Magnetically separable sulfonic acid catalysed one-pot synthesis of diverse indole derivatives

Article abstract of DOI:10.1016/j.tetlet.2015.08.043

Fe₃O₄-OSO₃H was identified as an efficient reusable catalyst for the facile synthesis of diarylmethyl indole derivatives under neat condition by C-C bond forming reaction. Fe₃O₄-OSO₃H catal

Full text of DOI:10.1016/j.tetlet.2015.08.043

Accepted Manuscript
Magnetically separable sulfonic acid catalysed one-pot synthesis of diverse in-
dole derivatives
Jagatheeswaran Kothandapani, Asaithampi Ganesan, Subramaniapillai Selva
Ganesan
PII:
S0040-4039(15)01345-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.08.043
TETL 46627
Reference:
Tetrahedron Letters
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17 August 2015
18 August 2015
Please cite this article as: Kothandapani, J., Ganesan, A., Ganesan, S.S., Magnetically separable sulfonic acid
catalysed one-pot synthesis of diverse indole derivatives, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/
j.tetlet.2015.08.043
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Magnetically separable sulfonic acid
catalysed one-pot synthesis of diverse indole
derivatives
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Jagatheeswaran Kothandapani, Asaithampi Ganesan and Subramaniapillai Selva Ganesan∗

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Magnetically separable sulfonic acid catalysed one-pot synthesis of diverse indole
derivatives
Jagatheeswaran Kothandapani, Asaithampi Ganesan and Subramaniapillai Selva Ganesan∗
a Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Thanjavur-613401, India Fax: +91(4362)264120; Tel:
+918973104963; E-mail:selva@biotech.sastra.edu.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Fe3O4-OSO3H was identified as efficient reusable catalyst for the facile synthesis of
diarylmethyl indole derivatives under neat condition by C-C bond forming reaction. Fe3O4-
OSO3H catalysis was further extended to C-N bond forming reactions and for the synthesis of
spermicidal 3,3′-di(indolyl)oxindole derivative. All the products were obtained in good to
excellent yield.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Diarylmethyl indole
Bioactive molecule
Iron oxide
Aminoalkylated indole
di(indolyl)oxindole
———
∗Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
Tetrahedron
1. Introduction
Multicomponent reactions circumvent step-wise
iterative synthesis to access densely functionalized bioactive
skeletons by forming multiple bonds in a single step.1 Solvent-
free multicomponent reactions gained significant attention in
green organic synthesis and Sheldon acclaimed solvent-free
reactions as “The best solvent is no solvent”.2 Use of
magnetically separable and reusable catalyst in a solvent-free
multicomponent reaction fulfils multiple green synthesis
requirements such as use of recyclable catalyst, employing less
hazardous solvent, achieving high atom economy, reducing the
number of reaction steps etc.
Scheme 2. Fe3O4 catalysed diarylmethyl indole synthesis.
2. Results and discussion
Magnetic Fe3O4 nanoparticles were prepared through aqueous
co-precipitation method25 and are characterized by powder XRD
technique (see electronic supporting information). Fe3O4 (10
mol%) catalyzed synthesis of diarylmethyl indole under neat
condition at 100 oC gave the product 3a in 34% yield along with
the corresponding bis(indolyl)methane by-product (Scheme 3).
Attempts to improve the reaction yield by varying the reaction
temperature, modifying substrate to catalyst mole ratio didn’t
improved the reaction outcome. The poor product yield could be
attributed to the mild acidic nature of Fe3O4 nanoparticles.
Figure 1. Representative examples of indole based bioactive skeletons.
Use of aforementioned conditions in substituted indole
synthesis is desirable since indole derivatives possess anti-
Scheme 3. Fe3O4 and sulfonic acid catalysed diarylmethyl indole synthesis.
viral,3
anti-HIV,4
anti-cancer,5
antiproliferative,6
It was previously reported in the literature that sulfonic acid
derivatives are good catalyst for the substituted indole derivatives
synthesis.26 Replacement of Fe3O4 catalyst with p-toluenesulfonic
acid gave 3a in 37% yield along with 31% of
bis(indolyl)methane. Use of chlorosulfonic acid improved the
product 3a yield to 48% along with the formation of 28% of
bis(indolyl)methane by-product (Scheme 3). Though the later
result is encouraging, chlorosulfonic acid is corrosive,
hygroscopic and lachrymatory in nature. Moreover, it reacts
violently with water to form HCl and H2SO4. Hence, we have
decided to synthesize and investigate catalytic potential of
sulfonic acid anchored Fe3O4 nanoparticles (Fe3O4-OSO3H).
Fe3O4-OSO3H was synthesized by closely following a literature
procedure and the product was obtained as fine brown powder
(Scheme 4).27
antibacterial,7 cytotoxic,8 antitubercular9 and anti-
inflammatory activities (Fig. 1).10
Iron oxides as well as functionalized iron oxides have been
widely used in reactions such as Hantzsch,11 Mannich,12
Sonogashira–Hagihara,13 Biginelli,14 Suzuki,15 Ugi16 and for the
synthesis of chromenes, pyrimidines and epoxide derivatives.17-19
Recently, Firouzabadi and co-workers reported functionalized
Fe3O4 catalysed bis(indolyl)methane synthesis (Scheme 1).20
Scheme 1. Fe3O4 catalysed bis(indolyl)methane synthesis.
However, reaction of two different nucleophiles such as
indole and N,N-dimethylaniline with benzaldehyde may result in
the formation of mixture of homocoupled by-products along with
diarylmethyl indole derivative (Scheme 2). Previously reported
diarylmethyl indoles synthesis required the use of stoichiometric
21
22
quantities of either ZnCl2
or CuCl2
reagents. Both
bis(ethylcyclopentadienyl)zirconium perfluorooctanesulfonate23
and FeCl324 were reasonably successful to carry out diarylmethyl
indoles synthesis in catalytic quantities. However, the scope of
these catalysts are marred by the use of carcinogenic 1,2-
dichloroethane as solvent and prolonged reaction time for
completion. Hence it is envisaged that Fe3O4 catalysed
diarylmethyl indole synthesis in an environmentally benign
medium is worth investigating.
Scheme 4. Synthesis of sulfonic acid functionalized Fe3O4
The formation of sulfonic acid embedded Fe3O4 was
confirmed by comparing IR spectrum of Fe3O4 before and after
functionalization (Figure 2A-B). The presence of characteristic
peaks at 3341, 1623 and 1208 cm-1 confirms the presence of
sulfonic acid moiety on the surface of Fe3O4 (Figure 2B). SEM
analysis of the Fe3O4-OSO3H showed the materials are of ~ 23
nm dimension (Figure 2C-D). The clustering nature of Fe3O4-
OSO3H in SEM analysis could be due to the hydrogen bonding
interaction between the sulfonic acid functional groups.27 The
sulfonic acid loading on Fe3O4 was found to be 0.70 mmol g-1 by
carrying out the following experiment.28 To an aqueous solution
of 25 mL of 1M NaCl (pH 6.32), 100 mg of Fe3O4-OSO3H was
added and stirred for 2 hours. The pH of the solution was
decreased into pH 2.60. To this solution, known excess of NaOH

3
o
was added and the solution was titrated against addition of
standard 0.1 M of HCl solution. From the equivalent point (9.3
mL), the loading of catalyst was found to be 0.70 mmol g-1.
substrates. Under neat condition at 100 C, Fe3O4-OSO3H (23
mg) efficiently catalyzed one-pot synthesis of diarylmethyl
indole 3a in 88% yield (Scheme 5, Table 1, entry 6).
Recyclability of the Fe3O4-OSO3H catalyst was checked for 3a
synthesis. The catalyst can be reusable up to 5 times without
significant loss in catalytic activity (Scheme 5). Atomic
absorption spectroscopic (AAS) studies carried out to identify the
possible leaching of the iron catalyst into the reaction medium
after first recycle showed only minimal leaching of iron catalyst
(0.217 ppm). Elemental analysis of the spent catalyst showed a
decrease in sulfur content after third cycle. This could be one of
the reasons for the marginal decrease in the product yield from
fourth cycle onwards.
(B)
(A)
Lewis acidic nature of the Fe3O4 is previously reported in the
literature.29a-b Synthesis of 3a carried out with Lewis acidic Fe3O4
gave the product in 34% yield (Table 1, entry 1) and the Bronsted
acidic chlorosulfonic acid gave 48% yield (Table 1, entry 9).
Interestingly, under similar reaction conditions, Fe3O4-OSO3H
yielded 88% of product 3a (Table 1, entry 6). We presume, the
high catalytic efficiency of Fe3O4-OSO3H could be due to the
combined Lewis and Brønsted acidic nature of the catalyst.
Replacement of either Fe3O4 with SiO2 or chlorosulfonic acid
with p-toluenesulfonic acid substantially decrease the product
yield (Table 1, entry 8,10). These results justify the synergetic
effect of Fe3O4-OSO3H in diarylmethyl indole synthesis. To
further emphasize the significance of acidic sulphonic acid
functionality on Fe3O4 in 3a synthesis, basic polyethylenimine
(PEI) coated Fe3O4 was synthesized and subjected to reaction
condition (Table 1, entry 7). Fe3O4-PEI was found to be
ineffective in 3a synthesis (Table 1, entry 7).
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber (cm-1
)
Figure 2. IR spectrum of (A) Fe3O4 (B) Fe3O4-OSO3H. SEM images of
Fe3O4-OSO3H (C) at 1 µm expansion (D) at 100 nm expansion.
o
Fe3O4-OSO3H catalysed 3a synthesis carried out at 80 C and
o
o
50 C instead of 100 C decreased the product yield (52% and
34%) and enhanced the bis(indolyl)methane by-product yield
(23% and 31%). These observations are in line with the literature
reports that lowering the reaction temperature favoured
kinetically stable bis(indolyl)methane by-product and higher
reaction temperature resulted in the formation of
thermodynamically stable diarylmethyl indole product.21,22
However, unlike ZnCl2 and CuCl2, Fe3O4-OSO3H catalysed
transformation of bis(indolyl)methane to diarylmethyl indole was
not observed. Increasing the catalyst loading from 23 mg to 46
mg or 69 mg didn’t alter the product yield. After optimizing the
reaction condition, diarylmethyl indole synthesis was screened
for various substituted aldehydes (Scheme 6 and Figure 3). The
reaction was found to be general for aldehydes with electron
donating and electron withdrawing substituents and the products
3a-3g were obtained in appreciable yields. Aliphatic aldehyde
also gave the product 3d within 30 minutes in good yield. This
could be attributed to the high reactivity of formaldehyde
(Scheme 6).
Scheme 5. Fe3O4-OSO3H catalysed 3a synthesis and catalyst recyclability
studies
Table 1. Reaction condition screening for 3a synthesisa
b
Entry
Catalyst
Solvent
Time (h)
Yield (%)
1
2
3
4
5
Fe3O4
-
1
2
2
2
2
1
1
3
1
1
34
8
Fe3O4-OSO3H
Fe3O4-OSO3H
Fe3O4-OSO3H
Fe3O4-OSO3H
Fe3O4-OSO3H
Toluene
CH3CN
Traces
<5
H2O
c
THF
NR
d
6
-
-
-
-
-
88
e
c
7
8
Fe3O4-PEI
NR
SiO2-OSO3H
67
48
f
9
Cl-SO3H
g
h
10
PTSA
37
aAll the reactions were carried out with indole (1mmol), 4-
chlorobenzaldehyde (1 mmol), N,N dimethylaniline (1mmol) and
10 mol% of catalyst at 100
2
o
C. bYields are for the isolated
R
C-C bond forming reaction
2
2
1
products. cNo reaction. dReducing the reaction temperature to 50
oC, resulted in the formation of more amounts of
bis(indolyl)methane product. ePolyethylenimine coated. fAlong with
product, 28% bis(indolyl)methane formed. gp-Toluenesulfonic acid.
hReaction performed with mixture of PTSA and Fe3O4 gave the
product in 16% yield.
N
R
R
R
2
N
R
Fe O -OSO H
3 4 3
1
R -CHO
o
Neat, 100
1 h
C
N
N
H
H
1
2
1
3a-3g
R
= 4-ClC H , 4-MeC H , 3-OMeC H , C H , 4-OMeC H , H
6 4 6 4 6 4 6 5 6 4
up to 89 %
2
R
= Me, Et
Fe3O4-OSO3H catalysed synthesis of 3a in non-polar
(toluene), polar aprotic (CH3CN) and polar protic (H2O) solvents
gave the product in <10 % yield (Table 1, entry 2-4). The poor
catalytic performance could be attributed to the sparingly soluble
nature of catalyst in the aforementioned solvents. The poor
catalyst solubility substantially reduces its interaction with the
Scheme 6. Fe3O4-OSO3H catalysed C-C bond forming reaction
After successfully finished C-C bond forming reactions, we
were interested to extend this methodology to C-N bond forming
reactions. Fe3O4-OSO3H catalysed reaction of Indole (1mmol), 4-
chlorobenzaldehyde (1mmol) and N-methylaniline (1mmol)
under solvent-free condition gave the product within 3 h at room

4
Tetrahedron
temperature itself (Scheme 7). Fe3O4-OSO3H catalysed C-N
Addition of N,N-dimethylaniline or N-methylaniline and
aldehyde may result in the formation of iminium intermediate.30
Nucleophilic addition of indole to the iminium intermediate
could result in the formation of diarylmethyl indole and
aminoalkylated indole products.
bond forming reaction was found to be general for aldehydes
with electron donating and electron withdrawing substituents
(Figure 3). To further improve the application of this
heterogeneous catalyst system, we have performed gram scale
synthesis of representative 3a and 5a with 10 mmol of substrates
and the corresponding products were obtained in 84% and 85%
yields respectively.
It is of interest to further extend the application of Fe3O4-
OSO3H catalysis to potential bioactive skeleton synthesis.
Oxindole skeletons are widely distributed in several natural
products and bioactive molecules.31 Mondal and co-workers
reported that 3,3′-di(indolyl)oxindole skeleton has good
spermicidal
activity.32
Fe3O4-OSO3H
catalysed
3,3′-
di(indolyl)oxindole synthesis was not successful under neat
condition. In ethanol, 3,3′-di(indolyl)oxindole was obtained in
92% yield (Scheme 9).
Scheme 7. Fe3O4-OSO3H catalysed C-N bond forming reaction
Scheme 9. Synthesis of 3,3′-di(indolyl)oxindole derivatives
In conclusion, we have developed an efficient and convenient
method for the synthesis of diversely functionalized indole
derivatives. All the products were obtained in good to excellent
yield and the catalyst was reusable up to five times without much
loss in catalytic activity.
Acknowledgements
S.S.G. thanks DST for DST-Fast Track Grant (No: SR/FT/CS-
09/2011). The authors thank the SASTRA University for
providing lab space and NMR facility. J.K thanks SASTRA
University for financial assistance. S.S.G. thanks Prof. M.
Periasamy for his constant encouragement and support.
Figure 3. Synthesized diarylmethyl indole and
aminoalkylated indole
The Fe3O4-OSO3H catalysed formation of diarylmethyl indole
and aminoalkylated indole can be rationalized by the considering
the following mechanism (Scheme 8).
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5
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General procedure for synthesis of diarylmethylindoles:
To a stirred mixture of indole (117.5 mg, 1.0 mmol), N,N-dialkylaniline (1.0
mmol) and aldehyde (1.0 mmol), Fe3O4-OSO3H catalyst (23 mg) was added
and the mixture was heated to 100 oC for an appropriate time (Products 3a-c,
3e stirred for 60 minutes; 3d stirred for 30 minutes at RT; 3f and 3g stirred
for 40 minutes). The progress of the reaction was monitored by TLC. After
completion of reaction, the reaction mixture was cooled to room temperature.
Then chloroform (1 × 5 mL) was added to the reaction mixture and the
catalyst was separated using an external magnet. The chloroform layer was
separated, evaporated under reduced pressure. The crude mixture purified
under silica gel column chromatography (Ethyl acetate and hexane 1:4).
Supplementary Material
Detailed experimental procedures and NMR spectras are
available as supplementary material.