Synthesis of molecular scaffolds assimilating both indolinone and thiazolidinone moieties under environmentally benevolent conditions

Article abstract of DOI:10.1016/j.tetlet.2013.07.052

A chromatography free synthesis of 2-amino-5-isatinylidenethiazol-4-ones from rhodanine, isatin, and amine under environmentally benevolent conditions is reported for the first time. The molecular scaffolds assimilating both indolinone and thiazolidinone moieties are reported to have great biological significance.

Full text of DOI:10.1016/j.tetlet.2013.07.052

Tetrahedron Letters 54 (2013) 5078–5082
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of molecular scaffolds assimilating both indolinone and
thiazolidinone moieties under environmentally benevolent
conditions
⇑
Suman Ray, Chhanda Mukhopadhyay
Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A chromatography free synthesis of 2-amino-5-isatinylidenethiazol-4-ones from rhodanine, isatin, and
amine under environmentally benevolent conditions is reported for the first time. The molecular scaf-
folds assimilating both indolinone and thiazolidinone moieties are reported to have great biological
significance.
Received 20 May 2013
Revised 4 July 2013
Accepted 7 July 2013
Available online 15 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Isatinylidenerhodanine
Ditopic catalyst
Reusable and heterogeneous catalyst
Post-translational modification of proteins by poly ADP-ribosyl-
ation regulates many cellular pathways that are critical for genome
stability including DNA damage repair, chromatin structure, mito-
sis, transcription, RNA metabolism, and telomere function.1 Poly
ADP-ribose (PAR) is composed of repeating ADP ribose units linked
via a unique glycosidic ribose–ribose bond.1a,b The poly(ADP-ri-
bose) polymerase (PARP) family of enzymes, most notably PARP-
1, use b-NAD+ in the synthesis of poly(ADP-ribose).1d,e The pres-
ence of PAR is transient due to the high specific activity of poly(-
ADP-ribose) glycohydrolase (PARG), the main enzyme involved in
the degradation of PAR.1d PARG catalyzes the hydrolysis of the
ribosyl-ribose bond of PAR chains; its deficiency leads to cell
death.1a,2 Thus, inhibition of PARG activity may be a viable strategy
for cancer treatment, selective small molecule inhibitors of PARG
would greatly aid in the interrogation of this interesting biological
target.1d Unfortunately, the lack of potent, specific, and easily syn-
thesized small molecule inhibitors of PARG has limited the study of
PARG’s function both in vitro and in vivo. In recent years an exten-
sive study revealed that from an in-house collection of 224 rhoda-
nine containing small molecules, 72 compounds containing the
isatinylidenerhodanine moiety were selected and screened for
isatinylidenerhodanines can also be used as potential therapeutics
for the treatment of neurodegenerative diseases,4 diabetes,5 sleep,
and mood disorders.6 Moreover, they have been used in developing
molecular probes to evaluate the activities of biological targets.7
Therefore, the quest of the organic chemists has been devoted to
access functionalized isatinylidenerhodanines in satisfactory yields
under mild conditions.
The ‘greening’ of global chemical processes has become a major
issue in the chemical industry and in biology both in terms of
selection of reactions and for the study of solvent and catalyst
effects.8 The development of new strategies for recycling catalysts,
which minimizes the consumption of auxiliary substances, energy,
and time required in achieving separations can result in significant
economic and environmental benefits.8a,9,10 Heterogenization of
catalysts through synthesizing inorganic–organic hybrid materials
has been an interesting approach during the past years. This strat-
egy enabled the research groups to overcome the limitations in-
volved in the separation and recycling of the homogeneous
catalysts. Immobilization of the homogeneous catalyst onto the so-
lid material through chemical bonding is one of the most powerful
strategies to overcome the negative aspects of catalyst leaching. To
achieve this goal, it is necessary to use a linker with chemical
bonding between catalyst and support.11 The use of a combination
of inorganic materials and organic functional groups often results
in synergetic effects that lead to increased physical stability and
enhanced chemical functionality.12 In this respect it should be
mentioned that silica has some additional advantages over other
heterogeneous solid supports, the most important of which is the
relatively easy covalent modification of the surface of silica with
their ability to inhibit PARG in vitro at 10 lM. Many of them
showed really promising PARG inhibitor activity (Fig. 1).1d
Isatinylidenerhodanine-containing biologically active mole-
cules have also been evaluated to show activity against gramposi-
tive and gram-negative bacterial infections.3 Substituted
⇑
Corresponding author. Tel.: +91 33 23371104.
E-mail address: cmukhop@yahoo.co.in (C. Mukhopadhyay).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.052

S. Ray, C. Mukhopadhyay / Tetrahedron Letters 54 (2013) 5078–5082
5079
Cl
Cl
Cl
H
N
H
N
Cl
Cl
Br
Br
H
N
H
N
H
N
H
N
NH2
N
N
N
Me
Me
O
O
O
O
Cl
Cl
Cl
Cl
O
O
O
O
N
O
N
Me
S
S
N
S
S
N
S
S
N
N
N
O
O
O
O
O
S
S
S
S
S
S
Br
Cl
OH
OH
OH
O
O
O
Cl
Cl
Cl
Br
N
H
N
H
N
H
N
N
N
O
O
O
O
O
F
O
O
Br
N
N
N
H
N
H
N
O
O
O
N
N
N
N
N
N
OH
N
N
Figure 1. Some isatinylidenerhodanine containing drug molecules.
Figure 2. Substrate scope for amine and isatin.
R1
Br
O
N
O
O
O
SiO2
Si
S
N
O
N
N
N
N
O
O
(4)
H
N
O
O
O
O
O
O
N
O
O
O
O
40 mg
S
N
O
S
NH
S
N
S
N
S
N
S
N
S
N
H2O (2 ml) + EtOH (2 ml)
Reflux
N
N
5d (78%)
5e (72%)
5b (88%)
5c (92%)
N
5a (92%)
N
S
(1)
R1
N
O
N
N
N
Me
Me
(3)
1 mmol
(2)
1 mmol
(5)
1 mmol
Me
H
N
Scheme 1. Synthesis of 2-amino-5-isatinylidenethiazol-4-ones.
H
N
H
N
H
H
N
O
N
O
O
O
O
N
O
O
organic, inorganic, or organometallic moieties due to the presence
of surface silanol groups. Additionally, silica possesses excellent
physicochemical properties and is inert under reaction and during
processing.13
Inspired by these foregoing discussions and given our interest
and experience in the area of heterogeneous catalysis in organic
synthesis,13–20 we herein report the preparation of a new type of
2-amino-5-isatinylidenethiazol-4-ones (5) with the aid of a re-
usable heterogeneous silica–pyridine based catalyst17,18 (4)
(Scheme 1) starting from rhodanine (1), isatin (2), and amine (3).
A survey of the literature revealed that albeit the Knoevenagel
condensation between isatin and rhodanine is seldom
reported,1d,3e,21 to the best of our knowledge no attempt has been
S
N
O
O
O
S
N
S
N
S
S
N
5f (91%)
N
N
5h(88%)
5i(86%)
5j (85%)
5g (91%)
N
N
N
N
N
O
N
N
Me
Cl
Cl
Cl
H
N
H
N
H
N
H
N
H
N
O
N
O
O
O
N
O
O
O
O
O
O
S
S
S
N
S
N
S
N
5k (79%)
5l (57%)
5m (86%)
5n (82%)
5o (79%)
N
N
NH
N
N
N
Me
Me
Me
Cl
Cl
Br
Br
Br
H
N
H
H
N
H
N
H
N
N
Table 1
O
O
O
O
O
Optimization of reaction conditionsa
O
O
O
O
O
S
N
S
N
S
N
S
N
S
N
5q (71%)
R1
N
N
O
5p (72%)
5r (87%)
5s (82%)
5t (75%)
N
O
N
N
N
N
Me
Me
O
O
O
SiO2
Si
S
O
O
H
N
O
O
Me
N
Br
S
N
O
S
NH
H
N
N
H2O (2 ml) + EtOH (2 ml)
Reflux
N
O
S
R1
O
S
N
5u (67%)
Entry
Solvent (4 ml)
Temp
Time (h)
Yieldb (%)
N
Me
Me
1
2
3
4
5
6
7
8
9
10
DCM
DCE
Toluene
Acetone
THF
MeOH
EtOH
H2O
25–30
80–85
90–100
50–55
60–65
60–65
75–80
90–100
80–90
55–60
48
24
16
24
24
16
16
20
12
16
15
35
40
38
42
45
85
61
88
50
Figure 3. Library of 2-amino-5-isatinylidenethiazol-4-ones synthesized.
made so far to investigate the 3-component reaction between rho-
danine, amine, and isatin to fabricate a new kind of thiazolidinone
derivative for further bioassay.
In order to ascertain the feasibility of this transformation, the
reaction between rhodanine, piperidine, and isatin was selected
as a model substrate and studied under a variety of conditions.
Several common solvents, viz. DCE, DCM, toluene, THF, EtOH,
MeOH, and water were tested (Table 1). Though the yields of the
reaction increased in polar-protic solvent than aprotic and non
EtOH–H2O (2+2 ml)
EtOH–H2O (2+2 ml)
a
Reaction condition: Rhodanine (1 mmol), isatin (1 mmol), piperidine (1 mmol),
40 mg catalyst (4), different solvents, different temperature, different time, and
reflux.
b
Isolated yields.

5080
S. Ray, C. Mukhopadhyay / Tetrahedron Letters 54 (2013) 5078–5082
indispensable for the Knoevenagel condensation between isatin
O
O
O
O
O
O
O
O
O
and the compound 6. The amines employed here cannot act as a
base since they all are consumed by compound 6 when they are
used in equivalent quantity. Although the reaction was successful
with 1.1 equiv of amine with silica as an acid catalyst, it produced
very low yield. Literature survey divulges that the detrimental ef-
fect of excess amine to the yield is presumably due to the forma-
tion of the unwanted product (8) whose quantity increases with
the strength of the base (Fig. 4).17,18,22 The latter may arise from
the nucleophilic displacement of an isatinylidenethiazolone group
by means of the anion generated on a second thiazolone moiety.
Again green chemistry aims to eliminate pollution by preventing
it from happening in the first place and by using resources for
chemical products that are renewable.8a,10 Therefore the excess
amine (3) must be replaced with a heterogeneous reusable catalyst
and if its basicity is lower than the amine (3) used then it is a dou-
ble achievement since green chemistry not only prioritizes the use
of reusable catalysts but also the product yield. Thus the best yield,
cleanest reaction, and most facile work-up were achieved employ-
ing 1.0 equiv of each of rhodanine (1), isatin (2), and amine (3)
employing 40 mg of silica based substituted pyridine (4) as the
right choice of catalyst and was demonstrated to be the key to ob-
tain good to excellent yields of (5).
On the basis of the foregoing discussion a plausible reaction
scenario for this one pot three-component reaction is outlined
in Scheme 2. From this we can conclude that both acid and
base functionalities are inevitable for this transformation. In
this present instance the silica-pyridine based catalyst (4) per-
forms efficiently as a heterogeneous ditopic catalyst containing
both acid and base functionalities. The key findings of high sig-
nificance of the catalyst described in this work are threefold.
Firstly the attack of the secondary amine (3) on C@S of rhoda-
nine (1) is catalyzed by acidic silica. Secondly the silanol
groups present on the surface of silica coordinate with the oxy-
gen atom of the isatin carbonyl which in turn increases its
electrophicity15–18 and the attack of rhodanine becomes easier
affording the compound (7). Subsequent water elimination from
(7) is also greatly assisted by the catalyst to give the target
compound (5).
+
+
Si
B
Si
B
H
Si
B
S
O
-H/+H
-H2S
O
O
HNR2R3
S
N
H
H
OH
OH
O
S
N
H
+
+
N
S
H
-H/+H
2R3RN
SH
NR2R3
(6)
O
O
O
O
NR2R3
N
H
O
O
Si
B
Si
B
H
N
S
O
O
O
N
H
O
O
H
O
H
O
N
S
S
O
H
NR2R3
O
O
NR2R3
N
H
N
H
(5)
(7)
pure covalent bonds
H-bond or other weak interactions
Scheme 2. Plausible mechanism for 2-amino-5-isatinylidenethiazol-4-ones
formation.
polar solvents, the reaction was not satisfactory in water (Table 1,
entry 8), possibly due to less homogeneity of the reaction mixture.
Therefore aqueous-ethanol (1:1 v/v) came out as a best choice of
solvent. Similarly, temperature appears to play a significant role
because there was only 50% conversion after stirring the reaction
mixture at 55–60 °C for 8 h (Table 1, entry 10) in aqueous ethanol
instead of 91% yield at 80–90 °C (Table 1, entry 9).
With the optimized conditions in hand, to delineate this ap-
proach, the scope and generality of this protocol was next exam-
ined by employing five different isatins and seven different
amines (Fig. 2). An assembly of 21 compounds was synthesized
using this protocol (Fig. 3).
Encouraged by the success of the above reaction, we became
interested in the mechanism (Scheme 2). For this purpose, we
investigated the reaction of rhodanine, N-allyl isatin, and morpho-
line. The process commenced with the reaction between rhodanine
and amine to afford compound (6) as evidenced from the crude
reaction mixture isolated after 1 h. The compounds detected in
the 1H NMR spectra of the crude reaction mixture isolated after
1 h were the intermediate (6) and the unconsumed N-allyl isatin
with only 7% of the target molecule (5c) (Figure given in Supple-
mentary data). Intermediate (6) was isolated from the crude reac-
tion mixture by chromatographic separation and its structure was
determined by NMR spectroscopy. Again the target compound (5c)
was also obtained when the intermediate (6) was refluxed in aque-
ous-ethanol with N-allyl isatin in presence of the catalyst (4) for
10 h. Thus the intermediacy of 6 in this transformation is clearly
established. These facts altogether support the proposed mecha-
nism. We have reported15 in one of our recent papers that the at-
tack of amine (3) on C@S of rhodanine (1) is an acid catalyzed
reaction and in the present work silica performs efficiently as an
acid catalyst to afford the in situ intermediate (6). The intermedi-
ate then suffers a concomitant Knoevenagel type condensation
with isatin to give the target compound (5). This step is catalyzed
by the covalently anchored pyridine moiety in the catalyst.17,18
Compound 6 was solely formed only with silica without the forma-
tion of any desired compound 5. Therefore a base catalyst is
The third high significance is that the leaching of the active site
is greatly avoided as the pyridine moiety is covalently attached
with the silica surface through a silanol group.
Good to excellent conversion was also achieved with different
homogeneous catalyst like NaOAc/AcOH, NH4OAc/AcOH, piperidi-
nium benzoate etc. However they required repeated work-up, neu-
tralization of acids and bases, and extensive chromatographic
purification. Ultimately the isolated yields were very low. The reac-
tions with different spinel metal oxide nano particles containing
both acidic and basic sites like ZnTiO3 and ZnFe2O4 afforded com-
paratively low yield.
The structures of the compounds (5) were determined by IR, 1H,
13C NMR, CHN, and X-ray single crystal analysis. The scanned cop-
ies of 1H and 13C NMR spectra of all the compounds are given in
Supplementary data. It is worthy to declare that the ‘Z’ geometry
of the olefinic bond was explicitly assigned from X-ray single crys-
tal analysis of (5d) (CCDC 939929) (Fig. 5). To the best of our
knowledge structural determination of isatinylidenerhodanine
compounds by X-ray single crystal analysis has not been reported.
O
NH
O
S
N
S
(8)
N
Figure 4. Possible side product in this reaction.

S. Ray, C. Mukhopadhyay / Tetrahedron Letters 54 (2013) 5078–5082
5081
250
4.5 nm
Adsorption
Desorption
(a)
(b)
(cylindr. pore, NLDFT adsorption
branch model)
0.010
0.005
0.000
200
BET surface area = 292 m2g-1
Pore Volume = 0.3421 cc/g
150
100
50
0.2
0.4
0.6
0.8
1.0
10
20
30
Pore width in nm
Relative pressure [P/P
]
0
300
250
200
150
100
50
0.012
0.008
0.004
0.000
4.2 nm
(d)
(c)
Adsorption
Desorption
Pore volume = 0.2985 cc/g
BET surface area = 199 m2g-1
Figure 5. ORTEP diagram of 5d (CCDC 939929).
0
0
5
10
15
20
0.2
0.4
0.6
0.8
1.0
Pore width (nm)
Relative pressure [P/P
]
0
Figure 8. (a) N2 adsorption isotherm and (b) PSD of silica; (c) N2 adsorption
isotherm, and (d) PSD of catalyst (4).
peaks at À58 ppm assigned to Si–OH of RSi(OSi)2(OH) group (T2)
and À66 ppm assigned to R–Si(OSi)3 group (T3), which provides di-
rect evidence that the hybrid catalyst (4) consists of a highly con-
densed siloxane network with an organic group covalently bonded
to the silica gel as a part of the silica wall structure.23
Nitrogen adsorption isotherms of different samples were re-
corded. The Brunauer–Emmett–Teller surface area of the silica ob-
tained by using N2 adsorption–desorption isotherm was found out
to be 292 m2 gÀ1 and pore volume was 0.3421 cc/g (Fig. 8, panel a
and b). We can find that the surface area (199 m2 gÀ1) and pore
volume (0.2985 cc/g) of the catalyst (4) decreases when compared
to pure silica (panel c and d). It is expected for organic-functional-
ized silica due to the occupation of large organic groups in the
small pores, that is, restricted access to the pores caused by organic
functional group. Therefore, the organic functionality is grafted
compactly and securely inside the pores while not fully occupying
the total available space, therefore still leaving room for N2 adsorp-
tion and molecular transport. NLDFT pore size distribution (PSD)
results of the catalyst showed a wide distribution of pores with
peak pore dimension of ca. 4.2 nm.
Figure 6. 13C CP MAS NMR spectra of catalyst (4).
Reactions were carried out using different amounts of the cata-
lyst and the optimum amount has been determined. We can see
that yield increases only marginally with increasing amount of cat-
alyst from 40 to 70 mg. Since we wanted to use minimum quantity
of catalyst, 40 mg was determined as the optimum amount. Deter-
mination of this optimum amount to achieve maximum yield was
very essential to establish the efficacy and broaden the applicabil-
Figure 7. 29Si MAS NMR spectra of catalyst (4).
Table 2
The catalyst was prepared according to the procedure we have
reported previously.16–18 In the 13C CP MAS NMR spectra (Fig. 6)
the catalyst showed peaks at d 12.0 for (a), 22.7 for (b), 33.0 for
(c and d), 130.4 for (e and g), 146.8, and 148.4 for (f, h, and i). This
confirmed the structure of the prepared silica based substituted
pyridine catalyst (4).
Optimization of the amount of catalysta
Entry
Amount of catalyst (mg)
Conversionb (%)
1
2
3
4
5
6
7
8
9
10
0
5
0
14
27
43
65
88
89
89
89
90
10
20
30
40
45
50
60
70
The 29Si MAS NMR spectral pattern for silica supported pyridine
catalyst is shown in (Fig. 7). Three up resonance peaks assigned to
tetrahedral Q2 (À96 ppm), Q3 (À101 ppm) and Q4 (À111 ppm) sil-
ica species,23 respectively, where Qn = Si(OSi)n(OH)4-n, n = 2–4.
Again the high Q4 percentage indicated highly condensed net-
work.24 Such a high Q4 concentration is of paramount importance
for the catalytic activity of the silica based catalyst, since the
reduction of surface silanols introduces high hydrophobicity (and
thus more affinity toward organic substrates).24 The down field
a
Reaction condition: Rhodanine(1 mmol), N-allyl isatin (1 mmol), N-methyl
piperazine (1 mmol), different amounts of silica based pyridine catalyst, and
aqueous ethanol (2+2 ml), 80–90 °C reflux for 12 h.
b
Percentage was calculated from crude 1H NMR spectra (300 MHz).

5082
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A.; MacDonald, C.; Weaver, R.; Christie, J.; Barber, S.; Mohammed, R.; Paul, M.;
90
80
70
60
50
40
% conversion
Cook, A.; Baxter, A. Bioorg. Med. Chem. Lett. 2011, 21, 2991; (c) Engels, K.; Beyer,
C.; Fernandez, M. L. S.; Bender, F.; Gassel, M.; Unden, G.; Marhofer, R. J.;
Mottram, J. C.; Selzer, P. M. Chem. Med. Chem. 2010, 5, 1259; (d) Fan, C. G.; Clay,
M. D.; Deyholos, M. K.; Vederas, J. C. Bioorg. Med. Chem. 2010, 18, 2141; (e) Xue,
F.; MacKerell, A. D.; Heinzl, G., Jr.; Hom, K. Tetrahedron Lett. 2013, 54,
1700.
4. Volynets, G. P.; Bdzhola, V. G.; Yarmoluk, S. M. FEBS J. 2011, 278, 340.
5. Niigata, K.; Okada, M.; Yoneda, T. Eur. Patent 2,371,381,987.
6. Szewczuk, L. M.; Saldanha, S. A.; Ganguly, S.; Bowers, E. M.; Javoroncov, M.;
Karanam, B.; Culhane, J. C.; Holbert, M. A.; Klein, D. C.; Abagyan, R.; Cole, P. A. J.
Med. Chem. 2007, 50, 5330.
0
1
2
3
4
5
6
7
Cycles
7. (a) Carlson, E. E.; May, J. F.; Kiessling, L. Chem. Biol. 2006, 13, 825; (b) Carlson, E.
E.; Higgin, M. L.; Kiessling, L. Biochemistry 2003, 42, 8620; (c) Hu, Y.; Heim, J. S.;
Chen, L.; Ginsberg, C.; Gross, B.; Kraybill, B.; Tiyanont, K.; Fang, X.; Wu, T.;
Walker, S. Chem. Biol. 2004, 11, 703.
Figure 9. Recycling of catalyst (4) for the reaction forming 5j.
8. (a) Rostamnia, S.; Xin, H.; Xiao, L.; Lamei, K. J. Mol. Catal. 2013, 374–375, 85; (b)
Anastas, P. T.; Warner, J. C. Green Chem.: Theory and Practice; Oxford University:
Oxford, 1998. pp. 1–30; (c) Choudhary, D.; Paul, S.; Gupta, R.; Clark, J. H. Green
Chem. 2006, 8, 479; (d) V-Rhijn, W. M.; Vos, D. D.; Sels, B. F.; Bossaert, W. D.;
Jacobs, P. A. Chem. Commun. 1998, 317.
9. (a) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025; (b) Nishina, Y.; Takami, K.
Green Chem. 2012, 14, 2380; (c) Shen, Z.-L.; Cheong, H.-L.; Lai, Y.-C.; Loo, W.-Y.;
Loh, T.-P. Green Chem. 2012, 14, 2626.
10. (a) Latham, A. H.; Williams, M. E. Acc. Chem. Res. 2008, 41, 411; (b) Vaddula, B.
R.; Saha, A.; Leazer, J.; Varma, R. S. Green Chem. 2012, 14, 2133; (c) Strubing, D.;
Neumann, H.; Klaus, S.; Hubner, S.; Beller, M. Tetrahedron 2005, 61, 11333.
11. Tayebeea, R.; Aminib, M. M.; Nehzata, F.; Sadeghib, O.; Armaghan, M. J. Mol.
Catal. A: Chem. 2013, 366, 140.
12. (a) Park, J. W.; Park, Y. J.; Jun, C. H. Chem. Commun. 2011, 4860; (b) Smaıhi, M.;
Jermoumi, T.; Marignan, J.; Noble, R. D. J. Membr. Sci. 1996, 116, 211; (c) Reetz,
M. T.; Zonta, A.; Simpelkamp, J. Angew. Chem. Int. Ed. Engl. 1995, 34, 301.
13. Ray, S.; Brown, M.; Bhaumik, A.; Dutta, A.; Mukhopadhyay, C. Green Chem.
2013. http://dx.doi.org/10.1039/c3gc40441b.
14. Ray, S.; Das, P.; Bhaumik, A.; Dutta, A.; Mukhopadhyay, C. Appl. Catal. A 2013,
458, 183.
15. Ray, S.; Bhaumik, A.; Dutta, A.; Butcher, R. J.; Mukhopadhyay, C. Tetrahedron
Lett. 2013, 54, 2164.
16. Mukhopadhyay, C.; Ray, S. Catal. Commun. 2011, 12, 1496.
17. Mukhopadhyay, C.; Ray, S. Tetrahedron 2011, 67, 7936.
18. Mukhopadhyay, C.; Ray, S. Tetrahedron Lett. 2011, 52, 6431.
19. Das, P.; Butcher, R. J.; Mukhopadhyay, C. Green Chem. 2012, 14, 1376.
20. Mukhopadhyay, C.; Rana, S. Catal. Commun. 2009, 11, 285.
21. (a) Johnson, S. L.; Chen, L. H.; Pellecchia, M. Bioorg. Chem. 2007, 35, 306; (b) Fan,
C.; Clay, M. D.; Deyholos, M. K.; Vederas, J. C. Bioorg. Med. Chem. 2010, 18, 2141;
(c) Zawahir, Z.; Dayam, R.; Deng, J.; Pereira, C.; Neamati, N. J. Med. Chem. 2009,
52, 20; (d) Foloppe, N.; Fisher, L. M.; Howes, R.; Potter, A.; Robertson, A. G. S.;
Surgenor, A. E. Bioorg. Med. Chem. 2006, 14, 4792.
ity of the proposed process. For this purpose the reaction forming
5b was chosen as a test reaction (see Table 2).
In the presence of the catalyst (preheated at 100 °C for 4 h) the
reaction between isatin, rhodanine, and morpholine occurred with
85% yield of 5j. The same reaction in the presence of the catalyst
after having it exposed to ambient atmosphere for 5 days produced
similar observation. Obviously, there was no deteriorating effect of
heat, aerial oxygen, or moisture toward the activity of the catalyst.
The recycled catalyst could be used at least seven times with al-
most the same efficiency as that of first run without any further
treatment (Fig. 9). Detailed characterization of the catalyst after
the 5th run showed that it was unaffected under the conditions
of the reaction.
Therefore, the aim of this protocol25 is to highlight the synergis-
tic effects of the combined use of multi-component reactions in an
environmentally benevolent solvent and the application of solid
base catalyst supported on silica with inherent properties like
reusability and robustness for the development of new eco-com-
patible strategy for heterocyclic synthesis. The spectral and analyt-
ical data26 of one representative compound (5a) is provided in the
main manuscript.
Acknowledgements
22. (a) Kandeel, K. A.; Youssef, A. M.; El-Bestawy, H. M.; Omar, M. T. J. Chem. Res.
Synop. 2003, 682; (b) Kandeel, K. A.; Youssef, A. M.; El-Bestawy, H. M.; Omar,
M. T. Monatsh. Chem. 2002, 133, 1211.
23. Gao, R.; Zhu, Q.; Dai, W. L.; Fan, K. Green Chem. 2011, 13, 702.
24. Samanta, S.; Laha, S. C.; Mal, N. K.; Bhaumik, A. J. Mol. Catal. A: Chem. 2004, 222,
235.
We acknowledge the UGC for financial support (F. No. 37-398/
2009 (SR) dated 11-01-2010), the CSIR for fellowship (SR), and
the NMR Research Centre, IISc, Bangalore-560012 for the solid
state 13C CP MAS, and Si-29 NMR spectrum.
25. General synthetic procedure for preparation of 2-amino-5-isatinylidenethiazol-4-
ones (5): In a typical reaction a solution of isatin (1 mmol), rhodanine (1 mmol),
amine (1.0 mmol) in EtOH–water (2+2 ml) were refluxed at 80–90 °C till
completion using 40 mg of the catalyst (4). The completion of the reaction was
indicated by the disappearance of the starting material in thin layer
chromatography. After completion of the reaction the crude mixture was
filtered, washed several times with water and then with ethanol. The residue
contained both the product and the catalyst. Then the crude product was taken
in DCM/MeOH (1:1 v/v) and again filtered to separate the product as filtrate.
The solvent was removed in rotary evaporator and crude product was
recrystallized from DCM/MeOH (1:1 v/v). The compounds (5) were
characterized by IR, 1H NMR, 13C NMR and CHN and X-ray single crystal
analysis.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.052.
References and notes
1. (a) Slade, D.; Dunstan, M. S.; Barkauskaite, E.; Weston, R.; Lafite, P.; Dixon, N.;
Ahel, M.; Leys, D.; Ahel, I. Nature 2011, 477, 616; (b) Hakme, A.; Wong, H. K.;
Dantzer, F.; Schreiber, V. EMBO Rep. 2008, 9, 1094; (c) D’Amours, D.; Desnoyers,
S.; D’Silva, I.; Poirier, G. G. Biochem. J. 1999, 342, 249; (d) Finch, K. E.; Knezevic,
C. E.; Nottbohm, A. C.; Partlow, K. C.; Hergenrother, P. J. ACS Chem. Biol. 2012, 7,
563; (e) Schreiber, V.; Dantzer, F.; Ame, J. C.; de Murcia, G. Nat. Rev. Mol. Cell
Biol. 2006, 7, 517; (f) Fagagna, F.; Hande, M. P.; Tong, W. M.; Lansdorp, P. M.;
Wang, Z. Q.; Jackson, S. P. Nat. Genet. 1999, 23, 76.
2. Koh, D. W.; Lawler, A. M.; Poitras, M. F.; Sasaki, M.; Wattler, S.; Nehls, M. C.;
Stoger, T.; Poirier, G. G.; Dawson, V. L.; Dawson, T. M. Proc. Natl. Acad. Sci. U.S.A.
2002, 101, 17699; (a) Hanai, S.; Kanai, M.; Ohashi, S.; Okamoto, K.; Yamada, M.;
Takahashi, H.; Miwa, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 82.
26. 1-Allyl-3-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidene)-1,3-dihydro-indol-2-one
5a: Orange solid, mp 140–142 °C (CH2Cl2+EtOAc, equal volumes); IR (KBr):
3434, 3042, 2923, 1593, 1509, and 1333 cmÀ1 1H NMR (300 MHz, CDCL3) d:
;
8.97 (1H, d, J = 7.8 Hz, aromatic-H), 7.09 (1H, t, J = 7.5 Hz, aromatic-H), 6.89
(1H, t, J = 7.8 Hz, aromatic-H), 6.59 (1H, d, J = 7.8 Hz, aromatic-H), 5.72-5.66
(1H, m, @CH), 5.03–4.97 (2H, m, @CH2), 4.19 (2H, d, J = 5.1 Hz, allylic–CH2),
3.80 (2H, br s, piperidine–CH2), 3.41 (2H, br s, piperidine–CH2), 1.52 (6H, br s,
piperidine–CH2); 13C NMR (75 MHz, CDCL3) d: 179.7, 176.3, 168.2, 143.1, 138.6,
131.1, 129.2, 125.1, 123.1, 120.6, 117.9, 108.6, 49.8, 49.7, 42.7, 26.3, 25.6, 23.9;
Anal. Calcd for C19H19N3O2S: C, 64.57; H, 5.42; N, 11.89%. Found C, 64.76; H,
5.50; N, 11.99%.
3. (a) Pardasani, R. T.; Pardasani, P.; Sherry, D.; Chaturvedi, V. Indian J. Chem., Sect
B 2001, 40, 1275; (b) Unitt, J.; Fagura, M.; Phillips, T.; King, S.; Perry, M.; Morley,