on-water synthesis of 3-substituted indoles via Knoevenagel/Michael addition sequence catalyzed by Cu doped ZnS NPs

Article abstract of DOI:10.1016/j.tetlet.2013.08.013

Cu doped ZnS NPs represent a green catalyst for an 'on-water' one-pot rapid synthesis of 3-substituted indole derivatives via Knoevenagel/Michael addition reaction of indane-1,3-dione, aromatic aldehydes, and indole. The catalytic activity of Cu doped ZnS NPs was about sevenfold higher as compared to the ZnS NPs. The Cu doped ZnS NPs catalyst could be recovered and reused for five reaction cycles, giving a total TOF = 201 h^-1.

Full text of DOI:10.1016/j.tetlet.2013.08.013

Tetrahedron Letters 54 (2013) 5711–5717
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
‘‘On-water’’ synthesis of 3-substituted indoles via Knoevenagel/
Michael addition sequence catalyzed by Cu doped ZnS NPs
a
a
a
b
b
Anshu Dandia a, , Shyam L. Gupta , Vijay Parewa , Amit Sharma , Kuldeep S. Rathore , Amit Sharma
⇑
a Centre of Advanced Studies, Department of Chemistry, University of Rajasthan, Jaipur 302004, India
b Semiconductor and Polymer Science Laboratory, Department of Physics, University of Rajasthan, Jaipur 302004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Cu doped ZnS NPs represent a green catalyst for an ‘on-water’ one-pot rapid synthesis of 3-substituted
indole derivatives via Knoevenagel/Michael addition reaction of indane-1,3-dione, aromatic aldehydes,
and indole. The catalytic activity of Cu doped ZnS NPs was about sevenfold higher as compared to the
ZnS NPs. The Cu doped ZnS NPs catalyst could be recovered and reused for five reaction cycles, giving
Received 30 March 2013
Revised 1 August 2013
Accepted 5 August 2013
Available online 11 August 2013
a total TOF = 201 hÀ1
.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Copper doped ZnS nanoparticles
Heterogeneous catalyst
On-water synthesis
Indane-1,3-dione
A diverse array of substituted indoles beholds an arena in the
field of bioactive molecules.1 In this regard, the 3-substituted in-
doles and their derivatives have attracted particular attention as
they are found to be the constituent of privileged motifs prevalent
in various pharmaceutical and agrochemical compounds.2 They
possess a wide range of biological activity covering anticoagulant,
bactericidal, neurotropic, antiphlogistic, radioprotective effects,
zoocide, insecticide, and fungicide. 3-Alkyl or acyl indoles are ver-
satile intermediates for the synthesis of a wide range of indole
derivatives (Fig. 1).3,4 The indane-1,3-dione moiety also represents
an important bio-active motif and attracts a progressive interest of
many researchers due to their widely observed biological and
pharmacological properties (Fig. 1).5
been used to catalyze Michael reaction,20 but many of the reported
procedures with homogeneous catalysts involve drawbacks such
as strong acidic conditions, expensive reagents, lower yield of
products, and longer reaction time. Therefore, the development
of an efficient, cost-effective, and environmentally benign catalyst
for Michael addition is desirable for this process.
Water is recognized as an effective reaction medium and in par-
ticular for ‘on-water’ reactions.21 The unique structure and physi-
cochemical properties of water lead to particular interactions like
polarity, hydrogen bonding, hydrophobic effect, and trans-phase
interactions that might greatly influence the reaction course. On
one hand the hydrophobic effect has encouraging effect on the rate
of reaction while hydrogen bonding has influence on reactants and
transition states, which may show additive outcomes. Trans-phase
interactions of water with transition states and reactants are very
effectual in case of highly insoluble reactants. The water-insolubil-
ity of products further facilitates the isolation of products (or phase
separation in the case of liquids). Last but not the least, due to its
high heat capacity and unique redox stability, water is by far one
of the most safest mediums to carry out organic reactions particu-
larly the exothermic ones.22 As a result, tremendous efforts have
been implemented in the development of catalytic processes by
employing water as a medium to accomplish greener syntheses.23
The fusion of a benign water medium and nano-catalyst seems
to be an attractive way to develop the next generation of green and
sustainable protocols.24 Because of its high surface area and high
density of active sites, nanosized metal particles exhibit superior
catalytic activities compared with the corresponding bulk materi-
als. In this context, searching for a method to incorporate the
Michael addition of heteroaromatics with electron deficient
unsaturated carbonyl compounds constitutes one of the powerful
methods for direct C–C bond formation.6 They are also found to
be atom efficient and thus are inherently green transformations.7
In the past decades, the reaction has been traditionally performed
with various basic catalysts or reagents, such as NaOH,8 Ba(OH)2,9
and Mg-Al-O-t-Bu hydrotalcite.10 Under the strong basic condi-
tions side reactions, such as aldol or self-aldol addition, polymer-
izations, retrogressions, and rearrangements, are frequently
encountered.11 During past few years, various Lewis and Bronsted
acid catalysts such as CuBr2,12 InBr3,13 [Al(DS)3]Á3H2O,14 Au(III),15
17,18
CeCl3Á7H2O–NaI,16 SmI3
and K10–FeO,19 and metal salts have
⇑
Corresponding author.
E-mail addresses: dranshudandia@yahoo.co.in (A. Dandia), kuldeep_ssr@
yahoo.com (K.S. Rathore).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.013

5712
A. Dandia et al. / Tetrahedron Letters 54 (2013) 5711–5717
indole and 1,3-indanedione moieties to synthesize
framework by nanocatalytic one pot reaction in aqueous medium
should be valuable and strongly desired.
Recently, we have used ZnS NPs as a heterogeneous catalyst in
the synthesis of spirooxindole derivatives in water under
ultrasonic irradiation.25 In continuation of this work, we were
a
hybrid
interested in enhancing the catalytic activity of ZnS NPs. In this
regard there have been few studies concerning the addition of
low levels of promoters to catalysts.26,27 Cu has been extensively
investigated as a promoter element to develop new or improved
catalytic system in the past.28 Doping with copper affected mea-
surable changes in the surface and catalytic properties of a ZnS
NH
N
H3C
CH3
N
N
H
O
OH
N
H
N
H
N
H
Bucindolol
(β-blocker )
Indalpine
(Serotonergic antidepressant drug)
DMT
O
O
O
O
O
O
(CH2)6 NH
N
O
N
Acetylcholinesterase inhibitors
(treatment of alzheimer's disease)
O
Vitamin K antagonist
Pravadoline
(Analgesic )
Figure 1. Biologically active indoles and indane-1,3-dione.
O
R
O
H
O
Cu doped ZnS
H2O/rt
R1
+
R
+
O
N
H
R1
N
H
4a-n
O
1a-k
2
3a-d
Scheme 1. Synthesis of novel 3-substituted indoles.
Table 1
Comparison of catalytic activity of catalyst for the synthesis of 2-[(4-chlorophenyl)(1H-indol-3-yl)methyl]-1H-indene-1,3(2H)-dione (4b)a
Cl
O
O
H
O
O
Catalyst
H2O
+
+
O
NH
N
H
Cl
2
3a
1b
4b
Entry
Catalyst
—
ZnSO4 (10 mol %)
ZnCl2 (10 mol %)
Zn dust (10 mol %)
Powder ZnS (10 mol %)
ZnS NPs (10 mol %)
Cu doped ZnS NPs (10 mol %)
Cu doped ZnS NPs (5 mol %)
Time (h)
Yieldb (%)
TOF (hÀ1
)
1
2
3
4
5
6
7
8
10
6
5.5
4.5
4
3.5
1.5
1.5
NR
39
43
54
63
74
95
95
—
10
12
18
24
32
95
201
NR-no reaction.
a
Reactions were performed on a 2 mmol scale of the reactants.
Isolated yield.
b

A. Dandia et al. / Tetrahedron Letters 54 (2013) 5711–5717
5713
Table 2
Effect of solvent on the synthesis of 2-[(4-chlorophenyl)(1H-indol-3-yl)methyl]-1H-indene-1,3(2H)-dione (4b)a
Cl
O
O
O
H
O
O
Cu doped ZnS (5 mol%)
Solvent
+
+
NH
N
H
Cl
2
3a
1b
4b
Entry
Solvent
Ethanol
Methanol
Acetonitrile
Toluene
THF
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
5
6
4
7
6
5.5
1.5
85
81
73
55
59
67
95
CH2Cl2
Water
a
Reactions were performed on a 2 mmol scale of the reactants and 5 mol % of Cu doped ZnS at room temperature stirring.
Isolated yield.
b
nanoparticles. A simple aqueous chemical method25,29 has been
used to prepare these nanomaterials. As a part of our continuing
activities to explore novel protocols30 for the synthesis of heterocy-
clic frameworks and nanomaterials, we describe herein the synthe-
sis and characterization of Cu doped ZnS NPs, which is
subsequently used for the one pot ‘on water’ reaction of indane-
1,3-dione, aromatic aldehydes, and indole via Knoevenagel/Mi-
chael addition sequence (Scheme 1). To the best of our knowledge,
this is the first Letter for the synthesis of novel 3-substituted indole
scaffolds using Cu doped ZnS NPs as a reusable catalyst.
The nanostructure of the nanoparticles has been characterized
by XRD, TEM, EDAX, ICP-AES, and UV–vis (Supplementary data).
2h values of about 28.5, 47.53, and 56.34 correspond to (002),
(110), and (200) planes of hexagonal phase of ZnS and the addi-
Table 3
Synthesis of 2-[(1H-indol-3-yl)(phenyl)methyl]-1H-indene-1,3(2H)-dione derivatives 4a–n
S. No.
R
R1
Time (h)
Product
Yielda (%)
MP (°C)
O
O
4a
4-H
H
2
90
160–162
HN
Cl
O
4b
4c
4d
4-Cl
H
H
H
1.5
95
89
94
242–244
O
O
HN
F
4-F
2
216–218
O
O
HN
HN
NO2
4-NO2
1.5
202–204
O
(continued on next page)

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A. Dandia et al. / Tetrahedron Letters 54 (2013) 5711–5717
Table 3 (continued)
S. No.
R
R1
Time (h)
Product
Yielda (%)
MP (°C)
Br
O
4e
4-Br
H
1.5
90
198–200
O
O
HN
HN
HN
OH
4f
4-OH
H
2
90
240–242
O
O
OCH3
4g
4-OCH3
H
2.5
92
120–122
O
O
Cl
Cl
4h
3,4-Cl
H
1.5
91
238–240
O
O
HN
PhO
4i
3-OPh
H
2.5
84
170–172
O
HN
H3CO
OCH3
O
OCH3
4j
3,4,5-(OCH3)3
H
2.5
92
196–198
O
HN
O
Cl
4k
2-Cl-6-F
H
1.5
91
186–188
F
O
HN
Cl
O
4l
4-Cl
C6H5
2.5
91
142–144
O
N
H

A. Dandia et al. / Tetrahedron Letters 54 (2013) 5711–5717
5715
Table 3 (continued)
S. No.
R
R1
Time (h)
Product
Yielda (%)
MP (°C)
Cl
O
O
4m
4-Cl
4-BrC6H4
3
88
148–150
N
H
Br
Cl
O
4n
4-Cl
4-OMeC6H4
2
93
154–156
O
N
H
MeO
a
Isolated yield.
tion of Cu to ZnS nanoparticles does not create any change in the
ZnS matrix (Supplementary data). The TEM images clearly indicate
that the pure and Cu doped samples are nanostructured and the
size of the particles is found to be in the range of 4–5 nm (Supple-
mentary data). The size distribution of the nanoparticles has also
been represented through histogram, from which it can predicted
that in pure ZnS nanoparticle sample, 5 nm is a dominating size
while 4.7 nm is a dominating size for Cu doped ZnS nanoparticle
sample (Supplementary data).
EDAX has been employed to confirm the Cu doping in the so
prepared samples of nanoparticles (Supplementary data). In UV a
slight blue shift is observed with doping of Cu (Supplementary
data). This shift is the outcome of the quantum confinement
effect produced due to the increased nucleation rate with an
increase in doping concentration.31 The surface Lewis acidity of
this material was confirmed through the adsorption of pyridine
vapour30e on the surface of the NPs. FT-IR spectra of pyridine ad-
sorbed on the catalysts surface are shown in Supplementary
data.
commonly employed organic solvents is quite clearly evident
from the results summarized in Table 2.
Next, we examined the generality of this protocol for the syn-
thesis of 2-[(1H-indol-3-yl)(phenyl)methyl]-1H-indene-1,3(2H)-
dione derivatives (Table 3). After the optimal reaction conditions
were established, namely, 5 mol % catalyst loading, room tempera-
ture, and use of water as solvent, the substrate generality was
probed using a range of benzaldehydes. As illustrated in Table 3,
various aromatic aldehydes with both electron-donating and elec-
tron-withdrawing substituents were successfully employed to pre-
pare the corresponding product in excellent yields, the electronic
factor of aromatic ring showed almost no effect on the yields. It
is observed that the substitution on the 2nd position of indole nu-
cleus gives the slightly lower yield of the final product (Table 3, en-
O
Ar
In order to evaluate the catalyst efficiency of synthesized
nanoparticles 32, 4-chlorobenzaldehyde 1b, indane-1,3-dione 2,
and indole 3a were chosen as model substrates for the reactions
in water (Table 1). There is no reaction in the absence of catalyst.
The reaction occurred smoothly in the presence of 10 mol % of ZnS
NPs affording product in 74% yield. Further the study of catalytic
ability of Cu doped ZnS nanoparticles showed that doping in-
creases the product yield up to 95% and reduces the reaction time
(1.5 h) with the decreased catalyst loading (5 mol %).33 ZnS NPs
were active in reaction with a turn-over frequency (TOF) of
32 hÀ1observed. When the Cu doped ZnS NPs were used, the cat-
alytic activity increases up to sevenfold (TOF 201 hÀ1). This result
is in agreement with working hypothesis that a higher concentra-
tion of acidic sites gives more products in the reaction. Therefore,
the lower catalyst loading is required for this transformation as
compared to many other catalytic systems. These results showed
that this method is superior to the other methods in terms of yield
and reaction time.
O
Lewis acid sites of nanoparticles
O
O
N
H
4
O
H
2
O
O
Ar
H
O
H
1
O
N
H
6
O
Lewis acid sites
of nanoparticles
O
O
H O
2
Ar
N
3
H
O
O
Ar
5
Further the analysis of the final product by ICP-AES showed
that there was no nanocatalyst present in the final product. With
the initial results in hand, a series of experiments were per-
formed using various solvents, to achieve optimal reaction condi-
tions. The superiority of water as solvent as compared to
Lewis acid sites of nanoparticles
Scheme 2. Plausible mechanistic pathway.

5716
A. Dandia et al. / Tetrahedron Letters 54 (2013) 5711–5717
doublet
References and notes
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Acknowledgments
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32. Cu doped ZnS NPs: ZnS Nanoparticles were prepared at room temperature
by dropping ZnSO4 (50 ml, 1 M) and Na2S (50 ml, 1 M) solutions
simultaneously into 200 ml of distilled water containing 50 ml of 0.1 M
solution of EDTA. This was vigorously stirred using a magnetic stirrer under
argon (Ar) atmosphere. The high insolubility of ZnS formed in the chemical
reaction caused the formation of a number of new nuclei which prevents
Financial assistance from the CSIR [02(0143)/13/EMR-II], New
Delhi is gratefully acknowledged. We are also thankful to the Cen-
tral Drug Research Institute (CDRI), Lucknow and IIT Delhi for the
spectral analyses.
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.
08.013.

A. Dandia et al. / Tetrahedron Letters 54 (2013) 5711–5717
the growth of already existing ones, thus limiting the particle size. The role 34. Compound 4b: Mp 242–244 °C; IR (KBr):
5717
max 3376, 1715, 1740, 1454 cmÀ1 1H
m
;
of EDTA was to stabilize the particles against aggregation which may lead to
an increase in the particle size. The doping of copper has been done by
adding 3 wt% of metal sulfate (CuSO4Á5H2O) to ZnSO4 (at the starting of the
reaction) for the formation of ZnS:Cu NPs. The precipitate was separated
from the reaction mixture and was dried at room temperature. After
sufficient drying, the precipitate was crushed to fine powder with the help
of mortar and pestle.
NMR (300 MHz, DMSO-d6) d 10.98 (s, 1H, NH), 7.94 (s, 1H, CH), 7.93–6.83 (m,
12H, Ar-H), 5.16 (d, J = 3.0 Hz, 1H), 4.31 (d, J = 3.0 Hz, 1H). 13C NMR (DMSO-d6,
75 MHz): d 200.3, 199.7, 142.6, 142.4, 140.8, 137.5, 136.4, 135.4, 131.8, 129.7,
127.2, 126.7, 125.9, 124.3, 123.5, 122.6, 120.5, 119.9, 117.9, 114.4, 112.9, 112.5,
110.8, 57.7, 41.0. MS (EI, m/z): 386 [M+H]+. Compound 4c: Mp 216–218 °C; IR
(KBr): mmax 3374, 1718, 1736, 1452 cmÀ1 1H NMR (300 MHz, DMSO-d6) d
;
10.96 (s, 1H, NH), 7.92 (s, 1H, CH), 7.91–6.83 (m, 12H, Ar-H), 5.17 (d, J = 2.4 Hz,
1H), 4.29 (d, J = 2.7 Hz, 1H). 13C NMR (DMSO-d6, 75 MHz): d 199.9, 199.4, 162.3,
159.1, 142.2, 142.0, 137.4, 136.0, 130.4, 130.3, 126.7, 126.3, 124.2, 123.9, 122.7,
121.1, 120.8, 118.5, 118.3, 115.4, 114.7, 114.5, 114.3, 112.4, 111.4, 58.2, 34.6;
MS (EI, m/z): 370 [M+H]+. Compound 4d: Mp 202–204 C; IR (KBr): mmax 3372,
33. General procedure for the synthesis of compounds (4b): In
a 50 ml round
bottom flask, 4-chlorobenzaldehyde 1b (2 mmol), indane-1,3-dione
2
(2 mmol), indole 3a (2 mmol), and catalyst (5 mol %) were added and
stirred in water (15 ml) at room temperature. The progress of the reaction
was checked on TLC. After completion, the reaction mixture was extracted
with ethyl acetate; the organic layer was removed under reduced pressure to
afford the crude products. The pure products were obtained by
recrystallization from ethanol. The structures of all the products were
unambiguously established on the basis of their spectral analysis (IR, 1H
NMR, 13C NMR, and mass spectral data).
1720, 1742, 1450 cmÀ1 1H NMR (300 MHz, DMSO-d6) d 10.95 (s, 1H, NH),
;
8.33(s, 1H, CH), 8.13–6.41 (m, 12H, Ar-H), 5.31 (d, J = 2.7 Hz, 1H), 4.44 (d,
J = 2.7 Hz, 1H). 13C NMR (DMSO-d6, 75 MHz): d 199.9, 199.3, 150.2, 146.5,
146.1, 142.4, 142.0, 136.6, 136.3, 134.6, 130.2, 129.9, 126.6, 124.8, 123.8, 123.5,
123.3, 121.7, 121.3, 119.1, 118.8, 113.4, 111.9, 111,8, 58.2, 36.2. (EI, m/z): 397
[M+H]+.