferating cells and even
other compounds 4f, 4o and 4g were found to be potentially
active against cancer cell lines with less cytotoxicity on breast
cancer cells as well as normal epithelium cells. The results
obtained for the active analogues are reported in Table 3. In most
of the cases these analogues were found to possess good activity
against cancer cells, if aromatic aldehydes contain EWG.
In summary, we have successfully developed an efficient
synthetic protocol for a domino reaction of γ-butyrolactam, aro-
matic aldehydes and substituted thiophenols using iodine as a
catalyst. The Lewis acidity of iodine shows enormous catalytic
activity making it capable of binding with the carbonyl oxygen
of aldehyde to yield the desired product. These synthesized
pyrrolidone (4) analogues have been evaluated for their antican-
cer activity and their stability in SGF and BSA. A few of these
compounds were found to be effective against different cancer
cell lines. Thus we conclude that these reactions offer several
advantages such as readily available starting materials, flexible
5 (a) J. D. Sunderhaus, C. Dockendorff and S. F. Martin, Org. Lett., 2007,
9, 4223; (b) F. Lieby-Muller, T. Constantieux and J. Rodriguez, J. Am.
Chem. Soc., 2005, 49, 17176; (c) Y. K. Chen and P. J. Walsh, J. Am.
Chem. Soc., 2004, 126, 3702; (d) M. Zhang, H. Jiang, H. Liu and
Q. Zhu, Org. Lett., 2007, 21, 4111; (e) Y. Yamamoto, J. Ishii,
H. Nishiyama and K. Itoh, J. Am. Chem. Soc., 2004, 12, 3712;
(f) A. Dondoni, A. Massi, E. Minghini, S. Sabbtini and V. Bertolasi,
J. Org. Chem., 2003, 16, 6172.
6 (a) H. Zhou, A. Liu, X. Li, X. Ma, W. Feng, W. Zhang and B. Yan,
J. Comb. Chem., 2008, 10, 303; (b) I. Ugi, A. Domling and B. Werner,
J. Heterocycl. Chem., 2000, 37, 647; (c) R. E. Dolle, B. L. Bourdonnec,
A. J. Goodman, G. A. Morales, J. M. Salvino and W. Zhang, J. Comb.
Chem., 2007, 9, 855.
7 (a) D. J. Ramon and M. Yus, Angew. Chem., Int. Ed., 2005, 44, 1602;
(b) A. Ulaczyk-Lesanko and D. G. Hall, Curr. Opin. Chem. Biol., 2005,
9, 266.
8 (a) M. W. Haenel, J. Narangerel, U. B. Richter and A. Rufinska, Angew.
Chem., Int. Ed., 2006, 45, 1061; (b) C. Wan, L. Gao, Q. Wang, J. Zhang
and Z. Wang, Org. Lett., 2010, 17, 3902; (c) J. Sun, Y. Dong, L. Cao,
X. Wang, S. Wang and Y. Hu, J. Org. Chem., 2004, 69, 8932;
(d) X. F. Li, S. L. Cui and Y. G. Wang, Tetrahedron Lett., 2006, 47, 3127;
(e) Q. Xu and E. Rozners, Org. Lett., 2005, 14, 2821; (f) X. Wang, Q. Li,
J. Wu and S. Tu, J. Comb. Chem., 2009, 3, 433.
9 (a) P. Phukan, J. Org. Chem., 2004, 11, 4005; (b) B. Jiang, C. Li, S. Tu and
F. Shi, J. Comb. Chem., 2010, 4, 482; (c) L. Zeng and C. Cai, J. Heterocycl.
Chem., 2010, 47, 1035; (d) S. K. Sharma, A. K. Mandadapu, B. Kumar
and B. Kundu, J. Org. Chem., 2011, 76, 6798; (e) L. Zeng and C. Cai,
J. Comb. Chem., 2010, 12, 35; (f) D. Prajapati, D. Bhuyan, M. Gohain and
W. Hu, Mol. Diversity, 2011, 15, 257.
10 (a) H. Li, G. Ramachandran, V. Satheesh, K. Sathiyanarayanan and
R. S. Rathore, Acta Crystallogr., Sect. E: Struct. Rep. Online, 2012, E68,
0768; (b) H. Li, G. Ramachandran, M. Sathishkumar,
K. Sathiyanarayanan and R. S. Rathore, Acta Crystallogr., Sect. E: Struct.
Rep. Online, 2012, E68, 0782.
11 (a) B. M. Corcoran, C. Stanton, G. F. Fitzgerald and R. P. Ross, Appl.
Environ. Microbiol., 2005, 71, 3060; (b) D. Debanjan and L. Senshang,
J. Pharm. Sci., 2005, 94, 1343.
12 (a) F. C. Raymond, J. Biol. Chem., 1967, 242, 173; (b) P. M. Sankar,
J. Surf. Sci. Technol., 2007, 23, 91.
5346 | Org. Biomol. Chem., 2012, 10, 5343–5346
This journal is © The Royal Society of Chemistry 2012