Catalyst-free, ethylene glycol promoted one-pot three component synthesis of 3-amino alkylated indoles via Mannich-type reaction Dedicated to Professor Richard A. Gibbs (1962-2014)

Article abstract of DOI:10.1016/j.tetlet.2014.03.112

A highly efficient and sustainable approach for the multi-component synthesis of biologically important 3-amino alkylated indoles has been investigated via Mannich-type reaction under catalyst-free, ethylene glycol as a recyclable promoting medium. The wide applicability of the present method was examined with various substrates viz substituted aldehydes, indoles and secondary amines. This method will be useful for a large scale synthesis of 3-amino alkylated indoles without the use of column chromatography. The present method provides higher environmental compatibility and sustainability factors such as smaller E-factor (0.433) and higher atom-economy (AE = 93.3%).

Full text of DOI:10.1016/j.tetlet.2014.03.112

Accepted Manuscript
Catalyst-free, ethylene glycol promoted one-pot three component synthesis of
3-amino alkylated indoles via Mannich-type reaction
U. Chinna Rajesh, Rohit Kholiya, V. Satya Pavan, Diwan S. Rawat
PII:
S0040-4039(14)00544-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.03.112
TETL 44434
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 January 2014
24 March 2014
25 March 2014
Please cite this article as: Chinna Rajesh, U., Kholiya, R., Satya Pavan, V., Rawat, D.S., Catalyst-free, ethylene
glycol promoted one-pot three component synthesis of 3-amino alkylated indoles via Mannich-type reaction,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.03.112
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Graphical Abstract
Catalyst-free, ethylene glycol promoted one-
pot three-component synthesis of 3-amino
alkylated indoles via Mannich-type reaction
Leave this area blank for abstract info.
U. Chinna Rajesh, Rohit Kholiya, V. Satya Pavan and Diwan S. Rawat*
R
NH
X
X
N
H
X
5
X
CHO
EG, 90 o
C
RII
R
+
HN
3
+
RII
N
Catalyst free
Low E-factor,
High atom economy
N
H
RI
R
RI
2
1
X
N
H

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Catalyst-free, ethylene glycol promoted one-pot three component synthesis of 3-
amino alkylated indoles via Mannich-type reaction+
U. Chinna Rajesh, Rohit Kholiya, V. Satya Pavan and Diwan S. Rawat*
Department of Chemistry, University of Delhi, Delhi-110007, Fax: (+) 91-11-27667501; *E-mail: dsrawat@chemistry.du.ac.in
+Dedicated to Professor Richard A Gibbs (1962 - 2014)
ARTICLE INFO
ABSTRACT
Article history:
Received
A highly efficient and sustainable approach for the multi-component synthesis of biologically
important 3-amino alkylated indoles has been investigated via Mannich-type reaction under
catalyst-free, ethylene glycol as a recyclable promoting medium. The wide applicability of the
present method was examined with various substrates viz substituted aldehydes, indoles, and
secondary amines. This method will be useful for large scale synthesis of 3-amino alkylated
indoles without the use of column chromatography. The present method provides higher
environmental compatibility and sustainability factors such as smaller E-factor (0.433) and
higher atom-economy (AE = 93.3%).
Received in revised form
Accepted
Available online
Keywords:
Multi-component reactions
E-factor and atom economy
indoles
2009 Elsevier Ltd. All rights reserved.
Mannich reaction
catalyst free
Multicomponent reactions (MCR) provide efficient method
for diversity-oriented synthesis of pharmacologically important
heterocyclic organic molecules.7 Mannich reaction is one such
MCR that provides highly versatile method for concomitant
formation of C-C and C-N bonds to synthesize numerous
pharmaceuticals and natural products.8 Indole and bis-indole
moiety is one such pharmacophore found in complex natural
products with broad range of biological activities.9 Among these,
3-substituted indoles have found a unique place in medicinal
chemistry due to its simple structure with potent biological
activities such as nonsteroidal aromatase inhibition against breast
cancer, cell proliferation of human colon carcinoma (HT-29),
human ovarian adenocarcinoma (SK-OV-3), HIV-1 integrase
inhibitor and antiviral activity against HSV-1.10
Catalyst-free one-pot multi-component reactions for the
synthesis of biologically important molecules has attracted the
attention of scientists working in academia as well as industries
with the goal of improving sustainable and “green” chemistry.1
The E-factor and atom-economy concept has played a significant
role in organic synthesis in view of minimizing waste generation
during the manufacture of fine chemicals and pharmaceutical
intermediates.2 In the past decade, a few solvents such as water,
ionic liquids, surfactants, polyethylene glycol and glycerol have
appeared as eco-friendly promoting medium in catalyst-free
organic conversions.3 Moreover, catalyst-free and green solvent
promoting organic synthesis has advantages such as ease of
handling, simple work-up, nontoxic, biodegradable, non-
flammable, recyclable, inexpensive and achieves the
environmental factors. It is well known that solvent allows a
better contact between the reactants, stabilizes or destabilizes
intermediates and/or transition states as well as determines the
choice of work-up procedures and recycling or disposal
strategies. Ethylene glycol (EG) is a relatively non-volatile and
hygroscopic liquid with low viscosity and It is completely
miscible with many polar solvents and slightly soluble in non-
polar solvents.4 Because of these unique properties, there are a
large number of reports on the applications of EG in various
industrial processes like plastics, automobiles, energy, textiles,
transportation and fine chemicals.5 EG is well known as a ligand,
indirect template/reducing agent in synthesis of various nano
materials and solvent/catalyst-free promoting medium in the
limited organic conversions.6
NH2
N
Br
NH
OH
HN
H
N
N
O
N
H
S
N
H
Br
O
O
NH
F
H2N
(-)-Eudistomin L
Dragmacidin F
Me
NHCH3
N
Me
N
O
N
Br
H2N
MeO
N
H
N
N
H
Et
Azolylbenzyl Indole
3-amino alkylated indole
Frovatriptan
Figure 1. Biologically active 3-substituted indoles.

2
Tetrahedron Letters
In 1996, Risch et al. reported the aminoalkylation of electron
PEG600, PEG400, diethylene glycol, triethylene glycol, glycerol
and ethylene glycol (EG). To our delight, almost all glycols
promoted reaction effectively with the formation of the desired
product in quantitative yield (table 1, entry 8-13). Interestingly,
ethylene glycol was found to be more active in the formation of
product 4a with 80% yield in short reaction time. We further
examined optimum condition as EG (1 mmol) at 90 oC in 30 min
for the desired product 4a in 90% isolated yield (entry 14).
However, at high temperature undesired bis-indole formation was
observed (Table 1, entry 15, 16) and at low temperature, the
progress of the reaction was slow leading to moderate yield as
shown in Table 1 (entry 17, 18).
rich aromatic compounds such as indoles, phenols and N,N-
dimethylaniline using pre-formed iminium salts of a secondary
aliphatic amine and aromatic aldehydes.11 Recently, wide array of
catalysts were developed for the synthesis of 3-substituted
indoles from the reaction between indoles, aldehydes and
aliphatic/aromatic secondary/primary amines.12
To the best of our knowledge, there is no report available on
the catalyst-free one-pot three-component synthesis of 3-amino
alkylated indoles. As a part of our ongoing effort towards the
synthesis of medicinally important molecules13 and development
of efficient catalytic systems to achieve the green principles and
sustainability factors in organic synthesis,14 herein we report the
ethylene glycol promoted multi-component synthesis of 3-amino
alkylated indoles via Mannich-type reaction (Scheme 1).
Moreover, EG is the best solvent system in terms of activity,
selectivity and greenness of the protocol by employing green
chemistry metrics2 to calculate the environmental impact
efficiency and waste generation. Thus, we have developed green
reaction conditions i.e., smaller E-factor (0.433) and process
mass intensity (PMI = 42.7), high atom-economy (AE = 93.3%)
and reaction mass efficiency (RME = 84.6%) with minimal usage
of organic solvent in process, and a simple work-up procedure
(see ESI for details of the calculations).
R
NH
X
X
N
H
X
5
X
CHO
+
RII
RI
EG, 90 o
C
+
R
HN
RII
N
H
Catalyst free
With these interesting results in our hand, we then
investigated the scope of the present method with various
indoles, secondary amines and wide range of aromatic aldehydes
as shown in Scheme 1 and the results are depicted in Table 2.15
The results clearly indicated that almost all substrates gave better
yields of 3-amino alkylated indoles 4 without formation of bis-
indole 5. The aromatic aldehydes bearing electron-donating and
withdrawing groups at ortho, meta and para positions showed
comparatively same reactivity and gave the product in good yield
(Table 2). Furthermore, in case of indole substituents, 5-
nitroindole showed less reactivity as compared with indole/5-
bromoindole/5-methoxyindole (Table 2, entries 17, 18). In case
of secondary amines, pyrrolidine and N-methyl aniline gave
better results when compared with piperidine and morpholine as
shown in Table 2. Next, we studied the applicability of the
present method at large scale (50 mmol) synthesis of 3-amino
alkylated indole 4a as described in Table 2.
R
N
2
1
3
RI
X
N
4
H
Where
X = H (1a); Br (1b); OMe (1c); NO2 (1d) etc.
R = H (2a); 4-NO2 (2b); 4-Cl (2c); 2-Cl (2d); 2,4-Cl (2e); 4-Br (2f); 4-OMe (2g); 3-OMe (2h); 4-OBn, 3-
OMe (2i); 2,5-OMe (2j); 3,4,5-OMe (2k); 4-tBu (2l); 4-Me (2m) etc.
RI = RII = pyrrolidine (3a), piperidine (3b) and morpholine (3c); N-methyl aniline (3d) etc.
Scheme 1. Synthesis of 3-amino alkylated indoles.
In order to find an efficient and sustainable method to
synthesize 3-amino alkylated indoles, a model reaction of indole,
benzaldehyde and pyrrolidine in various solvents at 80 oC under
catalyst-free condition was performed as shown in Table 1.
Table 1. Optimization study for the synthesis of 3-amino
alkylated indole 4a.a
Entry
Solvent
Temp
.(oC)
80
80
80
Time
(min)
240
240
240
240
300
180
180
120
120
120
60
Yield of
4a(%)b
30
32
35
Yield of
5a (%)b
The plausible mechanism of EG promoted one-pot
synthesis of 3-amino-alkylated indole 4a under catalyst-free
condition is depicted in Scheme 2. It is well known that EG is
less basic than other hydroxylic solvents such as water, ethanol
or methanol, ethers and its polymers (PEG) due to the tendency
to form hydrogen bonds (intra- and intermolecular) between two
adjacent hydroxyl groups. Thus, it results in the hydrogen atoms
of EG being more positive (acidic) to activate electron rich
carbonyl oxygen to form intermediate (i). Moreover, one oxygen
atom of EG is relatively basic than the other to attack on active
proton and leads to increase in B-strain in the intermediate (i, ii)
as shown in Scheme 2. The net result of the B-strain increases C-
O-H bond angle. Thus, probably oxygen atom of EG may
activate acidic proton to initiate the iminium ion (iii) formation
and then attacking of indole 1a on iminium ion (iii) followed by
proton abstraction from indole moiety (iv) to yield the final
product 4a as shown in Scheme 2.
1
2
DMSO
DMF
10
15
20
10
15
-
3
CH3CN
1,4-Dioxane
Toluene
EtOH
Water
PEG600
PEG400
Glycerol
Tri-EG
Di-EG
EG
4
5
80
80
30
40
6
80
80
50
60
7
-
8
9
80
80
70
75
trace
trace
-
10
11
12
13
14
15
16
17
18
80
80
80
80
73
80
79
80
-
-
60
30
-
EGc
EG
EG
90
30
30
90
75
-
110
130
50
15
25
30
25
30
180
70
45
EG
EG
rt
240
50
aReaction condition: Indole (1 mmol), benzaldehyde (1 mmol), and
b
pyrrolidine (1 mmol), solvent (1.5 mL). Isolated yield.cEG (1 mmol).
In summary, we developed a highly efficient, catalyst-free
and green method for the synthesis of 3-amino-alkylated indole
via one-pot three-component Mannich type reaction. It is easy
and safe to handle at large scale synthesis without the use of
column chromatography for purification of the final products.
Furthermore, it provides higher environmental compatibility and
sustainability factors such as smaller E-factor (4.05) and process
mass intensity for (PMI = 42.7), higher atom-economy (AE =
93.3%) and reaction mass efficiency (RME = 84.6%) etc.
The results indicate that progress of the reaction was very
slow in the presence of organic solvents such as DMSO, DMF,
acetonitrile, toluene, 1,4-dioxane and gave product 4a in poor
yield, however small amount of undesired bis-indole 5a was also
formed (Table 1, entry 1-5). The progress of the reaction was
improved in the presence of ethanol and water solvents and the
desired product 4a was obtained in moderate to good yield (Table
1, entry 6, 7). Next, we screened glycol based solvents such as

3
Table 2: One-pot three component synthesis of 3-amino alkylated indoles under catalyst-free condition.a
Entry
Indoles
(X) 1
Aldehyde (R)
2
Secondary amines
3
Product
4
Time (min)
Yield of 4 (%)b
1
2
3
4
5
6
7
H
H
H
H
H
H
H
H
4-Cl
2-Cl
2,4-Cl
4-Br
4-OMe
3-OMe
4-OBn,3-OMe
2,5-OMe
3,4,5-OMe
4-tBu
H
4-Cl
H
4-Cl
3-OMe
H
4-Cl
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
4a
4b
4c
4d
4e
4f
4g
25,c 25,d30e
25
30
35
25
90,c 90,d 91d
87
85
80
83
20
25
92
89
8
9
H
H
H
4h
4i
4j
30
40
30
25
25
30
30
25
84
83
87
82
86
83
85
82
Pyrrolidine
Pyrrolidine
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
H
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
Br
Br
OMe
OMe
OMe
NO2
NO2
H
25
50
88
74
45
90
80
80
90
30
25
30
76
70
73
75
73
90
92
85
H
Piperidine
Piperidine
H
3,4,5-OMe
H
2-Cl
H
4-NO2
4-Cl
4-Me
4-OMe
3-OMe
2-Cl
H
H
H
H
H
H
H
Morpholine
Morpholine
4u
4v
4w
4x
4y
4z
4aa
4bb
4cc
4dd
4ee
4ff
4gg
4hh
N-methyl aniline
N-methyl aniline
N-methyl aniline
N-methyl aniline
N-methyl aniline
N-methyl aniline
N-methyl aniline
N-methyl aniline
N-methyl aniline
N-methyl aniline
N-methyl aniline
N-methyl aniline
30
25
85
88
H
H
35
35
40
45
40
30
35
82
82
85
87
82
86
80
Br
Br
Br
OMe
OMe
H
4-Me
4-OMe
4-Cl
4-Me
aReaction condition: Indoles (1 mmol), aldehydes (1 mmol), and secondary amines (1 mmol), EG (1 mmol). bIsolated yield. cFresh EG, dafter 5 times recycled
EG, ereaction at 50 mmol scale.
H
O
O
H
O
H
O
O
Ph
+
H
H
N
OH
N
Iminium ion
Ph
N
iii
H
O
ii
H
O
Indole 1a
O
N
H
H
Ph
benzaldehyde2a
H
pyrrolidine 3a
i
H
O
H
O
H
O
Ph
Ph
N
H
N
N
H
N
H
4a
HO
HO
iv
Scheme 2. Plausible mechanism of EG promoted synthesis of 3-amino-alkylated indole 4a
The X-ray crystallographic structure of compound 4f (table 2,
entry 6) is shown in Figure 2 (CCDC 965703 and sees SI for X-
ray crystallographic data details).

4
Tetrahedron
1673. (c) Srihari, P.; Singh, V. K.; Bhunia, D. C.; Yadav, J. S.
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A.; Hajra, A. Synlett, 2011, 1165. (e) Das, B.; Kumar, J. N.; Kumar, A.
S.; Damodar, K. Synthesis, 2010, 914. (f) Rao, V. K.; Chhikara, B. S.;
Shirazi, A. N.; Tiwari, R.; Parang, K.; Kumar, A. Bioorg. Med. Chem.
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J.; Palaniappan, S. Synth. Commun., 2012, 42, 1593. (j) Yadav, D. K.;
Patel, R.; Srivastava, V. P.; Watal, G.; Yadav, L. D. S. Tetrahedron
Lett., 2010, 51, 5701. (k) Mi, X.; Luo, S.; Hea, J.; Cheng, J.
P. Tetrahedron Lett., 2004, 45, 4567. (l) Shirakawa, S.; Kobayashi, S.
Org. Lett., 2006, 8, 4939.
C20
O1
C17
C16
C18
C19
C15
C14
C9
13. (a) Manohar, S.; Rajesh, U. C.; Khan, S. I.; Tekwani, B. L.; Rawat, D. S.
ACS Med. Chem. Lett. 2012, 3, 555. (b) Beena.; Kumar, N.; Rohilla, R.
K.; Roy, N.; Rawat, D. S. Bioorg. Med. Chem. Lett. 2009, 19, 1396. (c )
Kumar, N.; Khan, S. I.; Sharma, M.; Atheaya, H.; Rawat, D. S.
Bioorg. Med. Chem. Lett. 2009, 19, 1675. (d) Atheaya, H.; Khan, S. I.;
Mamgain, R.; Rawat, D. S. Bioorg. Med. Chem. Lett. 2008, 18, 1446. (e)
Krzysiak, A. J.; Rawat, D. S.; Scott, S. A.; Pais, J. E.; Handley, M.;
Harrison, M. L.; Fierke, C. A.; Gibbs, R. A. ACS Chem. Biol. 2007, 2,
385. (f) Joshi, M. C.; Bisht, G. S.; Rawat, D. S. Bioorg. Med. Chem.
Lett. 2007, 17, 3226.
C13
C5
C2
C4
C6
C7
N2
C12
C11
C8
N1
C1
C10
C3
Figure 2. Molecular structure of 3-amino alkylated indole 4f.
14. (a) Arya, K.; Rajesh, U. C.; Rawat, D. S. Green Chem. 2012, 14, 3344.
(b) Thakur, A.; Tripathi, M.; Rajesh, U. C.; Rawat, D. S. RSC Adv. 2013,
3, 18142.
Acknowledgments
15. General procedure for the synthesis of 3-amino alkylated indoles (4a-
4hh): A mixture of aldehyde (1 mmol), secondary amine (1 mmol), indole
(1 mmol) and EG (1 mmol) were taken in a 10 mL round-bottom flask and
stirred in oil bath at 90 oC till the completion of the reaction (monitored by
TLC). After completion, the reaction mixture was diluted with hot water
(3 mL) and filtered. The obtained crude product was purified by
recrystallization from diethyl ether/n-hexane (1 mL/10 mL). The aqueous
layer containing EG was evaporated under reduced pressure at 60 °C to
give pure EG, which was used for the next run under similar reaction
conditions. All compounds were characterized by M.P, NMR, IR and
Mass spectral data.
DSR acknowledge the DU-PURSUE grant, New Delhi, India and
University of Delhi, Delhi, India for financial support. UCR, RK
and VSP are thankful to UGC for the award of senior, junior
research fellowship and UGC grant 41-202/2012 (SR) for
fellowship respectively. We Thank to USIC-CIF, University of
Delhi, for analytical data.
References and notes
Spectral data for unknown compounds:
3-((2,4-dichlorophenyl)(pyrrolidin-1-yl)methyl)-1H-indole (4d): Off
white solid; mp 141-143 oC; IR (KBr) 3413, 2923, 2798, 1586, 1461,
1.
2.
3.
(a) Zhou, Y. J.; Chen, D. S.; Li, Y. L.; Liu, Y.; Wang, X. S. ACS Comb.
Sci. 2013, 15, 498. (b) Azizi, N.; Aryanasab, F.; Saidi, M. R. Org. Lett.,
2006, 23, 5275.
1
1345, 1216, 1097, 735 cm−1; H NMR (400 MHz, CDCl3) δ (ppm) 8.04
(a) McGonagle, F. I.; Sneddon, H. F.; Jamieson, C.; Watson, A. J. B.
ACS Sus. Chem. Eng., 2013, dx.doi.org/10.1021/sc4004532. (b)
Sheldon, R. A. Chem. Commun. 2008, 3352.
(a) Hasaninejad, A.; Firoozi, S. Mol. Divers. 2013, 17, 459. (b)
Hasaninejad, A.; Zare, A.; Shekouhy, M.; Rad, J. A. J. Comb. Chem.
2010, 12, 844. (c) Tzani, A.; Douka, A.; Papadopoulos, A.; Pavlatou, E.
A.; Voutsas, E.; Detsi, A. ACS Sus. Chem. Eng. 2013, 1, 1180. (d) Jain,
S. L.; Singhal, S.; Sain, B. Green Chem. 2007, 9, 740. (e) Safaei, H. R.;
Shekouhy, M.; Rahmanpur, S.; Shirinfeshan, A. Green Chem. 2012, 14,
1696.
(br s, 1H), 7.91 (t, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.28 (d, J =
2.2 Hz, 1H), 7.22 (dd, J = 5.8 Hz, J = 2.2 Hz, 2H), 7.16 (t, J = 8.0 Hz,
1H), 7.10 (t, J = 7.3 Hz, 1H), 5.08 (s, 1H), 2.52 (d, J = 8.0 Hz, 4H), 1.78
(s, 4H); 13C NMR (100 MHz, CDCl3) δ (ppm) 140.47, 136.41, 133.77,
132.60, 130.72, 129.43, 127.56, 126.62, 123.02, 122.38, 120.40, 119.94,
118.08, 111.43, 63.03, 53.73, 23.93; HRMS (ES): Calcd 344.0847, found
344.0849; Anal. Calcd for C19H18Cl2N2: C, 66.09; H, 5.25; N, 8.11;
Found: C, 66.12; H, 5.22; N, 8.10
3-((4-bromophenyl)(pyrrolidin-1-yl)methyl)-1H-indole
o
(4e):
crystals; mp 145-147 C; IR (KBr) 3413, 2964, 2792, 1484, 1343, 1217,
White
4.
5.
6.
Dye, R. F. Korean J. Chem. Eng. 2001, 18, 571.
1
1098, 1009, 740 cm−1; H NMR (400 MHz, CDCl3) δ (ppm) 8.06, (br s,
Yue, H.; Zhao, Y.; Ma, X.; Gong, J. Chem. Soc. Rev. 2012, 41, 4218.
(a) Firouzabadi, H.; Iranpoor, N.; Gholinejad, M.; J. Hoseini, Adv.
Synth. Catal. 2011, 353, 125. (b) Liu, Y. S.; Tang, M. F.; Lii, K. H.
DaltonTrans. 2009, 9781.(c) Rajesh, U. C.; Manohar, S.; Rawat, D. S.
Adv. Synth. Catal. 2013, 355, 3170. (d) Jiang, X.; Wang, Y.; Herricks,
T.; Xia, Y. J. Mater. Chem. 2004, 14, 695. (e) Jenner, G.; Salem, R. B.
New J. Chem. 2000, 24, 203.
1H), 7.77 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.0
Hz, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.19-7.14 (m, 2H), 7.08 (t, J = 7.3 Hz,
1H), 4.56 (s, 1H), 2.51 (d, J = 8.0 Hz, 4H), 1.77 (s, 4H); 13C NMR (100
MHz, CDCl3) δ (ppm) 143.82, 136.43, 131.59, 129.72, 126.56, 122.33,
120.47, 119.97, 119.80, 119.21, 111.46, 67.63, 53.94, 23.83; HRMS
(ES): Calcd 354.0732, found 354.0734; Anal. Calcd for C19H19BrN2: C,
64.23; H, 5.39; N, 7.89; Found: C, 64.26; H, 5.42; N, 7.92
7. (a) Syamala, M. Org. Prep. Proced. Int. 2009, 41, 1. (b) Marek, I.
Tetrahedron, 2005, 61, 11309. (c) Weber, L.; Illgen, K.; Almstetter,
M. Synlett, 1999, 3, 366.
3-((4-methoxyphenyl)(pyrrolidin-1-yl)methyl)-1H-indole (4f): White
crystals; mp170-172°C; IR (KBr) 3419, 3045, 2827, 1489, 1341, 1214,
1158, 749 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.02 (br s, 1H),
7.77 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.0 Hz,
1H), 7.23 (t, J = 8.0 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz,
2H), 4.55 (s, 1H), 3.74 (s, 3H), 2.56-2.46 (m, 4H), 1.76 (s, 4H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 158.53, 137.03, 136.47, 129.07, 126.84,
122.14, 120.10, 120.05, 119.62, 113.84, 111.36, 67.61, 55.48, 54.00,
23.86; HRMS (ES): Calcd 306.1732, found 306.1739; Anal. Calcd for
C20H22N2O: C, 78.40; H, 7.24; N, 9.14; Found: C, 78.45; H, 7.19; N, 9.11
3-((4-(benzyloxy)-3-methoxyphenyl)(pyrrolidin-1-yl)methyl)-1H-
indole (4h): white solid; mp 92-94 oC; IR (KBr) 3404, 2960, 2790,
8. Evans, G. B.; Furneaux, R. H.; Tyler, P. C.; Schramm, V. L. Org. Lett.
2003, 5, 3639. (b) Arend, M.; Westermann, B.; Risch, N. Angew. Chem.
Int. Ed. 1998, 37, 1044.
9. (a) Casapullo, A.; Bifulco, G.; Bruno, I.; R. J. Nat. Prod. 2000, 63, 447.
(b) Horgen, F. D.; Santos, D. B. D.; Goetz, G.; Sakamoto, B.; Kan, Y.;
Nagai, H.; Scheuer, P. J. J. Nat. Prod. 2000, 63, 152.
10. 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) Borgne, M. L.; Marchand, P. M.; Seiller, B. D.;
Robert, J. M.; Baut, G. L.; Hartmann, R. W.; Palzer, M. Bioorg. Med.
Chem. Lett. 1999, 9, 333. (c) Deng, J.; Sanchez, T.; Neamati, N.; Briggs,
J. M. J. Med. Chem. 2006, 49, 1684. (d) 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
1506, 1455, 1340, 1217, 1132, 739 cm−1; H NMR (400 MHz, CDCl3)
δ (ppm) 8.28 (br s, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.41 (d, J = 7.3 Hz,
2H), 7.34 (t, J = 7.3 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.19-7.08 (m,
4H), 7.00 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 5.09 (s, 2H),
4.54 (s, 1H), 3.84 (s, 3H), 2.55 (d, J = 6.5 Hz, 4H), 1.78 (s, 4H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 149.72, 147.21, 138.09, 137.69,
136.45, 128.80, 128.04, 127.58, 126.83, 122.23, 122.16, 120.06,
11. Grumbach, H. J.; Arend, M.; Risch, N. Synthesis, 1996, 883.
12. (a) Kumar, A.; Gupta, M. K.; Kumar, M. Green Chem. 2012, 14, 290.
(b) Kumar, A.; Gupta, M. K.; Kumar, M.; Saxena, D. RSC Adv. 2013, 3,

5
119.81, 119.64, 113.74, 111.72, 111.42, 77.68, 71.33, 68.01, 56.34,
54.07, 23.85; HRMS (ES): Calcd 412.2151, found 412.2152; Anal.
Calcd for C27H28N2O2: C, 78.61; H, 6.84; N, 6.79; Found: C, 78.60; H,
6.81; N, 6.81.
5-Nitro-3-(phenyl(pyrrolidin-1-yl)methyl)-1H-indole (4q): Yellow
o
solid; mp 154-156 C; IR (KBr) 3399, 2924, 2791, 1515, 1463, 1322,
1089, 742 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.78 (s, 1H),
8.50 (br s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.31
(s, 1H), 7.24-7.22 (m, 2H), 7.21-7.20 (m, 1H), 7.12 (t, J = 7.3 Hz, 1H),
4.54 (s, 1H), 2.45 (m, 4H), 1.73 (s, 4H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 143.95, 141.93, 139.51, 128.79, 127.94, 127.36, 126.09,
125.24, 122.51, 117.97, 117.63, 111.42, 68.23, 54.03, 23.87; HRMS
(ES): Calcd 321.1477, found 321.1482; Anal. Calcd for C19H19N3O2:
C, 71.01; H, 5.96; N, 13.08; Found: C, 71.08; H, 5.94; N, 13.10
3-(pyrrolidin-1-yl(3,4,5-trimethoxyphenyl)methyl)-1H-indole
o
(4j):
White solid; mp 135-137 C; IR (KBr) 3421, 2921, 2780, 1592, 1458,
1
1330, 1216, 1126, 738 cm−1; H NMR (400 MHz, CDCl3) δ (ppm) 8.21
(br s, 1H), 7.87 (d, J = 7.3 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.21-7.09
(m, 3H), 6.80 (s, 2H), 4.49 (s, 1H), 3.82 (s, 6H), 3.78 (s, 3H), 2.54 (d, J
= 2.9 Hz, 4H), 1.78 (s, 4H); 13C NMR (100 MHz, CDCl3) δ (ppm)
153.23, 140.76, 136.63, 136.46, 126.81, 122.46, 122.16, 119.98,
119.63, 111.52, 104.77, 77.67, 68.57, 61.08, 56.37, 54.09; HRMS
(ES): Calcd 366.1943, found 366.1941; Anal. Calcd for C19H19BrN2: C,
72.11; H, 7.15; N, 7.64; Found: C, 72.15; H, 7.18; N, 7.59.
3-((4-chlorophenyl)(pyrrolidin-1-yl)methyl)-5-nitro-1H-indole
(4r):
Yellow solid; mp 116-118 oC; IR (KBr) 3366, 2924, 2798, 1516, 1325,
1215, 1090, 742 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.73 (s,
1H), 8.52 (br s, 1H), 8.00 (dd, J = 8.7 Hz, J = 2.2 Hz, 1H), 7.4 (d, J =
8.0 Hz, 2H), 7.29-7.26 (m, 2H), 7.17 (d, J = 8.7 Hz, 2H), 4.51 (s, 1H),
2.42 (s, 4H), 1.72 (s, 4H); 13C NMR (100 MHz, CDCl3) δ (ppm)
142.48, 142.01, 139.57, 132.88, 129.23, 128.93, 128.17, 125.90,
125.26, 122.11, 118.13, 117.53, 111.55, 67.50, 53.94, 23.89; HRMS
(ES): Calcd 355.1088, found 355.1084; Anal. Calcd for C19H18ClN3O2:
C, 64.13; H, 5.10; N, 11.81; Found: C, 64.18; H, 5.13; N, 11.84
3-((4-(tert-butyl)phenyl)(pyrrolidin-1-yl)methyl)-1H-indole
o
(4k):
White solid; mp 122-124 C; IR (KBr) 3416, 2961, 2794, 1509, 1454,
1
1297, 1217, 1113, 739 cm−1; H NMR (400 MHz, CDCl3) δ (ppm) 8.05
(br s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.30 (d, J
= 8.0 Hz, 1H), 7.26-7.22 (m, 3H), 7.13 (t, J = 7.5 Hz, 1H), 7.08 (t, J =
8.0 Hz, 1H), 4.54 (s, 1H), 2.56-2.46 (m, 4H), 1.76 (s, 4H), 1.25 (s, 9H);
13C NMR (100 MHz, CDCl3) δ (ppm) 149.54, 141.72, 136.39, 127.58,
126.93, 125.37, 122.24, 122.10, 120.13, 120.01, 119.59, 111.35, 68.08,
54.21, 34.68, 31.72, 23.84; HRMS (ES): Calcd 332.2252, found
332.2251; Anal. Calcd for C23H28N2: C, 83.09; H, 8.49; N, 8.43;
Found: C, 83.12; H, 8.52; N, 8.40
5-Bromo-3-(phenyl(pyrrolidin-1-yl)methyl)-1H-indole (4l): Light
o
yellow solid; mp 146-148 C; IR (KBr) 3424, 2964, 2792, 1564, 1329,
1
1271, 1105, 744 cm−1; H NMR (400 MHz, CDCl3) δ (ppm) 8.09 (br s,
1H), 7.94 (s, 1H), 7.48 (d, J = 7.3 Hz, 2H), 7.24-7.22 (m, 2H), 7.18-
7.17 (m, 2H), 7.14-7.10 (m, 2H), 4.48 (s, 1H), 2.50-2.43 (m, 4H), 1.74
(s, 4H); 13C NMR (100 MHz, CDCl3) δ (ppm) 144.43, 135.05, 128.65,
128.52, 127.94, 127.10, 125.06, 123.50, 122.59, 119.61, 113.07,
112.82, 68.26, 54.05, 23.86; HRMS (ES): Calcd 354.0732, found
354.0735; Anal. Calcd for C19H19BrN2: C, 64.23; H, 5.39; N, 7.89;
Found: C, 64.24; H, 5.43; N, 7.92
5-Bromo-3-((4-chlorophenyl)(pyrrolidin-1-yl)methyl)-1H-indole (4m):
Off white solid; mp 140-142 oC; IR (KBr) 3432, 2924, 2795, 1564,
1
1485, 1215, 1092, 746 cm−1; H NMR (400 MHz, CDCl3) δ (ppm) 8.13
(br s, 1H), 7.93 (s, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.7Hz,
3H), 7.18-7.16 (m, 2H), 4.49 (s, 1H), 2.48 (d, J = 5.8 Hz, 4H), 1.77 (s,
4H); 13C NMR (100 MHz, CDCl3) δ (ppm) 142.98, 135.08, 132.56,
129.22, 128.77, 128.28, 125.24, 123.46, 122.51, 119.21, 113.21,
112.90, 67.51, 53.92, 23.86; HRMS (ES): Calcd 388.0342, found
388.0345; Anal. Calcd for C19H18BrClN2: C, 58.56; H, 4.66; N, 7.19;
Found: C, 58.54; H, 4.69; N, 7.22
5-Methoxy-3-(phenyl(pyrrolidin-1-yl)methyl)-1H-indole (4n):
Off
white solid; mp 118-120 oC; IR (KBr) 3416, 2923, 2790, 1582, 1479,
1
1449, 1210, 1030, 748 cm−1; H NMR (400 MHz, CDCl3) δ (ppm) 7.95
(br s, 1H), 7.53 (d, J = 7.3 Hz, 2H), 7.28-7.27 (m, 2H), 7.23 (s, 1H),
7.18-7.13 (m, 3H), 6.80 (dd, J = 8.7 Hz, J = 2.2 Hz, 1H), 4.53 (s, 1H),
3.84 (s, 3H), 2.54-2.50 (m, 4H), 1.77 (s, 4H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 154.10, 144.74, 131.68, 128.52, 128.00, 127.26,
126.90, 123.20, 119.45, 112.05, 111.96, 102.29, 68.36, 56.26, 54.00,
23.86; HRMS (ES): Calcd 306.1732, found 306.1735; Anal. Calcd for
C20H22N2O: C, 78.40; H, 7.24; N, 9.14; Found: C, 78.40; H, 7.24; N,
9.14
3-((4-chlorophenyl)(pyrrolidin-1-yl)methyl)-5-methoxy-1H-indole
o
(4o): White solid; mp 112-114 C ; IR (KBr) 3431, 2964, 2790, 1583,
1
1483, 1212, 903, 720 cm−1; H NMR (400 MHz, CDCl3) δ (ppm) 7.96
(br s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.25-7.23 (m, 2H), 7.21-7.18 (m,
2H), 7.14 (br s, 1H), 6.84 (dd, J = 8.79 Hz, J = 2.9 Hz, 1H), 4.52 (s,
1H), 3.85 (s, 3H), 2.54-2.47 (m, 4H), 1.77 (s, 4H); 13C NMR (100
MHz, CDCl3) δ (ppm) 154.19, 143.33, 132.36, 131.72, 129.29, 128.64,
127.04, 123.11, 119.08, 112.17, 112.04, 102.30, 67.62, 56.28, 53.88,
23.89; HRMS (ES): Calcd 340.1342, found 340.1349; Anal. Calcd for
C20H21ClN2O: C, 70.48; H, 6.21; N, 8.22; Found: C, 70.52; H, 6.26; N,
8.24
5-Methoxy-3-((3-methoxyphenyl)(pyrrolidin-1-yl)methyl)-1H-indole
(4p): Off white solid; mp 156-158 oC; IR (KBr) 3414, 2924, 2789,
1
1588, 1480, 1449, 1261, 1043, 753 cm−1; H NMR (400 MHz, CDCl3)
δ (ppm) 7.96 (br s, 1H), 7.31 (s, 1H), 7.19-7.15 (m, 3H), 7.13-7.12 (m,
2H), 6.80 (dd, J = 8.0 Hz, J = 2.2 Hz, 1H), 6.71-6.69 (m, 1H), 4.50 (s,
1H), 3.85 (s, 3H), 3.76 (s, 3H), 2.53 (d, J = 3.6 Hz, 4H), 1.77 (s, 4H);
13C NMR (100 MHz, CDCl3) δ (ppm) 159.81, 154.11, 146.52, 131.66,
129.44, 127.23, 123.22, 120.46, 119.34, 113.70, 112.08, 111.99,
102.20, 68.35, 56.26, 55.46, 54.01, 23.88; HRMS (ES): Calcd
336.1838, found 336.1839; Anal. Calcd for C21H24N2O2: C, 74.97; H,
7.19; N, 8.33; Found: C, 74.97; H, 7.19; N, 8.33

6
Tetrahedron
Catalyst-free, ethylene glycol promoted
one-pot three component synthesis of 3-
amino alkylated indoles via Mannich-type
reaction+
U. Chinna Rajesh, Rohit Kholiya, V. Satya Pavan and
Diwan S. Rawat*
Department of Chemistry, University of Delhi, Delhi-110007,
India
Fax: (+)91-11-27667501; *E-mail:
dsrawat@chemistry.du.ac.in
+Dedicated to Professor Richard A Gibbs (1962 - 2014)
Highlights of present work
1. Catalyst free conditions for the synthesis of 3-
amino alkylated indoles
2. This Method is useful for large scale production
of 3-amino alkylated indoles.
3. Avoids the use of column chromatography for
the purification of final products.
4. Ethylene glycol is as a green promoted medium.