A convenient one-pot three component synthesis of 3-aminoalkylated indoles catalyzed by 3-chlorophenylboronic acid

Article abstract of DOI:10.1016/j.cclet.2013.03.024

An efficient protocol was developed for the synthesis of 3-aminoalkylated indoles using 3-chlorophenylboronic acid as a catalyst under ambient temperature conditions. The three-component reaction of indoles, aromatic aldehydes and N-methyl aniline offered corresponding 3-aminoalkylated indoles in excellent yields. This protocol presents some remarkable features such as mild reaction conditions, simple workup procedure and excellent yields.

Full text of DOI:10.1016/j.cclet.2013.03.024

Chinese Chemical Letters 24 (2013) 422–424
Contents lists available at SciVerse ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
A convenient one-pot three component synthesis of 3-aminoalkylated indoles
catalyzed by 3-chlorophenylboronic acid
*
Santosh V. Goswami, Prashant. B. Thorat, Vijay N. Kadam, Sachin A. Khiste, Sudhakar R. Bhusare
Department of Chemistry, Dnyanopasak College, Parbhani 431 401, MS, India
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient protocol was developed for the synthesis of 3-aminoalkylated indoles using 3-
chlorophenylboronic acid as a catalyst under ambient temperature conditions. The three-component
reaction of indoles, aromatic aldehydes and N-methyl aniline offered corresponding 3-aminoalkylated
indoles in excellent yields. This protocol presents some remarkable features such as mild reaction
conditions, simple workup procedure and excellent yields.
Received 24 January 2013
Received in revised form 26 February 2013
Accepted 4 March 2013
Available online 12 April 2013
ß 2013 Sudhakar R. Bhusare. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
3-Aminoalkylaed indoles
3-Chlorophenylboronic acid
Aromatic aldehyde
N-Methylaniline
Indoles
1. Introduction
is still need for the development of an efficient method for the
synthesis of 3-aminoalkylated indoles.
Indole is an important structural design present in a variety of
natural products and has pharmaceutical interest in several
therapeutic areas [1,2]. They have a variety of biological activities
such as antibacterial, anticonvulsant and antihypertension
activity [3]. Some indole derivatives are present in bioactive
metabolites of terrestrial and marine organisms [4,5]. Because of
the chemical and biological properties of indole molecules,
progress in effective methods for the synthesis of indole
derivatives constitutes a rising area in organic synthesis.
Recently, in synthetic organic chemistry, organoboron com-
pounds have been successfully used as catalysts in several organic
transformations as an efficient Lewis acid catalyst [16–19]. Thus,
we describe the synthesis of 3-aminoalkylated indoles using 3-
chlorophenylboronic acid as a catalyst under ambient temperature
conditions (Scheme 1) here.
2. Experimental
Recently, multi-component reactions (MCRs) have received
great attention from organic chemists as they offer important
advantages over conventional linear-type synthesis such as high
atom economy, low cost, reduction in overall reaction time and
operational simplicity [6–9]. There are only a few methods for the
synthesis of 3-aminoalkylated indoles which have been found in
Melting points were determined in an open capillary tube and
are uncorrected. The purity of the compounds was checked by TLC.
1H NMR and 13C NMR spectra were recorded on a Bruker 300 MHz
spectrometer in CDCl3 solvent and TMS as an internal standard.
Mass spectra were taken on Q-Star pulsar LC–MS.
various natural products. Recently,
a
one-pot method was
General procedure for the synthesis of 3-aminoalkylated
indoles (4a-l): To a mixture of aromatic aldehyde (1 mmol),
N-methyl aniline (2 mmol) and indole (1 mmol) in acetonitrile
(10 mL), a catalytic amount of 3-chlorophenylboronic acid
(20 mol%) was added and the reaction mixture was stirred at
room temperature for appropriate time (Scheme 1). After
completion of reaction as indicated by TLC, 25 mL cold distilled
water was added to the reaction mixture extracted with ethyl
acetate (2 Â 20 mL). Solvent was removed in vacuum to obtain
developed for the synthesis of 3-aminoalkylated indoles by the
reaction of aldehyde, amine and indole [10–15]. The reaction
requires a long reaction time, high temperature and is generally
accompanied by formation of bis-indolyl compounds. Thus, there
* Corresponding author.
E-mail address: bhusare71@yahoo.com (S.R. Bhusare).
1001-8417/$ – see front matter ß 2013 Sudhakar R. Bhusare. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.03.024

[
S.V. Goswami et al. / Chinese Chemical Letters 24 (2013) 422–424
423
B(OH)2
Cl
CH3
Table 1
Optimization of the solvent and catalytic loading for the one-pot synthesis of 3-
aminoalkylated indoles.a
CH3
Ar
HN
N
R
[DT$LINE]
R
+ Ar-CHO +
Cl
CH3CN, rt
N
H
N
H
1
2
3
4a-l
B(OH)2
Cl
CH3
CH3
CHO
HN
N
Scheme 1. One-pot synthesis of 3-aminoalkyalted indoles.
+
+
N
H
Solvent, r.t.
N
H
crude product. The crude mixture was purified with silica gel
column chromatography.
Cl
4a
1
2
3
N-[(4-Chlorophenyl)(1H-indol-3-yl)methyl]-N-methyl benzene-
amine (4a): 1H NMR (300 MHz, CDCl3):
2H, J = 4.4 Hz), 7.05–7.16 (m, 6H), 6.90 (d, 4H, J = 7.8 Hz), 6.50 (d,
2H, J = 7.8 Hz), 5.63 (s, 1H), 2.90 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 7.86 (s, 1H), 7.43 (d,
Entry
Solvent
3-Chlorophenylboronic
acid (mol%)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
Methanol
10
10
10
10
5
22
20
16
26
22
15
12
30
65
70
76
46
58
81
90
40
d
22.3, 30.8, 43.5, 110.8, 115.0, 120.0, 121.1, 121.8, 124.6, 128.0,
Ethanol
129.1, 129.5, 129.9, 133.4, 136.5, 139.0, 142.4, 149.0; Mass (LC/
MS): m/z 346.5365 (M+); Anal. Calcd. for C22H19ClN2: C 76.18, H
5.52, N 8.08 Found: C 76.15, H 5.55, N 8.10.
N-[(5-Bromo-1H-indol-3-yl)(p-tolyl)methyl]-N-methylbenzen-
amine (4k): 1H NMR (300 MHz, CDCl3):
d 10.31 (s, 1H), 7.35 (d, 1H,
Acetonitrile
Chloroform
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
15
20
0
J = 7.8 Hz), 7.20 (d, 2H, J = 4.2 Hz), 7.04–7.10 (m, 4H), 6.68 (d, 2H,
J = 4.2 Hz), 6.52 (d, 2H, J = 4.0 Hz), 6.34 (d, 2H, J = 8.0 Hz), 5.51(s,
a
Conditions: indole (1 mmol), 4-chlorobenzaldehyde (1 mmol), N-methylaniline
(2 mmol), solvent (10 mL) at room temperature. Reaction was monitored by thin
layer chromatography.
1H), 2.60 (s, 3H), 2.38 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 23.4,
b
Isolated yield.
35.2, 49.4, 110.2, 114.6, 116.9, 120.1, 122.2, 124.4, 127.1, 128.9,
129.4, 129.7, 132.8, 136.2, 140.2, 144.5, 150.2; Mass (LC/MS): m/z
404.2365 (M+); Anal. Calcd. for C23H21BrN2: C 68.15, H 5.22, N 6.91
Found: C 68.10, H 5.24, N 6.94.
Table 2
Synthesis of 3-amino-alkylated indole derivatives.a
N-[(4-Chlorophenyl)(5-methoxy-1H-indol-3-yl)methyl]-N-methyl
benzenamine (4l): 1H NMR (300 MHz, CDCl3):
d
7.62 (s, 1H), 7.21–
7.30 (m, 4H), 7.05 (d, J = 6.4 Hz, 2H), 6.52–6.96 (m, 6H), 5.89 (s, 1H),
3.70 (s, 3H), 2.96 (s, 3H); 13C NMR (75 MHz, CDCl3):
24.2, 34.2,
Entry
R
Ar
Product Time (h) Mp (oC)
Yield (%)b
1
2
H
H
H
H
H
H
H
H
H
Br
Br
4-Cl–C6H4
C6H5
4a
4b
4c
4d
4e
12
182–184 90
d
14
188–190 80
139–141 87
135–137 84
176–178 91
131–133 82
135–138 86
190–192 88
3
4-OH–C6H4
4-CH3–C6H4
4-OCH3–C6H4
12
45.6, 59.3, 106.2, 113.0, 116.3, 119.8, 122.9, 126.3, 128.0, 128.8,
130.2, 132.03, 136.2, 144.2, 149.6, 157.1; Mass (LC/MS): m/z
377.4236 (M+); Anal. Calcd. for C23H21ClN2O: C 73.30, H 5.62, N
7.43 Found: C 73.34, H 5.59, N 7.39.
4
12.5
14
5
6
3,4-(OCH3)2–C6H3 4f
14
7
3-OCH3–C6H4
3-NO2–C6H4
1-Naphthyl
C6H5
4g
4h
4i
12
8
13
9
14
82–85
86
3. Results and discussion
10
11
12
4j
12.5
12
210–212 88
196–198 90
204–206 87
4-CH3–C6H4
4k
4l
In continuation of our interest in the synthesis of heterocycles
[20–22] and organic transformation [23] in the presence of
catalytic amounts of arylboronic acids, herein we describe the
synthesis of 3-aminoalkylated indoles via one-pot, three-compo-
nent coupling reaction of an aromatic aldehyde, N-methyl aniline
and indole in presence of 3-chlorophenylboronic acid as a catalyst
in acetonitrile at room temperature conditions. Initially, we
studied optimization of suitable solvent and catalytic loading for
the model reaction of 4-chlorobenzaldehyde, N-methyl aniline and
indole at room temperature. Different solvents were screened to
test the effectiveness of 3-chlorophenylboronic acid (10 mol%) and
the results are listed in Table 1 (entries 1–8). The optimum result
was observed in acetonitrile, in which the catalyst worked most
efficiently (Table 1, entry 3). In addition, the reaction in methanol
and ethanol afforded 65% and 70% yield respectively (Table 1,
entries 1 and 2). In the non-polar solvent, chloroform desired
product was obtained in lower yields with longer reaction time
(Table 1, entry 4).
We also studied the effect of catalytic loading on the reaction in
acetonitrile solvent. It was noticed that amount of the catalyst
plays a major role in establishment of the desired product yield.
On decreasing catalytic loading of 3-chlorophenylboronic acid to
5 mol%, reaction gave low yield (58%) with extended reaction time
(Table 1, entry 5). When catalytic loading was raised to 15 mol%,
an enhanced result was observed. The reaction was completed in
15 h and offered good yield (81%) (Table 1, entry 6). The best
OMe 4-Cl–C6H4
13
a
Conditions: indole (1 mmol), aromatic aldehyde (1 mmol), N-methylaniline
(2 mmol), 3-chlorophenylboronic acid (20 mol%), acetonitrile (10 mL) at room
temperature. Reaction was monitored by thin layer chromatography.
b
Isolated yield.
optimized reaction condition was achieved at the catalytic
loading 20 mol% in acetonitrile. The reaction afforded product
4a in excellent yield (90%) within 12 h (Table 1, entry 7). The
model reaction in the absence of the catalyst in acetonitrile
showed poor performance with respect to the yield and reaction
time. When the reaction stirred for 30 h, it afforded only 40% yield
(Table 1, entry 8).
To examine the scope and generality of this protocol, we have
used different substituted aldehydes and indoles to afford
corresponding 3-aminoalkylated indole in high yields. The results
are summarized in Table 2 (entries 1–12). Benzaldehydes having
both electron-donating and electron-withdrawing groups were
used and afforded the desired products in high yields.
A plausible mechanism is proposed in Scheme 2. We assume
that when N-methylaniline is reacted with aromatic aldehyde in
the presence of 3-chlorophenylboronic acid, an iminium ion
intermediate II is formed. An imminium ion is then attacked by
an electron rich indole to get the desired 3-aminoalkylated
indole 4.

[
S.V. Goswami et al. / Chinese Chemical Letters 24 (2013) 422–424
Cl
Cl
H
N
OH
OH
OH
B
B
NH
OH
O
OH
N
N
-H2O
I
II
Cl
OH
B
H
OH
N
N
N
N
H
4
III
Scheme 2. Plausible mechanism for synthesis of 3-aminoalkylated indoles.
(b) N. Mizuno, M. Misono, Multicomponent reactions, Chem. Rev. 98 (1998) 199–
218.
4. Conclusion
[10] D.K. Yadav, R. Patel, V.P. Srivastava, G. Watel, L.D.S. Yadav, Bromodimethylsulfo-
nium bromide (BDMS)-catalyzed multicomponent synthesis of 3-aminoalkylated
indoles, Tetrahedron Lett. 51 (2010) 5701–5703.
[11] P. Srihari, V.K. Sing, D.C. Bhunia, J.S. Yadav, One-pot three-component coupling
reaction: solvent-free synthesis of novel 3-substituted indoles catalyzed by PMA-
SiO2, Tetrahedron Lett. 50 (2009) 3763–3766.
[12] B. Das, J.N. Kumar, A.S. Kumar, K. Damodar, Facile synthesis of 3-[(n-alkylanili-
no)(aryl)methyl]indoles using TCT, Synthesis (2010) 914–916.
[13] V.K. Rao, B.S. Chhikara, A.N. Shirazi, et al., 3-Substitued indoles: one-pot synthesis
and evaluation of anticancer and Src kinase inhibitory activities, Bioorg. Med.
Chem. Lett. 21 (2011) 3511–3514.
In conclusion, our results demonstrate that 3-chlorophenyl-
boronic acid worked efficiently in the reaction for the synthesis of
3-aminoalkylated indoles. This protocol offers several advantages
such as mild reaction conditions, excellent yield and simple
experimental work up. Both analytical and spectroscopic data of
synthesized compounds are in full agreement with the proposed
structures.
[14] V.K. Rao, M.S. Rao, N. Jain, J. Panwar, A. Kumar, Silver triflate catalyzed synthesis of
3-aminoalkylated indoles and evaluation of their antibacterial activities, Org.
Med. Chem. Lett. 1 (2011) 10.
Acknowledgments
[15] D. Kundu, A.K. Bagdi, A. Majee, A. Hajra, Zwitterionic-type molten salt: a mild and
efficient organocatalyst for the synthesis of 3-aminoalkylated indoles via three-
component coupling reaction, Synlett 8 (2011) 1165–1167.
We acknowledge Dr. P.L. More and Dr. W.N. Jadhav, Dnyano-
pasak College, Parbhani for providing necessary facilities and
Financial support for this work by DST-SERC, New Delhi (SR/FT/CS-
023/2008) is highly appreciated.
[16] H. Lopez-Ruiz, H. Briseno-Ortega, S. Rojas-Lima, R. Santillan, N. Farfan, Phenyl-
boronic acid catalyzed-cyanide promoted, one-pot synthesis of 2-(2-hydroxy-
phenyl)benzoxazole derivatives, Tetrahedron Lett. 52 (2011) 4308–4312.
[17] H. Zheng, D.G. Hall, Mild and efficient boronic acid catalysis of Diels–Alder
cycloadditions to 2-alkynoic acids, Tetrahedron Lett. 51 (2010) 3561–3564.
[18] H. Zheng, M. Lejkowski, D.G. Hall, Mild and selective boronic acid catalyzed 1,3-
transposition of allylic alcohols and Meyer–Schuster rearrangement of pro-
pargylic alcohols, Chem. Sci. 2 (2011) 1305–1310.
[19] G.D. Tibhe, M. Bedolla-Medrano, C. Cativiela, M. Ordonez, Phenylboronic acid as
efficient and eco-friendly catalyst for the one-pot, three-component synthesis of
a-aminophosphonates under solvent-free conditions, Synlett 31 (2012)
1931–1936.
References
[1] M. Lounasman, A. Tolvanen, Simple indole alkaloids and those with a nonrear-
ranged monoterpenoid unit, Nat. Prod. Rep. 17 (2000) 175–191.
[2] S. Hibino, T. Choshi, Simple indole alkaloids and those with a nonrearranged
monoterpenoid unit, Nat. Prod. Rep. 19 (2002) 148–180.
[3] J.F. Collinus, Antibiotics, proteins and nucleic acids, Br, Med. Bull. 21 (1965) 223–
228.
[4] T.R. Garbe, M. Kobayashi, N. Shimizu, N. Takesure, M. Ozawa, H. Yukawa, Indolyl
carboxylic acids by condensation of indoles with alpha-keto acids, J. Nat. Prod. 63
(2000) 596–598.
[20] S.V. Goswami, P.B. Thorat, S.R. Bhusare, A facile one-pot synthesis of dicycloalk-
enopyridines at ambient temperature conditions, Tetrahedron Lett. 53 (2012)
6771–6774.
[5] B. Bao, Q. Sun, X. Yao, et al., Cytotoxic bisindole alkaloids from a marine sponge
Spongosorites sp, J. Nat. Prod. 68 (2005) 711–715.
[6] J. Zhu, H. Bienayme´ (Eds.), Multicomponent Reactions, Wiley-VCH, Weinheim,
2005.
[7] H.R. Hobbs, N.R. Thomas, Biocatalysis in supercritical fluids, in fluorous solvents,
and under solvent-free conditions, Chem. Rev. 107 (2007) 2786–2820.
[8] A. Domling, Multicomponent reactions, Chem. Rev. 106 (2006) 17–89.
[9] (a) A. Domling, I. Ugi, Multicomponent reactions, Angew. Chem. Int. Ed. 39 (2000)
3168–3210;
[21] S.V. Goswami, P.B. Thorat, S.R. Bhusare, An efficient one-pot multi-component
synthesis of highly functionalized piperidines, Heterocycl. Commun. 18 (2012)
245–248.
[22] R.N. Adude, R.M. Tigote, S.V. Goswami, R.S. Bhusare, 3-Nitrophenylboronic acid-
catalyzed efficient one-pot synthesis of 1,4-dihydropyridines and polyhydroqui-
nolines, Int. J. Ind. Chem. 3 (2012) 6.
[23] S.V. Goswami, P.B. Thorat, A.V. Chakrawar, S.R. Bhusare, A mild and efficient one-
pot synthesis of b-amino carbonyl compounds via Mannich reaction under
ambient temperature condition, Mol. Divers. 17 (2013) 33–40.