Graphite oxide-promoted one-pot synthesis and oxidative aromatization of Hantzsch 1,4-dihydropyridines

Article abstract of DOI:10.1007/s00706-014-1259-9

A new and efficient method for the one-pot synthesis of pyridine compounds using three-component Hantzsch synthesis in high yields using graphite oxide, a readily available and inexpensive material, as a mild and efficient agent is described. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-014-1259-9

Monatsh Chem (2014) 145:1919–1924
DOI 10.1007/s00706-014-1259-9
ORIGINAL PAPER
Graphite oxide-promoted one-pot synthesis and oxidative
aromatization of Hantzsch 1,4-dihydropyridines
•
Maryam Mirza-Aghayan Fatemeh Asadi
•
Rabah Boukherroub
Received: 21 October 2013 / Accepted: 5 June 2014 / Published online: 5 September 2014
Ó Springer-Verlag Wien 2014
Abstract A new and efficient method for the one-pot
synthesis of pyridine compounds using three-component
Hantzsch synthesis in high yields using graphite oxide, a
readily available and inexpensive material, as a mild and
efficient agent is described.
naphthenate [15], KBrO3/SnCl4ꢀ5H2O [16], MnO2 [17],
silica-modified sulfuric acid/NaNO2 [18], silica-sulfuric
acid and Al(NO3)3ꢀ9H2O or Fe(NO3)3ꢀ9H2O [19], silica-
chromate [20], tetrakis(pyridine)cobalt(II) dichromate [21],
b-cyclodextrin [22], electrochemical catalysis [23], and
photochemical reaction [24]. It should be noted that for the
above methods, 1,4-dihydropyridines are first prepared and
then oxidized. Hantzsch synthesis is commonly carried out
in acetic acid or refluxing alcohol for a long time with low
yields [25]. Alternative strategies for the synthesis of 1,4-
dihydropyridines involving different catalysts and condi-
tions have been developed [26–30]. However, many of
these methodologies have been associated with several
problems such as long reaction times, expensive reagents,
harsh conditions, low product yields, and occurrence of
several side products. Although several reports have
described the oxidative aromatization of 1,4-dihydropyri-
dine derivatives, to the best of our knowledge, there are
only a few examples on the one-pot synthesis and oxidative
aromatization of Hantzsch derivatives [31, 32]. For
example, Cotterill et al. [32] have demonstrated the
applicability of the MICROCOS (Microwave-assisted
Combinatorial Synthesis) technology for generating com-
binatorial libraries of pyridine derivatives using the
Hantzsch synthesis.
Keywords Oxidative aromatization ꢀ Hantzsch ꢀ
1,4-Dihydropyridine derivatives ꢀ Graphite oxide ꢀ
Pyridine derivatives ꢀ One-pot reaction
Introduction
Heterocyclic compounds often play important roles in
biologically active natural products and synthetic com-
pounds in medicine [1–3]. The synthesis of highly
substituted pyridines has attracted much attention, and a
number of procedures have been developed [4–7]. Aro-
matization of 1,4-dihydropyridines (1,4-DHP) has been a
focus of considerable attention from researchers in recent
years, essentially since the discovery that the metabolism
of those drugs involves an oxidation step that is catalyzed,
in the liver, by cytochrome P-450 [8–11]. Several methods
have been utilized for this oxidative conversion such as
iodine [12], urea-hydrogen peroxide catalyzed by molec-
ular iodine [13], peroxydisulfate-Co(II) [14], Co-
In the last few years, graphite oxide (GO), prepared by
exhaustive oxidation of graphite has been explored as a
heterogeneous catalyst for various organic transformations
[33–38]. Kumar et al. [33] reported the Friedel–Crafts
addition of indoles to a,b-unsaturated ketones and nitro-
styrenes using GO as the catalyst. Recently, graphene
oxide was applied for the oxidation of alcohols and
alkenes, and the hydration of various alkynes into their
respective aldehydes and ketones in moderate to high
yields [34, 35].
M. Mirza-Aghayan (&) ꢀ F. Asadi
Chemistry and Chemical Engineering Research Center of Iran
(CCERCI), P. O. BOX 14335-186, Tehran, Iran
e-mail: m.mirzaaghayan@ccerci.ac.ir
R. Boukherroub
Institut de Recherche Interdisciplinaire (IRI, USR CNRS 3078),
Parc de la Haute Borne, 50 Avenue de Halley-BP70478, 59658
Villeneuve d’Ascq, France
123

1920
M. Mirza-Aghayan et al.
More recently, we have investigated GO as an effective
we report herein on the use of GO, a readily available and
inexpensive material, as a mild and efficient agent for the
one-pot synthesis of pyridine compounds using three-
component Hantzsch synthesis (Scheme 2).
oxidizing agent for the synthesis of aldehydes and ketones
from various alcohols under ultrasonic irradiation [39]. In
addition, GO is a cost-effective material and can be easily
recovered from the reaction mixture by a simple filtration.
Moreover, we have applied GO for the oxidative aroma-
tization of 1,4-dihydropyridine derivatives in a one-pot
reaction [40].
Results and discussion
Graphite oxide (GO) has been prepared using a
variety of techniques, though the most common are
embodied in the Hummers and Brodie/Staudenmaier
methods [41–43]. The most widely adopted structural
model of GO is that proposed by Lerf et al. [44],
wherein the surface functionality is dominated by
epoxides and alcohols, and the periphery is decorated
with carboxylic acids (Scheme 1).
We have first investigated the influence of solvent on the
reaction yield of an equimolar quantity of 3-nitrobenzal-
dehyde (1d, 1 eq.) and methyl 3-aminocrotonate (5 eq.) in
the presence of 0.6 g of GO, as indicated in Table 1. After
the time indicated in Table 1, the crude products were
poured into methylene chloride while stirring, filtered
through a sintered funnel and washed by methylene chlo-
ride. For further purification, the resulting filtrates were
evaporated and recrystallized from ethanol. Under solvent-
free conditions, the product 2d was obtained at trace con-
centration. The reaction gave essentially the Hantzsch 1,4-
dihydropyridine derivative 20d in 77 % yield (Table 1,
entry 1). When the reaction was conducted in reflux of
ethanol or acetonitrile in the presence of 0.6 g of GO, the
corresponding 1,4-dihydropyridine derivative was formed
in 56 and 74 % yield, respectively. Again, the yield of the
pyridine derivative remains still low: 18 % in ethanol and
10 % in acetonitrile (Table 1, entries 2, 3). A similar trend
was observed when water/ethanol mixture (1/1) was used
as solvent, i.e., formation of 20d in 55 %, while the pyri-
dine derivative 2d was present only at trace concentration
(Table 1, entry 4). Contrarily, when the reaction was per-
formed in water as solvent, 1,4-dihydropyridine derivative
20d and pyridine 2d were obtained in 10 and 55 % yield,
respectively (Table 1, entry 5). The results in Table 1
suggest that among the investigated solvents, water gave
the best yields of product 2d. Finding the suitable solvent,
the influence of the GO concentration on the reaction yield
was investigated. When the amount of GO was decreased
In a previous work, we have reported an efficient one-
pot method for the synthesis of 1,4-dihydropyridine
derivatives using chlorotrimethylsilane (TMSCl) or
Et3SiH/PdCl2/CH3I system under mild conditions [45]. In
continuation of our investigation on the use of GO for
different transformations and multicomponent reactions,
Scheme 1
Scheme 2
123

Hantzsch 1,4-dihydropyridines
1921
to 0.3 g, the yield of pyridine 2d decreased significantly
(13 %, Table 1, entry 6). On the other hand, increasing the
amount of GO to 1.2 g yielded pyridine 2d in 70 %
(Table 1, entry 7). Further increase of the amount of cat-
alyst did not show a significant effect on the reaction yield,
indicating that 1.2 g of GO is sufficient for this reaction.
The results suggest that there is an optimal amount of GO
to drive both 1,4-dihydropyridine formation and its sub-
sequent oxidative aromatization to the corresponding
pyridine derivative. We do believe that the reaction is a
step-wise chemical process, i.e., it occurs in two steps:
formation of 1,4-dihydropyridine, followed by its oxidation
to the corresponding pyridine derivative. This is evidenced
by the fact that at low GO amount (0.3 g), the 1,4-dihy-
dropyridine 20d is essentially formed, while at higher GO
amount (1.2 g), the pyridine derivative 2d is the main
reaction product.
The optimal conditions are reached when the reaction of
1 eq. of aldehyde 1 and methyl 3-aminocrotonate (5 eq.) in
the presence of 1.2 g of GO was performed at reflux of
water. Under these conditions, various aldehydes 1a–1f
reacted smoothly to give the corresponding pyridines 2a–2f
in 68–80 % yield (Table 2, entries 1–6). It should be noted
that the yield of pyridines 2g and 2h are very low in water
as solvent. By replacing water by acetonitrile and
increasing the amount of GO to 1.6 g, the pyridines 2g and
2h were obtained in a reasonable yield, i.e., 64 and 46 %,
respectively (Table 2, entries 7, 8). Under similar condi-
tions, the heterocyclic pyridine 2i was formed in 78 %
yield (Table 2, entry 9). In the case of an aliphatic alde-
hyde such as octanal, the heterocyclic pyridine 2j was
isolated in 36 % yield. Although aromatic aldehydes
bearing electron donating or withdrawing group react with
3-aminocrotonate in the presence of GO to yield the cor-
responding pyridine derivatives in reasonable yields,
limited reactivity is observed for aliphatic aldehydes. Even
though the origin of the low reactivity of the aliphatic
aldehydes under our experimental conditions is not clear, it
is likely that aldehyde–GO interaction (p stacking) is
necessary for this reaction.
Table 1 Effect of solvent and amount of GO on the formation of
pyridine 2d
Entry Solvent
GO/g Temp./°C Time/h Yield/%a
1
2
3
4
5
6
7
a
Solvent-free
0.6
0.6
0.6
80
2
7
7
7
7
7
7
Trace (77)
18 (56)
10 (74)
Trace (55)
55 (10)
13 (52)
70
Ethanol
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
From the obtained results, we do believe that the GO
functions as an acid catalyst to afford the 1,4-dihydro-
pyridines and an oxidant to obtain the corresponding
pyridines. On the one hand, GO surface comprises different
oxygen-containing groups such as hydroxyl, epoxy and
carbonyl groups, which confer an acidic character to the
material. This property has recently been applied for
esterification of organic acids with alcohols under mild
conditions [46]. On the other hand, the oxidative properties
of GO are known and described in several examples [37,
Acetonitrile
Water/ethanol (1/1) 0.6
Water
Water
Water
0.6
0.3
1.2
Isolated yield. Reaction conditions: 3-nitrobenzaldehyde (1d,
1 mmol), methyl 3-aminocrotonate (5 mmol), and GO under ambient
air. The number between parentheses indicates the yield of 1,4-
dihydropyridine 20d
Table 2 Synthesis of pyridines 2a–2j from aldehydes 1 and methyl 3-aminocrotonate in the presence of GO at reflux of water or acetonitrile
Entry
R
Product
Time/h
Solvent
Yield/%a
M.p./°C
Found
Reported
1
2
3
4
5
6
7
8
9
10
a
C6H5
2a
2b
2c
2d
2e
2f
5
5
Waterb
Waterb
Waterb
Waterb
Waterb
Waterb
Acetonitrilec
Acetonitrilec
Acetonitrilec
Acetonitrilec
80
70
78
70
70
68
64
46
78
36
135
141
148
123
139
137
116
192
72
135–137 [22]
140–142 [19]
148 [40]
p-Cl-C6H4
p-NO2-C6H4
m-NO2-C6H4
p-Br-C6H4
p-CH3-C6H4
p-CH3O-C6H4
p-HO-C6H4
2-Thienyl
C7H15
5
7
122–125 [47]
139–140 [19]
137–138 [40]
114–116 [22]
191–192 [40]
–
8
10
7
2g
2h
2i
7
6
2j
24
Oil
–
Isolated yield
b
c
Using 1.2 g of GO
Using 1.6 g of GO
123

1922
M. Mirza-Aghayan et al.
39, 40]. Indeed, we have recently demonstrated the effi-
ciency of GO for the oxidative aromatization of 1,4-
dihydropyridine into their corresponding pyridine deriva-
tives [40].
To evaluate the reusability of the GO after completion
of the reaction, methylene chloride was added and the
mixture was filtered through a sintered funnel and GO is
removed by simple filtration. The reaction of 1 eq. of
3-nitrobenzaldehyde (1d) and methyl 3-aminocrotonate
(5 eq.) in the presence of 1.2 g of the recycled GO at
reflux of water, gave the corresponding 1,4-dihydropyri-
dines derivative 20d in 68 % yield after 7 h. The result
indicates that the recycled GO is not efficient for the
oxidative aromatization of 1,4-dihydropyridines into the
corresponding pyridine derivatives. It should be noted that
XRD characterization and UV–Vis absorption spectra of
GO before and after reaction with 3-nitrobenzaldehyde
and methyl 3-aminocrotonate (5 eq.) at reflux of water
clearly suggested partial reduction of GO [48, 49]
(Figs. 1, 2). Indeed, the UV–Vis spectrum of an aqueous
solution of GO (0.05 mg/cm3) displays an absorption
bands at 227 nm attributed to p–p* transitions of aromatic
C=C bond (Fig. 1a). After reaction of GO with aldehyde
1 and methyl 3-aminocrotonate at reflux of water, a red-
shift of the p–p* transition band from 227 to 256 nm is
observed (Fig. 1b). The result is in accordance with pre-
viously published data on GO partial reduction using
different means [48, 49]. The partial reduction of GO was
further confirmed by X-ray diffraction (Fig. 2). The X-ray
diffraction pattern of the initial GO displays a peak at 2h
value of 12°. A new broad peak appears at 2h of *24°
after reaction of GO with aldehyde 1d and methyl
3-aminocrotonate at reflux of water, corresponding to
reduced GO.
Fig. 2 X-ray powder diffraction patterns of native graphite oxide
before (a), and after reaction with 3-nitrobenzaldehyde and methyl
3-aminocrotonate at reflux of water (b)
process. This explains the low efficiency of the reduced GO
for the formation of pyridine derivatives. To circumvent
GO thermal reduction (or disproportion) at elevated tem-
peratures, we have performed the reaction at lower
temperatures (40 °C). However, under these experimental
conditions, the reaction was very slow and only product 20
was obtained after 4 h.
In conclusion, we have developed a novel method using
graphite oxide, a cheap and easily available material, for
the one-pot synthesis and oxidative aromatization of Han-
tzsch 1,4-dihydropyridines through a condensation of an
aldehyde and methyl 3-aminocrotonate. The reaction is
carried out under mild conditions and affords high to
moderate yields of pyridine derivatives. The present
method has many advantages, including simplicity and the
generality of the method. Graphite oxide was synthesized
from inexpensive graphite using readily available reagents.
Further investigations using graphite oxide for other
chemical transformations such as the synthesis of xanthene
derivatives and esters from aldehydes are currently in
progress.
The reduction of GO consumes most of the oxygen-
related functionalities, responsible of the aromatization
Experimental
Melting points were determined in evacuated capillaries
with a Bu¨chi B-545 apparatus. 1H NMR spectra were
recorded on a Bruker 80 MHz in DMSO-d6 using tetra-
methylsilane as internal standard. 13C NMR spectra were
recorded on a Bruker 62.9 or 100 MHz in DMSO-d6. Mass
spectra were obtained on a FISONS GC 8000/TRIO 1000
under 70 eV. Infrared (IR) spectra were recorded from KBr
disks with a Bruker Vector 22 Fourier transform infrared
Fig. 1 UV-Vis absorption spectrum of native graphite oxide in water
(0.05 mg/cm3) before (a), and after reaction with 3-nitrobenzaldehyde
and methyl 3-aminocrotonate at reflux of water (b)
123

Hantzsch 1,4-dihydropyridines
1923
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1
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