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COMMUNICATION
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L-Proline
catalysed multicomponent synthesis of 3-amino alkylated indoles
via a Mannich-type reaction under solvent-free conditions†
Atul Kumar,* Maneesh Kumar Gupta and Mukesh Kumar
Received 18th October 2011, Accepted 19th October 2011
DOI: 10.1039/c1gc16297g
An efficient L-proline catalyzed one-pot synthesis of 3amino-alkylated indoles has been developed via a threecomponent Mannich-type reaction viz. secondary amines,
aldehyde and indoles under solvent-free conditions at room
temperature. Several amino acids (acidic, basic and neutral)
have been screened for the reaction but the best results were
obtained with L-proline.
Multicomponent reactions1 (MCRs) have gained much attention in synthetic organic chemistry due to their advantages
of intrinsic atom-economy, simpler procedures, structural diversity, energy savings and reduced waste. Due to the potential importance of multicomponent reactions (MCRs), highly
functionalized organic molecules can be synthesized to serve as
pharmacologically important heterocyclic precursors.2
There are many MCRs, such as the Mannich reaction,3 Biginelli reaction,4 Passerini reaction,5 Ugi reaction,6 and Hantzsch
reaction.7 From this list, the Mannich reaction is a particularly
powerful synthetic method for the synthesis of various novel
nitrogen containing biologically active organic molecules.
Small organic molecules like amino acids and cinchona
alkaloids8 have shown promising and highly efficient catalytic
activities for multi-component reactions. However, among all the
various organocatalysts, L-proline9 is one of the most versatile
organocatalysts for carbon–carbon bond formation.
Recently, there has been an increasing interest in the development of clean technologies to replace hazardous organic solvents
with relatively environmental benign solvents. Nowadays “green
chemistry” emphasises the optimization of synthetic methodologies to reduce pollution, cost and tedious work-ups. This new
challenge has led to a growing interest in the field of organic
synthesis under solvent-free conditions10 as well as reactions
preformed in water.11
3-Substituted indole12 moieties are of much importance
because they exist in many natural products. It is also considered
as a venerable pharmacophore and has a wide range of biological
applications e.g. aromatase inhibitor for breast cancer 1,13 HIV-1
Medicinal and Process Chemistry Division, Central Drug Research
Institute, CSIR, Lucknow, India. E-mail: [email protected];
Fax: 91-522-26234051; Tel: 91-522-2612411
† Electronic supplementary information (ESI) available: See DOI:
10.1039/c1gc16297g
290 | Green Chem., 2012, 14, 290–295
integrase inhibitor 2,14 Ergine 3, Gramine 4, and Sumatriptan 5
(Fig. 1).
Fig. 1
Some biologically active 3-substituted indoles.
In 1996, Nikolaus Risch et al. had synthesised 3-aminoalkylated indoles15 using the iminium salt of the aromatic
aldehyde and indole. Kobayashi et al. reported the synthesis
of 3-substituted indole derivatives using AFC (aza-Friedel–
Crafts) reactions, using only o-anisidine, therefore showing that
it has a substrate limitation (Scheme 1).16 Our strategy for
Scheme 1 Synthesis of the 3-amino-alkylated indole, (A) using iminium
salt, (B) catalysed by decanoic acid.
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the synthesis of 3-amino-alkylated indoles involves a threecomponent Mannich-type reaction17 by using L-proline as an
organocatalyst under solvent-free conditions.
Our preliminary work was on the organocatalysis and
MCRs for the synthesis of various biologically important heterocyclic compounds,18 following on from this we
wish to report the first organocatalysed solvent-free procedure for the preparation of 3-amino-alkylated indole derivatives via a one-pot three-component Mannich-type reaction
(Scheme 2).
Scheme 2 Synthesis of 3-amino-alkylated indole 10 catalyzed by Lproline under solvent-free conditions.
Our initial efforts were focused on finding an efficient catalyst
for the three-component Mannich-type reaction of indoles with
secondary amines and aromatic aldehydes. In order to screen the
catalysts, the reaction of the indole, benzaldehyde, and pyrrolidine was taken as a model reaction with p-toluenesulfonic acid
(PTSA) as a Brønsted acid catalyst in acetonitrile. Unfortunately
we obtained bis-indole 9 in major yield. Thus we tested several
other Brønsted acids (acetic acid, methane sulfonic acid and
trifluoroacetic acid (TFA)) for this multi-component synthesis.
However, all these Brønsted acids gave only bis-indole 9 in major
amount. As Brønsted acids failed to give us the desired product
we used metal Lewis acids. Several metal Lewis acids (Table 1)
were screened to synthesize the Mannich product 10a. None of
the Lewis acids tested gave the 3-amino-alkylated indole. The
use of silica supported acids viz. SiO2 -Cl, HClO4 –SiO2 were
also found to be inefficient to yield the desired compound 10a
(Table 1).
We then turned our attention towards amino acid organocatalysts due to their inexpensiveness and recyclability for various
organic reactions. In order to elaborate our study, various amino
acids (acidic, basic and neutral) were screened for the Mannichtype reaction using benzaldehyde, indole and pyrrolidine in
acetonitrile, the obtained results are summarized in Table 1.
Basic amino acids like L-lysine and L-histidine were found
ineffective to form either of the products (9, 10a). Whereas, acidic
amino acids (L-glutamic acid and L-aspartic acid) were found to
be a poor catalyst for the reaction. The desired product 10a was
obtained in a moderate yield when L-proline was used as the
organocatalyst with no formation of bisindole 9 (Table 1, entry
25). However, the available proline derivatives like L-thiaproline
(Table 1, entry 20) and trans-4-hydroxy-L-proline (Table 1, entry
21) were not found equally effective as proline and cause lower
yields.
This journal is © The Royal Society of Chemistry 2012
Table 1
Effect of catalyst on synthesis of amino-alkylated indolea , 19
Entry
Catalystb
Yield of
9 (%)c
Yield of
10a (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
20
21
22
23
24
25
26
27
28
29
TsOHd
Acetic acidd
MSAd
TFAd
CuBrd
Copper(II) triflated
Zinc(II) triflated
Iron(III) chlorided
ZrCl4 d
NiCl4 d
Zinc acetated
Copper(II) sulfated
SiO2 –Cld
HClO4 –SiO2 d
L-Lysinee
L-Histidinee
L-Glutamic acide
L-Asparatic acide
L-Thiaprolinee
trans-4-Hydroxy-L-prolinee
N-Methyl prolinee
N-Benzyl proline methyl estere
N-Methyl proline methyl estere
L-prolinee
L-prolinee f
L-prolinee g
L-prolinee h
L-prolinee i
60
62
56
68
69
65
70
55
90
60
60
65
85
87
—
—
25
40
—
—
30
—
—
—
—
—
—
—
12
13
12
10
—
—
—
—
—
—
—
—
Trace
Trace
—
—
14
18
38
40
—
—
—
51
60
67
46
67
a
The reaction was conducted with benzaldehyde (1 mmol), indole
(1 mmol), and pyrrolidine (1 mmol). b 10 mol% catalyst in acetonitrile
(2 ml). c Isolated yield. d Reaction time of 1 h. e Reaction time of 38 h.
f
20 mol% catalyst in acetonitrile (2 ml). g 30 mol% catalyst in acetonitrile
(2 ml). h 5 mol% catalyst in acetonitrile (2 ml). i 40 mol% catalyst in
acetonitrile (2 ml).
The advantage of using amino acids as organocatalysts
is their amphoteric nature, possessing both amine and acid
functionalities. The amino group could catalyze the reaction
via electrophilic imine formation and the carboxylic group
might stabilize the charge generated on the nitrogen. When Nmethyl proline was used in the reaction ,the desired product
(10a) was not obtained, likewise N-benzyl proline methyl ester
and N-methyl proline methyl ester were both found to be
unable to catalyse the reaction in the way desired and yielded
none of the products. These results indicate that the reaction
may be involving the formation of an imine intermediate (13).
Therefore, L-proline was found to be the best organocatalyst for
the Mannich-type reaction between benzaldehyde, indole and
pyrrolidine to afford the desired product 10a with no traces of
the bis-indole 9 (Table 1).
In order to optimize the amount of L-proline used for the
catalysis of the reaction to form the desired Mannich product
10a, we analyzed the reaction by varying the loading amount to
5, 10, 20, 30 and 40 mol% of L-proline. The optimum loading
amount of L-proline turns out to be 30 mol% in order to
obtain the best result, as no such significant improvement in
the yield was observed on increasing the loading to 40 mol%.
Whereas, decreasing the amount of L-proline to 5 mol% resulted
in lowering of the yield. The results of this study are summarized
in Table 1.
Green Chem., 2012, 14, 290–295 | 291
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Table 2 Effect of solvents on the synthesis of 3-amino alkyl indole
derivativesa , 19
Entry
Solvents
Time (h)b
Yield of 10a (%)c
1
2
3
4
5
9
10
11
12
13
14
15
MeOH
EtOH
iso-Propanol
DCM
THF
MeTHF
Benzene
Toluene
ACN
DMF
DMSO
Solvent free
48
48
48
48
48
48
62
62
38
38
38
5.5
28
28
23
Trace
Trace
Trace
Trace
Trace
67
55
72
87
a
The reaction was conducted with benzaldehyde(1 mmol), indole (1
mmol), and pyrrolidine (1 mmol) with 30 mol% L-proline catalyst.
b
Reaction time. c Isolated yield.
In order to study the solvent effect on the reaction of
benzaldehyde, indole and pyrrolidine catalysed by L-proline, we
carried out the reaction in different solvents. When the reaction
was performed in MeOH, EtOH, iso-propanol and acetonitrile,
lower yields of the Mannich product (10a) were obtained.
Whereas in DCM, THF, MeTHF, benzene and toluene, only
trace amounts of the Mannich product (10a) was formed. The
best result was obtained in DMSO in comparison to DMF.
Surprisingly however, when the reaction is carried out under
solvent-free conditions, both the yield and reaction time were
significantly improved. The results of this study are shown in
Table 2.
Under these optimized reaction conditions a number of
Mannich products were synthesized and the results obtained are
represented in Table 3. The reaction of N-alkylated indoles (Nmethyl indole and N-benzyl indole) were also considered during
the study. It was observed that the N-alkylated indole took
longer to form the respective products (10o, 10p) in comparison
to indole. However, other derivatives of indole easily form the respective Mannich products under the same reaction conditions.
Unfortunately, the result obtained in the case of aliphatic aldehyde was not as competent as in the case of the aromatic aldehyde
(Table 3).
MacMillan and co-workers20 have reported a Diels–Alder
cycloaddition reaction via the formation of an iminium ion21
(with a chiral secondary amine). They suggested that the LUMO
orbital of the iminium species is lower in energy. Keeping this
fact in mind, we hypothesized the mechanism of our reaction as
shown in Scheme 3. The reaction commences with the formation
of an imine intermediate from benzaldehyde with either proline
(11) or pyrrolidine (8). The formation of 12 may destabilized
by water molecules generated, whereas the imine intermediate
(13) with proline gets stabilized by the carboxylic acid group.
Thus favouring the nucleophilic addition of indole from C3 to
form the intermediate 14, which is susceptible towards nucleophilic attack of the pyrrolidine which then yields the desired
product (10).
The results were further supported by a computational study
(optimization of the structures was performed using RHF 3292 | Green Chem., 2012, 14, 290–295
Scheme 3 L-Proline catalyzed multicomponent synthesis of the 3amino-alkylated indole 10.
21G). The calculated LUMO (acceptor) and HOMO (donor)
energy gaps were found to be lower in the case of intermediate
13 than that of 12 which corroborates with the LUMO lowering
activation phenomenon22 (Fig. 2).
Fig. 2 LUMO–HOMO gap between donor and acceptor. Blue color
represents LUMO of intermediate and brown color represent HOMO
of donor.
In conclusion, we have developed a green and efficient
organocatalysed multicomponent reaction of aldehydes, secondary amines, and indoles for the synthesis of 3-aminoalkylated indole derivatives under solvent-free conditions. LProline is a very useful organocatalyst and forms imine intermediates through which the reaction proceeded in a more
favourable manner. The advantage of our presented methodology is improved conditions for the synthesis of 3-aminoalkylated indole derivatives without the formation of bisindole.
Experimental
General experimental procedure for synthesis of compounds
(10)
In a typical experiment, the aldehyde (1 mmol), secondary
amine (1 mmol), indole (1 mmol) and L-proline (30 mol%) were
placed in a 25 ml round-bottom flask. The reaction mixture
was stirred at room temperature until the reaction was complete
(monitored by TLC). After completion the reaction mixture
was diluted with water and extracted with ethyl acetate, dried
over sodium sulphate and evaporated under vacuum to give
the crude product, which was purified by silica gel (230–400
mesh) column chromatography to afford the corresponding
product.
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Table 3
catalysed synthesis of 3-amino-alkylated indole derivativesa , 19
Time (h)
Yieldc (%)
1
5.5
87
2
5.0
85
3
7.5
86
4
5.0
84
5
6.0
86
6
7.5
81
7
6.5
79
8
5.5
85
9
5.5
89
10
5.0
78
Entry
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L-Proline
Indole
Aldehyde
Secondary amine
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Productb (10)
Green Chem., 2012, 14, 290–295 | 293
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Table 3 (Contd.)
Time (h)
Yieldc (%)
11
5.0
79
12
5.5
84
13
5.0
81
14
18
68
14
8.5
84
15
8.5
84
16
5.0
86
17
5.0
81
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Entry
Indole
Aldehyde
Secondary amine
Productb (10)
a
The reaction was conducted with benzaldehyde (1 mmol), indole (1 mmol), secondary amine (1 mmol) and L-proline (30 mol%), solvent-free
conditions for the specified number of hours. b All products were characterized by 1 H and 13 C NMR, IR and mass spectroscopy. c Isolated yield. d 4
Å MS (50 mg) was added.
Acknowledgements
M. K. G. and M. K. acknowledge the CSIR-UGC, New Delhi
for the award of a SRF. We are thankful to Mr R. K. Purshottam
for providing the HPLC data. The authors also acknowledge the
SAIF-CDRI for providing spectral and analytical data. CDRI
communication No. 8150.
294 | Green Chem., 2012, 14, 290–295
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