One-pot three-component coupling reaction: solvent-free synthesis of novel 3-substituted indoles catalyzed by PMA-SiO2

Article abstract of DOI:10.1016/j.tetlet.2009.02.176

Solvent-free PMA-SiO₂-catalyzed synthesis of 3-substituted indole derivatives by a one-pot three-component coupling reaction between aldehyde, N-methyl aniline and indole is described.

Full text of DOI:10.1016/j.tetlet.2009.02.176

Tetrahedron Letters 50 (2009) 3763–3766
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Tetrahedron Letters
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One-pot three-component coupling reaction: solvent-free synthesis of novel
3-substituted indoles catalyzed by PMA–SiO2
*
P. Srihari , Vinay K. Singh, Dinesh C. Bhunia, J. S. Yadav
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Solvent-free PMA–SiO2-catalyzed synthesis of 3-substituted indole derivatives by a one-pot three-com-
ponent coupling reaction between aldehyde, N-methyl aniline and indole is described.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 30 December 2008
Revised 17 February 2009
Accepted 22 February 2009
Available online 26 February 2009
Concepts such as ‘atom economy’ and ‘green chemistry’ have fo-
cused significant interest on multicomponent reactions1 (MCR),
wherein at least three simple partners are added together to result
in a single diverse complex structure which allows the formation of
several new bonds. The strategy of multicomponent reactions has
been instrumental in playing a significant role in the preparation
of structurally diverse chemical libraries. The utility of MCR is well
represented in the synthesis of privileged medicinal scaffolds such
as 1,4-dihydropyridines, dihydropyrimidines, decahydroquinolin-
4-ones2 or substituted indoles3. Recently, indole derivatives have
become increasingly useful and important in the field of pharma-
ceuticals.4 Their biological properties have attracted many syn-
thetic chemists to explore different methods suitable for the
synthesis of substituted indoles. Despite several methods present
in the literature for the synthesis of substituted indoles,5 the devel-
opment of simple, efficient and environmentally benign ap-
proaches for indole derivatives is highly desirable.
In our previous reports, we have demonstrated that phospho-
molybdic acid (PMA) together with silica (SiO2) works efficiently
for organic transformations6 such as the nucleophilic substitution
reactions of aryl propargyl alcohols, propargylation of aromatic
compounds and synthesis of b-keto enol ethers. In continuation
of our efforts for exploring PMA–SiO2 as an acid catalyst for multi-
component coupling reactions,7 we herein describe a one-pot mul-
ticomponent condensation reaction of indole with aldehydes and
N-methylaniline to form a novel skeleton of 3-substituted indoles
(Scheme 1).
methylaniline and acetonitrile8 resulting in a novel 3-substituted
indole as a single product. This result encouraged us to investigate
further the scope of this methodology yielding 3-substituted
indoles.
In due course, owing to the importance of green chemistry, we
attempted similar transformations (coupling between benzalde-
hyde, N-methyl aniline and indole) in the absence of a solvent.
Interestingly, we found that the reaction occurs much faster
(1.75 h) than in the presence of a solvent (CH3CN, 3.5 h). To study
the role of PMA–SiO2, an experiment was conducted in the pres-
ence of silica without PMA and we found that the reaction pro-
ceeds with longer periods (36 h with 70% yield). However, when
PMA alone was used, the reaction occurred in 1.75 h resulting in
the formation of the desired product (80% yield) along with a
byproduct bisindolylmethane (10%). Thus the combination of
PMA–SiO2 was necessary to obtain a single desired product. With
respect to the quantity of the catalyst, there was no significant
enhancement in yields when the concentration was increased from
5 mol % to 20 mol %. Attempts were also made to study this proto-
col with TsOH and other Lewis acids such as NbCl5, FeCl3 and io-
dine (20 mol % each). With TsOH, the reaction progressed well
with the formation of the corresponding product (80%) along with
the byproduct bisindolylmethane (10%). In the case of NbCl5 and
FeCl3 the bis indolyl products were the major products formed
(>60%), whereas with iodine, the starting materials were recovered.
After optimizing the reaction conditions, different aldehydes,
both aromatic and aliphatic, aromatic aldehydes with electron-
donating and electron-withdrawing groups were investigated for
the present protocol.9 It was found that all the reactions proceeded
well and produced the corresponding products in good yields
(Table 1). All the products were characterized by 1H NMR, 13C
NMR, IR and mass spectroscopy.10 No significant change in yield
was observed when either substituted indoles or substituted aro-
matic aldehydes were used. Surprisingly, cinnamaldehyde, butyr-
aldehyde and n-octanal did not work under the present
protocol.11 Mechanistically, we presume that when N-methyl
Initially, we investigated the multicomponent reaction of benz-
aldehyde, aniline and indole in dichloromethane in the presence of
5 mol % PMA–SiO2 as a catalyst at room temperature. Unfortu-
nately, the reaction did not proceed according to expectations.
However, we were delighted to find that the reaction proceeded
well when aniline and dichloromethane were replaced with N-
* Corresponding author. Tel.: +91 40 27191490; fax: +91 40 27160512.
E-mail addresses: srihari@iict.res.in, sriharipabbaraja@yahoo.com (P. Srihari).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.176

3764
P. Srihari et al. / Tetrahedron Letters 50 (2009) 3763–3766
CH3
HN
CHO
R
CH3
PMA-SiO2
N
R'
+
+
R
CH3CN, rt.
N
R'
H
N
H
R = H, CH3, OH, OMe, Cl, NO2
R' = H, Br, OMe
Scheme 1.
Table 1
Synthesis of 3-substituted indoles via multicomponent coupling reaction
Entry
Indole
Aldehyde
Product
Yielda (%)
Timea (h)
Yieldb (%)
Timeb (h)
N
N
CHO
1
90
1.75
80
3.5
N
H
1a
N
H
OMe
CHO
2
92
1.75
83
3.5
N
H
2a
3a
N
H
OMe
CHO
N
3
93
1.75
85
3.75
N
H
N
H
NO2
CHO
N
N
4
89
2.5
78
4.0
N
H
N
H
4a
NO2
CHO
OH
5
95
1.75
84
3.0
N
H
OH
N
H
5a
6a
N
N
CHO
6
85
2.5
65
4.5
N
H
N
H
Cl
CHO
Cl
7
91
2.0
75
3.0
N
H
N
H
7a

P. Srihari et al. / Tetrahedron Letters 50 (2009) 3763–3766
3765
Table 1 (continued)
Entry Indole
Aldehyde
Product
Yielda (%)
Timea (h)
Yieldb (%)
Timeb (h)
CHO
N
8
91
2.5
76
3.5
N
H
N
H
8a
9a
CHO
N
N
N
9
92
2.5
80
4.0
N
N
N
N
CHO
CHO
10
11
90
92
2.5
2.5
80
83
4.25
3.75
10a
11a
Cl
Br
Br
Br
N
H
N
H
Cl
OMe
CHO
N
N
Br
12
90
2.75
82
4.0
N
H
OMe
N
H
12a
13a
14a
CHO
MeO
MeO
OMe
13
90
2.5
83
4.25
N
H
N
H
Cl
CHO
Cl
N
OMe
14
93
2.25
80
4.0
N
H
N
H
a
Reaction performed under solvent-free conditions.
Reaction performed with acetonitrile as solvent.
b
H
N
..
CH3
H3C
O
HN
+
N
N
H
H+
-H2O
H
+
N
H3C
Intermediate
Scheme 2.

3766
P. Srihari et al. / Tetrahedron Letters 50 (2009) 3763–3766
Smith, G. F. Heterocyclic Chemistry, 3rd ed.; Chapman & Hall: New York, 1995.
Chapter 17.
aniline is treated with aldehyde in the presence of acid, an iminium
ion intermediate is formed which is attacked by an electron rich in-
dole to get the 3-substituted indole (Scheme 2).
In conclusion, efficient synthesis of novel 3-substituted indoles
has been achieved by a one-pot three-component coupling reac-
tion of aldehyde, N-methylaniline and indole. Simple reaction pro-
cedures, inexpensive catalysts and single product formation make
this an attractive protocol over the existing procedures.
6. (a) Srihari, P.; Reddy, J. S. S.; Bhunia, D. C.; Mandal, S. S.; Yadav, J. S. Synth.
Commun. 2008, 38, 1448–1455; (b) Srihari, P.; Reddy, J. S. S.; Mandal, S. S.;
Satyanarayana, K.; Yadav, J. S. Synthesis 2008, 1853–1860; (c) Srihari, P.;
Mandal, S. S.; Reddy, J. S. S.; Srinivasa Rao, R.; Yadav, J. S. Chin. Chem. Lett. 2008,
767–770; (d) Yadav, J. S.; Raghavendra, S.; Satyanarayana, M.; Balanarsaiah, E.
Synlett 2005, 2461–2464.
7. Yadav, J. S.; Subba Reddy, B. V.; Srinivasa Rao, T.; Narender, R.; Gupta, M. K. J.
Mol. Catal. A: Chem. 2007, 278, 42–46.
8. The reaction also works with THF as the solvent. However the duration of the
reaction was found to be high (48 h with 80% yield) at rt.
Acknowledgements
9. General procedure for multicomponent coupling reaction: Solvent-free procedure:
A mixture of aldehyde (1 mmol), N-methyl aniline (2 mmol)12 and PMA–SiO2
(5 mol %) was stirred at rt for 1 h and to this was added indole (1 mmol) and
the reaction mixture was stirred till the completion of the reaction. The
reaction mixture was diluted with diethyl ether and filtered over a sintered
funnel. The filtrate was concentrated and the resulting product was purified by
column chromatography. Procedure with solvent (acetonitrile): To a mixture of
aldehyde (1 mmol), N-methyl aniline (2 mmol) in acetonitrile (5 mL) was
added PMA–SiO2 (5 mol%) and the reaction mixture was stirred at rt for 1 h. To
this was added indole (1 mmol) and the reaction mixture was stirred till the
completion of the reaction. The reaction mixture was filtered over a sintered
funnel. The filtrate was concentrated and the resulting product was purified by
column chromatography.
V.K.S. thanks UGC, New Delhi, and D.C.B. thanks CSIR, New Del-
hi, for financial assistance.
Supplementary data
Supplementary data (spectroscopic data of products 2a–5a, 7a
and 9a–13a) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2009.02.176.
10. Analytical data for few representative compounds: [(1H-Indol-3-yl)-phenyl-
methyl]-methyl-phenyl-amine (1a): Brown solid, mp = 145–147 °C. 1H NMR
(200 MHz, CDCl3): d 2.76 (s, 3 H), 5.54 (s, 1H), 6.51(d, J = 8.3 Hz, 3H), 6.09–7.04
(m, 3H), 7.09–7.38 (m, 9H), 7.81(s, 1H). 13C NMR (75 MHz, CDCl3): d 29.66,
47.91, 110.93, 112.37, 119.17 120.48, 121.86, 123.92,125.89, 127.03,128.11,
128.88, 129.65, 132.91, 136.65, 144.67, 147.52. IR (KBr): 453, 600, 738, 1450,
1611, 2855, 2923, 3417, 3361 cmÀ1. ESIMS:m/z 313(M++H). HRMS. calcd for
C22H21N2: 313.1704. Found 313.1701. [(Cyclohexyl-(1H-indol-3-yl)-methyl]-
methyl-phenyl-amine (6a): Brown solid mp = 110–112 °C. 1H NMR (200 MHz,
CDCl3): d.819–1.02 (m, 2 H), 1.05–1.32 (m, 3H), 1.47–1.80 (m, 4H), 2.65 (s, 3H),
3.65 (d, J = 9.5 Hz, 1H), 4.05 (dd, J = 7.3, 13.9 Hz, 1H), 6.36 (d, J = 8.8 Hz, 2H),
6.76 (m, 2H), 6.88–7.07 (m, 6H), 7.44–7.55 (m, 2H). 13C NMR (75 MHz, CDCl3):
d 48.89, 26.59, 30.81, 31.99, 32.46, 42.51, 48.89, 110.89, 118.80, 119.35, 119.82,
127.54, 128.91, 133.82, 147.01. IR (KBr): 422, 745, 1452, 1571, 1614, 2850,
References and notes
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Gore, J. Curr. Med. Chem. 2003, 10, 51–80; (f) Orru, R. V. A.; De Greef, M.
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2923, 3051, 3414 cmÀ1
.
ESIMS: m/z 319(M++H) HRMS calcd for
2. (a) Dondoni, A.; Massi, A.; Sabbatini, S.; Bertolasi, V. J. Org. Chem. 2002, 67,
6979–6994; (b) Lin, C.; Fang, H.; Tu, Z.; Liu, J.-T.; Yao, C.-F. J. Org. Chem. 2006,
71, 6588–6591; (c) Evdokimov, N. M.; Magedov, I. V.; Kireev, A. S.; Kornienko,
A. Org. Lett. 2006, 8, 899–902; (d) Dardennes, E.; Kovacs-Kulyassa, A.; Boisbrun,
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Org. Chem. 2008, 73, 6824–6827; For earlier work on condensation of indoles
with aldehydes and secondary amines to get substituted indoles see: (b)
Snyder, A. J. Am. Chem. Soc. 1959, 81, 2239–2241; (c) Bickert, E.; Funck, T. Chem.
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Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am. Chem. Soc. 2006, 128, 8156–8157;
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1621–1624; (d) Sundberg, R. J. Indoles; Academic Press: New York, 1996.
Chapter 11; (e) Wynne, J. H.; Stalick, W. M. J. Org. Chem. 2002, 67, 5850–5853;
(f) Mi, X.; Luo, S.; He, J.; Cheng, J.-P. Tetrahedron Lett. 2004, 45, 4567–4570.; (g)
Ottoni, O.; Neder, A. V. F.; Bias, A. K. B.; Cruz, R. P. A.; Aquino, L. B. Org. Lett.
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Blasé, F. R.; Hartz, R. A. Org. Lett. 1999, 1, 1263–1266; (i) Joule, J. A.; Mills, K.;
C22H27N2,329.2174. Found 329.1644. [(1H-Indol-3-yl)-naphth-2-yl-methyl]-
methyl-phenyl)-amine (8a): Brown solid mp = 75–80 °C. 1H NMR (300 MHz,
CDCl3): d 2.81 (s, 3 H), 6.27 (s, 1H), 6.41 (d, J = 2.1 Hz, 1H), 6.54 (d, J = 8.5 Hz,
2H), 6.87- 7.17 (m, 4H), 7.20–7.42 (m, 6H), 7.65–7.86 (m, 3H), 8.05 (d,
J = 7.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 50.38, 63.30, 130.47, 131.94,
138.75, 139.39, 139.96, 141.44, 143.93, 144.09, 144.72, 144.88, 145.31, 146.14,
146.40, 146.54, 148.06, 149.40, 151.40, 151.97, 153.39, 156.81, 159.79, 167.06.
IR (KBr): 486, 743, 788, 1092, 1453, 1515, 1612, 2922, 3048, 3412 cmÀ1. ESIMS:
m/z 362(M++H). HRMS calcd for C26H23N2,363.1861 Found 363.1850. [(4-
Chlorophenyl)-(5-methyloxy-1H-indol-3-yl)-methyl]-methyl-phenyl)-amine
(14a): Brown solid mp = 129–131 °C. 1H NMR (300 MHz, CDCl3): d 2.82 (s, 3H),
3.65 (s, 3H), 5.43 (s, 1H), 6.45–6.52 (m, 4H), 6.72–6.76 (m, 2H), 6.94 (d,
J = 8.3 Hz, 2H), 7.10–7.24 (m, 6H), 7.27 (s, 1H). 13C NMR (75 MHz, CDCl3): d
21.21, 31.10, 47.70, 55.98, 102.28, 111.78, 112.01, 112.57, 120.55, 124.86,
127.71, 135.48, 128.96, 129.02, 129.81, 132.03, 133.30, 141.84, 147.71, 153.77.
IR (KBr): 467, 818, 926, 1091, 1206, 1459, 1616, 1745, 2855, 2924, 3189, 3369
ESIMS: m/z 377(M++H). HRMS calcd for C23H22ClN2O 377.1420 Found
377.1410.
11. Cinnamaldehyde gave mixture of unidentified spots with no desired product,
whereas both n-octanal and n-butyraldehyde gave the corresponding
bisindolyl alkanes in 60% yield.
12. Excess amine was used for allowing the complete consumption of aldehyde
to give iminium ion leading to the formation of the desired product rather
than the bisindolyl alkanes which may result from the free aldehyde if
present.