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Published on the web June 5, 2013
Cellulose-Sulfonic Acid: An Efficient, Recyclable, and Biodegradable Solid Acid Catalyst
for the Synthesis of 3-Aminoalkylindoles
S. Satyanarayana,1 K. Praveen Kumar,1 P. Lakshmi Reddy,1 R. Narender,*1 G. Narasimhulu,2 and B. V. Subba Reddy*2
1Crop Protection Chemicals, Indian Institute of Chemical Technology, Hyderabad-500 007, India
2Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received April 20, 2013; CL-130370; E-mail: basireddy@iict.res.in)
Three-component coupling (3CC) of indoles, aldehydes, and
xanthenes, tetrahydroquinolines, and functionalized pyrroli-
dines.12,13 However, there are no reports on the use of
cellulose-SO3H for the preparation of 3-aminoalkylindoles
under mild reaction conditions.
N-alkylanilines has been accomplished using a catalytic amount
of cellulose-sulfonic acid under mild reaction conditions to
furnish the 3-aminoalkylindoles at room temperature in short
reaction times and in relatively good to excellent yields and
selectivity. The use of biodegradable cellulose-sulfonic acid
makes this method quite simple, convenient, and economically
viable for the synthesis of 3-aminoalkylindoles.
The cellulose-SO3H catalyst shows an excellent catalytic
activity and stability. The acidity of the catalyst is not affected
by air, water, or light. Due to low solubility and high stability,
cellulose acts as an efficient support. Cellulose-SO3H can easily
be prepared from cellulose and chlorosulfonic acid.12d To a
solution of cellulose (DEAE for column chromatography,
Sigma-Aldrich) in absolute ethanol was added chlorosulfonic
acid dropwise slowly at 0 °C. The resulting solid was filtered
and then washed with acetonitrile. After drying in oven for 3 h
at 70 °C, the cellulose-SO3H was obtained as a white pow-
der.12c,12d The number of active acid sites (H+) of cellulose-
SO3H was determined by acid-base titration, and it was found to
Indole derivatives are known to exhibit a wide range of
physiological properties such as antioxidant, antibacterial, and
insecticidal.1-3 They are found to exhibit anticancer activity
against human cancer cell lines4 and are also used as valuable
antibiotics.1 Among various derivatives of indoles, 3-substituted
indoles are of great importance as they are widely distributed
in nature and show a broad range of biological activities.5,6
Therefore, there is a growing interest in the development of
improved methods for the synthesis of 3-substituted indoles.7,8
In particular, 3-aminoalkyl or aryl-substituted indoles are
considered to be privileged scaffolds in medicinal chemistry.1
Furthermore, 3-aminoalkylindole core is often found in many
indole alkaloids such as gramine A, aspidospermine B, and 12-
chloro-19,20-dihydroakuammicine C (Figure 1).9
Despite several methods being reported for the synthesis
of 3-substituted indoles,7,8 only a few synthetic methods are
available for the preparation of 3-aminoalkylindoles via three-
component reaction.4b,10 Generally, acid catalysts are known to
catalyze the reaction of aromatic aldehyde, N-alkylaniline, and
indole. Therefore, the development of simple and efficient
methods would expand the scope of the synthesis of
3-aminoalkylindoles, which are very useful synthetic targets
for drug discovery.
¹1
be 0.50 mmol g (1 mequiv = 1 mmol/valence). This amount
corresponds to about 0.90% of the sulfur content, demonstrating
that most of the sulfur species are present in the form of sulfonic
acid groups.
Following our interest in the catalytic applications of solid
acid catalysts,14 we herein report, for the first time, a novel
method for the synthesis of 3-aminoalkylindoles using cellu-
lose-SO3H as the recyclable catalyst. As a preliminary study,
benzaldehyde (1) was treated with N-methylaniline (2) and
indole (3) in the presence of cellulose-SO3H in acetonitrile. The
reaction proceeded smoothly at room temperature, affording the
corresponding product, N-[(1H-indol-3-yl)(phenyl)methyl]-N-
methylaniline (4a) in 92% yield (Scheme 1). To optimize the
reaction conditions, we performed the reaction with various
amounts 0.04, 0.05, 0.06, and 0.07 g of cellulose-SO3H. The
¹1
best results were obtained with cellulose-SO3H (0.06 mmol g
in terms of reaction time and yields.
)
Recently, the use of heterogeneous catalysts has received
particular attention as user-friendly catalysts because of their
recyclability, operational simplicity, and minimal waste dis-
posal.11 In particular, cellulose-sulfonic acid (cellulose-SO3H)
is a biodegradable solid acid catalyst that has been used for the
synthesis of ¡-amino nitriles, quinolines, aryl-14H-dibenzo[a,j]-
In order to realize catalytic efficiency, we performed the
above reaction with various catalysts such as CAN, Mn(OAc)3,
DDQ, and CeCl3¢7H2O/LiI. The reaction was also performed
with some commonly used acid catalysts such as p-TSA,
camphor-sulfonic acid, Yb(OTf)3, Ce(OTf)3, ZnCl2, and Am-
berlyst-15, and the results are presented in Table 1. However, the
use of most of the above catalysts often involves long reaction
Me
N
N
N
Me
H
Me
N
CO2Et
N
H
Me
N
N
H
N
H
O
H
2
Cellulose-SO3H
CH3CN, r.t.
Cl
OMe
+
H
O
N
N
H
B
C
A
H
1
3
4a
Figure 1. Representative examples of 3-aminoalkylindole
alkaloids.
Scheme 1. 3CC synthesis of 3-aminoalkylindole 4a.
Chem. Lett. 2013, 42, 972-974
Satyanarayana
