Rapid room temperature liquid phase synthesis of diethyl 2-((4-nitroanilino) methylene)malonate

Article abstract of DOI:10.4067/s0717-97072018000304098

Diethyl 2-((4-nitroanilino)methylene)malonate [4-NANM-E] is an important molecule owing to its role of precursor in the multistage synthesis of several quinoline derivatives possessing biological activities such as antiviral, immunosuppressive, anticancer and photoprotector. This molecule is usually synthesized by a nucleophilic vinyl substitution (SNV) between 4-nitroaniline and diethylethoxymethylene malonate (EMA). Although several procedures are available to synthesize 4-NANM-E in liquid phase, more convenient method is necessary to synthesize in less reaction time and at room temperature. In this study, it is demonstrated that equimolar amounts of EMA and 4-nitroaniline dissolved in alcoholic KOH react within a few seconds at room temperature to produce 4-NANM-E which is purified by simple filtration after acidification with aqueous HCl and washing with alcohol. The reaction has the yield varying at the range 45-53% when it occurs in ethanol, 2-propanol, 2-butanol or 2-pentanol. Therefore, this synthesis method is an excellent alternative to produce 4-NANM-E on an industrial scale.

Full text of DOI:10.4067/s0717-97072018000304098

J. Chil. Chem. Soc., 63, Nº 3 (2018)
RAPID ROOM TEMPERATURE LIQUID PHASE SYNTHESIS OF DIETHYL 2-((4-NITROANILINO)
METHYLENE)MALONATE
a
a,*
b
HERNÁN VALLE , RAMALINGA VISWANATHAN MANGALARAJA , BERNABÉ L. RIVAS ,
c
a
JOSÉ BECERRA , AND SELVARAJ NAVEENRAJ
a
Advanced Ceramics and Nanotechnology Laboratory, Faculty of Engineering, University of Concepcion, Casilla 160, Chile.
b
Polymer Department, Faculty of Chemistry, University of Concepción, Casilla 160, Chile.
c
Laboratorio de Química de Productos Naturales, Facultad de Ciencias Naturales y Oceanográficas, Universidad de Concepción, Casilla 160, Chile.
ABSTRACT
Diethyl 2-((4-nitroanilino)methylene)malonate [4-NANM-E] is an important molecule owing to its role of precursor in the multistage synthesis of several
quinoline derivatives possessing biological activities such as antiviral, immunosuppressive, anticancer and photoprotector. This molecule is usually synthesized
by a nucleophilic vinyl substitution (S V) between 4-nitroaniline and diethylethoxymethylene malonate (EMA). Although several procedures are available to
N
synthesize 4-NANM-E in liquid phase, more convenient method is necessary to synthesize in less reaction time and at room temperature. In this study, it
is demonstrated that equimolar amounts of EMA and 4-nitroaniline dissolved in alcoholic KOH react within a few seconds at room temperature to produce
4
-NANM-E which is purified by simple filtration after acidification with aqueous HCl and washing with alcohol. The reaction has the yield varying at the range
4
5-53% when it occurs in ethanol, 2-propanol, 2-butanol or 2-pentanol. Therefore, this synthesis method is an excellent alternative to produce 4-NANM-E on an
industrial scale.
Keywords: Anilinomethylenemalonate, Room temperature synthesis, Quinoline, Methanolysis.
1
. INTRODUCTION
2. EXPERIMENTAL
Aryl substituted derivatives of diethyl anilinomethylenemalonate are
among the most commonly used precursors in the multistage synthesis of
approved and developing quinolinic drugs. From the anilinomethylenemalonate
derivatives, the respective 4-quinolone intermediates are obtained by the
Gould-Jacobs reaction or thermal cycling. To date, several researchers
have used diethyl 2-(4-nitroanilino)methylenemalonate [4-NANM-E] as
a precursor in the synthesis of different 6-nitro-4-quinolone derivatives
2.1. Materials and reagents
Diethylethoxymethylene malonate (EMA, ≥ 98%), 4-nitroaniline (4-NA,
≥ 98%), potassium hydroxide (KOH, pellets ≥ 95%), HCl aqueous solution
(6M), solvents of analytical grade: methanol, ethanol, 2-propanol, 2-butanol
and 2-pentanol were supplied by Merck. All reagents and solvents were used
without further purification. The pH of the reaction mixture was measured with
universal indicator paper (pH 1-10, Merck). Whatman N° 2 filter paper was
used for vacuum filtration. The thin layer chromatography (TLC) technique
was applied to confirm the identity and purity of the expected product. TLC
was developed using aluminum chromateplates (10 x 5 cm) with silica gel 60
F-254 (Merck), hexane-ethyl acetate (1: 1) as eluent, and a ultraviolet lamp
(CAMAG, 254 and 366 nm) was used as revelator for the chromatograms.
2.2. Synthesis of 4-NANM-E using alcohol-KOH without heating
40 mL of 2-propanol and 2 pellets of KOH (300 mg, approximately) were
mixed in a 100 mL open beaker (borosilicate glass) at room temperature (25°C)
using a magnetic stirrer. On continuous stirring, 691 mg of 4-nitroaniline
(5 mmol) was added to the 2-propanol-KOH solution. After the complete
dissolution of 4-nitroaniline, 1 mL of EMA (5 mmol) was added. After ~ 5
minutes, the above reaction mixture was acidified with 6M HCl until it reaches
the pH value of 3, and then the precipitate formed was filtered under vacuum,
washed with 2-propanol, and finally dried in an oven with air circulation at
60° C. For comparison purposes, the same procedure as above was repeated
four times by changing the solvent of the KOH, 2-propanol, for the following
solvents: methanol, ethanol, 2-butanol, and 2-pentanol.
1
,2
possessing medicinal properties, such as antibacterial,
antiviral,
immunostimulant, immunosuppressant, photoprotector, cognitive enhancer
3
-11
and calcium-activated potassium channels blocker (study of sleep disorders).
Anilinomethylenemalonate precursors are frequently obtained by nucleophilic
addition of a substituted aniline to the polarized and electron deficient double
bond of diethylethoxymethylene malonate (EMA), which forms a transitory
carbanion that finally undergoes the elimination of the ethoxyl group (leaving
1
2
group with charge negative). The rate of this reaction nucleophilic vinyl
substitution (S V) is less as the electron-attracting force of the substituent
N
on the aromatic ring increases and vice versa. In the particular case of the
synthesis of 4-NANM-E, the electron-attracting effect of the nitro group on
4
-nitroaniline, and the delocalization of nitrogen lone pair into the aromatic
ring (and nitro substituent) cause a lower electron density on the nitrogen atom
and also the lower pKa value when compared with other anilines, which makes
it a weak nucleophile and base that requires more time and heating to react with
13-16
EMA.
As a consequence, the large-scale production of 4-NANM-E using
conventional methodologies would imply high energy and time costs.
Although 4-NANM-E has been synthesized by the solvent-free synthesis
2.3. Synthesis of 4-NANM-E without solvent and using conventional
heating
1
7
using microwaves and K CO /Al O as a catalyst, this type of synthesis
2
3
2
3
requires very sophisticated and expensive reactors which also have some
limitations in their large-scale synthesis of molecules. Furthermore, the
use of microwave systems in organic synthesis is controversial since many
researchers found that the reactors used in most cases did not allow precise
control over power and temperature which is essential for good reproducibility
of results. In order to contribute a more convenient alternative methodology
for the preparation of 4-NANM-E, this study presents a fast and efficient
method of liquid phase synthesis at room temperature of this useful synthetic
intermediate, based on the use of alcohol-KOH as the reaction medium in the
condensation between EMA and 4-nitroaniline. No studies on the synthesis of
Standard 4-NANM-E was synthesized by following the Riegel’s
1
4
procedure.
2.4. Characterization
1
13
H (400 MHz) and C (100 MHz) NMR (nuclear magnetic resonance)
spectra were obtained on a Bruker 400 NMR spectrometer as solutions in
18
-1
deuterated DMSO (DMSO-d ) at a concentration of 30 mg mL and using
6
TMS as an internal standard. Infrared spectra (FTIR) were obtained with a
Spectrum One spectrometer (PerkinElmer) using the KBr pellet technique.
3. RESULTS AND DISCUSSION
4
-NANM-E using alcohol-KOH as reaction medium at room temperature were
found in the literature.
The dissolution of 4-nitroaniline and 2-propanol-KOH showed
a
“
translucent brownish yellow” color, but within a few seconds after adding
EMA (less than 10 seconds), it changed to “turbid reddish orange” followed by
the formation of a light-colored precipitate. The same happens in cases where
ethanol, 2-butanol, and 2-pentanol were used, although in the last two cases, a
4
098
e-mail: mangal@udec.cl

J. Chil. Chem. Soc., 63, Nº 3 (2018)
“
gel-like” suspension was formed due to the absorption of the solvent from the
along with the lower yield. During the acidification step (Scheme 1), at pH 3 all
reaction mixtures were discolored and a “beige” precipitate was more clearly
observed in the bottom of the beakers.
reaction mixture. When methanol-KOH was used, the “translucent brownish
yellow” color persisted even after the addition of EMA, and the formation of
the precipitate was slower (after 10 minutes at rest) than the previous cases
Scheme 1. Synthesis of 4-NANM-E using 2-propanol-KOH without heating.
All the precipitates (post-acidification) were soluble in THF and DMSO,
and were comparatively analyzed by TLC with the standard 4-NANM-E which
was previously synthesized by Riegel’s method and well characterized with
NMR and IR spectroscopy. A single spot was observed for each precipitate
with the same Rf value except for the precipitate formed with methanol-KOH
system in which three spots were observed. The absence of spots with Rf value
corresponding to the reagents confirmed the efficient purification of the product
by washing with alcohol. Among the three spots observed in the methanol-
KOH system, the one with the highest fluorescence has the lower Rf value
than that of the standard 4-NANM-E as well as the reactant EMA and slightly
higher value than that of the other reactant 4-nitroaniline.
Table 1. Identification of absorption peaks in the FTIR spectra of
compounds 4-NANM-E and 4-methyl-NANM.
-1
Peak (cm )
Attributed to
3227-3080
Stretching (ν) N-H of amino group
3
1
1
1
000-2850
686-1677
634-1619
582-1578
Stretching (ν) CH and CH , symmetric and unsymmetric
2
3
Stretching (ν) C=O of free carbonyl
Stretching (ν) C=O of chelated carbonyl (with NH group)
Bending (δ) N-H and stretching (ν) C=C (ring, vinyl)
1
515
Stretching (ν) C-NO unsymmetric
2
1
339-1335
Stretching (ν) C-NO symmetric
2
1
246-1233
Stretching (ν) C-NH and (ν) CO-O unsymmetric
Stretching (ν) COO-C unsymmetric
1104
1
In the H-NMR spectrum of Figure 2, the signal generated by the amino
group was observed between 10.74-10.78 ppm (low field) as a doublet (JNH,
=CH: 13.4 Hz) due to the coupling between the proton NH and the vinyl proton
at the adjacent alpha carbon. The doublet observed between 8.39-8.42 ppm
(JNH, =CH: 13.4 Hz) is attributed to the vinyl proton. The high value of coupling
constant (JNH, =CH: 13.4 Hz) suggests a “trans” relationship between the vinyl
and amino protons, and the hindrance to rotation around the C-N bond due to
1
9
the hydrogen bond between -NH and one of the carbonyls (C=O). Both the
1
3
free and chelated carbonyl groups were detected in the C NMR spectrum
as signals at 164.7 and 166.5 ppm, respectively (Figure 3). The other signals
1
13
Figure 1. FTIR spectra of the compounds 4-NANM-E (solid line) and
-methyl-NANM (dotted line). The stretching vibrations (ν) C-H of 4-methyl-
NANM (rectangular area) have bands of less intensity than the 4-NANM-E.
appearing in IR (Figure 1, Table 1), H-NMR (Figure 2) and C-NMR (Figure
3) spectra of the synthesized products confirmed the presence of the functional
groups characteristic of alkyl 4-NANM and its molecular formula.
4
While comparing the IR spectra of the synthesized products with the
standard 4-NANM-E, only the product obtained with methanol-KOH system
differed mainly in the lower intensity of the CH stretching vibration between
The formation of 4-NANM-methyl suggested that the ethyl ester groups
of EMA underwent nucleophilic substitution of ethoxy groups by methoxy
radicals (methanolysis) during the reaction with 4-nitroaniline in methanol-
KOH. This was confirmed after analyzing by proton NMR the reaction product
formed between EMA and methanol-KOH in the absence of 4-nitroaniline.
The product of this reaction (filtered solid, washed with methanol, and vacuum
-1
2
850-3000 cm (Figure 1, Table 1) which suggested the presence of methyl
ester groups instead of ethyl ester ones. It explains the higher polarity of the
product obtained with methanol-KOH which showed a lower Rf value than
that of the standard 4-NANM-E in TLC. Among all the signals shown in the
IR spectra of Figure 1 and Table 1, it is important to highlight the ones located
dried) showed only two proton signals (at D O) which corresponds to the vinyl
2
proton (9.17 ppm) and the six methyl protons (3.64 ppm), and this not only
indicates the occurrence of methanolysis of EMA, but also the formation of the
dimethyl 2-(hydroxymethylene)malonate potassium salt (Figure 4), which was
soluble only in water and DMSO.
-
1
-1
-
in the ranges: (i) 1686-1677 cm , (ii) 1634-1619 cm , and (iii) 3227-3080 cm
.
1
The first absorption signal is attributed to the stretching (ν) C=O of a free
carbonyl group, the second one to the stretching (ν) C=O of another carbonyl
group bonded intramolecularly with a hydrogen atom from an amino group,
and the third one to the stretching (ν) N-H of the mentioned amino group.
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J. Chil. Chem. Soc., 63, Nº 3 (2018)
Although the present study does not attempt to explain the reaction
mechanismbywhichalkyl4-NANMisobtainedundertheconditionsofalcohol-
KOH as solvent and without heating, it is likely that the 2-(hydroxymethylene)
malonate potassium salt is initially formed and then it reacts with 4-nitroaniline
1
2
following nucleophilic vinyl substitution. This argument coincides with the
Mulveyl’s method for the preparation of anilinomethylenmalonates, which
use an alkyl 2-(hydroxymethylene)malonate salt and a substituted aniline as
initial reagents, but in this case, the reaction solvent consists of a strong acid
2
0
dissolved in short chain aliphatic alcohol and the reaction is much slower. The
synthesis of diethyl/dimethyl 2-(hydroxymethylene)malonate by subjecting
the respective alkyl alkoxymethylenemalonates to mild basic conditions with
2
1
22
23
aqueous NaOH, KOH-water/diethyl ether, or KOH-methanol/diethyl ether
were already reported but these studies are intended to obtain the enol derivative
of the alkoxymethylenemalonate instead of anilinomethylenmalonates.
A possible explanation regarding the occurrence of methanolysis or
transesterification of EMA is the lower basicity of methanol compared to that
of KOH (pKa: 15.3 vs 15.7) which implies a greater capacity of the latter to
deprotonate methanol molecules, generating enough methoxide anions which
are the nucleophiles that attack the carbonylic carbons of EMA. In addition, it
has been confirmed from the previous studies that the nucleophilic character of
the alkoxide anions decreases as the length of the alkyl chain increases, and thus
2
4
increase the steric hindrance for a nucleophilic acyl substitution to take place.
1
Figure 2. H-NMR spectrum of 4-NANM-E obtained in the 2-propanol-
The transesterification of EMA did not occur in the reactions carried out with
ethanol, 2-propanol, 2-butanol and 2-pentanol due to the low nucleophilicity
and more basic nature than that of KOH (pKa: 16-18 vs 15.7) which makes
more difficult to deprotonate by the hydroxide compared to methanol, avoiding
the production of alkoxide radicals.
KOH system. The solvent (DMSO-d ) signal was removed for clarity.
6
The yields of the 4-NANM-E synthesis in the different alcohols were the
following: 45% in ethanol, 48% in 2-propanol, 53% in 2-butanol and 47% in
2
-pentanol. Only 16% yield of 4-NANM-methyl was obtained for the reaction
performed in methanol. The advantages of this 4-NANM-E synthesis method
are simply ease, less reaction time and highly pure product, which is necessary
if it is desired to obtain good yields of the respective quinolone by the Gould-
1
5
Jacob reaction.
4
. CONCLUSIONS
An efficient and a fast method for the synthesis of 4-NANM-E at room
temperature has been developed using equimolar amounts of EMA and 4-ni-
troaniline. The best yields are obtained using the alcohols: 2-butanol (53%),
2
-propanol (48%), 2-pentanol (47%), and ethanol (45%). The easy purifica-
tion, less time, and less cost of this method makes it an excellent alternative to
produce 4-NANM-E on an industrial scale.
ACKNOWLEDGMENTS
13
Figure 3. C-NMR spectrum of 4-NANM-E obtained in the 2-propanol-
KOH system. The solvent (DMSO-d ) signal was removed for clarity.
Hernan Valle is grateful to FONDECYT for the postdoctoral Grant N°
6
3
160296.
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