Application of Triphenylammonium Tricyanomethanide as an Efficient and Recyclable Nanostructured Molten-Salt Catalyst for the Synthesis of N -Benzylidene-2-arylimidazo[1,2- a ]pyridin-3-amines

Article abstract of DOI:10.1055/s-0036-1558965

Triphenylammonium tricyanomethanide (Ph ₃ NH)[C(CN) ₃ ] was synthesized and used as an efficient and recyclable nanostructured molten-salt (NMS) catalyst for the synthesis of N -benzylidene-2-arylimidazo[1,2- a ]pyridin-3-amines by the reaction of various (het)aryl aldehydes with trimethylsilyl cyanide and pyridin-2-amine under solvent-free conditions at 50 °C. The NMS catalyst could be simply recycled and reused several times without significant loss of its catalytic activity.

Full text of DOI:10.1055/s-0036-1558965

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
S. Baghery et al.
Letter
Synlett
Application of Triphenylammonium Tricyanomethanide as an Effi-
cient and Recyclable Nanostructured Molten-Salt Catalyst for the
Synthesis of N-Benzylidene-2-arylimidazo[1,2-a]pyridin-3-amines
Saeed Baghery*a
Mohammad Ali Zolfigol*a
N
N
Romana Schirhaglb
Masoumeh Hasanib,c
Ph3NH
O
N
N
(1 mol%)
Ar
Ar
N
Ar
H
N
+
SiMe3
a Department of Organic Chemistry, Faculty of Chemistry,
Bu-Ali Sina University, Hamedan 6517838683, Iran
saadybaghery@yahoo.com
zolfi@basu.ac.ir
mzolfigol@yahoo.com
solvent-free, 50 °C
NH2
N
isolated yield: 88–95%
time: 10–30 min
18 samples
N
b Groningen University, University Medical Center Groningen,
Antonius Deusinglaan 1, 9713 AV, Groningen, Netherlands
c Department of Analytical Chemistry, Faculty of Chemistry,
Bu-Ali Sina University, Hamedan 6517838683, Iran
Ar = Ph, mono- or disubstituted phenyl, 1- or 2-
naphthyl, cinnamyl, α-methylcinnamyl, 2-furyl, 2-
thienyl, 4-pyridyl
Received: 13.12.2016
Accepted after revision: 14.02.2017
Published online: 28.02.2017
a]pyridines display a wide variety of biological properties,
including antiinflammatory, antiviral, antitumor, antipyret-
ic, antibacterial, antiapoptotic, antifungal, antiprotozoal,
analgesic, hypnoselective, and anxioselective activities.14–24
Numerous synthetic methods using such systems as
KF/H2O,25 solvent-free/200 °C,26,27 BF3/MCM-41,28 bromo-
(dimethyl)sulfonium bromide,29 or a range of other sys-
tems30 have been developed for the synthesis of imid-
azo[1,2-a]pyridines.
DOI: 10.1055/s-0036-1558965; Art ID: st-2016-d0842-l
Abstract Triphenylammonium tricyanomethanide (Ph3NH)[C(CN)3]
was synthesized and used as an efficient and recyclable nanostructured
molten-salt (NMS) catalyst for the synthesis of N-benzylidene-2-arylim-
idazo[1,2-a]pyridin-3-amines by the reaction of various (het)aryl alde-
hydes with trimethylsilyl cyanide and pyridin-2-amine under solvent-
free conditions at 50 °C. The NMS catalyst could be simply recycled and
reused several times without significant loss of its catalytic activity.
In continuation of our studies on the development of
multicomponent reactions, molten salts, ionic liquids, and
green sustainable technology,31 we report the synthesis of
N-benzylidene-2-arylimidazo[1,2-a]pyridin-3-amines 4 by
the reaction of various aryl or hetaryl aldehydes 1 with
trimethylsilyl cyanide (3) and pyridin-2-amine (2) in the
presence of triphenylammonium tricyanomethanide
(Ph3NH)[C(CN)3], as an efficient and recyclable nanostruc-
tured molten-salt (NMS) catalyst, under solvent-free condi-
tions at 50 °C (Scheme 1).
Key words triphenylammonium tricyanomethanide, imidazopyri-
dines, nanostructured molten salt, aldehydes, pyridinamine, organoca-
talysis
Investigations into ionic liquids and molten salts have
shown that combinations of cation substitution and various
anions permit fine tuning of the solvent properties of these
substances.1,2 Modifications in the melting point, viscosity,
density, and solvation properties permit the rational design
of specific molten salts and ionic liquids. Applications of
these substances include, but are not confined to, their use
as green solvents for electrochemical systems, reactions,
and membrane separations, or as bulk fluids.3 Nowadays,
molten salts and ionic liquids have been shown to be more
than simple solvents, and they frequently play important
roles as catalysts. A significant feature of molten salts and
ionic liquids is the possibility of harmonizing their chemi-
cal properties and also of changing their solubilities to per-
mit phase separation.4,5 Many organic reactions have been
demonstrated to proceed in molten salts or ionic liquids
with excellent yields and high chemo- or stereoselectivi-
ties.6–10
N
N
N
H2O, 50 °C, 3 h
N
Ph3NH
+
Ph3N
N
N
triphenylammonium
tricyanomethanide
[Ph3NH][C(CN)3]
N
O
N
[Ph3NH][C(CN)3] (1 mol%)
solvent-free, 50 °C
Ar
Ar
H
SiMe3
N
3
1
+
N
NH2
4
Ar
2
N
Among nitrogen-fused azoles, imidazo[1,2-a]pyridines
have an important role due to their broad range of uses in
several disciplines, such as medicinal chemistry, organome-
tallic chemistry, or materials science.11–13 Imidazo[1,2-
Scheme 1 The synthesis of N-benzylidene-2-arylimidazo[1,2-a]pyri-
din-3-amines 4 catalyzed by (Ph3NH)[C(CN)3] as a nanostructured mol-
ten salt
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
S. Baghery et al.
Letter
Synlett
The structure of (Ph3NH)[C(CN)3] was investigated and
fully characterized by means of Fourier-transform IR, 1H
NMR, and 13C NMR spectroscopy; mass spectrometry; ther-
mogravimetry; differential thermal gravimetry; differential
thermal analysis; x-ray diffraction; and scanning and tun-
neling electron microscopy (see Supporting Information).
We found that 1 mol% of (Ph3NH)[C(CN)3] catalyzed the
model reaction of 4-nitrobenzaldehyde (1, Ar = 4-O2NC6H4)
with trimethylsilyl cyanide (2) and pyridin-2-amine (1) in a
short time to give high yields of N-(4-nitrobenzylidene)-2-
(4-nitrophenyl)imidazo[1,2-a]pyridin-3-amines (4, Ar = 4-
O2NC6H4) with short reaction times (Table 1, entries 8 and
9). There was no significant change in the yield when larger
amounts of the catalyst were used. The reaction was very
slow at room temperature (entries 4, 7, and 10), but pro-
ceeded efficiently at higher temperatures (entries 5, 6, 8, 9,
11, and 12), 50 °C being chosen as the optimal temperature.
At 50 °C with 1 mol% of catalyst, the product was isolated in
95% yield. In the absence of the catalyst, the reaction was
very slow and did not proceed to completion (entries 1–3).
Table 2 Effects of Solvent on the Reaction of 4-Nitrobenzaldehyde (1,
Ar = 4-O2NC6H4), Trimethylsilyl Cyanide (3), and Pyridin-2-amine (2) at
50 °C in the Presence of 1 mol% of (Ph3NH)[C(CN)3]a
Entry
Solvent
Time (min)
Yieldb (%)
1
2
3
4
5c
6
7
8
–
10
15
15
20
25
25
30
30
95
91
91
87
83
85
25
33
H2O
EtOH
MeCN
CH2Cl2
EtOAc
hexane
toluene
a Reaction conditions: 4-nitrobenzaldehyde (2 mmol, 0.302 g), TMSCN (1
mmol, 0.099 g), pyridin-2-amine (1 mmol, 0.094 g), (Ph3NH)[C(CN)3] (1
mol%, 0.0034 g), 50 °C.
b Isolated yield.
c Reflux conditions.
Having determined the optimal conditions for the reac-
tion, we tested the generality of this method for a range of
aldehydes 1 with TMSCN (3), and pyridin-2-amine (2). Aro-
matic aldehydes 1 with electron-donating or electron-with-
drawing substituents and several heteroaromatic aldehydes
gave good to excellent results (Table 3); aromatic aldehydes
with electron-withdrawing substituents underwent faster
reactions than those with electron-donating substituents.
Heteroaromatic aldehydes took longer to react than aro-
matic aldehydes and they gave lower yields of the corre-
sponding imidazo[1,2-a]pyridines.
Table 1 Optimization of the Amount of Catalyst and the Temperature
for the Reaction of 4-Nitrobenzaldehyde (1, Ar = 4-O2NC6H4), Trimeth-
ylsilyl Cyanide (3), and Pyridin-2-amine (2) in the Presence of
(Ph3NH)[C(CN)3] under Solvent-Free Conditionsa
Entry
Catalyst (mol%) Temp (°C)
Time (min)
Yieldb (%)
1
2
–
r.t.
50
60
60
60
45
30
30
30
10
10
30
10
10
trace
trace
trace
43
–
3
–
100
r.t.
4
0.5
0.5
0.5
1
To assess the recyclability of the catalyst, a series of six
sequential runs was performed using 4-nitrobenzaldehyde
(1, Ar = 4-O2NC6H4), TMSCN (3), and pyridin-2-amine (2).
After each cycle, the catalyst was recovered by adding wa-
5
50
57
6
100
r.t.
57
7
75
8
1
50
95
9
1
100
r.t.
95
10
11
12
2
71
2
50
93
2
100
93
a Reaction conditions: 4-nitrobenzaldehyde (2 mmol, 0.302 g), TMSCN (1
mmol, 0.099 g), pyridin-2-amine (1 mmol, 0.094 g); (Ph3NH)[C(CN)3]
(cat.).
b Isolated yield.
The reaction was also performed in several polar and
nonpolar solvents, including H2O, EtOH, MeCN, CH2Cl2,
EtOAc, hexane, and toluene, as well as under solvent-free
conditions (Table 2). We found that the reaction under sol-
vent-free conditions (Table 2, entry 1) gave the best results
in terms of the yield and reaction time. Consequently, sol-
vent-free conditions were used to explore the scope of the
method.
Figure 1 Investigation of the reusability of (Ph3NH)[C(CN)3] in the syn-
thesis of N-(4-nitrobenzylidene)-2-(4-nitrophenyl)imidazo[1,2-a]pyridin-
3-amines (4, Ar = 4-O2NC6H4) in 10 min.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
S. Baghery et al.
Letter
Synlett
Table 3 Synthesis of Imidazo[1,2-a]pyridines 4 by Using 1 mol% of (Ph3NH)[C(CN)3] under Solvent-Free Conditions at 50 °Ca
Product
Entry
Aldehyde 1, Ar
Time (min)
Mp (°C) (Lit.)
Physical state
Yieldb (%)
1
2
4-O2NC6H4
4-ClC6H4
10
15
20
20
15
25
15
30
25
25
20
20
20
30
30
30
30
30
163–165
brown solid
yellow solid
yellow solid
yellow solid
orange solid
brown solid
brown solid
brown solid
brown solid
brown solid
brown solid
yellow solid
yellow solid
brown solid
brown solid
brown solid
green solid
red solid
95
93
91
91
93
89
93
88
89
89
91
91
91
88
88
88
88
88
168–170 (170–172)29
158–160 (155–157)28
178–180 (172–176)28
297–299
3
4-MeC6H4
4-MeOC6H4
3-O2NC6H4
Ph
4
5
6
132–134 (160–163)28
178–180
7
1-naphthyl
PhCH=C(Me)
2,5-(MeO)2C6H3
3,4-(MeO)2C6H3
4-Me2NC6H4
2,4-Cl2C6H3
2-naphthyl
PhCH=CH
8
168–170
9
108–110
10
11
12
13
14
15
16
17
18
101–103
203–205
184–186
187–189 (182–185)29
151–153
2-furyl
157–159
2-thienyl
121–123 (125–128)29
143–145
4-HO-3-EtOC6H3
4-pyridyl
213–215
a Reaction conditions: aldehyde 1 (2 mmol), TMSCN (1 mmol, 0.099 g), pyridin-2-amine (1 mmol, 0.094 g), (Ph3NH)[C(CN)3] (1 mol%, 0.0034 g), 50 °C.
b Isolated yield.
ter, filtering to remove the products, washing the aqueous
phase with ethyl acetate, and finally drying at 80 °C under
vacuum. The procedure was repeated, and the results show
that the catalyst could be reused up to six times without
any significant loss of its activity (Figure 1). The reaction
was scaled up to 10 mmol of each substrate in the presence
of 10 mol% of catalyst at 50 °C under solvent-free condi-
tions.
In conclusion, triphenylammonium tricyanomethanide
(Ph3NH)[C(CN)3] has been found to be an efficient and recy-
clable nanostructured molten-salt catalyst for the synthesis
of N-benzylidene-2-arylimidazo[1,2-a]pyridin-3-amines in
good to excellent yields through a one-pot, three-compo-
nent, condensation reaction of various (het)aryl aldehydes,
TMSCN, and pyridin-2-amine under solvent-free conditions
at 50 °C.32 The catalyst can be recovered by filtration and re-
used several times without significant loss of its catalytic
activity.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1558965.
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(32) Triphenylammonium Tricyanomethanide (Ph3NH)[C(CN)3]
Ph3N (3 mmol, 0.736 g) was added to a solution of HC(CN)3 (3
mmol, 0.273 g) in H2O (5 mL), and the mixture was stirred for 3
h at 50 °C. The solvent was then evaporated under reduced
pressure and the resulting white powder was dried under
reduced pressure at 100 °C for 3 h. The white solid was washed
with Et2O to remove any unreacted starting materials and then
dried under vacuum to give a white solid; yield: 0.979 g (97%);
mp >350 °C. IR (KBr): 3377, 3037, 2987, 2228, 2110, 1639, 1474,
1389, 1062, 887 cm–1. 1H NMR (400 MHz, DMSO-d6): δ = 6.99 (d,
J = 8.4 Hz, 6 H, ArH), 7.04 (t, J = 7.4 Hz, 3 H, ArH), 7.31 (t, J = 8.0
Hz, 6 H, ArH), 8.55 (s, 1 H, NH). 13C NMR (100 MHz, DMSO-d6):
δ = 41.9, 123.3, 124.1, 129.9, 166.4, 166.6. MS: m/z = 336.3 [M+].
For full analytical data, see the Supporting Information.
N-benzylidene-2-arylimidazo[1,2-a]pyridin-3-amines 4; General
Procedure
(Ph3NH)[C(CN)3] (1 mol%; 0.0034 g) was added to and mixed
with aldehyde 1 (2 mmol), TMSCN (2; 2 mmol; 0.099 g), and
pyridin-2-amine (3; 1 mmol; 0.094 g), and the mixture was
heated at 50 °C for the appropriate time (Table 3). When the
reaction was complete [TLC, hexane–EtOAc (5:2)], the mixture
was washed with H2O (10 mL) and filtered to separate the cata-
lyst from the other materials. (The reaction mixture was insolu-
ble in H2O, and the catalyst was soluble in H2O.) The crude
product was purified by crystallization from EtOH–H2O (10:1).
All products were identified by comparison of their physical
data with those reported in the literature; for spectroscopic
data, see the Supporting Information.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D