2
Tetrahedron Letters
Table 1. Optimization of the reaction conditionsa
The pyridine nucleus has emerged as a privileged scaffold in
view of its prevalence in numerous natural products1 and its
value in biological and medicinal chemistry.2 Pyridines are also
involved in coordination chemistry,3 materials and surfaces,4
supramolecular structures,5 and organocatalysis.6 Among the
pyridine substructures, 2-amino-3-cyanopyridine derivatives
have attracted significant attention due to their biological
activities.7 Also, these compounds serve as useful intermediates
for the preparation of a variety of heterocyclic compounds.8
Therefore, development of new methods for their synthesis is still
a desirable goal. The most general route to these pyridine
derivatives is the multicomponent reaction (MCR) of aldehydes,
ketones, malononitrile and ammonium acetate. Recently, MCRs
have gained great attention due to their applications in organic,
medicinal and combinatorial chemistry,9 providing rapid and
straightforward access to complex molecules without the
isolation of intermediates.10 Due to the prominence of 2-amino-3-
cyanopyridine derivatives, a variety of reagents and catalysts
have been reported for the synthesis of these compounds.1,2,7,11,12
However, most of these procedures have limitations such as the
use of expensive metal catalysts1,13 toxic solvents,14 harsh
reaction conditions,15 complicated reaction procedures, and
tedious multistep syntheses and work-up procedures.7 In addition
to environmental and economic concerns, these limitations
narrow the reagent choice for the synthesis of these pyridine
derivatives. Thus, the development of safe, efficient and metal-
free catalytic systems for the synthesis of these compounds is still
of importance. Heterogeneous catalysts appear to be a potential
solution and carbon based materials16, 17 can be useful for this
purpose. Graphene oxide (GO, graphite oxide sheet), is the
product of chemical exfoliation of graphite powder using strong
oxidants and has been known for more than a century.18 The
harsh conditions introduce a wide range of polar oxygen-
containing functional groups on the sheet surface and allow GO
to function as a soft acid and mild oxidant. In fact, the presence
of these functional groups enable GO to catalyze various organic
transformations.19-23 Despite this potential activity and
advantages such as remarkable electronic and mechanical
properties,24 inexpensive nature, metal-free reactivity and easy
recovery from the reaction media, GO has been relatively less
explored as a catalyst or oxidant for facilitating organic
transformations. Inspired by the potential activity of GO and
continuing our ongoing interests in GO catalyzed organic
reactions,25,26 it was of interest to develop a green and safe
protocol for the construction of 2-amino-3-cyanopyridines using
GO as a heterogeneous catalyst. Herein, an eco-friendly
procedure for the synthesis of 2-amino-3-cyanopyridines via a
GO catalyzed four-component condensation is presented.
Solvent
Yield
(%)b
<10
81
Entry Catalyst (mol%)
Time (h)
(condition)
H2O, 80 °C
H2O, 80 °C
H2O, 80 °C
H2O, 80 °C
H2O, reflux
H2O, r.t.
1c
2
-
24
5
GO (5)
3d
GO (10)
GO (15)
GO (10)
GO (10)
GO (10)
GO (10)
GO (10)
GO (10)
GO (10)
Graphite
r-GO
5
90
4
5
88
5
5
87
6
24
5
44
7
CHCl3, reflux
THF, reflux
CH3CN, reflux
EtOAc, reflux
Toluene, reflux
H2O, 80 °C
H2O, 80 °C
H2O, 80 °C
H2O, 80 °C
H2O, 80 °C
H2O, 80 °C
70
8
5
73
9
5
84
10
11
12
13e
14
15
16
17
5
80
5
75
24
24
24
5
20
36
Activated carbon
Silica
57
49
H-beta zeolite
TiO2
5
66
5
40
aReaction conditions: acetophenone (1 mmol), 4-methylbenzaldehyde (1
mmol), ammonium acetate (1.5 mmol), malononitrile (1.3 mmol), catalyst
(type indicated), open to air, solvent (3 mL). bIsolated yields. cBlank
experiment without GO. dBold value signifies the optimal reaction
conditions. er-GO = reduced graphene oxide.
In the absence of GO, only a 8% yield of product 5a was
obtained, even after 24 h (Table 1, entry 1). Product 5a was
obtained in 81% yield at 80 °C using 5 mol% GO loading and 5 h
reaction time (entry 2). Further increase of the catalyst loading to
10 mol% resulted in an increased yield of product 5a after 5 h
(90%, entry 3). The yield could not be improved by further
increasing the catalyst loading (entry 4). Increasing the reaction
temperature did not show any beneficial effect (entry 5) but when
the reaction temperature was decreased to room temperature, a
low yield of product 5a was found (44%, entry 6). The effect of
different solvents on the reaction outcome was also investigated
and the results showed that a significant enhancement of the
reaction yield was accomplished when H2O was used (entry 3).
Other solvents afforded the desired compound in moderate yields
(entries 7-11). Lower yields were observed when GO was
replaced by other carbon based promoters such as natural flake
graphite, hydrazine-reduced graphene oxide17 and activated
carbon under the same conditions, even upon prolonging the
reaction time (24 h, entries 12-14). Moreover, the catalytic
activities of GO were also compared with typical solid acid
catalysts such as silica, H-beta zeolite and TiO2 (entries 15-17)
which clearly show that the GO affords better activity than
commercially available solid acids.
GO was synthesized by the oxidation of graphite powder
using the modified Hummers method, followed by exfoliation in
an aqueous solution. The prepared GO was characterized using
XRD, TGA, FT-IR, UV/Vis and Raman spectroscopy and also
with an AFM study to establish its characteristics (see ESI). In
order to carry out the quantitative characterization of GO, such as
the amounts of -COOH and -OH groups, a solid-based titrimetry
method was used.27 Based on the titration curves the amounts of -
COOH and -OH were evaluated to be 0.17±0.01% and
2.65±0.02% respectively. The pH value of a dispersion
containing GO was 4.6, at approximately 0.1 mg mL-1, which is
consistent with that reported in the literature.19,23
With the optimized reaction conditions in hand, the scope of
this methodology was explored (Table 2). It was observed that
the reactions of substituted aldehydes, including aromatic
aldehydes bearing electron donating (entries 1, 2) and electron
withdrawing substituents (entries 4-6), with acetophenone
proceeded smoothly and the rapid synthesis of pyridines 5a-f
occurred in good to excellent yields (89-97%). The substituent on
the aromatic aldehyde showed slightly different effects on the
yields. Reactions of electron deficient aromatic aldehydes
afforded slightly better yields than electron rich ones. In addition
to benzaldehyde derivatives, acetaldehyde as an aliphatic
aldehyde, was also applied to this protocol, and the desired
product 5g was obtained in good yield (79%, entry 7). The scope
This study began by investigating the four-component
condensation of acetophenone (1 mmol), ammonium acetate (1.5
mmol), 4-methylbenzaldehyde (1 mmol) and malononitrile (1.3
mmol) in the presence of catalytic GO under varying reaction
conditions. As GO can be easily dispersed in H2O, our initial goal
was to use this green medium for the condensation reaction.28 In
fact, the use of water as the reaction medium has attracted much
interest in the past few years mainly due to the economic and
environmental advantages.29
Khalili, Dariush
