A simple, solvent and catalyst-free green synthesis of novel N-[(1H-indol-3-yl)arylmethyl]heteroarylamines

Article abstract of DOI:10.1016/j.tetlet.2010.07.175

One-pot, three-component coupling reactions of indole, aromatic aldehydes, and heteroaryl amines under solvent-free conditions lead to the formation of the corresponding novel 3-[(N-heteroaryl)(aryl)methyl]indoles in moderate to high yields. The key features of this multi-component reaction are the simple reaction procedure, no organic solvent or acid catalyst, and easy product separation without further purification.

Full text of DOI:10.1016/j.tetlet.2010.07.175

Tetrahedron Letters 51 (2010) 6086–6089
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Tetrahedron Letters
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A simple, solvent and catalyst-free green synthesis of novel
N-[(1H-indol-3-yl)arylmethyl]heteroarylamines
a
b
a
a
Abolfazl Olyaei a, , Bahareh Shams , Mahdieh Sadeghpour , Fatemeh Gesmati , Zeinab Razaziane
*
a Department of Chemistry, Payame Noor University (PNU), Qazvin, Iran
b Department of Chemistry, Islamic Azad University, Takestan Branch, Qazvin, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
One-pot, three-component coupling reactions of indole, aromatic aldehydes, and heteroaryl amines
under solvent-free conditions lead to the formation of the corresponding novel 3-[(N-heteroaryl)-
(aryl)methyl]indoles in moderate to high yields. The key features of this multi-component reaction are
the simple reaction procedure, no organic solvent or acid catalyst, and easy product separation without
further purification.
Received 6 June 2010
Revised 18 July 2010
Accepted 30 July 2010
Available online 6 August 2010
Ó 2010 Published by Elsevier Ltd.
In recent years, significant interest has been devoted to the
preparation of substituted indoles due to their varied biological
activities including antioxidationantioxidant, antibacterial, and
insecticidal.1 They also act as colon cancer cell and tumor growth
inhibitors1d and are employed as valuable antibiotics.1a
catalyst and under solvent-free conditions. As such, the utilization
of environment-friendly conditions (absence of organic solvent)
gives the product not only via an easy work-up procedure, but also
in accordance with green chemistry principles.
As a model reaction, we initially examined the one-pot, three-
component reaction of indole, 2-aminopyrimidine, and benzalde-
hyde in water in the presence of formic acid as the catalyst under re-
flux conditions. It was found that at least 12 h were needed for the
reaction to be completed. After cooling, the pinkish precipitate
was filtered. Analysis of the product indicated that pure 1H,10H-
3,30-phenylmethanediyl-bis-indole (1) had been obtained. It should
be noted that the reaction of indole and benzaldehyde in formic acid
did not proceed under the reaction conditions (Scheme 1). There-
fore, it might be concluded that N-[(1H-indole-3-yl)(phenyl)-
methyl]pyrimidine-2-amine (4a) is initially formed as an intermedi-
ate. Then, in the presence of the acid catalyst, 2-aminopyrimidine is
eliminated and the resulting intermediate 5 is attacked by indole to
give the 3-substituted indole (1). The proposed mechanism is shown
in Scheme 1.
Among various derivatives of indoles, 3-substituted indoles
have been much studied and several synthetic methods have been
developed for the preparation of these compounds using indole or
3-indolecarboxaldehyde as starting materials. The Mannich reac-
tion,2 catalyzed Friedel–Crafts alkylation reactions of indoles,3 con-
jugate addition of indoles to unsaturated carbonyl compounds, and
the reaction of two equivalents of indoles with carbonyl groups in
the presence of either protic4,5 or Lewis acids6–8 are considered as
powerful carbon-carbon bond forming processes to afford
3-substituted indoles. Among 3-substituted indoles, 3-[(N-alkylan-
ilino)(aryl)methyl]indoles have not been studied in detail and only
a few synthetic methods have been developed for their prepara-
tion. These involve three-component reactions of indoles, benzal-
dehydes and N-alkylanilines or indole-3-carbaldehydes, and
amines in the presence of an acid catalyst, such as phosphomolyb-
dic acid (PMA) together with silica (SiO2) or 2,4,6-trichloro-1,3,5-
triazine (TCT) (Fig. 1).9–11 3-Indolylmethanamine derivatives are
important intermediates for natural and natural-like products.12
To the best of our knowledge, the synthesis of 3-substituted in-
doles via condensation of heteroaryl amines, aromatic aldehydes,
and indole has not previously been reported. In this article, in
continuation of our work on the development of solvent-free con-
ditions in one-pot, multi-component reactions,13,14 we describe the
synthesis of a series of novel 3-[(N-heteroaryl)(aryl)methyl]indoles
via a simple three-component, one-pot method, using aromatic
aldehydes, heteroaryl amines, and indole in the absence of an acid
When this reaction was carried out under solvent-free condi-
tions at 70–120 °C, the reaction proceeded to completion in 2 h.
The mixture was subjected to column chromatography (silica gel,
R3
CN
N
N
NH
R4
R2
R1
N
H
N
H
N
H
R1: H, Br, OMe; R2: H, Me; R3: H, 4-NO2,
4-Cl, 3-OH, 3,4-(OMe)2, 3,4,5-(OMe)3, 4-
OMe, 3-OMe, 4-Me; R4: Me, Et, Pr
* Corresponding author. Tel.: +98 281 2224024; fax: +98 281 2226400.
E-mail address: Olyaei_a@pnu.ac.ir (A. Olyaei).
Figure 1. Examples of 3-substituted indoles.
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.07.175

A. Olyaei et al. / Tetrahedron Letters 51 (2010) 6086–6089
6087
der these conditions, bis(indolyl)methane was formed 5% and the
3-[(N-heteroaryl)(aryl)methyl]indole was obtained as the major
product. Our investigation demonstrated that the best result was
obtained at 80 °C and the reaction was complete in 2 h.
One-pot, three-component coupling reactions of indole,
aromatic aldehydes (benzaldehyde, 4-chlorobenzaldehyde, 4-bro-
mobenzaldehyde, 4-fluorobenzaldehyde, 4-nitrobenzaldehyde,
2-chlorobenzaldehyde, and 2-chloro-6-fluorobenzaldehyde) 2a–g,
and heteroaryl amines (2-aminopyrimidine, 2-aminopyridine,
and 2-amino-4,6-dimethylpyrimidine) 3a–c at 80 °C afforded
3-[(N-heteroaryl)(aryl)methyl]indoles 4a–l in moderate to high
yields (Table 1, Scheme 2). After completion, ethanol was added
to the reaction mixture and the solution was poured into water.
The resulting colorless precipitate was filtered and dried.15
The crude product was stirred in boiling n-hexane and filtered
to afford pure product. Mechanistically, we assume that when
the heteroaryl amine is treated with an aldehyde, an imine inter-
mediate is formed which is attacked by indole to give the 3-substi-
tuted indole. Identification of products 4a–l was carried out on the
basis of spectroscopic information. For example, the 1H NMR spec-
trum of compound 4b showed a sharp singlet for the indole-NH at
d 10.95. The methine proton and NH proton of the amine appeared
H
N
NH2
N
CHO
N
HCOOH
H2O
N
N
+
+
N
H
N
H
4a
H
H
N
N
N
NH2
-
HCOOH
N
N
H
N
N
H
5
+
N
H
NH
HN
1
Scheme 1. Proposed mechanism for the synthesis of bis(indolyl)methane 1.
hexane/EtOAc) to afford two products including bis(indolyl)meth-
ane 1 and compound 4a. To avoid formation of compound 1, the
same reaction was repeated in the absence of the acid catalyst. Un-
Table 1
Synthesis of 3-substituted indoles under solvent-free conditions at 80 °C
Entry
Amine
Aldehyde
Product
Time (h)
Yield (%)
Mp (°C)
NH2
N
CHO
N
N
N
N
NH
1
3
90
182–183
N
H
4a
NH2
N
CHO
Cl
N
N
NH
2
3
4
4
87
75
89
161–163
155–157
180–182
Cl
N
H
4b
4c
NH2
N
CHO
Br
F
N
N
N
N
NH
6
Br
N
H
NH2
N
CHO
N
N
NH
2.5
F
N
H
4d
NH2
N
CHO
H3C
Cl
Br
CH3
N
N
N
H3C
H3C
CH3
NH
5
6
3.5
80
88
214–216
Cl
N
H
H3C
4e
NH2
N
CHO
Br
CH3
N
N
N
NH
CH3
4
219–220
N
H
4f
(continued on next page)

6088
A. Olyaei et al. / Tetrahedron Letters 51 (2010) 6086–6089
Table 1 (continued)
Entry
Amine
Aldehyde
Product
Time (h)
Yield (%)
Mp (°C)
NH2
N
CHO
H3C
F
CH3
N
N
N
NH
H3C
H3C
CH3
7
8
4
90
191–193
F
N
H
H3C
4g
NH2
N
CHO
NO2
O2N
CH3
N
N
N
CH3
NH
5
92
204–205
N
H
4h
NH2
N
CHO
H3C
Cl
CH3
N
N
N
N
H3C
H3C
CH3
9
4
4
87
84
237–238
178–179
NH
Cl
Cl
NH
4i
NH2
N
CHO
Cl
F
F
NH
N
CH3
10
N
CH3
N
H H3C
4j
NH2
N
CHO
Cl
N
NH
11
12
1.5
85
83
174–176
141–142
Cl
Cl
NH
4k
NH2
N
CHO
F
F
Cl
H
N
N
2
N
H
4l
indoles in the absence of an acid catalyst under solvent-free condi-
tions in moderate to high yields. The simple reaction procedure,
generality, easy product separation, and purification make this
protocol attractive. To the best of our knowledge, this is the first re-
port on the synthesis of 3-[(N-heteroaryl)(aryl)methyl]indole
derivatives.
Ar
NHAr'
Solvent-free
80 oC
+ ArCHO + Ar'NH2
N
H
N
H
4
2
3
Cl
Br
Ar:
F
Acknowledgment
F
NO2
The authors thank the Research Council of Payame Noor Univer-
sity of Qazvin for financial support.
Cl
Cl
CH3
N
N
N
Ar':
Supplementary data
N
N
CH3
Supplementary data (spectroscopic data of products 4c–l) asso-
ciated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.07.175.
Scheme 2. Synthesis of 3-[(N-heteroaryl) (aryl)methyl]indoles 4.
as two doublets at about d 6.57 and 7.97 and the 4-substituted
phenyl protons occurred as two well-resolved AB spin systems at
d 7.34 and 7.48. The pyrimidinyl moieties gave two well-resolved
AB2 spin systems at d 6.59 and 8.30. Upon addition of D2O, the
NH signals disappeared and the methine proton collapsed to a
singlet.
References and notes
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Med. Chem. Lett. 2007, 17, 2863.
In summary, we have developed a convenient and environmen-
tally green methodology for the synthesis of novel 3-substituted
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6089
3. (a) Ke, B.; Qin, Y.; He, Q.; Huang, Z.; Wang, F. Tetrahedron Lett. 2005, 46, 1751;
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M. A. Can. J. Chem. 1998, 76, 1256.
15. General procedure for the synthesis of 3-substituted indoles (4): A mixture of
heteroaryl amine (1 mmol) and aromatic aldehyde (1 mmol) was stirred in a
preheated oil bath at 80 °C. Indole (1 mmol) was added after 10 min and the
mixture was heated for the appropriate amount of time as indicated in Table 1.
The progress of the reaction was monitored by thin-layer chromatography
(TLC). After completion, the reaction mixture was cooled to room temperature
and EtOH (5 mL) was added. The solution was poured into water (50 mL). The
colorless precipitate that formed was filtered, washed with H2O and dried. The
crude product was stirred for 5 min in boiling n-hexane and the resulting white
precipitate was filtered. The product 4 thus obtained was found to be pure
upon TLC examination.
7. (a) Babu, G.; Sridhar, N.; Perumal, P. T. Synth. Commun. 2000, 30, 1609; (b) Chen,
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Cheng, J. P. Tetrahedron Lett. 2004, 45, 4567; (d) Nagarajan, R.; Perumal, P. T.
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Ronchi, A. J. Org. Chem. 2002, 67, 3700; (b) Yadav, J. S.; Abraham, S.; Subba
Reddy, B. V.; Sabitha, G. Tetrahedron Lett. 2001, 42, 8063; (c) Yadav, J. S.;
Abraham, S.; Subba Reddy, B. V.; Sabitha, G. Synthesis 2001, 2165; (d) Manabe,
K.; Aoyama, N.; Kobayashi, S. Adv. Synth. Catal. 2001, 174; (e) Yadav, J. S.; Subba
Reddy, B. V.; Murthy, V. S. R.; Mahesh Kumar, G.; Madan, C. Synthesis 2001, 783;
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190.
N-[(1H-Indole-3-yl)(phenyl)methyl]pyrimidine-2-amine (4a): IR (KBr): 3220,
3168, 1599, 1528, 1450, 1140 cmꢀ1 1H NMR (500 MHz, DMSO-d6) d: 6.57 (t,
;
1H, J = 4.7 Hz, pyrimidine-H5), 6.62 (d, 1H, J = 9.0 Hz, CH), 6.91–7.52 (m, 10H,
indole-H and Ph-H), 7.93 (d, 1H, J = 9.0 Hz, pyrimidine-NH), 8.29 (d, 2H,
J = 4.7 Hz, pyrimidine-H4, H6), 10.92 (s, 1H, indole-NH); 13C NMR (125 MHz,
DMSO-d6) d: 51.98, 111.12, 112.37, 117.94, 119.40, 119.65, 122.00, 124.23,
126.87, 127.38, 128.05, 128.90, 137.28, 144.61, 158.85, 162.48; MS (EI): m/z
300 [M+], 221, 206, 204, 178, 118, 80; Anal. Calcd for C19H16N4: C, 76.00; H,
5.33; N, 18.66. Found: C, 76.10; H, 5.29; N, 18.70.
N-[(1H-Indole-3-yl)(4-chlorophenyl)methyl]pyrimidine-2-amine (4b): IR (KBr):
3235, 1592, 1523, 1451, 1419, 1092 cmꢀ1 1H NMR (500 MHz, DMSO-d6) d:
;
6.57 (d, 1H, J = 8.9 Hz, CH), 6.59 (t, 1H, J = 4.7 Hz, pyrimidine-H5), 6.92–7.41 (m,
5H, indole-H), 7.37 (d, 2H, J = 8.4 Hz, ph-H), 7.52 (d, 2H, J = 8.4 Hz, ph-H), 7.97
(d, 1H, J = 8.9 Hz, pyrimidine-NH), 8.30 (d, 2H, J = 4.7 Hz, pyrimidine-H4, H6),
10.95 (s, 1H, indole-NH); 1H NMR (500 MHz, DMSO-d6 + D2O) d: 6.52 (s, 1H,
CH), 6.59 (t, 1H, J = 4.7 Hz, pyrimidine-H5), 6.91–7.36 (m, 5H, indole-H), 7.34
(d, 2H, J = 8.4 Hz, ph-H), 7.48 (d, 2H, J = 8.4 Hz, ph-H), 8.25 (d, 2H, J = 4.7 Hz,
pyrimidine-H4, H6); 13C NMR (125 MHz, DMSO-d6) d: 51.48, 111.30, 112.42,
117.39, 119.49, 119.59, 122.09, 124.34, 126.74, 128.88, 129.92, 131.90, 137.29,
10. Das, B.; Kumar, J. N.; Kumar, A. S.; Damodar, K. Synthesis 2010, 914.
11. Srihari, P.; Singh, V. K.; Bhunia, D. C.; Yadav, J. S. Tetrahedron Lett. 2009, 50,
3763.
12. Wynne, J. H.; Stalick, W. M. J. Org. Chem. 2002, 67, 5850.
13. Shockravi, A.; Sadeghpour, M.; Olyaei, A. Synth. Commun. 2009, 39, 2347.
14. Shockravi, A.; Sadeghpour, M.; Olyaei, A. J. Chem. Res. 2009, 556.
143.67, 158.86, 162.39; MS (EI): m/z 336 [M+ 37Cl)], 334 [M+ 35Cl)], 300, 255,
( (
240, 218, 204, 176, 118, 95, 80. Anal. Calcd for C19H15ClN4: C, 68.16; H, 4.48; N,
16.74. Found: C, 68.20; H, 4.50; N, 16.81.