Zwitterionic-type molten salt: A mild and efficient organocatalyst for the synthesis of 3-aminoalkylated indoles via three-component coupling reaction

Article abstract of DOI:10.1055/s-0030-1259940

A general and efficient method has been developed for the synthesis of 3-aminoalkylated indoles by a three-component coupling of indoles, aldehydes, and amines in the presence of a catalytic amount of zwitterionic-type molten salt under solvent-free condi

Full text of DOI:10.1055/s-0030-1259940

LETTER
1165
Zwitterionic-Type Molten Salt: A Mild and Efficient Organocatalyst for the
Synthesis of 3-Aminoalkylated Indoles via Three-Component Coupling
Reaction
Z
witterionic-Type
h
M
olte
n
Saltiman Kundu, Avik Kr. Bagdi, Adinath Majee, Alakananda Hajra*
Department of Chemistry, Visva Bharati University, Santiniketan, West Bengal 731235, India
Fax +91(3463)262728; E-mail: alakananda.hajra@visva-bharati.ac.in
Received 15 November 2010
The zwitterionic-type molten salt, 4-(1-imidazolium)-
Abstract: A general and efficient method has been developed for
the synthesis of 3-aminoalkylated indoles by a three-component
coupling of indoles, aldehydes, and amines in the presence of a cat-
alytic amount of zwitterionic-type molten salt under solvent-free
butane sulfonate (IBS) is a mild organocatalyst. In contin-
uation of our work on ionic liquid7 and zwitterionic-type
molten salt8 catalyzed organic transformations, we ob-
conditions. The non-hazardous experimental procedure, mild reac- served that treatment of indoles with aldehydes and sec-
tion conditions, and the reusability of the catalyst are the notable ad-
vantages of the present method.
ondary amines in the presence of molten salt afforded the
corresponding 3-aminoalkylated indoles under solvent-
Key words: 3-aminoalkylated indole, zwitterion, molten salt, orga-
nocatalyst, multicomponent
free conditions at 60 °C (Scheme 1). To the best of our
knowledge, this is the first report of zwitterionic-type
molten salt catalyzed multicomponent synthesis of 3-ami-
noalkylated indole derivatives.
Multicomponent reactions (MCR) play an important role
in modern synthetic organic chemistry since they produce
complex products with several degrees of structural diver-
sity from mixing three or more simple starting materials in
one pot.1 Indoles and their derivatives occur in a large
number of biologically active natural products, and they
have been widely used in chemical and pharmaceutical in-
dustry.2 Therefore, the syntheses and the reactions of in-
dole derivatives have received much attention.3 Since the
3-position of indole is the preferred site for electrophilic
substitution, 3-substituted indoles are versatile intermedi-
ates for the synthesis of a wide range of indole com-
pounds.4 3-Aminoalkylated indoles are important
intermediates in organic synthesis and they have been
found in many important natural products.5 Among 3-sub-
stituted indole derivatives, only a few methods are avail-
able for the synthesis of 3-aminoalkylated indoles6 and
those methods that are available lack general applicability
and are limited to aromatic aldehydes. Thus, development
of a versatile, efficient, and environmentally benign ap-
proach for the synthesis of 3-aminoalkylated indole deriv-
atives is highly desirable.
Initially we selected benzaldehyde, N-methylaniline, and
indole for screening the reaction conditions. Using 20
mol% of molten salt as the catalyst under solvent-free
conditions at 60 °C for three hours, the desired 3-[(N-me-
thylanilino)(phenyl)methyl]indole was obtained in 82%
yield. The best result was achieved by carrying out the re-
action with 1:1:2 mole ratios of benzaldehyde, indole and
N-methylaniline. N-Methylaniline was used in excess to
avoid the formation of bisindolyl products. At room tem-
perature the rate of the reaction was very slow and fur-
nished only a 32% yield of the desired product after 24
hours. When the reaction was carried out at 100 °C it pro-
duced a mixture of products. With respect to the quantity
of the catalyst, there was no significant enhancement in
yields when the amount of catalyst was increased from 20
mol% to 30 mol% while decreasing the amount of catalyst
decreased the yield. When reaction was carried out in the
absence of catalyst for 24 hours under otherwise identical
conditions, the yield of the desired product was very low
(<5%).
R4
R5
R3
N
R2
R2
R4
zwitterionic salt (20 mol%)
60 °C, neat
R3 CHO
R1
+
+
HN
R1
R5
N
N
H
H
R1 = H, Me; R2 = H, Br, OMe
3 = aryl, heteroaryl, aliphatic
R4, R5 = cyclic, acyclic
+
R
HN
N
zwitterionic salt:
–
SO3
Scheme 1
SYNLETT 2011, No. 8, pp 1165–1167
x
x.
x
x.
2
0
1
1
Advanced online publication: 07.04.2011
DOI: 10.1055/s-0030-1259940; Art ID: D30210ST
© Georg Thieme Verlag Stuttgart · New York

1166
D. Kundu et al.
LETTER
After determining the optimized reaction conditions, we 16) without accompanying polymerization. Piperonal also
turned our attention towards studying the scope of the afforded high yields without disturbing the methylene-
method. The results are summarized in Table 1.9 A wide dioxy functionality (entry 15). Cinnamaldehyde produced
range of structurally diverse aldehydes underwent con- multiple products which were difficult to characterize.
densation by this reaction to provide 3-aminoalkylated in- Both cyclic and acyclic secondary amines such as mor-
dole derivatives in excellent yields. Aromatic aldehydes pholine and N-methylaniline reacted well under these
with both activating and deactivating groups such as Me, conditions. 1H-Indole, 5-bromo-1H-indole, 5-methoxy-
OMe, OH, Cl, and NO2 reacted to afford the correspond- 1H-indole, and 2-methyl-1H-indole were employed as the
ing products in almost equally high yields. The present indole derivatives for this three-component reaction. In
method is equally effective, with aliphatic aldehydes such general, reactions were clean, conversion was complete
as n-butyraldehyde (entry 17), isobutyraldehyde (entry within 2–3.5 hours and the products were formed in high
18), and cyclohexanecarboxaldehyde (entry 19) produc- yields (80–90%).
ing the desired products in almost equally high yields. The
A plausible reaction mechanism for the IBS-catalyzed
catalytic system also worked well with acid-sensitive het-
reaction is outlined in Scheme 2. The initial iminium ion
eroaromatic aldehydes such as 2-pyridinecarboxaldehyde
formation is proposed to be facilitated by the electrophilic
to generate the corresponding product in 81% yield (entry
activation of the aldehyde carbonyl through hydrogen
Table 1 Synthesis of 3-Aminoalkylated Indoles
R4
R5
R3
N
R2
R2
R4
R5
zwitterionic salt (20 mol%)
60 °C, neat
R3 CHO
HN
R1
+
+
R1
N
N
H
H
Entry
1
R1
R2
H
H
H
H
H
H
H
H
R3
R4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R5
Time (h)
Yield (%)a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
3
82
86
84
85
88
84
84
85
84
86
90
80
87
90
2
4-MeC6H4
4-MeOC6H4
3-HOC6H4
4-ClC6H4
2.5
2.5
3
3
4
5
3
6
4-O2NC6H4
3,4,5-(MeO)3C6H2
1-naphthyl
4-MeC6H4
4-ClC6H4
3.5
3
7
8
3.5
2.5
2.5
2.5
3
9
OMe
OMe
Br
10
11
12
13
14
4-ClC6H4
Br
4-O2NC6H4
3,4,5-(MeO)3C6H2
4-ClC6H4
Br
3
H
morpholine
2
15
H
H
morpholine
2
84
O
O
16
Me
H
morpholine
2
81
N
17
18
19
H
H
H
H
H
H
n-Pr
morpholine
morpholine
Ph
2.5
3
80
84
83
i-Pr
c-Hex
Me
3.5
a Isolated yields.
Synlett 2011, No. 8, 1165–1167 © Thieme Stuttgart · New York

LETTER
Zwitterionic-Type Molten Salt
1167
+
O–
H
N
N
N
H
S
R4
R5
H
O
R3
R1
R4
O
H
O
N
R2
R4
R5
R2
+
+
+
HN
R1
N
R5
_ H2O
R3
N
R3
H
Scheme 2
J. Org. Chem. 2001, 66, 4865. (c) Zhang, H. C.; Bonaga,
L. V. R.; Ye, H.; Derian, C. K.; Damiano, B. P.; Maryanoff,
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(d) Bandini, M.; Eichholzer, A. Angew. Chem. Int. Ed. 2009,
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2006, 106, 2875.
bond formation with the C-2 hydrogen atom of the imida-
zolium moiety.10 In the next step, the indole reacts with
iminium ion intermediate to produce the 3-aminoalkylat-
ed indole. In this step, the catalyst might play a role by ac-
tivating the indole nucleus through the interaction of
sulfone functionality of the zwitterion with the NH hydro-
gen of the indole.
(4) (a) Moore, R. E.; Cheuk, C.; Patterson, C. G. M. L. J. Am.
Chem. Soc. 1984, 106, 6456. (b) Fridkin, G.; Boutard, N.;
Lubell, W. D. J. Org. Chem. 2009, 74, 5603.
The recovery and reusability of the catalyst were also in-
vestigated. After completion, the reaction mixture was ex-
tracted with diethyl ether (3 × 10 mL) and the catalyst, left
in the vessel was dried under vacuum for subsequent reac-
tions. The catalyst was reused for six times without no-
ticeable decrease in catalytic activity (79% for entry 1,
Table 1).
(5) Wynne, J. H.; Stalick, W. M. J. Org. Chem. 2002, 67, 5850.
(6) (a) Olyaei, A.; Shams, B.; Sadeghpour, M.; Gesmati, F.;
Razazaine, Z. Tetrahedron Lett. 2010, 51, 6086. (b) Yadav,
D. K.; Patel, R.; Srivastava, V. P.; Watel, G.; Yadav, L. D.
S. Tetrahedron Lett. 2010, 51, 5701. (c) Srihari, P.; Sing, V.
K.; Bhunia, D. C.; Yadav, J. S. Tetrahedron Lett. 2009, 50,
3763. (d) Das, B.; Kumar, J. N.; Kumar, A. S.; Damodar, K.
Synthesis 2010, 914. (e) Sharifi, A.; Mirzaei, M.; Naimi-
Jamal, M. R. Monatsh. Chem. 2001, 132, 875. (f) Dai,
H.-G.; Li, J.-T.; Li, T. S. Synth. Commun. 2006, 36, 1829.
(g) Zao, J.-L.; Liu, L.; Zhang, H.-B.; Wu, Y.-C.; Wang, D.;
Chen, Y.-F. Synlett 2006, 96. (h) Bello, J. S.; Amado, D. F.;
Kouznetsov, V. V. Rev. Soc. Quim. Peru 2008, 74, 190.
(i) Gruback, H.-J.; Arend, M.; Risch, N. Synthesis 1996,
883. (j) Saidi, M. R.; Azizi, N.; Naimi-Jamal, M. R.
Tetrahedron Lett. 2001, 42, 8111.
In conclusion, we have demonstrated a mild, simple, and
environmentally friendly one-pot synthesis of 3-ami-
noalkylated indole derivatives via a three-component cou-
pling of indole, aldehyde, and amine catalyzed by
zwitterionic-type molten salt under solvent-free condi-
tions. The present method is equally effective for aliphat-
ic, aromatic, and heteroaromatic aldehydes. The non-
hazardous experimental procedure, mild reaction condi-
tions and reusability of the catalyst are the notable advan-
tages of this procedure. Further procedures to broaden the
scope of this methodology towards the synthesis of bio-
logically important compounds are under investigation.
(7) (a) Das, S.; Rahman, M.; Kundu, D.; Majee, A.; Hajra, A.
Can. J. Chem. 2010, 88, 150. (b) Ranu, B. C.; Dey, S. S.;
Hajra, A. Tetrahedron 2003, 59, 2417.
(8) (a) Kundu, D.; Debnath, R. K.; Majee, A.; Hajra, A.
Tetrahedron Lett. 2009, 50, 6998. (b) Kundu, D.;Majee, A.;
Hajra, A. Catal. Commun. 2010, 11, 1157.
(9) Synthesis of 2-Methyl-3-(morpholin-4-ylpyridin-2-
ylmethyl)-1H-indole (Entry 16, Table 1): A mixture of 2-
pyridinecarboxaldehyde (190 mL, 214 mg, 2 mmol),
morpholine (350 mL, 348 mg, 4 mmol), and 2-methylindole
(262 mg, 2 mmol) was stirred in the presence of 4-(1-
imidazolium)butane sulfonate (82 mg, 20 mol%) at 60 °C for
2 h. After completion of the reaction (TLC) the reaction
mixture was extracted with Et2O (3 × 10 mL). Evaporation
of solvent furnished the crude product which was subjected
to column chromatography to obtain the pure product (498
mg, 81%) as a brown solid; mp 145–146 °C. IR (KBr): 3502,
2738, 1587, 1460, 1377 cm–1. 1H NMR (500 MHz, CDCl3):
d = 8.44 (d, J = 3.0 Hz, 1 H), 8.19 (s, 1 H), 8.07 (t, J = 3.0
Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.55 (t, J = 8.5 Hz, 1 H),
7.15–7.17 (m, 1 H), 7.02–7.10 (m, 3 H), 4.76 (s, 1 H), 3.72–
3.79 (m, 4 H), 2.58 (m, 2 H), 2.44 (s, 3 H), 2.37–2.41 (m, 2
H). 13C NMR (125 MHz, CDCl3): d = 162.6, 148.6, 136.8,
135.4, 133.4, 127.0, 122.1, 121.8, 121.0, 120.2, 119.6,
110.6, 110.4, 71.1, 67.4 (2 × C), 67.4 (2 × C), 12.5. Anal.
Calcd for C19H21N3O: C, 74.24; H, 6.89; N, 13.67. Found: C,
74.10; H, 6.72; N, 13.58. The catalyst, left in the reaction
vessel, was dried under vacuum and was reused for
subsequent reactions.
Acknowledgment
This work is supported by the Department of Science and Techno-
logy, Govt. of India (Grant No. SR/S5/GC-05/2010). D.K. and
A.K.B. thank the Council of Scientific and Industrial Research
(CSIR) for their fellowship. A.M. acknowledges financial support
from the CSIR [Grant No. 01(2251)/08/EMR-II].
References and Notes
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