[TBA][Gly] ionic liquid promoted multi-component synthesis of 3-substituted indoles and indolyl-4H-chromenes

Article abstract of DOI:10.1016/j.tetlet.2015.02.058

Tetrabutylammonium glycinate [TBA][Gly] ionic liquid was found to be an efficient recyclable and biodegradable organocatalyst for selective synthesis of 3-substituted indoles and indolyl-4H-chromenes. The reaction between substituted aliphatic/aromatic aldehydes, malononitrile, and indoles in the presence of [TBA][Gly] IL at 60 °C under solvent free conditions afforded 3-substituted indoles in excellent yields. Indolyl-4H-chromenes were achieved in excellent yields by replacing the benzaldehydes with salicylaldehyde under optimized reaction conditions.

Full text of DOI:10.1016/j.tetlet.2015.02.058

Accepted Manuscript
[
TBA][Gly] ionic liquid promoted multi-component synthesis of 3-substituted
indoles and indolyl-4H-chromenes
U. Chinna Rajesh, Rohit Kholiya, Anuj Thakur, Diwan S. Rawat
PII:
S0040-4039(15)00329-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.058
TETL 45927
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 December 2014
12 February 2015
13 February 2015
Please cite this article as: Chinna Rajesh, U., Kholiya, R., Thakur, A., Rawat, D.S., [TBA][Gly] ionic liquid promoted
multi-component synthesis of 3-substituted indoles and indolyl-4H-chromenes, Tetrahedron Letters (2015), doi:
http://dx.doi.org/10.1016/j.tetlet.2015.02.058
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Graphical Abstract
[TBA][Gly] ionic liquid promoted
Leave this area blank for abstract info.
multi-component synthesis of 3-substituted indoles
and indolyl-4H-chromenes
U. Chinna Rajesh, Rohit Kholiya, Anuj Thakur and Diwan S. Rawat*
CN
CN
R
X
N
OOC
Y
N
H
X
4a-4u
CN
NH2
R-CHO
1
+
+
Y
Solvent free, 60 o
C
NH
CN
2
N
X
H
Y
3
CN
O
NH2
6
a-6i

1
Tetrahedron Letters
journal homepage: www.elsevier.com
[TBA][Gly] ionic liquid promoted multi-component synthesis of 3-substituted indoles
and indolyl-4H-chromenes
U. Chinna Rajesh, Rohit Kholiya, Anuj Thakur and Diwan S. Rawat*
Department of Chemistry, University of Delhi, Delhi-110007, Fax: (+) 91-11-27667501; *E-mail: dsrawat@chemistry.du.ac.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Tetrabutylammonium glycinate [TBA][Gly] ionic liquid was found to be an efficient recyclable
and biodegradable organocatalyst for selective synthesis of 3-substituted indoles and indolyl-
4
H-chromenes. The reaction between substituted aliphatic/aromatic aldehydes, malononitrile
Available online
o
and indoles in the presence of [TBA][Gly] IL at 60 C under solvent free condition afforded 3-
substituted indoles in excellent yields. Indolyl-4H-chromenes were achieved in excellent yields
by replacing the benzaldehydes with salicylaldehyde under optimized reaction conditions.
Keywords:
[
3
TBA][Gly] IL
-substituted indoles
indolyl-4H-chromenes
green chemistry
2009 Elsevier Ltd. All rights reserved.
E-factor and atom economy
Introduction
stabilization of metal NPs and efficient chiral additive for various
reactions including Heck arylation, cycloaddition of CO2 to
Multi-component reactions (MCRs) played a pivotal role in the
field of modern medicinal and combinatorial chemistry,
however, metals/hazardous reagents catalyzed MCR causes a
serious problem of metal contamination in the products/waste
disposal in the environment. Still, there is a need of bringing
general awareness among synthetic chemists to design
methodologies for MCR in eco-friendly and sustainable manner
with metal free/less waste generation and greater economic
epoxides, α-amination of aldehydes and intramolecular
1
8-10
aldolization.
Indole nucleus has been found as an essential element in
medicinal and agricultural chemistry with significant biological
2
1
1
activities. 3-Substituted indoles are prominent structural motif
found in numerous natural products or therapeutic agents with
1
2
diverse pharmaceutical activities. 2-Amino-4H-chromenes are
3
benefits at industrial scale production. Green chemistry metrics
found to be potent pharmacological scaffolds with wide range of
1
3
have been introduced to overcome the aforementioned problems
and to achieve the advantages including both transmaterialization
and dematerialization strategies in the academic and industrial
biologically activies.
Indolyl-4H-chromenes are hybrid
scaffolds of vital importance in the field of medicinal chemistry.
Multi-component synthesis of 3-substituted indoles and
4
research. Moreover, it is well known that the solvents are a
indolyl-4H-chromenes have been achieved using few catalysts
major concern and can have significant impact on the amount of
waste generated from a multi-step synthetic pathway. In the past
14
15
such as Zn(salphen) complex, N,N1-dioxide Zn(II) complex,
5
16
copper (II) sulfonato salen complex, and tetrabutylammonium
fluoride. These methods have disadvantages including usage of
decade, green solvents such as water, polyethylene glycol,
glycerol and ionic liquids have been known to promote few
multi-component reactions with low E-factor and high atom
17
metal based catalysts, which results either metal contamination in
the products or more waste generation from the reaction mixture
or usage of organic solvents and toxic reagents with complicated
work up procedures. In order to overcome these limitations, and
6
economy. The E-factor of organic conversion can be calculated
as the ratio of mass of waste per unit of product i.e the total mass
of raw materials (m ) minus the total mass of product (m ),
divided by the total mass of the product (m) [E = m - m /m].
1
2
in continuation of our studies toward development of green
1
2
18
methods for organic synthesis,
we reported recyclable
Biodegradable ionic liquids generated from natural amino acids
AAIL) have attracted the attention of scientists working in
19
nanocatalysts such as functionalized Fe O NPs and RGO/ZnO
nanocomposites for the synthesis of indolyl-4H-chromenes and
-substituted indoles. Still, there is need of developing metal free
3
4
(
20
various fields, which mainly deals with the green and
sustainability factors. Especially, tetraalkylammonium cations
containing amino acid based ionic liquids [TBA][AA] ILs were
found to be an efficient medium for the absorption of CO and for
3
7
catalytic system, in this context, we developed an efficient metal
free, [TBA][Gly] ionic liquid promoted synthesis of 3-substituted
2

2
Tetrahedron Letters
indoles and indolyl-4H-chromenes under green conditions
With these interesting results in our hand, the generality of
method was investigated for a wide range of aromatic and
aliphatic aldehydes (1a-1k) and substituted indoles (3a-3c) under
optimized reaction conditions to afford the various 3-substituted
indoles (4a-4u) as shown in Scheme 1. The results showed that
almost all substrates gave best results to afford the products (4a-
4u) in good to excellent yields (65-93%) as shown in Table 2
(Entries 1-21). However, the progress of reaction was slow in
case of isopropyl aldehyde and afforded product 4u in 65% yield
in 120 min (Entry 21, Table 2). Whereas, Wan et al. reported the
synthesis of 4u using KH PO /PEG-200/H O catalytic system in
(
Figure 1).
CN
CN
R
X
Y
N
H
X
CN
4a-4u
[
TBA][Gly] Catal.
R-CHO
1
+
+
Y
Solvent free, 60 o
C
CN
2
N
NH
H
X
3
Y
CN
2
4
2
2
1
prolonged reaction time 12 days. (see ESI for experimental
procedures and characterization data of selected compounds).
O
a-6i
NH2
6
Figure 1: [TBA][Gly] promoted synthesis of 3-substituted
indoles (4a-4u) and indolyl-4H-chromenes (6a-6i)
R
CN
X
CN
[TBA][Gly] Catal.
CN
R-CHO
1
+
+
Y
X
Results and discussion
Solvent free, 60 oC
CN
2
N
Y
H
30-120 min, 65-93%
N
H
3
Initially, a model reaction between benzaldehyde (1a),
malononitrile (2a) and indole (3a) was performed using 10
mol% of [TBA][Gly] ionic liquid in the presence of various
4
a-4u
R = C6H5 (1a); 3-ClC6H4 (1b); 2-ClC6H4 (1c); 2-FC6H4 (1d);
Y = H; X = H (3a)
3
4
-FC6H4 (1e); 4-FC6H4 (1f); 2-BrC6H4(1g); 3-OMeC6H4 (1h); Y = H; X = Br (3b)
-tBuC6H4 (1i); C6H11 (1j); C3H7 (1k)
Y = Me; X = H (3c)
o
solvents and solvent free condition at 60 C (Table 1, Entries
Scheme 1: One-pot synthesis of 3-substituted indoles (4a-4u)
1
-9). The results revealed that solvent free condition was the
best to afford the product 4a in 93% yield in 30 min (Table
, Entry 9). However, the reaction proceeded smoothly even
Next, the model reaction was performed at 10 mmol scale
under optimized conditions afforded the 3-substituted indole 4a
in 92% yield (Table 2, Entry 1). It is important to mention here
that the purification of these compounds is very simple which
requires addition of water followed by filtration and
recrystalization of crude solid compounds. Moreover,
1
in the presence of water as a solvent to afford the product 4a
in 85% yield in 60 min (Entry 1). In case of organic
solvents, the progress of reaction was very slow to afford the
product 4a in poor to moderate yields (Table 1, Entries 2-8).
Moreover, other amino acid based ionic liquids including
[
TBA][Gly] ionic liquid is biodegradable, non-toxic, recyclable
[TBA][Ala], [TBA][His], [TBA][Ser], [TBA][Val] and
[TBA][Pro] gave product 4a in 80-88% yields in 60 min
(Entries 12-16). The product formation was not observed in
and greener catalyst. Thus the green chemistry metric
calculations for model reaction revealed that the method is
environmentally benign with the smaller E-factor (0.13) and high
atom economy (AE = 93.8%) (see ESI for calculations).
the absence of ionic liquid under optimized reaction
conditions (Table 1, Entry 17). Thus, the model reaction was
optimized using 10 mol% of [TBA][Gly] under solvent free
The versatility of [TBA][Gly] catalyst was studied for the
synthesis of indol-3-yl-4H-chromene derivatives 6a-6i from the
reaction between salicylaldehyde (5), active methylene
compounds (2) and substituted indoles (3) as shown in Scheme 2.
o
condition for 30 min at 60 C.
Table 1: Optimization study for one-pot synthesis of 3-
a
substituted indole (4a).
NH
CN
X
Y
2a, 2b
CN
R1
CHO
O
CN
Ionic Liquids
X
+
+
Solvents, Temp.
H
[TBA][Gly] Catal.
O
NH2
CN
2a
N
N
+
Y
+
H
H
60 oC, neat,
30 - 60 min
6a-6f 83-94%
OH
N
1
a
3a
4a
H
5
2
3
O
Entry
Ionic liquids
Solvents
Temp.
Time
(min)
60
Yield of
4a (%)
NH
o
b
CN
R1
X
(
C)
R2
R2
Y = H; X = H (3a)
OMe (3d)
Y
O
2c, 2d
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
[TBA][Gly]
[TBA][Gly]
[TBA][Gly]
[TBA][Gly]
[TBA][Gly]
[TBA][Gly]
[TBA][Gly]
[TBA][Gly]
[TBA][Gly]
[TBA][Gly]
[TBA][Gly]
[TBA][Ala]
[TBA][His]
[TBA][Ser]
[TBA][Val]
[TBA][Pro]
Blank
Water
EtOH
Acetone
MeOH
THF
60
60
60
60
60
60
60
60
60
100
rt
85
30
55
48
40
60
50
60
93
89
55
80
83
80
85
88
-
O
Br (3b)
180
120
180
180
180
180
180
30
30
180
60
60
60
Y = Me; X = H (3c)
R1 = CN (2a), CO2Et (2b); R2 = H (2c), Me (2d)
R2
O
R2
6
g-6i 69-72%
3
CH CN
Toluene
DMSO
neat
neat
Scheme 2: One-pot synthesis of indol-3-yl-4H-chromenes (6a-6i)
The model reaction between salicylaldehyde (5),
malononitrile (2a) and 2-methylindole (3c) was performed under
optimized condition using 10 mol% of [TBA][Gly] IL to afford
the product 6a in 89% yield (Table 3, Entry 1). The scope of
0
1
2
3
4
5
6
7
neat
neat
neat
neat
neat
neat
neat
60
60
60
60
60
60
[
TBA][Gly] catalyst was studied for various substrates as shown
in Scheme 2 and the results are depicted in Table 3. To our
delight, the reactions with all substrates proceeded smoothly to
afford the products 6a-6i in good to excellent yields 73-95%
Table 3, Entries 1-9). Whereas, in the case of 1,3-
cyclohexanedione (2c) and dimedone (2d), the expected products
60
60
240
a
Reaction condition: aldehyde (1 mmol), malononitrile (1 mmol), indole
1 mmol) and ionic liquid (10 mol%). Isolated yield.
(
b
(
6
g, 6h and 6i were formed in moderate yields (72%, 70% and
6
9%) along with the minor products as 2-(1-oxo-2,3,4,9-

3
tetrahydro-1H-xanthen-9-yl)cyclohexane-1,3-diones 7a and 7b
respectively (Table 3, Entries 7-9) (see ESI for experimental
procedures and characterization data of selected compounds).
(V) followed by Friedel-Crafts alkylation with indole 3a to
afford the indol-3-yl-4H-chromene 6e (Figure 2).
Y
NC
Y = H, (1a)
Y = OH, (5)
CN
Table 2: [TBA][Gly] promoted one-pot synthesis of 3-substituted
indole derivatives.
NC
H2N
COO NBu4
H
NC
H
H
a
N
Ph
Ph
2
a
O
NH
C
3
a
COO NBu4
Michael addition
Path-I
CN
H2N
N
H
C
N
N
H
Entry Aldehydes
1)
Indoles
(3)
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3c
Products
(4)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
Time
(min)
30
40
40
35
45
45
30
30
35
50
40
30
60
30
30
Yield
(%)
II
[TBA][Gly]
4a
NC
H2N
b
f Y = H
I
8
(
H2N
COO NBu4
c
NBu4
H2O
COO
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
C
2-ClC
3-ClC
4-FC
4-NO
2-NO
4-MeC
4-MeOC
3-MeOC
C
3-ClC
2-ClC
2-FC
3-FC
4-FC
2-BrC
C
4-ClC
4- BuC
C
C
6
H
5
93, 92
89
85
88
83
79
86
84
89
80
85
83
81
85
80
77
86
90
82
85
65
O
H
H
H
4
H
Knoevenagel
condensation
H
N
6
6
HN
NC
4
3a
CN
Y
CN
6
H
4
Y =
OH
CN
I
CN
Pinner reaction
Path-II
2
C
6
H
H
4
C
N
Friedel-Crafts reaction
O
O
III
NH
2
C
6
4
H2O
9
H
O
NH2
[
TBA][Gly]
H2N
NBu4
6e
H
4
COO
COONBu4
6
H2N
6
H
H
4
6
4
0
1
2
3
4
5
6
7
8
9
0
1
6
H
5
Figure 2: Plausible mechanism for [TBA][Gly] promoted
synthesis of 3-substituted indoles 4a and 6e.
6
6
H
H
4
4
6
6
6
H
4
H
4
H
4
The re-usability of [TBA][Gly] ionic liquid was
investigated for a model reaction between benzaldehyde 1a (10
mmol), malononitrile 2a (10 mmol) and indole 3a (10 mmol) in
the presence of 10 mol% (356 mg) of [TBA][Gly] catalyst under
optimized condition (Table 2, Entry 1) as shown in Figure 3.
After completion of the reaction (monitored by TLC), water was
added to the reaction mixture to afford the organic compound as a
precipitated solid in aqueous medium. The [TBA][Gly] ionic
liquid from aqueous layer was recovered and re-used for six
times by repeating the similar procedure. The results revealed
that there was no change in its catalytic activity to afford the
product 4a as depicted in Figure 2.
6
H
4
40
30
30
30
40
120
6
H
5
6
H
4
3c
3c
3a
3a
t
6
H
4
6
H
H
11
3
7
a
Reaction condition: aldehydes (1 mmol), malononitrile (1 mmol),
o
indoles (1 mmol) and [TBA][Gly] catalyst (10 mol%) at 60 C under
solvent free condition. Isolated yield. Reaction at 10 mmol scale.
b
c
Table 3: [TBA][Gly] promoted one-pot synthesis of indol-3-yl-
a
4
H-chromenes.
Entry Compound
2
b
Indoles
3
Product Time (min)
6
Yield (%)
1
00
90
80
1
2
3
4
5
6
7
8
9
2a
2a
2b
2b
2a
2b
2c
2c
2d
3c
6a
6b
6c
6d
6e
6f
6g
6h
6i
30
40
60
40
30
45
45
45
45
94
91
82
89
92
83
72
70
69
3b
3b
3c
3a
3a
3a
3d
3a
7
6
5
0
0
0
c
40
30
20
c
c
a
Reaction condition: salicylaldehydes (1 mmol), active methylene compounds
1
0
o
(
1 mmol) and indoles (1 mmol), [TBA][Gly] (10 mol%) were stirred at 60 C
0
b
c
under solvent free condition. Isolated yield. Side product formation was
observed (25-27%) (see ESI for details on minor products).
1
2
3
4
5
6
Cycle
Figure 3: Recylability of [TBA][Gly] promoted synthesis of 3-
substituted indole 4a.
The green chemistry metrics calculation for a model reaction
to afford the indol-3-yl-4H-chromene (6a) revealed that the present
protocol is an environmentally benign with high atom economy (AE)
=
90% and small E-factor (0.21) (see ESI for calculations).
Conclusions
The plausible mechanism for [TBA][Gly] IL promoted
Tetrabutylammonium glycinate [TBA][Gly] ionic liquid was
explored as a novel recyclable and biodegradable organocatalyst
for the selective synthesis of 3-substituted indoles and indolyl-
synthesis of 3-substituted indole 4a and indol-3-yl 4H-chromene 6e
is depicted in Figure 2. The uniqueness of [TBA][Gly] IL is the
presence of electrophilic bulky quaternary ammonium cation as a
conjugate acid and nucleophilic naked carboxylate anion as a
conjugate base. The carbonyl carbon of aldehydes 1a or 5 can be
activated by ammonium ion of IL and the carboxylate anion of IL
abstract the proton from malononitrile 2a to generate carbanion
which attacks on activated aldehydes 1a or 5 to form olefinated
products 8 or 9 respectively via Knoevenagel condensation. In path
4
H-chromenes. The present method is metal free and highly
efficient, biodegradable, and afforded products in excellent yields
in short reaction time. [TBA][Gly] IL was recyclable for six
times without loss in its catalytic activity. The present method
follows green chemistry metrics such as low E-factor and high
atom economy (AE). The further work on applications of chiral
amino acid based ILs as recyclable catalysts for asymmetric
organic conversions are underway.
1
, [TBA][Gly] initiated the Michael addition of indole 3a on
preformed olefinated product 8 to form an intermediate II which
further can rearrange into 3-substituted indole 4a (Figure 2). In path
II, [TBA][Gly] promoted the Pinner cyclization of preformed
Knoevenagel product 9 to obtain the iminochromene intermediate
Acknowledgments
DSR thanks DU-DST PURSE grant and University of Delhi, Delhi,
India for financial support. UCR, RK and AT are thankful to UGC

4
Tetrahedron Letters
and CSIR for the award of senior, junior research fellowship. We
Rajesh, U. C.; Rawat, D. S. RSC Adv. 2013, 3, 18142; (d) Arya, K.;
thank to USIC-CIF, University of Delhi, for analytical data.
Rajesh, U. C.; Rawat, D. S. Green Chem. 2012, 14, 3344.
1
9. Rajesh, U. C.; Divya; Rawat, D. S.; RSC Advances, 2014, 4, 41323.
Notes and references
Electronic Supplementary Information (ESI) available:
20. Rajesh, U. C.; Wang, J.; Prescott, S.; Tsuzuki, T.; Rawat, D. S. ACS
Sustainable Chem. Eng. 2015, 3, 9.
21. Wang, L.; Huang, M.; Zhu, X.; Wan, Y. Appl. Catal. A: General,
1
13
[
Green chemistry metrics calculation, H NMR and
C NMR
2
013, 454, 160.
spectra of selected compounds]
1
. (a) Slobbe, P.; Ruijter, E.; Orru, R. V. A. Med. Chem. Commun. 2012
,
3
, 1189; (b) Musonda, C. C.; Taylor, D.; Lehman, J.; Gut, J.;
Rosenthal, P. J.; Chibale, K. Bioorg. Med. Chem. Lett. 2004, 14,
3
3
901; (c) ꢀꢁꢂꢃꢄꢅ, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112,
083.
2
3
.
.
Sanderson, K. Nature, 2011, 469, 18.
(a) Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Green Chem. 2014, 16,
2
958; (b) McGonagle, F. I.; Sneddon, H. F.; Jamieson, C.; Watson, A.
J. B. ACS Sustainable Chem. Eng. 2014, 2, 523.
4
.
(a) Giraud, R. J.; Williams, P. A.; Sehgal, A.; Ponnusamy, E.;
Phillips, A. K.; Manley, J. B. ACS Sustainable Chem. Eng. 2014, 2,
2
237; (b) Robert, K. H.; Bleek, B. S.; Larderel, J. A.; Basile, G.;
Jansen, J. L.; Kuehr, R.; Thomas, P. P.; Suzuki, M.; Hawken, P.;
Wackernagel, M. J. Cleaner Production, 2002, 10, 197.
5
6
.
.
Lipshutz, B. H.; Ghoraib, S. Green Chem. 2014, 16, 3660.
Mohammad, A.; Inamuddin, Green Solvents I: Properties and
Applications in Chemistry, Springer Dordrecht Heidelberg, New
York, London, 2012, DOI: 10.1007/978-94-007-1712-1
7
8
.
.
Tao, G.; He, L.; Liu, W.; Xu, L.; Xiong, W.; Wang, T.; Kou, Y.;
Green Chem. 2006, 8, 639.
(a) Jiang, Y. Y.; Wang, G. N.; Zhou, Z.; Wu, Y. T.; Geng, J.; Zhang,
Z. B.; Chem. Commun. 2008, 505; (b) Feng, Z.; Gang, F. C.; Ting, W.
Y.; Tao, W. Y.; Min, L. A.; Bing, Z. Z. Chem. Eng. J. 2010, 160, 691;
(
c) Pernak, J.; Feder-Kubis, J. Chem. Eur. J. 2005, 11, 4441; (d) Yu,
H.; Wu, Y. T.; Jiang, Y. Y.; Zhou, Z.; Zhang, Z. B. New J. Chem.
009, 33, 2385.
(a) Morel, A.; Silarska, E.; Trzeciak, A. M.; Pernak, J. Dalton Trans.
013, 42, 1215; (b) Yan, J.; Wang, L. Synthesis, 2010, 3, 447.
0. (a) Zhang, S.; Huang, Y.; Jing, H.; Yao, W.; Yan, P. Green Chem.
009, 11, 935; (b) Blackmond, D. G.; Moran, A.; Hughes, M.;
2
9
1
.
2
2
Armstrong, A. J. Am. Chem. Soc. 2010, 132, 7598; (c) Itagaki, N.;
Kimura, M.; Sugahara, T.; Iwabuchi, Y. Org. Lett. 2005, 7, 4185.
1. (a) Hajicek, J.; Czech. Chem. Commun. 2007, 72, 821; (b) Metwally,
M. A.; Shaaban, S.; Abdel-Wahab, B. F.; El-Hiti, G. A. Curr. Org.
Chem. 2009, 13, 1475; (c) Casapullo, A.; Bifulco, G.; Bruno, I. R. J.
Nat. Prod. 2000, 63, 447.
1
1
2. (a) Le´ze´, M. P.; Borgne, M. L.; Marchand, P.; Loquet, D.; Kogler,
M.; Baut, G. L.; Palusczak, A.; Hartmann, R. W. J. Enzyme Inhib.
Med. Chem. 2004, 19, 549; (b) Deng, J.; Sanchez, T.; Neamati, N.;
Briggs, J. M. J. Med. Chem. 2006, 49, 1684; (c) Contractor, R.;
Samudio, I. J.; Estrov, Z.; Harris, D.; McCubrey, J. A.; Safe, S. H.;
Andreeff, M.; Konopleva, M. Cancer Res. 2005, 65, 2890.
1
3. (a) D. Kumar, V. B. Reddy, S. Sharad, U. Dube, S. Kapur, Eur. J.
Med. Chem. 2009, 44, 3805; (b) N. Foloppe, L. M. Fisher, R. Howes,
A. Potter, A. G. S. Robertson, A. E. Surgenor, Bioorg. Med. Chem.
2
006, 14, 4792.
1
1
1
1
1
4. Anselmo, D.; Adán, E. C. E.; Belmonte, M. M.; Kleij, A. W. Eur. J.
Inorg. Chem. 2012, 4694.
5. Chen, W.; Cai, Y.; Fu, X.; Liu, X.; Lin, L.; Feng, X. Org. Lett. 2011
3, 4910.
,
1
6. Qu, Y.; Ke, F.; Zhou, L.; Li, Z.; Xiang, H.; Wu, D.; Zhou, X. Chem.
Commun. 2011, 47, 3912.
7. Singh, N.; Allam, B. K.; Raghuvanshi, D. S.; Singh, K. N. Adv. Synth.
Catal. 2013, 355, 1840.
8. (a) Rajesh, U. C.; Kholiya, R.; Pavan, V. S.; Rawat, D. S. Tetrahedron
Lett. 2014, 55, 2977; (b) Rajesh, U. C.; Manohar, S.; Rawat, D. S.
Adv. Synth. Catal. 2013, 355, 3170; (c) Thakur, A.; Tripathi, M.;

[TBA][Gly] ionic liquid promoted multi-component synthesis of 3-substituted
indoles and indolyl-4H-chromenes
U. Chinna Rajesh, Rohit Kholiya, Anuj Thakur and Diwan S. Rawat*
Department of Chemistry, University of Delhi, Delhi-110007, Tel: 91-11-27662683; Fax: (+) 91-11-
27667501; *E-mail: dsrawat@chemistry.du.ac.in
Highlights of present work
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. Metal free approach for 3-substituted indoles and indolyl-4H-chromenes.
. [TBA][Gly] ionic liquid is a novel biodegradable and recyclable catalyst.
. All substrates afforded products in excellent yields in short reaction time.
. This method shows low E-factor and high atom economy (AE).