An eco-compatible multicomponent strategy for the synthesis of new 2-amino-6-(1H-indol-3-yl)-4-arylpyridine-3,5-dicarbonitriles in aqueous micellar medium promoted by thiamine-hydrochloride

Article abstract of DOI:10.1016/j.tetlet.2014.02.050

A thiamine hydrochloride (VB₁) accelerated, one-pot synthesis of 2-amino-6-(1H-indol-3-yl)-4-arylpyridine-3,5-dicarbonitriles was achieved via four-component reaction of 3-cyanoacetyl indole, aromatic aldehydes, ammonium acetate, and malononitrile in aqueous micellar conditions by a Knoevenagel condensation reaction followed by Michael-addition, which upon cyclization and dehydration yielded the corresponding product in excellent proportion.

Full text of DOI:10.1016/j.tetlet.2014.02.050

Tetrahedron Letters 55 (2014) 2201–2207
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An eco-compatible multicomponent strategy for the synthesis
of new 2-amino-6-(1H-indol-3-yl)-4-arylpyridine-3,5-dicarbonitriles
in aqueous micellar medium promoted by thiamine-hydrochloride
⇑
Shahin Fatma, Divya Singh, Preyas Ankit, Priya Mishra, Mandavi Singh, Jagdamba Singh
Department of Chemistry, University of Allahabad, Allahabad 211002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2013
Revised 10 February 2014
Accepted 16 February 2014
Available online 24 February 2014
A thiamine hydrochloride (VB1) accelerated, one-pot synthesis of 2-amino-6-(1H-indol-3-yl)-4-arylpyri-
dine-3,5-dicarbonitriles was achieved via four-component reaction of 3-cyanoacetyl indole, aromatic
aldehydes, ammonium acetate, and malononitrile in aqueous micellar conditions by a Knoevenagel con-
densation reaction followed by Michael-addition, which upon cyclization and dehydration yielded the
corresponding product in excellent proportion.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Thiamine hydrochloride
Cyano acetyl indole
One-pot
CTAB
Michael addition
Nitrogen containing heterocyclic compounds hold a special
place among pharmaceutically significant natural products and
synthetic compounds.1 One of the most important heterocyclic
core moieties is the pyridine ring system which exhibits diverse
biological and physiological activities.2
Among pyridines, 2-amino-3-cyanopyridine derivatives have
raised considerable attention owing to their activity to inhibit PrPSc
accumulation in scrapie-infected mouse neuroblastoma cells
(ScN2a),3a MAPK-activated PK-2,3b and IKK-2 for treating HBV
infection,3c and modulate androgen receptor function.3d In addi-
tion, they serve as potassium channel openers for the treatment
of urinary incontinence4 and also act as anti-prion,3a,5 anti-hepati-
tis-B virus,6 anti-bacterial,7 and anti-cancer3b agents. Recently,
some of these compounds have been recognized as potential
targets for the development of new drugs in the treatment of Par-
kinson’s disease, hypoxia, asthma, kidney disease, epilepsy, cancer8
and Creutzfeldt–Jakob disease.3a,5a,9,10
activities.13–20 The wide range of biological activities endowed
with pyridines and 3-substituted indole derivatives encouraged
us to synthesize novel compounds having additive effect of bio-
activities of both privileged scaffolds.
The use of various organic catalysts has gained wide interest in
organic synthesis due to their several advantages such as opera-
tional simplicity, environmentally benign procedure, recyclability,
low cost, and ease of isolation after completion of the reaction.21
In this regard, thiamine hydrochloride (VB1; Fig. 1) analogs,
as powerful catalysts have been applied in various organic
transformations.22,23 Currently, several VB1 catalyzed reactions for
the synthesisof heterocyclic compoundssuchas pyrimidnones,24 dihy-
dropyridines,25 benzo[4,5]imidazo[1,2-a]pyrimidine/[1,2,4]triazolo
[1,5-a]pyrimidine,26a and quinoxaline derivatives26b have been
reported.
With the development of modern synthetic approaches, it has
been widely acknowledged that there is a growing need for the
development of environmentally benign processes in the chemical
Another example of the ‘privileged scaffolds’ is indole frame-
work which is most ubiquitous in nature and also an important
structural component in many pharmaceutical agents.11 Among
indoles, 3-substituted indole scaffolds are found in a number of
biologically active compounds containing anticancer, antitumour,12
hypoglycemic, anti-inflammatory, analgesic, and antipyretic
Cl
NH3
CH3
Cl
OH
N
N
S
H3C
N
⇑
Corresponding author. Tel.: +91 9415218507.
E-mail address: dr.jdsau@gmail.com (J. Singh).
Figure 1. Structure of thiamine-hydrochloride (VB1).
http://dx.doi.org/10.1016/j.tetlet.2014.02.050
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

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S. Fatma et al. / Tetrahedron Letters 55 (2014) 2201–2207
R1
NC
R1
CN
2
VB1,57°C
CHO
+
H2O-CTAB
NH4OAc
1
NC
CN
4
R2
R2
O
N
NH2
CN
N
H
HN
3
5
for model reaction;
R1= 4-NO2
R2 = H
Scheme 1. One pot four-component synthesis of cyanoindolyl pyridines.
O
CN
cyanoacetic acid,Ac2O
60-700C ,5 min
N
H
N
H
Scheme 2.
Table 1
industry.27,28 In contrast to this, we noticed that the synthesis of
2-amino, 3-cyano pyridine derivatives is performed mostly in
presence of organic solvents such as pyridine and benzene.29,30
The reaction sometimes involves high temperature, microwave
assistance31 and rare earth metals as catalysts.32 Although a num-
ber of modified methods under improved conditions have been re-
ported, many of them suffer from one or more drawbacks, such as
unsatisfactory yields, high temperatures, long reaction times, and
the use of toxic organic solvents and catalysts.
Effect of different surfactants on the yield of the thiamine-hydrochloride (VB1)
catalyzed reaction (Scheme 1, R1 = 4-NO2, R2 = H)a
Entry
Surfactant
Concentration
(mol %)
Time
(min)
Yield
(%)
1
2
3
4
CTAB
CTAB
SDS
5
10
10
10
30
25
45
38
86
92
64
65
TTAB
a
Reaction conditions: VB1 (5 mol %), 4-nitrobenzaldehyde (1 mmol) + malono-
Thus, we found it necessary to develop an efficient and conve-
nient method to construct such type of extremely bio-active het-
erocyclic compounds in aqueous media. Water is the desirable
medium for reasons of cost, safety, and environmental impact.
Additionally, it can also influence the reaction rate and selectivity
due to extensive H-bonding and large dielectric constant.
A powerful approach is the use of aqueous micellar medium to
perform various multi-component reactions (MCRs). This approach
is of particular importance since it addresses various operational
difficulties that can be observed in plain aqueous medium.33a Mi-
celles are dynamic clusters of surfactant molecules having both
hydrophilic and hydrophobic moieties. They can concentrate the
reactants within a small volume, and stabilize substrate, interme-
diate, or products.33b Hence, they offer multiple advantages such as
enhanced solubility, reaction rate, regio- and stereo-selectivity,
and yield of the products.
nitrile (1 mmol) + cyanoacetyl indole (1 mmol) + ammonium acetate (3 mmol) at
57 °C.
Table 2
Optimization of concentration of catalyst thiamine-hydrochloride (VB1) for the
reaction (Scheme 1, R1 = 4-NO2, R2 = H)a
Entry
Catalyst conc. (mol %)
Time (min)
Yieldb (%)
1
2
3
4
5
0
3
5
5
10
30
25
25
25
25
35
70
92
85, 80c
92
a
Reaction conditions: catalyst + 4-nitrobenzaldehyde (1 mmol) + malononitrile
(1 mmol) + cyanoacetyl indole (1 mmol) + ammonium acetate (3 mmol), in CTAB-
H2O (10 mol % in 10 ml) at 57 °C.
b
Isolated yields after recrystallization.
Yields of products with recycled catalyst in 2-successive runs.
c
Here, VB1 catalyzed synthesis of novel indolyl pyridine deriva-
tives has been reported in aqueous micellar medium (Scheme 1).
The reaction is one-pot, multicomponent and to the best of our
knowledge, no reports are available for the synthesis of series of
these bioactive compounds.
recently by Bergman35 via a new facile approach starting from
indoles and cyanoacetic acid (Scheme 2).
Compounds such as 3-cyanoacetyl indoles (3; which have been
Initially, model reaction was performed by taking 4-nitrobenz-
aldehyde (1; R1 = 4-NO2), malononitrile 2, (3-cyanoacetyl)-indole
used here) were previously prepared by Kreher and Wagner34 and

S. Fatma et al. / Tetrahedron Letters 55 (2014) 2201–2207
2203
Table 3
contribute significantly to promote the reaction, since they act as
emulsifying agents when mixed with organic reagents to form col-
loidal dispersion. Surfactants can be conveniently isolated after
completion of the reaction by using the powdered activated carbon
method.37
An encouraging result was obtained when the reaction was car-
ried out with 5 mol % of cetyltrimethylammonium bromide (CTAB:
cmc value 0.92 mM)38a in 10 ml water producing 86% yield. When
CTAB concentration was increased to 10 mol %, 92% yield was
obtained. We have also studied the effect of other surfactants
(Table 1), such as anionic surfactant sodiumdodecylsulphate
(SDS: cmc value 8.1 mM)38b and cationic surfactant tetradecyltrim-
ethylammonium bromide (TTAB: cmc value 3.8 mM)38c on the
model reaction. We found that anionic surfactant SDS and cationic
surfactant TTAB had not given satisfactory yields (in comparison to
CTAB). So we decided to use CTAB as emulsifying agent to perform
Influence of solvents on the yield of compound 5a
Entry
Solvent
Temp
Time (h)
Yield (%)
1
2
3
4
5
6
7
THF
Reflux
100
6
6
6
6
3
3
30
50
60
30
70
85
92
Toluene
MeCN
DCM
EtOH
H2O
Reflux
Reflux
Reflux
Reflux
57 °C
H2O/CTAB
25 min
(3; R2 = H), and ammonium acetate 4 in water. Water was also cho-
sen as preferred solvent because cyclization reactions occur very
conveniently in polar solvents.36 The reaction could not occur
due to the partial solubility of one or more substrates in water.
To overcome this problem, we introduced surfactants, which
Table 4
Yields of condensation products 5a–n of VB1-catalyzed reaction of arylaldehydes 1, with malononitrile 2, (3-cyanoacetyl)-indole (3; R2 = H, CH3) and NH4OAc 4 (Scheme 1)a
Entry
R1
R2
Product (5a–n)
Yield (%)
NO2
N
N
1
4-NO2
H
92
H2N
N
NH
5a
O2N
N
N
2
3-NO2
H
92
H2N
N
NH
5b
Cl
N
N
3
4-Cl
H
90
H2
N
N
NH
5c
Cl
N
N
4
2-Cl
H
90
H2N
N
NH
5d
(continued on next page)

2204
S. Fatma et al. / Tetrahedron Letters 55 (2014) 2201–2207
Table 4 (continued)
Entry
R1
R2
Product (5a–n)
Yield (%)
Cl
Cl
N
N
5
2,4(Cl)2
H
92
H2
N
N
NH
5e
OMe
N
N
6
4-MeO
H
92
N
H2N
NH
5f
OMe
MeO
N
N
7
3,4-(MeO)2
H
92
H2
N
N
NH
5g
OMe
HO
N
N
8
3-HO, 4-MeO
H
94
H2N
N
NH
5h
OH
MeO
N
N
9
4-HO, 3-MeO
H
93
H2N
N
NH
5i

S. Fatma et al. / Tetrahedron Letters 55 (2014) 2201–2207
2205
Table 4 (continued)
Entry
R1
R2
Product (5a–n)
Yield (%)
OH
N
N
10
4-OH
H
91
H2N
N
NH
5j
NO2
N
N
11
4-NO2
6-CH3
91
CH3
H2
N
N
NH
5k
Cl
N
N
12
4-Cl
6-CH3
90
CH3
H2N
N
NH
5l
OMe
N
N
13
4-OMe
6-CH3
90
CH3
H2N
O2N
N
NH
5m
N
N
14
3-NO2
6-CH3
90
CH3
H2N
N
NH
5n
a
Conditions: arylaldehyde (1 mmol), (3-cyanoacetyl)-indole derivative (1 mmol), malononitrile (1 mmol), NH4OAc (3 mmol), VB1 (5 mol %), and CTAB (10 mol %) in H2O
(10 ml) at 57 °C.
the condensation reaction in water for the facile and convenient
conversion of reactants to product.
To study the effect of catalyst, we performed the reaction using
various concentrations of catalyst (Table 2). When the reaction was
carried out without catalyst, we got only 35% yield in 30 min at
57 °C temperature, but when the same reaction was performed
with VB1 in a catalytic amount (3 mol %), we recovered 70% yield
with slight reduction in time, that is, 25 min (Table 2). When the

2206
S. Fatma et al. / Tetrahedron Letters 55 (2014) 2201–2207
O
R1
R1
R1
CN
R
1
CN
+
CN
N
C
NC
A
1
2
NC
NC
CN
N
NC
CN
N
NC
C
H2N
C
NH
HN
NH
NH
2
HN
O
HN
NH3
NH
NH
C
B
3
R2
R2
R2
R2
R
2
R1
R1
NC
CN
NC
CN
VB1
N
H
NH2
N
NH2
HN
NH-moiety
HN
D
R2
R2
5(a-n)
Scheme 3. Plausible mechanism of the VB1 catalyzed synthesis of cyanoindolyl pyridines.
catalyst concentration was increased to 5 mol %, higher yield (92%)
of the product was achieved. Further increase of catalyst concen-
tration did not show any effect on product yield. It was therefore
concluded that the optimum concentration of catalyst was 5 mol %.
The catalyst was also screened for recyclability and efficiency in
successive catalytic runs. After product isolation by simple filtra-
tion, the filtrate containing catalyst was further applied by taking
the same reactants to perform two successive catalytic runs. Yields
were found to be 85% and 80%, respectively (Table 2, entry 4).
For solvent optimization, the reaction was also performed un-
der various organic solvents and best result was obtained when
water was used (Table 3).
Lastly, to explore the scope and generality of the reaction,
we extended our work under optimized reaction conditions to
various substituted arylaldehydes and, in almost all of the studied
examples, no considerable effect of the substituent on aldehydes
(electron withdrawing group or electron donating groups) was
noticed. In almost all cases, rapid synthesis of the products
occurred in good to excellent yields, with just 5 mol % of the cata-
lyst concentration (Table 4). All of the fourteen new compounds
were characterized by their spectral data and elemental analysis.
which on cyclization and dehydration gives the product 5 via inter-
mediate D. The role of VB1 as a catalyst may be postulated in terms
of the NH-proton of the VB1, leading to its interaction with the car-
bonyl oxygen atom of aldehyde as well as (3-cyanoacetyl)-indole,
thereby facilitating the polarization and promoting the cyclocon-
densation reaction.
In summary, we have developed a simple, highly efficient,
economical, versatile, and ecofriendly method for the synthesis
of novel 4-aryl-2-aminocyanopyridine derivatives containing
indole moieties, by one-pot four-component condensation reac-
tion in aqueous micellar medium, using catalytic amounts of
inexpensive and non-hazardous thiamine hydrochloride (VB1).
Clean, safe, convenient, eco-compatible, and high atom economi-
cal approach is the beauty of the proposed protocol. Biological
activity of newly synthesized compounds is under screening in
our laboratory.
Acknowledgements
We sincerely thank SAIF, Punjab University for providing micro-
analysis and spectra. The authors are also grateful to CSIR, New
Delhi for providing financial support in terms of junior/senior
research fellowship.
Plausible mechanism for the condensation reaction
From the mechanistic point of view, it is proposed (Scheme 3)
that first step is the formation of the intermediate A from the
Knoevenagel condensation between aldehyde 1 and malononitrile
Supplementary data
Supplementary data (newly synthesized compounds were fully
characterized by spectroscopic data) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2014.02.050.
2. Simultaneously (3-cyanoacetyl)-indole
3 reacts with NH3
generated in situ by decomposition of ammonium acetate) to give
intermediate B. Both A and B further react to give intermediate C,

S. Fatma et al. / Tetrahedron Letters 55 (2014) 2201–2207
2207
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