Micelle promoted multicomponent synthesis of 3-amino alkylated indoles via a Mannich-type reaction in water

Article abstract of DOI:10.1039/c2ra22428c

An efficient micelle promoted one-pot synthesis of 3-amino alkylated indoles has been developed via a three-component Mannich-type reaction from secondary amines, aldehydes and indoles in water under mild reaction conditions. In this Mannich-type reaction

Full text of DOI:10.1039/c2ra22428c

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Micelle promoted multicomponent synthesis of
3-amino alkylated indoles via a Mannich-type reaction
in water3
Cite this: RSC Advances, 2013, 3, 1673
Received 22nd July 2012,
Accepted 29th November 2012
Atul Kumar,* Maneesh Kumar Gupta, Mukesh Kumar and Deepti Saxena
DOI: 10.1039/c2ra22428c
www.rsc.org/advances
distributed in many important natural products.11 Besides, this
An efficient micelle promoted one-pot synthesis of 3-amino
alkylated indoles has been developed via a three-component
Mannich-type reaction from secondary amines, aldehydes and
indoles in water under mild reaction conditions. In this Mannich-
type reaction, micelles stabilize iminium ions, which undergo a
nucleophilic addition of the indole to give 3-amino alkylated
indoles in very good yields.
3-substituted indole is also an important class of pharmacophores
having many biological activities i.e. Sumatriptan, Frovatriptan,
Zolmitriptan and Rizatriptan are used for migraine headaches,12
whereas azolylbenzyl indole and bis-indole are used as a breast
cancer and HIV-1 integrase inhibitor, respectively (Fig. 1).13,14
In 1996, Risch et al. reported the synthesis of 3-amino alkylated
indole15 by the use of the iminium salt of a secondary aliphatic
amine and aromatic aldehyde with indole. Recently, a wide array
of catalysts, including ionic liquids,16 trichloro-1,3,5-triazine
(TCT),17 solid supported acid (PMA–SiO2),18 decanoic acid19 as
well as organocatalysts20 have been employed to synthesize
3-amino alkylated indole. These previous reports have a limited
scope of substrates. Our strategy is to find an eco-friendly synthetic
route of 3-amino alkylated indole via iminium formation in
organized aqueous media.
Although nature uses water for biological chemistry, as a solvent it
was generally avoided in synthetic chemistry until the end of the
last century. In the early 1980s, Breslow and Rideout1 exposed a
new pathway for green synthesis by performing Diels–Alder
reactions ‘in water’. Since then, significant progress has been
made in describing reactions ‘in water’ by Sharpless2 et al.
Recently, multicomponent reactions (MCRs)3 have played a
significant role in modern synthetic organic chemistry wherein at
least three or more reactants are added together in one pot to yield
diverse bioactive heterocyclic compounds. Nowadays, multicom-
ponent reactions with environmentally benign processes are of
emerging interest and have been successively achieved by
reactions proceeded in water4, ionic liquids5 or under solvent-
free conditions.6
Our preliminary work was on multicomponent reactions
(MCRs) for the synthesis of various biologically active heterocyclic
compounds,21 following on from this we wish to report a highly
efficient green procedure for the synthesis of 3-amino alkylated
indole derivatives via a one-pot three-component Mannich-type
reaction using SDS as a surfactant in water (Scheme 1).
Initially, we investigated the three-component Mannich-type
reaction of indole, piperidine and benzaldehyde in the presence of
boric acid in dioxane as a solvent. Unfortunately, the reaction did
not proceed according to our expectations and bis-indole (6) was
Because of the insolubility of organic substrates in water,
surfactants were usually added to the reaction mixture, which
solubilizes organic materials via micelle formation.7 Kobayashi
et al. found that in the presence of a catalytic amount of
surfactants, Aldol, Mannich, Michael, and esterification reactions
are successfully conducted in water.8 Deng et al. performed
asymmetric transfer hydrogenation (ATH) of ketones in aqueous
media containing micelles formed by the surfactant cetyltrimethy-
lammonium bromide (CTAB).9
The indole nucleus10 is an important structural unit that is
present in a number of drugs currently on the market. Most of
these belong to the 3-substituted indole family, which is an
important intermediate for chemical synthesis and widely
Medicinal and Process Chemistry Division, CSIR – Central Drug Research Institute,
Lucknow, India. E-mail: dratulsax@gmail.com; Fax: 91-522-26234051;
Tel: 91-522-2612411
Fig. 1 Some biologically active 3-substituted indoles.
Electronic supplementary information (ESI) available. See DOI: 10.1039/c2ra22428c
3
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SDS. Whereas on decreasing the amount of SDS from 20 to 5
mol% the product formation was not adequate (Table 1).
In order to study the effect of the surfactant, the reaction of
benzaldehyde, indole, and piperidine was performed in water
using various types of surfactant (ionic and non-ionic). Non-ionic
surfactants (Tween-20, Tween-80, Triton X-100, and Triton CF-10)
were found to be ineffective and gave a poor yield of the desired
product (4a). This is due to the lowering of the critical micelle
concentration (CMC) at higher temperatures. A Brønsted acid
surfactant (p-dodecylbenzenesulfonic acid) and a Lewis acid
surfactant (scandium tris-(dodecyl sulfate)) were also screened
but they provided bis-indole (6) with a poor yield of the desired
product. Whereas, when the reaction was carried out in the
absence of a surfactant, only bis-indole was formed with a low
yield even after 24 h. The desired product (4a) was also formed in a
poor yield when CTAB, tetra-n-butylammonium bromide (TBAB)
and tetra-n-butylammonium fluoride (TBAF) were used as
surfactants. Thus, the anionic surfactant SDS was found to be
the best surfactant for the synthesis of 3-amino alkylated
derivatives in water; this might be due to the formation of
hydrogen bonds with the indolic NH, which accelerates the
reaction. The results of this study are shown in Table 2.
Scheme 1 Synthesis of 3-amino alkylated indole catalyzed by SDS in water.
formed as a major compound. Therefore, we screened various
catalysts for the synthesis of 3-amino alkylated indole.
p-Toluenesulfonic acid (PTSA) and methane sulfonic acid (MSA)
did not afford the desired product (4a) in good yields. The use of
silica supported acids (SiO2–Cl, HClO4–SiO2) and solid supported
Brønsted acids (CellSA, StarSA) did not form the desired product
(4a) and only bis-indole was obtained along with a trace amount of
3-amino alkylated indole. All the non-metal/metal Lewis acids
(BF3?Et2O, CuSO4, FeCl3, ZrCl4, FeSO4) used in this reaction gave
only bis-indole. Whereas, when the reaction was carried out in
Under these optimized reaction conditions, the generality of
this procedure has been examined. Various 3-amino alkylated
indole derivatives were synthesized and the results of this study
are summarized in Table 3. All the indole derivatives showed equal
ease towards the product formation with the aldehyde and
secondary amine, except N-substituted indoles (N-methyl indole,
and N-benzyl indole). They required a longer reaction time than
other indoles. The reactions with aliphatic aldehydes (Table 3,
entries 22 and 23) required a longer time in comparison to
aromatic aldehydes for the formation of the corresponding
Mannich products under similar reaction conditions. It is
noteworthy that 2-amino alkylated indole derivatives were
obtained only with benzaldehyde, indole and cyclic/acyclic
secondary aliphatic amines in minor amounts (Table 3, entries
1, 5 and 7).
water and SDS (sodium dodecyl sulfate) as
a surfactant,
surprisingly we obtained the 3-amino alkylated indole in a major
amount, along with a minor amount of the 2-amino alkylated
indole (5a), without forming the bis-indole (6) but it required
considerably more time. This result encouraged us to optimize the
reaction conditions to improve the yield of the desired product. It
was observed that on heating the reaction mixture at 80 uC with a
higher amount of SDS, both the yield and the reaction time were
improved (Table 1). The best result was obtained with 20 mol%
Table 1 Effect of catalyst on the synthesis of 3-amino alkylated indolea
Entry
Catalystb
Time (h)
Yield of 6 (%)c
Yield of 4a (%)c
Kobayashi and co-workers reported a plausible mechanism for
the direct esterification of carboxylic acids with alcohols using a
1
2
3
3
4
5
6
7
Boric acid
TsOH
MSA
SiO2–Cl
HClO4–SiO2
CellSA
StarSA
BF3?Et2O
CuSO4
FeCl3
ZrCl4
FeSO4
SDS
SDS
SDS
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.5
1.0
1.0
1.0
1.0
24
59
60
62
56
68
74
72
68
72
60
88
64
—
—
—
—
—
10
12
13
trace
trace
10
10
15
—
—
—
—
Table 2 Effect of surfactant on synthesis of 3-amino alkylated indole derivativea
Entry
Catalyst
Time (h)
Yield of 4a/5a (%)b
8
9
1
2
3
4
5
6
7
8
SDS
2.0
8.0
8.0
8.0
8.0
6.0
6.0
4.5
4.5
4.5
24
80/12
10
11
12
13
14
15
16
Tween-20
Tween-80
Triton X-100
Triton CF-10
DBSA
Sc(DS)3
CTAB
TBAB
TBAF
—
47/trace
50/trace
53/trace
50/trace
45c
46
5d
67h
55h
71h
80i
6d,e
3d,f
2d,g
SDS
SDS
39c
51c/trace
53c/trace
52c/trace
9
10
11
a
The reaction was conducted with benzaldehyde (1 mmol), indole (1
b
c
mmol) and piperidine (1.2 mmol). 10 mol% catalyst in dioxane (2
mL) at room temperature. Isolated yield. Reaction was conducted
at 80 uC in water. 5 mol% catalyst. 15 mol% catalyst. 20 mol%
catalyst. Trace amount of 2-amino alkylated indole. 12% 2-amino
alkylated indole was formed.
—
c
d
e
f
g
a
The reaction was conducted with benzaldehyde (1 mmol), indole (1
mmol) and piperidine (1.2 mmol) with 20 mol% catalyst in water (2
h
i
b
c
mL) at 80 uC. Isolated yield. Bis-indole was also formed.
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Table 3 SDS catalyzed synthesis of 3-amino alkylated indole derivatives in watera
Entry
1
Indole
Aldehyde
Amine
Productb (4)
Time (h)
2.0
Yieldc (%)
80
f
2
3
4
3.5
2.0
2.5
80
78
82
e
5
6
2.0
2.0
78
85
f
7
8
2.5
5.5
79
85
f
d
9
12.0
12.0
81
83
d
10
11
12
14.5
3.5
81
94
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Table 3 (Continued)
Entry
13
Indole
Aldehyde
Amine
Productb (4)
Time (h)
2.0
Yieldc (%)
86
e
14
15
16
2.5
3.0
4.0
89
87
92
17
18
3.5
4.5
90
82
19
20
2.5
2.5
86
85
21
10.5
81
22
23
8.0
8.0
83
81
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Table 3 (Continued)
Entry
24
Indole
Aldehyde
Amine
Productb (4)
Time (h)
3.5
Yieldc (%)
93
25
3.5
91
a
The reaction was conducted with aldehyde (1 mmol), indole (1 mmol), secondary amine (1.2 mmol) and SDS (20 mol%) in water (2 mL) at
80 uC temperature for a given time. All products were characterized by 1H, 13C NMR, IR and mass spectroscopy. Isolated yield. 2 mmol
amine was used. Bis-indole was also formed. 2-Amino alkylated indole was formed (10–15% yield).
b
c
d
e
f
surfactant-type Brønsted acid-catalyst in water.8d Keeping this fact
in mind, we hypothesized the mechanism of the dehydration
reaction as shown in Scheme 2. The reaction starts with the
formation of the imine intermediate 7 by the condensation of the
aldehyde and secondary amine. This dehydrated imine is
stabilized by the micelle and the generated water molecule is
expelled from the intermicellar environment due to its hydro-
phobic nature.22 N-Alkylated indoles required a longer reaction
time to form the respective products in comparison to other
derivatives of indole under the optimized reaction conditions
(Table 1, entries 9, 10, 11 and 21). This might be explained on the
basis of the formation of hydrogen bonds between the indolic NH
and SO3O2 groups of SDS, which increases the electron density at
the C3 position of the indole, favoring nucleophilic addition to
form the intermediate 8. In the subsequent step aromatization
gives the desired 3-amino alkylated indole derivatives (4a–y).
The obtained results were further supported by a computa-
tional study. The molecular volume of the imine intermediate (7)
was # 170 Å3 (as calculated by Discovery Studio 2.0). Whereas,
Berkowitz et al.23 reported the hydrodynamic radii of the micelle
(SDS) to be about 22.0 Å (volume # 44 620 Å3), which indicates
that the imine intermediate is small enough that it could easily
enter the hydrophobic intermicellar core of SDS micelles.
Conclusions
In summary, we have demonstrated a highly efficient, rapid and
green method for the synthesis of 3-amino alkylated indoles via a
Mannich-type reaction of aromatic/heteroaromatic aldehydes,
secondary amine/N-alkylanilines and indoles in water. The
beneficial aspects of this procedure are a high yield, operational
simplicity, eco-friendliness and very mild reaction conditions for
the synthesis of 3-amino alkylated indole derivatives. We plan to
continue exploring the scope and synthetic applications of the
stabilized imine intermediate in water by surfactants in our
laboratory.
Experimental
Typical experimental procedure for the synthesis of 4
In a typical experiment, the aldehyde (1 mmol), secondary amine
(1.2 mmol) and SDS (20 mol%) were taken in water (2 mL) in a
round-bottom flask and stirred at 80 uC temperature for 5 min. A
white turbid mixture was obtained and then indole (1 mmol) was
added. The reaction mixture was stirred until completion of the
reaction (monitored by TLC). After completion of the reaction, the
mixture was 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 with hexane–ethyl acetate (2 : 3) as the eluent
to afford the corresponding product.
Acknowledgements
The authors (MK, MKG and DS) are thankful to CSIR-UGC New
Delhi for the award of a senior research fellowship. We also
gratefully acknowledge SAIF, CDRI for providing analytical
Scheme 2 Micelle-promoted three-component synthesis of 3-amino alkylated
indole in water.
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