Iron mediated one pot three component synthesis of 3-substituted indoles via aerobic iminium ion formation

Article abstract of DOI:10.1016/j.tetlet.2015.12.047

An efficient and economical method was developed for the synthesis of 3 substituted indoles by a highly efficient one-pot three component coupling reaction of substituted or unsubstituted benzyl alcohol, N-methyl aniline or pyrrolidine, and indoles or sub

Full text of DOI:10.1016/j.tetlet.2015.12.047

Accepted Manuscript
Iron mediated one pot three component synthesis of 3-substituted indoles via
aerobic iminium ion formation
Vinay K. Singh, Laxmi Kant Sharma, Rana Krishna Pal Singh
PII:
S0040-4039(15)30462-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.047
TETL 47094
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 October 2015
3 December 2015
8 December 2015
Please cite this article as: Singh, V.K., Sharma, L.K., Singh, R.K.P., Iron mediated one pot three component synthesis
of 3-substituted indoles via aerobic iminium ion formation, Tetrahedron Letters (2015), doi: http://dx.doi.org/
10.1016/j.tetlet.2015.12.047
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Graphical Abstract
Iron mediated one pot three component
synthesis of 3-substituted indoles via aerobic
iminium ion formation
Leave this area blank for abstract info.
Vinay K. Singh, Laxmi Kant Sharma and Rana Krishna Pal Singh*
R'
CH3
N
N
H
R''
(Fe(NO3)3.9H2O/
TEMPO), KOH
N
H3C
HO
R
R
NH
+
H3C
R'
R''
N
H

1
Tetrahedron Letters
Iron mediated one pot three component synthesis of 3-substituted indoles via aerobic
iminium ion formation
Vinay K. Singh, Laxmi Kant Sharma and Rana Krishna Pal Singh*
Electrochemical laboratory of green synthesis, Department of Chemistry, University of Allahabad, Allahabad 211002, India
 Corresponding author: Tel.: +91 532 2465287; fax: +91 532 2460533; E-mail address: rkp.singh@rediffmail.com (R. K. P. Singh)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and economical method was developed for synthesis of 3 substituted indoles by
highly efficient one-pot three component coupling reaction of substituted or unsubstituted
benzylalcohol, N-methyl aniline or pyrrolidine and indoles or substituted indoles.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction,
Atom economy
Indoles
Mannich reaction
Synthetic organic chemists have been continuously
synthesis of substituted indoles, the development of simple,
efficient, short and environmentally benign approaches for
synthesis of indole derivatives is highly desirable.
striving for improving the efficiency of organic synthesis,
especially in terms of the atom economy and cost effectiveness.
In this context, one-pot strategy involving the formation of multi
component reaction is highly attractive. Multi component
reactions (MCRs) play an important role in atom economy and
green chemistry1. These reactions are environmentally friendly,
energy saving and produces low wastage. Multi-component
reactions2 (MCRs), which combine in one pot several simple
building blocks, provide a most powerful platform to access
diversity as well as complexity in a limited number of reaction
steps. It is well utilized in the synthesis of medicinal compounds
such as substituted indoles3, decahydroquinolin-4-ones4, 1,4
dihydropyridines. Strategy of multicomponent reactions have
been playing a significant role in preparation of structurally
diverse chemical compound. The Indole is versatile synthetic
intermediates for biologically active compound which served as
scaffold in a number of natural and synthetic substituted indoles.
Recently Indole derivatives structural unit of many natural and
synthetic unit of biologically active compound which passes
various pharmacological properties.
F
Me
N
Me
N
N
Br
MeO
N
Et
N
H
Azolylbenzyl indole
3 Amino alkylated indole
Figure 1. Biologically active 3 substituted indoles
Previous work:
N
H3C
R2
catalyst
R'
R2
+
+
NH
N
H
O
H3C
R'
N
H
Indole derivatives multi-component are one of the most
abundant components of natural products as well as synthetic
compounds possessing a variety of biological, medicinal and
agrochemical chemistry. The biological activity of substituted
indole has attracted to explore different methods for synthesis of
indoles. Their biological properties5 have attracted many
synthetic chemists to explore different methods suitable for the
synthesis of substituted indoles. Though there are several
methods reported in literature for formation of three component
reaction. Despite several methods reported in the literature for the
R'
HN
R'
N
H
Present work:

2
Tetrahedron
(2a) (1.2 mmol), and N-methyl aniline (1a mmol) with 50 mole
R
N
N
H
CH3
N
(Fe(NO3)3.9H2O/
TEMPO), KOH
% of KOH in 0.5 ml of toluene in the presence 10/10 mol% of
(Fe(NO3)2.9H2O/ TEMPO) for 24-30 h to yield imine which was
again treated with indole, it gives desired novel 3 substituted
indole as a single product. It was found that base played crucial
role in the reaction as from table 1 (entry 1), reaction was initially
tested at room temperature with catalytic amount of KOH added
but only a low yield 30% was detected. Reaction yield can be
improved when it is heated at higher temperature yield 4a 85%
H3C
HO
+
R
R
NH
H3C
N
H
Scheme 1. Synthesis of 3 substituted indole.
In the earlier methods three component compounds
were prepared by formation of condensation method. Which
suffers the drawback of using the odorous3d and unstable
aldehyde3f, and also require in situ purification. Earlier methods
also require large excess amounts of oxidants, which will also
produce large amounts of undesired waste so developing
efficient and greener methods is still an important need.
Table1
o
should be achieved at 80 C using KOH as base (Table 1, entry
3).
During the course of reaction we attempted similar
transformation in various solvent such as CH2Cl2, DMSO, DMF,
THF, acetonitrile, benzene, toluene, dioxane among these solvent
benzene, toluene, dioxane and xylene (Table 1, entries 1-1-6 and
9-12) were found to be most efficient reaction media to give the
product in good yield (76-85) %.
Optimization of reaction conditionsa:
R
Furthermore catalyst condition were optimized by using
different variation of catalyst, catalyst loading and time period of
reaction screening showed that 10 mol % of CsOH, and t-BuOK
were used in place potassium hydroxide reaction. The yield was
very good when potassium hydroxide is used as base table 1
(entries 1-3) to facile this reaction. After optimization of reaction
condition different alcohols aliphatic and aromatic alcohol,
saturated and unsaturated alcohol reaction works well in aromatic
alcohols proceed in all condition except in aliphatic and
unsaturated alcohols and gives corresponding product in good
yields. Reaction proceeds well in both electron donating and
electron withdrawing group for present protocol reaction. The
result prompted us to investigate scope and generality of this
methodology yielding 3 substituted indoles. Pyrrolidine and N-
methyl aniline gave better results when compared with piperidine
and morpholine as shown in the table 2.
N
H
CH3
N
(Fe(NO3)3.9H2O/
TEMPO), KOH
N
H3C
HO
+
R
R
NH
H3C
N
H
Entry Fe(NO3)3.9 Solvent
H2O
Temp
rt
Baseb (mole %) Yield (%)c
(Mole %)
1
10
10
20
50
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Benzene
Benzene
Benzene
Dioxane
Dioxane
Xylene
KOH (10)
KOH (10)
KOH (10)
KOH (20)
KOH (50)
t-BuOK (10)
K2CO3 (10)
Et3N (10)
30
2
50 oC
55
3
80 oC
80 oC
80 oC
80 oC
80 oC
80 oC
80 oC
80 oC
80 oC
80 oC
80 oC
80 oC
80 oC
80 oC
80 oC
80 oC
80 oC
85
4
83
5
84
6
81
7
n.d.
n.d.
76
N
O
N
O
Fe+2
O2
CH2OH
R''
Fe+3
8
1/2O2
Base
9
t-BuOK (10)
t-BuOK(10)
KOH(10)
N
H
10
11
12
13
14
15
16
17
18
19
78
O
O
H
N
OH
81
R''
O
R''
83
KOH (10)
Et3N (10)
H
H
N
Xylene
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
Catalyst
CH3
R
DMF
KOH (10)
KOH (10)
KOH (10)
KOH (10)
KOH (10)
KOH (10)
CH3
N
R''
R
N
R
CH3CN
THF
H3C
H
N
R'
N
R'
DMSO
H
Scheme 2. A plausible mechanism for the formation for 3
substituted indole.
CH2Cl2
CH3CN+H2O
A plausible mechanism for this reaction is suggested in
Scheme 2. Mechnistically it was presumed that formation of 3-
substituted indole reaction was proceeded through formation of
imine7, followed by nucleophilic attack of indole to give 3
substituted indole as shown in scheme 2.
(4:1)
80oC
a
All reactions were run with 1a (1.0 mmol), 2a (1.0 mmol), 3a (1.2 mmol)
Fe(NO3)3.9H2O (10 mol %), and the base in toluene (0.5 mL) and solvent (3
mL) was heated under air in a 10 mL of sealed tube for 24 -30 h and then
added by indole and monitored by TLC at room temperature.
b 0.1 mmol of TEMPO was used along with base in all the cases.
c Isolated yield of 4a; n.d.= not detected.
Table 2
Reaction was carried out in sealed tube.
We initiated our studies of three-component reaction
with N-methyl aniline (1a) (1 mmol), benzyl alcohol (2a) (1.2
mmol), and indole (3a) (1 mmol) was taken as a model substrate
to optimize the reaction condition. Treatment of benzyl alcohol

3
Substrate scope for the preparation of 3 substituted indolesabc
In conclusion, we developed a highly efficient, short and green
method for the synthesis of 3-amino-alkylated indole via one-pot
three-component Mannich3d, 3g, 3m type reaction. The Mannich-
type reactions are very important carbon–carbon bond-forming
reactions in organic synthesis. It is easy and safe to handle at a
large scale synthesis for preparation of the final product make
R'
(Fe(NO3)3.9H2O/
TEMPO), KOH
N
H
CH3
N
R
R''
N
4
H3C
HO
R
+
NH
H3C
R'
R''
2
1
N
3
H
this an attractive protocol by using insitu iminium ion formation.
5
Acknowledgments
N
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing microanalyses and spectra. Vinay K. Singh is grateful
to the UGC, New Delhi, for the award of a DS Kothari
postdoctoral fellowship and financial support.
N
N
N
H
O2N
N
H
5b
N
H
5c
38 h, (80%)
5d
39 h, (84%)
39 h, (87%)
Supplementary data
N
N
N
Supplementary data (detailed experimental procedures, product
characterization, and NMR spectra of the products) associated with this
article can be found, in the online version.
N
H
N
H
MeO
OH
N
H
5f
Cl
5e
5g
36 h, (84%)
38 h, (85%)
34 h, (82%)
References and notes
1.
2.
(a) Zhou, Y. J.; Chen, D. S.; Li, Y. L.; Liu, Y.; Wang, X. S. ACS
Comb. Sci. 2013, 15, 498; (b) Azizi, N.; Aryanasab, F.; Saidi, M.
R. Org. Lett. 2006, 23, 5275.
N
N
N
N
N
H
N
H
For recent reviews on multicomponent reactions see: (a)
Domling, A. Chem. Rev. 2006, 106, 17; (b) Ramon, D. J.; Yus,
M. Angew. Chem., Int. Ed. 2005, 44, 1602; (c) Domling, A.;
Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168; (d) Tejedor, D.;
Garcia-Tellado, F. Chem. Soc. Rev. 2007, 36, 484; (e) Hulme,
C.; Gore, J. Curr. Med. Chem. 2003, 10, 51; (f) Orru, R. V. A.;
De Greef, M. Synthesis 2003, 1471; (g) Jacobi von Wangelin,
A.; Neumann, H.; Gordes, D.; Klaus, S.; Strubing, D.; Beller, M.
Chem. Eur. J. 2003, 9, 4286; (h) Nair, V.; Rajesh, C.; Vinod, A.
U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L.
Acc. Chem. Res. 2003, 36, 899; (i) Zhu, J. Eur. J. Org. Chem.
2003, 1133; (j) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J.
Org. Chem. 2004, 4957;(k) Tempest, P. Curr. Opin. Drug
Discovery Dev. 2005, 8, 776.
(a) Smith, A. B., III; Kanoh, N.; Minakawa, N.; Rainier, J. D.;
Blase, F. R.; Hartz, R. A. Org. Lett. 1999, 1, 1263; (b) Kumar,
A.; Gupta, M. K.; Kumar, M. Green Chem. 2012, 14, 290; (c)
Kumar, A.; Gupta, M. K.; Kumar, M.; Saxena, D. RSC Adv.
2013, 3, 1673; (d) Srihari, P.; Singh, V. K.; Bhunia, D. C.;
Yadav, J. S. Tetrahedron Lett. 2009, 50, 3763; (e) Kundu, D.;
Bagdi, A. K.; Majee, A.; Hajra, A. Synlett 2011, 1165; (f) Das,
B.; Kumar, J. N.; Kumar, A. S.; Damodar, K. Synthesis 2010,
914; (g) Rao, V. K.; Chhikara, B. S.; Shirazi, A. N.; Tiwari, R.;
Parang, K.; Kumar, A. Bioorg. Med. Chem. Lett. 2011, 21, 3511;
(h) Goswami, S. V.; Thorat, P. B.; Kadam, V. N.; Khiste, S. A.;
Bhusare, S. R. Chin. Chem. Lett. 2013, 24, 422; (i) Devi, C. L.;
Rao, V. J.; Palaniappan, S. Synth. Commun. 2012, 42, 1593; (j)
Yadav, D. K.; Patel, R. Srivastava, V. P.; Watal, G.; Yadav, L.
D. S. Tetrahedron Lett. 2010, 51, 5701; (k) Mi, X.; Luo, S.; Hea,
J.; Cheng, J. P. Tetrahedron Lett. 2004, 45, 4567; (l) Shirakawa,
S.; Kobayashi, S. Org. Lett. 2006, 8, 4939; (m) Rajesh, U. C.;
Kholiya, R.; Pavan, V. S; Rawat, D. S. Tetrahedron Lett. 2014,
55, 2977; (n) Ottoni, O.; Neder, A. V. F.; Bias, A. K. B.; Cruz,
R. P. A.; Aquino, L. B. Org. Lett.2001, 3, 1005.
(a) Dondoni, A.; Massi, A.; Sabbatini, S.; Bertolasi, V. J. Org.
Chem. 2002, 67, 6979; (b) Lin, C.; Fang, H.; Tu, Z.; Liu, J.-T.;
Yao, C.-F. J. Org. Chem. 2006, 71, 6588; (c) Evdokimov, N. M.;
Magedov, I. V.; Kireev, A. S.; Kornienko, A. Org. Lett. 2006, 8,
899; (d) Dardennes, E.; Kovacs-Kulyassa, A.; Boisbrun, M.;
Petermann, C.; Laronze, J.-Y.; Sapi, J. Tetrahedron: Asymmetry
2005, 16, 1329; (e) Dardennes, E.; Kovacs-Kulyassa, A.;
Renzetti, A.; Sapi, J.; Laronze, J.-Y. Tetrahedron Lett. 2003, 44,
221.
(a) Jiang, B.; Yang, C.-G.; Wang, J. J. Org. Chem. 2001, 66, 4865;
(b) Zhang, H.; Larock, R. C. Org. Lett. 2001, 3, 308; (c)
Sakagami, M.; Muratake, H.; Natsume, M. Chem. Pharm. Bull.
1994, 42, 1393; (d) Fukuyama, T.; Chen, X. J. Am. Chem. Soc.
1994, 116, 3125;
5j
5h
5i
38 h, (79%)
34 h, (86%)
35 h, (80%)
OMe
Br
N
N
N
N
N
5l
N
H
Cl
5m
5k
35 h, (83%)
32 h, (87%)
38 h, (84%)
O
N
3.
Br
OMe
N
N
MeO
N
N
H
N
H
Cl
H
5p
5o
5n
36 h, (84%)
38 h, (80%)
36 h, (87%)
Br
N
N
N
O
N
O
Cl
NH
5s
Cl
N
H
33 h, (81%)
H
5r
5q
38 h, (85%)
35 h, (82%)
O
O
N
N
Br
N
N
O
N
N
H
H
4
H
5v
5u
5t
38 h, (80%)
38 h, (84%)
36h, ( 80%)
———
a For experimental procedure, see supporting information.
b
All compounds are known and were characterized by
comparison of their spectral data with those reported in the
literature.3d,3m
5
c
Yields of isolated pure compounds 4a.

4
Tetrahedron
(f) Casapullo, A.; Bifulco, G.; Bruno, I.; Riccio, R. J. Nat. Prod.
2000, 63, 447; (g) Horgen, F. D.; Santos, D. B. D.; Goetz, G.;
Sakamoto, B.; Kan, Y.; Nagai, H.; Scheuer, P. J. J. Nat. Prod.
2000, 63, 152.
6
7
(a) Singh, S.; Sharma, L. K.; Saraswat, A.; Siddiqui, I. R.; Kehri,
H. K.; Singh, R. K. P.; RSC Adv. 2013, 3, 4237; (b) Siddiqui, I.
R.; Srivastava, A.; Shamim, S.; Srivastava, A.; Shireen,
Waseem, M. A.; Singh, R. K. P. Synlett 2013, 24, 2586; (c)
Siddiqui, I. R.; Srivastava, A.; Shamim, S.; Srivastava, A.;
Shireen, Waseem, M. A.; Abumhdi, A. A. H.; Srivastava, A.;
Rai. Pragati.; Singh, R. K. P. Asian j.org. chem 2013, 2, 519.
(a) Zhang,E.; Tian, H.; Yu, X.; Xu, Q.; Org. Lett. 2013, 15, 2704.