Bromodimethylsulfonium bromide (BDMS)-catalyzed multicomponent synthesis of 3-aminoalkylated indoles

Article abstract of DOI:10.1016/j.tetlet.2010.08.065

Bromodimethylsulfonium bromide (BDMS)-catalyzed three-component coupling reaction between indoles, aldehydes, and N-alkylanilines is reported to access substituted 3-aminoalkylated indoles at room temperature in high yields (82-96%) within 1.5-3.5 h. The

Full text of DOI:10.1016/j.tetlet.2010.08.065

Tetrahedron Letters 51 (2010) 5701–5703
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bromodimethylsulfonium bromide (BDMS)-catalyzed multicomponent
synthesis of 3-aminoalkylated indoles
Deepak K. Yadav a, Rajesh Patel b, Vishnu P. Srivastava b, Geeta Watal a, Lal Dhar S. Yadav b,
⇑
a Alternative Therapeutics Unit, Drug Development Division, Medicinal Research Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
b Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Bromodimethylsulfonium bromide (BDMS)-catalyzed three-component coupling reaction between
indoles, aldehydes, and N-alkylanilines is reported to access substituted 3-aminoalkylated indoles at
room temperature in high yields (82–96%) within 1.5–3.5 h. The salient features of this protocol are
the simplicity of the procedure, the ready accessibility of the catalyst, its cost effectiveness, and higher
yields in relatively short reaction times.
Received 15 July 2010
Revised 18 August 2010
Accepted 20 August 2010
Available online 24 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Bromodimethylsulfonium bromide (BDMS)
3-Substituted indoles
Multicomponent reaction
Catalytic process
N-Alkylanilines
Multicomponent reactions (MCRs) are of increasing importance
in organic and medicinal chemistry, as high degrees of molecular
diversity can be introduced by these reactions in a very fast, effi-
cient, and time saving manner without the isolation of any inter-
mediates.1 As a result, considerable attention has been paid to
the development of new and improved one-pot multicomponent
reactions in recent years.2 Besides this, the utility of MCRs is well
represented in the synthesis of privileged medicinal scaffolds such
as 1,4-dihydropyridines, dihydropyrimidines, decahydroquinolin-
4-ones, and substituted indoles.3,4
3-Substituted indole moieties are of much importance as they are
widely distributed in nature and reveal a broad range of biological
activities.5 Indoles with aminoalkyl/aryl substituents at the 3-posi-
tion are considered as venerable pharmacophores6 in drug discovery
and are found in various natural products7 such as 5-HT1B/1D with
receptor agonist activities used in the treatment of migraine, aroma-
tase inhibitor for breast cancer,8 and HIV-1 integrase inhibitors9
Gramine, Ergine, and Sumatriptant. The immense potential of indole
nucleus as drug candidates prompted among the synthetic chemists
to explore different methods suitable for the synthesis of 3-substi-
tuted indoles.
the development of clean and efficient methodologies for the prep-
aration of these derivatives through a convenient and environmen-
tally friendly method. Herein, we report a convenient method for
the synthesis of 3-aminoalkylated indoles via rapid three-compo-
nent coupling reaction between indoles, aldehydes, and N-alkylan-
ilines using bromodimethylsulfonium bromide (BDMS) as
catalyst as shown in Scheme 1.
a
Bromodimethylsulfonium bromide (BDMS),11 a commercially
available light orange solid compound, has gained considerable
interest in organic synthesis after the discovery by Meerwein11c
due to its easy handling, low cost, as well as its easy access, and
varied applications both as a catalyst12 and as an effective re-
agent.13 In continuation of our recent work on the development
of useful new synthetic methodologies using bromodimethylsulfo-
nium bromide (BDMS)14 we observed that the treatment of indoles
with aldehydes and N-alkylanilines at room temperature in the
presence of BDMS in ethanol afforded the corresponding 3-amin-
oalkylated indoles 1 (Scheme 1).
Initially, we investigated the multicomponent reaction of benz-
aldehyde, aniline, and indole in the presence of BDMS (10 mol %) as
a catalyst. Unfortunately, the reaction did not proceed according to
expectations. However, we were delighted to find that the reaction
proceeded well when aniline was replaced with N-methylaniline.
In the screening of different solvents to find the most suitable sol-
vent for this transformation, ethanol was found to be superior to
other solvents such as acetonitrile, THF, 1,4-dioxane, and DCM in
terms of both reaction times and yields obtained (Table 1, entries
1–5). Attempts were also made to study this protocol with Lewis
Despite several methods available in the literature for the syn-
thesis of substituted indoles,10 there are only a few reports on the
access of substituted 3-aminoalkylated indoles using MCR proto-
cols.10d,i–l It is thus evident that there remains a wide scope for
⇑
Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533.
E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.065

5702
D. K. Yadav et al. / Tetrahedron Letters 51 (2010) 5701–5703
Br
NHR3
R2
Br
S
R1
R1
BDMS
N
R3
R2CHO
EtOH, r t, 1.5-3.5 h
N
N
H
H
1
Scheme 1. Synthesis of 3-aminoalkylated indoles 1.
Table 1
trated with respect to different indoles, aldehydes, and N-alkylani-
lines and the results are summarized in Table 2.15 The conversion
was completed within 1.5–3.5 h and the product was formed in high
yields 82–96%. 1H-Indole, 5-bromo-1H-indole, and 5-methoxy-1H-
indole were employed as the indole derivatives, different aldehydes,
including aromatic aldehydes with electron-donating and electron-
withdrawing groups, and different N-alkylanilines such as
N-methyl-, N-ethyl-, and N-propylanilines, afforded the desired
products in high yields. N-Alkylanilines were used in excess to avoid
the formation of bis(indolyl)alkanes. Various functional groups such
as halogen, hydroxy, ether, and nitro groups remain intact. All the
products were characterized by 1H NMR, 13C NMR, IR, and mass
spectroscopy.
Optimization conditions for condensation of N-methylaniline, benzaldehyde, and
indolea
Entry
Solventb
Catalyst (mol %)
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
9
EtOH
CH3CN
THF
1,4-Dioxane
DCM
EtOH
EtOH
EtOH
EtOH
[Hmim]HSO4
BDMS (10)
BDMS (10)
BDMS (10)
BDMS (10)
BDMS (10)
BDMS (20)
BDMS (5)
Boric acid (10)
InCl3 (10)
—
2.5
4
4
4
4
2.5
4
2.5
2.5
2.5
96
90
40
40
50
96
80
20d
24d
12d
10
a
All reactions were performed using aldehyde 1 mmol, N-methylaniline, 2 mmol
A
plausible mechanism for BDMS-catalyzed formation of
and indole 1 mmol. For experimental details, see Ref. 15.
3-aminoalkylated indoles 1 is depicted in Scheme 2. N-alkylanilines
react with aldehydes in the presence of BDMS to form an iminium
ion intermediate along with Me2SO. Iminium ion intermediate is
then attacked by an electron rich indole to afford 3-aminoalkylated
indoles 1 (Scheme 2) with elimination of HBr. The reaction between
Me2SO and HBr then regenerates BDMS to complete the catalytic
cycle.
In summary, we have demonstrated the efficacy and generality
of bromodimethylsulfonium bromide (BDMS) as a versatile cata-
lyst for the synthesis of 3-aminoalkylated indoles via an efficient
and rapid three-component coupling reaction between indoles,
aldehydes, and N-alkylanilines at room temperature. The salient
features of the present protocol are the simplicity of the procedure,
the ready accessibility of the catalyst, and its cost effectiveness,
higher yields in relatively short reaction times. Thus, this atom–
b
1.0 mL was used.
Yields are related to isolated pure products.
Bis(indolyl)methane is the major product.
c
d
acids such as InCl3, boric acid (10 mol % each), and protic ionic
liquid [Hmim]HSO4-both as solvent and catalyst, but bis(indo-
lyl)methane was obtained as the major product (Table 1, entries
8–10).
The best catalytic activity of BDMS was optimized to be 10 mol %
(Table 1, entry 1) and any excess catalyst, beyond this proportion
(10 mol %), did not show further increase in the conversion and yield
of the product (Table 1, entry 6) while decreasing the amount of
catalyst from 10 to 5 mol % lowered the substrate conversion rate
(Table 1, entry 7). The scope and generality of this method is illus-
Table 2
BDMS-catalyzed multicomponent route to access substituted 3-aminoalkylated indoles 1a
Br
NHR3
R2
Br
S
R1
R1
BDMS
N
R3
R2CHO
EtOH, r t, 1.5-3.5 h
N
N
H
H
1
Entry
R1
R2
R3
Productb
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H
H
H
H
H
H
OMe
OMe
Br
Br
H
H
H
H
C6H5
4-ClC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
2.5
2.0
3.0
2.0
1.5
2.5
2.0
1.5
3.0
2.0
3.5
2.0
3.5
3.0
96
89
84
86
94
86
91
94
85
88
82
89
85
84
4-MeOC6H4
4-MeC6H4
4-O2NC6H4
C6H11
4-MeC6H4
4-ClC6H4
4-MeOC6H4
4-O2NC6H4
3,4-(MeO)2C6H3
4-O2NC6H4
3,4-(MeO)2C6H3
4-HOC6H4
Et
Pr
Pr
a
b
c
See Ref. 15 for general procedure.
All the products are known compounds10d,i and were characterized by comparison of their mp and spectral data with those of authentic samples.
Yields of pure isolated products after column chromatography.

D. K. Yadav et al. / Tetrahedron Letters 51 (2010) 5701–5703
5703
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N
H
1
Scheme 2. Plausible mechanistic illustration of BDMS-catalyzed formation of 3-
aminoalkylated indoles 1.
economic methodology would be a practical alternative to the
existing protocols for the synthesis of such kind of fine chemicals.
Acknowledgment
The authors are thankful to SAIF, Punjab University, Chandigarh,
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15. General procedure for the synthesis of 3-aminoalkylated indoles: A mixture of
aldehyde (1 mmol), N-alkylaniline (2 mmol) and, bromodimethylsulfonium
bromide (BDMS) (10 mol %) in EtOH (1 mL) was stirred at rt for 30 min
followed by addition of indole (1 mmol) and stirring is continued till the
completion of the reaction as indicated by TLC (Table 2). The reaction mixture
was diluted with water (15 mL) and extracted with ether (4 Â 5 mL). The
combined organic phase was dried over MgSO4, filtered, and evaporated under
reduced pressure. The resulting crude product was purified by column
chromatography (silica gel, hexane–EtOAc) to obtain analytically pure
indoles 1. All the products are known compounds10d,i and were characterized
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