A novel multi-component reaction of indole, formaldehyde, and tertiary aromatic amines

Article abstract of DOI:10.1016/j.tetlet.2009.08.046

A novel multi-component reaction of indoles, formaldehydes, and tertiary aromatic amines is described for the synthesis of dialkylaminoarylated indoles using silica-supported perchloric acid (HClO₄-SiO₂) as an inexpensive and highly efficient catalyst. The key features of this multi-component reactions are operational simplicity, mild reaction conditions, regioselectivity, and recycling of catalyst.

Full text of DOI:10.1016/j.tetlet.2009.08.046

Tetrahedron Letters 50 (2009) 5937–5940
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Tetrahedron Letters
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A novel multi-component reaction of indole, formaldehyde, and tertiary
aromatic amines
*
Atul Kumar , Siddharth Sharma, Ram Awatar Maurya
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel multi-component reaction of indoles, formaldehydes, and tertiary aromatic amines is described
for the synthesis of dialkylaminoarylated indoles using silica-supported perchloric acid (HClO4–SiO2) as
an inexpensive and highly efficient catalyst. The key features of this multi-component reactions are oper-
ational simplicity, mild reaction conditions, regioselectivity, and recycling of catalyst.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 17 June 2009
Revised 12 August 2009
Accepted 14 August 2009
Available online 20 August 2009
Keywords:
Multi-component reaction
Indole
HClO4–SiO2
Multi-component reactions (MCRs) have offered many fascinat-
ing and challenging transformations in organic synthesis.1 The
atom-economy, convergent character, operational simplicity,
structural diversity, and complexity of the molecules are the major
advantages associated with multi-component reactions. Besides
this multi-component reactions are emerging as a powerful tool
in the synthesis of biologically important compounds.2 Thus, the
discovery of novel multi-component reactions is of much impor-
tance. Most of the previously known MCRs were invented by ser-
endipity rather than logically designed multi-component
reactions. Recently, much effort is devoted for rational design of
new multi-component reactions. There are three major ways of
designing new MCRs such as combinatorial chemistry, MCR se-
quences, and smallest atom connectivity.
dates prompted us to design a novel substituted 3-alkyl indole
based on multi-component reactions.
In continuation of our work on MCRs,7 we report here a novel
multi-component reaction of indoles, formaldehydes, and tertiary
aromatic amines for the synthesis of dialkylaminoarylated indoles
using silica-supported perchloric acid as a catalyst (Scheme 1).
Our initial efforts were focused on the search for an efficient
catalyst for the three-component reaction of indoles with formal-
dehydes, and tertiary aromatic amines.8 In order to screen the
H
N
OH
N
F
N
We wish to report here a new multi-component reaction
involving indoles, formaldehydes, and tertiary aromatic amines
for the synthesis of dialkylaminoarylated indoles.
OH
Br
N
C2H5
N
H
Substituted 3-alkyl indole moieties are of much importance as
they are widely distributed in nature and reveal a broad range of
biological activity.3 Indoles with substituents at the 3-position
are considered as venerable pharmacophores4 in drug discovery
as well as found in various ranges of natural products such as
5-HT1B/1D receptor agonist activities used in the treatment of
migraine I, aromatase inhibitor for breast cancer II5 and HIV-1
integrase inhibitor III,6 Gramine IV, Ergine V, and Sumatriptan VI
(Fig. 1). The immense potential of indole nucleus as drug candi-
N
H
I
II
III
O
NH2
N
H
N
N
H
N
H3C
S
N
H
O
O
N
H
N
H
IV
V
VI
* Corresponding author. Tel.: +91 522 2612411; fax: +91 522 26233405.
E-mail address: dratulsax@gmail.com (A. Kumar).
Figure 1. Some biologically active 3-substituted indoles.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.046

5938
A. Kumar et al. / Tetrahedron Letters 50 (2009) 5937–5940
R1
R2
R1
N
N
R1
R1
R1
R1
R3
N
R3
HClO4-SiO2
MeOH
CH2O
R1
N
N
R2
R4
N
R1
R4
(Minor)
6a-6m
(Major)
Scheme 1. Three-component reaction of indoles, formaldehydes, and tertiary aromatic amines.
Table 1
catalysts, the reaction of indole, formaldehyde, and N,N-dimethyl-
aniline was taken as a model reaction. Several Bronsted acids
(hydrochloric acid, sulfuric acid, acetic acid, PTSA, methane sul-
fonic acid, and TFA) were employed for this multi-component syn-
thesis. However all these Bronsted acids gave poor yields of 6a
(Table 3), and 4,40-methylenebis(N,N-dimethylaniline) was formed
as a major product.
Then we turned our attention towards silica-supported acids
(HClO4, H2SO4), which have received considerable attention as
inexpensive and recyclable catalysts for numerous organic trans-
formations.9 HClO4–SiO2 was prepared by the reported procedure
of Chakraborti et al.9a Use of silica-supported perchloric acid as cat-
alyst gave excellent yield (84%) of 6a (Table 3) in methanol. Using
2 mol % of HClO4–SiO2 was sufficient to push the reaction forward,
and further increasing the amount of catalyst did not increase the
yields. While H2SO4–SiO2 afforded 6a as a major product, use of
other catalysts resulted in 7 (Fig. 2) also in considerable yields
(Table 1). A similar reaction with normal silica did not produce
any of the desired products even after 3 days at room temperature.
In addition to the simplicity of the product isolation, the catalyst
can be recycled several times.10 Even after five cycles, the catalyst
did not show any significant change in reactivity. The results of this
study are summarized in Table 1.
Condensation of indole, formaldehyde, and N,N-dimethylaniline under different
catalysts
Entry
Catalyst
Solvent
Time (h)
Yield 6aa (%)
Yield 7a (%)
1
2
3
4
5
6
7
8
9
—
HCl
Acetic acid
Sulfuric acid
PTSA
MSA
TFA
SiO2
H2SO4–SiO2
HClO4–SiO2
—
10
1
1
1
1
—
—
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
11
21
9
23
11
21
—
69
72
79
71
73
56
—
1
1
3b
1
71
84
24
Trace
10
1
a
Isolated yield.
Days
b
Table 2
Solvent effect on the coupling of indole, formaldehyde, and N,N-dimethylanilinea
Entry
Solvent
Yield 6ab (%)
Yield 7b (%)
1
2
3
4
5
EtOH
CH3CN
THF
CHCl3
MeOH
57
29
39
27
84
25
33
34
49
>5
Various solvents such as EtOH (57%), CH3CN (29%), THF (39%),
and CHCl3 (27%) were used to optimize the model reaction. Polar
solvents gave better yields in comparison to non-polar solvents
and best results were obtained with MeOH (84%). The results of
this study are shown in Table 2.
a
Reaction conditions: Indole (1.0 mmol), formaldehyde (1.0 mmol), N,N-
dimethylaniline (1.0 mmol), and HClO4–SiO2 (2 mol %), rt, 1 h.
b
Isolated yield.
H+
CH2O
In order to determine the scope of the reaction, we synthesized
a number of compounds using substituted indoles and tertiary aro-
matic amines using the optimized reaction protocols (Table 3). All
the compounds were well characterized by mass spectrometry,
NMR, and IR spectroscopy.11
N
N
N
H
-H2O
2
1
3
4
The plausible mechanism of the reaction is given in Figure 2.
Tertiary aromatic amine reacts with formaldehyde to generate an
N
N
-H+
H
intermediate
N-methyl-N-(4-methylenecyclohexa-2,5-dienylid-
ene)methanaminium 3, which on addition of indole gave the de-
sired N,N-dialkyl amino arylated indoles. Compound 7 was also
formed by the attack of tertiary aromatic amine 1 on intermediate
3.
N
H
N
H
5
6a
In summary, we have developed a novel three-component reac-
tion of indoles, formaldehydes, and tertiary aromatic amines using
silica- supported perchloric acid as a catalyst. The reaction is oper-
ationally simple and offers high yields of the 3-alkylated indoles.
Further work is in progress at utilizing these molecules for biolog-
ical activity studies.
N
N
N
N
1
3
7
Figure 2. Plausible mechanism of three component reaction.

A. Kumar et al. / Tetrahedron Letters 50 (2009) 5937–5940
5939
Table 3
A novel multi-component reaction of indoles, formaldehydes, and tertiary aromatic aminesa
R1
R2
N
R1
R1
R1
R3
N
HClO4-SiO2
MeOH
R3
CH2O
N
R4
R2
N
R4
6a-6m
S.No.
1
R1
R2
H
R3
H
R4
H
Product
Time (h)
0.5
Yieldb
N
CH3
84
81
82
88
6a
N
H
N
N
2
3
4
C2H5
CH3
CH3
H
H
H
H
H
H
H
0.5
0.5
0.5
6b
N
H
CH3
6c
N
H
N
N
H
6d
N
H
5
6
CH3
H
H
H
H
CH3
1
1
82
84
6e
N
N
N
N
C2H5
CH3
6f
7
8
9
CH3
CH3
CH3
CH3
H
CH3
CH3
H
1
73
68
76
6g
N
N
H
H
1.5
6h
N
N
H
Br
Br
1
6i
N
H
N
10
C2H5
H
Br
H
1
78
Br
6j
N
H
(continued on next page)

5940
A. Kumar et al. / Tetrahedron Letters 50 (2009) 5937–5940
Table 3 (continued)
S.No.
R1
R2
R3
Br
R4
H
Product
Time (h)
Yieldb
82
N
11
12
CH3
CH3
1
Br
6k
N
H
N
N
CH3
H
H
OCH3
OCH3
H
H
H3CO
H3CO
1
1
82
74
6l
N
H
13
C2H5
6m
N
H
a
Reaction conditions: Indole (1.0 mmol), formaldehyde (1.0 mmol), N,N-dialkylaniline (1.0 mmol), and HClO4–SiO2 (2 mol %), MeOH, rt, 0.5–1.5 h.
Isolated yield.
b
7. (a) Kumar, A.; Maurya, R. A. Tetrahedron Lett. 2008, 49, 5471; (b) Kumar, A.;
Maurya, R. A. Tetrahedron 2007, 64, 3477; (c) Kumar, A.; Maurya, R. A.
Tetrahedron Lett. 2007, 48, 4569; (d) Kumar, A.; Maurya, R. A. Tetrahedron Lett.
2007, 48, 3887.
Acknowledgments
S.S. and R.A.M. are thankful to CSIR, New Delhi, for financial
support. The authors also acknowledge SAIF-CDRI for providing
spectral and analytical data. CDRI Communication No. is 7838.
8. General experimental procedure: A mixture of indole (117 mg, 1.0 mmol), N,N-
dimethylaniline (121 mg, 1.0 mmol) and HClO4–SiO2 (2 mol %) was stirred in
MeOH (5 ml) at room temperature for 5 min. Thereafter formaldehyde
(formalin solution) 1.0 mmol, 0.086 ml was added dropwise to the stirred
solution. The reaction was monitored by TLC. The products precipitated from
the reaction mixture. The precipitate was filtered off, dissolved in hot MeOH
and the catalyst was removed by hot filtration. The filtrate was kept at room
temperature and the resulting crystallized product 6a was collected by
filtration and washed with cold EtOH to get 210 mg (84%) of the crystallized
product.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.08.046.
9. (a) Chakraborti, A. K.; Gulhane, R. Chem. Commun. 2003, 1896; (b) Misra, A.;
Tiwari, P.; Agnihotri, G. Synthesis 2005, 260; (c) Kamble, V. T.; Jamode, V. S.;
Joshi, N. S.; Biradar, A. V.; Deshmukh, R. Y. Tetrahedron Lett. 2006, 47, 5573; (d)
Du, Y.; Wei, G.; Cheng, S.; Hue, Y.; Linhardt, R. J. Tetrahedron Lett. 2006, 47, 307;
(e) Khan, A. T.; Choudhury, L. H.; Ghosh, S. J. Mol. Catal. A: Chem. 2006, 255, 230;
(f) Agarwal, A.; Rani, S.; Vankar, Y. D. J. Org. Chem. 2004, 69, 6137; (g) Khan, A.
T.; Parvin, T.; Choudhury, L. H. Synthesis 2006, 15, 2497; (h) Maheswara, M.;
Siddaiah, V.; Rao, Y. K.; Tzeng, Y.-M.; Sridhar, C. J. Mol. Catal. A: Chem. 2006, 260,
179; (i) Kantevari, S.; Vuppalapati, S. V. N.; Biradar, D. O.; Nagarapu, L. J. Mol.
Catal. A: Chem. 2007, 266, 104; (j) Narasimhulu, M.; Reddy, T. S.; Mahesh, K. C.;
Prabhkar, P.; Rao, C. B.; Venkateswarlu, Y. J. Mol. Catal. A: Chem. 2007, 266, 114;
(k) Kantevri, S.; Bantu, R.; Nagarapu, L. J. Mol. Catal. A: Chem. 2007, 269, 53.
10. Recycling of HClO4–SiO2 was done according to the reported procedure. The
catalyst was dried at 100 °C for 24 h to give recycled HClO4–SiO2. The reaction of
N,N-dimethylaniline, formaldehyde, and indole was repeated with recycled
catalyst and the yields were found to remain in the range of 80% for five recycles.
11. Spectral data for selected compounds: Table 3, 6a. Isolated yield 84%; White
crystals. 4-((1-H-indol-3-yl)methyl)-N,N-dimethylaniline; 1H NMR (300 MHz,
CDCl3) d 2.86 (S, 6H), 4.06 (s, 2H), 6.73 (2H, d, J = 8.42 Hz), 6.91 (s, 1H), 7.08–
7.13 (m, 1H), 7.18–7.23 (m, 3H), 7.35 (d, 1H, J = 8.01 Hz), 7.56 (d, 1H,
J = 8.01 Hz), 7.94 (s, 1H); 13C NMR (75 MHz) d 30.43, 40.96, 109.35, 113.13,
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