Catalytic effect of nanosized metal oxides on the knoevenagel reaction

Article abstract of DOI:10.1134/S1070427212040209

The effect of nanosized metal oxides (Al, Mg, Cu, Ni oxides) on the synthesis of chalcones that are key intermediate in the synthesis of Nitrendipine and Felodipine drugs was examined.

Full text of DOI:10.1134/S1070427212040209

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2012, Vol. 85, No. 4, pp. 656−660. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © Yu.A. Titova, O.V. Fedorova, I.G. Ovchinnikova, G.L. Rusinov, V.N. Charushin, 2012, published in Zhurnal Prikladnoi Khimii, 2012,
Vol. 85, No. 4, pp. 641−645.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Catalytic Effect of Nanosized Metal Oxides
on the Knoevenagel Reaction
Yu. A. Titova, O. V. Fedorova, I. G. Ovchinnikova, G. L. Rusinov, and V. N. Charushin
Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Yekaterinburg, Russia
e-mail: titova@ios.uran.ru
Received June 10, 2011
Abstract—The effect of nanosized metal oxides (Al, Mg, Cu, Ni oxides) on the synthesis of chalcones that are
key intermediate in the synthesis of Nitrendipine and Felodipine drugs was examined.
DOI: 10.1134/S1070427212040209
the treatment of cardiovascular diseases [1]. Industrial
synthesis of these substances is multistep:
Substituted dihydropyridines Ia and Ib of the Nife-
dipine series are widely used in medical practice for
R
R
EtO2C
H3C
R
R'
IIa, IIb
+
R'
EtO2C
H3C
R'
EtO2C
H3C
CO2CH3
CHO
O
+
N
CH3
H
CO2CH3
CO2CH3
CH3
Ia, Ib
(1a), (1б)
+ NH3
Ia nitrendipine;
Ib felodipine
H2N
CH3
O
III
where R = NO2, R' = H (Ia, IIa); R = R' = Cl (Ib, IIb).
The synthesis of benzylidene intermediate II (Knoevena-
gel reaction) is the most labor-consuming and expensive
step. The reaction is performed in alcohol on heating in
the presence of two catalysts (a weak base and a weak
acid); the yield is 70–80% [2, 3]. Procedures have been
suggested for performing Knoevenagel condensation
using Lewis acids (TiCl4, ZnCl2, HClO4–SiO2) [4–6],
ionic liquids [7], heterogeneous catalysts (zeolites, clays,
supported organic catalysts) [8, 9], and ultrasonic and
microwave radiation [10, 11]. Some of the suggested
procedures are indeed efficient and ensure high yields of
the target product. However, complex structure, difficult
availability, and high cost of the majority of the catalysts
do not allow these procedures to become generally ac-
cepted in industry and in laboratory practice.
The effect of nanosized metal oxides having highly
developed surface and containing various active sites on
the regio- and stereoselectivity of the Nitrendipine synthe-
sis was examined. It was shown that nanosized alumina
activates the starting reactants in the Hantzsch synthesis
(nitro-substituted benzaldehyde, acetoacetic acid ester,
and especially ammonia) and enhances the reactivity of
the intermediate chalcone II and enamine III [12].
656

CATALYTIC EFFECT OF NANOSIZED METAL OXIDES
657
The ratio of the starting aldehyde IVа, target product
IIa, and by product (cyclohexanone Va) and the isomer
ratio were determined from the integral intensities of the
characteristic proton signals in the Н NMR spectrum
(Table 1):
In this study we examined the effect of nanosized
metal oxides on the synthesis of the key intermediate of
the Nitrendipine synthesis, chalcone IIa (R = 3-NO2),
and optimized the conditions of its preparation. We found
that, under the conditions of heterogeneous catalysis, the
reaction yields cyclohexanone Va as by-product.
1
where R = NO2 (IIa, IVa, Va); R = R' = Cl (IIb, IVb,
R
OEt
O
R
R
R'
O
R'
H3C
O
+
O
+
+
R'
H3C
O
H3C
O
H3C
O
CHO
H3C
O
IVa, IVb
Z-isomer
E-isomer
IIa, IIb
R
R'
+
EtO2C
HO
CO2Et
O
CH3
Va, Vb
oxides, to the presence of a large amount of active surface
groups, and hence to high sorption power, compared to
bulk samples. Nanosized alumina appeared to be the
best (Table 2, entry no. 1). In the presence of nanosized
magnesia, relatively large amount of the by-product,
cyclohexanone Va, is formed along with the desired
chalcone IIa; furthermore, a large amount of the start-
ing aldehyde remains unchanged. Nanosized copper and
nickel oxides probably form a complex with IIа, because
Vb).
Because the catalytic properties of nanosized metal
oxide can depend on feature of the metal, we performed
experiments with a series of nanosized oxides (Cu,
Al, Mg, Ni oxides). For comparison, we examined the
catalytic properties of bulk aluminum and magnesium
oxides. We found that nanosized metal oxides are more
effective catalysts of the Knoevenagel reaction compared
to bulk oxides (Table 2, entry nos. 1, 17–19). This can
be attributed to the more developed surface of nanosized
1
in the Н NMR spectra all the signals are broadened.
Table 1. Characteristic proton signals of IIа, IVа, and Vа
Proton signal, δ, ppm
Compound
НС=О
–CH2–CH3
–
–CH2–CH3
–
CH
–
Me
–
IVа
IIа
10.16
–
4.28 q
Z-Isomer
1.21 t
Z-Isomer
2.49 s
Е-Isomer
1.29 t
Е-Isomer
2.40 s
Vа
–
3.83; 3.94 m
0.86; 0.96 t
5.13 s
1.30 s
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 85 No. 4 2012

658
TITOVA et al.
Table 2. Optimization of the synthesis of IIa
Nanosized
metal oxide
(0.1 mol)
Relative content of chal-
Catalyst (0.1 mol) cone IIa, % (ratio of E
and Z isomers)
Entry
no.
Yield of cyclo-
hexanone Va, %
τ, h
Т, °С
Solvent
1
2
20
20
20
20
20
20
20
20
20
20
20
20
10
30
50
20
20
20
20
20
20
20
20
40
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
40
22
40
CH3CN
CH2CI2
C6H6
Al2O3
Al2O3
Al2O3
Al2O3
Al2O3
Al2O3
Al2O3
Al2O3
Al2O3
Al2O3
Al2O3
Al2O3
Al2O3
Al2O3
Al2O3
No n/o
Bulk Al2O3
MgO
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
HCl
87.5 (1.0:4.5)
84.8 (1.0:3.7)
75.8 (1.0:4.1)
66.6 (1.0:3.3)
60.6 (1.0:2.4)
50.0 (1.0:2.0)
49.3 (1.0:2.0)
72.4 (1.0:2.3)
44.7 (1.0:1.5)
33.3 (1.0:2.0)
26.6 (1.0:2.4)
8.0 (1.0:7.0)
Traces
Traces
Traces
13.3
3
4
THF
5
DMF
18.8
6
H2O
22.5
7
CH3OH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
34.9
8
None
Traces
36.4
9
Acetic acid
Anabasine
Pyridine
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
None
None
Traces
Traces
Traces
8.6
No catalysts
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
71.9 (1.0:4.2)
82.6 (1.0:6.5)
89.2 (1.0:4.0)
78.1 (1.0:3.1)
70.9 (1.0:3.7)
22.5 (1.0:1.0)
45.8 (1.0:2.7)
All signals are broade
The same
Traces
45.9
Bulk MgO
NiO
27.5
CuO
Al2O3
Al2O3
Al2O3
96.2 (1.0:3.7)
77.5 (1.0:4.0)
96.3 (1.0:3.7)
Traces
Traces
Traces
We found that, in the presence of nanosized alumina,
Z-isomer of IIa, whose structure is the most favorable
for the formation of S-enantiomer of Nitrendipine [12],
is always formed in excess.
on chalcone IIa, followed by condensation.
Despite the fact that, according to published data, the
Knoevenagel reaction occurs under basic conditions,
under the conditions of heterogeneous catalysis, namely,
in the presence of nanosized alumina, the reaction is
catalyzed by both the base and the acid. Acid catalysts
ensure excellent regioselectivity of the process (Table 2,
entry nos. 8 and 9). It is interesting that, in the presence
of the commonly used catalyst of the Knoevenagel reac-
As seen from Table 2, the best solvent for the Kno-
evenagel reaction is acetonitrile. With strongly polar
solvents such as methanol, DMF, and water, the reaction
direction is shifted toward formation of cyclohexanone
Vа by attack of one more acetoacetic acid ester molecule
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 85 No. 4 2012

CATALYTIC EFFECT OF NANOSIZED METAL OXIDES
659
tion, pyridine, the yield of the target product was as low
as 26.6% (Table 2, entry no. 11), with the crude product
free of even traces of side cyclohexanone, according to
the 1Н NMR data. Structurally related anabasine showed
not only low yield, but also low regioselectivity of the
reaction (36.4% cyclohexanone, Table 2, run no. 10).
Morpholine showed better catalytic properties in the pres-
ence of nanosized alumina (Table 2, run no. 1).
(particle size 50−80 nm) prepared by the gas-phase
procedure [13].1
The melting points measured with combined Boёtius
stages were not subjected to additional correction. The
1Н NMR spectra were recorded with anAvance DRX-400
spectrometer (Bruker) operating at 400 MHz.
Preparation of chalcones II (general procedure).
Appropriate aldehyde, ethyl acetoacetate, nanosized
metal oxide, and catalyst were mixed in 1 : 1 : 0.1 :
0.1 molar ratio, and the solvent was added. The mixture
was stirred at the required temperature in a flask equipped
with a reflux condenser, after which the solvent was
distilled off and the crude product (yellow oil) was
analyzed by 1Н NMR.
As expected, the target product yield increased with
an increase in the reaction time (Table 2, run nos. 13–15).
At temperatures over 60°С, the starting reactants practi-
cally fully transform into the undesirable by-product,
cyclohexanone. The highest yield of chalcone IIа was
attained at 40°С (Table 2, run no. 22).
In some experiments, we found that a decrease in the
solvent volume leads to a decrease in the reaction time.
The reaction is more complete at the solvent volume suf-
ficient only for dissolving the starting reactants.
If necessary, the desired chalcone II was precipitated
from the oil with diethyl ether, filtered off, dried, and
recrystallized from ethanol.
Ethyl 2-acetyl-3-(3-nitrophenyl)acrylate (chalcone
IIа). Z Isomer. 1Н NMR spectrum (DMSO-d6), δ, ppm:
1.21 t [3H, С(О)CH2СН3], 2.49 s (3H, СН3), 4.28 q [2H,
С(О)CH2СН3], 7.99 s (Н, −СН=), 7.80 t [Н, С(5) Ar],
7.93 d [Н, С(6) Ar], 8.32 dd [Н, С(4) Ar], 8.40 s [Н,
С(2) Ar].
Thus, the optimal conditions for preparation of
chalcone IIa are morpholine and nanosized alumina as
catalysts, temperature of 40°С, acetonitrile as solvent,
and reaction time of 20 h.
In addition, we examined the possibility of preparing
under similar conditions compound IIb, a key inter-
mediate in the synthesis of Felodipine drug. We found
that, when the reaction was performed under the above-
described conditions at 40°С, the major product (yield
85%) was cyclohexanone Vb.At the process temperature
decreased to 22–25°С, the process became fully regio-
specific, because the 1Н NMR spectra of crude product
IIb contained only signals from the target chalcone,
with no signals from the starting aldehyde IVb and side
cyclohexanone Vb. The E to Z isomer ratio for IIb was
1.0 : 2.4.
1
E-Isomer. Н NMR spectrum (DMSO-d6), δ, ppm:
1.29 t [3H, С(О)CH2СН3], 2.40 s (3H, СН3), 4.28 q [2H,
С(О)CH2СН3], 7.79 s (Н, −СН=), 7.73 t [Н, С(5) Ar],
7.88 d [Н, С(6)Ar], 8.28 dd [Н, С(4)Ar], 8.40 s [Н, С(2)
Ar]; mp 105–106°С. Found, %: С 59.11, Н 4.97, N 5.29.
С13Н13О5N. Calculated, %: С 59.32, Н 4.94, N 5.32.
2,4-Bis(ethoxycarbonyl)-5-hydroxy-5-methyl-3-
(3-nitrophenyl)cyclohexanone Vа. 1Н NMR spectrum
(DMSO-d6), δ, ppm: 0.86 t, 0.96 t [6H, 2С(О)CH2СН3];
1.30 s (3H, СН3); 2.38 d, 2.97 d [2H, С(6), cyclohexa-
none]; 3.47 d [1H, С(4), cyclohexanone]; 3.83 m, 3.94 m
[4H, 2С(О)CH2СН3]; 4.01 t [1H, С(3), cyclohexanone];
4.13 d [1H, С(2), cyclohexanone]; 5.02 s (1H, ОН); 5.13 s
[Н, С(3)]; 7.60 t [Н, С(5)Ar]; 7.77 d [Н, С(6)Ar]; 8.21 dd
[Н, С(4)Ar]; 8.27 s [Н, С(2)Ar]; mp 143–146°С. Found,
%: С 58.05, Н 5.85, N 3.56. С17Н23О8N. Calculated, %:
С 58.01, Н 5.85, N 3.56.
EXPERIMENTAL
Experiments were performedwith3-nitrobenzaldehyde
(99%), 2,3-dichlorobenzaldehyde (99%), (–)-anabasine
(94%; Lancaster), ethyl acetoacetate (99%), morpholine
(98%), and pyridine (98%; Acros Organics). As
catalysts we took Al2O3 (analytically pure grade) and
MgO (chemically pure grade) produced by Khimsnab
association and nanosized Al2O3, MgO, NiO, and CuO
Ethyl 2-acetyl-3-(2,3-dichlorophenyl)acrylate
1
(chalcone IIb). Z Isomer. Н NMR spectrum (DMSO-
d6), δ, ppm: 1.06 t [3H, С(О)CH2СН3], 2.47 s (3H, СН3),
4.12 q [2H, С(О)CH2СН3], 7.89 s (Н, −СН=), 7.35 dd
[Н, С(6) Ar], 7.45 t [Н, С(5) Ar], 7.73 dd [Н, С(4) Ar].
–––––––––––––––
1 Samples were prepared at the Institute of Metal Physics, Ural Branch,
Russian Academy of Sciences, laboratory headed by Prof. A.E.
Ermakov.
1
Е-Isomer. Н NMR spectrum (DMSO-d6), δ, ppm:
1.28 t [3H, С(О)CH2СН3], 2.31 s (3H, СН3), 4.29 q
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 85 No. 4 2012

660
TITOVA et al.
[2H, С(О)CH2СН3], 7.76 s (Н, −СН=), 7.28 dd [Н, С(6)
Ar], 7.40 t [Н, С(5) Ar], 7.73 dd [Н, С(4) Ar]. Found, %:
С 53.58, Н 4.19. С13Н12О3Cl2. Calculated, %: С 54.35, Н 4.18.
no. NSh-65261.2010.3), and Ural Branch of the Russian
Academy of Sciences (project nos. 09-I-3-2004, 09-P-
23-2001, 09-P-3-2001).
2,4-Bis(ethoxycarbonyl)-5-hydroxy-5-methyl-
1
REFERENCES
3-(2,3-dichlorophenyl)cyclohexanone Vb. Н NMR
spectrum (DMSO-d6), δ, ppm: 0.80 t, 0.93 t [6H, 2 С(О)
CH2СН3]; 1.25 s (3H, СН3); 2.38 d, 2.81 d [2H, С(6),
cyclohexanone]; 3.35 d [1H, С(4), cyclohexanone];
3.82 m, 3.88 m [4H, С(О)CH2СН3]; 4.03 d [1H, С(2),
cyclohexanone]; 4.63 d [1H, С(3), cyclohexanone]; 5.02 s
(1H, ОН); 7.38 t [Н, С(5)Ar]; 7.50 d [Н, С(6)Ar]; 7.74 d
[Н, С(4) Ar]; mp 130–133°С. Found, %: С 54.50, Н 5.18.
С17Н22О6Cl2. Calculated, %: С 54.67, Н 5.27.
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